Publications by authors named "Xiaosheng Wang"

104 Publications

Identification of subtypes correlated with tumor immunity and immunotherapy in cutaneous melanoma.

Comput Struct Biotechnol J 2021 6;19:4472-4485. Epub 2021 Aug 6.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.

Because immune checkpoint inhibitors (ICIs) are effective for a subset of melanoma patients, identification of melanoma subtypes responsive to ICIs is crucial. We performed clustering analyses to identify immune subtypes of melanoma based on the enrichment levels of 28 immune cells using transcriptome datasets for six melanoma cohorts, including four cohorts not treated with ICIs and two cohorts treated with ICIs. We identified three immune subtypes (Im-H, Im-M, and Im-L), reproducible in these cohorts. Im-H displayed strong immune signatures, low stemness and proliferation potential, genomic stability, high immunotherapy response rate, and favorable prognosis. Im-L showed weak immune signatures, high stemness and proliferation potential, genomic instability, low immunotherapy response rate, and unfavorable prognosis. The pathways highly enriched in Im-H included immune, MAPK, apoptosis, calcium, VEGF, cell adhesion molecules, focal adhesion, gap junction, and PPAR. The pathways highly enriched in Im-L included Hippo, cell cycle, and ErbB. Copy number alterations correlated inversely with immune signatures in melanoma, while tumor mutation burden showed no significant correlation. The molecular features correlated with favorable immunotherapy response included immune-promoting signatures and pathways of PPAR, MAPK, VEGF, calcium, and glycolysis/gluconeogenesis. Our data recapture the immunological heterogeneity in melanoma and provide clinical implications for the immunotherapy of melanoma.
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http://dx.doi.org/10.1016/j.csbj.2021.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379294PMC
August 2021

Subtyping of head and neck squamous cell cancers based on immune signatures.

Int Immunopharmacol 2021 Oct 28;99:108007. Epub 2021 Jul 28.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

Although head and neck squamous cell cancer (HNSCC) is one of the cancer types in which immune checkpoint inhibitors (ICIs) has achieved a certain success, only a subset of HNSCC patients respond to ICIs. Thus, identification of HNSCC subtypes responsive to ICIs is crucial. Using hierarchical clustering, we identified three subtypes of HNSCC, termed Immunity-H, Immunity-M, and Immunity-L, based on the enrichment scores of 28 immune cells generated by the single-sample gene-set enrichment analysis of transcriptome data. We demonstrated that this subtyping method was stable and producible in four different HNSCC cohorts. Immunity-H had the highest levels of immune infiltrates and PD-L1 expression, lowest levels of stemness, intratumor heterogeneity and genomic instability, and favorable prognosis. In contrast, Immunity-L had the lowest levels of immune infiltrates and PD-L1 expression, highest levels of stemness, intratumor heterogeneity and genomic instability, and unfavorable prognosis. We found that somatic copy number alteration had a significant negative association with anti-tumor immunity in HNSCC, while tumor mutation burden showed no significant association. TP53, COL11A1, NSD1, and PKHD1L1 were more frequently mutated in Immunity-H versus Immunity-L, and their mutations were associated with increased immune signatures in HNSCC. Besides immune-related pathways, many stromal and oncogenic pathways were highly enriched in Immunity-H, including cell adhesion molecules, focal adhesion, ECM-receptor interaction, calcium signaling, MAPK signaling, apoptosis, VEGF signaling, and PPAR signaling. The high levels of PD-L1 expression and immune infiltration in Immunity-H indicate that this subtype responds best to ICIs. Our study recaptures the immunological heterogeneity in HNSCC and provide clinical implications for the immunotherapy of HNSCC.
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http://dx.doi.org/10.1016/j.intimp.2021.108007DOI Listing
October 2021

Factor structure and sex invariance of the temporal experience of pleasure scale (TEPS) in Chinese university students and clinical population.

BMC Psychiatry 2021 07 28;21(1):378. Epub 2021 Jul 28.

Medical Psychological Center, the Second Xiangya Hospital,Central South University, Changsha, 410011, China.

Background: A motivation dimension of the core psychiatric symptom anhedonia additional has been suggested. The Temporal Experience of Pleasure Scale (TEPS) has been reported to assess anticipatory and consummatory pleasure separately in multiple factor-structure models. This study explored the factor structure of a Chinese version of the 18-item TEPS and further explored the measurement invariance of the TEPS across sex and clinical status (non-clinical, psychiatric).

Methods: Best-fit factor structure of the TEPS was examined in a non-clinical cohort of 7410 undergraduates, randomized into sample 1 (N = 3755) for exploratory factor analysis (EFA) and sample 2 (N = 3663) for confirmatory factor analysis (CFA). Additionally, serial CFA was conducted to evaluate measurement invariance across sex and between clinical (N = 313) and non-clinical (N = 341) samples.

Results: EFA supported a new four-factor structure with a motivation component, based on the original two-factor model (consummatory pleasure with/without motivation drive, anticipatory pleasure with/without motivation drive). CFA confirmed the four-factor model as the best-fit structure and revealed a second-order hierarchy in non-clinical and clinical samples. Full scalar invariance was observed across clinical and non-clinical samples and across sex in the clinical sample; only partial scalar invariance was observed across sex in the non-clinical sample.

Conclusions: A four-factor structured TEPS can assess motivation-driving dimensions of anticipatory and consummatory pleasure, consistent with the recently advanced multidimensional structure of anhedonia. CFA and measurement invariance results support application of the TEPS for assessing motivation aspects of anhedonia.
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http://dx.doi.org/10.1186/s12888-021-03379-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317394PMC
July 2021

Pan-cancer analysis reveals that neurotrophin signaling correlates positively with anti-tumor immunity, clinical outcomes, and response to targeted therapies and immunotherapies in cancer.

Life Sci 2021 Oct 19;282:119848. Epub 2021 Jul 19.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

Aims: The crosstalk between cancer cells and nerves plays an important role in tumor biology. However, the correlation between the neurotrophin signaling (NS) and anti-tumor immunity and immunotherapy response in cancer remains unexplored.

Materials And Methods: We analyzed associations of NS with anti-tumor immune signatures, tumor immunity-related molecular and genomic features, and clinical features in 33 TCGA cancer types. We also explored the association between NS and the response to immune checkpoint inhibitors (ICIs) in four cancer cohorts.

Key Findings: NS scores had significant positive correlations with the enrichment scores of anti-tumor immune signatures, including CD8+ T cells, interferon response, natural killer cells, Toll-like receptor and NOD-like receptor signaling pathways in most cancer types. NS scores were inversely correlated with the scores of DNA damage repair pathways, tumor mutation burden, copy number alterations, intra-tumor heterogeneity, and tumor stemness in diverse cancers. In contrast, NS scores were significantly and positively correlated with the apoptosis pathway's scores in 32 of the 33 cancer types. NS scores were significantly lower in early-stage versus late-stage and in primary versus metastatic tumors in diverse cancers. Higher NS scores were correlated with better survival in pan-cancer and in eight individual cancer types. Moreover, the response rate to ICIs was higher in higher-NS-score than in lower-NS-score tumors in four cancer cohorts. Elevated NS was correlated with increased drug sensitivity for numerous anti-tumor targeted drugs.

Significance: NS is a positive biomarker for anti-tumor immune response, prognosis, and the response to targeted and immunotherapeutic drugs in cancer.
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http://dx.doi.org/10.1016/j.lfs.2021.119848DOI Listing
October 2021

Computational analysis of TMPRSS2 expression in normal and SARS-CoV-2-infected human tissues.

Chem Biol Interact 2021 Sep 17;346:109583. Epub 2021 Jul 17.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing, 211198, China. Electronic address:

The transmembrane serine protease 2 (TMPRSS2) is a key molecule for SARS-CoV-2 invading human host cells. To provide insights into SARS-CoV-2 infection of various human tissues and understand the potential mechanism of SARS-CoV-2 infection, we investigated TMPRSS2 expression in various normal human tissues and SARS-CoV-2-infected human tissues. Using publicly available datasets, we performed computational analyses of TMPRSS2 expression levels in 30 normal human tissues, and compared them between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) populations in these tissues. We found that TMPRSS2 expression levels were the highest in the prostate, stomach, pancreas, lungs, small intestine, and salivary gland. The TMPRSS2 protein had relatively high expression levels in the parathyroid gland, stomach, small intestine, pancreas, kidneys, seminal vesicle, epididymis, and prostate. However, TMPRSS2 expression levels were not significantly different between females and males or between younger and older populations in these tissues. The pathways enriched in TMPRSS2-upregulated pan-tissue were mainly involved in immune, metabolism, cell growth and proliferation, stromal signatures, and cancer and other diseases. Many cytokine genes displayed positive expression correlations with TMPRSS2 in pan-tissue, including TNF-α, IL-1, IL-2, IL-4, IL-7, IL-8, IL-12, IL-18, IFN-α, MCP-1, G-CSF, and IP-10. We further analyzed TMPRSS2 expression levels in nasopharyngeal swabs from SARS-CoV-2-infected patients. TMPRSS2 expression levels showed no significant difference between males and females or between younger and older patients. However, they were significantly lower in SARS-CoV-2-infected than in healthy individuals and patients with other viral acute respiratory illnesses. Interestingly, TMPRSS2 expression levels were positively correlated with the enrichment levels of four immune signatures (B cells, CD8 T cells, NK cells, and interferon response) in SARS-CoV-2-infected patients but likely to be negatively correlated with them in the normal lung tissue. Our data may provide insights into the mechanism of SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.cbi.2021.109583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285370PMC
September 2021

Predicting the development trend of the second wave of COVID-19 in five European countries.

J Med Virol 2021 10 23;93(10):5896-5907. Epub 2021 Jun 23.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

The second wave of COVID-19 has caused a dramatic increase in COVID-19 cases and deaths globally. An accurate prediction of its development trend is significant. We predicted the development trend of the second wave of COVID-19 in five European countries, including France, Germany, Italy, Spain, and the UK. We first built models to predict daily numbers of COVID-19 cases and deaths based on the data of the first wave of COVID-19 in these countries. Based on these models, we built new models to predict the development trend of the second wave of COVID-19. We predicted that the second wave of COVID-19 would have peaked around on November 16, 2020, January 10, 2021, December 1, 2020, March 1, 2021, and January 10, 2021, in France, Germany, Italy, Spain, and the UK, respectively. It will be basically under control on April 26, 2021, September 20, 2021, August 1, 2021, September 15, 2021, and August 10, 2021, in these countries, respectively. Their total number of COVID-19 cases will reach around 4,745,000, 7,890,000, 6,852,000, 8,071,000, and 10,198,000, respectively, and total number of COVID-19 deaths will be around 262,000, 262,000, 231,000, 253,000, and 350,000 during the second wave of COVID-19. The COVID-19 mortality rate in the second wave of COVID-19 is predicted to be about 3.4%, 3.5%, 3.4%, 3.4%, and 3.1% in France, Spain, Germany, France, and the UK. The second wave of COVID-19 is expected to cause many more cases and deaths, last for a much longer time, and have a lower COVID-19 mortality rate than the first wave.
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http://dx.doi.org/10.1002/jmv.27143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426755PMC
October 2021

DITHER: an algorithm for Defining IntraTumor Heterogeneity based on EntRopy.

Brief Bioinform 2021 Jun 7. Epub 2021 Jun 7.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.

Intratumor heterogeneity (ITH) is associated with tumor development, prognosis, immune evasion and therapeutic effects. We proposed the Defining ITH based on EntRopy (DITHER) algorithm for evaluating ITH. We first evaluated the entropies of somatic mutation profiles and copy number alteration (CNA) profiles in a tumor, respectively, and defined their average as the ITH level for the tumor. Using DITHER, we analyzed 33 cancer types from The Cancer Genome Atlas (TCGA) program. We demonstrated that the ITH defined by DITHER had the typical properties of ITH, namely its strong correlations with tumor progression, unfavorable phenotype, genomic instability and immune evasion. Compared with two other ITH evaluation methods: MATH and PhyloWGS, the DITHER ITH had more prominent characteristics of ITH. Moreover, different from MATH and PhyloWGS, DITHER scores were positively correlated with tumor purity, suggesting that DITHER tends to capture the ITH between tumor cells. Interestingly, microsatellite instability (MSI)-high tumors had significantly lower DITHER scores than microsatellite stability (MSS)/MSI-low tumors, although the former had significantly higher tumor mutation loads than the latter. It suggests that the hypermutability of MSI is homogeneous between different cellular populations in bulk tumors. The DITHER ITH may provide novel insights into tumor biology and potential clinical applications.
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http://dx.doi.org/10.1093/bib/bbab202DOI Listing
June 2021

Identification of gastric cancer subtypes based on pathway clustering.

NPJ Precis Oncol 2021 Jun 2;5(1):46. Epub 2021 Jun 2.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

Gastric cancer (GC) is highly heterogeneous in the stromal and immune microenvironment, genome instability (GI), and oncogenic signatures. However, a classification of GC by combining these features remains lacking. Using the consensus clustering algorithm, we clustered GCs based on the activities of 15 pathways associated with immune, DNA repair, oncogenic, and stromal signatures in three GC datasets. We identified three GC subtypes: immunity-deprived (ImD), stroma-enriched (StE), and immunity-enriched (ImE). ImD showed low immune infiltration, high DNA damage repair activity, high tumor aneuploidy level, high intratumor heterogeneity (ITH), and frequent TP53 mutations. StE displayed high stromal signatures, low DNA damage repair activity, genomic stability, low ITH, and poor prognosis. ImE had strong immune infiltration, high DNA damage repair activity, high tumor mutation burden, prevalence of microsatellite instability, frequent ARID1A mutations, elevated PD-L1 expression, and favorable prognosis. Based on the expression levels of four genes (TAP2, SERPINB5, LTBP1, and LAMC1) in immune, DNA repair, oncogenic, and stromal pathways, we developed a prognostic model (IDOScore). The IDOScore was an adverse prognostic factor and correlated inversely with immunotherapy response in cancer. Our identification of new GC subtypes provides novel insights into tumor biology and has potential clinical implications for the management of GCs.
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http://dx.doi.org/10.1038/s41698-021-00186-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172826PMC
June 2021

Identification of gastric cancer subtypes based on pathway clustering.

NPJ Precis Oncol 2021 Jun 2;5(1):46. Epub 2021 Jun 2.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

Gastric cancer (GC) is highly heterogeneous in the stromal and immune microenvironment, genome instability (GI), and oncogenic signatures. However, a classification of GC by combining these features remains lacking. Using the consensus clustering algorithm, we clustered GCs based on the activities of 15 pathways associated with immune, DNA repair, oncogenic, and stromal signatures in three GC datasets. We identified three GC subtypes: immunity-deprived (ImD), stroma-enriched (StE), and immunity-enriched (ImE). ImD showed low immune infiltration, high DNA damage repair activity, high tumor aneuploidy level, high intratumor heterogeneity (ITH), and frequent TP53 mutations. StE displayed high stromal signatures, low DNA damage repair activity, genomic stability, low ITH, and poor prognosis. ImE had strong immune infiltration, high DNA damage repair activity, high tumor mutation burden, prevalence of microsatellite instability, frequent ARID1A mutations, elevated PD-L1 expression, and favorable prognosis. Based on the expression levels of four genes (TAP2, SERPINB5, LTBP1, and LAMC1) in immune, DNA repair, oncogenic, and stromal pathways, we developed a prognostic model (IDOScore). The IDOScore was an adverse prognostic factor and correlated inversely with immunotherapy response in cancer. Our identification of new GC subtypes provides novel insights into tumor biology and has potential clinical implications for the management of GCs.
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http://dx.doi.org/10.1038/s41698-021-00186-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172826PMC
June 2021

Comparisons of the immunological landscape between COVID-19, influenza, and respiratory syncytial virus patients by clustering analysis.

Comput Struct Biotechnol J 2021 23;19:2347-2355. Epub 2021 Apr 23.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China.

Background: COVID-19 has stronger infectivity and a higher risk for severity than most other contagious respiratory illnesses. The mechanisms underlying this difference remain unclear.

Methods: We compared the immunological landscape between COVID-19 and two other contagious respiratory illnesses (influenza and respiratory syncytial virus (RSV)) by clustering analysis of the three diseases based on 27 immune signatures' scores.

Results: We identified three immune subtypes: Immunity-H, Immunity-M, and Immunity-L, which displayed high, medium, and low immune signatures, respectively. We found 20%, 35.5%, and 44.5% of COVID-19 cases included in Immunity-H, Immunity-M, and Immunity-L, respectively; all influenza cases were included in Immunity-H; 66.7% and 33.3% of RSV cases belonged to Immunity-H and Immunity-L, respectively. These data indicate that most COVID-19 patients have weaker immune signatures than influenza and RSV patients, as evidenced by 22 of the 27 immune signatures having lower enrichment scores in COVID-19 than in influenza and/or RSV. The Immunity-M COVID-19 patients had the highest expression levels of  and  and lowest viral loads and were the youngest. In contrast, the Immunity-H COVID-19 patients had the lowest expression levels of  and  and highest viral loads and were the oldest. Most immune signatures had lower enrichment levels in the intensive care unit (ICU) than in non-ICU patients. Gene ontology analysis showed that the innate and adaptive immune responses were significantly downregulated in COVID-19 versus healthy individuals.

Conclusions: Compared to influenza and RSV, COVID-19 displayed significantly different immunological profiles. Elevated immune signatures are associated with better prognosis in COVID-19 patients.
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http://dx.doi.org/10.1016/j.csbj.2021.04.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062909PMC
April 2021

Enhanced selectivity of the CO reverse water-gas reaction over a NiP/CeO catalyst.

Dalton Trans 2021 May 16;50(17):5978-5987. Epub 2021 Apr 16.

Department of Chemical Engineering, School of Petro-chemical and Energy Engineering, Zhejiang Ocean University, Zhoushan 316022, Zhejiang, People's Republic of China.

Ni catalysts tend to easily undergo methanation and metal sintering at high temperatures during the CO hydrogenation reaction. Herein, NiP, a typical kind of transition metal phosphide, had been demonstrated to be efficient for use in the reverse water gas (RWGS) reaction. Under weight hourly space velocity (WHSV) values of 150 000 and 300 000 mL g h, the NiP/CeO catalyst presented a high CO selectivity, better than that of the conventional Ni/CeO catalyst. The activity was also well maintained in a 20 h stability test. Detailed physicochemical characterization proved that the moderate adsorption strength of CO, as well as more strong adsorption active sites for H on the NiP/CeO surface, prevented the CO from further hydrogenating to CH, which accounted for the remarkable CO selectivity and stability of the CO RWGS reaction.
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http://dx.doi.org/10.1039/d1dt00424gDOI Listing
May 2021

Personality Inventory for DSM-5 in China: Evaluation of DSM-5 and ICD-11 Trait Structure and Continuity With Personality Disorder Types.

Front Psychiatry 2021 26;12:635214. Epub 2021 Mar 26.

Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, China.

The Personality Inventory for the DSM-5 (PID-5) is an established tool for assessing personality disorder (PD) traits that was developed based on section III of the DSM-5. It is composed of 220 items, organized into 25 facets, which are distributed among five domains. The psychometric properties of the Chinese version of the PID-5 remain to be demonstrated. Two samples were embodied in this study that included 3,550 undergraduates and 406 clinical patients. To probe the structure of the PID-5, parallel analyses were conducted to explore the unidimensionality of its 25 facets and a series of confirmatory factor analyses (CFAs) were carried out to confirm the 25 lower-order facets and their distribution among five higher-order domains. Then, the PID-5 was employed to measure the DSM-5 and ICD-11 trait models and to explore the relationship of DSM-IV categorical PDs with DSM-5 and ICD-11 personality traits. Correlation and regression analyses were conducted to probe how well DSM-IV categorical PDs correspond with maladaptive personality traits specified in the DSM-5 and five ICD-11 domains. The respective average internal reliability coefficients of the 25 facets obtained for undergraduate and clinical patient samples were 0.76 and 0.81, those obtained for the five DSM-5 domains were 0.89 and 0.91, and those obtained for the five ICD-11 domains were 0.87 and 0.89. Serial CFAs confirmed the rationality of the PID-5's lower-order 25-facet structure and higher-order five-domain structure in both samples. Correlation and regression analyses showed that DSM-5 specified traits explain the variance in PD presentation with a manifold stronger correlation ( = 0.24-0.44) than non-specified traits ( = 0.04-0.12). Overall, the PID-5 was shown to be a reliable, stable, and structurally valid assessment tool that captures pathological personality traits related to DSM-5 and ICD-11 PDs.
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http://dx.doi.org/10.3389/fpsyt.2021.635214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033014PMC
March 2021

Identification of COVID-19 subtypes based on immunogenomic profiling.

Int Immunopharmacol 2021 Jul 27;96:107615. Epub 2021 Mar 27.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

Although previous studies have shown that the host immune response is crucial in determining clinical outcomes in COVID-19 patients, the association between host immune signatures and COVID-19 patient outcomes remains unclear. Based on the enrichment levels of 11 immune signatures (eight immune-inciting and three immune-inhibiting signatures) in leukocytes of 100 COVID-19 patients, we identified three COVID-19 subtypes: Im-C1, Im-C2, and Im-C3, by clustering analysis. Im-C1 had the lowest immune-inciting signatures and high immune-inhibiting signatures. Im-C2 had medium immune-inciting signatures and high immune-inhibiting signatures. Im-C3 had the highest immune-inciting signatures while the lowest immune-inhibiting signatures. Im-C3 and Im-C1 displayed the best and worst clinical outcomes, respectively, suggesting that antiviral immune responses alleviated the severity of COVID-19 patients. We further demonstrated that the adaptive immune response had a stronger impact on COVID-19 outcomes than the innate immune response. The patients in Im-C3 were younger than those in Im-C1, indicating that younger persons have stronger antiviral immune responses than older persons. Nevertheless, we did not observe a significant association between sex and immune responses in COVID-19 patients. In addition, we found that the type II IFN response signature was an adverse prognostic factor for COVID-19. Our identification of COVID-19 immune subtypes has potential clinical implications for the management of COVID-19 patients.
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http://dx.doi.org/10.1016/j.intimp.2021.107615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023047PMC
July 2021

Evaluation of the Current Therapeutic Approaches for COVID-19: A Systematic Review and a Meta-analysis.

Front Pharmacol 2021 15;12:607408. Epub 2021 Mar 15.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

Limited data on the efficacy and safety of currently applied COVID-19 therapeutics and their impact on COVID-19 outcomes have raised additional concern. To estimate the efficacy and safety of COVID-19 therapeutics, we performed meta-analyses of the studies reporting clinical features and treatments of COVID-19 published from January 21 to September 6, 2020. We included 136 studies that involved 102,345 COVID-19 patients. The most prevalent treatments were antibiotics (proportion: 0.59, 95% CI: [0.51, 0.67]) and antivirals (proportion: 0.52, 95% CI: [0.44, 0.60]). The combination of lopinavir/ritonavir and Arbidol was the most effective in treating COVID-19 (standardized mean difference (SMD) = 0.68, 95% CI: [0.15, 1.21]). The use of corticosteroids was associated with a small clinical improvement (SMD = -0.40, 95% CI: [-0.85, -0.23]), but with a higher risk of disease progression and death (mortality: RR = 9.26, 95% CI: [4.81, 17.80]; hospitalization length: RR = 1.54, 95% CI: [1.39, 1.72]; severe adverse events: RR = 2.65, 95% CI: [2.09, 3.37]). The use of hydroxychloroquine was associated with a higher risk of death (RR = 1.68, 95% CI: [1.18, 2.38]). The combination of lopinavir/ritonavir, ribavirin, and interferon-β (RR = 0.34, 95% CI: [0.22, 0.54]); hydroxychloroquine (RR = 0.58, 95% CI: [0.39, 0.58]); and lopinavir/ritonavir (RR = 0.72, 95% CI: [0.56, 0.91]) was associated with reduced hospitalization length. Hydrocortisone (RR = 0.05, 95% CI: [0.03, 0.10]) and remdesivir (RR = 0.74, 95% CI: [0.62, 0.90]) were associated with lower incidence of severe adverse events. Dexamethasone was not significant in reducing disease progression (RR = 0.45, 95% CI: [0.16, 1.25]) and mortality (RR = 0.90, 95% CI: [0.70, 1.16]). The estimated combination of corticosteroids with antivirals was associated with a better clinical improvement than antivirals alone (SMD = -1.09, 95% CI: [-1.64, -0.53]). Antivirals are safe and effective in COVID-19 treatment. Remdesivir cannot significantly reduce COVID-19 mortality and hospitalization length, while it is associated with a lower incidence of severe adverse events. Corticosteroids could increase COVID-19 severity, but it could be beneficial when combined with antivirals. Our data are potentially valuable for the clinical treatment and management of COVID-19 patients.
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http://dx.doi.org/10.3389/fphar.2021.607408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005525PMC
March 2021

Personality inventory for DSM-5 brief form(PID-5-BF) in Chinese students and patients: evaluating the five-factor model and a culturally informed six-factor model.

BMC Psychiatry 2021 02 17;21(1):107. Epub 2021 Feb 17.

Medical Psychological Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.

Background: The Personality Inventory for DSM-5 Brief Form (PID-5-BF) is a 25-item measuring tool evaluating maladaptive personality traits for the diagnosis of personality disorders(PDs). As a promising scale, its impressive psychometric properties have been verified in some countries, however, there have been no studies about the utility of the PID-5-BF in Chinese settings. The current study aimed to explore the maladaptive personality factor model which was culturally adapted to China and to examine psychometric properties of the PID-5-BF among Chinese undergraduate students and clinical patients.

Methods: Seven thousand one hundred fifty-five undergraduate students and 451 clinical patients completed the Chinese version of the PID-5-BF. Two hundered twenty-eight students were chosen randomly for test-retest reliability at a 4-week interval. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted to discover the most suitable factor structure in China, measurement invariance(MI), internal consistency, and external validity were also calculated.

Results: The theoretical five-factor model was acceptable, but the exploratory six-factor model was more applicable in both samples (Undergraduate sample: CFI = 0.905, TLI = 0.888, RMSEA = 0.044, SRMR = 0.039; Clinical sample: CFI = 0.904, TLI = 0.886, RMSEA = 0.047, SRMR = 0.060). In the Chinese six-factor model, the Negative Affect domain was divided into two factors and the new factor was named "Interpersonal Relationships", which was in line with the Big-Six Personality model in Chinese. Measurement invariance across non-clinical and clinical sample was established (configural, weak, strong MI, and partial strict MI). Aside from acceptable internal consistency (Undergraduate sample: alpha = 0.84, MIC = 0.21; Clinical sample: alpha = 0.86, MIC = 0.19) and test-retest reliability(0.73), the correlation between the 25-item PID-5-BF and the 220-item PID-5 was significant(p < 0.01). The six PDs measured by Personality diagnostic questionnaire-4+ (PDQ-4+) were associated with and predicted by expected domains of PID-5-BF.

Conclusions: Both the theoretical five-factor model and the exploratory six-factor model of the PID-5-BF were acceptable to the Chinese population. The five-factor model could allow for comparison and integration with other work on the original theoretical model. However, the Chinese six-factor structure may be more culturally informed in East Asian settings. In sum, the PID-5-BF is a convenient and useful screening tool for personality disorders.
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http://dx.doi.org/10.1186/s12888-021-03080-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890813PMC
February 2021

Retrospective prediction of the epidemic trend of COVID-19 in Wuhan at four phases.

J Med Virol 2021 04 22;93(4):2493-2498. Epub 2021 Jan 22.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in December 2019 and was basically under control in April 2020 in Wuhan. To explore the impact of intervention measures on the COVID-19 epidemic, we established susceptible-exposed-infectious-recovered (SEIR) models to predict the epidemic characteristics of COVID-19 at four different phases (beginning, outbreak, recession, and plateau) from January 1st to March 30th, 2020. We found that the infection rate rapidly grew up to 0.3647 at Phase II from 0.1100 at Phase I and went down to 0.0600 and 0.0006 at Phase III and IV, respectively. The reproduction numbers of COVID-19 were 10.7843, 13.8144, 1.4815, and 0.0137 at Phase I, II, III, and IV, respectively. These results suggest that intensive interventions, including compulsory home isolation and rapid improvement of medical resources, can effectively reduce the COVID-19 transmission. Furthermore, the predicted COVID-19 epidemic trend by our models was close to the actual epidemic trend in Wuhan. Our phase-based SEIR models demonstrate that intensive intervention measures can effectively control COVID-19 spread even without specific medicines and vaccines against this disease.
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http://dx.doi.org/10.1002/jmv.26781DOI Listing
April 2021

Immunological classification of gliomas based on immunogenomic profiling.

J Neuroinflammation 2020 Nov 27;17(1):360. Epub 2020 Nov 27.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.

Background: Gliomas are heterogeneous in the tumor immune microenvironment (TIM). However, a classification of gliomas based on immunogenomic profiling remains lacking.

Methods: We hierarchically clustered gliomas based on the enrichment levels of 28 immune cells in the TIM in five datasets and obtained three clusters: immunity-high, immunity-medium, and immunity-low.

Results: Glioblastomas were mainly distributed in immunity-high and immunity-medium, while lower-grade gliomas were distributed in all the three subtypes and predominated in immunity-low. Immunity-low displayed a better survival than other subtypes, indicating a negative correlation between immune infiltration and survival prognosis in gliomas. IDH mutations had a negative correlation with glioma immunity. Immunity-high had higher tumor stemness and epithelial-mesenchymal transition scores and included more high-grade tumors than immunity-low, suggesting that elevated immunity is associated with tumor progression in gliomas. Immunity-high had higher tumor mutation burden and more frequent somatic copy number alterations, suggesting a positive association between tumor immunity and genomic instability in gliomas.

Conclusions: The identification of immune-specific glioma subtypes has potential clinical implications for the immunotherapy of gliomas.
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http://dx.doi.org/10.1186/s12974-020-02030-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694942PMC
November 2020

DBP-PSSM: Combination of evolutionary profiles with the XGBoost algorithm to improve the identification of DNA-binding proteins.

Comb Chem High Throughput Screen 2020 Nov 24. Epub 2020 Nov 24.

School of Mathematics and Physics Science and Engineering, Hebei University of Engineering, Handan 056038,. China.

Aim And Objective: Given the rapidly increasing number of molecular biology data available, computational methods of low complexity are necessary to infer protein structure, function, and evolution.

Method: In the work, we proposed a novel mthod, FermatS, which based on the global position information and local position representation from the curve and normalized moments of inertia, respectively, to extract features information of protein sequences. Furthermore, we use the generated features by FermatS method to analyze the similarity/dissimilarity of nine ND5 proteins and establish the prediction model of DNA-binding proteins based on logistic regression with 5-fold crossvalidation.

Results: In the similarity/dissimilarity analysis of nine ND5 proteins, the results are consistent with evolutionary theory. Moreover, this method can effectively predict the DNA-binding proteins in realistic situations.

Conclusion: The findings demonstrate that the proposed method is effective for comparing, recognizing and predicting protein sequences. The main code and datasets can download from https://github.com/GaoYa1122/FermatS.
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http://dx.doi.org/10.2174/1386207323999201124203531DOI Listing
November 2020

Factor Structure and Measurement Invariance of the Chinese version of the Snaith-Hamilton Pleasure Scale (SHAPS) in Non-clinical and Clinical populations.

J Affect Disord 2021 02 13;281:759-766. Epub 2020 Nov 13.

Medical Psychological Center, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China. Electronic address:

Background: Anhedonia, a key symptom of depression and schizophrenia, has emerged as a potential endophenotype. The aim of this study was to evaluate the psychometric properties of a Chinese version of the Snaith-Hamilton Pleasure Scale(SHAPS), a self-report anhedonia scale, in a non-clinical sample and clinical sample inclusive of major depressive disorder (MDD), schizophrenia, or a personality disorder.

Methods: A total of 4,722 undergraduate students and 352 clinical patients participated in this study. Internal consistency was assessed by calculating Cronbach's α and mean inter-item correlation (MIC) values. Test-retest reliability and convergent validity were assessed with Pearson r coefficients. The best fitting of six potential factor-structure models was determined by confirmatory factor analysis (CFA). Measurement invariance across genders and samples was determined by multi-group CFA.

Results: Internal consistency of the Chinese version of the SHAPS was acceptable in non-clinical (Cronbach's α = 0.90) and clinical (Cronbach's α = 0.91) samples. Four-week interval test-retest reliability was 0.60. Moreover, the Spanish four-factor structure had the best fit indexes in both samples. Scalar invariance was established across genders as well as across non-clinical sample and clinical sample. SHAPS was significantly related with the Temporal Experience of Pleasure Scale (TEPS) and Beck Depression Inventory (BDI).

Limitations: There was a restricted scope of convergent validity and the size of clinical sample is relatively small, psychometric properties in elderly sample is also required.

Conclusion: The Chinese version of the SHAPS is a reliable, effective, simple and convenient tool for assessing and screening for anhedonia.
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http://dx.doi.org/10.1016/j.jad.2020.11.068DOI Listing
February 2021

FermatS: A Novel Numerical Representation for Protein Sequence Comparison and DNA-binding Protein Identification.

Comb Chem High Throughput Screen 2021 ;24(10):1746-1753

School of Mathematics and Physics Science and Engineering, Hebei University of Engineering, Handan 056038, China.

Aims: Based on protein sequence information, a simple and effective method was used to analyze protein sequence similarity and predict DNA-binding protein.

Background: It is absolutely necessary that we generate computational methods of low complexity to accurate infer protein structure, function, and evolution in the rapidly growing number of molecular biology data available.

Objective: It is important to generate novel computational algorithms for analyzing and comparing protein sequences with the rapidly growing number of molecular biology data available.

Methods: Based on global and local position representation with the curves of Fermat spiral and normalized moments of inertia of the curve of Fermat spiral, respectively, moreover, composition of 20 amino acids to get the numerical characteristics of protein sequences.

Results: It has been applied to analyze the similarity/dissimilarity of nine ND5 proteins, the analysis results are consistent with the biological evolution theory. Furthermore, we employ the Logistic regression with 5-fold cross-validation to establish the prediction of DNA-binding proteins model, which outperformed the DNAbinder, iDNA-prot, DNA-prot and gDNA-prot by 0.0069-0.609 in terms of F-measure, 0.293-0.898 in terms of MCC in unbalanced dataset.

Conclusion: These results show that our method, namely FermatS, is effective to compare, recognition and prediction the protein sequences.
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http://dx.doi.org/10.2174/1386207323999201117111738DOI Listing
January 2021

Identifying Pathways and Networks Associated With the SARS-CoV-2 Cell Receptor ACE2 Based on Gene Expression Profiles in Normal and SARS-CoV-2-Infected Human Tissues.

Front Mol Biosci 2020 16;7:568954. Epub 2020 Oct 16.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

Because ACE2 is a host cell receptor of the SARS-CoV-2, an investigation of expression in normal and virus-infected human tissues is crucial for understanding the mechanism of SARS-CoV-2 infection. We identified pathways associated with expression and gene co-expression networks of in pan-tissue based on the gene expression profiles in normal human tissues. We found that the pathways significantly associated with upregulation were mainly involved in immune, stromal signature, metabolism, cell growth and proliferation, and cancer and other diseases. The number of genes having a significant positive expression correlation with in females far exceeded that in males. The estrogen receptors (ESR1 and ESR2) and androgen receptor (AR) genes had a significant positive expression correlation with . Meanwhile, the enrichment levels of immune cells were positively associated with the expression levels of and , while they were inversely associated with the expression levels of in pan-tissue and multiple individual tissues. It suggests that females are likely to have a more robust immune defense system against SARS-CoV-2 than males. was upregulated in SARS-CoV-2-infected tissues relative to normal tissues and in SARS-CoV-2-infected males relative to females, while its expression levels had no significant difference between healthy females and males. Numerous immune-related pathways were highly enriched in SARS-CoV-2-infected males relative to females. These data indicate that males are more susceptible and more likely to have an excessive immune response to SARS-CoV-2 infection than females. This study furnishes potentially cues explaining why females have better clinical outcomes of SARS-CoV-2 infections than males and warrant further investigation for understanding the mechanism of SARS-CoV-2 infection.
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http://dx.doi.org/10.3389/fmolb.2020.568954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597396PMC
October 2020

A novel construct of anhedonia revealed in a Chinese sample via the Revised Physical and Social Anhedonia Scales.

BMC Psychiatry 2020 11 9;20(1):529. Epub 2020 Nov 9.

Medical Psychological Center, the Second Xiangya Hospital, Central South University, Changsha, 410011, China.

Background: Anhedonia is a core clinical symptom of mental disorders. The Revised Physical Anhedonia Scale (RPAS) and the Revised Social Anhedonia Scale (RSAS) have been applied in clinical and non-clinical samples since 1980s. However, the construct of a unified RPAS&RSAS for comprehensive measurement of anhedonia has never been explored. Therefore, the purpose of our study was to examine the factor structure of the unified RPAS&RSAS among undergraduates and clinical patients.

Methods: A total of 3435 undergraduates from two universities and 294 clinical patients with mental disorders had completed the Chinese version of the RPAS and the RSAS. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were each conducted to reveal the constructs of the RPAS and the RSAS. CFA was used to evaluate first- and second-order models for the unified RPAS&RSAS in undergraduates and clinical patients. The internal consistency and test-retest reliability of the RPAS and the RSAS were also evaluated.

Results: EFA and CFA indicated 2-factor structures for RPAS and RSAS, with the factors being defined as anticipatory anhedonia and consummatory anhedonia. The second-order model of the unified RPAS&RSAS in the undergraduates and clinical patients both had satisfactory fit index values (Undergraduate sample: CFI = 0.901, TLI = 0.899, RMSEA = 0.055, SRMR = 0.086; Clinical sample: CFI = 0.922, TLI = 0.911, RMSEA = 0.052, SRMR = 0.078). The psychometric robustness of the RPAS&RSAS were confirmed by high internal consistency and test-retest reliability values.

Conclusions: The unified RPAS&RSAS with a second-order structure was confirmed in both undergraduates and clinical samples in Chinese. The construct of anhedonia was refreshed as covering physical and social domains, and each of them includes both anticipatory and consummatory components.
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http://dx.doi.org/10.1186/s12888-020-02900-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650163PMC
November 2020

The landscape of long non-coding RNAs in tumor stroma.

Life Sci 2021 Jan 6;264:118725. Epub 2020 Nov 6.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

Aims: Long non-coding RNAs (lncRNAs) are associated with cancer development, while their relationship with the cancer-associated stromal components remains poorly understood. In this review, we performed a broad description of the functional landscape of stroma-associated lncRNAs in various cancers and their roles in regulating the tumor-stroma crosstalk.

Materials And Methods: We carried out a systematic literature review of PubMed, Scopus, Medline, Bentham, and EMBASE (Elsevier) databases by using the keywords "LncRNAs in cancer," "LncRNAs in tumor stroma," "stroma," "cancer-associated stroma," "stroma in the tumor microenvironment," "tumor-stroma crosstalk," "drug resistance of stroma," and "stroma in immunosuppression" till July 2020. We collected the latest articles addressing the biological functions of stroma-associated lncRNAs in cancer.

Key Findings: These articles reported that dysregulated stroma-associated lncRNAs play significant roles in modulating the tumor microenvironment (TME) by the regulation of tumor-stroma crosstalk, epithelial to mesenchymal transition (EMT), endothelial to mesenchymal transition (EndMT), extracellular matrix (ECM) turnover, and tumor immunity.

Significance: The tumor stroma is a substantial portion of the TME, and the dysregulation of tumor stroma-associated lncRNAs significantly contributes to cancer initiation, progression, angiogenesis, immune evasion, metastasis, and drug resistance. Thus, stroma-associated lncRNAs could be potentially useful targets for cancer therapy.
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http://dx.doi.org/10.1016/j.lfs.2020.118725DOI Listing
January 2021

Identification of molecular features correlating with tumor immunity in gastric cancer by multi-omics data analysis.

Ann Transl Med 2020 Sep;8(17):1050

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

Background: Although immunotherapy has achieved success in treating various refractory malignancies including gastric cancers (GCs) with DNA mismatch repair deficiency, only a subset of cancer patients are responsive to immunotherapy. Therefore, the identification of useful biomarkers or interventional targets for improving cancer immunotherapy response is urgently needed.

Methods: We investigated the associations between various molecular features and immune signatures using three multi-omics GC datasets. These molecular features included genes, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), proteins, and pathways, and the immune signatures included CD8+ T cell infiltration, immune cytolytic activity (ICA), and expression. Moreover, we investigated the association between gene mutations and survival prognosis in a gastrointestinal (GI) cancer cohort receiving immunotherapy and two GC cohorts not receiving such a therapy.

Results: The mutations of some important oncogenes and tumor suppressor genes were appreciably associated with immune signatures in GC, including , , , , , , , and . Moreover, a number of genes exhibited a significant expression correlation with immune signatures in GC, including , , , , , , , , , and . We identified several proteins whose expression had a significant positive correlation with immune signatures in GC. These proteins included caspase-7, PI3K-p85, PREX1, Lck, Bcl-2, and transglutaminase. In contrast, acetyl-CoA carboxylase (ACC) had a significant inverse expression correlation with immune signatures in GC, suggesting that inhibiting ACC could enhance antitumor immunity in GC. Furthermore, we identified numerous miRNAs and lncRNAs with a significant expression correlation with GC immunity, including hsa-miR-150, 155, 142, 342, 146, 101, 511, 29, AC022706.1, LINC01871, and AC006033.2. We also identified numerous cancer-associated pathways whose activity was associated with GC immunity, including mTOR, PI3K-AKT, MAPK, HIF-1, and VEGF signaling pathways. Interestingly, we found seven genes (, , , , , , and ) whose mutations were associated with better OS in GI cancer patients receiving anti-PD-1/PD-L1 immunotherapy but were not associated with OS in GC patients without immunotherapy.

Conclusions: The molecular features significantly associated with GC immunity could be useful biomarkers for stratifying GC patients responsive to immunotherapy or intervention targets for promoting antitumor immunity and immunotherapy response in GC.
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http://dx.doi.org/10.21037/atm-20-922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575957PMC
September 2020

Identifying novel factors associated with COVID-19 transmission and fatality using the machine learning approach.

Sci Total Environ 2021 Apr 13;764:142810. Epub 2020 Oct 13.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

The COVID-19 virus has infected more than 38 million people and resulted in more than one million deaths worldwide as of October 14, 2020. By using the logistic regression model, we identified novel critical factors associated with COVID19 cases, death, and case fatality rates in 154 countries and in the 50 U.S. states. Among numerous factors associated with COVID-19 risk, economic inequality enhanced the risk of COVID-19 transmission. The per capita hospital beds correlated negatively with COVID-19 deaths. Blood types B and AB were protective factors for COVID-19 risk, while blood type A was a risk factor. The prevalence of HIV and influenza and pneumonia was associated with reduced COVID-19 risk. Increased intake of vegetables, edible oil, protein, vitamin D, and vitamin K was associated with reduced COVID-19 risk, while increased intake of alcohol was associated with increased COVID-19 risk. Other factors included age, sex, temperature, humidity, social distancing, smoking, health investment, urbanization level, and race. High temperature is a more compelling factor mitigating COVID-19 transmission than low temperature. Our comprehensive identification of the factors affecting COVID-19 transmission and fatality may provide new insights into the COVID-19 pandemic and advise effective strategies for preventing and migrating COVID-19 spread.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550892PMC
April 2021

Classification of gastric cancers based on immunogenomic profiling.

Transl Oncol 2021 Jan 20;14(1):100888. Epub 2020 Oct 20.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China. Electronic address:

Background: Extensive evidence showed that gastric cancer (GC) is heterogeneous, and many studies have been focused on identifying GC subtypes based on genomic profiles. However, few studies have specifically explored the GC classification and predicted the classification accuracy that may help facilitate the optimal stratification of GC patients responsive to immunotherapy.

Methods: Using two publicly available GC genomics datasets, we classified GC on the basis of 797 immune related genes. Unsupervised and supervised machine learning methods were used to predict the classification.

Results: We identified two GC subtypes that we named as Immunity-High (IM-H) and Immunity- Low (IM-L), and demonstrated that this classification was duplicable and predictable by analyzing other datasets. IM-H subtype was characterized by greater immune cell infiltration, stronger immune activities, lower tumor purity, as well as worse survival prognosis compared to IM-L subtype. Besides the immune signatures, some cancer-associated pathways were hyperactivated in IM-H, including TGF-beta signaling pathway, Focal adhesion, Cell adhesion molecules (CAMs), Calcium signaling pathway, mTOR signaling pathway, MAPK signaling pathway and Wnt signaling pathway. In contrast, IM-L presented depressed immune signatures and increased activation of base excision repair, DNA replication, homologous recombination, non-homologous end-joining and nucleotide excision repair pathways. Furthermore, we identified subtype-specific genomic or clinical features, and subtype-specific gene ontology and networks in IM-H and IM-L subtype.

Conclusions: We proposed and validated two reproducible immune molecular subtypes of GC, which has potential clinical implications for GC patient selection of immunotherapy.
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http://dx.doi.org/10.1016/j.tranon.2020.100888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576512PMC
January 2021

mutations promote antitumor immunity and immunotherapy response in cancer.

J Immunother Cancer 2020 10;8(2)

Biomedical Informatics Research Lab,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China

Background: kalirin RhoGEF kinase () is mutated in a wide range of cancers. Nevertheless, the association between mutations and the pathogenesis of cancer remains unexplored. Identification of biomarkers for cancer immunotherapy response is crucial because immunotherapies only show beneficial effects in a subset of patients with cancer.

Methods: We explored the correlation between mutations and antitumor immunity in 10 cancer cohorts from The Cancer Genome Atlas program by the bioinformatics approach. Moreover, we verified the findings from the bioinformatics analysis with in vitro and in vivo experiments. We explored the correlation between mutations and immunotherapy response in five cancer cohorts receiving immune checkpoint blockade therapy.

Results: Antitumor immune signatures were more enriched in -mutated than -wildtype cancers. Moreover, mutations displayed significant correlations with increased tumor mutation burden and the microsatellite instability or DNA damage repair deficiency genomic properties, which may explain the high antitumor immunity in -mutated cancers. Also, programmed cell death 1 ligand (PD-L1) expression was markedly upregulated in -mutated versus -wildtype cancers. The increased antitumor immune signatures and PD-L1 expression in -mutated cancers may favor the response to immune checkpoint blockade therapy in this cancer subtype, as evidenced in five cancer cohorts receiving antiprogrammed cell death protein 1 (PD-1)/PD-L1/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy. Furthermore, the significant association between mutations and increased antitumor immunity was associated with the fact that mutations compromised the function of KALRN in targeting Rho GTPases for the regulation of DNA damage repair pathways. In vitro and in vivo experiments validated the association of KALRN deficiency with antitumor immunity and the response to immune checkpoint inhibitors.

Conclusions: The mutation is a useful biomarker for predicting the response to immunotherapy in patients with cancer.
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http://dx.doi.org/10.1136/jitc-2019-000293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549479PMC
October 2020

Recent advances targeting C-C chemokine receptor type 2 for liver diseases in monocyte/macrophage.

Liver Int 2020 12 21;40(12):2928-2936. Epub 2020 Oct 21.

State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

Liver plays a critical role in metabolism, nutrient storage and detoxification. Emergency signals or appropriate immune response leads to pathological inflammation and breaks the steady state when liver dysfunction appears, which makes body more susceptible to chronic liver infection, autoimmune diseases and tumour. Compelling proof has illustrated the non-redundant importance of C-C chemokine receptor type 2 (CCR2), one of G-protein-coupled receptors, in different diseases. Selectively expressed on the surface of cells, CCR2 is involved in various signalling pathways and regulates the migration of cells. Especially, a peculiar role of CCR2 has been identified within decades in the onset and progression of hepatic diseases, which led to particular focusing on CCR2 as a new therapeutic and diagnostic target for non-alcoholic fatty liver disease and hepatocellular carcinoma. In this review, we discuss the effect of CCR2 in monocytes/macrophages on liver diseases. The application and translation of the decades of discoveries into therapies promise novel approaches in the treatment of liver disease.
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http://dx.doi.org/10.1111/liv.14687DOI Listing
December 2020

Comparative Review of SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza A Respiratory Viruses.

Front Immunol 2020 11;11:552909. Epub 2020 Sep 11.

Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

The 2019 novel coronavirus (SARS-CoV-2) pandemic has caused a global health emergency. The outbreak of this virus has raised a number of questions: What is SARS-CoV-2? How transmissible is SARS-CoV-2? How severely affected are patients infected with SARS-CoV-2? What are the risk factors for viral infection? What are the differences between this novel coronavirus and other coronaviruses? To answer these questions, we performed a comparative study of four pathogenic viruses that primarily attack the respiratory system and may cause death, namely, SARS-CoV-2, severe acute respiratory syndrome (SARS-CoV), Middle East respiratory syndrome (MERS-CoV), and influenza A viruses (H1N1 and H3N2 strains). This comparative study provides a critical evaluation of the origin, genomic features, transmission, and pathogenicity of these viruses. Because the coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 is ongoing, this evaluation may inform public health administrators and medical experts to aid in curbing the pandemic's progression.
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http://dx.doi.org/10.3389/fimmu.2020.552909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516028PMC
October 2020

Oroxylin A reverses hypoxia-induced cisplatin resistance through inhibiting HIF-1α mediated XPC transcription.

Oncogene 2020 11 25;39(45):6893-6905. Epub 2020 Sep 25.

State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.

Hypoxia is a key concern during the treatment of non-small cell lung cancer (NSCLC), and hypoxia-inducible factor 1 alpha (HIF-1α) has been associated with increased tumor resistance to therapeutic modalities such as cisplatin. Compensatory activation of nucleotide excision repair (NER) pathway is the major mechanism that accounts for cisplatin resistance. In the present study, we suggest a novel strategy to improve the treatment of NSCLC and overcome the hypoxia-induced cisplatin resistance by cotreatment with Oroxylin A, one of the main bioactive flavonoids of Scutellariae radix. Based on the preliminary screening, we found that xeroderma pigmentosum group C (XPC), an important DNA damage recognition protein involved in NER, dramatically increased in hypoxic condition and contributed to hypoxia-induced cisplatin resistance. Further data suggested that Oroxylin A significantly reversed the hypoxia-induced cisplatin resistance through directly binding to HIF-1α bHLH-PAS domain and blocking its binding to HRE3 transcription factor binding sites on XPC promoter which is important to hypoxia-induced XPC transcription. Taken together, our findings not only demonstrate a crucial role of XPC dependent NER in hypoxia-induced cisplatin resistance, but also suggest a previously unrecognized tumor suppressive mechanism of Oroxylin A in NSCLC which through sensitization of cisplatin-mediated growth inhibition and apoptosis under hypoxia.
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http://dx.doi.org/10.1038/s41388-020-01474-xDOI Listing
November 2020
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