Regulating Planarized Intramolecular Charge Transfer for Efficient Single-Phase White-Light Emission in Undoped Metal-Organic Framework Nanocrystals.

The technology of combining multiple emission centers to exploit white-light-emitting (WLE) materials by taking advantage of porous metal-organic frameworks (MOFs) is mature, but preparing undoped WLE MOFs remains a challenge. Herein, a pressure-treated strategy is reported to achieve efficient white photoluminescence (PL) in undoped [Zn(Tdc)(py)]n nanocrystals (NCs) at ambient conditions, where the Commission International del'Eclairage coordinates and color temperature reach (0.31, 0.37) and 6560 K, respectively. The initial [Zn(Tdc)(py)]n NCs exhibit weak-blue PL consisting of localized excited (LE) and planarized intramolecular charge transfer (PLICT) states. After pressure treatment, the emission contributions of LE and PLICT states are balanced by increasing the planarization of subunits, thereby producing white PL. Meanwhile, the reduction of nonradiative decay triggered by the planarized structure results in 5-fold PL enhancement. Phosphor-converted light-emitting diodes based on pressure-treated samples show favorable white-light characteristics. The finding provides a new platform for the development of undoped WLE MOFs.

Causal association of genetically determined plasma metabolites with osteoarthritis: a two-sample Mendelian randomization study.

Background: We aimed to elucidate the causal relationship between plasma metabolites and the vulnerability to Osteoarthritis (OA), encompassing both hip OA and knee OA. Methods: We conducted a two-way two-sample Mendelian randomization (MR) analysis to investigate the association of 1,400 plasma metabolites with OA. The Inverse Variance Weighted (IVW) model served as the primary two-sample MR Analysis method, with supplementary analysis using the Weighted Median (WM) and MR Egger methods. To ensure the robustness of our findings, sensitivity analyses were performed, incorporating Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and Leave-One-Out analyses. To validate the identified metabolites, we utilized the Steiger test and linkage disequilibrium score regression. Results: A total of 94 plasma metabolites were associated with osteoarthritis, with 60 associated with hip OA and 106 associated with knee OA. IVW analysis revealed that tryptophan levels showed the strongest positive association with hip OA (OR [95% CI]: 1.119 [1.024, 1.223]), while X-24757 levels exhibited the highest positive association with knee osteoarthritis (OR [95% CI]: 1.095 [1.032, 1.162]). Ethylparaben sulfate levels were found to have the greatest positive association with hip OA (OR [95% CI]: 1.118 [1.015, 1.231]). Notably, the plasma metabolite X-2475 showed a strong robust random effect across all three types of osteoarthritis. Metabolic pathway analysis revealed that the pathogenesis of osteoarthritis in the hip was mediated by acetylarginine, specifically in four important metabolic pathways: ethanol degradation (p = 0.044), amino sugar metabolism (p = 0.090), fatty acid biosynthesis (p = 0.095), and aspartate metabolism (p = 0.097816). Conclusion: There is a significant association between tryptophan levels and the risk of hip OA, as well as X-24757 levels and the risk of knee osteoarthritis. Additionally, X-24757 levels are also linked to the risk of hip OA. Moreover, this study has identified four crucial metabolic pathways in hip osteoarthritis, which are all regulated by acetylarginine. These findings provide valuable insights into potential biomarkers for OA and highlight potential pathways for its prevention and clinical intervention.

Construction of H-Doped PdB Nanocrystals as Electrocatalysts to Modulate Formic Acid Oxidation.

The strong ligand effect in B-doped Pd-based (PdB) catalysts renders them a promising anode for constructing formic acid fuel cells (FAFCs) exhibiting high power density and outstanding stability. However, the enhancement of the oxidation barrier is unavoidable in this alloy system owing to the electron transfer (ET) from B to Pd. In this study, a hydrogen doping strategy is employed to open charge freedom in PdB compounds and boost their formic acid oxidation reaction (FAOR) activity by suppressing the ET process. The resulting hydrogen-doped PdB (PdBH) exhibits an ultrahigh mass activity of up to 1.2A mg-1 Pd, which is 3.23 times that of the PdB catalyst and 9.55 times that of Pd black. Detailed experimental and theoretical studies show that the interstitial hydrogen leads to enhanced orbital hybridization and reduced electron density around Pd. This optimized ligand effect weakens the carbon monoxide adsorption and increases the direct pathway preference of PdBH, resulting in its outstanding catalytic activity for the FAOR. The development of this high-performance hydrogen-doped PdB catalyst is an important step toward the construction of advanced light element co-doped metal catalysts.

[A new fluoroscopic view to evaluate the medial and lateral articular reduction quality in patella fractures during internal fixation].

Objective: To introduce a new fluoroscopic method for assessing the quality of medial and lateral joint surface reduction during internal fixation of patellar fractures and to summarize the clinical outcomes of patients treated using this method. Methods: A retrospective analysis was conducted on the clinical data of 52 patients with patellar fractures treated between January 2018 and January 2022 who met the inclusion criteria. There were 27 male and 25 female patients, aged 21-75 years, with an average age of 62 years. The types of patellar fractures included 9 transverse fractures, 37 comminuted fractures, and 6 longitudinal fractures. According to the AO/Orthopaedic Trauma Association (AO-OTA)-2018 fracture classification, there were 21 cases of type 34A, 6 cases of type 34B, and 25 cases of type 34C. The time from injury to operation ranged from 1 to 5 days, with an average of 2.3 days. Treatments included internal fixation with hollow screws or hollow screw tension bands, with or without anchor repair. During operation, the medial and lateral joint surfaces of the patella were observed using the tangential fluoroscopic method to assess the smoothness of reduction of the median ridge, lateral joint surface, medial joint surface, and lateral joint edge. Patients were followed up regularly, and X-ray films were taken to observe fracture healing. Knee joint range of motion, Böstman score, and Lysholm score were used to evaluate functional recovery. Results: The tangential fluoroscopic method for the medial and lateral joint surfaces of the patella during operation showed satisfactory reduction of the joint surfaces and good positioning of the implants. All patients were followed up 12-16 months, with an average of 13.4 months. During the follow-up, fracture displacement occurred in 1 case and titanium cable breakage in 1 case. All patella fractures healed successfully, with a healing time of 8-16 weeks (mean, 11.4 weeks). At last follow-up, knee joint range of motion ranged from 120° to 140°, with an average of 136°. The Böstman score ranged from 20 to 30, with an average of 28, yielding excellent results in 45 cases and good results in 7 cases. The Lysholm score ranged from 88 to 100, with an average of 93, yielding excellent results in 40 cases and good results in 12 cases. Conclusion: The intraoperative application of the tangential fluoroscopic method for the medial and lateral joint surfaces of the patella can quickly determine the fluoroscopic plane of the patella, accurately assess the quality of fracture reduction and the position of internal fixator, thereby improving effectiveness.

Venous resection increases risk of chyle leak after total pancreatectomy for pancreatic tumors.

BACKGROUND: Existing research on chyle leak (CL) after pancreatic surgery is mostly focused on pancreaticoduodenectomy and lacks investigation on total pancreatectomy (TP). This study aimed to explore potential risk factors of CL and develop a predictive model for patients with pancreatic tumor undergoing TP. METHODS: This retrospective study enrolled 90 consecutive patients undergoing TP from January 2015 to December 2023 at Peking Union Medical College Hospital. According to the inclusion criteria, 79 patients were finally included in the following analysis. The LASSO regression and multivariate logistic regression analysis were performed to identify risk factors associated with CL and construct a predictive nomogram. Then, the ROC analysis, calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were performed to assess its discrimination, accuracy, and efficacy. Due to the small sample size, we adopted the bootstrap resampling method with 500 repetitions for validation. Lastly, we plotted and analyzed the trend of postoperative drainage volume in CL patients. RESULTS: We revealed that venous resection (OR = 4.352, 95%CI 1.404-14.04, P = 0.011) was an independent risk factor for CL after TP. Prolonged operation time (OR = 1.473, 95%CI 1.015-2.237, P = 0.052) was also associated with an increased incidence of CL. We included these two factors in our prediction model. The area under the curve (AUC) was 0.752 (95%CI 0.622-0.874) after bootstrap. The calibration curve, DCA and CIC showed great accuracy and clinical benefit of our nomogram. In patients with CL, the mean drainage volume was significantly higher in venous resection group and grade B CL group. CONCLUSION: Venous resection was an independent risk factor for chyle leak after TP. Patients undergoing vascular resection during TP should be alert for the occurrence of CL after surgery. We then constructed a nomogram consisted of venous resection and operation time to predict the odds of CL in patients undergoing TP.

Copper Nanodrugs with Controlled Morphologies through Aqueous Atom Transfer Radical Polymerization.

Copper (Cu) nanodrugs can be facilely prepared through atom transfer radical polymerization (ATRP) in an aqueous medium. However, it is difficult to control the morphology of Cu nanodrugs and thereby optimize their anticancer activity. In this work, aqueous ATRP was combined with polymerization-induced self-assembly (PISA) to prepare Cu nanodrugs with various morphologies. We mapped the relationship between polymerization condition and product morphology in which each morphology shows a wide preparation window. Decreasing the reaction temperature and feeding more Cu catalysts can improve the mobility of chains, facilitating the morphology evolution from sphere to other high-order morphologies. The resultant Cu nanodrugs with high monomer conversion and high Cu loading efficiency could be easily taken by cancer cells, showing excellent anticancer efficacy in vitro. This work proposed a potential strategy to prepare Cu nanodrugs with a specific morphology in batches, providing the method to optimize the anticancer efficacy through morphology control.

Percutaneous transhepatic stenting for acute superior mesenteric vein stenosis after pancreaticoduodenectomy with portal vein reconstruction: A case report.

BACKGROUND: Percutaneous transhepatic stent placement has become a common strategy for the postoperative treatment of portal vein (PV)/superior mesenteric veins (SMV) stenosis/occlusion. It has been widely used after liver transplantation surgery; however, reports on stent placement for acute PV/SMV stenosis after pancreatic surgery within postoperative 3 d are rare. CASE SUMMARY: Herein, we reported a case of intestinal edema and SMV stenosis 2 d after pancreatic surgery. The patient was successfully treated using stent grafts. Although the stenosis resolved after stent placement, complications, including bleeding, pancreatic fistula, bile leakage, and infection, made the treatment highly challenging. The use of anticoagulants was adjusted multiple times to prevent venous thromboembolism and the risk of bleeding. After careful treatment, the patient stabilized, and stent placement effectively managed postoperative PV/SMV stenosis. CONCLUSION: Stent placement is effective and feasible for treating acute PV/SMV stenosis after pancreatic surgery even within postoperative 3 d.

Comparison of patency rates and complications with or without antithrombotic therapy following portal vein stent placement after pancreatic surgery, a systematic review and meta-analysis.

BACKGROUND: Portal vein stent placement is used for portal vein stenosis. However, reports on post-pancreatic surgery cases are rare. Whether antithrombotic therapy should be administered remains controversial. In this paper, we reviewed current data to evaluate the influence of antithrombosis on stent patency after pancreatic surgery. MATERIALS AND METHODS: This systematic review and meta-analysis compared studies in which patients did or did not receive antithrombotic therapy after portal vein stent placement. We compared patency after stent placement and complication rate. RESULTS: There were 22 (n=207) studies in which patients received antithrombotic therapy and 8 (n=61) in which patients did not receive therapy. Antithrombotic agents, such as aspirin, clopidogrel, heparin, and warfarin, were used. The overall patency rates were similar between the groups (79.2% in the antithrombosis group vs. 88.0% in the non-antithrombosis group). Subgroup analyses included those for the etiology of stenosis, types of antithrombotic agents, acute or chronic stenosis, and causes of stent stenosis. None revealed a significant difference between the patency rates in the antithrombosis and non-antithrombosis groups. However, bleeding complications only occurred in patients who received antithrombotic therapy. CONCLUSION: There is no significant benefit of antithrombotic therapy after portal vein stent placement following pancreatic surgery. Antithrombotic therapy should be performed with caution because it may cause complications, such as bleeding.

Recent Progress on Microfluidics Integrated with Fiber-Optic Sensors for On-Site Detection.

This review introduces a micro-integrated device of microfluidics and fiber-optic sensors for on-site detection, which can detect certain or several specific components or their amounts in different samples within a relatively short time. Fiber-optics with micron core diameters can be easily coated and functionalized, thus allowing sensors to be integrated with microfluidics to separate, enrich, and measure samples in a micro-device. Compared to traditional laboratory equipment, this integrated device exhibits natural advantages in size, speed, cost, portability, and operability, making it more suitable for on-site detection. In this review, the various optical detection methods used in this integrated device are introduced, including Raman, ultraviolet-visible, fluorescence, and surface plasmon resonance detections. It also provides a detailed overview of the on-site detection applications of this integrated device for biological analysis, food safety, and environmental monitoring. Lastly, this review addresses the prospects for the future development of microfluidics integrated with fiber-optic sensors.

IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/ß-catenin signaling.

OBJECTIVES: Previously, Interferon-induced Protein with Tetratricopeptide Repeats 1 (IFIT1) has been shown to promote cancer development. Here, we aimed to explore the role of IFIT1 in the development and progression of pancreatic cancer, including the underlying mechanisms. METHODS: We explored IFIT1 expression in pancreatic cancer samples using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Cell Counting Kit-8 (CCK8), colony formation, scratch wound-healing and Transwell assays were performed to assess the proliferation, migration and invasion abilities of pancreatic cancer cells. Gene Set Enrichment Analysis (GSEA) and Western blotting were performed to assess the regulatory effect of IFIT1 on the Wnt/ß-catenin pathway. RESULTS: We found that upregulation of IFIT1 expression is common in pancreatic cancer and is negatively associated with overall patient survival. Knockdown of IFIT1 expression led to decreased proliferation, migration and invasion of pancreatic cancer cells. We also found that IFIT1 could regulate Wnt/ß-catenin signaling, and that a Wnt/ß-catenin agonist could reverse this effect. In addition, we found that IFIT1 can promote epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. CONCLUSIONS: Our data indicate that IFIT1 increases pancreatic cancer cell proliferation, migration and invasion by activating the Wnt/ß-catenin pathway. In addition, we found that EMT could be regulated by IFIT1. IFIT1 may serve as a potential therapeutic target for pancreatic cancer.

Whole transcriptome scanning and validation of negatively related genes in UC-MSCs.

Background: Human umbilical cord mesenchymal stem cells (UC-MSCs) are one of the most extensively researched stem cell types due to their potential for multi-lineage differentiation, secretion of regenerative factors, modulations of immunological activities, and the release of regenerative substances and influence immunological processes. Since UC-MSCs must be cultivated on a large scale for clinical use, selecting the appropriate storing passage, such as the usage-based passage of UC-MSCs, is critical for long-term autologous or allogeneic usage. Long-term cultivation of stem cells, on the other hand, causes them to lose their pluripotent differentiation capacity. As a result, distinguishing between high and low passages of UC-MSCs and identifying the particular variations associated with stem cells and their modes of action is essential for regenerative medicine. Therefore, we investigated the biological features and transcriptional changes of UC-MSCs over passages. Methods: UC-MSCs were isolated from the tissues of the human umbilical cord, and UC-MSCs from five passages (P1, P3, P5, P10 and P15) with three repetitions were compared and identified based on morphology, cell markers, differentiation capacity, and aging-related characteristics. It was previously assumed that the phenotype of cells before the P10 passage was stable, defined as early passage, and that culture could be continued until the 15th passage, defined as late passage. Next, the five passages of UC-MSCs were sequenced using high-throughput complete transcriptome sequencing. Fuzzy C-Means Clustering (FCM) and Weighted Gene Co-expression Network Analysis (WGCNA) were used to find hub genes, and gene silencing was performed to investigate the impact of missing genes on the stemness of UC-MSC cells. Results: UC-MSCs of different passages displayed similar surface markers, including CD73, CD105, CD90, CD34, CD45 and HLA-DR. However, the proliferation time of late-phase UC-MSCs was longer than that of early-phase UC-MSCs, and the expression of the senescence-associated (SA)-ß-gal staining marker was higher. At the same time, pluripotency markers (NANOG, OCT4, SOX2 and KIF4A) were down-regulated, and the multi-differentiation potential was reduced. Meanwhile, KIFC1 and UBE2C were down-regulated in late-phase UC-MSCs, which were involved in the maintenance of stemness. Conclusions: KIFC1 and UBE2C were highly expressed in early-UC-MSCs and showed a downward gradient trend with cell expansion in vitro. They regulated UC-MSC proliferation, colony sphere formation, multiple differentiation, stemness maintenance, and other biological manifestations. Therefore, they are anticipated to be new biomarkers for UC-MSCs quality identification in regenerative medicine applications.

Copper Nanodrugs by Atom Transfer Radical Polymerization.

In this study, some copper catalysts used for atom transfer radical polymerization (ATRP) were explored as efficient anti-tumor agents. The aqueous solution of copper-containing nanoparticles with uniform spheric morphology was in situ prepared through a copper-catalyzed activator generated by electron transfer (AGET) ATRP in water. Nanoparticles were then directly injected into tumor-bearing mice for antitumor chemotherapy. The copper nanodrugs had prolonged blood circulation time and enhanced accumulation at tumor sites, thus showing potent antitumor activity. This work provides a novel strategy for precise and large-scale preparation of copper nanodrugs with high antitumor activity.

Regulatory mechanisms underlying yeast chemical stress response and development of robust strains for bioproduction.

Yeast is widely studied in producing biofuels and biochemicals using renewable biomass. Among various yeasts, Saccharomyces cerevisiae has been particularly recognized as an important yeast cell factory. However, economic bioproduction using S. cerevisiae is challenged by harsh environments during fermentation, among which inhibitory chemicals in the culture media or toxic products are common experiences. Understanding the stress-responsive mechanisms is conducive to developing robust yeast strains. Here, we review recent progress in mechanisms underlying yeast stress response, including regulation of cell wall integrity, membrane transport, antioxidative system, and gene transcription. We highlight epigenetic regulation of stress response and summarize manipulation of yeast stress tolerance for improved bioproduction. Prospects in the application of machine learning to improve production efficiency are also discussed.

Development and validation of a nomogram model based on pretreatment ultrasound and contrast-enhanced ultrasound to predict the efficacy of neoadjuvant chemotherapy in patients with borderline resectable or locally advanced pancreatic cancer.

OBJECTIVES: To develop a nomogram using pretreatment ultrasound (US) and contrast-enhanced ultrasound (CEUS) to predict the clinical response of neoadjuvant chemotherapy (NAC) in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC). METHODS: A total of 111 patients with pancreatic ductal adenocarcinoma (PDAC) treated with NAC between October 2017 and February 2022 were retrospectively enrolled. The patients were randomly divided (7:3) into training and validation cohorts. The pretreatment US and CEUS features were reviewed. Univariate and multivariate logistic regression analyses were used to determine the independent predictors of clinical response in the training cohort. Then a prediction nomogram model based on the independent predictors was constructed. The area under the curve (AUC), calibration plot, C-index and decision curve analysis (DCA) were used to assess the nomogram's performance, calibration, discrimination and clinical benefit. RESULTS: The multivariate logistic regression analysis showed that the taller-than-wide shape in the longitudinal plane (odds ratio [OR]:0.20, p = 0.01), time from injection of contrast agent to peak enhancement (OR:3.64; p = 0.05) and Peaktumor/ Peaknormal (OR:1.51; p = 0.03) were independent predictors of clinical response to NAC. The predictive nomogram developed based on the above imaging features showed AUCs were 0.852 and 0.854 in the primary and validation cohorts, respectively. Good calibration was achieved in the training datasets, with C-index of 0.852. DCA verified the clinical usefulness of the nomogram. CONCLUSIONS: The nomogram based on pretreatment US and CEUS can effectively predict the clinical response of NAC in patients with BRPC and LAPC; it may help guide personalized treatment.

Lateral lymph node metastasis in papillary thyroid microcarcinoma: a study of 5241 follow-up patients.

PURPOSE: To investigate the impact of lateral lymph node metastasis in papillary thyroid microcarcinoma (PTMC). METHODS: 5241 PTMC patients with follow-up information were enrolled in the current study. These patients underwent primary surgery in our situation from January 1997 to December 2016. Additionally, a validation cohort consisting of 274 PTMC patients who underwent primary surgery between January 2020 and December 2021 was also included. Univariable and multivariate logistic analyses were conducted to identify the association between clinicopathologic features and lateral lymph node metastasis (LLNM). Kaplan-Meier survival curve analysis was used to calculate the disease-free survival (DFS) rate. The fitting curve was generated to identify the quantitative relationship between central lymph node metastases (CLNM) and LLNM. RESULTS: Of 5241 PTMC patients, cervical lymph node metastasis was detected in 1494 (28.5%) cases, including 1364 (26.0%) with CLNM only and 130 (2.5%) with LLNM. With a median follow-up time of 60 months (interquartile range [IQR], 44-81), recurrence was detected in 114 patients (2.2%). Multivariate Cox regression analyses showed that LNM was the only independent risk factor for recurrence, with HR values of 3.03 in CLNM and 11.14 in LLNM, respectively. Tumor diameter >0.5 cm (hazard ratio [HR]:1.80), multifocality (HR:2.59), bilaterality (HR:2.13), extrathyroidal invasion (HR:2.13), and CLNM (HR:5.11) were independent risk factors for LLNM. The prevalence of LLNM escalated significantly with increasing number of lymph node involvement in CLNM when stratified by the number of metastatic lymph nodes and trend was observed similarly in the validation cohort. The fitting curve showed that the incidence of LLNM could be as high as 20.7% when the number of CLNM ≥ 5. CONCLUSIONS: By analyzing a large database with follow-up information, our study provides evidence that LLNM is significantly correlated with tumor recurrence in patients with PTMC. Tumor size (>0.5 cm), multifocality, bilaterality, extrathyroidal extension (ETE) and CLNM are independent risk factors for LLNM.

Long-term impact of prophylactic central neck dissection in non-invasive classic papillary thyroid carcinoma.

BACKGROUND: The utilization of prophylactic central neck dissection (pCND) in cases of non-invasive clinical node-negative (cN0) papillary thyroid carcinoma (PTC) remains a topic of debate, with a dearth of long-term evidence. MATERIALS AND METHODS: We retrospectively reviewed 1181 cN0 PTC patients from 1997 to 2011. Of these, 641 underwent pCND (pCND + group) and 540 did not (pCND-group). Propensity score matching (PSM) was used to identify similar patients. Event-free survival and long-term complications including permanent hyperparathyroidism and permanent recurrent laryngeal nerve (RLN) paralysis were analyzed after PSM. RESULTS: The pCND + group had more aggressive characteristics. In the matched cohort after PSM, the 5-year, 10-year, and 15-year EFS rates were 98.9 %, 98.2 %, and 97.1 % for the pCND + group, and 97.7 %, 97.1 %, and 97.1 % for the pCND-group, respectively. There was no statistically significant difference in EFS rates between the two groups (Log Rank P = 0.38). There was no statistically significant difference in the incidence of permanent hyperparathyroidism (3.3 % vs. 1.5 %, P = 0.08) and permanent RLN paralysis (1.7 % vs. 0.9 %, P = 0.13) between the pCND+ and pCND- groups. CONCLUSION: Our study, with a median follow-up duration of 107 months, indicates that pCND does not lead to a significant reduction in nodal recurrence among non-invasive cN0 PTC patients.

PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation.

Mutations in the BRCA2 tumor suppressor gene have been associated with an increased risk of developing prostate cancer. One of the paradoxes concerning BRCA2 is the fact that its inactivation affects genetic stability and is deleterious for cellular and organismal survival, while BRCA2-mutated cancer cells adapt to this detriment and malignantly proliferate. Therapeutic strategies for tumors arising from BRCA2 mutations may be discovered by understanding these adaptive mechanisms. In this study, we conducted forward genetic synthetic viability screenings in Caenorhabditis elegans brc-2 (Cebrc-2) mutants and found that Ceubxn-2 inactivation rescued the viability of Cebrc-2 mutants. Moreover, loss of NSFL1C, the mammalian ortholog of CeUBXN-2, suppressed the spindle assembly checkpoint (SAC) activation and promoted the survival of BRCA2-deficient cells. Mechanistically, NSFL1C recruited USP9X to inhibit the polyubiquitination of AURKB and reduce the removal of AURKB from the centromeres by VCP, which is essential for SAC activation. SAC inactivation is common in BRCA2-deficient prostate cancer patients, but PP2A inhibitors could reactivate the SAC and achieve BRCA2-deficient prostate tumor synthetic lethality. Our research reveals the survival adaptation mechanism of BRCA2-deficient prostate tumor cells and provides different angles for exploring synthetic lethal inhibitors in addition to targeting DNA damage repair pathways.

MBD1 protects replication fork stability by recruiting PARP1 and controlling transcription-replication conflicts.

The replication-stress response is essential to ensure the faithful transmission of genetic information to daughter cells. Although several stress-resolution pathways have been identified to deal with replication stress, the precise regulatory mechanisms for replication fork stability are not fully understood. Our study identified Methyl-CpG Binding Domain 1 (MBD1) as essential for the maintaining genomic stability and protecting stalled replication forks in mammalian cells. Depletion of MBD1 increases DNA lesions and sensitivity to replication stress. Mechanistically, we found that loss of MBD1 leads to the dissociation of Poly(ADP-ribose) polymerase 1 (PARP1) from the replication fork, potentially accelerating fork progression and resulting in higher levels of transcription-replication conflicts (T-R conflicts). Using a proximity ligation assay combined with 5-ethynyl-2'-deoxyuridine, we revealed that the MBD1 and PARP1 proteins were recruited to stalled forks under hydroxyurea (HU) treatment. In addition, our study showed that the level of R-loops also increased in MBD1-delated cells. Without MBD1, stalled replication forks resulting from T-R conflicts were primarily degraded by the DNA2 nuclease. Our findings shed light on a new aspect of MBD1 in maintaining genome stability and providing insights into the mechanisms underlying replication stress response.

Spleen-dedicated stiffness measurement performed well to rule out high-risk varices in HBV-related hepatocellular carcinoma: Screening for high-risk varices in HCC.

BACKGROUND: Esophagogastroduodenoscopy (EGD) is required to screen for high-risk varices (HRV) in patients with hepatocellular carcinoma (HCC), especially since overall survival rates have dramatically improved with new systemic therapies. AIM: To assess the Baveno VI and Baveno VII algorithms' ability to rule out HRV in hepatitis B virus (HBV)-related HCC METHODS: We prospectively enrolled consecutive patients with HBV related, compensated cirrhosis and newly diagnosed HCC who underwent liver stiffness measurement, spleen stiffness measurement (SSM) using a 100-Hz shear wave frequency, and EGD. RESULTS: From September 2021 to August 2023, we enrolled 219 patients with HCC, with 107 (48.9%) Barcelona Clinic Liver Cancer (BCLC) A, 28 (12.8%) BCLC B and 84 (38.3%) BCLC C, respectively. HRV prevalence was 28.8% (63/219). Baveno VI criteria safely (HRV missing rate, 3.2%) avoided 27.4% unnecessary EGDs, while the Baveno VII algorithm avoided 49.3% with HRV missing rate at 7.9% (5/63). The SSM ≤40 kPa avoided 47.5% of EGDs safely (HRV missing rate, 4.8%), significantly better than the Baveno VI criteria (p < 0.001) and comparable to the Baveno VII algorithm (p = 0.390). The SSM ≤40 kPa safely avoided EGDs in patient subgroups within Milan criteria, with portal vein tumour thrombosis or BCLC B/C or candidates for systemic therapy. CONCLUSIONS: We validated that the SSM ≤40 kPa using a 100-Hz probe could safely eliminate more unnecessary EGDs than the Baveno VI criteria in patients with HBV-related HCC. However, the efficacy of the Baveno VII algorithm in patients with HCC requires further investigation.

Q&A with Weibin Wang.

Weibin Wang spoke with Cell Reports about his journey in science and his recent paper in which he and his fellow authors identified a protein that functions in DNA interstrand cross-link repair.