Amelanotic primary cervical malignant melanoma: A case report and review of literature.

BACKGROUND: Primary malignant melanoma of the cervix (PMMC) is an extremely rare disease that originates from primary cervical malignant melanoma and frequently represents a challenge in disease diagnosis due to unclarified clinical and histological presentations, particularly those without melanin. CASE SUMMARY: Here, we report a case of amelanotic PMMC, with a history of breast cancer and thyroid carcinoma. The patient was finally diagnosed by immunohistochemical staining and staged as IB2 based on the International Federation of Gynecology and Obstetrics with reference to National Comprehensive Cancer Network guidelines and was treated with radical hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy. She then received combination therapy consisting of immunotherapy with tislelizumab and radiofrequency hyperthermia. She has remained free of disease for more than 1 year. CONCLUSION: The differential diagnosis process reenforced the notion that immunohistochemical staining is the most reliable approach for amelanotic PMMC diagnosis. Due to the lack of established therapeutic guidelines, empirical information from limited available studies does not provide the rationale for treatment-decision making. By integrating 'omics' technologies and patient-derived xenografts or mini-patient-derived xenograft models this will help to identify selective therapeutic window(s) and screen the appropriate therapeutics for targeted therapies, immune checkpoint blockade or combination therapy strategies effectively and precisely that will ultimately improve patient survival.

Case report: Immunotherapy-based combination therapy achieving complete remission and prolonged survival in nasopharyngeal carcinoma with extensive bone marrow metastasis.

Nasopharyngeal carcinoma with bone marrow metastasis presents a rare and challenging clinical scenario associated with exceedingly poor prognosis. While standard treatment regimens offer limited efficacy and tolerability in such cases, individualized approaches are increasingly necessary. We present the case of a 64-year-old male diagnosed with recurrent nonkeratinizing undifferentiated nasopharyngeal carcinoma with extensive bone marrow metastasis (rTxN0M1). Treatment was initiated with immunotherapy-based combination therapy, consisting of pembrolizumab and low-dose cisplatin, which resulted in an initial response. Subsequently, there was a transition to standard-dose nab-paclitaxel-cisplatin chemotherapy in combination with pembrolizumab, followed by maintenance therapy with pembrolizumab plus fruquintinib. The patient achieved a sustained response with renormalization of tumor markers, imaging findings, and bone biopsies, resulting in complete remission. This case highlights the successful management of nasopharyngeal carcinoma with extensive bone marrow metastasis through an individualized treatment approach incorporating immunotherapy.

Programmable Optical Encryption Based on Electrical-Field-Controlled Exciton-Trion Transitions in Monolayer WS2.

Optical encryption is receiving much attention with the rapid growth of information technology. Conventional optical encryption usually relies on specific configurations, such as metasurface-based holograms and structure colors, not meeting the requirements of increasing dynamic and programmable encryption. Here, we report a programmable optical encryption approach using WS2/SiO2/Au metal-oxide-semiconductor (MOS) devices, which is based on the electrical-field-controlled exciton-trion transitions in monolayer WS2. The modulation depth of the MOS device reflection amplitude up to 25% related to the excitons ensures the fidelity of information, and the decryption based on the near excitonic resonance assures security. With such devices, we successfully demonstrate their applications in real-time encryption of ASCII codes and visual images. For the latter, it can be implemented at the pixel level. The strategy shows significant potential for low-cost, low-energy-consumption, easily integrated, and high-security programmable optical encryptions.

Unveiling promising drug targets for autism spectrum disorder: insights from genetics, transcriptomics, and proteomics.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder for which current treatments are limited and drug development costs are prohibitive. Identifying drug targets for ASD is crucial for the development of targeted therapies. Summary-level data of expression quantitative trait loci obtained from GTEx, protein quantitative trait loci data from the ROSMAP project, and two ASD genome-wide association studies datasets were utilized for discovery and replication. We conducted a combined analysis using Mendelian randomization (MR), transcriptome-wide association studies, Bayesian colocalization, and summary-data-based MR to identify potential therapeutic targets associated with ASD and examine whether there are shared causal variants among them. Furthermore, pathway and drug enrichment analyses were performed to further explore the underlying mechanisms and summarize the current status of pharmacological targets for developing drugs to treat ASD. The protein-protein interaction (PPI) network and mouse knockout models were performed to estimate the effect of therapeutic targets. A total of 17 genes revealed causal associations with ASD and were identified as potential targets for ASD patients. Cathepsin B (CTSB) [odd ratio (OR) = 2.66 95, confidence interval (CI): 1.28-5.52, P = 8.84 × 10-3], gamma-aminobutyric acid type B receptor subunit 1 (GABBR1) (OR = 1.99, 95CI: 1.06-3.75, P = 3.24 × 10-2), and formin like 1 (FMNL1) (OR = 0.15, 95CI: 0.04-0.58, P = 5.59 × 10-3) were replicated in the proteome-wide MR analyses. In Drugbank, two potential therapeutic drugs, Acamprosate (GABBR1 inhibitor) and Bryostatin 1 (CASP8 inhibitor), were inferred as potential influencers of autism. Knockout mouse models suggested the involvement of the CASP8, GABBR1, and PLEKHM1 genes in neurological processes. Our findings suggest 17 candidate therapeutic targets for ASD and provide novel drug targets for therapy development and critical drug repurposing opportunities.

The mediating effect of blood biomarkers in the associations between inflammatory bowel disease and incident psychiatric disorders: a prospective cohort study.

BACKGROUND: Despite the growing evidence of an association between inflammatory bowel disease (IBD) and psychiatric disorders, there has been limited research exploring the underlying mediating role of blood biomarkers on the gut-brain axis. This study aimed to examine the association between IBD and the risk of incident psychiatric disorders and investigate whether and how blood biomarkers mediate this association. METHODS: This prospective cohort study using data from the UK Biobank included participants without psychiatric diagnoses at baseline. The case cohort consisted of participants with a hospital-based diagnosis of IBD at baseline. The primary outcome was all psychiatric disorders. Secondary outcomes included 11 major psychiatric disorders. Cox regression models estimated adjusted hazard ratios (HRs) for psychiatric outcomes. Causal mediation models investigated the potential mediation effects of blood biomarkers. RESULTS: Among 491,131 participants, patients with IBD exhibited higher risks of overall psychiatric disorders (HR 1.23 [95% CI 1.13-1.33]), substance misuse (1.23 [1.09-1.38]), depression (1.36 [1.22-1.52]), anxiety (1.15 [1.01-1.30]) and post-traumatic stress disorder (1.87 [1.00-3.51]) compared with non-IBD participants. The association with incident substance misuse was only among patients with Crohn's disease (CD, 1.47 [1.23-1.76]), but not ulcerative colitis (UC, 1.01 [0.84-1.21]). Mediation analysis revealed 16, 14, 15, and 6 biomarkers partially mediated the associations for all psychiatric disorders, substance misuse, depression, and anxiety, respectively. Six blood markers showed the strongest mediating effects: neutrophil count (12.04%), C-reactive protein (10.29%), systemic immune-inflammatory index (8.94%), erythrocyte distribution width (16.51%), erythrocyte count (9.76%), and albumin (9.15%). Moreover, several blood mediators of CD identified in association with incident substance misuse may explain the risk discrepancy between IBD subtype. CONCLUSION: The blood biomarkers of inflammation, blood oxygen-carrying capacity, and metabolism mediate the effect of IBD on the risk of psychiatric outcomes and could be considered as a therapeutic target.

Investigating shared genetic architecture between inflammatory bowel diseases and primary biliary cholangitis.

Background & Aims: Inflammatory bowel disease (IBD) is commonly associated with extraintestinal complications, including autoimmune liver disease. The co-occurrence of IBD and primary biliary cholangitis (PBC) has been increasingly observed, but the underlying relationship between these conditions remains unclear. Methods: Using summary statistics from genome-wide association studies (GWAS), we investigated the causal effects between PBC and IBD, including Crohn's disease (CD) and ulcerative colitis (UC). We also analyzed the shared genetic architecture between IBD and PBC using data from GWAS, bulk-tissue RNA sequencing, and single cell RNA sequencing, and explored potential functional genes. Result: There was a strong positive genetic correlation between PBC and IBD (linkage disequilibrium score regression: rg = 0.2249, p = 3.38 × 10-5). Cross-trait analysis yielded 10 shared-risk single nucleotide polymorphisms (SNPs), as well as nine novel SNPs, which were associated with both traits. Using Mendelian randomization, a stable causal effect was established of PBC on IBD. Genetically predicted PBC was found to have a risk effect on IBD (1.105; 95% CI: 1.058-1.15; p = 1.16 × 10-10), but not vice versa. Shared tissue-specific heritability enrichment was identified for PBC and IBD (including CD and UC) in lung, spleen, and whole-blood samples. Furthermore, shared enrichment was observed of specific cell types (T cells, B cells, and natural killer cells) and their subtypes. Nine functional genes were identified based on summary statistics-based Mendelian randomization. Conclusions: This study detected shared genetic architecture between IBD and PBC and demonstrated a stable causal relationship of genetically predicted PBC on the risk of IBD. These findings shed light on the biological basis of comorbidity between IBD and PBC, and have important implications for intervention and treatment targets of these two diseases simultaneously. Impact and Implications: The discovery of novel shared single nucleotide polymorphisms (SNPs) and functional genes provides insights into the common targets between inflammatory bowel disease (IBD) and primary biliary cholangitis (PBC), serving as a basis for new drug development and contributing to the study of disease pathogenesis. Additionally, the established significant causality and genetic correlation underscore the importance of clinical intervention in preventing the comorbidity of IBD and PBC. The enrichment of SNP heritability in specific tissues and cell types reveals the role of immune factors in the potential disease mechanisms shared between IBD and PBC. This stimulates further research on potential interventions and could lead to the development of new targets for immune-based therapies.

Effects of atrazine on movement, metabolism and gene expression in Pelophylax nigromaculatus larvae under global warming.

Global warming and environmental pollutants both pose a threat to the behavior and physiology of animals, but research on the combined effects of the two is limited. Atrazine, a widely used herbicide, has toxic effects on organisms. In this study, the effects of environmental concentrations of atrazine exposure (100 µg/L) for seven days on the movement, metabolism and gene expression related to motility of Pelophylax nigromaculatus larvae (GS8) were investigated under global warming. The results showed that compared to the optimal growth temperature (18 °C), atrazine treatment under global warming (21 °C) significantly increased the average speed (about 11.2 times) and maximum acceleration (about 1.98 times) of P. nigromaculatus larvae, altered the relative abundance of 539 metabolites, including Formyl-5-hydroxykynurenamine, 2,4-Dihydroxybenzophenone, and FAPy-adenine, and changed the nucleotide metabolism, pyrimidine metabolism, glycerophospholipid metabolism, and purine metabolism, as well as increased the gene expression of SPLA2 (about 6.46 times) and CHK (about 3.25 times). In summary, atrazine treatment under global warming caused metabolic disorders in amphibian larvae and increased the expression of some movement-related genes in the brain, resulting in abnormally active.

A PTER-dependent pathway of taurine metabolism linked to energy balance.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites4,5. One such taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise7, nutritional taurine supplementation8, and alcohol consumption6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells6,7, the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related)10 is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

Optimal power-heat-carbon scheduling strategy for interconnected heterogeneous multi-microgrid considering hydrogen fuel cell vehicles.

The scale of multi-microgrid (MMG) and hydrogen fuel cell vehicles (HFCVs) is increasing dramatically with the increase in the new energy penetration ratio, and developing an integrated energy system containing a multi-microgrid for hydrogen fuel vehicles brings great challenges to power grid operation. Focusing on the difficulties of the access of multiple microgrids for the low-carbon and economic operation of the system, this paper proposes an optimal interconnected heterogeneous multi-microgrid power-heat-carbon scheduling strategy for hydrogen-fueled vehicles. Firstly, an HFCV model is established, and then an optimal scheduling model is constructed for the cooperative trading of power-heat-carbon in a multi-microgrid, on the basis of which the low-carbon economic operation of the multi-microgrid is realized. The results of the case study show that the scheduling strategy in this paper reduces carbon emissions by about 7.12% and costs by about 3.41% compared with the independent operation of the multi-microgrid. The degrees of interaction of each multi-microgrid are also analyzed under different HFCV penetration rates.

Interface Modulation for the Heterointegration of Diamond on Si.

Along with the increasing integration density and decreased feature size of current semiconductor technology, heterointegration of the Si-based devices with diamond has acted as a promising strategy to relieve the existing heat dissipation problem. As one of the heterointegration methods, the microwave plasma chemical vapor deposition (MPCVD) method is utilized to synthesize large-scale diamond films on a Si substrate, while distinct structures appear at the Si-diamond interface. Investigation of the formation mechanisms and modulation strategies of the interface is crucial to optimize the heat dissipation behaviors. By taking advantage of electron microscopy, the formation of the epitaxial ß-SiC interlayer is found to be caused by the interaction between the anisotropically sputtered Si and the deposited amorphous carbon. Compared with the randomly oriented ß-SiC interlayer, larger diamond grain sizes can be obtained on the epitaxial ß-SiC interlayer under the same synthesis condition. Moreover, due to the competitive interfacial reactions, the epitaxial ß-SiC interlayer thickness can be reduced by increasing the CH4/H2 ratio (from 3% to 10%), while further increase in the ratio (to 20%) can lead to the broken of the epitaxial relationship. The above findings are expected to provide interfacial design strategies for multiple large-scale diamond applications.

Solar-Blind Photodetector Arrays Fabricated by Weaving Strategy.

The quest for solar-blind photodetectors (SBPDs) with exceptional optoelectronic properties for imaging applications has prompted the investigation of SBPD arrays. Ga2O3, characterized by its ultrawide bandgap and low growth cost, has emerged as a promising material for solar-blind detection. In this study, SBPD arrays were fabricated by weaving Sn-doped ß-Ga2O3 microbelts (MBs). These MBs, which have a conductive core surrounded by a high-resistivity depletion surface layer resulting from the segregation of Sn and oxygen, are woven into a grid structure. Each intersection of the MBs functions as a photodetector pixel, with the intersecting MBs serving as the output electrodes of the pixel. This design simplifies the readout circuit for the photodetector array. The solar-blind photodetector array demonstrates superior solar-blind detection performance, including a dark current of 0.5 pA, a response time of 38.8 µs, a light/dark current ratio of 108, and a responsivity of 300 A/W. This research may provide a feasible strategy for the fabrication of photodetector arrays, thus pushing forward the application of photodetectors in imaging.

Long-term risks of respiratory diseases in patients infected with SARS-CoV-2: a longitudinal, population-based cohort study.

Background: In the post-pandemic era, growing apprehension exists regarding the potential sequelae of COVID-19. However, the risks of respiratory diseases following SARS-CoV-2 infection have not been comprehensively understood. This study aimed to investigate whether COVID-19 increases the long-term risk of respiratory illness in patients with COVID-19. Methods: In this longitudinal, population-based cohort study, we built three distinct cohorts age 37-73 years using the UK Biobank database; a COVID-19 group diagnosed in medical records between January 30th, 2020 and October 30th, 2022, and two control groups, a contemporary control group and a historical control group, with cutoff dates of October 30th, 2022 and October 30th, 2019, respectively. The follow-up period of all three groups was 2.7 years (the median (IQR) follow-up time was 0.8 years). Respiratory outcomes diagnosed in medical records included common chronic pulmonary diseases (asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease (PVD), and lung cancer. For the data analysis, we calculated hazard ratios (HRs) along with their 95% CIs using Cox regression models, following the application of inverse probability weights (IPTW). Findings: A total of 3 cohorts were included in this study; 112,311 individuals in the COVID-19 group with a mean age (±SDs) of 56.2 (8.1) years, 359,671 in the contemporary control group, and 370,979 in the historical control group. Compared with the contemporary control group, those infected with SARS-CoV-2 exhibited elevated risks for developing respiratory diseases. This includes asthma, with a HR of 1.49 and a 95% CI 1.28-1.74; bronchiectasis (1.30; 1.06-1.61); COPD (1.59; 1.41-1.81); ILD (1.81; 1.38-2.21); PVD (1.59; 1.39-1.82); and lung cancer (1.39; 1.13-1.71). With the severity of the acute phase of COVID-19, the risk of pre-described respiratory outcomes increases progressively. Besides, during the 24-months follow-up, we observed an increasing trend in the risks of asthma and bronchiectasis over time. Additionally, the HR of lung cancer for 0-6 month follow-up was 3.07 (CI 1.73-5.44), and the association of lung cancer with COVID-19 disease disappeared at 6-12 month follow-up (1.06; 0.43-2.64) and at 12-24 months (1.02; 0.45-2.34). Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of asthma (3.0; 1.32-6.84), COPD (3.07; 1.42-6.65), ILD (3.61; 1.11-11.8), and lung cancer (3.20; 1.59-6.45). Similar findings were noted when comparing with a historical cohort serving as a control group, including asthma (1.31; 1.13-1.52); bronchiectasis (1.53; 1.23-1.89); COPD (1.41; 1.24-1.59); ILD (2.53; 2.05-3.13); PVD (2.30; 1.98-2.66); and lung cancer (2.23; 1.78-2.79). Interpretation: Our research suggests that patients with COVID-19 may have an increased risk of developing respiratory diseases, and the risk increases with the severity of infection and reinfection. Even during the 24-month follow-up, the risk of asthma and bronchiectasis continued to increase. Hence, implementing appropriate follow-up strategies for these individuals is crucial to monitor and manage potential long-term respiratory health issues. Additionally, the increased risk in lung cancer in the COVID-19 individuals was probably due to the diagnostic tests conducted and incidental diagnoses. Funding: The National Natural Science Foundation of China of China Regional Innovation and Development Joint Foundation; National Natural Science Foundation of China; Program for High-level Foreign Expert Introduction of China; Natural Science Foundation for Distinguished Young Scholars of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital; VA Clinical Merit and ASGE clinical research funds.

A comparison of the postoperative outcomes between intraoperative leak testing and no intraoperative leak testing for gastric cancer surgery: a systematic review and meta-analysis.

BACKGROUND: Postoperative anastomotic leakage (PAL) is a serious complication of gastric cancer surgery. Although perioperative management has made considerable progress, anastomotic leakage (AL) cannot always be avoided. The purpose of this study is to evaluate whether intraoperative leak testing (IOLT) can reduce the incidence of PAL and other postoperative outcomes in gastric cancer surgery. MATERIALS AND METHODS: In this meta-analysis, we searched the PubMed, Embase, and Cochrane Library databases for clinical trials to assess the application of IOLT in gastric cancer surgery. All patients underwent laparoscopic radical gastrectomy for gastric cancer surgery. Studies comparing the postoperative outcomes of IOLT and no intraoperative leak testing (NIOLT) were included. Quality assessment, heterogeneity, risk of bias, and the level of evidence of the included studies were evaluated. PAL, anastomotic-related complications, 30-day mortality, and reoperation rates were compared between the IOLT and NIOLT group. RESULTS: Our literature search returned 721 results, from which six trials (a total of 1,666 patients) were included in our meta-analysis. Statistical heterogeneity was low. The primary outcome was PAL. IOLT reduced the incidence of PAL [2.09% vs 6.68%; (RR = 0.31, 95% Cl 0.19-0.53, P < 0.0001]. Anastomotic-related complications, which included bleeding, leakage, and stricture, were significantly higher in the NIOLT group than in the IOLT group [3.24% VS 10.85%; RR = 0.30, 95% Cl 0.18-0.53, P < 0.0001]. Moreover, IOLT was associated with lower reoperation rates [0.94% vs 6.83%; RR = 0.18, 95% CI 0.07-0.43, P = 0.0002]. CONCLUSION: Considering the observed lower incidence of postoperative anastomotic leakage (PAL), anastomotic-related complications, and reoperation rates, IOLT appears to be a promising option for gastric cancer surgery. It warrants further study before potential inclusion in future clinical guidelines.

T1-weighted MRI of targeting atherosclerotic plaque based on CD40 expression on engulfed USPIO's cell surface.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of cholesterol within the arterial wall. Its progression can be monitored via magnetic resonance imaging (MRI). Ultrasmall Superparamagnetic Particles of Iron Oxide (USPIO) (<5 nm) have been employed as T1 contrast agents for MRI applications. In this study, we synthesized USPIO with an average surface carboxylation of approximately 5.28 nm and a zeta potential of -47.8 mV. These particles were phagocytosed by mouse aortic endothelial cells (USPIO-MAECs) and endothelial progenitor cells (USPIO-EPCs), suggesting that they can be utilized as potential contrast agent and delivery vehicle for the early detection of atherosclerosis. However, the mechanism by which this contrast agent is delivered to the plaque remains undetermined. Our results demonstrated that with increasing USPIO concentration during 10-100 µg ml-1, consistent change appeared in signal enhancement on T1-weighted MRI. Similarly, T1-weighted MRI of MAECs and EPCs treated with these concentrations exhibited a regular change in signal enhancement. Prussian blue staining of USPIO revealed substantial absorption into MAECs and EPCs after treatment with 50 µg ml-1USPIO for 24 h. The iron content in USPIO-EPCs was much higher (5 pg Fe/cell) than in USPIO-MAECs (0.8 pg Fe/cell). In order to substantiate our hypothesis that CD40 protein on the cell surface facilitates migration towards inflammatory cells, we utilized AuNPs-PEI (gold nanoparticles-polyethylenimine) carrying siRNACD40to knockout CD40 expression in MAECs. It has been documented that gold nanoparticle-oligonucleotide complexes could be employed as intracellular gene regulation agents for the control of protein level in cells. Our results confirmed that macrophages are more likely to bind to MAECs treated with AuNPs-PEI-siRNANC(control) for 72 h than to MAECs treated with AuNPs-PEI-siRNACD40(reduced CD40 expression), thus confirming CD40 targeting at the cellular level. When USPIO-MAECs and MAECs (control) were delivered to mice (high-fat-fed) via tail vein injection respectively, we observed a higher iron accumulation in plaques on blood vessels in high-fat-fed mice treated with USPIO-MAECs. We also demonstrated that USPIO-EPCs, when delivered to high-fat-fed mice via tail vein injection, could indeed label plaques by generating higher T1-weighted MRI signals 72 h post injection compared to controls (PBS, USPIO and EPCs alone). In conclusion, we synthesized a USPIO suitable for T1-weighted MRI. Our results have confirmed separately at the cellular and tissue andin vivolevel, that USPIO-MAECs or USPIO-EPCs are more accessible to atherosclerotic plaques in a mouse model. Furthermore, the high expression of CD40 on the cell surface is a key factor for targeting and USPIO-EPCs may have potential therapeutic effects.

NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair.

Chemotherapeutic agents, including cisplatin, have remained a cornerstone of lung adenocarcinoma (LUAD) treatment and continue to play an essential role in clinical practice, despite remarkable progress in therapeutic strategies. Hence, a thorough comprehension of the molecular mechanisms underlying chemotherapeutic agent resistance is paramount. Our investigation centered on the potential involvement of the NPAS2 gene in LUAD, which is highly expressed in tumors and its high expression has been associated with unfavorable overall survival rates in patients. Intriguingly, we observed that the depletion of NPAS2 in LUAD cells resulted in increased susceptibility to cisplatin treatment. Furthermore, mRNA sequencing analysis revealed that NPAS2 deficiency downregulated genes crucial to DNA repair. Additionally, NPAS2 depletion significantly impairs γH2AX accumulation, a pivotal component of the DNA damage response. Further investigation demonstrates that NPAS2 plays a crucial role in DNA double-strand breakage repair via homology-directed repair (HDR). Our inquiry into the molecular mechanisms underlying NPAS2 regulation of DDR revealed that it may enhance the stability of H2AX mRNA by binding to its mRNA, thereby upregulating the DNA damage repair pathway. In-vivo experiments further confirmed the crucial role of NPAS2 in modulating the effect of cisplatin in LUAD. Taken together, our findings suggest that NPAS2 binds to and enhances the stability of H2AX mRNA, thereby decreasing the sensitivity of tumor cells to chemotherapy by augmenting DNA damage repair.

Cancer-associated fibroblast-derived extracellular vesicles promote lymph node metastases in oral cavity squamous cell carcinoma by encapsulating ITGB1 and BMI1.

BACKGROUND: Extracellular vesicles (EVs) have been revealed to facilitate the development of oral squamous cavity cell carcinoma (OCSCC), while its supporting role in lymph node metastases is under continuous investigation. This study aimed to examine the function of cancer-associated fibroblasts (CAF)-derived EVs (CAF-EVs) during lymph node metastasis in OCSCC and the mechanisms. METHODS: CAF were isolated from OCSCC tissues of patients, and CAF-EVs were extracted and identified. EdU, colony formation, wound healing, and Transwell assays were performed. The OCSCC cells before and after CAF-EVs treatment were injected into mice to probe the effects of CAF-EVs on tumor growth and lymph node metastasis, respectively. The effect of CAF-EVs treatment on transcriptome changes in OCSCC cells was analyzed. Clinical data of patients with OCSCC were analyzed to determine the prognostic significance of the selected genes. Finally, loss-of-function assays were conducted to corroborate the involvement of polycomb complex protein BMI-1 (BMI1) and integrin beta1 (ITGB1). RESULTS: CAF-EVs promoted the malignant behavior of OCSCC cells and accelerated tumor growth and lymph node metastasis in mice. CAF-EVs significantly increased the expression of BMI1 and ITGB1, and the expression of BMI1 and ITGB1 was negatively correlated with the overall survival and relapse-free survival of OCSCC patients. Knockdown of BMI1 or ITGB1 in OCSCC cells abated the promoting effects of CAF-EVs in vitro and in vivo. CONCLUSION: CAF-EVs elicited the metastasis-promoting properties in OCSCC by elevating BMI1 and ITGB1, suggesting that BMI1 and ITGB1 could be potential biomarkers and therapeutic targets for OCSCC.

Subchronic toxicity evaluation of Huobahuagen extract and plasma metabolic profiling analysis combined with conventional pathology methods.

Huobahua, namely, Tripterygium hypoglaucum (Levl.) Hutch, known as a traditional Chinese herbal medicine, especially its underground parts, has been widely developed into several Tripterygium agents for the treatment of rheumatoid arthritis and other autoimmune diseases. It has sparked wide public concern about its safety, such as multi-organ toxicity. However, the toxic characteristics and damage mechanism of Huobahuagen extract (HBHGE) remain unclear. In the present study, subchronic oral toxicity study of HBHGE (10.0 g crude drug/kg/day for 12 weeks) was performed in male rats. Hematological, serum biochemical, and histopathological parameters, urinalysis, and plasma metabolic profiling were assessed. The single-dose subchronic toxicity results related to HBHGE exhibited obvious toxicity to the testis and epididymis of male rats. Furthermore, plasma metabolomics analysis suggested that a series of metabolic disorders were induced by oral administration of HBHGE, mainly focusing on amino acid (glutamate, phenylalanine, and tryptophan) metabolisms, pyrimidine metabolism, glutathione metabolism, and steroid hormone biosynthesis. Moreover, it appeared that serum testosterone in male rats treated with HBHGE for 12 weeks, decreased significantly, and was susceptible to the toxic effects of HBHGE. Taken together, conventional pathology and plasma metabolomics for preliminarily exploring subchronic toxicity and underlying mechanism can provide useful information about the reduction of toxic risks from HBHGE and new insights into the development of detoxification preparations.

Removal of cationic dyes from aqueous solution using polyacrylic acid modified hemp stem.

Water pollution caused by dyes is a pressing environmental challenge due to their persistence and difficulty in degradation. Herein, an anionic adsorbent (HS-PAANa) was synthesized by grafting polyacrylic acid (PAA) onto the agricultural waste-hemp stem (HS). The obtained HS-PAANa adsorbent exhibited rapid adsorption kinetics, high adsorption capacity, and a favorable preference for cationic dyes, such as methylene blue (MB) and crystal violet (CV). The experimental data fit well with the pseudo-second-order kinetic model and Langmuir isotherm, demonstrating the efficiency of HS-PAANa in dye removal. Notably, the optimal adsorption capacities of HS-PAANa for MB and CV were found to be 1296.65 mg/g and 1451.43 mg/g, respectively. In the cationic/anionic dyes (MB/MO) binary systems, HS-PAANa exhibited enhanced selective adsorption of cationic dyes (MB), indicating its potential for targeted removal of specific dyes from mixed solutions. Moreover, HS-PAANa adsorption shows an excellent recyclability, after five cycles, HS-PAANa still maintained MB and CV removal rates of 93.85% and 95.08%, respectively. Therefore, the bioadsorbent HS-PAANa exhibits high potential as a highly efficient adsorbent for the effective treatment of cationic pollutants in wastewater.

The lncRNA FENDRR inhibits colorectal cancer progression via interacting with and triggering GSTP1 ubiquitination by FBX8.

Background: Colorectal cancer (CRC) is characterized by its aggressiveness and high fatality rate. Long noncoding RNAs (lncRNAs) as molecular scaffolding in CRC have received little attention. Methods: The TCGA database was used to find putative anti-oncogenic lncRNAs in CRC. The effect of FENDRR on CRC was evaluated using the colony formation assay, transwell assays, and wound healing assays, and FENDRR expression was validated by qRT-PCR. The location of the FENDRR binding proteins was determined by an RNA pull-down experiment, and the retrieved proteins were recognized by mass spectrometry. RNA immunoprecipitation (RIP) studies were used to demonstrate the interaction of GSTP1, FBX8, and FENDRR. Co-IP and immunofluorescence were utilized to confirm the connection between GSTP1 and FBX8. To determine the precise signaling pathways implicated in the action of FENDRR in CRC, we performed next-generation sequencing (NGS) on CRC cells transfected with a vector overexpressing FENDRR. Results: The expression of FENDRR was significantly downregulated in CRC tissue and cells. The results of the function experiments showed that overexpression of FENDRR reduced CRC cells' ability to proliferation, invasion, migration and tube formation. In terms of mechanism, FENDRR could bind both GSTP1 and FBX8, act as a molecular scaffold, and utilize FBX8 to regulate the stability of GSTP1's protein. Additionally, the outcomes of NGS and qRT-PCR demonstrated that the expression of genes linked to the HIF-1 pathway was down-regulated following FENDRR overexpression. Lastly, rescue tests demonstrated that overexpression of GSTP1 in CRC cells could completely restore the inhibition induced by FENDRR. Conclusion: In this study, we found that the molecular scaffolding protein FENDRR regulates the ubiquitination of GSTP1 and the suppression of the HIF-1 signaling pathway in the development of CRC. Our research provides more evidence of FENDRR's crucial role in the emergence of CRC and identifies it as a potential therapeutic target for CRC patients.