Community, Family, and Partner-Related Stigma Experienced by Pregnant and Postpartum Women with HIV in Ho Chi Minh City, Vietnam

Pregnant and postpartum women with HIV often face stigma and discrimination at home and in the community. In Vietnam, associations between HIV and the “social evils” of drug use and sex work contribute to stigmatization of people with HIV. We conducted a qualitative study to explore discrimination experienced by HIV-positive pregnant and postpartum women in Ho Chi Minh City at home and in the community. We conducted 20 in-depth interviews and two focus group discussions. Participants described managing disclosure of their HIV infection because of fear of stigma and discrimination, particularly to the wider community. In cases where their HIV status was disclosed, women experienced both discrimination and support. The findings highlight the need for targeted interventions to support pregnant and postpartum women with HIV, particularly during this period when they are connected to the healthcare system and more readily available for counseling

Sulfated non-anticoagulant heparin blocks Th2-induced asthma by modulating the IL-4/signal transducer and activator of transcription 6/Janus kinase 1 pathway

Abstract Background The efficacy of heparins and low-MW-heparins (LMWH) against human asthma has been known for decades. However, the clinical utility of these compounds has been hampered by their anticoagulant properties. Much effort has been put into harnessing the anti-inflammatory properties of LMWH but none have been used as therapy for asthma. Sulfated-non-anticoagulant heparin (S-NACH) is an ultra-LMWH with no systemic anticoagulant effects. Objective The present study explored the potential of S-NACH in blocking allergic asthma and examined the potential mechanism by which it exerts its effects. Methods Acute and chronic ovalbumin-based mouse models of asthma, splenocytes, and a lung epithelial cell line were used. Mice were challenged with aerosolized ovalbumin and administered S-NACH or saline 30 min after each ovalbumin challenge. Results Sulfated-non-anticoagulant heparin administration in mice promoted a robust reduction in airway eosinophilia, mucus production, and airway hyperresponsiveness even after chronic repeated challenges with ovalbumin. Such effects were linked to suppression of Th2 cytokines IL-4/IL-5/IL-13/GM-CSF and ovalbumin-specific IgE without any effect on IFN-γ. S-NACH also reduced lung fibrosis in mice that were chronically-exposed to ovalbumin. These protective effects of S-NACH may be attributed to modulation of the IL-4/JAK1 signal transduction pathway through an inhibition of STAT6 phosphorylation and a subsequent inhibition of GATA-3 and inducible NO synthase expression. The effect of the drug on STAT6 phosphorylation coincided with a reduction in JAK1 phosphorylation upon IL-4 treatment. The protective effects of S-NACH treatment was associated with reduction of the basal expression of the two isoforms of arginase ARG1 and ARG2 in lung epithelial cells. Conclusions Our study demonstrates that S-NACH constitutes an opportunity to benefit from the well-known anti-asthma properties of heparins/LMWH while bypassing the risk of bleeding. Our results show, for the first time, that such anti-asthma effects may be associated with reduction of the IL-4/JAK1/STAT6 pathway

PARP-1 is critical for recruitment of dendritic cells to the lung in a mouse model of asthma but dispensable for their differentiation and function

Dendritic cells (DCs) are critical in asthma and many other immune diseases. We previously demonstrated a role for PARP-1 in asthma. Evidence on PARP-1 playing a role in Th2-associated DC function is not clear. In this study, we examined whether PARP-1 is critical for DC differentiation and function using bone marrow progenitors and their migration to the lung in an ovalbumin-based mouse model of asthma. Results show that changes in PARP-1 levels during GM-CSF-induced DC differentiation from bone marrow progenitors were cyclic and appear to be part of an array of changes that included STAT3/STAT5/STAT6/GRAIL/RAD51. Interestingly, PARP-1 gene deletion affected primarily STAT6 and γH2AX. PARP-1 inhibition significantly reduced the migration of DCs to the lungs of ovalbumin-challenged mice, which was associated with a concomitant reduction in lung levels of the adhesion molecule VCAM-1. The requirement of PARP-1 for VCAM-1 expression was confirmed using endothelial and lung smooth muscle cells. PARP-1 expression and activity were also required for VCAM-1 in differentiated DCs. An assessment of CD11b+/CD11c+/MHCIIhigh DCs in spleens and lymph nodes of OVA-sensitized mice revealed that PARP-1 inhibition genetically or by olaparib exerted little to no effect on DC differentiation, percentage of CD80+/CD86+/CD40+-expressing cells, or their capacity to promote proliferation of ovalbumin-primed (OTII) CD4+ T cells. These findings were corroborated using GM-CSF-induced differentiation of DCs from the bone marrow. Surprisingly, the PARP-1-/- DCs exhibited a higher intrinsic capacity to induce OTII CD4+ T cell proliferation in the absence of ovalbumin. Overall, our results show that PARP-1 plays little to no role in DC differentiation and function and that the protective effect of PARP-1 inhibition against asthma is associated with a prevention of DC migration to the lung through a reduction in VCAM-1 expression. Given the current use of PARP inhibitors (e.g., olaparib) in the clinic, the present results may be of interest for the relevant therapies

Targeting PARP-1 with metronomic therapy modulates MDSC suppressive function and enhances anti-PD-1 immunotherapy in colon cancer

Background Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) are effective against BRCA-mutated cancers at/near maximum tolerated doses by trapping PARP-1 on damaged chromatin, benefitting only small patient proportions. The benefits of targeting non-DNA repair aspects of PARP with metronomic doses remain unexplored.Methods Colon epithelial cells or mouse or human bone marrow (BM)-derived-myeloid-derived suppressor cells (MDSCs) were stimulated to assess the effect of partial PARP-1 inhibition on inflammatory gene expression or immune suppression. Mice treated with azoxymethane/four dextran-sulfate-sodium cycles or APCMin/+ mice bred into PARP-1+/− or treated with olaparib were used to examine the role of PARP-1 in colitis-induced or spontaneous colon cancer, respectively. Syngeneic MC-38 cell-based (microsatellite instability, MSIhigh) or CT-26 cell-based (microsatellite stable, MSS) tumor models were used to assess the effects of PARP inhibition on host responses and synergy with anti-Programmed cell Death protein (PD)-1 immunotherapy.Results Partial PARP-1 inhibition, via gene heterozygosity or a moderate dose of olaparib, protected against colitis-mediated/APCMin-mediated intestinal tumorigenesis and APCMin-associated cachexia, while extensive inhibition, via gene knockout or a high dose of olaparib, was ineffective or aggravating. A sub-IC50-olaparib dose or PARP-1 heterozygosity was sufficient to block tumorigenesis in a syngeneic colon cancer model by modulating the suppressive function, but not intratumoral migration or differentiation, of MDSCs, with concomitant increases in intratumoral T cell function and cytotoxicity, as assessed by granzyme-B/interferon-γ levels. Adoptive transfer of WT-BM-MDSCs abolished the protective effects of PARP-1 heterozygosity. The mechanism of MDSC modulation involved a reduction in arginase-1/inducible nitric oxide synthase/cyclo-oxygenase-2, but independent of PARP-1 trapping on chromatin. Although a high-concentration olaparib or the high-trapping PARP inhibitor, talazoparib, activated stimulator of interferon gene (STING) in BRCA-proficient cells and induced DNA damage, sub-IC50 concentrations of either drug failed to induce activation of the dsDNA break sensor. STING expression appeared dispensable for MDSC suppressive function and was not strictly required for olaparib-mediated effects. Ironically, STING activation blocked human and mouse MDSC function with no additive effects with olaparib. A metronomic dose of olaparib was highly synergistic with anti-PD-1-based immunotherapy, leading to eradication of MSIhigh or reduction of MSS tumors in mice.Conclusions These results support a paradigm-shifting concept that expands the utility of PARP inhibitor and encourage testing metronomic dosing of PARP inhibitor to enhance the efficacy of checkpoint inhibitor-based immunotherapies in cancer

Convolutional Neural Networks Improve Radiologists’ Performance in Breast Cancer Screening for Vietnamese patients

Nowadays, breast cancer is one of the leading cancers in Vietnam, and it causes approximately 6000 deaths every year. The rate of breast cancer patients was calculated as 26.4/100000 persons in 2018. There are 21,555 new cases reported in 2020. However, these figures can be reduced with early detection and diagnosis of breast cancer disease in women through mammographic imaging. In many hospitals in Vietnam, there is a lack of experienced breast cancer radiologists. Therefore, it is helpful to develop an intelligent system to improve radiologists’ performance in breast cancer screening for Vietnamese patients. Our research aims to develop a convolutional neural network-based system for classifying breast cancer X-Ray images into three classes of BI-RADS categories as BI-RADS 1 (“normal”), BI-RADS 23 (“benign”) and BI-RADS 045 (“incomplete and malignance”). This classification system is developed based on the convolutional neural network with ResNet 50. The system is trained and tested on a breast cancer image dataset of Vietnamese patients containing 7912 images provided by Hanoi Medical University Hospital radiologists. The system accuracy uses the testing set achieved a macAUC (a macro average of the three AUCs) of 0.754. To validate our model, we performed a reader study with the breast cancer radiologists of the Hanoi Medical University Hospital, reading about 500 random images of the test set. We confirmed the efficacy of our model, which achieved performance comparable to a committee of two radiologists when presented with the same data. Additionally, the system takes only 6 seconds to interpret a breast cancer X-Ray image instead of 450 seconds interpreted by a Vietnamese radiologist. Therefore, our system can be considered as a “second radiologist,” which can improve radiologists’ performance in breast cancer screening for Vietnamese patients

Phylogenetic partitioning of the third-largest vertebrate genus in the world, Cyrtodactylus Gray, 1827 (Reptilia; Squamata; Gekkonidae) and its relevance to taxonomy and conservation

The gekkonid genus Cyrtodactylus is the third most speciose vertebrate genus in the world, containing well over 300 species that collectively range from South Asia to Melanesia across some of the most diverse landscapes and imperiled habitats on the planet. A genus-wide phylogeny of the group has never been presented because researchers working on different groups were using different genetic markers to construct phylogenies that could not be integrated. We present here Maximum likelihood and Bayesian inference mitochondrial and mito-nuclear phylogenies incorporating of 310 species that include dozens of species that had never been included in a genus-wide analysis. Based on the mitochondrial phylogeny, we partition Cyrtodactylus into 31 well-supported monophyletic species groups which, if used as recommended herein, will increase the information content of future integrative taxonomic analyses that continue to add new species to this genus at an ever-increasing annual rate. Data presented here reiterate the outcome of several previous studies indicating that Cyrtodactylus comprises an unprecedented number of narrow-range endemics restricted to single mountain tops, small islands, or karst formations that still remain unprotected. This phylogeny can provide a platform for various comparative ecological studies that can be integrated with conservation management programs across the broad diversity of landscapes and habitats occupied by this genus. Additionally, these data indicate that the true number of Cyrtodactylus remains substantially underrepresented