The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia.

With an increase in global aging, the number of people affected by cerebrovascular diseases is also increasing, and the incidence of vascular dementia-closely related to cerebrovascular risk-is increasing at an epidemic rate. However, few therapeutic options exist that can markedly improve the cognitive impairment and prognosis of vascular dementia patients. Similarly in Alzheimer's disease and other neurological disorders, synaptic dysfunction is recognized as the main reason for cognitive decline. Nitric oxide is one of the ubiquitous gaseous cellular messengers involved in multiple physiological and pathological processes of the central nervous system. Recently, nitric oxide has been implicated in regulating synaptic plasticity and plays an important role in the pathogenesis of vascular dementia. This review introduces in detail the emerging role of nitric oxide in physiological and pathological states of vascular dementia and summarizes the diverse effects of nitric oxide on different aspects of synaptic dysfunction, neuroinflammation, oxidative stress, and blood-brain barrier dysfunction that underlie the progress of vascular dementia. Additionally, we propose that targeting the nitric oxide-sGC-cGMP pathway using certain specific approaches may provide a novel therapeutic strategy for vascular dementia.

Pulmonary artery smooth muscle cell pyroptosis promotes the proliferation of PASMCs by paracrine IL­1ß and IL­18 in monocrotaline­induced pulmonary arterial hypertensive rats.

Pulmonary arterial hypertension (PAH) is a common vascular disease, and pulmonary vascular remodeling is a pivotal pathophysiological mechanism of PAH. Major pathological changes of pulmonary arterial remodeling, including proliferation, hypertrophy and enhanced secretory activity, can occur in pulmonary artery smooth muscle cells (PASMCs). Multiple active factors and cytokines play important roles in PAH. However, the regulatory mechanisms of the active factors and cytokines in PAH remain unclear. The present study aimed to reveal the crucial role of PASMC pyroptosis in PAH and to elucidate the intrinsic mechanisms. To establish the PAH rat models, Sprague-Dawley rats were injected intraperitoneally with monocrotaline (MCT) at a dose of 60 mg/kg. The expression of proteins and interleukins were detected by western blotting and ELISA assay. The results indicated that the pyroptosis of PASMCs is significantly increased in MCT-induced PAH rats. Notably, pyroptotic PASMCs can secret IL-1ß and IL-18 to promote the proliferation of PASMCs. On this basis, inhibiting the secretion of IL-1ß and IL-18 can markedly inhibit PASMC proliferation. Collectively, the findings of the present study indicate a critical role for PASMC pyroptosis in MCT-induced PAH rats, prompting a new preventive and therapeutic strategy for PAH.

A transcription factor of SHI family AaSHI1 activates artemisinin biosynthesis genes in Artemisia annua.

BACKGROUND: Transcription factors (TFs) of plant-specific SHORT INTERNODES (SHI) family play a significant role in regulating development and metabolism in plants. In Artemisia annua, various TFs from different families have been discovered to regulate the accumulation of artemisinin. However, specific members of the SHI family in A. annua (AaSHIs) have not been identified to regulate the biosynthesis of artemisinin. RESULTS: We found five AaSHI genes (AaSHI1 to AaSHI5) in the A. annua genome. The expression levels of AaSHI1, AaSHI2, AaSHI3 and AaSHI4 genes were higher in trichomes and young leaves, also induced by light and decreased when the plants were subjected to dark treatment. The expression pattern of these four AaSHI genes was consistent with the expression pattern of four structural genes of artemisinin biosynthesis and their specific regulatory factors. Dual-luciferase reporter assays, yeast one-hybrid assays, and transient transformation in A. annua provided the evidence that AaSHI1 could directly bind to the promoters of structural genes AaADS and AaCYP71AV1, and positively regulate their expressions. This study has presented candidate genes, with AaSHI1 in particular, that can be considered for the metabolic engineering of artemisinin biosynthesis in A. annua. CONCLUSIONS: Overall, a genome-wide analysis of the AaSHI TF family of A. annua was conducted. Five AaSHIs were identified in A. annua genome. Among the identified AaSHIs, AaSHI1 was found to be localized to the nucleus and activate the expression of structural genes of artemisinin biosynthesis including AaADS and AaCYP71AV1. These results indicated that AaSHI1 had positive roles in modulating artemisinin biosynthesis, providing candidate genes for obtaining high-quality new A. annua germplasms.

Associations between abnormal sleep behavior and indoor environmental risk factors among children with a chronic cough in Wuxi, China: a cross-sectional study.

BACKGROUND: Indoor environmental factors, such as pet ownership, presence of cockroaches, mattress quality, fuel usage (gas or electricity), use of biomass for cooking and heating, exposure to tobacco smoke or household molds can significantly affect the sleep quality of children with chronic cough. However, data regarding the effects of indoor environmental conditions on sleep in this population are limited. This study aimed to assess the prevalence of abnormal sleep behaviors and to establish associations between indoor environmental factors and sleep behaviors among children with chronic cough in Wuxi, China. METHODS: A cross-sectional design was employed in this study, involving children aged 3-18 years. Data on sociodemographic factors, allergies, home environmental exposures, and sleep characteristics of the participants were collected using paper-based questionnaires. The association between indoor environmental factors and sleep behaviors in children with chronic cough was analyzed using logistic regression models. RESULTS: The findings demonstrated that the prevalence of chronic cough among children in Wuxi was 15.50%. The chronic cough group exhibited a significantly higher incidence of eczema, wheezing, rhinitis, food allergy, and nasosinusitis than the non-chronic cough group. In addition, children with chronic cough also tended to have a family history of sleep disorders and adenoid hypertrophy (P < 0.01). After adjusting for confounding factors, a significant association was observed between bruxism (teeth grinding) and chronic cough (sometimes: odds ratio [OR] = 1.04; confidence interval [CI] = 1.01-1.08; always: OR = 1.11; CI = 1.04-1.19; P < 0.01). Among children with chronic cough, recent home decoration was associated with sleepwalking (OR = 1.04; CI = 1.00-1.07; P < 0.05), mold exposure was associated with bruxism (OR = 1.15; CI = 1.0-1.31; P < 0.05), and carpet use at home was associated with apnea (OR = 1.09; CI = 1.02-1.17; P < 0.05), twitching during sleep (OR = 1.13; CI = 1.00-1.27; P < 0.01) and morning headache (OR = 1.14; CI = 1.05-1.23; P < 0.01). CONCLUSION: Children with chronic cough are more prone to some abnormal sleep behaviors than children without chronic cough. Household decoration within a year, household mold exposure, and carpet use were all significantly positively associated with abnormal sleep behaviors in children with chronic cough. Our study provides novel insights into the impact of the indoor environment on children's sleep and the occurrence of chronic cough, offering guidance for tailored health promotion programs for families.

Genipin promotes the apoptosis and autophagy of neuroblastoma cells by suppressing the PI3K/AKT/mTOR pathway.

This study investigated the underlying function and mechanism of genipin in neuroblastoma (NB). Using flow cytometry analysis and cytotoxicity tests, in vitro studies were conducted to assess the effects of genipin on the SK-N-SH cell line. The mechanism of action of genipin was explored through immunofluorescence staining, Western blotting, and caspase-3 activity assays. In addition, we also created a xenograft tumour model to investigate the effects of genipin in vivo. This research confirmed that genipin suppressed cell viability, induced apoptosis, and promoted autophagy, processes that are likely linked to the inhibition of the PI3K/AKT/mTOR signalling pathway. Autophagy inhibition increases the sensitivity of SK-N-SH cells to genipin. Furthermore, combination treatment with a PI3K inhibitor enhanced the therapeutic efficacy of genipin. These results highlight the potential of genipin as a candidate drug for the treatment of NB.

Associations between type 2 diabetes mellitus and risk of falls among community-dwelling elderly people in Guangzhou, China: a prospective cohort study.

BACKGROUND: Several studies have demonstrated that older adults with type 2 diabetes mellitus (T2DM) have a higher risk of falls compared to those without T2DM, which may lead to disability and a lower quality of life. While, limited prospective studies have quantified the associations in southern China. We conducted a longitudinal cohort study to quantify the associations between T2DM and falls and investigate the risk factors of falls among community-dwelling elderly people in Guangzhou, China. METHODS: The population-based study included 8800 residents aged 65 and over in 11 counties of Guangzhou at baseline in 2020 and then prospectively followed up through 2022. Of 6169 participants had complete follow-up and were included in the present study. A fall event was identified by self-reported. The Cox regression was applied to quantify the associations between T2DM and falls, and hazard ratios (HRs) were calculated to the factors associated with falls among participants. RESULTS: The median follow-up time for participants was 2.42 years. During the follow-up period, the incidence of falls among all participants was 21.96%. After adjusting for covariates in Cox regression models, T2DM remained a significant risk factor for falls, with HR of 1.781 (95% CI: 1.600-1.983) in the unadjusted covariates model and 1.757 (1.577-1.957) in the adjusted covariates model. Female (1.286, 1.136-1.457), older age (≥ 80: 1.448, 1.214-1.729), single marital status (1.239, 1.039-1.477), lower education level (primary school and below: 1.619, 1.004-1.361), hypertension (1.149, 1.026-1.286) and stroke (1.619, 1.176-2.228) were associated with a higher risk of falls, whereas everyday physical exercise (0.793, 0.686-0.918) was associated with a lower risk of falls. CONCLUSION: Falls are common, with risks between T2DM and falls quantified and several factors investigated in the longitudinal cohort study among community-dwelling elderly people in Guangzhou, China. Targeted action on the risk factors may reduce the burden of falls in elderly people with T2DM in the future.

Choice intention for the national volume-based procurement drug and its associated factors: a cross-sectional study on patients with late-life depression in China.

BACKGROUND: The national volume-based procurement (NVBP) policy has significantly decreased prices and increased the accessibility of NVBP drugs. Nevertheless, issues such as heightened adverse reactions and suboptimal efficacy have arisen. Concerns regarding the quality of low-cost medications and the absence of long-term research have been widely recognized. This has led to caution among patients with late-life depression (LLD) due to their delicate health and the severity of their condition. This study evaluated the choice intention for NVBP drugs and associated factors in older patients with LLD. METHODS: A weighted sample of 408 participants between December 2022 and March 2023 were included. Data were collected via face-to-face interviews and questionnaires. To identify significant associated factors of choice intention, a multilevel logistic regression model was employed. RESULTS: Over half (53.68%) of older patients with LLD intended to choose NVBP drugs. Associated factors included self-assessed poor economy, higher out-of-pocket expenses, monthly household income exceeding CNY 6000, absence of other non-communicable chronic diseases, ordinary registration, urban employee medical insurance, no requirements for brand-name drugs, adverse reactions after using NVBP drugs, and rejection of physicians' recommendation for NVBP drugs. The interaction effect between the real economic condition and patients self-assessed economy significantly influences choice intention for NVBP drugs. Among 124 patients with self-assessed poor economy, 75 showed a higher intention to use NVBP drugs. In these patients, age, medical insurance reimbursement, and brand awareness were significantly associated with choice intention. CONCLUSION: Economic factors, physical conditions, medical needs, and physician recommendations significantly influenced the choice intention for NVBP drugs. The choice intention can be improved by strengthening physician-patient communication, increasing the scope and proportion of medical insurance reimbursement, improving substitution studies, and conducting post-marketing re-evaluations of NVBP drugs.

Postoperative delayed gastric emptying: may gut microbiota play a role?

Postoperative delayed gastric emptying is a prevalent complication following surgical procedures, imposing heavy physical and financial burdens on patients. However, current treatment options remain suboptimal. In recent years, an increasing number of studies have highlighted that the gut microbiota and its metabolites are closely associated with postoperative complications. Various factors can disrupt the gut microbiome after surgery. This review discusses the potential mechanisms by which the gut microbiota and their metabolites may contribute to the pathogenesis of postoperative delayed gastric emptying. However, the current knowledge base is limited in terms of fully understanding the exact mechanisms involved. It is therefore evident that further research is required to fully elucidate the role of the gut microbiome in postoperative delayed gastric emptying, with the aim of uncovering new possibilities for preventive measures and therapeutic treatments.

Factors associated with an inconclusive result from commercial homologous recombination deficiency testing in ovarian cancer.

INTRODUCTION: Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result. METHODS: GIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020-August 2023. Clinical data were abstracted from the medical record. RESULTS: Of 477 HRD test results identified, 57 (12%) were inconclusive. High-grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p < .001). Most HRD cases were of high-grade serous histology; no cases with clear cell or endometrioid histology were HRD-positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self-reported race, and histology were not associated with an inconclusive result. CONCLUSIONS: Surgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results.

The effect of self-rated health on depressive symptoms in Chinese older adults: The mediating role of social participation and spouse health.

This study investigates the relationship between self-rated health, social participation, spouse health, and depressive symptoms in older adults. It also analyzed the moderating effects of gender, drinking, visual function, diet, quality of life, and economic level on the model. We analyzed data from 5119 participants aged 60 and above, from the CLHLS. We used a partial least squares structural equation model to explore the correlation between self-rated health, spouse health, social participation, and depressive symptoms. Self-rated health was significantly correlated with spouse health, social participation, and depressive symptoms (P < 0.001). Social participation (ß=-0.034) and spouse health (ß=-0.029) were mediators of self-rated health to depressive symptoms. In addition, gender, drinking, visual function, diet, quality of life, and economic level were mediated factors. This study provides evidence that self-rated health has direct or indirect associations with depressive symptoms in older people, with social participation and spouse health playing a crucial mediating role.

Dynamic functional connectivity and gene expression correlates in temporal lobe epilepsy: insights from hidden markov models.

BACKGROUD: Temporal lobe epilepsy (TLE) is associated with abnormal dynamic functional connectivity patterns, but the dynamic changes in brain activity at each time point remain unclear, as does the potential molecular mechanisms associated with the dynamic temporal characteristics of TLE. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) was acquired for 84 TLE patients and 35 healthy controls (HCs). The data was then used to conduct HMM analysis on rs-fMRI data from TLE patients and an HC group in order to explore the intricate temporal dynamics of brain activity in TLE patients with cognitive impairment (TLE-CI). Additionally, we aim to examine the gene expression profiles associated with the dynamic modular characteristics in TLE patients using the Allen Human Brain Atlas (AHBA) database. RESULTS: Five HMM states were identified in this study. Compared with HCs, TLE and TLE-CI patients exhibited distinct changes in dynamics, including fractional occupancy, lifetimes, mean dwell time and switch rate. Furthermore, transition probability across HMM states were significantly different between TLE and TLE-CI patients (p < 0.05). The temporal reconfiguration of states in TLE and TLE-CI patients was associated with several brain networks (including the high-order default mode network (DMN), subcortical network (SCN), and cerebellum network (CN). Furthermore, a total of 1580 genes were revealed to be significantly associated with dynamic brain states of TLE, mainly enriched in neuronal signaling and synaptic function. CONCLUSIONS: This study provides new insights into characterizing dynamic neural activity in TLE. The brain network dynamics defined by HMM analysis may deepen our understanding of the neurobiological underpinnings of TLE and TLE-CI, indicating a linkage between neural configuration and gene expression in TLE.

First Report of Fusarium avenaceum Causing Root Rot of Raspberry (Rubus corchorifolius) in China.

Raspberry (Rubus corchorifolius) plants hold historical, economic, and medicinal importance in China (Yang et al. 2022). Raspberries are cultivated to generate income for local farmers in Lintao County, Dingxi City, Gansu Province. However, farmers encountered challenges due to raspberry plants exhibiting root rot disease, resulting in plant death. During a thorough field survey conducted in June 2022, symptoms ranging from leaf yellowing and wilting to necrotic lesions and root rots were observed, where approximately 30% of raspberry plants were affected. Five diseased and healthy plants were collected from the farmers' fields in Lintao (35.53oN, 103.84oE) for pathogen identification. Symptomatic and asymptomatic root tissues were surface sterilized with 75% ethanol for 30 s and 3% NaOCl for 5 min, followed by three rinses in sterile water. Small pieces (0.5 × 0.5 cm) were cut and incubated on potato dextrose agar (PDA) plates at 25°C for 7-10 days. Twenty-two pure Fusarium isolates, which displayed four distinct colony groups morphologically, were obtained. Pathogenicity tests on isolates RB10, RB1, RB30, and RB23, representing each colony group, revealed that RB10 exhibited symptoms similar to those observed in the field. The RB10 strain produced yellowish-white to greyish-white colonies on PDA and was then cultured in a carboxymethylcellulose (CMC) broth for enhanced conidia production (Zhang et al. 2020). Macroconidia were sickle-shaped or slightly curved, with three to five septa (19.2 to 38.5 x 3.1 to 5.8 µm, n =40). Microconidia were oval to ellipsoidal, non-septate or featuring 1 to 2 septa (4.8 to 10.5 x 2.1 to 5.2 µm, n=20). These morphological features indicated the isolate was similar to Fusarium avenaceum (Leslie and Summerell, 2006). For further identification of the strains, genomic regions (ITS-rDNA, TEF-1α, and RPB2) were amplified and sequenced using specific primers ITS1/ITS4, EF-1/EF-2, and 5f2/7cr, respectively (O'Donnell et al. 2010; Uwaremwe et al. 2021; Zarrin et al. 2016). PCR BLASTn queries of NCBI GenBank revealed a 99.8% (522 bp), 99.4% (355 bp) and 99.6% (985 bp) homology with F. avenaceum (MZ724839.1, MN271631.1, and MK185026.1), respectively. Sequences were deposited in GenBank (ITS, OR735571; TEF-1α, PP216660; RPB2, PP857820). One-year-old raspberry seedlings were planted in pots with a sterile soil mix (2:2:1 v/v ratio of soil, peat, and vermiculite) under controlled greenhouse conditions (23-26°C, 16h light/8h dark). A month post-planting, taproots were wounded in six pots and inoculated with 20 ml of conidia suspension (106 conidia/ml), while the other six pots were maintained as controls. After 14 days, RB10-infected plants showed symptoms similar to field observations, while controls remained healthy. The experiment was conducted twice, and re-isolation confirmed both the pathogenicity and identity of the pathogen. In the concatenated phylogenetic tree of ITS, TEF-1α and RPB2, strain RB10 was clustered with the F. avenaceum representative strains KG502, KG431 and F094. Studies revealed F. avenaceum varied pathogenicity across plants (Bugingo, 2022; Moparthi et al. 2020& 2024; Yli-Mattila et al. 2018), and it has been reported to induce raspberry fruit rot (Wang et al. 2017). However, no previous reports linked this fungus to raspberry root rot. This report is crucial for understanding the impact of root rot disease on raspberry cultivation and developing effective management strategies.

Transport and spatio-temporal conversion of sugar facilitate the formation of spatial gradients of starch in wheat caryopses.

Wheat grain starch content displays large variations within different pearling fractions, which affecting the processing quality of corresponding flour, while the underlying mechanism on starch gradient formation is unclear. Here, we show that wheat caryopses acquire sugar through the transfer of cells (TCs), inner endosperm (IE), outer endosperm (OE), and finally aleurone (AL) via micro positron emission tomography-computed tomography (PET-CT). To obtain integrated information on spatial transcript distributions, developing caryopses are laser microdissected into AL, OE, IE, and TC. Most genes encoding carbohydrate transporters are upregulated or specifically expressed, and sugar metabolites are more highly enriched in the TC group than in the AL group, in line with the PET-CT results. Genes encoding enzymes in sucrose metabolism, such as sucrose synthase, beta-fructofuranosidase, glucose-1-phosphate adenylyltransferase show significantly lower expression in AL than in OE and IE, indicating that substrate supply is crucial for the formation of starch gradients. Furthermore, the low expressions of gene encoding starch synthase contribute to low starch content in AL. Our results imply that transcriptional regulation represents an important means of impacting starch distribution in wheat grains and suggests breeding targets for enhancing specially pearled wheat with higher quality.

A pre-operative scoring model to estimate the risk of blood transfusion over an ovarian cancer debulking surgery (BLOODS score): a Memorial Sloan Kettering Cancer Center Team Ovary study.

OBJECTIVES: To develop a pre-operative tool to estimate the risk of peri-operative packed red blood cell transfusion in primary debulking surgery. METHODS: We retrospectively reviewed an institutional database to identify patients who underwent primary debulking surgery for ovarian cancer at a single center between January 1, 2001 and May 31, 2019. Receiver operating characteristic curve and area under the receiver operating characteristic curve (AUC) were calculated. Five-fold cross-validation was applied to the multivariate model. Significant variables were assigned a 'BLOODS' (BLood transfusion Over an Ovarian cancer Debulking Surgery) score of +1 if present. A total BLOODS score was calculated for each patient, and the odds of receiving a transfusion was determined for each score. RESULTS: Overall, 1566 patients met eligibility criteria; 800 (51%) underwent a peri-operative blood transfusion. Odds ratios (OR) were statistically significant for American Society of Anesthesiologists scores of 3 and 4 (OR 1.34, 95% confidence interval (95% CI) 1.09 to 1.63), pre-operative levels of cancer antigen 125 (CA125) (OR 2.43, 95% CI 1.98 to 2.99), platelets (OR 1.59, 95% CI 1.45 to 1.74), obesity (OR 0.76, 95% CI 0.60 to 0.96), presence of carcinomatosis (OR 2.45, 95% CI 1.93 to 3.11), bulky upper abdominal disease (OR 2.86, 95% CI 2.32 to 3.54), pre-operative serum albumin level (OR 0.31, 95% CI 0.24 to 0.40), and pre-operative hemoglobin level (OR 0.56, 95% CI 0.51 to 0.61). The corrected AUC was 0.748 (95% CI 0.693 to 0.804). BLOODS scores of 0 and 5 corresponded to 11% and 73% odds, respectively, of receiving a peri-operative blood transfusion. CONCLUSIONS: We developed a universal pre-operative scoring system, the BLOODS score, to help identify patients with ovarian cancer who would benefit from surgical planning and blood-saving techniques. The BLOODS score was directly proportional to the American Society of Anesthesiologists score, presence of upper abdominal disease, carcinomatosis, CA125 level, and platelets level. We believe this model can help physicians with surgical planning and can benefit patient outcomes.

Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer.

OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.

ChatGPT compared to national guidelines for management of ovarian cancer: Did ChatGPT get it right? - A Memorial Sloan Kettering Cancer Center Team Ovary study.

OBJECTIVES: We evaluated the performance of a chatbot compared to the National Comprehensive Cancer Network (NCCN) Guidelines for the management of ovarian cancer. METHODS: Using NCCN Guidelines, we generated 10 questions and answers regarding management of ovarian cancer at a single point in time. Questions were thematically divided into risk factors, surgical management, medical management, and surveillance. We asked ChatGPT (GPT-4) to provide responses without prompting (unprompted GPT) and with prompt engineering (prompted GPT). Responses were blinded and evaluated for accuracy and completeness by 5 gynecologic oncologists. A score of 0 was defined as inaccurate, 1 as accurate and incomplete, and 2 as accurate and complete. Evaluations were compared among NCCN, unprompted GPT, and prompted GPT answers. RESULTS: Overall, 48% of responses from NCCN, 64% from unprompted GPT, and 66% from prompted GPT were accurate and complete. The percentage of accurate but incomplete responses was higher for NCCN vs GPT-4. The percentage of accurate and complete scores for questions regarding risk factors, surgical management, and surveillance was higher for GPT-4 vs NCCN; however, for questions regarding medical management, the percentage was lower for GPT-4 vs NCCN. Overall, 14% of responses from unprompted GPT, 12% from prompted GPT, and 10% from NCCN were inaccurate. CONCLUSIONS: GPT-4 provided accurate and complete responses at a single point in time to a limited set of questions regarding ovarian cancer, with best performance in areas of risk factors, surgical management, and surveillance. Occasional inaccuracies, however, should limit unsupervised use of chatbots at this time.

A Room-Temperature All-Solid-State Na-Ag Battery with a Long Cycle Life and Low Overpotential.

Aqueous Zn-Ag batteries have been developed and commercialized for nearly a century, offering stable discharge and high specific energies. Sodium, with its lower redox potential, smaller charge-to-mass ratio, and abundant resources, presents a promising alternative to zinc. In this study, we successfully developed an all-solid-state Na-Ag battery system. This battery demonstrates stable discharge and charge voltages, low overpotential (0.27 V), high energy efficiency (>91%), and long cycle life under moderate humidity at room temperature. The reaction mechanism was elucidated through combined analyses using differential electrochemical mass spectrometry (DEMS), X-ray diffraction (XRD), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). Our findings indicate that metallic Ag in the cathode materials acts as an effective catalyst for the oxygen reduction reaction during the initial discharge process, forming NaOH as the discharge product. Ag is then oxidized during the charging process and recovered during discharge, serving as an active reactant in the Na-Ag battery. This work demonstrates superior performance of all-solid-state Na-Ag battery over aqueous Zn-Ag battery. Na-Ag battery may be of interest in applications with stringent requirements on stable discharge voltage and high specific energy.

Association between blood lead levels and parathyroid hormone among United States adolescents aged 12-19: a cross-sectional study.

Aims: Studies on the association between serum lead levels and parathyroid function in adolescents are lacking. Therefore, in this study, we elucidated the possible association between blood lead levels (BLLs) and the parathyroid hormone (PTH) in adolescents aged 12-19 years in the United States. Methods: In this study, information from the database of the National Health and Nutrition Examination Survey was utilized. The study included 3919 participants from survey cycles between 2003-2004 and 2005-2006. Multivariable linear regression analysis was performed to determine the correlation between BLLs and PTH. Furthermore, smooth curve fitting was utilized to analyze the dose-response relationship between BLLs and PTH. Results: Multivariable linear regression analysis revealed that every 1 µg/dL increase in BLLs was associated with 0.67 pg/mL increase in PTH (ß = 0.67, 95% CI: 0.16-1.18, p < 0.01). However, sex-stratified subgroup analysis revealed that this positive association was only observed in males (ß = 1.16, 95% CI: 0.50-1.83 p < 0.01). Smooth curve fitting revealed a positive correlation between BLLs and PTH. Conclusions: In adolescents in the United States, BLLs are positively correlated with PTH, particularly in males.

ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability-high (MSI-H) molecular subtype.

Anti-HER2 therapy is indicated for erb-b2 receptor tyrosine kinase 2 (ERBB2)-amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2-mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2-mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor-normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2-amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2-mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2-amplified. Compared to ERBB2-wildtype ECs (with or without ERBB2 amplification), ERBB2-mutated/non-amplified ECs were enriched for the microsatellite instability-high (MSI-H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2-mutated/non-amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2-wildtype and ERBB2-amplified ECs.

Deletion of Bmal1 in aggrecan-expressing cells leads to mouse temporomandibular joint osteoarthritis.

INTRODUCTION: Articular cartilage is the major affected tissue during the development of osteoarthritis (OA) in temporomandibular joint (TMJ). The core circadian rhythm molecule Bmal1 regulates chondrocyte proliferation, differentiation and apoptosis; however, its roles in condylar cartilage function and in TMJ OA have not been fully elucidated. MATERIALS AND METHODS: TMJ OA mouse model was induced by unilateral anterior crossbite (UAC) and Bmal1 protein expression in condylar cartilage were examined by western blot analysis. To determine the role of Bmal1 in TMJ OA, we generated cartilage-specific Bmal1 conditional knockout (cKO) mice (Bmal1Agc1CreER mice) and hematoxylin and eosin staining, toluidine blue and Safranin O/fast green, immunohistochemistry, TUNEL assay, real-time PCR analysis and Western blot assay were followed. RESULTS: Bmal1 expression was reduced in condylar cartilage in a TMJ OA mouse model induced by UAC. The Bmal1 cKO mice displayed decreased cartilage matrix synthesis, reduced chondrocyte proliferation, increased chondrocyte hypertrophy and apoptosis as well as the upregulation of YAP expression in TMJ condylar cartilage. CONCLUSIONS: We demonstrated that Bmal1 was essential for TMJ tissue homeostasis and loss-of-function of Bmal1 in chondrocytes leads to the development of TMJ OA.