Microwave hyperthermia enhances radiosensitization by decreasing DNA repair efficiency and inducing oxidative stress in PC3 prostatic adenocarcinoma cells.

PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.

SiRNA-HIF-1α delivered by attenuated Salmonella enhances the efficacy of Lenvatinib against hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) remains a major challenge in the medical field. Lenvatinib, a multi-target tyrosine kinase inhibitor, has demonstrated anti-HCC effects by targeting and inhibiting pathways such as vascular endothelial growth factor receptor 1-3 (VEGFR1-3). However, the therapeutic efficacy of Lenvatinib is subject to various influences, with the hypoxic microenvironment of the tumor being a pivotal factor. Consequently, altering the hypoxic milieu of the tumor emerges as a viable strategy to augment the efficacy of Lenvatinib. Hypoxia-inducible factor-1α (HIF-1α), synthesized by tumor cells in response to oxygen-deprived conditions, regulates the expression of resistance genes, promotes tumor angiogenesis and cell proliferation, enhances tumor cell invasion, and confers resistance to radiotherapy and chemotherapy. Thus, we constructed a self-designed siRNA targeting HIF-1α to suppress its expression and improve the efficacy of Lenvatinib in treating HCC. The therapeutic efficacy of siRNA-HIF-1α in combination with Lenvatinib on HCC were evaluated through in vivo and in vitro experiments. The results showed that the recombinant Salmonella delivering siRNA-HIF-1α in combination with Lenvatinib effectively inhibited tumor growth and prolonged the survival of tumor-bearing mice. This treatment approach reduced cell proliferation and angiogenesis in HCC tissues while promoting tumor cell apoptosis. Additionally, this combined therapy significantly increased the infiltration of T lymphocytes and M1 macrophages within the tumor microenvironment, as well as elevated the proportion of immune cells in the spleen, thereby potentiating the host's immune response against the tumor.

BAP31 Promotes Angiogenesis via Galectin-3 Upregulation in Neuroblastoma.

Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis remains unexplored. This study investigated BAP31 modulation of pro-angiogenic factors in SH-SY5Y NB cells. Through protein overexpression, knockdown, antibody blocking, and quantification experiments, we demonstrated that overexpression of BAP31 led to increased levels of vascular endothelial growth factor A (VEGFA) and Galectin-3 (GAL-3), which are known to promote angiogenesis. Conditioned medium derived from BAP31-overexpressing neuroblastoma cells stimulated migration and tube formation in endothelial cells, indicating its pro-angiogenic properties. Also, we demonstrated that BAP31 enhances capillary tube formation by regulating hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream target, GAL-3. Furthermore, GAL-3 downstream proteins, Jagged 1 and VEGF receptor 2 (VEGFR2), were up-regulated, and blocking GAL-3 partially inhibited the BAP31-induced tube formation. These findings suggest that BAP31 promotes angiogenesis in NB by modulating GAL-3 and VEGF signaling, thereby shaping the tumor microenvironment. This study provides novel insights into the pro-angiogenic role of BAP31 in NB.

A Novel Signature Based on m6A Regulator-Mediated Genes Along Glycolytic Pathway Predicts Prognosis and Immunotherapy Responses of Gastric Cancer Patients.

N6-methyladenosine (m6A) modification is involved in many aspects of gastric cancer (GC). Moreover, m6A and glycolysis-related genes (GRGs) play important roles in immunotherapeutic and prognostic implication of GC. However, GRGs involved in m6A regulation have never been analyzed comprehensively in GC. Herein, the study aims to identify and validate a novel signature based on m6A-related GRGs in GC patients. Therefore, a m6A-related GRGs signature is established, which can predict the survival of patients with GC and remain an independent prognostic factor in multivariate analyses. Clinical significance of the model is well validated in internal cohort and independent validation cohort. In addition, the expression levels of risk model-related GRGs in clinical samples are validated. Consistent with the database results, all model genes are up-regulated in expression except DCN. After regrouping the patients based on this risk model, the study can effectively distinguish between them in respect to immune-cell infiltration microenvironment and immunotherapeutic response. Additionally, candidate drugs targeting risk model-related GRGs are confirmed. Finally, a nomogram combining risk scores and clinical parameters is created, and calibration plots show that the nomogram can accurately predict survival. This risk model can serve as a reliable assessment tool for predicting prognosis and immunotherapeutic responses in GC patients.

Liriogerphines E-U, further unique sesquiterpene-alkaloid hybrids from the rare Chinese tulip tree.

Seventeen undescribed sesquiterpene-alkaloid hybrids (liriogerphines E-U, 1-17) were isolated and identified during a further phytochemical investigation on the branches and leaves of Chinese tulip tree (Liriodendron chinense), a rare medicinal and ornamental plant endemic to China. These unique heterodimers are conjugates of germacranolide-type sesquiterpenoids with structurally diverse alkaloids [i.e., aporphine- (1-15), proaporphine- (16), and benzyltetrahydroisoquinoline-type (17)] via the formation of a C-N bond. The previously undescribed structures were elucidated by comprehensive spectroscopic data analyses and electronic circular dichroism calculations. Such a class of sesquiterpene-alkaloid hybrids presumably biosynthesized via an aza-Michael addition is quite rare from terrestrial plants. In particular, the sesquiterpene-benzyltetrahydroisoquinoline hybrid skeleton has never been reported until the present study. All the isolates were evaluated for their cytotoxic effects against a small panel of leukemia cell lines (Raji, Jeko-1, Daudi, Jurkat, MV-4-11 and HL-60), and some of them exhibited considerable activities.

BAP31-Mediated miR-206/133b Cluster Promotes Transendothelial Migration and Metastasis of Colorectal Cancer.

Dysregulated B cell receptor-associated protein 31 (BAP31) plays a crucial role in tumor progression. This study aimed to investigate the functions and molecular mechanism of BAP31 on the miR-206/133b cluster in colorectal cancer (CRC). qPCR was conducted to detect miRNA and mRNA levels in tissues and cells. Western blot assays were used to assess the levels of biomarkers and targets, as well as the levels of BAP31 and HOXD10. Wound healing, coculture and transwell assays were conducted to assess the transendothelial migration abilities of CRC cells. A luciferase assay was employed to assess miRNA binding effects on targets, as well as the initiating transcription effect of genomic fragments. Tumor growth and lung metastatic models were established through an in vivo animal study. BAP31 overexpression in CRC cells led to a reduction in the expression of the miR-206/133b cluster. The expression of the miR-206/133b cluster was correlated with the transendothelial migration capability of CRC cells. The miR-206/133b cluster was found to directly regulate cell division cycle 42 (CDC42) and actin-related protein 2/3 complex subunit 5 (ARPC5) in the tight junction pathway (hsa04530). Moreover, a potential transcription regulator of the miR-206/133b cluster was also found to be Homeobox D10 (HOXD10). We further elucidated the molecular mechanisms and functional mechanisms of BAP31's regulatory role in the expression levels of the miR-206/133b cluster by inhibiting HOXD10 translocation from the cytoplasm to the nucleus. In conclusion, this study provides valuable insights into how BAP31 regulates the transcription of the miR-206/133b cluster and how BAP31-related lung metastases arise in CRC.

Differential effects of aneuploidy on growth and differentiation in human intestinal stem cells.

Aneuploidy, a near ubiquitous genetic feature of tumors, is a context-dependent driver of cancer evolution; however, the mechanistic basis of this role remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigate how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Single-cell RNA sequencing reveals that the gene expression signature across over 100 unique aneuploid karyotypes is enriched with p53 responsive genes. The primary driver of p53 activation is karyotype complexity. Complex aneuploid cells with multiple unbalanced chromosomes activate p53 and undergo G1 cell-cycle arrest, independent of DNA damage and without evidence of senescence. By contrast, simple aneuploid cells with 1-3 chromosomes gained or lost continue to proliferate, demonstrated by single cell tracking in colonoids. Notably, simple aneuploid cells exhibit impaired differentiation when niche factors are withdrawn. These findings suggest that while complex aneuploid cells are eliminated from the normal epithelium due to p53 activation, simple aneuploid cells can escape this checkpoint and may contribute to niche factor-independent growth of cancer-initiating cells.

Cytoskeletal activation of NHE1 regulates cell volume and DNA methylation.

The regulation of mammalian cell volume is crucial for maintaining key cellular processes. Cells can rapidly respond to osmotic and hydrostatic pressure imbalances during environmental challenges, generating fluxes of water and ions that alter volume within minutes. While the role of ion pump and leak in cell volume regulation has been well-established, the role of the actomyosin cytoskeleton and its substantial interplay with ion transporters are still unclear. In this work, we discover a system of cell volume regulation controlled by cytoskeletal activation of ion transporters. Under hypotonic shock, NIH-3T3 and MCF-10A display a 20% secondary volume increase (SVI) following the initial regulatory volume decrease. We show that SVI is initiated by Ca 2+ influx through stretch activated channel Piezo1 and subsequent actomyosin remodeling. Rather than contracting cells, actomyosin triggers cell swelling by activating Na + -H + exchanger 1 (NHE1) through their co-binding partner ezrin. Cytoskeletal activation of NHE1 can be similarly triggered by mechanical stretch and attenuated by soft substrates. This mechanism is absent in certain cancer cell lines such as HT1080 and MDA-MB-231, where volume regulation is dominated by intrinsic response of ion transporters. Moreover, cytoskeletal activation of NHE1 during SVI induces nuclear deformation, leading to DNA demethylation and a significant, immediate transcriptomic response in 3T3 cells, a phenomenon that is absent in HT1080 cells. Overall, our findings reveal the central role of Ca 2+ and actomyosin-mediated mechanosensation in the regulation of ion transport, cell volume, DNA methylation, and transcriptomics.

ZEB1 Transcriptionally Activates PHGDH to Facilitate Carcinogenesis and Progression of HCC.

BACKGROUND & AIMS: Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the de novo serine synthesis pathway (SSP), has been implicated in the carcinogenesis and metastasis of hepatocellular carcinoma (HCC) because of its excessive expression and promotion of SSP. In previous experiments we found that SSP flux was diminished by knockdown of zinc finger E-box binding homeobox 1 (ZEB1), a stimulator of HCC metastasis, but the underlying mechanism remains largely unknown. Here, we aimed to determine how SSP flux is regulated by ZEB1 and the contribution of such regulation to carcinogenesis and progression of HCC. METHODS: We used genetic mice with Zeb1 knockout in liver specifically to determine whether Zeb1 deficiency impacts HCC induced by the carcinogen diethylnitrosamine plus CCl4. We explored the regulatory mechanism of ZEB1 in SSP flux using uniformly-labeled [13C]-glucose tracing analyses, liquid chromatography-mass spectrometry, real-time quantitative polymerase chain reaction, luciferase report assay, and chromatin immunoprecipitation assay. We determined the contribution of the ZEB1-PHGDH regulatory axis to carcinogenesis and metastasis of HCC by cell counting assay, methyl thiazolyl tetrazolium (MTT) assay, scratch wound assay, Transwell assay, and soft agar assay in vitro, orthotopic xenograft, bioluminescence, and H&E assays in vivo. We investigated the clinical relevance of ZEB1 and PHGDH by analyzing publicly available data sets and 48 pairs of HCC clinical specimens. RESULTS: We identified that ZEB1 activates PHGDH transcription by binding to a nonclassic binding site within its promoter region. Up-regulated PHGDH augments SSP flux to enable HCC cells to be more invasive, proliferative, and resistant to reactive oxygen species and sorafenib. Orthotopic xenograft and bioluminescence assays have shown that ZEB1 deficiency significantly impairs the tumorigenesis and metastasis of HCC, and such impairments can be rescued to a large extent by exogenous expression of PHGDH. These results were confirmed by the observation that conditional knockout of ZEB1 in mouse liver dramatically impedes carcinogenesis and progression of HCC induced by diethylnitrosamine/CCl4, as well as PHGDH expression. In addition, analysis of The Cancer Genome Atlas database and clinical HCC samples showed that the ZEB1-PHGDH regulatory axis predicts poor prognosis of HCC. CONCLUSIONS: ZEB1 plays a crucial role in stimulating carcinogenesis and progression of HCC by activating PHGDH transcription and subsequent SSP flux, deepening our knowledge of ZEB1 as a transcriptional factor in fostering the development of HCC via reprogramming the metabolic pathway.

STAT5A modulates gastric cancer progression via upregulation of CD44.

OBJECTIVE: Signal transduction and transcriptional activator 5A (STAT5A), which has been reported to be frequently phosphorylated in tumors, plays pivotal roles in tumor progression. However, the role of STAT5A in gastric cancer (GC) progression and the downstream targets of STAT5A remain largely unknown. METHODS: The expression of STAT5A and CD44 were assessed. GC cells were treated with altered STAT5A and CD44 to evaluate their biological functions. Nude mice were given injections of genetically manipulated GC cells and growth of xenograft tumors and metastases was measured. RESULTS: The increased level of p-STAT5A is associated with tumor invasion and poor prognosis in GC. STAT5A promoted GC cell proliferation by upregulating CD44 expression. STAT5A directly binds to the CD44 promoter and promotes its transcription. CONCLUSIONS: The STAT5A/CD44 pathway plays a critical role in GC progression, promising potential clinical applications for improving treatment of GC.

NOD-like receptor NLRC5 promotes neuroinflammation and inhibits neuronal survival in Parkinson's disease models.

Parkinson's disease (PD) is mainly characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and neuroinflammation mediated by overactivated microglia and astrocytes. NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) has been reported to participate in various immune disorders, but its role in neurodegenerative diseases remains unclear. In the current study, we found that the expression of NLRC5 was increased in the nigrostriatal axis of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced PD, as well as in primary astrocytes, microglia and neurons exposed to different neurotoxic stimuli. In an acute MPTP-induced PD model, NLRC5 deficiency significantly reduced dopaminergic system degeneration and ameliorated motor deficits and striatal inflammation. Furthermore, we found that NLRC5 deficiency decreased the expression of the proinflammatory genes IL-1ß, IL-6, TNF-α and COX2 in primary microglia and primary astrocytes treated with neuroinflammatory stimuli and reduced the inflammatory response in mixed glial cells in response to LPS treatment. Moreover, NLRC5 deficiency suppressed activation of the NF-κB and MAPK signaling pathways and enhanced the activation of AKT-GSK-3ß and AMPK signaling in mixed glial cells. Furthermore, NLRC5 deficiency increased the survival of primary neurons treated with MPP+ or conditioned medium from LPS-stimulated mixed glial cells and promoted activation of the NF-κB and AKT signaling pathways. Moreover, the mRNA expression of NLRC5 was decreased in the blood of PD patients compared to healthy subjects. Therefore, we suggest that NLRC5 promotes neuroinflammation and dopaminergic degeneration in PD and may serve as a marker of glial activation.

In vivo imaging of heart failure with preserved ejection fraction by simultaneous monitoring of cardiac nitric oxide and glutathione using a three-channel fluorescent probe.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains unclear, making the diagnosis and treatment challenging. Cardiac oxidative and nitrative stress are strongly implicated in the pathogenesis of HFpEF. Herein, we present a unique three-channel fluorescent probe for evaluating cardiac oxidative and nitrative stress in HFpEF by simultaneous detection of NO and GSH. The probe exhibits a native green fluorescence (probe channel), while the presence of GSH and NO can sensitively turn the native green fluorescence into red fluorescence (GSH channel) and near-infrared fluorescence (NO channel), respectively. The probe clearly reveals that both GSH and NO levels are upregulated in cardiomyocytes and heart tissue with HFpEF. Moreover, it uncovers that the enhancement in NO and GSH levels are closely associated with increased level of iNOS (inducible nitric oxide synthase) and activation of the Keap1 (Kelch-like ECH-associated protein 1)/Nrf2 (nuclear factor erythroid 2-related factor 2)/ARE (antioxidant response element) signaling pathway in cardiomyocytes, respectively. This work proposes a promising approach for distinguishing normal heart and HFpEF heart by in vivo noninvasive imaging of both GSH and NO, and greatly contributing to the improvement of the diagnosis and treatment of HFpEF.

Exosome-Mediated Immunosuppression in Tumor Microenvironments.

Exosomes are membranous structures secreted by nearly all cell types. As critical messengers for intercellular communication, exosomes deliver bioactive cargoes to recipient cells and are involved in multiple physiopathological processes, including immunoregulation. Our pioneering study revealed that cancer cells release programmed death-ligand 1-positive exosomes into the circulation to counter antitumor immunity systemically via T cells. Tumor cell-derived exosomes (TDEs) also play an immunosuppressive role in other immunocytes, including dendritic cells (DCs), macrophages, natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). Moreover, exosomes secreted by nontumor cells in the tumor microenvironments (TMEs) also exert immunosuppressive effects. This review systematically provides a summary of the immunosuppression induced by exosomes in tumor microenvironments, which modulates tumor growth, invasion, metastasis, and immunotherapeutic resistance. Additionally, therapeutic strategies targeting the molecular mechanism of exosome-mediated tumor development, which may help overcome several obstacles, such as immune tolerance in oncotherapy, are also discussed. Detailed knowledge of the specific functions of exosomes in antitumor immunity may contribute to the development of innovative treatments.

Liriogerphines A-D, a Class of Sesquiterpene-Alkaloid Hybrids from the Rare Chinese Tulip Tree Plant.

Liriogerphines A-D (1-4, respectively), an unprecedented class of hybrids of germacranolide-type sesquiterpenoids and aporphine-type alkaloids, were isolated from the rare medicinal plant Liriodendron chinense. Their structures were elucidated by comprehensive spectroscopic analyses combined with electronic circular dichroism calculations and X-ray crystallographic data. Biosynthetically, an aza-Michael addition reaction is proposed to be involved in the assemblies of this class of hybrids. Compound 4 exhibited cytotoxicity against leukemia cells via inducing apoptosis and inhibiting Bcl-2 expression.

Association and mechanism of garlic consumption with gastrointestinal cancer risk: A systematic review and meta-analysis.

Gastrointestinal cancer is one of the most commonly diagnosed cancer type worldwide, with millions of cases per year. The aim of this review was to investigate the relationship between garlic intake and the risk reduction of gastrointestinal cancer. We performed saturated data mining on various public domain databases, including PubMed (https://pubmed.ncbi.nlm.nih.gov/), Embase (https://www.embase.com/landing?status=grey), and Cochrane Library (https://www.cochranelibrary.com/), with key terms including: 'garlic', 'allium', 'stomach', 'gastric', 'colon', 'neoplasms', 'cancer' and 'tumor'. Furthermore, we identified additional references through expert manual curation. Finally, a meta-analysis was conducted to determine whether garlic intake reduces the risk of gastric and/or colorectal cancer. The association between garlic intake and reduction in the risk of gastric cancer [odds ratio (OR)=0.65, 95% confidence interval (CI)=0.49-0.87, P<0.001] were clear. Nine studies on garlic intake and colorectal cancer showed that garlic reduced cancer risk with a statistical significance (OR=0.75, 95% CI=0.65-0.87, P<0.001). We summarized that four main organic sulfides in garlic, diallyl disulfide (DADS), diallyl trisulfide (DATS), S-allylmercaptocysteine (SAMC) and allicin, may contribute to the regulation of tumor cell apoptosis, migration and the cell cycle. We identified the association between garlic intake and reduced risk of gastric and colorectal cancers and hypothesized that the active ingredients in garlic may act on multiple pathways to reduce the risk of gastrointestinal tumors according to published papers. Importantly, the potential tumor-preventing effect of these garlic ingredients warrants further investigation in regards to the specific mechanism of the underlying antitumor activities.

Association between the ABCA1 (R219K) polymorphism and lipid profiles: a meta-analysis.

Conflicting evidence was found about the relationship between lipid profiles and R219K polymorphism in adenosine triphosphate-binding cassette exporter A1 (ABCA1) gene. In this study, four meta-analyses were conducted to assess the effect of R219K on lipid levels, including high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, total cholesterol, and triglycerides (TG). A total of 125 samples of 87 studies (about 60,262 subjects) were included. The effect of each study was expressed using the standard mean difference (SMD) and 95% confidence interval (95% CI) and pooled by meta-analysis in the random-effects model. Subgroup and meta-regression analyses were conducted to explore potential heterogeneity sources. The overall pooled effect showed the following results. (1) The R219K was significantly associated with HDLC level (SMD = - 0.25 mmol/L, 95%CI - 0.32 to - 0.18, z = - 6.96, P < 0.01, recessive genetic model). People with different genotypes had significantly different HDLC levels under the recessive, codominant and dominant genetic models (all Ps < 0.01). (2) A weak and indeterminate relationship between R219K and TG level was observed (SMD = 0.18 mmol/L, 95%CI 0.06-0.30, z = 3.01, P < 0.01, recessive genetic model). These findings suggested that R219K was associated with HDLC and TG levels, which might implicate a promising clinical application for lipid-related disorders, though the influences of race, health status, BMI, and other heterogeneity sources should be considered when interpreting current findings. The protocol was registered at PROSPERO (registration number: CRD42021231178).

Implementation of HIV non-occupational post-exposure prophylaxis for men who have sex with men in 2 cities of Southwestern China.

ABSTRACT: Non-occupational post-exposure prophylaxis (nPEP) has often relied on the joint work of emergency physicians and infectious disease specialists in busy emergency departments and human immunodeficiency virus (HIV)/sexually transmitted infections clinics abroad, where adherence education and follow-up are invariably reactive. In our pilot study, community-based organizations (CBOs) were invited to together implement the nPEP tailored to men who have sex with men (MSM) in 2 cities of Guangxi in Southwestern China, of which experiences and lessons drawn from would be provided to the promotion of nPEP in China.The study population enrolled MSM individuals prescribed nPEP from September 2017 to December 2019. One-to-one follow-ups by CBOs were applied through the treatment. Predictors of treatment completion were assessed by logistic regression.Of 271 individuals presented for nPEP, 266 MSM with documented treatment completion or non-completion, 93.6% completed the 28-day course of medication. Completion was associated with reporting side effects (aOR = .10; 95% CI: 0.02-0.38; P = .001). The follow-up rate of 91.9% was achieved based on the definition of loss to follow-up. No documented nPEP failures were found, although 1 MSM subsequently seroconverted to HIV due to ongoing high-risk behavior.CBOs' engagement in HIV nPEP, especially the "one-to-one" follow-up supports by peer educators partly ensure adherence and retention to nPEP. Tailored interventions are needed to address the subsequent high-risk behaviors among the MSM population.

Correlation between craniofacial structures, anthropometric measurements, and nasopharyngeal dimensions in black adolescents.

OBJECTIVES: To evaluate the correlation between craniofacial structures, anthropometric measurements, and bony and soft tissue nasopharyngeal dimensions in African Black adolescents. METHODS: This retrospective cross-sectional study was conducted on 483 healthy adolescents (250 females and 233 males), randomly selected from one dental clinic. The inclusion criteria were skeletal and dental Class I, Black ethnicity, pubertal growth period as determined by the Greulich and Pyle atlas criteria, and no history of orthodontic treatment. Anthropometric measurements (stature, upper body height, lower body height, and BMI) and radiographic records (hand-wrist radiographs, and lateral cephalograms) were obtained. One investigator traced and analysed all cephalograms to determine three skeletal craniofacial parameters (maxillary length [Ar- ANS], mandibular length [Ar-Gn], and lower anterior facial height [ANS-Me]), and 14 (8 skeletal and 6 soft tissue) nasopharyngeal parameters. Pearson correlation coefficients and stepwise multiple linear regression analyses were conducted. RESULTS: The mean skeletal ages of females and males were 11.31±2.31y and 12.66±1.85y, respectively. Multiple linear regression analyses showed that stature, posterior height of nasal cavity (S-PNS), length of nasal floor (AA-PNS), and mean area of bony nasopharynx (Area 1) were significantly correlated with maxillary length, P<.001. Stature, BMI, S-PNS, vertical angle of nasopharynx (Ba-S-PNS), Area 1, adenoid height (AD), and linear hyoid bone measurements (H-AA, H-RGN, H-Ax) were all correlated with mandibular length, P<.05. Lower facial height showed sexual dimorphism and was significantly associated with vertical nasopharyngeal measurements, BMI and upper body height. CONCLUSIONS: Craniofacial structures were significantly associated with stature and upper body height. Maxillary growth was associated with bony nasopharyngeal variables. Mandibular growth and lower facial height were associated with bony and soft tissue nasopharyngeal variables. The sexual dimorphism in lower facial height warrants future studies to fully understand and manage the craniofacial complex and nasopharyngeal airway in African Black adolescents.

Transcriptomic and Metabolomic Profiling in Helicobacter pylori-Induced Gastric Cancer Identified Prognosis- and Immunotherapy-Relevant Gene Signatures.

Background: Chronic Helicobacter pylori (HP) infection is considered the major cause of non-cardia gastric cancer (GC). However, how HP infection influences the metabolism and further regulates the progression of GC remains unknown. Methods: We comprehensively evaluated the metabolic pattern of HP-positive (HP+) GC samples using transcriptomic data and correlated these patterns with tumor microenvironment (TME)-infiltrating characteristics. The metabolic score was constructed to quantify metabolic patterns of individual tumors using principal component analysis (PCA) algorithms. The expression alterations of key metabolism-related genes (MRGs) and downstream metabolites were validated by PCR and untargeted metabolomics analysis. Results: Two distinct metabolic patterns and differential metabolic scores were identified in HP+ GC, which had various biological pathways in common and were associated with clinical outcomes. TME-infiltrating profiles under both patterns were highly consistent with the immunophenotype. Furthermore, the analysis indicated that a low metabolic score was correlated with an increased EMT subtype, immunosuppression status, and worse survival. Importantly, we identified that the expression of five MRGs, GSS, GMPPA, OGDH, SGPP2, and PIK3CA, was remarkably correlated with HP infection, patient survival, and therapy response. Furthermore, the carbohydrate metabolism and citric acid may be downstream regulators of the function of metabolic genes in HP-induced GC. Conclusion: Our findings suggest that there is cross talk between metabolism and immune promotion during HP infection. MRG-specific transcriptional alterations may serve as predictive biomarkers of survival outcomes and potential targets for treatment of patients with HP-induced GC.

The deficiency of NRSF/REST enhances the pro-inflammatory function of astrocytes in a model of Parkinson's disease.

Neuroinflammation, as an important pathological characteristic of Parkinson's disease (PD), is primarily mediated by activated astrocytes and microglia. Neuron-restrictive silencer factor/repressor element 1 (RE1)-silencing transcription factor (NRSF/REST) regulates many genes and signal pathways involved in the inflammatory process in astrocytes. In the present study, we established the GFAP-Cre:NRSFflox/flox conditional knockout (cKO) mice. The expression of inflammation-associated molecules were measured in primary astrocytes from wild type (WT) and cKO mice after stimulation by 1-Methyl-4-phenylpyridine (MPP+), LPS, and conditioned medium (CM) of LPS-treated BV-2 microglial cells. The inflammatory molecule expression in BV-2 microglial cells exposed to conditioned medium of MPP+-treated primary astrocytes were also analyzed. Moreover, a subacute regimen of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP) was used to establish mouse PD model and the damages to the nigrostriatal pathway were comprehensively evaluated in WT and cKO mice. We found that MPP+ induced a remarkable increase of NRSF expression in cultured astrocytes. Compared to WT astrocytes, the expression of inflammatory molecules IL-1ß, IL-6, COX-2, and iNOS increased dramatically in NRSF deficient astrocytes challenged with CM of LPS-treated BV-2 cells. COX-2 and IL-1ß transcripts were significantly elevated in BV-2 microglial cells exposed to CM of MPP+-treated NRSF deficient astrocytes compared to WT astrocytes. In cKO mice, the activation of astrocytes and microglial cells was more obvious, and the nigrostriatal dopaminergic system was more heavily injured compared to their WT counterparts after MPTP administration. Our results suggest that reactive NRSF deficient astrocytes orchestrated with microglial cells aggravate the pathophysiological progress in PD.