A novel plasma proteomic-based model for predicting liver fibrosis in HIV/HBV co-infected adults.

To establish a plasma model to predict the risk of liver fibrosis in HIV/HBV co-infected individuals. Quantitative liquid chromatography-tandem mass spectrometry(LC-MS/MS) was used to identify differentially expressed proteins (DEPs) in plasma collected from HIV/HBV co-infected individuals with and without liver fibrosis. In total, 97 DEPs were identified, among which 11 were further validated as potential biomarkers, with immunoglobulin and complement components being the most common proteins. These markedly altered proteins were found to mediate pathophysiological pathways, including humoral immune response, complement and coagulation cascades, and complement activation. A visual logistic model, in which immunoglobulin heavy variable 3-20 (IGHV3-20), immunoglobulin heavy variable 1-24 (IGHV1-24), and macrophage colony-stimulating factor 1 receptor (CSF1R) proteins were included, has been established to predict liver fibrosis in HIV/HBV co-infected individuals. The preliminary conclusion showed that the combination of IGHV3-20, IGFHV1-24, and CSF1R is expected to become a predictive model for liver fibrosis in the context of HIV/HBV co-infection and a further validation should be performed.

Plasma proteomic analysis reveals altered protein abundances in HIV-infected patients with or without non-Hodgkin lymphoma.

The identification of circulating proteins associated with acquired immunodeficiency syndrome-related non-Hodgkin lymphoma (AIDS-NHL) may help in the development of promising biomarkers for screening, diagnosis, treatment, and prognosis. Here, we used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins (DEPs) in plasma collected from patients with AIDS-NHL and human immunodeficiency virus (HIV)-infected patients without NHL (HIV+ ). Proteins with a log2 (fold change) in abundance >0.26 and p < 0.05 were considered differentially abundant. In total, 84 DEPs were identified, among which 20 were further validated as potential biomarkers, with immunoglobulin and complement components being the most common proteins. Some of the proteins were further verified in a retrospective analysis of the medical records of patients in a larger cohort. These markedly altered proteins were found to mediate pathophysiological pathways that likely contribute to AIDS-NHL pathogenesis, such as the humoral immune response, complement activation, and complement and coagulation cascades. Our findings provide a new molecular understanding of AIDS-NHL pathogenesis and provide new evidence supporting the identification of these proteins as possible biomarkers in AIDS-NHL.

Analysis of melanoma tumor antigens and immune subtypes for the development of mRNA vaccine.

Melanoma has a high degree of malignancy and mortality. While there are some hopeful clinical trials for melanoma treatment in progress, they have not yet to yield significant long-term cure rates. Cancer vaccines including mRNA are currently one of the most promising strategy for tumor immunotherapy. The aim of this study was to analyze the potential tumor antigens in melanoma that could be used to develop mRNA vaccines and identify suitable vaccine populations. The gene expression data and complete clinical information of 471 melanoma samples and 1 normal tissue were retrieved from TCGA. Then, 812 samples of normal skin and their corresponding gene expression data were obtained from GTEx. Overexpressed genes, mutated genes and IRDEGs are used to identify potential tumor antigens. The relationship between the expression level of potential antigen and prognosis was analyzed in GEPIA, and then the immune cell infiltration was estimated based on TIMER algorithm. The expression profiles of IRDEGs were used to identify consensus clusters and immune subtypes of melanoma. Finally, mutational status and immune microenvironment characterization in immune subtypes were analyzed. Five tumor antigens (PTPRC, SIGLEC10, CARD11, LILRB1, ADAMDEC1) were identified as potential tumor antigens according to overexpressed genes, mutated genes and immune-related genes. They were all associated with OS, DFS and APCs. We identified two immune subtypes of melanoma, named IS1 and IS2, which exhibit different clinical features and immune landscapes. Based on the different immune landscape, we may conclude that IS1 is immunophenotypically "cold", while IS2 is "hot". The present research implicates that PTPRC, SIGLEC10, CARD11, LILRB1 and ADAMDEC1 may be the antigenic targets for melanoma mRNA vaccines and IS2 patients may be more effective to these vaccines.

Combination antiretroviral therapy is associated with reduction in liver fibrosis scores in patients with HIV and HBV co-infection.

BACKGROUND: Liver fibrosis is common in individuals with HIV/HBV co-infection, but whether cART could reverses liver fibrosis is unclear. METHODS: This was a retrospective observational study. Binary logistic regression was used to assess predictors of liver fibrosis in individuals with HIV/HBV co-infection. Comparison of FIB-4 scores before and after cART were compared using X2 test and t test. RESULTS: Four hundred and fifty-eight individuals with HIV/HBV co-infection were included in this study. It was found that cART (HR 0.016, 95% CI: 0.009-0.136; P < 0.001) was one of protection factors to against liver fibrosis. Forty individuals who had normal levels of ALT, AST and PLT during the whole course of diseases were stratified into FIB-4 < 1.45 (n = 14), 1.45 ≤ FIB-4 ≤ 3.25 (n = 19) and FIB-4 > 3.25 (n = 7) groups by their FIB-4 scores before cART. In 1.45 ≤ FIB-4 ≤ 3.25 group, 57.9%(11/19) of the individuals dropped to FIB-4 < 1.45 group by cART; in FIB-4 > 3.25 group, 85.7%(6/79) dropped to 1.45 ≤ FIB-4 ≤ 3.25 group, while 14.3%(1/7) dropped to FIB-4 < 1.45 group. In cART-naive group, 1 year, 2-5 years and 5-10 years post-cART groups, FIB-4 scores were 4.29 ± 0.43, 3.63 ± 0.38, 2.90 ± 0.36 and 2.52 ± 0.38, respectively (P = 0.034); and the incidence of liver fibrosis were 7.38%(104/141), 63.6%(98/154), 60.8%(62/102) and 47.5%(29/61), respectively (P = 0.004). CONCLUSION: cART was associated with decreased FIB-4 scores and the benefit of cART in reversing liver fibrosis can sustain for a decade in patients with HIV/HBV co-infection.

Long-term observation on hepatitis B surface antigen seroclearance in therapy experienced HIV/HBV co-infected Chinese.

The aim of this retrospective study was to observe hepatitis B surface antigen (HBsAg) seroclearance and explore predictors of HBsAg loss in HIV/HBV-co-infected patients receiving long-term lamivudine or both tenofovir and lamivudine containing therapies. Quantification of HBsAg, hepatitis B e antigen and HBV DNA before and after initiation of HBV-active antiretroviral therapy in a total of 268 HIV/HBV-co-infected patients started treatment between 2005 and 2017 were performed. Over a median of 65.63 months of follow-up, 10 (3.7%) were observed HBsAg loss and the quantification of HBsAg in 7 (2.6%) patients were less than 50 IU/mL. With the prolongation of antiretroviral therapy duration time, the rates of HBsAg seroclearance tended to increase gradually, rising from 1.8% (3/163) during 2-4 years treatment to 29.4% (10/34) after antiretroviral therapy for up to 10 years. Lower baseline qHBsAg and HBV DNA levels and strong 12-month declines in qHBsAg were significantly associated with HBsAg seroclearance. The event of HBsAg seroclearance is uncommon among Chinese individuals with HIV/HBV co-infection who have been treated with anti-HBV containing antiretroviral therapy, and lifelong therapy for HBV is needed for HIV/HBV co-infected patients. Baseline qHBsAg and HBV DNA levels and qHBsAg decline rate were predictors for HBsAg seroclearance.

The role of methylprednisolone on preventing disease progression for hospitalized patients with severe COVID-19.

BACKGROUND: COVID-19 is a public health emergency that is spreading worldwide and seriously affecting the global economy. Data on the effectiveness and safety of the use of methylprednisolone for patients with severe COVID-19 remain limited. METHODS: In this retrospective study, epidemiological, clinical, laboratory, treatment and outcomes data of hospitalized patients with severe COVID-19 in Zhongnan Hospital of Wuhan University from January 1 to 7 March 2020, were collected. Binary logistic regression model was used to analyse risk factors for disease progression from severe COVID-19 illness to critical illness. The effectiveness and safety of the use of methylprednisolone for patients with severe COVID-19 disease were evaluated. RESULTS: The results of the multivariate analysis from 175 patients with severe COVID-19 indicate that the use of methylprednisolone was a protective factor against disease progression from severe to critical illness(P < .001; OR: 0.054 95% CI: 0.017-0.173). Among patients with severe COVID-19 aged < 65 years, both the proportion of patients who progressed to critical illness (42.2% vs 90.0%, P = .000) and the mortality(6.7% vs 30.0%, P = .002) were lower for patients in methylprednisolone group, compared with those in the non-methylprednisolone group, whereas no statistical differences between the methylprednisolone group and the non-methylprednisolone group were found among patients with COVID-19 older than 65 years. Moreover, both the levels of CD4+ T lymphocyte counts (646 vs 463/µL, P = .007) and IL-6 (241.9 vs 82.8 pg/mL, P = .025) were higher among patients with severe COVID-19 aged < 65 years, compared with those patients ≥ 65 years old. CONCLUSION: Data from the limited sample showed that the early use of low or medium doses of methylprednisolone has a positive effect for patients with severe COVID-19 younger than 65 years old, and excessive immune response and cytokine storm may be some of the reasons for the effectiveness.

Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms underlying lung cancer development have not been fully understood. The functions of histone deacetylases (HDACs), a class of total eighteen proteins (HDAC1-11 and SIRT1-7 in mammals) that deacetylate histones and non-histone proteins, in cancers are largely unknown. METHODS: Hdac7 +/-/K-Ras mice and HDAC7-depleted human lung cancer cell lines were used as models for studying the function of Hdac7 gene in lung cancer. Kaplan-Meier survival analysis was performed to explore the relationship between HDAC7 expression and prognosis of human lung cancers. Recombinant lentivirus-mediated in vivo gene expression or knockdown, Western blotting, and pull-down assay were applied to investigate the underlying molecular mechanism by which Hdac7 promotes lung tumorigenesis. RESULTS: The number and burden of lung tumor were dramatically reduced in Hdac7 +/-/K-Ras mice compared to control K-Ras mice. Also, in Hdac7 +/-/K-Ras mice, cell proliferation was significantly inhibited and apoptosis in lung tumors was greatly enhanced. Similarly, cell proliferation and anchorage-independent growth of human lung cancer cell lines expressing shHDAC7 were also significantly suppressed and apoptosis was dramatically elevated respectively. Mechanistic study revealed that Hdac7 mutation in mouse lung tumors or HDAC7 depletion in human tumor cell lines resulted in significantly enhanced acetylation and tyrosine-phosphorylation of Stat3 and HDAC7 protein directly interacted with and deacetylateed STAT3. The Hdac7 mutant-mediated inhibitory effects on lung tumorigenesis in mice and cell proliferation/soft agar colony formation of human lung cancer cell lines were respectively reversed by expressing dnStat3. Finally, the high HDAC7 mRNA level was found to be correlated with poor prognosis of human lung cancer patients. CONCLUSION: Our study suggests that Hdac7 promotes lung tumorigenesis by inhibiting Stat3 activation via deacetylating Stat3 and may shed a light on the design of new therapeutic strategies for human lung cancer.

Bioinformatics analysis highlights CCNB1 as a potential prognostic biomarker and an anti-kidney renal papillary cell carcinoma drug target.

Kidney renal papillary cell carcinoma (KIRP) is a common urinary tumor that causes lymph node invasion. Once metastatic, the prognosis is poor and there is a lack of effective early diagnostic markers for this tumor. The expression of CCNB1 in KIRP tumor tissues was significantly higher than that in normal tissues in The Cancer Genome Atlas database with or without the genotype-tissue expression database, and a consistent result was obtained in 32 paired tissues. In addition, CCNB1 expression increased remarkably with the progression of the T and M stages. Moreover, using the online HPA database, we verified that the immunohistochemical scores of CCNB1 in KIRP were higher than those in the normal kidney tissues. The higher expression group of CCNB1 showed a worse prognosis in KIRP. Moreover, the receiver operating characteristic curve, univariate and multivariate analyses, and construction of the column diagram further illustrated that CCNB1 was an independent prognostic factor for KIRP. Meanwhile, CCNB1 could better predict the 1- and 3-year survival rates of KIRP. Six genes were significantly and positively co-expressed with CCNB1. We also found that the CCNB1 high-expression group was enriched in the ECM_RECEPTOR_INTERACTION and FOCAL_ADHESION pathways. Finally, drug sensitivity analysis combined with molecular docking identified 5 targeting drugs with the strongest binding activity to CCNB1. CCNB1 is a potential and reliable biomarker for KIRP diagnosis and can be used to predict the survival of patients with KIRP. The 5 selected drugs targeting CCNB1 may provide new hopes for patients with KIRP metastasis.

Characteristics of Hepatitis B Virus, Hepatitis C Virus, and Syphilis Coinfection in People With HIV/AIDS Contracted Through Different Sources: Retrospective Study.

BACKGROUND: The burden of hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis coinfections remains disproportionately high among people living with HIV/AIDS. Hubei province is located in central China, where there are distinct regional characteristics of the distribution of people living with HIV/AIDS acquired via diverse transmission routes and the AIDS epidemic itself. OBJECTIVE: We aimed to estimate the magnitude of HBV, HCV, or syphilis coinfections among people living with HIV/AIDS with blood-borne transmission, which includes former paid blood donors, contaminated blood recipients, and intravenous drug users, as well as among people with sex-borne HIV transmission (including heterosexual people and men who have sex with men) and people with mother-to-child HIV transmission. METHODS: From January 2010 to December 2020, people living with HIV/AIDS were tested for hepatitis B surface antigen (HBsAg), HCV antibodies, and syphilis-specific antibodies. The positive patients were further tested for HBV markers, HBV DNA, and HCV RNA, and received a rapid plasma reagin circle card test. All people living with HIV/AIDS were first divided into transmission groups (blood, sex, and mother-to-child); then, people with blood-borne HIV transmission were divided into former paid blood donors, contaminated blood recipients, and intravenous drug users, while people with sex-borne HIV transmission were divided into heterosexual people and men who have sex with men. RESULTS: Among 6623 people living with HIV/AIDS, rates of chronic HCV infection were 80.3% (590/735) in former paid blood donors, 73.3% (247/337) in intravenous drug users, 57.1% (444/777) in contaminated blood recipients, 19.4% (21/108) in people with mother-to-child HIV transmission, 8.1% (240/2975) in heterosexual people, and 1.2% (21/1691) in men who have sex with men. Chronic HBV infection rates were similar among all people with blood-borne HIV transmission. However, compared to heterosexual people, the chronic HBV infection rate was greater in men who have sex with men (213/1691, 12.6% vs 308/2975, 10.4%; χ21=5.469; P=.02), although HBV exposure was less common (827/1691, 48.9% vs 1662/2975, 55.9%; χ21=20.982; P<.001). Interestingly, the combination of HBsAg and hepatitis B e antigen (HBeAg) was found in 11 patients with sex-borne HIV transmission, but in 0 people with blood-borne HIV transmission (11/196, 5.6% vs 0/521, 0%; χ21=29.695, P<.001). In people with sex-borne HIV transmission, the proportions of patients with a syphilis titer ≥1:16 and neurosyphilis were 8.6% (105/1227) and 7.8% (37/473), respectively, whereas these values were 0 in people with blood-borne HIV transmission. CONCLUSIONS: In people living with HIV/AIDS, HCV transmission intensity was significantly associated with specific exposure modes of blood or sexual contact. The rate of chronic HBV infection among men who have sex with men was higher than in any other population. Attention should be paid to the high prevalence of neurosyphilis in people living with HIV/AIDS who contract HIV by sexual intercourse.

Accuracy of FIB-4 and APRI scores compared to transient elastography for liver fibrosis in patients with HIV and HBV co-infection.

BACKGROUND: Due to economic shortages and concern about occupational exposure to HIV, liver biopsy and transient elastography (TE) are rarely available in patients with HIV/HBV co-infection in China, where HIV/HBV co-infection is prevalent. METHODS: The accuracy of FIB-4 and APRI for predicting liver fibrosis was compared with TE results in a series of 460 HIV/HBV co-infected patients. RESULTS: FIB-4 and APRI scores were strongly correlated to liver stiffness measurement scores by TE, and the correlation index was 81.4-96.3. An FIB-4 index >1.5 had a positive predictive value of 95.2% to consider fibrosis with a sensitivity of 85.7%. An APRI index >0.5 had a positive predictive value of 98.2% to consider fibrosis with a sensitivity of 76.0%. A FIB-4 value <1.5 or APRI <0.5 were concordant with TE results to exclude fibrosis in 94.4% and 96.8%, respectively. A FIB-4 value >1.5 or APRI >0.5 were concordant with fibrosis diagnosed by TE in 77.6-89.4% and 70.7-80.9%, respectively. CONCLUSIONS: In areas with limited resources, FIB-4 and APRI indexes were accurate, simple and inexpensive methods for assessing liver fibrosis in patients with HIV/HBV co-infection.

Characteristics of refined lymphocyte subsets changes in people living with HIV/AIDS during antiretroviral therapy period: An observation from Wuhan, China.

Background: To analyze the changing characteristics of continuous monitoring of refined lymphocyte subsets in people living with HIV/AIDS (PLWHA) during ART period. Methods: Refined lymphocyte subsets was continuously monitored using flow cytometry for 173 PLWHA, who were hospitalized in Zhongnan Hospital of Wuhan University from August 17, 2021 to September 14, 2022. The effect of ART status and duration of ART on changes of refined lymphocyte subsets were compared in different groups. Then, the levels of refined lymphocyte subsets in PLWHA treated for more than 10 years were compared to those of 1086 healthy individuals. Results: In addition to conventional CD4+ T lymphocytes and CD4+/CD8+ ratio, gradually increasing in numbers of CD3+CD4+CD45RO cells, CD3+CD4+CD45RA cells, CD45RA+CD3+CD4+CD25+CD127low and CD45RO+CD3+CD4+CD25+CD127low cells were found with the increase of ART duration. The number of CD4+CD28+ cells and CD8+CD28+ cells were 174/ul and 233/ul at 6 months post-ART, which gradually increased to 616/ul and 461/ul after ART initiation more than 10 years. Moreover, in ART ≤ 6 months, 6 months-3years, 3-10 years and >10 years groups, the percentage of CD3+CD8+HLA-DR+/CD8 were 79.66%, 69.73%, 60.19% and 57.90%, respectively, and the differences between groups showed statistical significance (F=5.727, P=0.001). For those PLWHA with ART more than 10 years, the levels of CD4+ T lymphocytes, CD3+CD4+CD45RO cells, CD3+CD4+CD45RA cells, CD4+CD28+ cells and CD8+CD28+ cells can increase to levels similar to those of healthy control. However, for those PLWHA with ART more than 10 years, CD4+/CD8+ ratio was 0.86 ± 0.47, which was lower than that of healthy control (0.86 ± 0.47 vs 1.32 ± 0.59, t=3.611, P=0.003); absolute counts and percentage of CD3+CD8+HLA-DR+ cells were 547/ul and 57.90%, which were higher than those of healthy control(547/ul vs 135/ul, t=3.612, P=0.003; 57.90% vs 22.38%, t=6.959, P<0.001). Conclusion: Persistent ART can gradually improve the immune status of PLWHA, which is manifested in the increase of lymphocytes, function recovery of lymphocytes and reduction of aberrant activation status of the immune system. After 10 years of standardized ART, most lymphocytes could return to levels of healthy persons, although it may take longer to complete recovery for CD4+/CD8+ ratio and CD3+CD8+HLA-DR+ cells.

Bioinformatics Analysis of the Prognostic Significance of VPS16 in Hepatocellular Carcinoma and Its Role in Drug Screening.

Background: Vacuolar protein sorting 16 (VPS16) overexpression was recently considered related to cancer growth and drug resistance; however, little is known about whether VPS16 plays a vital role in liver hepatocellular carcinoma (LIHC). Methods: The TIMER2 online database was used to analyze the expression of VPS16 in pancancer, and the Xena Browser was used to explore the correlation between VPS16 expression level and survival time. R language was used to test the survival data of 374 LIHC cases in the TCGA database. DESeq2 was used for differentially expressed gene (DEG) analysis. The HPA database was used to verify the expression level of VPS16 in LIHC. The clusterProfiler package was used to analyze functions and related signaling pathways via GO/KEGG enrichment analysis. Drug sensitivity analysis and molecular docking technology were used to screen the most sensitive drugs targeting VPS16 molecules. Results: Pancancer analysis showed that VPS16 was highly expressed in various tumors, especially in LIHC. With the increase in the T stage and grade of LIHC, the expression level of VPS16 was also increased. The expression of VPS16 was negatively correlated with the overall survival of LIHC patients. The stage can be used as an independent prognostic factor. A total of 63 sensitive drugs were found, and 19 drugs were displaying strong molecular binding energy with VPS16. Conclusion: VPS16 may be a potential biomarker for the diagnosis and prognosis of LIHC. Drugs targeting VPS16 may be used in the treatment of LIHC in the future.

Serum protein biomarkers for HCC risk prediction in HIV/HBV co-infected people: a clinical proteomic study using mass spectrometry.

Background: HBV coinfection is frequent in people living with HIV (PLWH) and is the leading cause of hepatocellular carcinoma (HCC). While risk prediction methods for HCC in patients with HBV monoinfection have been proposed, suitable biomarkers for early diagnosis of HCC in PLWH remain uncommon. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to examine serum protein alterations in HCC and non-HCC patients with HIV and HBV co-infection. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) enrichment analysis were performed on the differentially expressed proteins (DEPs). The risk prediction model was created using five-cross-validation and LASSO regression to filter core DEPs. Results: A total of 124 DEPs were discovered, with 95 proteins up-regulated and 29 proteins down-regulated. Extracellular matrix organization and membrane component were the DEPs that were most abundant in the categories of biological processes (BP) and cellular components (CC). Proteoglycans in cancer were one of the top three DEPs primarily enriched in the KEGG pathway, and 60.0% of DEPs were linked to various neoplasms in terms of DO enrichment. Eleven proteins, including GAPR1, PLTP, CLASP2, IGHV1-69D, IGLV5-45, A2M, VNN1, KLK11, ANPEP, DPP4 and HYI, were chosen as the core DEPs, and a nomogram was created to predict HCC risk. Conclusion: In HIV/HBV patients with HCC, several differential proteins can be detected in plasma by mass spectrometry, which can be used as screening markers for early diagnosis and risk prediction of HCC. Monitoring protease expression differences can help in the diagnosis and prognosis of HCC.

A Novel Ferroptosis-Related lncRNAs Signature Predicts Clinical Prognosis and Is Associated With Immune Landscape in Pancreatic Cancer.

Pancreatic cancer is one of the most lethal malignancies and currently therapies are severely lacking. In this study, we aimed to establish a novel ferroptosis-related lncRNAs signature to predict the prognosis of patients with pancreatic cancer and evaluate the predictive abilities of candidate lncRNAs. According to The Cancer Genome Atlas (TCGA) database, a total of 182 patients with pancreatic cancer were included in our study. Ferroptosis-related lncRNAs were screened by Pearson correlation analysis with 60 reported ferroptosis-related genes. Through univariate, least absolute shrinkage and selection operator (LASSO) regression and multivariate regression analyses, a novel signature based on five ferroptosis-related lncRNAs(ZNF236-DT, CASC8, PAN3-AS1, SH3PXD2A-AS1, LINP1) was constructed. Risk-related differentially expressed genes (DEGs) were subjected to enrichment analyses for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The results revealed that immune cell infiltration, immune-related functions and checkpoints were factors to affect prognoisis of pancreatic cancer. In summary, we identified the prognostic ferroptosis-related lncRNAs(ZNF236-DT, CASC8, PAN3-AS1, SH3PXD2A-AS1, LINP1) in pancreatic cancer and these lncRNAs may serve as therapeutic targets for pancreatic cancer.

Clinical progression and changes of chest CT findings among asymptomatic and pre-symptomatic patients with SARS-CoV-2 infection in Wuhan, China.

OBJECTIVES: To analyze characteristics of asymptomatic/pres-ymptomatic patients with SARS-CoV-2 infection. METHODS: Chest computed tomography(CT), indicators for organ and coagulation function, inflammation cytokines, of asymptomatic/pre-symptomatic patients with SARS-CoV-2 infection were retrospectively analyzed in Zhongnan Hospital of Wuhan University from 20 December 2019, to 8 March 2020. RESULTS: The proportion of normal chest CT in asymptomatic and pre-symptomatic patients with SARS-CoV-2 infection were 35.4% (17/48) and 3.3%(2/61), respectively (P< 0.001). In 17 asymptomatic patients, their images of chest CT maintained normal during the whole course of diseases, while the normal images of chest CT in 2 pre-symptomatic patients progressed to abnormal later (P< 0.001). All the six asymptomatic patients with SARS-CoV-2 infection maintained unilateral lesion, while the proportion was 29.4%(5/17) in pre-symptomatic patients(P= 0.003). Compared with asymptomatic patients, pre-symptomatic COVID-19 patients had worse levels of Lymphocyte count (P= 0.001), Albumin (P= 0.045), Aspartate aminotransferase (P= 0.044), γ-glutamyl transpeptadase (P= 0.016), Globulin (P= 0.036), Creatinine (P= 0.021), Lactate dehydrogenase (P= 0.008), C-reactive protein (P< 0.001), Serum amyloid A (P< 0.001), and Erythrocyte sedimentation rate (P< 0.001). Except for above indicators, Alkaline phosphatase (P= 0.009), Procalcitonin (P= 0.010), and D-dimer(P< 0.001) increased further during periods of symptoms compared with those levels in pre-symptomatic period. CONCLUSION: In early stage after SARS-CoV-2 infection, images of chest CT and blood tests of asymptomatic patients were different from pre-symptomatic patients.

The indicative role of markers for liver injury on the severity and prognosis of coronavirus disease 2019 patients.

BACKGROUND: Liver injury in coronavirus disease 2019 (COVID-19) patients was poorly understood. METHODS: The markers of liver injury, severity of disease and prognosis among 495 COVID-19 patients in Zhongnan Hospital of Wuhan University from 1st January 2019 to 11th March 2019 were retrospectively analyzed. RESULTS: The levels of aspartate aminotransferase (AST) (50.1 ± 38.4 vs. 31.4 ± 39.1, P < 0.001), gamma-glutamyl transpeptidase (GGT) (70.3 ± 70.2 vs. 34.1 ± 34.7, P < 0.001) and fibrinogen-to-albumin-ratio (FAR) (13.4 ± 4.0 vs. 10.4 ± 3.4, P < 0.001) were greater than mild COVID-19 patients, whereas the levels of albumin(35.0 ± 6.2 vs. 39.9 ± 3.7, P < 0.001) and albumin/globulin (A/G) ratio (1.21 ± 0.24 vs. 1.50 ± 0.31, P < 0.001) were lower in severe COVID-19 patients. By comparing the changes of liver injury markers 7-10 days after hospitalization, the level of albumin deteriorated from 35.0 ± 6.2 to 30.20 ± 5.5 (P < 0.001), A/G ratio from 1.21 ± 0.24 to 1.06 ± 0.25 (P < 0.001), and FAR from 13.4 ± 4.0 to 15.4 ± 2.9(P < 0.001) in severe COVID-19 patients, while the changes of albumin, A/G ratio and FAR showed opposite patterns in mild COVID-19 patients. FAR > 12 [2.566 (1.410-4.670), P = 0.012) on admission and changes of albumin >5g/l [22.489 (6.422-78.757), P = 0.001] were two risk factors for death, and the sensitivity and specificity for the poor prognosis were 80.8% and 64.0%, 82.6% and 76.3%, respectively. CONCLUSION: The levels of AST, GGT, albumin and FAR are correlated with disease severity after severe acute respiratory syndrome coronavirus-2 infection. FAR > 12 on admission and changes of albumin > 5 g/l were good predictors for the prognosis of COVID-19 patients.

Clinical characteristics of COVID-19 patients with HIV coinfection in Wuhan, China.

BACKGROUND: Information about the impact of HIV coinfection on clinical characteristics of COVID-19 patients remains limited. METHODS: Maximum body temperatures, fever duration, chest CT and viral shedding, lymphocyte counts, and titer of SARS-CoV-2 antibody were compared between COVID-19 patients with and without HIV infection in Zhongnan Hospital of Wuhan University from January 20th to February 14th, 2020. RESULTS: Compared with 53 COVID-19 patients without HIV infection, the patients with SARS-CoV-2 and HIV coinfection had higher maximum body temperatures (38.7°C vs 37.6°C, P = 0.044), longer duration of fever (8.7 ± 4.5 vs 4.2 ± 2.1 days, P = 0.038), longer time to have improvement of chest CT images (22 vs 15 days from the onset of illness, P = 0.011), lower level of SARS-CoV-2 IgG (5.11 ± 32.33 vs 37.45 ± 15.48 AU/ml, P = 0.042). However, no statistically significant difference of duration of SARS-CoV-2 shedding in the two groups was found (12.3 ± 2.6 vs 13.4 ± 2.4 days, , P = 0.813). CONCLUSION: Lower level of CD4+ T lymphocyte counts caused by HIV infection itself might be one of reasons for relatively weak ability to produce SARS-CoV-2 specific antibodies. The effects of anti-HIV drugs in prevention and treatment of COVID-19 appears to be limited.

Cell death and pathological findings of the spleen in COVID-19 patients.

The coronavirus disease 2019(COVID-19) is recognized as systemic inflammatory response syndrome. It was demonstrated that a rapid increase of cytokines in the serum of COVID-19 patients is associated with the severity of disease. However, the mechanisms of the cytokine release are not clear. By using immunofluorescence staining we found that the number of CD11b positive immune cells including macrophages in the spleens of died COVID-19 patients, was significantly higher than that of the control patients. The incidence of apoptosis as measured by two apoptotic markers, TUNEL and cleaved caspase-3, in COVID-19 patients' spleen cells is higher than that in control patients. By double immunostaining CD11b or CD68 and SARS-CoV-2 spike protein, it was found that up to 67% of these immune cells were positive for spike protein, suggesting that viral infection might be associated with apoptosis in these cells. Besides, we also stained the autophagy-related molecules (p-Akt、p62 and BCL-2) in spleen tissues, the results showed that the number of positive cells was significantly higher in COVID-19 group. And compared with non-COVID-19 patients, autophagy may be inhibited in COVID-19 patients. Our research suggest that SARS-CoV-2 may result in a higher rate of apoptosis and a lower rate of autophagy of immune cells in the spleen of COVID-19 patients. These discoveries may increase our understanding of the pathogenesis of COVID-19.

p27(Kip1) deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process.

BACKGROUND: p27 is a cell cycle suppressor gene, whose protein is a negative regulator of cyclin/cdk complexes. p27 is also a potential target of retinoids in cancer prevention studies. In benign prostate hyperplasia (BPH), and in most carcinomas, p27(Kip1) is down-regulated, suggesting its potential resistance to retinoids. To test this hypothesis, we examined the efficacy of 9-cis retinoic acid (9cRA) to suppress prostate cell proliferation (PECP) and carcinogenesis in p27(Kip1) deficient mice. METHODS: p27(Kip1) deficient (-/-), heterozygous (+/-) and homozygous (+/+) mice were treated for 7 days with testosterone, 9cRA, or with both, and cell proliferation in dorsolateral prostate (DLP) was determined by BrdU labeling. Prostate carcinogenesis was induced by N-Methyl-N-Nitrosourea (MNU) and hormone stimulation. RESULTS: PECP in DLP of two-month-old mice of all genotypes was similar but significantly increased in old p27-/- mice only. Testosterone treatment increased PECP in all three p27 genotypes with the highest values in p27-/- mice. p27(Kip1) deficiency did not affect the response of PEC to 9cRA and to 9cRA+testosterone. The decrease of p27(Kip1) in p27+/- and p27-/- mice progressively increased the incidence and frequency of PIN and tumors. 9cRA suppressed PIN in all three p27 genotypes and this was associated with decreased PECP and increased cellular senescence. CONCLUSIONS: This data indicates that p27(Kip1) deficiency promotes prostate cell proliferation and carcinogenesis but does not affect 9cRA's potential to suppress prostate carcinogenesis, suggesting that patients with PIN and carcinomas lacking or having a low level of p27(Kip1) expression may also benefit from clinical trials with retinoids.