Alleviating effects of microplastics together with tetracycline hydrochloride on the physiological stress of Closterium sp.

Microplastics have significant influence on both freshwater cyanobacteria and marine microalgae, especially under co-exposure with other pollutants such as heavy metals, antibiotics, and pharmaceuticals. In the present study, combined effects of microplastics (polyethylene terephthalate (PET) or polybutylene terephthalate (PBT)) and tetracycline hydrochloride (TCH) on the microalgae Closterium sp. were studied to evaluate their acute toxicity, and the cell density, total chlorophyll concentration, photosynthetic activity, antioxidant system, and subcellular structure of Closterium sp. under different treatments were used to explain the physiological stress mechanism of the combined effects. The results indicate that both the single and combined treatments have inhibition effects on the cell growth and photosynthetic activity, with inhibition efficiencies (in terms of cell density) of 5.0%, 9.2%, 66.7%, 55.1%, and 59.8% for PET (100 mg L-1), PBT (100 mg L-1), TCH (10 mg L-1), PET/TCH (PET 100 mg L-1 and TCH 10 mg L-1), and PBT/TCH (PBT 100 mg L-1 and TCH 10 mg L-1), respectively, and relative electron-transport rates (rETRs) of 7.3%, 12.7%, 66.8%, 54.0%, and 59.9%, respectively, for each treatment compared with the control on the 7th day. Moreover, both PET and PBT have positive effects in alleviating TCH toxicity toward Closterium sp., and at the same time, the malondialdehyde level (MDA), superoxide dismutase (SOD) activity, and catalase (CAT) activity induced by the combined treatments were much higher than those from the single microplastic treatments but lower than those from TCH treatment after 7 days. It was demonstrated that TCH causes a much more serious oxidative stress than PET/TCH and PBT/TCH, and the lower oxidative stress of the PET/TCH and PBT/TCH groups could be attributed to the adsorption of TCH to PET or PBT. This work improves the understanding of the combined toxicity effects of microplastics and TCH on Closterium sp.

Chemical characterization and influencing factors of gaseous and particulate components in cooking oil fume (COF) from traditional Chinese dishes: Insights from high-resolution mass spectrometry.

Cooking oil fumes (COF) are known to emit a wide range of organic compounds with significant impacts on human health and urban air quality. This study used HPLC-QToF-MS and Vocus PTR-TOF to explore the chemical constituents and influencing factors of the COF generated from eight typical Chinese dishes representing different areas in a laboratory kitchen. The results revealed that both CHO and CHON compounds exhibited strong reducibility and saturability, with CHO compounds being the dominant and CHON compounds showing greater diversity. 24 among 168 CHO compounds were identical with those generated from heating soybean oil, representing 72.4%-92.3% in abundance and 22.2%-29.2% in quantity. That was 5 among 113 CHON compounds, accounting for 7.8%-10% in abundance and 4.7%-6.7% in quantity. These findings suggest that the major CHO compounds from heating soybean oil continued to dominate the abundances in dishes. The diversity of CHO compounds and the presence of CHON compounds were influenced by the food ingredients. The VOC analysis indicated that oxygen-containing organics were the major components. 6 identical VOC species between cooking dishes and heating soybean oil were identified, comprising 36.02%-67.84% of the total VOCs mass. Notably, poor ventilation could result in even higher COF concentrations in the connected room compared to the kitchen itself.

A chitosan-based light-curing hydrogel dressing for accelerated healing of infected wounds.

Bacterial infections, excessive reactive oxygen species (ROS) accumulation and a persistent inflammatory response severely impede the wound healing process. In this study, we developed a novel multifunctional hydrogel dressing (LCPN) based on lipoic acid modified chitosan (LAMC), polypyrrole nanoparticles (PPy NPs) and nicotinamide mononucleotide (NMN) for accelerated healing of infected wounds. The synthesized LCPN hydrogel has several properties. Modification of lipoic acid significantly enhances the water solubility of chitosan making it easier to dissolve and absorb wound secretions. Interestingly, owing to the breaking and restructuring of disulfide bonds, LCPN hydrogel can be quickly bonded under UV light without relying on photoinitiators. In addition, the incorporation of PPy NPs not only enhances the electrical conductivity of LCPN hydrogel, but also confers photothermal antimicrobial capability to LCPN hydrogel. More importantly, the sustained release of NMN in LCPN hydrogel can significantly enhance cell proliferation, migration and antioxidant capacity, which is conducive to accelerated wound healing. In vitro and in vivo experiments have shown that LCPN hydrogel has excellent biocompatibility and the ability to promote wound healing. Therefore, the prepared multifunctional hydrogel is expected to be used as a novel dressing to accelerate wound healing.

Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.

AIMS: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL. METHODS: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution. The drug sensitivity assay was used to determine the impact of relapse-specific FPGS mutations on sensitivity to different antifolates and chemotherapeutics in ALL cells. We used liquid chromatography-mass spectrometry (LC-MS) to quantify MTX and folate polyglutamate levels in folylpoly-γ-glutamate synthetase (FPGS) mutant ALL cells. Enzymatic activity and protein degradation assays were also conducted to characterize the catalytic properties and protein stabilities of FPGS mutants. An ALL cell line-derived mouse leukemia xenograft model was used to evaluate the in vivo impact of FPGS inactivation on leukemogenesis and sensitivity to the polyglutamatable antifolate MTX as well as non-polyglutamatble lipophilic antifolate trimetrexate (TMQ). RESULTS: We found a significant decrease in folate polyglutamylation network activities during ALL relapse using RNA-seq data. Supported by functional evidence, we identified multifactorial mechanisms of FPGS inactivation in relapsed ALL, including its decreased network activity and gene expression, focal gene deletion, impaired catalytic activity, and increased protein degradation. These deleterious FPGS alterations induce MTX resistance and inevitably cause marked intracellular folate shrinkage, which could be efficiently targeted by a polyglutamylation-independent lipophilic antifolate TMQ in vitro and in vivo. CONCLUSIONS: MTX resistance in relapsed ALL relies on FPGS inactivation, which inevitably induces a folate metabolic vulnerability, allowing for an efficacious antifolate ALL treatment strategy that is based upon TMQ, thereby surmounting chemoresistance in relapsed ALL.

Telomerase related molecular subtype and risk model reveal immune activity and evaluate prognosis and immunotherapy response in prostate cancer.

BACKGROUND: Prostate cancer ranks among the six most lethal malignancies worldwide. Telomerase, a reverse transcriptase enzyme, plays a pivotal role in extending cellular telomeres and is intimately associated with cell proliferation and division. However, the interconnection between prostate cancer and telomerase-related genes (TEASEs) remains unclear. METHODS: Somatic mutations and copy number alterations of TEASEs were comprehensively analyzed. Subsequently, the transcripts of prostate cancer patients in TCGA and GEO databases were integrated to delineate new molecular subtypes. Followed by constructing a risk model containing nine characteristic genes through Lasso regression and Cox prognostic analysis among different subtypes. Various aspects including prognosis, tumor microenvironment (TME), landscape of immunity, tumor mutational burden (TMB), stem cell correlation, and median inhibitory concentration amongst different risk groups were compared. Finally, the expression, prognosis, and malignant biological behavior of ZW10 interactor (ZWINT) in vitro was explored. RESULTS: TEASEs exhibited a notably high mutation frequency. Three distinct molecular subtypes and two gene subclusters based on TEASEs were delineated, displaying significant associations with prognosis, immune function regulation, and clinical characteristics. Low-risk patients demonstrated superior prognosis and better response to immunotherapy. Conversely, high-risk patients exhibited higher TMB and stronger stem cell correlations. It was also found that the patients' sensitivity to chemotherapy agents was impacted by the risk score. Finally, ZWINT's potential as a novel diagnostic and prognostic biomarker for prostate cancer was validated. CONCLUSIONS: TEASEs play a pivotal role in modulating immune regulation and immunotherapeutic responses, thereby significantly impacting the diagnosis, prognosis, and treatment strategies for affected patients.

Clinical characteristics and treatment of Marjolin's ulcer at a major burn center in northwest China: a retrospective review of 126 cases.

OBJECTIVE: Marjolin's ulcer (MU) is a rare, aggressive skin tumor. There are numerous case reports but large long-term studies are lacking, necessitating further exploration of its treatment. This study aimed to summarize and analyze the characteristics, treatment methods, and prognosis of MU. METHODS: We retrospectively analyzed the clinical data of 126 patients with MU, treated between January 2013 and January 2023 at the burn center. Demographic data, clinical characteristics, treatment, and prognosis were statistically analyzed. RESULTS: Of the 126 included patients, 104 were followed up for 0.1-10.2 years. The most common cause of the primary injury was flame burn (50.8%). Lesions were commonly observed on the lower limbs (47.6%). The predominant histopathological type was squamous cell carcinoma (92.8%). Among the 126 patients, 35 (27.8%) presented with bone invasion, 37 (29.4%) presented with enlarged lymph nodes, and 9 (7.1%) had lymph node metastasis. Extensive local excision (83.3%) was the most common surgical procedure; the defect was repaired using skin grafting (41.9%), free flaps (37.1%), and local flaps (21.0%). Multivariate analysis revealed that bone invasion and lymph node involvement were risk factors for postoperative recurrence. Survival analysis showed that age, latency period, pathological type, and recurrence were significant risk factors for survival. CONCLUSIONS: Extensive local resection is necessary to eradicate tumors, and patient follow-up should be more frequent within 1 year postoperatively. As MU is preventable, it is essential to reach a quick diagnosis and avoid delayed management before the occurrence of deadly metastases.

Pulmonary function test-related prognostic models in non-small cell lung cancer patients receiving neoadjuvant chemoimmunotherapy.

Background: This study aimed to establish a comprehensive clinical prognostic risk model based on pulmonary function tests. This model was intended to guide the evaluation and predictive management of patients with resectable stage I-III non-small cell lung cancer (NSCLC) receiving neoadjuvant chemoimmunotherapy. Methods: Clinical pathological characteristics and prognostic survival data for 175 patients were collected. Univariate and multivariate Cox regression analyses, and least absolute shrinkage and selection operator (LASSO) regression analysis were employed to identify variables and construct corresponding models. These variables were integrated to develop a ridge regression model. The models' discrimination and calibration were evaluated, and the optimal model was chosen following internal validation. Comparative analyses between the risk scores or groups of the optimal model and clinical factors were conducted to explore the potential clinical application value. Results: Univariate regression analysis identified smoking, complete pathologic response (CPR), and major pathologic response (MPR) as protective factors. Conversely, T staging, D-dimer/white blood cell ratio (DWBCR), D-dimer/fibrinogen ratio (DFR), and D-dimer/minute ventilation volume actual ratio (DMVAR) emerged as risk factors. Evaluation of the models confirmed their capability to accurately predict patient prognosis, exhibiting ideal discrimination and calibration, with the ridge regression model being optimal. Survival analysis demonstrated that the disease-free survival (DFS) in the high-risk group (HRG) was significantly shorter than in the low-risk group (LRG) (P=2.57×10-13). The time-dependent receiver operating characteristic (ROC) curve indicated that the area under the curve (AUC) values at 1 year, 2 years, and 3 years were 0.74, 0.81, and 0.79, respectively. Clinical correlation analysis revealed that men with lung squamous cell carcinoma or comorbid chronic obstructive pulmonary disease (COPD) were predominantly in the LRG, suggesting a better prognosis and potentially identifying a beneficiary population for this treatment combination. Conclusion: The prognostic model developed in this study effectively predicts the prognosis of patients with NSCLC receiving neoadjuvant chemoimmunotherapy. It offers valuable predictive insights for clinicians, aiding in developing treatment plans and monitoring disease progression.

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

Equality of healthcare resource allocation between impoverished counties and non-impoverished counties in Northwest China: a longitudinal study.

BACKGROUND: The Health and Medical Assistance Program for Poverty Alleviation is part of China's targeted poverty elimination strategy, which aims to protect poor people's right to health and prevent them from becoming trapped in or returning to poverty because of illness. Many tasks have been defined in this program, including raising the medical insurance level, providing a triage system, improving medical and health services, and enhancing people's health. One pivotal aspect of this initiative involves equitable health resource allocation, a key measure aimed at bolstering medical and health services. This study aimed to analyze and compare health resource allocations in different counties in Northwest China after the implementation of the program. METHODS: The Gini coefficient quantifies the level of distributional equality, the Theil index assesses the sources of inequality, and the Health Resource Agglomeration Degree gauges the accessibility of health resources. RESULTS: 1) The health resource allocation distributed based on population(Gini Coefficient < 0.45) was more equitable than that distributed based on area(Gini Coefficient > 0.35) among counties in Northwest China. 2) The contribution rate within non-impoverished counties is higher than that of impoverished counties, which means the inequality within non-impoverished counties. 3) The allocation of beds in medical institutions by area in non-impoverished counties was better than that in impoverished counties, and accessibility to health services for residents in non-impoverished counties was better than that in impoverished counties. CONCLUSION: The analysis of health resource allocation among the five provinces in Northwest China revealed significant differences in equality among the five provinces in Northwest China, and the differences were mainly derived from the non-impoverished counties. Although the equality is gradually improving, the number of health resources in impoverished counties remain lower than that in non-impoverished counties.Subsequently, it is essential to ensure equitable distribution of healthcare resources while also taking into account their utilization and quality.

The vacated space of volume/price of the drugs centralized procurement with quantity in secondary and above public hospitals of China.

BACKGROUND: In 2018, the National Centralized Drug Procurement (NCDP) policy has been implemented in 11 provinces, and promoted across the country in 2019. The main feature of the policy is "volume for price", therefore, it is necessary to measure the price relationship, not only to reduce the price of drugs, reduce the burden of patients' medical costs, but also facilitate pharmaceutical companies to access enough innovation incentives. The aim of this study was to assess the vacated space effect of the drug centralized procurement by national organizations in exchange of price for quantity. METHODS: A difference-in-differences (DID) model was employed to analyze the effect of the 4 + 7 pilot drugs centralized purchasing policy on drug sales volume and selected versus clinically substitutable unselected varieties, using observational data from 2018 to 2019. We compared drug procurement data between secondary and above public hospitals in pilot and non-pilot cities throughout China. RESULTS: The study showed that the average treatment effect (ATE) of sales in the in-hospital market for the selected supply varieties in centralized purchasing is -0.42, and with a sales volume of 0.49. This indicates a volume-price vacated space of 1.16 ~ 1.17 DDD (defined daily dose)/Yuan, implying that for every 1 defined daily dose (DDD) increase in reported volume, the standardized price decreased by 1.16-1.17 Yuan. The ATE of in-hospital market sales for drugs not selected in centralized procurement shows a decrease of 0.13. This finding highlights the presence of the price linkage effect. The ATE of sales volume is 0.57, indicating a volume-price space of 4.38 ~ 4.39 DDD/Yuan for unselected drugs, approximately 3.75 higher relative to that of the selected ones. CONCLUSIONS: The ratio of the volume-price space of clinically substitutable unselected and selected drugs may serve as direct evidence for evaluating the shift from centralized purchasing of drug varieties to clinically substitutable other ones. To strengthen the volume-based negotiation approach and maximize the effectiveness of centralized purchasing policies, we recommend the strategic implementation of a three-tiered centralized purchasing system, the expansion of drug coverage, and the introduction of relevant constraints and incentives.

Topological Transformation of Hydrogen-Terminated Germanium to Germanium Nanosheets for Fast Lithium Storage.

Germanium has been recognized as a promising anode material for lithium-ion batteries (LIBs) due to its high theoretical capacity and excellent lithium-ion diffusivity. Nonetheless, it is challenging to enhance both the high-rate performance and long-term cycling stability simultaneously. This study introduces a novel heterostructure composed of germanium nanosheets integrated with graphene (Ge NSs@Gr). These nanosheets undergo an in situ phase transformation from a hydrogen-terminated multilayer germanium compound termed germanane (GeH) derived via topochemical deintercalation from CaGe2. This approach mitigates oxidation and prevents restacking by functionalizing the exfoliated germanane with octadecenoic organic molecules. The resultant germanium nanosheets retain their structural integrity from CaGe2 and present an exposed, active (111) surface that features an open crystal lattice, facilitating swift lithium-ion migration conducive to lithium storage. The composite material delivers a substantial reversible capacity of 1220 mA h g-1 at a current density of 0.2 C and maintains a capacity of 456 mA h g-1 even at an ultrahigh current density of 10 C over extended cycling. Impressively, a capacity of 316 mA h g-1 remains after 5000 cycles. The exceptional high-rate performance and durable cycling stability underscore the Ge NSs@Gr anode's potential as a highly viable option for LIBs.

Cryptogenic Multifocal Ulcerating Stenosing Enteropathy: A Rare Case of Small Bowel Stenosis.

BACKGROUND Cryptogenic multifocal ulcerating stenosing enteropathy (CMUSE) is a rare noninfectious chronic inflammatory disease of the digestive tract confined to the small bowel. Chronic inflammatory wasting leads to protein loss and weight reduction, and some patients eventually develop small bowel stenosis. The etiopathogenesis of CMUSE remains unknown. CASE REPORT A thin 62-year-old man was admitted to the hospital with abdominal pain and distension accompanied by bilateral lower-extremity edema for 2 months. After a series of medical tests, rheumatic or immune-related diseases, hyperthyroidism, and tuberculosis were excluded, and common digestive system diseases were also excluded. Abdominal CT showed incomplete obstruction of the small bowel. Enteroscopy showed small-bowel luminal narrowing. The patient subsequently underwent partial resection of the small bowel with end-to-side anastomosis. The small-bowel stricture was about 120 cm from the ileocecal junction, and about 12 cm of small bowel was resected. Postoperative pathology of the resected material revealed multifocal ulceration of the mucosa with massive inflammatory cell infiltration and extensive hyperplastic fibrous tissue, consistent with the characteristics of CMUSE disease. At follow-up 6 months after surgery, he had no abdominal pain or distension, and his anemia and lower-extremity edema were improved. CONCLUSIONS CMUSE diagnosis requires a combination of patient history, imaging, endoscopy, pathology, and exclusion of other digestive disorders, such as Crohn's disease. It is a chronic wasting disease, often accompanied by weight loss, abdominal pain, melena, and hypoproteinemia. Surgery is an important treatment for intestinal strictures caused by CMUSE.

Distribution and biomagnification of Hexabromocyclododecanes (HBCDs) in edible marine fish in the Beibu Gulf, China: Implication for seafood dietary risk.

Hexabromocyclododecanes (HBCDs) are legacy additive brominated flame retardant. In present study, the distribution, biomagnification and potential human health risk associated with HBCDs were investigated in six edible marine fish species collected from three bays in the Beibu Gulf, China, between March and October 2021. The concentration of HBCDs ranged from 0.05 to 200 ng/g lipid weight (lw), with Scoliodon laticaudus and Trichiurus nanhaiensis having the highest and lowest concentration, respectively. The α-HBCD was dominant in most studied fish, expect for Scoliodon laticaudus. Dietary source was the primary factor for the diastereomeric profiles of HBCDs in fish. Only γ-HBCD demonstrated trophic magnification in the studied fish species. Finally, the estimated daily intake (EDI) was 0.18 ng/kg/day for adults, 0.17 ng/kg/day for teenager and children, and all corresponding margin of exposure (MOE) values were lager than 8 indicating relatively low human exposure risks from fish consumption.

Surface-programmed microbiome assembly in phycosphere to microplastics contamination.

Recalcitrance in microplastics accounts for ubiquitous white pollution. Of special interest are the capabilities of microorganisms to accelerate their degradation sustainably. Compared to the well-studied pure cultures in degrading natural polymers, the algal-bacterial symbiotic system is considered as a promising candidate for microplastics removal, cascading bottom-up impacts on ecosystem-scale processes. This study selected and enriched the algae-associated microbial communities hosted by the indigenous isolation Desmodesmus sp. in wastewater treatment plants with micro-polyvinyl chloride, polyethylene terephthalate, polyethylene, and polystyrene contamination. Results elaborated that multiple settled and specific affiliates were recruited by the uniform algae protagonist from the biosphere under manifold microplastic stress. Alteration of distinct chemical functionalities and deformation of polymers provide direct evidence of degradation in phycosphere under illumination. Microplastic-induced phycosphere-derived DOM created spatial gradients of aromatic protein, fulvic and humic acid-like and tryptophan components to expanded niche-width. Surface thermodynamic analysis was conducted to simulate the reciprocal and reversible interaction on algal-bacterial and phycosphere-microplastic interface, revealing the enhancement of transition to stable and irreversible aggregation for functional microbiota colonization and microplastics capture. Furthermore, pangenomic analysis disclosed the genes related to the chemotaxis and the proposed microplastics biodegradation pathway in enriched algal-bacterial microbiome, orchestrating the evidence for common synthetic polymer particles and ultimately to confirm the effectiveness and potential. The present study emphasizes the necessity for future endeavors aimed at fully leveraging the potential of algal-bacterial mutualistic systems within sustainable bioremediation strategies targeting the eradication of microplastic waste.

Cytokines in cerebrospinal fluid as a prognostic predictor after treatment of nusinersen in SMA patients.

OBJECTIVES: Recent studies have suggested that neuroinflammation may play a role in the progression of spinal muscular atrophy (SMA), and this may influence the efficacy of antisense oligonucleotide treatment. This study explored the biomarkers associated with SMA and the efficacy of nusinersen therapy. METHODS: Fifteen patients with SMA were enrolled and their motor function (World Health Organization motor milestone, Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb Module [RULM] scores, and 6-minute walking test) was evaluated before, during (63 days), and after (6 months) nusinersen treatment. The concentrations of monocyte chemoactive protein 1 (MCP1), tumour necrosis factor-alpha (TNF-α), and interleukin (IL)-10 in the cerebrospinal fluid were measured at the indicated time points, and their correlations with motor function were analysed. RESULTS: A significant increase in MCP1 was observed after 6 month's treatment compared with that before treatment, while TNF-α gradually decreased over the course of treatment. IL-10 levels were negatively correlated with HFMSE scores before treatment, and reductions in IL-10 levels were correlated with improvements in RULM scores. CONCLUSIONS: This study suggests that neuroinflammation may be associated with the severity of SMA and with the therapeutic effects of nusinersen, which could have clinical implications in the treatment of SMA.

GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma.

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.

HDAC8 Enhances the Function of HIF-2α by Deacetylating ETS1 to Decrease the Sensitivity of TKIs in ccRCC.

Drug resistance after long-term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time of patients with clear cell renal cell carcinoma (ccRCC). Here, genome-wide CRISPR-based screening to reveal that HDAC8 is involved in decreasing the sensitivity of ccRCC cells to sunitinib is applied. Mechanically, HDAC8 deacetylated ETS1 at the K245 site to promote the interaction between ETS1 and HIF-2α and enhance the transcriptional activity of the ETS1/HIF-2α complex. However, the antitumor effect of inhibiting HDAC8 on sensitized TKI is not very satisfactory. Subsequently, inhibition of HDAC8 increased the expression of NEK1, and up-regulated NEK1 phosphorylated ETS1 at the T241 site to promote the interaction between ETS1 and HIF-2α by impeded acetylation at ETS1-K245 site is showed. Moreover, TKI treatment increased the expression of HDAC8 by inhibiting STAT3 phosphorylation in ccRCC cells is also found. These 2 findings highlight a potential mechanism of acquired resistance to TKIs and HDAC8 inhibitors in ccRCC. Finally, HDAC8-in-PROTACs to optimize the effects of HDAC8 inhibitors through degrading HDAC8 and overcoming the resistance of ccRCC to TKIs are synthesized. Collectively, the results revealed HDAC8 as a potential therapeutic candidate for resistance to ccRCC-targeted therapies.

Constrained patterning of orientated metal chalcogenide nanowires and their growth mechanism.

One-dimensional metallic transition-metal chalcogenide nanowires (TMC-NWs) hold promise for interconnecting devices built on two-dimensional (2D) transition-metal dichalcogenides, but only isotropic growth has so far been demonstrated. Here we show the direct patterning of highly oriented Mo6Te6 NWs in 2D molybdenum ditelluride (MoTe2) using graphite as confined encapsulation layers under external stimuli. The atomic structural transition is studied through in-situ electrical biasing the fabricated heterostructure in a scanning transmission electron microscope. Atomic resolution high-angle annular dark-field STEM images reveal that the conversion of Mo6Te6 NWs from MoTe2 occurs only along specific directions. Combined with first-principles calculations, we attribute the oriented growth to the local Joule-heating induced by electrical bias near the interface of the graphite-MoTe2 heterostructure and the confinement effect generated by graphite. Using the same strategy, we fabricate oriented NWs confined in graphite as lateral contact electrodes in the 2H-MoTe2 FET, achieving a low Schottky barrier of 11.5 meV, and low contact resistance of 43.7 Ω µm at the metal-NW interface. Our work introduces possible approaches to fabricate oriented NWs for interconnections in flexible 2D nanoelectronics through direct metal phase patterning.

Distinct oral-associated gastric microbiota and Helicobacter pylori communities for spatial microbial heterogeneity in gastric cancer.

The gastric microbial community plays a fundamental role in gastric cancer (GC), and the two main anatomical subtypes of GC, non-cardia and cardia GC, are associated with different risk factors (Helicobacter pylori for non-cardia GC). To decipher the different microbial spatial communities of GC, we performed a multicenter retrospective analysis to characterize the gastric microbiota in 223 GC patients, including H. pylori-positive or -negative patients, with tumors and paired adjacent normal tissues, using third-generation sequencing. In the independent validation cohort, both dental plaque and GC tumoral tissue samples were collected and sequenced. The prevalence of H. pylori and oral-associated bacteria was verified using fluorescence in situ hybridization (FISH) assays in GC tumoral tissues and matched nontumoral tissues. We found that the vertical distribution of the gastric microbiota, at the upper, middle, and lower third sites of GC, was likely an important factor causing microbial diversity in GC tumor tissues. The oral-associated microbiota cluster, which included Veillonella parvula, Streptococcus oralis, and Prevotella intermedia, was more abundant in the upper third of the GC. However, H. pylori was more abundant in the lower third of the GC and exhibited a significantly high degree of microbial correlation. The oral-associated microbiota module was co-exclusive with H. pylori in the lower third site of the GC tumoral tissue. Importantly, H. pylori-negative GC patients with oral-associated gastric microbiota showed worse overall survival, while the increase in microbial abundance in H. pylori-positive GC patients showed no difference in overall survival. The prevalence of V. parvula in both the dental plaque and GC tissue samples was concordant in the independent validation phase. We showed that the oral-associated species V. parvula and S. oralis were correlated with overall survival. Our study highlights the roles of the oral-associated microbiota in the upper third of the GC. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for H. pylori-negative GCs. IMPORTANCE: Our study highlights the roles of the oral-associated microbiota in the upper third of gastric cancer (GC).We showed that the oral-associated species Veillonella parvula and Streptococcus oralis were correlated with overall survival. In addition, oral-associated species may serve as noninvasive screening tools for the management of GC and an independent prognostic factor for Helicobacter pylori-negative GCs.