Secondary cytoreductive surgery followed by olaparib tablets as maintenance therapy in patients with BRCA mutated recurrent ovarian cancer: A multi-center retrospective study.

OBJECTIVE: To evaluate the effect of secondary cytoreductive surgery (SeCRS) followed by platinum-based chemotherapy (PBC) and olaparib tablets as maintenance therapy in patients with BRCA mutated recurrent epithelial ovarian cancer. METHODS: This was a retrospective study of a prospective database. We collected information on 623 patients diagnosed with BRCA mutated recurrent epithelial ovarian cancer, all of whom underwent SeCRS followed by PBC in combination with or without olaparib. Overall survival and progression-free survival were measured to evaluate treatment effectiveness. RESULTS: Of the 623 patients recruited, 240 underwent SeCRS plus hyperthermic intraperitoneal chemotherapy followed by PBC and olaparib maintenance therapy (Group A), 248 underwent SeCRS followed by PBC and olaparib maintenance therapy (Group B), and 135 underwent SeCRS followed by PBC only upon recurrence (Group C). The median progression-free survival for Group A was significantly longer than that for Group B (32.5 vs. 24.2 months, P<0.001), and Group B was significantly longer than Group C (24.2 vs. 15.1 months, P<0.001). The median overall survival for Groups A was significantly longer than that for Group B (71.4 vs. 63.5 months, P<0.001), and Group B was significantly longer than Group C (63.5 vs. 47.5 months, P<0.001). CONCLUSIONS: This study suggested that SeCRS followed by PBC and olaparib maintenance therapy resulted in longer overall survival and progression-free survival than SeCRS followed by PBC only in patients with BRCA mutated recurrent ovarian cancer, especially in patients treated with SeCRS plus hyperthermic intraperitoneal chemotherapy.

Establishment and Validation of a Machine Learning-Based Prediction Model for Termination of Pregnancy via Cesarean Section.

Objective: This study aimed to investigate the risk factors of cesarean section and establish a prediction model for cesarean section based on the characteristics of pregnant women. Methods: The clinical characteristics of 2552 singleton pregnant women who delivered a live baby between January 2020 and December 2021 were retrospectively reviewed. They were divided into vaginal delivery group (n = 1850) and cesarean section group (n = 702). These subjects were divided into training set (2020.1-2021.6) and validation set (2021.7-2021.12). In the training set, univariate analysis, Lasso regression, and Boruta were used to screen independent risk factors for cesarean section. Four models, including Logistic Regression (LR), K-Nearest Neighbor (KNN), Classification and Regression Tree (CART), and Random forest (RF), were established in the training set using K-fold cross validation, hyperparameter optimization, and random oversampling techniques. The best model was screened, and Sort graph of feature variables, univariate partial dependency profile, and Break Down profile were delineated. In the validation set, the confusion matrix parameters were calculated, and receiver operating characteristic curve (ROC), precision recall curve (PRC), calibration curve, and clinical decision curve analysis (DCA) were delineated. Results: The risk factors of cesarean section included age and height of women, weight at delivery, weight gain, para, assisted reproduction, abnormal blood glucose during pregnancy, pregnancy hypertension, scarred uterus, premature rupture of membrane (PROM), placenta previa, fetal malposition, thrombocytopenia, floating fetal head, and labor analgesia. RF had the best performance among the four models, and the accuracy of confusion matrix parameters was 0.8956357. The Matthews correlation coefficient (MCC) was 0.753012. The area under ROC (AUC-ROC) was 0.9790787, and the area under PRC (AUC-PRC) was 0.957888. Conclusion: RF prediction model for caesarean section has high discrimination performance, accuracy and consistency, and outstanding generalization ability.

A retrospective analysis of secondary cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy in patients with recurrent ovarian cancer.

AIM: To evaluate the effect of secondary cytoreductive surgery (SeCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in recurrent epithelial ovarian cancer patients. METHODS: This retrospective study analyzed a prospective database. We collected information of 389 patients who were diagnosed with recurrent epithelial ovarian cancer. All patients underwent SeCRS with or without HIPEC. Overall survival and progression-free survival (PFS) were used to evaluate the treatment effectiveness. RESULTS: Of the 389 patients collected, 123 underwent primary or interval cytoreductive surgery at initial treatment and SeCRS at recurrence (Group A), 130 underwent primary or interval cytoreductive surgery at initial and SeCRS plus HIPEC at recurrence (Group B), and 136 underwent primary or interval cytoreductive surgery plus HIPEC at initial and SeCRS plus HIPEC at recurrence (Group C). The median overall survival for Groups A, B, and C were 49.1 months (95% confidence interval [CI]: 47.6-50.5), 56.0 months (95% CI: 54.2-57.7), and 64.4 months (95% CI: 63.1-65.6), respectively. The median PFS for Groups A, B, and C were 13.1 months (95% CI: 12.6-13.5), 15.0 months (95% CI: 14.2-15.7), and 16.8 months (95% CI: 16.1-17.4), respectively. There were no significant difference in incidence and grade of adverse events among groups. CONCLUSIONS: This study suggested that SeCRS plus HIPEC followed by chemotherapy resulted in longer overall survival and PFS than only SeCRS followed by chemotherapy in patients with recurrent ovarian cancer, especially in patients who were treated with repeat HIPEC.

Human Umbilical Cord Mesenchymal Stem Cell-Derived Conditioned Medium Promotes Human Endometrial Cell Proliferation through Wnt/ß-Catenin Signaling.

Purpose: Mesenchymal stem cells (MSCs) and their derivant are among the promising treatments for intrauterine adhesion (IUA); they have been reported to repair the endometrial injury by proliferating endometrial cells. However, the signal pathways involved are not clear. This study investigated the role of human umbilical cord mesenchymal stem cell-derived conditioned medium (hUCMSC-CM) in relieving IUA to find out whether Wnt/ß-catenin signaling was involved, and if so, to determine the possible ligands. Methods: After endometrial epithelial cells (EECs) were treated with hUCMSC-CM, their proliferation and migration were measured by the CCK8 assay and the scratch assay. The activation of Wnt/ß-catenin signaling was measured by Western blots, fluorescent staining, and T-cell factor/lymphoid enhancer factor (TCF/LEF) luciferase. A Wnt inhibitor (XAV393) was used to inhibit the proliferation effect of hUCMSC-CM in EECs. Wnt5a expression in hUCMSC was measured by Western blots and fluorescent staining, and Wnt5a in hUCMSC-CM was detected by enzyme-linked immunosorbent assay (ELISA), to further clarify the mechanism. Results: As shown by the CCK8 assay, hUCMSC-CM promoted proliferation and migration of EECs. The expression of ß-catenin, c-myc, and cyclin D1 increased in EECs after being treated with hUCMSC-CM. Moreover, hUCMSC-CM was found to promote ß-catenin delivery into nuclei by Western blot and fluorescent staining; meanwhile, the inhibitor (XAV393) could restrain this process and inhibit the effect of hUCMSC-CM on EEC proliferation. Wnt5a was detected in hUCMSCs and hUCMSC-CM, which might be a potential therapeutic target. Conclusion: This study demonstrated that hUCMSC-CM promoted human endometrial cell proliferation through Wnt/ß-catenin signaling, and Wnt5a might be a potential activator. This would be one of the activating signal pathways in the MSC-related treatment of IUA.

Effects of a ketogenic diet in women with PCOS with different uric acid concentrations: a prospective cohort study.

RESEARCH QUESTION: Do overweight/obese women with PCOS with different uric acid concentrations show different effects after a ketogenic diet intervention? DESIGN: The study involved women with PCOS with a body mass index (BMI) of ≥24 kg/m2. Groups showing different uric acid concentrations were given ketogenic diet guidance for 12 weeks. Weight, BMI, body fat percentage, fasting blood glucose, triacylglyerols, total cholesterol, uric acid and other metabolism-related indexes were measured. RESULTS: After 12 weeks of the ketogenic diet intervention, body weight (hyperuricaemia group: P=0.001; non-hyperuricaemia group: P<0.001), BMI (hyperuricaemia group: P = 0.025; non-hyperuricaemia group: P<0.001) and body fat percentage (hyperuricaemia group: P<0.001; non-hyperuricaemia group: P<0.001) were decreased in both groups. There was greater weight loss in the non-hyperuricaemia group (hyperuricaemia group 11.2±4.6 kg versus non-hyperuricaemia group 14.7±4.8 kg; P < 0.05). In the non-hyperuricaemia group, uric acid concentrations increased significantly after 6 weeks of the ketogenic diet intervention (week 0: 5.69±0.84 mg/dl versus week 6: 8.41 ± 2.33 mg/dl; P < 0.001) and reached the concentrations of the hyperuricaemia group (week 6: 9.37 ± 2.43 mg/dl; P > 0.05). CONCLUSIONS: A ketogenic diet intervention is beneficial for overweight/obese women with PCOS with different serum uric acid concentrations. Participants with normal basal uric acid concentrations showed a greater fluctuation of serum uric acid concentrations during the ketogenic diet intervention and had a greater weight loss.

Gitelman syndrome in pregnancy: a case series.

OBJECTIVE: To evaluate maternal and fetal outcomes in women with Gitelman syndrome (GS). METHODS: Retrospective analysis of the clinical data of five patients with the clinical diagnosis of GS during pregnancy, who were admitted to Beijing Shijitan Hospital, Capital Medical University between 2013 and 2019, was conducted. RESULTS: Five women with GS during pregnancy who finally gave birth to a total of eight newborns have been included. Three cases were primiparas and two cases were multiparas. Two cases were diagnosed before pregnancy and three cases were diagnosed in first or second trimester. The primary treatment was oral or intravenous electrolytes supplement. Three patients delivered through the vagina, and shoulder dystocia occurred in one patient. Two patients delivered by cesarean section, with one because of symptom of limb weakness during the course of labor and the other owing to gestational diabetes with fetal macrosomia. Postpartum hemorrhage and urinary retention were not reported in these cases. In perinatal period all the infants had good outcome. The children, aged between six months and five years, were healthy and well-developed during follow-up. CONCLUSION: The maternal and perinatal outcome is usually favorable. We should pay attention to electrolyte examination in the first trimester in order to diagnose and manage the GS efficiently. Well-controlled patients with Gitelman syndrome can deliver through the vagina.

Risk factors of pleural effusion after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in late-stage and recurrent ovarian cancer.

BACKGROUND: Pleural effusion (PE) is one of the most common complications of advanced recurrent ovarian cancer. However, no studies have revealed the risk factors for PE after surgery. The purpose of this study is to observe the incidence and risk factors of PE after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with late-stage and recurrent ovarian cancer. METHODS: A retrospective analysis of 77 patients with late-stage and recurrent ovarian cancer after CRS + HIPEC was conducted. According to the presence of PE within 7 days after operation, two groups were formed. The basic information, surgical process, and laboratory examinations of the two groups were analyzed and compared to conduct a regression analysis. RESULTS: The incidence of postoperative PE was 57.1% (44/77 patients). Among these patients, the prevalence of grade I-II and grade III-IV PE was 42.8% (33/77 patients) and 14.3% (11/77 patients), respectively. There were statistically significant differences between the two groups in terms of preoperative PE, the duration of surgery, intraoperative blood loss, postoperative level of albumin, intestinal involvement, and diaphragmatic involvement. Among these, preoperative PE and diaphragmatic involvement were identified as independent risk factors of postoperative PE. CONCLUSIONS: Patients with late-stage and recurrent ovarian cancer invariably develop postoperative PE after CRS + HIPEC. Preoperative PE and diaphragmatic involvement are independent risk factors of postoperative PE. It is estimated that the incidence of postoperative PE among patients with these two independent risk factors is approximately 100%. Hence, we should promote the prevention and treatment of PE to improve its prognosis.

A fluorescent probe based on reversible Michael addition-elimination reaction for the cycle between cysteine and H2O2.

Cysteine oxidation by H2O2, generating either cysteine sulfenic acid (CSOH) or disulfide (CSSC), is involved in redox homeostasis and signaling. Compared with quantification of the cysteine content, monitoring the cysteine dynamics in real-time, in particular, takes on even greater importance. However, existing fluorescent probes suffer from low specificity or irreversible recognition mechanisms. In the present work, we have successfully developed a reversible fluorescent probe for the cycle between cysteine and H2O2 based on the Michael addition-elimination reaction. This probe features a specific and quantitative response to cysteine. The reversible detection was realized repeatedly with the addition of cysteine and H2O2 in order. We also demonstrated its usage for monitoring exogenous and endogenous cysteine in living cells. Eventually, this probe was capable of imaging cysteine dynamically in real-time.

In Vitro Light-Up Visualization of a Subunit-Specific Enzyme by an AIE Probe via Restriction of Single Molecular Motion.

Enzymes contain several subunits to maintain different biological functions. However, it remains a great challenge for specific discrimination of one subunit over another. Toward this end, the fluorescent probe TPEMA is now presented for highly specific detection of the B subunit of cytosolic creatine (CK) kinase isoenzyme (CK-B). Owing to its aggregation-induced emission property, TPEMA shows highly boosted emission toward CK-B with a fast response time and very low interference from other analytes, including the M subunit of CK (CK-M). With the aid of a Job plot assay, ITC assay and molecular dynamics simulation, it was directly confirmed that the remarkably enhanced fluorescence of TPEMA in the presence of CK-B results from the restriction of single molecular motion in the cavity. Selective wash-free fluorescence imaging of CK-B in macrophages under different treatments was successfully demonstrated.

Inferring fetal fractions from read heterozygosity empowers the noninvasive prenatal screening.

PURPOSE: Fetal fraction (FF) is the percent of cell-free DNA (cfDNA) in the mother's peripheral blood that is of fetal origin, which plays a pivotal role in noninvasive prenatal screening (NIPS). We present a method that can reliably estimate FFs by examining autosome single-nucleotide polymorphisms (SNPs). METHODS: Even at a very low sequencing depth, there are plenty of SNPs covered by more than one read. At those SNPs, we define read heterozygosity and demonstrate that the percent of read heterozygosity is a function of FF, which allows FF to be inferred. RESULTS: We first demonstrated the effectiveness of our method in inferring FF. Then we used the inferred FF as an informative alternative prior to computing Bayes factors to test for aneuploidy, and observed better power than the Z-test. In analysis of clinical samples, we were able to identify female-male twins thanks to the accurate FF inference. CONCLUSION: Knowing FF improves efficacy of NIPS. It brings a powerful Bayesian method, allows "no call" for samples with small FFs, renders screening for XXY syndrome simpler, and permits an adaptive design to sequence at a higher depth for samples with small FFs.

Correction: Inferring fetal fractions from read heterozygosity empowers the noninvasive prenatal screening.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hyaluronic Acid Hydrogel Integrated with Mesenchymal Stem Cell-Secretome to Treat Endometrial Injury in a Rat Model of Asherman's Syndrome.

Stem cell therapies have made strides toward the efficacious treatment of injured endometrium and the prevention of intrauterine adhesions, or Asherman's syndrome (AS). Despite this progress, they are limited by their risk of tumor formation, low engraftment rates, as well as storage and transportation logistics. While attempts have been made to curb these issues, there remains a need for simple and effective solutions. A growing body of evidence supports the theory that delivering media, conditioned with mesenchymal stem cells, might be a promising alternative to live cell therapy. Mesenchymal stem cell-secretome (MSC-Sec) has a superior safety profile and can be stored without losing its regenerative properties. It is versatile enough to be added to a number of delivery vehicles that improve engraftment and control the release of the therapeutic. Thus, it holds great potential for the treatment of AS. Here, a new strategy for loading crosslinked hyaluronic acid gel (HA gel) with MSC-Sec is reported. The HA gel/MSC-Sec treatment paradigm creates a sustained release system that repairs endometrial injury in rats and promotes viable pregnancy.

Cell and biomaterial-based approaches to uterus regeneration.

Asherman's syndrome (AS) is an endometrial disorder in which intrauterine adhesions crowd the uterine cavity and wall. The fibrotic adhesions are primarily the result of invasive uterine procedures that usually involve the insertion of surgical equipment into the uterus. This syndrome is accompanied by a number of clinical manifestations, including irregular or painful menstruation and infertility. The most prevalent treatment is hysteroscopy, which involves the physical removal of the fibrous strands. Within the last decade, however, the field has been exploring the use of cell-based therapeutics, in conjunction with biomaterials, to treat AS. This review is a recapitulation of the literature focused on cellular therapies for treating AS.

Antibody-Armed Platelets for the Regenerative Targeting of Endogenous Stem Cells.

Stem cell therapies have shown promise in treating acute and chronic ischemic heart disease. However, current therapies are limited by the low retention and poor integration of injected cells in the injured tissue. Taking advantage of the natural infarct-homing ability of platelets, we engineered CD34 antibody-linked platelets (P-CD34) to capture circulating CD34-positive endogenous stem cells and direct them to the injured heart. In vitro, P-CD34 could bind to damaged aortas and capture endogenous stem cells in whole blood. In a mouse model of acute myocardial infarction, P-CD34 accumulated in the injured heart after intravenous administration, leading to a concentration of endogenous CD34 stem cells in the injured heart for effective heart repair. This represents a new technology for endogenous stem cell therapy.

Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair.

Stem cell therapy is one of the promising strategies for the treatment of ischemic heart disease. However, the clinical application of stem cells transplantation is limited by low cell engraftment in the infarcted myocardium. Taking advantage of pretargeting and bioorthogonal chemistry, we engineered a pretargeting and bioorthogonal chemistry (PTBC) system to capture endogenous circulating stem cells and target them to the injured heart for effective repair. Two bioorthogonal antibodies were i.v. administrated with a pretargeting interval (48 h). Through bioorthogonal click reaction, the two antibodies are linked in vivo, engaging endogenous stem cells with circulating platelets. As a result, the platelets redirect the stem cells to the injured heart. In vitro and in vivo studies demonstrated that bioorthogonal click reaction was able to induce the conjugation of platelets and endothelial progenitor cells (EPCs) and enhance the binding of EPCs to collagen and injured blood vessels. More importantly, in a mouse model of acute myocardial infarction, the in vivo results of cardiac function, heart morphometry, and immunohistochemistry assessment all confirmed effective heart repair by the PTBC system.