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Phuc Van Pham,1 Hanh Thi Le,1 Binh Thanh Vu,1 Viet Quoc Pham,1 Phong Minh Le,1 Nhan Lu-Chinh Phan,1 Ngu Van Trinh,1 Huyen Thi-Lam Nguyen,1 Sinh Truong Nguyen,1 Toan Linh Nguyen,2 Ngoc Kim Phan1 1Laboratory of Stem Cell Research and Application, University of Science, Vietnam National University, Ho Chi Minh City, 2Vietnam Military Medical University, Ha Dong, Ha Noi, Vietnam Background: Breast cancer (BC) is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs) are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs) to treat tumor-bearing humanized mice models. Materials and methods: NOD/SCID mice were used to produce the humanized mice by transplantation of human hematopoietic stem cells. Human BCSCs were injected into the mammary fat pad to produce BC humanized mice. Both hematopoietic stem cells and DCs were isolated from the human umbilical cord blood, and immature DCs were produced from cultured mononuclear cells. DCs were matured by BCSC-derived antigen incubation for 48 hours. Mature DCs were vaccinated to BC humanized mice with a dose of 106 cells/mice, and the survival percentage was monitored in both treated and untreated groups. Results: The results showed that DC vaccination could target BCSCs and reduce the tumor size and prolong survival. Conclusion: These results suggested that targeting BCSCs with DCs is a promising therapy for BC. Keywords: breast cancer, breast cancer stem cells, targeting cancer therapy, humanized mice, targeting cancer stem cells

Phuc Van Pham, Nhung Thi Nguyen, Hoang Minh Nguyen, Lam Tan Khuat, Phong Minh Le, Viet Quoc Pham, Sinh Truong Nguyen, Ngoc Kim Phan Laboratory of Stem Cell Research and Application, University of Science, Vietnam National University, Ho Chi Minh City, Vietnam Background: Dendritic cell (DC) therapy is a promising therapy for cancer-targeting treatments. Recently, DCs have been used for treatment of some cancers. We aimed to develop an in vitro assay to evaluate DC therapy in cancer treatment using a breast cancer model. Methods: DCs were induced from murine bone marrow mononuclear cells in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with GM-CSF (20 ng/mL) and IL-4 (20 ng/mL). Immature DCs were primed with breast cancer stem cell (BCSC)-derived antigens. BCSCs were sorted from 4T1 cell lines based on aldehyde dehydrogenase expression. A mixture of DCs and cytotoxic T lymphocytes (CTLs) were used to evaluate the inhibitory effect of antigen-primed DCs on BCSCs. BCSC proliferation and doubling time were recorded based on impedance-based cell analysis using the xCELLigence system. The specification of inhibitory effects of DCs and CTLs was also evaluated using the same system. Results: The results showed that impedance-based analysis of BCSCs reflected cytotoxicity and inhibitory effects of DCs and CTLs at 72 hours. Differences in ratios of DC:CTL changed the cytotoxicity of DCs and CTLs. Conclusion: This study successfully used impedance-based cell analysis as a new in vitro assay to evaluate DC efficacy in cancer immunotherapy. We hope this technique will contribute to the development and improvement of immunotherapies in the near future. Keywords: CTLs, cytotoxicity assay, dendritic cells, immunotherapy, targeting therapy

Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, using an immunolocalization approach combined with high-resolution confocal microscopy, we investigated whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule included those with putative anti-inflammatory, proresolution roles, such as regulatory T cells (FoxP3 + CD4 + ) and M2 macrophages (CD68 + arginase 1 + IL-10 + ). The frequency of these lens capsule-associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. Our results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU., Competing Interests: Disclosure Statement None declared., (Copyright © 2024. Published by Elsevier Inc.)

Background: Inflamm-aging is associated with the rate of aging and is significantly related to diseases such as Alzheimer's disease, Parkinson's disease, atherosclerosis, heart disease, and age-related degenerative diseases such as type II diabetes and osteoporosis. This study aims to evaluate the safety and efficiency of autologous adipose tissue-derived mesenchymal stem cell (AD-MSC) transplantation in aging-related low-grade inflammation patients., Methods: This study is a single-group, open-label, phase I clinical trial in which patients treated with 2 infusions (100 million cells i.v) of autologous AD-MSCs were initially evaluated in 12 inflamm-aging patients who concurrently had highly proinflammatory cytokines and 2 of the following 3 diseases: diabetes, dyslipidemia, and obesity. The treatment effects were evaluated based on plasma cytokines., Results: During the study's follow-up period, no adverse effects were observed in AD-MSC injection patients. Compared to baseline (D-44), the inflammatory cytokines IL-1α, IL-1β, IL-8, IL-6, and TNF-α were significantly reduced after 180 days (D180) of MSC infusion. IL-4/IL-10 at 90 days (D90) and IL-2/IL-10 at D180 increased, reversing the imbalance between proinflammatory and inflammatory ratios in the patients., Conclusion: AD-MSCs represent a potential intervention to prevent age-related inflammation in patients., Trial Registration: ClinicalTrials.gov number is NCT05827757, first registered on 13th Oct 2020., (© 2024. The Author(s).)

α-catenin (α-cat) displays force-dependent unfolding and binding to actin filaments through direct and indirect means, but features of adherens junction structure and function most vulnerable to loss of these allosteric mechanisms have not been directly compared. By reconstituting an α-cat F-actin-binding domain unfolding mutant known to exhibit enhanced binding to actin (α-cat-H0-FABD + ) into α-cat knockout Madin Darby Canine Kidney (MDCK) cells, we show that partial loss of the α-cat catch bond mechanism (via an altered H0 α-helix) leads to stronger epithelial sheet integrity with greater colocalization between the α-cat-H0-FABD + mutant and actin. α-cat-H0-FABD + -expressing cells are less efficient at closing scratch-wounds, suggesting reduced capacity for more dynamic cell-cell coordination. Evidence that α-cat-H0-FABD + is equally accessible to the conformationally sensitive α18 antibody epitope as WT α-cat and shows similar vinculin recruitment suggests this mutant engages lower tension cortical actin networks, as its M-domain is not persistently open. Conversely, α-cat-M-domain salt-bridge mutants with persistent recruitment of vinculin and phosphorylated myosin light chain show only intermediate monolayer adhesive strengths, but display less directionally coordinated and thereby slower migration speeds during wound-repair. These data show α-cat M- and FABD-unfolding mutants differentially impact cell-cell cohesion and migration properties, and suggest signals favoring α-cat-cortical actin interaction without persistent M-domain opening may improve epithelial monolayer strength through enhanced coupling to lower tension actin networks.

Site-specific carbon isotope ratio measurements by quantitative 13 C NMR ( 13 C-qNMR), Orbitrap-MS, and GC-IRMS offer a new dimension to conventional bulk carbon isotope ratio measurements used in food provenance, forensics, and a number of other applications. While the site-specific measurements of carbon isotope ratios in vanillin by 13 C-qNMR or Orbitrap-MS are powerful new tools in food analysis, there are a limited number of studies regarding the validity of these measurement results. Here we present carbon site-specific measurements of vanillin by GC-IRMS and 13 C-qNMR for methoxy carbon. Carbon isotope delta (δ 13 C) values obtained by these different measurement approaches demonstrate remarkable agreement; in five vanillin samples whose bulk δ 13 C values ranged from -31‰ to -26‰, their δ 13 C values of the methoxy carbon ranged from -62.4‰ to -30.6‰, yet the difference between the results of the two analytical approaches was within ±0.6‰. While the GC-IRMS approach afforded up to 9-fold lower uncertainties and required 100-fold less sample compared to the 13 C-qNMR, the 13 C-qNMR is able to assign δ 13 C values to all carbon atoms in the molecule, not just the cleavable methoxy group.

Objectives: We investigate the anticancer activity and human stimulator of interferon genes pathway activation by a new hydrated-prenylated tetraoxygenated xanthone, garcicowanone I (1) and two known xanthones (2 and 3) that were isolated from the root bark of Garcinia cowa Roxb. ex Choisy., Methods: The anticancer activity of each compound was evaluated by sulforhodamine B assay in immortalized cancer cell lines. Stimulator of interferon genes pathway activation was assessed by western blot analysis using human THP-1-derived macrophages. The production of pro-inflammatory cytokines from these macrophages was also evaluated via enzyme-linked immunosorbent assay., Key Findings: Both compounds 1 and 3 displayed moderate inhibitory effects on the cancer cells, including a cisplatin-resistant cell line, with IC50 values in the range of 10-20 µM. All three xanthones activated the stimulator of interferon genes, as evidenced by phosphorylation of tank-binding kinase 1, the stimulator of interferon genes protein and interferon regulatory factor 3. Furthermore, treatment of these macrophages with compounds 1-3 led to the production of pro-inflammatory cytokines, including interleukin 6, tumour necrosis factor α and interleukin 1β., Conclusions: In conclusion, the isolated xanthones, including the novel garcicowanone I, displayed promising anticancer and immunomodulatory activity that warrants further research., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recurrent epithelial erosions develop in the cornea due to prior injury or genetic predisposition. Studies of recurrent erosions in animal models allow us to gain insight into how erosions form and are resolved. While slowing corneal epithelial cell migration and reducing their proliferation following treatment with mitomycin C reduce erosion formation in mice after sterile debridement injury, additional factors have been identified related to cytokine expression and immune cell activation. The relationship between recruitment of immune cells to the region of the cornea where erosions form and their potential roles in erosion formation and/or erosion repair remains unexplored in the C57BL/6 mouse recurrent erosion model. Here, high resolution imaging of mouse corneas was performed at D1, D7, and D28 after dulled-blade debridement injury in C57BL/6 mice. Around 50% of these mice have frank corneal erosions at D28 after wounding. A detailed assessment of corneas revealed the involvement of M2 macrophages in both frank and developing erosions at early stages of their formation.

The eye is an immune-privileged site, with both vasculature and lymphatics absent from the central light path. Unique adaptations have made it possible for immune cells to be recruited to this region of the eye in response to ocular injuries and pathogenic insults. The induction of such immune responses is typically activated by tissue resident immune cells, considered the sentinels of the immune system. We discovered that, despite the absence of an embedded vasculature, the embryonic lens becomes populated by resident immune cells. The paths by which they travel to the lens during development were not known. However, our previous studies show that in response to corneal wounding immune cells travel to the lens from the vascular-rich ciliary body across the zonules that link these two tissues. We now examined whether the zonule fibers provide a path for immune cells to the embryonic lens, and the zonule-associated matrix molecules that could promote immune cell migration. The vitreous also was examined as a potential source of lens resident immune cells. This matrix-rich site in the posterior of the eye harbors hyalocytes, an immune cell type with macrophage-like properties. We found that both the zonules and the vitreous of the embryonic eye contained fibrillin-2-based networks and that migration-promoting matrix proteins like fibronectin and tenascin-C were linked to these fibrils. Immune cells were seen emerging from the ciliary body, migrating along the ciliary zonules to the lens, and invading through the lens capsule at its equator. This is just adjacent to where immune cells take up residence in the embryonic lens. In contrast, the immune cells of the vitreous were not detected in the region of the lens. These results strongly suggest that the ciliary zonules are a primary path of immune cell delivery to the developing lens.

Vanillin, one of the world's most popular flavor used in food and pharmaceutical industries, is extracted from vanilla beans or obtained (bio)-synthetically. The price of natural vanillin is considerably higher than that of its synthetic alternative which leads increasingly to counterfeit vanillin. Here, we describe the workflow of combining carbon isotope ratio combustion mass spectrometry with quantitative carbon nuclear magnetic resonance spectrometry ( 13 C-qNMR) to obtain carbon isotope measurements traceable to the Vienna Peedee Belemnite (VPDB) with 0.7‰ combined standard uncertainty (or expanded uncertainty of 1.4‰ at 95% confidence level). We perform these measurements on qualified Bruker 400 MHz instruments to certify site-specific carbon isotope delta values in two vanillin materials, VANA-1 and VANB-1, believed to be the first intramolecular isotopic certified reference material (CRMs)., (© 2022. Crown.)

Objective: This systematic review estimated the pooled R0 for early COVID-19 outbreaks and identified the impact of study-related factors such as methods, study location and study period on the estimated R0., Methods: We searched electronic databases for human studies published in English between 1 December 2019 and 30 September 2020 with no restriction on country/region. Two investigators independently performed the data extraction of the studies selected for inclusion during full-text screening. The primary outcome, R0, was analysed by random-effects meta-analysis using the restricted maximum likelihood method., Results: We identified 26,425 studies through our search and included 151 articles in the systematic review, among which 81 were included in the meta-analysis. The estimates of R0 from studies included in the meta-analysis ranged from 0.4 to 12.58. The pooled R0 for COVID-19 was estimated to be 2.66 (95% CI, 2.41-2.94). The results showed heterogeneity among studies and strong evidence of a small-study effect., Conclusions: The high heterogeneity in studies makes the use of the R0 for basic epidemic planning difficult and presents a huge problem for risk assessment and data synthesis. Consensus on the use of R0 for outbreak assessment is needed, and its use for assessing epidemic risk is not recommended.

Objective: To determine the relationship between team dynamics with healthcare coordination and clinical job satisfaction of the community health workers (CHWs)., Methods: A cross-sectional study was conducted among 133 health workers (including doctors, nurses, or midwives) at 21 Commune Health Cent in Quoc Oai District, Vietnam, from July 2015 to May 2017. A self-administered questionnaire consisting of 5-Likert items regarding team dynamics and healthcare coordination clinical work satisfaction was utilised. Descriptive statistics and correlation matrix were applied for seven factors of team dynamic, clinical work satisfaction, and patient care coordination queried by primary care providers. Bayesian model averaging (BMA) was used to identify the predictors of the level of team dynamics and healthcare coordination., Results: The mean score of overall team dynamics among the study participants was 4.08. Clinical work satisfaction and patient care coordination scores among resident physicians were higher than those of attending clinicians; however, the differences were not statistically significant. The results of BMA analysis indicated that team dynamics significantly associated with clinical work satisfaction, and it explains 9% of the total variance in clinical work satisfaction. Team dynamics level was also positively associated with patient care coordination. Patient care coordination was not a significant mediator between team dynamics and clinical work satisfaction., Conclusion: Team dynamics is a potential contributor to improving patient care coordination and clinical job satisfaction of CHWs. As no significant correlation between patient care coordination and clinical job satisfaction was observed, to improve team performance, providing conditions that facilitate team building and teamwork should be conducted for CHWs in CHCs., (© 2022 John Wiley & Sons Ltd.)

Background: Movement towards Universal Health Coverage (UHC) can improve health services, risk factor management, and inequality in non-communicable diseases (NCD); conversely, prioritizing and monitoring NCD management can support pathways to UHC in resource-limited settings. We aimed to estimate trends in NCD management indicators in Vietnam from 2010, and projections to 2030 at national and sub-national levels; compute the probability of reaching UHC targets; and measure inequalities in NCD management indicators at demographic, geographic, and socio-economic levels., Methods: We included data of 37,595 households from four nationally representative surveys from 2010. We selected and estimated the coverage of NCD health service and risk management indicators nationally and by six sub-national groups. Using Bayesian models, we provided trends and projections and calculated the probability of reaching UHC targets of 80% coverage by 2030. We estimated multiple inequality indices including the relative index of inequality, slope index of inequality, and concentration index of inequality, and provided an assessment of improvement in inequalities over the study period., Findings: Nationally, all indicators showed a low probability of achieving 2030 targets except sufficient use of fruit and vegetables (SUFV) and non-use of tobacco (NUT). We observed declining trends in national coverage of non-harmful use of alcohol (NHUA), sufficient physical activity (SPA), non-overweight (NOW), and treatment of diabetes (TOD). Except for SPA, no indicator showed the likelihood of achieving 2030 targets at any regional level. Our model suggested a non-achievement of 2030 targets for all indicators in any wealth quintile and educational level, except for SUFV and NUT. There were diversities in tendency and magnitude of inequalities with widening gaps between genders (SPA, TOD), ethnic groups (SUFV), urban-rural areas (TOH), wealth quintiles, and educational levels (TOD, NUT, NHUA)., Interpretation: Our study suggested slow progress in NCD management at the national level and among key sub-populations in Vietnam, together with existing and increasing inequalities between genders, ethnicities, geographic areas, and socioeconomic groups. We emphasised the necessity of continuously improving the healthcare system and facilities, distributing resources between geographic areas, and simultaneously integrating economic, education, and gender intervention and programs., Funding: None., Competing Interests: We declare no conflict of interest., (© 2022 The Author(s).)

Lithium-sulfur (Li-S) batteries are one of the most promising next-generation energy storage technologies due to their high theoretical energy and low cost. However, Li-S cells with practically high energy still suffer from a very limited cycle life with reasons which remain unclear. Here, through cell study under practical conditions, it is proved that an internal short circuit (ISC) is a root cause of early cell failure and is ascribed to the crosstalk between the S cathode and Li anode. The cathode topography affects S reactions through influencing the local resistance and electrolyte distribution, particularly under lean electrolyte conditions. The inhomogeneous reactions of S cathodes are easily mirrored by the Li anodes, resulting in exaggerated localized Li plating/stripping, Li filament formation, and eventually cell ISC. Manipulating cathode topography is proven effective to extend the cell cycle life under practical conditions. The findings of this work shed new light on the electrode design for extending cycle life of high-energy Li-S cells, which are also applicable for other rechargeable Li or metal batteries., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.

Tumor-associated epitopes presented on MHC-I that can activate the immune system against cancer cells are typically identified from annotated protein-coding regions of the genome, but whether peptides originating from novel or unannotated open reading frames (nuORFs) can contribute to antitumor immune responses remains unclear. Here we show that peptides originating from nuORFs detected by ribosome profiling of malignant and healthy samples can be displayed on MHC-I of cancer cells, acting as additional sources of cancer antigens. We constructed a high-confidence database of translated nuORFs across tissues (nuORFdb) and used it to detect 3,555 translated nuORFs from MHC-I immunopeptidome mass spectrometry analysis, including peptides that result from somatic mutations in nuORFs of cancer samples as well as tumor-specific nuORFs translated in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs are an unexplored pool of MHC-I-presented, tumor-specific peptides with potential as immunotherapy targets., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We translated the Effort-Reward imbalance questionnaire, an instrument for measuring work stress, into the Vietnamese language and investigated its psychometric properties among nurses in Vietnam. In a hospital-based cross-sectional study design, we sampled and interviewed 207 nurses working full-time (response rate 83%). We evaluated the internal consistency using standardized Cronbach's alpha coefficients and structural validity using confirmatory factor analysis. Discriminative validity was assessed by comparing the measured scores between age groups, gender, education levels, income groups, and job positions. In addition, we confirmed the criterion validity by investigating its association with self-reported health using simple and multiple logistic regression models. Most of the participants were female (73.3%), young (average 28.5 years old), and had education levels of college or higher (53.5%). We observed sufficient internal consistency in effort, reward, and over-commitment scales (Cronbach's alpha 0.80, 0.76, and 0.68, respectively). Confirmatory factor analysis of the three-factor hierarchical model showed an acceptable fit and fair construct validity with most moderate or stronger (>0.3) factor loading coefficients. Poor self-rated health was more likely in respondents in both Effort-Reward ratio's middle tertile (adjusted Odd-Ratio = 2.80, p-value = 0.031) and highest tertile (adjusted Odd-Ratio = 2.64, p-value = 0.05), adjusting for age, gender, and education levels. The Effort-reward imbalance scale has adequate reliability and validity for assessing work stress among nurses in Vietnam. Its significant association with poor self-rated health warrants further investigation. The validated instrument can help measure the effort-reward imbalance to manage better work-related emotional strains and mental health issues among nurses and ensure human resources' stability in healthcare in Vietnam., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Inc.)

Although Vietnam has promoted the utilisation of highly active antiretroviral therapy (HAART) towards HIV elimination targets, adherence to treatment has remained under-investigated. We aimed to describe high-risk behaviours and clinical characteristics by adherence status and to identify the factors associated with non-adherence. We included 426 people living with HIV (PLWH) currently or previously involved in HAART. Most participants were men (75.4%), young (33.6 years), with low income and low education levels. Non-adherent PLWH (11.5%) were more likely to have a larger number of sex partners ( p -value = 0.053), sex without condom use ( p -value = 0.007) and not receive result at hospital or voluntary test centre ( p -value = 0.001). Multiple logistic regression analysis showed that demographic (education levels), sexual risk behaviours (multiple sex partners and sex without using condom) and clinical characteristics (time and facility at first time received HIV-positive result) were associated with HAART non-adherence. There are differences in associated factors between women (education levels and place of HIV testing) and men (multiple sex partners). Gender-specific programs, changing risky behaviours and reducing harms among PLWH may benefit adherence. We highlight the need to improve the quantity and quality of HIV/AIDS services in Vietnam, especially in pre- and post-test counselling, to achieve better HAART adherence, working towards ending AIDS in 2030.

Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses 1-3 ; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8 + T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide-human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: To assess the reproductive, maternal, newborn and child health (RMNCH) service coverage in Vietnam with trends in 2000-2014, projections and probability of achieving targets in 2030 at national and sub-national levels; and to analyze the socioeconomic, regional and urban-rural inequalities in RMNCH service indicators., Methods: We used national population-based datasets of 44,624 households in Vietnam from 2000 to 2014. We applied Bayesian regression models to estimate the trends in and projections of RMNCH indicators and the probabilities of achieving the 2030 targets. Using the relative index, slope index, and concentration index of inequality, we examined the patterns and trends in RMNCH coverage inequality., Findings: We projected that 9 out of 17 health service indicators (53%) would likely achieve the 2030 targets at the national level, including at least one and four ANC visits, BCG immunization, access to improved water and adequate sanitation, institutional delivery, skilled birth attendance, care-seeking for pneumonia, and ARI treatment. We observed very low coverages and zero chance of achieving the 2030 targets at national and sub-national levels in early initiation and exclusive breastfeeding, family planning needs satisfied, and oral rehydration therapy. The most deprived households living in rural areas and the Northwest, Northeast, North Central, Central Highlands, and Mekong River Delta regions would not reach the 80% immunization coverage of DPT3, Polio3, Measles and full immunization. We found socioeconomic, regional, and urban-rural inequalities in all RMNCH indicators in 2014 and no change in inequalities over 15 years in the lowest-coverage indicators., Interpretation: Vietnam has made substantial progress toward UHC. By improving the government's health system reform efforts, re-allocating resources focusing on people in the most impoverished rural regions, and restructuring and enhancing current health programs, Vietnam can achieve the UHC targets and other health-related SDGs., Funding: The authors did not receive any funds for conducting this study., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Objectives: To estimate trends in and projections of annual HIV testing and condom use at last higher-risk sex and to calculate the probability of reaching key United Nations Programme on AIDS (UNAIDS)'s target., Design: We included 114 nationally-representative datasets in 38 African countries from Demographic and Health Surveys and Multiple Indicator Cluster Surveys with 1 456 224 sexually active adults age 15-49 from 2003 to 2018., Methods: We applied Bayesian mixed effect models to estimate the coverage of annual HIV testing and condom use at last higher-risk sex for every country and year to 2030 and the probability of reaching UNAIDS testing and condom use targets of 95% coverage by 2030., Results: Seven countries saw downward trends in annual HIV testing and four saw decreases in condom use at higher-risk sex, whereas most countries have upward trends in both indicators. The highest coverage of testing in 2030 is predicted in Swaziland with 92.6% (95% credible interval: 74.5-98.1%), Uganda with 90.5% (72.2-97.2%), and Lesotho with 90.5% (69.4%-97.6%). Meanwhile, Swaziland, Lesotho, and Namibia will have the highest proportion of condom use in 2030 at 85.0% (57.8-96.1%), 75.6% (42.3-93.6%), and 75.5% (42.4-93.2%). The probabilities of reaching targets were very low for both HIV testing (0-28.5%) and condom use (0-12.1%)., Conclusions: We observed limited progress on annual HIV testing and condom use at last higher-risk sex in Africa and little prospect of reaching global targets for HIV/AIDS elimination. Although some funding agencies are considering withdrawal from supporting Africa, more attention to funding and expanding testing and treatment is needed in this region., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Towards the elimination of this global epidemic, understanding the high-risk behaviors of people newly diagnosed with HIV/AIDS (PNDWH) is essential. This study aimed to describe the general characteristics and high-risk behaviors of PNDWH and identify associated factors for adopting high-risk behaviors. A cross-sectional survey was conducted in Vietnam to explore the high-risk behaviors of 506 PNDWH. Associated factors were identified using multivariable logistic regressions. 83.2% of participants had sex without using a condom, and 27.9% had more than two sex partners. Among injected drug users, 44% had shared needles with an average number of 2.1 shared partners. Male, Kinh ethnicity (Vietnamese), high income, and high educational level were risk factors for high-risk behaviors. Our findings revealed the first time a comprehensive picture of PNDWH and emphasized the high prevalence of STIs, including untreated STIs and the long delay since the early HIV diagnosis. Also, our model found much higher risk behaviors among participants who were non-adherent to ART and those currently enrolled in ART. By better managing newly-diagnosed cases, better integrating STI management services and prevention consultants, as well as improving ART adherence programs, Vietnam can make better progress towards the complete control of HIV for its most vulnerable populations.

Background: The prevalence of HIV among men who have sex with men (MSM) in southwest China is still increasing. This study aimed to investigate the trend in HIV incidence and its associated risk factors among MSM in Chengdu, China., Method: Incidence data were collected from the largest local non-governmental organization (NGO) serving MSM in Chengdu between 2012 and 2018, while information on sexual behaviors was collected from 2014. All MSM who received voluntary counseling and testing services (VCT) in the collaborating NGO at least twice during the study period were included. We calculated the HIV incidence density among MSM every 2 years and the overall incidence rate. A Cox proportional hazards regression model was employed to identify risk factors for HIV infection., Result: A total of 4578 HIV-negative participants were included in the cohort. The total incidence density was 5.95 (95% CI: 5.37-6.56)/100 person-years (PYs) between 2012 and 2018. The segmented incidence density was 9.02 (95% CI: 7.46-10.78), 5.85 (95% CI: 4.86-6.97), 5.43 (95% CI: 4.53-6.46), and 3.09 (95% CI: 2.07-4.41)/100 PYs in 2012-2013, 2014-2015, 2016-2017, and 2018, respectively. After adjusting for sociodemographic characteristics, compared to participants without sexual partners within 6 months, MSM with one fixed partner (Adjusted Hazard Ratio, AHR = 1.18, 95% CI: 0.44-3.19) and more than five partners (AHR = 2.24, 95% CI: 0.81-6.20) had increased risk of HIV infection. MSM who used condom inconsistently had a higher risk of HIV infection (AHR = 1.87, 95% CI: 1.46-2.38) compared to consistent condom users., Conclusion: The decreased HIV incidence density among MSM was potentially related to the successful comprehensive HIV prevention strategies in Chengdu. Multiple male sexual partnerships and inconsistent condom use during anal intercourse were risk factors associated with HIV occurrence.

The 2020 summer Olympic and Paralympic Games in Tokyo were postponed to July-September 2021 due to the coronavirus disease 2019 (COVID-19) pandemic. While COVID-19 has emerged as a monumental health threat for mass gathering events, heat illness must be acknowledged as a potentially large health threat for maintaining health services. We examined the number of COVID-19 admissions and the Tokyo rule for emergency medical care, in Tokyo, from March to September 2020, and investigated the weekly number of emergency transportations due to heat illness and weekly averages of the daily maximum Wet Bulb Globe Temperature (WBGT) in Tokyo in the summer (2016-2020). The peak of emergency transportations due to heat illness overlapped the resurgence of COVID-19 in 2020, and an increase of heat illness patients and WBGT has been observed. Respect for robust science is critical for the decision-making process of mass gathering events during the pandemic, and science-based countermeasures and implementations for COVID-19 will be warranted. Without urgent reconsiderations and sufficient countermeasures, the double burden of COVID-19 and heat-related illnesses in Tokyo will overwhelm the healthcare provision system, and maintaining essential health services will be challenging during the 2021 summer Olympic and Paralympic Games.

MS is the most effective method to directly identify peptides presented on human leukocyte antigen (HLA) molecules. However, current standard approaches often use 500 million or more cells as input to achieve high coverage of the immunopeptidome, and therefore, these methods are not compatible with the often limited amounts of tissue available from clinical tumor samples. Here, we evaluated microscaled basic reversed-phase fractionation to separate HLA peptide samples offline followed by ion mobility coupled to LC-MS/MS for analysis. The combination of these two separation methods enabled identification of 20% to 50% more peptides compared with samples analyzed without either prior fractionation or use of ion mobility alone. We demonstrate coverage of HLA immunopeptidomes with up to 8107 distinct peptides starting with as few as 100 million cells. The increased sensitivity obtained using our methods can provide data useful to improve HLA-binding prediction algorithms as well as to enable detection of clinically relevant epitopes such as neoantigens., Competing Interests: Conflict of interest D. A. B. reported nonfinancial support from Bristol-Myers Squibb, honoraria from LM Education/Exchange Services, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside the submitted work. P. A. O. has received research funding from and has advised Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences, and Roche/Genentech, outside the submitted work. D. B. K. has previously advised Neon Therapeutics and has received consulting fees from Neon Therapeutics. D. B. K. owns equity in Agenus, Armata Pharmaceuticals, Breakbio, BioMarin Pharmaceutical, Bristol Myers Squibb, Celldex Therapeutics, Chinook Therapeutics, Editas Medicine, Exelixis, Gilead Sciences, IMV, Lexicon Pharmaceuticals, Moderna, and Regeneron Pharmaceuticals. BeiGene, a Chinese biotech company, supports unrelated research at TIGL. C. J. W. holds equity in BioNTech, Inc and receives research funding from Pharmacyclics, Inc. S. A. C. is a member of the scientific advisory boards of Kymera, PTM BioLabs, and Seer and an ad hoc scientific advisor to Pfizer and Biogen. All the other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Coping with the COVID-19 pandemic has been painful and no single model for such a purpose is perfect. However, sharing experiences is the best way for countries to learn real-time lessons and adapt to this rapidly changing pandemic. This commentary shares with the international community how an adaptive model of health system organization and responses helped Vietnam to break transmission of coronavirus. We find that an effective model is adaptive to time and context, and mobilizes and engages the wider society. We identify merging of different health system units into Center for Diseases Controls as a health system organization that saved massive resources. The early establishment of a formal committee responding to the pandemic helped unify every public health strategy. The mobilization of different stakeholders and communities added resources and facilitated a synchronous implementation of response strategies, even where those strategies involved significant personal or financial sacrifice. National training on Covid-19 treatment for healthcare professionals across the entire hospital system was useful to expand the health service availability. Quickly published response guidelines helped to activate every level of the health system and involve every sector of society. A strategy of keeping high alert and preemptive action is also essential for coping with the pandemic., (© 2020 John Wiley & Sons, Ltd.)

Natural products remain a viable source of novel therapeutics, and as detection and extraction techniques improve, we can identify more molecules from a broader set of plant tissues. The aim of this study was an investigation of the cytotoxic and anti-plasmodial activities of the methanol extract from Stephania dielsiana Y.C. Wu leaves and its isolated compounds. Our study led to the isolation of seven alkaloids, among which oxostephanine ( 1 ) is the most active against several cancer cell lines including HeLa, MDA-MB231, MDA-MB-468, MCF-7, and non-cancer cell lines, such as 184B5 and MCF10A, with IC 50 values ranging from 1.66 to 4.35 μM. Morever, oxostephanine ( 1 ) is on average two-fold more active against cancer cells than stephanine ( 3 ), having a similar chemical structure. Cells treated with oxostephanine ( 1 ) are arrested at G2/M cell cycle, followed by the formation of aneuploidy and apoptotic cell death. The G2/M arrest appears to be due, at least in part, to the inactivation of Aurora kinases, which is implicated in the onset and progression of many forms of human cancer. An in-silico molecular modeling study suggests that oxostephanine ( 1 ) binds to the ATP binding pocket of Aurora kinases to inactivate their activities. Unlike oxostephanine ( 1 ), thailandine ( 2 ) is highly effective against only the triple-negative MDA-MB-468 breast cancer cells. However, it showed excellent selectivity against the cancer cell line when compared to its effects on non-cancer cells. Furthermore, thailandine ( 2 ) showed excellent anti-plasmodial activity against both chloroquine-susceptible 3D7 and chloroquine-resistant W2 Plasmodium falciparum strains. The structure-activity relationship of isolated compound was also discussed in this study. The results of this study support the traditional use of Stephania dielsiana Y.C. Wu and the lead molecules identified can be further optimized for the development of highly effective and safe anti-cancer and anti-plasmodial drugs.

Prediction of HLA epitopes is important for the development of cancer immunotherapies and vaccines. However, current prediction algorithms have limited predictive power, in part because they were not trained on high-quality epitope datasets covering a broad range of HLA alleles. To enable prediction of endogenous HLA class I-associated peptides across a large fraction of the human population, we used mass spectrometry to profile >185,000 peptides eluted from 95 HLA-A, -B, -C and -G mono-allelic cell lines. We identified canonical peptide motifs per HLA allele, unique and shared binding submotifs across alleles and distinct motifs associated with different peptide lengths. By integrating these data with transcript abundance and peptide processing, we developed HLAthena, providing allele-and-length-specific and pan-allele-pan-length prediction models for endogenous peptide presentation. These models predicted endogenous HLA class I-associated ligands with 1.5-fold improvement in positive predictive value compared with existing tools and correctly identified >75% of HLA-bound peptides that were observed experimentally in 11 patient-derived tumor cell lines.

Authentication of natural products is of major relevance in the context of manufactured drugs or herbal supplements since such active products generate a lucrative market. The analytical method to identify and quantify valuable natural products is critical for quality control and product assignment of herbal supplements. In this framework, we propose to apply a recently developed quantitative 2D NMR approach called Q QUIPU (Quick QUantItative Perfected and pUre shifted) in combination with 1D 1 H NMR capable to access the concentration of three major alkaloids, berberine, β-hydrastine and canadine, in the root extract of goldenseal (Hydrastis canadensis), one of the 20 most popular herbal supplements used worldwide. We highlight the complementarity of 1D and 2D quantitative NMR to accurately assess the amount of alkaloids with different range of concentrations and stability within extracts. In particular, unstable natural products having non-overlapped signals like berberine could only be quantified by sensitive and fast 1D 1 H, while overlapped signals of β-hydrastine and low intense ones of canadine could only be quantified with the recent 2D Q QUIPU HSQC. Results obtained from this combined approach have led to a good accuracy (<10%) as compared with coupled UHPLC-MS/UV techniques. This quantitative NMR approach paves the way to numerous applications where the accurate quantification of targeted compounds in complex mixtures is required, for instance in agricultural, food and pharmaceuticals products., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses 1,2 and can function as bona fide antigens that facilitate tumour rejection 3 . Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma 4-6 , is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load 1,7 and an immunologically 'cold' tumour microenvironment 8 . We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4 + and CD8 + T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.

The bone marrow microenvironment, also known as the bone marrow niche, is a complex network of cell types and acellular factors that supports normal hematopoiesis. For many years, leukemia was believed to be caused by a series of genetic hits to hematopoietic stem and progenitor cells, which transform them to preleukemic, and eventually to leukemic, cells. Recent discoveries suggest that genetic alterations in bone marrow niche cells, particularly in osteogenic cells, may also cause myeloid leukemia in mouse models. The osteogenic niche, which consists of osteoprogenitors, preosteoblasts, mature osteoblasts, osteocytes and osteoclasts, has been shown to play a critical role in the maintenance and expansion of hematopoietic stem and progenitor cells as well as in their oncogenic transformation into leukemia stem/initiating cells. We have recently shown that acute myeloid leukemia cells induce osteogenic differentiation in mesenchymal stromal cells to gain a growth advantage. In this review, we discuss the role of the osteogenic niche in the maintenance of hematopoietic stem and progenitor cells, as well as in their transformation into leukemia cells. We also discuss the signaling pathways that regulate osteogenic niche-hematopoietic stem and progenitor cells or osteogenic niche-leukemic stem/initiating cell interactions in the bone marrow, together with novel approaches for therapeutically targeting these interactions., (Copyright© 2018 Ferrata Storti Foundation.)

The bifunctional alkylating agents epichlorohydrin (ECH) and diepoxybutane (DEB) have been linked to increased cancer risks in industrial workers. These compounds react with DNA and proteins, leading to genotoxic effects. We used the comet assay to monitor formation of cross-links in HL-60 cells treated with ECH, DEB, and the structurally related anti-cancer drug mechlorethamine (HN2). We report a time- and dose-dependent cytotoxicity that correlated with cross-linking activity, following the order HN2 > DEB > ECH. The rate of cross-link repair also varied with drug, with ECH-induced lesions the fastest to repair. High drug doses led to the formation of saturating amounts of HN2 cross-links that were repaired inefficiently. DEB and ECH produced fewer overall cross-links, but some were also resistant to repair. These persistent cross-links may activate cell-cycle arrest to allow repair of damage, with prolonged arrest triggering apoptosis. Quantitative reverse transcription polymerase chain reaction experiments revealed that treatment of HL-60 cells with DEB and ECH results in up-regulation of several genes involved in the intrinsic (mitochondrial) apoptosis pathway, including BAX, BAK1, CASP-9, APAF-1, and BCL-2. These findings contribute to our understanding of the principles underlying the carcinogenic potentials of these xenobiotics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mesenchymal stromal cells (MSC) support acute myeloid leukemia (AML) cell survival in the bone marrow (BM) microenvironment. Protein expression profiles of AML-derived MSC are unknown. Reverse phase protein array analysis was performed to compare expression of 151 proteins from AML-MSC (n=106) with MSC from healthy donors (n=71). Protein expression differed significantly between the two groups with 19 proteins over-expressed in leukemia stromal cells and 9 over-expressed in normal stromal cells. Unbiased hierarchical clustering analysis of the samples using these 28 proteins revealed three protein constellations whose variation in expression defined four MSC protein expression signatures: Class 1, Class 2, Class 3, and Class 4. These cell populations appear to have clinical relevance. Specifically, patients with Class 3 cells have longer survival and remission duration compared to other groups. Comparison of leukemia MSC at first diagnosis with those obtained at salvage (i.e. relapse/refractory) showed differential expression of 9 proteins reflecting a shift toward osteogenic differentiation. Leukemia MSC are more senescent compared to their normal counterparts, possibly due to the overexpressed p53/p21 axis as confirmed by high β-galactosidase staining. In addition, overexpression of BCL-X L in leukemia MSC might give survival advantage under conditions of senescence or stress and overexpressed galectin-3 exerts profound immunosuppression. Together, our findings suggest that the identification of specific populations of MSC in AML patients may be an important determinant of therapeutic response., (Copyright © 2018 Ferrata Storti Foundation.)