Immune microniches shape intestinal Treg function.

The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (Treg) cell development and function have been identified3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive Treg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector Treg (eTreg) cell function. eTreg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103+SIRPα+ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206+ macrophages and eTreg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.

Review of dietary patterns and gastric cancer risk: epidemiology and biological evidence.

Due to rapid research expansion on dietary factors and development of cancer prevention guidelines, the field of dietary pattern and its relationship to cancer risk has gained more focus. Numerous epidemiology studies have reported associations between Gastric Cancer (GC) and both data-driven posteriori dietary pattern and priori dietary pattern defined by predetermined dietary indexes. As dietary patterns have evolved, a series of patterns based on biological markers has advanced, offering deeper insights into the relationship between diet and the risk of cancer. Although researches on dietary patterns and cancer risk are booming, there is limited body of literature focusing specifically on GC. In this study, we compare the similarities and differences among the specific components of dietary patterns and indices, summarize current state of knowledge regarding dietary patterns related to GC and illustrate their potential mechanisms for GC prevention. In conclusion, we offer suggestions for future research based on the emerging themes within this rapidly evolving field.

Atlas and source of the microplastics of male reproductive system in human and mice.

Regarding the impact of microplastics (MPs) on the male reproductive system, previous studies have identified a variety of MPs in both human semen and testicular samples. These studies have put forward the hypothesis that small particles can enter the semen through the epididymis and seminal vesicles. Here, we performed qualitative and quantitative analyses of MPs in human testis, semen, and epididymis samples, as well as in testis, epididymis, seminal vesicle, and prostate samples from mice via pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS). The goal of this approach was to comprehensively characterize the distribution of MPs within the male reproductive system. Additionally, we aimed to evaluate potential sources of MPs identified in semen, as well as to identify possible sources of overall MP exposure. Our results highlighted a general atlas of MPs in the male reproductive system and suggested that MPs in semen may originate from the epididymis, seminal vesicles, and prostate. An exposure questionnaire, coupled with the characteristics of the MPs detected in the male reproductive system, revealed that high urbanization, home-cooked meals, and using scrub cleansers were important sources of MP exposure in men. These findings may provide novel insights into alleviating the exposure of men to MPs.

Exosome-transmitted podoplanin promotes tumor-associated macrophage-mediated immune tolerance in glioblastoma.

AIMS: Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy. METHODS: Bulk RNA-seq and single-cell RNA-seq of glioma patients from public databases were comprehensively analyzed to illustrate macrophage infiltration patterns and molecular characteristics of podoplanin (PDPN). Multiplexed fluorescence immunohistochemistry staining of PDPN, GFAP, CD68, and CD163 were performed in glioma tissue microarray. The impact of PDPN on macrophage immunosuppressive polarization was investigated using a co-culture system. Bone marrow-derived macrophages (BMDMs) and OT-II T cells isolated from BALB/c and OT-II mice respectively were co-cultured to determine T-cell adherence. Pathway alterations were probed through RNA sequencing and western blot analyses. RESULTS: Our findings demonstrated that PDPN is notably correlated with the expression of CD68 and CD163 in glioma tissues. Additionally, macrophages phagocytosing PDPN-containing EVs (EVsPDPN ) from GBM cells presented increased CD163 expression and augmented secretion of immunoregulatory cytokine (IL-6, IL-10, TNF-α, and TGF-ß1). PDPN within EVs was also associated with enhanced phagocytic activity and reduced MHC II expression in macrophages, compromising CD4+ T-cell activation. CONCLUSIONS: This investigation underscores that EVsPDPN derived from glioblastoma cells contributes to M2 macrophage-mediated immunosuppression and is a potential prognostic marker and therapeutic target in glioblastoma.

Understanding risky driving behaviors among young novice drivers in Nigeria: A latent class analysis coupled with association rule mining approach.

Traffic crashes are significant public health concern in Nigeria, particularly among young drivers. The study aims to explore the underlying pattern of risky driving behaviors and the associations with demographic factors among young drivers in Nigeria. A combined approach of Latent Class Analysis (LCA) and Association Rule Mining is applied to the dataset comprising responses from 684 young drivers who complete the "Behavior of Young Novice Drivers Scale" (BYND) questionnaires. The LCA identifies four distinct classes of drivers based on the risky behavior profiles: Reckless-Speedsters, Cautious Drivers, Distracted Multitaskers, and Emotion-impacted Drivers. Association rule mining further connects these driver classes to demographic and driving history variables, uncovering intriguing insights. Reckless-Speedsters predominantly consist of young males who engage in riskier driving behaviors, including exceeding speed limits and disregarding traffic rules. Conversely, Cautious Drivers, also predominantly young males, exhibit a safer driving profile marked by rule adherence and a notably lower crash rate. Distracted Multitaskers, sharing a demographic profile with Cautious Drivers, diverge significantly due to their higher crash involvement, hinting at a propensity for distracted driving practices. Lastly, Emotion-Impacted Drivers, primarily comprising young employed males, display behaviors influenced by emotions, shorter driving distances, and prior unsupervised driving experience. Most of the behaviors are attributed to inadequate traffic control, absence of traffic signs in most of the roads, preferential treatment, and lack of strict law enforcement in the country. The findings hold substantial implications for road safety interventions in Nigeria, urging targeted approaches to address the unique challenges presented by each driver class. With acknowledging the study limitations and advocating for future research in objective measures and emotion-behavior interactions, the comprehensive approach provides a robust foundation for enhancing road safety in the Nigerian context.

How well do neural signatures of resting-state EEG detect consciousness? A large-scale clinical study.

The assessment of consciousness states, especially distinguishing minimally conscious states (MCS) from unresponsive wakefulness states (UWS), constitutes a pivotal role in clinical therapies. Despite that numerous neural signatures of consciousness have been proposed, the effectiveness and reliability of such signatures for clinical consciousness assessment still remains an intense debate. Through a comprehensive review of the literature, inconsistent findings are observed about the effectiveness of diverse neural signatures. Notably, the majority of existing studies have evaluated neural signatures on a limited number of subjects (usually below 30), which may result in uncertain conclusions due to small data bias. This study presents a systematic evaluation of neural signatures with large-scale clinical resting-state electroencephalography (EEG) signals containing 99 UWS, 129 MCS, 36 emergence from the minimally conscious state, and 32 healthy subjects (296 total) collected over 3 years. A total of 380 EEG-based metrics for consciousness detection, including spectrum features, nonlinear measures, functional connectivity, and graph-based measures, are summarized and evaluated. To further mitigate the effect of data bias, the evaluation is performed with bootstrap sampling so that reliable measures can be obtained. The results of this study suggest that relative power in alpha and delta serve as dependable indicators of consciousness. With the MCS group, there is a notable increase in the phase lag index-related connectivity measures and enhanced functional connectivity between brain regions in comparison to the UWS group. A combination of features enables the development of an automatic detector of conscious states.

Challenges and perspectives in computational deconvolution of genomics data.

Deciphering cell-type heterogeneity is crucial for systematically understanding tissue homeostasis and its dysregulation in diseases. Computational deconvolution is an efficient approach for estimating cell-type abundances from a variety of omics data. Despite substantial methodological progress in computational deconvolution in recent years, challenges are still outstanding. Here we enlist four important challenges related to computational deconvolution: the quality of the reference data, generation of ground truth data, limitations of computational methodologies, and benchmarking design and implementation. Finally, we make recommendations on reference data generation, new directions of computational methodologies, and strategies to promote rigorous benchmarking.

Hypoxia-activated XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of ΔNp63α expression and promote breast cancer metastasis independent of HIF1α.

Hypoxia is a hallmark of cancer development. However, the molecular mechanisms by which hypoxia promotes tumor metastasis are not fully understood. In this study, we demonstrate that hypoxia promotes breast cancer metastasis through suppression of ΔNp63α in a HIF1α-independent manner. We show that hypoxia-activated XBP1s forms a stable repressor protein complex with HDAC2 and EZH2 to suppress ΔNp63α transcription. Notably, H3K27ac is predominantly occupied on the ΔNp63 promoter under normoxia, while H3K27me3 on the promoter under hypoxia. We show that XBP1s binds to the ΔNp63 promoter to recruit HDAC2 and EZH2 in facilitating the switch of H3K27ac to H3K27me3. Pharmacological inhibition or the knockdown of either HDAC2 or EZH2 leads to increased H3K27ac, accompanied by the reduced H3K27me3 and restoration of ΔNp63α expression suppressed by hypoxia, resulting in inhibition of cell migration. Furthermore, the pharmacological inhibition of IRE1α, but not HIF1α, upregulates ΔNp63α expression in vitro and inhibits tumor metastasis in vivo. Clinical analyses reveal that reduced p63 expression is correlated with the elevated expression of XBP1, HDAC2, or EZH2, and is associated with poor overall survival in human breast cancer patients. Together, these results indicate that hypoxia-activated XBP1s modulates the epigenetic program in suppression of ΔNp63α to promote breast cancer metastasis independent of HIF1α and provides a molecular basis for targeting the XBP1s/HDAC2/EZH2-ΔNp63α axis as a putative strategy in the treatment of breast cancer metastasis.

The effects of obstructive sleep apnea on blood pressure variability and load in patients with hypertension.

BACKGROUND: Hypertension frequently coexists with obstructive sleep apnea (OSA), and their interplay substantially impacts the prognosis of affected individuals. Investigating the influence of OSA on blood pressure variability (BPV) and blood pressure load (BPL) in hypertensive patients has become a focal point of clinical research. METHODS: This cross-sectional study recruited hypertensive patients (n = 265) without discrimination and classified them into four groups based on their apnea-hypopnea index (AHI): control group (n = 40), AHI < 5; mild group (n = 74), 5 ≤ AHI ≤ 15; moderate group (n = 68), 15 < AHI ≤ 30; severe group (n = 83), AHI > 30. All participants underwent comprehensive assessments, including polysomnography (PSG) monitoring, 24-h ambulatory blood pressure (ABP) monitoring, cardiac Doppler ultrasound, and additional examinations when indicated. RESULTS: BPV and BPL exhibited significant elevations in the moderate and severe OSA groups compared to the control and mild OSA groups (P < 0.05). Moreover, interventricular septum thickness and left ventricular end-diastolic volume (LVEDV) demonstrated higher values in the moderate and severe OSA groups (P < 0.05). Multiple stepwise regression analysis identified noteworthy risk factors for elevated BPV in hypertensive patients with OSA, including AHI, maximum apnea time, total times of oxygen reduction, and mean time of apnea. CONCLUSION: Hypertensive patients with moderate to severe OSA exhibited substantially increased BPV and BPL. Moreover, BPV was correlated with AHI, maximum apnea time, total times of oxygen reduction, and mean time of apnea in hypertensive patients with OSA.

Emerging roles of circular RNAs in regulating the hallmarks of thyroid cancer.

Thyroid cancer is a prevalent endocrine malignancy with increasing incidence in recent years. Although most thyroid cancers grow slowly, they can become refractory, leading to a high mortality rate once they exhibit recurrence, metastasis, resistance to radioiodine therapy, or a lack of differentiation. However, the mechanisms underlying these malignant characteristics remain unclear. Circular RNAs, a type of closed-loop non-coding RNAs, play multiple roles in cancer. Several studies have demonstrated that circular RNAs significantly influence the development of thyroid cancers. In this review, we summarize the circular RNAs identified in thyroid cancers over the past decade according to the hallmarks of cancer. We found that eight of the 14 hallmarks of thyroid cancers are regulated by circular RNAs, whereas the other six have not been reported to be correlated with circular RNAs. This review is expected to help us better understand the roles of circular RNAs in thyroid cancers and accelerate research on the mechanisms and cure strategies for thyroid cancers.

Bi-allelic variants in chromatoid body protein TDRD6 cause spermiogenesis defects and severe oligoasthenoteratozoospermia in humans.

BACKGROUND: The association between the TDRD6 variants and human infertility remains unclear, as only one homozygous missense variant of TDRD6 was found to be associated with oligoasthenoteratozoospermia (OAT). METHODS: Whole-exome sequencing and Sanger sequencing were employed to identify potential pathogenic variants of TDRD6 in infertile men. Histology, immunofluorescence, immunoblotting and ultrastructural analyses were conducted to clarify the structural and functional abnormalities of sperm in mutated patients. Tdrd6-knockout mice were generated using the CRISPR-Cas9 system. Total RNA-seq and single-cell RNA-seq (scRNA-seq) analyses were used to elucidate the underlying molecular mechanisms, followed by validation through quantitative RT-PCR and immunostaining. Intracytoplasmic sperm injection (ICSI) was also used to assess the efficacy of clinical treatment. RESULTS: Bi-allelic TDRD6 variants were identified in five unrelated Chinese individuals with OAT, including homozygous loss-of-function variants in two consanguineous families. Notably, besides reduced concentrations and impaired motility, a significant occurrence of acrosomal hypoplasia was detected in multiple spermatozoa among five patients. Using the Tdrd6-deficient mice, we further elucidate the pivotal role of TDRD6 in spermiogenesis and acrosome identified. In addition, the mislocalisation of crucial chromatoid body components DDX4 (MVH) and UPF1 was also observed in round spermatids from patients harbouring TDRD6 variants. ScRNA-seq analysis of germ cells from a patient with TDRD6 variants revealed that TDRD6 regulates mRNA metabolism processes involved in spermatid differentiation and cytoplasmic translation. CONCLUSION: Our findings strongly suggest that TDRD6 plays a conserved role in spermiogenesis and confirms the causal relationship between TDRD6 variants and human OAT. Additionally, this study highlights the unfavourable ICSI outcomes in individuals with bi-allelic TDRD6 variants, providing insights for potential clinical treatment strategies.

PPIP5K2 Facilitates Proliferation and Metastasis of Non-Small Lung Cancer (NSCLC) through AKT Signaling Pathway.

Through facilitating DNA homologous recombination repair, PPIP5K2 has been proven to be essential for improving colorectal cancer survival in our previous research. However, its function in the tumorigenesis of NSCLC, the most common cancer and the primary cause of cancer-related death globally, is still unknown. Here, we initially discovered that PPIP5K2 had significant effects on proliferation of NSCLC cells through loss- and gain-of-function assays in vitro and in vivo. Moreover, PPIP5K2 is capable of regulating NSCLC cells metastasis in an EMT-dependent manner. In terms of mechanism exploration, we found that PPIP5K2 knockdown can significantly inhibit the phosphorylation of AKT/mTOR signaling pathway, whereas the overexpression of PPIP5K2 resulted in converse effects. By employing AKT signaling related agonists or antagonists, we further demonstrated that PPIP5K2 regulates NSCLC tumorigenesis partly via the AKT/mTOR pathway. In conclusion, PPIP5K2 plays a key oncogenic role in NSCLC by the activation of the AKT/mTOR signaling axis. It is anticipated that targeting PPIP5K2 might emerge as a viable therapeutic approach for NSCLC patients.

Transarterial Chemoembolization Plus Tyrosinkinase Inhibitors and PD-1 Inhibitors for Spontaneously Ruptured Hepatocellular Carcinoma.

PURPOSE: To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) in combination with tyrosinkinase inhibitors (TKI) and PD-1 inhibitors, versus TACE monotherapy for the treatment of ruptured hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study included 104 patients with ruptured HCC receiving either combination therapy or TACE monotherapy at two centers between June 2015 and June 2022. Propensity score matching (PSM) analysis was used at a 1:2 ratio to reduce bias between the two groups. The primary outcome measures were overall survival (OS) and progression-free survival (PFS), and the secondary outcome measures were the occurrence of adverse events (AEs, Common Terminology Criteria for AEs, version 5.0.) and the peritoneal metastasis rate. RESULTS: A total of 69 patients were enrolled after PSM, including 23 patients in the combination group and 46 patients in the monotherapy group. The combination group exhibited a significantly longer median OS (553 days, 95% confidence interval [CI] 222.6-883.9) compared to the monotherapy group (105 days, 95% CI 81.2-128.7; P < 0.001). Similarly, the combination group showed a better median PFS (356 days, 95% CI 299.5-412.4) compared to the monotherapy group (97 days, 95% CI 75.9-118.1; P < 0.001). Moreover, there was no significant difference in the peritoneal metastasis rate (combination group: 8.6% vs. monotherapy group: 26.1%, P = 0.119). Grade 3 AEs occurred at a rate of 21.7% and 13% in combination and monotherapy groups, respectively. No Grade 4/5 AEs were observed in either group. CONCLUSIONS: Our study demonstrated that the combination of TACE with TKI and PD-1 inhibitors significantly enhances OS and PFS compared to TACE monotherapy in ruptured HCC patients. Furthermore, this combined approach exhibited an acceptable safety profile.

Hydroxysafflor Yellow A and Tenuigenin Exhibit Neuroprotection Effects Against Focal Cerebral Ischemia Via Differential Regulation of JAK2/STAT3 and SOCS3 Signaling Interaction.

Numerous natural bioactive compounds extracted from Chinese medicines have been proved to be promising and potent agents in the treatment of ischemic stroke. Hydroxysafflor yellow A (HSYA), separated from Carthamus tinctorius, has increasingly attracted attention for its broad spectrum of pharmacological effects, especially of its neuroprotective action. Our previous studies revealed that HSYA plays significant beneficial roles in a dose-dependent manner in rats with focal cerebral ischemia. However, treatment with higher doses of HSYA appeared to bring about adverse reactions in the rats. In present study, we adopted tenuigenin (TEN), extracted from the Polygala tenuifolia root, in combination with HSYA to optimize the therapeutic strategy against ischemic stroke, and further explored the underlying mechanisms of action of the combination in vivo and in vitro. We firstly confirmed the pharmacological efficacies of co-treatment of HSYA and TEN in middle cerebral ischemia occlusion (MCAO) rats and observed the synergistic improvement of infarct volume, cerebral edema, and morphology of neuron cell body. Behavioral experiments indicated that combination of HSYA and TEN could synergistically improve motor and cognitive function in MCAO rats. We also observed increased viability and suppressed cell apoptosis after HSYA and TEN co-treatments in the oxygen-glucose deprivation/reperfusion (OGD/R) SH-SY5Y cells. Furthermore, JAK2/STAT3 and SOCS3 signaling interaction was demonstrated to be a critical responsor to the co-treatment of HSYA and TEN. In the subsequent experiments with silencing SOCS3 in OGD/R-exposed cells, we found that HSYA and TEN might suppress JAK2/STAT3 pathway through different regulatory mechanisms targeting SOCS3-negative feedback signaling. HSYA seemed to impose excessive activation of JAK2/STAT3 to trigger SOCS3-negative feedback signaling, while TEN appeared to provoke SOCS3 inhibitory feedback role directly to further attenuate JAK2-mediated signaling. Collectively, HSYA and TEN might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways in different manners that eventually contributed to their synergistic therapeutic effects against cerebral ischemic stroke.

Chinese expert consensus on imaging diagnosis of drug-resistant pulmonary tuberculosis.

Tuberculosis (TB) remains one of the major infectious diseases in the world with a high incidence rate. Drug-resistant tuberculosis (DR-TB) is a key and difficult challenge in the prevention and treatment of TB. Early, rapid, and accurate diagnosis of DR-TB is essential for selecting appropriate and personalized treatment and is an important means of reducing disease transmission and mortality. In recent years, imaging diagnosis of DR-TB has developed rapidly, but there is a lack of consistent understanding. To this end, the Infectious Disease Imaging Group, Infectious Disease Branch, Chinese Research Hospital Association; Infectious Diseases Group of Chinese Medical Association of Radiology; Digital Health Committee of China Association for the Promotion of Science and Technology Industrialization, and other organizations, formed a group of TB experts across China. The conglomerate then considered the Chinese and international diagnosis and treatment status of DR-TB, China's clinical practice, and evidence-based medicine on the methodological requirements of guidelines and standards. After repeated discussion, the expert consensus of imaging diagnosis of DR-PB was proposed. This consensus includes clinical diagnosis and classification of DR-TB, selection of etiology and imaging examination [mainly X-ray and computed tomography (CT)], imaging manifestations, diagnosis, and differential diagnosis. This expert consensus is expected to improve the understanding of the imaging changes of DR-TB, as a starting point for timely detection of suspected DR-TB patients, and can effectively improve the efficiency of clinical diagnosis and achieve the purpose of early diagnosis and treatment of DR-TB.

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.

The immune system comprises multiple cell lineages and heterogeneous subsets found in blood and tissues throughout the body. While human immune responses differ between sites and over age, the underlying sources of variation remain unclear as most studies are limited to peripheral blood. Here, we took a systems approach to comprehensively profile RNA and surface protein expression of over 1.25 million immune cells isolated from blood, lymphoid organs, and mucosal tissues of 24 organ donors aged 20-75 years. We applied a multimodal classifier to annotate the major immune cell lineages (T cells, B cells, innate lymphoid cells, and myeloid cells) and their corresponding subsets across the body, leveraging probabilistic modeling to define bases for immune variations across donors, tissue, and age. We identified dominant tissue-specific effects on immune cell composition and function across lineages for lymphoid sites, intestines, and blood-rich tissues. Age-associated effects were intrinsic to both lineage and site as manifested by macrophages in mucosal sites, B cells in lymphoid organs, and T and NK cells in blood-rich sites. Our results reveal tissue-specific signatures of immune homeostasis throughout the body and across different ages. This information provides a basis for defining the transcriptional underpinnings of immune variation and potential associations with disease-associated immune pathologies across the human lifespan.

Aletrisguangxiensis (Nartheciaceae), a new species from Guangxi, China.

Aletrisguangxiensis Y. Nong & Y. F. Huang (Nartheciaceae), a new species from Guangxi, China, is described and illustrated. This new species is most similar to A.scopulorum, but it can be easily distinguished by its sparsely glandular, 5-18 cm long scape, glandular inflorescence axis, distinctly pedicellate flowers, sparsely glandular, 5-10 mm long pedicel, bract borne at base of pedicel, glabrous perianth divided to the base, strongly recurved or revolute perianth lobes and turbinate, obovoid to oblong-obovoid capsule. An identification key for 24 species and 1 hybrid of Aletris is also provided.

A Human Adenovirus C Infection-Related Gene Panel for Predicting Survival and Treatment Responsiveness in Glioma Patients.

BACKGROUND: Viruses are critical for the regulation of cancer development and for therapy. Human adenovirus C (HadVC) has been detected in central nervous system and glioma tissue. The objective of the present study was the development of a robust prognostic model based on HadVC infection (HadVCi)-relevant genes. METHODS: The genome, transcriptome, and virome were systemically analyzed using The Cancer Genome Atlas dataset for training and 2 cohorts from the Chinese Glioma Genome Atlas and an immunotherapy trial cohort with 17 patients receiving anti-PD-1 treatment for validation. HadVCi-relevant gene selection from differentially expressed genes between HadVC-infected and non-HadVC-infected glioma patients using least absolute shrinkage and selection operator regression was followed by Cox regression modeling to establish a prognostic HadVCi score. Kaplan-Meier and receiver operating characteristic curve analyses were performed to estimate the predictive capacity of the HadVCi score. The χ2, Spearman, and Mann-Whitney U tests were used to identify the correlation with the clinicopathological parameters, treatment responsiveness, and immune landscape. Temozolomide-resistant glioma cells were established and analyzed at the transcriptional level using RNA sequencing data. RESULTS: The HadVCi score was (-0.2526673∗TRPC6) + (-0.2244276∗RNF207) + (-0.0894468∗SEC31B) + (-0.0190214∗ZCRB1) + (-0.017122∗DNPH1) + (0.0495818∗CCDC34) + (0.1196349∗PURG) + (0.1778997∗LILRA5). The score possesses a strong ability to predict overall survival. Further analysis revealed a higher HadVCi score correlated with a malignant phenotype and poorer treatment responsiveness to temozolomide-based chemotherapy and combined therapies. Additionally, transcriptomic analysis showed malignancy-, stemness-, and radioresistant-related gene activation in the HadVCi group, which characterized the poor outcomes and limited sensitivity to standard therapy. CONCLUSIONS: The HadVCi score could be an effective tool for survival prediction and treatment guidance for patients with glioma.

Aggregation-Induced Emission Photosensitizer-Engineered Anticancer Nanomedicine for Synergistic Chemo/Chemodynamic/Photodynamic Therapy.

Photodynamic therapy (PDT) with aggregation-induced emission (AIE) photosensitizers (PSs) is a promising therapeutic strategy to achieve better anticancer results. However, eradicating solid tumors completely by PDT alone can be difficult owing to the inherent drawbacks of this treatment, and the combination of PDT with other therapeutic modalities provides opportunities to achieve cooperative enhancement interactions among various treatments. Herein, this work presents the construction of a biocompatible nanocomposite, namely CaO2@DOX@ZIF@ASQ, featuring light-responsive reactive oxygen species (ROS) generation and tumor-targeting oxygen and hydrogen peroxide discharge, as well as controlled doxorubicin (DOX) and copper ion release, thus allowing the combined PDT/CT/CDT effect by AIE PS-enhanced PDT, DOX-based chemotherapy (CT), and copper-involved Fenton-like reaction-driven chemodynamic therapy (CDT). In vitro and in vivo studies verify that the generation of both ROS and O2 by this nanomedicine, stimulated by light, exhibits superior anticancer efficacy, alleviating tumor hypoxia and achieving synergistic PDT/CT/CDT therapeutic effect. This multifunctional nanomedicine remarkably suppresses the tumor growth with minimized systemic toxicity, providing a new strategy for constructing multimodal PDT/CT/CDT therapeutic systems to overcome hypoxia limitations, and potentially increase the antitumor efficacy at lower doses of PSs and chemotherapeutic drugs, thus minimizing potential toxicity to non-malignant tissues.

Novel MEIOB pathogenic variants including a homozygous non-canonical splicing variant, cause meiotic arrest and human non-obstructive azoospermia.

Non-obstructive azoospermia (NOA) is the most severe form of human male infertility, and the genetic causes of NOA with meiotic arrest remain largely unclear. In this study, we identified novel compound heterozygous MEIOB variants (c.814C > T: p.R272X and c.976G > A: p.A326T) and a previously undescribed homozygous non-canonical splicing variant of MEIOB (c.528 + 3A > C) in two NOA-affected individuals from two irrelevant Chinese families. MEIOB missense variant (p.A326T) significantly reduced protein abundance and nonsense variant (p.R272X) produced a truncated protein. Both of two variants impaired the MEIOB-SPATA22 interaction. The MEIOB non-canonical splicing variant resulted in whole Exon 6 skipping by minigene assay, which was predicted to produce a frameshift truncated protein (p.S111Rfs*32). Histological and immunostaining analysis indicated that both patients exhibited a similar phenotype as we previously reported in Meiob mutant mice, that is, absence of spermatids in seminiferous tubules and meiotic arrest. Our study identified three novel pathogenic variants of MEIOB in NOA patients, extending the mutation spectrum of the MEIOB and highlighting the contribution of meiotic recombination related genes in human fertility.