tbuckley/cabot-search huggingface dataset:
Toward a mechanistic understanding of the impact of food insecurity on obesity
Authors: Simone Dohle, Wilhelm Hofmann
Journal: Behavioral and Brain Sciences (2017)

Abstract Nettle et al. provide a useful but incomplete analysis of the drivers of obesity. In this commentary, we argue that a dual-motives conceptualization of self-control, together with insights from the psychology of (perceived and actual) scarcity, might help advance a more fine-grained mechanistic understanding of the observed association between food insecurity and obesity.
The histone H3 variant H3.3 regulates gene body DNA methylation in Arabidopsis thaliana
Authors: Heike Wollmann, Hume Stroud, Ramesh Yelagandula, Yoshiaki Tarutani, Danhua Jiang, Li Jing, Bhagyshree Jamge, Hidenori Takeuchi, Sarah Holec, Xin Nie, Tetsuji Kakutani, Steven E. Jacobsen, Frédéric Berger
Journal: Genome biology (2017)

Gene bodies of vertebrates and flowering plants are occupied by the histone variant H3.3 and DNA methylation. The origin and significance of these profiles remain largely unknown. DNA methylation and H3.3 enrichment profiles over gene bodies are correlated and both have a similar dependence on gene transcription levels. This suggests a mechanistic link between H3.3 and gene body methylation.
Heart Disease and Stroke Statistics—2010 Update
Authors: Donald Lloyd-Jones, Robert J. Adams, Todd M. Brown, Mercedes Carnethon, Shifan Dai, Giovanni De Simone, T. Bruce Ferguson, Earl Ford, Karen Furie, Cathleen Gillespie, Alan Go, Kurt Greenlund, Nancy Haase, Susan Hailpern, P. Michael Ho, Virginia Howard, Brett Kissela, Steven Kittner, Daniel Lackland, Lynda Lisabeth, Ariane Marelli, Mary M. McDermott, James Meigs, Dariush Mozaffarian, Michael Mussolino, Graham Nichol, Véronique L. Roger, Wayne Rosamond, Ralph Sacco, Paul Sorlie, Randall Stafford, Thomas Thom, Sylvia Wasserthiel-Smoller, Nathan D. Wong, Judith Wylie-Rosett
Journal: Circulation (2009)
2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease
Authors: Rick A. Nishimura, Catherine M. Otto, Robert O. Bonow, Blase A. Carabello, John P. Erwin, Robert A. Guyton, Patrick T. O’Gara, Carlos E. Ruiz, Nikolaos J. Skubas, Paul Sorajja, Thoralf M. Sundt, James D. Thomas
Journal: Journal of the American College of Cardiology (2014)
Abstract P026: Development of Autologous Tissue Small-Diameter Vascular Grafts (BIOTUBEs)
Authors: Masashi Yamanami, Taiji Watanabe, Keiichi Kanda, Tomonori Oie, Keiichi Takamizawa, Hatsue Ishibashi-Ueda, Hitoshi Yaku, Yasuhide Nakayama
Journal: Circulation Research (2011)

Objectives: There are actually no small-caliber synthetic vascular grafts (&lt; 6 mm) with acceptable patency rate for the use of coronary bypass or peripheral vascular repair below the knee in case the autologous vessels are not available. We developed autologous small-caliber vascular grafts “BIOTUBEs” using simple, safe and economical in vivo tissue engineering. In this study, we summarize the development of BIOTUBEs. Methods: Silicone rod molds (diameter: 1.5∼5 mm, length: 20∼50 mm) were placed into subcutaneous pouches of Wister rats, Japan white rabbits or Beagle dogs. After 1 month, BIOTUBEs formed around the molds were auto-implanted to the aorta (1.5 mm; rats) or the carotid arteries (2 mm; rabbits and 5 mm; dogs) of the respective animals. They were evaluated after determined period of implantation. Results: Irrespective of species, BIOTUBEs had thin wall (ca. 0.1mm) and mainly consisted of autologous fibroblasts and collagen fibers. Rats; After 12-week implantation, other than the oriented endothelial layer and smooth muscle layer, multilayered elastin fiber formation was observed in the grafts. Rabbits; Little thrombus was formed on the luminal surfaces completely covered with endothelial cells within 2 weeks. During 2 year-implantation, neither formation of aneurysms nor rupturing was observed in BIOTUBEs. Dogs; Longest follow up is 3 years under arterial pulsatile pressure condition without any degenerative changes in the grafts. Conclusions: BIOTUBEs could be ideal small caliber vascular prostheses that greatly facilitate healing process and exhibit excellent biocompatibility.
Updated Recommendations for Use of MenB-FHbp Serogroup B Meningococcal Vaccine — Advisory Committee on Immunization Practices, 2016
Authors: Monica E. Patton, David Stephens, Kelly Moore, Jessica R. MacNeil
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Two serogroup B meningococcal (MenB) vaccines are currently licensed for use in persons aged 10-25 years in the United States. The two vaccines are MenB-FHbp (Trumenba, Pfizer, Inc.) (1) and MenB-4C (Bexsero, GlaxoSmithKline Biologicals, Inc.) (2). In February 2015, the Advisory Committee on Immunization Practices (ACIP) recommended use of MenB vaccines among certain groups of persons aged ≥10 years who are at increased risk for serogroup B meningococcal disease* (Category A) (3), and in June 2015, ACIP recommended that adolescents and young adults aged 16-23 years may be vaccinated with MenB vaccines to provide short-term protection against most strains of serogroup B meningococcal disease (Category B†) (4). Consistent with the original Food and Drug Administration (FDA) licensure for the two available MenB vaccines, ACIP recommended either a 3-dose series of MenB-FHbp or a 2-dose series of MenB-4C. Either MenB vaccine can be used when indicated; ACIP does not state a product preference. The two MenB vaccines are not interchangeable; the same vaccine product must be used for all doses in a series. In April 2016, changes to the dosage and administration of MenB-FHbp were approved by FDA to allow for both a 2-dose series (administered at 0 and 6 months) and a 3-dose series (administered at 0, 1-2, and 6 months) (5,6). In addition, the package insert now states that the choice of dosing schedule depends on the patient's risk for exposure and susceptibility to serogroup B meningococcal disease. These recommendations are regarding use of the 2- and 3-dose schedules of MenB-FHbp vaccine (Trumenba) and replace previous ACIP recommendations for use of MenB-FHbp vaccine published in 2015 (3,4). Recommendations regarding use of MenB-4C (Bexsero) are unchanged (3,4).
Abstract 413: Engineering Targeted Growth Factors for Selective Pro-survival Signaling in Apoptotic Cardiomyocytes Following Ischemic Injury
Authors: Timothy R Stowe, Laura D Jennings-Antipov, Kristopher M Kuchenbecker, Yan Zhang, Shawdee Eshghi, Bjorn L Millard, Andrea D Nickerson, Ulrik B Nielsen, Matthew D Onsum
Journal: Circulation Research (2015)

Background: Despite the benefits of reperfusion therapy after myocardial infarction (MI), most patients still progress to heart failure. MI patients suffer irreversible loss of heart function due to cardiomyocyte (CM) death and tissue scarring. Growth factors (GFs) reduce scar size and limit CM apoptosis in preclinical studies, however native GFs have poor drug-like qualities and have not been successful in the clinic. Silver Creek Pharmaceuticals is developing a new class of targeted, growth factor-based therapeutics (Smart Growth Factors) that are engineered to have optimized pharmacokinetics, dynamics and safety profiles. Our first generation of SGFs use annexin-V (AnxV) to target IGF-1 to damaged CMs and selectively activate pro-survival signaling. Methods and Results: We used biophysical simulation to design an IGF-1-based SGF that selectively activated the PI3K pathway in damaged cells. SGFs were engineered to target IGF-1 to damaged cells through the binding of AnxV to phosphatidylserine exposed on the surface of apoptotic cells. These bispecific proteins were constructed with half-life modulators and linkers, then screened for their ability to selectively increase pAKT levels in apoptotic iPSC-derived human CMs. We identified a subset of SGFs that were able to selectively increase pAKT levels in apoptotic cells as compared to healthy cells (p&lt;0.05). Based on these data, we tested the ability of SGFs to activate pro-survival signaling and reduce infarct size in a rat ischemia/reperfusion model of acute MI (AMI). SGFs were able to selectively prolong pAKT in the infarcted region of the left ventricle without activating signaling in remote healthy tissue out to 2 hours post-reperfusion (n=3-6/group, p&lt;0.05). For efficacy studies, rats were subjected to 60 minutes of ischemia followed by 72 hours of reperfusion. A single IV dose of SGF (600 pmol/kg) administered at time of reperfusion was able to significantly reduce infarct size relative to the area-at-risk (infarct/AAR%) as compared to controls (p&lt;0.05; SGF 12.7±5% n=10; wt IGF-1 20.3±3% n=8 and vehicle 27.6±7% n=12). Conclusions: This work demonstrates that SGFs selectively activate pro-survival signals in distressed CMs and lead to reduced infarct size in vivo without off-target effects.
Pulmonary Arterial Hypertension
Authors: Harrison W. Farber, Joseph Loscalzo
Journal: New England Journal of Medicine (2004)

This review of the mechanism of pulmonary hypertension is focused on pulmonary arterial hypertension, a disorder that can be idiopathic or can occur in association with other disorders, such as infection with the human immunodeficiency virus. The authors suggest that an abnormality involving intracellular signaling mediated by transforming growth factor β underlies the various forms of pulmonary arterial hypertension.
Significance of chromosome 17 polysomy in breast cancer.
Authors: Robert W. Galamaga, Rachel Mariani, Imad Almanaseer, Jacob D. Bitran
Journal: Journal of Clinical Oncology (2012)

e12002 Background: Human epidermal growth factor receptor 2 (HER-2) overexpression occurs in up to 30% of breast cancers and has been associated with poor clinical outcomes that have improved with advances in HER-2 directed therapy. The HER-2 gene resides on the long arm of chromosome 17 and amplification is typically assessed via immunohistochemistry or fluorescence in situ hybridization (FISH); HER-2 is interpreted as amplified, non-amplified, or equivocal. The effect and clinical impact of chromosome 17 polysomy in specimens interpreted as HER-2 non-amplified has not been well-established in breast cancer patients. This subgroup may represent a unique set of patients who may benefit from HER-2 directed therapy given the increase in HER-2 gene copy number. If tumors with polysomy 17 share biologic similarities with those positive for HER-2 amplification this may significantly influence the approach to treating these patients. In a single institution study we reviewed all breast cancer cases diagnosed in 2008 which were reported as HER-2 equivocal or non-amplified via FISH and with chromosome 17 polysomy in order to extrapolate disease-free and overall survival data within this subset. Methods: HER-2 expression via FISH from patients diagnosed with breast cancer in 2008 was reviewed. In those patients with equivocal or non-amplified HER-2 expression we selected those with chromosome 17 polysomy defined as a chromosome 17 centromere copy number of &gt; 3 per tumor cell. A total of 9 patients were identified. Results: The median age was 74 (36-88). Median tumor size was 1.6 cm (0.7-4.9) and 8 patients (88%) had both estrogen and progesterone positive tumors. Stage distribution was as follows: stage IA: 4 (44%); stage IIA: 2 (22%); stage IIB: 2 (22%) and stage IIIA: 1 (11%). The actuarial 3 year disease free survival was 67%. Conclusions: Breast cancers with equivocal or non-amplified HER-2 expression with chromosome 17 polysomy represent a unique subset of tumors with a biology that is not well-understood. Previously published studies have yielded conflicting results regarding the prognostic significance of this genotype. Our study reflects a three year survival of 67% which suggests that these patients represent an aggressive subset.
Reducing musculoskeletal injury and concussion risk in schoolboy rugby players with a pre-activity movement control exercise programme: a cluster randomised controlled trial
Authors: Michael D Hislop, Keith A Stokes, Sean Williams, Carly D McKay, Mike E England, Simon P T Kemp, Grant Trewartha
Journal: British Journal of Sports Medicine (2017)

Background Injury risk in youth rugby has received much attention, highlighting the importance of establishing evidence-based injury reduction strategies. Aim To determine the efficacy of a movement control exercise programme in reducing injuries in youth rugby players and to investigate the effect of programme dose on injury measures. Methods In a cluster-randomised controlled trial, 40 independent schools (118 teams, 3188 players aged 14–18 years) were allocated to receive either the intervention or a reference programme, both of which were to be delivered by school coaches. The intervention comprised balance training, whole-body resistance training, plyometric training, and controlled rehearsal of landing and cutting manoeuvres. Time-loss (&gt;24 hours) injuries arising from school rugby matches were recorded by coaches and medical staff. Results 441 time-loss match injuries (intervention, 233; control, 208) were reported across 15 938 match exposure-hours (intervention, 9083; control, 6855). Intention-to-treat results indicated unclear effects of trial arm on overall match injury incidence (rate ratio (RR)=0.85, 90% confidence limits 0.61 to 1.17), although clear reductions were evident in the intervention arm for concussion incidence (RR=0.71, 0.48 to 1.05). When trial arm comparisons were limited to teams who had completed three or more weekly programme sessions on average, clear reductions in overall match injury incidence (RR=0.28, 0.14 to 0.51) and concussion incidence (RR=0.41, 0.17 to 0.99) were noted in the intervention group. Conclusion A preventive movement control exercise programme can reduce match injury outcomes, including concussion, in schoolboy rugby players when compared with a standardised control exercise programme, although to realise the greatest effects players should complete the programme at least three times per week.
Enhancement of Glucuronide-Conjugating Capacity in a Hyperbilirubinemic Infant Due to Apparent Enzyme Induction by Phenobarbital
Authors: Sumner J. Yaffe, Gerhard Levy, Tai Matsuzawa, Tadla Baliah
Journal: New England Journal of Medicine (1966)

GLUCURONIDE conjugation is an important mechanism for the elimination of endogenous and exogenous substances from the human body.1 A defect in this mechanism leads to increased concentrations of unconjugated bilirubin in the blood, and the latter is therefore frequently a reflection of impaired glucuronide synthesis.2 Patients with unusually low capacity for the conjugation of bilirubin show a similar reduced capacity for glucuronide conjugation of certain drugs that are ordinarily metabolized and eliminated by that process.3 , 4 Congenital, nonobstructive, nonhemolytic jaundice, which is thought to be due to a functional impairment of the glucuronyl transferase system, presents a particularly serious and difficult . . .
Abstract 116: Myelopoiesis Following Myocardial Ischemia (MI) Involves Activation of the Nlrp3 Inflammasome by Neutrophil-derived S100a8/a9
Authors: Prabhakara R Nagareddy, Rahul Annabathula, Saojing Ye, Yuri Klyachkin, Ahmed Abdel-Latif, Susan Smyth
Journal: Circulation Research (2015)

Ischemic myocardial damage triggers leukocytosis particularly the production of monocytes and neutrophils from the bone marrow and spleen (myelopoiesis). These cells infiltrate the evolving myocardial wound, degrade extracellular matrix and aid in the clearance of dead cardiac myocytes and their debris. Although this inflammatory process is a prerequisite for tissue healing, it is non-specific and often blunt. If unchecked, excessive production of monocytes and neutrophils may result in abnormal ventricular remodeling and heart failure. The myocardial cellular and molecular events that orchestrate with the BM/spleen to regulate myelopoiesis remain unclear. We report here that the number of circulating monocytes and neutrophils peak within 24 hours following coronary artery ligation (LAD) in mice. This is due to expansion and proliferation of hematopoietic stem and multi-potential progenitor cells (HSPC) in the BM as well as extra medullary hematopoiesis in the spleen. MI induced -myelopoiesis was associated with a dramatic increase in the expression of S100a8/a9 (a damage associated molecular pattern), its receptor (Tlr4), the Nlrp3 inflammasome and pro-IL1β in the heart. Cell separation studies revealed that the infiltrating neutrophils and cardiac fibroblasts are the predominant source of S100a8/a9 and the Nlrp3 inflammasome respectively in the heart. Further, deletion of s100a8/a9 not only reduced MI -induced myelopoiesis but also significantly improved the mortality and cardiac function in mice following LAD. These data supports our hypothesis that neutrophil-derived S100a8/a9 interact with Tlr4 on cardiac fibroblasts to induce the Nlrp3 inflammasome and produce IL1β, which in turn stimulates IL-1R on HSPCs to promote myelopoiesis. Pharmacological strategies aimed at inhibition of S100a8a/9 or the Nlrp3 inflammasome-mediated production of IL1β may be a promising approach to limit inflammation following acute coronary syndrome.
Cancer cost evaluation in chemotherapy (chemo)-naive patients (pts) treated under a payer-sponsored pathway program.
Authors: Bruce A. Feinberg, Janna Radtchenko, Tim Olson
Journal: Journal of Clinical Oncology (2014)

6562 Background: US cancer costs are projected to increase to over $173 billion in 2020. Clinical pathways can help curb rising costs by reducing unnecessary and costly treatment variation while improving pt outcomes. Initial treatment may have the greatest pathway impact as it influences pt outcomes and subsequent care. We evaluated cost savings of a payer-sponsored pathway program for pts with cancer receiving first chemo intervention. Methods: A large payer for the Mid-Atlantic region of the US collaborated with its community oncology provider network to create a 3-year pathway program, managed by Cardinal Health, for chemo-naïve pts. Using claims data, 3 years of chemo and supportive care drug use were evaluated to establish a baseline cost trend for pts with breast cancer (BC), colorectal cancer (CRC), and lung cancer. Using this baseline as historical control, pts who started first-line treatment in pathway year 1 were included in the analysis. All drug costs were standardized to average sales price effective in the last quarter of the program year. Although voluntary, participating physicians received financial incentives for additional work required to manage the program. Results: The pathway cohort consisted of 453 pts; historic control cohorts for years 1-3 consisted of 362, 325, and 387 pts, respectively. Arms were well balanced; 24% were diagnosed with CRC in the study arm vs 26% in the control arm; 45% vs 44% for BC, and 31% vs 30% for lung cancer, respectively. Savings relative to projected cost/pt/year for pathway cohorts were $21,106 for CRC and $2,964 for lung cancer. For BC, cost increased $9,271. Overall mean cost/pt, adjusted for trastuzumab use (29% study vs 21% control), decreased 5% ($1,698 pt/yr) for an aggregate savings of $750,436. Conclusions: Voluntary pathway participation can lower drug cost of common malignancies even in first-line treatment. The approach of limiting pathway inclusion to chemo-naive pts will provide the greatest clarity of pathway impact throughout the duration of illness. This is our third report of reduced cancer care cost despite enhanced physician reimbursement. We believe the body of evidence dispels concerns about reproducibility of pathways benefits.
A randomized phase II study of cediranib (CED) alone versus CED plus dasatinib (DAS) in patients (pts) with castration-resistant prostate cancer (CRPC).
Authors: Anna Spreafico, Kim N. Chi, Srikala S. Sridhar, David C Smith, Michael Anthony Carducci, Peter Kavsak, Tracy S Wong, Lisa Wang, S. Percy Ivy, Som Dave Mukherjee, Christian K. Kollmannsberger, Sebastien J. Hotte
Journal: Journal of Clinical Oncology (2013)

5039 Background: Activation of the Vascular Endothelial Growth Factor Receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of CRPC in preclinical models. CED and DAS are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of CED (Karakunnel et al ASCO 2009) and DAS (Yu et al Urology 2011) in CRPC have shown single agent activity. Methods: Docetaxel-preteated CRPC pts were randomized to arm A: CED alone (20 mg/day) vs arm B: CED (20 mg/day) plus DAS (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12 week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results: 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles = 4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A vs 18 % in arm B (p = 0.03). Median PFS in months (arm A vs B) was: 5.2 vs 2.6 (95% CI: 1.9-6.5 vs 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in both arms A and B. Conclusions: Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in pts with CRPC. Clinical trial information: NCT01260688.
Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer
Authors: Sophia N. Karagiannis, Debra H. Josephs, Heather J. Bax, James F. Spicer
Journal: Cancer Research (2017)

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy.