tbuckley/cabot-search huggingface dataset:
Physical activity trajectories and mortality: population based cohort study
Authors: Alexander Mok, Kay-Tee Khaw, Robert Luben, Nick Wareham, Soren Brage
Journal: BMJ (2019)

Abstract Objective To assess the prospective associations of baseline and long term trajectories of physical activity on mortality from all causes, cardiovascular disease, and cancer. Design Population based cohort study. Setting Adults from the general population in the UK. Participants 14 599 men and women (aged 40 to 79) from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, assessed at baseline (1993 to 1997) up to 2004 for lifestyle and other risk factors; then followed to 2016 for mortality (median of 12.5 years of follow-up, after the last exposure assessment). Main exposure Physical activity energy expenditure (PAEE) derived from questionnaires, calibrated against combined movement and heart rate monitoring. Main outcome measures Mortality from all causes, cardiovascular disease, and cancer. Multivariable proportional hazards regression models were adjusted for age, sex, sociodemographics, and changes in medical history, overall diet quality, body mass index, blood pressure, triglycerides, and cholesterol levels. Results During 171 277 person years of follow-up, 3148 deaths occurred. Long term increases in PAEE were inversely associated with mortality, independent of baseline PAEE. For each 1 kJ/kg/day per year increase in PAEE (equivalent to a trajectory of being inactive at baseline and gradually, over five years, meeting the World Health Organization minimum physical activity guidelines of 150 minutes/week of moderate-intensity physical activity), hazard ratios were: 0.76 (95% confidence interval 0.71 to 0.82) for all cause mortality, 0.71 (0.62 to 0.82) for cardiovascular disease mortality, and 0.89 (0.79 to 0.99) for cancer mortality, adjusted for baseline PAEE, and established risk factors. Similar results were observed when analyses were stratified by medical history of cardiovascular disease and cancer. Joint analyses with baseline and trajectories of physical activity show that, compared with consistently inactive individuals, those with increasing physical activity trajectories over time experienced lower risks of mortality from all causes, with hazard ratios of 0.76 (0.65 to 0.88), 0.62 (0.53 to 0.72), and 0.58 (0.43 to 0.78) at low, medium, and high baseline physical activity, respectively. At the population level, meeting and maintaining at least the minimum physical activity recommendations would potentially prevent 46% of deaths associated with physical inactivity. Conclusions Middle aged and older adults, including those with cardiovascular disease and cancer, can gain substantial longevity benefits by becoming more physically active, irrespective of past physical activity levels and established risk factors. Considerable population health impacts can be attained with consistent engagement in physical activity during mid to late life.
Intensification of Oral Methotrexate Is Not Superior to Standard Methotrexate Dosing during Maintenance in Children with National Cancer Institute (NCI) Standard-Risk B Acute Lymphoblastic Leukemia (SR B-ALL): A Report from Children's Oncology Group (COG) Study AALL0932
Authors: Anne Angiolillo, Reuven Schore, Meenakshi Devidas, Xiaomin Lu, Karen R. Rabin, Patrick A. Zweidler-McKay, Michael Borowitz, Brent Wood, Andrew J. Carroll, Nyla A. Heerema, Cindy Wang, Kelly Maloney, Naomi Winick, William L. Carroll, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger
Journal: Blood (2017)
Abstract 17981: Quantitative High Efficiency SPECT With Cadmium-Zinc-Telluride and Dedicated Parallel Collimation System in Obese Patients: A Result From a Multi-Center Study
Authors: Ryo Nakazato, Mathews Fish, Ronald G Schwartz, Sean W Hayes, Reza Arsanjani, Louise E Thomson, John D Friedman, Maria L Mackin, Benjamin Peterson, Arielle M Schwartz, Piotr J Slomka, Daniel S Berman
Journal: Circulation (2013)

Background: Obesity is a significant and independent risk factor for cardiovascular disease, and assessing ischemia in obese patients is clinically important but often difficult due to imaging arti...
Abstract P261: Overweight/Obese Mother-Child Dyads Underestimate Size - A Present and Future Problem for Cardiovascular Risk
Authors: Tracy K Paul, Michael L Bier, Robert R Sciacca, Juviza K Rodriguez, Elsa-Grace V Giardina
Journal: Circulation (2013)

Introduction: Perception of body size is a key influence driving health behavior. Mothers directly influence children’s nutritional and exercise behaviors. Mothers of ethnic minority groups and/or ...
Abstract PR13: PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas
Authors: Kristen S. Hill, Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, Minjung Kim
Journal: Cancer Research (2020)

Abstract Melanoma is one of the most highly mutated cancer types, harboring numerous alterations with unknown significance. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten and Cdkn2a null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K-mutant melanoma. Using a quantitative tyrosine phospho-proteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3α/β signaling pathways. This study also identifies PTPN11 as a novel and actionable therapeutic target for BRAF wild-type melanoma. This abstract is also being presented as Poster A14. Citation Format: Kristen S. Hill, Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, Minjung Kim. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR13.
Abstract 327: The impact of PIK3CA/PTEN/AKT1 genes in advanced NSCLC patients with acquired EGFR-TKI resistance and clinical response to EGFR-TKI plus everolimus combination therapy
Authors: Wenfeng Fang, Yihua Huang, Jiadi Gan, Yunpeng Yang, Yifen Wu, Jingbin Huang, Zhiyong Xu, Wenjing Wang, Li Zhang
Journal: Cancer Research (2019)

Abstract Background EGFR-TKIs have shown remarkable effect in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. Nevertheless, several mechanisms including activation of PI3K/AKT/mTOR pathway have been proved to generate acquired assistance to EGFR-TKIs. In this study, we investigated the genomic characteristics of PI3K pathway in NSCLC patients with acquired resistance to EGFR-TKIs and whether both targeting EGFR and mTOR could reverse resistance. Methods A total of 605 NSCLC cases who received prior TKI treatment were reviewed, in which 328 patients harboring EGFR-mutants were confirmed to have progressed on one or more TKI and finally enrolled. FFPE tumor or blood samples were collected at the onset of TKI resistance for NGS based panel assay (PIK3CA/PTEN/AKT1 genes and NSCLC driver genes are included). Six patients with co-mutations in EGFR and PI3K pathway who had been heavily treated and progressed on EGFR-TKI received EGFR-TKI plus mTOR inhibitor everolimus combination therapy. Results In a total of 328 patients, 294 (89.6%) of the patients were adenocarcinomas, 4(12.2%) were small cell lung cancer, while the rest were squamous carcinoma or NSCLC not otherwise specified (30, 9.2%). Forty nine (14.9%) patients with TKI resistant have genomic alterations in PI3K pathway. PIK3CA, PTEN and AKT1variations were detected in 31(9.5%), 18(5.5%) and 3(0.9%) of patients respectively. Three patients had both PIK3CA and PTEN mutations and one patient had co-mutation of PIK3CA/PTEN/AKT1. PIK3CA hotspot mutations of E545, H1047 and E542 accounted for 60.5% of PIK3CA mutations. Six patients were treated with everolimus (5mg) plus EGFR-TKI (2 patients with gefitinib, 250mg; 1 patient with afatinib, 30mg; 3 patients with osimertinib 80mg, daily) combination therapy. One (1/6, 16.7%) patient achieved partial response and the rest (5/6, 83.3%) achieved stable disease. The most common adverse events were dental ulcer (6/6), rash (2/6), pruritis (1/6) and diarrhea (1/6). One patient withdrew combination treatment due to grade 3 dental ulcer. Conclusions Our study revealed that PI3K pathway was activated in approximately 15% of EGFR-TKI resistant patients. Combination therapy of EGFR-TKIs and everolimus revealed limited antitumor activity in EGFR-TKI resistant NSCLC patients with dysregulation of PI3K pathway. Citation Format: Wenfeng Fang, Yihua Huang, Jiadi Gan, Yunpeng Yang, Yifen Wu, Jingbin Huang, Zhiyong Xu, Wenjing Wang, Li Zhang. The impact of PIK3CA/PTEN/AKT1 genes in advanced NSCLC patients with acquired EGFR-TKI resistance and clinical response to EGFR-TKI plus everolimus combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 327.
Abstract 17690: Low-Voltage Area in Roof/Posterior Wall of Left Atrium is Associated With Poor Outcome of Af Ablation
Authors: Takuya Ohashi, Masaharu Masuda, Masashi Fujita, Osamu Iida, Shin Okamoto, Takayuki Ishihara, Kiyonori Nanto, Takashi Kanda, Takuya Tsujimura, Shota Okuno, Yasuhiro Matsuda, Hiroyuki Kawai, Aki Tsuji, Yosuke Hata, Hiroyuki Uematsu, Yuki Sato, Toshiaki Mano
Journal: Circulation (2017)

Background: Left atrial (LA) low-voltage area (LVA) has been reported to be associated with poor outcome of AF ablation. Although a regional distribution of LVA is various, AF ablation outcome in t...
Abstract 1207: Reversing lactate-driven immunosuppression using the novel, potent and selective MCT4 inhibitor AZD0095
Authors: Susan E. Critchlow, Gareth Hughes, Anna Staniszewska, Matt King, Filippos Michopoulos, Lorna Hopcroft, Martin R. Brown, Jenna Bradley, Beverley Hammond, Pablo MorentinGutierrez, Larissa Carnevalli, Elizabeth Hardaker, Frederick W. Goldberg
Journal: Cancer Research (2019)

Abstract Metabolic adaptation to a Warburg phenotype is a hallmark of cancer, where tumors rely on glucose to produce ATP and building blocks required to support rapid tumor growth. Glycolytic metabolism requires continuous export of lactate from cells by monocarboxylate transporters (MCTs) resulting in accumulation of lactic acid in the tumor microenvironment. Tumor-derived lactate is immune-suppressive and has been shown to modify immune cell function. Inhibition of the MCT4 lactate transporter has the potential to reduce lactate in the tumor microenvironment and reverse immune suppression. AZD0095 is a highly selective, potent inhibitor of MCT4 with a cellular activity of 1-3 nM with a &amp;gt;1000-fold selectivity over MCT1. We confirm that lactic acid inhibits T cell proliferation and viability. AZD0095 does not inhibit T cell proliferation or survival (IC50 &amp;gt; 10 μM). Oral administration of AZD0095 (10-100 mg/kg BID) modulates lactate transport in mouse syngeneic models which do not express the MCT1 lactate transporter. AZD0095 treatment causes an increase in tumor-infiltrating lymphocytes and an increase in cytotoxic T cells in combination with α-PD1. AZD0095 treatment suppresses myeloid infiltration as a monotherapy and in combination with checkpoint inhibitor. Consistent with the observed changes in immune cell infiltration, the combination of AZD0095 with checkpoint inhibitors α-PD1 or α-CTLA4 (10 mg/kg 3x week) enhances the anti-tumor activity of checkpoint inhibitor monotherapy in MC-38 and EMT6 (MCT1 knock-out) mouse syngeneic models. These data demonstrate that AZD0095 can reverse lactate-driven immunosuppression and enhance response to checkpoint inhibition in pre-clinical models. Citation Format: Susan E. Critchlow, Gareth Hughes, Anna Staniszewska, Matt King, Filippos Michopoulos, Lorna Hopcroft, Martin R. Brown, Jenna Bradley, Beverley Hammond, Pablo MorentinGutierrez, Larissa Carnevalli, Elizabeth Hardaker, Frederick W. Goldberg. Reversing lactate-driven immunosuppression using the novel, potent and selective MCT4 inhibitor AZD0095 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1207.
Thioesterase PPT1 balances viral resistance and efficient T cell crosspriming in dendritic cells
Authors: Pengju Ou, Lifen Wen, Xiaoli Liu, Jiancheng Huang, Xiaoling Huang, Chaofei Su, Ling Wang, Hai Ni, Boris Reizis, Cliff Y. Yang
Journal: The Journal of Experimental Medicine (2019)

Conventional type 1 dendritic cells (cDC1s) are inherently resistant to many viruses but, paradoxically, possess fewer acidic phagosomes that enable antigen retention and cross-presentation. We report that palmitoyl-protein thioesterase 1 (PPT1), which catabolizes lipid-modified proteins in neurons, is highly expressed in cDC1s. PPT1-deficient DCs are more susceptible to vesicular stomatitis virus (VSV) infection, and mice with PPT1 deficiency in cDC1s show impaired response to VSV. Conversely, PPT1-deficient cDC1s enhance the priming of naive CD8+ T cells into tissue-resident KLRG1+ effectors and memory T cells, resulting in rapid clearance of tumors and Listeria monocytogenes. Mechanistically, PPT1 protects steady state DCs from viruses by promoting antigen degradation and endosomal acidification via V-ATPase recruitment. After DC activation, immediate down-regulation of PPT1 is likely to facilitate efficient cross-presentation, production of costimulatory molecules and inflammatory cytokines. Thus, PPT1 acts as a molecular rheostat that allows cDC1s to crossprime efficiently without compromising viral resistance. These results suggest potential therapeutics to enhance cDC1-dependent crosspriming.
Abstract 19733: Long Term Outcomes of 78,808 Patients Undergoing Valve Heart Surgery in a Middle-income Country
Authors: Regina M Xavier, Vitor M Azevedo, Paulo H Godoy, Arn Migowski, Antonio Luiz P Ribeiro, Rogerio B Chaves, Bernardo R Tura, Braulio Santos, Marcelo G Correia, Carolina A Xavier, Lucas A Hashimoto, Clara Weksler, Nelson A Souza e Silva
Journal: Circulation (2015)

Background: The outcomes of heart valve surgery (HVS) are unknown in middle-income countries. Objectives: To analyze in-hospital and survival of HVS from 2001 to 2007 in Brazil. Methods: This is a retrospective observational study of 78,806 patients. Two national databases were used, the Hospital Information System and the Mortality Information System. Kaplan-Meier and log-rank tests were performed. The outcome measures were in-hospital mortality and all-cause mortality during follow-up. These measures have been obtained by probabilistic record linkage of the databases. Results: The maximum and median follow-up was 7.7 and 2.8 years. Sex distribution was similar. Median age was 50.0 (35.9 - 62.5). Valve replacement (VRp) accounted for 69.1%. The most common valve injury was mitral stenosis with 38.9%, and was rheumatic heart disease (RHD) in 94.7%. The median age in RHD was lower (44.2) than in the remaining cohort (57.5) (p&lt;0.001). In-hospital mortality was 7.6%. It was higher for females (7.8% versus 7.3% - p&lt;0.001), for concomitant CABG patients (14.6%; p&lt;0.001), and for the elderly (18.42%; p&lt;0.001). Overall survival was 69.9% at the end of the follow-up time. Survival by sex at the year 1 and 5 were respectively, for female 85.0% and 76.5%, for male 84.2% and 72.5%. At the end of the first and fifth year of follow-up time, the survival rates of the age ≥80 group and 20 and 39 years group were respectively 64.7%, and 46.4%, against 91.5% and 85.1%. Survival for concomitant CABG at year 1 and year 5 of follow up were 72.1% and 58.1% and for those who underwent solely HVS, 85.9% and 76.0%, respectively. Concomitant CABG showed increased risk (HR 1.3123, CI95%1.2271 - 1.4033, p&lt;0.0001), and age contributed as secondary increasing factor (HR 1.0216, CI95% 1.0203 - 1.0229, p&lt;0.0001). In non-concomitant CABG, patients submitted to valve repair compared with VRp or multiple surgeries showed a reduced risk (HR 0.6937, CI95%0.6296 - 0.7645, p&lt;0.0001), but age contributed as secondary increasing factor in this set (HR 1.0209, CI95%1.0195 - 1.0222, p&lt;0.0001). Conclusions: The magnitude of RHD in Brazil is still great. In-hospital mortality and survival of HVS were less satisfactory compared to those reported in high-income countries.
End of phase I results of ZUMA-3, a phase 1/2 study of KTE-X19, anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in adult patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).
Authors: Bijal D. Shah, Michael Russell Bishop, Olalekan O. Oluwole, Aaron Logan, Maria R. Baer, William Bruce Donnellan, Kristen Marie Carr-O'Dwyer, Houston Holmes, Martha Lucia Arellano, Armin Ghobadi, John M. Pagel, Yi Lin, Ryan Daniel Cassaday, Jae Hong Park, Armen Mardiros, Tong Shen, Lovely Goyal, Remus Vezan, Rajul K. Jain, William G. Wierda
Journal: Journal of Clinical Oncology (2019)

7006 Background: KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for adult R/R ALL. In an interim analysis of Phase 1 of ZUMA-3, we reported manageable safety and encouraging efficacy of KTE-X19; 72% of pts achieved a complete remission (CR) or CR with incomplete bone marrow (BM) recovery (CRi; Wierda et al, ASH 2018. #897). Here, we present end of Phase 1 results. Methods: Adults with R/R B cell ALL, &gt; 5% BM blasts, and ECOG 0-1 received 2, 1, or 0.5 × 10 6 KTE-X19 cells/kg after conditioning chemotherapy. Revised adverse event management (rAE mgmt) was implemented for additional pts in a 1 × 10 6 dose cohort: corticosteroids were given earlier at onset of Grade ≥ 2 neurologic events (NEs) and tocilizumab was used only for active toxicity. The primary endpoint was the dose-limiting toxicity (DLT) rate. Key additional endpoints were KTE-X19 levels, incidence of AEs, minimal residual disease (MRD), and CR/CRi rate. Results: As of 9/27/18, 45 pts had received KTE-X19 (median follow-up [f/u], 16 mo). The median age was 46 y (range, 18–77); 30 pts (66%) had ≥ 3 prior therapies and the median pre-conditioning BM blasts was 70% (range, 0–97). Six, 23, and 16 pts received 2, 1, and 0.5 × 10 6 cells/kg, respectively. There were no DLTs in the DLT-evaluable pts. The most common Grade ≥ 3 AEs were hypotension (38%), pyrexia (38%) and thrombocytopenia (31%). There were 2 previously reported KTE-X19–related Grade 5 AEs of cerebral infarction and multiorgan failure, both in the context of CRS. Grade ≥ 3 CRS and NEs occurred in 13 (29%) and 17 (38%) pts, respectively. Of 41 pts with ≥ 2 mo of f/u, 68% had CR/CRi, and 73% had undetectable MRD. Of 19 pts with ≥ 2 mo of f/u treated with 1 × 10 6 cells/kg, 16 (84%) had a CR/CRi and the median event-free survival was 15 mo. In 9 pts treated with 1 × 10 6 cells/kg and rAE mgmt, 2 (22%) had Grade 3 CRS and 1 (11%) had Grade 3 NE with no Grade 4/5 events. Conclusions: KTE-X19 dosing and safety mgmt have been successfully refined by testing 3 cell doses and evaluating a new AE mgmt guideline with altered corticosteroids/tocilizumab use for NE/CRS. Pivotal Phase 2 is ongoing at the 1 × 10 6 dose with rAE mgmt. Clinical trial information: NCT02614066.
Abstract 1422: Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma
Authors: Pierre Dillard, Hakan Köksal, Sarah Josefsson, Solrun Melkorka Maggadottir, Sylvie Pollmann, Anne Fåne, Yngvild Nuvin Blaker, Klaus Beiske, Kanutte Huse, Ane Kolstad, Harald Holte, Gunnar Kvalheim, Erlend Bremertun Smeland, June Myklebust, Else Marit Inderberg, Sebastien Wälchli
Journal: Cancer Research (2019)

Abstract T cells modified to express chimeric antigen receptor (CAR) targeting CD19 have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19-negative tumor cells. Hence, development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-ALL and B-NHL. Here, we confirmed previous data by showing that B-NHL overall have high expression of CD37. A second generation CD37CAR was designed and its efficacy in T cells was compared to that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon co-culture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the two CARs. In an aggressive B-cell lymphoma xenograft model, CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model, using U2932 lymphoma cells containing a CD19-negative subpopulation, CD37CAR T cells efficiently controlled tumors and cured the mice while CD19CAR T cells had limited effect. We further show that, unlike CD19CAR, CD37CAR was not sensitive to antigen masking. Finally, CD37CAR reactivity was restricted to B-lineage cells. Collectively, our results demonstrated that CD37CAR T cells effectively can eradicate B-cell lymphoma tumors also when CD19 antigen expression is lost, and support further clinical testing for patients with relapsed/refractory B-NHL. Citation Format: Pierre Dillard, Hakan Köksal, Sarah Josefsson, Solrun Melkorka Maggadottir, Sylvie Pollmann, Anne Fåne, Yngvild Nuvin Blaker, Klaus Beiske, Kanutte Huse, Ane Kolstad, Harald Holte, Gunnar Kvalheim, Erlend Bremertun Smeland, June Myklebust, Else Marit Inderberg, Sebastien Wälchli. Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1422.