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.

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.

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.

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.

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.

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.

Chemotherapy effect on myocardial fibrosis markers in patients with gynecologic cancer and low cardiovascular risk.

Background: Patients with gynecologic cancers experience side effects of chemotherapy cardiotoxicity. We aimed to quantify cardiac magnetic resonance (CMR) markers of myocardial fibrosis in patients with gynecologic cancer and low cardiovascular risk who undergo chemotherapy. Methods: This study is part of a registered clinical research. CMR T1 mapping was performed in patients with gynecologic cancer and low cardiovascular risk undergoing chemotherapy. The results were compared with those of age-matched healthy control subjects. Results: 68 patients (median age = 50 years) and 30 control subjects were included. The median number of chemotherapy cycles of patients was 9.0 (interquartile range [IQR] 3.3-17.0). Extracellular volume fraction (ECV) (27.2% ± 2.7% vs. 24.5% ± 1.7%, P < 0.001) and global longitudinal strain (-16.2% ± 2.8% vs. -17.4% ± 2.0%, P = 0.040) were higher in patients compared with controls. Patients with higher chemotherapy cycles (>6 cycles) (n=41) had significantly lower intracellular mass indexed (ICMi) compared with both patients with lower chemotherapy cycles (≤6 cycles) (n=27) (median 27.44 g/m2 [IQR 24.03-31.15 g/m2] vs. median 34.30 g/m2 [IQR 29.93-39.79 g/m2]; P = 0.002) and the control group (median 27.44 g/m2 [IQR 24.03-31.15 g/m2] vs. median 32.79 g/m2 [IQR 27.74-35.76 g/m2]; P = 0.002). Patients with two or more chemotherapy regimens had significantly lower ICMi compared with both patients with one chemotherapy regimen (27.45 ± 5.16 g/m2 vs. 33.32 ± 6.42 g/m2; P < 0.001) and the control group (27.45 ± 5.16 g/m2 vs. 33.02 ± 5.52 g/m2; P < 0.001). The number of chemotherapy cycles was associated with an increase in the ECV (Standard regression coefficient [ß] = 0.383, P = 0.014) and a decrease in the ICMi (ß = -0.349, P = 0.009). Conclusion: Patients with gynecologic cancer and low cardiovascular risk who undergo chemotherapy have diffuse extracellular volume expansion, which is obvious with the increase of chemotherapy cycles. Myocyte loss may be part of the mechanism in patients with a higher chemotherapy load. Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR-DDD-17013450.

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.

Opportunistic cervical cancer screening for elderly women without standardized screening.

Objective: This study aimed to investigate the importance of opportunistic cervical cancer screening for elderly women without standardized screening and also investigate the best opportunistic screening strategy. Methods: The participants were high-risk human papillomavirus (HPV)-positive elderly women, aged more than 65 years, who did not undergo standardized cervical cancer screening from June 2017 to June 2021. They had undergone an opportunistic cervical cancer screening. High-risk HPV distribution and the accuracy of different screening methods (only cytology, only HPV, HPV + cytology triage, and non-HPV 16/18 + cytology triage or HPV 16/18) for CINII + were analyzed. Results: A total of 848 elderly women with high-risk HPV infection were included, with 325 (38.3%) CINII + patients and 145 (17.1%) patients with invasive cancer. The top five HPV subtypes were HPV16, HPV52, HPV58, HPV53, and HPV56, and the infection rate was 31.4%, 21.9%, 19.7%, 11.6%, and 11.6%, respectively. The area under the receiver operating characteristic curve of the five screening strategies was 0.715 (0.681-0.750) (ASCUS+), 0.498 (0.458-0.538), 0.623 (0.584-0.663), 0.714 (0.680-0.748) (ASCUS+), and 0.698 (0.664-0.733) (ASCUS+). Conclusion: Elderly women who have not undergone standardized cervical cancer screening should be given a chance to be screened for cervical cancer; the standardized screening program is suitable for elderly women.

PHANTOM AND CLINICAL STUDIES ON LOW-DOSE CT PROTOCOL FOR APPLICATOR RECONSTRUCTION IN THREE-DIMENSIONAL BRACHYTHERAPY USING SIZE-SPECIFIC DOSE ESTIMATES BASED ON WATER EQUIVALENT DIAMETER.

To verify the feasibility of low-dose computed tomography (CT) protocol for applicator reconstruction in three-dimensional brachytherapy among patients of different sizes, using size-specific dose estimate based on water equivalent diameter (SSDEdw) in phantom and clinical studies. Pre-scans of a female pelvic phantom were followed by reconstruction of each image set with iDose4 levels 3-5. Imaging data from 64 cervical cancer patients were divided into low, standard and high weight groups. Among two to five CT scans required for applicator reconstruction, the first scan was adopted by routine-dose CT protocol (tube voltage = 120 kV, tube current-exposure time product = 320 mA.s) and the remaining by low-dose CT protocol (tube voltage = 120 kV, tube current-exposure time product = 80 mA.s). The SSDEdw and image quality parameters were compared among the groups, and correlations between SSDEdw and body mass index, area of reference plane (AreaROI3) and mean CT value of reference plane (CTROI3) were analyzed. According to the phantom test results, we determined tube voltage to 120 kV and tube current-exposure time product to 80 mA.s as the low-dose protocol. Clinical study revealed no statistically significant differences in signal-to-noise ratio (SNR) and contrast-noise-ratio (CNR) between low-dose and routine-dose CT in Groups A and B; in Group C, these were significantly lower in the former. The SSDEdw was significantly lower under low-dose than routine-dose protocol in all groups, with strong negative correlation with BMI and AreaROI3 in Groups A and B and moderate-to-strong negative correlation in Group C. Because of the characteristics of three-dimensional brachytherapy, in patients with BMI < 24.0 kg per m2, low-dose CT protocol can minimize radiation exposure and achieve precise, individualized treatment.

Ferroptosis contributes to nickel-induced developmental neurotoxicity in zebrafish.

Nickel (Ni) is a widely utilized heavy metal that can cause environmental pollution and health hazards. Its safety has attracted the attention of both the environmental ecology and public health fields. While the central nervous system (CNS) is one of the main targets of Ni, its neurotoxicity and the underlying mechanisms remain unclear. Here, by taking advantage of the zebrafish model for live imaging, genetic analysis and neurobehavioral studies, we reveal that the neurotoxic effects induced by exposure to environmentally relevant levels of Ni are closely related to ferroptosis, a newly-described form of iron-mediated cell death. In vivo two-photon imaging, neurobehavioral analysis and transcriptome sequencing consistently demonstrate that early neurodevelopment, neuroimmune function and vasculogenesis in zebrafish larvae are significantly affected by environmental Ni exposure. Importantly, exposure to various concentrations of Ni activates the ferroptosis pathway, as demonstrated by physiological/biochemical tests, as well as the expression of ferroptosis markers. Furthermore, pharmacological intervention of ferroptosis via deferoxamine (DFO), a classical iron chelating agent, strongly implicates iron dyshomeostasis and ferroptosis in these Ni-induced neurotoxic effects. Thus, this study elucidates the cellular and molecular mechanisms underlying Ni neurotoxicity, with implications for our understanding of the physiologically damaging effects of other environmental heavy metal pollutants.

A real-world study of PARP inhibitors in 75 patients with platinum-sensitive recurrent ovarian cancer from China.

Objective: The aim of this study is to assess the efficacy and safety of poly (ADP-ribose) polymerase inhibitor (PARPi) as a maintenance therapy for patients with platinum-sensitive recurrent epithelial ovarian cancer (PSROC) at the largest center of gynecologic oncology in Western China. Patients and methods: The efficacy of PARPi was evaluated by progression-free survival (PFS) and overall survival (OS) in this real-world single-center retrospective cohort study conducted at West China Second University Hospital. The safety of PARPi was assessed using Common Terminology Criteria for Adverse Events Version 5.0. Results: In this study, we included a total of 75 eligible patients, of which 54 (72.0%) received olaparib and 21 (28.0%) received niraparib. Among these patients, 24 (32.0%) had breast cancer susceptibility gene (BRCA) mutations, 27 (36.0%) achieved complete response after their last platinum-based therapy, and 22 (29.3%) had previously received ≥3rd-line chemotherapy. The median progression-free survival (mPFS) was 19.1 months (95% CI 8.5-29.7), and the median overall survival (mOS) had not been reached. Log-rank analysis revealed that age (<65 years old V.S. ≥65 years old) and previous lines of chemotherapy (2nd-line V.S. 3rd-line V.S. ≥4th-line) were associated with prolonged PFS (P <0.05). However, multivariate COX regression analysis did not identify any independent factors associated with prognosis (P >0.05). The most common grade≥3 adverse events in the olaparib group were anemia, thrombocytopenia, and leukopenia, while in the niraparib group, they were anemia and thrombocytopenia. Conclusion: This study confirmed that olaparib and niraparib are effective and tolerate for PSROC in real-world settings. At the follow-up endpoint, no independent prognostic factor associated with prolonged PFS was identified.

Frailty and long-term survival of patients with ovarian cancer: A systematic review and meta-analysis.

Background: Frailty has been related with poor prognosis of various diseases, including ovarian cancer. We performed a systematic review and meta-analysis to evaluate the association between frailty and long-term survival of patients with ovarian cancer. Methods: Relevant cohort studies were retrieved by search of PubMed, Embase, Cochrane's Library, and Web of Science electronic databases. Two authors independently performed literature search, data collection, and statistical analyses. A random-effect model incorporating the possible influence of heterogeneity was used to pool the results. Results: Nine cohort studies including 2497 women with confirmed diagnosis of ovarian cancer contributed to the meta-analysis, and 536 (21.5%) of them were with high frailty. The median follow-up durations varied between 24 and 69 months. Compared to patients with low or non-frailty, OC patients with high frailty were associated with poor overall survival (risk ratio [RR]: 1.61, 95% confidence interval [CI]: 1.41 to 1.85, p < 0.001; I2 = 0%) and progression-free survival (RR: 1.51, 95% CI: 1.20 to 1.89, p < 0.001; I2 = 0%). Subgroup analyses according to study design, cancer stage, age of patients, scales for frailty evaluation, follow-up duration, and quality score of the included study showed consistent association between high frailty and poor overall survival in women with ovarian cancer (p for subgroup effects all < 0.05). After considering GRADE criteria for strength of the evidence, it was rated low for both the two outcomes. Conclusion: High frailty may be an independent risk factor of poor survival in women with ovarian cancer. Evaluating frailty may be important for predicting the prognosis and determining the optimal anticancer treatments in women with ovarian cancer. Systematic Review Registration: https://inplasy.com/, identifier INPLASY202290028.

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.

Myocardial edema during chemotherapy for gynecologic malignancies: A cardiac magnetic resonance T2 mapping study.

Objective: Myocardial edema is an early manifestation of chemotherapy-related myocardial injury. In this study, we used cardiac magnetic resonance (CMR) T2 mapping to assess myocardial edema and its changes during chemotherapy for gynecologic malignancies. Methods: We enrolled 73 patients receiving chemotherapy for gynecologic malignancies, whose the latest cycle was within one month before the beginning of this study, and 41 healthy volunteers. All participants underwent CMR imaging. Of the 73 patients, 35 completed CMR follow-up after a median interval of 6 (3.3 to 9.6) months. The CMR sequences included cardiac cine, T2 mapping, and late gadolinium enhancement. Results: Myocardial T2 was elevated in patients who were treated with chemotherapy compared with healthy volunteers [41ms (40ms to 43ms) vs. 41ms (39ms to 41ms), P = 0.030]. During follow-up, myocardial T2 rose further [40ms (39ms to 42ms) vs. 42.70 ± 2.92ms, P < 0.001]. Multivariate analysis showed that the number of chemotherapy cycles was associated with myocardial T2 elevation (ß = 0.204, P = 0.029). After adjustment for other confounders, myocardial T2 elevation was independently associated with a decrease in left ventricular mass (ß = -0.186; P = 0.024). Conclusion: In patients with gynecologic malignancies, myocardial edema developed with chemotherapy cycles increase, and was associated with left ventricular mass decrease. T2 mapping allows the assessment of myocardial edema and monitoring of its change during chemotherapy.

Association between the atherogenic index of plasma and new-onset non-alcoholic fatty liver disease in non-obese participants.

Introduction: Non-alcoholic fatty liver disease (NAFLD) in the non-obese population accounts for a large proportion of NAFLD. Atherogenic index of plasma (AIP, defined as the logarithm of the triglyceride/high-density lipoprotein cholesterol ratio.) can provide a stronger reflection of dyslipidemia and studies on the longitudinal association between AIP and NAFLD were limited in non-obese participants, especially in different BMI groups. Methods: We performed a post-hoc analysis of data obtained from the Dryad data repository (Dryad is a nonprofit open database of medicine.) and explored the predictive value of AIP on the risk of NAFLD among non-obese participants. Results: This study included 16173 participants with AIP, of which 2322(14.4%) non-obese participants developed into individuals with NAFLD with the 5-year follow-up examination. The difference between AIP quartiles in the cumulative estimation of new-onset NAFLD was significant, and with increased AIP, the cumulative new-onset NAFLD gradually increased. Participants in higher AIP quartiles had a significantly increased risk of NAFLD. In the fully adjusted model 3, hazard ratios of the new-onset NAFLD for subjects in Q2, Q3, and Q4 of AIP were 2.00 (1.59, 2.53), 2.61 (2.09, 3.72), and 4.49 (3.62, 5.57) respectively. Meanwhile, the trend test for the association between AIP quartiles and the new-onset NAFLD presented that AIP quartile was positively and strongly associated with the new-onset NAFLD (adjusted hazard ratio (95%CI) in Model 3: 1.59 (1.51, 1.67), P<0.001). We found that AIP was also positively and strongly associated with new-onset NAFLD in different sex groups and different age groups in female patients. Moreover, the predictive ability of AIP was no significant difference in different sex groups and different age groups in female patients. In the subgroup analysis, we found that in the low BMI population, the predictive effect of AIP for new-onset NAFLD was expanded by 2-3 times for each quality increase of AIP. Conclusion: This study found that AIP was a strong independent risk factor for new-onset NAFLD among non-obese individuals especially in the low BMI participants, and screening for AIP in this population can be used to prevent future NAFLD.

Understanding physiological mechanisms of variation in grain filling of maize under high planting density and varying nitrogen applicate rate.

Grain filling is a critical process for achieving a high grain yield in maize (Zea mays L.), which can be improved by optimal combination with genotype and nitrogen (N) fertilization. However, the physiological processes of variation in grain filling in hybrids and the underlying mechanisms of carbon (C) and N translocation, particularly under various N fertilizations, remain poorly understood. The field experiment was conducted at Gongzhuling Farm in Jilin, China. In this study, two maize hybrids, i.e., Xianyu 335 (XY335) and Zhengdan958 (ZD958) were grown with N inputs of 0, 150, and 300 kg N ha-1 (N0, N150, and N300) in 2015 and 2016. Results showed that the N application significantly optimized grain-filling parameters for both maize hybrids. In particular, there was an increase in the maximum filling rate (G max ) and the mean grain-filling rate (G mean ) in XY335 by 8.1 and 7.1% compared to ZD958 under the N300 kg ha-1 (N300) condition, respectively. Simultaneously, N300 increased the small and big vascular bundles area of phloem, and the number of small vascular bundles in peduncle and cob at the milking stage for XY335. XY335 had higher root bleeding sap (10.4%) and matter transport efficiency (8.4%) of maize under N300 conditions, which greatly enhanced the 13C assimilates and higher C and N in grains to facilitate grain filling compared to ZD958. As a result, the grain yield and the sink capacity for XY335 significantly increased by 6.9 and 6.4% compared to ZD958 under N300 conditions. These findings might provide physiological information on appropriate agronomy practices in enhancing the grain-filling rate and grain yield for maize under different N applications, namely the optimization variety and N condition noticeably increased grain filling rate after silking by improving ear vascular structure, matter transport efficiency, and enhancing C and N assimilation translocation to grain, eventually a distinct improvement in the grain sink and the grain yield.

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.

What is the appropriate treatment strategy for cryptogenic multifocal ulcerative stenosing enteritis? A single-center experience from China.

Background: There are few reports on standard treatment and long-term prognosis in patients with cryptogenic multifocal ulcerative stenosing enteritis (CMUSE), particularly in patients in whom remission could not be induced by steroids. The aim of this study was to evaluate the treatment response and progression-free periods of patients with CMUSE and to identify the factors predictive of steroid resistance. Methods: This was a retrospective cohort study that included 25 patients with clinically confirmed CMUSE between 1984 and 2021 from the enteropathy clinic of a tertiary care center. For statistical analyses, chi-square test or Fisher's exact test were used for categorical variables. Survival curves were plotted using the Kaplan-Meier method. Results: The overall median progression-free period was 48 months (range, 1-108 months) after comprehensive therapy, and initial manifestation with severe bleeding rather than ileus was associated with the long-term efficacy. Patients with steroid resistance (N = 10, 55.6%) had poor prognosis, and non-responders had more favorable baseline clinical characteristics, with a higher percentage of female patients (60% vs. 12.5%), earlier disease onset (26.5 years vs. 39 years), rapid progression (42 vs. 108 months), severe anemia (80% vs. 50%), and hypoalbuminemia (50% vs. 0%), in accord with lymphangiectasia or angioectasia identified in pathology. Conclusion: There is no guaranteed treatment strategy in the maintenance of long-term clinical remission for CMUSE patients, particularly in whom with steroid resistance. Female patients with early symptoms onset, severe gastrointestinal hemorrhage and hypoalbuminemia seem to have poor long-term prognosis.

BRCA Variants Do Not Increase the Risk of Adverse Reactions in Patients With Ovarian Cancer: A Single-Center Real-World Study.

Objective: To study the correlation between BRCA mutation status and the risk of adverse reactions in patients with ovarian cancer. Method: A real-world study was conducted at the largest gynecological oncology center in western China, the West China Second University Hospital of Sichuan University. The research subjects were patients diagnosed with ovarian cancer who were initially treated in our hospital from January 2016 to January 2020 and had their BRCA gene status evaluated. Multivariate Cox analysis was conducted to investigate the correlation between the BRCA mutation status and adverse reactions in ovarian cancer patients during initial treatment. Results: A total of 349 ovarian cancer patients were enrolled, including 79 patients with pathogenic BRCA variants, resulting in a pathogenic mutation rate of 22.6%. Among these 79 patients, 57 had BRCA1 variants and 22 had BRCA2 variants, yielding a pathogenic mutation rate of 16.3% and 6.3%, respectively. Multivariate COX analysis revealed that pathogenic BRCA variants were not related to the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs (P>0.05), during the initial treatment of ovarian cancer. Conclusion: BRCA variants did not increase the risk of adverse reactions, such as myelosuppression and allergies to chemotherapy drugs, in ovarian cancer patients during initial treatment.