Microbial Biotransformation of 1-Methyl-L-tryptophan into Herbicidal Indole Alkaloids by Endophytic Fungus Nigrospora chinensis GGY-3.

Indole alkaloids are privileged secondary metabolites, and their production may be achieved by the microbial biotransformation of tryptophan analogues. By feeding 1-methyl-L-tryptophan (1-MT) into the culture of endophytic Nigrospora chinensis GGY-3, six novel (1-6) and seven known indole alkaloids (7-13) were generated. Their structures were elucidated by means of NMR spectroscopy, experimental electronic circular dichroism (ECD) spectra, and X-ray crystallography analysis. A Friedel-Crafts reaction was proposed as the key reaction responsible for the formation of the new compounds. Racemates 4 and 6 were separated into isomers by chiral HPLC, with their absolute configurations determined by X-ray and ECD calculation. Compounds 3, 4, and 8 display good herbicidal activity against dicotyledon weed Eclipta prostrata, of which 4 and 8 exhibited 88.50% and 100% inhibition rates on the radicle at 200 µg/mL, respectively, a similar effect compared to the positive control penoxsulam.

Arginine on immune function and post-operative obstructions in colorectal cancer patients: a meta-analysis.

BACKGROUND: The aim of this study is to investigate the impact of arginine on immune function and postoperative complications in colorectal cancer (CRC) patients. METHODS: We conducted a comprehensive search to identify eligible RCTs in various databases, such as PubMed, Cochrane Library, EMBASE, Web of Science, MEDLINE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP Medicine Information System (VIP), and Chinese Biomedical Database (CBM). This study aimed to examine IgA, IgG, and IgM levels as well as CD4+ and CD8+ counts as well as the CD4+/CD8+ ratio. Anastomotic leaking, length of stay (LOS), and surgical site infection (SSI) were included as secondary outcomes. Stata (StataCorp, version 14.0) was utilized for data analysis. To ensure the results were reliable, we used meta-regression, sensitivity analysis, and publication bias analysis. RESULTS: A total of 24 publications (including 1883 patients) out of 681 that were retrieved fulfilled the inclusion criteria. The arginine group showed notable improvements in humoral immunity, with gains in IgA (SMD=0.45, 95% CI: 0.30-0.60), IgG (SMD=0.80, 95% CI: 0.64-0.96), and IgM (SMD=0.66, 95% CI: 0.39-0.93). With regards to cellular immunity, the arginine group exhibited a substantial increase in the CD4+ T cell count (SMD = 1.03, 95% CI: 0.67-1.38) compared to the control group. However, the CD4+/CD8+ ratio decreased significantly (SMD=1.37, 95% CI: 0.88-1.86) in the same arginine group, indicating a change in the balance between these two cell types. Additionally, the CD8+ T cell count showed a notable decrease (SMD=-0.70, 95% CI: -1.09 to -0.32) in the arginine group when compared to the control group. Anastomotic leakage was also considerably lower in the arginine group (SMD=-0.05, 95% CI: -0.08 to -0.02), the rate of SSIs was lower (RR = -0.02, 95% CI: -0.05-0), and the length of time patients spent in the hospital was shorter (SMD=-0.15, 95% CI: -0.38 to -0.08). CONCLUSIONS: After radiation treatment for CRC, arginine improves immune function and decreases the risk of infection problems. TRIAL REGISTRATION: Registration with PROSPERO for this meta-analysis is number CRD42024520509.

Impact of MAOA Gene Polymorphism on the Efficacy of Antidepressant Treatment and Craving Severity for Betel Quid Use Disorder.

Betel quid (BQ) use disorder (BUD) is prevalent in many Asian countries, impacting approximately 600 million people. We conducted a randomized clinical trial to analyze the impact of MAOA genetic variations on the severity of BQ craving. This was measured using DSM-5 criteria and the Yale-Brown Obsessive-Compulsive Scale modified for betel quid use (Y-BOCS-BQ). Participants were grouped according to the severity of BUD and MAOA gene single-nucleotide polymorphism (SNP) rs5953210 genotypes. The Y-BOCS-BQ scores were assessed at baseline (week 0) and during follow-up at weeks 2, 4, 6, and 8. The AA genotype group showed significantly greater reductions in Y-BOCS-BQ at weeks 2 (p = 0.0194), 4 (p = 0.0078), 6 (p = 0.0277), and 8 (p = 0.0376) compared to the GG genotype group. Additionally, within the antidepressant group, the AA genotype showed significant reductions in the Y-BOCS-BQ scores at weeks 2 (p = 0.0313), 4 (p = 0.0134), 6 (p = 0.0061), and 8 (p = 0.0241) compared to the GG genotype. The statistical analysis revealed a significant interaction between the treatment and placebo groups based on MAOA genotypes, with the AA genotype in the treatment group exhibiting a more pronounced decrease in Y-BOCS-BQ score (p interaction <0.05) at week 6. Our study highlights the importance of considering genetic factors when developing personalized treatment plans for BUD.

Risk of Traumatic Intracranial Hemorrhage After Stroke: A Nationwide Population-Based Cohort Study in Taiwan.

BACKGROUND: Stroke and traumatic intracranial hemorrhage (tICH) are major causes of disability worldwide, with stroke exerting significant negative effects on the brain, potentially elevating tICH risk. In this study, we investigated tICH risk in stroke survivors. METHODS AND RESULTS: Using relevant data (2017-2019) from Taiwan's National Health Insurance Research Database, we conducted a population-based retrospective cohort study. Patients were categorized into stroke and nonstroke groups, and tICH risk was compared using a Cox proportional-hazards model. Among 164 628 patients with stroke, 1004 experienced tICH. Patients with stroke had a higher tICH risk than nonstroke counterparts (adjusted hazard ratio [HR], 3.49 [95% CI, 3.17-3.84]). Subgroup analysis by stroke type revealed higher tICH risk in hemorrhagic stroke survivors compared with ischemic stroke survivors (HR, 5.64 [95% CI, 4.97-6.39] versus 2.87 [95% CI, 2.58-3.18], respectively). Older patients (≥45 years) with stroke had a higher tICH risk compared with their younger counterparts (<45 years), in contrast to younger patients without stroke (HR, 7.89 [95% CI, 6.41-9.70] versus 4.44 [95% CI, 2.99-6.59], respectively). Dementia and Parkinson disease emerged as significant tICH risk factors (HR, 1.69 [95% CI, 1.44-2.00] versus 2.17 [95% CI, 1.71-2.75], respectively). In the stroke group, the highest tICH incidence density occurred 3 months after stroke, particularly in patients aged >65 years. CONCLUSIONS: Stroke survivors, particularly those with hemorrhagic stroke and those aged ≥45 years, face elevated tICH risk. Interventions targeting the high-risk period are vital, with fall injuries potentially contributing to tICH incidence.

Low-methoxy-pectin and chlorogenic acid synergistically promote lipolysis and ß-oxidation by regulating AMPK signaling pathway in obese mice.

Chlorogenic acid (CGA) displays various biological activities in preventing high-calorie diet-induced metabolic complications. The absorption efficiency of CGA in the stomach and small intestine is relatively low, with approximately 70 % of CGA being metabolized by colonic microorganisms before it enters the bloodstream. In this study, we successfully developed CGA-LMP (Low-methoxy-pectin) conjugates to improve the absorption rate of CGA. C57BL/6J mice were fed high-fat diets (HFD) supplemented with CGA, LMP, or CGA-LMP conjugates for a duration of eight weeks. The results demonstrated that the CGA, LMP, or CGA-LMP conjugates prevented HFD-induced hyperlipidemia, inflammation, liver steatosis, and adipocyte hypertrophy in obese mice. Notably, the CGA-LMP conjugates demonstrated superior efficacy in alleviating obesity compared to CGA or LMP alone. Further studies revealed that the primary mechanism of weight loss was the activation of the AMPK signaling pathway, which facilitates lipolysis and lipid ß-oxidation. These findings highlight that the enhanced the anti-obesity effectiveness of CGA-LMP conjugates, expanding their potential applications in the field of functional nutrition and foods.

An organic cathode for low-temperature processed, flexible ternary organic solar cells with high-performance.

In this study, we developed a flexible cathode for fabricating high-performance ternary organic solar cells (OSCs). With solvent engineering and acid treatment, the conductivity of the poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) electrode was significantly enhanced with the sheet resistance reduced from 1081 to 83 Ω sq-1. After being coated with polyethylenimine, work function of the PEDOT:PSS electrode was tuned from -5.07 to -4.12 eV, which is beneficial for electron collection in OSCs. With this technique, the OSCs (on glass) showed an average power conversion efficiency (PCE) of 16.3%, which is comparable to that of conventional inverted OSCs with commonly used indium-tin oxide and sol-gel-processed zinc oxide. However, the processing temperature of the inverted OSCs was dramatically lowered from 200 to 120 °C. The flexible OSCs (on polyethylene naphthalate/PEDOT:PSS/PEIE) exhibited a high PCE of 14.1%. After being bended for 300 cycles, the PCE was only degraded by 8.5%, indicating the excellent bendability of the flexible OSCs with the organic cathode.

Transcriptome and metabolism study reveals impact of nitrogen fertilizer on triticale.

Autumn-sown forage triticale can effectively leverage the optimal light and heat conditions in Ningxia, a region that boasts an abundance of light and heat resources sufficient for a single seasonal crop, but limited for two seasons. This not only fully utilizes the limited growing season but also significantly improves grass yield and economic efficiency per unit area. To enhance triticale yield in low-light and low-temperature environments, we investigated the impact of applying different concentrations of nitrogen fertilizer on triticale forage yield. Our findings revealed that nitrogen fertilizer application significantly increased triticale biomass, with the N4 treatment group exhibiting the most profound effect. To further explore the mechanisms behind nitrogen fertilizer's regulation of triticale growth and development, we conducted transcriptomic and metabolomic studies. These studies revealed that nitrogen fertilizer application significantly heightened transcription activity and protein synthesis in triticale, fostering the development of its seeds. Additionally, appropriate concentrations of nitrogen fertilizer significantly promoted photosynthesis. Metabolomic analysis revealed that nitrogen fertilizer application increased the levels of proline and O-phosphoethanolamine, enhancing triticale's stress resistance and supporting its growth and development under adverse conditions.

Polystyrene influence on Pb bioavailability and rhizosphere toxicity: Challenges for ramie (Boehmeria nivea L.) in soil phytoremediation.

Microplastics (MPs) and heavy metals often coexist in soil, however their interactions and effects on the soil-plant system remain largely unclear. In this study, ramie (Boehmeria nivea L.) was exposed to soil contaminated with lead (Pb) and polystyrene (PS) of different sizes, dosages, and surface-charged functional groups. This design aimed to simulate the effects of MPs on phytoremediation. The experimental results revealed that PS exacerbated the damaging effects of Pb on ramie. Compared to the effect of Pb alone, PS-COOH had a greater influence on root vigor, leading to a 15.6 % reduction in the active absorption ratio. Laser scanning confocal microscope showed PS entered the roots. Adsorption/desorption experiments demonstrated that PS had a weaker adsorption capacity for Pb than soil but a greater desorption rate than soil when simulating rhizosphere secretion. Moreover, PS reduced soil pH and increased the reducible state of Pb by 6-12 %. After 100 days of phytoremediation, Pb content in the soil with PS-5 µm was 150 µg g-1 less than that in the soil without PS. These results demonstrated that PS improved Pb bioavailability and enhanced the efficiency of Pb uptake by ramie. The redundancy analysis demonstrated that PS mitigated the toxicity of Pb to rhizosphere microorganisms, potentially via its effects on metal chemical fractions, dehydrogenase activity (S-DHA), cation exchange capacity (CEC), and soil organic matter (SOM). This study indicates that the presence of PS could potentially enhance the phytoremediation efficiency of ramie in Pb-contaminated land by influencing soil microenvironmental properties. This study provides insights into the complex interactions of MPs with soil-plant-microbial systems during metal remediation, thereby enhancing our understanding of their environmental impacts.

Association of MTHFR C677T, MTHFRA1298C and MTRRA66G gene polymorphisms with hyperhomocysteinemia and its modulation by the combined effect of vitamin B12 and folate in a hypertensive Chinese population.

BACKGROUND: In China, the MTHFR 677T allele, unlike in most Western populations, is a rare genetic variant linked to various disorders. The contributing nutritional and genetic factors to this genetic risk remain unclear. OBJECTIVE: This study aimed to elucidate the interactions between genetic variations in total homocysteine (tHcy) pathway genes, serum tHcy levels, and nutritional factors in a hypertensive Chinese population. METHODS: This study analyzed 1,304 hypertensive Chinese adults aged 18 years and older enrolled in the China Precision Nutrition and Health KAP Real World Study (CPNAS). Serum levels of vitamin B12 and folate were measured using the magnetic microparticle chemiluminescence method, and tHcy levels were measured using Hcy Assay kits. Identification of the MTHFR C677T, MTHFR A1298C, and MTRR A66G polymorphisms was performed via time-of-flight nucleic spectrometry. RESULTS: Our findings revealed significant sex differences in tHcy levels, with males exhibiting higher tHcy levels than females (13.95 µmol/L vs. 11.15 µmol/L, p < 0.001). Individuals deficient in both vitamin B12 and folate had an increased risk of H-Hcy (57.4%). In contrast, the prevalence of H-Hcy was lower among those deficient in either vitamin B12 (31.1%) or folate (23.2%) alone. Significant associations were identified between the MTHFR C677T and A1298C polymorphisms and elevated serum tHcy levels, particularly in individuals homozygous for the T allele. Conversely, the MTRR A66G genotype did not show a significant correlation with tHcy levels. Optimal vitamin B12 concentrations significantly modulated the genotypic effect on tHcy levels, with individuals having adequate vitamin B12 and folate exhibiting low tHcy levels, even among high-risk genotypes (TT). CONCLUSIONS: Adequate levels of folate and vitamin B12 significantly reduce serum tHcy concentrations and mitigate the genotypic impact on tHcy levels, highlighting the potential for targeted nutritional interventions to manage cardiovascular risks associated with hyperhomocysteinemia. TRIAL REGISTRATION: The Clinical Study Protocol for the Trial (CPNAS) has been officially registered at ClinicalTrials.gov under the identification number ChiCTR2100051983.

Photolithography-Free, Solution-Processable Perovskite Electrodes for High-Performance Organic Transistors.

Solution-processable electrodes are promising for next-generation electronics due to their simplicity, cost-effectiveness, and potential for large-area fabrication. However, current solution-processable electrodes based on conductive polymers, carbon-based compounds, and metal nanowires face challenges related to stability, patterning, and production scalability. Here we introduce a novel approach using 3D tin halide perovskites (THPs) combined with a photolithography-free solution patterning technique to fabricate solution-processed electrodes. We demonstrate the preparation of highly conductive CsSnI3 films (234.9 S cm-1) and the fabrication of patterned 35 × 35 perovskite electrode arrays on a 4-in. silicon wafer. These electrodes, used as source/drain electrodes in organic transistors, resulted in devices showing high uniformity and stability. This electrode fabrication strategy is also applicable to other 3D THPs like FASnI3 and MASnI3, showcasing versatility for diverse applications. The results highlight the feasibility and advantages of using 3D THPs as solution-processable electrodes, providing a new material system for the advancement of solution-processed electronics.

Whether mTICI 3 or mTICI 2b is better in patients with vertebrobasilar artery occlusion undergoing endovascular treatment depends on pc-ASPECTS.

BACKGROUND: The clinical relevance of differentiating between mTICI (modified Thrombolysis In Cerebral Infarction) 2b and mTICI 3 in patients with vertebrobasilar artery occlusion (VBAO) remains unclear. This study aimed to investigate whether mTICI 3 improves functional outcomes compared with mTICI 2b in patients with VBAO and whether this improvement differs according to extent of ischemic damage. METHODS: This retrospective study enrolled patients with VBAO within 24 hours of the estimated occlusion time at 65 stroke centers in a nationwide registration in China. The primary outcome was favorable functional outcome (modified Rankin scale score 0-3) at 90 days. Patients were matched by final mTICI grade using propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). Logistic regression and ordinal regression models were used to assess the impact of mTICI 2b versus mTICI 3 grading on prognosis, based on different extent of ischemia damage (posterior circulation Alberta Stroke Program Early CT Score-pc-ASPECTS of 9-10, 7-8, and 3-6) and treatment strategies (bridging therapy and direct endovascular therapy (EVT)). RESULTS: A total of 2075 patients with VBAO and successful reperfusion were included, 652 patients (31.4%) achieved mTICI 2b and 1423 patients (68.6%) achieved mTICI 3. After adjustment for confounders, achieving mTICI 3 following EVT in patients with VBAO and pc-ASPECTS 9-10 (OR 1.54, 95% CI 1.16 to 2.03) and pc-ASPECTS 7-8 (OR 1.80, 95% CI (1.26 to 2.56) were associated with favorable functional outcome compared with mTICI 2b, especially in those receiving direct EVT. However, in patients with pc-ASPECTS≤6, functional outcomes at 90 days did not differ between mTICI 3 and mTICI 2b (OR 1.12, 95% CI 0.67 to 1.88), irrespective of using bridging therapy or direct EVT. CONCLUSION: In patients with VBAO undergoing EVT with pc-ASPECTS>6, achieving mTICI 3 favors better outcomes compared with mTICI 2b, especially in those receiving direct EVT. However, in patients with pc-ASPECTS≤6, mTICI 3 did not improve functional outcomes compared with mTICI 2b. Interventionalists should carefully assess the risk-benefit of additional maneuvers once mTICI 2b reperfusion is restored in EVT for patients with VBAO and pc-ASPECTS≤6. Further studies are needed to guide treatment decisions in these cases.

Physiological, molecular, and morphological adjustment to waterlogging stress in ramie and selection of waterlogging-tolerant varieties.

Waterlogging stress is a severe abiotic challenge that impedes plant growth and development. Ramie (Boehmeria nivea L.) is a Chinese traditional characteristic economic crop, valued for its fibers and by-products. To investigate the waterlogging tolerance of ramie and provide the scientific basis for selecting waterlogging-tolerant ramie varieties, this study examined the morphological, physiological, biochemical, and molecular responses of 15 ramie germplasms (varieties) under waterlogging stress. The results revealed varied impacts of waterlogging stress across the 15 ramie varieties, characterized by a decrease in SPAD values, net photosynthesis rates, and relative water content of ramie leaves, along with a significant increase in relative conductivity and the activities of antioxidant enzymes such as SOD, POD, CAT, and APX. Additionally, the levels of soluble sugars, soluble proteins, and free proline exhibited varying degrees of increase. Through Principal Component Analysis (PCA), ZZ_2 and ZSZ_1 were identified as relatively tolerant and susceptible varieties. Transcriptome analysis showed that the differential expressed genes between ZZ_2 and ZSZ_1 were significantly enriched in metabolic pathways, ascorbate and aldarate metabolism, and inositol phosphate metabolism, under waterlogging stress. In addition, the expression of hypoxia-responsive genes was higher in ZZ_2 than in ZSZ_1 under waterlogging stress. These differences might account for the varied waterlogging responses between the two varieties. Therefore, this study explored the morpho-physiological responses of ramie under waterlogging stress and identified the molecular mechanisms involved, providing valuable insights for improving ramie varieties and breeding new ones.

Repurposing antihypertensive drugs for pain disorders: a drug-target mendelian randomization study.

Objective: Addressing the rising prevalence of pain disorders and limitations of current analgesics, our study explores repurposing antihypertensive drugs for pain management, inspired by the link between hypertension and pain. We leverage a drug-target Mendelian Randomization (MR) approach to explore their dual benefits and establish causal connections. Methods: A comprehensive compilation of antihypertensive drug classes was undertaken through British National Formulary, with their target genes identified using the DrugBank database. Relevant single nucleotide polymorphisms (SNPs) associated with these targets were selected from published genomic studies on systolic blood pressure (SBP) as genetic instruments. These SNPs were validated through MR against acute coronary artery disease (CAD) to ensure genes not linked to CAD were excluded from acting as proxies for antihypertensive drugs. An MR analysis of 29 pain-related outcomes was conducted using the FinnGen R10 database employing the selected and validated genetic instruments. We utilized the Inverse Variance Weighted (IVW) method for primary analysis, applying Bonferroni correction to control type I error. IVW's multiplicative random effects (MRE) addressed heterogeneity, and MR-PRESSO managed pleiotropy, ensuring accurate causal inference. Results: Our analysis differentiates strong and suggestive evidence in linking antihypertensive drugs to pain disorder risks. Strong evidence was found for adrenergic neuron blockers increasing migraine without aura risk, loop diuretics reducing panniculitis, and vasodilator antihypertensives lowering limb pain risk. Suggestive evidence suggests alpha-adrenoceptor blockers might increase migraine risk, while beta-adrenoceptor blockers could lower radiculopathy risk. Adrenergic neuron blockers also show a potential protective effect against coxarthrosis (hip osteoarthritis) and increased femgenpain risk (pain and other conditions related to female genital organs and menstrual cycle). Additionally, suggestive links were found between vasodilator antihypertensives and reduced radiculopathy risk, and both alpha-adrenoceptor blockers and renin inhibitors possibly decreasing dorsalgianas risk (unspecified dorsalgia). These findings highlight the intricate effects of antihypertensive drugs on pain disorders, underlining the need for further research. Conclusion: The findings indicate that antihypertensive medications may exert varied effects on pain management, suggesting a repurposing potential for treating specific pain disorders. The results advocate for further research to confirm these associations and to explore underlying mechanisms, to optimize pain management practices.

The effects of complement-independent, autoantibody-induced apoptosis of platelets in immune thrombocytopenia (ITP).

Autoantibodies that cause platelet apoptosis may play a role in the development of immune thrombocytopenia (ITP), specifically antibodies that target GPIIbIIIa and GPIbα. Our research aims to compare the impact of the antigen specificity of antiplatelet antibodies on normal platelets under conditions that do not rely on complement. Using a modified monoclonal antibody-specific immobilization of platelet antigen (MAIPA) assay, we detected the levels of autoantibodies against specific platelet membrane glycoproteins (GPIIb/IIIa, GPIb/IX) in the plasma of 36 patients diagnosed with chronic ITP. IgG was isolated and purified using a protein A agarose affinity chromatography column, and their concentrations were measured using spectrophotometry. We obtained normal platelets and treated them with the purified IgG anti-GPIIb/IIIa and/or anti-GPIb/IX antibodies, as well as an IgG-free buffer and healthy control IgG. Flow cytometry was used to analyze markers of apoptosis, including phosphatidylserine (PS) exposure, mitochondrial inner membrane potential (ΔΨm), and platelet particle formation. Our results indicate that ITP patients with GPIb/IX-specific autoantibodies can induce platelet apoptosis and platelet particle formation through complement-independent pathways, which are not associated with platelet activation, while GPIIb/IIIa-specific autoantibodies did not have this effect. This suggests that specific autoantibodies may serve as a valuable predictive tool to identify patients who could potentially benefit from complement-inhibiting therapy in the future.

Efficacy and safety of first- and second-line antibiotics for cellulitis and erysipelas: a network meta-analysis of randomized controlled trials.

This study systematically evaluated and ranked the efficacy of first- and second-line antibiotics antibiotic options for the clinical management of cellulitis and erysipelas through a network meta-analysis approach. From inception to July 04, 2024, a search for relevant randomized clinical trials (RCTs) was carried out using several databases. Antibiotics including azithromycin, cefaclor, cephalexin, cloxacillin, erythromycin, cephalexin plus trimethoprim-sulfamethoxazole, cephalexin plus placebo, flucloxacillin, clindamycin, ceftriaxone, penicillin, roxithromycin, and pristinamycin were assessed regarding cure rate, the eradication of baseline pathogens, diarrhea or vomiting, and rash. In total, 10 RCTs with 1,936 cellulitis or erysipelas patients were eligible for inclusion. There were no significant differences in the cure rates for cellulitis among the antibiotics analysed, with cefaclor demonstrating the most favorable profile for curative outcomes. In terms of side effects, ceftriaxone was identified as the least likely to induce diarrhea or vomiting. For erysipelas, pristinamycin showed the most promising results in achieving cure rates. Although a comparison of the three antibiotics revealed no significant differences in rash as a side effect in erysipelas, pristinamycin was observed to carry the highest risk for rash. Our findings indicate no significant differences in cure rates among antibiotics for cellulitis. However, ceftriaxone had the fewest gastrointestinal side effects. Pristinamycin showed the highest cure rates for erysipelas but with a higher risk of rash. Future research should focus on optimizing antibiotic selection for cellulitis and erysipelas.

Prognostic impact of DTA mutation and co-occurring mutations in patients with myelodysplastic syndrome.

OBJECTIVE: To evaluate the frequency and prognostic significance of DTA (DNMT3A、TET2、ASXL1) gene mutation and co-occurring mutations in patients with myelodysplastic syndrome (MDS). METHODS: The clinical data of 102 newly diagnosed MDS patients who accepted Next Generation Sequencing (NGS) was retrospectively analyzed. According to whether the patients had DTA gene mutation, the patients were divided into DTA mutated (DTA-mut) group and wild type (DTA-wt) group, and the relationship between gene mutation and clinical characteristics and prognosis was analyzed. RESULTS: Among the 102 MDS patients, 96% (98/102) presented with mutation, while the mean number of mutations was 3.04 mutations/patient. DTA-mut was detected in 56.9% (58/102) patients. The most frequent co-mutated genes in DTA-mut group were SF3B1 (25.8%), RUNX1 (24.1%), U2AF1 (18.9%), SRSF2, EZH2, SETBP1 (17.2%), STAG2 (15.5%), IDH2 (12.1%) and BCOR, CBL (10.3%). The two groups showed no significant differences in ages, blood parameters, bone marrow blasts, WHO 2022 classification, IPSS-R risk category and rate of conversion to leukemia. Compared with the DTA-wt group, the mutation frequency of RUNX1 was higher (P = 0.02), while mutation frequency of TP53 was lower (P = 0.001) and the mutation frequency of ≥ 3 co-mutated genes was higher in DTA-mut group (P = 0.00). Survival analysis showed that the overall survivals (OS) of DTA-mut patients was significantly inferior to that of DTA-wt patients (P = 0.0332). According to IPSS-R classification, a statistically significant difference in OS was only observed in higher risk (IPSS-R > 3.5) group (P = 0.0058). In the context of DTA mutation, the OS of patients with RUNX1 mutation was shorter than that of patients without RUNX1 mutation significantly (P = 0.0074). The OS of patients with SF3B1 mutation was longer than that of patients without SF3B1 mutation, but there was no statistical difference (P = 0.0827). DTA mutations were not independent prognostic factors when DTA and co-mutated genes with frequency > 10% were considered in Cox regression model (P = 0.329). However, multivariate analysis confirmed an independently adverse prognosis of RUNX1 co-mutation (P = 0.042, HR = 2.426, 95% CI:1.031-5.711) in DTA-mut cohort. Moreover, our multivariable analysis suggests that SRSF2-mut was an independent poor prognostic factor for all MDS patients (P = 0.047), but lost significance (P = 0.103) for DTA-mut patients. CONCLUSIONS: DTA mutations are frequently observed in patients with MDS, often accompanied by genes involved in RNA splicing and transcription factors like SF3B1 and RUNX1. DTA and concomitant mutations affect prognosis in MDS patients and RUNX1 was identified as an independent poor prognostic factor in patients with DTA mutations.

Nitrogen fixation by alkali and alkaline earth metal hydrides assisted by plasma.

The chemical behaviors of alkali and alkaline earth metal hydrides including LiH, KH, MgH2, CaH2, and BaH2 under nitrogen plasma differ significantly from one another, exhibiting an ammonia production trend that contrasts with that observed under thermal conditions. A prominent feature of KH is its ability to facilitate plasma-assisted N2 fixation without generating H2 byproduct, showing high atomic economy in utilization of hydride ions for N2 reduction.

Sintilimab (anti-PD-1 antibody) combined with high-dose methotrexate, temozolomide, and rituximab (anti-CD20 antibody) in primary central nervous system lymphoma: a phase 2 study.

Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18-70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1-5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81-99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.

Ocular adverse events associated with antibody-drug conjugates in oncology: a pharmacovigilance study based on FDA adverse event reporting system (FAERS).

Background: Antibody-drug conjugates (ADCs) have emerged as the focus and hotspots in the cancer field, yet the accompanying ocular toxicity has often been underestimated. We aimed to comprehensively and comparatively analyze the risk of ocular toxicity associated with various ADCs using the FDA Adverse Event Reporting System (FAERS) database. Methods: Data were extracted from the FAERS database from Q3 2011 to Q3 2023. We analyzed the clinical characteristics of ADCs-related ocular adverse events (AEs). These data were further mined by proportional analysis and Bayesian approach to detect signals of ADCs-induced ocular AEs. Moreover, the time to onset of ocular toxicity was also evaluated. Results: A total of 1,246 cases of ocular AEs were attributed to ADCs. Ocular toxicity signals were observed in patients treated with belantamab mafodotin, brentuximab vedotin, enfortumab vedotin, mirvetuximab soravtansine, sacituzumab govitecan, trastuzumab deruxtecan, and trastuzumab emtansine. Of these, belantamab mafodotin, trastuzumab emtansine, and mirvetuximab soravtansine, whose payloads are microtubule polymerization inhibitors, were more susceptible to ocular toxicity. The ten most common ADCs-related ocular AEs signals are keratopathy [ROR = 1,273.52, 95% CI (1,129.26-1,436.21)], visual acuity reduced [ROR = 22.83, 95% CI (21.2-24.58)], dry eye [ROR = 9.69, 95% CI (8.81-10.66)], night blindness [ROR = 259.87, 95% CI (228.23-295.89)], vision blurred [ROR = 1.78, 95% CI (1.57-2.02)], photophobia [ROR = 10.45, 95% CI (9.07-12.05)], foreign body sensation in eyes [ROR = 23.35, 95% CI (19.88-27.42)], ocular toxicity [ROR = 144.62, 95% CI (117.3-178.32)], punctate keratitis [ROR = 126.21, 95% CI (101.66-156.69)], eye disorder [ROR = 2.71, 95% CI (2.21-3.32)]. In terms of onset time, sacituzumab govitecan displayed an earlier onset of 21 days, while trastuzumab deruxtecan exhibited the latest onset of 223 days. Conclusion: ADCs may increase the risk of ocular toxicity in cancer patients, leading to serious mortality. With the widespread application of newly launched ADCs, combining the FAERS data with other data sources is crucial for monitoring the ocular toxicity of ADCs. In addition, novel ocular toxicity signals not documented in product labeling were detected. Further research will be necessary to validate our findings in the future.

Impact of the nail insertion angle on the wedge effect in intramedullary nail fixation of intertrochanteric hip fractures.

BACKGROUND: The wedge effect is known to be influenced by the insertion of the proximal femoral intramedullary nail through the fracture line and the large proximal diameter of the nail. However, the impact of the nail insertion angle (NIA) on the wedge effect remains unclear. This study aimed to investigate: (1) how to evaluate the NIA intraoperatively, (2) whether the NIA is associated with the wedge effect, (3) whether the NIA can serve as a reliable predictor of the wedge effect, (4) which factors affect the NIA, and (5) which surgical techniques can prevent the occurrence of the wedge effect associated with the NIA. HYPOTHESIS: We hypothesized that an excessive NIA is related to the wedge effect and that lateral deviation of the entry point is associated with an excessive NIA. PATIENTS AND METHODS: Intraoperative fluoroscopy images of patients who underwent intramedullary nail fixation for intertrochanteric hip fractures between 2013 and 2023 were analyzed. NIA and insertion point distance (IPD) were measured on hip anteroposterior radiographs with the guidewire inserted. Femoral shaft lateralization (FSL) and neck-shaft angle (NSA) were measured on hip anteroposterior radiographs before and after nail insertion; differences in FSL and NSA were calculated. A negative difference in FSL combined with a positive difference in NSA indicated the occurrence of the wedge effect. Pearson's correlation test was used to determine relationships between continuous variables (NIA, FSL, NSA, and IPD). Binary logistic regression analyzed the association between NIA and the wedge effect. Receiver operating characteristic (ROC) curve analysis was used to determine the threshold value of NIA, with predictive performance assessed using the area under the ROC curve (AUC). Other potential factors influencing the wedge effect were also examined. RESULTS: A total of 408 patients were included. The mean NIA was 15.61 ± 4.49 °. Post-nail insertion, the average increase in FSL was 3.20 mm, and the average decrease in NSA was 1.90 °. Pearson's correlation test revealed that NIA was negatively correlated with the difference in FSL (R = 0.565, P < 0.001) and positively correlated with the difference in NSA (R = 0.509, P < 0.001). Binary logistic regression showed a significant correlation between NIA and the wedge effect (P < 0.001). ROC analysis indicated that the AUC for NIA was 0.813, with an optimal cutoff point of 14.85 °. IPD was positively correlated with NIA (R = 0.519, P < 0.001). Unstable fractures were associated with increased lateralization of the femoral shaft after nail insertion (P = 0.003). DISCUSSION: The NIA is positively correlated with the wedge effect in intramedullary nail fixation of intertrochanteric hip fractures. The wedge effect tends to occur when the NIA is >14.85 °, particularly in unstable fractures. Lateral deviation of the entry point is associated with an excessive NIA. Adducting the affected limb, moving the entry point slightly medial and using a medial pusher may help control the NIA to less than 14.85 ° to reduce the wedge effect. LEVEL OF EVIDENCE: III.