GATIS score for predicting the prognosis of rectal neuroendocrine neoplasms: A Chinese multicenter study of 12-year experience.

BACKGROUND: There is currently a shortage of accurate, efficient, and precise predictive instruments for rectal neuroendocrine neoplasms (NENs). AIM: To develop a predictive model for individuals with rectal NENs (R-NENs) using data from a large cohort. METHODS: Data from patients with primary R-NENs were retrospectively collected from 17 large-scale referral medical centers in China. Random forest and Cox proportional hazard models were used to identify the risk factors for overall survival and progression-free survival, and two nomograms were constructed. RESULTS: A total of 1408 patients with R-NENs were included. Tumor grade, T stage, tumor size, age, and a prognostic nutritional index were important risk factors for prognosis. The GATIS score was calculated based on these five indicators. For overall survival prediction, the respective C-indexes in the training set were 0.915 (95% confidence interval: 0.866-0.964) for overall survival prediction and 0.908 (95% confidence interval: 0.872-0.944) for progression-free survival prediction. According to decision curve analysis, net benefit of the GATIS score was higher than that of a single factor. The time-dependent area under the receiver operating characteristic curve showed that the predictive power of the GATIS score was higher than that of the TNM stage and pathological grade at all time periods. CONCLUSION: The GATIS score had a good predictive effect on the prognosis of patients with R-NENs, with efficacy superior to that of the World Health Organization grade and TNM stage.

The efficacy and safety of antiangiogenesis tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: A meta-analysis of prospective studies.

BACKGROUND: The poor prognosis of anaplastic thyroid cancer (ATC) patients is associated with limited effective therapeutic strategies. Multiple antiangiogenesis tyrosine kinase inhibitors (TKIs) have been applied in later-line treatment of ATC; however, the results reported in clinical trials were controversial. In this study, we reconstructed the patient-level data to pooled-analyze the survival data, responses, and adverse events. METHODS: Online databases (PubMed, Web of Science, Embase, and Cochrane CENTRAL) were searched on September 03, 2023. R software combined with the "metaSurvival" and "meta" packages were used to reconstruct the survival curves and summarize the response rates. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were survival rate, objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events. RESULTS: Six prospective clinical trials involving 140 ATC patients were enrolled. Four types of TKIs (imatinib, pazopanib, sorafenib, and lenvatinib) were included. When advanced ATC patients were treated with the TKIs, the median OS was 4.8 months and the median PFS was 2.6 months. The pooled ORR and DCR were 9% and 53%. Hypertension, decreased appetite, rash, and lymphopenia were the most common grade ≥ 3 treatment-related adverse events. CONCLUSION: Mono-anitangiogenesis TKI therapy showed limited improvements in treating advanced ATC patients. Combining antiangiogenesis TKI therapy with chemotherapy, radiotherapy, or immunotherapy could be the direction of future studies.

Hsa-miR-483-5p/mRNA network that regulates chemotherapy resistance in locally advanced rectal cancer identified through plasma exosome transcriptomics.

BACKGROUND: Chemoresistance is the primary contributor to distant metastasis in the context of neoadjuvant chemoradiotherapy (nCRT) for rectal cancer. However, the underlying mechanisms remain elusive. AIM: To detect the differential expression profiles of plasma exosomal microRNAs (miRNAs) in poor and good responders and explore the potential mechanisms of chemoresistance. METHODS: In this study, the profiles of plasma exosomal miRNAs were compared in two dimensions according to treatment responses (poor/good responders) and treatment courses (pre/post-nCRT) using RNA sequencing. RESULTS: Exosome hsa-miR-483-5p was up-regulated in good responders post-nCRT. Bioinformatics analysis revealed that the target genes of hsa-miR-483-5p were mainly enriched in tumor-specific pathways, such as the MAPK signaling pathway, EGFR tyrosine kinase inhibitor resistance, Toll-like receptor signaling pathway, VEGF signaling pathway, and mTOR signaling pathway. Further analysis indicated that MAPK3, RAX2, and RNF165 were associated with inferior recurrence-free survival in patients with rectal cancer, and the profiles of MAPK3, TSPYL5, and ZNF417 were correlated with tumor stage. In addition, the expression profiles of MAPK3, RNF165, and ZNF417 were negatively correlated with inhibitory concentration 50 values. Accordingly, an hsa-miR-483-5p/MAPK3/RNF 165/ZNF417 network was constructed. CONCLUSION: This study provides insights into the mechanism of chemoresistance in terms of exosomal miRNAs. However, further research is required within the framework of our established miRNA-mRNA network.

Discovery, Optimization, and Biological Evaluation of Novel Pyrazol-5-yl-phenoxybenzamide Derivatives as Potent Succinate Dehydrogenase Inhibitors.

The diphenyl ether molecular pharmacophore has played a significant role in the development of fungicidal compounds. In this study, a variety of pyrazol-5-yl-phenoxybenzamide derivatives were synthesized and evaluated for their potential to act as succinate dehydrogenase inhibitors (SDHIs). The bioassay results indicate certain compounds to display a remarkable and broad-spectrum in their antifungal activities. Notably, compound 12x exhibited significant in vitro activities against Valsa mali, Gaeumannomyces graminis, and Botrytis cinerea, with EC50 values of 0.52, 1.46, and 3.42 mg/L, respectively. These values were lower or comparable to those of Fluxapyroxad (EC50 = 12.5, 1.93, and 8.33 mg/L, respectively). Additionally, compound 12x showed promising antifungal activities against Sclerotinia sclerotiorum (EC50 = 0.82 mg/L) and Rhizoctonia solani (EC50 = 1.86 mg/L), albeit lower than Fluxapyroxad (EC50 = 0.23 and 0.62 mg/L). Further in vivo experiments demonstrated compound 12x to possess effective protective antifungal activities against V. mali and S. sclerotiorum at a concentration of 100 mg/L, with inhibition rates of 66.7 and 89.3%, respectively. In comparison, Fluxapyroxad showed inhibition rates of 29.2 and 96.4% against V. mali and S. sclerotiorum, respectively. Molecular docking analysis revealed that compound 12x interacts with SDH through hydrogen bonding, π-cation, and π-π interactions, providing insights into the probable mechanism of action. Furthermore, compound 12x exhibited greater binding energy and SDH enzyme inhibitory activity than Fluxapyroxad (ΔGcal = -46.8 kcal/mol, IC50 = 1.22 mg/L, compared to ΔGcal = -41.1 kcal/mol, IC50 = 8.32 mg/L). Collectively, our results suggest that compound 12x could serve as a promising fungicidal lead compound for the development of more potent SDHIs for crop protection.

The burden of diagnostic error in dentistry: A study on periodontal disease misclassification.

BACKGROUND: Periodontal disease constitutes a widely prevalent category of non-communicable diseases and ranks among the top 10 causes of disability worldwide. Little however is known about diagnostic errors in dentistry. In this work, by retrospectively deploying an electronic health record (EHR)-based trigger tool, followed by gold standard manual review, we provide epidemiological estimates on the rate of diagnostic misclassification in dentistry through a periodontal use case. METHODS: An EHR-based trigger tool (a retrospective record review instrument that uses a list of triggers (or clues), i.e., data elements within the health record, to alert reviewers to the potential presence of a wrong diagnosis) was developed, tested and run against the EHR at the two participating sites to flag all cases having a potential misdiagnosis. All cases flagged as potentially misdiagnosed underwent extensive manual reviews by two calibrated domain experts. A subset of the non-flagged cases was also manually reviewed. RESULTS: A total of 2,262 patient charts met the study's inclusion criteria. Of these, the algorithm flagged 1,124 cases as potentially misclassified and 1,138 cases as potentially correctly diagnosed. When the algorithm identified a case as potentially misclassified, compared to the diagnosis assigned by the gold standard, the kappa statistic was 0.01. However, for cases the algorithm marked as potentially correctly diagnosed, the review against the gold standard showed a kappa statistic of 0.9, indicating near perfect agreement. The observed proportion of diagnostic misclassification was 32 %. There was no significant difference by clinic or provider characteristics. CONCLUSION: Our work revealed that about a third of periodontal cases are misclassified. Diagnostic errors have been reported to happen more frequently than other types of errors, and to be more preventable. Benchmarking diagnostic quality is a first step. Subsequent research endeavor will delve into comprehending the factors that contribute to diagnostic errors in dentistry and instituting measures to prevent them. CLINICAL SIGNIFICANCE: This study sheds light on the significance of diagnostic excellence in the delivery of dental care, and highlights the potential role of technology in aiding diagnostic decision-making at the point of care.

Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

Emerging chemotherapy-based treatments in anaplastic thyroid cancer: an updated analysis of prospective studies.

Background: For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively. Methods: For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs). Results: Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%). Conclusion: Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations.

Compact In Situ Electrochemical NMR with Wireless and Anti-interference Strategy in Multiscenario Applications.

The integration of electrochemistry with nuclear magnetic resonance (NMR) spectroscopy recently offers a powerful approach to understanding oxidative metabolism, detecting reactive intermediates, and predicting biological activities. This combination is particularly effective as electrochemical methods provide excellent mimics of metabolic processes, while NMR spectroscopy offers precise chemical analysis. NMR is already widely utilized in the quality control of pharmaceuticals, foods, and additives and in metabolomic studies. However, the introduction of additional and external connections into the magnet has posed challenges, leading to signal deterioration and limitations in routine measurements. Herein, we report an anti-interference compact in situ electrochemical NMR system (AICISENS). Through a wireless strategy, the compact design allows for the independent and stable operation of electrochemical NMR components with effective interference isolation. Thus, it opens an avenue toward easy integration into in situ platforms, applicable not only to laboratory settings but also to fieldwork. The operability, reliability, and versatility were validated with a series of biomimetic assessments, including measurements of microbial electrochemical systems, functional foods, and simulated drug metabolisms. The robust performance of AICISENS demonstrates its high potential as a powerful analytical tool across diverse applications.

Acceleration of Photoinduced Electron Transfer by Modulating Electronegativity of Substituents in Stable Zr-Metal-Organic Frameworks to Boost Photocatalytic CO2 Reduction.

Photoreduction of CO2 with water into chemical feedstocks of fuels provides a green way to help solve both the energy crisis and carbon emission issues. Metal-organic frameworks (MOFs) show great potential for CO2 photoreduction. However, poor water stability and sluggish charge transfer could limit their application. Herein, three water-stable MOFs functionalized with electron-donating methyl groups and/or electron-withdrawing trifluoromethyl groups are obtained for the CO2 photoreduction. Compared with UiO-67-o-CF3-CH3 and UiO-67-o-(CF3)2, UiO-67-o-(CH3)2 achieves excellent performance with an average CO generation rate of 178.0 µmol g-1 h-1 without using any organic solvent or sacrificial reagent. The superior photocatalytic activity of UiO-67-o-(CH3)2 is attributed to the fact that compared with trifluoromethyl groups, methyl groups could not only elevate CO2 adsorption capacity and reduction potential but also promote photoinduced charge separation and migration. These are evidenced by gas physisorption, photoluminescence, time-resolved photoluminescence, electrochemical impedance spectroscopy, transient photocurrent characteristics, and density functional theory calculations. The possible working mechanisms of electron-donating methyl groups are also proposed. Moreover, UiO-67-o-(CH3)2 demonstrates excellent reusability for the CO2 reduction. Based on these results, it could be affirmed that the strategy of modulating substituent electronegativity could provide guidance for designing highly efficient photocatalysts.

Efficacy and safety of combined stent retriever and contact aspiration vs. stent retriever alone on revascularization in patients with acute ischemic stroke: a systematic review and meta-analysis.

Objective: Whether the efficacy of combined stent retriever and contact aspiration (S + A) is superior to stent retriever (S) alone for revascularisation in patients with large vessel occlusive stroke remains uncertain. The aim of this meta-analysis was to assess the safety and efficacy of combined stent retriever and contact aspiration for the treatment of acute ischaemic stroke with large vessel occlusion by comparing it with stent retriever alone. Methods: We systematically searched the PubMed, Embase, Web of Science, and The Cochrane Library databases for randomised controlled trials and observational studies (case-control and cohort studies) published before 1 October 2023 comparing the efficacy of combined stent retriever and contact aspiration versus tent retriever alone in patients with large vessel occlusive stroke. The end point of the primary efficacy observed in this meta-analysis study was the rate of first pass nearly complete or complete recanalisation (mTICI 2c-3). Secondary effectiveness nodes were: rate of first pass successful recanalisation (mTICI 2b-3), rate of near-complete or complete recanalisation of the postoperative vessel, rate of successful recanalisation of the postoperative vessel, and MRS 0-2 within 90 days. Safety endpoints were interoperative embolism, symptomatic intracranial haemorrhage, and mortality within 90 days. Results: A total of 16 studies were included in the literature for this meta-analysis, with a total of 7,320 patients (S + C group: 3,406, S group: 3,914). A comprehensive analysis of the included literature showed that combined stent retriever and contact aspiration had a higher rate of near-complete or complete recanalisation of the postoperative vessel [OR = 1.53, 95% CI (1.24, 1.88), p < 0.0001] and rate of successful recanalisation of the postoperative vessel compared to stent retriever alone [OR = 1.83, 95% CI (1.55, 2.17), p < 0.00001]; there were no statistically significant differences between the two groups in terms of the rate of first pass nearly complete or complete recanalisation [OR = 1.00, 95% CI (0.83, 1.19), p = 0.96], rate of first pass successful recanalisation [OR = 1.02, 95% CI (0.85, 1.24), p = 0.81], interoperative embolism [OR = 0.93, 95% CI (0.72, 1.20), p = 0.56], symptomatic intracranial haemorrhage [OR = 1.14, 95% CI (0.87, 1.48), p = 0.33], MRS 0-2 within 90 days [OR = 0.89, 95% CI (0.76, 1.04), p = 0.14] and mortality within 90 days [OR = 1.11, 95% CI (0.94, 1.31), p = 0.22]. Conclusion: Combined stent retriever and contact aspiration has a higher rate of postprocedural revascularisation (mTICI 2c-3/mTICI 2b-3) compared with stent retriever alone in patients with large vessel occlusion stroke. In addition, it was not superior to stenting alone in terms of the rate of first pass recanalisation (mTICI 2c-3/mTICI 2b-3), interoperative embolisation, symptomatic intracranial haemorrhage, good functional prognosis within 90 days and mortality within 90 days.

CDK4/6 inhibitor abemaciclib combined with low-dose radiotherapy enhances the anti-tumor immune response to PD-1 blockade by inflaming the tumor microenvironment in Rb-deficient small cell lung cancer.

Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors have shown significant activity against several solid tumors by reducing the phosphorylation of the canonical CDK4/6 substrate retinoblastoma (Rb) protein, while the anti-tumor effect of CDK4/6 inhibitors on Rb-deficient tumors is not clear. Most small cell lung cancers (SCLCs) are Rb-deficient and show very modest response to immune checkpoint blockade (ICB) despite recent advances in the use of immunotherapy. Here, we aimed to investigate the direct effect of CDK4/6 inhibition on SCLC cells and determine its efficacy in combination therapy for SCLC. Methods: The immediate impact of CDK4/6 inhibitor abemaciclib on cell cycle, cell viability and apoptosis in four SCLC cell lines was initially checked. To explore the effect of abemaciclib on double-strand DNA (ds-DNA) damage induction and the combination impact of abemaciclib coupled with radiotherapy (RT), western blot, immunofluorescence (IF) and quantitative real-time polymerase chain reaction (qRT-PCR) were performed. An Rb-deficient immunocompetent murine SCLC model was established to evaluate efficacy of abemaciclib in combination therapy. Histological staining, flow cytometry analysis and RNA sequencing were performed to analyze alteration of infiltrating immune cells in tumor microenvironment (TME). Results: Here, we demonstrated that abemaciclib induced increased ds-DNA damage in Rb-deficient SCLC cells. Combination of abemaciclib and RT induced more cytosolic ds-DNA, and activated the STING pathway synergistically. We further showed that combining low doses of abemaciclib with low-dose RT (LDRT) plus anti-programmed cell death protein-1 (anti-PD-1) antibody substantially potentiated CD8+ T cell infiltration and significantly inhibited tumor growth and prolonged survival in an Rb-deficient immunocompetent murine SCLC model. Conclusions: Our results define previously uncertain DNA damage-inducing properties of CDK4/6 inhibitor abemaciclib in Rb-deficient SCLCs, and demonstrate that low doses of abemaciclib combined with LDRT inflame the TME and enhance the efficacy of anti-PD-1 immunotherapy in SCLC model, which represents a potential novel therapeutic strategy for SCLC.

Clinical characteristics and risk factors of post-operative intestinal flora disorder following laparoscopic colonic surgery: A propensity-score-matching analysis.

BACKGROUND: Intestinal flora disorder (IFD) poses a significant challenge after laparoscopic colonic surgery, and no standard criteria exists for its diagnosis and treatment. AIM: To analyze the clinical features and risk factors of IFD. METHODS: Patients with colon cancer receiving laparoscopic surgery were included using propensity-score-matching (PSM) methods. Based on the occurrence of IFD, patients were categorized into IFD and non-IFD groups. The clinical characteristics and treatment approaches for patients with IFD were analyzed. Multivariate regression analysis was performed to identify the risk factors of IFD. RESULTS: The IFD incidence after laparoscopic surgery was 9.0% (97 of 1073 patients). After PSM, 97 and 194 patients were identified in the IFD and non-IFD groups, respectively. The most common symptoms of IFD were diarrhea and abdominal, typically occurring on post-operative days 3 and 4. All patients were managed conservatively, including modulation of the intestinal flora (90.7%), oral/intravenous application of vancomycin (74.2%), and insertion of a gastric/ileus tube for decompression (23.7%). Multivariate regression analysis identified that pre-operative intestinal obstruction [odds ratio (OR) = 2.79, 95%CI: 1.04-7.47, P = 0.041] and post-operative antibiotics (OR = 8.57, 95%CI: 3.31-23.49, P < 0.001) were independent risk factors for IFD, whereas pre-operative parenteral nutrition (OR = 0.12, 95%CI: 0.06-0.26, P < 0.001) emerged as a protective factor. CONCLUSION: A stepwise approach of probiotics, vancomycin, and decompression could be an alternative treatment for IFD. Special attention is warranted post-operatively for patients with pre-operative obstruction or early use of antibiotics.

Survival rate of teeth adjacent and nonadjacent to dental implants: A retrospective cohort study.

BACKGROUND: The aim of this retrospective study was to investigate the risk of tooth loss for teeth adjacent and nonadjacent to dental implants. METHODS: A total of 787 patients with an average follow-up of 57.1 months were examined to define the tooth loss, cumulative survival rate, and odds ratio (OR) for teeth adjacent versus nonadjacent to implants. A multivariate logistic regression was employed to assess the association between dental history and various recorded etiologies of tooth loss among teeth adjacent to implants. RESULTS: The incidence of tooth loss for teeth adjacent to implants was 8.1% at the tooth level and 15.1% at the patient level, while 0.7% and 9.5% at the tooth and patientlevel for teeth nonadjacent to implants. The 10-year cumulative survival rate for teeth adjacent to implants was 89.2%, and the primary etiology of tooth loss was root fracture (45.2%). The risk of tooth loss among teeth adjacent versus nonadjacent to implants was significantly higher (OR 13.15). Among teeth adjacent to implants, root canal-treated teeth had a significantly higher risk of tooth loss due to root fracture (OR 7.72), a history of existing restoration significantly increased the risk of tooth loss due to caries (OR 3.05), and a history of periodontitis significantly increased the risk of tooth loss due to periodontitis (OR 38.24). CONCLUSION: The present study demonstrated that after patients received dental implant treatment, teeth adjacent to implants showed a 13.2-fold higher risk of tooth loss compared to teeth nonadjacent to implants, with the primary etiology being root fracture.

Pt-S Bond-Enabled Temperature-Dependent Phosphorescence in S-Heteroaryl Tetradentate Pt(S

This study presents the rare examples of S-heteroaryl tetradentate Pt(S^C^N^O) luminescent complexes (PtSZ and PtSZtBu) containing a Pt-S bond. The presence of the Pt-S bond allows the novel Pt(S^C^N^O) complexes to exhibit temperature-dependent phosphorescent emission behavior. The PtSZtBu exhibits dual-emission phenomena and biexponential transient decay spectra above 250 K, indicating the presence of two minimal excited states in the potential energy surface (PES) of the T1 state. Through complementary experimental and computational studies, we have identified changes in orbital composition between Pt(dxy)-S(px) and Pt(dyz)-S(pz) in excited states with increasing temperature. This results in two energy minima, enabling the excited states to decay selectively and radiatively at different temperatures. Consequently, this leads to remarkable steady-state and transient emission spectra changes. Our work not only provides valuable insights for the development of novel Pt-S bond-based tetradentate Pt(II) complexes but also enhances our understanding of the distinctive properties governed by the Pt-S bond.

Identification of benzo[b]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors.

The increased de novo serine biosynthesis confers many advantages for tumorigenesis and metastasis. Phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in serine biogenesis, exhibits hyperactivity across multiple tumors and emerges as a promising target for cancer treatment. Through screening our in-house compound library, we identified compound Stattic as a potent PHGDH inhibitor (IC50 = 1.98 ± 0.66 µM). Subsequent exploration in structural activity relationships led to the discovery of compound B12 that demonstrated the increased enzymatic inhibitory activity (IC50 = 0.29 ± 0.02 µM). Furthermore, B12 exhibited robust inhibitory effects on the proliferation of MDA-MB-468, NCI-H1975, HT1080 and PC9 cells that overexpress PHGDH. Additionally, using a [U-13C6]-glucose tracing assay, B12 was found to reduce the production of glucose-derived serine in MDA-MB-468 cells. Finally, mass spectrometry-based peptide profiling, mutagenesis experiment and molecular docking study collectively suggested that B12 formed a covalent bond with Cys421 of PHGDH.

Subjective sleep more predictive of global cognitive function than objective sleep in older adults: A specification curve analysis.

OBJECTIVES: Sleep is associated with cognitive function in older adults. In the current study, we examined this relationship from subjective and objective perspectives, and determined the robustness and dimensional specificity of the associations using a comprehensive modelling approach. METHODS: Multiple dimensions of subjective (sleep quality and daytime sleepiness) and objective sleep (sleep stages, sleep parameters, sleep spindles, and slow oscillations), as well as subjectively reported and objectively measured cognitive function were collected from 55 older adults. Specification curve analysis was used to examine the robustness of correlations for the effects of sleep on cognitive function. RESULTS: Robust associations were found between sleep and objectively measured cognitive function, but not with subjective cognitive complaints. In addition, subjective sleep showed robust and consistent associations with global cognitive function, whereas objective sleep showed a more domain-specific association with episodic memory. Specifically, subjective sleep quality and daytime sleepiness correlated with global cognitive function, and objective sleep parameters correlated with episodic memory. CONCLUSIONS: Overall, associations between sleep and cognitive function in older adults depend on how they are measured and which specific dimensions of sleep and domains of cognitive function are considered. It highlights the importance of focusing on specific associations to ameliorate the detrimental effects of sleep disturbance on cognitive function in later life.

Design, Synthesis, and Fungicidal Activities of Novel N-(Pyrazol-5-yl)benzamide Derivatives Containing a Diphenylamine Moiety.

To accelerate the development of novel fungicides, a variety of N-(pyrazol-5-yl)benzamide derivatives with a diphenylamine moiety were designed and synthesized using a pharmacophore recombination strategy based on the structure of pyrazol-5-yl-aminophenyl-benzamides. The bioassay results demonstrated that most of the target compounds had excellent in vitro antifungal activities against Sclerotinia sclerotiorum, Valsa mali, and Botrytis cinerea. In particular, compound 5IIIh exhibited remarkable activity against S. sclerotiorum (EC50 = 0.37 mg/L), which was similar to that of fluxapyroxad (EC50 = 0.27 mg/L). In addition, compound 5IIIc (EC50 = 1.32 mg/L) was observed to be more effective against V. mali than fluxapyroxad (EC50 = 12.8 mg/L) and comparable to trifloxystrobin (EC50 = 1.62 mg/L). Furthermore, compound 5IIIh demonstrated remarkable in vivo protective antifungal properties against S. sclerotiorum, with an inhibition rate of 96.8% at 100 mg/L, which was close to that of fluxapyroxad (99.6%). Compounds 5IIIc (66.7%) and 5IIIh (62.9%) exhibited good in vivo antifungal effects against V. mali at 100 mg/L, which were superior to that of fluxapyroxad (11.1%) but lower than that of trifloxystrobin (88.9%). The succinate dehydrogenase (SDH) enzymatic inhibition assay was conducted to confirm the mechanism of action. Molecular docking analysis further revealed that compound 5IIIh has significant hydrogen-bonding, π-π, and p-π conjugation interactions with ARG 43, SER 39, TRP 173, and TYR 58 in the binding site of SDH, and the binding mode was similar to that of the commercial fungicide fluxapyroxad. All of the results suggest that compound 5IIIh could be a potential SDH inhibitor, offering a valuable reference for future studies.

Caspase-11/GSDMD contributes to the progression of hyperuricemic nephropathy by promoting NETs formation.

Hyperuricemia is an independent risk factor for chronic kidney disease (CKD) and promotes renal fibrosis, but the underlying mechanism remains largely unknown. Unresolved inflammation is strongly associated with renal fibrosis and is a well-known significant contributor to the progression of CKD, including hyperuricemia nephropathy. In the current study, we elucidated the impact of Caspase-11/Gasdermin D (GSDMD)-dependent neutrophil extracellular traps (NETs) on progressive hyperuricemic nephropathy. We found that the Caspase-11/GSDMD signaling were markedly activated in the kidneys of hyperuricemic nephropathy. Deletion of Gsdmd or Caspase-11 protects against the progression of hyperuricemic nephropathy by reducing kidney inflammation, proinflammatory and profibrogenic factors expression, NETs generation, α-smooth muscle actin expression, and fibrosis. Furthermore, specific deletion of Gsdmd or Caspase-11 in hematopoietic cells showed a protective effect on renal fibrosis in hyperuricemic nephropathy. Additionally, in vitro studies unveiled the capability of uric acid in inducing Caspase-11/GSDMD-dependent NETs formation, consequently enhancing α-smooth muscle actin production in macrophages. In summary, this study demonstrated the contributory role of Caspase-11/GSDMD in the progression of hyperuricemic nephropathy by promoting NETs formation, which may shed new light on the therapeutic approach to treating and reversing hyperuricemic nephropathy.