Home Medicine Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
Article Open Access

Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer

  • , , , , , EMAIL logo and EMAIL logo
Published/Copyright: June 1, 2023

Abstract

The aim of this study is to investigate the prognostic immune-related factors in breast cancer (BC) metastasis. The gene expression chip GSE159956 was downloaded from the gene expression omnibus database. Differentially expressed genes (DEGs) were selected using GEO2R online tools based on lymph node and metastasis status. The intersected survival-associated DEGs were screened from the Kaplan–Meier curve. Gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) annotation analyses were performed to determine the survival-associated DEGs. Immune-related prognostic factors were screened based on immune infiltration. The screened prognostic factors were verified by the Cancer Genome Atlas (TCGA) database and single-sample gene set enrichment analysis (ssGSEA). As a result, twenty-eight upregulated and three downregulated genes were generated by the survival analysis. The enriched GO and KEGG pathways were mostly correlated with “regulation of cellular amino acid metabolic process,” “proteasome complex,” “endopeptidase activity,” and “proteasome.” Six of 19 (17 upregulated and 2 downregulated) immune-related prognostic factors were verified by the TCGA database. Four immune-related factors were obtained after ssGSEA, and three significant immune-related factors were selected after univariate and multivariate analyses. Based on the risk score receiver operating characteristic, the three immune-related prognosis factors could be potential biomarkers of BC metastasis. In conclusion, APPL1, RPS6KB2, and GALK1 may play a pivotal role as potential biomarkers for prediction of BC metastasis.

1 Introduction

Breast cancer (BC) accounts for the majority of new cancer cases and is the second leading cause of cancer-related deaths in female patients in the United States [1]. Approximately 297,790 women will be diagnosed with BC in 2023 [2]. According to molecular characteristics, BC could be divided into at least four subtypes: luminal A, luminal B, human epidermal growth factor receptor 2 positive (HER2+), and triple-negative BC (TNBC) [3]. More than 150,000 BC survivors are living with metastatic disease [4], and BC frequently metastasizes to lymph nodes (LN) [5]. The status of LN metastasis is a prognostic factor in early BC [5] and is highly related to immune infiltration status [6]. Studies indicated that BC with higher immune infiltrating degree may have favorable prognostic outcomes [7,8]. BC metastasis to distant organs is a fatal process and accounts for a majority of BC-related deaths. Once the tumor metastasizes, a surgery is difficult to perform and no effective drugs can be used to cure metastatic BC [9]. The immunotherapy has been generally studied, and triumphantly used in several kinds of metastatic cancers, such as non-small cell lung cancer [10], and melanoma cancer [11]. Because BC has no generally accepted immunogenic therapy targets and immunotherapy in treating BC has not been actively performed [9]. But there is still some immunotherapy clinical research that has been carried in the aggressive BC subtype targeting several immune checkpoints, such as PD-1, CTLA-4, etc. [12]. For the metastasis BC, there is still lack of deep studies.

Here the gene expression omnibus (GEO) dataset GSE159956 was downloaded and categorized into metastasis and non-metastasis groups or LN-positive and -negative groups. Differentially expressed genes (DEGs) were obtained by GEO2R online tools. Overlapping DEGs were analyzed by Kaplan–Meier plotter (KM-plotter). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation of significant prognosis factor were also performed. Six immune-related prognosis factors were verified by the Cancer Genome Atlas (TCGA) database. Four of the six genes were chosen by single sample gene set enrichment analysis (ssGSEA). Finally, three immune-related prognosis factors were selected by univariate and multivariate Cox analyses.

Although, from the previous reports, we could know that high expression of COLL11A1 was closely related to LN metastasis and involved in the regulation of BC immune infiltration [13], high expression of OSR1 [14] and CXCL14 [15] devote to LN metastasis related death of BC. And CD2 is closely related to immune microenvironment of BC tumors [16]. But combining the LN regulated immune infiltration with distant metastasis was rarely reported.

Hence, LN metastasis, distant metastasis, and immune-related prognostic markers should be identified to accurately predict the potential risks of metastasis and administer therapeutic targets to treat patients with metastatic BC.

2 Method

2.1 Data collection and processing

The RAN transcriptome series matrix file (GSE159956) was downloaded from the GEO database (https://www.ncbi.nlm.nih.gov/geo/) based on the GPL2567 platform. The patients characteristics and treatment received as previous reported [17,18]. The file consists of 151 LN-positive and 144 LN-negative patients as well as 194 distant metastatic and 101 non-distant metastatic patients. Based on the series matrix file and GPL file, the gene expression matrix file was obtained. Then, the DEGs based on the two groups were analyzed by GEO2R online tools. P value ≤0.5 and |log2 fold change (FC)| > 1 were used as the screening standard. Intersected metastasis-related DEGs were obtained by Venn online tools (http://bioinformatics.psb.ugent.be/webtools/Venn/).

2.2 GO and KEGG annotations

The GO and KEGG annotations were downloaded from the official websites (http://current.geneontology.org/products/pages/downloads.html, https://www.genome.jp/kegg-bin/get_htext?hsa00001+3101). Data were cleaned into 2 × 2 contingency format using Perl (Version 5.32.1) software, and hypertension formula in R software was used to calculate enrichment values.

2.3 Survival analysis

Overlapping DEGs were separated into two groups based on the median expression level, and KM-plotter analysis was conducted to determine prognosis-related metastasis factors using GrandPrism software (Version 5.0). Values at P ≤ 0.05 were considered statistically significant.

2.4 Immune clustering

Tumor cellularity and the different infiltrating normal cells also called ESTIMATE. The stromal and immune cells that form the major non-tumor constituents of tumor samples promote and facilitate specific signatures related to the infiltration of stromal and immune cells in tumor tissues. The stromal and immune scores usually predict the level of infiltrating stromal and immune cells and these carry the basis for the ESTIMATE score to illustrate tumor purity in tumor tissue [19].

The strength of immune infiltration was categorized into high and low groups to identify immune infiltration affected prognosis factors. Results were verified by ESTIMATE score, immune score, stromal score, and tumor purity. Immune-related prognosis factors were tested by Wilcoxon test, and values at P value ≤0.05 were considered significant.

2.5 Validation of metastasis prognosis factors by the TCGA database

The TCGA_BRCA dataset and corresponding clinical information were downloaded from the TCGA database by using the TCGA assemble package (Version 2.0) of R software. According to metastasis status, the patients were divided into metastasis and non-metastasis groups. Immune-related prognosis factors were examined by t-test on Grand Prism (Version 5.0) software. Finally, six immune-related prognosis factors were selected.

2.6 Identification and confirmation of immune-related prognostic features by the ssGSEA

LASSO regression analysis was performed to confirm the immune-related prognosis factors. High- and low-risk groups were defined by the median of risk score by using the survminer package of R software. Univariate and multivariate Cox regression analyses were conducted, and three prognostic features were selected. Time-dependent receiver operating characteristics (t-ROC) were analyzed to determine the predicting ability of the prognosis factors. From the t-ROC curves, three factors could be used to predict BC metastasis.

2.7 Statistical analysis

R software (Version 4.2.2) and GrandPrism were used for statistical analysis. Differences among different risk groups were compared by log-rank test and survival analysis. The P value of <0.05 was considered to be statistically significant.

3 Results

3.1 Analysis of datasets

The microarray gene chip GSE159956 was used in this study. The DEGs were analyzed using GEO2R online tools. A total of 1,231 upregulated and 937 downregulated DEGs were found in the distant metastasis group compared with those in the non-distant metastasis group (Figure 1b). About 544 upregulated and 249 downregulated GEGs were obtained under the LN-positive compared with LN-negative conditions (Figure 1c). The overlapped LN metastasis related 64 upregulated and 12 downregulated DEGs were acquired by the Venn diagram (Figure 1a, d, and e).

Figure 1 
                  DEGs in metastasis and non-metastasis groups and LN-positive and LN-negative groups. (a) Heatmap of overlapping DEGs based on metastasis status and LN conditions. (b and c) Volcano map of all mRNAs based on metastasis status and LN conditions. (d and e) Overlapping DEGs between metastasis and non-metastasis groups as well as LN-positive and LN-negative groups.
Figure 1

DEGs in metastasis and non-metastasis groups and LN-positive and LN-negative groups. (a) Heatmap of overlapping DEGs based on metastasis status and LN conditions. (b and c) Volcano map of all mRNAs based on metastasis status and LN conditions. (d and e) Overlapping DEGs between metastasis and non-metastasis groups as well as LN-positive and LN-negative groups.

3.2 Survival analysis of DEGs

In order to obtain the prognosis related DEGs, the prognoses of 72 overlapping DEGs were investigated using KM-plotter. Finally, 28 upregulated and 3 downregulated DEGs were found to be involved in the prognosis (Figure 2a and b).

Figure 2 
                  Survival-associated DEGs. (a) Twenty-eight upregulated prognosis-associated DEGs. (b) Three downregulated prognosis-associated DEGs.
Figure 2

Survival-associated DEGs. (a) Twenty-eight upregulated prognosis-associated DEGs. (b) Three downregulated prognosis-associated DEGs.

3.3 GO and KEGG annotations

For the survey of the potential function and pathway of 31 prognostic DEGs, GO and KEGG annotations were performed. Prognostic DEGs were mostly enriched in the “regulation of cellular amino acid metabolic process,” “proteasome complex,” “endopeptidase activity” in biological process and cellular component, and molecular function segments (Figure 3a–c). The “Proteasome” KEGG pathway was mostly enriched (Figure 3d). From the KEGG and GO annotation we can know that proteasome related amino acid metabolic process may be mostly involved in the distant and LN metastasis process.

Figure 3 
                  GO and KEGG enrichment analyses of survival-associated DEGs. (a–c) GO analysis of survival-associated DEGs. (d) KEGG analysis of survival-associated DEGs.
Figure 3

GO and KEGG enrichment analyses of survival-associated DEGs. (a–c) GO analysis of survival-associated DEGs. (d) KEGG analysis of survival-associated DEGs.

3.4 Immune clustering and verification

The samples were separated into high and low immune infiltration clusters and verified using ESTIMATE score, immune score, stromal score, and tumor purity (Figure 4a–e). Immune-related prognosis factors were evaluated by Wilcoxon test, and 17 upregulated and 2 downregulated factors were significantly influenced in the high and low immune infiltration clusters (Figure 5a and b).

Figure 4 
                  Construction and validation of BC immune infiltration clustering. (a) Enrichment levels of 29 immune-related cells and types in the high and low immune infiltration groups. The ESTIMATE Score, Stromal Score, Immune Score, and Tumor Purity of every patient combined with the clustering information. (b–e) Differences in ESTIMATE Score, Stromal Score, Immune Score, and Tumor Purity, respectively, between two clusters.
Figure 4

Construction and validation of BC immune infiltration clustering. (a) Enrichment levels of 29 immune-related cells and types in the high and low immune infiltration groups. The ESTIMATE Score, Stromal Score, Immune Score, and Tumor Purity of every patient combined with the clustering information. (b–e) Differences in ESTIMATE Score, Stromal Score, Immune Score, and Tumor Purity, respectively, between two clusters.

Figure 5 
                  Immune infiltration-associated DEGs. (a) Seventeen upregulated immune infiltration-associated DEGs. (b) Two downregulated immune infiltration-associated DEGs.
Figure 5

Immune infiltration-associated DEGs. (a) Seventeen upregulated immune infiltration-associated DEGs. (b) Two downregulated immune infiltration-associated DEGs.

3.5 Six metastasis prognosis factors were picked out by the TCGA database

According to the distant metastasis status, the TCGA_BRCA dataset expression files were divided into two parts. The abovementioned 17 upregulated and 2 downregulated immune prognostic features were compared, and 5 upregulated and 1 downregulated features were significantly different in the non-distant metastasis and distant metastasis groups (Figure 6).

Figure 6 
                  Expression validation of 19 immune infiltration-associated DEGs by using TCGA datasets. Five upregulated and one downregulated immune infiltration-associated DEGs were verified in metastasis (M) and non-metastasis (NM) groups by using the TCGA database.
Figure 6

Expression validation of 19 immune infiltration-associated DEGs by using TCGA datasets. Five upregulated and one downregulated immune infiltration-associated DEGs were verified in metastasis (M) and non-metastasis (NM) groups by using the TCGA database.

3.6 Three immune-associated prognostic features were recognized by the ssGSEA

LASSO regression was carried out, and four prognosis factors were selected (Figure 7a and b). High- and low-risk groups were separated based on the median of risk score. The survival status of the patients is shown in Figure 7c and d. Consequently, univariate and multivariate Cox regression analyses showed that two upregulated (RPS6KB2 and GALK1) and one downregulated (APPL1) prognosis factors were significant. The results of the univariate and multivariate analyses are shown in Figure 8a and b, and the heatmap is shown in Figure 8c. Furthermore, t-ROC was produced, and the areas under the curve (AUC) were 0.733, 0.759, and 0.691 in 3, 5, and 10 years, respectively (Figure 8d). This finding indicated that the three genes influenced by the LN status and immune infiltration could be used as prognostic factors to predict BC distant metastasis.

Figure 7 
                  Verification of immune-related prognostic genes by LASSO regression. (a) The LASSO Cox analysis identified four genes associated with prognosis. (b) The optimal values of the penalty parameter were defined by 1,000-round cross validation. (c) The risk curve of every sample was arranged by risk score. (d) The scatter plot of BC samples indicating survival.
Figure 7

Verification of immune-related prognostic genes by LASSO regression. (a) The LASSO Cox analysis identified four genes associated with prognosis. (b) The optimal values of the penalty parameter were defined by 1,000-round cross validation. (c) The risk curve of every sample was arranged by risk score. (d) The scatter plot of BC samples indicating survival.

Figure 8 
                  Evaluation of independent prognostic value. (a) Univariate and multivariate analyses and (b) Cox regression, where three genes were selected. (c) The heatmap of three genes based on risk score. (d) AUC of the three genes based on the ROC curve.
Figure 8

Evaluation of independent prognostic value. (a) Univariate and multivariate analyses and (b) Cox regression, where three genes were selected. (c) The heatmap of three genes based on risk score. (d) AUC of the three genes based on the ROC curve.

4 Discussion

BC is the leading cause of cancer-associated deaths among women worldwide [20]. Because of breast screening, most of the patients are diagnosed at early stage, which has a 5 year survival rate and can be as high as 100% [21]. Although most patients with early BC can be cured, a considerable number of patients, 20–30%, will still develop local recurrence or distant metastasis within 2 years of diagnosis of the primary tumor [22,23]. And causes of high incidence rate for BC patients [23]. BC cells are usually spread by lymphatic or hematogenous mode, and LN is often the first site of metastasis; LN-positive status can greatly increase the risk of the distant metastasis of BC [24,25].

Here the gene expression file GSE159956 was downloaded from the GEO database. A total of 295 patients were categorized into two groups based on metastasis status and LN status. LN-affected by metastasis genes was selected using GEO2R online tools. The overlapping 31 prognosis-related DEGs were selected using KM-plotter. GO and KEGG annotations were performed to determine the potential function of prognostic features, and the results showed that amino acid metabolic related pathway may influence the BC distant metastasis. For the known immune related prognostic factors, patients with high and low immune infiltration rates were clustered and verified by ESTIMATE, stromal scores, and tumor purity. Nineteen immune-associated prognosis factors were obtained by Wilcoxon test based on the high and low immune infiltrating groups. In addition, 6 of the 19 factors were confirmed by the TGCA_BRCA dataset. After LASSO regression and univariate and multivariate analyses, one downregulated (APPL1) and two upregulated (RPS6KB2 and GALK1) immune-related metastatic factors were selected. Finally, from the t-ROC we could know that the three factors could be used to predict BC metastasis. The detailed information about the 3 prognostic factors is presented as follows.

APPL was originally found as an AKT2 binding protein in a yeast two-hybrid screening system [26] and is named after its unique structure, an adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif [27]. APPL1 has implicated roles in insulin sensitivity and regulating insulin signaling pathways [28,29]. In addition, it affects cell functions, such as cell growth, migration, apoptosis, prognosis, endosomal trafficking, etc., by regulating some signaling events [27,30,31]. The expression levels of APPL1 was not only downregulated in kidney renal clear cell carcinoma tissues, and closely relate with Treg infiltration and immune checkpoints, but also inhibits Caki-1 cell migrations and growths [32]. Yet, APPL1 was highly expressed in the prostate cancer tissues [33]. Whereas, the functions of APPL1 on the BC metastasis are still unclear. In the present study, we found that low APPL1 expression could be used as a potential BC metastasis biomarker.

RPS6KB2, also known as S6K2, is the unheeded member of the S6K family [34] and shares nearly 80% of the amino acid sequence with the studied homolog S6K1. RPS6KB2 undertakes a downstream effective apparatus of PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways [34]. Therefore, RPS6KB2 is usually linked to cell proliferation and prognosis, such as in BC and prostate cancer [35,36]. High RPS6KB2 expression is correlated with chemotherapy resistance and prognosis of BC patients [37], indicating its potential role in cancer treatment. RPS6KB2 is also highly expressed in about 5% of patients with gastric carcinoma [38]; this high expression is associated with decreased overall survival rates of patients with the late-stage disease [34]. Hence, RPS6KB2 may be a BC metastasis indicator.

Galactokinase (GALK1) plays an important role in the first stage of catalysis metabolism of galactose and the conversion of galactose into galactose-1-phosphate at the consumption of ATP [39,40]. In addition, GALK1 could be a new therapeutic target for liver cancer treatment [41]. Inhibiting GALK1 could reduce the proliferation rate of HepG2 cells [42]. GALK1 in BC has been rarely reported. Here we used integrated bioinformatics methods and found that GALK1 could be a biomarker for predicting BC metastasis.

5 Conclusion

We identified three BC distant metastasis-related genes that were found to be significantly associated with prognosis. Combining with LN status, the three genes could be used to predict BC distant metastasis. However, further validations in clinical experiments are needed. These findings provide an approach for predicting BC distant metastasis and potential therapeutic targets for BC treatment.


# These authors contributed equally to this work.


  1. Funding information: The current work was funded by the Yantai Science and technology Innovation Development Plan (2022YD029) and the Natural Science Foundation of Shandong Province (ZR2021MH340).

  2. Author contributions: Gang Chen designed and drafted the manuscript; Kun Zhang was responsible for data analysis; Zhi Liang, Song Zhang, Yuanping Dai, Guangdong Qiao, and Yizi Cong revised the manuscript; Gang Chen and Kun Zhang equally contributed to this study. The above authors approved our eventual version for submission.

  3. Conflict of interest: All authors claim that there exists no competing interest.

  4. Data availability statement: The data used to support the findings of this study are available from the corresponding author upon reasonable request.

References

[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.10.3322/caac.21654Search in Google Scholar PubMed

[2] Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.10.3322/caac.21763Search in Google Scholar PubMed

[3] Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.10.1038/35021093Search in Google Scholar PubMed

[4] Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72(5):409–36.10.3322/caac.21731Search in Google Scholar PubMed

[5] Takada K, Kashiwagi S, Asano Y, Goto W, Kouhashi R, Yabumoto A, et al. Prediction of lymph node metastasis by tumor-infiltrating lymphocytes in T1 breast cancer. BMC Cancer. 2020;20(1):598.10.1186/s12885-020-07101-ySearch in Google Scholar PubMed PubMed Central

[6] Park M, Kim D, Ko S, Kim A, Mo K, Yoon H. Breast Cancer Metastasis: Mechanisms and Therapeutic Implications. Int J Mol Sci. 2022;23:12.10.3390/ijms23126806Search in Google Scholar PubMed PubMed Central

[7] Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G. The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017;14(12):717–34.10.1038/nrclinonc.2017.101Search in Google Scholar PubMed

[8] Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.10.1038/nrc3245Search in Google Scholar PubMed

[9] Kim MY. Breast cancer metastasis. Adv Exp Med Biol. 2021;1187:183–204.10.1007/978-981-32-9620-6_9Search in Google Scholar PubMed

[10] Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39.10.1056/NEJMoa1507643Search in Google Scholar PubMed PubMed Central

[11] Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.10.1056/NEJMoa1003466Search in Google Scholar PubMed PubMed Central

[12] Keenan TE, Tolaney SM. Role of immunotherapy in triple-negative breast cancer. J Natl Compr Canc Netw. 2020;18(4):479–89.10.6004/jnccn.2020.7554Search in Google Scholar PubMed

[13] Luo Q, Li J, Su X, Tan Q, Zhou F, Xie S. COL11A1 serves as a biomarker for poor prognosis and correlates with immune infiltration in breast cancer. Front Genet. 2022;13:935860.10.3389/fgene.2022.935860Search in Google Scholar PubMed PubMed Central

[14] Li Y, Qin J, Wu J, Dai X, Xu J. High expression of OSR1 as a predictive biomarker for poor prognosis and lymph node metastasis in breast cancer. Breast Cancer Res Treat. 2020;182(1):35–46.10.1007/s10549-020-05671-wSearch in Google Scholar PubMed

[15] Xu K, Zhang W, Wang C, Hu L, Wang R, Wang C, et al. Integrative analyses of scRNA-seq and scATAC-seq reveal CXCL14 as a key regulator of lymph node metastasis in breast cancer. Hum Mol Genet. 2021;30(5):370–80.10.1093/hmg/ddab042Search in Google Scholar PubMed

[16] Chen Y, Meng Z, Zhang L, Liu F. CD2 is a novel immune-related prognostic biomarker of invasive breast carcinoma that modulates the tumor microenvironment. Front Immunol. 2021;12:664845.10.3389/fimmu.2021.664845Search in Google Scholar PubMed PubMed Central

[17] Van't Veer LJ, Dai H, Van De Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530–6.10.1038/415530aSearch in Google Scholar PubMed

[18] Regua A, Papp C, Grageda A, Porter BA, Caza T, Bichindaritz I, et al. ABI1-based expression signature predicts breast cancer metastasis and survival. Mol Oncol. 2022;16(14):2632–57.10.1002/1878-0261.13175Search in Google Scholar PubMed PubMed Central

[19] Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.10.1038/ncomms3612Search in Google Scholar PubMed PubMed Central

[20] Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 2010;19(8):1893–907.10.1158/1055-9965.EPI-10-0437Search in Google Scholar PubMed

[21] Moleyar-Narayana P, Ranganathan S. Cancer screening. Treasure Island (FL): StatPearls; 2023.Search in Google Scholar

[22] AlSendi M, O’Reilly D, Zeidan YH, Kelly CM. Oligometastatic breast cancer: Are we there yet? Int J Cancer. 2021;149(8):1520–8.10.1002/ijc.33693Search in Google Scholar PubMed

[23] Zou Y, Ye F, Kong Y, Hu X, Deng X, Xie J, et al. The Single-Cell Landscape of Intratumoral Heterogeneity and The Immunosuppressive Microenvironment in Liver and Brain Metastases of Breast Cancer. Adv Sci (Weinh). 2023;10(5):e2203699.10.1002/advs.202203699Search in Google Scholar PubMed PubMed Central

[24] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.10.3322/caac.21262Search in Google Scholar PubMed

[25] de Boer M, van Dijck JA, Bult P, Borm GF, Tjan-Heijnen VC. Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastases. J Natl Cancer Inst. 2010;102(6):410–25.10.1093/jnci/djq008Search in Google Scholar PubMed

[26] Mitsuuchi Y, Johnson SW, Sonoda G, Tanno S, Golemis EA, Testa JR. Identification of a chromosome 3p14.3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Oncogene. 1999;18(35):4891–8.10.1038/sj.onc.1203080Search in Google Scholar PubMed

[27] Deepa SS, Dong LQ. APPL1: role in adiponectin signaling and beyond. Am J Physiol Endocrinol Metab. 2009;296(1):E22–36.10.1152/ajpendo.90731.2008Search in Google Scholar PubMed PubMed Central

[28] Ryu J, Galan AK, Xin X, Dong F, Abdul-Ghani MA, Zhou L, et al. APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep. 2014;7(4):1227–38.10.1016/j.celrep.2014.04.006Search in Google Scholar PubMed PubMed Central

[29] Kido K, Ato S, Yokokawa T, Sato K, Fujita S. Resistance training recovers attenuated APPL1 expression and improves insulin-induced Akt signal activation in skeletal muscle of type 2 diabetic rats. Am J Physiol Endocrinol Metab. 2018;314(6):E564–71.10.1152/ajpendo.00362.2017Search in Google Scholar PubMed

[30] Diggins NL, Webb DJ. APPL1 is a multifunctional endosomal signaling adaptor protein. Biochem Soc Trans. 2017;45(3):771–9.10.1042/BST20160191Search in Google Scholar PubMed PubMed Central

[31] Liu Z, Xiao T, Peng X, Li G, Hu F. APPLs: More than just adiponectin receptor binding proteins. Cell Signal. 2017;32:76–84.10.1016/j.cellsig.2017.01.018Search in Google Scholar PubMed

[32] Yang M, Gong C, Song K, Huang N, Chen H, Gong H, et al. APPL1 is a prognostic biomarker and correlated with treg cell infiltration via oxygen-consuming metabolism in renal clear cell carcinoma. Oxid Med Cell Longev. 2023;2023:5885203.10.1155/2023/5885203Search in Google Scholar PubMed PubMed Central

[33] Martini C, Logan JM, Sorvina A, Gordon C, Beck AR, SYU B, et al. Aberrant protein expression of APPL1, Sortilin and Syndecan-1 during the biological progression of prostate cancer. Pathology. 2023;55(1):40–51.10.1016/j.pathol.2022.08.001Search in Google Scholar PubMed

[34] Pardo OE, Seckl MJ. S6K2: The neglected S6 kinase family member. Front Oncol. 2013;3:191.10.3389/fonc.2013.00191Search in Google Scholar PubMed PubMed Central

[35] Sridharan S, Basu A. Distinct roles of mTOR targets S6K1 and S6K2 in breast cancer. Int J Mol Sci. 2020;21(4):1199.10.3390/ijms21041199Search in Google Scholar PubMed PubMed Central

[36] Amaral CL, Freitas LB, Tamura RE, Tavares MR, Pavan IC, Bajgelman MC, et al. S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells. BMC Cancer. 2016;16:602.10.1186/s12885-016-2629-ySearch in Google Scholar PubMed PubMed Central

[37] Perez-Tenorio G, Karlsson E, Waltersson MA, Olsson B, Holmlund B, Nordenskjold B, et al. Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer. Breast Cancer Res Treat. 2011;128(3):713–23.10.1007/s10549-010-1058-xSearch in Google Scholar PubMed

[38] Yoshida S, Matsumoto K, Arao T, Taniguchi H, Goto I, Hanafusa T, et al. Gene amplification of ribosomal protein S6 kinase-1 and -2 in gastric cancer. Anticancer Res. 2013;33(2):469–75.Search in Google Scholar

[39] Timson DJ, Reece RJ. Functional analysis of disease-causing mutations in human galactokinase. Eur J Biochem. 2003;270(8):1767–74.10.1046/j.1432-1033.2003.03538.xSearch in Google Scholar PubMed

[40] Yasmeen A, Riazuddin SA, Kaul H, Mohsin S, Khan M, Qazi ZA, et al. Autosomal recessive congenital cataract in consanguineous Pakistani families is associated with mutations in GALK1. Mol Vis. 2010;16:682–8.Search in Google Scholar

[41] Wu Z, Wen Z, Li Z, Yu M, Ye G. Identification and prognostic value of a glycolysis-related gene signature in patients with bladder cancer. Med (Baltim). 2021;100(3):e23836.10.1097/MD.0000000000023836Search in Google Scholar PubMed PubMed Central

[42] Tang M, Etokidem E, Lai K. The Leloir pathway of galactose metabolism - a novel therapeutic target for hepatocellular carcinoma. Anticancer Res. 2016;36(12):6265–71.10.21873/anticanres.11221Search in Google Scholar PubMed

Received: 2023-03-13
Revised: 2023-05-04
Accepted: 2023-05-14
Published Online: 2023-06-01

© 2023 the author(s), published by De Gruyter

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

Articles in the same Issue

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
Downloaded on 30.3.2026 from https://www.degruyterbrill.com/document/doi/10.1515/med-2023-0732/html
Scroll to top button