DCAF13 promotes ovarian cancer progression by activating FRAS1-mediated FAK signaling pathway.

Cullin-RING ubiquitin ligase 4 (CRL4) is closely correlated with the incidence and progression of ovarian cancer. DDB1- and CUL4-associated factor 13 (DCAF13), a substrate-recognition protein in the CRL4 E3 ubiquitin ligase complex, is involved in the occurrence and development of ovarian cancer. However, its precise function and the underlying molecular mechanism in this disease remain unclear. In this study, we confirmed that DCAF13 is highly expressed in human ovarian cancer and its expression is negatively correlated with the overall survival rate of patients with ovarian cancer. We then used CRISPR/Cas9 to knockout DCAF13 and found that its deletion significantly inhibited the proliferation, colony formation, and migration of human ovarian cancer cells. In addition, DCAF13 deficiency inhibited tumor proliferation in nude mice. Mechanistically, CRL4-DCAF13 targeted Fraser extracellular matrix complex subunit 1 (FRAS1) for polyubiquitination and proteasomal degradation. FRAS1 influenced the proliferation and migration of ovarian cancer cell through induction of the focal adhesion kinase (FAK) signaling pathway. These findings collectively show that DCAF13 is an important oncogene that promotes tumorigenesis in ovarian cancer cells by mediating FRAS1/FAK signaling. Our findings provide a foundation for the development of targeted therapeutics for ovarian cancer.

The association of preoperative radiotherapy and surgery for AJCC stage I-III rectal adenocarcinoma: a population-based study.

BACKGROUND: With the increasing application of neoadjuvant therapy in rectal adenocarcinoma, there remain many controversies in clinical practical applications. Preoperative radiotherapy (PR) can limit the surgical plane and potentially affect the quality of surgical treatment. This study aimed to investigate the potential impact of PR on the surgical quality of rectal adenocarcinoma. METHODS: This retrospective study analyzed the clinicopathological data from 6,585 AJCC stage I-III rectal adenocarcinoma in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. Kaplan-Meier survival analysis and multivariate Cox proportional were used to assess the impact of PR on survival. Propensity score matching (PSM) was employed to balance the baseline covariates between the PR and non-PR groups and to compare postoperative pathological differences. RESULTS: After PSM, PR did not improve overall survival (OS) in stages I (p = 0.33), II (p = 0.37), and III (p = 0.14) patients. Multivariate Cox analysis indicated that PR was not an independent prognostic factor for patients. Restricted cubic spline (RCS) analysis demonstrated a nonlinear negative correlation between OS hazard ratios and both circumferential resection margin (CRM) and lymph node evaluation (LNE). Compared to the non-PR group, patients in the PR group had lower tumor deposits (TD) (p < 0.001), positive CRM (p = 0.191), and perineural invasion (PNI) (p = 0.001). CONCLUSION: PR is not an independent prognostic factor for rectal adenocarcinoma patients. However, PR can reduce the likelihood of TD, CRM, and PNI, thereby potentially influencing the quality of surgery.

Reinforcement Learning Interventions on Boundedly Rational Human Agents in Frictionful Tasks.

Many important behavior changes are frictionful; they require individuals to expend effort over a long period with little immediate gratification. Here, an artificial intelligence (AI) agent can provide personalized interventions to help individuals stick to their goals. In these settings, the AI agent must personalize rapidly (before the individual disengages) and interpretably, to help us understand the behavioral interventions. In this paper, we introduce Behavior Model Reinforcement Learning (BMRL), a framework in which an AI agent intervenes on the parameters of a Markov Decision Process (MDP) belonging to a boundedly rational human agent. Our formulation of the human decision-maker as a planning agent allows us to attribute undesirable human policies (ones that do not lead to the goal) to their maladapted MDP parameters, such as an extremely low discount factor. Furthermore, we propose a class of tractable human models that captures fundamental behaviors in frictionful tasks. Introducing a notion of MDP equivalence specific to BMRL, we theoretically and empirically show that AI planning with our human models can lead to helpful policies on a wide range of more complex, ground-truth humans.

WDR20 prevents hepatocellular carcinoma senescence by orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc.

The dysfunction of the ubiquitin-proteasome system (UPS) facilitates the malignant progression of hepatocellular carcinoma (HCC). While targeting the UPS for HCC therapy has been proposed, identifying effective targets has been challenging. In this study, we conducted a focused screen of siRNA libraries targeting UPS-related WD40 repeat (WDR) proteins and found that silencing WDR20, a deubiquitinating enzyme activating factor, selectively inhibited the proliferation of HCC cells without affecting normal hepatocytes. Moreover, the downregulation of WDR20 expression induced HCC cellular senescence and suppressed tumor progression in xenograft, sleeping beauty transposon/transposase, and hydrodynamic tail vein injection-induced HCC models, and Alb-Cre+/MYC+ HCC transgenic mouse models. Mechanistically, we found that WDR20 silencing disturbed the protein stability of c-Myc, orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc, thereby promoting the transcriptional activation of CDKN1A. Further investigation revealed a positive coexpression of WDR20 and c-Myc in a tissue microarray with 88 HCC clinical samples. By employing three patient-derived organoids from individuals with HCC, we have validated the decrease in c-Myc expression and the significant induction of senescence and growth inhibition following silencing of WDR20. This study not only uncovers the biological function of WDR20 and elucidates the molecular mechanism underlying its negative regulation of HCC cellular senescence but also highlight the potential of WDR20 as a promising target for HCC therapy.

Neutrophil extracellular traps induce intrahepatic thrombotic tendency and liver damage in cholestatic liver disease.

BACKGROUND: Cholestatic liver diseases induce local and systemic hypercoagulation, with neutrophil extracellular traps (NETs) serving as major drivers. These NETs have been linked to decreased liver function in patients with obstructive jaundice. However, the impact of NETs on liver hypercoagulation in cholestatic liver disease remains unknown. METHODS: We utilized bile duct ligation to create experimental mice and analyzed NETs formation in the liver. Fibrin deposition, tissue factor expression, and inflammation in the liver were visualized through western blot and immunohistochemical techniques. LSECs were incubated with isolated NETs, and we detected endothelial procoagulant activity using coagulation protein production assays and measuring endothelial permeability. In both in vivo and in vitro settings, DNase I was applied to clarify the effect of NETs on intrahepatic hypercoagulability, hepatotoxicity, LSEC, and macrophage activation or injury. RESULTS: Bile duct ligation mice exhibited significantly increased levels of NETs in liver tissue, accompanied by neutrophil infiltration, tissue necrosis, fibrin deposition, and thrombophilia compared to sham mice. Notably, NETs resulted in phosphatidylserine and tissue factor exposure on LSEC, enhancing coagulation Factor Xa and thrombin production. The enhanced procoagulant activity could be reversed by degrading NETs with DNase I. Additionally, NETs-induced permeability changes in LSECs, characterized by increased VE-cadherin expression and F-actin retraction, which could be rescued by DNase I. Meanwhile, NET formation is associated with KC activation and the formation of inflammatory factors. CONCLUSIONS: NETs promote intrahepatic activation of coagulation and inflammation, leading to liver tissue injury. Strategies targeting NET formation may offer a potential therapeutic approach for treating cholestatic liver disease.

Ultra-compact SOI-based higher-order mode pass wavelength demultiplexer.

We propose an ultra-compact mode filtering wavelength demultiplexer design with a footprint of 3µm×3µm. Our device can route input T E 1 mode signals at 1310 nm and 1550 nm to different output ports while simultaneously blocking fundamental transverse electric (T E 0) mode input. Our device is designed based on the topology optimization algorithm, which results in an ultra-compact footprint combining wavelength routing and mode filtering functions for the first time, to the best of our knowledge. Our final optimized devices demonstrated insertion losses of 1.26 dB and 1.47 dB for the C- and O-band output ports, respectively, with inter-port crosstalk as low as -21.25d B and -30.99d B. The extinction ratios between T E 1 mode and T E 0 mode are 24.02 dB and 30.12 dB at the 1310 nm and 1550 nm output ports. The combination of small footprint, broad transmission bandwidth, T E 1 to T E 0 mode selectively filtering, and C- and O-band T E 1 mode demultiplexing functions make this a uniquely versatile device that can play an important role in future high density mode-wavelength multiplexing systems.

Comparative analysis of whole cell-derived vesicular delivery systems for photodynamic therapy of extrahepatic cholangiocarcinoma.

This first-in-its-class proof-of-concept study explored the use of bionanovesicles for the delivery of photosensitizer into cultured cholangiocarcinoma cells and subsequent treatment by photodynamic therapy (PDT). Two types of bionanovesicles were prepared: cellular vesicles (CVs) were fabricated by sonication-mediated nanosizing of cholangiocarcinoma (TFK-1) cells, whereas cell membrane vesicles (CMVs) were produced by TFK-1 cell and organelle membrane isolation and subsequent nanovesicularization by sonication. The bionanovesicles were loaded with zinc phthalocyanine (ZnPC). The CVs and CMVs were characterized (size, polydispersity index, zeta potential, stability, ZnPC encapsulation efficiency, spectral properties) and assayed for tumor (TFK-1) cell association and uptake (flow cytometry, confocal microscopy), intracellular ZnPC distribution (confocal microscopy), dark toxicity (MTS assay), and PDT efficacy (MTS assay). The mean ±â€¯SD diameter, polydispersity index, and zeta potential were 134 ±â€¯1 nm, -16.1 ±â€¯0.9, and 0.220 ±â€¯0.013, respectively, for CVs and 172 ±â€¯3 nm, -16.4 ±â€¯1.1, and 0.167 ±â€¯0.022, respectively, for CMVs. Cold storage for 1 wk and incorporation of ZnPC increased bionanovesicular diameter slightly but size remained within the recommended range for in vivo application (136-220 nm). ZnPC was incorporated into CVs and CMVs at an optimal photosensitizer:lipid molar ratio of 0.006 and 0.01, respectively. Both bionanovesicles were avidly taken up by TFK-1 cells, resulting in homogenous intracellular ZnPC dispersion. Photosensitization of TFK-1 cells did not cause dark toxicity, while illumination at 671 nm (35.3 J/cm2) produced LC50 values of 1.11 µM (CVs) and 0.51 µM (CMVs) at 24 h post-PDT, which is superior to most LC50 values generated in tumor cells photosensitized with liposomal ZnPC. In conclusion, CVs and CMVs constitute a potent photosensitizer platform with no inherent cytotoxicity and high PDT efficacy in vitro.

CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to prevent DNA hypermethylation and ensure normal transcription in growing oocytes.

The DNA methylation is gradually acquired during oogenesis, a process sustained by successful follicle development. However, the functional roles of methyl-CpG-binding protein 2 (MeCP2), an epigenetic regulator displaying specifical binding with methylated DNA, remains unknown in oogenesis. In this study, we found MeCP2 protein was highly expressed in primordial and primary follicle, but was almost undetectable in secondary follicles. However, in aged ovary, MeCP2 protein is significantly increased in both oocyte and granulosa cells. Overexpression of MeCP2 in growing oocyte caused transcription dysregulation, DNA hypermethylation, and genome instability, ultimately leading to follicle growth arrest and apoptosis. MeCP2 is targeted by DCAF13, a substrate recognition adaptor of the Cullin 4-RING (CRL4) E3 ligase, and polyubiquitinated for degradation in both cells and oocytes. Dcaf13-null oocyte exhibited an accumulation of MeCP2 protein, and the partial rescue of follicle growth arrest induced by Dcaf13 deletion was observed following MeCP2 knockdown. The RNA-seq results revealed that large amounts of genes were regulated by the DCAF13-MeCP2 axis in growing oocytes. Our study demonstrated that CRL4DCAF13 E3 ubiquitin ligase targets MeCP2 for degradation to ensure normal DNA methylome and transcription in growing oocytes. Moreover, in aged ovarian follicles, deceased DCAF13 and DDB1 protein were observed, indicating a potential novel mechanism that regulates ovary aging.

Reducing Re-fractures Post Percutaneous Kyphoplasty: The Impact of Zoledronic Acid with Calcium and Vitamin D3 in Osteoporotic Patients.

Background: Osteoporosis poses a significant health challenge characterized by reduced bone density and increased fracture risk. Percutaneous kyphoplasty, a common treatment, aims to stabilize vertebral fractures. However, adjunctive therapies like zoledronic acid remain underexplored in improving postoperative outcomes and bone health in these patients. Objective: This study aims to evaluate the efficacy of zoledronic acid combined with calcium carbonate and vitamin D3 in treating osteoporosis, providing valuable clinical insights. Methods: A cohort of sixty-six osteoporosis patients who underwent percutaneous kyphoplasty and received subsequent treatment at our hospital between March 2020 and March 2022 were selected. Thirty-three patients received calcium carbonate and vitamin D3 (control group), while the remaining thirty-three patients were treated with zoledronic acid alongside calcium carbonate and vitamin D3 (research group). Pre- and post-treatment assessments included bone mineral density measurements, bone metabolism and turnover marker evaluations, symptom improvement assessments using the Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI), monitoring of adverse reactions, and assessment of quality of life using the Core Quality of Life questionnaire (QOL-C30). A one-year follow-up was conducted to determine re-fracture incidence. Results: Post-treatment, the research group exhibited significantly lower VAS, ODI, tartrate-resistant acid phosphatase-5b, and osteocalcin levels compared to the control group, while bone alkaline phosphatase levels were higher (P < .05). There was no significant difference in adverse reaction incidence between the groups (P > .05), but the research group demonstrated higher QOL-C30 scores (P < .05). Follow-up analysis revealed no notable difference in re-fracture rates between the groups (P > .05). Conclusions: Zoledronic acid in combination with calcium carbonate and vitamin D3 effectively enhances bone health in osteoporosis patients, warranting its clinical recommendation. This regimen shows promise for improving patient outcomes in osteoporosis management.

Missed Nursing Care as a Mediator in the Relationship between Career Calling and Turnover Intention.

AIM: To explore the role of missed nursing care in mediating the relationship between career calling and intention to leave among nurses. INTRODUCTION: Increasing nurse turnover is still a major concern in the global healthcare system. The most reliable indicator of turnover is turnover intention. It is crucial to understand its affecting elements to suggest measures to lower nurses' turnover intention. BACKGROUND: Turnover intention has been linked to career calling and missed nursing care. Little empirical research has investigated the possibility that missed nursing care mediates between career calling and turnover intention. METHODS: A cross-sectional survey of 347 nurses was conducted. The survey instruments included the General Information Questionnaire, Calling Scale, Missed Nursing Care Scale and Turnover Intention Questionnaire. Structural equation models were used to build the model. This study made use of the STROBE checklist. RESULTS: For 43.8% of nurses, turnover intention was high or very high. Missed nursing care and turnover intention were negatively correlated with career calling. Missed nursing care and turnover intention were positively related. Missed nursing care mediated the relationship between career calling and turnover intention. DISCUSSION: Career calling and missed nursing care can both influence turnover intention. Career calling can reduce the likelihood of turnover by preventing missed nursing care. CONCLUSION: Missed nursing care mediated the relationship between career calling and intention to leave. IMPLICATIONS FOR NURSING AND NURSING POLICY: Nursing managers should improve nurses' career calling through professional education and minimize missed nursing care by using electronic nursing reminder devices to reduce turnover intention.

S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway.

Cell senescence deters the activation of various oncogenes. Induction of senescence is, therefore, a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study, we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells. S1PR1 deletion promoted ovarian cancer cell senescence and sensitized ovarian cancer cells to cisplatin chemotherapy. Exposure of ovarian cancer cells to sphingosine-1-phosphate (S1P) increased the expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased the expression of large tumor suppressor 1/2 (LATS1/2), and induced phosphorylation of Yes-associated protein (p-YAP). Opposite results were obtained in S1PR1 knockout cells following pharmacological inhibition. After silencing LATS1/2 in S1PR1-deficient ovarian cancer cells, senescence was suppressed and S1PR1 expression was increased concomitantly with YAP expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.

Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China.

The rearranged during transfection (RET) gene is one of the receptor tyrosine kinases and cell-surface molecules responsible for transmitting signals that regulate cell growth and differentiation. In non-small cell lung cancer (NSCLC), RET fusion is a rare driver gene alteration associated with a poor prognosis. Fortunately, two selective RET inhibitors (sRETi), namely pralsetinib and selpercatinib, have been approved for treating RET fusion NSCLC due to their remarkable efficacy and safety profiles. These inhibitors have shown the ability to overcome resistance to multikinase inhibitors (MKIs). Furthermore, ongoing clinical trials are investigating several second-generation sRETis that are specifically designed to target solvent front mutations, which pose a challenge for first-generation sRETis. The effective screening of patients is the first crucial step in the clinical application of RET-targeted therapy. Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). Each of these methods has its advantages and limitations. To streamline the clinical workflow and improve diagnostic and treatment strategies for RET fusion NSCLC, our expert group has reached a consensus. Our objective is to maximize the clinical benefit for patients and promote standardized approaches to RET fusion screening and therapy.

The Unintended Consequences of Discount Regularization: Improving Regularization in Certainty Equivalence Reinforcement Learning.

Discount regularization, using a shorter planning horizon when calculating the optimal policy, is a popular choice to restrict planning to a less complex set of policies when estimating an MDP from sparse or noisy data (Jiang et al., 2015). It is commonly understood that discount regularization functions by de-emphasizing or ignoring delayed effects. In this paper, we reveal an alternate view of discount regularization that exposes unintended consequences. We demonstrate that planning under a lower discount factor produces an identical optimal policy to planning using any prior on the transition matrix that has the same distribution for all states and actions. In fact, it functions like a prior with stronger regularization on state-action pairs with more transition data. This leads to poor performance when the transition matrix is estimated from data sets with uneven amounts of data across state-action pairs. Our equivalence theorem leads to an explicit formula to set regularization parameters locally for individual state-action pairs rather than globally. We demonstrate the failures of discount regularization and how we remedy them using our state-action-specific method across simple empirical examples as well as a medical cancer simulator.

Hosimosines A-E, structurally diverse cytisine derivatives from the seeds of Ormosia hosiei Hemsl. et Wils.

Ormosia hosiei Hemsl. et Wils (Fabaceae family) is an arbor species endemic to China. The seeds of O. hosiei have been used as traditional Chinese medicine to treat hernia, abdominal pain, blood stasis and amenorrhea. Cytisine-like and angustifoline type alkaloids were main components identified from this plant. In our research on the bioactive alkaloids from the promising Chinese medicinal plants, four new angustifoline type alkaloids (1-4) and a new cytisine-like alkaloid (5), named hosimosine A-E, together with 13 known analogues (6-18) were isolated from the seeds of O. hosiei. Their structures were elucidated by the extensive spectroscopic methods, especially the interpretation of NMR spectra and specific rotations, along with the methods of NMR and ECD calculation. Compounds 1-4 were identified as two pairs of epimers, whose relative configurations were deduced from density functional theory (DFT) calculations of NMR chemical shifts and DP4+ analysis, and absolute configurations were determined by comparison of their experimental and theoretical ECD spectra. Compound 5 displayed two sets of NMR data caused by the existence of tautomeric forms. Compounds 14, 17 and 18 were determined to be enantiomers of literature compounds. Some of the isolates exhibited moderate cytotoxic effects against HepG2, A2780 and MCF-7 cells.

Exploration on the first-line treatment of ERBB2-altered advanced non-small cell lung cancer: A multicenter retrospective study.

BACKGROUND: Although the treatment of ERBB2-altered non-small cell lung cancer (NSCLC) has been studied for many years, there are no comprehensive studies to evaluate the benefits of various therapies as first-line treatment. Through the development of immunotherapy, more and more different combination treatments were applicated in clinical practice, therefore, we conducted a multicenter retrospective study to evaluate the efficacy of different treatments. METHODS: We enrolled patients with ERBB2-altered NSCLC who had undergone at least one-line systemic anticancer treatment to evaluate the efficacy of first-line chemotherapy alone (Chemo), anti-ERBB2 tyrosine kinase inhibitor (TKI), chemotherapy plus immunotherapy (Chemo + Immuno), chemotherapy plus anti-angiogenesis therapy (Chemo + Antiangio) and chemotherapy combined with immunotherapy and anti-angiogenesis therapy (Chemo + Immuno + Antiangio). The clinical outcomes included objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), one-year and three-year survival rate. RESULTS: We enroll 36 patients harboring ERBB2 mutation and 29 with ERBB2 amplification. The overall ORR was 30.8%, DCR was 69.2% and mPFS was 5.7 months. Chemo + Immuno and Chemo + Antiangio both achieved longer mPFS than TKI (7.8 vs 3.6 months, HR: 0.24, 95 %CI: 0.09-0.64, P = 0.002; 5.9 vs 3.6 months, HR: 0.36, 95 %CI: 0.15-0.88, P = 0.019; respectively), while there was no significant difference in mPFS between Chemo + Immuno or Chemo + Antiangio and Chemo (both P > 0.05), the mPFS of the first two was longer. For ERBB2-mutant patients, the mPFS was 5.9 months, and Chemo + Immuno and Chemo + Antiangio both achieved longer mPFS than TKI (12.9 vs 2.9 months, HR: 0.15, 95 %CI: 0.03-0.68, P = 0.005; 7.1 vs 2.9 months, HR: 0.50, 95 %CI: 0.29-0.88, P = 0.009, respectively). In the same therapies, patients with ERBB2 mutation or ERBB2 amplification showed no statistical significance in PFS (both P > 0.05). CONCLUSIONS: In the first-line treatment of ERBB2-altered NSCLC, chemotherapy combined with immunotherapy or anti-angiogenesis therapy may have greater survival benefits than ERBB2-target therapy, but the efficacy may not be better than that of chemotherapy.

Chinese expert consensus on the diagnosis and treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a malignant tumor originating from the pleura, and its incidence has been increasing in recent years. Due to the insidious onset and strong local invasiveness of MPM, most patients are diagnosed in the late stage and early screening and treatment for high-risk populations are crucial. The treatment of MPM mainly includes surgery, chemotherapy, and radiotherapy. Immunotherapy and electric field therapy have also been applied, leading to further improvements in patient survival. The Mesothelioma Group of the Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) developed a national consensus on the clinical diagnosis and treatment of MPM based on existing clinical research evidence and the opinions of national experts. This consensus aims to promote the homogenization and standardization of MPM diagnosis and treatment in China, covering epidemiology, diagnosis, treatment, and follow-up.

Role of Exosomes in the Invasion and Metastasis of Ovarian Cancer and Application Potential of Clinical Diagnosis and Treatment.

Ovarian cancer is a highly lethal form of cancer in females, largely due to extensive metastases that often accompany the initial diagnosis. Exosomes are microvesicles size from 30 to 100nm, which can be secreted by most cells. These special extracellular vesicles play a vital role in the metastasis of ovarian cancer. In this study, we conducted a comprehensive review of current research pertaining to the role of exosomes in ovarian cancer, utilizing the PubMed® and Web of Science databases. Our review highlights the progress in elucidating the mechanisms by which exosomes facilitate ovarian cancer progression. Additionally, we discuss the potential of exosomes as a novel therapeutic target for ovarian cancer treatment. Overall, our review provides valuable insights into the current state of research on exosomes in ovarian cancer therapy.

[Follow-up and prognostic study of infants with positional plagiocephaly]. / å©´å„¿ä½“ä½æ€§æ–œå¤´å¼‚å¸¸çš„éšè®¿å’Œé¢„åŽç ”ç©¶.

OBJECTIVES: To study the effects of infantile positional plagiocephaly on the growth and neural development. METHODS: A retrospective study was conducted on the medical data of 467 children who underwent craniographic examination and were followed up to 3 years of age in Peking University Third Hospital from June 2018 to May 2022. They were divided into four groups: mild positional plagiocephaly (n=108), moderate positional plagiocephaly (n=49), severe positional plagiocephaly (n=12), and normal cranial shape (n=298). The general information of the four groups and the weight, length, head circumference, visual acuity screening results, hearing test results, and the scores of Pediatric Neuropsychological Developmental Scales/Gesell Developmental Schedules of the four groups from 6 to 36 months old were compared. RESULTS: The rates of adverse perinatal factors, congenital muscular torticollis, and supine fixed sleeping posture in the mild, moderate, and severe positional plagiocephaly groups were higher than the normal cranial group (P<0.05). There was no significant difference in weight, length, and head circumference among the four groups at 6, 12, 24 and 36 months of age (P>0.05). The incidence rate of abnormal vision in the severe positional plagiocephaly group was higher than that in the mild positional plagiocephaly, moderate positional plagiocephaly and normal cranial shape groups at 24 and 36 months of age (P<0.05). The scores of the Pediatric Neuropsychological Developmental Scales at 12 and 24 months of age and the scores of the Gesell Developmental Schedules at 36 months of age in the severe positional plagiocephaly group were lower than those in the mild positional plagiocephaly, moderate positional plagiocephaly and normal cranial shape groups, but the difference was not statistically significant (P>0.05). CONCLUSIONS: Adverse perinatal factors, congenital muscular torticollis, and supine fixed sleeping position may be associated with infantile positional plagiocephaly. Mild or moderate positional plagiocephaly has no significant impact on the growth and neural development of children. Severe positional plagiocephaly have adverse effects on the visual acuity. However, it is not considered that severe positional plagiocephaly can affect the neurological development.

Efficacy and safety of a triple combination of atezolizumab, bevacizumab plus GEMOX for advanced biliary tract cancer: a multicenter, single-arm, retrospective study.

Background: Anti-programmed cell death ligand 1/vascular endothelial growth factor inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit, but it has not been investigated in advanced biliary tract cancer (BTC). Objectives: We investigated the efficacy and safety of atezolizumab, bevacizumab, and gemcitabine plus oxaliplatin (GEMOX) in advanced BTC and explore the potential biomarkers related to the response. Design: Multicenter, single-arm, retrospective study. Methods: Advanced BTC patients, who received a triple combination therapy at three medical centers between 18 March 2020 and 1 September 2021, were included. Treatment response was evaluated via mRECIST and RECIST v1.1. Endpoints included the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The whole exome sequencing of pathological tissues was conducted for bioinformatic analysis. Results: In all, 30 patients were enrolled. The best ORR was 76.7% and the DCR was 90.0%. The median PFS was 12.0 months, and the median OS was not reached. During the treatment, 10.0% (3/30) of patients suffered from ⩾grade 3 treatment-related adverse events (TRAEs). Furthermore, fever (73.3%), neutropenia (63.3%), increased aspartate transaminase and alanine aminotransferase levels (50.0% and 43.3%, respectively) are the most common TRAEs. Bioinformatics analysis revealed patients with altered ALS2CL had a higher ORR. Conclusion: The triple combination of atezolizumab, bevacizumab, and GEMOX may be efficacious and safe for patients with advanced BTC. ALS2CL may be a potential predictive biomarker for the efficacy of triple combination therapy.

Intensity-modulated radiotherapy combined with systemic atezolizumab and bevacizumab in treatment of hepatocellular carcinoma with extrahepatic portal vein tumor thrombus: A preliminary multicenter single-arm prospective study.

Background and aims: The efficacy and safety of systemic atezolizumab and bevacizumab (atezo/bev) in treatment of patients with unresectable hepatocellular carcinoma (HCC) have been demonstrated. However, the efficacy of this treatment in patients with HCC and extrahepatic portal vein tumor thrombus (ePVTT) is not satisfactory. This study aimed to study the efficacy and safety of combining intensity-modulated radiotherapy (IMRT) with systemic atezo/bev in treatment of these patients. Methods: This multicenter prospective study included patients with ePVTT treated with IMRT combined with atezo/bev from March to September 2021 in three centers in China. The outcomes of this study included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and association between response and tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) were analyzed to assess safety. Results: Of 30 patients in this study, the median follow-up was 7.4 months. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the ORR was 76.6%, the median OS for the entire cohort was 9.8 months, the median PFS was 8.0 months, and the median TTP was not reached. This study failed to establish a significant correlation between TMB with any of the following outcomes, including ORR, OS, PFS or TTP. The most common TRAEs at all levels were neutropenia (46.7%), and the most common grade 3/4 TRAE was hypertension (16.7%). There was no treatment-related deaths. Conclusions: IMRT combined with atezo/bev showed encouraging treatment efficacy with an acceptable safety profile, making this treatment to be a promising option for HCC patients with ePVTT. Further studies are required to support the findings of this preliminary study. Clinical trial registration: http://www.chictr.org.cn, Identifier ChiCTR2200061793.