tbuckley/cabot-search huggingface dataset:
Abstract 19245: Heart of Stone: A Mysterious Case of Diastolic Dysfunction
Authors: Alok Sharma, Marc Pritzker, Charles A Herzog, Steven Goldsmith, Peter Eckman
Journal: Circulation (2013)

A 27 year old Somali female initially presented with renal failure and a creatinine of 10mg/dl. A kidney biopsy showed crystalline nephropathy and she was initiated on hemodialysis. A year later while she was pregnant she had multiple heart failure admissions. Echocardiograms (echo) showed normal ejection fraction (EF). A month after delivery she was admitted again with heart failure. Vital signs were stable with elevated JVP and a pansystolic murmur at the apex. Chest x ray showed pulmonary edema. Echo showed moderately concentric left ventricular hypertrophy (LVH) with an EF of 40% and severe mitral regurgitation (MR). Doppler echo showed restrictive filling pattern. Pulmonary artery pressure (PA) was 99 mm of Hg + right atrial pressure (RA) with dilated vena cava. Repeat echocardiogram post ultrafiltration of just 1 liter of volume reduced PA pressures from 99 mm+RA to about 35 mm Hg+ RA with a simultaneous reduction in MR, demonstrating marked preload dependency of left sided filing pressures. Her myocardium demonstrated an echodense speckled reflection and infiltrative cardiomyopathy was suspected. EKG showed LVH making amyloidosis unlikely diagnosis. Right ventricular endomyocardial biopsy showed extensive deposition of calcium oxalate crystals in myocardium. Further tests showed increased serum oxalate level: 140 μmoles/L (ref. upto 27), increased urinary oxalic acid excretion:171 μgm (ref. &lt; 57) and increased urine glycolate: 101 μg/mg Cr (ref. &lt; 79) . Liver biopsy showed very low AGT (Alanine glyoxylate aminotransferase) activity of 3.0 μmol/h/mg protein (Ref. 19.1-47.9) along with negative AGT immunoreactivity . These results confirmed diagnosis of primary hyperoxaluria type 1 (PH1) . She was started on intense hemodialysis regimen and underwent a deceased donor combined liver-kidney transplantation (CLKT). Repeat echo 6 months later shows normal EF, normal PA pressures, regression of infiltrative process with improvement in diastolic function. This is a rare case of PH1 with cardiac involvement leading to progressive infiltrative restrictive cardiomyopathy and recurrent heart failure. Early recognition of the disease is important because CLKT may achieve long-term survival and regression of cardiomyopathy.
STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation
Authors: Henrique Lemos, Eslam Mohamed, Lei Huang, Rong Ou, Gabriela Pacholczyk, Ali S. Arbab, David Munn, Andrew L. Mellor
Journal: Cancer Research (2016)

Cytosolic DNA sensing is an important process during the innate immune response that activates the stimulator of interferon genes (STING) adaptor and induces IFN-I. STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists, and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). Although STING also induced IDO in tumor-draining lymph nodes (TDLN) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8(+) T-cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL10 production in the TME. Depletion of CD8(+) T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8(+) T-cell effector functions during tumorigenesis. In contrast with native LLC tumors, STING signaling neither promoted growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity and how IDO inhibition can overcome this state by attenuating tumor tolerance. Furthermore, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials. Cancer Res; 76(8); 2076-81. ©2016 AACR.
Type 1 diabetes in adults: supporting self management
Authors: Monika Reddy, Sian Rilstone, Philippa Cooper, Nick S Oliver
Journal: BMJ (2016)

Type 1 diabetes affects 300 000 people in the United Kingdom. 1 2 Despite regular specialist multidisciplinary input, responsibility for glucose monitoring and insulin administration is devolved to the person with diabetes, or their care giver.Empowering effective self management of type 1 diabetes is critical to achieve HbA 1c targets, minimise hypoglycaemia and optimise quality of life.Structured education programmes for diabetes self management should be offered to everyone with type 1 diabetes.It is important for healthcare providers to understand what structured education involves before referral.This review examines the meaning and evidence for self management, and provides advice on how general physicians and non-specialists can support and enable people with type 1 diabetes to self manage their condition.
Clinical and Molecular Characteristics of <i>NF1</i>-Mutant Lung Cancer
Authors: Amanda J. Redig, Marzia Capelletti, Suzanne E. Dahlberg, Lynette M. Sholl, Stacy Mach, Caitlin Fontes, Yunling Shi, Poornima Chalasani, Pasi A. Jänne
Journal: Clinical Cancer Research (2016)

NF1 is a tumor suppressor that negatively regulates Ras signaling. NF1 mutations occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of NF1 mutant lung cancers with comparison to tumors with KRAS mutations.Between July 2013 and October 2014, 591 non-small cell lung cancer (NSCLC) tumors underwent targeted next-generation sequencing in a 275 gene panel that evaluates gene mutations and genomic rearrangements. NF1 and KRAS cohorts were identified, with subsequent clinical and genomic analysis.Among 591 patients, 60 had NF1 mutations (10%) and 141 (24%) had KRAS mutations. 15 NF1 mutations (25%) occurred with other oncogenic mutations [BRAF (2); ERBB2 (2); KRAS (9); HRAS (1); NRAS (1)]. There were 72 unique NF1 variants. NF1 tumor pathology was diverse, including both adenocarcinoma (36, 60%) and squamous cell carcinoma (10, 17%). In contrast, KRAS mutations occurred predominantly in adenocarcinoma (136, 96%). Both mutations were common in former/current smokers. Among NF1 tumors without concurrent oncogenic alterations, TP53 mutations/2-copy deletions occurred more often (33, 65%) than with KRAS mutation (46, 35%; P < 0.001). No difference between cohorts was seen with other tumor suppressors.NF1 mutations define a unique population of NSCLC. NF1 and KRAS mutations present in similar patient populations, but NF1 mutations occur more often with other oncogenic alterations and TP53 mutations. Therapeutic strategies targeting KRAS activation, including inhibitors of MAP kinase signaling, may warrant investigation in NF1 mutant tumors. Tumor-suppressor inactivation patterns may help further define novel treatment strategies. Clin Cancer Res; 22(13); 3148-56. ©2016 AACR.
Development of a VEGFR-2 antagonist based on a novel protein scaffold (AdNectin)
Authors: R. Mamluk, I. M. Carvajal, J. M. Bates, D. M. Kamen, B. A. Morse, A.-C. Lim, J. Gokemeijer, M. J. Storek, J. Wang, A. S. Harris, G. Wong
Journal: Journal of Clinical Oncology (2005)

3150 Background: Shortcomings of traditional antibody technology have prompted the development of antagonists using addressable fibronectin proteins (AdNectins). The benefits of AdNectins include the ability to rapidly identify high affinity binders with tailored binding kinetics, as well as the ability to produce these proteins by economic E. coli-based production Methods: Using this technology an AdNectin antagonist to VEGFR-2 was developed. VEGFR-2 was chosen as a target because of its well validated role in angiogenesis. Methods: The anti-VEGFR-2 AdNectin, CT322, was evaluated pre-clinically for its biophysical characteristics, ability to block VEGFR-2 activity on endothelial cells, pharmacokinetics, inhibition of VEGF activity in vivo, and effects on tumor progression in mouse models. Results: CT322, is a PEGylated 10 kDa monomeric protein that is highly stable at 37°C. CT322 binds human and mouse VEGFR-2 with affinities of 0.2 nM and 4 nM, respectively. CT322 efficiently blocked VEGF-induced endothelial cell proliferation, migration and tube formation. Pharmacokinetic in rats: UnPEGylated CT322 was rapidly cleared (70 ml/hr/kg) via the kidneys. Addition of a 40 kDa polyethylene glycol reduced the clearance rate to 5.2 ml/hr/kg leading to 10 fold increase in bioavailability. No accumulation of CT322 in normal tissues was observed. In vivo, CT322 inhibited VEGF-induced vascular permeability at 5 mg/kg dose indicating an effective blockage of VEGFR-2 activity in mice. CT322 significantly inhibited tumor growth in a range of mouse and human xenografts tumor models at dose range of 10 - 40 mg/kg (i.p. 3x week). Conclusions: CT322 is a VEGFR-2 antagonist based on a novel alternative protein scaffold and has high target specificity and affinity, as well as favorable biophysical properties. CT322 block human VEGFR-2 and murine VEGFR-2 (Flk1). Consequently, CT322 has been shown to be very effective in inhibiting tumor growth in multiple pre-clinical models. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Compound Theraeutics, Gokemeijer
Estimation of Human Tumor Growth Rate From Distribution of Tumor Size at Detection2
Authors: Barry W. Brown, E. Neely Atkinson, Robert Bartoszynski, James R. Thompson, Eleanor D. Montague
Journal: JNCI Journal of the National Cancer Institute (1984)

Methods are presented for estimating the growth curve of a tumor (up to an unknown scale factor of time) from the distribution of volumes at detection on the basis of two assumptions: 1) the existence of a common growth curve and 2) the assumption that the probability of detecting a tumor in a period of time is proportional to the tumor volume. These methods can accommodate variation between individuals in speed of traversal of the growth curve. The methods are applied to volumes of tumor at detection of a large series of breast cancers. The simplest, adequate description is exponential growth with great individual-to-individual variation in tumor doubling time. The data are consistent with bounded growth (Gompertzian or logistic form) as well as exponential growth. However, there is no evidence that the bound on growth is within the range of the data. The shape of the distribution of volumes does not yield an effective lower limit on such a bound.
Tumor size and stage distribution among the newly diagnosed breast cancer patients in an inner-city hospital in Brooklyn
Authors: B. S. Kamenova, J. Sanmugarajah, W. Solomon
Journal: Journal of Clinical Oncology (2005)

902 Background: The implementation of screening mammography is expected to increase the proportion of the newly diagnosed small breast tumors at early stage. For example from the newly diagnosed patients in Rhode Island in 1999–2001 53.5% had stage I, 36.7%-stage II, and only 5.7% and 4.1% had stage III and IV disease respectively. However the minority of the newly diagnosed patients in a Brooklyn inner-city hospital have early stage disease. Methods: We collected the names of all newly diagnosed breast cancer patients for the first 6months of 2004 from our hospital Tumor Registry. Their charts were reviewed for tumor size, grade, hormone receptor status, her-2 neu status and number of lymph node involvement. Results: For the first 6 months of 2004yr there were 24 newly diagnosed breast cancer patients. 5 of them (20.83%) had DCIS. From the 19 invasive cancers one patient was not staged after the biopsy. From the rest (18) 6 were diagnosed as metastatic or stage IV (33.33%), 5 with stage III disease (27.78%), 4 with stage II (22.22%) and 3 with stage I disease (16.67%). From the 12 nonmetastatic cases 4 (33.33%) had tumors less than 2cm, 4 had tumors between 2 and 5cm (33.33%) and 4 had tumors more than 5 cm in diameter (33.33%). There were 4 women less than 50 years of age (16.6%), 16 women were between ages 50 and 65 (66.66%) and 4 were more than 65 years old(16.6%) among all newly diagnosed patients. From the invasive cancers the grade was not available for 1. From the rest 8 were grade I and II (44.44%) and 10 were grade III (55.55%).12 cancers were ER pos (63.16%) and 7 were ER neg (36.84%). Her2neu was assessed by IHC. 13 invasive cancers were IHC 0,1+ and 2+ (68.42%) and 6 were 3+ and 4+(31.58%). Conclusions: As opposed to the national average there is a striking predominance of the larger breast tumors with higher morphological grade and advanced stages at the time of presentation in our hospital. Most of our patients are African Americans. Poor socioeconomic status, ethnicity and race are well known factors that contribute to the diagnosis of breast cancer at an advance stage and a larger size. Aggressive community based screening and education are essential to improve the early detection of breast cancer in this community. No significant financial relationships to disclose.
Significant Activity Of The mTOR Inhibitor Sirolimus and HDAC Inhibitor Vorinostat In Heavily Pretreated Refractory Hodgkin Lymphoma Patients
Authors: Filip Janku, Ignacio Garrido-Laguna, Vivianne Velez-Bravo, Gerald S. Falchook, Vivek Subbiah, David S. Hong, Yasuhiro Oki, Jason R. Westin, Cesar A. Nunez, Luis E Fayad, Larry W. Kwak, Elizabeth J Shpall, Jennifer J. Wheler, Winnie Liang, Bodour Salhia, Funda Meric-Bernstam, Razelle Kurzrock, Michelle Fanale
Journal: Blood (2013)
Abstract 10947: Longer and Faster Non-sustained Ventricular Tachycardia in Hypertrophic Cardiomyopathy Patients Predicts for Implantable Cardioverter Defibrillator Shocks and Sudden Cardiac Death
Authors: Weijia Wang, Zhesi Lian, Ethan Rowin, Martin Maron, Mark Link
Journal: Circulation (2015)

Introduction: Non-sustained ventricular tachycardia (NSVT) may be underestimated in patients with hypertrophic cardiomyopathy (HCM). Its impact on the risk of sudden cardiac death (SCD) in HCM is controversial. There is no distinction made in the guidelines as to the length or rate of NSVT as a risk marker for SCD. Hypothesis: NSVT may be nearly universal in HCM patients with high risk of SCD and not found because of the limited time frame of monitoring. NSVT may be associated with appropriate Implantable Cardioverter Defibrillator (ICD) shocks and SCD. Methods: A retrospective study of 181 HCM patients who had an ICD and were followed for at least 6 months from 2000 to 2013 at Tufts Medical Center was performed. The pre-operative evaluations as well as routine ICD follow up notes were reviewed. Results: ICD was implanted in 175 (96.7%) patients as primary prevention and in 6 (3.3%) patients as secondary prevention for SCD. Ninety six (53.0%) patients total had NSVT, including 48 (26.5%) before and 77 (42.5%) after ICD implantation. The agreement for detecting NSVT between Holter monitoring and ICD interrogation was poor (Kappa=0.18, p=0.054). Eighteen (18.75%) patients with NSVT and 6 (7.06%) patients without NSVT had appropriate ICD shocks or SCD (Figure 1). In multivariable analysis, NSVT was independently associated with appropriate ICD shocks and SCD (OR 3.69, 95%CI: 1.31 - 10.43) and remained significant in the 175 patients who had ICD implanted as primary prevention (OR 3.86, 95%CI: 1.13 - 13.18). More rapid NSVT (Cl &lt; 310ms) predicted appropriate ICD shocks and SCD (OR 7.7, 95%CI: 1.6, 36.8), and longer NSVT (&gt; 18beats) also predicted appropriate ICD shocks and SCD (OR=23.7, 95%CI: 2.7, 204.9). Conclusion: The agreement for detecting NSVT between Holter and ICD interrogation is poor. NSVT is significantly associated with appropriate ICD shocks and SCD. Faster and longer NSVT are even more predictive. Extending rhythm monitor time merits consideration in HCM patients.
Abstract 48: Cardiac-Targeted TRPM7 Deletion Induces Cardiomyopathy, Heart Block and Impaired Ventricular Repolarization via Downregulation of Kcnd2 and Hcn4
Authors: Rajan Sah, Pietro Mesirca, Xenos Mason, Christopher Bates-Withers, William Gibson, Janice Robertson, Matteo Mangoni, David Clapham
Journal: Circulation Research (2012)

Transient Receptor Potential Melastatin-7 (TRPM7) is a divalent permeant channel-kinase of unknown function. It is concentrated in myocardium during embryonic development, and TRPM7-like current has been reported in adult ventricular myocytes. In atrial cardiac fibroblasts, TRPM7 has been implicated in fibrogenesis in patients with atrial fibrillation, however its function in ventricular myocardium is unexplored. We tested the hypothesis that TRPM7 is required for ventricular function by crossing TRPM7fl/- mice with the cardiac-targeted αMHC-Cre line (αMHC-TRPM7 KO). We show that TRPM7 forms a functional current in adult murine ventricular cardiomyocytes and demonstrate that ∼50% of αMHC-TRPM7 KO mice develop a cardiomyopathy with left ventricular dysfunction and cardiac hypertrophy, associated with heart block and impaired ventricular repolarization. This phenotype is associated with robust elevations in mRNA of Postn, Nppa, Timp1, Acta and reductions in Hdac9, Kcnv2, Kcnj3, Kcnd2, Lgi1 and Hcn4. Consistent with mRNA expression analysis and the observed electrical remodeling, patch-clamp of αMHC-Cre-TRPM7 KO ventricular myocytes (RV and LV) reveals significant action potential prolongation (2.5 to 4-fold increase in APD50) due to a 2 to 4-fold reduction in transient outward current (Ito, encoded by Kcnd2). Similarly, the funny current (If), encoded by Hcn4, is diminished 4-fold in atrioventricular nodal cells isolated from αMHC-Cre-Trpm7 KO hearts, accounting for the observed heart block. The ∼50% of αMHC-Cre-Trpm7 KO mice that do not develop cardiomyopathy are devoid of heart block, show normal expression levels of hypertrophy genes Postn, Nppa, and Acta, but continue to show significant reductions in Kcnd2, Lgi1, Kcnj3, Kcnv2, and Hdac9 expression. In conclusion, these results demonstrate that cardiac-targeted TRPM7 deletion dysregulates the expression of ion channels important for cardiomyocyte repolarization (Kcnd2) and atrioventricular conduction (Hcn4), leading to impaired ventricular repolarization and heart block in mice. The observed cardiomyopathy may arise from hemodynamic stresses secondary to chronic bradycardia from heart block in the setting of down-regulated histone deacetylase 9 (HDAC9).
Non-Invasive Detection of Genomic Imbalances in Hodgkin/Reed-Sternberg Cells in Early and Advanced Stage Hodgkin Lymphoma By Sequencing of Circulating Cell-Free DNA
Authors: Peter Vandenberghe, Iwona Wlodarska, Thomas Tousseyn, Luc Dehaspe, Daan Dierickx, Magali Verheecke, Anne Uyttebroeck, Oliver Bechter, Michel Delforge, Vincent Vandecaveye, Nathalie Brison, Gregor EG Verhoef, Eric Legius, Frederic Amant, Joris R Vermeesch
Journal: Blood (2014)
Abstract 13060: Clinical Factors Affecting Interpretation of Left Ventricular Fractional Anisotropy Obtained from ex-vivo Diffusion Tensor Magnetic Resonance Imaging
Authors: Wendy Tsang, Cole Holmgren, Xiaodong Guo, Michael Bateman, Paul Iaizzo, Michael Vannier, Roberto M Lang, Amit R Patel
Journal: Circulation (2013)

Purpose: Diffusion-weighted cardiac MRI has the potential to non-invasively quantify the architecture of myofibers. However, the impact of clinical factors on fibre architecture has not been explor...
Abstract 045: Race-Sex Differences in Risk for Incident Acute Coronary Heart Disease in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Monika M Safford, Paul Muntner, Christopher Gamboa, Ronald Prineas, Todd Brown, Raegan Durant, George Howard, Virginia Howard, Mary Cushman, Stephen Glasser
Journal: Circulation (2012)

National death certificate data suggest that racial disparities in acute coronary heart disease (CHD) mortality widened over the past decade for both men and women. To better understand this disparity, we examined black:white race-sex differences in overall, fatal and nonfatal acute CHD incidence in a large national biracial cohort. REGARDS is following 30,239 community-dwellers age ≥;45 years recruited between 2003-7 from 48 states. Recruitment was designed to balance race and sex; the final sample was 55% female and 41% black. Participants are telephoned every 6 months for CVD endpoints, with retrieval of medical records, death certificates, interviews with next-of-kin, and expert adjudication following national consensus recommendations. Acute CHD was defined as definite or probable myocardial infarction (MI) or acute CHD death. Among participants free of CHD at baseline, we examined black:white hazards for incident overall acute CHD, and, separately, fatal and nonfatal acute CHD for men and women through 2008, adjusting incrementally for sampling, sociodemographics and CHD risk factors. The study sample numbered 24,431 with mean age 64.1 (SD±9.3). Over a mean follow-up of 3.4 (maximum 5.9) years, 48.7% (55/113) of black men, 33.0% (38/115) of black women, 23.0% (46/200) of white men and 24.1% (21/87) of white women died at their presentation of acute CHD. Black:white hazard ratios for overall, fatal and nonfatal acute CHD from incrementally adjusted models stratified on sex are presented in the Table. Black men and women had over twice the age-adjusted hazard of incident fatal acute CHD compared to whites, not entirely explained by excess risk factor burden among blacks. Although socio-economic and CHD risk factors among blacks continue to be major contributors to fatal incident acute CHD, known risk factors did not fully explain the disparity between black and white men; causes of the elevated risk among black men need to be better understood if widening CHD mortality disparities are to be reversed.