tbuckley/cabot-search huggingface dataset:
Precision medicine and actionable alterations in lung cancer.
Authors: Isa Mambetsariev, Sorena Nadaf, Yingyu Wang, Chen Chen, Blake Hewelt, Rebecca Pharaon, Erminia Massarelli, Marianna Koczywas, Karen L. Reckamp, Ravi Salgia
Journal: Journal of Clinical Oncology (2019)

e20707 Background: In recent years, healthcare centers have become more reliant on the advent of new technology, testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians, researchers, and the medical community. This aggregate of information stands to be a powerful tool that can enable one to perform highly complex investigations more easily, as well as aid physicians in their efforts to provide personalized medicine to patients. However, in order to take advantage of vital clinical and research data, we must initially make an effort to create an effective infrastructure for the collection, storage, utilization, and protection of this information with uniquely designed disease-specific registries that have adequate informatics support to allow for the collection of a large number of patients. Methods: In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry. Results: Of the 415 patients in the analysis, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The frequency of the most commonly occurring oncogenes was 50% EGFR (n = 207/415), 28% KRAS (n = 97/352), and 7% ALK rearrangement (n = 28/377), while the most commonly occurring tumor suppressor genes consisted of TP53 (n = 140/283 [49%]), LRP1B (n = 63/228 [28%]), and STK11 (n = 39/278 [14%]). The most common actionable alterations were identified in EGFR L858R/exon 19 deletion (n = 177/415 [42.7%]), ALK rearrangement (n = 28/377 [7.4%]), ROS1 rearrangement (n = 3/257 [1.2%]), BRAF V600E (n = 7/288 [2.4%]) and MET exon 14 splice site/deletion (n = 7/287 [2.4%]). While there were no median OS differences in patients who were tested under a broad-panel vs small-panel (33.4 months vs 33.5 months; 95% CI; P = 0.36), there was a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 patients who were wild-type with a median OS of 26.0 months (95% CI; P &lt; 0.001). In addition, we identified an unprecedented number of patients with actionable alterations [53.5% (222/415)], including distinct individual alteration rates, as compared with 15.0% and 22.3% in TCGA and GENIE respectively. Conclusions: The use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes.
Abstract 14383: Neighborhood and Individual Resilience in Cardiovascular Health of Blacks: A Multi-Level Investigation From Morehouse-Emory Cardiovascular (MECA) Center for Health Equity
Authors: Jeong Hwan Kim, Mattew Topel, Peter Baltrus, Priscilla Pemu, Yi-An Ko, Tené Lewis, Viola Vaccarino, Chang Liu, Mohamed Mubasher, Charles Searles, Sandra Dunbar, Arshed Quyyumi, Herman Taylor
Journal: Circulation (2018)

Introduction: Despite well-known inter-racial cardiovascular (CV) disparities, intra-racial heterogeneity within Blacks remains understudied. Factors promoting CV health among Blacks at neighborhoo...
Abstract P255: Decrease in Serum Lipids among 5th Grade CARDIAC Participants, 2002-2012
Authors: Yohannes Gebremariam, Christa Ice, William Neal
Journal: Circulation (2013)

The presence of multiple cardiovascular risk factors such as elevations in body mass index (BMI), systolic blood pressure (SBP), serum low-density lipoprotein (LDL) cholesterol, and the related non high-density lipoprotein (non-HDL) cholesterol in children is predictive of later cardiovascular disease. LDL and non-HDL have recent decreases in the US adult and youth population despite increases in obesity rates. The purpose of this study was to assess these trends among Appalachian 5 th grade children. Methods: 47,198 children, mostly between 10-11 years old, participated in a cross-sectional statewide CARDIAC (Coronary Artery Risk Detection In Appalachian Communities) screening between 2002-2012 and had a complete fasting lipid profile (FLP). Consistent with state demographics, 92.6% were Caucasian and 53.6% female. LDL (Mean = 92.9, sd = 25.5) and non-HDL (M=111, sd = 28.9) cholesterol levels were normally distributed. Covariates included race, gender, age, SBP and BMI (M = 21.36, sd = 5.2). Generalized Linear Models (GLM) and orthogonal contrast matrices were used to test the hypothesis of a linear (v. non-linear) trend over time for LDL and non-HDL values. Results: Models predicting LDL and non-HDL were significant and fit a linear trend (p-value &lt; 0.0001) attributable to the explanatory variables (race was not significant and excluded from the final models). For LDL, year of screening was significant (p&lt;0.0001) as was gender, age and BMI (all p &lt; 0.0001). For non-HDL, year of screening was also significant (p&lt;0.0001), as was gender (p=0.0194), age (p&lt;0.0001), BMI (p&lt;0.0001), and SBP (p=0.0013). There was a decreasing trend in LDL (dot) and non-HDL (broken line) over time (Figure 1). Although some non-linear trends were also significant (e.g., a quartic trend, p &lt; 0.001), the linear trend provided the best fit for both models. Conclusion: The mean values for LDL and non-HDL of a cross-sectional sample of children in 5 th grade Appalachia has decreased over time even after adjusting for age, BMI, gender, race and SBP.
Abstract 1120: Proinflammatory milieu promotes leptomeningeal metastasis by activation of LCN2
Authors: Yudan Chi
Journal: Cancer Research (2019)

Abstract The tumor microenvironment is emerging as a critical regulator of cancer progression, especially in metastatic brain malignancies. The unique properties of leptomeningeal metastasis (LM) require a specific framework for acquisition of metastatic traits within the fluid-filled leptomeningeal space. Here, we discuss a number of the distinct features of the proinflammatory environment, including cancer cells and relevant immune cells. We also highlight the exact role of its contribution to cancer growth in the development of LM. Proinflammatory cytokines induce the secretion of cancer-derived LCN2. Mechanistically, we have uncovered that iron, transported by LCN2, supports cancer cell growth. By pharmacologic interference with iron uptake, we will prove its therapeutic beneficence for targeting LM in pre-clinical models. Citation Format: Yudan Chi. Proinflammatory milieu promotes leptomeningeal metastasis by activation of LCN2 [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 1120.
Wnt5a-Mediated Neutrophil Recruitment Has an Obligatory Role in Pressure Overload–Induced Cardiac Dysfunction
Authors: Ying Wang, Soichi Sano, Kosei Oshima, Miho Sano, Yosuke Watanabe, Yasufumi Katanasaka, Yoshimitsu Yura, Changhee Jung, Atsushi Anzai, Filip K. Swirski, Noyan Gokce, Kenneth Walsh
Journal: Circulation (2019)

Background: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. Methods: To examine the regulation and function of neutrophils in pressure overload–induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction. Results: Neutrophil depletion diminished transverse aortic constriction–induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction–treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression–induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5a transgenic mice. Conclusions: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload–induced heart failure.
Lucy Wright: seeing patients in their own environment
Authors: Adrian O’Dowd
Journal: BMJ (2019)

Lucy Wright: seeing patients in their own environment The occupational health physician tells Adrian O'Dowd how her specialty allows doctors a unique way of tapping into and improving people's health Adrian O'Dowd London, UK Family businessBoth my parents were doctors, my grandma was a nurse, and my grandpa was a pharmacist, so it never occurred to me not to be a doctor.After qualifying I was initially interested in surgery and enjoyed learning surgical techniques.
Abstract 3483: The African-specific S47 variant of the p53 tumor suppressor gene alters cell metabolism
Authors: Keerthana Gnanapradeepan, Subhasree Basu, Che-Pei Kung, Thibaut Barnoud, Madeline Good, William Quinn, Joyce Lee, Kathryn Wellen, Zachary Schug, Joseph Baur, Donna George, Maureen Murphy
Journal: Cancer Research (2019)

Abstract The TP53 gene, often referred to as the guardian of the genome, is the most frequently mutated gene in human cancer. This gene encodes the tumor suppressor p53, a master regulator of various processes such as programmed cell death, growth arrest and senescence. However, there is increasing evidence that highlights the role of p53 in tumor suppression with regards to maintaining metabolic homeostasis. Our lab has identified a polymorphic variant of p53 that encodes a serine residue instead of a proline at amino acid 47 (hereafter S47). This variant is most prevalent in African and African-American individuals, and mice and humans carrying this variant have increased cancer risk and impaired response to therapy. Using both mouse models and human cells, we have found that S47 cells have significantly altered metabolism compared to the WT counterpart. Specifically, S47 mice have increased weight and increased lean content compared to WT mice. These mice also show increased fitness in treadmill studies. Analyses of cell metabolism in S47 murine and human cells indicate that S47 cells show increased glycolysis and glycolytic flux, along with increased oxygen consumption rate on a Seahorse analyzer. The combined data support the premise that the S47 variant confers increased cancer risk but also increased metabolic fitness; the latter may explain the high rate of this variant in certain regions of Africa. By clearly elucidating the roles of WT p53 and the S47 variant in the context of metabolism, we hope to uncover new therapeutic avenues and ultimately enable more personalized medicine approaches for individuals who carry this variant. Citation Format: Keerthana Gnanapradeepan, Subhasree Basu, Che-Pei Kung, Thibaut Barnoud, Madeline Good, William Quinn, Joyce Lee, Kathryn Wellen, Zachary Schug, Joseph Baur, Donna George, Maureen Murphy. The African-specific S47 variant of the p53 tumor suppressor gene alters cell metabolism [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 3483.
Abstract 5242: To investigate the molecular mechanism and therapeutic roles of PSF-1 in leukemia
Authors: Han-Yun Hsieh, Wei-Zhen Jia, Nobuyuki Takakura
Journal: Cancer Research (2019)

Abstract Recently, DNA replication protein PSF-1 gets more and more attention on the research field, PSF-1 not only plays the critical role in normal cell DNA replication but also involves in cancer cell proliferation and anti-apoptosis. PSF1 highly expressed in many types of cancers, such as non-small lung cancer, breast cancer, and colon carcinoma. However, the role and mechanism of PSF1 in leukemia are still uncleared. Compared to the human normal peripheral blood mononuclear cells (PBMCs), the expression level of PSF1 was significantly increased in several types of leukemia, including acute and chronic type leukemia. We also found that PSF1 participate in leukemic cell proliferation and anti-apoptosis. Since PSF1 presents in many types of leukemia, PSF-1 might act as a potential therapeutic target of pan-leukemia. However, in order to enhance the therapeutic effect of leukemia, against its recurrence and metastasis, leukemic stem cells (LSCs) become the novel therapeutic research target. Previous studies indicated that PSF-1 is essential for stem cell proliferation. Based on the study, we selected PSF-1 as the candidate. In this research, we would like to investigate the role of PSF-1 in leukemia and its cancer stem cell niche. Further to establish the new therapeutic method of LSC-specific clinical treatment. Citation Format: Han-Yun Hsieh, Wei-Zhen Jia, Nobuyuki Takakura. To investigate the molecular mechanism and therapeutic roles of PSF-1 in leukemia [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 5242.
Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): A reanalysis of the JAKARTA-2 study.
Authors: Claire N. Harrison, Nicolaas Schaap, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Eric Jourdan, Richard T. Silver, Harry C. Schouten, Francesco Passamonti, Sonja Zweegman, Moshe Talpaz, Srdan Verstovsek, Torsten Gerike, Shelonitda Rose, Mingyu Li, Carrie Brownstein, Ruben A. Mesa
Journal: Journal of Clinical Oncology (2019)

7057 Background: MF is a life-threatening MPN for which RUX is the only approved treatment (Tx) option. Patients (pts) who are relapsed/refractory (R/R) or intolerant to RUX have a particularly high unmet medical need. FEDR is an oral selective JAK2 inhibitor active against wt and mut JAK2. The JAKARTA-2 study demonstrated ≥35% spleen volume responses (SVR) in pts resistant or intolerant to RUX per investigator assessment. This JAKARTA-2 reanalysis employs a more stringent definition of RUX failure than used in the previous analysis. Methods: Adult pts previously treated with RUX with intermediate or high-risk primary, post-PV, or post-ET MF, palpable splenomegaly, ECOG PS ≤2, and platelet counts ≥50 × 10 9 /L received FEDR 400 mg QD in continuous 28-day cycles. The primary endpoint was spleen volume response rate (SVRR): ≥35% SVR from baseline (BL) at cycle 6 end per blinded central review of MRI/CT scans. A key secondary endpoint was symptom RR (≥50% decrease in total symptom score from BL). Results: 79/97 enrolled pts (81%) met the more stringent criteria for RUX R/R (n=65, 82%) or intolerance (n=14, 18%). Median BL spleen volume was 2946 mL (~14× normal). Median prior RUX Tx duration was 11.5 mo (range 1.0–62.4). Median number of FEDR Tx cycles was 7 (1–20). SVRR with FEDR was 30% (95% CI 21, 42). KM estimated median spleen response duration was not estimable (95% CI 7.2 mo, NE). Symptom RR was 27%. Safety was consistent with prior reports. Conclusions: FEDR provided clinically meaningful reductions in splenomegaly and symptom burden in pts with MF who met more stringent criteria for R/R or intolerance to RUX. Clinical trial information: NCT01523171. [Table: see text]
Abstract 4882: Expression atlas of FGF and FGFR genes in pan-cancer uncovered predictive biomarkers for FGFR inhibition response in clinical trials
Authors: Yuan Li, Long Wu, Yanlei Cheng, Weiping Tao, Dawei Wu, Fei Ma, Ning Li
Journal: Cancer Research (2019)

Abstract Genomic variation of FGFR has been intensively investigated in cancer for years, however, clinical trials on the basis of FGFR mutation or amplification as a druggable target of FGFR inhibitors have produced disappointing clinical outcomes. Therefore, the identification of predictive biomarkers for FGFR-targeted agents has remained a crucial issue. Expression profiles of FGF and FGFR in 8,111 patients with 24 types of solid tumors and 879 tumor cell lines along with drug sensitivity data were obtained from public databases. Differential expression, survival and correlation analyses were performed to uncover the clinical relevance of FGF and FGFR genes expression in pan-cancer. As results, FGF and FGFR were frequently dysregulated in pan-cancer. Moreover, almost all the FGF and FGFR were significantly associated with overall survival in at least two cancer types, however, mixed prognostic values were seen in pan-cancer. More importantly, tumor cell lines with high FGFR1/3 expression were more sensitive to FGFR inhibitor PD173074, especially in breast cancer, liver cancer, lung squamous cell carcinoma and ovarian cancer. The predicted positive ratios of FGFR1/2/3/4 were generally over 10% in most tumor types, especially in squamous cell carcinoma. High positive FGFR1 or 3 expression ratio were predicted in cholangiocarcinoma (58%), followed by bladder cancer (42%), endometrial carcinoma (35%), ovarian cancer (34%) and head and neck squamous cell carcinoma (34%). FGFR expression were promising predictive biomarkers for FGFR inhibition response in clinical trials and different combination of FGFR genes should be used in screening for patients in certain tumor types. Citation Format: Yuan Li, Long Wu, Yanlei Cheng, Weiping Tao, Dawei Wu, Fei Ma, Ning Li. Expression atlas of FGF and FGFR genes in pan-cancer uncovered predictive biomarkers for FGFR inhibition response in clinical trials [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 4882.
Abstract 269: DNA-PK inhibitor, M3814, as a new combination partner of Mylotarg in the treatment of acute myeloid leukemia
Authors: Astrid Zimmermann, Michael Carr, Frank T. Zenke, Andree Blaukat, Lyubomir T. Vassilev
Journal: Cancer Research (2019)

Abstract Despite significant advances in the development of new treatments for acute myeloid leukemia (AML) the therapeutic success remains relatively poor. There remains an urgent need for improved therapies with increased tumor potency and selectivity. Mylotarg is the first AML drug from a new generation of antibody drug conjugate (ADC) therapies targeting the acute leukemia cell compartment with increased specificity. This agent targets leukemia cells for apoptosis with a cytotoxic warhead, calicheamicin, carried by a CD33-specific antibody. Calicheamicin induces DNA double strand breaks (DSB) which, if left unrepaired, lead to cell cycle arrest and apoptosis in cancer cells. However, repair of DSBs by the non-homologous end joining pathway driven by DNA-PK (DNA-dependent protein kinase) can reduce the efficacy of calicheamicin. M3814 is a novel, potent and selective inhibitor of DNA-PK protein kinase. This compound effectively blocks DSB repair, strongly potentiates the antitumor activity of ionizing radiation and DSB-inducing chemotherapeutics and is currently under clinical investigation. Suppressing DSB repair with M3814 synergistically enhanced the apoptotic activity of calicheamicin in cultured AML cells. Combination of M3814 with Mylotarg in two AML xenograft models, MV4-11 and HL-60, demonstrated increased efficacy and significantly improved survival benefit without elevated body weight loss. Our results support a new application for pharmacological DNA-PK inhibitors as enhancers of Mylotarg efficacy and a potential new combination treatment option for AML patients. Citation Format: Astrid Zimmermann, Michael Carr, Frank T. Zenke, Andree Blaukat, Lyubomir T. Vassilev. DNA-PK inhibitor, M3814, as a new combination partner of Mylotarg in the treatment of acute myeloid leukemia [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 269.
Abstract 278: System xc- inhibition shares features of necroptosis and ferroptosis in hepatocellular carcinoma cells
Authors: Md Abdullah, Do Hyung Kim, Seung Jin Lee
Journal: Cancer Research (2019)

Abstract Ferroptosis is characterized by iron-dependent non-apoptotic cell death involving the accumulation of lipid peroxides. Inhibition of system xc- which uptake L-cystine with the exchange of L-glutamate decreases glutathione synthesis, leading to ferroptosis. However, molecular interplay between ferroptosis and necroptosis has not been clearly identified. In this study, we investigated molecular process for cell death by SLC7A11 inhibition in hepatocellular carcinoma cell lines. The sensitivity for SLC7A11 inhibition by sulfasalazine was in the order of HepG2, Huh7 and Huh6, and then PLC/PRF/5. The decrease of cell viability by sulfasalazine and erastin was prevented by co-treatment of β-mercaptoethanol in all kinds of cell lines, indicating that the limited supply of L-cystine may contribute to cell death. Both ferrostatin and necrostatin, an inhibitor of ferroptosis and necroptosis, respectively, rescued sulfasalazine-induced growth inhibition by 60% in Huh7 and Huh6 and by 20% in HepG2. However, they failed to restore cell survival in PLC/PRF/5 cells. Sulfasalazine at the dose inducing equivalent level of cell death significantly increased lipid peroxidation in Huh7 and Huh6, but not in HepG2 and PLC/PRF/5 cells, as determined by C11-BODIPY dye. RIPK activation in necroptosis pathway by sulfasalazine was monitored in these cell lines. These results suggest that SLC7A11 inhibition triggers mixed-type of cell death via ferroptosis and necroptosis in a context-dependent manner in hepatocellular carcinoma cells (MD Abdullah and DH Kim are equally contributed to this work). Citation Format: Md Abdullah, Do Hyung Kim, Seung Jin Lee. System xc- inhibition shares features of necroptosis and ferroptosis in hepatocellular carcinoma cells [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 278.
NHS global recruitment must not come at the expense of poorer countries, charity warns
Authors: Aimee Miller
Journal: BMJ (2019)

Recruiting a new “Windrush generation” to fill NHS vacancies must not come at the expense of low and middle income countries (LMICs) in Africa and Asia, the healthcare charity the Tropical Health and Education Trust (THET) has said.1

The charity has published a report in response to the interim NHS People Plan, which calls for the NHS to increase international recruitment.2

Speaking at the launch of the plan in June, health and social care secretary Matt …