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Evaluation of COVID-19 based on ACE2 expression in normal and cancer patients

  • Peng Ren , Caifeng Gong and Shaohua Ma EMAIL logo
Published/Copyright: July 7, 2020

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is now a serious public health problem. Angiotensin-converting enzyme 2 (ACE2) recognized as the receptor of SARS-CoV is also necessary for SARS-CoV-2. However, the impact of ACE2 on SARS-CoV-2 susceptibility and the situation of malignant tumor patients in this outbreak are unclear. So, it is important to understand the expressions of ACE2 in different normal tissues and cancers. The results showed that the kidneys, duodenum, intestine, gallbladder and testis had the highest ACE2 expressions, followed by the colon, rectum and seminal vesicles. The lungs had a very low expression. ACE2 expressions were upregulated in renal cancer, gastrointestinal tumor and lung cancer. ACE2 expression levels may affect SARS-CoV-2 infection and severity. A total of 3,421 cases with COVID-19 have been collected. Among them, 43 cases (1.26%) had malignant tumor coexisting conditions. The rate of severe events for malignant tumor patients was 39.02% (16/41), while the rate of severe events for all patients was 10.79% (194/1,798). The clinical symptoms and signs were studied for the following three systems: respiratory (31–92%), digestive (10–13%) and urinary systems (3.38%). It seems that symptom severity is not related to protein expression levels. This might be the reason for SARS-CoV-2 showing higher regeneration index and susceptibility. More research is needed to explore the mechanisms and treatments.

1 Introduction

Several unexplained pneumonia cases were reported in December 2019, caused by a novel coronavirus [1,2,3]. Patients presented with fever, dry cough, weakness and dyspnea, and some patients were seriously ill with acute respiratory distress syndrome (ARDS) or even died. The International Committee on Taxonomy of Viruses named the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By April 26, 2020, the rapid spread of the virus resulted in more than 2.8 million cases and more than 1,90,000 deaths worldwide, and cases have been reported in 211 countries (including the United States, Italy and Spain). The WHO has announced that the 2019 new coronavirus disease (COVID-19) caused by SARS-CoV-2 is a public health emergency of international concern (https://covid19.who.int/). Angiotensin-converting enzyme 2 (ACE2) has been first implicated in heart functioning, hypertension and diabetes, with its effects being mediated, in part, through its ability to convert angiotensin II to angiotensin-1 to 7 [4]. Unexpectedly, previous studies on SARS-CoV have shown that ACE2 was a receptor through which the virus enters cells [5]. Genetic analysis of SARS-CoV-2 has shown that this new virus has approximately 80% sequence identity with SARS-CoV, and further results indicated that SARS-CoV-2 was likely to also use the same receptor ACE2 as the entry receptor [6,7,8,9]. The expression of ACE2 in different tissues is closely related to the susceptibility to and severity of the virus infection [10,11].

Studies have reported that organ dysfunctions such as shock, ARDS, acute cardiac injury, acute kidney injury (AKI) and death can occur in severe cases of COVID-19 [12,13]. More clinical data analysis showed that severe infections were more likely to affect older men with comorbidities such as hypertension, diabetes, cardiovascular disease and cerebrovascular disease [14]. Malignant tumor is one of the most common diseases affecting people’s survival status. These patients will have pathological changes in the body, especially in the immune system. As the incidence of tumors is getting higher and higher, it is now developing chronically and has become the common comorbidity of COVID-19. However, the current situation of tumor patients in this outbreak has not been clearly reported in detail. Therefore, we would like to evaluate the differences in ACE2 expression in various tissue types and cancers. Then, the influence of these differences on the impact of SARS-CoV-2 infections was analyzed. In addition, tumor patients with COVID-19 were briefly evaluated to assess the susceptibility and severity.

2 Materials and methods

2.1 Data source

The genomic location of the ACE2 gene was downloaded from GeneCard (https://www.genecards.org). COMPARTMENTS was used for gene subcellular location confidence analysis. The mRNA and protein expressions of ACE2 in different normal tissues were obtained from the Human Protein Atlas (HPA). Gene expressions of ACE2 were verified using Genotype Tissue Expression (GTEx) projects. Comparison of the expressions between tumors and normal tissues was performed using the Gene Expression Profiling Interactive Analysis (GEPIA) dataset and ONCOMINE. Protein expression levels and immunohistochemistry (IHC) images were obtained from the HPA. Clinical data in published references for COVID-19 (Coronavirus Disease 2019) patients infected with SARS-CoV-2 were collected. All datasets and clinical data were retrieved from the published literature, so it was confirmed that written informed consent was obtained. Therefore, approval from local ethics committee is not required for this study.

2.2 COMPARTMENTS localization

COMPARTMENTS localization data are integrated from literature manual curation, high-throughput microscopy-based screens, predictions from primary sequences and automatic text mining (see COMPARTMENTS: unification and visualization of protein subcellular localization evidence). Unified confidence scores of the localization evidence are assigned based on evidence type and source. The results were visualized in the schematic cell image.

2.3 GEPIA analysis

ACE2 mRNA expressions in tumors and normal tissues were obtained from the GEPIA dataset (http://gepia.cancer-pku.cn). It is a newly developed interactive web server for analyzing the RNA sequencing expression data of 9,736 tumors and 8,587 normal samples from the Cancer Genome Atlas and GTEx projects, using a standard processing pipeline. ACE2 expressions of samples in survival analysis were divided into two groups using median expression (high vs low expression) and assessed using a Kaplan–Meier survival plot, with the log-rank test. Significant difference was regarded as P < 0.05.

2.4 ONCOMINE analysis

ONCOMINE gene expression array datasets (https://www.oncomine.org), an online cancer microarray database, were used to analyze the gene expression of ACE2 in different cancers. The expressions of ACE2 in clinical cancer specimens were compared with those in normal controls, using Student’s t test to generate a P value. The threshold settings were as follows: P value: 1 × 10−4; fold change: 2; gene rank: top 10%; and data type: all.

2.5 HPA

The mRNA and protein expressions of ACE2 were identified differentially in human normal and cancer tissues using the HPA, a website (https://www.proteinatlas.org) that contains IHC-based expression data for approximately 20 most common types of cancers, with 12 individual tumors in each cancer. ACE2 mRNA levels of different normal tissues were obtained from the Consensus dataset. Consensus Normalized eXpression levels for 55 tissue types and 6 blood cell types were created by combining the data from three transcriptomics datasets (HPA, GTEx and FANTOM5) using the internal normalization pipeline. Protein expression data are shown for each of the 44 normal tissues. Renal cancer, colorectal cancer and lung cancer along with kidney, colon and lung normal tissues with IHC staining of ACE2 protein were chosen with antibody CAB026174.

2.6 System review of malignant tumors in COVID-19 patients infected with SARS-CoV-2

Studies recently published describing the clinical characteristics of COVID-19 due to SARS-CoV-2 were screened and analyzed. Studies describing patients’ malignant tumor status were enrolled. The number of patients and severity rate combined with malignant tumors were calculated. Clinical symptoms and signs due to COVID-19 were collected. Studies with incomplete symptom descriptions were excluded. Excel was used to classify the symptoms into three groups: respiratory, digestive and urinary systems. The virus detection information was transformed from the publication [15].

3 Results

3.1 Expression of ACE2 in normal tissues

GeneCard showed that the ACE2 gene was located in the X chromosome (Xp22.2), encoding a type I transmembrane glycoprotein composed of 805 amino acid residues (Figure 1a). Subcellular locations from COMPARTMENTS revealed confidence 5 in the plasma membrane and extracellular space, confidence 2 in the cytoskeleton, mitochondrion, peroxisome, nucleus, endoplasmic reticulum, endosome, cytosol and lysosome and only confidence 1 in the Golgi apparatus, respectively (Figure 1b). The Consensus dataset using the HPA showed that the mRNA expression of ACE2 in normal tissues from high to low was in five groups. Tissues in the most expressive groups were the small intestine, colon, duodenum, kidney, testis, gallbladder and heart muscle with a score from 122 to 10. The tissues in the second expressive group were the adipose tissue, thyroid gland, epididymis, ductus deferens, breast, pancreas, rectum, ovary, esophagus, liver, seminal vesicle, salivary gland and placenta with a score from 5 to 1. The tissues in three medium expressive groups were the vagina, lung, appendix, skeletal muscle, fallopian tube, lymph node, tongue, stomach and prostate with a score from 0.9 to 0.5. The parathyroid gland, bone marrow, monocytes, B-cells, NK-cells, dendritic cells and total peripheral blood mononuclear cell had no expression of ACE2, and others in the low expressive group had a score from 0.4 to 0.1 (Figure 1c). Immunohistochemical analysis confirmed that ACE2 was highly expressed in the duodenum, gallbladder, kidneys, small intestine and testis, and there was a low expression in the adrenal glands, colon, rectum and seminal vesicles (Figure 1c and 1d). The ACE2 gene has 19 exons, and its expression level showed the same trend as in the HPA which was verified using GTEx (Figure 2).

Figure 1 Location and expression of ACE2 in normal tissues. (a) Genomic location of the ACE2 gene obtained from GeneCard. (b) Cellular location of the ACE2 gene (COMPARTMENTS). Confidence scale is color coded, ranging from light green for low confidence to dark green for high confidence. White indicates the absence of localization evidence. (c) The mRNA (left side top, Consensus dataset) and protein (left side down) expressions of ACE2 in normal tissues from the HPA. Color-coding is based on tissue groups, each consisting of tissues with common functional features. (d) Respective images of normal tissue with IHC staining of ACE2 protein in the HPA (scale 200 µm). ACE2: angiotensin-converting enzyme 2; HPA: Human Protein Atlas.
Figure 1

Location and expression of ACE2 in normal tissues. (a) Genomic location of the ACE2 gene obtained from GeneCard. (b) Cellular location of the ACE2 gene (COMPARTMENTS). Confidence scale is color coded, ranging from light green for low confidence to dark green for high confidence. White indicates the absence of localization evidence. (c) The mRNA (left side top, Consensus dataset) and protein (left side down) expressions of ACE2 in normal tissues from the HPA. Color-coding is based on tissue groups, each consisting of tissues with common functional features. (d) Respective images of normal tissue with IHC staining of ACE2 protein in the HPA (scale 200 µm). ACE2: angiotensin-converting enzyme 2; HPA: Human Protein Atlas.

Figure 2 Gene expression of ACE2 in normal tissue (GTEx). (a) Gene expression of ACE2 (ENSG00000130234.10). (b) Exon expression of ACE2 (source: HGNC symbol; Acc: HGNC:13557). ACE2: angiotensin-converting enzyme 2.
Figure 2

Gene expression of ACE2 in normal tissue (GTEx). (a) Gene expression of ACE2 (ENSG00000130234.10). (b) Exon expression of ACE2 (source: HGNC symbol; Acc: HGNC:13557). ACE2: angiotensin-converting enzyme 2.

3.2 Expression and prognostic value of ACE2 in malignant tumors

Using the GEPIA dataset, we compared the mRNA expression of ACE2 between cancer and normal samples. The results indicated that almost all cancer tissues can express ACE2, and the highest expression level was in renal cancer (Figure 3a). The mRNA expressions of ACE2 were significantly overexpressed in colon adenocarcinoma, kidney renal papillary cell carcinoma, pancreatic adenocarcinoma, rectum adenocarcinoma (READ) and stomach adenocarcinoma (STAD) (Figures 3a and c and 4a). There were significantly lower expressions in kidney chromophobe, sarcoma, testicular germ cell tumors and thyroid carcinoma than those in normal tissues (Figure 3a and d). The gene expressions of ACE2 in cancers and those in normal samples were verified by using ONCOMINE databases (Figures 3b and 4a). ACE2 expressions in lung cancer and breast cancer were upregulated compared with normal tissues. After that, we investigated prognosis value of ACE2 using the GEPIA databases in pan-cancer. Patients in survival analysis were divided into two groups using median ACE2 expression (high vs low expression) and assessed using an overall Kaplan–Meier plot. There were no significant differences in overall survival (OS) between the two ACE2 expression levels. But it seemed that the high ACE2 expression group with READ and STAD had the trend of better OS compared with the low ACE2 expression group (Figure 3e).

Figure 3 Expression and prognostic value of ACE2 in pan-cancer. Expressions of ACE2 were evaluated in pan-cancer compared with normal tissue from the GEPIA (a) and ONCOMINE (b). ACE2 was overexpressed in five cancer types (c) and decreased in four cancer types (d). The prognostic value of ACE2 in nine cancer types from the GEPIA (e). *P < 0.05. ACE2: angiotensin-converting enzyme 2; GEPIA: Gene Expression Profiling Interactive Analysis.
Figure 3

Expression and prognostic value of ACE2 in pan-cancer. Expressions of ACE2 were evaluated in pan-cancer compared with normal tissue from the GEPIA (a) and ONCOMINE (b). ACE2 was overexpressed in five cancer types (c) and decreased in four cancer types (d). The prognostic value of ACE2 in nine cancer types from the GEPIA (e). *P < 0.05. ACE2: angiotensin-converting enzyme 2; GEPIA: Gene Expression Profiling Interactive Analysis.

Figure 4 Differences of ACE2 expression and clinical symptoms. (a) Respective images of renal cancer, colorectal cancer and lung cancer compared with normal tissue with IHC staining of ACE2 protein (CAB026174) in the HPA (scale 200 µm). (b) Frequency of three-system related symptoms of COVID-19 patients infected with SARS-CoV-2. ACE2: angiotensin-converting enzyme 2; HPA: Human Protein Atlas; COVID-19: Coronavirus Disease 2019; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
Figure 4

Differences of ACE2 expression and clinical symptoms. (a) Respective images of renal cancer, colorectal cancer and lung cancer compared with normal tissue with IHC staining of ACE2 protein (CAB026174) in the HPA (scale 200 µm). (b) Frequency of three-system related symptoms of COVID-19 patients infected with SARS-CoV-2. ACE2: angiotensin-converting enzyme 2; HPA: Human Protein Atlas; COVID-19: Coronavirus Disease 2019; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

3.3 Malignant tumors in COVID-19 patients infected with SARS-CoV-2

Studies recently published describing the clinical characteristics of COVID-19 due to SARS-CoV-2 were screened and analyzed. Overall, six studies that evaluated patients’ malignant tumor status were enrolled [12,13,14,16,17,18]. A total of 3,421 cases in China have been confirmed in these studies. Among them, 43 cases (1.26%) had malignant tumor coexisting conditions. Among cancer patients, men and lung cancer patients were more likely to have COVID-19 (Supplementary Table 1). The rate of severe events for malignant tumor patients was 39.02% (16/41), while the rate of severe events for all patients was 10.79% (194/1,798) (Table 1). The clinical symptoms and signs due to COVID-19 were divided into three groups of systems: respiratory, digestive and urinary systems; there were two studies that described symptoms related to all the three systems (Table 2 and Figure 4b). Respiratory symptoms and signs with fever (91.98%), cough (68.78%) and dyspnea (31.22%) were the most frequent in the range from 31% to 92%. Digestive system related symptoms and signs were abdominal pain with/without diarrhea (8.02%) and nausea with/without vomiting (8.02%). We used AKI to represent the urinary system damage, which had the lowest frequency of 3.38%. The ACE2 protein expressions with IHC staining obtained from the HPA were very weak in the lungs, medium in the colon and high in the kidneys, and the same trend was found in the cancer tissues (Figure 4a).

Table 1

Number and severity of malignant tumor patients infected with SARS-CoV-2

ReferencesTotal case (%)Malignant tumor (%)Severe events of tumor patientsTotal severe events (%)
Yes (%)No (%)
Dawei Wang et al. (2020)13810 (7.25)4 (40.00)6 (60.00)36 (26.09)
Lei Chen et al. (2020)291 (3.45)NANA14 (48.28)
Nanshan Chen et al. (2020)991 (1.01)NANANA
Chaolin Huang et al. (2020)411 (2.44)0 1 13 (31.71)
Jing Yu et al. (2020)1,52412 (0.79)3 (25.00)9 (75.00)NA
Wenhua Liang et al. (2020)1,59018 (1.13)9 (50.00)9 (50.00)131 (3.83)
Total3,42143 (1.26)16 (39.02)a25 (60.98)b194 (10.79)c
  1. a

    16/41.

  2. b

    7/41.

  3. c

    194/179.

Table 2

Representative three-system related symptoms of COVID-19 patients infected with SARS-CoV-2

Symptoms and signsDawei Wang et al. (2020)Nanshan Chen et al. (2020)Total
n = 138(%)n = 99(%)n = 237(%)
Respiratory symptoms and signs (31–92%)
Fever136(98.55)82(82.83)218(91.98)
Cough82(59.42)81(81.82)163(68.78)
Dyspnea43(31.16)31(31.31)74(31.22)
Digestive symptoms and signs (8–13%)
Abdominal pain, diarrhea17(12.32)2(2.02)19(8.02)
Nausea, vomiting18(13.04)1(1.01)19(8.02)
Urinary symptoms and signs (3.38%)
AKI5(3.62) 3(3.03)8(3.38)

AKI, acute kidney injury; COVID-19, Coronavirus Disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

4 Discussion

SARS-CoV-2 infection is a serious public health problem. As the number of cases has been increasing and as it spreads quickly, people keep a close eye on the future development of this disease. ACE2 as the receptor of SARS-CoV was recognized to be also necessary for the cells infected by SARS-CoV-2, and in vitro experiments proved that cells without the ACE2 receptor were not infected by the virus [6,7,9]. Some proposed that the reproduction rate of SARS-CoV-2 is higher than that of SARS-CoV [19]. ACE2 protein is closely related to the entry of this virus, and the distribution of this receptor might reflect the susceptibility to this virus and virus replication. However, the impact of ACE2 on SARS-CoV-2 susceptibility and the situation of malignant tumor patients in this outbreak are unclear. So, it is important to understand the expressions of ACE2 in different tissues and cancers. In our study, results showed that ACE2 was found in almost all the normal tissues, indicating that all the organs were potentially infected. The virus was detected in different samples not only in nasopharyngeal or oropharyngeal swabs but also in stool [15]. There is a possibility of transmission of this virus by the fecal-oral route. Wang et al. had reported ten cases (7.2%) with acute cardiac injury in 138 hospitalized patients with SARS-CoV-2 infection [14]. The expression of ACE2 was also detected in the heart using the mRNA level, so acute cardiac injury might be caused by the virus attacking the heart. Multiple organ functions should be given attention in clinical treatments.

Based on the ACE2 protein expression level, the kidney had a high expression, and the colon in digestive organs had a medium expression. The lungs in the respiratory system had a very low basic expression of mRNA. But SARS-CoV-2 is transmitted mainly through the respiratory tract, and the lungs become the main target of the SARS-CoV-2 attack with the respiratory symptoms being the most frequent in COVID-19. Holshue et al. detected the virus four times in different samples from one COVID-19 patient showing that the initial respiratory specimens (nasopharyngeal and oropharyngeal swabs) obtained were positive four times with a higher Ct value. The digestive system related samples (stool) had only one positive. All the urinary system related samples (urine) were negative [15]. These results suggest that the symptoms might be consistent with virus detection levels, indicating that the more severe the symptoms, the more the virus replicates inducing damage. But the severity of symptoms is not related to the ACE2 expression level. Yu et al. found that vimentin had direct interaction with SARS-CoV spike protein during viral entry in SARS-CoV infection, which might also influence the susceptibility [20]. The SARS-CoV-2 seems more likely to invade tissues with low expression of ACE2. This interesting phenomenon may be caused by the polybasic furin type cleavage site present at the S1–S2 junction in the SARS-CoV-2 spike protein, which is not present in SARS-CoV [21]. Studies on SARS have shown that inserting a multivalent cleavage site in the S1–S2 region of SARS-CoV will result in a moderate but significant increase in fusion activity, which may lead to increased virus entry in low-density ACE2 expressing tissues [22].

Moreover, malignant tumor patients are usually weaker and may be more severely affected by this outbreak. Our results showed that 4.23% of 307 cases had malignant tumor coexisting conditions. The rate of intensive care unit (ICU) admission of COVID-19 patients with malignant tumors (36.36%) showed a higher trend than that for all patients (30.9%). But there was no statistically significant difference. The number of tumor patients was insufficient in the included studies, and further studies are needed for confirmation. The susceptibility of malignant tumor patients and the intensity degree differences could be evaluated by ACE2 expression exploration. The results indicated that almost all cancer tissues can express ACE2, suggesting that all the tumor patients are susceptible to this new SARS-CoV-2. ACE2 expressions in some cancer types such as gastrointestinal tumor and lung cancer were upregulated. Changes in expression levels may affect the susceptibility and disease severity. One of the main causes of death in patients with SARS-CoV-2 is ARDS. The relationship between ACE2 and ARDS has attracted much attention from researchers. Imai et al. found that ACE2 gene knockout in a mice model resulted in increased vascular permeability and increased pulmonary edema, eventually leading to ARDS. However, the use of ACE2 inhibitor significantly reduced the occurrence of ARDS in the mice model [23]. Further research showed that infection of SARS-CoV caused downregulation of ACE2 expression in lung tissues in vivo and in vitro, which might induce ARDS [24,25]. These results suggested that the expression of ACE2 in mice has a protective effect on the occurrence of ARDS, and changes in ACE2 expression levels are closely related to the severity of this disease. SARS-CoV downregulated ACE2 in the model of respiratory failure, and the viral spike protein induced TNF-alpha-converting enzyme-dependent shedding of the ACE2 ectodomain and led to tissue damage [26]. Increasing ACE2 expression is a potential strategy to prevent ARDS in COVID-19 patients. We should carefully use treatments such as ACE2 inhibitors.

5 Conclusion

In summary, our study found ACE2 expressions in different tissues. The normal tissues of the kidneys, duodenum, intestine, gallbladder and testis had the highest expression, followed by the colon, rectum and seminal vesicles. The lungs had very low expression suggesting that low expression of ACE2 is enough for the infection of SARS-CoV-2. ACE2 expressions were upregulated in renal cancer, gastrointestinal tumor and lung cancer. There was no significant difference in severity of COVID-19 in malignant tumor patients. In particular, organ damage was likely consistent with virus detection levels but negatively related to the protein expression level. The mechanism of virus entry into human cells may require other receptors or cofactors. These findings may help to develop anti-SARS-CoV-2 agents.

Abbreviations

COAD

Colon adenocarcinoma

COVID-19

Coronavirus disease 2019

ACE2

Angiotensin-converting enzyme 2

AKI

Acute kidney injury

ARDS

Acute respiratory distress syndrome

GEPIA

Gene expression profiling interactive analysis

GTEx

Genotype tissue expression

HPA

Human protein atlas

ICTV

International committee on taxonomy of viruses

ICU

Intensive care unit

IHC

Immunohistochemistry

KICH

Kidney chromophobe

KIRP

Kidney renal papillary cell carcinoma

NCIP

Novel coronavirus

NX

Normalized eXpression

OS

Overall survival

PAAD

Pancreatic adenocarcinoma

READ

Rectum adenocarcinoma

SARC

Sarcoma

SRAS-CoV2

Severe acute respiratory syndrome coronavirus 2

STAD

Stomach adenocarcinoma

TACE

Tumor necrosis factor-alpha-converting enzyme

TCGA

The cancer genome atlas

TGCT

Testicular germ cell tumors

THCA

Thyroid carcinoma


These authors contributed equally to this work and are co-first authors.


  1. Consent for publication: Not applicable.

  2. Availability of data and materials: IHC images for renal cancer, colorectal cancer, lung cancer and normal tissues with ACE2 protein expression were downloaded from the HPA (https://www.proteinatlas.org).

  3. Conflict of interest: The authors declare that they have no competing interests.

  4. Funding: This study was supported by research funds of Clinical Key projects of Peking University Third Hospital, Improvement and promotion of thoracoscopic combined with laparoscopic radical operation of esophageal.

  5. Author contributions: Dr Peng Ren is responsible for data collection and experimental proceeding. The co-first author is Dr Caifeng Gong, who is responsible for data collection and analysis. Dr Shaohua Ma supervised the project. All authors read and approved the final manuscript.

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Received: 2020-03-10
Revised: 2020-04-26
Accepted: 2020-06-10
Published Online: 2020-07-07

© 2020 Peng Ren et al., published by De Gruyter

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

Articles in the same Issue

  1. Research Article
  2. MicroRNA-451b participates in coronary heart disease by targeting VEGFA
  3. Case Report
  4. A combination therapy for Kawasaki disease with severe complications: a case report
  5. Vitamin E for prevention of biofilm-caused Healthcare-associated infections
  6. Research Article
  7. Differential diagnosis: retroperitoneal fibrosis and oncological diseases
  8. Optimization of the Convolutional Neural Networks for Automatic Detection of Skin Cancer
  9. NEAT1 promotes LPS-induced inflammatory injury in macrophages by regulating miR-17-5p/TLR4
  10. Plasma matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 as prognostic biomarkers in critically ill patients
  11. Effects of extracorporeal magnetic stimulation in fecal incontinence
  12. Case Report
  13. Mixed germ cell tumor of the endometrium: a case report and literature review
  14. Bowel perforation after ventriculoperitoneal-shunt placement: case report and review of the literature
  15. Research Article
  16. Prognostic value of lncRNA HOTAIR in colorectal cancer : a meta-analysis
  17. Case Report
  18. Treatment of insulinomas by laparoscopic radiofrequency ablation: case reports and literature review
  19. Research Article
  20. The characteristics and nomogram for primary lung papillary adenocarcinoma
  21. Undiagnosed pheochromocytoma presenting as a pancreatic tumor: A case report
  22. Bioinformatics Analysis of the Expression of ATP binding cassette subfamily C member 3 (ABCC3) in Human Glioma
  23. Diagnostic value of recombinant heparin-binding hemagglutinin adhesin protein in spinal tuberculosis
  24. Primary cutaneous DLBCL non-GCB type: challenges of a rare case
  25. LINC00152 knock-down suppresses esophageal cancer by EGFR signaling pathway
  26. Case Report
  27. Life-threatening anaemia in patient with hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)
  28. Research Article
  29. QTc interval predicts disturbed circadian blood pressure variation
  30. Shoulder ultrasound in the diagnosis of the suprascapular neuropathy in athletes
  31. The number of negative lymph nodes is positively associated with survival in esophageal squamous cell carcinoma patients in China
  32. Differentiation of pontine infarction by size
  33. RAF1 expression is correlated with HAF, a parameter of liver computed tomographic perfusion, and may predict the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients
  34. LncRNA ZEB1-AS1 regulates colorectal cancer cells by miR-205/YAP1 axis
  35. Tissue coagulation in laser hemorrhoidoplasty – an experimental study
  36. Classification of pathological types of lung cancer from CT images by deep residual neural networks with transfer learning strategy
  37. Enhanced Recovery after Surgery for Lung Cancer Patients
  38. Case Report
  39. Streptococcus pneumoniae-associated thrombotic microangiopathy in an immunosuppressed adult
  40. Research Article
  41. The characterization of Enterococcus genus: resistance mechanisms and inflammatory bowel disease
  42. Case Report
  43. Inflammatory fibroid polyp: an unusual cause of abdominal pain in the upper gastrointestinal tract A case report
  44. Research Article
  45. microRNA-204-5p participates in atherosclerosis via targeting MMP-9
  46. LncRNA LINC00152 promotes laryngeal cancer progression by sponging miR-613
  47. Can keratin scaffolds be used for creating three-dimensional cell cultures?
  48. miRNA-186 improves sepsis induced renal injury via PTEN/PI3K/AKT/P53 pathway
  49. Case Report
  50. Delayed bowel perforation after routine distal loopogram prior to ileostomy closure
  51. Research Article
  52. Diagnostic accuracy of MALDI-TOF mass spectrometry for the direct identification of clinical pathogens from urine
  53. The R219K polymorphism of the ATP binding cassette subfamily A member 1 gene and susceptibility to ischemic stroke in Chinese population
  54. miR-92 regulates the proliferation, migration, invasion and apoptosis of glioma cells by targeting neogenin
  55. Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma
  56. NF2 inhibits proliferation and cancer stemness in breast cancer
  57. Body composition indices and cardiovascular risk in type 2 diabetes. CV biomarkers are not related to body composition
  58. S100A6 promotes proliferation and migration of HepG2 cells via increased ubiquitin-dependent degradation of p53
  59. Review Article
  60. Focus on localized laryngeal amyloidosis: management of five cases
  61. Research Article
  62. NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p
  63. Pericentric inversion in chromosome 1 and male infertility
  64. Increased atherogenic index in the general hearing loss population
  65. Prognostic role of SIRT6 in gastrointestinal cancers: a meta-analysis
  66. The complexity of molecular processes in osteoarthritis of the knee joint
  67. Interleukin-6 gene −572 G > C polymorphism and myocardial infarction risk
  68. Case Report
  69. Severe anaphylactic reaction to cisatracurium during anesthesia with cross-reactivity to atracurium
  70. Research Article
  71. Rehabilitation training improves nerve injuries by affecting Notch1 and SYN
  72. Case Report
  73. Myocardial amyloidosis following multiple myeloma in a 38-year-old female patient: A case report
  74. Research Article
  75. Identification of the hub genes RUNX2 and FN1 in gastric cancer
  76. miR-101-3p sensitizes non-small cell lung cancer cells to irradiation
  77. Distinct functions and prognostic values of RORs in gastric cancer
  78. Clinical impact of post-mortem genetic testing in cardiac death and cardiomyopathy
  79. Efficacy of pembrolizumab for advanced/metastatic melanoma: a meta-analysis
  80. Review Article
  81. The role of osteoprotegerin in the development, progression and management of abdominal aortic aneurysms
  82. Research Article
  83. Identification of key microRNAs of plasma extracellular vesicles and their diagnostic and prognostic significance in melanoma
  84. miR-30a-3p participates in the development of asthma by targeting CCR3
  85. microRNA-491-5p protects against atherosclerosis by targeting matrix metallopeptidase-9
  86. Bladder-embedded ectopic intrauterine device with calculus
  87. Case Report
  88. Mycobacterial identification on homogenised biopsy facilitates the early diagnosis and treatment of laryngeal tuberculosis
  89. Research Article
  90. The will of young minors in the terminal stage of sickness: A case report
  91. Extended perfusion protocol for MS lesion quantification
  92. Identification of four genes associated with cutaneous metastatic melanoma
  93. Case Report
  94. Thalidomide-induced serious RR interval prolongation (longest interval >5.0 s) in multiple myeloma patient with rectal cancer: A case report
  95. Research Article
  96. Voluntary exercise and cardiac remodeling in a myocardial infarction model
  97. Electromyography as an intraoperative test to assess the quality of nerve anastomosis – experimental study on rats
  98. Case Report
  99. CT findings of severe novel coronavirus disease (COVID-19): A case report of Heilongjiang Province, China
  100. Commentary
  101. Directed differentiation into insulin-producing cells using microRNA manipulation
  102. Research Article
  103. Culture-negative infective endocarditis (CNIE): impact on postoperative mortality
  104. Extracorporeal shock wave therapy for the treatment of chronic pelvic pain syndrome
  105. Plasma microRNAs in human left ventricular reverse remodelling
  106. Bevacizumab for non-small cell lung cancer patients with brain metastasis: A meta-analysis
  107. Risk factors for cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage
  108. Problems and solutions of personal protective equipment doffing in COVID-19
  109. Evaluation of COVID-19 based on ACE2 expression in normal and cancer patients
  110. Review Article
  111. Gastroenterological complications in kidney transplant patients
  112. Research Article
  113. CXCL13 concentration in latent syphilis patients with treatment failure
  114. A novel age-biomarker-clinical history prognostic index for heart failure with reduced left ventricular ejection fraction
  115. Case Report
  116. Clinicopathological analysis of composite lymphoma: A two-case report and literature review
  117. Trastuzumab-induced thrombocytopenia after eight cycles of trastuzumab treatment
  118. Research Article
  119. Inhibition of vitamin D analog eldecalcitol on hepatoma in vitro and in vivo
  120. CCTs as new biomarkers for the prognosis of head and neck squamous cancer
  121. Effect of glucagon-like peptide-1 receptor agonists on adipokine level of nonalcoholic fatty liver disease in rats fed high-fat diet
  122. 72 hour Holter monitoring, 7 day Holter monitoring, and 30 day intermittent patient-activated heart rhythm recording in detecting arrhythmias in cryptogenic stroke patients free from arrhythmia in a screening 24 h Holter
  123. FOXK2 downregulation suppresses EMT in hepatocellular carcinoma
  124. Case Report
  125. Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  126. Research Article
  127. Clinical prediction for outcomes of patients with acute-on-chronic liver failure associated with HBV infection: A new model establishment
  128. Case Report
  129. Combination of chest CT and clinical features for diagnosis of 2019 novel coronavirus pneumonia
  130. Research Article
  131. Clinical significance and potential mechanisms of miR-223-3p and miR-204-5p in squamous cell carcinoma of head and neck: a study based on TCGA and GEO
  132. Review Article
  133. Hemoperitoneum caused by spontaneous rupture of hepatocellular carcinoma in noncirrhotic liver. A case report and systematic review
  134. Research Article
  135. Voltage-dependent anion channels mediated apoptosis in refractory epilepsy
  136. Prognostic factors in stage I gastric cancer: A retrospective analysis
  137. Circulating irisin is linked to bone mineral density in geriatric Chinese men
  138. Case Report
  139. A family study of congenital dysfibrinogenemia caused by a novel mutation in the FGA gene: A case report
  140. Research Article
  141. CBCT for estimation of the cemento-enamel junction and crestal bone of anterior teeth
  142. Case Report
  143. Successful de-escalation antibiotic therapy using cephamycins for sepsis caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia: A sequential 25-case series
  144. Research Article
  145. Influence factors of extra-articular manifestations in rheumatoid arthritis
  146. Assessment of knowledge of use of electronic cigarette and its harmful effects among young adults
  147. Predictive factors of progression to severe COVID-19
  148. Procedural sedation and analgesia for percutaneous trans-hepatic biliary drainage: Randomized clinical trial for comparison of two different concepts
  149. Acute chemoradiotherapy toxicity in cervical cancer patients
  150. IGF-1 regulates the growth of fibroblasts and extracellular matrix deposition in pelvic organ prolapse
  151. NANOG regulates the proliferation of PCSCs via the TGF-β1/SMAD pathway
  152. An immune-relevant signature of nine genes as a prognostic biomarker in patients with gastric carcinoma
  153. Computer-aided diagnosis of skin cancer based on soft computing techniques
  154. MiR-1225-5p acts as tumor suppressor in glioblastoma via targeting FNDC3B
  155. miR-300/FA2H affects gastric cancer cell proliferation and apoptosis
  156. Hybrid treatment of fibroadipose vascular anomaly: A case report
  157. Surgical treatment for common hepatic aneurysm. Original one-step technique
  158. Neuropsychiatric symptoms, quality of life and caregivers’ burden in dementia
  159. Predictor of postoperative dyspnea for Pierre Robin Sequence infants
  160. Long non-coding RNA FOXD2-AS1 promotes cell proliferation, metastasis and EMT in glioma by sponging miR-506-5p
  161. Analysis of expression and prognosis of KLK7 in ovarian cancer
  162. Circular RNA circ_SETD2 represses breast cancer progression via modulating the miR-155-5p/SCUBE2 axis
  163. Glial cell induced neural differentiation of bone marrow stromal cells
  164. Case Report
  165. Moraxella lacunata infection accompanied by acute glomerulonephritis
  166. Research Article
  167. Diagnosis of complication in lung transplantation by TBLB + ROSE + mNGS
  168. Case Report
  169. Endometrial cancer in a renal transplant recipient: A case report
  170. Research Article
  171. Downregulation of lncRNA FGF12-AS2 suppresses the tumorigenesis of NSCLC via sponging miR-188-3p
  172. Case Report
  173. Splenic abscess caused by Streptococcus anginosus bacteremia secondary to urinary tract infection: a case report and literature review
  174. Research Article
  175. Advances in the role of miRNAs in the occurrence and development of osteosarcoma
  176. Rheumatoid arthritis increases the risk of pleural empyema
  177. Effect of miRNA-200b on the proliferation and apoptosis of cervical cancer cells by targeting RhoA
  178. LncRNA NEAT1 promotes gastric cancer progression via miR-1294/AKT1 axis
  179. Key pathways in prostate cancer with SPOP mutation identified by bioinformatic analysis
  180. Comparison of low-molecular-weight heparins in thromboprophylaxis of major orthopaedic surgery – randomized, prospective pilot study
  181. Case Report
  182. A case of SLE with COVID-19 and multiple infections
  183. Research Article
  184. Circular RNA hsa_circ_0007121 regulates proliferation, migration, invasion, and epithelial–mesenchymal transition of trophoblast cells by miR-182-5p/PGF axis in preeclampsia
  185. SRPX2 boosts pancreatic cancer chemoresistance by activating PI3K/AKT axis
  186. Case Report
  187. A case report of cervical pregnancy after in vitro fertilization complicated by tuberculosis and a literature review
  188. Review Article
  189. Serrated lesions of the colon and rectum: Emergent epidemiological data and molecular pathways
  190. Research Article
  191. Biological properties and therapeutic effects of plant-derived nanovesicles
  192. Case Report
  193. Clinical characterization of chromosome 5q21.1–21.3 microduplication: A case report
  194. Research Article
  195. Serum calcium levels correlates with coronary artery disease outcomes
  196. Rapunzel syndrome with cholangitis and pancreatitis – A rare case report
  197. Review Article
  198. A review of current progress in triple-negative breast cancer therapy
  199. Case Report
  200. Peritoneal-cutaneous fistula successfully treated at home: A case report and literature review
  201. Research Article
  202. Trim24 prompts tumor progression via inducing EMT in renal cell carcinoma
  203. Degradation of connexin 50 protein causes waterclefts in human lens
  204. GABRD promotes progression and predicts poor prognosis in colorectal cancer
  205. The lncRNA UBE2R2-AS1 suppresses cervical cancer cell growth in vitro
  206. LncRNA FOXD3-AS1/miR-135a-5p function in nasopharyngeal carcinoma cells
  207. MicroRNA-182-5p relieves murine allergic rhinitis via TLR4/NF-κB pathway
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