PDCD4 deficiency improved 4-vinylcyclohexene dioxide-induced mouse premature ovarian insufficiency.

RESEARCH QUESTION: What role does programmed cell death 4 (PDCD4) play in premature ovarian insufficiency (POI)? DESIGN: A PDCD4 gene knockout (PDCD4-/-) mouse model was constructed, a POI mouse model was established similar to human POI with 4-vinylcyclohexene dioxide (VCD), a PDCD4-overexpressed adenovirus was designed and the regulatory role in POI in vitro and in vivo was investigated. RESULTS: PDCD4 expression was significantly increased in the ovarian granulosa cells of patients with POI (P ≤ 0.002 protein and mRNA) and mice with VCD-induced POI (P < 0.001 protein expression in both mouse ovaries and granulosa cells). In POI-induced mice model, PDCD4 knockouts significantly increased anti-Müllerian hormone, oestrodiol and numbers of developing follicles, and the PI3K-AKT-Bcl2/Bax signalling pathway is involved in it. CONCLUSION: The expression and regulation of PDCD4 significantly affects the POI pathology in a mouse model. This effect is closely related to the regulation of Bcl2/Bax and the activation of the PI3K-AKT signalling pathway.

Regulation of TAK-TAB Complex Activation through Ubiquitylation.

Transforming growth factor-ß (TGF-ß) activated kinase 1 (TAK1), also named mitogen-activated protein kinase 7 (MAPK7), forms a pivotal signaling complex with TAK1-binding proteins (TAB1, TAB2, and TAB3), orchestrating critical biological processes, including immune responses, cell growth, apoptosis, and stress responses. Activation of TAK1 by stimuli, such as tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), and Toll-like receptors (TLRs), underscores its central role in cellular signaling. Given the critical role of the TAK1-binding protein (TAK1-TAB) complex in cellular signaling and its impact on various biological processes, this review seeks to understand how ubiquitination thoroughly regulates the TAK1-TAB complex. This understanding is vital for developing targeted therapies for diseases where this signaling pathway is dysregulated. The exploration is significant as it unveils new insights into the activity, stability, and assembly of the complex, underscoring its therapeutic potential in disease modulation.

An advanced machine learning method for simultaneous breast cancer risk prediction and risk ranking in Chinese population: A prospective cohort and modeling study.

BACKGROUND: Breast cancer (BC) risk-stratification tools for Asian women that are highly accurate and can provide improved interpretation ability are lacking. We aimed to develop risk-stratification models to predict long- and short-term BC risk among Chinese women and to simultaneously rank potential non-experimental risk factors. METHODS: The Breast Cancer Cohort Study in Chinese Women, a large ongoing prospective dynamic cohort study, includes 122,058 women aged 25-70 years old from the eastern part of China. We developed multiple machine-learning risk prediction models using parametric models (penalized logistic regression, bootstrap, and ensemble learning), which were the short-term ensemble penalized logistic regression (EPLR) risk prediction model and the ensemble penalized long-term (EPLT) risk prediction model to estimate BC risk. The models were assessed based on calibration and discrimination, and following this assessment, they were externally validated in new study participants from 2017 to 2020. RESULTS: The AUC values of the short-term EPLR risk prediction model were 0.800 for the internal validation and 0.751 for the external validation set. For the long-term EPLT risk prediction model, the area under the receiver operating characteristic curve was 0.692 and 0.760 in internal and external validations, respectively. The net reclassification improvement index of the EPLT relative to the Gail and the Han Chinese Breast Cancer Prediction Model (HCBCP) models for external validation was 0.193 and 0.233, respectively, indicating that the EPLT model has higher classification accuracy. CONCLUSIONS: We developed the EPLR and EPLT models to screen populations with a high risk of developing BC. These can serve as useful tools to aid in risk-stratified screening and BC prevention.

An Improved Training Algorithm Based on Ensemble Penalized Cox Regression for Predicting Absolute Cancer Risk.

Introduction: Biases in cancer incidence characteristics have led to significant imbalances in databases constructed by prospective cohort studies. Since they use imbalanced databases, many traditional algorithms for training cancer risk prediction models perform poorly. Methods: To improve prediction performance, we introduced a Bagging ensemble framework to an absolute risk model based on ensemble penalized Cox regression (EPCR). We then tested whether the EPCR model outperformed other traditional regression models by varying the censoring rate of the simulated data. Results: Six different simulation studies were performed with 100 replicates. To assess model performance, we calculated mean false discovery rate, false omission rate, true positive rate, true negative rate, and the areas under the receiver operating characteristic curve (AUC) values. We found that the EPCR procedure could reduce the false discovery rate (FDR) for important variables at the same true positive rate (TPR), thereby achieving more accurate variable screening. In addition, we used the EPCR procedure to build a breast cancer risk prediction model based on the Breast Cancer Cohort Study in Chinese Women database. AUCs for 3- and 5-year predictions were 0.691 and 0.642, representing improvements of 0.189 and 0.117 over the classical Gail model, respectively. Discussion: We conclude that the EPCR procedure can overcome challenges posed by imbalanced data and improve the performance of cancer risk assessment tools.

Reappraise the effect of redo-Kasai for recurrent jaundice following Kasai operation for biliary atresia in the era of liver transplantation.

PURPOSE: This study was conducted to reappraise the efficacy of redo-Kasai (or revision) in the era of liver transplantation as a treatment option in those patients with recurrent jaundice after initially successful Kasai procedure. METHODS: We studied ten patients that received redo-Kasai, among a total of 102 patients diagnosed with biliary atresia after receiving Kasai operation from 1986 to 2011. RESULTS: Kasai operation was done at a median age of 55 days and redo-Kasai at 150 days. The bilirubin levels returned to normal in six patients after the procedure. Four of six enjoyed jaundice-free survival with native liver till the time of last follow-up. Three patients died and three received liver transplantation (LT). Only one out of seven patients with three or more episodes of cholangitis survived with native liver, while all the three patients with 1 or 0 episode survived with native liver. The difference was significant (P = 0.033). Re-do Kasai did not result in more blood loss or operative time during LT. CONCLUSION: Redo-Kasai is still valuable in the era of LT and the episodes of cholangitis are the decisive factors affecting the outcome of the procedure.

Integrated Multi-Omics Analysis Model to Identify Biomarkers Associated With Prognosis of Breast Cancer.

Background: With the rapid development and wide application of high-throughput sequencing technology, biomedical research has entered the era of large-scale omics data. We aim to identify genes associated with breast cancer prognosis by integrating multi-omics data. Method: Gene-gene interactions were taken into account, and we applied two differential network methods JDINAC and LGCDG to identify differential genes. The patients were divided into case and control groups according to their survival time. The TCGA and METABRIC database were used as the training and validation set respectively. Result: In the TCGA dataset, C11orf1, OLA1, RPL31, SPDL1 and IL33 were identified to be associated with prognosis of breast cancer. In the METABRIC database, ZNF273, ZBTB37, TRIM52, TSGA10, ZNF727, TRAF2, TSPAN17, USP28 and ZNF519 were identified as hub genes. In addition, RPL31, TMEM163 and ZNF273 were screened out in both datasets. GO enrichment analysis shows that most of these hub genes were involved in zinc ion binding. Conclusion: In this study, a total of 15 hub genes associated with long-term survival of breast cancer were identified, which can promote understanding of the molecular mechanism of breast cancer and provide new insight into clinical research and treatment.

Laparoscopic reduction of intussusception in children by a single surgeon in comparison with open surgery.

The surgical approach for managing intussusception is controversial. In this study, a retrospective analysis of patients undergoing surgical reduction for intussusception over a period of five years was conducted. All patients received either open surgery or laparoscopic approach after failing enema reduction of intussusception. The clinical and operative data were collected and analyzed. Eight patients received open surgery (OPEN group), and 37 patients received laparoscopic surgery, while two (5.4%) of them converted to open surgery. The remaining 35 patients were included in the LAP group. There was no difference in age, gender, clinical symptoms and signs, duration of symptoms, level of intussusception, and complications between the OPEN and LAP groups. In contrast, the operation time and length of hospital stay in the LAP group were significantly shorter than those in the OPEN group (P = 0.013 and P = 0.001 respectively). No recurrence was disclosed in the OPEN group but three patients in the LAP group had recurrent intussusception (8.6%); however, the difference of the recurrence rate between these two groups was not statistically significant (P = 0.40). In conclusion, reducing intussusception with the laparoscopic approach is highly successful and can be performed first for stable patients requiring surgical intervention.

Self-Healable Porous Polyampholyte Hydrogels with Higher Water Content as Cell Culture Scaffolds for Tissue Engineering Applications.

In this paper, we first demonstrate the control of the film pore size using neutral hydrophilic 2-hydroxyethyl methacrylate (HEMA) content. To improve the mechanical properties of a polyampholyte (PA), both HEMA and the cross-linker N,N'-methylenebisacrylamide (Bis-Am) were introduced into the PA chain. The predesigned copolymers showed great mechanical properties and optical behavior. The introduction of HEMA significantly increased the water content of the polymer, leading to the formation of porous structures in xerogels. The dynamic interaction between the positive and negative termini of the PA endowed the hydrogels with self-healing ability. The synthesized chemically cross-linked PA gels showed high stability in saline solution. The biocompatibility of the PA gels was confirmed using a cytotoxicity test of cells attached to the synthesized PA-X-2 and PA/HEMA-90/10-X-0.5. The results of this investigation indicate that the synthesized PA gels are applicable as a polymeric scaffold for cell culture.

Effect of acupuncture on aromatase inhibitor-induced arthralgia in patients with breast cancer: A meta-analysis of randomized controlled trials.

PURPOSE: Aromatase inhibitor (AI)-induced arthralgia (AIA) is a common side effect that may lead to premature discontinuation of effective hormonal therapy in patients with breast cancer. Acupuncture may relieve joint pain in patients with AIA. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the effectiveness of acupuncture in pain relief in AIA. METHODS: The PubMed, Embase, Cochrane Library, and Scopus databases and the ClinicalTrials.gov registry were searched for studies published before February 2017. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate the pooled effect size by using a random effect model. Pain was assessed using the Brief Pain Inventory (BPI) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 3-4, 6-8, and 12 weeks. Secondary outcomes included disability level, upper extremity function, physical performance, and quality of life. RESULTS: Five trials involving 181 patients were reviewed. Significant pain reduction was observed after 6-8 weeks of acupuncture treatment. Patients receiving acupuncture showed a significant decrease in the BPI worst pain score (weighted mean difference [WMD]: -3.81, 95% confidence interval [CI]: -5.15 to -2.47) and the WOMAC pain score (WMD: -130.77, 95% CI: -230.31 to -31.22) after 6-8 weeks of treatment. One of the 4 trials reported 18 minor adverse events in 8 patients during 398 intervention episodes. CONCLUSION: Acupuncture is a safe and viable nonpharmacologic treatment that may relieve joint pain in patients with AIA. Additional studies involving a higher number of RCTs are warranted.

Heat shock protein 90 is involved in the regulation of HMGA2-driven growth and epithelial-to-mesenchymal transition of colorectal cancer cells.

High Mobility Group AT-hook 2 (HMGA2) is a nonhistone chromatin-binding protein which acts as a transcriptional regulating factor involved in gene transcription. In particular, overexpression of HMGA2 has been demonstrated to associate with neoplastic transformation and tumor progression in Colorectal Cancer (CRC). Thus, HMGA2 is a potential therapeutic target in cancer therapy. Heat Shock Protein 90 (Hsp90) is a chaperone protein required for the stability and function for a number of proteins that promote the growth, mobility, and survival of cancer cells. Moreover, it has shown strong positive connections were observed between Hsp90 inhibitors and CRC, which indicated their potential for use in CRC treatment by using combination of data mining and experimental designs. However, little is known about the effect of Hsp90 inhibition on HMGA2 protein expression in CRC. In this study, we tested the hypothesis that Hsp90 may regulate HMGA2 expression and investigated the relationship between Hsp90 and HMGA2 signaling. The use of the second-generation Hsp90 inhibitor, NVP-AUY922, considerably knocked down HMGA2 expression, and the effects of Hsp90 and HMGA2 knockdown were similar. In addition, Hsp90 knockdown abrogates colocalization of Hsp90 and HMGA2 in CRC cells. Moreover, the suppression of HMGA2 protein expression in response to NVP-AUY922 treatment resulted in ubiquitination and subsequent proteasome-dependant degradation of HMGA2. Furthermore, RNAi-mediated silencing of HMGA2 reduced the survival of CRC cells and increased the sensitivity of these cells to chemotherapy. Finally, we found that the NVP-AUY922-dependent mitigation of HMGA2 signaling occurred also through indirect reactivation of the tumor suppressor microRNA (miRNA), let-7a, or the inhibition of ERK-regulated HMGA2 involved in regulating the growth of CRC cells. Collectively, our studies identify the crucial role for the Hsp90-HMGA2 interaction in maintaining CRC cell survival and migration. These findings have significant implications for inhibition HMGA2-dependent tumorigenesis by clinically available Hsp90 inhibitors.

Sac ligation in inguinal hernia repair: A meta-analysis of randomized controlled trials.

BACKGROUND: Traditionally, hernia sac ligation during inguinal hernia repair is considered mandatory to prevent postoperative development of hernia. However, ligation may induce postoperative pain. The aim of this study was to evaluate the outcomes of hernia sac ligation after inguinal hernia repair. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials to investigate the outcomes of hernia sac ligation for open or laparoscopic inguinal hernia repair. Incidence of hernia recurrence was assessed following the surgery. The secondary outcomes included pain scores and postoperative complications. RESULTS: Five trials were selected and their results were summarized. These 5 trials were published between 1984 and 2014, and the sample sizes ranged from 50 to 467 patients. Four trials had recruited patients with inguinal hernia who underwent open repair, and one study enrolled patients who underwent laparoscopic procedures. We observed no difference in the incidence of hernia recurrence and postoperative complications between the sac ligation and nonligation groups. Postoperatively, the intensity of pain was significantly higher in the ligation group than in the nonligation group at Day 7 (Weight mean difference 1.46; 95% confident interval: 0.98-1.95). CONCLUSION: Hernia sac ligation was associated with higher postoperative pain, and did not show any benefit over sac nonligation regarding the incidence of recurrence and postoperative complications in patients undergoing open tension-free mesh repair or laparoscopic procedures.

A new simplified one-port laparoscopic technique for peritoneal dialysis catheter placement.

BACKGROUND: Various techniques for laparoscopic insertion of a peritoneal dialysis catheter have been described. Usually 2 - 3 ports are required, and complications related to the port sites (such as abdominal wall hernia, leakage, and hemorrhage) cannot be avoided. To minimize the potential complications, we designed a simplified 1-port laparoscopic technique for peritoneal dialysis catheter placement. ♢ METHODS: We conducted a retrospective data review of 44 patients who underwent 1-port laparoscopic insertion of a Tenckhoff catheter from June 2009 to February 2011. All patient data, including postoperative complications, were analyzed. ♢ RESULTS: The mean follow-up period was 11.52 months. All catheters were working properly, except in 1 patient who developed peritonitis 3 months after catheter placement. (The catheter was removed.) No postoperative abdominal wall hemorrhage, early leaks, hernias, or catheter migration occurred. No exit-site or tunnel infections were observed. ♢ CONCLUSIONS: Our 1-port laparoscopic technique provides excellent catheter fixation, avoids excessive port sites, and yields good cosmesis. The low complication rate and the simplicity of the method justify its standard use for Tenckhoff catheter placement.

Transumbilical 1-port laparoscopic resection of benign ovarian tumor.

BACKGROUND/PURPOSE: We evaluated the effectiveness of transumbilical 1-port laparoscopic resection of benign ovarian tumors in children with limited working space. METHODS: This study involved 15 children and adolescents with benign ovarian tumors treated from January 2006 to December 2010. Preoperative evaluation included physical findings, tumor markers, and imaging studies. A single surgeon performed the procedure using a 10-mm 0° operative laparoscope with a 5-mm working channel. The fallopian tube was suspended with transabdominal suspensory sutures passing through the mesosalpinx to expose the tumor and remove it after aspiration of the contents. The tumor was contained in the endobag and chopped into pieces before removal through the small umbilical wound. RESULTS: The patients' age ranged from 2 to 17 years (mean, 9.7 years). Tumor size ranged from 3.6 to 23 cm. Tumor markers including α-fetoprotein, ß-human chorionic gonadotropin, cancer antigen 125, and carcinoembryonic antigen were negative. The average operating time was 134 minutes. Except for 1 patient with associated encephalomyelitis, all patients were discharged within 3 days after surgery. Pathologic examination and follow-up studies revealed benign tumors, with no residual lesions in the abdomen or recurrence. CONCLUSIONS: Transumbilical 1-port laparoscopic resection is effective for resection of benign ovarian tumors in children, with a satisfactory cosmetic outcome. However, to prevent inadequate resection of a potential malignant lesion, thorough preoperative evaluation with physical signs, tumor markers, and imaging studies, as well as flexible intraoperative tactics, should be adopted.

Augmented healing of critical-size calvarial defects by baculovirus-engineered MSCs that persistently express growth factors.

Repair of large calvarial bony defects remains clinically challenging because successful spontaneous calvarial re-ossification rarely occurs. Although bone marrow-derived mesenchymal stem cells (BMSCs) genetically engineered with baculovirus (BV) for transient expression of osteogenic/angiogenic factors hold promise for bone engineering, we hypothesized that calvarial bone healing necessitates prolonged growth factor expression. Therefore, we employed a hybrid BV vector system whereby one BV expressed FLP while the other harbored the BMP2 (or VEGF) cassette flanked by Frt sequences. Transduction of rabbit BMSCs with the FLP/Frt-based BV vector led to FLP-mediated episome formation, which not only extended the BMP2/VEGF expression beyond 28 days but augmented the BMSCs osteogenesis. After allotransplantation into rabbits, X-ray, PET/CT, µCT and histological analyses demonstrated that the sustained BMP2/VEGF expression remarkably ameliorated the angiogenesis and regeneration of critical-size (8 mm) calvarial defects, when compared with the group implanted with BMSCs transiently expressing BMP2/VEGF. The prolonged expression by BMSCs accelerated the bone remodeling and regenerated the bone through the natural intramembranous pathway, filling ≈83% of the area and ≈63% of the volume in 12 weeks. These data implicated the potential of the hybrid BV vector to engineer BMSCs for sustained BMP2/VEGF expression and the repair of critical-size calvarial defects.

The role of adipose-derived stem cells engineered with the persistently expressing hybrid baculovirus in the healing of massive bone defects.

Massive segmental defects arising from trauma or tumor resection remain a challenging clinical problem. To repair large, segmental bone defects using adipose-derived stem cells (ASCs) which alone cannot heal massive defects, we hypothesized that sustained expression of factors promoting osteogenesis (BMP2) and angiogenesis (VEGF) provides continuous stimuli to augment the healing. Baculovirus is a vector for gene delivery into stem cells, but it only mediates transient expression. Therefore we developed a dual system whereby one baculovirus expressed FLP recombinase (BacFLP) while the other hybrid baculovirus harbored an Frt-flanking transgene cassette. Within the ASCs transduced with BacFLP and the hybrid baculovirus, the transduction efficiency reached 98% and the FLP/Frt-mediated recombination efficiency approached 46%, leading to cassette excision off the baculovirus genome, enabling transgene persistence in episomal form and prolonging the expression to >28 days. ASCs engineered by the conventional baculovirus transiently expressing BMP2/VEGF (S group) only healed the critical-size (10mm) segmental femoral bone defects in 40% of New Zealand White rabbits at 12 weeks post-implantation, whereas ASCs engineered by the hybrid vectors persistently expressing BMP2/VEGF (L group) healed the critical-size defects in 12 out of 12 animals in 8 weeks. Compared with the S group, the L group not only accelerated the healing, but also ameliorated the bone quality (metabolism, volume, density, mechanical properties) and angiogenesis, thereby attesting our hypothesis that persistent BMP2/VEGF expression is essential. Use of ASCs engineered by the hybrid BV vector thus holds promise to treat massive segmental defects necessitating sustained stimuli.

Incomplete duplication of trachea with bronchogenic cyst: a case report.

Tracheal duplication is a very rare infant congenital airway anomaly. We report a bronchogenic cyst communicating with a tracheal duplication. This is the first reported case of pathologically confirmed duplication of trachea communicating with a bronchogenic cyst.