tbuckley/cabot-search huggingface dataset:
Clinical features and outcome in never-smoker (NS) non-small cell lung cancer (NSCLC) patients (pts): A single-institution observational analysis.
Authors: Chiara Bennati, Rita Chiari, Giulio Metro, Daniela Iacono, Marileila Varella-Garcia, Dara Aisner, Vincenzo Minotti, Marialuisa Meacci, Luca Paglialunga, Verena De Angelis, Luca Marcomigni, Vienna Ludovini, Francesca Romana Tofanetti, Sara Baglivo, Guido Bellezza, Lucio Crino
Journal: Journal of Clinical Oncology (2014)

e22152 Background: NSCLC in NS often harbors proto-oncogene aberrations, showing enrichment for targetable alterations compared to unselected populations. Objectives of this study were to define the proportions of the driver gene alterations and to examine survival in genotype-specific subsets of NS NSCLC. Methods: We identified 243 NS NSCLC pts treated at our Institution from October 2003 to January 2014. Pts with tissue available for biological analysis were as follows: 207 pts (85.1%) assessable for EGFR/KRAS mutation, 77 (31.6%) for ALK rearrangement, 37 (15.2%) for ROS1 rearrangement, 33 (13.5%) and 32 (13.1%) for RET fusion and HER2 mutation. The cohort comprised 58% women, median age 62, 86% advanced adenocarcinomas (10% brain metastases at diagnosis). Results: Out of 207 tumors, frequency of EGFR and KRAS mutation was 42.5% (88 pts) and 7.7% (16), respectively. Among pts screened for ALK, ROS1, RET, HER2, the proportion of individual testing, were 25.9% (20), 13.5% (5), 9% (3), 0%. 228 pts were evaluable for treatment and outcomes.158 pts (69%) received at least one line of an EGFR tyrosine kinase inhibitor (TKI), of which 42 (27%) as first line. 16 pts (7%) received an ALK/ROS1 inhibitor, and 8 pts (4%) had both treatments, 50 pts (21%) received exclusively chemotherapy. Median progression-free survival (PFS) after treatment with first line EGFR TKI was 13.2 months (mo) vs 5.3 mo for chemotherapy (p<0.001). Median PFS after a II line TKI (114 pts) was 14.1 mo. Median overall survival (OS) for EGFR mutans, ALK/ROS1 positive and chemotherapy-only treated pts was: 31.8 mo, not reached, and 14.1 mo, respectively (p<0.001). Median OS for KRAS mutated vs KRASwt pts was 32.2 mo vs 17.4 mo (p 0.363). Conclusions: The study confirmed the clinical and outcome features which make lung cancer in NS a distinct disease. Of particular note is the marked increase in OS with EGFR TKI therapy when evaluating this subset in contrast to previous studies not specifically focusing on NS.
Minimal Change in CAR T Cell Manufacturing Can Impact in Expansion and Side Effect of the CAR T Cell Therapy
Authors: Francesco Ceppi, Colleen Annesley, Olivia Finney, Corinne Summers, Stephanie Rhea, Isaac C. Jenkins, Qian V. Wu, Wen Yang, Michael A. Pulsipher, Alan S. Wayne, Julie R. Park, Rebecca Gardner, Michael C. Jensen
Journal: Blood (2018)
Abstract 10624: Proteasomal Degradation of O-GlcNAc Transferase Enhances Hypoxia-mediated Vascular Endothelial Inflammatory Response
Authors: Hongtao Liu, Yu Li, Jian Xu
Journal: Circulation (2013)

Hypoxia enhances vascular endothelial inflammatory response by mechanism not fully understood. Emerging evidence implicates O-GlcNAc transferase (OGT) in both hypoxia and vascular inflammation. We ...
Trends in the quality of preventive care before and after prostate cancer diagnosis.
Authors: Lauren P. Wallner, Jeffrey M Slezak, Ronald K. Loo, Roshan Bastani, Steven J. Jacobsen
Journal: Journal of Clinical Oncology (2014)

6605 Background: Most men diagnosed with prostate cancer will die from other causes, making preventive care for comorbid diseases of aging critical. However, concerns exist that the diagnosis often focuses subsequent care on prostate-related issues rather than overall health. Therefore, we examined the use of preventive services before and after diagnosis among men with prostate cancer and compared it to non-cancer controls. Methods: 15,631 men enrolled in Kaiser Permanente Southern California who were newly diagnosed with prostate cancer from 2002 through 2008 were matched 1:1 to non-cancer controls on age, race and timing of PSA test. They were passively followed through electronic medical records to determine the use of preventive services, including screening for colorectal cancer (CRC) (colonoscopy and/or fecal occult blood tests), tests for diabetes (glucose and hemoglobin A1c (HbA1c)) and heart disease (lipid panel test) and vaccinations (influenza and pneumococcal) in the 5 years before and diagnosis (or index date for controls). Rates of use were calculated for cases and controls separately and compared using Poisson regression. Results: CRC screening rates were 3-fold greater after diagnosis compared to before and were equivalent across group (Relative Rate (RR): 2.97, 95%CI: 2.89-3.05). The rates of lipid testing were similar before and after diagnosis, but increased an additional 10% in cases relative to controls after diagnosis (RR: 1.10, 95%CI: 1.14-1.25). HbA1c rates were lower among cases when compared to controls both before and after diagnosis (RR: 0.73, 95%CI: 0.72-0.74). Rates of glucose testing increased 25% more in the cases after diagnosis relative to the controls (RR: 1.25, 1.23-1.27), with the highest rate in the first 6 months after diagnosis. Influenza vaccination rates increased 24% after diagnosis in both groups (RR: 1.24, 95%CI: 1.22-1.26). Conclusions: Our results suggest that in this system, once diagnosed with prostate cancer, no less attention is paid to general preventive care. The increased use of preventive services may be the result of an integrated care model, further supporting the importance of the provider and system in the delivery of high quality survivorship care.
Proportion of Cancer Cases Attributable to Excess Body Weight by US State, 2011-2015
Authors: Farhad Islami, Ann Goding Sauer, Susan M. Gapstur, Ahmedin Jemal
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Excess body weight (EBW) is an established cause of cancer. Despite variations in the prevalence of EBW among US states, there is little information on the EBW-related cancer burden by state; this information would be useful for setting priorities for cancer-control initiatives. <h3>Objective</h3> To calculate the population attributable fraction (PAF) of incident cancer cases attributable to EBW among adults 30 years or older in 2011 to 2015 in all 50 states and the District of Columbia. <h3>Design, Setting, and Participants</h3> State-level, self-reported body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) data from the Behavioral Risk Factor Surveillance System were adjusted by sex, age, race/ethnicity, and education using objectively measured BMI values from the National Health and Nutrition Examination Survey. Age- and sex-specific cancer incidence data by state were obtained from the US Cancer Statistics database. All analyses were performed between February 15, 2018, and July 17, 2018. <h3>Main Outcomes and Measures</h3> Sex-, age-, and state-specific adjusted prevalence estimates for 4 high BMI categories and corresponding relative risks from large-scale pooled analyses or meta-analyses were used to compute the PAFs for each US state for esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colorectum, liver, gallbladder, pancreas, female breast, corpus uteri, ovary, kidney and renal pelvis, and thyroid. <h3>Results</h3> Each year, an estimated 37 670 cancer cases in men (4.7% of all cancer cases excluding nonmelanoma skin cancers) and 74 690 cancer cases in women (9.6%) 30 years or older in the United States were attributable to EBW from 2011 to 2015. In both men and women, there was at least a 1.5-fold difference in the proportions of cancers attributable to EBW between states with the highest and lowest PAFs. Among men, the PAF ranged from 3.9% (95% CI, 3.6%-4.3%) in Montana to 6.0% (95% CI, 5.6%-6.4%) in Texas. The PAF for women was approximately twice as high as for men, ranging from 7.1% (95% CI, 6.7%-7.6%) in Hawaii to 11.4% (95% CI, 10.7%-12.2%) in the District of Columbia. The largest PAFs were found mostly in southern and midwestern states, as well as Alaska and the District of Columbia. <h3>Conclusions and Relevance</h3> The proportion of cancers attributable to EBW varies among states, but EBW accounts for at least 1 in 17 of all incident cancers in each state. Broad implementation of known community- and individual-level interventions is needed to reduce access to and marketing of unhealthy foods (eg, through a tax on sugary drinks) and to promote and increase access to healthy foods and physical activity, as well as preventive care.
Imatinib Suspension and Validation (ISAV) Study: Final Results at 79 Months
Authors: Silvia Mori, Philipp le Coutre, Elisabetta Abruzzese, Bruno Martino, Ester Pungolino, Chiara Elena, Micaela Bergamaschi, Sarit Assouline, Eros Di Bona, Antonella Gozzini, Marcio Andrade, Fabio Stagno, Alessandra Iurlo, Dong-Wook Kim, Michela Luciani, Alessandra Pirola, Maria Luisa Bonanomi, Patrizia Crivori, Rocco Piazza, Carlo Gambacorti-Passerini
Journal: Blood (2018)
Distinct Chromatin Accessibility Profiles of Lymphoma Subtypes Revealed By Targeted Cell Free DNA Profiling
Authors: Mahya Mehrmohamadi, Mohammad S Esfahani, Joanne Soo, Florian Scherer, Joseph G Schroers-Martin, Binbin Chen, David M. Kurtz, Emily Hamilton, Chih Long Liu, Maximilian Diehn, Ash A. Alizadeh
Journal: Blood (2018)
Serum-derived immunoglobulin and the alleviation of irinotecan-induced mucositis.
Authors: Emma Hazel Bateman, Eric Weaver, Gerald Klein, Erin Plews, Anthony Wignall, Belinda Wozniak, Dorothy Mary Kate Keefe
Journal: Journal of Clinical Oncology (2014)

e20717 Background: Gastrointestinal (GI) mucositis is associated with diarrhoea and intestinal barrier dysfunction caused by apoptosis, immune dysfunction, and microbiome alterations. Serum-derived bovine immunoglobulin (SBI) has been shown to ameliorate intestinal inflammation in colitis models. In human studies, SBI has been shown to improve HIV-induced enteropathy and nutritional status and is being investigated in post-surgical recovery in oncology patients. We investigated in a rat model whether SBI was effective in alleviating symptoms of irinotecan-induced GI mucositis. Methods: Animals were gavaged with 250 or 500mg/kg of SBI twice daily, before intraperitoneal administration of 200mg/kg irinotecan on day 4, and for 6 days post-irinotecan. Animals were monitored for bodyweight and diarrhoea. Tissues and blood samples were collected at necropsy 6, 48, 96 and 144 hours post-irinotecan. H&E-stained colon and jejunum were analysed for histological damage. Results: The overall incidence, severity and duration of diarrhoea, and clinical symptoms of mucositis, were decreased in irinotecan-treated animals that had received SBI. Animals receiving 500 mg SBI/kg also tended to lose less bodyweigh than animals treated only with irinotecan (P>0.10). Animals receiving SBI had less pronounced irinotecan-induced changes in neutrophil (P=0.04959) and lymphocyte (P=0.0035) levels, and lower tissue damage scores than those receiving irinotecan alone (P<0.0001). Conclusions: Twice daily oral gavage of SBI was well-tolerated, and reduced the incidence, severity and duration of irinotecan-induced mucositis. SBI was associated with less pronounced changes in inflammatory cell levels and tissue damage to colon and jejunum. Ongoing experiments aim to elucidate the mechanisms of SBI-associated gastrointestinal protection.
A Global-Level Model of the Potential Impacts of Climate Change on Child Stunting via Income and Food Price in 2030
Authors: Simon J. Lloyd, Mook Bangalore, Zaid Chalabi, R. Sari Kovats, Stèphane Hallegatte, Julie Rozenberg, Hugo Valin, Petr Havlík
Journal: Environmental Health Perspectives (2018)

Background: In 2016, 23% of children (155 million) aged <5 were stunted. Global-level modeling has consistently found climate change impacts on food production are likely to impair progress on reducing undernutrition. Objectives: We adopt a new perspective, assessing how climate change may affect child stunting via its impacts on two interacting socioeconomic drivers: incomes of the poorest 20% of populations (due to climate impacts on crop production, health, labor productivity, and disasters) and food prices. Methods: We developed a statistical model to project moderate and severe stunting in children aged <5 at the national level in 2030 under low and high climate change scenarios combined with poverty and prosperity scenarios in 44 countries. Results: We estimated that in the absence of climate change, 110 million children aged <5 would be stunted in 2030 under the poverty scenario in comparison with 83 million under the prosperity scenario. Estimates of climate change–attributable stunting ranged from 570,000 under the prosperity/low climate change scenario to >1 million under the poverty/high climate change scenario. The projected impact of climate change on stunting was greater in rural vs. urban areas under both socioeconomic scenarios. In countries with lower incomes and relatively high food prices, we projected that rising prices would tend to increase stunting, whereas in countries with higher incomes and relatively low food prices, rising prices would tend to decrease stunting. These findings suggest that food prices that provide decent incomes to farmers alongside high employment with living wages will reduce undernutrition and vulnerability to climate change. Conclusions: Shifting the focus from food production to interactions between incomes and food price provides new insights. Futures that protect health should consider not just availability, accessibility, and quality of food, but also the incomes generated by those producing the food. https://doi.org/10.1289/EHP2916
The regulatory role of glucosylceramide synthase on gene expression contributes to drug resistance in breast cancer cells
Authors: Yong Y. Liu, Jing Y. Yu, Valerie Gouaze, Armando E. Giuliano, Myles C. Cabot
Journal: Cancer Research (2004)

615  Glucosylceramide synthase (GCS) has been recognized as a factor in drug resistance in cancer, and overexpression of GCS has been shown to be associated with MDR1 in a number of multidrug resistant (MDR) cancer cell lines. Our previous work showed that antisense GCS (asGCS) transfection reverses drug resistance in cancer cell lines that overexpress several drug resistance-associated genes. From this we hypothesized that GCS could exert influence on other drug resistance molecules in cancer cells and thus have pleiotropic effects. Employing gene transfection and gene expression analysis, we examined the influence of GCS on the expression of several MDR genes. Through gene array analysis, we found that asGCS transfection substantially decreased the expression of MDR genes including MDR1, MDR4, MRP3, BCSG1, GSTT1 and VEGF, and increased pro-apoptosis genes including HSP-90, GATA3 and HIF1A. To confirm the influence of GCS on MDR1 expression, we assessed MDR1 mRNA levels in several transfected cell lines (MCF-7-AdrR/GCS, MCF-7-AdrR cells transfected with GCS; MCF-7-AdrR/asGCS, MCF-7-AdrR cells transfected with antisense GCS) and in MCF-7-AdrR cells treated with a 20-mer antisense oligonucleotide (asGCS ODN-7). Analysis showed that MDR1 expression was enhanced 5-fold in MCF-7-AdrR/GCS cells and decreased 80% in MCF-7-AdrR/asGCS cells, compared to parental MCF-7-AdrR cells. MDR1 expression was also decreased 70% in MCF-7-AdrR cells after treatment with asGCS ODN-7 (400 nM, 48 hr). MDR1 expression in drug resistant cells could also be diminished by treatment with chemical inhibitors of GCS (see, Gouaze V., Y. Y. Liu, A. E. Giuliano, and M. C. Cabot). This study shows that GCS regulates the expression of multidrug resistance genes in cancer cells. Although GCS is an enzyme that catalyzes the glycosylation of ceramide, inhibition of GCS by either post-transcriptional regulation (antisense approach) or enzyme blockers, significantly depresses MDR1 gene expression. This suggests that glycolipids are involved in regulation of gene expression and contribute to MDR genesis in cancer cells.
Heat-shock protein 90 inhibition in pediatric sarcomas.
Authors: Fernanda Irene Arnaldez, Erin Gombos, Toby Terwilliger, Arnulfo Mendoza, Choh Yeung, Len Neckers, Lee J. Helman
Journal: Journal of Clinical Oncology (2014)

10057 Background: Hsp90 is a molecular chaperone that regulates post-translational folding, stability, and function of many client proteins, which play critical roles in key signal transduction pathways implicated in cell growth, differentiation, and survival. Several relevant oncogenic proteins are described as clients, such as IGF1R, AKT/PKB, and Src-family kinases. Signaling through these molecules is critical in the biology of rhabdomyosarcoma (RMS) and Ewing's sarcoma (ES). Novel therapies for these tumors are clearly needed since patients with relapsed and metastatic disease continue to have poor outcomes. Ganetespib (Synta Pharmaceuticals) is a small molecule Hsp90 inhibitor that binds to the ATP pocket in the N-terminus of Hsp90, leading to down-regulation of Hsp90 client protein levels. Methods: We sought to evaluate the preclinical activity of ganetespib in a panel of ES and RMS cell lines. We evaluated in vitro activity of ganetespib in ES cell lines (TC71, TC32, EW8, RDES) and in RMScell lines (RD, RH30) using kinetic proliferation assays and MTS. Results: In all cases, a marked inhibition of cell growth was achieved in a dose-dependent manner with drug concentrations in the low nanomolar range (3-6 nM). We found that ganetespib exposure is associated with induction of apoptosis using caspase 3/7 assay; as well as alterations in cell cycle progression. In addition to upregulation of Hsp70, which is considered a biomarker of Hsp90 inhibition, ganetespib treatment was associated with loss of expression of IGF1R-beta as well as downregulation of key signaling pathways such as mammalian target of rapamycin (mTOR), pAKT, and Src-family kinases, particularly YES1, a kinase we identified as critical in RMS biology. Moreover, we observed a cooperative effect between Hsp90 inhibition and IGF1R blockade with R1507, a monoclonal antibody targeting this receptor (Hoffman-La Roche). Furthermore, a synergistic effect was seen when ganetespib treatment was combined with SFK inhibition using dasatinib. Conclusions: Ganetespib exhibited activity alone and in combination in ES and RMS cell lines and is an attractive strategy to explore in the therapy of pediatric sarcomas; possibly in combination with other targeted therapies.
Established organ damage reduces belimumab efficacy in systemic lupus erythematosus
Authors: Ioannis Parodis, Alvaro Gomez, Sharzad Emamikia, Katerina Chatzidionysiou
Journal: Annals of the Rheumatic Diseases (2019)

Post hoc analyses of the phase III trials of belimumab BLISS-521 and BLISS-762 revealed superiority of belimumab over placebo in patients with systemic lupus erythematosus (SLE) with high baseline disease activity, positive anti–double-stranded (ds)DNA titres and low complement levels, as well as in patients receiving corticosteroids.3 Later, real-life observations demonstrated that established organ damage prior to treatment initiation predicted reduced belimumab efficacy.4 We aimed at validating this finding in the BLISS-52 and BLISS-76 SLE populations. Access to data was granted by GlaxoSmithKline (Uxbridge, UK).

In total, 1684 patients were included in the analysis. The BLISS-52 trial comprised 865 and the BLISS-76 trial 819 patients with SLE who were randomised to receive belimumab 1 mg/kg, belimumab 10 mg/kg or placebo, along with standard-of-care treatment.

Organ damage was assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).5 Response to treatment was defined as fulfilment of the SLE responder index 4 (SRI-4) conditions at week 52 (primary endpoint of the BLISS trials).1 2 Patients who withdrew or required changes in the background therapy other than those permitted by protocol …
Clinical activity of single-agent gemcitabine in a single-center series of 83 malignant pleural mesothelioma after failure of pemetrexed-based chemotherapy.
Authors: Federica Grosso, Annalisa Roveta, Daniela Degiovanni, Ezio Piccolini, Stefano Barbero, Francesco Musante, Gabriele Ferretti, Massimo Pastormerlo, Alberto Muzio, Mario Botta
Journal: Journal of Clinical Oncology (2014)

e18547 Background: No standard second line chemotherapy (CT) has been yet established for Malignant Plural Mesothelioma (MPM) after failure of pemetrexed based CT. Aim of this study was to evaluate the clinical activity of gemcitabine (G) as second/further line CT in a series of MPM patients treated at our Oncological Department, located in a particularly asbestos polluted area in Piedmont (Italy). Methods: Patients consecutively diagnosed, treated and included in our clinical database between 2005/1 and 2011/12 were considered for this study. Clinical and pathological data, treatments, response to CT and outcomes were analysed. The same expert pathologist always did diagnosis. Results: Out of 355 patients, 83 (21F, 62M) (23%) received G as second/further line after failure of pemetrexed based CT. Asbestos exposure was occupational certain in 20, possible in 9, domestic in 12 and environmental in 42 pts. Median age was 62 (range 40-83) years. Histology was epithelioid in 65 (78%), biphasic in 14 (17%) and sarcomatoid in 4 (5%) pts. G was administered at 1000 mg/sm day 1,8 every 21 until disease progression/intolerance and as second line in 53 and in further line in 30 pts. A total of 337 courses were given, median 4 courses (range 1-12) for pt. Overall response rate was as follows: 4 PR (5%), 20 SD (24%), 47 PD (57%) with 12 (14%) pts not evaluable for response. Median progression free survival was 4,6 (95%CI 3,8-5,2) months. Median OS was 18 (95%CI 16,4-21,7) months. Conclusions: G has a modest activity in pemetrexed pre-treated MPM but given its well defined favourable tolerability profile it could be considered as palliative treatment in the real clinical practice especially when no experimental studies are available.