tbuckley/cabot-search huggingface dataset:
Outcomes of cancer patients with takotsubo cardiomyopathy.
Authors: Achuta Kumar Guddati, Gagan Kumar, Iuliana Shapira, Parijat Saurav Joy
Journal: Journal of Clinical Oncology (2017)

e18101 Background: Chemotherapy induced cardiomyopathy is an important complication of some chemotherapeutic agents. The stress of a cancer diagnosis and ongoing chemotherapy may contribute to cardiac morbidity in these patients. The burden of Takotsubo Cardiomyopathy (TCP) in cancer patients is unknown. The incidence of TCP and related outcomes in cancer patients was investigated in this study. Methods: The 2007-2013 National Inpatient Sample (NIS) was analyzed for patients with a prior and new diagnosis of TCP with and without malignancy. Risk factors for mortality were adjusted for associated conditions by multivariable logistic regression analysis. Results: From 2007 through 2013, an estimated 122,750 adults were admitted with a diagnosis of TCP. In 2013, the incidence of admissions in US of patients with coexisting TCP and malignancy was 1.13%. Admissions in 34,957 patients were for a primary diagnosis of TCP with 91.7% females; overall, 665 (2.1%) had solid organ cancer, 237 (0.74%) had hematological malignancy and 354 (1.11%) had metastatic cancer. Patients admitted for TCP with coexisting malignancy had a significantly higher mortality (13.8% vs. 2.9%, p &lt; 0.0001), length of stay (7 vs. 4 days, p &lt; 0.0001) and total charges ($29291 vs. $ 36231, p &lt; 0.0001), compared to those with no malignancy. In patients with a primary diagnosis of TCP and without any underlying malignancy, males had a higher mortality (4.02% vs. 1.03%, p &lt; 0.0001) whereas there was no gender difference in mortality in those with coexisting malignancy (6.25% vs 6.45%, p = 0.965). On multivariable logistic regression analysis, risk factors associated with mortality were solid cancer (OR 3.43, p = 0.008), stroke (OR 18.33, p &lt; 0.0001), venous thromboembolic disease (OR 4.52, p = 0.004), malnutrition (OR 2.41, p = 0.006) and heart failure (OR 1.918, p = 0.004). Conclusions: Outcomes are significantly worse in patients with TCP and solid malignancy. Hence, this patient population must be regarded as high-risk and early diagnostic consideration for TCP is warranted. Early intervention may help lower mortality, decrease resource utilization and reduce the health care costs in these patients.
Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer
Authors: Rayna Rosati, Lisa Polin, Charles Ducker, Jing Li, Xun Bao, Dakshnamurthy Selvakumar, Seongho Kim, Besa Xhabija, Martha Larsen, Thomas McFall, Yanfang Huang, Benjamin L. Kidder, Andrew Fribley, Janice Saxton, Hiroki Kakuta, Peter Shaw, Manohar Ratnam
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Testosterone suppression in prostate cancer is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for AR-dependent growth in various hormone-dependent and castration-resistant prostate cancer models. The amino-terminal domain of AR docks at two sites on ELK1 to coactivate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1–AR interaction in the spectrum of prostate cancer, inhibiting AR activity in a manner that would predict functional tumor selectivity. Experimental Design: Small-molecule drug discovery and extensive biological characterization of a lead compound. Results: We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3′. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of prostate cancer cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line–derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6 hours, and maintenance of its antitumor effect is limited by self-induced metabolism at its 3′-hydroxyl. Conclusions: The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development.
Dietary exacerbation of metabolic stress leads to accelerated hepatic carcinogenesis in glycogen storage disease type Ia
Authors: Monika Gjorgjieva, Julien Calderaro, Laure Monteillet, Marine Silva, Margaux Raffin, Marie Brevet, Caroline Romestaing, Damien Roussel, Jessica Zucman-Rossi, Gilles Mithieux, Fabienne Rajas
Journal: Journal of Hepatology (2018)
Abstract 17494: Exome Sequencing Reveals a Novel SNP in TRPC6 in Pulmonary Arterial Hypertension
Authors: Heather Lynn, Ankit Desai, Vineet Nair, Akash Gupta, Arlette Cordery, Ryan Sprissler, Kenneth Knox, Brandon Larson, Joe G Garcia, Jason X Yuan
Journal: Circulation (2016)

Introduction: The Ca2+ sensing receptor TRPC6 has been reported to promote pulmonary vascular disease. A functional promoter SNP (-254(C/G) has also been previously reported to be over-represented in patients with PAH. We hypothesized that there may be other novel SNPs associated with PAH in TRPC6. Methods: Whole-exome sequencing (WES) was performed on lung tissue DNA collected at the time of transplant or autopsy from 12 patients with PAH (WHO Group I). Standard BWA, SAMTOOLS, and GATK protocols were used to analyze WES data. Filtered SNPs on were compared against 1000 genomes and dbSNP databases for case-control analysis. In a separate PAH cohort (n=47, WHO Group I) with available clinical data, genotyping of a top candidate SNP, rs191383391, was performed via PCR. Association between genotype [wild-type (GG), homozygous recessive (TT)] and clinical phenotypes including right heart catheterization-defined pulmonary vascular resistance (PVRi), cardiac index (CI), cardiac MRI-defined right ventricular eje...
Correlation of RNA levels of certain members of the semaphorin/plexin/neuropilin family with the oncogenic ERG transcription factor in prostate cancer homogenate.
Authors: Axel Hegele, Hendrik Heers, P Jakubowski, Susanne Lingelbach, Ralf Kinscherf, Eberhard Weihe, Peter Rexin, Peter Jochen Olbert, Rainer Hofmann, Joerg Haenze
Journal: Journal of Clinical Oncology (2016)

e16561 Background: Innervation of prostate cancer tissue by autonomic nerves impacts tumor progression and metastasis. Semaphorins (SEMAs) and their receptors namely plexins (PLXNs) and neuropilins (NRPs) affect cell motility, migration and metastasis with possible impact on tumor innervation. The gene fusion TMPRSS2-ERG occurs with a frequency of about 50% in prostate cancer resulting in enhanced androgen-dependent induction of the oncogenic transcription factor ERG. Here, we analyzed the expression levels of certain semaphorins and their receptors in relation to ERG in prostate cancer patients. Methods: We investigated a prostate cancer cohort that underwent radical prostatectomy for treatment. RNA obtained from paraffin embedded prostate cancer tissue was analyzed for gene fusion status, for levels of ERG and for several semaphorins, plexins and neuropilins by relative quantitative RT-PCR. Examinations were approved by the local Ethical Review Board (AZ 65/11). Results: We observed significant positive correlations of RNA levels of ERG with NRP2 (p < 0.05, n = 52), with PLXNA2 (p < 0.001, n = 77), PLXNB1 (p < 0.01, n = 78) and with SEMA4B (p < 0.01, n = 78). Conclusions: We suggest that NRP2, PLXNA2, PLXNB1, and SEMA4B may be at least partially under the control of ERG. Future studies will focus on a functional link of these components with metastasis and prostate cancer innervation.
Inherited mutations in breast cancer patients with and without multiple primary cancers.
Authors: Kara Noelle Maxwell, Joseph Vijai, Jenna Lilyquist, Thomas Paul Slavin, Abha Kulkarni, Olivia Vaccaro, Bradley Wubbenhorst, Susan L. Neuhausen, Steven Hart, Vignesh Ravichandran, Tinu Thomas, Chunling Hu, Kasmintan A Schrader, Angela DeMichele, Kenneth Offit, Jeffrey N. Weitzel, Fergus Couch, Susan M. Domchek, Katherine Nathanson
Journal: Journal of Clinical Oncology (2018)

1503 Background: Women with breast cancer have a 5-12% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer (MP-BC) over those with a single breast cancer (S-BC) is unknown. Methods: We identified pathogenic germline mutations in cancer susceptibility genes in BRCA1/2 negative patients in two differently ascertained cohorts: Cohort #1, high risk breast cancer program (MP-BC, n = 551 vs S-BC, n = 464) and Cohort #2, familial breast cancer research study (MP-BC, n = 340 vs S-BC, n = 1464). Mutation rates in patients of European descent were compared to ExAC. Results: Overall pathogenic mutation rates for cancer panel testing genes were two-fold higher in patients with MP-BC versus S-BC in both cohorts (8.7% vs 4.1%, p = 0.003 and 8.2% vs 4.2%, p = 0.003, respectively). However, there were differences in individual gene mutation rates between cohorts (Table). In comparison to a race and ethnicity matched control group, mutations in TP53 and MSH6 were statistically significantly enriched in MP-BC but not S-BC patients. Mutations in ATM, CHEK2 and PALB2 were statistically significantly enriched in both MP-BC and S-BC patients relative to controls. Conclusions: These data demonstrate that mutations in high risk genes are typically found in patients with multiple primary cancers; whereas rates of moderate penetrance gene mutations are similar. Patients with multiple primary cancers should be offered multiplex panel testing. Mutation rates in MP-BC vs S-BC patients in two cohorts. Gene COHORT #1 COHORT #2 MP-BC S-BC p MP-BC S-BC p n % of 551 n % of 464 n % of 340 n % of 1464 TP53 12 2.2% 1 0.2% 0.005 3 0.9% 6 0.4% 0.38 PALB2 3 0.5% 1 0.2% 0.63 5 1.5% 13 0.9% 0.36 CDH1 1 0.2% 0 0.0% Nd 0 0.0% 2 0.1% Nd PTEN 1 0.2% 0 0.0% Nd 0 0.0% 0 0.0% Nd STK11 0 0.0% 0 0.0% Nd 0 0.0% 0 0.0% Nd CHEK2 14 2.5% 9 1.9% 0.67 9 2.7% 17 1.2% 0.07 ATM 5 0.9% 7 1.5% 0.40 8 2.4% 16 1.1% 0.11 NBN 0 0.0% 0 0.0% Nd 0 0.0% 1 0.1% Nd MSH6 6 1.1% 0 0.0% 0.03 3 0.9% 1 0.1% 0.02 PMS2 3 0.5% 0 0.0% 0.25 0 0.0% 2 0.1% 1.00 MSH2 2 0.4% 0 0.0% 0.50 0 0.0% 3 0.2% 1.00 MLH1 0 0.0% 1 0.2% Nd 0 0.0% 0 0.0% Nd CDKN2A 2 0.4% 0 0.0% 0.50 0 0.0% 0 0.0% Nd MUTYH monoallelic 5 0.9% 6 1.3% 0.56 7 2.1% 21 1.4% 0.46 CHEK2 Low Risk 15 2.7% 5 1.1% 0.03 3 0.9% 17 1.2% 1.00
Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis
Authors: Nafees Ahmad, Shama D Ahuja, Onno W Akkerman, Jan-Willem C Alffenaar, Laura F Anderson, Parvaneh Baghaei, Didi Bang, Pennan M Barry, Mayara L Bastos, Digamber Behera, Andrea Benedetti, Gregory P Bisson, Martin J Boeree, Maryline Bonnet, Sarah K Brode, James C M Brust, Ying Cai, Eric Caumes, J Peter Cegielski, Rosella Centis, Pei-Chun Chan, Edward D Chan, Kwok-Chiu Chang, Macarthur Charles, Andra Cirule, Margareth Pretti Dalcolmo, Lia D'Ambrosio, Gerard de Vries, Keertan Dheda, Aliasgar Esmail, Jennifer Flood, Gregory J Fox, Mathilde Fréchet-Jachym, Geisa Fregona, Regina Gayoso, Medea Gegia, Maria Tarcela Gler, Sue Gu, Lorenzo Guglielmetti, Timothy H Holtz, Jennifer Hughes, Petros Isaakidis, Leah Jarlsberg, Russell R Kempker, Salmaan Keshavjee, Faiz Ahmad Khan, Maia Kipiani, Serena P Koenig, Won-Jung Koh, Afranio Kritski, Liga Kuksa, Charlotte L Kvasnovsky, Nakwon Kwak, Zhiyi Lan, Christoph Lange, Rafael Laniado-Laborín, Myungsun Lee, Vaira Leimane, Chi-Chiu Leung, Eric Chung-Ching Leung, Pei Zhi Li, Phil Lowenthal, Ethel L Maciel, Suzanne M Marks, Sundari Mase, Lawrence Mbuagbaw, Giovanni B Migliori, Vladimir Milanov, Ann C Miller, Carole D Mitnick, Chawangwa Modongo, Erika Mohr, Ignacio Monedero, Payam Nahid, Norbert Ndjeka, Max R O'Donnell, Nesri Padayatchi, Domingo Palmero, Jean William Pape, Laura J Podewils, Ian Reynolds, Vija Riekstina, Jérôme Robert, Maria Rodriguez, Barbara Seaworth, Kwonjune J Seung, Kathryn Schnippel, Tae Sun Shim, Rupak Singla, Sarah E Smith, Giovanni Sotgiu, Ganzaya Sukhbaatar, Payam Tabarsi, Simon Tiberi, Anete Trajman, Lisa Trieu, Zarir F Udwadia, Tjip S van der Werf, Nicolas Veziris, Piret Viiklepp, Stalz Charles Vilbrun, Kathleen Walsh, Janice Westenhouse, Wing-Wai Yew, Jae-Joon Yim, Nicola M Zetola, Matteo Zignol, Dick Menzies
Journal: The Lancet (2018)
Evaluating predictors of relapse in locally advanced head and neck cancer patients in community oncology: Retrospective review of treatment outcomes in rural New Mexico.
Authors: Tareq Braik, Ajaz Bulbul, Prashanthi Konda, Masoud Khorsand-Sahbaie, Sadaf Rashad, Helda Barakat, Donald Donigan
Journal: Journal of Clinical Oncology (2016)

e17536 Background: For patients with potentially operable locally advanced head and neck cancer, functional organ preservation can be achieved with chemoradiation. Lack of comparative prospective data means that treatment decisions in community practices are based on preferences. Our aim was to compare the risk of relapse in patients treated with cisplatin or cetuximab. Methods: We retrospectively analyzed the data of 84 locally advanced head and neck cancer patients treated in our community cancer center between 2003 and 2015. Categorical variables were compared between groups using Pearson X2 test and logistic regression model was used to determine risk of relapse. Results: The median age of the study population was 63. All patients received radiation treatment concurrently with systemic therapy. Thirty-nine (37%) patients were treated with cetuximab and 42 (53%) received cisplatin. Sixty three patients (75%) were less than 70 years old and 21 (25%) were 70 years old or above. We identified factors associated with decreased risk of relapse: using cisplatin (OR 0.52, 95% CI: 0.17, 1.52), HPV positive (OR 0.7, 95% CI: 0.1, 4.3). Delaying treatment more than 50 days (OR 2.39, 95% CI:0.76 ,7.52), age more than 70 (OR 1.54, 95% CI: 0.52, 4.57) increased the risk of relapse. The adjusted predictive probability of relapse in patient treated with cetuximab was 35% ,95% CI: (0.17, 0.53) and 22% in patient treated with cisplatin 95%(0.09, 0.35) P < 000.1). Conclusions: Our database provides real world insights into patterns of care in a rural community practice. In locally advanced head and neck cancer patients, the use of cisplatin as compared to cetuximab was associated with less risk of relapse. Age over 70 , delaying treatment more than 50 days was associated with higher risk of relapse. A direct prospective comparison between cisplatin and cetuximab is required to validate our findings. Cisplatin Cetuximab P value age < 70 40 14 < 0.0001 age > 70 2 15 Female 6 5 0.84 Male 36 24 Oropharynx 17 11 < 0.0001 Larynx 17 7 Hypopharynx 1 2 Oral cavity 3 2 HPV Positive 4 2 0.71 HPV negative 17 9 Adjusted probability of relapse 22% 35% < 0.0001
Pioglitazone Use After Stroke
Authors: Jesse Dawson
Journal: Circulation (2018)

Approximately one-quarter of people with stroke will suffer recurrence within a 4-year period. 1 Recurrence risk is increased in people with cardiovascular risk factors such as hypertension and also in people with insulin resistance, 2 which may affect as many as 50% of people with ischemic stroke. 3Although the rate of recurrence is highest within the first few weeks after a first stroke, 4 most recurrent strokes occur many years later, leaving substantial potential for secondary prevention. 5Although recurrent stroke is the most common second vascular event, people with stroke are also at risk of future myocardial infarction.If only there were a cheap, widely available drug that, when added to guidelinebased preventative treatment, could remove up to one-quarter of this risk.Well, actually, there is.The IRIS trial (Insulin Resistance After Ischemic Stroke) showed that people with insulin resistance (but no diabetes mellitus) and recent ischemic stroke or transient ischemic attack treated with pioglitazone had a lower risk of myocardial infarction and recurrent stroke than people treated with placebo. 6In relative terms, the treatment effect was similar to both antiplatelet and high-dose lipid-lowering therapy. 7It is odd, then, that uptake of pioglitazone use after stroke has been limited.This is largely because of the fear of side effects.Pioglitazone, a thiazolidinedione, has been reported to increase risk of weight gain, bone fracture, and heart failure, all of particular concern in stroke survivors.The combination of stroke and heart failure is associated with poor outcome, 8 stroke survivors are already at increased risk of fracture, 9 and weight gain will impact on mobility and is associated with increased risk of recurrence. 10oung and colleagues, 11 in this issue of Circulation, report a post hoc analysis of heart failure in the IRIS trial.No excess of heart failure serious adverse events with pioglitazone was reported in IRIS, but there was an increase in ankle edema.In this more granular analysis of heart failure outcomes, Young and colleagues 11 explored whether certain people were more at risk of pioglitazone-associated heart failure.They confirmed no overall excess of any confirmed heart failure, hospitalized heart failure, or nonhospitalized heart failure with pioglitazone.This finding was consistent across 7 individual heart failure risk factors and across the range of a combined heart failure risk score.One treatment interaction was significant: pioglitazone treatment was associated with increased risk of heart failure in people with a baseline HbA1c level of 6.5% to 6.9%, although the effect estimate lacked precision.It is important to note that this level of HbA1c would now denote diabetes mellitus but did not at the start of the IRIS trial.This finding is consistent with a subgroup analysis of people with previous stroke in the PROactive trial (PROspective Pioglitazone Clinical Trial in Macrovascular Events). 12This trial demonstrated a reduction in total recurrent stroke with pioglitazone, and although there was no sta-
Targeting the hedgehog pathway in esophageal adenocarcinoma (EAC) using Itraconazole.
Authors: Amir Ansari, Tomoharu Miyashita, Frank Lay, A. Karim Ahmed, Aerielle E Matsangos, Louis Born, Christopher Ng, Randy Michael Cohen, Anne-Heloise Stricker-Krongrad, Kevan Salimian, Guy P Marti, Ken-ichi Mukaisho, Maryam Kherad Pezhouh, Kristen Marrone, Stephen J. Meltzer, Michelle A. Rudek, Christine H. Chung, Marcia Canto, John W Harmon, Ronan Joseph Kelly
Journal: Journal of Clinical Oncology (2018)

e13552 Background: Up-regulated progenitor cell proliferation induced by abnormal activation of the hedgehog (HH) signaling pathway contributes to carcinogenesis in the esophagus and HH is considered a leading candidate as a molecular mediator of Barrett’s Esophagus (BE). Repositioned use of existing off-patent, safe and cheap drugs that can inhibit HH, such as the antifungal Itraconazole (I) aligns with the NIH drug repurposing initiative and could prevent progression of BE to EAC. Methods: The efficacy of I in inhibiting SHH and preventing EAC was investigated using a surgical rat reflux model of Barrett’s metaplasia (BM) created by an end to side esophago-jejunostomy. 200mg/Kg weekly IP injections of saline (control group, CG) or I (treatment group) started at 24 weeks post-surgery and esophageal tissue was harvested at 40 weeks. Immunohistochemistry (IHC) was performed for SHH and samples were assessed by blinded pathologists. In addition, SHH and downstream pathway proteins in patients with resistant BE were assessed using IHC. BE and normal squamous epithelium (SE) were stained for SHH, bone morphogenic protein 4 (BMP4), and Indian hedgehog (IHH). In vitro SKGT4 human esophageal adenocarcinoma cell line experiments will be presented. Results: BM was present in the CG 29/31(93%) versus I group 22/24 (91%). EAC was significantly lower in the I group 2/24 (8%) vs CG 10/31 (32%), respectively (p = 0.033). Esophageal SHH levels, were lower in the preclinical I group compared to the CG (p = 0.12). In humans with resistant BE, SHH and IHH levels were higher in distal BE compared to proximal SE, OR = 6.1 (95% CI: 1.6, 23.4) and OR = 6.4 (95% CI: 1.2, 32.8) respectively. Distal human SE had higher levels of SHH and IHH compared to proximal human SE (ORs greater than 1.0). BMP levels were higher in human BE vs SE, OR = 12.1 (95% CI: 1.86, 79.0), p = 0.009. Conclusions: Itraconazole has HH pathway inhibitory properties and results in significantly fewer EACs than saline and lower expression of SHH preclinically. In human, resistant BE is associated with higher SHH expression compared to SE. Itraconazole should be investigated as a chemopreventive agent.
Abstract 13396: The Association Between Oxidative Balance Score and Elevated C-Reactive Protein in the Reasons for Geographic and Racial Differences in Stroke Cohort
Authors: Sindhu Lakkur, William McClellan, William D Flanders, David Warnock, Suzanne Judd, Michael Goodman
Journal: Circulation (2012)

Previous research has shown that summing a combination of individual pro- and anti- oxidant exposures, incorporated into an a comprehensive Oxidative Balance Score (OBS) may be associated with various conditions in the absence of associations with individual factors. Although OBS was designed to reflect oxidative stress related exposures, a compelling argument can be made that it may also affect inflammation. Nearly all OBS components also act as pro- and anti-inflammatory factors. An important marker of inflammation is C- reactive protein (CRP) which at elevated levels (>3.0 mg/L) has been shown to mark high risk for cardiovascular diseases (CVD). We examined the association of OBS with CRP among 20,169 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. CRP was measured using a high-sensitivity assay. Thirteen different dietary and lifestyle-related components were incorporated in the OBS and the resulting score was then divided into five equal interval ordinal ...