tbuckley/cabot-search huggingface dataset:
Digital assessment of tertiary lymphoid structures and therapeutic responses in gastric cancer: A multi-centric retrospective study
Authors: Yan Chen, Zepang Sun, Junmei Yin, M. Usman Ahmad, Zixia Zhou, Wanying Feng, Fan Yang, Kangneng Zhou, Jingjing Xie, Caiqun Bie, Hongzhuan Chen, Yuming Jiang
Journal: International Journal of Surgery (2024)

Background: Tertiary lymphoid structures (TLSs) are associated with favorable prognosis and enhanced response to anti-cancer therapy. A digital assessment of TLSs could provide an objective alternative that mitigates variability inherent in manual evaluation. This study aimed to develop and validate a digital gene panel based on biological prior knowledge for assessment of TLSs, and further investigate its associations with survival and multiple anti-cancer therapies. Materials and Methods: The present study involved 1,704 patients with gastric cancer from seven cancer centers. TLSs were identified morphologically through hematoxylin-and-eosin staining. We further developed a digital score based on targeted gene expression profiling to assess TLSs status, recorded as gene signature of tertiary lymphoid structures (gsTLS). For enhanced interpretability, we employed the SHapley Additive exPlanation (SHAP) analysis to elucidate its contribution to the prediction. We next evaluated the signature’s associations with prognosis, and investigated its predictive accuracy for multiple anti-cancer therapies, including adjuvant chemotherapy and immunotherapy. Results: The gsTLS panel with nine gene features achieved high accuracies in predicting TLSs status in the training, internal and external validation cohorts (area under the curve, range: 0.729–0.791). In multivariable analysis, gsTLS remained an independent predictor of disease-free and overall survival (hazard ratio, range: 0.346–0.743, all P &lt; 0.05) after adjusting for other clinicopathological variables. SHAP analysis highlighted gsTLS as the strongest predictor of TLSs status compared with clinical features. Importantly, patients with high gsTLS (but not those with low gsTLS) exhibited substantial benefits from adjuvant chemotherapy ( P &lt; 0.05). Furthermore, we found that the objective response rate to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy was significantly higher in the high-gsTLS group (40.7%) versus the low-gsTLS group (5.6%, P = 0.036), and the diagnosis was independent from Epstein–Barr virus (EBV), tumor mutation burden (TMB), and programmed cell death-ligand 1 (PD-L1) expression. Conclusion: The gsTLS digital panel enables accurate assessment of TLSs status, and provides information regarding prognosis and responses to multiple therapies for gastric cancer.
Early admission is better-the time to admission (TTA) is associated with one-year mortality in hip fracture
Authors: Bin-Fei Zhang, Shuai-Liang Xu, Zhi Yang, Peng Xu
Journal: International Journal of Surgery (2024)

Objective: This study evaluated the probable association between time to admission (TTA) and one-year mortality in geriatric hip fractures. Methods: Older adult patients with hip fractures were screened between January 2015 and September 2019. The demographic and clinical characteristics of the patients were collected at the largest trauma center in northwest China. TTA can be obtained from the medical record system and converted into a categorical variable. Multivariate binary logistic regression and generalized additive model were used to identify the linear and nonlinear association between TTA and one-year mortality. Analyses were performed using EmpowerStats and the R software. Results: Two thousand three hundred and sixty-one patients who met the criteria were finally included. There were 1618 (68.53%) female and 743 (31.47%) male patients. All patients were divided into three groups according to their TTA. The proportions of patients with low (&lt;=6 h), middle (&gt;6, &lt;=24 h), and high (&gt;24 h) waiting times were 995, 654, and 712, respectively, and the corresponding one-year mortality rates were 62 (6.23%), 72 (11.01%), and 82 (11.52%). We found a curve relationship between TTA and one-year mortality by two-piecewise linear regression, and 9 hours was an inflection point. When TTA was less than 9 hours, the one-year mortality of patients increased by 9% for every 1-hour increase in TTA (OR=1.09, 95%CI: 1.03-1.16; P &lt;0.01). When TTA was greater than 9 hours, the mortality of patients no longer increased with the rise of TTA (OR=1.00, 95%CI:1.00-1.00; P =0.26). Conclusion: TTA is a probable predictor of one-year mortality. We found that 9 hours is an inflection point. If TTA is less than 9 hours, the mortality rate of patients will be lower. If it takes more than 9 hours, the mortality will be higher. Therefore, the elderly who are found to have possible hip fractures should be admitted to the hospital as soon as possible.
Optimum tacrolimus trough levels for enhanced graft survival and safety in kidney transplantation: a retrospective multicenter real-world evidence study
Authors: Ahram Han, Ae Jeong Jo, Hyunwook Kwon, Young Hoon Kim, Juhan Lee, Kyu Ha Huh, Kyo Won Lee, Jae Berm Park, Eunju Jang, Sun Cheol Park, Joongyub Lee, Jeongyun Lee, Younghye Kim, Mohamed Soliman, Sangil Min
Journal: International Journal of Surgery (2024)

Background: The current study aimed to determine the optimal tacrolimus trough levels for balancing graft survival and patient safety following kidney transplantation. Materials and Methods: We conducted a retrospective cohort study involving 11,868 kidney transplant recipients from five medical centers. The association between tacrolimus exposures (periodic mean trough level, coefficient of variability, time in therapeutic range) and composite allograft outcome (de novo donor specific antibody, biopsy-proven rejection, kidney dysfunction, and graft failure), as well as safety outcomes (severe infection, cardiovascular events, malignancy, and mortality) were assessed. Data were sourced from Clinical Data Warehouses and analyzed using advanced statistical methods, including Cox marginal structural models with inverse probability treatment weighting. Results: Tacrolimus levels of 5.0–7.9 ng/mL and 5.0–6.9 ng/mL during the 2–12 month and 12–72 month post-transplantation periods, respectively, were associated with reduced risks of composite allograft outcomes. During the first post-transplant year, the adjusted hazard ratios (aHR) for composite allograft outcomes were: 0.69 (95% CI 0.55–0.85, P &lt;0.001) for 5.0–5.9 ng/mL; 0.81 (95% CI 0.67–0.98, P =0.033) for 6.0–6.9 ng/mL; and 0.73 (95% CI 0.60–0.89, P =0.002) for 7.0–7.9 ng/mL (compared to levels ≥8.0 ng/mL). For the 6-year composite outcomes, aHRs were 0.68 (95% CI 0.53–0.87, P =0.002) for 5.0–5.9 ng/mL and 0.65 (95% CI 0.50–0.85, P =0.001) for 6.0–6.9 ng/mL. These optimal ranges showed reduced rates of severe infection (6 y), malignancy (6 y), and mortality (1 y). Conclusion: This multicenter study provides robust evidence for optimal tacrolimus trough levels during the periods 2–12 and 12–72 months following kidney transplantation.
CT-Based AI model for predicting therapeutic outcomes in ureteral stones after single extracorporeal shock wave lithotripsy through a cohort study
Authors: Huancheng Yang, Xiang Wu, Weihao Liu, Zhong Yang, Tianyu Wang, Weifan You, Baiwei Ye, Bingni Wu, Kai Wu, Haoyang Zeng, Hanlin Liu
Journal: International Journal of Surgery (2024)

Objectives: Exploring the efficacy of an artificial intelligence (AI) model derived from the analysis of computed tomography (CT) images to precisely forecast the therapeutic outcomes of singular-session extracorporeal shock wave lithotripsy (ESWL) in the management of ureteral stones. Methods: A total of 317 patients diagnosed clinically with ureteral stones were included in this investigation. Unenhanced CT was administered to the participants within the initial fortnight preceding the inaugural ESWL. The internal cohort consisted of 250 individuals from a local healthcare facility, whereas the external cohort comprised 67 participants from another local medical institution. The proposed framework comprises three main components: an automated semantic segmentation model developed using 3D U-Net, a feature extractor that integrates radiomics and autoencoder techniques, and an ESWL efficacy prediction model trained with various machine learning algorithms. All participants underwent thorough postoperative follow-up examinations 4 weeks hence. The efficacy of ESWL was defined by the absence of stones or residual fragments measuring ≤2 mm in KUB X-ray assessments. Model stability and generalizability were judiciously validated through a fivefold cross-validation approach and a multicenter external test strategy. Moreover, Shapley Additive Explanations (SHAP) values for individual features were computed to elucidate the nuanced contributions of each feature to the model’s decision-making process. Results: The semantic segmentation model the authors constructed exhibited an average Dice coefficient of 0.88±0.08 on the external testing set. ESWL classifiers built using Support Vector Machine (SVM), Random Forest (RF), XGBoost (XB), and CatBoost (CB) achieved AUROC values of 0.78, 0.84, 0.85, and 0.90, respectively, on the internal validation set. For the external testing set, SVM, RF, XB, and CB predicted ESWL with AUROC values of 0.68, 0.79, 0.80, and 0.83, respectively, with the last one being the optimal algorithm. The radiomics features and auto-encoder features made significant contributions to the decision-making process of the classification model. Conclusions: This investigation unmistakably underscores the remarkable predictive prowess exhibited by a scrupulously crafted AI model using CT images to precisely anticipate the therapeutic results of a singular session of ESWL for ureteral stones.
Application of indocyanine green fluorescence imaging in hepatobiliary surgery
Authors: Jia Zhou, Zhiguo Tan, Bo Sun, Yufang Leng, Sulai Liu
Journal: International Journal of Surgery (2024)

Indocyanine green (ICG) is a fluorescent dye with an emission wavelength of about 840 nm, which is selectively absorbed by the liver after intravenous or bile duct injection, and then it is excreted into the intestines through the biliary system. With the rapid development of fluorescence laparoscopy, ICG fluorescence imaging is safe, feasible, and widely used in hepatobiliary surgery. ICG fluorescence imaging is of great significance in precise preoperative and intraoperative localization of liver lesions, real-time visualization of hepatic segmental anatomy, intrahepatic and extrahepatic biliary tract visualization, and liver transplantation. ICG fluorescence imaging facilitates efficient intraoperative hepatobiliary decision-making and improves the safety of minimally invasive hepatobiliary surgery. Advances in imaging systems will increase the use of fluorescence imaging as an intraoperative navigation tool, improving the safety and accuracy of open and laparoscopic/robotic hepatobiliary surgery. Herin, we have reviewed the status of ICG applications in hepatobiliary surgery, aiming to provide new insights for the development of hepatobiliary surgery.
The role of immune cell signatures in the pathogenesis of ovarian-related diseases: a causal inference based on mendelian randomization
Authors: Yangguang Lu, Yingyu Yao, Sijia Zhai, Feitian Ni, Jingyi Wang, Feng Chen, Yige Zhang, Haoyang Li, Hantao Hu, Hongzhi Zhang, Bohuai Yu, Hongbo Chen, Xianfeng Huang, Weiguo Ding, Di Lu
Journal: International Journal of Surgery (2024)

Background: Immune cells play a pivotal role in maintaining ovarian function. However, the specific contributions of different immune cell phenotypes to the pathogenesis of specific ovarian-related diseases remain poorly understood. We aim to investigate the correlation between 731 immunophenotypes and ovarian-related diseases. Materials and Methods: Utilizing publicly available genetic data, we undertook a series of quality control measures to identify instrumental variables (IVs) associated with exposure. Subsequently, we conducted two-sample Mendelian randomization (MR) using inverse variance weighting to explore the causal relationships between 731 immune cell features and six ovarian-related diseases: ovarian cysts, ovarian dysfunction, premature ovarian failure (POF), polycystic ovary syndrome (PCOS), benign neoplasm of ovary, and malignant neoplasm of ovary at the genetic level. Sensitivity analyses, including leave-one-out and other MR analysis models, were performed. Finally, Bayesian colocalization (COLOC) analysis was employed to identify specific co-localized genes, thereby validating the MR results. Results: At the significance level corrected by Bonferroni, four immune phenotypes, including CD25 on IgD- CD38- B cells, were associated with ovarian cysts; four immune phenotypes, including CD39+ CD4+ T cell Absolute Count, were associated with ovarian dysfunction; eight immune phenotypes, including SSC-A on HLA DR+ CD8+ T cells, were associated with POF; five immune phenotypes, including CD20- CD38- B cell Absolute Count, were associated with PCOS; five immune phenotypes, including CD4+ CD8dim T cell Absolute Count, were associated with benign ovarian tumors; and three immune phenotypes, including BAFF-R on IgD- CD38+ B cells, were associated with malignant ovarian tumors. Sensitivity analysis indicated robust results. COLOC analysis identified four immune cell co-localized variants (rs150386792, rs117936291, rs75926368, rs575687159) with ovarian diseases. Conclusion: Our study elucidates the close genetic associations between immune cells and six ovarian-related diseases, thereby providing valuable insights for future research endeavors and clinical applications.
Mitoferrin2 is a synthetic lethal target for chromosome 8p deleted cancers
Authors: Stephan Krieg, Thomas Rohde, Tobias Rausch, Luise Butthof, Lena Wendler-Link, Christoph Eckert, Kai Breuhahn, Bruno Galy, Jan Korbel, Maximilian Billmann, Marco Breinig, Darjus F. Tschaharganeh
Journal: Genome Medicine (2024)

Somatic copy number alterations are a hallmark of cancer that offer unique opportunities for therapeutic exploitation. Here, we focused on the identification of specific vulnerabilities for tumors harboring chromosome 8p deletions. We developed and applied an integrative analysis of The Cancer Genome Atlas (TCGA), the Cancer Dependency Map (DepMap), and the Cancer Cell Line Encyclopedia to identify chromosome 8p-specific vulnerabilities. We employ orthogonal gene targeting strategies, both in vitro and in vivo, including short hairpin RNA-mediated gene knockdown and CRISPR/Cas9-mediated gene knockout to validate vulnerabilities. We identified SLC25A28 (also known as MFRN2), as a specific vulnerability for tumors harboring chromosome 8p deletions. We demonstrate that vulnerability towards MFRN2 loss is dictated by the expression of its paralog, SLC25A37 (also known as MFRN1), which resides on chromosome 8p. In line with their function as mitochondrial iron transporters, MFRN1/2 paralog protein deficiency profoundly impaired mitochondrial respiration, induced global depletion of iron-sulfur cluster proteins, and resulted in DNA-damage and cell death. MFRN2 depletion in MFRN1-deficient tumors led to impaired growth and even tumor eradication in preclinical mouse xenograft experiments, highlighting its therapeutic potential. Our data reveal MFRN2 as a therapeutic target of chromosome 8p deleted cancers and nominate MFNR1 as the complimentary biomarker for MFRN2-directed therapies.
CRISPR-Cas9 screens reveal common essential miRNAs in human cancer cell lines
Authors: Daniel J. Merk, Linda Paul, Foteini Tsiami, Helen Hohenthanner, Ghazal Mohseni Kouchesfahani, Lara A. Haeusser, Bianca Walter, Adam Brown, Nicole S. Persky, David E. Root, Ghazaleh Tabatabai
Journal: Genome Medicine (2024)

Abstract Background Genome-wide functional screening using the CRISPR-Cas9 system is a powerful tool to uncover tumor-specific and common genetic dependencies across cancer cell lines. Current CRISPR-Cas9 knockout libraries, however, primarily target protein-coding genes. This limits functional genomics-based investigations of miRNA function. Methods We designed a novel CRISPR-Cas9 knockout library (lentiG-miR) of 8107 distinct sgRNAs targeting a total of 1769 human miRNAs and benchmarked its single guide RNA (sgRNA) composition, predicted on- and off-target activity, and screening performance against previous libraries. Using a total of 45 human cancer cell lines, representing 16 different tumor entities, we performed negative selection screens to identify miRNA fitness genes. Fitness miRNAs in each cell line were scored using a combination of supervised and unsupervised essentiality classifiers. Common essential miRNAs across distinct cancer cell lines were determined using the 90th percentile method. For subsequent validation, we performed knockout experiments for selected common essential miRNAs in distinct cancer cell lines and gene expression profiling. Results We found significantly lower off-target activity for protein-coding genes and a higher miRNA gene coverage for lentiG-miR as compared to previously described miRNA-targeting libraries, while preserving high on-target activity. A minor fraction of miRNAs displayed robust depletion of targeting sgRNAs, and we observed a high level of consistency between redundant sgRNAs targeting the same miRNA gene. Across 45 human cancer cell lines, only 217 (12%) of all targeted human miRNAs scored as a fitness gene in at least one model, and fitness effects for most miRNAs were confined to small subsets of cell lines. In contrast, we identified 49 common essential miRNAs with a homogenous fitness profile across the vast majority of all cell lines. Transcriptional profiling verified highly consistent gene expression changes in response to knockout of individual common essential miRNAs across a diverse set of cancer cell lines. Conclusions Our study presents a miRNA-targeting CRISPR-Cas9 knockout library with high gene coverage and optimized on- and off-target activities. Taking advantage of the lentiG-miR library, we define a catalogue of miRNA fitness genes in human cancer cell lines, providing the foundation for further investigation of miRNAs in human cancer.
Phase 3 randomized <scp>COMMODORE</scp> 2 trial: Crovalimab versus eculizumab in patients with <scp>paroxysmal nocturnal hemoglobinuria</scp> naive to complement inhibition
Authors: Alexander Röth, Guangsheng He, Hongyan Tong, Zenghua Lin, Xiaoqin Wang, Chatree Chai‐Adisaksopha, Je‐Hwan Lee, Andres Brodsky, Chattree Hantaweepant, Teresita E. Dumagay, Roberta Demichelis‐Gómez, Ponlapat Rojnuckarin, Jing Sun, Martin Höglund, Jun Ho Jang, Anna Gaya, Fernando Silva, Naoshi Obara, Richard J. Kelly, Leigh Beveridge, Simon Buatois, Sammy Chebon, Brittany Gentile, Pontus Lundberg, Sasha Sreckovic, Jun‐ichi Nishimura, Antonio Risitano, Bing Han
Journal: American Journal of Hematology (2024)

Abstract Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low‐volume self‐administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open‐label, multicenter, phase 3 trial evaluating the non‐inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor‐naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co‐primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT‐Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non‐inferior to eculizumab in the co‐primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, −2.8 [−15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, −3.9 [−14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [−11.4, 16.3]). A clinically meaningful improvement in FACIT‐Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit–risk profile of crovalimab.
Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma
Authors: Diogo Maia-Silva, Patrick J. Cunniff, Allison C. Schier, Damianos Skopelitis, Marygrace C. Trousdell, Philip Moresco, Yuan Gao, Vahag Kechejian, Xue-Yan He, Yunus Sahin, Ledong Wan, Aktan Alpsoy, Jynelle Liverpool, Adrian R. Krainer, Mikala Egeblad, David L. Spector, Douglas T. Fearon, Camila O. dos Santos, Dylan J. Taatjes, Christopher R. Vakoc
Journal: Nature Genetics (2024)
Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial
Authors: Steven M. Horwitz, Ajit J. Nirmal, Jahan Rahman, Ran Xu, Esther Drill, Natasha Galasso, Nivetha Ganesan, Theresa Davey, Helen Hancock, Leslie Perez, Catherine Maccaro, Alexandra Bahgat, Evan Marzouk, Elizabeth Cathcart, Alison Moskowitz, Ariela Noy, Anita Kumar, Eric Jacobsen, David C. Fisher, Neha Mehta-Shah, Youn H. Kim, Michael Khodadoust, Nikita Kotlov, Anastasia Nikitina, Olga Kudryashova, Valeria Zubareva, Ksenia Zornikova, Nara Shin, Maria Sorokina, Sandrine Degryse, Ekaterina Postovalova, Aleksander Bagaev, Kinga Hosszu, Devin McAvoy, Jaap J. Boelens, Wenchao Wu, Zoe Ciantra, Jackson W. Appelt, Christopher Trevisani, Sam Amaka, David M. Weinstock, Santosha A. Vardhana
Journal: Nature Medicine (2024)
Women’s health and rights in the twenty-first century
Authors: Samuel Akombeng Ojong, Marleen Temmerman, Rajat Khosla, Flavia Bustreo
Journal: Nature Medicine (2024)

In the twenty-first century, the complex relationship between women's health and rights has been influenced by a range of interconnected challenges, including gender inequity, reproductive health disparities, maternal mortality and morbidity, and women's inability to access life-saving, high-quality healthcare services including family planning. Going forward, the world needs to find ways to implement the unfinished agenda of the International Conference on Population and Development (ICPD) 1994 and the Sustainable Development Goals (SDGs), thus prioritizing health and rights for women and girls as essential not only to their survival but also to their progress, agency and empowerment. It is also important to consider the interconnection between women's health and rights and climate change, with its disproportionate impact on the well-being of girls and women, and to address the impact and opportunities afforded by digital technologies. By embracing a holistic approach, societies might be able to advance the cause of women's health and rights in a more inclusive and sustainable manner. This Review explores the intersectionality between women's sexual and reproductive health and rights against the backdrop of technological advances and global crises and provides a set of actionable priorities to advance this cause.