tbuckley/cabot-search huggingface dataset:
Abstract 231: Bendavia, a Novel Mitochondria-Targeting Peptide, Improves Contraction and Relaxation of Failing Cardiomyocytes Isolated From Dogs With Chronic Heart Failure
Authors: Hani N Sabbah, Ramesh C Gupta
Journal: Circulation Research (2015)

Background: Mitochondria (MITO) of humans and dogs with heart failure (HF) manifest functional abnormalities characterized by poor respiration, reduced rate of ATP synthesis and increased production of reactive oxygen species (ROS) that adversely impact LV systolic and diastolic function. We previously showed that chronic therapy with Bendavia (BEN, MTP-131), a novel mitochondria-targeting peptide, improves global LV function in dogs with HF without affecting heart rate or blood pressure. This improvement was associated with a reversal of MITO abnormalities and normalization of rate of ATP synthesis. This study tested the hypothesis that the improvement in global LV function seen in dogs with HF during treatment with BEN results primarily from enhanced function of constituent LV cardiomyocytes. Methods: Cardiomyocytes were isolated from the LV free wall of 8 untreated dogs with coronary microembolization-induced HF (LV ejection fraction &lt;30%). A collagenase-based enzymatic process was used for the isolation and yielded ~70% viable rod-shaped cardiomyocytes that excluded trypan blue. Extent of cardiomyocytes shortening, shortening velocity and lengthening velocity were assessed during 1.0 Hz electrical field stimulation delivered via a MyoPacer (ION Optix). Measurements were made at baseline and were repeated after one hour of gradual exposure of the same cardiomyocytes to BEN at a concentration of 0.1 μM. Results: At baseline, the extent of cardiomyocyte shortening was 3.7 ± 0.8 μm, shortening velocity was 62.8 ± 16.9 μm /sec and lengthening velocity was -53.8 ± 16.5 μm/sec. Exposure of cardiomyocyte to BEN significantly increased the extent of cardiomyocyte shortening to 5.4 ± 1.1 μm (p&lt;0.012), shortening velocity to 94.5 ± 21.9 μm/sec (p&lt;0.020) and lengthening velocity to -96.8 ± 21.1 μm/sec (p&lt;0.016) compared to baseline. Conclusions: Exposure of failing isolated cardiomyocytes to BEN elicits improvements in the rate of cardiomyocyte shortening and re-lengthening indicative of improved cell contractility and relaxation. This improvement is likely mediated by increased availability of ATP along with reduced ROS production both secondary to improved mitochondrial function elicited by treatment with BEN.
Prognostic value of Ki-67 labeling index according to age in patients with non-metastasic triple-negative breast cancer.
Authors: Victor Zenzola, María Antonia Cabezas-Quintario, Andrea Correa, Irene Moreno, Manuel Pedregal, Federico Rojo, Miguel Arguelles, Elia Perez Fernandez, Jesus Garcia-Foncillas
Journal: Journal of Clinical Oncology (2017)

e12118 Background: The prognostic value of Ki67 in triple negative breast cancer (TNBC) is yet unclear because the cut-off points employed differ widely and its predictive effect may vary according to age. The purpose of this study was to analyze the role of Ki-67 among patients with TNBC, and determined the optimal Ki-67 cut-off point to demonstrate its prognostic relevance associated with patient age and treatment strategy. Methods: 201 patients treated for primary TNBC from 1999 to 2014 were identified from the breast surgery database. Clinicopathologic characteristics and outcomes were compared between patients treated with neoadjuvant or adjuvant chemotherapy. We used time-dependent receiver operating characteristic (ROC) curve and time-dependent area under the ROC curve (AUC) to evaluate the discriminative ability of Ki-67 at 3 and 5 years of follow up. A Ki-67 cut-off point was set up to maximize sensitivity and specificity. Interaction effect between age and Ki-67 on disease-free survival (DFS) and overall survival (OS) was evaluated by stratified analysis. Results: There was a non-significant Ki-67 cut off value to predict OS and DFS at 3 and 5 years neither in the whole serie (201) nor in the adjuvant group (125), and only a slightly better threshold for DFS in the neoadjuvant one (N = 46) at 5 years (AUC = 0.697). According to the coordinates of the ROC curves, the best cut-off point for Ki-67 was 60%. In the multivariate analysis (COX proportional hazards regression), high Ki-67 ( &gt; 60%), was a poor prognostic factor for DFS in patients &gt; 40 yo. Among the patients &lt; 40 yo, high Ki-67 was a better prognosis factor. Conclusions: Our data suggest that a threshold of Ki-67 of 60% could provide a usefull tool to define patients with significantly different outcome in TNBC.
Comparison of pharmacokinetics of S-1 between the initial and reduced dose in patients with locally advanced head and neck cancer.
Authors: Tomoko Yamazaki, Hiroto Ishiki, Yoko Yajima, Takehiko Kobayashi, Tomohiro Enokida, Sadamoto Zenda, Satoko Arahira, Mitsuhiko Kawashima, Makoto Tahara
Journal: Journal of Clinical Oncology (2013)

e13586 Background: S-1 is an oral fluoropyrimidine that combines tegafur (FT) with two modulators, gimeracil (CDHP) and oteracil potassium (Oxo). CDHP augments 5-FU activity by inhibiting dihydropyrimidine dehydrogenase (DPD). As 50% of CDHP is excreted in the urine, renal dysfunction may directly affect the inhibitory effect on DPD and lead to increased 5-FU concentrations, and dose modification is recommended if renal dysfunction occurs (M.Tahara et. al; Cancer Science, 2011). However, the method of dose modification has not been established. We compared the pharmacokinetics of S-1 between the initial and reduced dose in patients with locally advanced head and neck cancer. Methods: This was a prospective study at a single institution. Eligibility required histologically or cytologically confirmed carcinoma of the head and neck with unresectable locally advanced disease. Chemotherapy consisted of administration of S-1 twice daily on days 1-14 at 60 mg/m 2 /day, and cisplatin at 20 mg/m 2 /day on days 8-11, repeated twice at a 5-week interval. Single daily radiation of 70 Gy in 35 fractions was given concurrently startingon day 1. Two additional cycles of chemotherapy wereplanned after the completion of CRT. S-1 dose was reduced to 40 or 30 mg/m 2 /day in accordance with adverse events. Peripheral blood samples were drawn before and at 1, 2, 4, 8, and 10 hours on day 7 in the first cycle and in the cycle with dose reduction. Primary endpoint was the change in 5-FU AUC ss0-10 between the initial and reduced S-1 dose. Results: Eight patients were enrolled between July 2010 and July 2011, and 30 cycles of chemotherapy were administered. Four pts required S-1 dose reduction due to mucosal infection (n=2), febrile neutropenia (n=1), or renal dysfunction (n=1). PK parameters are compared below. Conclusions: AUC ss0-10 for 5FU with a reduced dose of S-1 was significantly lower than with the initial dose.Further investigation with more patients is warranted. [Table: see text]
Intravenous Bortezomib Plus Dexamethasone Exhibits Similar Therapeutic Response As Subcutaneous Bortezomib-Based Triple Drug Regimen in Newly-Diagnosed Multiple Myeloma
Authors: Kiyomi Morita, Junji Koya, Takashi Toya, Fumihiko Nakamura, Mineo Kurokawa
Journal: Blood (2016)
Spontaneous food allergy in <i>Was</i><sup><i>−/−</i></sup> mice occurs independent of Fcε<scp>RI</scp>‐mediated mast cell activation
Authors: W. S. Lexmond, J. A. Goettel, B. F. Sallis, K. McCann, E. H. H. M. Rings, E. Jensen‐Jarolim, S. Nurko, S. B. Snapper, E. Fiebiger
Journal: Allergy (2017)

Food allergies are a growing health problem, and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was-/- mice recapitulates the pathology of a conventional disease model and/or human food allergy.Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was-/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed, and the role of the high-affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was-/- Fcer1a-/- mice.Polysensitization to food was detected in both WAS and food-allergic patients which was recapitulated in the Was-/- model. Oral administration of ovalbumin (OVA) in Was-/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was-/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was-/- mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells (MCs) and basophils.Was-/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food.
Application of Zone Model Predictive Control Artificial Pancreas During Extended Use of Infusion Set and Sensor: A Randomized Crossover-Controlled Home-Use Trial
Authors: Gregory P. Forlenza, Sunil Deshpande, Trang T. Ly, Daniel P. Howsmon, Faye Cameron, Nihat Baysal, Eric Mauritzen, Tatiana Marcal, Lindsey Towers, B. Wayne Bequette, Lauren M. Huyett, Jordan E. Pinsker, Ravi Gondhalekar, Francis J. Doyle, David M. Maahs, Bruce A. Buckingham, Eyal Dassau
Journal: Diabetes Care (2017)

OBJECTIVE As artificial pancreas (AP) becomes standard of care, consideration of extended use of insulin infusion sets (IIS) and continuous glucose monitors (CGMs) becomes vital. We conducted an outpatient randomized crossover study to test the safety and efficacy of a zone model predictive control (zone-MPC)–based AP system versus sensor augmented pump (SAP) therapy in which IIS and CGM failures were provoked via extended wear to 7 and 21 days, respectively. RESEARCH DESIGN AND METHODS A smartphone-based AP system was used by 19 adults (median age 23 years [IQR 10], mean 8.0 ± 1.7% HbA1c) over 2 weeks and compared with SAP therapy for 2 weeks in a crossover, unblinded outpatient study with remote monitoring in both study arms. RESULTS AP improved percent time 70–140 mg/dL (48.1 vs. 39.2%; P = 0.016) and time 70–180 mg/dL (71.6 vs. 65.2%; P = 0.008) and decreased median glucose (141 vs. 153 mg/dL; P = 0.036) and glycemic variability (SD 52 vs. 55 mg/dL; P = 0.044) while decreasing percent time &amp;lt;70 mg/dL (1.3 vs. 2.7%; P = 0.001). AP also improved overnight control, as measured by mean glucose at 0600 h (140 vs. 158 mg/dL; P = 0.02). IIS failures (1.26 ± 1.44 vs. 0.78 ± 0.78 events; P = 0.13) and sensor failures (0.84 ± 0.6 vs. 1.1 ± 0.73 events; P = 0.25) were similar between AP and SAP arms. Higher percent time in closed loop was associated with better glycemic outcomes. CONCLUSIONS Zone-MPC significantly and safely improved glycemic control in a home-use environment despite prolonged CGM and IIS wear. This project represents the first home-use AP study attempting to provoke and detect component failure while successfully maintaining safety and effective glucose control.
Abstract P235: Endothelium-Specific Prokineticin Receptor 1 Inactivation in Mice Leads to Endothelial Dysfunction and Metabolic Syndrome
Authors: Canan G Nebigil
Journal: Circulation Research (2011)

Reciprocal relationships between endothelial dysfunction and insulin resistance result in a vicious cycle, linking between cardiovascular and metabolic disorders. Here we provide the first evidence that endothelial specific loss of prokineticin receptor-1 (PKR1) in mice leads to endothelial dysfunction and low capillary formation, ultimately contributing cardiovascular, kidney disorders and development of insulin resistance. Endothelial cells derived from these mutant hearts displayed an impaired proliferation rate and vessel-like formation. Low capillary formation in mutant heart, kidney, pancreas and adipose tissues was evident. The mutant aortas displayed increased collagen deposition, fenestrated endothelium with junctional defects, and impaired relaxation due to nitric oxide synthesize-deficits without altering blood pressure. Mutant hearts have thin ventricular wall due to an increase in apoptotic cardiomyocytes. Mutant kidneys have abnormal glomerulus structure with an increase in apoptotic cell numbers and phosphate excretion. Mutant mice exhibited low fasting blood glucose and high serum insulin levels. They cleared the blood glucose at a considerably slower rate than control mice accompanied with impaired insulin tolerance. The insulin resistance induces compensatory β cell hypertrophy but not expansion due to impaired survival signaling. Induction of cell death and fibrosis is induced by hypoxia in mutant adipocytes leads to increase in HIF1a and collagen expression. Moreover, an increase in serum FFA and inhibition of insulin-signaling pathway in adipocytes may represent an early event in systemic insulin resistance. This mutation provides a genetic model for metabolic syndrome and should facilitate studies of both the pathogenesis and therapy of cardiovascular, renal and metabolic disorders in humans.
Pediatricians, Firearms, and the First Amendment
Authors: Frederick P. Rivara, Mary D. Fan
Journal: JAMA Pediatrics (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Angiogenesis: Affinity-Immobilization of VEGF on Laminin Porous Sponge Enhances Angiogenesis in the Ischemic Brain (Adv. Healthcare Mater. 11/2017)
Authors: Mio Oshikawa, Kei Okada, Naoko Kaneko, Kazunobu Sawamoto, Itsuki Ajioka
Journal: Advanced Healthcare Materials (2017)

Itsuki Ajioka and co-workers report a laminin-sponge (purple) with affinity-immobilized VEGF (yellow), which is an angiogenic growth factor. Neovascularization from existing blood vessels (red) in ischemic brain can potentially prevent the excess death of neurons (cyan) and improve functional recovery. The angiogenic activity of this sponge in vivo in a mouse stroke model is demonstrated in article number 1700183.
Abstract TMEM-118: ROLES OF T-LAK CELL-ORIGINATED KINASE (TOPK) AND THE MICROENVIRONMENT IN DRIVING OVARIAN CANCER PROGRESSION
Authors: Mark A. Eckert, Fabian Coscia, Shawn Pan, Chun-Yi Chiang, Stephanie McGregor, Ricardo Lastra, S. Diane Yamada, Matthias Mann, Ernst Lengyel
Journal: Clinical Cancer Research (2017)

Abstract Ovarian cancer (OvCa) therapy is confounded by late detection and a lack of effective therapeutics. After debulking surgery, most patients initially respond to platinum-based chemotherapeutics, however their tumors inevitably develop resistance and recur. Developing new treatments for OvCa will depend on a thorough understanding of OvCa biology. We recently identified T-LAK cell-originated kinase (TOPK), a serine-threonine kinase, as highly expressed in OvCa. A member of the cancer/testis antigen (CTA) family, TOPK is induced by mutant TP53 and is expressed in early, in situ serous tubal intraepithelial carcinoma lesions. Targeting TOPK with a small-molecule inhibitor in a mouse model of OvCa led to significant reductions in tumor burden. To better understand the interplay between TOPK and the tumor and stroma in ovarian cancer progression, we performed compartment-resolved, quantitative shotgun proteomics on microdissected tumor and stromal samples across a hypothetical progression series of ovarian cancer from in situ STIC to omental metastases. With a highly-sensitive platform, we were able to accurately quantify proteins across the progression series and confirmed expression of known tumor and stromal markers in the data set. Interestingly, we observed a conserved stromal response associated with metastasis. This signature included both genes known to play a role in cancer-associated fibroblasts, as well as proteins with no previously described roles in the tumor stroma. Many components of the signature are also representative of the previously described “mesenchymal” subgroup of ovarian cancer. In vitro and in vivo functional assays have confirmed essential roles for several of these proteins in regulating the cancer-associated fibroblast phenotype. This work establishes TOPK as a potential therapeutic target for ovarian cancer and emphasizes the importance of compartment resolved studies in understanding the individual roles of the tumor and stroma in ovarian cancer progression. Citation Format: Mark A. Eckert, Fabian Coscia, Shawn Pan, Chun-Yi Chiang, Stephanie McGregor, Ricardo Lastra, S. Diane Yamada, Matthias Mann, and Ernst Lengyel. ROLES OF T-LAK CELL-ORIGINATED KINASE (TOPK) AND THE MICROENVIRONMENT IN DRIVING OVARIAN CANCER PROGRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-118.
THE EFFECTS OF A 5-WEEK GOLF SPECIFIC STRENGTH AND CONDITIONING INTERVENTION ON SWING PERFORMANCE FACTORS
Authors: Daisy-May Kenny, Jessica Presnall, Ludmila Cosio-Lima, Eric Greska
Journal: British Journal of Sports Medicine (2017)

Background The effects of golf specific strength and conditioning interventions on performance are scarcely researched. However, a multitude of research exists relative to golf related injuries. From those studies, it has been postulated that an increase in the X-Factor Stretch (XFS) variable increases the probability of a lower back injury. As the XF has been identified as a performance variable, it is of interest to determine how it is influenced by a golf specific intervention. Objective To examine the effects of a 5-week strength and conditioning intervention on golf swing performance factors. Design Quasi-experimental. Setting Laboratory and gym. Participants Nine female NCAA Division II collegiate golfers (age 20.7±2.7 yrs; height 175 ±9.81 cm; body mass 76.5 ±9.2 kg), maintaining a handicap of ≤3. Intervention The 5-week strength and conditioning intervention was implemented to improve the subject's golf swing.The majority of the exercises were lower body orientated, and included rotational aspects. Main Outcome Measurements The pre- and post-testing procedures included a biomechanical analysis using 3D motion analysis. The dependent variables were clubhead velocity (CV; m/s), hip velocity (HV; °/s), XFS angle (°), and ball speed (BS; m/s). It was hypothesized that CV, HV, and BS would increase without an increase in the XFS. T-tests were used to define statistical significance (p&lt;0.05). Results From pre- to post-intervention, subjects significantly increased HV (8.2±0.5°/s to 8.8±0.7°/s; p&lt;0.001), and CV (35.8±0.9 m/s to 36.8±2.5 m/s; p=0.018) and significantly decreased XFS (−54.9±10.2° to −47.9±4.2°; p&lt;0.001). We did not detect a significant change in BS from pre- to post-intervention (52.7±2.8 m/s to 53.2±5.1 m/s). Conclusions It was demonstrated that the intervention increased CV, HV, and BS; but decreased the XFS. Thus, it can be suggested that a golf specific strength and conditioning program can increase golf swing performance factors, without increasing the risk of lower back injury.
Effects of morphine on coronary and left ventricular dynamics in conscious dogs.
Authors: S F Vatner, J D Marsh, J A Swain
Journal: Journal of Clinical Investigation (1975)

We studied the effects of i.v. 2 mg/kg morphine sulfate (MS) on coronary blood flow and resistance, left ventricular (LV) diameter and pressure (P), rate of change of pressure (dP/dt), and dP/dt/P in conscious dogs. An initial transient reduction in coronary vascular resistance, associated with increases in heart rate, dP/dt, dP/dt/P, and reductions in LV end-diastolic and end-systolic size were observed. This was followed by a prolonged increase in mean coronary vascular resistance, lasting from 5 to 30 min, while heart rate, arterial pressure, and LV end-diastolic diameter returned to control levels and dP/dt/P remained slightly but significantly above control. At 10 min, late diastolic coronary flow had fallen from 44 plus or minus 3 ml/min to a minimum level of 25 plus or minus 3 ml/min, while late diastolic coronary resistance had risen from 1.68 plus or minus 0.10 to 3.04 plus or minus 0.28 mm Hg/ml/min. Morphine also induced substantial coronary vasoconstriction when heart rate was held constant. Neither the MS-induced coronary vasoconstriction nor the positive inotropic response was abolished by bilateral adrenalectomy. The positive inotropic response of MS was reversed after beta blockade, but not the coronary vasoconstriction. Alpha receptor blockade abolished the late coronary vasoconstriction effects of morphine, and only dilatation occurred. In anesthetized dogs MS failed to produce late coronary vasoconstriction. Coronary after a respiratory-depressant dose of morphine, 10 mg/kg i.v. Smaller doses of MS, 0.25 mg/kg every 15 min, produced significant coronary vasoconstriction after a total dose of 0.75 mg/kg in the conscious dogs. The effects of morphine may differ in the normal dog and man and may vary depending upon the presence or absence of coronary artery disease. However, in the normal conscious dog, MS elicits a mild beta adrenergic increase in contractility and an important coronary vasoconstrictor effect, which is mediated through alpha adrenergic receptors.