Positive and Negative Impacts of Interfacial Hydrogen Bonds on Photocatalytic Hydrogen Evolution.

Understanding the behavior of water molecules at solid-liquid interfaces is crucial for various applications such as photocatalytic water splitting, a key technology for sustainable fuel production and chemical transformations. Despite extensive studies conducted in the past, the impact of the microscopic structure of interfacial water molecules on photocatalytic reactivity has not been directly examined. In this study, using real-time mass spectrometry and Fourier-transform infrared spectroscopy, we demonstrated the crucial role of hydrogen bond (H-bond) networks on the photocatalytic hydrogen evolution in thickness-controlled water adsorption layers on various TiO2 photocatalysts. Under controlled water vapor environments with relative humidity (RH) below 70%, we observed a monotonic increase in the H2 formation rate with increasing RH, indicating that reactive water molecules were present not only in the first adsorbed layer but also in several overlying layers. In contrast, at RH > 70%, when more than three water layers covered the catalyst surface, the H2 formation rate turned to decrease dramatically because of the structural rearrangement and hardening of the interfacial H-bond network induced during further water adsorption. This unique many-body effect of interfacial water was consistently observed for various TiO2 particles with different crystalline structures, including brookite, anatase, and a mixture of anatase and rutile. Our results demonstrated that depositing several water layers in a water vapor environment with RH ∼ 70% is optimal for photocatalytic hydrogen evolution rather than liquid-phase reaction conditions in aqueous solutions. This study provides molecular-level insights into designing interfacial water conditions to enhance photocatalytic performance.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Effect of orthostatic hypotension on long-term prognosis of elderly patients with stable coronary artery disease: a retrospective cohort study.

Background: The long-term prognosis of patients with stable coronary artery disease (CAD) combined with orthostatic hypotension (OH) has rarely been reported. This research was designed to examine whether OH increases the risk of all-cause mortality and cardiovascular death among patients with stable CAD. Methods: We retrospectively analyzed retired military personnel over 65 years of age who were hospitalized at the General Hospital of Southern Theater Command of the Chinese People's Liberation Army between March and July 2010. A total of 924 patients with stable CAD were included, among whom 263 had OH. The risk of all-cause mortality and cardiovascular death in OH and non-OH groups were analyzed with the Cox proportional hazards models, and restricted cubic spline plots were utilized for subgroup analyses. Furthermore, competing risk models were applied for sensitivity analyses. Results: The median age of the patients was 82.00 (80.00-85.00) years. Over 159 months of follow-up, the loss to follow-up rate was 2.27%, and all-cause mortality was observed in 574 (63.57%) patients, including 184 with OH. Moreover, cardiovascular death occurred in 127 patients (13.73%), with 58 cases associated with OH. Although the relationship between OH and all-cause mortality was non-significant [body mass index (BMI) < 25 group, adjusted hazard ratio (HR) = 1.10 with a 95% confidence interval (CI): 0.82-1.40; BMI ≥ 25 group, adjusted HR = 1.30, 95% CI: 0.98-1.70], it was independently related to a growing risk of cardiovascular death (adjusted HR = 1.80, 95% CI: 1.20-2.60). This finding was further validated by using a competing risk model (subdistribution HR = 1.74, 95% CI: 1.22-2.49). Moreover, age, low-density lipoprotein cholesterol, and frequency of hospital admissions were identified as risk factors of cardiovascular death among patients with OH (P < 0.05). Conclusion: Our study, based on retired military personnel with stable CAD, found that OH led to a significantly higher risk of cardiovascular death, but it was not noticeably associated with all-cause mortality on long-term prognosis.

Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT).

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

Metastatic pericardial mass and cardiophrenic lymph nodes resection in ovarian cancer.

Introduction: Epithelial Ovarian cancer most commonly presents at advanced stages with extra-abdominal disease metastasis. Notably, enlarged cardiophrenic lymph nodes are found in 10.5-62 % of patients with advanced ovarian cancer. However, the safety and feasibility of cardiophrenic lymph nodes dissection as a component of debulking surgery remains controversial (Acs et al., 2022, Agusti et al., 2024). Case/methods: We present a surgical video demonstrating the technique of bulky pericardial mass and metastatic cardiophrenic lymph nodes resection by transdiaphragmatic approach in advanced ovarian cancer. After the complete excision of intra-abdominal disease at laparotomy, the diaphragm is exposed, following the liver mobilization. According to the preoperative radiological examinations, the pericardial mass in the diaphragmatic space is reconfirmed, and then carefully removed by blunt and sharp dissection. Next, the pericardial cavity is closed by continuous suture. Through the transdiaphragmatic access to thoracic cavity, the pericardial fat pad containing cardiophrenic lymph nodes is explored and completely resected in view throughout. The diaphragm incision is closed continuously using non-absorbable suture with a biofilm, meanwhile, performing air aspiration in thoracic cavity. Conclusion: We demonstrate that advanced ovarian cancer with extra-abdominal diseases, such as bulky pericardial mass and cardiophrenic lymph nodes, should not be an absolute contraindication to a planned complete debulking surgery. Based on our growing experience, transdiaphragmatic approach is a safe and feasible access for metastatic cardiophrenic lymph nodes dissection.

A phase I dose-finding trial of hyperthermic intraperitoneal docetaxel combined with cisplatin in patients with advanced-stage ovarian cancer.

OBJECTIVE: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m²) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. METHODS: In this phase I trial, a time-to-event Bayesian optimal interval design was used. Docetaxel was given at a starting dose of 60 mg/m² and was increased in 5 mg/m² increments until the MTD was determined or the maximum dose level of 75 mg/m² was reached. The dose-limiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. RESULTS: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m², no DLT was reported. DLTs were observed in one patient who received 70 mg/m² docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m² docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m² in combination with cisplatin 75 mg/m² had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. CONCLUSION: Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m²), can be used safely at intraperitoneal doses of 75 mg/m² in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05410483.

Safety of fertility-sparing surgery in young women with stage I endometrioid epithelial and mucinous ovarian cancer: A population-based analysis.

INTRODUCTION: The aim of this study was to assess the safety of fertility-sparing surgery (FSS) in stage I endometrioid epithelial cancer (EEOC) and mucinous ovarian cancer (MOC). METHODS: A retrospective case‒controlled study was conducted using the Surveillance, Epidemiology, and End Results (SEER) database, focusing on stage I EEOC and MOC between 2000 and 2016. The effects of FSS on overall survival (OS) were compared using log-rank tests. Univariate and multivariate Cox analyses were performed to control for confounders. RESULTS: The study identified 970 patients with FIGO stage I EEOC and 810 with stage I MOC. Of these patients, 116 (12.0%) EEOC and 268 (33.1%) MOC patients underwent fertility-sparing surgery. The results showed that patients with G3 EEOC had a worse 5-year OS than patients with G1 EEOC (96.1% vs. 90.1%, p = 0.020). IC stage MOC patients had a worse prognosis than IA and IB stage patients (94.9% vs. 88.7%, p = 0.001). FSS did not significantly affect the 5-year OS of patients with EEOC (94.8% vs. 95.4%, p = 0.687) or MOC (95.9% vs. 92.3%, p = 0.071). Further subgroup analysis according to tumor stage and histological grade did not show a worse OS with FSS in stage I EEOC or MOC patients, even with high-risk types such as G3 histology and IC phase. In a multivariable analysis, the application of FSS was not associated with inferior OS in EEOC or MOC. CONCLUSIONS: FSS for patients with stage I EEOC or MOC does not lead to worse outcomes than radical surgery, making it a viable option for young patients with early-stage disease wishing to preserve fertility.

Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. METHODS: This multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. RESULTS: Twenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02-0.42), and this dose was selected as the MTD. CONCLUSION: Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

Cumulative remnant cholesterol predicts cardiovascular outcomes in elderly patients with atherosclerotic cardiovascular disease.

AIMS: Remnant cholesterol (RC) reportedly mediates residual cardiovascular risk in atherosclerotic cardiovascular diseases (ASCVD). However, few studies have characterized long-term cumulative RC exposure among elderly people. The study aimed to evaluate the association between cumulative exposure to RC and incident major adverse cardiovascular events (MACE) by analysing a cohort of elderly patients with ASCVD. METHODS AND RESULTS: This retrospective multicentre cohort study enrolled ASCVD participants aged ≥75 years with baseline visits occurring from 2006 to 2012 followed by four in-person visits. Cumulative RC was estimated as the area under the curve using measurements from the first to fourth visits by using 9-year data. The time-weighted average (TWA) RC was expressed as cumulative exposure to RC averaged by years. All outcomes were follow-up from the fourth visit to the year 2021. Outcomes included a composite of MACE (stroke, unstable angina pectoris, myocardial infarction, and cardiac death). We included 4,680 participants (73.1% male, mean age 79.3 ± 2.5 years). The median follow-up duration was 6.1 years (interquartile range: 3.4-6.6 years). In the multivariable model adjusted for traditional cardiovascular risk factors, low-density lipoprotein cholesterol level, and most recent RC level, the hazard ratios for MACE that compared the high and low tertiles of the RC variables were 1.30 [95% confidence interval (CI), 1.16-1.44] for cumulative RC and 1.36 (95% CI, 1.23-1.52) for TWA RC. Consistent significant associations were observed among most propensity score analyses. CONCLUSIONS: Long-term cumulative RC was independently associated with incident MACE in elderly participants with ASCVD, suggesting that achieving and maintaining optimal RC levels later in life may still improve cardiovascular outcomes.

This retrospective multicentre cohort study, enrolling 4680 participants aged ≥75 years with pre-existing atherosclerotic cardiovascular diseases (ASCVD), found that greater cumulative exposure to remnant cholesterol (RC) across a 9-year span was independently associated with an increased incidence of cardiovascular events, suggesting that cumulative RC may be a powerful predictor of cardiovascular outcomes in patients with ASCVD.

Incremental Benefit of Lipid Lowering in a Large Chinese Population Aged 75 Years and Older With Established Atherosclerotic Cardiovascular Disease.

OBJECTIVE: To explore the optimal low-density lipoprotein cholesterol (LDL-C) level in patients aged 75 years and older with established atherosclerotic cardiovascular disease (ASCVD). PATIENTS AND METHODS: We conducted a retrospective multicenter cohort study of veterans aged 75 years and older with ASCVD who were regularly hospitalized or medically examined in 15 medical institutions in southern China from January 1, 2006, to December 31, 2013. Follow-up continued through October 1, 2021. The time-weighted average (TWA) LDL-C level represented the average LDL-C level during follow-up. Participants were divided into TWA LDL-C groups of 55.0 mg/dL or lower, 55.1 to 70.0 mg/dL, 70.1 to 85.0 mg/dL, 85.1 to 100.0 mg/dL, and greater than 100.0 mg/dL. The subgroup with LDL-C levels lower than 55.0 mg/dL was further subdivided into groups with LDL-C levels from 40.1 to 55.0 mg/dL and 40.0 mg/dL or less. The association of TWA LDL-C levels with outcomes was evaluated with Cox proportional hazards models. RESULTS: Overall, 6387 patients aged 75 years or older with ASCVD were included (mean age, 79.4 years). In total, 4267 major adverse cardiovascular events, 1518 stroke events, and 515 myocardial infarction events occurred during a mean follow-up of 12.7 years. Generally, lower TWA LDL-C level was associated with a lower risk of cardiovascular events but was not associated with a higher risk of adverse events in elderly individuals with ASCVD, with the lowest cardiovascular risk observed for LDL-C levels of less than 55.0 mg/dL. After multivariable adjustment, the risk of a major adverse cardiovascular event was 1.30 (95% CI, 1.26 to 1.34; P<.001) for a per SD increment in TWA LDL-C level. Compared with TWA LDL-C levels of 40.1 to 55.0 mg/dL, TWA LDL-C levels of 40.0 mg/dL or less were associated with an increased risk of hemorrhagic stroke (hazard ratio, 3.71; 95% CI, 1.89 to 7.26). CONCLUSION: Low-density lipoprotein cholesterol levels from 40.1 to 55.0 mg/dL exhibited the maximum cardiovascular benefit in patients aged 75 years and older who had ASCVD. Lowering LDL-C levels to 40.0 mg/dL or less might increase the risk of hemorrhagic stroke.

A ribosomal gene panel predicting a novel synthetic lethality in non-BRCAness tumors.

Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most exciting classes of targeted therapy agents for cancers with homologous recombination (HR) deficiency. However, many patients without apparent HR defects also respond well to PARP inhibitors/cisplatin. The biomarker responsible for this mechanism remains unclear. Here, we identified a set of ribosomal genes that predict response to PARP inhibitors/cisplatin in HR-proficient patients. PARP inhibitor/cisplatin selectively eliminates cells with high expression of the eight genes in the identified panel via DNA damage (ATM) signaling-induced pro-apoptotic ribosomal stress, which along with ATM signaling-induced pro-survival HR repair constitutes a new model to balance the cell fate in response to DNA damage. Therefore, the combined examination of the gene panel along with HR status would allow for more precise predictions of clinical response to PARP inhibitor/cisplatin. The gene panel as an independent biomarker was validated by multiple published clinical datasets, as well as by an ovarian cancer organoids library we established. More importantly, its predictive value was further verified in a cohort of PARP inhibitor-treated ovarian cancer patients with both RNA-seq and WGS data. Furthermore, we identified several marketed drugs capable of upregulating the expression of the genes in the panel without causing HR deficiency in PARP inhibitor/cisplatin-resistant cell lines. These drugs enhance PARP inhibitor/cisplatin sensitivity in both intrinsically resistant organoids and cell lines with acquired resistance. Together, our study identifies a marker gene panel for HR-proficient patients and reveals a broader application of PARP inhibitor/cisplatin in cancer therapy.

Dosage Optimization of Digoxin in Older Patients with Heart Failure and Chronic Kidney Disease: A Population Pharmacokinetic Analysis.

BACKGROUND: Renal function is an important index for digoxin dose adjustment, especially in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is common in older patients with cardiovascular disease. OBJECTIVE: The aim of this study was to establish a digoxin population pharmacokinetic model in older patients with heart failure and CKD and to optimize the digoxin dose strategy. METHODS: Older patients with heart failure and CKD aged > 60 years from January 2020 to January 2021 and who had an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 or urine protein production were enrolled in this retrospective study. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using NONMEN software. The precision and stability of the final model were analyzed by graphical and statistical methods. RESULTS: Overall, 269 older patients with heart failure were enrolled. A total of 306 digoxin concentrations were collected, with a median value of 0.98 ng/mL (interquartile range [IQR] 0.62-1.61, range 0.04-4.24). The median age was 68 years (IQR 64-71, range 60-94) and eGFR was 53.6 mL/min/1.73 m2 (IQR 38.1-65.2, range 11.4-89.8). A one-compartment model with first-order elimination was developed to describe the digoxin pharmacokinetics. Typical values for clearance and volume of distribution were 2.67 L/h and 36.9 L, respectively. Dosage simulations were stratified by eGFR and metoprolol. Doses of 62.5 and 125 µg were recommended for older patients with eGFR < 60 mL/min/1.73 m2. CONCLUSIONS: A population pharmacokinetic model of digoxin in older patients with heart failure and CKD was established in this study. A novel digoxin dosage strategy was recommended in this vulnerable population.

Association of long-term time in target range for systolic blood pressure with cardiovascular risk in the elderly: a Chinese veteran cohort study.

AIMS: Short-term blood pressure (BP) time in target range (TTR) independently predicts cardiovascular (CV) outcomes in adults. However, there are limited data regarding long-term TTR for BP among elderly participants. We aimed to determine whether future CV risk varies for those who can maintain a long-term systolic BP (SBP) target range by assessing TTR in elderly individuals with hypertension. METHODS AND RESULTS: The Chinese veteran cohort study included 943 elderly participants with hypertension aged over 75 years. The primary outcome was the first occurrence of CV events during annual visits. Time in target range was estimated over 15 years of follow-up using linear interpolation. The target range was defined as 120-140 mmHg according to guidelines. The association between SBP TTR and CV outcomes was estimated using multivariable Cox proportional hazards models. During the 15 year follow-up, the probability of CV events gradually decreased with increasing TTR for SBP. After multivariable adjustment for traditional CV risk factors and mean BP, comparing the highest vs. lowest quartiles of TTR for SBP, the hazard ratios (HRs) [95% confidence intervals (CIs)] were 0.424 (0.289-0.624) for the primary outcome. For each 1 SD increase in TTR, the risk of the primary outcome decreased by 25.4% (HR: 0.746; 95% CI: 0.666-0.834). Consistent findings were observed in sensitivity analyses. CONCLUSION: Greater long-term TTR for SBP was associated with a decreased risk of CV events in elderly individuals independent of mean BP, suggesting that SBP TTR might serve as a modifiable risk factor for future CV health in elderly patients with hypertension. LAY SUMMARY: This ongoing Chinese veteran cohort study adds to the understanding of the relationship between higher long-term systolic blood pressure (SBP) time in target range (TTR) and cardiovascular benefits among elderly individuals with hypertension.

Higher long-term systolic blood pressure (SBP) time in target range (TTR) is associated with a significantly decreased risk of cardiovascular events independent of mean SBP, suggesting that TTR might serve as an essential measure for monitoring BP status. It might be helpful for lowering the risk of cardiovascular events when the time in SBP target range is maintained after antihypertensive therapy.

MYH10 Combines with MYH9 to Recruit USP45 by Deubiquitinating Snail and Promotes Serous Ovarian Cancer Carcinogenesis, Progression, and Cisplatin Resistance.

The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non-muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co-immunoprecipitation, GST pull-down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non-muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin-specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co-expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10-MYH9-snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention.

Reactive oxygen species-induced long intergenic noncoding RNA p21 accelerates abdominal aortic aneurysm formation by promoting secretary smooth muscle cell phenotypes.

Whether long noncoding RNAs participate in the formation of abdominal aortic aneurysms (AAAs) through the regulation of SMC phenotypic switching is unknown. lincRNA-p21 induced by reactive oxygen species (ROS) is likely functionally associated with SMC phenotypic switching. We thus investigated the role of lincRNA-p21 in SMC phenotypic switching-associated AAA formation and its underlying mechanisms. An analysis of human and mouse abdominal aortic samples revealed that the lincRNA-p21 levels were significantly higher in AAA tissue. Stimulation with hydrogen peroxide upregulated the expression of lincRNA-p21 in a dose-dependent manner and converted SMCs from a contractile phenotype to a synthetic, proteolytic, and proinflammatory phenotype in vitro. Moreover, lincRNA-p21 promoted fracture of elastic fibres, reconstruction of the vascular wall, and AAA formation in vivo by modulating SMC phenotypic switching in two mouse models of AAA induced by angiotensin II or porcine pancreatic elastase (PPE) perfusion. Using a bioinformatics prediction method and luciferase reporter gene assays, we further proved that lincRNA-p21 sponged miR-204-5p to release the transcriptional activity of Mekk3 and promoted the NF-κB pathway and thereby played a role in the SMC phenotypic switch and AAA formation. The ROS levels were positively correlated with the lincRNA-p21 levels in human and mouse AAA tissues. The knockdown of lincRNA-p21 in a PPE-induced mouse AAA model increased the miR-204-5p levels and reduced the expression of Mekk3, whereas lincRNA-p21 overexpression had the opposite effect. Collectively, the results indicated that ROS-induced lincRNA-p21 sponges miR-204-5p to accelerate synthetic and proinflammatory SMC phenotypes through the Mekk3/NF-κB pathway in AAA formation. Thus, lincRNA-p21 may have therapeutic potential for AAA formation.

Bacterial Vaginosis Decreases the Risk of Cervical Cytological Abnormalities.

Genital tract infections, including vulvovaginal candidiasis and bacterial vaginosis, have emerged as potential modulators of persistent human papillomavirus (HPV) infections causing cervical cytologic abnormalities and cervical cancer. This study aimed to investigate whether vulvovaginal candidiasis or bacterial vaginosis had an additional effect on HPV infection and thus caused such abnormalities. ThinPrep cytologic tests were used to detect cytologic abnormalities, vulvovaginal candidiasis, and bacterial vaginosis in 14,679 women. Cytologic abnormalities included atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions, atypical squamous cells-cannot exclude HSIL, and squamous cell carcinoma. Logistic regression Model 1 (univariate regression) and Model 2 (multivariate logistic regression analysis adjusted for age combined with HPV infection) were used to analyze the association between bacterial vaginosis and cytologic abnormalities, or vulvovaginal candidiasis and cytologic abnormalities, alone or in the presence of HPV infection. Bacterial vaginosis infection rates were found to be significantly higher in the cytology-negative group among all participants and those with HPV infection (P = 0.003, P < 0.001, respectively). Analyses using Model 1 and Model 2 both pointed to bacterial vaginosis as a protective factor against cytologic abnormalities for all participants (OR = 0.36, 0.17, respectively, P < 0.05) and for HPV-infected participants (OR = 0.17, 0.16, respectively, P < 0.05). Neither vulvovaginal candidiasis nor vulvovaginal candidiasis + HPV was significantly associated with the incidence of cytologic abnormalities based on Model 1 (OR = 0.94, 0.71, respectively, P > 0.05) and Model 2 (OR = 0.91, 0.74, respectively, P > 0.05). Furthermore, neither vulvovaginal candidiasis nor bacterial vaginosis increased the incidence of cytologic abnormalities regardless of HPV infection status, while bacterial vaginosis might possibly prevent cytologic abnormalities in women coinfected by HPV. PREVENTION RELEVANCE: Neither vulvovaginal candidiasis nor bacterial vaginosis was found to increase the incidence of cervical cytologic abnormalities with or without the presence of HPV. On the contrary, bacterial vaginosis may play a role in preventing cytologic abnormalities in women with HPV coinfection.

Safety and efficacy of liraglutide on reducing visceral and ectopic fat in adults with or without type 2 diabetes mellitus: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of liraglutide to reduce visceral and ectopic fat in adults with or without type 2 diabetes mellitus (T2DM). METHODS: Four databases were searched up to 6 May 2022 for randomized clinical trials assessing the effect of liraglutide on visceral and ectopic fat. The mean and standard deviation of the values of visceral fat, ectopic fat and body mass index were calculated. Subgroup analyses were performed based on the type of disease (T2DM or non-T2DM), duration of intervention, dosage of liraglutide and whether life interventions were added to liraglutide therapy. We extracted and integrated the safety assessments reported in each article. RESULTS: Sixteen randomized clinical trials with, in total, 845 participants were included in the meta-analysis. Liraglutide could significantly decrease visceral fat [standard mean difference (SMD) = -0.72, 95% confidence interval (CI; -1.12, -0.33)], liver fat [SMD = -0.78, 95% CI (-1.24, -0.32)] and body mass index [weighted mean difference = -1.44, 95% CI (-1.95, -0.92)] in adult patients with or without T2DM when compared with the control group. However, reduction of epicardial fat by liraglutide [SMD = -0.74, 95% CI (-1.82, 0.34)] was not statistically significant. Subgroup analysis revealed that an adequate dosage (≥1.8 mg/day) and appropriate duration of treatment (ranging from 16 to 40 weeks) were the decisive factors for liraglutide to reduce visceral fat effectively. Mild gastrointestinal reactions were the main adverse event of liraglutide. CONCLUSIONS: Liraglutide significantly and safely reduces visceral and ectopic liver fat irrespective of T2DM status, and reduces visceral fat provided adequate dosage and duration of therapy are ensured.

Effects of neoadjuvant hyperthermic intraperitoneal chemotherapy on chemotherapy response score and recurrence in high-grade serous ovarian cancer patients with advanced disease: A multicentre retrospective cohort study.

OBJECTIVE: To investigate whether the combination of neoadjuvant hyperthermic intraperitoneal chemotherapy (NHIPEC) plus intravenous neoadjuvant chemotherapy (IV NACT) has superior efficacy to IV NACT alone. DESIGN: Retrospective cohort study. SETTING: Two tertiary referral university hospitals. POPULATION: Patients with ovarian cancer who received NACT-interval debulking surgery (IDS) between 2012 and 2020. METHODS: The tumour response to NACT was evaluated with the chemotherapy response score (CRS) system. Survival outcomes were compared. MAIN OUTCOME MEASURES: CRS 3, progression-free survival (PFS), and overall survival (OS). RESULTS: In total, 127 patients were included, and 46 received NHIPEC plus IV NACT. The addition of NHIPEC was independently associated with an increased likelihood of CRS 3 (p = 0.033). Patients who received NHIPEC + IV NACT had significantly improved PFS compared with those who received IV NACT alone (median PFS: 22 versus 16 months, p < 0.001). The use of NHIPEC was identified as an independent predictor of PFS (p < 0.0001). OS did not differ significantly between treatment groups (p = 0.062), although a trend favouring NHIPEC was noted. Incidence of grade 3-4 adverse events and the surgical complexity score of IDS were similar between the two groups. CONCLUSIONS: Compared with IV NACT alone, the combination of NHIPEC and IV NACT resulted in improved tumour response and longer PFS. The addition of NHIPEC did not increase the risk of adverse effects or affect the complexity of IDS.

Deep learning magnetic resonance imaging predicts platinum sensitivity in patients with epithelial ovarian cancer.

Objective: The aim of the study is to develop and validate a deep learning model to predict the platinum sensitivity of patients with epithelial ovarian cancer (EOC) based on contrast-enhanced magnetic resonance imaging (MRI). Methods: In this retrospective study, 93 patients with EOC who received platinum-based chemotherapy (≥4 cycles) and debulking surgery at the Sun Yat-sen Memorial Hospital from January 2011 to January 2020 were enrolled and randomly assigned to the training and validation cohorts (2:1). Two different models were built based on either the primary tumor or whole volume of the abdomen as the volume of interest (VOI) within the same cohorts, and then a pre-trained convolutional neural network Med3D (Resnet 10 version) was transferred to automatically extract 1,024 features from two MRI sequences (CE-T1WI and T2WI) of each patient to predict platinum sensitivity. The performance of the two models was compared. Results: A total of 93 women (mean age, 50.5 years ± 10.5 [standard deviation]) were evaluated (62 in the training cohort and 31 in the validation cohort). The AUCs of the whole abdomen model were 0.97 and 0.98 for the training and validation cohorts, respectively, which was better than the primary tumor model (AUCs of 0.88 and 0.81 in the training and validation cohorts, respectively). In k-fold cross-validation and stratified analysis, the whole abdomen model maintained a stable performance, and the decision function value generated by the model was a prognostic indicator that successfully discriminates high- and low-risk recurrence patients. Conclusion: The non-manually segmented whole-abdomen deep learning model based on MRI exhibited satisfactory predictive performance for platinum sensitivity and may assist gynecologists in making optimal treatment decisions.

Genomic and expressional dynamics of ovarian cancer cell lines in PARPi treatment revealed mechanisms of acquired resistance.

BACKGROUND: Patients with epithelial ovarian cancer (EOC) can benefit from poly- (ADP ribose) polymerase inhibitors (PARPi) therapy. However, PARPi resistance has become a challenge in clinical practice, and its mechanism requires further exploration. METHODS: We established three PARPi-resistant cell strains following olaparib exposure. CCK-8, clonogenic survival, transwell, wound healing, cell cycle, RT-qPCR and western blot assays were performed to explore the functional phenotype of the resistant cells. Whole-exome sequencing and RNA-sequencing were performed to identify the altered genes. Stable knockdown and overexpression were used to investigate the role of EP300, an upstream regulator of E-cadherin and epithelial-mesenchymal transition (EMT), in cell lines. We further validated the finding in clinical ovarian cancer samples by immunohistochemistry. RESULTS: We combined public datasets to obtain an integrated PARPi sensitivity profile in EOC cells, which indicated that primary PARPi resistance could not be fully explained by mutations in BRCA1/2 or homologous recombination deficiency related genes. Genomic and transcriptome analyses revealed distinct mechanisms between primary and acquired resistance. Long-term PARPi treatment induced accumulation of de novo single nucleotide variants (SNV), and the complete frame-shift deletion of PARP1 was detected in the A2780 resistant strain. Additionally, the depressed histone acetyltransferase of EP300 could cause resistant phenotype through activated EMT process in vitro, and associated with PARPi-resistance in EOC patients. CONCLUSION: Long-term PARPi treatment led to evolutionary genomic and transcriptional alterations that were associated with acquired resistance, among which depressed EP300 partly contributed to the resistant phenotype.