tbuckley/cabot-search huggingface dataset:
Abstract 11299: Economic Impact and Cost-Effectiveness of Cardiac Resynchronization Therapy versus Optimal Medical Therapy in Mild Heart Failure: Long-Term Follow-Up and Projections From REVERSE
Authors: Michael R Gold, Stylianos I Tsintzos, Manpreet K Sidhu, Stuart Mealing, KerriAnne Fortier, Amie Padhiar, William T Abraham
Journal: Circulation (2013)

BACKGROUND: The REVERSE Study, a prospective double-blinded randomized trial, assessed whether or not Cardiac Resynchronization Therapy (CRT) together with Optimal Medical Therapy (OMT) limited the progression of Heart Failure (HF) compared to OMT alone in Class I/II HF subjects with QRS ≥120 ms and LVEF ≤40%. Patients were implanted with CRT (either with pacing capabilities only “CRT-P”, or combined with a defibrillator “CRT-D”) and randomized to CRT-ON or CRT-OFF. CRT-OFF patients were unblinded after 12 (US/Canada) or 24 months (Europe) and crossed-over to CRT-ON with pre-planned follow-up for 5 years. Our analysis investigates the cost-effectiveness of CRT in this cohort. METHODS: Outcomes were modeled using regression-based techniques informed by actual 5 year data; Cost-Effectiveness for both CRT-ON vs. CRT-OFF and CRT-D vs. CRT-P were assessed. Co-variables used in all analyses were QRS Duration, Ischemic Etiology, LBBB, Gender and Age. NYHA Class based mortality as well as advanced statistical met...
Expression Divergence Is Correlated with Sequence Evolution but Not Positive Selection in Conifers
Authors: Kathryn A. Hodgins, Sam Yeaman, Kristin A. Nurkowski, Loren H. Rieseberg, Sally N. Aitken
Journal: Molecular Biology and Evolution (2016)

The evolutionary and genomic determinants of sequence evolution in conifers are poorly understood, and previous studies have found only limited evidence for positive selection. Using RNAseq data, we compared gene expression profiles to patterns of divergence and polymorphism in 44 seedlings of lodgepole pine (Pinus contorta) and 39 seedlings of interior spruce (Picea glauca × engelmannii) to elucidate the evolutionary forces that shape their genomes and their plastic responses to abiotic stress. We found that rapidly diverging genes tend to have greater expression divergence, lower expression levels, reduced levels of synonymous site diversity, and longer proteins than slowly diverging genes. Similar patterns were identified for the untranslated regions, but with some exceptions. We found evidence that genes with low expression levels had a larger fraction of nearly neutral sites, suggesting a primary role for negative selection in determining the association between evolutionary rate and expression level. There was limited evidence for differences in the rate of positive selection among genes with divergent versus conserved expression profiles and some evidence supporting relaxed selection in genes diverging in expression between the species. Finally, we identified a small number of genes that showed evidence of site-specific positive selection using divergence data alone. However, estimates of the proportion of sites fixed by positive selection (α) were in the range of other plant species with large effective population sizes suggesting relatively high rates of adaptive divergence among conifers.
Phase I study of bevacizumab, sorafenib, and low-dose cyclophosphamide (CYC) in children and young adults with refractory solid tumors.
Authors: V. M. Santana, S. D. Baker, B. McCarville, C. F. Stewart, J. Wu, C. Billups, S. L. Spunt, W. L. Furman, L. M. McGregor, S. Hu, J. C. Panetta, W. E. Reddick, A. Davidoff, W. H. Leung, F. Navid
Journal: Journal of Clinical Oncology (2011)

9500 Background: Angiogenesis is necessary for tumor growth, metastasis, and survival. Endothelial cells and pericytes, key cellular components of blood vessels, are primarily regulated by VEGF and PDGF signaling. We therefore performed a phase I trial to determine the feasibility and toxicity profile of agents combined to inhibit angiogenesis by targeting PDGFR-β and VEGFR2 with sorafenib, VEGF with bevacizumab, and endothelial cells with continuous low-dose CYC. Methods: Cohorts of 3-6 eligible patients with recurrent solid tumors received CYC and escalating dosages of sorafenib and then of bevacizumab (see table). Each course of therapy was 21 days. We used standard physical exams and laboratory tests to assess toxicities. Results: 19 patients (11 males; median age, 9.2 years) received a median of 4 courses (range, 1-23). The table summarizes dose levels explored and dose-limiting toxicities (DLTs) in course 1. With additional 71 courses of therapy, the most common nonhematologic toxicities ≥ grade 3 included rashes (5) and febrile neutropenia (2). Predominant hematologic toxicities were neutropenia and lymphopenia. Five of 17 evaluable patients had partial tumor responses (2 rhabdoid, 1 rhabdomyosarcoma, 1 medulloblastoma, 1 synovial sarcoma), and 9 had disease stabilization. First-dose pharmacokinetics results from 14 patients follow. The median (range) apparent CYC clearance was 2.03 L/hr/m2 (1.8-2.1 L/hr/m2), and the absorption rate constant was 0.12 hr-1 (0.08-0.23 hr-1). Sorafenib at 90 and 110 mg/m2yielded the following respective median (range) values: Cmax, 1.1 (0.37-2.4) and 1.6 (0.91-2.4) mg/L; Tmax, 8.5 (3.9-17.5) and 10.7 (8.2-14.1) h; AUC (0-12h), 10.4 (2.6-23.0) and 13.6 (8.0-20.4) mg*h/L. Conclusions: The recommended phase II doses are sorafenib, 90 mg/m2/dose BID; bevacizumab, 15 mg/kg q3 weeks; and CYC, 50 mg/m2 once daily. This regimen is feasible with promising evidence of anti-tumor activity that warrants further investigation. No. pts* Sorafenib (mg/m2) PO BID Bevacizumab (mg/kg) IV q3 wks No. DLT DLT course 1 3 90 5 0 None 4 110 5 2 Grd 3 rash, ↑lipase 6 90 10 1 Grd 3 thrombus 6 90 15 1 Grd 3 rash, anorexia *All received CYC (50 mg/m2) PO once daily.
Clinical evidence of efficacy of the temozolomide/gemcitabine combination against non-small cell (nsclc) and small cell (sclc) lung cancers
Authors: R. Goel, S. Z. Gertler, D. J. Stewart, S. A. Laurie, G. D. Goss, M. N. Reaume, M. C. Cripps, D. A. Bedard, A. Rodgers, D. L. Cutler
Journal: Journal of Clinical Oncology (2005)

7338 Background: A phase I study of (TZ)/(GC) combination has been completed, and the results previously presented at ESMO (Ann Oncol 15(3):198, 2004). Here, we report on this regimen’s activity in patients with nsclc and sclc. Methods: Four dose levels (DL) of TZ/GC were assessed. Two dose-limiting toxicities (ie two patients with Grade 3/4 neutropenia, with one toxic death) occured at DL 4 (i.e. TZ 150 mg/m2, days 1–7 and 15–21; GC 750 mg/m2 days 1, 8, and 15, every 28 days). Results: Patient characteristics (nsclc): male 5/female 3; median age 57 (range 49–63); performance status (PS) 1 (n=4), and 2 (n=4); prior therapy: platinum-based chemotherapy 8, taxanes 3; sites of metastases: liver 3, lung 3, bone 1, lymph nodes 1, pleura 2, brain 1, no metastases (locally advanced disease) 1. Two patients were treated at DL 1, 1 at DL 2, 4 at DL 3, and 1 at DL 4. Four patients were not evaluable for response (3 patients had one cycle of therapy and 1 patient died after cycle 2, without being evaluated for response). Four patients were evaluable for response. They received 2,2,4, and 9 cycles of therapy, respectively. Two patients had stable disease for ≥2 cycles (one patient had a minor response); one patient had a partial response, and one patient had progressive disease The progression-free survival (PFS) in these 4 patients was (in days) 55, 58, 108, and 283, respectively. One patient with sclc was treated. He was a 66 years old with PS=0. He had one prior cycle of cisplatin/etoposide chemotherapy for limited stage disease. He developed neutropenic fever, and declined further therapy. A few months later, he developed intra-abdominal lymphadenopathy, and declined further cisplatin/etoposide. He received 6 cycles of study therapy. He experienced a partial response. His PFS was 240 days. Conclusions: Encouraging activity of the regimen is suggested in this group of pre-treated patients with locally advanced/metastatic nsclc, and extensive stage sclc. These data suggest that this regimen can be considered for testing in a phase II study format in carefully selected patients with these 2 conditions, who have failed platinum-based chemotherapy. Supported by Schering-Plough Research Institute. No significant financial relationships to disclose.
<i>TBX5</i>mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians
Authors: Ji-Fang Ma, Fan Yang, Saagar N. Mahida, Ling Zhao, Xiaomin Chen, Michael L. Zhang, Zhijun Sun, Yan Yao, Yi-Xin Zhang, Gu-Yan Zheng, Jie Dong, Ming-Jun Feng, Rui Zhang, Jian Sun, Shuo Li, Qun-Shan Wang, Huiqing Cao, Emelia J. Benjamin, Patrick T. Ellinor, Yi-Gang Li, Xiao-Li Tian
Journal: Cardiovascular Research (2016)

Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated.We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-α (MHC-α) and myosin light chain-2α (MLC-2α). Overexpression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. To replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (ΔAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects.Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40.
Bulging and Pulsating Conjunctiva
Authors: Sanjay Pandey, Shruti Jain
Journal: JAMA Neurology (2016)

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Results of a phase I study of bevacizumab (BV), everolimus (EV), and erlotinib (E) in patients with advanced solid tumors
Authors: J. C. Bendell, D. George, A. Nixon, D. Yu, W. Petros, R. Beci, C. Arrowood, D. Lockamy, M. O’Neill, H. Hurwitz
Journal: Journal of Clinical Oncology (2007)

3548 Background: BV inhibits vascular endothelial growth factor (VEGF). EV is an mTOR (mammalian target of rapamycin) inhibitor. E inhibits epidermal growth factor receptor (EGFR) tyrosine kinase. VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects alone and in combination in preclinical models. As a combination targeted therapy, we evaluated BV + EV + E in a phase I, pharmacokinetic (PK), biomarker study. Methods: Cycle length was 28 days. Doses: BV 10mg/kg IV q14d. EV 5mg PO QD, escalating to 10mg QD. Once the recommended phase II dose (RPTD) of BV + EV was reached, E was added, starting at 75 mg PO QD. DLT was defined as any treatment-related grade 4 heme or grade 3/4 non-heme event in Cycle 1. Results: 34 pts have been enrolled (18 F, 16 M), 28 evaluable for DLT, 24 for efficacy. Median age is 58y (range 29–73). Dose level 1 (BV 10mg/EV 5mg) had no DLT’s. Dose level 2 (BV 10mg/EV 10mg) had no DLT’s and the cohort was expanded to 13 evaluable pts. E (75mg) was added to BV 10mg/ EV 10mg. 2/6 patients had DLT (grade 3 mucositis and grade 3 rash). The doses were adjusted to BV 5mg/EV 5mg/E 75mg. 3 patients had no DLT and this dose is the MTD and RPTD for the 3-drug combination. 20 more patients are being enrolled at the RPTD for biomarker studies. Other grade ¾ toxicity included: nephrotic syndrome, cardiac ischemia, ventricular thrombus, portacath thrombosis, and bowel perforation. 2 patients had PR: 1 renal and 1 osteosarcoma. 16/24 pts had SD (10–112+ weeks). 5/6 patients with colorectal cancer (CRC) previously progressing on BV had SD (16+ - 112 weeks). One CRC patient had 19% radiologic decrease. Conclusions: BV + EV + E preliminary clinical activity (notably in refractory CRC) and class-related side effects were seen. The MTD is BV 5mg/kg IV q14d + EV 5mg PO QD + E 75mg PO QD. Updated data will be presented. No significant financial relationships to disclose.
Abstract 1540: Weather/Temperature Change and Heart Disease
Authors: Andrew Chase-Ziolek, Jeremy Carlsen, Dawn LeRoy, Karyn Holm
Journal: Circulation (2007)

STUDY OBJECTIVE: Although recent studies have examined the effect of weather on acute coronary syndrome and heart failure, few have examined the influence of extreme weather and rapid temperature change on emergency department admissions for acute coronary syndrome and heart failure, METHODS: We reviewed presentations of acute coronary syndrome (n = 2381) and heart failure (n = 1802) for the years 2003 to 2006 at an urban Level I Trauma Center and Accredited Chest Pain Center, examining presentation frequency on the warmest and coldest days of their respective years. In addition, we examined the frequency of presentation on days where the absolute difference between the mean temperature of one day and the next differed by 5, 10, and 15 degrees Fahrenheit. For each of these sample sets, we analyzed the data by gender and age. RESULTS: Frequency of presentation did not significantly change on the hottest and coldest days of the year for acute coronary syndrome (p = 0.89 hot, p = 0.63 cold) or heart failure (p = 0.51 cold, p = 0.66 hot). No significant correlation was noted between gender and temperature extremes for acute coronary syndrome (p = 0.71 cold, p = 0.62 hot) or for heart failure (p = 0.83 cold, p = 0.59 hot). Age was not significantly correlated with temperature extremes for presentations of acute coronary syndrome (p = 0.72 cold, p = 0.63 hot) or heart failure (p = 0.95 cold, p = 0.99 hot). Changes in presentation frequency for either acute coronary syndrome (ACS) or heart failure (HF) at ΔT = 5°F were not significant (p = 0.70 ACS, p = 0.67 HF), nor were they significant at ΔT = 10°F (p = 0.97 ACS, p = 0.26 HF) or ΔT = 15°F (p = 0.17 ACS, p = 0.57 HF). CONCLUSIONS: In theses patients, no significant correlations were noted between extreme weather events, temperature change and the presentation of acute coronary syndrome. In addition, no significant correlations were found between temperature differentials of 5, 10, or 15 °F and a diagnosis of acute coronary syndrome or heart failure.
Abstract 17163: A Recombinant Atrial Natriuretic Peptide Prevents Aberrant Ca2+ Leakage Through Ryanodine Receptor by Suppression of Mitochondrial Reactive Oxygen Species Production in Failing Cardiomyocytes
Authors: Wakako Murakami, Shigeki Kobayashi, Hironori Ishiguchi, Takeki Myoren, Shigehiko Nishimura, Takayoshi Kato, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
Journal: Circulation (2014)

Introduction: Catecholamine induces intracellular reactive oxygen species (ROS), enhances diastolic Ca2+ leak through the ryanodine receptor in failing myocytes. The aim of the present study is to clarify the mechanism by which an exogenous atrial natriuretic peptide (ANP) exerts cardioprotective effect in failing cardiomyocytes.

Methods: Myocytes was isolated from the LV of canine heart failure (HF) model by 4 weeks rapid ventricular pacing. First, mitochondrial oxidized DNA damage was evaluated by double immunohistochemical (IHC) staining using anti-VDAC antibody for mitochondria and anti 8-hydroxy-2′-deoxyguanosine (8-OHdG) antibody for oxidized DNA. Then, we investigated the effect of ANP on intracellular ROS production by DCFH-DA, diastolic Ca2+ sparks by confocal microscopy using Fluo 4-AM, and survival rate of myocytes after 48h.

Results: The double IHC study revealed that isoproterenol (ISO) markedly increased oxidized DNA in mitochondria in failing myocytes (not normal myocytes), and the ISO-induced DNA damage was markedly inhibited by the co-presence of ANP (10 nM). Intracellular ROS production was not increased in normal myocytes (relative fluorescence intensity of DCFH-DA; 100%), whereas the ROS production was already increased even at baseline in failing myocytes (180%). Moreover, the ROS was much increased in the presence of ISO (250%). The Ca2+ spark frequency in failing myocytes (CaSF: 313%) was significantly increased as compared with CaSF in normal myocytes (100%). The CaSF was much increased by addition of ISO (625%), in parallel with an increase in the ROS. Interestingly, in failing myocytes, ANP (10 nM) significantly suppressed the ISO-induced ROS production (170%) and CaSF (237%), respectively. Eventually, the survival rate (%) in failing myocytes was significantly lower in the presence of ISO than in its absence, while it was significantly increased by co-incubation of ISO plus ANP (Survival rate; Baseline 59%, ANP 63%, ISO 33%, ISO plus ANP 55%).

Conclusions: ANP has a potent antioxidant action against ISO-induced ROS, which may correct aberrant diastolic Ca2+ sparks, eventually contribute to improvement of myocytes survival in HF. The mechanism may be attributed to the suppression of ISO-induced ROS in mitochondria.
Lesson of the Week: Male ritual circumcision resulting in acute renal failure
Authors: J D Eason, M McDonnell, G Clark
Journal: BMJ (1994)

NIGolf is a low intensity sport with little danger of body collision.Issues requiring further study include:* Identifying causes of sudden death during physical exercise * The appropriateness, cost, and practicality of cardiovascular screening of presumably healthy children and adolescents before they participate in sport and of other people before th.ey continue or return to sport * Counselling patients with known cardiac abnormalities about their levels of activity and about the risk and safety of specific sporting events * Establishing guidelines for disqualifica- tion from competition Mitral valve prolapseThe approach to mitral valve prolapse should be pragmatic.In the absence of symptoms and signs or associated lesions and with a negative family history, full sporting participation should be allowed.In the presence ofpalpitations, dizziness, or near syncope, both Holter monitoring and stress testing are invaluable for estimation ofthe mechanism ofthe symptoms.Associated problems that might exclude sporting activity include an associated prolonged QT syndrome or a family history of sudden death associated with a mitral valve prolapse. Valve replacementIn patients who have had valvuloplasty or annuloplasty, contact sports should be avoided.Athletes with a prosthetic valve and normal cardiac function may engage in low intensity sports.
Factors associated with contralateral prophylactic mastectomy use among breast cancer patients in a metropolitan hospital system
Authors: A. K. Arrington, S. L. Jarosek, B. A. Virnig, E. B. Habermann, T. M. Tuttle
Journal: Journal of Clinical Oncology (2009)

6558 Background: A recent population-based study reported the proportion of women with unilateral breast cancer who underwent contralateral prophylactic mastectomy (CPM) increased by 150% between 1998 and 2003. This study evaluated all patients undergoing breast cancer surgery in a metropolitan-based hospital system to identify factors not available from tumor registries that may be associated with increased CPM rates. Methods: We reviewed the records of all patients who underwent breast cancer surgery in 2006 and 2007 in a single health care system in the Twin Cities, including one university, two suburban, and three smaller rural hospitals. Exclusion criteria included bilateral breast cancer, stage IV disease, and prior breast cancer. We recorded patient and tumor characteristics, surgery and surgeon characteristics. Logistic regression models were used to determine predictors of CPM use. Results: Of 571 eligible patients, 276 (48.3%) underwent lumpectomy, 130 (22.8%) underwent unilateral mastectomy, and 165 (28.9%) underwent mastectomy and a CPM. Among mastectomy patients, 55.9% underwent CPM. Young patients (&lt;40 v. &gt;55), larger tumors (&gt;5cm v. &lt;2cm), positive family history, lobular histology, multicentric disease, and surgeon gender (female) were independent predictors of increased CPM rates. Body mass index (BMI), tumor grade, estrogen receptor status, and preoperative breast magnetic resonance imaging were not associated with increased CPM rates. Conclusions: This cohort of patients has a much higher CPM rate than reported from population-based studies. We confirmed the role of patient age, tumor size and lobular histology as factors associated with CPM. Interestingly, factors not available through cancer registries, including positive family history and surgeon gender, are also independent predictors of CPM use. Since this study includes patients from diverse surgical practices, our findings are generally reflective of CPM use in metropolitan areas. [Table: see text] No significant financial relationships to disclose.
Effect of Normal Serum and Antithymocyte Serum on Friend Disease in Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Larson, C. L., Ushijima, R. N., Baker, R. E., Baker, M. B., Gillespie, C. A.
Journal: JNCI Journal of the National Cancer Institute (1972)

Journal Article Effect of Normal Serum and Antithymocyte Serum on Friend Disease in Mice Get access C. L. Larson, C. L. Larson Stella Duncan Memorial Institute, University of Montana, Missoula, Montana 59801 Search for other works by this author on: Oxford Academic PubMed Google Scholar R. N. Ushijima, R. N. Ushijima Stella Duncan Memorial Institute, University of Montana, Missoula, Montana 59801 Search for other works by this author on: Oxford Academic PubMed Google Scholar R. E. Baker, R. E. Baker Stella Duncan Memorial Institute, University of Montana, Missoula, Montana 59801 Search for other works by this author on: Oxford Academic PubMed Google Scholar M. B. Baker, M. B. Baker Stella Duncan Memorial Institute, University of Montana, Missoula, Montana 59801 Search for other works by this author on: Oxford Academic PubMed Google Scholar C. A. Gillespie C. A. Gillespie Stella Duncan Memorial Institute, University of Montana, Missoula, Montana 59801 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 48, Issue 5, May 1972, Pages 1403–1407, https://doi.org/10.1093/jnci/48.5.1403 Published: 01 May 1972 Article history Received: 02 November 1971 Accepted: 19 January 1972 Published: 01 May 1972