tbuckley/cabot-search huggingface dataset:
PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression
Authors: Teresa Gagliano, Kalpit Shah, Sofia Gargani, Liyan Lao, Mansour Alsaleem, Jianing Chen, Vasileios Ntafis, Penghan Huang, Angeliki Ditsiou, Viviana Vella, Kritika Yadav, Kamila Bienkowska, Giulia Bresciani, Kai Kang, Leping Li, Philip Carter, Graeme Benstead-Hume, Timothy O’Hanlon, Michael Dean, Frances M.G. Pearl, Soo-Chin Lee, Emad A. Rakha, Andrew R. Green, Dimitris L. Kontoyiannis, Erwei Song, Justin Stebbing, Georgios Giamas
Journal: Journal of Clinical Investigation (2020)

As there is growing evidence for the tumor microenvironment's role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple-negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of cancer progression. Although PIK3Cδ was expressed in primary fibroblasts derived from TNBC patients, it was barely detectable in breast cancer (BC) cell lines. Genetic and pharmacological gain- and loss-of-function experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3Cδ confers its protumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, that led to upregulation of NR4A1 in TNBC cells, where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, along with a decrease in tumor metastasis, emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA data sets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease-free survival, highlighting it as a therapeutic target for TNBC.
Abstract MP11: Effects of Metformin and Behavioral Weight Loss on the Gut Microbiome
Authors: Noel T Mueller, Moira K Differding, Nisa Maruthur, Stephen Juraschek, Edgar R Miller, Hsin-Chieh Yeh
Journal: Circulation (2020)

Background: Evidence suggests metformin and behavioral weight loss alter the gut microbiome, with weight loss associated with higher diversity and metformin with higher Escherichia Coli . Yet randomized trials on these interventions are limited. Objective: To examine the hypothesis that metformin increases E. Coli and and behavioral weight loss increases diversity. Methods: We conducted a parallel-arm, randomized trial in which we enrolled overweight or obese adult cancer survivors who had been previously treated for solid tumors, but without active disease or ongoing cancer treatment. We randomized participants (n=121) to: 1) coach-directed behavioral weight loss (with advice on the DASH diet), 2) metformin, or 3) self-directed weight loss (control). We collected stool at baseline, 6 mo. and 12 mo. and extracted microbial DNA from stool to measure the microbiome with 16S rRNA sequencing of the V4 region. We used ‘Aldex2’ in R to examine the effect of treatments on the change in relative abundance of microbial taxa amplicon sequence variants from baseline to 6 mo. and 12 mo. Results: Groups did not differ by sex (79% female), race (45% black) or age (mean 60 yrs). Mean weight loss was 3.9%, 2.7%, and 0.9% in coach-directed, metformin, and self-directed arms at 6-mo., respectively (both P s&lt;0.05 compared to self-directed.) There were no differences within or between arms in measures of alpha or beta diversity ( P s&gt;0.05). Only the metformin arm altered the relative abundance of microbiota ( Figure ). From baseline, metformin increased relative abundance of E. Coli and decreased relative abundance of butyrate-producing Ruminococcus Intestinalis and Intestinibacter Bartletti at 6 mo. and 12 mo. Metformin also decreased Roseburia Faecis at 6 mo. and increased Ruminococcus Torques at 12 mo. ( Figure ). Conclusion: Metformin increased E. Coli and decreased several butyrate-producing genera, but was not associated with microbiome diversity. Moderate behavioral weight loss (~3.9%) did not alter microbiome diversity or composition.
PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer
Authors: Brian Diskin, Salma Adam, Marcelo F. Cassini, Gustavo Sanchez, Miguel Liria, Berk Aykut, Chandan Buttar, Eric Li, Belen Sundberg, Ruben D. Salas, Ruonan Chen, Junjie Wang, Mirhee Kim, Mohammad Saad Farooq, Susanna Nguy, Carmine Fedele, Kwan Ho Tang, Ting Chen, Wei Wang, Mautin Hundeyin, Juan A. Kochen Rossi, Emma Kurz, Muhammad Israr Ul Haq, Jason Karlen, Emma Kruger, Zennur Sekendiz, Dongling Wu, Sorin A. A. Shadaloey, Gillian Baptiste, Gregor Werba, Shanmugapriya Selvaraj, Cynthia Loomis, Kwok-Kin Wong, Joshua Leinwand, George Miller
Journal: Nature Immunology (2020)
Evaluation of gemcitabine plus carboplatin in pretreated, metastatic breast cancer patients: Final analysis of a phase II trial
Authors: D. Laessig, U. Vehling-Kaiser, H. J. Stemmler, P. Fasching, F. Melchert, H. Koelbl, M. Stauch, A. Scharl, G. Morack, V. Heinemann
Journal: Journal of Clinical Oncology (2007)

1074 Background: There is an increasing proportion of metastatic breast cancer patients (pts) who have been exposed to anthracyclines and taxanes either during perioperative treatment or during intial therapy of metastatic disease. The efficacy of gemcitabine plus cisplatin has been consistently demonstrated in several trials. This study evaluates the combination of gemcitabine plus carboplatin as a treatment option for intensively pretreated breast cancer pts. Methods: Metastatic breast cancer pts were treated with gemcitabine (1,000 mg/m 2 iv on days 1 and 8) and carboplatin (AUC 4 iv on day 1) in a 3-week regimen. The trial was performed as a 2-stage phase II study according to the optimal design described by Simon (p 0 = 0.1, p 1 = 0.3, a = 0.05, β = 0.1) with overall remission rate (according to RECIST) as the primary objective. Results: 39 pts were recruited, median age was 60 years (29–77 yrs): median Karnofsky performance status was 90% (range, 70–100%), 77% of pts were ER- and/or PR-positive, and 28% of pts presented with Her-2 overexpression (IHC 3+ or FISH-positive). 87% of pts had visceral metastasis and 79.5% had =2 sites of metastasis. All patients had received prior chemotherapy and 92% of pts had received prior anthracyclines (87%) and/or taxanes (67%). Prior endocrine therapy had been applied to 77% of patients. Median follow-up time was 13.2 months (1–27 months) during which 207 treatment cycles were documented with a median number of 5 cycles per pt (range 1–12). A CR was observed in 1 pt, a PR in 11 pts for an overall remission rate of 31% (95%-CI: 17–48%). Stable disease was documented in 12 pts (31%) resulting in a disease control rate of 61.5%. Median time to remission was 2.6 months (1.3–5.1 months), median time to progression was 4.9 months (95%CI, 2.6–6.7 months), and overall survival was 13,2 months (95% CI, 8.7–16.7 months). Grade 3–4 leucopenia (NCI-CTC) was observed in 64%, neutropenia in 51%, thrombocytopenia in 49%, and anemia in 10% of pts. Conclusion: Gemcitabine plus carboplatin is an effective and well tolerated treatment option in intensively pretreated breast cancer pts. No significant financial relationships to disclose.
The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis
Authors: Mengnuo Chen, Chun-Ming Wong
Journal: Molecular Cancer (2020)

Abstract Liver cancer is a common cancer worldwide. Although the etiological factors of liver carcinogenesis are well defined, the underlying molecular mechanisms remain largely elusive. Epigenetic deregulations, such as aberrant DNA methylation and histone modifications, play a critical role in liver carcinogenesis. Analogous to DNA and core histone proteins, reversible chemical modifications on mRNA have recently been recognized as important regulatory mechanisms to control gene expression. N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in mammalian cells. m6A modification is important for controlling many cellular and biological processes. Deregulation of m6A modification has been recently implicated in human carcinogenesis, including liver cancer. In this review, we summarize the recent findings on m6A regulation and its biological impacts in normal and cancer cells. We will focus on the deregulation of m6A modification and m6A regulators in liver diseases and liver cancers. We will highlight the clinical relevance of m6A deregulation in liver cancer. We will also discuss the potential of exploiting m6A modification for cancer diagnosis and therapeutics.
Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit
Authors: Jianlei Cao, Xiaorong Hu, Wenlin Cheng, Lei Yu, Wen-Jun Tu, Qiang Liu
Journal: Intensive Care Medicine (2020)

In December, 2019, a series of pneumonia cases of unknown cause emerged in Wuhan, Hubei, China [1] and further a novel coronavirus was isolated from lower respiratory tract samples, which was further named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) [2].The SARS-CoV-2 disease was officially given the name of Corona Virus Disease 2019 (COVID-19) on 11 February, 2020.In this study, we examine which treatments are being used, assess clinical and laboratory features and short-term outcomes of patients with COVID-19 in intensive care unit (ICU).This retrospective case series involved 102 adult patients with COVID-19 admitted to Wuhan University Zhongnan Hospital in Wuhan, China, between January 3 and February 1, 2020.All those patients received a laboratory-confirmed SARS-CoV-2 infection diagnosis [3].Epidemiological, clinical, radiological characteristics, underlying diseases, laboratory tests at admission and during hospitalization, treatment, complications and outcomes data were collected [3,4].Patients outcomes (discharge or death) and admission to ICU (yes or no) were followed up at discharge until February 15, 2020.The study was approved by Zhongnan Hospital Ethics Committee, and oral consent was obtained from patients or relatives.Demographic details of the included 102 patients are shown in the supplementary table 1.All patients were
A clinical assessment of MedisGroups
Authors: L I Iezzoni, M A Moskowitz
Journal: JAMA (1988)

Interest has focused recently on measuring severity of illness, both to improve the fairness of diagnosis related group-based reimbursement and to facilitate judgments about hospital quality of care. MedisGroups is a prominent, proprietary severity-measurement system, recently mandated for use by all Pennsylvania hospitals. We reviewed MedisGroups and its key clinical findings. MedisGroups produces admission scores, from 0 through 4, indicating increasing risk of imminent organ failure. Score computation is independent of diagnosis, but many key clinical findings are disease specific and require particular diagnostic technologies. Using a database including patients 65 years of age and older from 24 hospitals, we found that fewer than 1% of patients with scores of 0 or 1 died in-hospital, compared with 60% of those with scores of 4. Questions remain about the impact of the procedural nature of many key clinical findings and the independence from diagnosis. Further study is needed to determine the utility of MedisGroups for policy purposes.
Abstract P311: Engagement of a Community Advisory Board Informs an Exercise Intervention in Older African-American Couples
Authors: Lyndsey M Hornbuckle, Amy Rauer
Journal: Circulation (2020)

Introduction: Older African-Americans (AA) are vulnerable to cardiometabolic health disparities. As physical inactivity is highly prevalent in this population and regular exercise can help mitigate cardiometabolic disease, collaborations between the local community and academic researchers are needed to create sustainable exercise interventions. To this end, the current investigators formed a community advisory board (CAB) to consult on an interdisciplinary pilot intervention study that would examine the effects of couples-based resistance training plus walking on: 1) exercise adherence; 2) cardiometabolic risk factors (abdominal obesity, blood pressure, insulin resistance, hemoglobin A1c, high-density lipoprotein and total cholesterol, triglycerides, C-reactive protein, fibrinogen); and 3) the provision of partner support and receptivity to partner health influence in older AA romantic couples. Hypothesis: CAB consultation would enhance the proposed pilot study methods and facilitate community engagement. Methods: Seven local community members/leaders with a stake in the health of the AA community were invited to participate in two CAB meetings. In the meetings, investigators proposed ideas to pilot a novel exercise intervention in older AA couples and solicited input in four key areas: 1) priority health concerns of the target population; 2) the proposed study protocol; 3) cultural relevance; 4) and sustainability. Recorded responses were summarized and coded using a qualitative thematic analysis approach. Results: Multiple themes surfaced within each of the four focus areas including confirmation of the need to study cardiometabolic disease risk (e.g. hypertension, diabetes) in this population, potential recruitment challenges and suggestions to relax exclusion criteria, exclusion of potentially beneficial program components (e.g. flexibility training, education), the need for culturally-specific adaptations (e.g. incorporating music, providing AA role models), and long-term community engagement (i.e. future efforts to launch the intervention at the community level). Investigators made multiple study modifications per CAB recommendations. Conclusions: CAB feedback suggested the proposed intervention would be well-received and considered both beneficial and relevant by the community. CAB-recommended study modifications underscore the value of a community-partnered approach to intervention design that promotes cultural relevance and sustainability. These characteristics support the ultimate goal of reducing cardiometabolic health disparities in AA communities. Although the investigators recognize the current method deviates from true community-based participatory research that originates within a community, the model presented is beneficial as it engages the community in the developmental stage of evidence-based research.
Abstract P282: A Simple Clinical Scoring System Using Readily Available Clinical Measures for Prediction of Non-alcoholic Fatty Liver Disease: Evidence From the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Luis A Rodriguez, Stephen Shiboski, Patrick Bradshaw, Alicia Fernandez, David M Herrington, Jingzhong Ding, Ryan D Bradley, Alka M Kanaya
Journal: Circulation (2020)

Background: Many patients have risk factors for non-alcoholic fatty liver disease (NAFLD), the leading cause of liver disease in the US. Screening all patients with risk factors for NAFLD using ultrasound or computed tomography (CT) is not always possible. We present a practical scoring tool for predicting presence of NAFLD based on common anthropometric measurements, clinical parameters and patient characteristics. Methods: We used cross-sectional data from 6,194 white, African American, Hispanic, and Chinese American participants from the Multi-Ethnic Study of Atherosclerosis, ages 45-85 years. Liver fat attenuation was measured by CT scans ( &lt; 40 Hounsfield units identifies hepatic steatosis). We selected risk factors that are routinely available in clinical practice. We used random forest-derived variable importance to select 9 final predictors among 18 candidates. These were used to develop a logistic regression-based score predicting occurrence of NAFLD in a random 2/3 derivation subset of the sample. Calibration and discrimination performance was assessed in the remaining 1/3 validation sample using goodness of fit measures, area under the receiver operating characteristic curve (AUC) and Brier scores. Results: NAFLD prevalence was 6.2% in the overall sample (n=6,194). The table shows the 9 predictors with beta coefficients, OR (95% CI) and points. Using the point-based system, the derivation set achieved an AUC of 0.84 (95% CI, 0.84 to 0.86), and the validation set an AUC of 0.81 (0.78 to 0.85). The Hosmer-Lemeshow goodness-of-fit test had a p=0.15, and the Brier score was 0.06 for the validation set, indicating that our validation model was well calibrated with acceptable prediction performance. At &gt; 27 points, sensitivity was 83%, specificity 66% and Youden’s index was 0.49. Conclusions: Our NAFLD point system is a simple but highly predictive score system that can allow clinicians to identify individuals at high risk of NAFLD. Future studies should evaluate prediction performance in an external dataset.
Abstract P444: Changes in Glucose-Lowering Medication Prescriptions After an Incident Cardiovascular Event Across eGFR Levels in an Integrated Health System
Authors: Jung-Im Shin, Elizabeth Selvin, Lesley Inker, Jodie Reider, Alex R CHANG, Morgan Grams
Journal: Circulation (2020)

Introduction: Cardiovascular disease is a major complication among patients with diabetes, and may merit changes in both antihypertensive medications (e.g., to beta blockers and ACE inhibitors) and glucose-lowering medications (e.g., to sodium-glucose cotransporter 2 inhibitors [SGLT2i] and glucagon-like peptide 1 receptor agonists [GLP1 RA], medication classes with evidence of cardiovascular outcome benefit). The objective of this study was to assess how glucose-lowering medication prescriptions changed after a cardiovascular event among persons with diabetes. Hypothesis: There are changes in glucose-lowering medication prescription following a cardiovascular event. Methods: We identified adult patients with diabetes and estimated glomerular filtration rate (eGFR)≥15mL/min/1.73 m 2 who experienced a cardiovascular event (myocardial infarction, stroke, or heart failure) from 2005-2018 in the Geisinger Health System (cases). We selected control patients with diabetes but without a cardiovascular event by 1:1 matching on demographics, diabetes duration, HbA1c, eGFR, and calendar year. Results: In 15,918 matched case and control patients with diabetes (mean age 65 years, 52% female, mean HbA1c 7.55%, median diabetes duration 5.6 years, and 28% eGFR&lt;60 mL/min/1.73 m 2 ), insulin prescriptions increased and metformin prescriptions decreased after a cardiovascular event among cases compared with controls in all eGFR categories ( Table ). There were no differences between cases and controls with respect to changes in SGLT2i, GLP1 RA, or dipeptidyl peptidase 4 inhibitors (DPP4i). Conclusions: In a real-world setting, insulin prescriptions increased and metformin prescriptions decreased, after a cardiovascular event regardless of eGFR level. Prescriptions for SGLT2i and GLP1 RA did not change following a cardiovascular event in all eGFR categories. More efforts are needed to provide optimal therapies for cardiovascular risk reduction in patients with diabetes and cardiovascular disease.
Abstract P2-05-07: Pan-cancer analysis of PARP inhibition reveals a suite of biomarkers that correlate with PARP1/2 activity in breast cancer
Authors: Martina SJ McDermott, Dylan F Conklin, Neil A O'Brien, Kevin Chau, Dennis J Slamon
Journal: Cancer Research (2020)

Abstract The development of multiple PARP inhibitors in BRCA mutant cancers has been one of the most successful implementations of molecularly targeted therapies in oncology. The recent approval of niraparib in BRCA WT Ovarian cancers demonstrates the potential for expansion of PARP inhibitors to other BRCA WT indications. The successful development of PARP inhibitors into new cancer indications will depend on using molecular biomarkers to identify tumors with a unique dependency on PARP1/2 activity. We screened a large (N=523), diverse panel of human cancer cell lines for response to three approved PARP inhibitors: olaparib, niraparib, and talazoparib. Despite differences in relative potency, there was a strong correlation between sensitive and resistant cell lines to all three compounds. In vitro experimentation revealed the inhibitors share a similar biologic mechanism of response, namely a global decrease in PARylation, as well as PARP-trapping at DNA nicks leading to G2 arrest and ultimately cell death. A suite of baseline genomic and proteomic characteristics were found to be strongly associated with response to PARP1/2 inhibition, and were largely consistent between different cancer types. Special attention was paid to BRCA1/2 variants, which represent the only approved patient selection biomarkers. Notably, neither mutations in BRCA1 nor BRCA2 were found to be associated with response to PARP1/2 inhibition in our panel, even when restricting to those with confirmed deleterious ClinVar scores. The molecular predictors of response identified in our screen may ultimately be used to develop diagnostic tools for enrollment into biomarker-enriched clinical trials to expand the use of this promising class of drug into areas of high unmet need. Triple-negative breast cancer represents one of the most intriguing spaces for development. The clinical failures in this space may be partially explained by the lack of empirical predictive biomarkers in the trial design. Our diagnostics may finally allow for the efficacious deployment of PARP inhibitors to triple-negative breast cancer. In particular we have identified a panel of biomarkers that can predict for sensitivity to PARP inhibitors in breast cancer that could be used as patient selection criteria for the expanded clinical development of these compounds into PARP-naïve patient populations with high unmet need. Citation Format: Martina SJ McDermott, Dylan F Conklin, Neil A O'Brien, Kevin Chau, Dennis J Slamon. Pan-cancer analysis of PARP inhibition reveals a suite of biomarkers that correlate with PARP1/2 activity in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-07.
Novel side-by-side metal stent placement for recurrent hepatic hilar obstruction after placement of multiple metal stents
Authors: Yoshikuni Nagashio, Susumu Hijioka, Yuya Kanai, Akihiro Ohba, Yuta Maruki, Takuji Okusaka, Yutaka Saito
Journal: Endoscopy (2020)

Endoscopic re-intervention following placement of multiple self-expandable metal stents (SEMSs) is challenging [1] [2] [3]. A suitable re-intervention for malignant hilar biliary obstruction (MHBO) is not available. Plastic stents are used for re-intervention following placement of multiple SEMSs, but advancing the plastic stents through the mesh of the SEMS is difficult. This report describes successful side-by-side (SBS) metal stent deployment for recurrent MHBO after placement of SEMSs.
Abstract 15468: Healthcare Resource Utilization and Costs Among US Patients With Worsening Chronic Heart Failure: Analysis of PINNACLE Registry Linked With Claims Data
Authors: Michael M Givertz, Eileen Fonseca, Mei Yang, Gregory P Hess, Thomas Rhodes, Massimiliano A Manzi, Mahesh J Patel, Javed Butler
Journal: Circulation (2017)

Introduction: The annual total cost of heart failure (HF) in the US is over $30 billion, a large component of which is due to the >1 million HF hospitalizations. As patients develop progressive sym...