Related barriers to using HIV pre-exposure prophylaxis among MSM: A multicentre cross-sectional survey.

OBJECTIVE: The objective of this study was to gain insight into the barriers hindering the use of pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) in five cities in China. METHODS: MSM were recruited via community-based organizations in an online "snowball" manner. Participants completed the questionnaire anonymously and shared it with key MSM peers (seeds) in five cities in China. Based on the results of univariate analysis, we used a structural equation model to analyse the role of PrEP knowledge awareness, PrEP counselling, and other behavioural variables on PrEP use. RESULTS: The study collected a total of 4223 valid questionnaires, and 18.2% of participants reported PrEP use. The results of the standardized total effects showed that the following paths were statistically significant (p < 0.05): from the age of first sex with men to PrEP knowledge awareness (ß = -0.113) and PrEP use (ß = 0.042); from high-risk sexual behaviour scores to PrEP counselling (ß = 0.039) and PrEP use (ß = 0.103); from the number of HIV tests in the last year to PrEP knowledge awareness (ß = 0.034), PrEP counselling (ß = 0.170), and PrEP use (ß = 0.197); from the level of self-perceived risk of HIV infection to PrEP counselling (ß = -0.115); from PrEP knowledge awareness to PrEP use (ß = -0.049); and from PrEP counselling to PrEP use (ß = 0.420). CONCLUSIONS: The proportion of PrEP use among MSM was relatively low. Age at first sex with men, number of HIV tests, high-risk sexual behaviour, and PrEP counselling had a positive effect on PrEP use, whereas PrEP knowledge awareness had an inverse effect on PrEP use.

Analysis of HIV drug prophylaxis services cascade in healthcare workers: a cross-sectional study in China.

BACKGROUND: Human immunodeficiency virus (HIV) drug prophylaxis, including post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP), has not yet been generally recognized and accepted by the whole society in China, and the utilization coverage among high-risk populations is low. Healthcare workers (HCWs) are important to the promotion and implementation of HIV drug prophylaxis strategy. This study analyzed the HIV drug prophylaxis services cascade (knowledge, attitude, and service) in HCWs, and explored the correlations between PEP and PrEP. METHODS: A cross-sectional study was conducted among 1066 HCWs in 20 designated hospitals for HIV antiretroviral therapy in 20 cities in China. We collected information on participants' essential characteristics, HIV drug prophylaxis services cascade (knowledge, attitude, and service) and so on. The Chi-square test was used to analyse whether the differences and correlations between categorical variables were statistically significant, and Pearson contingency coefficient was used to analyse the strength of correlations. Multivariable logistic regression was used to analyse associated factors. RESULTS: Among three stages of HIV drug prophylaxis services cascade, a high percentage of 1066 participants had knowledge of HIV drug prophylaxis (PEP: 78.2%, PrEP: 80.0%). Of them, almost all had supportive attitudes towards HIV drug prophylaxis (PEP: 99.6%, PrEP: 98.6%). Only about half of them would provide HIV drug prophylaxis services (PEP: 53.5%, PrEP: 48.5%). There were positive correlations between knowledge of PEP and PrEP (r = 0.292), between attitudes toward PEP and PrEP (r = 0.325), and between provision of PEP services and PrEP services (r = 0.555) in HCWs. CONCLUSIONS: There was a positive correlation between PEP and PrEP in HCWs. At the stage of providing HIV drug prophylaxis services, training, advocacy and education for HCWs, should be targeted and also combine PEP and PrEP to maximize the effects, so as to improve the enthusiasm of HCWs to provide HIV drug prophylaxis services.

Comparative analysis of co-culture and monoculture models in simulating diabetic neurovascular dysfunction: insights into diabetic retinopathy.

Background: Interaction between retinal vascular endothelial cells and neurons plays a critical role in the pathogenesis of diabetic retinopathy (DR). This study aims to compare an in vitro model over a monoculture model to simulate the neurovascular coupling under the hyperglycemic microenvironment of diabetes. Methods: Rat retinal vascular endothelial cells (RRMECs) and ganglion cells (RGCs) were seeded mono- or co-cultured in a normal (NG, 5.5 mM) and high (HG, 75 mM) glucose concentrations culture medium. Cell viability was detected by the cell counting kit-8 (CCK-8) assay. The ability of migration and lumen formation of RRMECs were determined by scratch wound, transwell migration, and lumen formation assays. The apoptosis index of cells was calculated and detected by propidium iodide (PI)/Hoechst staining. Quantitative and morphological analysis of RGCs was performed through the labeling of RGCs by brain-specific homeobox/POU domain protein 3A (BRN3A) and anti-beta-III tubulin (TUJ1). The gene and protein expression levels of occludin (OCLN) and zonula occludens-1 (ZO-1) were evaluated by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Results: The viability, migration, and lumen formation abilities of RRMECs in the HG group significantly increased (P<0.05) in both mono- and co-culture models. Migration and lumen formation abilities of RRMECs in the co-culture with HG were lower than that in the monoculture group (P<0.05). The viability of RGCs cells with HG significantly decreased in both mono- and co-culture models (Pmono<0.001, Pco<0.001), the apoptosis index of RGCs in the co-culture with HG was higher than that in the monoculture (P=0.010). The protein and gene expression of OCLN, and ZO-1 in RRMECs significantly decreased with HG culture medium in both culture models (P<0.05). In the HG group, the protein and gene expression level of the ZO-1 and OCLN of RRMECs significantly decreased in the co-culture model than that in the monoculture model (P<0.05). Conclusion: Compared with mono cell culture, the established co-culture in vitro system for diabetic neurovascular dysfunction can better stimulate the micro-environment of the retinal neurovascular unit.

Pre-exposure prophylaxis uptake for high-risk men who have sex with men in China: a multi-city cross-sectional survey.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is a proven biomedical strategy to prevent HIV transmission among men who have sex with men (MSM). Despite oral PrEP is safe and effective in MSM, the use of PrEP has been discouraging, especially in high-risk MSM. And there are no relevant studies showing the use of PrEP in high-risk MSM. The purpose of this study was to get the rate of PrEP use and the factors influencing PrEP use among high-risk MSM. METHODS: A cross-sectional study was conducted through an electronic questionnaire on the "i guardian Platform", and "snowballing" method was used to recruit MSM in six cities in China, including Beijing, Shenzhen, Chengdu, Changsha, Jinan and Nanjing in China, from January to April 2021. Univariate and multivariate logistic regression analysis were used to analyze the factors associated with the use of PrEP among high-risk MSM who had heard about PrEP. RESULTS: Among the 1865 high-risk MSM who had heard of PrEP, the rates of those who were willing to use PrEP, had knowledge awareness of PrEP, and had used PrEP were 96.7%, 24.7%, and 22.4%, respectively. Multivariate logistic regression analysis of PrEP use in high-risk MSM showed that more PrEP was used by those who were 26 years or older (OR = 1.86, 95%CI 1.17 ~ 2.99), had master degree or above (OR = 2.37, 95% CI 1.21 ~ 4.72), had unstable work (OR = 1.86, 95% CI 1.16 ~ 2.96), had tested five or more HIV times in the past year (OR = 3.09, 95% CI 1.65 ~ 6.04), had consulted PrEP (OR = 22.05, 95% CI 14.87 ~ 33.91) and had PrEP knowledge awareness (OR = 1.90, 95% CI 1.41 ~ 2.55) (P < 0.05). CONCLUSIONS: The rate of PrEP use in high-risk MSM was relatively low. PrEP was used more by high-risk MSM with unstable jobs, higher education, frequent HIV testing, and PrEP counseling. Public education on PrEP for MSM should continue to be enhanced to help them use PrEP in a timely and accurate manner.

Analysis of Knowledge Level and Use of Antiretroviral Pre-Exposure and Post-Exposure Prophylaxis Among MSM - China, 2019-2022.

What is already known on this topic?: Men who have sex with men (MSM) in China have a high rate of human immunodeficiency virus (HIV) infection. Pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) have been shown to be effective in preventing HIV, which may help to contain the HIV epidemic among MSM. What is added by this report?: This study found that knowledge and usage of PrEP were low among MSM, indicating that this population is at high risk for HIV infection. Promotion of PrEP and PEP among MSM is necessary to reduce the risk of HIV infection in this population. What are the implications for public health practice?: PrEP and PEP are novel HIV prevention strategies that have been demonstrated to be effective and safe. To further reduce HIV transmission among MSM in China, it is necessary to promote the use of PrEP and PEP.

Dysregulated Serum Lipid Metabolism Promotes the Occurrence and Development of Diabetic Retinopathy Associated With Upregulated Circulating Levels of VEGF-A, VEGF-D, and PlGF.

Purpose: This study aims to explore the correlations of arteriosclerosis-associated plasma indices with various severity levels of diabetic retinopathy (DR) and to test the hypothesis that elevated circulating level of known angiogenic cytokines induced by hyperglycemia is associated with dyslipidemia on DR. Methods: This cross-sectional study consists of 131 patients with type 2 diabetes. The patients were categorized based on their DR status into those with no DR (diabetes mellitus, DM), non-proliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR) groups. The biochemical profile including fasting glucose, glycated hemoglobin (HbA1c), lipid profile were estimated, plasma angiogenic cytokines (vascular endothelial growth factor, VEGF-A, -C, -D) and placental growth factor (PlGF) were analyzed by protein microarrays. The atherogenic plasma index (API) was defined as low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C); atherogenic index (AI) was calculated as (TC-(HDL-C))/HDL-C and atherogenic index of plasma (AIP) was defined as log (TG/HDL-C). Results: No significant differences were detected in the duration of hypertension, age, and gender between the three groups. Serum TC and LDL-C, AI, and API in the NPDR group and PDR group were significantly higher than those in the DM group. The circulating level of PlGF, VEGF-A, and VEGF-C were significantly correlated with the severity of DR. VEGF-D is a risk factor independent of API (Z = -2.61, P = 0.009) and AI (Z = -2.40, P = 0.016). Multivariate logistic regression showed that AI and API are strong risk factors for the occurrence and severity of DR. Associated with AI and API, VEGF-D and PlGF contribute to DR: VEGF-D [AI: P = 0.038, odd ratio (OR) = 1.38; VEGF-D: P = 0.002, OR = 1.00. API: P = 0.027, OR = 1.56, VEGF-D:P = 0.002, OR = 1.00] and PlGF [AI: P = 0.021, OR = 1.43; VEGF-D: P = 0.004, OR = 1.50. API: P = 0.011, OR = 1.66; VEGF-D: P = 0.005, OR = 1.49]. Conclusions: Total cholesterol (TC) and LDL-C are risk factors for presence of any DR. Atherogenic index and API are novel and better predictive indicators for the occurrence and severity of DR in comparion with the traditional lipid profiles. Abnormal lipid metabolism are associated with the upregulation of circulating cytokines that are linked to the severity of DR.

Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing.

Targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for treating melanoma, gastric cancer (GC) and bladder cancer with clinical benefit. Nevertheless, many patients failed to respond to anti-PD-1/PD-L1 treatment, so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy. Here with the data from The Cancer Genome Atlas (TCGA) and our in-house tissue library, PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7 (USP7) in GC. Furthermore, USP7 directly interacted with PD-L1 in order to stabilize it, while abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo. Besides, USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo. Collectively, our findings indicate that in addition to inhibiting cancer cells proliferation, USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously. Hence, these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor.

Cytokines/Chemokines: Potential Biomarkers for Non-paraneoplastic Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Objective: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common type of autoimmune encephalitis. This study focuses on finding new biomarkers to evaluate the clinical condition and provide new directions for treatment. Methods: A total of 44 cytokines/chemokines in the cerebrospinal fluid of 10 non-paraneoplastic patients and nine controls were measured. We selected some of the cytokines/chemokines that significantly increased in patients. Six selected cytokines/chemokines, including IL-10, CXCL10, CCL22, CCL3, IL-7, TNF-α, and three previously reported (IL-2, IL-6, and IL-17A), were measured in seven other patients who provided repeat samples. We compared their levels and explored correlations with severity of disease and antibody titers. Results: The levels of Th1 axis (CXCL10, TNF-α, IFN-γ, CCL3), Th2 axis (CCL1, CCL8, CCL17, CCL22), Treg axis (IL-10), Th17 axis (IL-7), and B cell axis (CXCL13) cytokines, as well as IL-12 p40 and IL-16, were significantly higher in patients compared to those in controls. The level of IL-2 was significantly decreased at the intermediate stage of treatment compared with that before treatment. The severity of disease is positively correlated with levels of CXCL10, CCL3, IL-10, CCL22, and IL-6. The level of CCL3 in the high antibody titer group was greater than that in the low antibody titer group. Conclusion: The pathogenesis of anti-NMDAR encephalitis involves T cell and B cell cytokines. T cells likely assist B cells to produce antibodies. IL-2, CXCL10, CCL3, IL-10, CCL22, and IL-6 may represent new biomarkers in anti-NMDAR encephalitis. Given the lack of research on IL-10, CCL3, and CCL22 in this disease, it will be informative to explore their potential role in pathogenesis in larger studies.

USP7: Novel Drug Target in Cancer Therapy.

Ubiquitin specific protease 7 (USP7) is one of the deubiquitinating enzymes (DUB) that erases ubiquitin and protects substrate protein from degradation. Full activity of USP7 requires the C-terminal Ub-like domains fold back onto the catalytic domain, allowing the remodeling of the active site to a catalytically competent state by the C-terminal peptide. Until now, numerous proteins have been identified as substrates of USP7, which play a key role in cell cycle, DNA repair, chromatin remodeling, and epigenetic regulation. Aberrant activation or overexpression of USP7 may promote oncogenesis and viral disease, making it a target for therapeutic intervention. Currently, several synthetic small molecules have been identified as inhibitors of USP7, and applied in the treatment of diverse diseases. Hence, USP7 may be a promising therapeutic target for the treatment of cancer.

Discovery and synthesis of novel indole derivatives-containing 3-methylenedihydrofuran-2(3H)-one as irreversible LSD1 inhibitors.

Lysine-specific demethylase 1 (LSD1), demethylase against mono- and di - methylated histone3 lysine 4, has emerged as a promising target in oncology. More specifically, it has been demonstrated as a key promoter in acute myeloid leukemia (AML), and several LSD1 inhibitors have already entered into clinical trials for the treatment of AML. In this paper, a series of new indole derivatives were designed and synthesized based on a lead compound obtained by a high-throughput screening with our in-house compound library. Among the synthetic compounds, 9e was characterized as a potent LSD1 inhibitor with an IC50 of 1.230 µM and can inhibit the proliferation of THP-1 cells effectively. And most importantly, this is the first irreversible LSD1 inhibitor that is not derived from monoamine oxidase inhibitors. Hence, the discovery of 9e may serve as a proof of concept work for AML treatment.

Sanggenon O induced apoptosis of A549 cells is counterbalanced by protective autophagy.

Sanggenon O (SO) is a Diels-Alder type adduct extracted fromMorus alba, which has been used for its anti-inflammatory action in the Oriental medicine. However, whether it has regulatory effect on human cancer cell proliferation and what the underlying mechanism remains unknown. Here, we found that SO could significantly inhibit the growth and proliferation of A549 cells and induce its pro-apoptotic action through a caspase-dependent pathway. It could also impair the mitochondria which can be reflected by mitochondrial membrane permeabilization. Besides, SQSTM1 up-regulation and autophagic flux measurement demonstrated that exposure to SO led to autophagosome accumulation, which plays a protective role in SO-treated cells. In addition, knocking down of LC3B increased SO triggered apoptotic cell rates. These results indicated that SO has great potential as a promising candidate combined with autophagy inhibitor for the treatment of NSCLC. In conclusion, our results identified a novel mechanism by which SO exerts potent anticancer activity.

An injectable enzymatically crosslinked tyramine-modified carboxymethyl chitin hydrogel for biomedical applications.

The in-situ forming injectable hydrogels have received much attention as scaffolds in the biomedical field, providing a minimally invasive surgical procedure to fill the damaged area. In the present work, carboxymethyl chitin (CMCH) synthesized homogenously was further functionalized with tyramine, resulted in a new injectable enzymatically crosslinked in-situ forming hydrogel under physiological conditions. This new tyramine-modified carboxymethyl chitin (CMCH-Tyr) hydrogel showed much better mechanical properties than those of the thermosensitive in-situ forming physical-crosslinking CMCH hydrogel. The CMCH-Tyr hydrogels remained stable under physiological conditions and could be degraded by lysozyme. The gelation time, strength and biodegradation rate of the CMCH-Tyr hydrogels can be adjusted by varying the concentrations of the horseradish peroxidase and H2O2 in the certain range. In vitro cytotoxicity assays and in vivo in-situ injection study showed non-toxicity, favorable gel formation, and good tissue biocompatibility of the enzyme-catalyzed CMCH-Tyr hydrogel. Thus, the biodegradable and biocompatible CMCH-Tyr hydrogels may hold great potential for three dimensional cell culture and tissue engineering.

Archimedes' law explains penetration of solids into granular media.

Understanding the response of granular matter to intrusion of solid objects is key to modelling many aspects of behaviour of granular matter, including plastic flow. Here we report a general model for such a quasistatic process. Using a range of experiments, we first show that the relation between the penetration depth and the force resisting it, transiently nonlinear and then linear, is scalable to a universal form. We show that the gradient of the steady-state part, K ϕ , depends only on the medium's internal friction angle, ϕ, and that it is nonlinear in µ = tan ϕ, in contrast to an existing conjecture. We further show that the intrusion of any convex solid shape satisfies a modified Archimedes' law and use this to: relate the zero-depth intercept of the linear part to K ϕ and the intruder's cross-section; explain the curve's nonlinear part in terms of the stagnant zone's development.

Photocrosslinked methacrylated carboxymethyl chitin hydrogels with tunable degradation and mechanical behavior.

Photocrosslinked hydrogels are being investigated for many tissue engineering applications because of the ability to form these materials in-situ in a minimally invasive manner by injection of aqueous solution under physiological conditions. In this work, carboxymethyl chitin (CMCH) synthesized homogenously was further modified with methacrylic anhydride and photocrosslinked into hydrogel with tunable degradation and mechanical properties. This new methacrylated carboxymethyl chitin (Me-CMCH) hydrogel formed in-situ photocrosslinked under UV irradiation showed much higher storage modulus than that of the thermosensitive in-situ forming physical-crosslinking CMCH hydrogel. The Me-CMCH hydrogels remained stable under physiological conditions and could be degraded by lysozyme. Cytotoxicity test indicated that the photo-induced Me-CMCH hydrogels were non-cytotoxic. The mechanical property, morphology, swelling and biodegradation behavior of the Me-CMCH hydrogels could be tuned by controlling the degree of methacrylation of Me-CMCH. These biodegradable photocrosslinkable Me-CMCH hydrogels may hold great promises for various biomedical applications.

[Effect of anti-TGF-beta antibody on ex vivo expansion and expression of adhesion molecules of human cord blood CD34+ cells].

TGF-beta, as an inhibitor of hemopoiesis, excreted by hematopoietic stem and progenitor cells, down-regulates the expression of cytokines such as Flt-3 ligand, SCF, IL-3 etc on the stem and progenitor cells. The effect of anti-TGF-beta antibody on ex vivo expansion and expression of adhesive molecules on cord blood CD34(+) cells was studied in this research. The CD34(+) cells from six units of fresh umbilical cord blood were enriched by density gradient sedimentation and purified by miniMACS cell isolation system, and plated them into the SFEM serum free culture system which containing SCF, Flt-3L, TPO and IL-3 in the condition of 37 degrees C, 5% CO2, and saturated moisture. There were three groups in this experiment: (1) blank group: same as the culture system described above; (2) control group: added with normal rabbit IgG into the mentioned culture system; (3) test group: the same culture system with anti-TGF-beta1 antibo-dy. Cultured for 6 days, the number of mononuclear cells (MNC) was counted, the expression of CD34 antigen, CD117 (c-kit) antigen, CD11a antigen, CD49d antigen and CD33 antigen was tested with FCM. Meanwhile, cells of the three groups were plated in the methylcellulose culture system for 14 days, the number of CFU-GEMM, BFU-E, CFU-GM was counted. The results indicated that the expansion multiples of MNC, CD34(+) cells, CD34(+)c-kit(+) cells, CFU-GEMM in the test group (41.82 +/- 13.49, 15.62 +/- 6.95, 13.36 +/- 6.12, 11.07 +/- 4.05) were significantly higher than in the control group (28.86 +/- 9.03, 10.40 +/- 4.98, 9.04 +/- 4.40, 6.36 +/- 2.37) (P = 0.001, 0.002, 0.003, 0.002) respectively. The expansion multiple of more primitive CD34(+)c-kit(-) subpopulation in the test group (69.10 +/- 41.06) was even higher than in the control group (27.29 +/- 10.40) (P = 0.024). Adhesion molecule expression on the CD34(+) cells after short-term expansion: the expression of CD11a on the CD34(+) cells of the original cord blood was (61.73 +/- 4.13)%, and CD49d was (55.12 +/- 5.22)%. After expansion in each group the expression of CD11a on the CD34(+) cells did not change with statistical significance (P > 0.05), the expression of CD49d increased (P < 0.05). Compared with blank group and control group, anti-TGF-beta antibody did not impact on the expression of CD11a and CD49d (P > 0.05). It is concluded that anti-TGF-beta antibody can synergize other cytokines to effectively enhance the proliferation of cord blood NC, CD34(+) cells, progenitor subpopulation of CD34(+)c-kit(-) cells, and increase the output of more primitive progenitor colony, CFU-GEMM and BFU-E. At the same time, anti-TGF-beta antibody did not depresss the expression of adhesion molecules on CD34(+) cells.