Structural mechanisms for regulation of GSDMB pore-forming activity.

Cytotoxic lymphocyte-derived granzyme A (GZMA) cleaves GSDMB, a gasdermin-family pore-forming protein1,2, to trigger target cell pyroptosis3. GSDMB and the charter gasdermin family member GSDMD4,5 have been inconsistently reported to be degraded by the Shigella flexneri ubiquitin-ligase virulence factor IpaH7.8 (refs. 6,7). Whether and how IpaH7.8 targets both gasdermins is undefined, and the pyroptosis function of GSDMB has even been questioned recently6,8. Here we report the crystal structure of the IpaH7.8-GSDMB complex, which shows how IpaH7.8 recognizes the GSDMB pore-forming domain. We clarify that IpaH7.8 targets human (but not mouse) GSDMD through a similar mechanism. The structure of full-length GSDMB suggests stronger autoinhibition than in other gasdermins9,10. GSDMB has multiple splicing isoforms that are equally targeted by IpaH7.8 but exhibit contrasting pyroptotic activities. Presence of exon 6 in the isoforms dictates the pore-forming, pyroptotic activity in GSDMB. We determine the cryo-electron microscopy structure of the 27-fold-symmetric GSDMB pore and depict conformational changes that drive pore formation. The structure uncovers an essential role for exon-6-derived elements in pore assembly, explaining pyroptosis deficiency in the non-canonical splicing isoform used in recent studies6,8. Different cancer cell lines have markedly different isoform compositions, correlating with the onset and extent of pyroptosis following GZMA stimulation. Our study illustrates fine regulation of GSDMB pore-forming activity by pathogenic bacteria and mRNA splicing and defines the underlying structural mechanisms.

FoxO1 target Gpr17 activates AgRP neurons to regulate food intake.

Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity.

Pretreatment multiparametric MRI radiomics-integrated clinical hematological biomarkers can predict early rapid metastasis in patients with nasopharyngeal carcinoma.

BACKGROUND: To establish and validate a predictive model combining pretreatment multiparametric MRI-based radiomic signatures and clinical characteristics for the risk evaluation of early rapid metastasis in nasopharyngeal carcinoma (NPC) patients. METHODS: The cutoff time was used to randomly assign 219 consecutive patients who underwent chemoradiation treatment to the training group (n = 154) or the validation group (n = 65). Pretreatment multiparametric magnetic resonance (MR) images of individuals with NPC were employed to extract 428 radiomic features. LASSO regression analysis was used to select radiomic features related to early rapid metastasis and develop the Rad-score. Blood indicators were collected within 1 week of pretreatment. To identify independent risk variables for early rapid metastasis, univariate and multivariate logistic regression analyses were employed. Finally, multivariate logistic regression analysis was applied to construct a radiomics and clinical prediction nomogram that integrated radiomic features and clinical and blood inflammatory predictors. RESULTS: The NLR, T classification and N classification were found to be independent risk indicators for early rapid metastasis by multivariate logistic regression analysis. Twelve features associated with early rapid metastasis were selected by LASSO regression analysis, and the Rad-score was calculated. The AUC of the Rad-score was 0.773. Finally, we constructed and validated a prediction model in combination with the NLR, T classification, N classification and Rad-score. The area under the curve (AUC) was 0.936 (95% confidence interval (95% CI): 0.901-0.971), and in the validation cohort, the AUC was 0.796 (95% CI: 0.686-0.905). CONCLUSIONS: A predictive model that integrates the NLR, T classification, N classification and MR-based radiomics for distinguishing early rapid metastasis may serve as a clinical risk stratification tool for effectively guiding individual management.

Synthesis and biological evaluation of triazolones/oxadiazolones as novel urease inhibitors.

Urease is the main virulence factor of infectious gastritis and gastric ulcers. Urease inhibitors are regarded as the first choice for the treatment of such diseases. Based on the triazolone/oxadiazolone skeleton, a urea-like fragment being able to specifically bind the urease activity pocket and prevent urea from hydrolysis, we designed and synthesized 45 triazolones/oxadiazolones as urease inhibitors. Eight compounds were proved to show excellent inhibitory activity against Helicobacter pylori urease, being more potency than the clinically used urease inhibitor acetohydroxamic acid. The most active inhibitor with IC50 value of 1.2 µM was over 20-fold higher potent than the positive control. Enzymatic kinetic assays showed that these novel inhibitors reversibly inhibited urease with a mixed competitive mechanism. Molecular dockings provided evidence for the observations in enzyme assays. Furthermore, these novel inhibitors were proved as drug-like compounds with very low cytotoxicity to mammalian cells and favorable water solubility. These results suggested that triazolone and oxadiazolone were promising scaffolds for the design and discovery of novel urease inhibitors, and were expected as good candidates for further drug development.

Carrier doping modulates the magnetoelectronic and magnetic anisotropic properties of two-dimensional MSi2N4 (M = Cr, Mn, Fe, and Co) monolayers.

Through extensive density functional theory (DFT) calculations, our investigation delves into the stability, electrical characteristics, and magnetic behavior of monolayers (MLs) of MSi2N4. Computational analyses indicate intrinsic antiferromagnetic (AFM) orders within the MSi2N4 MLs, as a result of direct exchange interactions among transition metal (M) atoms. We further find that CrSi2N4 and CoSi2N4 MLs with primitive cells (pcells) exhibit half-metallic properties, with respective spin-ß electron gaps of 3.661 and 2.021 eV. In contrast, MnSi2N4 and FeSi2N4 MLs with pcells act as semiconductors, having energy gaps of 0.427 and 0.282 eV, respectively. When the SOC is considered, the CrSi2N4, MnSi2N4 and FeSi2N4 MLs are metals, while the CoSi2N4 ML is a semiconductor. Our findings imply the dynamics and thermodynamic stability of MSi2N4 MLs. We have also explored the influence of carrier doping on the electromagnetic attributes of MSi2N4 MLs. Interestingly, charge doping could transform CrSi2N4, MnSi2N4, and CoSi2N4 MLs from their original AFM state into a ferromagnetic (FM) order. Moreover, carrier doping transformed CrSi2N4 and CoSi2N4 MLs from spin-polarized metals to half-metals (HMs). It is of particular note that doping of CrSi2N4 MLs with +0.9 e per pcell or more holes caused a switch in the easy axis (EA) to the [001] axis. The demonstrated intrinsic AFM order, excellent thermodynamic and kinetic stability, adjustable magnetism, and half-metallicity of the MSi2N4 family suggest its promising potential for applications in the realm of spintronics.

Comprehensive assessment of fine motor movement and cognitive function among older adults in China: a cross-sectional study.

BACKGROUND: Fine motor skills are closely related to cognitive function. However, there is currently no comprehensive assessment of fine motor movement and how it corresponds with cognitive function. To conduct a complete assessment of fine motor and clarify the relationship between various dimensions of fine motor and cognitive function. METHODS: We conducted a cross-sectional study with 267 community-based participants aged ≥ 60 years in Beijing, China. We assessed four tests performance and gathered detailed fine motor indicators using Micro-Electro-Mechanical System (MEMS) motion capture technology. The wearable MEMS device provided us with precise fine motion metrics, while Chinese version of the Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. We adopted logistic regression to analyze the relationship between fine motor movement and cognitive function. RESULTS: 129 (48.3%) of the participants had cognitive impairment. The vast majority of fine motor movements have independent linear correlations with MoCA-BJ scores. According to logistic regression analysis, completion time in the Same-pattern tapping test (OR = 1.033, 95%CI = 1.003-1.063), Completion time of non-dominant hand in the Pieces flipping test (OR = 1.006, 95%CI = 1.000-1.011), and trajectory distance of dominant hand in the Pegboard test (OR = 1.044, 95%CI = 1.010-1.068), which represents dexterity, are related to cognitive impairment. Coordination, represented by lag time between hands in the Same-pattern tapping (OR = 1.663, 95%CI = 1.131-2.444), is correlated with cognitive impairment. Coverage in the Dual-hand drawing test as an important indicator of stability is negatively correlated with cognitive function (OR = 0.709, 95%CI = 0.6501-0.959). Based on the above 5-feature model showed consistently high accuracy and sensitivity at the MoCA-BJ score (ACU = 0.80-0.87). CONCLUSIONS: The results of a comprehensive fine-motor assessment that integrates dexterity, coordination, and stability are closely related to cognitive functioning. Fine motor movement has the potential to be a reliable predictor of cognitive impairment.

Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.

The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 µg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.

Bioactivities and Action Mechanisms of Ellipticine Derivatives Reported Prior to 2023.

Currently, natural products are one of the priceless options for finding novel chemical pharmaceutical entities. Ellipticine is a naturally occurring alkaloid isolated from the leaves of Ochrosia elliptica Labill. Ellipticine and its derivatives are characterized by multiple biological activities. The purpose of this review was to provide a critical and systematic assessment of ellipticine and its derivatives as bioactive molecules over the last 60 years. Publications focused mainly on the total synthesis of alkaloids of this type without any evaluation of bioactivity have been excluded. We have reviewed papers dealing with the synthesis, bioactivity evaluation and mechanism of action of ellipticine and its derivatives. It was found that ellipticine and its derivatives showed cytotoxicity, antimicrobial ability, and anti-inflammatory activity, among which cytotoxicity toward cancer cell lines was the most investigated aspect. The inhibition of DNA topoisomerase II was the most relevant mechanism for cytotoxicity. The PI3K/AKT pathway, p53 pathway, and MAPK pathway were also closely related to the antiproliferative ability of these compounds. In addition, the structure-activity relationship was deduced, and future prospects were outlined. We are confident that these findings will lay a scientific foundation for ellipticine-based drug development, especially for anticancer agents.

Frailty and social isolation before and during the coronavirus disease 2019 pandemic among older adults: A path analysis.

AIM: To explore the prevalence of social isolation among Japanese community-dwelling older adults before and during the COVID-19 pandemic as well as determine how family and friend connections before and during the pandemic affected frail older adults during the pandemic. DESIGN: A cross-sectional study. METHODS: A total of 852 community-dwelling older adults in Hokkaido and Tokyo, Japan were surveyed conducted between April and November 2021 using convenience sampling. The Lubben social network scale-6, frailty screening index, and geriatric depression scale were used to assess social isolation, frailty and depression, respectively. A path analysis was conducted to evaluate the effect of social isolation on frailty. RESULTS: Participants had a mean age of 76.8 ± 6.6 years. Overall, 46% and 59% of participants were socially isolated before and during the COVID-19 pandemic, respectively. Frailty was found in 19% of participants during the pandemic. Friends and family connectedness before the pandemic had no direct relationship with frailty; only friend connectedness affected frailty indirectly via depression. Family connectedness during the pandemic had a significant, negative and direct relationship with frailty. CONCLUSION: The findings show that connectedness with family and friends is critical for older people's physical and mental health. IMPACT: Nurses in the community should consider these findings to reduce mental health problems and physical decline among older adults. It is important to identify older adults who are socially isolated from their families or friends and provide resources to help them build relationships within their communities. PATIENT OR PUBLIC CONTRIBUTION: Community centre staff and community volunteers assisted in data collection. The public was not involved in data analysis, interpretation or manuscript preparation.

Diastolic/systolic blood pressure ratio for predicting febrile children with sepsis and progress to septic shock in the emergency department.

OBJECTIVE: Given the scarcity of studies analyzing the clinical predictors of pediatric septic cases that would progress to septic shock, this study aimed to determine strong predictors for pediatric emergency department (PED) patients with sepsis at risk for septic shock and mortality. METHODS: We conducted chart reviews of patients with ≥ 2 age-adjusted quick Sequential Organ Failure Assessment score (qSOFA) criteria to recognize patients with an infectious disease in two tertiary PEDs between January 1, 2021, and April 30, 2022. The age range of included patients was 1 month to 18 years. The primary outcome was development of septic shock within 48 h of PED attendance. The secondary outcome was sepsis-related 28-day mortality. Initial important variables in the PED and hemodynamics with the highest and lowest values during the first 24 h of admission were also analyzed. RESULTS: Overall, 417 patients were admitted because of sepsis and met the eligibility criteria for the study. Forty-nine cases progressed to septic shock within 48 h after admission and 368 were discharged without progression. General demographics, laboratory data, and hemodynamics were analyzed by multivariate analysis. Only the minimum diastolic blood pressure/systolic blood pressure ratio (D/S ratio) during the first 24 h after admission remained as an independent predictor of progression to septic shock and 28-day mortality. The best cutoff values of the D/S ratio for predicting septic shock and 28-day mortality were 0.52 and 0.47, respectively. CONCLUSIONS: The D/S ratio is a practical bedside scoring system in the PED and had good discriminative ability in predicting the progression of septic shock and in-hospital mortality in PED patients. Further validation is essential in other settings.

Micro-positive pressure significantly decreases greenhouse gas emissions by regulating archaeal community during industrial-scale dairy manure composting.

In this study, the effects of micro-positive pressure formed by covering with a semipermeable membrane in the heating phase of dairy manure composting on greenhouse gas emissions and the mechanism of reducing methane emissions by the archaeal community were investigated. A large-scale experiment was conducted with semipermeable membrane-covered composting (SMC), forced aeration composting (FAC), and traditional static composting (TSC) groups. The results showed that the oxygen concentration and methanogen abundance were key factors in regulating methane emissions. In the heating phase of SMC, the micro-positive pressure could enhance the O2 utilization rate and heating rate, resulting in Methanobrevibacter and Methanobacterium greatly decreasing, and the abundance of mcrA decreased by 90.03%, while that of pmoA did not increase. Compared with FAC and TSC, the cumulative methane emissions in SMC decreased by 51.75% and 96.04%, respectively. Therefore, the micro-positive pressure could effectively reduce greenhouse gas emissions by inhibiting the growth of methanogens.

Tailoring the physicochemical properties of starch: impact of integrated ultrasonic and ethanol pretreatment on the oil uptake of infrared fried ginkgo seeds.

BACKGROUND: The structural changes of starch would have a more crucial impact on oil absorption and quality changes in starch-rich fruits and vegetables during frying process with enhanced heat transfer (such as infrared frying). In the present study, the influence of integrated ultrasonic and ethanol (US + ethanol) pretreatment on oil uptake in infrared fried (IF) ginkgo seeds was evaluated regarding modifications in the physicochemical properties of starch. The pretreatment was performed with ultrasonic (40 kHz, 300 W) and ethanol osmotic (95%, v/v) treatment individually or integrated for 40 min. RESULTS: The mass transfer in the pretreatment was facilitated by combined ultrasound and ethanol. The swelling power, solubility, and gelatinization degree of starch was significantly increased. Low-frequency-NMR curves and images revealed that the bound water fraction in ginkgo seeds was increased and the water distribution was homogenized. The results of Fourier transform-infrared spectrum and differential scanning calorimeter revealed that the crystalline regions of starch were reduced and the thermal enthalpy was decreased after US + ethanol pretreatment. The total, surface and structural oil content in IF ginkgo seeds with US + ethanol pretreatment was reduced by 29.10%, 34.52% and 29.73%, respectively. The US + ethanol pretreatment led to a thinner crust layer with increased porosity and smaller-sized pores in the IF ginkgo seeds as observed by stereo microscopy and scanning electron microscopy. CONCLUSION: The changes in structural and physicochemical properties of starch by combined ultrasound and ethanol affect the crust ratio and pore characteristics in fried high-starch fruits and vegetables, thereby reducing oil absorption. © 2024 Society of Chemical Industry.

Measurement error models with zero inflation and multiple sources of zeros, with applications to hard zeros.

We consider measurement error models for two variables observed repeatedly and subject to measurement error. One variable is continuous, while the other variable is a mixture of continuous and zero measurements. This second variable has two sources of zeros. The first source is episodic zeros, wherein some of the measurements for an individual may be zero and others positive. The second source is hard zeros, i.e., some individuals will always report zero. An example is the consumption of alcohol from alcoholic beverages: some individuals consume alcoholic beverages episodically, while others never consume alcoholic beverages. However, with a small number of repeat measurements from individuals, it is not possible to determine those who are episodic zeros and those who are hard zeros. We develop a new measurement error model for this problem, and use Bayesian methods to fit it. Simulations and data analyses are used to illustrate our methods. Extensions to parametric models and survival analysis are discussed briefly.

Bayesian kinetic modeling for tracer-based metabolomic data.

BACKGROUND: Stable Isotope Resolved Metabolomics (SIRM) is a new biological approach that uses stable isotope tracers such as uniformly [Formula: see text]-enriched glucose ([Formula: see text]-Glc) to trace metabolic pathways or networks at the atomic level in complex biological systems. Non-steady-state kinetic modeling based on SIRM data uses sets of simultaneous ordinary differential equations (ODEs) to quantitatively characterize the dynamic behavior of metabolic networks. It has been increasingly used to understand the regulation of normal metabolism and dysregulation in the development of diseases. However, fitting a kinetic model is challenging because there are usually multiple sets of parameter values that fit the data equally well, especially for large-scale kinetic models. In addition, there is a lack of statistically rigorous methods to compare kinetic model parameters between different experimental groups. RESULTS: We propose a new Bayesian statistical framework to enhance parameter estimation and hypothesis testing for non-steady-state kinetic modeling of SIRM data. For estimating kinetic model parameters, we leverage the prior distribution not only to allow incorporation of experts' knowledge but also to provide robust parameter estimation. We also introduce a shrinkage approach for borrowing information across the ensemble of metabolites to stably estimate the variance of an individual isotopomer. In addition, we use a component-wise adaptive Metropolis algorithm with delayed rejection to perform efficient Monte Carlo sampling of the posterior distribution over high-dimensional parameter space. For comparing kinetic model parameters between experimental groups, we propose a new reparameterization method that converts the complex hypothesis testing problem into a more tractable parameter estimation problem. We also propose an inference procedure based on credible interval and credible value. Our method is freely available for academic use at https://github.com/xuzhang0131/MCMCFlux . CONCLUSIONS: Our new Bayesian framework provides robust estimation of kinetic model parameters and enables rigorous comparison of model parameters between experimental groups. Simulation studies and application to a lung cancer study demonstrate that our framework performs well for non-steady-state kinetic modeling of SIRM data.

Glycyrrhizin ameliorates impaired glucose metabolism and ovarian dysfunction in a polycystic ovary syndrome mouse model.

The aim of this study was to determine the impact of glycyrrhizin, an inhibitor of high mobility group box 1, on glucose metabolic disorders and ovarian dysfunction in mice with polycystic ovary syndrome. We generated a polycystic ovary syndrome mouse model by using dehydroepiandrosterone plus high-fat diet. Glycyrrhizin (100 mg/kg) was intraperitoneally injected into the polycystic ovary syndrome mice and the effects on body weight, glucose tolerance, insulin sensitivity, estrous cycle, hormone profiles, ovarian pathology, glucolipid metabolism, and some molecular mechanisms were investigated. Increased number of cystic follicles, hormonal disorders, impaired glucose tolerance, and decreased insulin sensitivity in the polycystic ovary syndrome mice were reverted by glycyrrhizin. The increased high mobility group box 1 levels in the serum and ovarian tissues of the polycystic ovary syndrome mice were also reduced by glycyrrhizin. Furthermore, increased expressions of toll-like receptor 9, myeloid differentiation factor 88, and nuclear factor kappa B as well as reduced expressions of insulin receptor, phosphorylated protein kinase B, and glucose transporter type 4 were restored by glycyrrhizin in the polycystic ovary syndrome mice. Glycyrrhizin could suppress the polycystic ovary syndrome-induced upregulation of high mobility group box 1, several inflammatory marker genes, and the toll-like receptor 9/myeloid differentiation factor 88/nuclear factor kappa B pathways, while inhibiting the insulin receptor/phosphorylated protein kinase B/glucose transporter type 4 pathways. Hence, glycyrrhizin is a promising therapeutic agent against polycystic ovary syndrome.

Compact topological polarization beam splitter based on all-dielectric fishnet photonic crystals.

Conventional polarization beam splitters (PBSs) suffer energy loss and signal distortion due to backscattering caused by disturbances. Topological photonic crystals provide backscattering immunity and anti-disturbance robustness transmission owing to the topological edge states. Here, we put forward a kind of dual-polarization air hole-type fishnet valley photonic crystal with a common bandgap (CBG). The Dirac points at the K point formed by different neighboring bands for transverse magnetic and transverse electric polarizations are drawn closer via changing the filling ratio of the scatterer. Then the CBG is constructed by lifting the Dirac cones for dual polarizations within a same frequency range. We further design a topological PBS using the proposed CBG via changing the effective refractive index at the interfaces which guide polarization-dependent edge modes. Based on these tunable edge states, the designed topological PBS (TPBS) achieves efficient polarization separation and is robust against sharp bends and defects, verified by simulation results. The TPBS's footprint is approximately 22.4 × 15.2 µ m 2, allowing high-density on-chip integration. Our work has potential application in photonic integrated circuits and optical communication systems.

Challenges and opportunities in animal models of psoriatic arthritis.

OBJECTIVE: To review the preparation, characteristics and research progress of different PsA animal models. METHODS: Computerized searches were conducted in CNKI, PubMed and other databases to classify and discuss the relevant studies on PsA animal models. The search keywords were "PsA and animal model(s), PsA and animal(s), PsA and mouse, PsA and mice, PsA and rat(s), PsA and rabbit(s), PsA and dog(s)" RESULTS: The experimental animals currently used to study PsA are mainly rodents, including mice and rats. According to the different methods of preparing the models, the retrieved animal models were classified into spontaneous or genetic mutation, transgenic and induced animal models. These PsA animal models involve multiple pathogenesis, some experimental animals' lesions appear in a short and comprehensive cycle, some have a high success rate in molding, and some are complex and less reproducibility. This article summarizes the preparation methods, advantages and disadvantages of different models. CONCLUSIONS: The animal models of PsA aim to mimic the clinicopathological alterations of PsA patients through gene mutation, transgenesis or targeted proinflammatory factor and to reveal new pathogenic pathways and therapeutic targets by exploring the pathological features and clinical manifestations of the disease. This work will have very far-reaching implications for the in-depth understanding of PsA and the development of new drugs.

The sound and surprise: overlapping meta-analyses on the topic of safety and efficacy of PD-1 and PD-L1 inhibitors in the treatment of non-small cell lung cancer.

PURPOSE: To analyze the characteristics of overlapping meta-analyses based on randomized controlled trials (RCTs) which reported PD-1/PD-L1 inhibitors in non-small cell cancer (NSCLC). METHODS: Meta-analyses were identified from English and Chinese databases until January 1, 2022. Differences in characteristics of overlapping meta-analyses that conducted in China and other countries were compared to assess their publication propensity. The corrected covered area (CCA) and coverage of relevant RCTs were analyzed for subtopics according to detailed intervention types. The waste and redundancy of evidence were assessed in the case of PD-1/PD-L1 inhibitor monotherapy for second-line treatment for NSCLC. RESULTS: Fifty-nine meta-analyses published in English and 17 meta-analyses published in Chinese reporting 26 RCTs were identified. Fifty-three (69.74%) meta-analyses were conducted in China. The overlapping meta-analyses in China were more likely to be from hospitals, supported by government funding, integrate first and second-line therapies. Five of the six subtopics had overlapping meta-analyses according to specific types of interventions. The CCA of overlapping meta-analyses ranged from 33.33 to 63.19%, and the coverage of relevant RCTs ranged from 63.64 to 100%. All the conclusions of overlapping meta-analyses have been consistent in the subtopic of PD-1/PD-L1 inhibitor monotherapy for second-line treatment since 2017. CONCLUSION: Overlapping meta-analyses of PD-1/PD-L1 inhibitors in NSCLC hints that meta-analyses under this topic probably exist serious redundancy. Future research should focus on prospective registration of protocols for systematic reviews/meta-analyses, scientific designed PICO, and cumulative meta-analysis to reduce redundant and wasted studies. Journals should strengthen the requirement for reviewing previously published evidence in manuscript review.

Identification of (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids as novel urease inhibitors and the mechanism exploration.

Thirty-three (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids were synthesized in an effort to develop novel urease inhibitors. Among these compounds, 2-(N-(3-nitrophenyl)-N-(4-tert-butylphenylsulfonyl))aminoacetohydroxamic acid (e2) exhibited excellent inhibitory activity against Helicobacter pylori urease with no perceptible cytotoxicity to mammalian cells. Compound e2 showed over 690-fold higher potency than the clinical used urease inhibitor acetohydroxamic acid, reversibly inhibiting urease with a mixed mechanism. Molecular modeling revealed that (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids may possibly bind Ni ions and two hydrophobic regions with a 'Y'-like shape.

The therapeutic utility of combining dynamic contrast-enhanced magnetic resonance imaging with arterial spin labeling in the staging of nasopharyngeal carcinoma.

BACKGROUND: To research the pathological and clinical staging uses of arterial spin labeling (ASL) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: 64 newly diagnosed nasopharyngeal carcinoma (NPC) patients were enrolled from December 2020 to January 2022, and 3.0 T MRI (Discovery 750W, GE Healthcare, USA) were used for ASL and DCE-MRI scans. The DCE-MRI and ASL raw data were processed post-acquisition on the GE image processing workstation (GE Healthcare, ADW 4.7, USA). The volume transfer constant (Ktrans), blood flow (BF), and accompanying pseudo-color images were generated automatically. Draw the region of interest (ROIs), and the Ktrans and BF values for each ROI were recorded separately. Based on pathological information and the most recent AJCC staging criteria, patients were divided into low T stage groups = T1-2 and high T stage groups = T3-4, low N stage groups = N0-1 and high N stage groups = N2-3, and low AJCC stage group = stage I-II and high AJCC stage group = stage III-IV. The association between the Ktranst and BF parameters and the T, N, and AJCC stages was compared using an independent sample t-test. Using a receiver operating characteristic (ROC) curve, the sensitivity, specificity, and AUC of Ktranst, BFt, and their combined use in T and AJCC staging of NPC were investigated and assessed. RESULT: The tumor-BF (BFt) (t = - 4.905, P < 0.001) and tumor-Ktrans (Ktranst) (t = - 3.113, P = 0.003) in the high T stage group were significantly higher than those in the low T stage group. The Ktranst in the high N stage group was significantly higher than that in the low N stage group (t = - 2.071, P = 0.042). The BFt (t = - 3.949, P < 0.001) and Ktranst (t = - 4.467, P < 0.001) in the high AJCC stage group were significantly higher than those in the low AJCC stage group. BFt was moderately positively correlated with the T stage (r = 0.529, P < 0.001) and AJCC stage (r = 0.445, P < 0.001). Ktranst was moderately positively correlated with T staging (r = 0.368), N staging (r = 0.254), and AJCC staging (r = 0.411). There was also a positive correlation between BF and Ktrans in gross tumor volume (GTV) (r = 0.540, P < 0.001), parotid (r = 0.323, P < 0.009) and lateral pterygoid muscle (r = 0.445, P < 0.001). The sensitivity of the combined application of Ktranst and BFt for AJCC staging increased from 76.5 and 78.4 to 86.3%, and the AUC value increased from 0.795 and 0.819 to 0.843, respectively. CONCLUSION: Combining Ktrans and BF measures may make it possible to identify the clinical stages in NPC patients.