tbuckley/cabot-search huggingface dataset:
Abstract 3422: The influence of genetic and clinical factors on the outcome following a diagnosis of small cell carcinoma of the ovary, hypercalcemic type
Authors: Leora Witkowski, Catherine Goudie, Pilar Ramos, Anthony N. Karnezis, Talia Boshari, Patricia Pautier, Michel Longy, James A. Knost, Emmanouil Saloustros, W Glenn McCluggage, Martin Hasselblatt, William P. Hendricks, David Huntsman, Douglas A. Levine, Jeffrey Trent, William D. Foulkes
Journal: Cancer Research (2016)

Abstract Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian tumor diagnosed in women below the age of 40. While it is uncommon, with only ∼500 cases reported, it is an extremely aggressive tumor, with long term survival rates of &amp;lt;30% in early stage disease. Recently, we discovered that SCCOHT is a monogenic disease, attributable to germline and somatic deleterious mutations in the chromatin remodeling gene, SMARCA4. Since then, single case reports have been published on women affected with SCCOHT, but no large studies have been conducted on the effect of these mutations, germline or somatic, on the disease. Furthermore, while numerous publications have described the therapies used in single cases or small cohorts of SCCOHT patients, treatment remains varied, with no standardized protocols. In an attempt to clarify which factors have an effect on the course of the disease, we reviewed all published and a cohort of unpublished SCCOHT cases and collected information on the following factors: stage at diagnosis, age at diagnosis, treatment modality used (chemotherapy/radiotherapy/high dose chemotherapy), mutation type (germline/somatic), and length of survival. We were able to acquire information in at least 2 of these parameters in 267 cases and performed multiple analyses. Clinically, we found that the greatest influence on patient outcome was related to stage at diagnosis (p &amp;lt; 0.001) and treatment modality (p = 0.01), while age at diagnosis had no significant effect (p = 0.72). Molecularly, the presence of a germline mutation in the patient did not affect the age of onset (p = 0.86), nor did it have an effect on the length of survival of the patient (p = 0.63). Overall, this is the largest study conducted to date analyzing the influence of clinical factors on the outcome of patients diagnosed with SCCOHT, and is the first large study to analyze the effect of germline mutations on the outcome of these patients. Citation Format: Leora Witkowski, Catherine Goudie, Pilar Ramos, Anthony N. Karnezis, Talia Boshari, Patricia Pautier, Michel Longy, James A. Knost, Emmanouil Saloustros, W Glenn McCluggage, Martin Hasselblatt, William P. Hendricks, David Huntsman, Douglas A. Levine, Jeffrey Trent, William D. Foulkes. The influence of genetic and clinical factors on the outcome following a diagnosis of small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3422.
ZAP-70 Protein Retains Its Prognostic Significance within Interphase Cytogenetic Groups in B-Cell Chronic Lymphocytic Leukemia (B-CLL).
Authors: Maria Ilaria Del Principe, Giovanni Del Poeta, Maria Christina Cox, Paola Panetta, Luca Maurillo, Adriano Venditti, Maria Irno Consalvo, Valter Gattei, Francesco Lo Coco, Sergio Amadori
Journal: Blood (2004)
PD-006 Gemcitabine and Oxaliplatin (GEMOX) with or without Panitumumab as First-Line Treatment in Advanced Biliary Tract Cancer; final results and subgroup analysis of the Vecti-BIL Study
Authors: D. Marino, R. Filippi, S. Cereda, C. Belli, R. Spadi, G. Nasti, M. Montano, A. Amatu, S. Lutrino, C. Cagnazzo, L. Ferrari, S. Siena, L. Ciuffreda, M. Reni, M. Aglietta, F. Leone
Journal: Annals of Oncology (2015)
S97 Severity of lung but not liver disease impacts cardiovascular risk in alpha-1 antitrypsin deficiency: Abstract S97 Table 1
Authors: S Samanta, AD Saleh, B Gooptu, A Marshall, D Thorburn, DA Lomas, JR Hurst
Journal: Thorax (2015)

<h3>Introduction</h3> Alpha-1 antitrypsin deficiency (AATD) is a genetic condition associated with COPD; patients homozygous for the mutant ‘Z’ allele (PiZZ) are predisposed to severe, early-onset emphysema of the lung, and also progressive fibrosis and cirrhosis of the liver. There is a well-known association between COPD and cardiovascular disease, with around 1 in 3 COPD deaths attributed to a cardiac cause.<sup>1</sup> We hypothesised that cardiovascular risk in AATD may be independently modified by the severity of lung and liver disease, through common or related pathophysiological processes. <h3>Methods</h3> Cardiovascular risk was ascertained in 43 patients with PiZZ AATD using QRISK2 score and aortic pulse wave velocity (aPWV). These values were correlated with indicators of lung (FEV<sub>1</sub>, D<sub>LCO</sub>, K<sub>CO</sub>, RV) and structural liver disease (transient elastography and liver ultrasound). <h3>Results</h3> The severity of airflow obstruction (FEV1), emphysema (gas transfer) and gas trapping (RV) all related to cardiovascular risk as assessed by aPWV and QRISK2, Table 1. In contrast, there was no significant association between the presence or increased severity of structural liver disease, as assessed by ultrasound and transient elastography respectively, and either indicator of cardiovascular risk (p &lt; 0.05). <h3>Conclusions</h3> These findings demonstrate that the severities of emphysema and airflow obstruction are associated with increased cardiovascular risk in AATD. In contrast, there was no association between the severity of structural liver disease and cardiovascular risk. Therefore, in conclusion, cardiovascular risk varies in PiZZ A1AD patients according to disease phenotype. <h3>Reference</h3> 1 McGarvey LP, <i>et al</i>.<i> Thorax</i> 2007;<b>62</b>(5):411–15
Reply
Authors: Salvatore Piano, Paolo Angeli
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. We appreciate the interest of O'Brien et al. in our article recently published in Hepatology.1 We thank them for highlighting two important concepts that were reported in our article: (1) a broad‐spectrum empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis (SBP) should be considered only in centers with a high prevalence of multidrug‐resistant (MDR) bacteria; and (2) a rapid de‐escalation of antibiotics should be done once cultures results are available. Some of the points raised by O'Brien et al. require clarification. PMN cell count is not a surrogate marker of SBP, but is the widely accepted standard to establish the diagnosis of SBP and has been for over 20 years.2 Thus, the suggestion that antibiotics should not be administered to patients with SBP in whom cultures are negative is unjustified and dangerous, because it has been demonstrated that an effective first‐line treatment is the strongest predictor of survival in patients with SBP, and that a correlation exists between the delay to start antibiotic therapy and the rate of mortality attributed to the infection.5 Regarding the ability to predict the right antibiotic for the right patient, although philosophically desirable, there is no scientific evidence yet that would allow us to do this. The best we can do now is choose the antibiotic that is more likely to be effective, based on local epidemiology of SBP and pharmacokinetics/pharmacodynamics of antibiotics. Again, the statement by O'Brien et al. that declares that current strategies "will fail because in the future the patients will die for lack of effective therapy" is philosophical. The concern for the development of MDR bacteria should not restrain physicians from administering broad‐spectrum antibiotics when indicated, otherwise patients will die not for a lack of effective therapy, but because an effective therapy was not used at all. Finally, O'Brien et al. did not suggest any viable strategy for the management of nosocomial SBP. While recognizing again that our results cannot be generalized to all patients worldwide, we state that they represent a small step forward in the knowledge of the treatment of nosocomial SBP, based on a randomized, controlled trial and not on personal opinion.
Ten-year change in sedentary behaviour, moderate-to-vigorous physical activity, cardiorespiratory fitness and cardiometabolic risk: independent associations and mediation analysis
Authors: Sara Knaeps, Jan G Bourgois, Ruben Charlier, Evelien Mertens, Johan Lefevre, Katrien Wijndaele
Journal: British Journal of Sports Medicine (2016)

We aimed to study the independent associations of 10-year change in sedentary behaviour (SB), moderate-to-vigorous physical activity (MVPA) and objectively measured cardiorespiratory fitness (CRF), with concurrent change in clustered cardiometabolic risk and its individual components (waist circumference, fasting glucose, high-density lipoprotein (HDL) cholesterol, triglycerides and blood pressure). We also determined whether associations were mediated by change in CRF (for SB and MVPA), waist circumference (for SB, MVPA and CRF) and dietary intake (for SB).A population-based sample of 425 adults (age (mean±SD) 55.83±9.40; 65% men) was followed prospectively for 9.62±0.52 years. Participants self-reported SB and MVPA and performed a maximal cycle ergometer test to estimate peak oxygen uptake at baseline (2002-2004) and follow-up (2012-2014). Multiple linear regression and the product of coefficients method were used to examine independent associations and mediation effects, respectively.Greater increase in SB was associated with more detrimental change in clustered cardiometabolic risk, waist circumference, HDL cholesterol and triglycerides, independently of change in MVPA. Greater decrease in MVPA was associated with greater decrease in HDL cholesterol and increase in clustered cardiometabolic risk, waist circumference and fasting glucose, independent of change in SB. Greater decrease in CRF was associated with more detrimental change in clustered cardiometabolic risk and all individual components. Change in CRF mediated the associations of change in SB and MVPA with change in clustered cardiometabolic risk, waist circumference and, only for MVPA, HDL cholesterol. Change in waist circumference mediated the associations between change in CRF and change in clustered cardiometabolic risk, fasting glucose, HDL cholesterol and triglycerides.A combination of decreasing SB and increasing MVPA, resulting in positive change in CRF, is likely to be most beneficial towards cardiometabolic health.
Comment on Rosenstock and Ferrannini. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care 2015;38:1638–1642
Authors: William G. Cushard
Journal: Diabetes Care (2016)

I felt uneasy about the assessment by Rosenstock and Ferrannini (1) that euglycemic diabetic ketoacidosis (euDKA) associated with sodium–glucose cotransporter 2 inhibitor (SGLT2i) therapy is predictable.

My patient got up, ate breakfast, and went to work only to become symptomatic later that morning. By that evening she was in the intensive care unit with arterial pH 6.8 and β-hydroxybutyrate 9.95 mmol/L (normal range 0.02–0.27) associated with blood glucose 182 mg%, creatinine 0.84 mg%, and lactate 1.4 mmol/L (0.05–2.2) and with negative results on salicylates, acetaminophen, ethylene glycol, lipase, blood cultures, transaminase, human chorionic gonadotropin, and toxicology screening. She was not known to have any of …
Single dose denileukin diftitox does not enhance vaccine-induced T cell responses or effectively deplete Tregs in advanced melanoma: immune monitoring and clinical results of a randomized phase II trial
Authors: Jason J. Luke, Yuanyuan Zha, Karen Matijevich, Thomas F. Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2016)

Depletion of CD25(+) Tregs improves anti-tumor immunity in preclinical models. Denileukin diftitox is a recombinant fusion protein of human IL-2 and diptheria toxin fragment that also can kill CD25(+) T cells. Prior clinical trials of denileukin diftitox suggested reduction of FoxP3(+) Tregs and some clinical responses.To investigate the immunologic effects of denileukin difitox on vaccine-specific immune responses in melanoma, a randomized clinical trial of single dose denileukin diftitox prior to vaccination versus vaccination alone in subjects with HLA-A2(+) metastatic melanoma was performed. Treatment included randomization to a 4-peptide vaccine (Melan-A, gp100, MAGE3 and NA17 with GM-CSF emulsified in Montanide) alone or after single dose of denileukin diftitox (18 mcg/kg). Vaccine was given every 2 weeks for 3 doses and, absent clinical progression, continued every 2 weeks. Blood and tumor biopsies were obtained pretreatment and after 3 vaccinations for immunologic assessments.In 17 treated subjects there were no drug-related G3-4 adverse events. One partial response and 8 stable disease were observed in 9 subjects (4 DD: 5 vaccine only) with no impact of denileukin diftitox on time to progression. Total peripheral Tregs were not significantly altered, and in 1 patient biopsy intra-tumoral FoxP3 transcripts were not reduced following denileukin diftitox. ELISA for IL2R-α demonstrated no impact on outcomes by soluble CD25 level. Immune monitoring suggested the development of modest vaccine-specific CD8(+) T cell responses in the control group, however immunization efficacy was actually reduced in the denileukin diftitox group.Our results indicate that denileukin diftitox did not effectively deplete Tregs, augment T cell responses, or improve clinical activity in melanoma. Clinicaltrials.gov ID: NCT00515528; Registered August 9, 2007.
Abstract 3701: Transcriptomic consequences of MDMX (MDM4) oncoprotein expression knockdown in MDMX-amplified breast cancer cells
Authors: Yi-hsuan Ho, Claire Hutton, Herbie Newell, John Lunec
Journal: Cancer Research (2016)

Abstract The tumour suppressor p53 is activated by cellular stress to induce cell cycle arrest and/or apoptosis. Although the TP53 gene is frequently mutated in cancer, approximately half of human cancers express wild type and functional p53. However, p53 activity is often suppressed by its negative regulators, MDM2 and MDMX. Small molecule antagonists have been developed to inhibit p53-MDM2 binding to release the growth inhibitory and/or pro-apoptotic functions of p53. Previous studies have indicated that MDMX amplification and/or increased protein expression may be associated with resistance to MDM2-p53 binding antagonists. However, specific inhibitors for MDMX have yet to be developed and an MDM2/MDMX-p53 co-inhibitor (RO-5963) does not show better efficacy against high MDMX expressing cells than single target MDM2 inhibitors. To better understand the cellular function and therapeutic potential of targeting MDMX, we have investigated the downstream transcriptomic consequences of knocking down MDMX expression. Knockdown of MDMX protein expression, demonstrated by Western blot analysis, was achieved in MRK-nu-1 MDMX amplified and TP53 wild-type breast carcinoma cells using both lentiviral shRNA and siRNA. MRK-nu-1 cell growth suppression was observed after knockdown of MDMX. Affymetrix Human Transcriptome Array 2.0 was used to detect differences in the expression of full genes and alternatively spliced forms between negative control and MDMX knockdown groups. Transcriptome Analysis Console 3.0 software was used to analyse the microarray data to identify significant changes in gene expression, alternative splicing and associated functional pathways. Alterations in mRNA expression for a selected panel of genes was confirmed by qRT-PCR. A greater degree of MDMX expression knockdown was achieved with the siRNA (&amp;gt;95%) than the lentiviral shRNA (&amp;gt;50%) This was reflected by increased suppression of growth and larger changes in gene expression patterns with the siRNA knockdown. Although a similar set of genes was affected by both the siRNA and shRNA knockdown, the magnitude of changes was greater following the more pronounced knockdown with siRNA. The expression of a number of p53 transcriptional target genes was found to be altered, including CDKN1A, MDM2, CCNG2, RRM2B, BTG2, ZMAT3 and FAS consistent with a role for MDMX in suppression of p53 function in these MDMX amplified cells. Citation Format: Yi-hsuan Ho, Claire Hutton, Herbie Newell, John Lunec. Transcriptomic consequences of MDMX (MDM4) oncoprotein expression knockdown in MDMX-amplified breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3701.
Global Burden of Stroke
Authors: Valery L. Feigin, Bo Norrving, George A. Mensah
Journal: Circulation Research (2017)

On the basis of the GBD (Global Burden of Disease) 2013 Study, this article provides an overview of the global, regional, and country-specific burden of stroke by sex and age groups, including trends in stroke burden from 1990 to 2013, and outlines recommended measures to reduce stroke burden. It shows that although stroke incidence, prevalence, mortality, and disability-adjusted life-years rates tend to decline from 1990 to 2013, the overall stroke burden in terms of absolute number of people affected by, or who remained disabled from, stroke has increased across the globe in both men and women of all ages. This provides a strong argument that "business as usual" for primary stroke prevention is not sufficiently effective. Although prevention of stroke is a complex medical and political issue, there is strong evidence that substantial prevention of stroke is feasible in practice. The need to scale-up the primary prevention actions is urgent.
Abstract 3448: ERG-negative index tumor status combined with obesity predict prostate cancer progression in Caucasian American prostate cancer patients
Authors: Jennifer Cullen, Denise Young, Yongmei Chen, Michael S. Degon, Wagner Baptiste, James S. Farrell, Jason S. Sedarsky, Huai-Ching Kuo, Jacob Kagan, Sudhir Srivastava, Inger L. Rosner, Gyorgy Petrovics, Albert Dobi, David G. McLeod, Shiv Srivastava, Isabell A. Sesterhenn
Journal: Cancer Research (2016)

Abstract Introduction: and Objectives: A significantly lower prevalence of ERG oncoprotein has been reported for African American (AA) compared to Caucasian American (CA) prostate cancer (PCa) patients. This difference has been observed when examining prostate cancer (PCa) index tumors as well as for comparisons of non-index tumor foci. To evaluate the potential of ERG status in predicting disease progression, this study examined a large cohort of AA and CA PCa patients within a racially diverse, equal access, military health care center. Methods: Representative sections of whole mounted prostatectomy specimens from AA (n = 373) and CA (n = 684) patients were evaluated for ERG oncoprotein status by immunohistochemistry. Demographic, clinical, and pathologic patient features, including body mass index, were compared across ERG status (positive vs. negative). Time to event regression analysis was used to model ERG status as a putative predictor of biochemical recurrence (BCR) and distant metastasis. Results: A significantly lower prevalence of ERG positivity was noted in both index and non-index tumors of AA patients as compared to CA patients. Among CA patients only, ERG-negative index tumors were associated with greater odds of developing BCR and metastasis. Similarly, among CA patients only, having an ERG negative index tumor and being obese at time of prostatectomy was strongly associated with developing biochemical recurrence and metastasis. Conclusions: These provocative data warrant further investigation of the combined roles between race, obesity, and ERG status on PCa progression. Despite a robust sample size of AA men, the absence of statistically significant associations between ERG and obesity status on disease progression among AA patients could be attributed to insufficient statistical power. Source of Funding: This research was supported by the National Cancer Institute R01CA162383 grant to SS, by the Center for Prostate Disease Research and by the EDRN/NCI ACN12011-001 to GP, AD, IAS, DGM and SS. Citation Format: Jennifer Cullen, Denise Young, Yongmei Chen, Michael S. Degon, Wagner Baptiste, James S. Farrell, Jason S. Sedarsky, Huai-Ching Kuo, Jacob Kagan, Sudhir Srivastava, Inger L. Rosner, Gyorgy Petrovics, Albert Dobi, David G. McLeod, Shiv Srivastava, Isabell A. Sesterhenn. ERG-negative index tumor status combined with obesity predict prostate cancer progression in Caucasian American prostate cancer patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3448.
Abstract 3644: Identification of existing targeted agents that inhibit NTRK and ROS1 in lung cancer
Authors: Curtis Chong, Dalia Ercan, Magda Bahcall, Marzia Capelletti, Nathanael Gray, Pasi Janne
Journal: Cancer Research (2015)

Abstract All patients with oncogenic driver mutations in non-small cell lung cancer (NSCLC) who are treated with a targeted agent will eventually develop resistance. In an effort to identify inhibitors of NTRK1 and ROS1, which are inappropriately activated in NSCLC, we created and screened a library of existing targeted drugs against BaF3 cells transformed with these oncogenes. This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1 (IC50 = 9 nM), including the crizotinib-resistant mutants G2032R (IC50 = 26 nM) and L2026M (IC50 = 11 nM), with no inhibition of the parental BaF3 cells (IC50 &amp;gt; 10 μM). AP26113, a dual ALK/EGFR inhibitor undergoing phase I/II clinical trials, also potently inhibited CD74-ROS1 (IC50 = 4 nM), including the crizotinib-resistant mutants G2032R (IC50 = 206 nM) and L2026M (IC50 = 84 nM), with weak inhibition of the parental BaF3 cells (IC50 &amp;gt; 1 μM). Both cabozantinib and AP26113 inhibited ROS1 autophosphorylation and downstream ERK activation in CD74-ROS transformed BaF3 cells and in the ROS1-rearranged NSCLC cell line HCC78. The FGFR3 inhibitor dovitinib, which is in phase III clinical trials for renal cell carcinoma, potently inhibited NTRK1 compared to parental BaF3 cells (IC50 = 69 nM vs &amp;gt; 1 μM), and blocked NTRK1 autophosphorylation and ERK activation. While acquired resistance to targeted therapies is a major clinical problem, this study highlights other existing agents that may overcome resistance, and identifies several promising candidates for clinical trials. Citation Format: Curtis Chong, Dalia Ercan, Magda Bahcall, Marzia Capelletti, Nathanael Gray, Pasi Janne. Identification of existing targeted agents that inhibit NTRK and ROS1 in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3644. doi:10.1158/1538-7445.AM2015-3644