tbuckley/cabot-search huggingface dataset:
First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma
Authors: Patrick Y. Wen, Timothy F. Cloughesy, Alan G. Olivero, Kari M. Morrissey, Timothy R. Wilson, Xuyang Lu, Lars U. Mueller, Alexandre F. Coimbra, Benjamin M. Ellingson, Elizabeth Gerstner, Eudocia Q. Lee, Jordi Rodon
Journal: Clinical Cancer Research (2020)

Abstract Purpose: GDC-0084 is an oral, brain-penetrant small-molecule inhibitor of PI3K and mTOR. A first-in-human, phase I study was conducted in patients with recurrent high-grade glioma. Patients and Methods: GDC-0084 was administered orally, once daily, to evaluate safety, pharmacokinetics (PK), and activity. Fluorodeoxyglucose-PET (FDG-PET) was performed to measure metabolic responses. Results: Forty-seven heavily pretreated patients enrolled in eight cohorts (2–65 mg). Dose-limiting toxicities included 1 case of grade 2 bradycardia and grade 3 myocardial ischemia (15 mg), grade 3 stomatitis (45 mg), and 2 cases of grade 3 mucosal inflammation (65 mg); the MTD was 45 mg/day. GDC-0084 demonstrated linear and dose-proportional PK, with a half-life (∼19 hours) supportive of once-daily dosing. At 45 mg/day, steady-state concentrations exceeded preclinical target concentrations producing antitumor activity in xenograft models. FDG-PET in 7 of 27 patients (26%) showed metabolic partial response. At doses ≥45 mg/day, a trend toward decreased median standardized uptake value in normal brain was observed, suggesting central nervous system penetration of drug. In two resection specimens, GDC-0084 was detected at similar levels in tumor and brain tissue, with a brain tissue/tumor-to-plasma ratio of &amp;gt;1 and &amp;gt;0.5 for total and free drug, respectively. Best overall response was stable disease in 19 patients (40%) and progressive disease in 26 patients (55%); 2 patients (4%) were nonevaluable. Conclusions: GDC-0084 demonstrated classic PI3K/mTOR–inhibitor related toxicities. FDG-PET and concentration data from brain tumor tissue suggest that GDC-0084 crossed the blood–brain barrier.
Assessment of Additional Medical Costs Among Older Adults in Japan With a History of Childhood Maltreatment
Authors: Aya Isumi, Takeo Fujiwara, Hirotaka Kato, Taishi Tsuji, Daisuke Takagi, Naoki Kondo, Katsunori Kondo
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Childhood maltreatment can have significant consequences on health through the life course, but its association with health care costs in later life is not widely known. <h3>Objective</h3> To assess whether a history of childhood maltreatment is associated with additional medical costs among older adults in Japan. <h3>Design, Setting, and Participants</h3> This population-based cross-sectional study used data from the Japan Gerontological Evaluation Study, 2013, linked with national health insurance claims data from April 2012 to March 2014 for 1 municipality that participated in the Japan Gerontological Evaluation Study, 2013. The municipality had more than 1.5 million residents, and 978 independent individuals aged 65 to 75 years were included in the analysis. Data were analyzed from October 2017 to February 2019. <h3>Exposures</h3> Childhood maltreatment, including physical abuse, emotional neglect, emotional abuse, and witnessing intimate partner violence. <h3>Main Outcomes and Measures</h3> Mean annual medical costs between April 2012 and March 2013 and between April 2013 and March 2014. <h3>Results</h3> Among 978 independent older adults (mean [SD] age, 70.6 [2.9] years; 426 [43.6%] men), 44 (4.5%) witnessed intimate partner violence, 19 (1.9%) were physically abused, 104 (10.6%) were emotionally neglected, and 56 (5.7%) were emotionally abused in childhood. In total, 176 older adults (18.0%) experienced at least 1 type of childhood maltreatment. Mean annual medical costs of those who experienced any childhood maltreatment were significantly higher than of those who did not (difference, ¥136 456 [US$1255]; 95% CI, ¥38 155-¥234 757 [US$351-US$2160];<i>P</i> = .007). Those who experienced emotional neglect incurred more mean medical costs than those who did not (difference, ¥161 400 [US$1485]; 95% CI, ¥42 779-¥280 021 [US$394-US$2576];<i>P</i> = .008). The association of any childhood maltreatment with medical costs remained significant after controlling for age and sex (average marginal effect, ¥116 098 [US$1068]; SE, ¥53 620 [US$493]; 95% CI, ¥11 004-¥221 192 [US$101-US$2035];<i>P</i> = .03). The estimated additional costs associated with childhood maltreatment would be more than ¥333 billion (US$3.1 billion) per year nationwide. <h3>Conclusions and Relevance</h3> In this study, childhood maltreatment was associated with additional medical costs among older adults living in Japan. This finding underlines the importance of primary and secondary prevention of child maltreatment.
Mamasteam: Bevacizumab (BVZ) in the Treatment of Breast Cancer in Advanced Lines of Treatment, a New Model for the Assessment of Activity in Advanced Cancer
Authors: J. La Haba De Rodriguez, A. Gonzalez Martin, A. Rodriguez-Lescure, G. Pulido, A. Sanchez-MuÑoz, R. Marquez, M. Guirado Rueño, D. Torrejon Castro, E. Alba-Conejo, J. Cortes
Journal: Annals of Oncology (2012)
Trihalomethanes in Drinking Water and Bladder Cancer Burden in the European Union
Authors: Iro Evlampidou, Laia Font-Ribera, David Rojas-Rueda, Esther Gracia-Lavedan, Nathalie Costet, Neil Pearce, Paolo Vineis, Jouni J.K. Jaakkola, Francis Delloye, Konstantinos C. Makris, Euripides G. Stephanou, Sophia Kargaki, Frantisek Kozisek, Torben Sigsgaard, Birgitte Hansen, Jörg Schullehner, Ramon Nahkur, Catherine Galey, Christian Zwiener, Marta Vargha, Elena Righi, Gabriella Aggazzotti, Gunda Kalnina, Regina Grazuleviciene, Kinga Polanska, Dasa Gubkova, Katarina Bitenc, Emma H. Goslan, Manolis Kogevinas, Cristina M. Villanueva
Journal: Environmental Health Perspectives (2020)

Background: Trihalomethanes (THMs) are widespread disinfection by-products (DBPs) in drinking water, and long-term exposure has been consistently associated with increased bladder cancer risk. Objective: We assessed THM levels in drinking water in the European Union as a marker of DBP exposure and estimated the attributable burden of bladder cancer. Methods: We collected recent annual mean THM levels in municipal drinking water in 28 European countries (EU28) from routine monitoring records. We estimated a linear exposure–response function for average residential THM levels and bladder cancer by pooling data from studies included in the largest international pooled analysis published to date in order to estimate odds ratios (ORs) for bladder cancer associated with the mean THM level in each country (relative to no exposure), population-attributable fraction (PAF), and number of attributable bladder cancer cases in different scenarios using incidence rates and population from the Global Burden of Disease study of 2016. Results: We obtained 2005–2018 THM data from EU26, covering 75% of the population. Data coverage and accuracy were heterogeneous among countries. The estimated population-weighted mean THM level was 11.7μg/L [standard deviation (SD) of 11.2]. The estimated bladder cancer PAF was 4.9% [95% confidence interval (CI): 2.5, 7.1] overall (range: 0–23%), accounting for 6,561 (95% CI: 3,389, 9,537) bladder cancer cases per year. Denmark and the Netherlands had the lowest PAF (0.0% each), while Cyprus (23.2%), Malta (17.9%), and Ireland (17.2%) had the highest among EU26. In the scenario where no country would exceed the current EU mean, 2,868 (95% CI: 1,522, 4,060; 43%) annual attributable bladder cancer cases could potentially be avoided. Discussion: Efforts have been made to reduce THM levels in the European Union. However, assuming a causal association, current levels in certain countries still could lead to a considerable burden of bladder cancer that could potentially be avoided by optimizing water treatment, disinfection, and distribution practices, among other possible measures. https://doi.org/10.1289/EHP4495
S-1 Plus Docetaxel Versus S-1 for Advanced Gastric Cancer (START TRIAL) Update 2012 (JACCRO AND KCSG STUDY GROUP)
Authors: K. Yoshida, M. Fujii, W. Koizumi, H. Kim, Y.H. Kim, M. Takeuchi, T. Nakajima
Journal: Annals of Oncology (2012)
Efficacy and Prognostic Factors of Neoadjuvant Chemotherapy in Resectable Locally-Advanced Muscle-Invasive Bladder Cancer (MIBC) Patients (P) in an Off-Protocol Clinical Setting
Authors: J.L. Cuadra Urteaga, M. Domenech, P. Celiz, J.J. Sánchez, N. Pardo, C. Buges, J. Malet, M. Arzoz, J. Areal, A. Font
Journal: Annals of Oncology (2012)
Prognostic Factors in Early-Stage Triple Negative Breast Cancer (TNBC): The Limits Of Clinical and Pathological Features
Authors: N. Pécuchet, M. Le Frère Belda, T. Popovski, S. Haouas, F. Chamming'S, F. Lécuru, S. Oudard, J. Medioni
Journal: Annals of Oncology (2012)
<i>In Situ</i>DESI-MSI Lipidomic Profiles of Breast Cancer Molecular Subtypes and Precursor Lesions
Authors: Adriana Leandra Santoro, Rodrigo D. Drummond, Israel Tojal Silva, Severino S. Ferreira, Luiz Juliano, Pedro H. Vendramini, Monique Batista da Costa Lemos, Marcos N. Eberlin, Victor Piana Andrade
Journal: Cancer Research (2020)

Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma in situ (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 μm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis. SIGNIFICANCE: These findings present the first in situ metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.
High-Cost Patients and Preventable Spending: A Population-Based Study
Authors: Claire de Oliveira, Joyce Cheng, Kelvin Chan, Craig C. Earle, Murray Krahn, Nicole Mittmann
Journal: Journal of the National Comprehensive Cancer Network (2020)

Although high-cost (HC) patients make up a small proportion of patients, they account for most health system costs. However, little is known about HC patients with cancer or whether some of their care could potentially be prevented. This analysis sought to characterize HC patients with cancer and quantify the costs of preventable acute care (emergency department visits and inpatient hospitalizations).This analysis examined a population-based sample of all HC patients in Ontario in 2013. HC patients were defined as those above the 90th percentile of the cost distribution; all other patients were defined as non-high-cost (NHC). Patients with cancer were identified through the Ontario Cancer Registry. Sociodemographic and clinical characteristics were examined and the costs of preventable acute care for both groups by category of visit/condition were estimated using validated algorithms.Compared with NHC patients with cancer (n=369,422), HC patients with cancer (n=187,770) were older (mean age 70 vs 65 years), more likely to live in low-income neighborhoods (19% vs 16%), sicker, and more likely to live in long-term care homes (8% vs 0%). Although most patients from both cohorts tended to be diagnosed with breast, prostate, or colorectal cancer, those with multiple myeloma or pancreatic or liver cancers were overrepresented among the HC group. Moreover, HC patients were more likely to have advanced cancer at diagnosis and be in the initial or terminal phase of treatment compared with NHC patients. Among HC patients with cancer, 9% of spending stemmed from potentially preventable/avoidable acute care, whereas for NHC patients, this spending was approximately 30%.HC patients with cancer are a unique subpopulation. Given the type of care they receive, there seems to be limited scope to prevent acute care spending among this patient group. To reduce costs, other strategies, such as making hospital care more efficient and generating less costly encounters involving chemotherapy, should be explored.
c‐Jun NH2‐Terminal Protein Kinase Phosphorylates the Nrf2‐ECH Homology 6 Domain of Nuclear Factor Erythroid 2–Related Factor 2 and Downregulates Cytoprotective Genes in Acetaminophen‐Induced Liver Injury in Mice
Authors: Yiping Chen, Kaihua Liu, Jingwen Zhang, Yan Hai, Peng Wang, Hongyan Wang, Qiuyan Liu, Catherine C.L. Wong, Jun Yao, Yang Gao, Yijiao Liao, Xiuwen Tang, Xiu Jun Wang
Journal: Hepatology (2020)

Background and Aims Acetaminophen (APAP) overdose induces severe liver injury and hepatic failure. While the activation of c‐Jun NH 2 ‐terminal kinase (JNK) has been implicated as a mechanism in APAP‐induced liver injury, the hepatic defense system controlled by nuclear factor erythroid 2–related factor 2 (Nrf2) plays a central role in the mitigation of APAP toxicity. However, the link between the two signaling pathways in APAP‐induced liver injury (AILI) remains unclear. Approach and Results In this study, we demonstrated that the activation of JNK in mouse liver following exposure to APAP was correlated with the phosphorylation of Nrf2 and down‐regulation of the antioxidant response element (ARE)‐driven genes, NAD(P)H:quinone dehydrogenase 1, glutathione S ‐transferase α3, glutathione S ‐transferase M1, glutathione S ‐transferase M5, and aldo‐keto reductase 1C. The JNK inhibitor, SP600125, or knockdown of JNK by infection of adenovirus expressing JNK small interfering RNA, ameliorated the APAP induced liver toxicity, and inhibited the phosphorylation of Nrf2 and down‐regulation of detoxifying enzymes by stabilizing the transcription factor. Mechanistically, JNK antagonized Nrf2‐ and ARE‐driven gene expression in a Kelch‐like ECH‐associated protein 1–independent manner. Biochemical analysis revealed that phosphorylated JNK (P‐JNK) directly interacted with the Nrf2‐ECH homology (Neh) 1 domain of Nrf2 and phosphorylated the serine‐aspartate‐serine motif 1 (SDS1) region in the Neh6 domain of Nrf2. Conclusions Mass spectrometric analysis identified serine 335 in the SDS1 region of mNrf2 as the major phosphorylation site for modulation of Nrf2 ubiquitylation by P‐JNK. This study demonstrates that Nrf2 is a target of P‐JNK in AILI. Our finding may provide a strategy for the treatment of AILI.
The European Ipilimumab Expanded Access Programme (EAP): Efficacy and Safety Data from the Italian Cohort of Patients with Pretreated, Advanced Melanoma
Authors: P.A. Ascierto, V. Chiarion Sileni, M. Del Vecchio, M. Altomonte, F. De Galitiis, L. Ridolfi, F. Cognetti, A. Testori, M.G. Bernengo, P. Queirolo
Journal: Annals of Oncology (2012)
Cyclooxygenase-2 Inhibition Enhances the Anti-Tumoral Activity of the Multi-Target Kinase Inhibitor AEE788 in Colorectal Cancer Cells
Authors: A.M. Valverde Estepa, A. Cañas, V. Hernández Nieto, C. Lopez Pedrera, J.La Haba De Rodriguez, A. Rodríguez Ariza, E. Aranda Aguilar
Journal: Annals of Oncology (2012)
Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention
Authors: Ernesto S. Nakayasu, Farooq Syed, Sarah A. Tersey, Marina A. Gritsenko, Hugh D. Mitchell, Chi Yuet Chan, Ercument Dirice, Jean-Valery Turatsinze, Yi Cui, Rohit N. Kulkarni, Decio L. Eizirik, Wei-Jun Qian, Bobbie-Jo M. Webb-Robertson, Carmella Evans-Molina, Raghavendra G. Mirmira., Thomas O. Metz
Journal: Cell Metabolism (2020)
IL33 contributes to diesel pollution‐mediated increase in experimental asthma severity
Authors: Eric B. Brandt, Paige E. Bolcas, Brandy P. Ruff, Gurjit K. Khurana Hershey
Journal: Allergy (2020)

Abstract Background Exposure to traffic pollution, notably diesel exhaust particles (DEP), increases risk for asthma and asthma exacerbations. The contribution of cytokines generated by stressed lung epithelial cells (IL25, IL33, TSLP) to DEP‐induced asthma severity remains poorly understood. Methods BALB/c mice were exposed intratracheally once to DEP or 9 times over 3‐weeks to either saline, DEP, and/or house dust mite extract (HDM). Airway hyper‐responsiveness (AHR), pulmonary inflammation, and T‐cell subsets were assessed 24 hours after the last exposure in mice sufficient and deficient for the IL33 receptor ST2. Results DEP exposure induces oxidative stress, IL6, neutrophils and pulmonary accumulation of IL33, but not IL25 or TSLP or other features of allergic disease. When mice are co‐exposed to DEP and low doses of HDM, DEP increases IL33 lung levels and Th2 responses. ST2 deficiency partially protected mice from HDM + DEP induced AHR in association with decreased type 2 inflammation and lung levels of IL5 + IL17A + co‐producing T‐cells. Upon in vitro HDM challenge of lung cells from HDM ± DEP exposed ST2 −/− mice, secretion of IL5, IL13, IL6 and IL17A was abrogated by a mechanism involving IL33 signaling in both dendritic cells and T‐cells. HDM + DEP exposed bone marrow derived dendritic cells and IL33 pulsed BMDC promote a mixed Th2/Th17 response that was dependent on ST2 expression by CD4 + T‐cells. Conclusion IL33 contributes to DEP mediated increase in allergen‐induced Th2 inflammation and AHR in a mouse model of severe steroid resistant asthma, potentially through the accumulation of pathogenic IL5 + IL17A + CD4 + effector T‐cells.
Overcoming Erlotinib Resistance in EGFR Mutation-Positive Non-Small-Cell Lung Cancer Cells by Targeting Survivin
Authors: K. Okamoto, I. Okamoto, E. Hatashita, K. Kuwata, H. Yamaguchi, A. Kita, K. Yamanaka, M. Ono, K. Nakagawa
Journal: Annals of Oncology (2012)
P-0096 Palliative Radiotherapy Versus celiac Neurolysis for Pain Relief in Patients with Locally Advanced Cancer Pancreas
Authors: Ellithy Mahmoud, Mohammed Elbassiouny, Ahmed Abdelbar, Hesham Elwakil, Rashad Salama, Sherin Moftah, Lamia Elwakil, Amr Abdelmonem
Journal: Annals of Oncology (2012)
Bevacizumab–Capecitabine (BEV–CAP) After Initial 1st-Line Bevacizumab–Docetaxel (BEV–DOC) in Patients (PTS) With HER2-Negative Metastatic Breast Cancer (MBC): Safety Analysis of the IMELDA Trial
Authors: J. Gligorov, E. Alba-Conejo, J. Bines, P.A. Cortes, D.C. Doval, Z. Jiang, U. Freudensprung, G. Mustacchi
Journal: Annals of Oncology (2012)
Role of magnesium and aluminum substitution on the structural properties and bioactivity of bioglasses synthesized from biogenic silica
Authors: Burcu Karakuzu-Ikizler, Pınar Terzioğlu, Yeliz Basaran-Elalmis, Bilge Sema Tekerek, Sevil Yücel
Journal: Bioactive Materials (2020)

The objective of this study was to investigate the effect of magnesium (1 wt%) and aluminum (1 wt%) incorporation on the in vitro bioactivity and biodegradation behavior of 45S5 bioactive glasses synthesized from rice husk biogenic silica. The performance of biogenic silica-based samples was compared well with commercial silica-based counterparts. The in vitro biodegradation behavior of bioactive glasses was evaluated by the weight loss of samples and pH variation in the Tris buffer solution. Based on composition, bioglasses possessed different properties before and after simulated body fluid (SBF) immersion. The incorporation of magnesium (Mg) and aluminum (Al) enhanced the Vickers hardness of bioglasses. All the bioglasses showed the hydroxyapatite layer formation after SBF treatment as confirmed by the dissolution, FTIR, SEM and XRD analysis, however it was more prominent in the rice husk silica-based 45S5 bioglass. The biogenic silica seems to be a promising starting material for bioglass systems to be used in bone tissue engineering applications.
Time Trends in Cardiovascular Disease Mortality Across the BRICS
Authors: Zhiyong Zou, Karly Cini, Bin Dong, Yinghua Ma, Jun Ma, David P. Burgner, George C. Patton
Journal: Circulation (2020)

Brazil, Russia, India, China, and South Africa (BRICS) are emerging economies making up almost half the global population. We analyzed trends in cardiovascular disease (CVD) mortality across the BRICS and associations with age, period, and birth cohort.Mortality estimates were derived from the Global Burden of Disease Study 2017. We used age-period-cohort modeling to estimate cohort and period effects in CVD between 1992 and 2016. Period was defined as survey year, and period effects reflect population-wide exposure at a circumscribed point in time. Cohort effects are defined as differences in risks across birth cohort. Net drift (overall annual percentage change), local drift (annual percentage change in each age group), longitudinal age curves (expected longitudinal age-specific rate), and period (cohort) relative risks were calculated.In 2016, there were 8.4 million CVD deaths across the BRICS. Between 1992 and 2016, the reduction in CVD age-standardized mortality rate in BRICS (-17%) was less than in North America (-39%). Eighty-eight percent of the increased number of all-cause deaths resulted from the increase in CVD deaths. The age-standardized mortality rate from stroke and hypertensive heart disease declined by approximately one-third across the BRICS, whereas ischemic heart disease increased slightly (2%). Brazil had the largest age-standardized mortality rate reductions across all CVD categories, with improvement both over time and in recent birth cohorts. South Africa was the only country where the CVD age-standardized mortality rate increased. Different age-related CVD mortality was seen in those ≥50 years of age in China, ≤40 years of age in Russia, 35 to 60 years of age in India, and ≥55 years of age in South Africa. Improving period and cohort risks for CVD mortality were generally found across countries, except for worsening period effects in India and greater risks for ischemic heart disease in Chinese cohorts born in the 1950s and 1960s.Except for Brazil, reductions of CVD mortality across the BRICS have been less than that in North America, such that China, India, and South Africa contribute an increasing proportion of global CVD deaths. Brazil's example suggests that prevention policies can both reduce the risks for younger birth cohorts and shift the risks for all age groups over time.