tbuckley/cabot-search huggingface dataset:
Targeted Inhibition of the Molecular Chaperone Hsp90 Overcomes ALK Inhibitor Resistance in Non–Small Cell Lung Cancer
Authors: Jim Sang, Jaime Acquaviva, Julie C. Friedland, Donald L. Smith, Manuel Sequeira, Chaohua Zhang, Qin Jiang, Liquan Xue, Christine M. Lovly, John-Paul Jimenez, Alice T. Shaw, Robert C. Doebele, Suqin He, Richard C. Bates, D. Ross Camidge, Stephan W. Morris, Iman El-Hariry, David A. Proia
Journal: Cancer Discovery (2013)

Abstract EML4–ALK gene rearrangements define a unique subset of patients with non–small cell lung carcinoma (NSCLC), and the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy. Here, we show that the Hsp90 inhibitor ganetespib induced loss of EML4–ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, leading to greater in vitro potency, superior antitumor efficacy, and prolonged animal survival compared with results obtained with crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a patient with crizotinib-resistant NSCLC. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC. Significance: In addition to direct kinase inhibition, pharmacologic blockade of the molecular chaperone Hsp90 is emerging as a promising approach for treating tumors driven by oncogenic rearrangements of ALK. The bioactivity profile of ganetespib presented here underscores a new therapeutic opportunity to target ALK and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC. Cancer Discov; 3(4); 430–43. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 363
Integrative Genomics Identifies Distinct Molecular Classes of Neuroblastoma and Shows That Multiple Genes Are Targeted by Regional Alterations in DNA Copy Number
Authors: Qun Wang, Sharon Diskin, Eric Rappaport, Edward Attiyeh, Yael Mosse, Daniel Shue, Eric Seiser, Jayanti Jagannathan, Suzanne Shusterman, Manisha Bansal, Deepa Khazi, Cynthia Winter, Erin Okawa, Gregory Grant, Avital Cnaan, Huaqing Zhao, Nai-Kong Cheung, William Gerald, Wendy London, Katherine K. Matthay, Garrett M. Brodeur, John M. Maris
Journal: Cancer Research (2006)

Abstract Neuroblastoma is remarkable for its clinical heterogeneity and is characterized by genomic alterations that are strongly correlated with tumor behavior. The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors using an oligonucleotide-based microarray. Genomic copy number status at the prognostically relevant loci 1p36, 2p24 (MYCN), 11q23, and 17q23 was determined by PCR and was aberrant in 26, 20, 40, and 38 cases, respectively. In addition, 72 diagnostic neuroblastoma primary tumors assayed in a different laboratory were used as an independent validation set. Unsupervised hierarchical clustering showed that gene expression was highly correlated with genomic alterations and clinical markers of tumor behavior. The vast majority of samples with MYCN amplification and 1p36 loss of heterozygosity (LOH) clustered together on a terminal node of the sample dendrogram, whereas the majority of samples with 11q deletion clustered separately and both of these were largely distinct from the copy number neutral group of tumors. Genes involved in neurodevelopment were broadly overrepresented in the more benign tumors, whereas genes involved in RNA processing and cellular proliferation were highly represented in the most malignant cases. By combining transcriptomic and genomic data, we showed that LOH at 1p and 11q was associated with significantly decreased expression of 122 (61%) and 88 (27%) of the genes mapping to 1p35-36 and all of 11q, respectively, suggesting that multiple genes may be targeted by LOH events. A total of 71 of the 1p35-36 genes were also differentially expressed in the independent validation data set, providing a prioritized list of candidate neuroblastoma suppressor genes. Taken together, these data are consistent with the hypotheses that the neuroblastoma transcriptome is a sensitive marker of underlying tumor biology and that chromosomal deletion events in this cancer likely target multiple genes through alteration in mRNA dosage. Lead positional candidates for neuroblastoma suppressor genes can be inferred from these data, but the potential multiplicity of transcripts involved has significant implications for ongoing gene discovery strategies. (Cancer Res 2006; 66(12): 6050-62)
The Human Brain Project: neuroinformatics tools for integrating, searching and modeling multidisciplinary neuroscience data
Authors: Gordon M. Shepherd, Jason S. Mirsky, Matthew D. Healy, Michael S. Singer, Emmanouil Skoufos, Michael S. Hines, Prakash M. Nadkarni, Perry L. Miller
Journal: Trends in Neurosciences (1998)

What is neuroinformatics? What is the Human Brain Project? Why should you care? Supported by a consortium of US funding agencies, the Human Brain Project aims to bring to the analysis of brain function the same advantages of Internet-accessible databases and database tools that have been crucial to the development of molecular biology and the Human Genome Project. The much greater complexity of neural data, however, makes this a far more challenging task. As a pilot project in this new initiative, we review some of the progress that has been made and indicate some of the problems, challenges and opportunities that lie ahead. Trends Neurosci. (1998) 21, 460–468
Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells
Authors: Clément Larrue, Estelle Saland, Héléna Boutzen, François Vergez, Marion David, Carine Joffre, Marie-Anne Hospital, Jérôme Tamburini, Eric Delabesse, Stéphane Manenti, Jean Emmanuel Sarry, Christian Récher
Journal: Blood (2015)
ASPIRE registry: Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre
Authors: J. Hurdman, R. Condliffe, C.A. Elliot, C. Davies, C. Hill, J.M. Wild, D. Capener, P. Sephton, N. Hamilton, I.J. Armstrong, C. Billings, A. Lawrie, I. Sabroe, M. Akil, L. O’Toole, D.G. Kiely
Journal: European Respiratory Journal (2011)

Pulmonary hypertension (PH) is a heterogeneous condition. To date, no registry data exists reflecting the spectrum of disease across the five diagnostic groups encountered in a specialist referral centre. Data was retrieved for consecutive, treatment-naïve cases diagnosed between 2001 and 2010 using a catheter-based approach. 1,344 patients were enrolled, with a mean follow-up of 2.9 yrs. The 3-yr survival was 68% for pulmonary arterial hypertension (PAH), 73% for PH associated with left heart disease, 44% for PH associated with lung disease (PH-lung), 71% for chronic thromboembolic PH (CTEPH) and 59% for miscellaneous PH. Compared with PAH, survival was inferior in PH-lung and superior in CTEPH (p&lt;0.05). Multivariate analysis demonstrated that diagnostic group independently predicted survival. Within PAH, Eisenmenger’s survival was superior to idiopathic PAH, which was superior to PAH associated with systemic sclerosis (p&lt;0.005). Within PH-lung, 3-yr survival in sleep disorders/alveolar hypoventilation (90%) was superior to PH-lung with chronic obstructive pulmonary disease (41%) and interstitial lung disease (16%) (p&lt;0.05). In CTEPH, long-term survival was best in patients with surgically accessible disease undergoing pulmonary endarterectomy. In this large registry of consecutive, treatment-naïve patients identified at a specialist PH centre, outcomes and characteristics differed between and within PH groups. The current system of classification of PH has prognostic value even when adjusted for age and disease severity, emphasising the importance of systematic evaluation and precise classification.
An Agent Independent Axis for Executed and Modeled Choice in Medial Prefrontal Cortex
Authors: Antoinette Nicolle, Miriam C. Klein-Flügge, Laurence T. Hunt, Ivo Vlaev, Raymond J. Dolan, Timothy E.J. Behrens
Journal: Neuron (2012)

SummaryAdaptive success in social animals depends on an ability to infer the likely actions of others. Little is known about the neural computations that underlie this capacity. Here, we show that the brain models the values and choices of others even when these values are currently irrelevant. These modeled choices use the same computations that underlie our own choices, but are resolved in a distinct neighboring medial prefrontal brain region. Crucially, however, when subjects choose on behalf of a partner instead of themselves, these regions exchange their functional roles. Hence, regions that represented values of the subject's executed choices now represent the values of choices executed on behalf of the partner, and those that previously modeled the partner now model the subject. These data tie together neural computations underlying self-referential and social inference, and in so doing establish a new functional axis characterizing the medial wall of prefrontal cortex.Highlights•Valuation and choice for self and other exhibit parallel computations in PFC•vmPFC computes choices that will be executed, whether for self or other•Rostral dmPFC computes choices that are modeled, whether for self or other•A similar gradient is present in temporoparietal cortex
CLINICAL PROFILE, ACUTE CARE AND OUTCOME OF COCAINE-ASSOCIATED ST-ELEVATION MYOCARDIAL INFARCTION IN A VULNERABLE URBAN COMMUNITY
Authors: Noel Kayo, Sanyog Shitole, Azadeh Beheshtian, Vankeepuram Srinivas, James Scheuer, Jorge Kizer
Journal: Journal of the American College of Cardiology (2014)
Racial Differences in Early-Onset Renal Disease among Young Adults
Authors: Catherine O. Stehman-Breen, Daniel Gillen, Michael Steffes, David R. Jacobs, Cora E. Lewis, Catarina I. Kiefe, David Siscovick
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Although 11 million people in the United States have chronic renal insufficiency, little is known about ethnic/racial disparities for early-onset renal impairment. This study sought to determine whether there is an independent association between race/ethnicity and early-onset renal impairment and to identify other risk factors that might account for observed disparities. All Coronary Artery Risk Development in Young Adults subjects in which serum creatinine was measured at the year 15 examination were identified (n = 3554), excluding those who were pregnant at year 15. Potential risk factors at study entry (ages 18 to 30 yr, 1985 to 1986) included age, weight, gender, race/ethnicity, glucose, uric acid, and systolic BP. Renal impairment was defined as creatinine ≥1.5 mg/dl for men and ≥1.2 mg/dl for women at year 15 (ages 33 to 45 yr). Fifty-two (2.7%) women and 39 (2.4%) men had renal impairment at the year 15 examination. In bivariate analyses, the odds of renal impairment among black women was estimated to be 2.4-fold that of white women, and among black men, the odds of renal impairment were 9.0-fold that of white men. In multivariate analysis, the odds of an elevated creatinine among black women compared with white women reduced to a nonsignificant 1.5-fold, whereas among men, the odds of an elevated creatinine among blacks was 11.4-fold that of whites. Although adjustment for baseline glucose levels accounted for much of the association between ethnicity and elevated creatinine among women, adjustment for weight, systolic BP, uric acid, glucose, and socioeconomic status did not account for the association between ethnicity and renal impairment among men. The data suggest that there are ethnic differences in the development of early-onset renal dysfunction. Among women, these differences are modest and largely accounted for by differences in glucose levels early in adult life. Differences in race/ethnicity related risk of early-onset renal impairment are particularly large among men and are not accounted for by the metabolic or socioeconomic factors evaluated. E-mail: [email protected]
The political economy of healthcare; a clinical perspective
Authors: H J N Andreyev
Journal: Gut (2006)

group-specific and species-specific probes, with no trends detected in precolonoscopy and postcolonoscopy samples.We analysed 96-clone libraries from all three stools per patient (GenBank DQ904637-DQ905931, DQ905933-DQ905956).By using the #-Libshuff programme, 10 we determined which of the libraries originated from the same source, and whether they were subsets or were derived from different sources.For none of the patients did all three libraries derive from the same source, indicating variation in microflora composition.For patient A, the libraries before and 6-8 weeks afterwards originated from the same source (DC X1,Y3 and DC Y1,X3 .0.009), and the library before was a subset of the library detected 2-4 weeks afterwards.For patient B, all libraries originated from different sources (all DC X,Y and DC Y,X ,0.009).For patient C, the libraries at 2-4 and 6-8 weeks after the procedure originated from the same source (DC X2,Y3 and DC Y2,X3 .0.009).For patient D, the library generated after 6-8 weeks was a subset of both other libraries (DC Y1,X3 and DC Y2,X3 .0.009).For patient E, the libraries after the procedure were a subset of the precolonoscopy library (DC Y1,X2 and DC Y1,X3 .0.009) and the library 2-4 weeks afterwards was a subset of that after 6-8 weeks (DC Y3,X2 .0.009).Our observations with different methods did not agree in many details, probably due to different biases inherent in each method.However, all methods indicated that microbiota composition is disturbed in patients undergoing screening colonoscopy, which might have implications for potential health effects that we do not yet understand.Simple DGGE profiling, with universal and groupspecific primer sets, might currently be most efficient for monitoring the complex human microbiota composition over time.There is a clear need for improving our understanding of the dynamics in microbiota composition.
Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: Results from the NSABP P1 and P2 Clinical Trials
Authors: Matthew P. Goetz, Daniel J. Schaid, D. Lawrence Wickerham, Stephanie Safgren, Taisei Mushiroda, Michiaki Kubo, Anthony Batzler, Joseph P. Costantino, Victor G. Vogel, Soonmyung Paik, Erin E. Carlson, David A. Flockhart, Norman Wolmark, Yusuke Nakamura, Richard M. Weinshilboum, James N. Ingle, Matthew M. Ames
Journal: Clinical Cancer Research (2011)

Abstract Background: Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however, this association in the primary prevention of breast cancer is unknown. Methods: We conducted a nested case–control study in the context of the NSABP P1 and P2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, and metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both noninvasive and invasive) while on 5 years of selective estrogen receptor modulators therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was conducted for alleles associated with absent (*3, *4, *5, and *6), reduced (*10, *17, and *41), and increased (*1XN and *2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded. Results: A total of 591 cases were matched to 1,126 controls and DNA was genotyped in more than 97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR (extensive/poor metabolizer): 0.90; 95% CI: 0.46–1.74, P = 0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI: 0.575–1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI: 0.669–1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene-treated patients. Conclusion: In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy. Clin Cancer Res; 17(21); 6944–51. ©2011 AACR.
Health-related quality of life measures in advanced non-small cell lung cancer patients receiving sorafenib
Authors: K. Gondek, R. Dhanda, R. Simantov, U. Gatzemeier, G. R. Blumenschein, M. Reck
Journal: Journal of Clinical Oncology (2006)

17085 Background: A multicenter, international, single-arm Phase II study evaluated the efficacy, safety, and tolerability of sorafenib in patients with advanced non-small-cell lung cancer (NSCLC). In addition, patients’ health-related quality of life (HRQL) and symptoms were assessed. Methods: HRQL was measured by the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire that was self-administered at baseline, at every other cycle during the study treatment period, and at the end-of-treatment (EOT) visit. Patients responded to each item on a five-point Likert-type scale ranging from 0 (not at all) to 4 (very much). Five subscale scores and an overall function score were calculated, with higher scores reflecting better function and symptom response. A change of two points, the minimum important difference (MID), in each of the five domains (physical well-being [PWB], emotional well-being [EWB], social well-being [SWB], lung cancer symptoms [LCS], and functional well-being [FWB]) was determined to be clinically meaningful. The total score of the treatment outcome index (TOI) was also assessed. Results: A total of 52 patients were evaluated. Data were collected at baseline, Cycle 2, Cycle 4, and EOT for 50/52 (96%), 42/52 (81%), 21/52 (40%), and 20/52 (38%) of patients, respectively. The mean total FACT-L scores were 99.3, 106.5, and 83.7 at Cycles 2, 4, and EOT, respectively. The mean changes from baseline in the total FACT-L score were -4.6, -0.2, and -14.6 at Cycles 2, 4, and EOT, respectively. The mean change from baseline in the each subscale scores were: -0.6, -1.0, -5.8 for PWB; -0.4, -0.8, -0.6 for SWB; -0.0, 2.1, -1.1 for EWB; -0.7, 0.9, -3.9 for FWB; -0.5, -1.0, -3.6 for LCS; and -2.6, -1.0, -13.2 for TOI, at Cycles 2, 4, and EOT, respectively. An improvement greater than the MID was observed in EWB at Cycle 4. Decreases below MID were observed for EWB at Cycle 2 and EOT, and all other subscales of the FACT-L at Cycles 2, 4, and EOT. Conclusions: These findings are encouraging and suggest that sorafenib did not adversely impact patient-reported outcomes in function and symptom response during the treatment period. As there is no comparator arm, interpretation of results is limited. [Table: see text]
Endocrine Manifestations of Stimulatory G Protein α-Subunit Mutations and the Role of Genomic Imprinting
Authors: Lee S. Weinstein, Shuhua Yu, Dennis R. Warner, Jie Liu
Journal: Endocrine Reviews (2001)

Abstract The heterotrimeric G protein Gs couples hormone receptors (as well as other receptors) to the effector enzyme adenylyl cyclase and is therefore required for hormone-stimulated intracellular cAMP generation. Receptors activate Gs by promoting exchange of GTP for GDP on the Gs α-subunit (Gsα) while an intrinsic GTPase activity of Gsα that hydrolyzes bound GTP to GDP leads to deactivation. Mutations of specific Gsα residues (Arg201 or Gln227) that are critical for the GTPase reaction lead to constitutive activation of Gs-coupled signaling pathways, and such somatic mutations are found in endocrine tumors, fibrous dysplasia of bone, and the McCune-Albright syndrome. Conversely, heterozygous loss-of-function mutations may lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, brachydactyly, sc ossifications, and mental deficits. Similar mutations are also associated with progressive osseous heteroplasia. Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate Gs in their target tissues (pseudohypoparathyroidism type IA). Studies in Gsα knockout mice demonstrate that Gsα is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues (e.g., renal proximal tubule, the major site of renal PTH action), while being biallelically expressed in most other tissues. Disrupting mutations in the maternal allele lead to loss of Gsα expression in proximal tubules and therefore loss of PTH action in the kidney, while mutations in the paternal allele have little effect on Gsα expression or PTH action. Gsα has recently been shown to be also imprinted in human pituitary glands. The Gsα gene GNAS1 (as well as its murine ortholog Gnas) has at least four alternative promoters and first exons, leading to the production of alternative gene products including Gsα, XLαs (a novel Gsα isoform that is expressed only from the paternal allele), and NESP55 (a chromogranin-like protein that is expressed only from the maternal allele). A fourth alternative promoter and first exon (exon 1A) located approximately 2.5 kb upstream of the Gsα promoter is normally methylated on the maternal allele and transcriptionally active on the paternal allele. In patients with isolated renal resistance to PTH (pseudohypoparathyroidism type IB), the exon 1A promoter region has a paternal-specific imprinting pattern on both alleles (unmethylated, transcriptionally active), suggesting that this region is critical for the tissue-specific imprinting of Gsα. The GNAS1 imprinting defect in pseudohypoparathyroidism type IB is predicted to decrease Gsα expression in renal proximal tubules. Studies in Gsα knockout mice also demonstrate that this gene is critical in the regulation of lipid and glucose metabolism.