tbuckley/cabot-search huggingface dataset:
Intraoperative Evaluation of Breast Tissues During Breast Cancer Operations Using the MasSpec Pen
Authors: Kyana Y. Garza, Mary E. King, Chandandeep Nagi, Rachel J. DeHoog, Jialing Zhang, Marta Sans, Anna Krieger, Clara L. Feider, Alena V. Bensussan, Michael F. Keating, John Q. Lin, Min Woo Sun, Robert Tibshirani, Christopher Pirko, Kirtan A. Brahmbhatt, Ahmed R. Al-Fartosi, Alastair M. Thompson, Elizabeth Bonefas, James Suliburk, Stacey A. Carter, Livia S. Eberlin
Journal: JAMA Network Open (2024)

Importance Surgery with complete tumor resection remains the main treatment option for patients with breast cancer. Yet, current technologies are limited in providing accurate assessment of breast tissue in vivo, warranting development of new technologies for surgical guidance. Objective To evaluate the performance of the MasSpec Pen for accurate intraoperative assessment of breast tissues and surgical margins based on metabolic and lipid information. Design, Setting, and Participants In this diagnostic study conducted between February 23, 2017, and August 19, 2021, the mass spectrometry–based device was used to analyze healthy breast and invasive ductal carcinoma (IDC) banked tissue samples from adult patients undergoing breast surgery for ductal carcinomas or nonmalignant conditions. Fresh-frozen tissue samples and touch imprints were analyzed in a laboratory. Intraoperative in vivo and ex vivo breast tissue analyses were performed by surgical staff in operating rooms (ORs) within 2 different hospitals at the Texas Medical Center. Molecular data were used to build statistical classifiers. Main Outcomes and Measures Prediction results of tissue analyses from classification models were compared with gross assessment, frozen section analysis, and/or final postoperative pathology to assess accuracy. Results All data acquired from the 143 banked tissue samples, including 79 healthy breast and 64 IDC tissues, were included in the statistical analysis. Data presented rich molecular profiles of healthy and IDC banked tissue samples, with significant changes in relative abundances observed for several metabolic species. Statistical classifiers yielded accuracies of 95.6%, 95.5%, and 90.6% for training, validation, and independent test sets, respectively. A total of 25 participants enrolled in the clinical, intraoperative study; all were female, and the median age was 58 years (IQR, 44-66 years). Intraoperative testing of the technology was successfully performed by surgical staff during 25 breast operations. Of 273 intraoperative analyses performed during 25 surgical cases, 147 analyses from 22 cases were subjected to statistical classification. Testing of the classifiers on 147 intraoperative mass spectra yielded 95.9% agreement with postoperative pathology results. Conclusions and Relevance The findings of this diagnostic study suggest that the mass spectrometry–based system could be clinically valuable to surgeons and patients by enabling fast molecular-based intraoperative assessment of in vivo and ex vivo breast tissue samples and surgical margins.
Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding
Authors: Alvi A. Rahman, Robert W. Platt, Sarah Beradid, Jean-François Boivin, Soham Rej, Christel Renoux
Journal: JAMA Network Open (2024)

Importance Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants associated with a small increased risk of major bleeding. However, the risk of bleeding associated with the concomitant use of SSRIs and oral anticoagulants (OACs) has not been well characterized. Objectives To assess whether concomitant use of SSRIs with OACs is associated with an increased risk of major bleeding compared with OAC use alone, describe how the risk varies with duration of use, and identify key clinical characteristics modifying this risk. Design, Setting, and Participants A population-based, nested case-control study was conducted among patients with atrial fibrillation initiating OACs between January 2, 1998, and March 29, 2021. Patients were from approximately 2000 general practices in the UK contributing to the Clinical Practice Research Datalink. With the use of risk-set sampling, for each case of major bleeding during follow-up, up to 30 controls were selected from risk sets defined by the case and matched on age, sex, cohort entry date, and follow-up duration. Exposures Concomitant use of SSRIs and OACs (direct OACs and vitamin K antagonists [VKAs]) compared with OAC use alone. Main Outcomes and Measures The main outcome was incidence rate ratios (IRRs) of hospitalization for bleeding or death due to bleeding. Results There were 42 190 patients with major bleeding (mean [SD] age, 74.2 [9.3] years; 59.8% men) matched to 1 156 641 controls (mean [SD] age, 74.2 [9.3] years; 59.8% men). Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OACs alone (IRR, 1.33; 95% CI, 1.24-1.42). The risk peaked during the initial months of treatment (first 30 days of use: IRR, 1.74; 95% CI, 1.37-2.22) and persisted for up to 6 months. The risk did not vary with age, sex, history of bleeding, chronic kidney disease, and potency of SSRIs. An association was present both with concomitant use of SSRIs and direct OACs compared with direct OAC use alone (IRR, 1.25; 95% CI, 1.12-1.40) and concomitant use of SSRIs and VKAs compared with VKA use alone (IRR, 1.36; 95% CI, 1.25-1.47). Conclusions and Relevance This study suggests that among patients with atrial fibrillation, concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OAC use alone, requiring close monitoring and management of risk factors for bleeding, particularly in the first few months of use.
Stroke rehabilitation in adults: summary of updated NICE guidance
Authors: Eugene Tang, Nicola Moran, Mark Cadman, Stephen Hill, Claire Sloan, Elizabeth Warburton
Journal: BMJ (2024)

### What you need to know Globally, stroke is the second leading cause of death and the third leading cause of death and disability combined.1 Around 100 000 people have strokes each year, and around 1.3 million people in the UK have survived a stroke.2 High quality rehabilitation can minimise the physical, emotional, cognitive, and social impacts for people who have had a stroke and their carers, and yield substantial cost savings to society.3 The National Institute for Health and Care Excellence (NICE) first published guidance on stroke rehabilitation in adults in 2013.4 The guidance was updated in October 2023 to include appraisal of new evidence.5 This guideline summary covers selected new and updated recommendations in the 2023 update, and will focus on those most relevant to primary care and community rehabilitation settings. NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the guideline development group's experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italics in square brackets. Evidence certainty is based on GRADE criteria (box 1). Box 1 ### GRADE Working Group grades of evidenceRETURN TO TEXT
The effects of pregnancy, its progression, and its cessation on human (maternal) biological aging
Authors: Hung Pham, Tara Thompson-Felix, Darina Czamara, Jerod M. Rasmussen, Adam Lombroso, Sonja Entringer, Elisabeth B. Binder, Pathik D. Wadhwa, Claudia Buss, Kieran J. O’Donnell
Journal: Cell Metabolism (2024)
Effect of allogeneic hematopoietic stem cell transplantation on sickle cell disease‐related organ complications: A systematic review and meta‐analysis
Authors: Elisabeth Dovern, Mesire Aydin, Michael R. DeBaun, Komeil Alizade, Bart J. Biemond, Erfan Nur
Journal: American Journal of Hematology (2024)

Sickle cell disease (SCD)-related organ complications are a major cause of morbidity and mortality in patients with SCD. We sought to assess whether hematopoietic stem cell transplantation (HSCT) stabilizes, attenuates, or exacerbates organ decline. We performed a systematic review and meta-analysis of trials investigating organ function before and after HSCT in patients with SCD. We searched MEDLINE/PubMed and EMBASE up to September 21, 2023. Continuous data were expressed as standardized mean difference (SMD) and pooled in a weighted inverse-variance random-effects model; binomial data were expressed as risk ratio (RR) using the Mantel-Haenszel random-effects meta-analyses. Of 823 screened studies, 34 were included in this review. Of these, 17 (774 patients, 23.6% adults, 86.3% HLA-identical sibling donor, 56.7% myeloablative conditioning regimen) were included in the meta-analyses. Pulmonary function remained stable. Mean tricuspid regurgitant jet velocity decreased but did not reach statistical significance. In children, estimated glomerular filtration rate decreased (SMD -0.80, p = .01), and the presence of proteinuria increased (RR 2.00, p = <.01), while splenic uptake and phagocytic function improved (RR 0.31, p = <.01; RR 0.23, p = <.01). Cerebral blood flow improved (SMD -1.39, p = <.01), and a low incidence of stroke after transplantation in high-risk patients was found. Retinopathy and avascular osteonecrosis were investigated in only one study, showing no significant changes. While HSCT can improve some SCD-related organ dysfunctions, transplantation-related toxicity may have an adverse effect on others. Future research should focus on identifying individuals with SCD who might benefit most from HSCT and which forms of organ damage are more likely to exacerbate post-transplantation.
ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype
Authors: Naveen Sharma, Xiaozhou Fan, Oluwatomisin T. Atolagbe, Zhongqi Ge, Kelly N. Dao, Padmanee Sharma, James P. Allison
Journal: The Journal of Experimental Medicine (2024)

We have previously demonstrated synergy between ICOS costimulation (IVAX; ICOSL-transduced B16-F10 cellular vaccine) and CTLA-4 blockade in antitumor therapy. In this study, we employed CyTOF and single-cell RNA sequencing and observed significant remodeling of the lymphoid and myeloid compartments in combination therapy. Compared with anti-CTLA-4 monotherapy, the combination therapy enriched Th1 CD4 T cells, effector CD8 T cells, and M1-like antitumor proinflammatory macrophages. These macrophages were critical to the therapeutic efficacy of anti-CTLA-4 combined with IVAX or anti-PD-1. Macrophage depletion with clodronate reduced the tumor-infiltrating effector CD4 and CD8 T cells, impairing their antitumor functions. Furthermore, the recruitment and polarization of M1-like macrophages required IFN-γ. Therefore, in this study, we show that there is a positive feedback loop between intratumoral effector T cells and tumor-associated macrophages (TAMs), in which the IFN-γ produced by the T cells polarizes the TAMs into M1-like phenotype, and the TAMs, in turn, reshape the tumor microenvironment to facilitate T cell infiltration, immune function, and tumor rejection.
Abstract 3378: Acinar cell susceptibility for tumor development in the pancreas: Targeting the critical regulators for therapy
Authors: Zhaolong Pan, Jan-Lars Van den Bossche, Eva Rodriguez-Aznar, Pauline Janssen, Olaya Lara, Gamze Ates, Ann Massie, Diedert Luc De Paep, Isabelle Houbracken, Marco Mambretti, Ilse Rooman
Journal: Cancer Research (2024)

Abstract Acinar to ductal metaplasia (ADM) or acinar cell dedifferentiation is one of the most notable features of chronic pancreatitis. It is also considered the initial step of pancreatic cancer development when oncogenic mutations accumulate. However, its precise mechanism and regulatory pathways remain unclear. This study profiled the transcriptome of dedifferentiated acinar cells from both humans and mice. Differential expression analysis integrated with a systematic literature search revealed several potential regulators (e.g., GDF15, GFRA1, MXRA5, CXCL17), of which the expression pattern over time was validated by qRT-PCR. We also focused on multiple conserved pathways of cell survival, among which SLC7A11 (xCT) is transiently upregulated in both species. The xCT subunit, integral to the cystine/glutamate antiporter system xc-, plays a critical role in cell survival across various cell types. To elucidate its role in acinar dedifferentiation, we employed gene silencing, pharmacological inhibition, and a knock-out mouse model. Acinar cells with diminished xCT function exhibit increased ferroptosis linked to lipid peroxidation. Antioxidants such as N-acetylcysteine and ferroptosis inhibitors like Ferrostatin-1 can mitigate lower glutathione levels and lipid ROS accumulation. Similarly, in mouse acute pancreatitis, xCT prevents lipid peroxidation. Our findings indicate that xCT fuels the glutathione pool and maintains ROS balance during ADM, thereby preventing pancreatic acinar cells from ferroptosis, a form of cell death rarely reported in relation to ADM. Next to xCT, a future and similar comprehensive study of the aforementioned genes could provide valuable insights into the dynamic changes that occur during acinar cell dedifferentiation and pave the way to the discovery of new intervention targets to suppress tumorigenesis in chronic pancreatitis. Citation Format: Zhaolong Pan, Jan-Lars Van den Bossche, Eva Rodriguez-Aznar, Pauline Janssen, Olaya Lara, Gamze Ates, Ann Massie, Diedert Luc De Paep, Isabelle Houbracken, Marco Mambretti, Ilse Rooman. Acinar cell susceptibility for tumor development in the pancreas: Targeting the critical regulators for therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3378.
Abstract 896: Predicting metastatic transcriptomes of patient tumors with deep learning
Authors: Gang Li, Evan Béal, Dean Sumner, Giorgio G. Galli, Viviana Cremasco, Joshua M. Korn, Frank Dondelinger, David Ruddy, Audrey Kauffmann, Slavica Dimitrieva
Journal: Cancer Research (2024)

Abstract Metastases are the primary cause of cancer-related death, and improving the means of predicting and targeting their development is one of the major goals in cancer research. While surgical resection and neo-adjuvant therapy can cure well-confined primary tumors, our ability to effectively treat cancer is largely dependent on our capacity to interdict the process of metastasis. The recent accumulation of ‘omics data from metastatic tumors provides an unprecedented opportunity to develop machine learning models to predict the molecular changes during metastasis and explore the patterns of metastasis formation. With this in mind, we developed MetMapper, a deep learning model trained on primary and metastatic tumors from &amp;gt; 13 000 patients integrating data from 11 published data resources. MetMapper can predict the transcriptomic changes of a primary tumor when it metastasizes to different distant organs. The results were extensively validated using transcriptomics data from matched primary and metastatic tumor biopsies extracted from the same patients. Furthermore, MetMapper’s predictions revealed that the non-random patterns of cancer metastases can be partly explained by the degree of transcriptome reprogramming needed during metastasis: primary tumors tend to metastasize to organs that require minimal changes to their transcriptomes. Using MetMapper, we derived a metastatic potential score for patient tumors and demonstrate that this score can be used to stratify patients into high and low survival groups across different indications. The predicted metastatic potential of patient tumors significantly correlates with experimentally characterized metastatic potential of cancer cell lines. Additionally, by performing in-silico perturbations of genes and oncogenic pathways that can alter the metastatic potential of patient tumors, we identified genomic features that are highly associated with metastases to specific organs, some of which were reported by existing pan-cancer clinical sequencing studies. Our results demonstrate the utility of MetMapper as a novel AI-powered methodology for investigating mechanisms and patterns of metastatic dissemination, as well as forecasting metastatic outcomes of patient tumors. Citation Format: Gang Li, Evan Béal, Dean Sumner, Giorgio G. Galli, Viviana Cremasco, Joshua M. Korn, Frank Dondelinger, David Ruddy, Audrey Kauffmann, Slavica Dimitrieva. Predicting metastatic transcriptomes of patient tumors with deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 896.
Abstract 90: <i>In vitro</i> functional evaluation of immuno-oncology drug candidates in customized bioassays
Authors: Martijn Vlaming, Emmanuelle Sidot, Jezabel Lefèvre, Ellen Boelen, Sofie Pattyn
Journal: Cancer Research (2024)

Abstract Increased understanding of the complex tumor microenvironment and its interactors has boosted therapeutic interest and highlighted the importance of the development of innovative in vitro bioassays to represent all the players of the cancer immune response and thereby potentially provide pivotal information on the functional dynamics of candidate therapeutics. Regulatory T cells play an important role by downregulating the anti-tumor response. Their regulation mechanisms constitute an important target for new therapeutics. To study these mechanisms in a human model, suppressive Treg bioassays, mimicking the suppressive action of these cells, were developed and optimized. We further highlight the study of neutrophil function in vitro using flow-cytometry or the Incucyte® live imaging system to monitor neutrophil functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), Neutrophil Extracellular Traps (NETs) formation and the release of Reactive Oxygen Species (ROS). Additionally, multiplex cytokine and peroxidase enzyme analysis after activation and stimulation of neutrophils can be evaluated using ELISA or Luminex technology. Moreover, to refine/reduce non-human primate (NHP) usage, we aimed to develop cost-effective NHP in vitro assays with predictive value for in vivo studies. We isolated Cynomolgus Macaque monocytes and successfully differentiated/polarized them into M0- and M2-like macrophages with a cell surface phenotype comparable to that of their human counterparts. We further developed a Cynomolgus Macaque PBMC x human dendritic cell (DC) mixed lymphocyte reaction (MLR) assay for functional evaluation of test compounds, effectively generated Cynomolgus Macaque immature DCs and implemented Cynomolgus Macaque cytokine release assays.Using high quality primary human immune cells from our own biobank, in vitro bioassays have been developed with superior robustness and reproducibility to screen candidate Immuno-Oncology therapeutics. Citation Format: Martijn Vlaming, Emmanuelle Sidot, Jezabel Lefèvre, Ellen Boelen, Sofie Pattyn. In vitro functional evaluation of immuno-oncology drug candidates in customized bioassays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 90.
Abstract 5683: lncRNA-protein interactions that predict response to endocrine therapy in HR+ breast cancer
Authors: Kacie D. Waiters, Maram Quttina, Ashfia F. Khan, Samaneh Karami, Anthony S. Peidl, Funmi Babajide, Tasneem Bawa-Khalfe
Journal: Cancer Research (2024)

Abstract Hormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed BCa type accounting for 70% of all breast cancer cases. A large population of HR+ BCa patients (30-40%) are resistant to mainstay endocrine therapy and develop incurable metastatic disease. Hence, it is imperative to identify viable biomarkers that stratify patients as drug responders or non-responders. Emerging scientific literature highlights the essential role of long non-coding RNAs (lncRNA) in cancer drug resistance and metastatic transformation; lncRNA include RNAs over 200 nucleotides in length that do not encode protein. Major biological functions of lncRNA rely on association with select protein interactors. As lncRNA equally bind proteins with and without canonical RNA-binding motifs, it is unclear what facilitates this lncRNA-protein interaction. Our recent studies show that SUMO post-translational modification (or SUMOylation) of target proteins potentiates binding with lncRNA, particularly at the chromatin. Using a small-scale screening, we see that SUMO-modification works to enhance association with lncRNAs for proteins with and without a canonical RNA binding domain (RBD). SUMOylation of RBD-expressing heterochromatin protein 1 α (HP1α) drives interaction with multiple chromatin-associated lncRNA both within and outside canonical heterochromatin foci. Interaction with lncRNA supports SUMOylated HP1α’s unconventional function as a transcriptional repressor at select euchromatic loci. We now report an inverse relationship in which SUMOylated HP1α directs the stability of its lncRNA binding partner. Specifically, SUMO-modified HP1α directs cell-cycle dependent recruitment of the RNA degradation machinery to the chromatin and facilitates clearance of chromatin-bound lncRNA. This dynamic lncRNA degradation process is disturbed with cancer onset and instead favors aberrant cancer cell transformation. Consistently, restoring lncRNA degradation homeostasis decreases metastatic properties of HR+ BCa cells and increases sensitivity to targeted therapeutics currently in clinical trials. Our studies define a fundamental mechanism that dictates lncRNA stability and/or degradation in BCa cells. In addition, we present viable biomarkers that predict sensitivity to ET and alternative targeted therapies. Citation Format: Kacie D. Waiters, Maram Quttina, Ashfia F. Khan, Samaneh Karami, Anthony S. Peidl, Funmi Babajide, Tasneem Bawa-Khalfe. lncRNA-protein interactions that predict response to endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5683.