Startseite Medizin Advances in synthetic lethality modalities for glioblastoma multiforme
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Advances in synthetic lethality modalities for glioblastoma multiforme

  • Seidu A. Richard EMAIL logo
Veröffentlicht/Copyright: 10. Juni 2024
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Aus der Zeitschrift Open Medicine Band 19 Heft 1

Abstract

Glioblastoma multiforme (GBM) is characterized by a high mortality rate, high resistance to cytotoxic chemotherapy, and radiotherapy due to its highly aggressive nature. The pathophysiology of GBM is characterized by multifarious genetic abrasions that deactivate tumor suppressor genes, induce transforming genes, and over-secretion of pro-survival genes, resulting in oncogene sustainability. Synthetic lethality is a destructive process in which the episode of a single genetic consequence is tolerable for cell survival, while co-episodes of multiple genetic consequences lead to cell death. This targeted drug approach, centered on the genetic concept of synthetic lethality, is often selective for DNA repair-deficient GBM cells with restricted toxicity to normal tissues. DNA repair pathways are key modalities in the generation, treatment, and drug resistance of cancers, as DNA damage plays a dual role as a creator of oncogenic mutations and a facilitator of cytotoxic genomic instability. Although several research advances have been made in synthetic lethality modalities for GBM therapy, no review article has summarized these therapeutic modalities. Thus, this review focuses on the innovative advances in synthetic lethality modalities for GBM therapy.

Keywords: GBM; DNA; chemotherapy; synthetic; lethality; resistance

1 Introduction

Glioblastoma multiforme (GBM) is characterized by a high mortality rate, high resistance to cytotoxic chemotherapy, and radiotherapy due to its highly aggressive nature [1,2]. Also, it is the most typical primary malignant brain cancer, with no satisfactory surgical curability [1,2,3]. Furthermore, the prognosis of patients with GBM is often less than 1 year, notwithstanding modern innovative therapeutic modalities [1,4]. The pathophysiology of GBM is characterized by multifarious genetic abrasions that deactivate tumor suppressor genes, induce transforming genes, and oversecrete pro-survival genes, resulting in oncogene sustainability [5,6,7,8,9].

Most recently, targeted small molecule treatment modalities to block stimulated oncogenes with the aim of blocking several oncogenic pathways to synergize and destroy tumor cells have been ongoing [10]. Nevertheless, targeted small-molecule blockers are limited to a subset of all possible targets, called the “druggable genome,” and thus restrict the existing interruptible synergistic pathways [11,12]. Furthermore, recurrent tumors treated with targeted small molecules typically selected for targeted gene secondary-site mutations result in drug resistance due to mutator phenotypes [10,13]. Therefore, it is necessary to engineer selective anti-GBM treatment modalities based on GBM genetics that stimulate a synthetic lethal response that can change as rapidly as the GBM genetic landscape changes.

It is worth noting that cancer cells are imperiled to DNA damage and, more specifically, damage from double-strand breaks (DSBs), similar to normal cells [1,14]. Also, cells induce the DNA damage response (DDR) network as a feedback reaction to DNA damage, permitting DNA repair via the modulation of cell cycle succession, DNA damage repair, or apoptosis [1,15]. Synthetic lethality is a destructive process in which the episode of a single genetic consequence is tolerable for cell survival, while co-episodes of multiple genetic consequences lead to cell death [1,16]. This targeted drug approach, centered on the genetic concept of synthetic lethality, is often selective for DNA repair-deficient GBM cells with restricted toxicity to normal tissues [17,18].

Remarkably, DNA repair pathways are key modalities in the generation, treatment, and drug resistance of cancers, as DNA damage plays a dual role, such as a creator of oncogenic mutations and a facilitator of cytotoxic genomic instability [17,19]. Additionally, gene paralogs are potentially auspicious bases for synthetic lethal interactions, as they typically demonstrate robust sequence homology and functional redundancy. Although several research advances have been made in synthetic lethality modalities in GBM therapy, no review article has summarized these therapeutic modalities. Therefore, this review focuses on innovative advances in synthetic lethality modalities in glioblastoma therapy.

The “Boolean logic” was used to search for articles on synthetic lethality modalities for GBM in PubMed and PubMed central as well as google scholar. Notably, only preclinical studies of synthetic lethality modalities for GBM have been reviewed. Also, clinical studies were excluded from this review. The combinations of the literature search teams are shown in Figure 1. This figure also shows the detailed potential pairing of agents for synthetic lethality modalities in GBM therapy.

Figure 1 Combinations of literature search teams. It also shows the potential pairing of agents for synthetic lethality modalities in GBM therapy. Note: Refer to the text for detailed explanations. Also, refer to general abbreviation list for meaning of abbreviations.
Figure 1

Combinations of literature search teams. It also shows the potential pairing of agents for synthetic lethality modalities in GBM therapy. Note: Refer to the text for detailed explanations. Also, refer to general abbreviation list for meaning of abbreviations.

2 Phosphatase and tension homologue (PTEN)

Loss of PTEN has been implicated in chromosomal instability, susceptibility to DNA damaging agents and compromised genomic integrity [20,21,22]. PETN has also been associated with DNA DSB repair [22,23]. Moreover, DNA DSBs are the most lethal form of DNA damage, and they are repaired by two key PETN pathways: non-homologous end-joining (NHEJ) and homology-directed repair (HDR) [20]. Also, PTEN deletion on chromosome 10 adversely stimulates the phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/rapamycin (mTOR) signaling pathway, resulting in cellular differentiation, proliferation, and apoptosis [17,20].

However, mutated or deleted PTEN has been associated with resistance to radiotherapy and chemotherapy GBM patients [17,24,25]. In addition, nuclear PTEN is an essential factor in the maintenance of genomic stability because its loss is linked to chromosomal aberrations and impaired DSB repair capability [26,27]. Thus, PTEN’s function in various cellular processes, including the DDR, makes its deficiency in GBM a promising target for synthetic lethality therapeutic strategies [28,29,30].

2.1 PTEN and PI3Ks

In GBM, the stimulation of PI3K occurred autonomously with the upregulation of epidermal growth factor receptor (EGFR) via gain-of-function mutations in the structural gene for PI3Kα (PIK3CA) and by the loss of PTEN, a downregulator of PI3K signaling (Table 1) [31,32]. It was observed that blockade of PI3K efficiently inhibited survival signaling pathways via AKT, whereas blockade of PI3K alone and in combination with blockade of EGFR and of the down-regulatory kinase mTOR failed to stimulate cell death in vitro or in vivo in preclinical schemes (Table 1) [33,34].

Table 1

Summarizes cell death agents and cell survival agents and their mechanism of synthetic lethality in GBM

Agents for cell death Agent for cell survival Synthetic lethality mechanisms in GBM Citation
PTEN PI3K Stimulation of PI3K occurred autonomously with upregulation of EGFR via gain-of-function mutations in the structural gene for PI3Kα (PIK3CA) and by loss of PTEN in GBM [31,32]
Blockade of PI3K efficiently inhibited survival signaling pathways via AKT, implying that P13K is key for survival of GBM [33,34]
PARP & TMZ PARP-1 blockade and PTEN deficiency offered synthetic lethality in TMZ cells deficient in MGMT and MGMT‑inhibited cells [45]
The 3-combination triggered G2/M arrest because of the generation of DSBs, perhaps via the alteration of N-methylpurine abrasions, which were not removed because of repair intervention by PARPi, leading to the induction of apoptosis in GBM [45]
Irrepairzepine It stimulated synthetic lethality in the genetic architecture of PTEN loss due to its exhibited capacities of inhibiting DSB repair in GBM [17]
Irrepairzepine augmented irradiation cytotoxic consequences with a reduction in cell survival detected in the PTEN-deficient cells as compared to only radiotherapy [17]
Symbiotic Macrophage PTEN inactivation induced the stimulation of multiple down-regulatory signaling pathways such as AKT and SRC in GBM cells, and LOX blockade impaired GBM progression via the inhibition of macrophage infiltration without directly influencing GBM cells [49,52]
LOX expression from PTEN-deficient GBM cells and incorporation into macrophages is a continuous process that is capable of stimulating PYK2 signaling, and lysosomal degradation may influence LOX-regulated down-regulatory pathways [49]
RAD51 PTEN/RAD51 signaling axis functions in response to replication stress to guarantee effective DNA replication because loss of PTEN resulted in replication stress in GBM [54]
3E10, a RAD51 facilitator, influenced the cellular viability of PTEN-deficient cells, and blockade of HDR with 3E10 triggered cytotoxicity in PTEN-deficient cells in GBM [20]
GBM cells deficient in PTEN are sensitive to the combination of 3E10 and an ATR inhibitor (VE-822) [20]
VRK1 VRK2 VRK1 is a paralog synthetic-lethal target in VRK2-methylated GBM because silencing of VRK1 in VRK2-null and VRK2-low secreting GBM cell lines is lethal, and leads to defective nuclear envelope formation, G2-M arrest, and consequently DNA damage [56]
TMZ & Olaparib Depletion of VRK1 in combination with TMZ and olaparib in GBM cells triggered an upsurge in DNA damage at lower doses, which led to the death of tumor cells [38,79,42]
Radiation & DXR VRK1 depletion triggered synthetic lethality in combination with IRT or DXR, and VRK1 depletion resulted in a significant reduction in the dose needed to achieve a similar effect in GBM [67,80]
HDAC1/2 ClpP HDAC inhibitors and imipridones have opposite effects on oxidative metabolism, while HDAC inhibitors and imipridones inhibit tumor cell’s respiration in GBM [85]
Imipridones suppress the secretion of respiratory complexes in an approach mainly determined by the ClpP protease, whereas HDAC inhibitors transcriptionally upregulate enzymes and transcription factors that accelerate oxidative metabolism in GBM [85]
TRAP1 Gamitrinib and its target TRAP1 were capable of thwarting HDAC inhibitor-triggered stimulation of tumor respiration via disruption of the electron transport chain in GBM [84,100]
Bcl-2/Bcl-xL IDH1 Blockade of Bcl-xL triggers synthetic lethality in IDH1-mutated GBM cells in vitro and in vivo, and their influences are mediated by the oncometabolite, 2-HG, which decreases Mcl-1 protein concentrations [103]
IDH1 R132H facilitated the inhibitory effects of Bcl-xL either via siRNA or pharmacologically via the BH3-mimetic, ABT263 in tumor cells [103]
c-MET c-MET blockade, along with dual Bcl-2/Bcl-xL blockade, triggered synthetic lethality in stem-like and established GBM cells, which was pharmacologically epitomized by the drug combination of ABT263 and Crizotinib [101]
siRNA RNAi siRNAs directly targeted truncated EGFRvIII and AKT2 and synergized to stimulate an apoptotic synthetic lethal RNAi response in an orthotopic GBM xenograft mouse model [16,117]
CaMKII GSCs A synthetic curcumin derivative HBC, a Ca2+/CaM antagonist, blocked not only the self-renewal capacity but also the metastatic potential of GSCs by inhibiting the CaM/CaMKII/c-Met signaling pathway [123,128]
NK1R blockers, such as SR 140333 and aprepitant, have substantial chemical synthetic lethal activity against CaMKII blockers, such as HBC, berbamine, and KN93, in GSCs [123]
A synthetic lethal association between CaMKII and NK1R via RNAi in GSCs and the synergistic therapeutic effect of the combination of CaMKII and NK1R blockers on GSCs was linked to the downregulation of PI3K/AKT/NF-κB and Ca2+-signaling in GBM [123]
The lethal consequence of CaMKII and NK1R blockers on GSCs was correlated with a significant decrease in the secretion of key GSC markers, such as ALDH1A1, CD44, CD133, Oct4, Sox2, and integrin α6 in GBM [123]
The synergistic anti-GBM consequence of CaMKII and NK1R blockers against GSCs was triggered by the facilitation of ROS-dependent apoptosis via robust stimulation of the caspase cascade intermediated by p53 [123]
miR-1193 DNA-PKcs Perturbation of both DSB repair pathways like HR/MMEJ and NHEJ via concurrent blockade of miR-1193 and ablation of DNA-PKcs is capable of triggering obvious loss of viability in GBM [1]
Concurrent blockade of these distinctive DSB repair pathways resulted in the stimulation of the ATR/CHK1/p53 axis and consequently facilitated tumor cell apoptosis [1]
Silencing of DNA-PKcs and the blockade of miR-1193 in GBM is a potential synthetic lethality target for patients with GBM [1]

Note: refer to general abbreviation list for the meaning of abbreviations.

The imidazopyridine blocker PIK-75 is capable of stimulating apoptosis rather than growth arrest in gliomas [31]. However, the broad target profile and comprehensive toxicity of PIK-75 have hindered its clinical development because of its lack of stability in solution and in vivo [35,36]. Nevertheless, using a PI3Kα-specific blocker in amalgamation with a clinical blocker of cyclin-dependent kinase (CDK)-1 and CDK2, the apoptotic effects of the parental compound were reiterated, resulting in the development of an amalgamated therapy that exhibited decreased toxicity and stimulated apoptosis in vivo in murine xenografts [31]. Further studies on synthetic lethality modalities using PIK-75 and PTEN are needed.

2.2 PTEN, PARP, and temozolomide (TMZ)

Poly (ADP-ribose) polymerase (PARP) inhibitors are able to overcome limitations due to cancer-driving breast cancer gene (BRCA) mutations via the blockade of compensatory repair pathways that BRCA-deficient cancer cells depend on for survival because of their dysfunctional homologous recombination-mediated DSB repair [30,37,23]. In addition, PARP inhibitors and DNA damage in ataxia-telangiectasia mutated (ATM) signaling protein kinases have been shown to eliminate PTEN-deficient cancer cells in different tumor types [38,39,40]. TMZ is an alkylating agent that alters DNA, resulting in 06-meG, N3-meG, N7-meG, and N3-meA abrasions [41,42]. Also, resistance to TMZ therapy arises in GBM cells secreting high concentrations of O-6-methylguanine-DNA methyltransferase (MGMT), an enzyme that directly deletes the methyl group added by TMZ to O6-mG [43,44].

Notably, GBM cells have a high DDR, which allows them to repair abrasions caused by TMZ [43,44]. MGMT is a key gene that triggers TMZ resistance during GBM chemotherapy [45]. Many studies have focused on the influence of PTEN deficiency on repair pathways and the effects of PARP-1 blockade and PTEN deficiency in terms of synthetic lethality in TMZ-treated GBM cells [46,47,48]. It was observed that the combined treatment with TMZ and NU1025 was efficient in decreasing cell viability and clonogenic survival rates exhibited by TMZ-resistant cells, such as T98G and LN18, which are MGMT-proficient cells (Table 1) [45]. Also, a potentiating effect was observed when TMZ and PARP inhibitor (PARPi) were combined, which was independent of MGMT activity in U251MG sensitive-TMZ cells deficient in MGMT and MGMT‑inhibited cells in T98G and LN18 cell lines (Table 1) [45].

Interestingly, this drug combination triggered G2/M arrest because of the generation of DSBs, perhaps via alteration of N-methylpurine abrasions, which were not removed because of repair intervention by PARPi, leading to the induction of apoptosis in T98G and LN18 cells [45]. Moreover, the reduction in viability of U87MG cells transpired as a result of TMZ-induced DSBs in the combined therapies [45]. In these cells, the augmented quantity of unrepaired DNA damage was initiated by the blockade of PARP-1 via NU1025, resulting in cell death following combined drug treatments [45]. On the other hand, the use of PARPi, such as GPI 15427, in which MGMT enzyme activity was absent, revealed contrary results in TMZ-sensitive U87MG cells [46].

2.3 PTEN and irrepairzepine (IPZ)

A crude fungal isolate, E14504F, exhibited selective cytotoxicity in PTEN-deficient GBM cells compared to isogenic PTEN-proficient cells, with a 33% difference in survival [17]. It was established that the endophyte generated a compound that is active in the cellular architecture made up of PTEN loss, which was established by the absence of activities in cell lines mutated in the tumor-associated genes, such as Kirsten rat sarcoma viral oncogene homologue and BRCA2 [17].

Furthermore, activity-guided structural classification showed that the endophyte generated an azepine core-containing alkaloid called IPZ [17]. This novel molecule stimulated synthetic lethality in the genetic architecture of PTEN loss owing to its ability to inhibit DSB repair in GBM (Table 1) [17]. In addition, in a cell viability assay, E14504F exhibited dose-dependent cytotoxicity in U251 cells, with synthetic lethality in PTEN-null cells persisting across all tested doses [17]. Thus, IPZ can potentially act as an anticancer molecule for the further development and treatment of PTEN-deficient GBMs [17].

It was observed that IPZ treatment alone was adequate in the stimulation of appreciably more DNA damage in the PTEN-deficient cells compared to PTEN-proficient cells, signifying potential blockade in the repair of intuitively occurring DSBs and IPZ selectively suppressed DSB repair in GBM (Table 1) [17]. Furthermore, IPZ treatment augmented irradiation cytotoxic consequences with a reduction in cell survival detected in the PTEN-deficient cells compared to only radiotherapy (IRT) (Table 1) [17]. Thus, IPZ’s capability of significantly eradicating PTEN-deficient GBM cells, in addition to sensitizing these cells to IRT-induced DNA damage, makes it a possible drug for combination with IRT [17].

2.4 PTEN and symbiotic macrophage

It has been established that PTEN deficiency facilitated yes-associate protein (YAP)-1-driven lysyl oxidase (LOX) secretion in GBM cells and that LOX stimulated the β1 integrin-proline-rich tyrosine kinase (PYK)-2 pathway in macrophages to facilitate their infiltration into the GBM tumor microenvironment (TME) [49]. Also, tumor-associated microphages (TAMs) are known to facilitate GBM cell survival and angiogenesis in addition to influencing the function of other immune cells in the GBM TME [50,51].

Remarkably, PTEN inactivation induces the stimulation of multiple downstream signaling pathways, such as AKT and SRC, in GBM cells (Table 1) [49,52]. Moreover, LOX blockade impairs GBM progression by inhibiting macrophage infiltration without directly influencing GBM cells (Table 1) [49]. Also, macrophage β1 integrin was capable of facilitating LOX uptake and drove the LOX responsiveness of macrophages in GBM [49]. Furthermore, PYK2, but not focal adhesion kinase (FAK), is required for LOX-stimulated macrophage infiltration in GBM [49].

Interestingly, LOX expression in PTEN-deficient GBM cells and its incorporation into macrophages is a continuous process that is capable of stimulating PYK2 signaling, and lysosomal degradation may influence LOX-regulated downregulatory pathways (Table 1) [49]. Thus, LOX precisely recruits macrophages to GBM via the β1 integrin-PYK2 pathway [49]. Furthermore, LOX blockade augmented the survival of PTEN-deficient GBM models, coupled with the fact that the LOX blocker is BBB-penetrable, which should influence the testing of β-aminopropionitrile, precisely in PTEN-deficient GBM patients [49].

2.5 PTEN and anti-RAD51 antibody

RAD51 is a crucial stimulus in stalled replication forks and the repair of DNA breaks in collapsed forks [20,53]. Also, XRCC3 and RAD51-mediated strand invasion can trigger fork restart if stalled replication forks are undamaged [53]. Furthermore, a new source of firing is often obligatory to rescue replication in situations of collapsed replication forks, and repair of collapsed forks is determined by classical RAD51-mediated HDR [53]. It has been established that the PTEN/RAD51 signaling axis functions in response to replication stress to guarantee effective DNA replication because loss of PTEN results in replication stress (Table 1) [54]. Also, 3E10, a RAD51 facilitator, influences the viability of PTEN-deficient cells and blockade of HDR with 3E10-triggered cytotoxicity in PTEN-deficient cells (Table 1) [20].

Interestingly, cytotoxicity occurred because PTEN-deficient cells are both deficient in NEHJ and have a substantial standard burden of DNA damage and replication stress that was aggravated by 3E10 treatment, as shown by the stimulation of ɣH2Ax and p53BP1 foci and the manifestation of micronuclei after 3E10 scFv treatment [20,27]. Also, the cellular and replicative stresses triggered by 3E10 in PTEN-deficient cells sensitize these cells to a small molecule inhibitor of ATM- and Rad3-related (ATR) kinase [20]. ATR kinase is recruited to replicate protein A (RPA)-coated single-stranded DNA at stalled replication forks and sites of DNA damage [55]. Thus, cells deficient in PTEN are sensitive to a combination of 3E10 and an ATR inhibitor (VE-822) (Table 1) [20].

3 Vaccinia-related kinases (VRKs)

VRKs are a group of serine/threonine kinases that participate in the regulation of transcription factors, chromatin transformation, nuclear envelope configuration, and cell-cycle succession [56,57]. This group consists of three members: VRK1, VRK2, and pseudo-kinase VRK3 [56,57]. VRK1 is localized in both the nucleus and cytosol, while VRK2 is localized to the endomembrane of the endoplasmic reticulum and the nuclear envelope [57]. VRK1 is associated with phosphorylation and multiple substrates in both cell-cycle progression and cell-cycle arrest [56,57].

Specifically, VRK1 phosphorylates histones H3 and H2AX to accelerate chromatin remodeling, transcription factors ATF2, CREB, Sox2, and farnesoid X nuclear receptor HR1H4 to stimulate cell cycle succession, and a barrier to autointegration factor (BAF) to modulate nuclear envelope formation in response to mitogenic stimuli [58,59]. Also, VRK1 phosphorylates p53, c-Jun, and 53BP1 to induce cell-cycle arrest for DNA damage repair in response to stress signals such as DNA damage [58,59].

However, the precise functional role of VRK2 remains a matter of debate. Nevertheless, it has been implicated in the downregulation of apoptosis via direct interaction with antiapoptotic proteins, such as B-cell lymphoma-extra large (Bcl-xL), and via downregulation of proapoptotic protein like B-cell lymphoma 2 (Bcl-2)-associated X protein [60]. Furthermore, p53 and BAF have been implicated as substrates for VRK2 [61]. Also, cells with low VRK2 secretion exhibit augmented sensitivity to chemotherapeutics [60].

Notably, VRK1 is one of the most abundant nuclear kinases in human cells, and its over-secretion is related to poor outcomes in GBM and neuroblastoma [62,63,64]. Moreover, VRK1 has been implicated as a potential new cancer treatment target in the context of cancer dependency after several CRISPR-enabled functional genomic screening experiments [65,66]. VRK1 depletion is beneficial for cells deficient in ATM or p53, which widens the number of tumor categories and may be used as an effective therapy [67,68].

3.1 VRK1 and VRK2

Notably, VRK1 was identified as a paralog synthetic-lethal target in VRK2-methylated GBM and neuroblastoma cell lines [56]. They indicated that silencing of VRK1 in VRK2-null and VRK2-low secreting GBM cell lines is lethal and leads to defective nuclear envelope formation, G2-M arrest, and consequent DNA damage (Table 1) [56]. Their synthetic-lethal association was repeated in vivo in a VRK2-methylated U251MG GBM xenograft prototype, where VRK1 silencing resulted in tumor regression [56]. They further established that the enzymatic activity of VRK1 was a prerequisite for VRK1–VRK2 synthetic lethality, which specifies a path for small-molecule drug discovery [56].

Therefore, VRK1 is a promising synthetic-lethal drug target for VRK2-methylated brain tumors [56]. Initial studies have demonstrated that VRK1 modulates the cell cycle with roles in G1-S progression as well as mitosis [69,70,71,72,73]. Also, VRK1 depletion led to a preserved interaction of nuclear envelope fragments with mitotic chromosomes, resulting in aberrant nuclear envelope reassembly, nuclear bridging between daughter cells, and eventually DNA damage and apoptotic cell death [74].

3.2 VRK1, TMZ, and Olaparib

Olaparib is a selective and effective inhibitor of PARP enzymes such as PARP1 and PARP2 [42,67]. Olaparib targets the base excision repair (BER) pathway, which repairs alkylating lesions in the DNA [42,75]. Olaparib is a therapeutic agent for tumors that already have modifications in some DDR pathways, such as BRCA1, BRCA2, or WRN mutations [76,77,78]. Studies have shown that VRK1 depletion sensitizes tumor cells to TMZ and olaparib (Table 1) [38,79]. Depletion of VRK1 in combination with TMZ and olaparib in GBM cells triggered an upsurge in DNA damage at lower doses, which led to the death of tumor cells (Table 1) [42]. Thus, targeting VRK1 may be a potential therapeutic option when precise VRK1 inhibitors are developed [42]. The combined use of olaparib and VRK1 inhibitors has potential as a cancer therapeutic regimen with less severe or fewer adverse effects and toxicity with better tolerance [42].

3.3 VRK1, radiation, and doxorubicin (DXR)

Synthetic lethality of VRK1 depletion was observed when used in combination with other DNA damage treatments, as previously described [67]. Studies have shown that VRK1 depletion triggered synthetic lethality in combination with radiation (IRT) or DXR, and VRK1 depletion resulted in a significant reduction in the dose needed to achieve a similar effect in GBM (Table 1) [67,80]. Pyrimidine-based inhibitors have also exhibited high affinity and specificity for the VRK1 kinase, which can be a candidate for future drug development [81]. Further studies on the synthetic lethality of VRK1, IRT, and TMZ are required.

4 Histone deacetylase

Global and selective HDAC inhibitors are capable of disrupting the Warburg effect by targeting super-enhancers of genes such as HK2, GAPDH, and ENO1 [82,83]. Studies have observed that partial cell eradication and the survival of GBM cells resulted in a decrease in glycolytic activity; in order to sustain survival, they accelerated tumor respiration following treatment with HDAC inhibitors [84,82]. Nguyen et al. demonstrated that global (panobinostat) and selective (romidepsin) HDAC inhibitors combined with gamitrinib synergistically decreased the viability of a broad diversity of GBM models [84]. Nguyen et al. demonstrated that specific stimulation of the Y118A is synthetically lethal with either HDAC1 or HDAC2 blockade via the stimulation of intrinsic apoptosis based on both antiapoptotic Bcl-xL and Mcl-1 GBM models [85].

Furthermore, dopamine receptors were discovered as targets for imipridones, and subsequently, high concentrations of dopamine receptors DRD2 bestowed augmented susceptibility of cancer cells to the cytotoxic effects of imipridones [86]. Studies have also implicated imipridones in mitochondrial energy metabolism because ONC201, ONC206, and ONC212 interfere with the oxygen consumption rate (OCR), mitochondrial respiration, and coupled respiration [85,87]. Moreover, imipridones regulate glycolysis in a cell type- and context-dependent manner [87]. Studies have demonstrated that imipridone-mediated upregulation of activating transcription factor 4 (ATF4) partially induces the serine glycine synthesis pathway by stimulating PHGDH, PSAT1, and PSPH, along with the inhibition of tumor energy metabolism [87,88].

4.1 HDAC1/2 and caseinolytic protease proteolytic (ClpP)

Notably, GBMs have critical metabolic dependencies, such as carbohydrates, amino acids, and fatty acid metabolism [89,90,91,92]. Thus, GBMs have a central core that typically depends on glycolysis, which is enclosed by a periphery determined by oxidative metabolisms, such as the beta oxidation of fatty acids [93,85]. Interestingly, the ClpP protein can cleave respiratory complexes associated with metabolism, resulting in cellular respiration and ATP production via oxidative phosphorylation upon stimulation [94,95,96].

Remarkably, the ClpP protease (Y118A) mutant was primarily active, whereas ClpP (D190A) rendered the enzyme inactive [94,95,96]. Also, this combination therapy exerts its influence partly by inhibiting oxidative energy metabolism in an approach strongly determined by ClpP protease because the ClpP-D190A mutant abolished the killing effects and the metabolic effects of the combination therapy[85]. Notably, these compounds are effective stimulators of the death ligand TRAIL [97,98]. However, it is now clear that imipridones (i.e., ONC201) have anti-tumor effects by blocking the proliferation or regulation of intrinsic apoptosis via suppression of Mcl-1 [99,85]. Also, ClpP is a new target for imipridones and is associated with ClpP protease in tumor respiration and oxidative phosphorylation [99,94,95,96].

Furthermore, these compounds are capable of stimulating integrated stress response with an obvious increase in ATF4 [85]. Interestingly, HDAC inhibitors and imipridones have opposite effects on oxidative metabolism, while HDAC inhibitors drive imipridones to inhibit tumor cell respiration (Table 1) [85]. Also, imipridones suppress the secretion of respiratory complexes in an approach mainly determined by the ClpP protease, whereas HDAC inhibitors transcriptionally upregulate enzymes and transcription factors that accelerate oxidative metabolism (Table 1) [85]. Thus, panobinostat may be successfully combined with clinically certified imipridones such as ONC201, ONC206, and ONC212 [85].

4.2 HDAC1/2 and TNF receptor-associated protein 1 (TRAP1)

Interestingly, gefitinib and its target TRAP1 were capable of thwarting HDAC inhibitor-triggered stimulation of tumor respiration, asgamitrinib was conspicuously recognized as a disruptor of the electron transport chain in GBM (Table 1) [84,100]. Thus, these drug combinations, including gamitrinib and HDAC inhibitors, seem to be efficient against a wide variety of GBM models, signifying their potentially broad applicability, specifically with regard to heterogeneity [84]. Furthermore, the combined blockade of TRAP1 and HDACs is a potential novel strategy to combat recalcitrant GBM [84].

5 Bcl-2

Bcl-2 proteins are key regulators with pro- and antiapoptotic functions. Notably, the antiapoptotic Bcl-2 sub-groups are inhibited by selective compounds called Bcl-2 homology domain 3 (BH3)-mimetics, which elicit on-target efficiency in the nanomole range [101,102]. BH3-mimetics have been utilized in numerous preclinical and clinical drug combination treatment regimes because they are elegant and a new approach to tackling tumor cells [102]. In contrast, antiapoptotic Bcl-2 sub-groups, such as Bcl-xL and myeloid cell leukemia-1 (Mcl-1), are highly secreted in human GBM and have been implicated in substantial anti-GBM activity [103]. However, the disadvantage of the blockade of Bcl-xL is that the function of platelets is determined by Bcl-xL, and extensive blockade of Bcl-xL may trigger thrombocytopenia [104]. Interestingly, short interfering RNA (siRNA) analyses revealed that Noxa was associated with cell death triggered by Bcl-2/Bcl-xL blockade and 2-HG treatment, signifying that Noxa is required in the death and not a “bystander” effect [103].

5.1 IDH1 and Bcl-xL

Mutations in isocitrate dehydrogenase (IDH)-1 and, to a lesser extent, in IDH2 predict appreciably enhanced overall survival in comparison with wild-type IDH GBMs and IDH-mutant GBMs [103,105]. Also, whereas IDH1 resides in the cytoplasm, IDH2 and IDH3 are localized to the mitochondria [105]. Furthermore, IDH1 and IDH2 catalyze irreversible reactions, resulting in the generation of NADPH2 and alpha-ketoglutarate, whereas IDH3 often reversibly utilizes NADH2 [103,105]. Moreover, NADPH2 is capable of facilitating an anabolic state in cancer cells by delivering electrons for certain steps in metabolic synthesis, such as fatty acid and nucleotide synthesis, such as ribonucleotide reductase [103,105].

In IDH1-mutated GBM, NADPH2 functions as a cofactor for the reduction of alpha-ketoglutarate to 2-HG and 2-HG at substantial concentrations (30 mM) [103]. Furthermore, 2-HG disrupts the normal function of dioxygenases that utilize alpha-ketoglutarate as a cofactor because of its structural similarity to alpha-ketoglutarate [106]. Moreover, these dioxygenases are particularly relevant in histone and DNA demethylation, which trigger a hypermethylated phenotype in IDH1-mutated tumors [107]. Notably, blockade of Bcl-xL triggers synthetic lethality in IDH1-mutated GBM cells in vitro and in vivo, and their effects are mediated by the oncometabolite 2-HG, which decreases Mcl-1 protein concentration (Table 1) [103]. Markedly, it was detected that IDH1 R132H facilitated the inhibitory effects of Bcl-xL either via siRNA or pharmacologically via the BH3-mimetic ABT263 in tumor cells (Table 1) [103].

Nevertheless, IDH1-mutated GBM and engineered IDH1-mutated GBM cells exhibited lower concentrations of Mcl-1 and treatment with a cell-permeable form of 2-HG inhibited Mcl-1 protein concentration in IDH1 wild-type cells [103]. Also, the 2-HG-mediated decrease in Mcl-1 protein concentration was associated with less protein synthesis and a partial shutdown of mTORC1 signaling, which supports the fact that 2-HG lengthens the lifespan of C. elegans in part by blocking mTORC1 signaling [108,109]. Furthermore, both mutant IDH1- and 2-HG-treated cells exhibited lower baseline OCRs and ATP levels, which in part mediated a decrease in protein synthesis, mTORC1 signaling, and ultimately a reduction in Mcl-1 concentrations [103].

5.2 Bcl-2/Bcl-xL and c-MET

c-Mesenchymal-epithelial transition factor (c-MET) is essential for the growth and maintenance of stem-like GBM cells, a group of tumor cells within glial brain tumors responsible for therapeutic resistance and progression [101,110,111]. Remarkably, Mcl-1 blocks mitochondrial outer membrane permeabilization and release of cytochrome-c into the cytosol after binding to BCL-2 antagonist/killer (BAK) [101]. Also, Mcl-1 absorbs BAK to counteract cell death by inhibiting Bcl-xL and Bcl-2, and Mcl-1 is pivotal for the survival of cancer cells [101]. Furthermore, Mcl-1 is localized in the mitochondrial matrix, directly regulates OXPHOS, and aids in driving oxygen-determined ATP generation [112].

Moreover, GBM sphere cultures exhibited augmented phosphorylation of c-MET, which mediates transcription factor modulation reprogramming essential for a “stem-cell” state [101]. Notably, ectopic secretion of c-MET blocks the differentiation of stem-like GBM cells in a Nanog-dependent fashion, affirming the pivotal function of this kinase pathway in GBM stem cells [111]. Additionally, c-MET modulates the secretory levels of Mcl-1 protein in human GBM models, and GBM stem-like cells exhibit elevated concentrations of c-MET [101].

Interestingly, an important association between c-MET signaling and Mcl-1 in this essential cell population specified that interference with c-MET is a new target for the suppression of Mcl-1 concentrations [101]. Remarkably, c-MET blockade, along with dual Bcl-2/Bcl-xL blockade, triggered synthetic lethality in stem-like and established GBM cells, which were pharmacologically epitomized by the drug combination of ABT263 and Crizotinib, which are currently being tested and used in treating patients (Table 1) [101].

6 RNA interference (RNAi) and siRNA

siRNA is 20–25 nucleotide-long double-stranded RNA (dsRNA) molecules that are capable of selectively inhibiting specific genes via sequence-specific mRNA transcript mortification [113,114,115]. Studies have identified 16 genes that are functionally linked to cell death pathways. Also, the products of these genes function as nuclear hormone receptors such as GTPases, G-protein coupled receptors, oxidases, and mutases, whereas numerous genes were uncategorized [113,116]. Notably, 9 of the 16 genes have been implicated in high secretory levels in GBM [116].

Studies have shown that RNAi is capable of detecting nonessential target genes via in vitro screening for synthetic lethality by means of siRNA/shRNA libraries such as small-molecule compound libraries and, in parallel, using in vitro and in vivo models [16,117,118]. Also, an amalgamation of RNAi responses was capable of augmenting target knockdown efficiency, and up to ten independent mRNAs were potentially targeted by RNAi [117,119]. Furthermore, one siRNA screen-detected blockade of multiple kinases was robust in sensitizing CAL51 and HeLa cells to the DNA repair enzyme PARP inhibition [117,120].

Inhibition of CDK2 by RNAi resulted in the stimulation of synthetic lethality in NMYC-augmented neuroblastoma cell lines but not in single-copy NMYC neuroblastoma cell lines [16,117]. GBM is associated with hyperactivation of AKT and augmentation or truncated mutations of EGFR [121]. Experimentally, a peptide transduction delivery domain (PTD) fused to a dsRNA-binding domain (PTD-DRBD) was utilized to deliver siRNAs that directly targeted truncated EGFRvIII and AKT2 and synergized to stimulate an apoptotic synthetic lethal RNAi response in an orthotopic GBM xenograft mouse model (Table 1) [16,117].

Nevertheless, targeting EGFRvIII, AKT1, or AKT3 does not stimulate a synthetic lethal RNAi response [16]. However, a protein transduction domain derived from the HIV transactivator of transcription (TAT) transports siRNA into GBM cells to stimulate its RNAi effect[16]. In addition, an siRNA delivery method that uses the recognized macromolecular delivery potential of PTDs combined with the sequence-independent dsRNA binding avidity of DRBD allows for the transportation of all siRNA sequences [16].

7 CaMKII and GSCs

Calcium (Ca2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII), one of the most critical modulators of Ca2+-signaling and multifunctional serine/threonine kinase [122,123]. Studies have demonstrated that CaMKII is very essential for the survival, proliferation, invasion, and differentiation of numerous cancer cells via the stimulation of multiple signaling pathways, such as the extracellular signal-regulated kinase, the signal transducer and activator of transcription 3 (STAT3), AKT, and Wnt/β-catenin signaling pathways [124,125]. GBM stem-like cells (GSCs) are produced by GBM and participate in tumor initiation, immune evasion, cancer invasion, radiotherapy, chemotherapy resistance, and recurrence [126,127].

Notably, a synthetic curcumin derivative, hydrazinobenzoylcurcumin (HBC), a Ca2+/CaM antagonist, blocked not only the self-renewal capacity, but also the metastatic potential of GSCs by inhibiting the CaM/CaMKII/c-Met signaling pathway [123,128]. Also, a selective CaMKII inhibitor, KN93, is capable of blocking the growth of GSCs and secretion of GSC stemness markers [128]. Furthermore, CaMKIIγ silencing reduced the stem-like characteristics of GBM cells [128].

Remarkably, neurokinin 1 receptor (NK1R) blockers, such as SR 140333 and aprepitant, have substantial synthetic lethal activity against CaMKII blockers, such as HBC, berbamine, and KN93, in GSCs (Table 1) [123]. Moreover, combined therapy with CaMKII and NK1R blockers not only reduced GSC viability but also potently suppressed GSC-derived tumor growth in an in vivo model of tumorigenesis [123]. Thus, there is a synthetic lethal association between CaMKII and NK1R via RNAi in GSCs [123]. Also, the synergistic therapeutic effect of the combination of CaMKII and NK1R blockers on GSCs was linked to the downregulation of PI3K/AKT/NF-κB and Ca2+signaling in GBM (Table 1) [123].

Furthermore, the lethal consequences of CaMKII and NK1R blockers on GSCs were correlated with a significant decrease in the secretion of key GSC markers such as ALDH1A1, CD44, CD133, Oct4, Sox2, and integrin α6 in GBM (Table 1) [123]. Specifically, the synergistic anti-GBM effect of CaMKII and NK1R blockers against GSCs was triggered by the facilitation of ROS-dependent apoptosis via robust stimulation of the caspase cascade mediated by p53 (Table 1) [123]. Furthermore, NK1R agonists, such as SP and hemokinin-1 (HK-1), facilitate GBM cell proliferation and migration, whereas NK1R antagonists, such as aprepitant, essentially block GBM cell growth in vitro and in vivo [129,130]. Thus, NK1R may function as an upstream modulator of CaMKIIγ activity[123].

8 DNA-PKcs and miR-1193

MicroRNAs (miRNAs or miRs) are small, and extremely preserved, noncoding RNA molecules that typically inhibit gene translation by attaching to complementary sequences in the 3′ untranslated regions (3′UTRs) of their target mRNAs [1,131]. Studies have shown that miRNAs are essential for the initiation, progression, and recurrence of human cancers [132,133,134]. In retinoblastoma formation, synthetic lethality between the miR-17-92 cluster and tumor suppressor p53 was discovered [135]. Synthetic lethality between miR-206 and c-Myc via direct blockade of MAP3K13 was also discovered [136].

Flap endonuclease1 (FEN1), a structure-specific endonuclease, has been implicated in DSB repair via HR and MMEJ and via the long patch BER (LP-BER) pathway[137,138]. FEN1 has also been implicated as a potential strategy for GBM therapy because silencing FEN1 triggered augmented cisplatin sensitivity in GBM [139]. In contrast, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is essential for DSB repair via the NHEJ pathway, whereas DNA-PKcs deficiency is one of the most typical characteristics of GBMs [140].

Notably, the miR-1193/YY1AP1/YY1/FEN1 axis modulates homologous recombination (HR) and MMEJ-mediated DSB repair, offering a compensatory pathway in DNA-PKc-positive cells in which NHEJ-mediated DSB repair is effective [1]. Thus, perturbation of both DSB repair pathways, such as HR/MMEJ and NHEJ, via concurrent blockade of miR-1193 and ablation of DNA-PKcs, is capable of triggering obvious loss of viability in GBM (Table 1) [1]. Also, concurrent blockade of these distinctive DSB repair pathways resulted in stimulation of the ATR/CHK1/p53 axis and consequently facilitated tumor cell apoptosis (Table 1) [1]. Thus, anti-miR-1193 could potentially be used as a single-agent therapy for DNA-PKC-deficient GBM tumors [1].

Interestingly, the silencing of DNA-PKcs and blockade of miR-1193 in GBM is a potential synthetic lethality target for patients with GBM (Table 1) [1]. Furthermore, studies have shown that miRNA inhibition is an essential approach for achieving synthetic lethality in certain tumors with specific genetic deficiencies [141,142]. Chemical modifications of antisense oligonucleotides targeting miRNAs, such as 2′-O-methyl modification, can decrease off-target consequences and considerably increase in vivo delivery efficiency [143]. It was further established that a thiol- and cholesterol-conjugated 2′-O-methyl-modified antagonist might be implemented to validate miR-1193 as a potential treatment target for DNA-PKC-deficient GBMs [1]. This emphasizes the significance of the miR-1193/YY1AP1/YY1/FEN1 axis as a potential treatment target for DNA-PKcs-deficient GBMs, with synthetic lethality as the mechanism of action [1].

8.1 Future perspective of synthetic lethal effect on glioblastoma

Tumor heterogeneity is one of the most critical hallmarks of the GBM milieu and is characterized by various genetic modulations that allow for the classification of GBM into different molecular subtypes. Notably, GBM has been categorized into four distinctive subtypes, classical, mesenchymal, proneural, and neural, based on the mutational landscape in amalgamation with transcriptional profiles determined via bulk RNA sequencing experiments. Thus, it is possible to design permutations in GBM therapies that can concurrently account for multiple distinct therapeutic effects based on these distinctive GBM subtypes.

Notably, the DDR pathway plays a critical role in the synthetic lethal effect of GBM. Also, the detection of synthetic lethal effects associated with several tumor-specific genotypes led to the permutation of genotype-specific cell-blockade modalities. Permutation of therapeutic modalities may be a way forward in personalizing chemotherapeutic regimens to attain specific effects in GBM. Nevertheless, the combined evaluation of multiple synthetic lethal interactions to identify new combinations of treatment modalities has not been adequately investigated. Specifically, synthetic lethality modalities in biological pathways, such as metabolic reprogramming and oxidative stress in GBM, may be advantageous in GBM therapy. Also, synthetic lethality mechanisms targeting key receptors in GBM may augment the efficiency of therapy.

GBM heterogeneity is accountable for current challenges in synthetic lethal effects because a portion of GBM cells respond to therapy, whereas other portions of the cells are ineffective for therapy. Notably, there are still many difficulties in transforming these synthetic lethal interactions and synergetic therapies into clinical benefits because of the magnitude of specific synthetic lethal effects in GBM. Interestingly, some of the synthetic lethal interactions exhibited adequate significance and biological effects but were incapable of achieving clinical effects because of their minute efficacy in the trials. Furthermore, the DDR pathway, which comprises intricate mechanisms and genes, makes the detection of potential targets problematic.

9 Conclusions

The permutation of therapeutic modalities may be the way forward in personalizing chemotherapeutic regimes to attain specific effects in GBM. Currently, PTEN and PI3K; PTEN, PARP, and TMZ; PTEN and IPZ; PTEN and symbiotic macrophage; VRK1 and VRK’, VRK1, TMZ, and olaparib; VRK1, radiation, and DXR; RNAi and siRNA; HDAC1/2 and ClpP; HDAC1/2 and TRAP1; IDH1 and Bcl-xL; Bcl-2/Bcl-xL, and c-MET; CaMKII and GSCs; and DNA-PKcs and miR-1193 constitute potential synthetic lethality targets for the treatment of GBMs. Adequate preclinical and clinical investigations are still needed to establish the most effective and clinically applicable therapeutic modalities for GBM.

Abbreviations

3′-UTRs

3′-untranslated regions

AKT

Protein kinase B

ATF4

Activating transcription factor 4

ATM

Ataxia-telangiectasia mutated

ATP

Adenosine triphosphate

ATR

ATM-and Rad3-related

BAF

Barrier to autointegration factor

BAK

BCL-2 antagonist/killer

BAPN

β-Aminopropionitrile

Bax

Bcl-2-associated X protein

BBB

Blood–brain barrier

Bcl-xL

B-cell lymphoma-extra large

BER

Base excision repair

BRCA

Breast cancer gene

Ca2+

Calcium

CaM

calmodulin

CaMKII

Calmodulin (CaM)-dependent protein kinase II

CDK

Cyclin-dependent kinase

ClpP

Caseinolytic protease proteolytic

c-MET

C-mesenchymal–epithelial transition factor

DDR

DNA damage response

DNA-PKcs

DNA-dependent protein kinase catalytic subunit

Doxorubicin

DXR

DSBs

Double-strand breaks

dsRNA

Double-stranded RNA

EGFR

Epidermal growth factor receptor

ERK

Extracellular signal-regulated kinase

FAK

Focal adhesion kinase

FEN1

Flap endonuclease1

GBM

Glioblastoma multiforme

GSCs

GBM stem-like cells

HBC

Hydrazinobenzoylcurcumin

HDAC

Histone deacetylase

HDR

Homology directed repair

HK-1

Hemokinin-1

HR

Homologous recombination

IDH

Isocitrate dehydrogenase

IPZ

Irrepairzepine

IRT

Irradiation/radition

IRT

Radiotherapy

KRAS

Kirsten rat sarcoma viral oncogene homologue

LOX

Lysyl oxidase

MGMT

Neurokinin 1 receptor NK1R,O-6-methylguanine-DNA methyltransferase

mTOR

Rapamycin

NHEJ

Non-homologous end-joining

OCR

Oxygen consumption rate

OXPHOS

Oxidative phosphorylation

PARP

Poly(ADP-ribose) polymerase

PARPi

PARP inhibitor

PI3K

Phosphoinositide 3-kinases

PTD

Peptide transduction delivery domain

PTD-DRBD

PTD fused to a dsRNA-binding domain

PTEN

Phosphatase and tension homologue

PYK

Proline-rich tyrosine kinase

RNAi

RNA interference

RPA

Replication protein A

siRNA

Short interfering RNA

STAT

Signal transducer and activator of transcription

TAMs

Tumor-associated microphages

TAT

Transactivator of transcription

TME

Tumor microenvironment

TMZ

Temozolomide

VRKs

Vaccinia-related kinase

YAP

Yes-associate protein

tel: +233508404595

Acknowledgements

Not applicable.

  1. Funding information: None.

  2. Author contributions: The author confirms the sole responsibility for the conception of the study, presented results and manuscript preparation.

  3. Conflict of interest: None declared.

  4. Data availability statement: No data was analyzed in this article.

References

[1] Zhang J, Jing L, Tan S, Zeng EM, Lin Y, He L, et al. Inhibition of miR-1193 leads to synthetic lethality in glioblastoma multiforme cells deficient of DNA-PKcs. Cell Death Dis. 2020;11(7):602. 10.1038/s41419-020-02812-3.Suche in Google Scholar PubMed PubMed Central

[2] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–66. 10.1016/s1470-2045(09)70025-7.Suche in Google Scholar

[3] Richard SA. Explicating the pivotal pathogenic, diagnostic, and therapeutic biomarker potentials of myeloid-derived suppressor cells in glioblastoma. Dis Markers. 2020;2020:8844313. 10.1155/2020/8844313.Suche in Google Scholar PubMed PubMed Central

[4] Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012;26(8):756–84. 10.1101/gad.187922.112.Suche in Google Scholar PubMed PubMed Central

[5] Richard SA, Eugene KD. The pivotal immunomodulatory and anti-inflammatory effect of histone-lysine n-methyltransferase in the glioma microenvironment: its biomarker and therapy potentials. Analytical Cellular Pathology. 2021;2021:4907167.10.1155/2021/4907167Suche in Google Scholar PubMed PubMed Central

[6] Richard SA. EPAC2: A new and promising protein for glioma pathogenesis and therapy. Oncology Reviews. 2020;14:1.10.4081/oncol.2020.446Suche in Google Scholar PubMed PubMed Central

[7] Richard SA. Novel pathogenic, biomarker and therapeutic potentials of foxm1 in glioma. NeuroQuantology. 2019;17:6.10.14704/nq.2019.17.6.2227Suche in Google Scholar

[8] Huang PH, Xu AM, White FM. Oncogenic EGFR signaling networks in glioma. Sci Signal. 2009;2(87):re6. 10.1126/scisignal.287re6.Suche in Google Scholar PubMed

[9] Aoki T, Hashimoto N, Matsutani M. Management of glioblastoma. Expert Opin Pharmacother. 2007;8(18):3133–46. 10.1517/14656566.8.18.3133.Suche in Google Scholar PubMed

[10] Mason WP. Emerging drugs for malignant glioma. Expert Opin Emerg Drugs. 2008;13(1):81–94. 10.1517/14728214.13.1.81.Suche in Google Scholar PubMed

[11] Hopkins AL, Groom CR. The druggable genome. Nat Rev Drug Discov. 2002;1(9):727–30. 10.1038/nrd892.Suche in Google Scholar PubMed

[12] Cheng AC, Coleman RG, Smyth KT, Cao Q, Soulard P, Caffrey DR, et al. Structure-based maximal affinity model predicts small-molecule druggability. Nature biotechnology. 2007;25(1):71–5. 10.1038/nbt1273.Suche in Google Scholar PubMed

[13] Loeb LA, Bielas JH, Beckman RA. Cancers exhibit a mutator phenotype: clinical implications. Cancer Res. 2008;68(10):3551–7. discussion 7. 10.1158/0008-5472.Can-07-5835.Suche in Google Scholar

[14] Harper JW, Elledge SJ. The DNA damage response: ten years after. Mol Cell. 2007;28(5):739–45. 10.1016/j.molcel.2007.11.015.Suche in Google Scholar PubMed

[15] Reinhardt HC, Yaffe MB. Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Curr Opin Cell Biol. 2009;21(2):245–55. 10.1016/j.ceb.2009.01.018.Suche in Google Scholar PubMed PubMed Central

[16] Michiue H, Eguchi A, Scadeng M, Dowdy SF. Induction of in vivo synthetic lethal RNAi responses to treat glioblastoma. Cancer Biol Ther. 2009;8(23):2306–13. 10.4161/cbt.8.23.10271.Suche in Google Scholar PubMed

[17] Adaku N, Park HB, Spakowicz DJ, Tiwari MK, Strobel SA, Crawford JM, et al. A DNA repair inhibitor isolated from an ecuadorian fungal endophyte exhibits synthetic lethality in PTEN-deficient glioblastoma. J Nat Prod. 2020;83(6):1899–908. 10.1021/acs.jnatprod.0c00012.Suche in Google Scholar PubMed

[18] Hartman JL, Garvik B, Hartwell L. Principles for the buffering of genetic variation. Science. 2001;291(5506):1001–4. 10.1126/science.291.5506.1001.Suche in Google Scholar PubMed

[19] Torgovnick A, Schumacher B. DNA repair mechanisms in cancer development and therapy. Frontiers in genetics. 2015;6:157. 10.3389/fgene.2015.00157.Suche in Google Scholar PubMed PubMed Central

[20] Turchick A, Liu Y, Zhao W, Cohen I, Glazer PM. Synthetic lethality of a cell-penetrating anti-RAD51 antibody in PTEN-deficient melanoma and glioma cells. Oncotarget. 2019;10(13):1272–83. 10.18632/oncotarget.26654.Suche in Google Scholar PubMed PubMed Central

[21] Planchon SM, Waite KA, Eng C. The nuclear affairs of PTEN. J Cell Sci. 2008;121(Pt 3):249–53. 10.1242/jcs.022459.Suche in Google Scholar PubMed

[22] Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 2007;128(1):157–70. 10.1016/j.cell.2006.11.042.Suche in Google Scholar PubMed

[23] Mansour WY, Tennstedt P, Volquardsen J, Oing C, Kluth M, Hube-Magg C, et al. Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer. Sci Rep. 2018;8(1):3947. 10.1038/s41598-018-22289-7.Suche in Google Scholar PubMed PubMed Central

[24] Li HF, Kim JS, Waldman T. Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells. Radiat Oncol. 2009;4:43. 10.1186/1748-717x-4-43.Suche in Google Scholar PubMed PubMed Central

[25] Jiang Z, Pore N, Cerniglia GJ, Mick R, Georgescu MM, Bernhard EJ, et al. Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. Cancer Res. 2007;67(9):4467–73. 10.1158/0008-5472.Can-06-3398.Suche in Google Scholar

[26] Bassi C, Ho J, Srikumar T, Dowling RJ, Gorrini C, Miller SJ, et al. Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress. Science. 2013;341(6144):395–9. 10.1126/science.1236188.Suche in Google Scholar PubMed PubMed Central

[27] Sulkowski PL, Scanlon SE, Oeck S, Glazer PM. PTEN regulates nonhomologous end joining by epigenetic induction of NHEJ1/XLF. Mol Cancer Res. 2018;16(8):1241–54. 10.1158/1541-7786.Mcr-17-0581.Suche in Google Scholar PubMed PubMed Central

[28] Gupta A, Yang Q, Pandita RK, Hunt CR, Xiang T, Misri S, et al. Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair. Cell Cycle. 2009;8(14):2198–210. 10.4161/cc.8.14.8947.Suche in Google Scholar PubMed

[29] Kang YJ, Balter B, Csizmadia E, Haas B, Sharma H, Bronson R, et al. Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival. Nat Commun. 2017;8:14013. 10.1038/ncomms14013.Suche in Google Scholar PubMed PubMed Central

[30] McEllin B, Camacho CV, Mukherjee B, Hahm B, Tomimatsu N, Bachoo RM, et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 2010;70(13):5457–64. 10.1158/0008-5472.Can-09-4295.Suche in Google Scholar

[31] Cheng CK, Gustafson WC, Charron E, Houseman BT, Zunder E, Goga A, et al. Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma. Proc Natl Acad Sci U S A. 2012;109(31):12722–7. 10.1073/pnas.1202492109.Suche in Google Scholar PubMed PubMed Central

[32] Network CGAR. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8. 10.1038/nature07385.Suche in Google Scholar PubMed PubMed Central

[33] Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell. 2006;9(5):341–9. 10.1016/j.ccr.2006.03.029.Suche in Google Scholar PubMed PubMed Central

[34] Fan QW, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res. 2007;67(17):7960–5. 10.1158/0008-5472.Can-07-2154.Suche in Google Scholar PubMed PubMed Central

[35] Hayakawa M, Kawaguchi K, Kaizawa H, Koizumi T, Ohishi T, Yamano M, et al. Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem. 2007;15(17):5837–44. 10.1016/j.bmc.2007.05.070.Suche in Google Scholar PubMed

[36] Hayakawa M, Kaizawa H, Kawaguchi K, Ishikawa N, Koizumi T, Ohishi T, et al. Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem. 2007;15(1):403–12. 10.1016/j.bmc.2006.09.047.Suche in Google Scholar PubMed

[37] Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS, et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med. 2009;1(6–7):315–22. 10.1002/emmm.200900041.Suche in Google Scholar PubMed PubMed Central

[38] Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–27. 10.1056/NEJMoa1903387.Suche in Google Scholar PubMed PubMed Central

[39] McCabe N, Hanna C, Walker SM, Gonda D, Li J, Wikstrom K, et al. Mechanistic rationale to target PTEN-deficient tumor cells with inhibitors of the DNA damage response kinase ATM. Cancer Res. 2015;75(11):2159–65. 10.1158/0008-5472.Can-14-3502.Suche in Google Scholar PubMed

[40] Li K, Yan H, Guo W, Tang M, Zhao X, Tong A, et al. ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin. Exp Cell Res. 2018;366(1):24–33. 10.1016/j.yexcr.2018.03.006.Suche in Google Scholar PubMed

[41] Daniel P, Sabri S, Chaddad A, Meehan B, Jean-Claude B, Rak J, et al. Temozolomide induced hypermutation in glioma: evolutionary mechanisms and therapeutic opportunities. Front Oncol. 2019;9:41. 10.3389/fonc.2019.00041.Suche in Google Scholar PubMed PubMed Central

[42] Navarro-Carrasco E, Lazo PA. VRK1 depletion facilitates the synthetic lethality of temozolomide and olaparib in glioblastoma cells. Front Cell Dev Biol. 2021;9:683038. 10.3389/fcell.2021.683038.Suche in Google Scholar PubMed PubMed Central

[43] Lee SY. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 2016;3(3):198–210. 10.1016/j.gendis.2016.04.007.Suche in Google Scholar PubMed PubMed Central

[44] Zhang J, Stevens MF, Bradshaw TD. Temozolomide: mechanisms of action, repair and resistance. Curr Mol Pharmacol. 2012;5(1):102–14. 10.2174/1874467211205010102.Suche in Google Scholar PubMed

[45] Montaldi AP, Lima SCG, Godoy P, Xavier DJ, Sakamoto-Hojo ET. PARP‑1 inhibition sensitizes temozolomide‑treated glioblastoma cell lines and decreases drug resistance independent of MGMT activity and PTEN proficiency. Oncol Rep. 2020;44(5):2275–87. 10.3892/or.2020.7756.Suche in Google Scholar PubMed

[46] Tentori L, Ricci-Vitiani L, Muzi A, Ciccarone F, Pelacchi F, Calabrese R, et al. Pharmacological inhibition of poly(ADP-ribose) polymerase-1 modulates resistance of human glioblastoma stem cells to temozolomide. BMC Cancer. 2014;14:151. 10.1186/1471-2407-14-151.Suche in Google Scholar PubMed PubMed Central

[47] Erice O, Smith MP, White R, Goicoechea I, Barriuso J, Jones C, et al. MGMT expression predicts PARP-mediated resistance to temozolomide. Mol Cancer Ther. 2015;14(5):1236–46. 10.1158/1535-7163.Mct-14-0810.Suche in Google Scholar

[48] Balvers RK, Lamfers ML, Kloezeman JJ, Kleijn A, Berghauser Pont LM, Dirven CM, et al. ABT-888 enhances cytotoxic effects of temozolomide independent of MGMT status in serum free cultured glioma cells. J Transl Med. 2015;13:74. 10.1186/s12967-015-0427-y.Suche in Google Scholar PubMed PubMed Central

[49] Chen P, Zhao D, Li J, Liang X, Li J, Chang A, et al. Symbiotic macrophage-glioma cell interactions reveal synthetic lethality in PTEN-null glioma. Cancer Cell. 2019;35(6):868–84.e6. 10.1016/j.ccell.2019.05.003.Suche in Google Scholar PubMed PubMed Central

[50] Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20–7. 10.1038/nn.4185.Suche in Google Scholar PubMed PubMed Central

[51] Richard SA. The pivotal immunoregulatory functions of microglia and macrophages in glioma pathogenesis and therapy. J Oncol. 2022;2022:8903482. 10.1155/2022/8903482.Suche in Google Scholar PubMed PubMed Central

[52] Dey N, Crosswell HE, De P, Parsons R, Peng Q, Su JD, et al. The protein phosphatase activity of PTEN regulates SRC family kinases and controls glioma migration. Cancer Res. 2008;68(6):1862–71. 10.1158/0008-5472.Can-07-1182.Suche in Google Scholar

[53] Petermann E, Orta ML, Issaeva N, Schultz N, Helleday T. Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol Cell. 2010;37(4):492–502. 10.1016/j.molcel.2010.01.021.Suche in Google Scholar PubMed PubMed Central

[54] He J, Kang X, Yin Y, Chao KS, Shen WH. PTEN regulates DNA replication progression and stalled fork recovery. Nat Commun. 2015;6:7620. 10.1038/ncomms8620.Suche in Google Scholar PubMed PubMed Central

[55] Maréchal A, Zou L. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol. 2013;5(9):a012716. 10.1101/cshperspect.a012716.Suche in Google Scholar PubMed PubMed Central

[56] Shields JA, Meier SR, Bandi M, Mulkearns-Hubert EE, Hajdari N, Ferdinez MD, et al. VRK1 Is a synthetic-lethal Target in VRK2-deficient glioblastoma. Cancer Res. 2022;82(21):4044–57. 10.1158/0008-5472.Can-21-4443.Suche in Google Scholar

[57] Klerkx EP, Lazo PA, Askjaer P. Emerging biological functions of the vaccinia-related kinase (VRK) family. Histol Histopathol. 2009;24(6):749–59. 10.14670/hh-24.749.Suche in Google Scholar PubMed

[58] Martín-Doncel E, Rojas AM, Cantarero L, Lazo PA. VRK1 functional insufficiency due to alterations in protein stability or kinase activity of human VRK1 pathogenic variants implicated in neuromotor syndromes. Sci Rep. 2019;9(1):13381. 10.1038/s41598-019-49821-7.Suche in Google Scholar PubMed PubMed Central

[59] Valbuena A, Sanz-García M, López-Sánchez I, Vega FM, Lazo PA. Roles of VRK1 as a new player in the control of biological processes required for cell division. Cell Signal. 2011;23(8):1267–72. 10.1016/j.cellsig.2011.04.002.Suche in Google Scholar PubMed

[60] Monsalve DM, Merced T, Fernández IF, Blanco S, Vázquez-Cedeira M, Lazo PA. Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression. Cell Death Dis. 2013;4(2):e513. 10.1038/cddis.2013.40.Suche in Google Scholar PubMed PubMed Central

[61] Blanco S, Klimcakova L, Vega FM, Lazo PA. The subcellular localization of vaccinia-related kinase-2 (VRK2) isoforms determines their different effect on p53 stability in tumour cell lines. Febs J. 2006;273(11):2487–504. 10.1111/j.1742-4658.2006.05256.x.Suche in Google Scholar PubMed

[62] Santos CR, Rodríguez-Pinilla M, Vega FM, Rodríguez-Peralto JL, Blanco S, Sevilla A, et al. VRK1 signaling pathway in the context of the proliferation phenotype in head and neck squamous cell carcinoma. Mol Cancer Res. 2006;4(3):177–85. 10.1158/1541-7786.Mcr-05-0212.Suche in Google Scholar

[63] Ben Z, Gong L, Qiu Y. High expression of VRK1 is related to poor prognosis in glioma. Pathol Res Pract. 2018;214(1):112–8. 10.1016/j.prp.2017.10.014.Suche in Google Scholar PubMed

[64] Colmenero-Repiso A, Gómez-Muñoz MA, Rodríguez-Prieto I, Amador-Álvarez A, Henrich KO, Pascual-Vaca D, et al. Identification of VRK1 as a new neuroblastoma tumor progression marker regulating cell proliferation. Cancers. 2020;12(11). 10.3390/cancers12113465.Suche in Google Scholar PubMed PubMed Central

[65] Kiessling MK, Schuierer S, Stertz S, Beibel M, Bergling S, Knehr J, et al. Identification of oncogenic driver mutations by genome-wide CRISPR-Cas9 dropout screening. BMC Genomics. 2016;17(1):723. 10.1186/s12864-016-3042-2.Suche in Google Scholar PubMed PubMed Central

[66] McDonald ER, de Weck 3rd A, Schlabach MR, Billy E, Mavrakis KJ, Hoffman GR, et al. Project DRIVE: A compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell. 2017;170(3):577–92.e10. 10.1016/j.cell.2017.07.005.Suche in Google Scholar PubMed

[67] Campillo-Marcos I, Lazo PA. Olaparib and ionizing radiation trigger a cooperative DNA-damage repair response that is impaired by depletion of the VRK1 chromatin kinase. J Exp Clin Cancer Res. 2019;38(1):203. 10.1186/s13046-019-1204-1.Suche in Google Scholar PubMed PubMed Central

[68] Campillo-Marcos I, Lazo PA. Implication of the VRK1 chromatin kinase in the signaling responses to DNA damage: a therapeutic target? Cell Mol Life Sci. 2018;75(13):2375–88. 10.1007/s00018-018-2811-2.Suche in Google Scholar PubMed PubMed Central

[69] Kang TH, Park DY, Choi YH, Kim KJ, Yoon HS, Kim KT. Mitotic histone H3 phosphorylation by vaccinia-related kinase 1 in mammalian cells. Mol Cell Biol. 2007;27(24):8533–46. 10.1128/mcb.00018-07.Suche in Google Scholar

[70] Jeong MW, Kang TH, Kim W, Choi YH, Kim KT. Mitogen-activated protein kinase phosphatase 2 regulates histone H3 phosphorylation via interaction with vaccinia-related kinase 1. Mol Biol Cell. 2013;24(3):373–84. 10.1091/mbc.E12-06-0456.Suche in Google Scholar PubMed PubMed Central

[71] Moura DS, Campillo-Marcos I, Vázquez-Cedeira M, Lazo PA. VRK1 and AURKB form a complex that cross inhibit their kinase activity and the phosphorylation of histone H3 in the progression of mitosis. Cell Mol Life Sci. 2018;75(14):2591–611. 10.1007/s00018-018-2746-7.Suche in Google Scholar PubMed PubMed Central

[72] Kang TH, Park DY, Kim W, Kim KT. VRK1 phosphorylates CREB and mediates CCND1 expression. J Cell Sci. 2008;121(Pt 18):3035–41. 10.1242/jcs.026757.Suche in Google Scholar PubMed

[73] Valbuena A, López-Sánchez I, Lazo PA. Human VRK1 is an early response gene and its loss causes a block in cell cycle progression. PLoS One. 2008;3(2):e1642. 10.1371/journal.pone.0001642.Suche in Google Scholar PubMed PubMed Central

[74] So J, Mabe NW, Englinger B, Chow KH, Moyer SM, Yerrum S, et al. VRK1 as a synthetic lethal target in VRK2 promoter-methylated cancers of the nervous system. JCI Insight. 2022;7(19):e158755. 10.1172/jci.insight.158755.Suche in Google Scholar PubMed PubMed Central

[75] Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nature reviews Molecular cell biology. 2017;18(10):610–21. 10.1038/nrm.2017.53.Suche in Google Scholar PubMed PubMed Central

[76] Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34. 10.1056/NEJMoa0900212.Suche in Google Scholar PubMed

[77] Tewari KS, Eskander RN, Monk BJ. Development of olaparib for BRCA-deficient recurrent epithelial ovarian cancer. Clin Cancer Res. 2015;21(17):3829–35. 10.1158/1078-0432.Ccr-15-0088.Suche in Google Scholar

[78] Lohse I, Kumareswaran R, Cao P, Pitcher B, Gallinger S, Bristow RG, et al. Effects of combined treatment with ionizing radiation and the PARP inhibitor olaparib in BRCA mutant and wild type patient-derived pancreatic cancer xenografts. PLoS One. 2016;11(12):e0167272. 10.1371/journal.pone.0167272.Suche in Google Scholar PubMed PubMed Central

[79] Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33. 10.1056/NEJMoa1706450.Suche in Google Scholar PubMed

[80] García-González R, Morejón-García P, Campillo-Marcos I, Salzano M, Lazo PA. VRK1 phosphorylates Tip60/KAT5 and is required for H4K16 acetylation in response to DNA damage. Cancers. 2020;12(10):2986. 10.3390/cancers12102986.Suche in Google Scholar PubMed PubMed Central

[81] Serafim RAM, de Souza Gama FH, Dutra LA, Dos Reis CV, Vasconcelos SNS, da Silva Santiago A, et al. Development of pyridine-based inhibitors for the human vaccinia-related kinases 1 and 2. ACS Med Chem Lett. 2019;10(9):1266–71. 10.1021/acsmedchemlett.9b00082.Suche in Google Scholar PubMed PubMed Central

[82] Nguyen TTT, Zhang Y, Shang E, Shu C, Torrini C, Zhao J, et al. HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models. J Clin Invest. 2020;130(7):3699–716. 10.1172/jci129049.Suche in Google Scholar PubMed PubMed Central

[83] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33. 10.1126/science.1160809.Suche in Google Scholar PubMed PubMed Central

[84] Nguyen TTT, Zhang Y, Shang E, Shu C, Quinzii CM, Westhoff MA, et al. Inhibition of HDAC1/2 Along with TRAP1 causes synthetic lethality in glioblastoma model systems. Cells. 2020;9(7):1661. 10.3390/cells9071661.Suche in Google Scholar PubMed PubMed Central

[85] Nguyen TTT, Shang E, Schiffgens S, Torrini C, Shu C, Akman HO, et al. Induction of synthetic lethality by activation of mitochondrial ClpP and inhibition of HDAC1/2 in glioblastoma. Clinical cancer research: an official journal of the American Association for Cancer Research. 2022;28(9):1881–95. 10.1158/1078-0432.Ccr-21-2857.Suche in Google Scholar PubMed PubMed Central

[86] Kline CLB, Ralff MD, Lulla AR, Wagner JM, Abbosh PH, Dicker DT, et al. Role of Dopamine Receptors in the Anticancer Activity of ONC201. Neoplasia. 2018;20(1):80–91. 10.1016/j.neo.2017.10.002.Suche in Google Scholar PubMed PubMed Central

[87] Ishida CT, Zhang Y, Bianchetti E, Shu C, Nguyen TTT, Kleiner G, et al. Metabolic reprogramming by Dual AKT/ERK inhibition through imipridones elicits unique vulnerabilities in glioblastoma. Clinical cancer research: an official journal of the American Association for Cancer Research. 2018;24(21):5392–406. 10.1158/1078-0432.Ccr-18-1040.Suche in Google Scholar

[88] Pruss M, Dwucet A, Tanriover M, Hlavac M, Kast RE, Debatin KM, et al. Dual metabolic reprogramming by ONC201/TIC10 and 2-Deoxyglucose induces energy depletion and synergistic anticancer activity in glioblastoma. Br J Cancer. 2020;122(8):1146–57. 10.1038/s41416-020-0759-0.Suche in Google Scholar PubMed PubMed Central

[89] Guo D, Reinitz F, Youssef M, Hong C, Nathanson D, Akhavan D, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 2011;1(5):442–56. 10.1158/2159-8290.Cd-11-0102.Suche in Google Scholar

[90] Masui K, Harachi M, Cavenee WK, Mischel PS, Shibata N. mTOR complex 2 is an integrator of cancer metabolism and epigenetics. Cancer letters. 2020;478:1–7. 10.1016/j.canlet.2020.03.001.Suche in Google Scholar PubMed

[91] Bi J, Chowdhry S, Wu S, Zhang W, Masui K, Mischel PS. Altered cellular metabolism in gliomas - an emerging landscape of actionable co-dependency targets. Nat Rev Cancer. 2020;20(1):57–70. 10.1038/s41568-019-0226-5.Suche in Google Scholar PubMed

[92] Gimple RC, Kidwell RL, Kim LJY, Sun T, Gromovsky AD, Wu Q, et al. Glioma stem cell-specific superenhancer promotes polyunsaturated fatty-acid synthesis to support EGFR signaling. Cancer Discov. 2019;9(9):1248–67. 10.1158/2159-8290.Cd-19-0061.Suche in Google Scholar

[93] Randall EC, Lopez BGC, Peng S, Regan MS, Abdelmoula WM, Basu SS, et al. Localized metabolomic gradients in patient-derived xenograft models of glioblastoma. Cancer Res. 2020;80(6):1258–67. 10.1158/0008-5472.Can-19-0638.Suche in Google Scholar

[94] Ishizawa J, Zarabi SF, Davis RE, Halgas O, Nii T, Jitkova Y, et al. Mitochondrial ClpP-Mediated proteolysis induces selective cancer cell lethality. Cancer Cell. 2019;35(5):721–37.e9. 10.1016/j.ccell.2019.03.014.Suche in Google Scholar PubMed PubMed Central

[95] Graves PR, Aponte-Collazo LJ, Fennell EMJ, Graves AC, Hale AE, Dicheva N, et al. Mitochondrial protease ClpP is a target for the anticancer compounds ONC201 and related analogues. ACS Chem Biol. 2019;14(5):1020–9. 10.1021/acschembio.9b00222.Suche in Google Scholar PubMed PubMed Central

[96] Prabhu VV, Morrow S, Rahman Kawakibi A, Zhou L, Ralff M, Ray J, et al. ONC201 and imipridones: Anticancer compounds with clinical efficacy. Neoplasia. 2020;22(12):725–44. 10.1016/j.neo.2020.09.005.Suche in Google Scholar PubMed PubMed Central

[97] Wagner J, Kline CL, Pottorf RS, Nallaganchu BR, Olson GL, Dicker DT, et al. The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anticancer activity. Oncotarget. 2014;5(24):12728–37. 10.18632/oncotarget.2890.Suche in Google Scholar PubMed PubMed Central

[98] Prabhu VV, Talekar MK, Lulla AR, Kline CLB, Zhou L, Hall J, et al. Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies. Cell Cycle. 2018;17(4):468–78. 10.1080/15384101.2017.1403689.Suche in Google Scholar PubMed PubMed Central

[99] Bonner ER, Waszak SM, Grotzer MA, Mueller S, Nazarian J. Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells. Neuro Oncol. 2021;23(4):542–56. 10.1093/neuonc/noaa283.Suche in Google Scholar PubMed PubMed Central

[100] Chae YC, Angelin A, Lisanti S, Kossenkov AV, Speicher KD, Wang H, et al. Landscape of the mitochondrial Hsp90 metabolome in tumours. Nat Commun. 2013;4:2139. 10.1038/ncomms3139.Suche in Google Scholar PubMed PubMed Central

[101] Zhang Y, Ishida CT, Shu C, Kleiner G, Sanchez-Quintero MJ, Bianchetti E, et al. Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma. Sci Rep. 2018;8(1):7373. 10.1038/s41598-018-25802-0.Suche in Google Scholar PubMed PubMed Central

[102] Karpel-Massler G, Ishida CT, Zhang Y, Halatsch ME, Westhoff MA, Siegelin MD. Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma. Expert Opin Drug Discovery. 2017;12(10):1031–40. 10.1080/17460441.2017.1356286.Suche in Google Scholar PubMed PubMed Central

[103] Karpel-Massler G, Ishida CT, Bianchetti E, Zhang Y, Shu C, Tsujiuchi T, et al. Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat Commun. 2017;8(1):1067. 10.1038/s41467-017-00984-9.Suche in Google Scholar PubMed PubMed Central

[104] Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015;7(279):279ra40. 10.1126/scitranslmed.aaa4642.Suche in Google Scholar PubMed

[105] Horbinski C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta Neuropathol. 2013;125(5):621–36. 10.1007/s00401-013-1106-9.Suche in Google Scholar PubMed PubMed Central

[106] Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30. 10.1016/j.ccr.2010.12.014.Suche in Google Scholar PubMed PubMed Central

[107] Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483(7390):479–83. 10.1038/nature10866.Suche in Google Scholar PubMed PubMed Central

[108] Faber AC, Coffee EM, Costa C, Dastur A, Ebi H, Hata AN, et al. mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. Cancer Discov. 2014;4(1):42–52. 10.1158/2159-8290.Cd-13-0315.Suche in Google Scholar PubMed PubMed Central

[109] Fu X, Chin RM, Vergnes L, Hwang H, Deng G, Xing Y, et al. 2-Hydroxyglutarate inhibits ATP synthase and mTOR signaling. Cell Metab. 2015;22(3):508–15. 10.1016/j.cmet.2015.06.009.Suche in Google Scholar PubMed PubMed Central

[110] Rath P, Lal B, Ajala O, Li Y, Xia S, Kim J, et al. In vivo c-met pathway inhibition depletes human glioma xenografts of tumor-propagating stem-like cells. Transl Oncol. 2013;6(2):104–11. 10.1593/tlo.13127.Suche in Google Scholar PubMed PubMed Central

[111] Li Y, Li A, Glas M, Lal B, Ying M, Sang Y, et al. c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci U S A. 2011;108(24):9951–6. 10.1073/pnas.1016912108.Suche in Google Scholar PubMed PubMed Central

[112] Perciavalle RM, Stewart DP, Koss B, Lynch J, Milasta S, Bathina M, et al. Antiapoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol. 2012;14(6):575–83. 10.1038/ncb2488.Suche in Google Scholar PubMed PubMed Central

[113] Thaker NG, Zhang F, McDonald PR, Shun TY, Lazo JS, Pollack IF. Functional genomic analysis of glioblastoma multiforme through short interfering RNA screening: a paradigm for therapeutic development. Neurosurg Focus. 2010;28(1):E4. 10.3171/2009.10.Focus09210.Suche in Google Scholar

[114] Robinson R. RNAi therapeutics: how likely, how soon. PLoS Biol. 2004;2(1):E28. 10.1371/journal.pbio.0020028.Suche in Google Scholar PubMed PubMed Central

[115] Sachse C, Echeverri CJ. Oncology studies using siRNA libraries: the dawn of RNAi-based genomics. Oncogene. 2004;23(51):8384–91. 10.1038/sj.onc.1208072.Suche in Google Scholar PubMed

[116] Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007;9(2):166–80. 10.1593/neo.07112.Suche in Google Scholar PubMed PubMed Central

[117] Kacsinta AD, Dowdy SF. Current views on inducing synthetic lethal RNAi responses in the treatment of cancer. Expert Opin Biol Ther. 2016;16(2):161–72. 10.1517/14712598.2016.1110141.Suche in Google Scholar PubMed

[118] Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39. 10.1038/nrc2559.Suche in Google Scholar PubMed

[119] Possik PA, Müller J, Gerlach C, Kenski JC, Huang X, Shahrabi A, et al. Parallel in vivo and in vitro melanoma RNAi dropout screens reveal synthetic lethality between hypoxia and DNA damage response inhibition. Cell Rep. 2014;9(4):1375–86. 10.1016/j.celrep.2014.10.024.Suche in Google Scholar PubMed

[120] Turner NC, Lord CJ, Iorns E, Brough R, Swift S, Elliott R, et al. A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. Embo j. 2008;27(9):1368–77. 10.1038/emboj.2008.61.Suche in Google Scholar PubMed PubMed Central

[121] Hulleman E, Helin K. Molecular mechanisms in gliomagenesis. Adv Cancer Res. 2005;94:1–27. 10.1016/s0065-230x(05)94001-3.Suche in Google Scholar PubMed

[122] Hook SS, Means AR. Ca2+/CaM-dependent kinases: from activation to function. Annu Rev Pharmacol Toxicol. 2001;41:471–505. 10.1146/annurev.pharmtox.41.1.471.Suche in Google Scholar PubMed

[123] Han JM, Kim YJ, Jung HJ. Discovery of a new CaMKII-targeted synthetic lethal therapy against glioblastoma stem-like cells. Cancers. 2022;14(5):1315. 10.3390/cancers14051315.Suche in Google Scholar PubMed PubMed Central

[124] Wang YY, Zhao R, Zhe H. The emerging role of CaMKII in cancer. Oncotarget. 2015;6(14):11725–34. 10.18632/oncotarget.3955.Suche in Google Scholar PubMed PubMed Central

[125] Wang T, Guo S, Liu Z, Wu L, Li M, Yang J, et al. CAMK2N1 inhibits prostate cancer progression through androgen receptor-dependent signaling. Oncotarget. 2014;5(21):10293–306. 10.18632/oncotarget.2511.Suche in Google Scholar PubMed PubMed Central

[126] Finocchiaro G. TLRgeting evasion of immune pathways in glioblastoma. Cell stem cell. 2017;20(4):422–4. 10.1016/j.stem.2017.03.018.Suche in Google Scholar PubMed

[127] Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157–73. 10.1016/j.ccr.2006.02.019.Suche in Google Scholar PubMed

[128] Shin HJ, Lee S, Jung HJ. A curcumin derivative hydrazinobenzoylcurcumin suppresses stem-like features of glioblastoma cells by targeting Ca(2 +)/calmodulin-dependent protein kinase II. J Cell Biochem. 2019;120(4):6741–52. 10.1002/jcb.27972.Suche in Google Scholar PubMed

[129] Akazawa T, Kwatra SG, Goldsmith LE, Richardson MD, Cox EA, Sampson JH, et al. A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. J Neurochem. 2009;109(4):1079–86. 10.1111/j.1471-4159.2009.06032.x.Suche in Google Scholar PubMed PubMed Central

[130] Zhang H, Kanduluru AK, Desai P, Ahad A, Carlin S, Tandon N, et al. Synthesis and evaluation of a Novel (64)Cu- and (67)Ga-Labeled neurokinin 1 receptor antagonist for in vivo targeting of NK1R-positive tumor xenografts. Bioconjug Chem. 2018;29(4):1319–26. 10.1021/acs.bioconjchem.8b00063.Suche in Google Scholar PubMed

[131] He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31. 10.1038/nrg1379.Suche in Google Scholar PubMed

[132] Garofalo M, Condorelli G, Croce CM. MicroRNAs in diseases and drug response. Curr Opin Pharmacol. 2008;8(5):661–7. 10.1016/j.coph.2008.06.005.Suche in Google Scholar PubMed

[133] Xu H, Sun J, Shi C, Sun C, Yu L, Wen Y, et al. miR-29s inhibit the malignant behavior of U87MG glioblastoma cell line by targeting DNMT3A and 3B. Neurosci Lett. 2015;590:40–6. 10.1016/j.neulet.2015.01.060.Suche in Google Scholar PubMed

[134] Sana J, Hajduch M, Michalek J, Vyzula R, Slaby O. MicroRNAs and glioblastoma: roles in core signalling pathways and potential clinical implications. J Cell Mol Med. 2011;15(8):1636–44. 10.1111/j.1582-4934.2011.01317.x.Suche in Google Scholar PubMed PubMed Central

[135] Nittner D, Lambertz I, Clermont F, Mestdagh P, Köhler C, Nielsen SJ, et al. Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation. Nat Cell Biol. 2012;14(9):958–65. 10.1038/ncb2556.Suche in Google Scholar PubMed

[136] Han H, Chen Y, Cheng L, Prochownik EV, Li Y. microRNA-206 impairs c-Myc-driven cancer in a synthetic lethal manner by directly inhibiting MAP3K13. Oncotarget. 2016;7(13):16409–19. 10.18632/oncotarget.7653.Suche in Google Scholar PubMed PubMed Central

[137] Zeng X, Qu X, Zhao C, Xu L, Hou K, Liu Y, et al. FEN1 mediates miR-200a methylation and promotes breast cancer cell growth via MET and EGFR signaling. Faseb J. 2019;33(10):10717–30. 10.1096/fj.201900273R.Suche in Google Scholar PubMed

[138] Mengwasser KE, Adeyemi RO, Leng Y, Choi MY, Clairmont C, D’Andrea AD, et al. Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets. Mol Cell. 2019;73(5):885–99.e6. 10.1016/j.molcel.2018.12.008.Suche in Google Scholar PubMed PubMed Central

[139] Chen YD, Zhang X, Qiu XG, Li J, Yuan Q, Jiang T, et al. Functional FEN1 genetic variants and haplotypes are associated with glioma risk. J Neurooncol. 2013;111(2):145–51. 10.1007/s11060-012-1007-0.Suche in Google Scholar PubMed

[140] Lees-Miller SP, Godbout R, Chan DW, Weinfeld M, Day RS 3rd, Barron GM, et al. Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science. 1995;267(5201):1183–5. 10.1126/science.7855602.Suche in Google Scholar PubMed

[141] Neijenhuis S, Bajrami I, Miller R, Lord CJ, Ashworth A. Identification of miRNA modulators to PARP inhibitor response. DNA Repair (Amst). 2013;12(6):394–402. 10.1016/j.dnarep.2013.02.003.Suche in Google Scholar PubMed

[142] Plantamura I, Cosentino G, Cataldo A. MicroRNAs and DNA-damaging drugs in breast cancer: strength in numbers. Front Oncol. 2018;8:352. 10.3389/fonc.2018.00352.Suche in Google Scholar PubMed PubMed Central

[143] Jackson AL, Linsley PS. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat Rev Drug Discov. 2010;9(1):57–67. 10.1038/nrd3010.Suche in Google Scholar PubMed

Received: 2024-02-01
Revised: 2024-04-24
Accepted: 2024-05-20
Published Online: 2024-06-10

© 2024 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  26. Development and validation of a novel model to predict pulmonary embolism in cardiology suspected patients: A 10-year retrospective analysis
  27. Downregulation of lncRNA XLOC_032768 in diabetic patients predicts the occurrence of diabetic nephropathy
  28. Circ_0051428 targeting miR-885-3p/MMP2 axis enhances the malignancy of cervical cancer
  29. Effectiveness of ginkgo diterpene lactone meglumine on cognitive function in patients with acute ischemic stroke
  30. The construction of a novel prognostic prediction model for glioma based on GWAS-identified prognostic-related risk loci
  31. Evaluating the impact of childhood BMI on the risk of coronavirus disease 2019: A Mendelian randomization study
  32. Lactate dehydrogenase to albumin ratio is associated with in-hospital mortality in patients with acute heart failure: Data from the MIMIC-III database
  33. CD36-mediated podocyte lipotoxicity promotes foot process effacement
  34. Efficacy of etonogestrel subcutaneous implants versus the levonorgestrel-releasing intrauterine system in the conservative treatment of adenomyosis
  35. FLRT2 mediates chondrogenesis of nasal septal cartilage and mandibular condyle cartilage
  36. Challenges in treating primary immune thrombocytopenia patients undergoing COVID-19 vaccination: A retrospective study
  37. Let-7 family regulates HaCaT cell proliferation and apoptosis via the ΔNp63/PI3K/AKT pathway
  38. Phospholipid transfer protein ameliorates sepsis-induced cardiac dysfunction through NLRP3 inflammasome inhibition
  39. Postoperative cognitive dysfunction in elderly patients with colorectal cancer: A randomized controlled study comparing goal-directed and conventional fluid therapy
  40. Long-pulsed ultrasound-mediated microbubble thrombolysis in a rat model of microvascular obstruction
  41. High SEC61A1 expression predicts poor outcome of acute myeloid leukemia
  42. Comparison of polymerase chain reaction and next-generation sequencing with conventional urine culture for the diagnosis of urinary tract infections: A meta-analysis
  43. Secreted frizzled-related protein 5 protects against renal fibrosis by inhibiting Wnt/β-catenin pathway
  44. Pan-cancer and single-cell analysis of actin cytoskeleton genes related to disulfidptosis
  45. Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1
  46. Autologous liver transplantation for unresectable hepatobiliary malignancies in enhanced recovery after surgery model
  47. Clinical analysis of incomplete rupture of the uterus secondary to previous cesarean section
  48. Abnormal sleep duration is associated with sarcopenia in older Chinese people: A large retrospective cross-sectional study
  49. No genetic causality between obesity and benign paroxysmal vertigo: A two-sample Mendelian randomization study
  50. Identification and validation of autophagy-related genes in SSc
  51. Long non-coding RNA SRA1 suppresses radiotherapy resistance in esophageal squamous cell carcinoma by modulating glycolytic reprogramming
  52. Evaluation of quality of life in patients with schizophrenia: An inpatient social welfare institution-based cross-sectional study
  53. The possible role of oxidative stress marker glutathione in the assessment of cognitive impairment in multiple sclerosis
  54. Compilation of a self-management assessment scale for postoperative patients with aortic dissection
  55. Left atrial appendage closure in conjunction with radiofrequency ablation: Effects on left atrial functioning in patients with paroxysmal atrial fibrillation
  56. Effect of anterior femoral cortical notch grade on postoperative function and complications during TKA surgery: A multicenter, retrospective study
  57. Clinical characteristics and assessment of risk factors in patients with influenza A-induced severe pneumonia after the prevalence of SARS-CoV-2
  58. Analgesia nociception index is an indicator of laparoscopic trocar insertion-induced transient nociceptive stimuli
  59. High STAT4 expression correlates with poor prognosis in acute myeloid leukemia and facilitates disease progression by upregulating VEGFA expression
  60. Factors influencing cardiovascular system-related post-COVID-19 sequelae: A single-center cohort study
  61. HOXD10 regulates intestinal permeability and inhibits inflammation of dextran sulfate sodium-induced ulcerative colitis through the inactivation of the Rho/ROCK/MMPs axis
  62. Mesenchymal stem cell-derived exosomal miR-26a induces ferroptosis, suppresses hepatic stellate cell activation, and ameliorates liver fibrosis by modulating SLC7A11
  63. Endovascular thrombectomy versus intravenous thrombolysis for primary distal, medium vessel occlusion in acute ischemic stroke
  64. ANO6 (TMEM16F) inhibits gastrointestinal stromal tumor growth and induces ferroptosis
  65. Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis
  66. The role of enhanced expression of Cx43 in patients with ulcerative colitis
  67. Choosing a COVID-19 vaccination site might be driven by anxiety and body vigilance
  68. Role of ICAM-1 in triple-negative breast cancer
  69. Cost-effectiveness of ambroxol in the treatment of Gaucher disease type 2
  70. HLA-DRB5 promotes immune thrombocytopenia via activating CD8+ T cells
  71. Efficacy and factors of myofascial release therapy combined with electrical and magnetic stimulation in the treatment of chronic pelvic pain syndrome
  72. Efficacy of tacrolimus monotherapy in primary membranous nephropathy
  73. Mechanisms of Tripterygium wilfordii Hook F on treating rheumatoid arthritis explored by network pharmacology analysis and molecular docking
  74. FBXO45 levels regulated ferroptosis renal tubular epithelial cells in a model of diabetic nephropathy by PLK1
  75. Optimizing anesthesia strategies to NSCLC patients in VATS procedures: Insights from drug requirements and patient recovery patterns
  76. Alpha-lipoic acid upregulates the PPARγ/NRF2/GPX4 signal pathway to inhibit ferroptosis in the pathogenesis of unexplained recurrent pregnancy loss
  77. Correlation between fat-soluble vitamin levels and inflammatory factors in paediatric community-acquired pneumonia: A prospective study
  78. CD1d affects the proliferation, migration, and apoptosis of human papillary thyroid carcinoma TPC-1 cells via regulating MAPK/NF-κB signaling pathway
  79. miR-let-7a inhibits sympathetic nerve remodeling after myocardial infarction by downregulating the expression of nerve growth factor
  80. Immune response analysis of solid organ transplantation recipients inoculated with inactivated COVID-19 vaccine: A retrospective analysis
  81. The H2Valdien derivatives regulate the epithelial–mesenchymal transition of hepatoma carcinoma cells through the Hedgehog signaling pathway
  82. Clinical efficacy of dexamethasone combined with isoniazid in the treatment of tuberculous meningitis and its effect on peripheral blood T cell subsets
  83. Comparison of short-segment and long-segment fixation in treatment of degenerative scoliosis and analysis of factors associated with adjacent spondylolisthesis
  84. Lycopene inhibits pyroptosis of endothelial progenitor cells induced by ox-LDL through the AMPK/mTOR/NLRP3 pathway
  85. Methylation regulation for FUNDC1 stability in childhood leukemia was up-regulated and facilitates metastasis and reduces ferroptosis of leukemia through mitochondrial damage by FBXL2
  86. Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis
  87. Risk factors of postoperative airway obstruction complications in children with oral floor mass
  88. Expression levels and clinical significance of serum miR-19a/CCL20 in patients with acute cerebral infarction
  89. Physical activity and mental health trends in Korean adolescents: Analyzing the impact of the COVID-19 pandemic from 2018 to 2022
  90. Evaluating anemia in HIV-infected patients using chest CT
  91. Ponticulus posticus and skeletal malocclusion: A pilot study in a Southern Italian pre-orthodontic court
  92. Causal association of circulating immune cells and lymphoma: A Mendelian randomization study
  93. Assessment of the renal function and fibrosis indexes of conventional western medicine with Chinese medicine for dredging collaterals on treating renal fibrosis: A systematic review and meta-analysis
  94. Comprehensive landscape of integrator complex subunits and their association with prognosis and tumor microenvironment in gastric cancer
  95. New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study
  96. Population pharmacokinetics of meropenem in critically ill patients
  97. Comparison of the ability of newly inflammatory markers to predict complicated appendicitis
  98. Comparative morphology of the cruciate ligaments: A radiological study
  99. Immune landscape of hepatocellular carcinoma: The central role of TP53-inducible glycolysis and apoptosis regulator
  100. Serum SIRT3 levels in epilepsy patients and its association with clinical outcomes and severity: A prospective observational study
  101. SHP-1 mediates cigarette smoke extract-induced epithelial–mesenchymal transformation and inflammation in 16HBE cells
  102. Acute hyper-hypoxia accelerates the development of depression in mice via the IL-6/PGC1α/MFN2 signaling pathway
  103. The GJB3 correlates with the prognosis, immune cell infiltration, and therapeutic responses in lung adenocarcinoma
  104. Physical fitness and blood parameters outcomes of breast cancer survivor in a low-intensity circuit resistance exercise program
  105. Exploring anesthetic-induced gene expression changes and immune cell dynamics in atrial tissue post-coronary artery bypass graft surgery
  106. Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism
  107. Analysis of the risk factors of the radiation-induced encephalopathy in nasopharyngeal carcinoma: A retrospective cohort study
  108. Reproductive outcomes in women with BRCA 1/2 germline mutations: A retrospective observational study and literature review
  109. Evaluation of upper airway ultrasonographic measurements in predicting difficult intubation: A cross-section of the Turkish population
  110. Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer
  111. Postural stability after operative reconstruction of the AFTL in chronic ankle instability comparing three different surgical techniques
  112. Research trends related to emergence agitation in the post-anaesthesia care unit from 2001 to 2023: A bibliometric analysis
  113. Frequency and clinicopathological correlation of gastrointestinal polyps: A six-year single center experience
  114. ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation
  115. Affibody-based molecular probe 99mTc-(HE)3ZHER2:V2 for non-invasive HER2 detection in ovarian and breast cancer xenografts
  116. Effectiveness of nutritional support for clinical outcomes in gastric cancer patients: A meta-analysis of randomized controlled trials
  117. The relationship between IFN-γ, IL-10, IL-6 cytokines, and severity of the condition with serum zinc and Fe in children infected with Mycoplasma pneumoniae
  118. Paraquat disrupts the blood–brain barrier by increasing IL-6 expression and oxidative stress through the activation of PI3K/AKT signaling pathway
  119. Sleep quality associate with the increased prevalence of cognitive impairment in coronary artery disease patients: A retrospective case–control study
  120. Dioscin protects against chronic prostatitis through the TLR4/NF-κB pathway
  121. Association of polymorphisms in FBN1, MYH11, and TGF-β signaling-related genes with susceptibility of sporadic thoracic aortic aneurysm and dissection in the Zhejiang Han population
  122. Application value of multi-parameter magnetic resonance image-transrectal ultrasound cognitive fusion in prostate biopsy
  123. Laboratory variables‐based artificial neural network models for predicting fatty liver disease: A retrospective study
  124. Decreased BIRC5-206 promotes epithelial–mesenchymal transition in nasopharyngeal carcinoma through sponging miR-145-5p
  125. Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway
  126. Assessment of iron metabolism and iron deficiency in incident patients on incident continuous ambulatory peritoneal dialysis
  127. Tibial periosteum flap combined with autologous bone grafting in the treatment of Gustilo-IIIB/IIIC open tibial fractures
  128. The application of intravenous general anesthesia under nasopharyngeal airway assisted ventilation undergoing ureteroscopic holmium laser lithotripsy: A prospective, single-center, controlled trial
  129. Long intergenic noncoding RNA for IGF2BP2 stability suppresses gastric cancer cell apoptosis by inhibiting the maturation of microRNA-34a
  130. Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis
  131. Parental control attitudes over their pre-school children’s diet
  132. The role of auto-HSCT in extranodal natural killer/T cell lymphoma
  133. Significance of negative cervical cytology and positive HPV in the diagnosis of cervical lesions by colposcopy
  134. Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin
  135. ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway
  136. The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study
  137. The unusual location of primary hydatid cyst: A case series study
  138. Intraoperative changes in electrophysiological monitoring can be used to predict clinical outcomes in patients with spinal cavernous malformation
  139. Obesity and risk of placenta accreta spectrum: A meta-analysis
  140. Shikonin alleviates asthma phenotypes in mice via an airway epithelial STAT3-dependent mechanism
  141. NSUN6 and HTR7 disturbed the stability of carotid atherosclerotic plaques by regulating the immune responses of macrophages
  142. The effect of COVID-19 lockdown on admission rates in Maternity Hospital
  143. Temporal muscle thickness is not a prognostic predictor in patients with high-grade glioma, an experience at two centers in China
  144. Luteolin alleviates cerebral ischemia/reperfusion injury by regulating cell pyroptosis
  145. Therapeutic role of respiratory exercise in patients with tuberculous pleurisy
  146. Effects of CFTR-ENaC on spinal cord edema after spinal cord injury
  147. Irisin-regulated lncRNAs and their potential regulatory functions in chondrogenic differentiation of human mesenchymal stem cells
  148. DMD mutations in pediatric patients with phenotypes of Duchenne/Becker muscular dystrophy
  149. Combination of C-reactive protein and fibrinogen-to-albumin ratio as a novel predictor of all-cause mortality in heart failure patients
  150. Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease
  151. Ferroptosis-related prognostic model of mantle cell lymphoma
  152. Observation of choking reaction and other related indexes in elderly painless fiberoptic bronchoscopy with transnasal high-flow humidification oxygen therapy
  153. A bibliometric analysis of Prader-Willi syndrome from 2002 to 2022
  154. The causal effects of childhood sunburn occasions on melanoma: A univariable and multivariable Mendelian randomization study
  155. Oxidative stress regulates glycogen synthase kinase-3 in lymphocytes of diabetes mellitus patients complicated with cerebral infarction
  156. Role of COX6C and NDUFB3 in septic shock and stroke
  157. Trends in disease burden of type 2 diabetes, stroke, and hypertensive heart disease attributable to high BMI in China: 1990–2019
  158. Purinergic P2X7 receptor mediates hyperoxia-induced injury in pulmonary microvascular endothelial cells via NLRP3-mediated pyroptotic pathway
  159. Investigating the role of oviductal mucosa–endometrial co-culture in modulating factors relevant to embryo implantation
  160. Analgesic effect of external oblique intercostal block in laparoscopic cholecystectomy: A retrospective study
  161. Elevated serum miR-142-5p correlates with ischemic lesions and both NSE and S100β in ischemic stroke patients
  162. Correlation between the mechanism of arteriopathy in IgA nephropathy and blood stasis syndrome: A cohort study
  163. Risk factors for progressive kyphosis after percutaneous kyphoplasty in osteoporotic vertebral compression fracture
  164. Predictive role of neuron-specific enolase and S100-β in early neurological deterioration and unfavorable prognosis in patients with ischemic stroke
  165. The potential risk factors of postoperative cognitive dysfunction for endovascular therapy in acute ischemic stroke with general anesthesia
  166. Fluoxetine inhibited RANKL-induced osteoclastic differentiation in vitro
  167. Detection of serum FOXM1 and IGF2 in patients with ARDS and their correlation with disease and prognosis
  168. Rhein promotes skin wound healing by activating the PI3K/AKT signaling pathway
  169. Differences in mortality risk by levels of physical activity among persons with disabilities in South Korea
  170. Review Articles
  171. Cutaneous signs of selected cardiovascular disorders: A narrative review
  172. XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis
  173. A narrative review on adverse drug reactions of COVID-19 treatments on the kidney
  174. Emerging role and function of SPDL1 in human health and diseases
  175. Adverse reactions of piperacillin: A literature review of case reports
  176. Molecular mechanism and intervention measures of microvascular complications in diabetes
  177. Regulation of mesenchymal stem cell differentiation by autophagy
  178. Molecular landscape of borderline ovarian tumours: A systematic review
  179. Advances in synthetic lethality modalities for glioblastoma multiforme
  180. Investigating hormesis, aging, and neurodegeneration: From bench to clinics
  181. Frankincense: A neuronutrient to approach Parkinson’s disease treatment
  182. Sox9: A potential regulator of cancer stem cells in osteosarcoma
  183. Early detection of cardiovascular risk markers through non-invasive ultrasound methodologies in periodontitis patients
  184. Advanced neuroimaging and criminal interrogation in lie detection
  185. Maternal factors for neural tube defects in offspring: An umbrella review
  186. The chemoprotective hormetic effects of rosmarinic acid
  187. CBD’s potential impact on Parkinson’s disease: An updated overview
  188. Progress in cytokine research for ARDS: A comprehensive review
  189. Utilizing reactive oxygen species-scavenging nanoparticles for targeting oxidative stress in the treatment of ischemic stroke: A review
  190. NRXN1-related disorders, attempt to better define clinical assessment
  191. Lidocaine infusion for the treatment of complex regional pain syndrome: Case series and literature review
  192. Trends and future directions of autophagy in osteosarcoma: A bibliometric analysis
  193. Iron in ventricular remodeling and aneurysms post-myocardial infarction
  194. Case Reports
  195. Sirolimus potentiated angioedema: A case report and review of the literature
  196. Identification of mixed anaerobic infections after inguinal hernia repair based on metagenomic next-generation sequencing: A case report
  197. Successful treatment with bortezomib in combination with dexamethasone in a middle-aged male with idiopathic multicentric Castleman’s disease: A case report
  198. Complete heart block associated with hepatitis A infection in a female child with fatal outcome
  199. Elevation of D-dimer in eosinophilic gastrointestinal diseases in the absence of venous thrombosis: A case series and literature review
  200. Four years of natural progressive course: A rare case report of juvenile Xp11.2 translocations renal cell carcinoma with TFE3 gene fusion
  201. Advancing prenatal diagnosis: Echocardiographic detection of Scimitar syndrome in China – A case series
  202. Outcomes and complications of hemodialysis in patients with renal cancer following bilateral nephrectomy
  203. Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy
  204. Recurrent opportunistic infections in a HIV-negative patient with combined C6 and NFKB1 mutations: A case report, pedigree analysis, and literature review
  205. Letter to the Editor
  206. Letter to the Editor: Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  207. Erratum
  208. Erratum to “Bladder-embedded ectopic intrauterine device with calculus”
  209. Retraction
  210. Retraction of “XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis”
  211. Corrigendum
  212. Corrigendum to “Investigating hormesis, aging, and neurodegeneration: From bench to clinics”
  213. Corrigendum to “Frankincense: A neuronutrient to approach Parkinson’s disease treatment”
  214. Special Issue The evolving saga of RNAs from bench to bedside - Part II
  215. Machine-learning-based prediction of a diagnostic model using autophagy-related genes based on RNA sequencing for patients with papillary thyroid carcinoma
  216. Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening
  217. Elevated mRNA level indicates FSIP1 promotes EMT and gastric cancer progression by regulating fibroblasts in tumor microenvironment
  218. Special Issue Advancements in oncology: bridging clinical and experimental research - Part I
  219. Ultrasound-guided transperineal vs transrectal prostate biopsy: A meta-analysis of diagnostic accuracy and complication rates
  220. Assessment of diagnostic value of unilateral systematic biopsy combined with targeted biopsy in detecting clinically significant prostate cancer
  221. SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins
  222. MARK1 suppress malignant progression of hepatocellular carcinoma and improves sorafenib resistance through negatively regulating POTEE
  223. Analysis of postoperative complications in bladder cancer patients
  224. Carboplatin combined with arsenic trioxide versus carboplatin combined with docetaxel treatment for LACC: A randomized, open-label, phase II clinical study
  225. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part I
  226. Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma
  227. Identification of signatures associated with microsatellite instability and immune characteristics to predict the prognostic risk of colon cancer
  228. Single-cell analysis identified key macrophage subpopulations associated with atherosclerosis
https://doi.org/10.1515/med-2024-0981
Schlagwörter für diesen Artikel
GBM; DNA; chemotherapy; synthetic; lethality; resistance
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Articles
  2. EDNRB inhibits the growth and migration of prostate cancer cells by activating the cGMP-PKG pathway
  3. STK11 (LKB1) mutation suppresses ferroptosis in lung adenocarcinoma by facilitating monounsaturated fatty acid synthesis
  4. Association of SOX6 gene polymorphisms with Kashin-Beck disease risk in the Chinese Han population
  5. The pyroptosis-related signature predicts prognosis and influences the tumor immune microenvironment in dedifferentiated liposarcoma
  6. METTL3 attenuates ferroptosis sensitivity in lung cancer via modulating TFRC
  7. Identification and validation of molecular subtypes and prognostic signature for stage I and stage II gastric cancer based on neutrophil extracellular traps
  8. Novel lumbar plexus block versus femoral nerve block for analgesia and motor recovery after total knee arthroplasty
  9. Correlation between ABCB1 and OLIG2 polymorphisms and the severity and prognosis of patients with cerebral infarction
  10. Study on the radiotherapy effect and serum neutral granulocyte lymphocyte ratio and inflammatory factor expression of nasopharyngeal carcinoma
  11. Transcriptome analysis of effects of Tecrl deficiency on cardiometabolic and calcium regulation in cardiac tissue
  12. Aflatoxin B1 induces infertility, fetal deformities, and potential therapies
  13. Serum levels of HMW adiponectin and its receptors are associated with cytokine levels and clinical characteristics in chronic obstructive pulmonary disease
  14. METTL3-mediated methylation of CYP2C19 mRNA may aggravate clopidogrel resistance in ischemic stroke patients
  15. Understand how machine learning impact lung cancer research from 2010 to 2021: A bibliometric analysis
  16. Pressure ulcers in German hospitals: Analysis of reimbursement and length of stay
  17. Metformin plus L-carnitine enhances brown/beige adipose tissue activity via Nrf2/HO-1 signaling to reduce lipid accumulation and inflammation in murine obesity
  18. Downregulation of carbonic anhydrase IX expression in mouse xenograft nasopharyngeal carcinoma model via doxorubicin nanobubble combined with ultrasound
  19. Feasibility of 3-dimensional printed models in simulated training and teaching of transcatheter aortic valve replacement
  20. miR-335-3p improves type II diabetes mellitus by IGF-1 regulating macrophage polarization
  21. The analyses of human MCPH1 DNA repair machinery and genetic variations
  22. Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy
  23. Comprehensive analysis based on the disulfidptosis-related genes identifies hub genes and immune infiltration for pancreatic adenocarcinoma
  24. Changes of serum CA125 and PGE2 before and after high-intensity focused ultrasound combined with GnRH-a in treatment of patients with adenomyosis
  25. The clinical value of the hepatic venous pressure gradient in patients undergoing hepatic resection for hepatocellular carcinoma with or without liver cirrhosis
  26. Development and validation of a novel model to predict pulmonary embolism in cardiology suspected patients: A 10-year retrospective analysis
  27. Downregulation of lncRNA XLOC_032768 in diabetic patients predicts the occurrence of diabetic nephropathy
  28. Circ_0051428 targeting miR-885-3p/MMP2 axis enhances the malignancy of cervical cancer
  29. Effectiveness of ginkgo diterpene lactone meglumine on cognitive function in patients with acute ischemic stroke
  30. The construction of a novel prognostic prediction model for glioma based on GWAS-identified prognostic-related risk loci
  31. Evaluating the impact of childhood BMI on the risk of coronavirus disease 2019: A Mendelian randomization study
  32. Lactate dehydrogenase to albumin ratio is associated with in-hospital mortality in patients with acute heart failure: Data from the MIMIC-III database
  33. CD36-mediated podocyte lipotoxicity promotes foot process effacement
  34. Efficacy of etonogestrel subcutaneous implants versus the levonorgestrel-releasing intrauterine system in the conservative treatment of adenomyosis
  35. FLRT2 mediates chondrogenesis of nasal septal cartilage and mandibular condyle cartilage
  36. Challenges in treating primary immune thrombocytopenia patients undergoing COVID-19 vaccination: A retrospective study
  37. Let-7 family regulates HaCaT cell proliferation and apoptosis via the ΔNp63/PI3K/AKT pathway
  38. Phospholipid transfer protein ameliorates sepsis-induced cardiac dysfunction through NLRP3 inflammasome inhibition
  39. Postoperative cognitive dysfunction in elderly patients with colorectal cancer: A randomized controlled study comparing goal-directed and conventional fluid therapy
  40. Long-pulsed ultrasound-mediated microbubble thrombolysis in a rat model of microvascular obstruction
  41. High SEC61A1 expression predicts poor outcome of acute myeloid leukemia
  42. Comparison of polymerase chain reaction and next-generation sequencing with conventional urine culture for the diagnosis of urinary tract infections: A meta-analysis
  43. Secreted frizzled-related protein 5 protects against renal fibrosis by inhibiting Wnt/β-catenin pathway
  44. Pan-cancer and single-cell analysis of actin cytoskeleton genes related to disulfidptosis
  45. Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1
  46. Autologous liver transplantation for unresectable hepatobiliary malignancies in enhanced recovery after surgery model
  47. Clinical analysis of incomplete rupture of the uterus secondary to previous cesarean section
  48. Abnormal sleep duration is associated with sarcopenia in older Chinese people: A large retrospective cross-sectional study
  49. No genetic causality between obesity and benign paroxysmal vertigo: A two-sample Mendelian randomization study
  50. Identification and validation of autophagy-related genes in SSc
  51. Long non-coding RNA SRA1 suppresses radiotherapy resistance in esophageal squamous cell carcinoma by modulating glycolytic reprogramming
  52. Evaluation of quality of life in patients with schizophrenia: An inpatient social welfare institution-based cross-sectional study
  53. The possible role of oxidative stress marker glutathione in the assessment of cognitive impairment in multiple sclerosis
  54. Compilation of a self-management assessment scale for postoperative patients with aortic dissection
  55. Left atrial appendage closure in conjunction with radiofrequency ablation: Effects on left atrial functioning in patients with paroxysmal atrial fibrillation
  56. Effect of anterior femoral cortical notch grade on postoperative function and complications during TKA surgery: A multicenter, retrospective study
  57. Clinical characteristics and assessment of risk factors in patients with influenza A-induced severe pneumonia after the prevalence of SARS-CoV-2
  58. Analgesia nociception index is an indicator of laparoscopic trocar insertion-induced transient nociceptive stimuli
  59. High STAT4 expression correlates with poor prognosis in acute myeloid leukemia and facilitates disease progression by upregulating VEGFA expression
  60. Factors influencing cardiovascular system-related post-COVID-19 sequelae: A single-center cohort study
  61. HOXD10 regulates intestinal permeability and inhibits inflammation of dextran sulfate sodium-induced ulcerative colitis through the inactivation of the Rho/ROCK/MMPs axis
  62. Mesenchymal stem cell-derived exosomal miR-26a induces ferroptosis, suppresses hepatic stellate cell activation, and ameliorates liver fibrosis by modulating SLC7A11
  63. Endovascular thrombectomy versus intravenous thrombolysis for primary distal, medium vessel occlusion in acute ischemic stroke
  64. ANO6 (TMEM16F) inhibits gastrointestinal stromal tumor growth and induces ferroptosis
  65. Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis
  66. The role of enhanced expression of Cx43 in patients with ulcerative colitis
  67. Choosing a COVID-19 vaccination site might be driven by anxiety and body vigilance
  68. Role of ICAM-1 in triple-negative breast cancer
  69. Cost-effectiveness of ambroxol in the treatment of Gaucher disease type 2
  70. HLA-DRB5 promotes immune thrombocytopenia via activating CD8+ T cells
  71. Efficacy and factors of myofascial release therapy combined with electrical and magnetic stimulation in the treatment of chronic pelvic pain syndrome
  72. Efficacy of tacrolimus monotherapy in primary membranous nephropathy
  73. Mechanisms of Tripterygium wilfordii Hook F on treating rheumatoid arthritis explored by network pharmacology analysis and molecular docking
  74. FBXO45 levels regulated ferroptosis renal tubular epithelial cells in a model of diabetic nephropathy by PLK1
  75. Optimizing anesthesia strategies to NSCLC patients in VATS procedures: Insights from drug requirements and patient recovery patterns
  76. Alpha-lipoic acid upregulates the PPARγ/NRF2/GPX4 signal pathway to inhibit ferroptosis in the pathogenesis of unexplained recurrent pregnancy loss
  77. Correlation between fat-soluble vitamin levels and inflammatory factors in paediatric community-acquired pneumonia: A prospective study
  78. CD1d affects the proliferation, migration, and apoptosis of human papillary thyroid carcinoma TPC-1 cells via regulating MAPK/NF-κB signaling pathway
  79. miR-let-7a inhibits sympathetic nerve remodeling after myocardial infarction by downregulating the expression of nerve growth factor
  80. Immune response analysis of solid organ transplantation recipients inoculated with inactivated COVID-19 vaccine: A retrospective analysis
  81. The H2Valdien derivatives regulate the epithelial–mesenchymal transition of hepatoma carcinoma cells through the Hedgehog signaling pathway
  82. Clinical efficacy of dexamethasone combined with isoniazid in the treatment of tuberculous meningitis and its effect on peripheral blood T cell subsets
  83. Comparison of short-segment and long-segment fixation in treatment of degenerative scoliosis and analysis of factors associated with adjacent spondylolisthesis
  84. Lycopene inhibits pyroptosis of endothelial progenitor cells induced by ox-LDL through the AMPK/mTOR/NLRP3 pathway
  85. Methylation regulation for FUNDC1 stability in childhood leukemia was up-regulated and facilitates metastasis and reduces ferroptosis of leukemia through mitochondrial damage by FBXL2
  86. Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis
  87. Risk factors of postoperative airway obstruction complications in children with oral floor mass
  88. Expression levels and clinical significance of serum miR-19a/CCL20 in patients with acute cerebral infarction
  89. Physical activity and mental health trends in Korean adolescents: Analyzing the impact of the COVID-19 pandemic from 2018 to 2022
  90. Evaluating anemia in HIV-infected patients using chest CT
  91. Ponticulus posticus and skeletal malocclusion: A pilot study in a Southern Italian pre-orthodontic court
  92. Causal association of circulating immune cells and lymphoma: A Mendelian randomization study
  93. Assessment of the renal function and fibrosis indexes of conventional western medicine with Chinese medicine for dredging collaterals on treating renal fibrosis: A systematic review and meta-analysis
  94. Comprehensive landscape of integrator complex subunits and their association with prognosis and tumor microenvironment in gastric cancer
  95. New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study
  96. Population pharmacokinetics of meropenem in critically ill patients
  97. Comparison of the ability of newly inflammatory markers to predict complicated appendicitis
  98. Comparative morphology of the cruciate ligaments: A radiological study
  99. Immune landscape of hepatocellular carcinoma: The central role of TP53-inducible glycolysis and apoptosis regulator
  100. Serum SIRT3 levels in epilepsy patients and its association with clinical outcomes and severity: A prospective observational study
  101. SHP-1 mediates cigarette smoke extract-induced epithelial–mesenchymal transformation and inflammation in 16HBE cells
  102. Acute hyper-hypoxia accelerates the development of depression in mice via the IL-6/PGC1α/MFN2 signaling pathway
  103. The GJB3 correlates with the prognosis, immune cell infiltration, and therapeutic responses in lung adenocarcinoma
  104. Physical fitness and blood parameters outcomes of breast cancer survivor in a low-intensity circuit resistance exercise program
  105. Exploring anesthetic-induced gene expression changes and immune cell dynamics in atrial tissue post-coronary artery bypass graft surgery
  106. Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism
  107. Analysis of the risk factors of the radiation-induced encephalopathy in nasopharyngeal carcinoma: A retrospective cohort study
  108. Reproductive outcomes in women with BRCA 1/2 germline mutations: A retrospective observational study and literature review
  109. Evaluation of upper airway ultrasonographic measurements in predicting difficult intubation: A cross-section of the Turkish population
  110. Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer
  111. Postural stability after operative reconstruction of the AFTL in chronic ankle instability comparing three different surgical techniques
  112. Research trends related to emergence agitation in the post-anaesthesia care unit from 2001 to 2023: A bibliometric analysis
  113. Frequency and clinicopathological correlation of gastrointestinal polyps: A six-year single center experience
  114. ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation
  115. Affibody-based molecular probe 99mTc-(HE)3ZHER2:V2 for non-invasive HER2 detection in ovarian and breast cancer xenografts
  116. Effectiveness of nutritional support for clinical outcomes in gastric cancer patients: A meta-analysis of randomized controlled trials
  117. The relationship between IFN-γ, IL-10, IL-6 cytokines, and severity of the condition with serum zinc and Fe in children infected with Mycoplasma pneumoniae
  118. Paraquat disrupts the blood–brain barrier by increasing IL-6 expression and oxidative stress through the activation of PI3K/AKT signaling pathway
  119. Sleep quality associate with the increased prevalence of cognitive impairment in coronary artery disease patients: A retrospective case–control study
  120. Dioscin protects against chronic prostatitis through the TLR4/NF-κB pathway
  121. Association of polymorphisms in FBN1, MYH11, and TGF-β signaling-related genes with susceptibility of sporadic thoracic aortic aneurysm and dissection in the Zhejiang Han population
  122. Application value of multi-parameter magnetic resonance image-transrectal ultrasound cognitive fusion in prostate biopsy
  123. Laboratory variables‐based artificial neural network models for predicting fatty liver disease: A retrospective study
  124. Decreased BIRC5-206 promotes epithelial–mesenchymal transition in nasopharyngeal carcinoma through sponging miR-145-5p
  125. Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway
  126. Assessment of iron metabolism and iron deficiency in incident patients on incident continuous ambulatory peritoneal dialysis
  127. Tibial periosteum flap combined with autologous bone grafting in the treatment of Gustilo-IIIB/IIIC open tibial fractures
  128. The application of intravenous general anesthesia under nasopharyngeal airway assisted ventilation undergoing ureteroscopic holmium laser lithotripsy: A prospective, single-center, controlled trial
  129. Long intergenic noncoding RNA for IGF2BP2 stability suppresses gastric cancer cell apoptosis by inhibiting the maturation of microRNA-34a
  130. Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis
  131. Parental control attitudes over their pre-school children’s diet
  132. The role of auto-HSCT in extranodal natural killer/T cell lymphoma
  133. Significance of negative cervical cytology and positive HPV in the diagnosis of cervical lesions by colposcopy
  134. Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin
  135. ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway
  136. The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study
  137. The unusual location of primary hydatid cyst: A case series study
  138. Intraoperative changes in electrophysiological monitoring can be used to predict clinical outcomes in patients with spinal cavernous malformation
  139. Obesity and risk of placenta accreta spectrum: A meta-analysis
  140. Shikonin alleviates asthma phenotypes in mice via an airway epithelial STAT3-dependent mechanism
  141. NSUN6 and HTR7 disturbed the stability of carotid atherosclerotic plaques by regulating the immune responses of macrophages
  142. The effect of COVID-19 lockdown on admission rates in Maternity Hospital
  143. Temporal muscle thickness is not a prognostic predictor in patients with high-grade glioma, an experience at two centers in China
  144. Luteolin alleviates cerebral ischemia/reperfusion injury by regulating cell pyroptosis
  145. Therapeutic role of respiratory exercise in patients with tuberculous pleurisy
  146. Effects of CFTR-ENaC on spinal cord edema after spinal cord injury
  147. Irisin-regulated lncRNAs and their potential regulatory functions in chondrogenic differentiation of human mesenchymal stem cells
  148. DMD mutations in pediatric patients with phenotypes of Duchenne/Becker muscular dystrophy
  149. Combination of C-reactive protein and fibrinogen-to-albumin ratio as a novel predictor of all-cause mortality in heart failure patients
  150. Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease
  151. Ferroptosis-related prognostic model of mantle cell lymphoma
  152. Observation of choking reaction and other related indexes in elderly painless fiberoptic bronchoscopy with transnasal high-flow humidification oxygen therapy
  153. A bibliometric analysis of Prader-Willi syndrome from 2002 to 2022
  154. The causal effects of childhood sunburn occasions on melanoma: A univariable and multivariable Mendelian randomization study
  155. Oxidative stress regulates glycogen synthase kinase-3 in lymphocytes of diabetes mellitus patients complicated with cerebral infarction
  156. Role of COX6C and NDUFB3 in septic shock and stroke
  157. Trends in disease burden of type 2 diabetes, stroke, and hypertensive heart disease attributable to high BMI in China: 1990–2019
  158. Purinergic P2X7 receptor mediates hyperoxia-induced injury in pulmonary microvascular endothelial cells via NLRP3-mediated pyroptotic pathway
  159. Investigating the role of oviductal mucosa–endometrial co-culture in modulating factors relevant to embryo implantation
  160. Analgesic effect of external oblique intercostal block in laparoscopic cholecystectomy: A retrospective study
  161. Elevated serum miR-142-5p correlates with ischemic lesions and both NSE and S100β in ischemic stroke patients
  162. Correlation between the mechanism of arteriopathy in IgA nephropathy and blood stasis syndrome: A cohort study
  163. Risk factors for progressive kyphosis after percutaneous kyphoplasty in osteoporotic vertebral compression fracture
  164. Predictive role of neuron-specific enolase and S100-β in early neurological deterioration and unfavorable prognosis in patients with ischemic stroke
  165. The potential risk factors of postoperative cognitive dysfunction for endovascular therapy in acute ischemic stroke with general anesthesia
  166. Fluoxetine inhibited RANKL-induced osteoclastic differentiation in vitro
  167. Detection of serum FOXM1 and IGF2 in patients with ARDS and their correlation with disease and prognosis
  168. Rhein promotes skin wound healing by activating the PI3K/AKT signaling pathway
  169. Differences in mortality risk by levels of physical activity among persons with disabilities in South Korea
  170. Review Articles
  171. Cutaneous signs of selected cardiovascular disorders: A narrative review
  172. XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis
  173. A narrative review on adverse drug reactions of COVID-19 treatments on the kidney
  174. Emerging role and function of SPDL1 in human health and diseases
  175. Adverse reactions of piperacillin: A literature review of case reports
  176. Molecular mechanism and intervention measures of microvascular complications in diabetes
  177. Regulation of mesenchymal stem cell differentiation by autophagy
  178. Molecular landscape of borderline ovarian tumours: A systematic review
  179. Advances in synthetic lethality modalities for glioblastoma multiforme
  180. Investigating hormesis, aging, and neurodegeneration: From bench to clinics
  181. Frankincense: A neuronutrient to approach Parkinson’s disease treatment
  182. Sox9: A potential regulator of cancer stem cells in osteosarcoma
  183. Early detection of cardiovascular risk markers through non-invasive ultrasound methodologies in periodontitis patients
  184. Advanced neuroimaging and criminal interrogation in lie detection
  185. Maternal factors for neural tube defects in offspring: An umbrella review
  186. The chemoprotective hormetic effects of rosmarinic acid
  187. CBD’s potential impact on Parkinson’s disease: An updated overview
  188. Progress in cytokine research for ARDS: A comprehensive review
  189. Utilizing reactive oxygen species-scavenging nanoparticles for targeting oxidative stress in the treatment of ischemic stroke: A review
  190. NRXN1-related disorders, attempt to better define clinical assessment
  191. Lidocaine infusion for the treatment of complex regional pain syndrome: Case series and literature review
  192. Trends and future directions of autophagy in osteosarcoma: A bibliometric analysis
  193. Iron in ventricular remodeling and aneurysms post-myocardial infarction
  194. Case Reports
  195. Sirolimus potentiated angioedema: A case report and review of the literature
  196. Identification of mixed anaerobic infections after inguinal hernia repair based on metagenomic next-generation sequencing: A case report
  197. Successful treatment with bortezomib in combination with dexamethasone in a middle-aged male with idiopathic multicentric Castleman’s disease: A case report
  198. Complete heart block associated with hepatitis A infection in a female child with fatal outcome
  199. Elevation of D-dimer in eosinophilic gastrointestinal diseases in the absence of venous thrombosis: A case series and literature review
  200. Four years of natural progressive course: A rare case report of juvenile Xp11.2 translocations renal cell carcinoma with TFE3 gene fusion
  201. Advancing prenatal diagnosis: Echocardiographic detection of Scimitar syndrome in China – A case series
  202. Outcomes and complications of hemodialysis in patients with renal cancer following bilateral nephrectomy
  203. Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy
  204. Recurrent opportunistic infections in a HIV-negative patient with combined C6 and NFKB1 mutations: A case report, pedigree analysis, and literature review
  205. Letter to the Editor
  206. Letter to the Editor: Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  207. Erratum
  208. Erratum to “Bladder-embedded ectopic intrauterine device with calculus”
  209. Retraction
  210. Retraction of “XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis”
  211. Corrigendum
  212. Corrigendum to “Investigating hormesis, aging, and neurodegeneration: From bench to clinics”
  213. Corrigendum to “Frankincense: A neuronutrient to approach Parkinson’s disease treatment”
  214. Special Issue The evolving saga of RNAs from bench to bedside - Part II
  215. Machine-learning-based prediction of a diagnostic model using autophagy-related genes based on RNA sequencing for patients with papillary thyroid carcinoma
  216. Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening
  217. Elevated mRNA level indicates FSIP1 promotes EMT and gastric cancer progression by regulating fibroblasts in tumor microenvironment
  218. Special Issue Advancements in oncology: bridging clinical and experimental research - Part I
  219. Ultrasound-guided transperineal vs transrectal prostate biopsy: A meta-analysis of diagnostic accuracy and complication rates
  220. Assessment of diagnostic value of unilateral systematic biopsy combined with targeted biopsy in detecting clinically significant prostate cancer
  221. SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins
  222. MARK1 suppress malignant progression of hepatocellular carcinoma and improves sorafenib resistance through negatively regulating POTEE
  223. Analysis of postoperative complications in bladder cancer patients
  224. Carboplatin combined with arsenic trioxide versus carboplatin combined with docetaxel treatment for LACC: A randomized, open-label, phase II clinical study
  225. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part I
  226. Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma
  227. Identification of signatures associated with microsatellite instability and immune characteristics to predict the prognostic risk of colon cancer
  228. Single-cell analysis identified key macrophage subpopulations associated with atherosclerosis
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Heruntergeladen am 25.12.2025 von https://www.degruyterbrill.com/document/doi/10.1515/med-2024-0981/html
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