Decreased NMIIA heavy chain phosphorylation at S1943 promotes mitoxantrone resistance by upregulating BCRP and N-cadherin expression in breast cancer cells.

Mitoxantrone (MX) is an effective treatment for breast cancer; however, high efflux of MX that is accomplished by breast cancer resistance protein (BCRP) leads to acquired multidrug resistance (MDR), reducing MX's therapeutic efficacy in breast cancer. Non-muscle myosin IIA (NMIIA) and its heavy phosphorylation at S1943 have been revealed to play key roles in tumor metastasis and progression, including in breast cancer; however, their molecular function in BCRP-mediated MDR in breast cancer remains unknown. In this study, we revealed that the expression of NMIIA heavy chain phosphorylation at S1943 was downregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and stable expression of NMIIA-S1943A mutant increased BCRP expression and promoted the resistance of MCF-7/MX cells to MX. Meanwhile, NMIIA S1943 phosphorylation induced by epidermal growth factor (EGF) was accompanied by the downregulation of BCRP in MCF-7/MX cells. Furthermore, stable expression of NMIIA-S1943A in MCF-7/MX cells resulted in upregulation of N-cadherin and the accumulation of ß-catenin on the cell surface, which inhibited the nucleus translocation of ß-catenin and Wnt/ß-catenin-based proliferative signaling. EGF stimulation of MCF-7/MX cells showed the downregulation of N-cadherin and ß-catenin. Our results suggest that decreased NMIIA heavy phosphorylation at S1943 increases BCRP expression and promotes MX resistance in breast cancer cells via upregulating N-cadherin expression.

Metformin Alleviates Sepsis-Associated Myocardial Injury by Enhancing AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Signaling Pathway-Mediated Autophagy.

ABSTRACT: Sepsis-associated myocardial injury is one of the main causes of death in intensive care units, and current clinical treatments have not been satisfactory. Therefore, finding an effective intervention is an urgent requirement. Metformin, an anti-type 2 diabetes drug, has been reported to be an autophagic activator agent that confers protection in some diseases. However, it is unclear whether it can provide defense against sepsis-associated myocardial injury. In this study, we investigated the cardioprotective effects of metformin pretreatment against lipopolysaccharide (LPS)-induced myocardial injury in C57BL/6J mice or H9c2 cells and the possible underlying mechanisms. Metformin was administered at a dose of 100 mg/kg for a week before LPS intraperitoneal injection. Twenty-four hours after LPS intervention, echocardiographic evaluation, reactive oxygen species measurement, Hoechst staining, western blotting, hematoxylin and eosin staining, and enzyme-linked immunosorbent assay were performed. Inhibitors of autophagy and AMP-activated protein kinase (AMPK) were used to further clarify the mechanisms involved. Metformin pretreatment effectively attenuated cardiac dysfunction, reduced the levels of myocardial enzymes, and alleviated cardiac hydroncus in LPS-treated mice. In addition, metformin restored the LPS-disrupted antioxidant defense and activated LPS-reduced autophagy by modulating the AMPK/mammalian target of rapamycin (AMPK/mTOR) pathway both in vivo and in vitro. The antioxidant effects of metformin on cardiomyocytes were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Treatment with compound C, an AMPK inhibitor, reversed the metformin-induced autophagy in LPS-treated H9c2 cells. In conclusion, metformin pretreatment alleviates LPS-induced myocardial injury by activating AMPK/mTOR pathway-mediated autophagy.

Myocardial microvascular function assessed by CMR first-pass perfusion in patients treated with chemotherapy for gynecologic malignancies.

OBJECTIVES: Cancer chemotherapy potentially increases the risk of myocardial ischemia. This study assessed myocardial microvascular function by cardiac magnetic resonance (CMR) first-pass perfusion in patients treated with chemotherapy for gynecologic malignancies. METHODS: A total of 81 patients treated with chemotherapy for gynecologic malignancies and 39 healthy volunteers were prospectively enrolled and underwent CMR imaging. Among the patients, 32 completed CMR follow-up, with a median interval of 6 months. The CMR sequences comprised cardiac cine, rest first-pass perfusion, and late gadolinium enhancement. RESULTS: There were no significant differences in the baseline characteristics between the patients and normal controls (all p > 0.05). Compared with the normal controls, the patients had a lower myocardial perfusion index (PI) (13.62 ± 2.01% vs. 12% (11 to 14%), p = 0.001) but demonstrated no significant variation with an increase in the number of chemotherapy cycles at follow-up (11.79 ± 2.36% vs. 11.19 ± 2.19%, p = 0.234). In multivariate analysis with adjustments for clinical confounders, a decrease in the PI was independently associated with chemotherapy treatment (ß = - 0.362, p = 0.002) but had no correlation with the number of chemotherapy cycles (r = - 0.177, p = 0.053). CONCLUSION: Myocardial microvascular dysfunction was associated with chemotherapy treatment in patients with gynecologic malignancies, and can be assessed and monitored by rest CMR first-pass perfusion. KEY POINTS: • Chemotherapy was associated with but did not aggravate myocardial microvascular dysfunction in patients with gynecologic malignancies. • Rest CMR first-pass perfusion is an ideal modality for assessing and monitoring alterations in myocardial microcirculation during chemotherapy treatment.

The influence of different proton pump inhibitors and potassium-competitive acid blockers on indomethacin-induced small intestinal injury.

BACKGROUND AND AIM: The influence of gastric acid inhibitors (GAIs) on nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy is controversial. Herein, the influences of different GAIs on NSAID-induced intestinal injury and the underlying mechanisms are clarified. METHODS: Indomethacin (IND; 10 mg/kg/day) was administered to mice to induce small intestinal injury. Disease activity was examined macroscopically and histologically. The permeability of small intestine was evaluated by measuring plasma lipopolysaccharide levels. 16S rDNA sequencing was performed to determine the composition of intestinal flora. RESULTS: Among the four GAIs, ilaprazole (IPZ) significantly attenuated IND-induced small intestinal injury and maintained the integrity of the mucosal barrier. Omeprazole (OPZ) and vonoprazan (VPZ) ameliorated ulceration without significant differences, while rabeprazole (RPZ) failed to protect against the injury. To explore the potential mechanism, we investigated changes in the gut microbiota mediated by GAIs. After 5-day administration, GAIs significantly altered the composition of the gut microbiota. The IND group had a significant decrease in alpha diversity compared with the control group, and this decrease was reversed by OPZ and IPZ treatment, respectively. After IPZ treatment, the community membership was more assembled in the control group than the IND group. Further, we found that Lactobacillus was significantly increased in the groups of OPZ, IPZ, and VPZ, while Bacteroides was significantly increased in the RPZ group. CONCLUSION: Our results indicated that GAIs have different influences on the mucosal barrier, possibly by altering the composition of intestinal microbiota, and the impacts mediated by various GAIs in the IND-induced intestinal damage model seem different.

Wnt/ß-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging.

Cadmium (Cd) is a toxic heavy metal and worldwide environmental pollutant which seriously threatens human health and ecosystems. It is easy to be adsorbed and deposited in organisms, exerting adverse effects on various organs including the brain. In a very recent study, making full use of a zebrafish model in both high-throughput behavioral tracking and live neuroimaging, we explored the potential developmental neurotoxicity of Cd2+ at environmentally relevant levels and identified multiple connections between Cd2+ exposure and neurodevelopmental disorders as well as microglia-mediated neuroinflammation, whereas the underlying neurotoxic mechanisms remained unclear. The canonical Wnt/ß-catenin signaling pathway plays crucial roles in many biological processes including neurodevelopment, cell survival, and cell cycle regulation, as well as microglial activation, thereby potentially presenting one of the key targets of Cd2+ neurotoxicity. Therefore, in this follow-up study, we investigated the implication of the Wnt/ß-catenin signaling pathway in Cd2+-induced developmental disorders and neuroinflammation and revealed that environmental Cd2+ exposure significantly affected the expression of key factors in the zebrafish Wnt/ß-catenin signaling pathway. In addition, pharmacological intervention of this pathway via TWS119, which can increase the protein level of ß-catenin and act as a classical activator of the Wnt signaling pathway, could significantly repress the Cd2+-induced cell cycle arrest and apoptosis, thereby attenuating the inhibitory effects of Cd2+ on the early development, behavior, and activity, as well as neurodevelopment of zebrafish larvae to a certain degree. Furthermore, activation and proliferation of microglia, as well as the altered expression profiles of genes associated with neuroimmune homeostasis triggered by Cd2+ exposure could also be significantly alleviated by the activation of the Wnt/ß-catenin signaling pathway. Thus, this study provided novel insights into the cellular and molecular mechanisms of Cd2+ toxicity on the vertebrate central nervous system (CNS), which might be helpful in developing pharmacotherapies to mitigate the neurological disorders resulting from exposure to Cd2+ and many other environmental heavy metals.

The effect of consolidation chemotherapy after concurrent chemoradiation on the prognosis of locally advanced cervical cancer: a systematic review and meta-analysis.

To verify the role of consolidation chemotherapy after concurrent chemoradiotherapy for bulky and locally advanced cervical cancer, a meta-analysis was performed. Based on articles published up to Jun 2020 a literature search in PubMed, EMBASE and Cochrane Library was conducted to identify eligible studies. A total of 4 articles consisting of 1659 patients were enrolled. The pooled results revealed that overall survival (OS) of patients treated with consolidation chemotherapy after concurrent chemoradiotherapy (CCRT + CT) was significantly superior to concurrent chemoradiotherapy (CCRT) alone (HR = 0.78, 95% CI: 0.69-0.88, p < .0001). The meta-analysis reviewed that the progression-free survival rate (PFS) of patients treated with CCRT + CT was significantly superior to CCRT alone (HR = 0.80, 95% CI: 0.73-0.87, p < .00001). The pooled results revealed a significant reduction of local recurrence rate for the CCRT + CT group (RR = 0.66, 95% CI: 0.55-0.79, p < .00001). The pooled meta-analysis also showed a significant reduction of distant recurrence rate for the CCRT + CT group (RR = 0.55, 95% CI: 0.44-0.69, p < .00001). The pooled results of grade 3/4 bone marrow suppression were calculated as OR and presented with a 95% CI (OR = 15.85; 95% CI: 9.48, 26.5, p < .00001), indicating patients who received CCRT + CT are more likely to suffer 3/4 bone marrow suppression than those treated with CCRT alone. In conclusion, patients who received chemoradiation with consolidation chemotherapy showed a significantly longer PFS, longer OS, lower local recurrence rate and distant recurrence rate compared to traditional concurrent chemoradiotherapy.Impact statementWhat is already known on this subject? Since CCRT was recommended as the standard treatment for cervical cancer, there was still a 20-30% chance of local recurrence, and 18-25% of distant recurrence for cervical cancer patients. Aiming to completely eradicate potential undetected micrometastases, consolidation chemotherapy came into the area of interest. We conducted a meta-analysis to verify the role of consolidation chemotherapy in cervical cancer.What do the results of this study add? The addition of consolidation CT resulted in a longer overall survival rate (OS) and progression-free survival rate (PFS), mainly due to control of local and distant relapses, especially the latter one. Toxicity followed consolidation CT increased but still clinically manageable.What are the implications of these findings for clinical practice and/or further research? In the future, we need more clinical studies with high quality to verify the role of consolidation CT in cervical cancer, and further to optimise the criteria for it.

The distribution and prevalence of human papillomavirus in women in mainland China.

We conducted a systematic review of the epidemiology of high-risk human papillomavirus (HPV) infections in mainland Chinese women to provide a general profile for the application and subsequent effectiveness evaluation of HPV vaccines. The PubMed, Web of Science, Medline (Ovid), China National Knowledge Infrastructure, and Wanfang databases were used for the literature search. The epidemiological studies published from January 2000 to June 2018 on high-risk HPVs in mainland Chinese women were investigated to systematically evaluate their epidemiological status. A total of 198 eligible studies were included. The results of meta-analysis showed that the overall infection rate of high-risk HPVs in mainland Chinese women was 19.0% (95% confidence interval [CI], 17.1%-20.9%), and the top 5 subtypes with the highest infection rates were 16, 52, 58, 53, and 18. The overall infection rates of cervical intraepithelial neoplasia I (CINI), CINII+, and cervical cancer patients were 59.6% (95% CI, 52.7%-66.4%), 84.8% (95% CI, 81.2%-88.5%), and 89.9% (95% CI, 86.6%-93.1%), respectively. The high-risk HPV infections and common subtypes in women of various ages in various regions were different, and the high-risk HPVs and subtypes in cervical cancer patients in various regions were also different. In conclusion, we systematically analyzed the HPV infections in women who live on the Chinese mainland. The epidemiology of high-risk HPVs in mainland Chinese women is basically consistent with that for the rest of the world. The HPV vaccines currently licensed in China could cover the major prevalent high-risk HPV subtypes in China, providing a basis for the development of a cervical cancer screening strategy and vaccine implementation in China.

Dephasing-Insensitive Quantum Information Storage and Processing with Superconducting Qubits.

A central task towards building a practical quantum computer is to protect individual qubits from decoherence while retaining the ability to perform high-fidelity entangling gates involving arbitrary two qubits. Here we propose and demonstrate a dephasing-insensitive procedure for storing and processing quantum information in an all-to-all connected superconducting circuit involving multiple frequency-tunable qubits, each of which can be controllably coupled to any other through a central bus resonator. Although it is generally believed that the extra frequency tunability enhances the control freedom but induces more dephasing impact for superconducting qubits, our results show that any individual qubit can be dynamically decoupled from dephasing noise by applying a weak continuous and resonant driving field whose phase is reversed in the middle of the pulse. More importantly, we demonstrate a new method for realizing a two-qubit phase gate with inherent dynamical decoupling via the combination of continuous driving and qubit-qubit swapping coupling. We find that the weak continuous driving fields not only enable the conditional dynamics essential for quantum information processing, but also protect both qubits from dephasing during the gate operation.

Antiviral Merosesquiterpenoids Produced by the Antarctic Fungus Aspergillus ochraceopetaliformis SCSIO 05702.

Five new highly oxygenated α-pyrone merosesquiterpenoids, ochraceopones A-E (1-5), together with one new double bond isomer of asteltoxin, isoasteltoxin (6), and two known asteltoxin derivatives, asteltoxin (7) and asteltoxin B (8), were isolated from an Antarctic soil-derived fungus, Aspergillus ochraceopetaliformis SCSIO 05702. Their structures were determined through extensive spectroscopic analysis, CD spectra, quantum mechanical calculations, and X-ray single-crystal diffraction. Ochraceopones A-D (1-4) are the first examples of α-pyrone merosesquiterpenoids possessing a linear tetracyclic carbon skeleton, which has not been previously described. All the isolated compounds were tested for their antiviral, cytotoxic, antibacterial, and antitubercular activities. Among these compounds, ochraceopone A (1), isoasteltoxin (6), and asteltoxin (7) exhibited antiviral activities against the H1N1 and H3N2 influenza viruses with IC50 values of >20.0/12.2 ± 4.10, 0.23 ± 0.05/0.66 ± 0.09, and 0.54 ± 0.06/0.84 ± 0.02 µM, respectively. A possible biosynthetic pathway for ochraceopones A-E (1-5) was proposed.

Platinum desensitization therapy and its impact on the prognosis of ovary high-grade serous adenocarcinoma: a real world-data.

Background: To examine the value of five-step platinum desensitization therapy in epithelial ovarian cancer. Methods: A retrospective study was conducted on the high-grade serous adenocarcinoma of the ovary (HGSAO) patients who developed a platinum allergy during treatment and received desensitization therapy between January, 2016 and December, 2020. The logistic-regression was adopted to analyze the relationship between platinum desensitization therapy and prognosis in HGSAO patients. Results: 92 HGSAO patients were included in the study. Among these, 35 patients (38.0%) experienced mild allergic reactions, 51 (55.4%) experienced moderate allergic reactions, and 6 (6.5%) experienced severe allergic reactions. The desensitization therapy was successful in 86 patients (93.5%). Six patients had desensitization failure, of which five experienced severe allergic reactions during desensitization. The logistic-regression analysis revealed no significant correlation between platinum desensitization therapy and progression-free survival (PFS) or overall survival (OS) of patients (P < 0.05). However, the subgroup analysis demonstrated that the success or failure of platinum desensitization therapy significantly impacted the OS of patients who were platinum-sensitive recurrence. The patients who had successful desensitization therapy had a superior OS. Conclusion: Five-step platinum desensitization therapy has potential application value in patients who were platinum-sensitive recurrence after first-line treatment but may bear the risk of severe allergic reactions.

Advances and challenges in the origin and evolution of ovarian cancer organoids.

Despite advancements in cancer research, epithelial ovarian cancer remains a leading threat to women's health with a low five-year survival rate of 48%. Prognosis for advanced cases, especially International Federation of Gynecology and Obstetrics (FIGO) III-IV, is poor. Standard care includes surgical resection and platinum-based chemo, but 70-80% face recurrence and chemoresistance. In recent years, three- dimensional (3D) cancer models, especially patients-derived organoids (PDOs), have revolutionized cancer research for personalized treatment. By transcending the constraints of conventional models, organoids accurately recapitulate crucial morphological, histological, and genetic characteristics of diseases, particularly in the context of ovarian cancer. The extensive potential of ovarian cancer organoids is explored, spanning from foundational theories to cutting-edge applications. As potent preclinical models, organoids offer invaluable tools for predicting patient treatment responses and guiding the development of personalized therapeutic strategies. Furthermore, in the arena of drug evaluation, organoids demonstrate their unique versatility as platforms, enabling comprehensive testing of innovative drug combinations and novel candidates, thereby pioneering new avenues in pharmaceutical research. Notably, organoids mimic the dynamic progression of ovarian cancer, from inception to systemic dissemination, shedding light on intricate and subtle disease mechanisms, and providing crucial insights. Operating at an individualized level, organoids also unravel the complex mechanisms underlying drug resistance, presenting strategic opportunities for the development of effective treatment strategies. This review summarizes the emerging role of ovarian cancer organoids, meticulously cultivated cellular clusters within three-dimensional models, as a groundbreaking paradigm in research.

The role of B7-H4 in ovarian cancer immunotherapy: current status, challenges, and perspectives.

Immunotherapy stands as a critical and auspicious therapeutic approach in the fight against cancer nowadays. Immune checkpoint inhibitors, in particular, have garnered widespread employment and delivered groundbreaking therapeutic outcomes across various malignancies. However, the efficacy is unsatisfactory in the ovarian cancer. The pressing concerns of the substantial non-response rate require immediate attention. The pursuit of novel targets and the formulation of synergistic combination therapy approaches are imperative for addressing this challenge. B7-H4, a member of the B7 family of co-inhibitory molecules, exhibits high expression levels in ovarian cancer, correlating closely with tumor progression, drug resistance, and unfavorable prognosis. B7-H4 has the potential to serve as a valuable biomarker for evaluating the immune response of patients. Recent investigations and preclinical trials focusing on B7-H4 in the context of ovarian cancer immunotherapy highlight its emergence as a promising immunotherapeutic target. This review aims to discuss these findings and anticipate the future prospects of leveraging B7-H4 in ovarian cancer immunotherapy and targeted therapy.

Clinical and pathological characteristics of cervical clear cell carcinoma in patients not exposed to diethylstilbestrol: a comprehensive analysis of 49 cases.

Purpose: This study aimed to investigate the clinical and pathological characteristics, treatment strategies, and prognosis of cervical clear cell carcinoma (CCCC) in patients not exposed to diethylstilbestrol in utero. Methods: The patients diagnosed with CCCC at West China Second University Hospital of Sichuan University between January 2011 and Jun 2023 were enrolled for this retrospective study. The clinical characteristics and information on treatment and follow-up were collected. The Kaplan-Meier method and Cox regression analysis were performed to identify the relative variables for predicting progression-free survival (PFS) and overall survival (OS). Results: Of the 49 patients included, the Federation International of Gynecology and Obstetrics (FIGO) (2018) stage distribution was 37 (75.5%) stage I, 6 (12.2%) stage II, and 6 (12.2%) stage III. The median follow-up interval was 24.1 months. Six (12.2%) patients had a recurrence, and five (10.2%) patients died. The 5-year PFS rate was 86.8%, and the 5-year OS rate was 88.2%. No recurrence or death was detected in two patients who successfully completed fertility-preserving treatment and seven patients who underwent surgery to preserve ovaries. Two patients became pregnant, giving birth to two babies. The univariate analysis showed that FIGO stage, Pelvic lymph node (PLN) metastasis, lymph vascular space invasion, and depth of stromal invasion (P < 0.05) were significantly associated with PFS and OS. However, no significant prognostic factors were identified in the multivariate analysis. Conclusion: Ovary-preserving treatment and fertility-preserving surgery are safe and feasible in early-stage CCCC. Surveillance other than adjuvant treatment may be a better choice for early-stage CCCC without any pathological risk factors. More targeted therapies and immunotherapy should be pursued in future studies.

Intestinal Akkermansia muciniphila is Beneficial to Functional Recovery Following Ischemic Stroke.

Recent studies have demonstrated the interaction between gut microbiota and brain on ischemic stroke, but the roles of gut microbiota in the pathophysiology of ischemic stroke remain largely unclear. In this study, we detected a significant increase of intestinal Akkermansia muciniphila (AKK) following ischemic stroke by a rose bengal photothrombosis model. To investigate the function and mechanism of AKK on ischemic stroke, we performed the AKK administration prior to stroke surgery. The results showed that mice treated with AKK gained significantly higher body weight and behaved better than those in PBS group at 3 days after ischemic stroke. Consistently, AKK administration remarkably decreased the infarct volumes as well as the density of degenerating neurons and apoptotic cells after ischemic stroke. Notably, AKK is a potential therapeutic target in immune-related disorders connected to the microbiota, and inflammation is crucially involved in the pathophysiological process of ischemic stroke. For the determination of underlying mechanisms of this protective effect, we investigated whether there are associations between AKK and neuroinflammation following ischemic stroke. The results suggested that AKK administration significantly reduced the activation of astrocytes and microglia but up-regulated multiple anti-inflammatory factors following ischemic stroke. Therefore, our study highlighted the beneficial roles of intestinal AKK on ischemic stroke and provided a new perspective for the treatment of ischemic stroke.

Multisample lipidomic profiles of irritable bowel syndrome and irritable bowel syndrome-like symptoms in patients with inflammatory bowel disease: new insight into the recognition of the same symptoms in different diseases.

BACKGROUND: Overlapping clinical manifestations of irritable bowel syndrome (IBS) and IBS-like symptoms in patients with inflammatory bowel disease (IBD-IBS) present challenges in diagnosis and management. Both conditions are associated with alterations in metabolites, but few studies have described the lipid profiles. Our aim was to pinpoint specific lipids that contribute to the pathogenesis of IBS and IBD-IBS by analyzing multiple biologic samples. METHODS: Diarrhea-predominant IBS (IBS-D) patients (n = 39), ulcerative colitis in remission with IBS-like symptoms patients (UCR-IBS) (n = 21), and healthy volunteers (n = 35) were recruited. IBS-D patients meet the Rome IV diagnostic criteria, and UCR-IBS patients matched mayo scores ≤ two points and Rome IV diagnostic criteria. Serum, feces, and mucosa were collected for further analysis. Lipid extraction was carried out by ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). RESULTS: Lipidomics of mucosa and serum samples significantly differed among the three groups. Feces showed the most altered lipid species, and the enrichment analysis of 347 differentially abundant metabolites via KEGG pathway analysis revealed that alpha-linolenic acid metabolism was significantly altered in the two groups (P < 0.01). The ratio of omega-6/omega-3 fatty acid were imbalance in serum samples. CONCLUSIONS: This study revealed a comprehensive lipid composition pattern between IBS-D patients and UCR-IBS patients. We found several distinctive lipids involved in alpha-linolenic acid metabolism, reflecting an imbalance in the omega-6/omega-3 fatty acid ratio. Compared to mucosa and serum samples, fecal samples might have more advantages in lipidomics studies due to the convenience of sample collection and effectiveness in reflecting metabolic information.

PARP inhibitor maintenance treatment for newly diagnosed ovarian cancer patients: a real-world study from China.

Purpose: This study evaluated the efficacy and safety in a real-world population of epithelial ovarian cancer (EOC) treated with poly (ADP-ribose) polymerase inhibitor (PARPi) as first-line maintenance therapy in the largest gynecologic oncology center in Western China. Methods: This study included patients newly diagnosed EOC who received PARPi as first-line maintenance therapy in West China Second University Hospital from August 1, 2018 to September 31, 2022. The primary endpoints were progression-free survival (PFS) and safety evaluated by Common Terminology Criteria for Adverse Events Version 5.0(CTCAE 5.0). The secondary endpoints were overall survival (OS) and prognostic factors influencing the PFS of patients in real world. Results: Among the eligible 164 patients, 104 patients received olaparib and 60 patients received niraparib. 100 patients (61.0%) had mutations in breast cancer susceptibility gene (BRCA). 87 patients (53.0%) received primary debulking surgery (PDS) while 77 patients (47.0%) received interval debulking surgery (IDS). 94 patients (94/164, 57.3%) achieved R0 and 39 patients (23.8%) achieved R1 after PDS/IDS. 112 (68.3%) achieved complete response (CR) after first-line chemotherapy, while 49 (29.9%) achieved partial response (PR). The median follow-up time was 17.0 months (95% CI 15.6-18.4), and the median PFS has not been reached yet. Multivariate analysis demonstrated that BRCA mutations and CR/PR after platinum-based chemotherapy were independent factors associated with prolonged PFS. Hematologic toxicity was the most common grade≥3 AE. There were no incidence of myelodysplastic syndromes/acute myelogenous leukemia (MDS/AML). Conclusion: Focusing on PARPi as first-line maintenance therapy for patients with EOC, this study represented the largest single-center real-world study in China to date. Two independent factors were identified to prolong the PFS of patients: BRCA mutated type and CR/PR after primary treatment, which should be further confirmed with long-term follow-up and large sample sizes.

Oseltamivir phosphate (Tamiflu) alters neurobehavior of zebrafish larvae by inducing mitochondrial dysfunction.

Antiviral drugs are widely used, yet their potential risks during early development, particularly within the central nervous system, remain contentious. Oseltamivir phosphate (OSE), a commonly prescribed antiviral, is increasingly detected in various environments. However, its toxicity to organisms and the underlying mechanisms are not well understood. In this study, we employed the zebrafish model to evaluate the developmental neurotoxic effects of OSE at environmentally and therapeutically relevant doses, through high-throughput behavioral analysis, in vivo two-photon imaging, transcriptomic sequencing, pharmacological intervention, and biochemical and molecular assays. Our results indicated that OSE exposure increased heart rate and induced pericardial edema in zebrafish larvae. Additionally, OSE-exposed larvae exhibited hyperactive behavior, impaired social interactions, and reduced habitual learning capacity. Although OSE at our selected levels did not significantly affect neuron count in the brain, it activated neuroinflammatory responses, altered blood vessel morphology, modulated neurotransmitter levels and the expression of neurodevelopment-related genes. Transcriptomic analysis revealed upregulation of mitochondria-related genes associated with oxidative phosphorylation. Further assessments of mitochondrial function demonstrated altered activities of respiratory chain complexes, reduced mitochondrial membrane potential (MMP), and decreased ATP content. Notably, co-treatment with mitochondrial protectants acetyl-l-carnitine-hydrochloride (ALC) or nicotinamide riboside (NR) effectively mitigated OSE-induced neurobehavioral disorders. These findings suggest that overuse of OSE can pose neurodevelopmental risks for both humans and animals, potentially attributable to mitochondrial dysfunction.

Effects of bone marrow sparing radiotherapy on acute hematologic toxicity for patients with locoregionally advanced cervical cancer: a prospective phase II randomized controlled study.

OBJECTIVE: To evaluate effects of bone marrow sparing (BMS) radiotherapy on decreasing the incidence of acute hematologic toxicity (HT) for locoregionally advanced cervical cancer (LACC) patients treated by pelvic irradiation. MATERIALS AND METHODS: LACC patients were recruited prospectively from May 2021 to May 2022 at a single center and were evenly randomized into the BMS group and the control group. All patients received pelvic irradiation with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy and BM V40 < 25% in the BMS group was additionally prescribed. Acute HT was assessed weekly. Binary logistic regression model and receiver operating characteristic (ROC) curve were used for predictive value analysis. The trial was registered with Chinese clinical trial registry (ChiCTR2200066485). RESULTS: A total of 242 patients were included in the analysis. Baseline demographic, disease and treatment characteristics were balanced between the two groups. In the intention-to-treat population, BMS was associated with a lower incidence of grade ≥ 2 and grade ≥ 3 acute HT, leukopenia and neutropenia s(72.70% v 90.90%, P < 0.001*; 16.50% vs. 65.30%, P < 0.001*; 66.10% vs. 85.10%, P = 0.001*; 13.20% vs. 54.50%, P < 0.001*; 37.20% vs. 66.10%, P < 0.001*; 10.70% vs. 43.80%, P < 0.001*). BMS also resulted in decreased dose delivered to the organs at risk (OARs) including rectum, bladder and left and right femoral head. Univariate and multivariate analyses showed that BM V40 was an independent risk factor for grade ≥ 3 acute HT (odds ratio [OR] = 2.734, 95% confidence interval [CI] = 1.959-3.815, P < 0.001*). Cutoff value was 25.036% and area under the curve (AUC) was 0.786. The nomogram was constructed, which was rigorously evaluated and internally cross-validated, showing good predictive performance. CONCLUSIONS: Receiving BMS pelvic irradiation could reduce the incidence of acute HT in LACC patients, and BM V40 < 25% may be a significant factor in reducing the risks of acute HT.

Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China.

DNA damage response (DDR) pathways are responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cellular genome, including homologous recombination repair (HRR) pathway, mismatch repair (MMR) pathway, etc. In ovarian cancer, current studies are focused on HRR genes, especially BRCA1/2, and the results show regional and population differences. To characterize germline mutations in DDR genes in ovarian cancer in Southwest China, 432 unselected ovarian cancer patients underwent multi-gene panel testing from October 2016 to October 2020. Overall, deleterious germline mutations in DDR genes were detected in 346 patients (80.1%), and in BRCA1/2 were detected in 126 patients (29.2%). The prevalence of deleterious germline mutations in BRCA2 is higher than in other studies (patients are mainly from Eastern China), and so is the mismatch repair genes. We identified three novel BRCA1/2 mutations, two of which probably deleterious (BRCA1 p.K1622* and BRCA2 p.L2987P). Furthermore, we pointed out that deleterious mutations of FNACD2 and RECQL4 are potential ovarian cancer susceptibility genes and may predispose carriers to ovarian cancer. In conclusion, our study highlights the necessity of comprehensive germline mutation detection of DNA damage response genes in ovarian cancer patients, which is conducive to patient management and genetic counseling.

Clinical manifestation, lifestyle, and treatment patterns of chronic erosive gastritis: A multicenter real-world study in China.

BACKGROUND: Although chronic erosive gastritis (CEG) is common, its clinical characteristics have not been fully elucidated. The lack of consensus regarding its treatment has resulted in varied treatment regimens. AIM: To explore the clinical characteristics, treatment patterns, and short-term outcomes in CEG patients in China. METHODS: We recruited patients with chronic non-atrophic or mild-to-moderate atrophic gastritis with erosion based on endoscopy and pathology. Patients and treating physicians completed a questionnaire regarding history, endoscopic findings, and treatment plans as well as a follow-up questionnaire to investigate changes in symptoms after 4 wk of treatment. RESULTS: Three thousand five hundred sixty-three patients from 42 centers across 24 cities in China were included. Epigastric pain (68.0%), abdominal distension (62.6%), and postprandial fullness (47.5%) were the most common presenting symptoms. Gastritis was classified as chronic non-atrophic in 69.9% of patients. Among those with erosive lesions, 72.1% of patients had lesions in the antrum, 51.0% had multiple lesions, and 67.3% had superficial flat lesions. In patients with epigastric pain, the combination of a mucosal protective agent (MPA) and proton pump inhibitor was more effective. For those with postprandial fullness, acid regurgitation, early satiety, or nausea, a MPA appeared more promising. CONCLUSION: CEG is a multifactorial disease which is common in Asian patients and has non-specific symptoms. Gastroscopy may play a major role in its detection and diagnosis. Treatment should be individualized based on symptom profile.