Efficacy of Danlou tablets in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a multicenter prospective cohort study.

Background: Danlou tablets (DLTs) have been widely used to treat coronary heart disease in China. However, the benefits associated with DLT for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in routine practice require further investigation. Purpose: To investigate the effectiveness of DLT in patients with ACS undergoing PCI. Methods: This multicenter prospective cohort study for patients with ACS undergoing PCI was conducted in 40 centers in mainland China from February 2012 to December 2018. This trial is registered under ChiCTR-OOC-14005552. Patients were assigned to either the DLT group or the conventional medicine (CM) group based on whether they used DLT prior to enrollment. The duration of DLT use (1.5 g, three times a day) was 12 months. The primary endpoint comprised of cardiac death, non-fatal myocardial infarction, and urgent revascularization. Secondary endpoint included rehospitalization owing to ACS, heart failure, stroke, and other thrombotic events. The Seattle Angina Questionnaire (SAQ) was used to assess quality of life (QOL). Primary and secondary endpoints were followed up for 36 months, and the SAQ was followed up for 12 months. The Cox proportional hazards regression model was used to analyze the independent effect of DLT on primary and secondary endpoints. Propensity score matching (PSM) analyses were performed to mitigate bias. Survival estimation was performed using Kaplan-Meier survival curves and log-rank tests in the PSM cohort, and landmark analyses were used for further evaluation of primary and secondary endpoints. Subgroup analyses and interactions confirmed the robustness of the findings. Linear mixed effects models were used to assess the QOL. Results: Overall, 936 patients were enrolled in this cohort study, of whom 875 completed follow-up. The primary and secondary endpoints had no significantly difference between the DLT and CM groups after Cox proportional hazards models. Kaplan-Meier survival curves and log-rank tests performed in the PSM cohort also found no significant differences between the two groups on primary and secondary endpoints. However, landmark analysis showed significant benefit in the primary endpoint for the DLT group after 200 days (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.22-0.93, P = 0.03). Landmark analysis also showed a significant benefit in the secondary endpoint in the DLT group within 200 days (HR 0.33, 95% CI 0.15-0.73, P = 0.006). Moreover, DLT improves the SAQ summary score, and scores in the physical limitation, treatment satisfaction, and disease perception domains for patients with ACS undergoing PCI. Conclusions: DLT combined with conventional treatment reduced the risk of the primary endpoint after 200 days and the secondary endpoint within 200 days during the 3-year follow-up. Additionally, DLT can improve the QOL without adverse effects.

Dissection of Targeting Molecular Mechanisms of Celastrol-induced Nephrotoxicity via A Combined Deconvolution Strategy of Chemoproteomics and Metabolomics.

Celastrol (Cel), derived from the traditional herb Tripterygium wilfordii Hook. f., has anti-inflammatory, anti-tumor, and immunoregulatory activities. Renal dysfunction, including acute renal failure, has been reported in patients following the administration of Cel-relative medications. However, the functional mechanism of nephrotoxicity caused by Cel is unknown. This study featured combined use of activity-based protein profiling and metabolomics analysis to distinguish the targets of the nephrotoxic effects of Cel. Results suggest that Cel may bind directly to several critical enzymes participating in metabolism and mitochondrial functions. These enzymes include voltage-dependent anion-selective channel protein 1 (essential for maintaining mitochondrial configurational and functional stability), pyruvate carboxylase (involved in sugar isomerization and the tricarboxylic acid cycle), fatty acid synthase (related to ß-oxidation of fatty acids), and pyruvate kinase M2 (associated with aerobic respiration). Proteomics and metabolomics analysis confirmed that Cel-targeted proteins disrupt some metabolic biosynthetic processes and promote mitochondrial dysfunction. Ultimately, Cel aggravated kidney cell apoptosis. These cumulative results deliver an insight into the potential mechanisms of Cel-caused nephrotoxicity. They may also facilitate development of antagonistic drugs to mitigate the harmful effects of Cel on the kidneys and improve its clinical applications.

Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability.

Collecting duct carcinoma (CDC) is an aggressive rare subtype of kidney cancer with unmet clinical needs. Little is known about its underlying molecular alterations and etiology, primarily due to its rarity, and lack of preclinical models. This study aims to comprehensively characterize molecular alterations in CDC and identify its therapeutic vulnerabilities. Through whole-exome and transcriptome sequencing, we identified KRAS hotspot mutations (G12A/D/V) in 3/13 (23%) of the patients, in addition to known TP53, NF2 mutations. 3/13 (23%) patients carried a mutational signature (SBS22) caused by aristolochic acid (AA) exposures, known to be more prevalent in Asia, highlighting a geologically specific disease etiology. We further discovered that cell cycle-related pathways were the most predominantly dysregulated pathways. Our drug screening with our newly established CDC preclinical models identified a CDK9 inhibitor LDC000067 that specifically inhibited CDC tumor growth and prolonged survival. Our study not only improved our understanding of oncogenic molecular alterations of Asian CDC, but also identified cell-cycle machinery as a therapeutic vulnerability, laying the foundation for clinical trials to treat patients with such aggressive cancer.

Glycyrrhizic acid ameliorates hepatic fibrosis by inhibiting oxidative stress via AKR7A2.

BACKGROUND: Hepatic fibrosis is a reversible pathological phenomenon caused by the abnormal proliferation of connective tissues in the liver for self-repair after persistent liver injury. Among these tissues, the activation status of hepatic stellate cells (HSCs) is crucial. Glycyrrhizic acid (GA) agents have been proven to have excellent anti-fibrosis effects, but their targets are unclear. PURPOSE: To investigate the anti-hepatic fibrosis effect of GA and its target in activated HSCs. METHODS: A mouse model of hepatic fibrosis was prepared with 20 % carbon tetrachloride (CCl4) and GA was administered continuously for 4 weeks. Subsequently, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), type Ⅲ procollagen peptide (P III P), laminin (LN), hyaluronic acid (HA), and type Ⅳ collagen (Col Ⅳ) were measured. Liver tissues were subjected to hematoxylin and eosin (HE), Masson, and Sirius red staining and proteome sequencing analysis. Based on LX-2 cells, activity-based protein profiling (ABPP) was used to investigate the potential targets of GA, which was further validated by the cellular thermal shift assay (CETSA), immunofluorescence co-localization, molecular docking, small interfering RNA (siRNA) and western blot (WB) assays. RESULTS: In vivo, GA significantly reduced serum ALT, AST, HA, P III P, Col IV, and LN levels. HE, Masson, and Sirius red staining showed that GA significantly ameliorated hepatic inflammatory response and collagen deposition in CCl4-treated mice. Proteome sequencing results showed that GA mainly regulated glutathione S-transferase family members involved in glutathione metabolism. In vitro, GA significantly inhibited LX-2 cell proliferation and reduced reactive oxygen species accumulation. ABPP suggested that aldo-keto reductase family 7 member A2 (AKR7A2) was the major binding protein of GA in LX-2 cells. CETSA, fluorescence co-localization, molecular docking, and surface plasmon resonance further validated GA binding to AKR7A2. The WB results showed that GA up-regulated AKR7A2 expression both in vitro and in vivo and was corroborated by siRNA experiments. CONCLUSION: GA targeted AKR7A2 in LX-2 cells to defend against sustained oxidative stress injury, thereby inhibiting the proliferation of activated HSCs and reversing hepatic fibrosis.

Effectiveness and Safety of Qishen Yiqi Dripping Pill in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: 3-Year Results from a Multicentre Cohort Study.

OBJECTIVES: To evaluate the effectiveness and safety of Qishen Yiqi Dripping Pill (QSYQ) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: This multicentre prospective cohort study was conducted at 40 centers in China. Patients with ACS after PCI entered either the QSYQ or Western medicine (WM) groups naturally based on whether they had received QSYQ before enrollment. QSYQ group received QSYQ (0.52 g, 3 times a day for 12 months) in addition to WM. The primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization. The secondary endpoint included rehospitalization due to ACS, heart failure, stroke, and other thrombotic events. Quality of life was assessed by the Seattle Angina Questionnaire (SAQ). RESULTS: A total of 936 patients completed follow-up of the primary endpoint from February 2012 to December 2018. Overall, 487 patients received QSYQ and WM. During a median follow-up of 566 days (inter quartile range, IQR, 517-602), the primary endpoint occurred in 46 (9.45%) and 65 (14.48%) patients in QSYQ and WM groups respectively [adjusted hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.41-0.90; P=0.013]. The secondary endpoint occurred in 61 (12.53%) and 74 (16.48%) patients in QSYQ and WM groups, respectively (adjusted HR 0.76, 95% CI 0.53-1.09; P=0.136). In sensitivity analysis, the results still demonstrated that WM combined with QSYQ reduced the risk of the primary endpoint (HR 0.67, 95% CI 0.46-0.98; P=0.039). Moreover, QSYQ improved the disease perception domain of the SAQ (P<0.05). CONCLUSION: In patients with ACS after PCI, QSYQ combined with WM reduced the incidence of the primary endpoint. These findings provide a promising option for managing ACS after PCI and suggest the potential treatment for reducing the risk of primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization through intermittent administration of QSYQ (Registration No. ChiCTR-OOC-14005552).

4EBP1-mediated SLC7A11 protein synthesis restrains ferroptosis triggered by MEK inhibitors in advanced ovarian cancer.

Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here, we show that ferroptosis negative regulation signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High-throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor-resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/eIF4E binding protein 1 (4EBP1) signaling promoted solute carrier family 7 member 11 (SLC7A11) protein synthesis, leading to ferroptosis inhibition in MEK inhibitor-resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR/4EBP1 axis to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.

CDK4/6 inhibition augments anti-tumor efficacy of XPO1 inhibitor selinexor in natural killer/T-cell lymphoma.

XPO1 is an attractive and promising therapeutic target frequently overexpressed in multiple hematological malignancies. The clinical use of XPO1 inhibitors in natural killer/T-cell lymphoma (NKTL) is not well documented. Here, we demonstrated that XPO1 overexpression is an indicator of poor prognosis in patients with NKTL. The compassionate use of the XPO1 inhibitor selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed (R/R) NKTL patients. Selinexor induced complete tumor regression and prolonged survival in sensitive xenografts but not in resistant xenografts. Transcriptomic profiling analysis indicated that sensitivity to selinexor was correlated with deregulation of the cell cycle machinery, as selinexor significantly suppressed the expression of cell cycle-related genes. CDK4/6 inhibitors were identified as sensitizers that reversed selinexor resistance. Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL.

Assessment of the impact of residual tumors at different sites post-neoadjuvant chemotherapy on prognosis in breast cancer patients and development of a disease-free survival prediction model.

Background: Residual disease after neoadjuvant chemotherapy (NAC) in breast cancer patients predicts worse outcomes than pathological complete response. Differing prognostic impacts based on the anatomical site of residual tumors are not well studied. Objectives: The study aims to assess disease-free survival (DFS) in breast cancer patients with different residual tumor sites following NAC and to develop a nomogram for predicting 1- to 3-year DFS in these patients. Design: A retrospective cohort study. Methods: Retrospective analysis of 953 lymph node-positive breast cancer patients with residual disease post-NAC. Patients were categorized into three groups: residual disease in breast (RDB), residual disease in lymph nodes (RDN), and residual disease in both (RDBN). DFS compared among groups. Patients were divided into a training set and a validation set in a 7:3 ratio. Prognostic factors for DFS were analyzed to develop a nomogram prediction model. Results: RDB patients had superior 3-year DFS of 94.6% versus 85.2% for RDN and 81.8% for RDBN (p < 0.0001). Clinical T stage, N stage, molecular subtype, and postoperative pN stage were independently associated with DFS on both univariate and multivariate analyses. Nomogram integrating clinical tumor-node-metastasis (TNM) stage, molecular subtype, pathological response demonstrated good discrimination (C-index 0.748 training, 0.796 validation cohort), and calibration. Conclusion: The location of residual disease has prognostic implications, with nodal residuals predicting poorer DFS. The validated nomogram enables personalized DFS prediction to guide treatment decisions.

Understanding the impact of residual tumor location on prognosis after breast cancer treatment After receiving neoadjuvant chemotherapy, a treatment to shrink tumors before surgery, some breast cancer patients may still have residual tumor cells. Our study focuses on how the location of these remaining tumors ­ whether in the breast, lymph nodes, or both ­ affects the likelihood of the cancer not returning within the next 1 to 3 years. This likelihood is known as 'disease-free survival' (DFS). We analyzed data from 953 breast cancer patients who underwent neoadjuvant chemotherapy and still had residual tumors. By comparing DFS among patients with tumors remaining in different locations, we discovered that the specific location of the residual tumor significantly impacts the patient's long-term health and recovery. Additionally, we developed a predictive tool called a 'nomogram' to help doctors and patients assess the risk of cancer recurrence in the next 1 to 3 years. This tool considers various factors such as the size and type of the tumor, as well as the location and extent of the residual tumor after chemotherapy. Our research offers new insights into understanding the risk of recurrence after breast cancer treatment. This work not only enhances our comprehension of breast cancer management but also aids in devising more personalized and effective treatment strategies for patients in the future.

Targeting AURKA to induce synthetic lethality in CREBBP-deficient B-cell malignancies via attenuation of MYC expression.

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

Fast, intelligent and high-precision adaptive null interferometry for optical freeform surfaces by backpropagation.

In the past 10 years, adaptive wavefront interferometry (AWI) has been employed for measuring freeform surface profiles. However, existing AWI techniques relying on stepwise and model-free stochastic optimizations have resulted in inefficient tests. To address these issues, deterministic adaptive wavefront interferometry (DAWI) is firstly introduced in this paper based on backpropagation (BP), which employs a loss function to simultaneously reconstruct and sparsify initial incomplete interferometric fringes until they are nulled. Each iteration of BP requires two phase shifts. Through simulations, we have verified that freeform wavefront error with a peak-to-valley (PV) of up to 168 λ can be fully compensated in tens of iterations using a 1024 × 1024 pixel area of a liquid-crystal spatial light modulator. In experiments, we accomplished a null test of a freeform surface with 80% missing interference fringes in 39 iterations, resulting in a surface profile error PV of 66.22 λ and measurement error better than λ/4. The DAWI has at least 20 times fewer iterations in fringe reconstruction than the 3-step AWI methods, and nearly an order of magnitude fewer iterations in the whole process, paving the way for significantly enhanced efficiency, generality and precision in freeform surface adaptive interferometry.

Fbxw7 suppresses carcinogenesis and stemness in triple-negative breast cancer through CHD4 degradation and Wnt/ß-catenin pathway inhibition.

BACKGROUND: Cancer stem cells (CSCs) are a small population of cells in tumor tissues that can drive tumor initiation and promote tumor progression. A small number of previous studies indirectly mentioned the role of F-box and WD repeat domain-containing 7 (FBXW7) as a tumor suppressor in Triple-negative breast cancer (TNBC). However, few studies have focused on the function of FBXW7 in cancer stemness in TNBC and the related mechanism. METHODS: We detected FBXW7 by immunohistochemistry (IHC) in 80 TNBC patients. FBXW7 knockdown and overexpression in MD-MBA-231 and HCC1937 cell models were constructed. The effect of FBXW7 on malignant phenotype and stemness was assessed by colony assays, flow cytometry, transwell assays, western blot, and sphere formation assays. Immunoprecipitation-Mass Spectrometry (IP-MS) and ubiquitination experiments were used to find and verify potential downstream substrate proteins of FBXW7. Animal experiments were constructed to examine the effect of FBXW7 on tumorigenic potential and cancer stemness of TNBC cells in vivo. RESULTS: The results showed that FBXW7 was expressed at low levels in TNBC tissues and positively correlated with prognosis of TNBC patients. In vitro, FBXW7 significantly inhibited colony formation, cell cycle progression, cell migration, EMT process, cancer stemness and promotes apoptosis. Further experiments confirmed that chromodomain-helicase-DNA-binding protein 4 (CHD4) is a novel downstream target of FBXW7 and is downregulated by FBXW7 via proteasomal degradation. Moreover, CHD4 could promote the nuclear translocation of ß-catenin and reverse the inhibitory effect of FBXW7 on ß-catenin, and ultimately activate the Wnt/ß-catenin pathway. Rescue experiments confirmed that the FBXW7-CHD4-Wnt/ß-catenin axis was involved in regulating the maintenance of CSC in TNBC cells. In animal experiments, FBXW7 reduced CSC marker expression and suppressed TNBC cell tumorigenesis in vivo. CONCLUSIONS: Taken together, these results highlight that FBXW7 degrades CHD4 protein through ubiquitination, thereby blocking the activation of the Wnt/ß-catenin pathway to inhibit the stemness of TNBC cells. Thus, targeting FBXW7 may be a promising strategy for therapeutic intervention against TNBC.

Pharmacological modulation of RB1 activity mitigates resistance to neoadjuvant chemotherapy in locally advanced rectal cancer.

Resistance to neoadjuvant chemotherapy leads to poor prognosis of locally advanced rectal cancer (LARC), representing an unmet clinical need that demands further exploration of therapeutic strategies to improve clinical outcomes. Here, we identified a noncanonical role of RB1 for modulating chromatin activity that contributes to oxaliplatin resistance in colorectal cancer (CRC). We demonstrate that oxaliplatin induces RB1 phosphorylation, which is associated with the resistance to neoadjuvant oxaliplatin-based chemotherapy in LARC. Inhibition of RB1 phosphorylation by CDK4/6 inhibitor results in vulnerability to oxaliplatin in both intrinsic and acquired chemoresistant CRC. Mechanistically, we show that RB1 modulates chromatin activity through the TEAD4/HDAC1 complex to epigenetically suppress the expression of DNA repair genes. Antagonizing RB1 phosphorylation through CDK4/6 inhibition enforces RB1/TEAD4/HDAC1 repressor activity, leading to DNA repair defects, thus sensitizing oxaliplatin treatment in LARC. Our study identifies a RB1 function in regulating chromatin activity through TEAD4/HDAC1. It also provides the combination of CDK4/6 inhibitor with oxaliplatin as a potential synthetic lethality strategy to mitigate oxaliplatin resistance in LARC, whereby phosphorylated RB1/TEAD4 can serve as potential biomarkers to guide the patient stratification.

Prediction Model of Adverse Pregnancy Outcome in Pre-Eclampsia Based on Logistic Regression and Random Forest Algorithm.

Aim: To construct a prediction model for adverse pregnancy outcomes of preeclampsia (PE). Thus assisting clinicians to identify high-risk patients. Provide guidance for treatment intervention. Methods: A retrospective study was conducted on 319 PE patients admitted to the Huzhou Maternal and Child Health Hospital from April 2021 to December 2022, The patients were divided into an adverse group (93 cases) and a non-adverse group (226 cases) based on whether they had adverse pregnancy outcomes after admission. Collect clinical data from patients, using a single factor analysis to screen statistically significant indicators as input variables, the outcome of the analysis is dependent on the incidence of PE adverse pregnancy outcomes. Divide patients into training and testing sets in a 7:3 ratio, Logistic regression model and random forest model were constructed respectively. Evaluate the predictive performance of two statistical models. Results: Among the 319 PE patients included 93 had adverse pregnancy outcomes after admission. Among them, Age (OR: 1.702, 95%CI: 1.069~2.710), small gestational age (OR: 0.757,95%CI: 0.607~0.945), more clinical symptoms (OR: 3.618, 95%CI: 1.682~7.783), high 24 h proteinuria (OR: 2.532, 95%CI: 1.290~4.968), low PLT index (OR: 0.616, 95%CI: 0.419~0.906), high AST index (OR: 1.554, 95%CI: 1.012~2.387), high D-Dimer index (OR:1.966, 95%CI: 1.183~3.267) were the influencing factors of adverse pregnancy outcomes in PE patients. The test set found that the random forest model was superior to the Logistic regression model in predicting the risk of adverse pregnancy outcomes in PE patients. Conclusions: The random forest model has good stability in predicting the risk of adverse pregnancy outcomes in PE, and its prediction efficiency is better than the Logistic regression model.

The Impact of Sentinel Lymph Node Biopsy on Female Patients With T3-4c Breast Cancer and 1-2 Positive Lymph Nodes: A Population-Based Cohort Study.

PURPOSE: This study aimed to evaluate the efficacy of sentinel lymph node biopsy (SLNB) in patients diagnosed with cT3-4c breast cancer with no more than 2 positive sentinel lymph nodes. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) database, this retrospective study identified patients diagnosed with T3-4c breast cancer between 2010 and 2015. These patients were then categorized into 2 groups: the SLNB group, which underwent examination of 1-5 regional lymph nodes and the axillary lymph node dissection (ALND) group, which underwent examination of ≥10 regional lymph nodes. Propensity score matching analysis was used to assess the efficacy of SLNB in cT3-4c patients. RESULTS: A total of 1139 patients were included in the analysis, with 423 and 716 patients in the SLNB and ALND groups, respectively. The 10-year overall survival (OS) and breast cancer-specific survival (BCSS) rates in the SLNB group were 66.1% and 76.3%, respectively, compared with 66.0% and 73.8%, respectively. Statistical analysis revealed no significant differences between the 2 groups in terms of OS (HR = 1.00, 95% CI = 0.80-1.25, P = .997) and BCSS (HR = 1.08, 95% CI = 0.83-1.41, P = .551). Even after 1:1 propensity score matching, there were no significant differences in OS (HR = 0.87, 95% CI = 0.65-1.16, P = .341) and BCSS (HR = 0.82, 95% CI = 0.59-1.16, P = .266) between the 2 groups. CONCLUSION: This study demonstrates that SLNB does not adversely affect the survival of cT3-4c breast cancer patients with 1-2 sentinel lymph node metastases.

Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies.

OBJECTIVES: Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling. DESIGN: Integrative multiomics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining and single-cell spatial transcriptomics were used to explore the immunogenicity of diverse CCA. RESULTS: We identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth in in vitro and in vivo models. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH-mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive to oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intratumour differences in AA mutation load were correlated to intratumour variation of different immune cell populations. CONCLUSION: Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumourigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits.

Research hotspots and trends in the relationship between genetics and major depressive disorder: A scientometric analysis from 2003 to 2023.

To determine current research objectives and predict future trends in studies on the relationship between genetics and major depressive disorder (MDD). We collected the publications in the last 20 years (2003-2023) related to genetics and MDD in the Web of Science database, and applied Citespace to assess the knowledge mapping. The number of manuscripts about genetics and MDD totaled 9200, with a faster increase after 2013. The country, institution, and author with the most publications are the USA, the University of London, and Serretti, Alessandro. BIOL PSYCHIAT published the most articles in this field. In addition, the most co-cited reference is Sullivan PF (2000) (673). Genetic and MDD research, including the hippocampus, and HPA axis may become the focus of research in the future. Based on a 20-year scientometric investigation, we know the USA, China, and Germany have emerged as the important research forces in this discipline. The strongest collaborations between developed countries and renowned institutions are beneficial to the advancement of genetic and MDD research. Serotonin is the strongest citation bursts keyword.

Research hotspots and trends on post-cesarean section analgesia: A scientometric analysis from 2001 to 2021.

This study aims to demonstrate current research priorities and predict future trends of post-cesarean section analgesia by scientometric analysis. We collected nearly 20 years (2002-2021) of publications related to post-cesarean section analgesia in the web of science database. Citespace was applied to evaluate the knowledge mapping. There are 2735 manuscripts about the post-cesarean section in total. The country, institution, and author posted the most separately are the USA, Univ Calif Irvine, and BRENDAN CARVALHO. INTERNATIONAL JOURNAL OF OBSTETRIC ANESTHESIA (21) publishes the most articles of this type, and ANESTHESIOLOGY has the greatest impact (1496 co-citations). In addition, the most key cited reference is McDonnell, J.G (43). Post-cesarean section analgesia research, including spinal anesthesia, postoperative pain, and epidural analgesia, has been a research hotspot in recent years. Through scientometric analysis of the past 20 years, we know the TAP blocks and drug selection in patient-controlled analgesia are the focus of future research. The USA, China, and Turkey have become the main research forces in this field, with high publication rates and centrality. This is important for accurately and quickly locating trends in this field.

Enhancer remodeling activates NOTCH3 signaling to confer chemoresistance in advanced nasopharyngeal carcinoma.

Acquired resistance to chemotherapy is one of the major causes of mortality in advanced nasopharyngeal carcinoma (NPC). However, effective strategies are limited and the underlying molecular mechanisms remain elusive. In this study, through transcriptomic profiling analysis of 23 tumor tissues, we found that NOTCH3 was aberrantly highly expressed in chemoresistance NPC patients, with NOTCH3 overexpression being positively associated with poor clinical outcome. Mechanistically, using an established NPC cellular model, we demonstrated that enhancer remodeling driven aberrant hyperactivation of NOTCH3 in chemoresistance NPC. We further showed that NOTCH3 upregulates SLUG to induce chemo-resistance of NPC cells and higher expression of SLUG have poorer prognosis. Genetic or pharmacological perturbation of NOTCH3 conferred chemosensitivity of NPC in vitro and overexpression of NOTCH3 enhanced chemoresistance of NPC in vivo. Together, these data indicated that genome-wide enhancer reprogramming activates NOTCH3 to confer chemoresistance of NPC, suggesting that targeting NOTCH3 may provide a potential therapeutic strategy to effectively treat advanced chemoresistant NPC.

A Nomogram for Identifying HR+/Her2- Breast Cancer Patients with Positive Sentinel Lymph Nodes and Omitted Axillary Lymph Node Dissection Who Need Abemaciclib Therapy.

BACKGROUND The efficacy of abemaciclib in high-risk patients with early-stage HR+/Her2- breast cancer has been verified by MonarchE. However, accurately determining the number of axillary lymph node (ALN) metastases remains challenging. The Z0011 trial changed the axillary management strategy, eliminating the need for axillary lymph node dissection (ALND) in patients with 1-2 sentinel lymph node (SLN) metastases. Therefore, further exploration is needed to identify patients who could benefit from abemaciclib therapy. MATERIAL AND METHODS This retrospective study included cT1-2N0M0 HR+/Her2- patients with 1-2 positive SLNs who underwent ALND. Clinicopathological data were collected, and logistic regression analyses identified independent predictors for ≥4 positive ALNs. A predictive nomogram was developed, and discrimination and calibration were evaluated using the C-index and calibration curve. Clinical efficacy was assessed using decision curve analysis (DCA). RESULTS We enrolled 444 patients, with 77 (17.3%) having ≥4 positive ALNs. Independent predictors for ≥4 positive ALNs included abnormal ALN on ultrasound, mammographic calcifications, T stage, and the number of positive SLNs. The nomogram demonstrated an AUC of 0.777 (95% CI: 0.735-0.815, P<0.001), and internal validation showed good calibration and discrimination (C-index, 0.802; 95% CI: 0.779-0.824). DCA revealed a positive net benefit for risk levels ranging from 5% to 54%. CONCLUSIONS This nomogram is a convenient and reliable tool to predict the risk of ≥4 positive ALNs in HR+/Her2- patients. It aids in protocol selection by identifying SLN-positive patients who may benefit from abemaciclib therapy without ALND.

A novel machine learning model for predicting clinical pregnancy after laparoscopic tubal anastomosis.

BACKGROUND: Laparoscopic tubal anastomosis (LTA) is a treatment for women who require reproduction after ligation, and there are no reliable prediction models or clinically useful tools for predicting clinical pregnancy in women who receive this procedure. The prediction model we developed aims to predict the individual probability of clinical pregnancy in women after receiving LTA. METHODS: Retrospective analysis of clinical data of patients undergoing LAT in the Second Hospital of Lanzhou University from July 2017 to December 2021. Least absolute shrinkage and selection operator (LASSO) regression was used for data dimension reduction and feature selection. We incorporated the patients' basic characteristics, preoperative laboratory tests and laparoscopic tubal anastomosis procedure signature and obtained a nomogram. The model performance was evaluated in terms of its calibration, discrimination, and clinical applicability. The prediction model was further internally validated using 200 bootstrap resamplings. RESULTS: A total of 95 patients were selected to build the predictive model for clinical pregnancy after LTA. The LASSO method identified age, intrauterine polyps, pelvic adhesion and thyroid stimulating hormone(TSH) as independent predictors of the clinical pregnancy rate. The prediction nomogram included the abovementioned four predictive parameters. The model showed good discrimination with an area under the curve (AUC) value of 0.752. The Hosmer‒Lemeshow test of calibration showed that χ2 was 4.955 and the p value was 0.838, which indicates a satisfactory goodness-of-fit. Decision curve analysis demonstrated that the nomogram was clinically useful. Internal validation shows that the predictive model performs well. CONCLUSION: This study presents a nomogram incorporating age, intrauterine polyps, pelvic adhesion and TSH based on the LASSO regression model, which can be conveniently used to facilitate the individualized prediction of clinical pregnancy in women after LTA.