Identification of molecular subtypes based on chromatin regulator-related genes and experimental verification of the role of ASCL1 in conferring chemotherapy resistance to breast cancer.

Objective: The aim of this study was to identify the molecular subtypes of breast cancer based on chromatin regulator-related genes. Methods: The RNA sequencing data of The Cancer Genome Atlas-Breast Cancer cohort were obtained from the official website, while the single-cell data were downloaded from the Gene Expression Omnibus database (GSE176078). Validation was performed using the Molecular Taxonomy of Breast Cancer International Consortium dataset. Furthermore, the immune characteristics, tumor stemness, heterogeneity, and clinical characteristics of these molecular subtypes were analyzed. The correlation between chromatin regulators and chemotherapy resistance was examined in vitro using the quantitative real-time polymerase chain reaction (qRT-PCR) and Cell Counting Kit-8 (CCK8) assays. Results: This study identified three stable molecular subtypes with different prognostic and pathological features. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction analyses revealed that the differentially expressed genes were associated with disease processes, such as mitotic nuclear division, chromosome segregation, condensed chromosome, and specific chromosome region. The T stage and subtypes were correlated with the clinical features. Tumor heterogeneity (mutant-allele tumor heterogeneity, tumor mutational burden, purity, and homologous recombination deficiency) and tumor stemness (RNA expression-based stemness score, epigenetically regulated RNA expression-based stemness score, DNA methylation-based stemness score, and epigenetically regulated DNA methylation-based stemness score) significantly varied between the three subtypes. Furthermore, Western blotting, qRT-PCR, and CCK8 assays demonstrated that the expression of ASCL1 was positively correlated with chemotherapy resistance in breast cancer. Conclusion: This study identified the subtypes of breast cancer based on chromatin regulators and analyzed their clinical features, gene mutation status, immunophenotype, and drug sensitivity. The results of this study provide effective strategies for assessing clinical prognosis and developing personalized treatment strategies.

Circ_0003945: an emerging biomarker and therapeutic target for human diseases.

Due to the rapid development of RNA sequencing techniques, a circular non-coding RNA (ncRNA) known as circular RNAs (circRNAs) has gradually come into focus. As a distinguished member of the circRNA family, circ_0003945 has garnered attention for its aberrant expression and biochemical functions in human diseases. Subsequent studies have revealed that circ_0003945 could regulate tumor cells proliferation, migration, invasion, apoptosis, autophagy, angiogenesis, drug resistance, and radio resistance through the molecular mechanism of competitive endogenous RNA (ceRNA) during tumorigenesis. The expression of circ_0003945 is frequently associated with some clinical parameters and implies a poorer prognosis in the majority of cancers. In non-malignant conditions, circ_0003945 also holds considerable importance in diseases pathogenesis. This review aims to recapitulate molecular mechanism of circ_0003945 and elucidates its potential as a diagnostic and therapeutic target in neoplasms and other diseases.

Efficacy of Xianling Gubao capsule vs. its combination therapy in the treatment of primary osteoporosis: A network meta-analysis of randomized controlled trials.

Objective: This study aimed to evaluate the efficacy of the Xianling Gubao (XLGB) capsule alone and its combination therapy in primary osteoporosis (POP). Methods: Databases including PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Data, VIP, and SinoMed were searched from their inception to January 16, 2024, for randomized controlled trials (RCTs) investigating the XLGB treatment for POP. A network meta-analysis (NMA) was performed to evaluate the efficacy and safety of multiple interventions in the treatment of POP. The Cochrane risk-of-bias tool was used to assess the quality of RCTs included in the meta-analysis. Software Stata (version 15.0) was used for statistical analysis. The surface under the cumulative ranking curve (SUCRA) method was used to present the findings from this NMA numerically and graphically by ranking multiple interventions. Results: A total of 107 RCTs were included in the meta-analysis, involving 10,032 participants and 21 interventions. Meta-analysis showed that XLGB + calcium (Ca) + calcitonin (99.9 %) was the most desirable treatment option for improving clinical efficacy. XLGB + Ca + bisphosphonate (BP) was most effective for improving bone mineral density (BMD) at the lumbar spine, femoral neck BMD, and serum bone Gla protein (BGP). SUCRA values for improving these three outcome measures by XLGB + Ca + BP were 87.4 %, 77.2 %, and 84.3 %, respectively. XLGB + calcitonin was the optimal option in terms of safety evaluation and improving visual analogue scale (VAS), with the SUCRA values being 89.6 % and 94.9 %, respectively. Conclusions: The XLGB combination therapy is a desirable option for treating POP as it can effectively improve the therapeutic effects, BMD, and serum BGP, as well as relieve pain in patients with POP.

A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness.

BACKGROUND: Due to the high mortality and disability rate of intracranial hemorrhage, headache is not the main focus of research on cerebral arteriovenous malformation (AVM), so research on headaches in AVM is still scarce, and the clinical understanding is shallow. This study aims to delineate the risk factors associated with headaches in AVM and to compare the effectiveness of various intervention treatments versus conservative treatment in alleviating headache symptoms. METHODS: This study conducted a retrospective analysis of AVMs who were treated in our institution from August 2011 to December 2021. Multivariable logistic regression analysis was employed to assess the risk factors for headaches in AVMs with unruptured, non-epileptic. Additionally, the effectiveness of different intervention treatments compared to conservative management in alleviating headaches was evaluated through propensity score matching (PSM). RESULTS: A total of 946 patients were included in the analysis of risk factors for headaches. Multivariate logistic regression analysis identified that female (OR 1.532, 95% CI 1.173-2.001, p = 0.002), supply artery dilatation (OR 1.423, 95% CI 1.082-1.872, p = 0.012), and occipital lobe (OR 1.785, 95% CI 1.307-2.439, p < 0.001) as independent risk factors for the occurrence of headaches. There were 443 AVMs with headache symptoms. After propensity score matching, the microsurgery group (OR 7.27, 95% CI 2.82-18.7 p < 0.001), stereotactic radiosurgery group(OR 9.46, 95% CI 2.26-39.6, p = 0.002), and multimodality treatment group (OR 8.34 95% CI 2.87-24.3, p < 0.001) demonstrate significant headache relief compared to the conservative group. However, there was no significant difference between the embolization group (OR 2.24 95% CI 0.88-5.69, p = 0.091) and the conservative group. CONCLUSIONS: This study identified potential risk factors for headaches in AVMs and found that microsurgery, stereotactic radiosurgery, and multimodal therapy had significant benefits in headache relief compared to conservative treatment. These findings provide important guidance for clinicians when developing treatment options that can help improve overall treatment outcomes and quality of life for patients.

Ketogenic diet time-dependently prevents NAFLD through upregulating the expression of antioxidant protein metallothionein-2.

BACKGROUND & AIMS: The past few decades have witnessed a rapid growth in the prevalence of nonalcoholic fatty liver disease (NAFLD). While the ketogenic diet (KD) is considered for managing NAFLD, the safety and efficacy of the KD on NAFLD has been a controversial topic. Here, we aimed to investigate the effect of KD of different durations on metabolic endpoints in mice with NAFLD and explore the underlying mechanisms. METHODS: NAFLD mice were fed with KD for 1, 2, 4 and 6 weeks, respectively. The blood biochemical indexes (blood lipids, AST, ALT and etc.) and liver fat were measured. The LC-MS/MS based proteomic analysis was performed on liver tissues. Metallothionein-2 (MT2) was knocked down with adeno-associated virus (AAV) or small interfering RNA (siRNA) in NAFLD mice and AML-12 cells, respectively. H&E, BODIPY and ROS staining were performed to examine lipid deposition and oxidative stress. Furthermore, MT2 protein levels, nucleus/cytoplasm distribution and DNA binding activity of peroxisome proliferators-activated receptors α (PPARα) were evaluated. RESULTS: KD feeding for 2 weeks showed the best improvement on NAFLD phenotype. Proteomic analysis revealed that MT2 was a key candidate for different metabolic endpoints of NAFLD affected by different durations of KD feeding. MT2 knockdown in NAFLD mice blocked the effects of 2 weeks of KD feeding on HFD-induced steatosis. In mouse primary hepatocytes and AML-12 cells, MT2 protein levels were induced by ß-hydroxybutyric acid (ß-OHB). MT2 Knockdown blunted the effects of ß-OHB on alleviating PA-induced lipid deposition. Mechanistically, 2 weeks of KD or ß-OHB treatment reduced oxidative stress and upregulated the protein levels of MT2 in nucleus, which subsequently increased its DNA binding activity and PPARα protein expression. CONCLUSIONS: Collectively, these findings indicated that KD feeding prevented NAFLD in a time dependent manner and MT2 is a potential target contributing to KD improvement on steatosis.

Lesion-Filling Index from Quantitative DSA Correlates with Hemorrhage of Cerebral AVM.

BACKGROUND AND PURPOSE: Rupture is the most life-threatening manifestation of cerebral AVMs. This study aimed to explore the hemodynamic mechanism of AVM rupture. We introduced a new quantitative DSA parameter that can reflect the degree of intranidal blood stasis, called the lesion-filling index. MATERIALS AND METHODS: This study examined patients with AVMs who had undergone both DSA and MR imaging between 2013 and 2014. Clinical presentations, angioarchitecture, and hemodynamic parameters generated from quantitative DSA were analyzed using univariate and multivariable logistic regression. The lesion-filling index was defined as the arterial diagnostic window divided by the volume of the AVM. To assess the correlation between the lesion-filling index and rupture, we incorporated the lesion-filling index into 2 published prediction models widely recognized for predicting AVM rupture risk, R2eD and VALE. The DeLong test was used to examine whether the addition of the lesion-filling index improved predictive efficacy. RESULTS: A total of 180 patients with AVMs were included. The mean lesion-filling index values in the ruptured group were higher compared with the unruptured group (390.27 [SD, 919.81] versus 49.40 [SD, 98.25]), P < .001). A higher lesion-filling index was significantly correlated with AVM rupture in 3 different multivariable logistic models, adjusting for angioarchitecture factors (OR = 1.004, P = .02); hemodynamic factors (OR = 1.005, P = .009); and combined factors (OR = 1.004, P = .03). Both R2eD (area under the curve, 0.601 versus 0.624; P = .15) and VALE (area under the curve, 0.603 versus 0.706; P < .001) predictive models showed improved predictive performance after incorporating the lesion-filling index and conducting 10-fold cross-validation. CONCLUSIONS: The lesion-filling index showed a strong correlation with AVM rupture, suggesting that overperfusion is the hemodynamic mechanism leading to AVM rupture.

From spear to trident: Upgrading arsenal of CAR-T cells in the treatment of multiple myeloma.

Multiple myeloma (MM), marked by abnormal proliferation of plasma cells and production of monoclonal immunoglobulin heavy or light chains in the majority of patients, has traditionally been associated with poor survival, despite improvements achieved in median survival in all age groups since the introduction of novel agents. Survival has significantly improved with the development of new drugs and new treatment options, such as chimeric antigen receptor T-cell therapy (CAR-T), which have shown promise and given new hope in MM therapy. CARs are now classified as first-, second-, and third-generation CARs based on the number of monovalent to trivalent co-stimulatory molecules incorporated into their design. The scope of this review was relatively narrow because it was mainly about a comparison of the literature on the clinical application of CAR-T therapy in MM. Thus, our goal is to provide an overview of the new advances of CAR-T cells in the cure of MM, so in this review we looked at the progress of the clinical use of CAR-T cells in MM to try to provide a reference for their clinical use when managing MM.

Genetically engineered nanomodulators elicit potent immunity against cancer stem cells by checkpoint blockade and hypoxia relief.

Rapid development of checkpoint inhibitors has provided significant breakthroughs for cancer stem cell (CSC) therapy, while the therapeutic efficacy is restricted by hypoxia-mediated tumor immune evasion, especially hypoxia-induced CD47 overexpression in CSCs. Herein, we developed a genetically engineered CSC membrane-coated hollow manganese dioxide (hMnO2@gCMs) to elicit robust antitumor immunity by blocking CD47 and alleviating hypoxia to ultimately achieve the eradication of CSCs. The hMnO2 core effectively alleviated tumor hypoxia by inducing decomposition of tumor endogenous H2O2, thus suppressing the CSCs and reducing the expression of CD47. Cooperating with hypoxia relief-induced downregulation of CD47, the overexpressed SIRPα on gCM shell efficiently blocked the CD47-SIRPα "don't eat me" pathway, synergistically eliciting robust antitumor-mediated immune responses. In a B16F10-CSC bearing melanoma mouse model, the hMnO2@gCMs showed an enhanced therapeutic effect in eradicating CSCs and inhibiting tumor growth. Our work presents a simple, safe, and robust platform for CSC eradication and cancer immunotherapy.

The novel HLA-DPB1*05:01:20 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-DPB1*05:01:20 differs from HLA-DPB1*05:01:01:01 by one nucleotide in exon 3.

The novel HLA-B*15:659 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*15:659 differs from HLA-B*15:02:01:01 by one nucleotide in exon 2.

Silk fibroin-based scaffolds for tissue engineering.

Silk fibroin is an important natural fibrous protein with excellent prospects for tissue engineering applications. With profound studies in recent years, its potential in tissue repair has been developed. A growing body of literature has investigated various fabricating methods of silk fibroin and their application in tissue repair. The purpose of this paper is to trace the latest developments of SF-based scaffolds for tissue engineering. In this review, we first presented the primary and secondary structures of silk fibroin. The processing methods of SF scaffolds were then summarized. Lastly, we examined the contribution of new studies applying SF as scaffolds in tissue regeneration applications. Overall, this review showed the latest progress in the fabrication and utilization of silk fibroin-based scaffolds.

Trichohepatoenteric syndrome and cytomegalovirus infection: Case report and literature summary.

Trichohepatoenteric syndrome is a rare autosomal recessive genetic disease caused by TTC37 (also known as SKIC3) or SKIV2L gene variant. We present a severely affected 2-month-old male infant with recurrent fever and unexplained diarrhea. Additionally, clinical data of 11 patients with trichohepatoenteric syndrome in China from 1 to 60 days of onset was presented. The infant's condition was not substantially relieved after cefotaxime sulbactam and meropenem treatment. Whole-exome sequencing revealed compound heterozygous variants (c.1708C>T and c.3342-9T>G) in TTC37 of the child whose parents were heterozygous carriers of the corresponding locus. The c.3342-9T>G variant originated from his mother and was reported for the first time. Combined with the clinical manifestations, the infant was diagnosed with trichohepatoenteric syndrome and treated with ganciclovir antiviral, intravenous nutritional support, and liver function protection. The infant was discharged with no fever and high stool frequency, but his condition improved. Therefore, trichohepatoenteric syndrome should be considered for recurrent fever and unexplained diarrhea.

Expert Consensus on Prevention and Treatment of Aging-Related Gonadal Dysfunction.

Aging-related hypogonadism involves complex mechanisms in humans, predominantly relating to the decline of multiple hormones and senile gonads. Late-onset hypogonadism (LOH) and erectile dysfunction (ED) are the main manifestations in men, while premature ovarian insufficiency (POI) and menopause are the main forms in women. Anti-aging measures include lifestyle modification and resistance training, hormonal supplementation, stem cell therapy, metformin, and rapamycin. In this expert consensus, the mechanisms, efficacy, and side effects of stem cell therapy on aging gonadal function are reviewed. Furthermore, various methods of stem cell therapy, administered intravenously, intracavernously, and intra-ovarially, are exemplified in detail. More clinical trials on aging-related gonadal dysfunction are required to solidify the foundation of this topic.

The novel HLA-B*15:02:15 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*15:02:15 differs from HLA-B*15:02:01:01 by one nucleotide in exon 2.

Key drivers of the oxidative potential of PM2.5 in Beijing in the context of air quality improvement from 2018 to 2022.

The mass concentration of atmospheric particulate matter (PM) has been continuously decreasing in the Beijing-Tianjin-Hebei region. However, health endpoints do not exhibit a linear correlation with PM mass concentrations. Thus, it is urgent to clarify the prior toxicological components of PM to further improve air quality. In this study, we analyzed the long-term oxidative potential (OP) of water-soluble PM2.5, which is generally considered more effective in assessing hazardous exposure to PM in Beijing from 2018 to 2022 based on the dithiothreitol assay and identified the crucial drivers of the OP of PM2.5 based on online monitoring of air pollutants, receptor model, and random forest (RF) model. Our results indicate that dust, traffic, and biomass combustion are the main sources of the OP of PM2.5 in Beijing. The complex interactions of dust particles, black carbon, and gaseous pollutants (nitrogen dioxide and sulfur dioxide) are the main factors driving the OP evolution, in particular, leading to the abnormal rise of OP in Beijing in 2022. Our data shows that a higher OP is observed in winter and spring compared to summer and autumn. The diurnal variation of the OP is characterized by a declining trend from 0:00 to 14:00 and an increasing trend from 14:00 to 23:00. The spatial variation in OP of PM2.5 was observed as the OP in Beijing is lower than that in Shijiazhuang, while it is higher than that in Zhenjiang and Haikou, which is primarily influenced by the distribution of black carbon. Our results are of significance in identifying the key drivers influencing the OP of PM2.5 and provide new insights for advancing air quality improvement efforts with a focus on safeguarding human health in Beijing.

Comparing combined application of biochar and nitrogen fertilizer in paddy and upland soils: Processes, enhancement strategies, and agricultural implications.

Recently, biochar and N fertilizers have been used to tackle low N use efficiency (NUE) in crops across diverse environmental conditions. The coupling of biochar and N fertilizer may impact crop N utilization through different pathways in various soil types. However, there is currently a lack of comprehensive assessment of how coupling effects specifically influence N utilization in paddy and upland crops. We conducted a meta-analysis of 175 peer-reviewed studies to assess the responses of soil properties and crop traits in paddy and upland fields under coupling effects. The results indicate that NUE (+26.1 %) and N uptake (+15.0 %) in paddy fields increase more than in upland fields (+23.7 % and +8.0 %, respectively), with the coupling effect providing NH4+ predominantly for rice and NO3- for upland crops. NH4+ increases in paddy fields (+6.9 %) but decreases in upland fields (-0.7 %), while microbial biomass carbon (MBC) decreases in paddy fields (-2.9 %) and increases in upland fields (+36.0 %). These findings suggest that coupling effects supply soil inorganic nutrients in paddies and affect microbes in uplands, thereby positively affecting crop N utilization. Specifically, the greatest increase in paddy crop yield and N use efficiency occurs when the ratio of N fertilizer to biochar exceeds 1.5 %, and in uplands, it manifests when applying 10-20 t·ha-1 of biochar and <150 kg·ha-1 N fertilizer. In conclusion, this meta-analysis explores the differential effects of biochar and N fertilizer coupling in different arable land types, offering novel insights into the utilization strategies of biochar in agricultural fields.

Traumatic Cerebral Venous Sinus Thrombosis: Management and Outcomes.

BACKGROUND: Traumatic brain injury (TBI) with skull fractures parallel to or crossing venous sinuses is a recognized risk factor for traumatic cerebral venous sinus thrombosis (tCVST). Despite the recognition of this traumatic pathology in the literature, no consensus regarding management has been achieved. This study aimed to evaluate the impact of tCVST on TBI outcomes and related complications. METHOD: Patients within a prospective registry at a Level I trauma center from 2014 to 2023 were reviewed to identify tCVST cases. The impact of tCVST presence on Glasgow Outcome Scale (GOS) scores at 6-months, 30-day mortality, and hospital length of stay were evaluated in multivariable-adjusted analyses. RESULTS: Among 607 patients with TBI, 61 patients were identified with skull fractures extending to the vicinity of venous sinuses with dedicated venography. Twenty-eight of these 61 patients (44.3%) had tCVST. The majority (96.4%) of tCVST were located in the unilateral transverse or sigmoid sinus. Complete recanalization was observed in 28% of patients on follow-up imaging (7/25 with follow-up imaging). None of the 28 patients suffered attributable venous infarcts or thrombus propagation. In the adjusted analysis, there was no difference in the 30-day mortality or GOS at 6-months between patients with and without tCVST. CONCLUSION: Unilateral traumatic cerebral venous sinus thrombosis follows a benign clinical course without associated increased mortality or morbidity. The management of traumatic CVST should be distinct as compared to spontaneous CVST, likely without need for anticoagulation.

Preparation of S-C3N4/AgCdS Z-Scheme Heterojunction Photocatalyst and Its Effectively Improved Photocatalytic Performance.

In this study, S-doped graphitic carbon nitride (S-C3N4) was prepared using the high-temperature polymerization method, and then S-C3N4/AgCdS heterojunction photocatalyst was obtained using the chemical deposition method through loading Ag-doped CdS nanoparticles (AgCdS NPs) on the surface of S-C3N4. Experimental results show that the AgCdS NPs were evenly dispersed on the surface of S-C3N4, indicating that a good heterojunction structure was formed. Compared to S-C3N4, CdS, AgCdS and S-C3N4/CdS, the photocatalytic performance of S-C3N4/AgCdS has been significantly improved, and exhibits excellent photocatalytic degradation performance of Rhodamine B and methyl orange. The doping of Ag in collaboration with the construction of a Z-scheme heterojunction system promoted the effective separation and transport of the photogenerated carriers in S-C3N4/AgCdS, significantly accelerated its photocatalytic reaction process, and thus improved its photocatalytic performance.

Research Progress on the Mechanism of the Antitumor Effects of Cannabidiol.

Cannabidiol (CBD), a non-psychoactive ingredient extracted from the hemp plant, has shown therapeutic effects in a variety of diseases, including anxiety, nervous system disorders, inflammation, and tumors. CBD can exert its antitumor effect by regulating the cell cycle, inducing tumor cell apoptosis and autophagy, and inhibiting tumor cell invasion, migration, and angiogenesis. This article reviews the proposed antitumor mechanisms of CBD, aiming to provide references for the clinical treatment of tumor diseases and the rational use of CBD.

Cryo-EM Structure of Porphyromonas gingivalis RNA Polymerase.

Porphyromonas gingivalis, an anaerobic CFB (Cytophaga, Fusobacterium, and Bacteroides) group bacterium, is the keystone pathogen of periodontitis and has been implicated in various systemic diseases. Increased antibiotic resistance and lack of effective antibiotics necessitate a search for new intervention strategies. Here we report a 3.5 Å resolution cryo-EM structure of P. gingivalis RNA polymerase (RNAP). The structure displays new structural features in its ω subunit and multiple domains in ß and ß' subunits, which differ from their counterparts in other bacterial RNAPs. Superimpositions with E. coli RNAP holoenzyme and initiation complex further suggest that its ω subunit may contact the σ4 domain, thereby possibly contributing to the assembly and stabilization of initiation complexes. In addition to revealing the unique features of P. gingivalis RNAP, our work offers a framework for future studies of transcription regulation in this important pathogen, as well as for structure-based drug development.