tbuckley/cabot-search huggingface dataset:
A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors
Authors: Alexander Drilon, Ramamoorthy Nagasubramanian, James F. Blake, Nora Ku, Brian B. Tuch, Kevin Ebata, Steve Smith, Veronique Lauriault, Gabrielle R. Kolakowski, Barbara J. Brandhuber, Paul D. Larsen, Karyn S. Bouhana, Shannon L. Winski, Robyn Hamor, Wen-I Wu, Andrew Parker, Tony H. Morales, Francis X. Sullivan, Walter E. DeWolf, Lance A. Wollenberg, Paul R. Gordon, Dorothea N. Douglas-Lindsay, Maurizio Scaltriti, Ryma Benayed, Sandeep Raj, Bethany Hanusch, Alison M. Schram, Philip Jonsson, Michael F. Berger, Jaclyn F. Hechtman, Barry S. Taylor, Steve Andrews, S. Michael Rothenberg, David M. Hyman
Journal: Cancer Discovery (2017)

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.
The Frequency of Uniparental Disomy in Prader-Willi Syndrome
Authors: Maria J. Mascari, Wayne Gottlieb, Peter K. Rogan, Merlin G. Butler, David A. Waller, John A.L. Armour, Alec J. Jeffreys, Roger L. Ladda, Robert D. Nicholls
Journal: New England Journal of Medicine (1992)

Prader—Willi syndrome is a genetic disorder characterized by infantile hypotonia, obesity, hypogonadism, and mental retardation, but it is difficult to diagnose clinically in infants and young children. In about two thirds of patients, a cytogenetically visible deletion can be detected in the paternally derived chromosome 15 (15q11q13). Recently, patients with Prader—Willi syndrome have been described who do not have the cytogenetic deletion but instead have two copies of the 15q11q13 region that are inherited from the mother (with none inherited from the father). This unusual form of inheritance is known as maternal uniparental disomy. Using molecular genetic techniques, we sought to determine the frequency of uniparental disomy in Prader—Willi syndrome.
P53 mutation and differential response to neoadjuvant chemotherapy in women with locally advanced breast cancer: Results from the I-SPY trial (CALGB 150007/1500012 and ACRIN 6657)
Authors: S. M. Pradhan, L. Carey, S. Edmiston, N. Hylton, E. Parrish, D. Moore, K. Conway
Journal: Journal of Clinical Oncology (2009)

11099 Background: Independent of other factors, p53 status may influence sensitivity to anthracycline (A)- and taxane (T)-based chemotherapy. We investigated p53 as a predictive marker of differential neoadjuvant chemoresponse by examining change in MRI longest diameter (LD) during sequential A- then T-based chemotherapy in a prospective clinical trial. Methods: 171 patients (pts) with newly diagnosed locally advanced breast cancer received neoadjuvant A- then T-based chemotherapy. LD were obtained pretherapy, between regimens, and posttherapy but prior to surgery. P53 mutation analysis was performed on pretherapy tissue using gene chip technology, SSCP, and sequencing. Subtypes were by IHC: LumA (ER/PR+/HER2-), LumB (ER/PR+/HER2+), Basal (triple negative), HER2 (HER2+/ER/PR-). Results: 99 pts had p53 mutant (M) tumors and 72 were wildtype (WT). M and WT did not differ by age, menopausal status, or HER2. M were significantly more common among basal (71%) and HER2 (59%) than Lum A (24%). Anthracycline response did not differ between WT and M within subtypes. Within HER2, Basal, and LumB, WT had higher taxane- and overall responses than M; within LumB these were statistically significant (p=0.03 and 0.05 respectively). Conclusions: P53 mutation status may affect chemosensitivity even within hormone receptor/HER2 subsets. In this dataset response to anthracycline appeared independent of p53 status within subtypes, while WT tumors responded better to taxanes and overall in LumB, with a similar trend among basal and HER2. Mutational subset and correlative analyses with gene expression, molecular subtyping, and IHC data are ongoing and will be presented. [Table: see text] No significant financial relationships to disclose.
Sound Health
Authors: Francis S. Collins, Renée Fleming
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Right ventricular dyssynchrony and exercise capacity in idiopathic pulmonary arterial hypertension
Authors: Roberto Badagliacca, Silvia Papa, Gabriele Valli, Beatrice Pezzuto, Roberto Poscia, Manuela Reali, Giovanna Manzi, Elisa Giannetta, Daniele Berardi, Susanna Sciomer, Paolo Palange, Francesco Fedele, Robert Naeije, Carmine Dario Vizza
Journal: European Respiratory Journal (2017)

Survival in patients with pulmonary arterial hypertension (PAH) is determined by right ventricular (RV) function adaptation to afterload. How altered RV function impacts on exercise capacity in PAH is not exactly known. 104 idiopathic PAH (IPAH) patients aged 52±14 years underwent a diagnostic right heart catheterisation, a comprehensive echocardiography including two-dimensional speckle tracking for RV dyssynchrony evaluation and a cardiopulmonary exercise test. Multivariate analyses were performed to identify independent predictors of peak oxygen uptake (peak V ′ O 2 ). A first multivariate analysis of only resting haemodynamic variables identified cardiac index, right atrial (RA) pressure and pulmonary arterial compliance as independent predictors, with low predictive capacity (r 2 =0.31; p&lt;0.001). A second multivariate analysis model which considered only echocardiographic parameters but without RV dyssynchrony, identified RV fractional area change (FAC) and RA area as independent predictors with still low predictivity (r 2 =0.35; p&lt;0.001). Adding RV dyssynchrony to the second model increased its predictivity (r 2 =0.48; p&lt;0.001). Repetition of the three multivariate analyses in patients with preserved RVFAC confirmed that inclusion of RV dyssynchrony results in the highest predictive capability of peak V ′ O 2 (r 2 =0.53; p=0.001). A comprehensive echocardiography with speckle tracking-derived assessment of the heterogeneity of RV contraction improves the prediction of aerobic exercise capacity in IPAH.
Evaluation of the Role of Radiological Imaging and Bone Marrow Biopsy in Staging of Cutaneous B-Cell Lymphoma
Authors: Pankit Vachhani, Christopher J. Cancino, Paul Bogner, Charles L. Roche, Gyorgy Paragh, Marcelle A. Grassi, Vishala T. Neppalli, Francisco J. Hernandez-Ilizaliturri
Journal: Blood (2016)
Effects of phosphorylation of human thymidylate synthase by casein kinase 2 on ligand binding
Authors: Brittnaie J. Bell, Al-Motessem Yousef, Saphronia R. Johnson, Lukasz Lebioda, Sondra H. Berger
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1026 

Thymidylate synthase (TS) is an essential enzyme for DNA synthesis and cell growth that has been studied extensively as a target for the chemotherapy of breast, head/neck, and colon cancers. Previous investigations revealed that the serine/threonine protein kinase, CK2, can mediate in vitro phosphorylation of human TS (hTS) and that phosphorylation of hTS is dependent upon protein structure. In addition, metabolic labeling studies with a CK2 activator and inhibitor indicated that CK2 plays a role in the in situ phosphorylation of hTS in tumor cell lines. TS is inactivated by binding to substrate analogs, such as 5-fluoro-2′-deoxyuridylate (FdUMP), a metabolite of 5-fluorouracil and capecitabine. We analyzed the role of CK2 phosphorylation in the binding of FdUMP to hTS. We observed that phosphorylated hTS binds FdUMP, albeit with lower affinity than the unphosphorylated protein. We also analyzed the effect of ligation with FdUMP on phosphorylation of hTS and on murine TS (mTS). We observed that ligation with FdUMP inhibited phosphorylation of both TSs. The data indicate that phosphorylation of hTS and ligation with FdUMP are interdependent and that CK2-mediated phosphorylation of hTS could lead to resistance to pro-drugs of FdUMP. To identify the site(s) of phosphorylation, we utilized an Internet accessible server, PhosoBase and the three-dimensional structure of hTS. Our analyses led to the prediction that serine residues at positions 66 and 124 are most likely to be phosphorylated by CK2. We have created S/A and S/D mutants of hTS, with replacements at one or both sites. We are examining the site of phosphorylation and the effect of serine substitution on ligand binding and protein structure.
Biodegradation and biocompatibility of haloarchaea-produced poly(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymers
Authors: Jing Han, Lin-Ping Wu, Xiao-Bin Liu, Jing Hou, Li-Li Zhao, Jun-Yu Chen, Da-He Zhao, Hua Xiang
Journal: Biomaterials (2017)
Central amygdala circuits modulate food consumption through a positive-valence mechanism
Authors: Amelia M Douglass, Hakan Kucukdereli, Marion Ponserre, Milica Markovic, Jan Gründemann, Cornelia Strobel, Pilar L Alcala Morales, Karl-Klaus Conzelmann, Andreas Lüthi, Rüdiger Klein
Journal: Nature Neuroscience (2017)
Analysis of transcription and protein expression changes in the 786-O human renal cell carcinoma tumor xenograft model in response to treatment with the multi-kinase inhibitor sorafenib (BAY 43-9006)
Authors: Joan B. Levy, Nicole Pauloski, Deborah Braun, Mary Derome, Jerold Jordan, Hong Shi, Daniel Weaver, Yong Chang, Elizabeth Bortolon, Arris Henderson, Paul Fracasso, Amy Burd, James Elting, Mark Lynch, Sanjeeva Reddy, Scott M. Wilhelm
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

906 

Renal cell carcinoma (RCC) is the 6th leading cause of cancer death and is marked by a high prevalence of mutations of the VHL gene which results in the deregulation of VEGF and increased tumor angiogenesis. BAY 43-9006 (sorafenib) is an orally active, multi-kinase inhibitor that targets the serine/threonine kinase RAF (RAF-1 and B-RAF) and receptor tyrosine kinases (VEGFR-2/PDGFR-β) involved in tumor growth and angiogenesis. It is currently being evaluated in phase III clinical trials for the treatment of RCC, hepatocellular carcinoma and melanoma. In the VHL-/- 786-O tumor xenograft model, once daily oral dosing of sorafenib produces partial tumor growth inhibition at 15 mg/kg and complete tumor stasis at doses of 30 mg/kg or higher associated with inhibition of tumor microvessel formation and visible areas of tumor necrosis (Chang, YS et al. EORTC 2005). To gain a better understanding of the early gene and protein expression changes associated with tumor stasis upon treatment with sorafenib, drug and vehicle treated tumors were harvested at 4 and 24 hours after the third 60 mg/kg dose. Affymetrix GeneChip™ analysis revealed significant increases in mRNA levels of the inflammatory and angiogenic cytokines, IL-6 and IL-8, as well as the matrix metalloproteinases, MMP-1 and MMP-10 upon treatment with sorafenib. These changes were confirmed by Taqman using human mRNA specific primers. Sorafenib induced modest increases in expression of the angiogenic factor, VEGF, whereas no significant changes were observed in the mRNA levels of the angiogenic factors, FGF-1 and FGF-2, or TGF-α, a known autocrine growth factor for RCC. Measurement of protein levels of IL-6, IL-8, MMP1 and VEGF from vehicle and sorafenib-treated 786-O tumor extracts were determined by ELISA using antibodies specific for the human protein. Increases in mRNA expression in sorafenib-treated 786-O RCC tumors corresponded to increases at the protein level, which were statistically significant for IL-6, IL-8, and MMP-1. The observed changes in VEGF expression are consistent with published clinical observations of modulation of VEGF in the plasma or serum of patients treated with inhibitors targeting VEGFR. Additional studies are underway to evaluate the utility of IL-6, IL-8, and MMP-1 as pharmacodynamic biomarkers for clinical response to sorafenib.
Expression of Poly [ADP-Ribose] Polymerase 1 (PARP-1) and Uridine-Cytidine Kinase (UCK) 1 and 2 in Myelodysplastic Syndrome
Authors: Panagiotis Theodorou Diamantopoulos, Panagiotis Zervakis, Maria Sofotasiou, Konstantinos Zervakis, Argiris Symeonidis, Kodandreopoulou Elina, Galanopoulos Athanassios, Pappa Vassiliki, Kotsianidis Ioannis, Christopoulou Georgia, Papadopoulou Vasiliki, Mantzourani Marina, Nora-Athina Viniou
Journal: Blood (2016)
Abstract P097: Endothelial Overexpression of LOX-1 Decreases Arterial Thrombosis and TF Expression in Vivo: Role of SIRT-1 and NFκB
Authors: Alexander Akhmedov, Giovani G Camici, Simona Stivala, Erik W Holy, Alexander Breitenstein, Christine Lohmann, Juerg-Hans Beer, Christian M Matter, Thomas F Luescher
Journal: Circulation Research (2011)

Background  -The hallmark of the initiation of atherosclerotic lesion is foam cell formation, and oxidized LDL (OxLDL) is believed to play a key role in the initiation of the atherosclerotic process. OxLDL is internalized by several receptors, such as SR-AI/II, SR-BI, CD36, and CD68. OxLDL is also internalized by endothelial cells, but this uptake depends on receptors other than the classic scavenger receptors. In 1997, a lectin-like oxidized LDL receptor-1 (LOX-1, OLR1) was identified in bovine aortic endothelial cells. LOX-	1 is a type II membrane glycoprotein with an apparent molecular weight of 50 kDa. It has a C-terminal extracellular C-type lectin-like domain. This lectin-like domain is essential for binding to OxLDL. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO, which may trigger the onset of cardiovascular events or accelerate the development of atherosclerosis.    Methods and Results  - We generated endothelial-specific  LOX-1  transgenic mice using the Tie2 promoter ( LOX-1TG ). 12-week-old male  LOX-1TG  and wild-type (WT) mice were applied for carotid artery thrombosis model.  LOX-1TG  mice developed carotid artery thrombosis within a mean occlusion time of 36.96±4.83 min, while WT control mice occluded within a mean time period of 22.75±3.87 min (n=10, P  LOX-1TG  mice, reactive oxygen species were increased and the transcription factors NF-κB and Oct-1 activated. In atherosclerotic  LOX-1TG/ApoE −/−   mice,high cholesterol diet increased VCAM-1 expression, number of macrophages, T-cells as well as plaque size.    Conclusions  -Thus, our data suggest that  LOX-1  plays a protective role in the arterial thrombosis when expressed at unphysiological levels. Therefore,  LOX-1  might represent a novel therapeutic target for atherosclerosis.
Breast Cancer Disparities at Home and Abroad: A Review of the Challenges and Opportunities for System-Level Change
Authors: Katherine E. Reeder-Hayes, Benjamin O. Anderson
Journal: Clinical Cancer Research (2017)

Abstract Sizeable disparities exist in breast cancer outcomes, both between Black and White patients in the United States, and between patients in the United States and other high-income countries compared with low- and middle-income countries (LMIC). In both settings, health system factors are key drivers of disparities. In the United States, Black women are more likely to die of breast cancer than Whites and have poorer outcomes, even among patients with similar stage and tumor subtype. Over-representation of higher risk “triple-negative” breast cancers contributes to breast cancer mortality in Black women; however, the greatest survival disparities occur within the good-prognosis hormone receptor–positive (HR+) subtypes. Disparities in access to treatment within the complex U.S. health system may be responsible for a substantial portion of these differences in survival. In LMICs, breast cancer mortality rates are substantially higher than in the United States, whereas incidence continues to rise. This mortality burden is largely attributable to health system factors, including late-stage presentation at diagnosis and lack of availability of systemic therapy. This article will review the existing evidence for how health system factors in the United States contribute to breast cancer disparities, discuss methods for studying the relationship of health system factors to racial disparities, and provide examples of health system interventions that show promise for mitigating breast cancer disparities. We will then review evidence of global breast cancer disparities in LMICs, the treatment factors that contribute to these disparities, and actions being taken to combat breast cancer disparities around the world. Clin Cancer Res; 23(11); 2655–64. ©2017 AACR. See all articles in this CCR Focus section, “Breast Cancer Research: From Base Pairs to Populations.”
Facteurs de risque de mauvaise préparation colique: un score prédictif validé
Journal: Endoscopy (2017)

Les conséquences d’une mauvaise préparation colique, problématique quotidienne pour tout gastro-entérologue, ne sont plus à démontrer: diminution du taux de détection d’adénome, majoration du temps d’examen, des coûts de prise en charge, du délai au diagnostic et probablement du taux de complication.
Who benefits from radiotherapy for gastric cancer? A meta-analysis.
Authors: Nitin Ohri, Madhur Garg, Santiago Aparo, Andreas Kaubisch, Wolfgang A. Tome, Timothy J. Kennedy, Shalom Kalnicki, Chandan Guha
Journal: Journal of Clinical Oncology (2013)

4093 Background: Randomized trials have demonstrated significant survival benefits with the use of adjuvant (including neoadjuvant) chemotherapy or chemoradiotherapy for gastric cancer. The importance of adjuvant radiotherapy (RT) remains unclear. Here we perform an up-to-date meta-analysis of randomized trials testing the use of radiotherapy for resectable gastric cancer. Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials testing adjuvant RT for resectable gastric cancer. Hazard ratios describing the impact of adjuvant RT on overall survival (OS) and disease-free survival (DFS) were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. Subgroup analyses were performed to determine if the efficacy of RT varies with chemotherapy use, RT timing, geographic region, type of nodal dissection performed, and lymph node status. Results: Thirteen studies met all inclusion criteria and were used for this analysis. Adjuvant RT was associated with a significant improvement in both OS (HR=0.78, 95% CI: 0.70 to 0.86, p&lt;0.001) and DFS (HR=0.71, 95% CI: 0.63 to 0.80, p&lt;0.001). In the five studies that tested adjuvant chemoradiotherapy against adjuvant chemotherapy, similar effects were seen for OS (HR=0.83, 95% CI: 0.67 to 1.03, p=0.087) and DFS (HR=0.77, 95% CI: 0.91 to 0.65, p=0.002). Available data did not reveal any subgroup of patients that does not benefit from adjuvant RT. Conclusions: In randomized trials for resectable gastric cancer, adjuvant RT provides an approximately 20% improvement in both DFS and OS. Available data do not reveal a subgroup of patients that does not benefit from adjuvant RT. Further study is required to optimize the implementation of adjuvant RT for gastric cancer with regards to patient selection and integration with systemic therapy.