Single-cell landscape of immunological responses in patients with COVID-19.

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.

Single-Cell Sequencing of Peripheral Mononuclear Cells Reveals Distinct Immune Response Landscapes of COVID-19 and Influenza Patients.

The coronavirus disease 2019 (COVID-19) pandemic poses a current world-wide public health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19- and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients and XIAP associated factor 1 (XAF1)-, tumor necrosis factor (TNF)-, and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) versus IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of interleukin (IL)6R and IL6ST expression in COVID-19 patients but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased proinflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients.

A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2.

An outbreak of coronavirus disease 2019 (COVID-19)1-3, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)4, has spread globally. Countermeasures are needed to treat and prevent further dissemination of the virus. Here we report the isolation of two specific human monoclonal antibodies (termed CA1 and CB6) from a patient convalescing from COVID-19. CA1 and CB6 demonstrated potent SARS-CoV-2-specific neutralization activity in vitro. In addition, CB6 inhibited infection with SARS-CoV-2 in rhesus monkeys in both prophylactic and treatment settings. We also performed structural studies, which revealed that CB6 recognizes an epitope that overlaps with angiotensin-converting enzyme 2 (ACE2)-binding sites in the SARS-CoV-2 receptor-binding domain, and thereby interferes with virus-receptor interactions by both steric hindrance and direct competition for interface residues. Our results suggest that CB6 deserves further study as a candidate for translation to the clinic.

Expected Eight-Week Prenatal Versus Twelve-Week Perinatal Tenofovir Alafenamide Prophylaxis to Prevent Mother-To-Child Transmission of Hepatitis B Virus: A Multicenter, Prospective, Open-label, Randomized Controlled Trial.

INTRODUCTION: The course of maternal antiviral prophylaxis to prevent mother-to-child transmission of hepatitis B virus (HBV-MTCT) varies greatly, and it has not been demonstrated in a randomized controlled study. METHODS: In this multicenter, open-label, randomized controlled trial, eligible pregnant women with HBV DNA of 5.3-9.0 log10 IU/mL who received tenofovir alafenamide fumarate (TAF) from the first day of 33 gestational weeks to delivery (expected eight-week) or to four-week postpartum (expected twelve-week) were randomly enrolled at a 1:1 ratio and followed until six-month postpartum. All infants received standard immunoprophylaxis (hepatitis B immunoglobulin and vaccine). The primary endpoint was the safety of mothers and infants. The secondary endpoint was infants' HBV-MTCT rate at seven months of age. RESULTS: Among 119 and 120 intention-to-treat pregnant women, 115 and 116 women were followed until delivery, and 110 and 112 per-protocol mother-infant dyads in two groups completed the study. Overall, TAF was well tolerated, no one discontinued therapy due to adverse events (0/239, 0%, 95% confidence interval [CI] 0%-1.6%), and no infant had congenital defects or malformations at delivery (0/231, 0%, 95% CI 0%-1.6%). The infants' physical development at birth (n=231) and at seven months (n=222) were normal. Furthermore, 97.0% (224/231, 95% CI 93.9%-98.5%) of women achieved HBV DNA <5.3 log10 IU/mL at delivery. The intention-to-treat and per-protocol infants' HBV-MTCT rates were 7.1% (17/239, 95% CI 4.5%-11.1%) and 0% (0/222, 95% CI 0%-1.7%) at seven months of age. Comparatively, 15.1% (18/119, 95% CI 9.8%-22.7%) versus 18.3% (22/120, 95% CI 12.4%-26.2%) of women in the two groups had mildly elevated alanine aminotransferase levels at three-month and six-month postpartum, respectively (P=0.507); notably, no one experienced alanine aminotransferase flare (0% [0/119, 95% CI 0%-3.1%] versus 0% [0/120, 0%-3.1%]). DISCUSSION: Maternal TAF prophylaxis to prevent HBV-MTCT is generally safe and effective, and expected eight-week prenatal duration is feasible. ClinicalTrials.gov, NCT04850950.

Artificial intelligence in drug discovery: applications and techniques.

Artificial intelligence (AI) has been transforming the practice of drug discovery in the past decade. Various AI techniques have been used in many drug discovery applications, such as virtual screening and drug design. In this survey, we first give an overview on drug discovery and discuss related applications, which can be reduced to two major tasks, i.e. molecular property prediction and molecule generation. We then present common data resources, molecule representations and benchmark platforms. As a major part of the survey, AI techniques are dissected into model architectures and learning paradigms. To reflect the technical development of AI in drug discovery over the years, the surveyed works are organized chronologically. We expect that this survey provides a comprehensive review on AI in drug discovery. We also provide a GitHub repository with a collection of papers (and codes, if applicable) as a learning resource, which is regularly updated.

Self-supervised semantic segmentation of retinal pigment epithelium cells in flatmount fluorescent microscopy images.

MOTIVATION: Morphological analyses with flatmount fluorescent images are essential to retinal pigment epithelial (RPE) aging studies and thus require accurate RPE cell segmentation. Although rapid technology advances in deep learning semantic segmentation have achieved great success in many biomedical research, the performance of these supervised learning methods for RPE cell segmentation is still limited by inadequate training data with high-quality annotations. RESULTS: To address this problem, we develop a Self-Supervised Semantic Segmentation (S4) method that utilizes a self-supervised learning strategy to train a semantic segmentation network with an encoder-decoder architecture. We employ a reconstruction and a pairwise representation loss to make the encoder extract structural information, while we create a morphology loss to produce the segmentation map. In addition, we develop a novel image augmentation algorithm (AugCut) to produce multiple views for self-supervised learning and enhance the network training performance. To validate the efficacy of our method, we applied our developed S4 method for RPE cell segmentation to a large set of flatmount fluorescent microscopy images, we compare our developed method for RPE cell segmentation with other state-of-the-art deep learning approaches. Compared with other state-of-the-art deep learning approaches, our method demonstrates better performance in both qualitative and quantitative evaluations, suggesting its promising potential to support large-scale cell morphological analyses in RPE aging investigations. AVAILABILITY AND IMPLEMENTATION: The codes and the documentation are available at: https://github.com/jkonglab/S4_RPE.

Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC.

BACKGROUND AND AIMS: HBV shapes the T-cell immune responses in HBV-related HCC. T cells can be recruited to the nidus, but limited T cells participate specifically in response to the HBV-related tumor microenvironment and HBV antigens. How epigenomic programs regulate T-cell compartments in virus-specific immune processes is unclear. APPROACH AND RESULTS: We developed Ti-ATAC-seq. 2 to map the T-cell receptor repertoire, epigenomic, and transcriptomic landscape of αß T cells at both the bulk-cell and single-cell levels in 54 patients with HCC. We deeply investigated HBV-specific T cells and HBV-related T-cell subsets that specifically responded to HBV antigens and the HBV + tumor microenvironment, respectively, characterizing their T-cell receptor clonality and specificity and performing epigenomic profiling. A shared program comprising NFKB1/2-, Proto-Oncogene, NF-KB Sub unit, NFATC2-, and NR4A1-associated unique T-cell receptor-downstream core epigenomic and transcriptomic regulome commonly regulated the differentiation of HBV-specific regulatory T-cell (Treg) cells and CD8 + exhausted T cells; this program was also selectively enriched in the HBV-related Treg-CTLA4 and CD8-exhausted T cell-thymocyte selection associated high mobility subsets and drove greater clonal expansion in HBV-related Treg-CTLA4 subset. Overall, 54% of the effector and memory HBV-specific T cells are governed by transcription factor motifs of activator protein 1, NFE2, and BACH1/2, which have been reported to be associated with prolonged patient relapse-free survival. Moreover, HBV-related tumor-infiltrating Tregs correlated with both increased viral titer and poor prognosis in patients. CONCLUSIONS: This study provides insight into the cellular and molecular basis of the epigenomic programs that regulate the differentiation and generation of HBV-related T cells from viral infection and HBV + HCC unique immune exhaustion.

Prevalence and viral suppression of hepatitis B virus infection among people living with HIV on antiretroviral therapy in Sierra Leone.

OBJECTIVE: Sub-Saharan Africa is one of the regions with the highest burdens of HIV and hepatitis B virus (HBV), but data on the impact of antiretroviral therapy (ART) on HBV DNA suppression is limited. In this study, we aimed to determine the prevalence and associated factors of a positive hepatitis B surface antigen (HBsAg) among people living with HIV, and assess the suppression of ART on HBV replication in people living with HIV in Sierra Leone. METHODS: A cross-sectional study was designed to recruit people living with HIV aged 18 years or older in ten public hospitals in Sierra Leone between August 2022 and January 2023. Statistical analyses were performed using R software. Logistic regression analysis was used to assess factors independently associated with positive HBsAg and HBV DNA suppression. RESULTS: Of the 3106 people living with HIV recruited in this study, 2311 (74.4%) were women. The median age was 36 years, 166 (5.3%) had serological evidence of HBV vaccination. The overall prevalence of HBsAg positivity was 12.0% (95% CI: 10.9% to 13.2%). Male sex (adjusted OR (aOR) 2.11, 95% CI: 1.67 to 2.68; p<0.001) and being separated (aOR 1.83, 95% CI: 1.06 to 3.16, p=0.031; reference group: being married) were independent predictors of HBsAg seropositivity. Among 331 people living with HIV and HBV receiving ART, 242 (73.1%) achieved HBV DNA suppression (below 20 IU/mL). HBV suppression rate was higher in HIV-virally suppressed patients than those with unsuppressed HIV viral load (p<0.001). In addition, the male sex was more likely to have unsuppressed HBV DNA (aOR 1.17, 95% CI: 1.17 to 3.21; p=0.010). CONCLUSIONS: We reported a high prevalence of HBsAg seropositivity and low HBV immunisation coverage in people living with HIV in Sierra Leone. In addition, we observed that ART can efficiently result in a viral suppression rate of HBV infection. Therefore, achieving the global target of eliminating HBV infection by 2030 requires accelerated access to care for people living with HIV and HBV, including HBV testing, antiviral treatment and hepatitis B vaccination.

Vitamin B6 ameliorates acute pancreatitis by suppressing the caspase3 signaling pathway.

BACKGROUND: Acute pancreatitis (AP) is a prevalent exocrine inflammatory disorder of the pancreas characterized by pancreatic inflammation and injury to acinar cells. Vitamin B6 (VB6) is a vital nutrient that plays a significant role in preserving human health and has anti-inflammatory and anti-apoptotic effects. METHODS: This study aimed to explore the potential pancreatic protective effects of VB6 in mitigating pancreatic inflammation and apoptosis induced by taurocholate sodium (TLCS) in an AP model and to assess the underlying mechanism of action. AP was induced in Sprague‒Dawley (SD) rats through TLCS administration and lipopolysaccharide (LPS)-treated AR42J cells, followed by treatment with VB6. RESULTS: Various parameters associated with AP were assessed in both plasma and pancreatic tissues. VB6 has been shown to ameliorate the severity of AP through various mechanisms. It effectively reduces the levels of serum amylase, lipase, and inflammatory factors, thereby mitigating histological injury to the pancreas. Moreover, VB6 inhibited pancreatic apoptosis by downregulating bax expression and up-regulating Bcl2 expression in TLCS-treated rats. Additionally, VB6 suppressed the expression of caspase3. The anti-inflammatory and anti-apoptotic effects of VB6 observed in LPS-treated AR42J cells are consistent with those observed in a rat model of AP. CONCLUSIONS: These results suggest that VB6 exerts anti-inflammatory and anti-apoptotic effects through inhibition of the caspase3 signaling pathway and has a protective effect against AP.

Functional cure induced by tenofovir alafenamide plus peginterferon-alpha-2b in young children with chronic hepatitis B: a case series study.

BACKGROUND AND AIMS: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. METHODS: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. RESULTS: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. CONCLUSIONS: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.

Preclinical and phase I studies of an antisense oligonucleotide drug targeting IGF-1R in liver cancer.

Aim: To evaluate a novel antisense oligonucleotide drug targeting human IGF-1R in preclinical and phase I studies of liver cancer.Materials & methods: The tolerability and safety of an investigational new drug were evaluated in a dose-escalation trial involving 17 patients with advanced liver cancer after preclinical assessment of pharmacokinetics and pharmacodynamics.Results: The drug exposure levels in the phase I trial were determined by the in vivo efficacy with pharmacokinetics evaluation in rats and rhesus monkeys. This clinical study showed that the maximum tolerated dose was 3.96 mg/kg, and the dose-limiting toxicity dose was 4.4 mg/kg.Conclusion: The drug was safe and tolerable in patients with advanced liver cancer.Clinical Trial Registration: ChiCTR2100044235 (www.chictr.org.cn).

CT102 is a potential new drug for liver cancer treatment. It belongs to a new form of medicine using gene therapy technology called antisense oligonucleotides. There are some antisense oligonucleotides approved for treating rare diseases. This study evaluated the antitumor effect, metabolism and safety of CT102 in preclinical and clinical trials. The results showed that CT102 could inhibit tumor growth in mice with liver cancer and maintain high levels in the liver. It was found that CT102 was safe and tolerable in patients with advanced liver cancer. This suggests that CT102 has therapeutic potential for liver cancer treatment. The good tolerability and safety of CT102 in patients supports further studies on liver cancer treatment.

Clinical characteristics and effects of inhaled corticosteroid in patients with post-COVID-19 chronic cough during the Omicron variant outbreak.

BACKGROUND: Chronic cough is a common symptom in patients post the coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the efficacy of inhaled corticosteroids (ICS) and the clinical characteristics of patients with post-COVID-19 chronic cough during the Omicron era. METHODS: An ambispective, longitudinal cohort study was conducted that included patients with post-COVID-19 who attended the respiratory clinic at our hospital between January 1, 2023, and March 31, 2023 with a complaint of persistent cough lasting more than 8 weeks. At 30 and 60 days after the first clinic visit for post-COVID-19 chronic cough, enrolled patients were prospectively followed up. We compared the changes in symptoms and pulmonary function between patients receiving ICS treatment (ICS group) and those not receiving ICS treatment (NICS group) at the two visits. RESULTS: A total of 104 patients with post-COVID-19 chronic cough were enrolled in this study (ICS group, n = 51; NICS group, n = 53). The most common symptoms accompanying post-COVID-19 chronic cough were sputum (58.7%, 61/104) and dyspnea (48.1%, 50/104). Seventy-one (82.6%, 71/86) patients had airway hyperresponsiveness, and 49 patients (47.1%, 49/104) were newly diagnosed with asthma. Most patients (95.2%, 99/104) exhibited improvement at 60 days after the first visit. The pulmonary function parameters of the patients in the ICS group were significantly improved compared to the baseline values (P < 0.05), and the improvement in the FEV1/FVC was significantly greater than that in the NICS group (P = 0.003) after 60 days. CONCLUSIONS: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may contribute to the pathogenesis of asthma, which could be the underlying cause of persistent cough post-COVID-19 infection. Post-COVID-19 chronic cough during the Omicron era was often accompanied by sputum, dyspnea, and airway hyperresponsiveness. ICS treatment did not have a significant impact on symptom management of post-COVID-19 chronic cough; however, it can improve impaired lung function in in these individuals.

Engineered anti-PDL1 with IFNα targets both immunoinhibitory and activating signals in the liver to break HBV immune tolerance.

OBJECTIVE: The purpose of this study is to develop an anti-PDL1-based interferon (IFN) fusion protein to overcome the chronic hepatitis B virus (HBV)-induced immune tolerance, and combine this immunotherapy with a HBV vaccine to achieve the functional cure of chronic hepatitis B (CHB) infection. DESIGN: We designed an anti-PDL1-IFNα heterodimeric fusion protein, in which one arm was derived from anti-PDL1 antibody and the other arm was IFNα, to allow targeted delivery of IFNα into the liver by anti-PDL1 antibody. The effect of the anti-PDL1-IFNα heterodimer on overcoming hepatitis B surface antigen (HBsAg) vaccine resistance was evaluated in chronic HBV carrier mice. RESULTS: The anti-PDL1-IFNα heterodimer preferentially targeted the liver and resulted in viral suppression, the PD1/PDL1 immune checkpoint blockade and dendritic cell activation/antigen presentation to activate HBsAg-specific T cells, thus breaking immune tolerance in chronic HBV carrier mice. When an HBsAg vaccine was administered soon after anti-PDL1-IFNα heterodimer treatment, we observed strong anti-HBsAg antibody and HBsAg-specific T cell responses for efficient HBsAg clearance in chronic HBV carrier mice that received the combination treatment but not in those that received either single treatment. CONCLUSIONS: Targeting the liver with an engineered anti-PDL1-IFNα heterodimer can break HBV-induced immune tolerance to an HBsAg vaccine, offering a promising translatable therapeutic strategy for the functional cure of CHB.

Single-cell RNA sequencing reveals intrahepatic and peripheral immune characteristics related to disease phases in HBV-infected patients.

OBJECTIVE: A comprehensive immune landscape for HBV infection is pivotal to achieve HBV cure. DESIGN: We performed single-cell RNA sequencing of 2 43 000 cells from 46 paired liver and blood samples of 23 individuals, including six immune tolerant, 5 immune active (IA), 3 acute recovery (AR), 3 chronic resolved and 6 HBV-free healthy controls (HCs). Flow cytometry and histological assays were applied in a second HBV cohort for validation. RESULTS: Both IA and AR were characterised by high levels of intrahepatic exhausted CD8+ T (Tex) cells. In IA, Tex cells were mainly derived from liver-resident GZMK+ effector memory T cells and self-expansion. By contrast, peripheral CX3CR1+ effector T cells and GZMK+ effector memory T cells were the main source of Tex cells in AR. In IA but not AR, significant cell-cell interactions were observed between Tex cells and regulatory CD4+ T cells, as well as between Tex and FCGR3A+ macrophages. Such interactions were potentially mediated through human leukocyte antigen class I molecules together with their receptors CANX and LILRBs, respectively, contributing to the dysfunction of antiviral immune responses. By contrast, CX3CR1+GNLY+ central memory CD8+ T cells were concurrently expanded in both liver and blood of AR, providing a potential surrogate marker for viral resolution. In clinic, intrahepatic Tex cells were positively correlated with serum alanine aminotransferase levels and histological grading scores. CONCLUSION: Our study dissects the coordinated immune responses for different HBV infection phases and provides a rich resource for fully understanding immunopathogenesis and developing effective therapeutic strategies.

A spatial attention guided deep learning system for prediction of pathological complete response using breast cancer histopathology images.

MOTIVATION: Predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients accurately is direly needed for clinical decision making. pCR is also regarded as a strong predictor of overall survival. In this work, we propose a deep learning system to predict pCR to NAC based on serial pathology images stained with hematoxylin and eosin and two immunohistochemical biomarkers (Ki67 and PHH3). To support human prior domain knowledge-based guidance and enhance interpretability of the deep learning system, we introduce a human knowledge-derived spatial attention mechanism to inform deep learning models of informative tissue areas of interest. For each patient, three serial breast tumor tissue sections from biopsy blocks were sectioned, stained in three different stains and integrated. The resulting comprehensive attention information from the image triplets is used to guide our prediction system for prognostic tissue regions. RESULTS: The experimental dataset consists of 26 419 pathology image patches of 1000×1000 pixels from 73 TNBC patients treated with NAC. Image patches from randomly selected 43 patients are used as a training dataset and images patches from the rest 30 are used as a testing dataset. By the maximum voting from patch-level results, our proposed model achieves a 93% patient-level accuracy, outperforming baselines and other state-of-the-art systems, suggesting its high potential for clinical decision making. AVAILABILITY AND IMPLEMENTATION: The codes, the documentation and example data are available on an open source at: https://github.com/jkonglab/PCR_Prediction_Serial_WSIs_biomarkers. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Serum globulin levels are associated with HIV reservoir size and immune restoration during long-term ART.

OBJECTIVES: The objectives of this study were to analyze the relationship between serum globulin levels and immune restoration and HIV reservoir size during long-term antiretroviral therapy (ART). METHODS: We enrolled 13 patients living with HIV who had been receiving ART for 5 years. We measured levels of serum globulin, cell-associated (CA) HIV DNA and RNA, and p24 antibody at 0, 1, 3, and 5 years of ART. CD38 and human leukocyte antigen - DR isotype (HLA-DR) were used as activation markers for T-cell activation. Serum concentrations of the inflammatory cytokines interferon gamma-inducible protein (IP)-10 and soluble CD163 (sCD163) were detected by enzyme-linked immunosorbent assay. We analyzed the relationship between serum globulin levels, HIV reservoir size, immune restoration, T-cell immune activation, and inflammatory levels during long-term ART. RESULTS: Our data showed that serum globulin levels in people living with HIV were higher than in healthy controls and significantly decreased during the first year of ART. Serum globulin levels during long-term ART were positively correlated with CA HIV DNA, CA HIV RNA, p24 antibody levels, and CD8+ T-cell counts and negatively correlated with CD4+ T-cell counts and CD4/CD8 ratios. Moreover, serum globulin levels were positively correlated with CD4+ and CD8+ T-cell activation and the concentrations of inflammatory biomarkers IP-10 and sCD163 during long-term ART. CONCLUSIONS: Our findings suggest that serum globulin levels may be associated with HIV reservoir size and immune restoration during long-term ART.

Local characteristics of molecular epidemiolgy of Acinetobacter baumannii in Jilin province (northeast China).

A. Baumannii is an opportunistic nosocomial pathogen which has severe antibiotic resistance. However, the epidemiology is less clearly understood in Jilin province and China. Thus, 89 A. baumannii isolates from a single hospital in Jilin province between 2013-2017 were performed by MLST. In order to better understanding of the epidemiology of Jilin isolates, Chinese strains originated from other domestic regions and worldwide isolates in MLST database were analyzed by silico phylogenetic tools together. A total of 22 STs in Jilin were identified, and 10 STs were found to be novel. The top three predominant sequence types are ST195 (n = 34, 38.2%), ST208 (n = 14, 15.7%) and ST540 (n = 13, 14.6%). ST369 is predicted to be group founder and ST195, ST540 are subgroup founders of the majority STs in Jilin Province. Some newly discovered singletons showed close relationship with strains from other countries, which suggest that nation-cross transmission is one of important origin of Jilin strains. The majority of Jilin STs showed clonality and close relationship with the majorities from other regions of China. But occupation of individual STs in Jilin were different from that of other domestic regions. The aggregation trend and genetic relationship proved that predominant Jilin STs continue to mutate during transmission. Drug resistance facilitated transmission of Jilin A.baumannii isolates because more than 94% of isolates are resistant to at least one carbapenem and the STs with strong resistance to carbapenems usually has more isolates. In conclusion, high diversity and different occupation of STs, and occupation of novel STs proved that epidemiology of A. baumannii in Jilin has special regional characteristics, and drug resistance facilitated transmission of domestic strains and foreign strains.

Cancer-associated fibroblasts-derived exosomes from chemoresistant patients regulate cisplatin resistance and angiogenesis by delivering VEGFA in colorectal cancer.

The purpose of this study was to investigate the effect of chemoresistant cancer-associated fibroblasts (R-CAFs) against cisplatin (DDP) on colorectal cancer (CRC) progression. First, clinical tissue samples of chemoresistant or chemosensitive CRC patients were collected to isolate R-CAFs or chemosensitive CAFs (S-CAFs), respectively. HT29 cells or HUVECs were co-cultured with R-CAFs by transwell device. Then the proliferation and apoptosis of HT29 cells were detected with Cell Counting Kit-8 (CCK-8) and flow cytometry. Transwell assay and tube formation assay was used to detect the migration and angiogenesis of HUVECs. In addition, a colorectal cancer transplantation model was established subcutaneously in nude mice by injecting stably transfected HT29 cells and exosomes from different CAF groups, and then the tumor volume and weight were measured and recorded. Hematoxylin and eosin staining, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) staining were performed to characterize the histopathological characteristics and apoptosis level of tumor tissues, respectively. S-CAFs and R-CAFs were isolated successfully. HT29 cell co-culture with R-CAFs significantly affected the proliferation and apoptosis of HT29 cells. Exosomes derived from R-CAFs (R-CAFs-Exo) were delivered to HT29 cells, which could induce viability, suppress apoptosis and accelerate the angiogenesis of CRC. In addition, VEGFA was highly expressed in R-CAFs-Exo, which might indicate that R-CAFs could transmit VEGFA through exosomes. Overexpressed VEGFA in R-CAFs apparently regulates the viability, apoptosis, DDP resistance, and angiogenesis of CRC. In-vivo experiments confirmed that R-CAFs-Exo promoted the progression of CRC and DDP resistance by delivering VEGFA . R-CAFs-derived exosomes promote the viability, apoptosis, DDP resistance, and angiogenesis of CRC by delivering VEGFA .

Characteristics of blood immune cell profile and their correlation with disease progression in patients infected with HIV-1.

BACKGROUND: Antiretroviral therapy (ART) can reduce viral load in individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals still cannot achieve optimal immune recovery even after ART. Hence, we described the profile of peripheral immune cells and explored the association with disease progression in patients infected with HIV-1. METHODS: Mass cytometry analysis was used to characterize the circulating immune cells of 20 treatment-naïve (TNs), 20 immunological non-responders (INRs), 20 immunological responders (IRs), and 10 healthy controls (HCs). Correlation analysis was conducted between cell subpopulation percentages and indicators including HIV-1 cell-associated (CA)-RNA, DNA, CD4+ T cell count, and CD4/CD8 ratio. RESULTS: Global activation, immunosenescence, and exhaustion phenotypes were observed in myeloid cells and T cells from individuals with HIV-1 infection. We also found that specific subsets or clusters of myeloid, CD4+ T, and CD8+ T cells were significantly lost or increased in TN individuals, which could be partially restored after receiving ART. The percentages of several subpopulations correlated with HIV-1 CA-RNA, DNA, CD4+ T cell count, and CD4/CD8 ratio, suggesting that changes in immune cell composition were associated with therapeutic efficacy. CONCLUSION: These data provide a complete profile of immune cell subpopulations or clusters that are associated with disease progression during chronic HIV-1 infection, which will improve understanding regarding the mechanism of incomplete immune recovery in INRs.

Incidence and risk factors of hypertriglyceridemia in males with human immunodeficiency virus who are treated with combination antiretroviral therapy: a retrospective cohort study.

BACKGROUND: Hypertriglyceridemia is associated with subclinical atherosclerosis and vascular inflammation even when low-density lipoprotein cholesterol levels are normal. However, few cohort studies on hypertriglyceridemia have been conducted in males with higher susceptibility to human immunodeficiency virus (HIV)-related deterioration of arterial structure and function. Our objective was to investigate the incidence of hypertriglyceridemia during treatment with combination antiretroviral therapy (cART) in males with HIV and explore its related risk factors. METHODS: In this retrospective study, we included 309 males living with HIV (median age 31 years [interquartile range 26-42.5]) who initiated cART treatment in our hospital from January 2013 to December 2018. We collected follow-up data on serum triglycerides and other related information as of June 31, 2021. A Cox proportional hazards regression model was used to analyze the related risk factors. RESULTS: In 666.7 person-years, hypertriglyceridemia occurred in 140 patients (triglyceride ≥2.3 mmol/L [200 mg/dL]), and the incidence rate was 21.0 per 100 person-years (Patients who took the lamivudine [3TC] + tenofovir disoproxil fumarate [TDF] + efavirenz [EFV] regimen accounted for 77.0% of the total patients.). Multiple Cox regression analysis showed that baseline CD4/CD8 ratio < 0.20 (hazard ratio [HR], 2.705 [95% confidence interval (CI): 1.381-5.296]; P = 0.004}, body mass index (BMI) ≥ 24.0 kg/m2 (HR, 1.768 [95% CI: 1.225-2.552]; P = 0.002), borderline high triglyceride at baseline (HR, 3.457 [95% CI: 2.162-5.527]; P < 0.001), and 3TC + zidovudine (AZT) + EFV regimen (HR, 2.702 [95% CI: 1.593-4.581]; P < 0.001), or 3TC + TDF + lopinavir/ritonavir (LPV/r) regimen (HR, 4.349 [95% CI: 2.664-7.102]; P < 0.001) were independent risk factors for hypertriglyceridemia. CONCLUSION: During the course of cART treatment, the incidence of hypertriglyceridemia in males with HIV was high. The main risk factors influencing its occurrence are a low baseline CD4/CD8 ratio, overweight and obesity, and the use of AZT or LPV/r in the cART regimen.