tbuckley/cabot-search huggingface dataset:
Abstract 247: Comparing radiation therapy and ipilimumab to ipilimumab alone in metastatic melanoma patients
Authors: Kirtesh R. Patel, Daniel E. Oliver, Derick Okwan-Dadu, Yuan Liu, Ragini R. Kudchadkar, David H. Lawson, Mohammad K. Khan
Journal: Cancer Research (2015)

Abstract Purpose/Objective: With evidence suggesting ipilimumab and intracranial stereotactic radiosurgery (SRS) improves survival compared to SRS alone, we compared toxicity, response rates (RRs), and outcomes of metastatic melanoma patients receiving radiation (RT) and ipilimumab to ipilimumab alone. Methods and Materials: We reviewed records of metastatic melanoma patients receiving ipilimumab 3mg/kg between 2010-2014. RRs, measured by immune RECIST criteria, and toxicity were compared by Fischer's exact text. Overall survival (OS) was estimated by the Kaplan Meier method. Results: 61 patients received ipilimumab, with 35 (57.4%) also receiving radiation within 4 months of ipilimumab. The radiation cohort was similar at baseline except for greater systemic burden of disease (82.9% vs. 42.3%, p = 0.005), higher dexamethasone use (14.3% vs. 0%, p = 0.048), and more brain involvement (74.3% vs. 0% p&amp;lt;0.001). 92.3% of brain metastases received SRS. Grade 3 toxicity was not statistically different between cohorts (5.9% vs. 20.0%, p = 0.113); one grade 4 was experienced (1.6%), while no grade 5 occurred. While the ipilimumab alone group demonstrated a trend toward higher 1-year OS (49.4% vs. 73.2%, p = 0.090), the cohort did not have any patients with brain metastases; therefore, comparing only patients with extra-cranial metastases, 1-year OS was similar (76.2% vs. 73.2%, p = 0.587). RR between both cohorts was similar (20.0% vs. 11.5%, p = 0.494). Pre-ipilimumab absolute lymphocyte count greater than 1000 was the only significant predictor for increased RR in multivariable analysis (Odds Ratio: 8.56, 95% CI: 1.82-40.42; p = 0.007). Comparing 2-5 fractions of radiation to ipilimumab alone demonstrated a trend towards higher response rate (42.9% vs. 11.5%, p = 0.074). Conclusion: Despite poorer prognostic characteristics in the RT with ipilimumab cohort, toxicity, RR and OS were similar between the arms. Prospective studies investigating the ideal radiation fractionation to improve ipilimumab response rates are warranted. ALC &amp;lt; 1000 should be considered an exclusion criteria for these trials. Citation Format: Kirtesh R. Patel, Daniel E. Oliver, Derick Okwan-Dadu, Yuan Liu, Ragini R. Kudchadkar, David H. Lawson, Mohammad K. Khan. Comparing radiation therapy and ipilimumab to ipilimumab alone in metastatic melanoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 247. doi:10.1158/1538-7445.AM2015-247
Abstract 1864: Selective estrogen receptor degrader (SERD) activity in ESR1 mutant models
Authors: Wei Zhou, Robert A. Blake, Jim Nonomiya, Jing Qian, Lorna Kategaya, Ingrid Wertz, Anneleen Daemen, Thomas O'Brien, John Sensintaffar, Michael Moon, Michelle A. Nannini, Jason Oeh, Deepak Sampath, Xiaojing Wang, Nicholas Smith, Daniel Brigham, James Joseph, Jeffrey H. Hager, Lori S. Friedman
Journal: Cancer Research (2015)

Abstract The majority of breast cancers express and rely on ERα for tumor growth, thus endocrine therapy is the mainstay of ER-positive breast cancer treatment. Despite the effectiveness of current therapies, many patients relapse with tumors still dependent on ER for growth via both estrogen-dependent and estrogen-independent mechanisms. Acquired mutations in ESR1 were recently identified in the ligand-binding domain of ERα in patients who progressed after aromatase inhibitors and tamoxifen. It is estimated that more than 20% of relapsed ER-positive breast cancer patients acquire activating mutations in ESR1. We created a variety of model systems to study the functional consequences of ESR1 mutations. In stable overexpressing cell lines, the mutant ER protein eventually becomes down-regulated, thus we generated cell lines with dox-inducible and CRISPR engineered ESR1 hotspot mutations. We confirmed ligand-independent transcriptional activity of ESR1 hotspot mutations including Y537S and D538G. Cell lines and patient derived xenograft (PDX) models were utilized in ER ChIP-seq studies. Additionally, we investigated therapeutic response and resistance in the context of ESR1 activating mutations for tamoxifen, fulvestrant, and next generation oral SERDs including ARN-810, also known as GDC-0810. ARN-810 is efficacious in MCF7 ESR1 Y537S xenografts and WHIM20 Y537S PDX tumors, indicating that SERDs may be effective for ER mutants. Citation Format: Wei Zhou, Robert A. Blake, Jim Nonomiya, Jing Qian, Lorna Kategaya, Ingrid Wertz, Anneleen Daemen, Thomas O'Brien, John Sensintaffar, Michael Moon, Michelle A. Nannini, Jason Oeh, Deepak Sampath, Xiaojing Wang, Nicholas Smith, Daniel Brigham, James Joseph, Jeffrey H. Hager, Lori S. Friedman. Selective estrogen receptor degrader (SERD) activity in ESR1 mutant models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1864. doi:10.1158/1538-7445.AM2015-1864
Abstract 16376: Increased Affinity of Calmodulin Binding to Cardiac Ryanodine Receptor Corrects the Defective Channel Gating in Failing Hearts
Authors: Akihiro Hino, Masafumi Yano, Masakazu Fukuda, Takeshi Suetomi, Makoto Ono, Xiaojuan Xu, Hitoshi Uchinoumi, Takehisa Susa, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Takeshi Yamamoto, Masunori Matsuzaki
Journal: Circulation (2010)

Calmodulin (CaM) is well known to modulate the channel function of the cardiac ryanodine receptor (RyR2). Here, we investigated the pathogenic role of RyR2-bound CaM on channel dysfunction in heart...
Exercise-Induced Pulmonary Artery Hypertension
Authors: Stephanie Kiencke, Alain Bernheim, Marco Maggiorini, Manuel Fischler, Schlomo V. Aschkenasy, Lorenz Dorschner, Johann Debrunner, Konrad Bloch, Heimo Mairbäurl, Hans Peter Brunner-La Rocca
Journal: Journal of the American College of Cardiology (2008)
Abstract 15789: Cardiac MRI With Adenosine Identifies Coronary Stenosis, Perfusion Defects, and Delayed Enhancement in Pediatric Patients With Anomalous Aortic Origin of a Coronary Artery Before and After Surgical Repair
Authors: Julie A Brothers, Timothy S Kim, Mark A Fogel, Kevin K Whitehead, Stephen A Paridon, Matthew A Harris
Journal: Circulation (2014)

Background: Anomalous aortic origin of a coronary artery (AAOCA) with an interarterial course is associated with sudden cardiac death in children. Objectives: Using cardiac MRI with adenosine, we evaluated coronary ostial stenosis, proximal coronary size, and left ventricular (LV) function in children with AAOCA. Methods: We prospectively enrolled children 5-18 years old with interarterial AAOCA. MRIs were reviewed for coronary artery origin, proximal course, dimensions, and cardiac function. Surgery consisted of the modified unroofing procedure. We used descriptive statistics and paired t-tests to evaluate for statistical significance. Results: Between 2/2009 and 5/2014, 24 subjects with AAOCA underwent 29 MRIs. The majority were male (N=19, 79%) with anomalous right coronary artery (AAORCA, N=20, 83%). Mean age was 12.8 years at time of initial MRI. MRI was performed an average of 7 months post-operatively in 8 subjects who underwent surgery. In all, the proximal anomalous coronary arose tangential to the aorta with an elliptical, slit-like ostium. The anomalous coronary measured smaller proximally (0.20 mm) compared to distally (0.31 mm, P=&lt; 0.0001), and after surgical repair, the post-operative origin was significantly larger (0.36 vs. 0.21 mm, P=0.02). Other abnormalities at initial MRI included fixed inferior wall (N=1) and reversible subendocardial septal/inferior wall (N=1) perfusion defects. Post-operatively, the neo-ostium was round in 6 (see Figure), but in 2, the orifice remained elliptical. One patient had a new small mid-myocardial scar and one had dyskinetic septal wall motion. LV function was normal both before and after surgery (mean ejection fraction =68.1% vs. 67.5%, P=0.85). Conclusions: Cardiac MRI with adenosine is an important tool for the evaluation of anomalous anatomy, myocardial function, and ischemia/injury and should be considered for the initial and, when applicable, post-operative assessment of children with AAOCA.
Abstract 16637: Antioxidant-1, a Novel Cu-Dependent Transcription Factor for NADPH Oxidase p47phox, Promotes Wound Healing by Regulating Inflammation and Angiogenesis
Authors: Archita Das, Gin-Fu Chen, Ha Won Kim, Seock-Won Youn, Sudhahar Varadarajan, Ronald D McKinney, Lydia Finney, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2014)

Background: Wound healing is important repair process after injury associated with inflammation and angiogenesis. Copper (Cu) plays an important role in wound healing and angiogenesis; however, underlying mechanism is unknown. Bioavailability of Cu is tightly controlled by transport proteins (Cu importer CTR1 and Cu exporter ATP7A) and chaperone (antioxidant-1, Atox1) which transfers Cu to ATP7A. We reported that Atox1 also functions as a Cu-dependent transcription factor; however, its role in wound healing is unclear. Results: Using mouse skin puncture model, here we show that, Atox 1 protein (8 fold) and Cu level (by X-ray Fluorescence Microscope; 2.5 fold) increased in skin after wounding in WT mice at day 7 when Atox1 was localised in the nucleus of dermis endothelial cell (ECs) and ATP7A was markedly decreased. ATP7A transgenic mice showed impaired wound healing. Atox1 knockout (KO) mice exhibited decrease in wound repair (40% inhibition vs. WT, day 7) which was rescued by Atox1 gene transfer by lentivirus. Macrophage which secrets angiogenic cytokines/chemokines was significantly reduced which resulted in decreased VEGF and SDF-1α protein and angiogenesis at day 7. In cultured human ECs, inflammatory cytokine TNF-stimulation significantly decreased ATP7A protein (80%) and increased intracellular Cu and Atox1 in nucleus. ATP7A knockdown with siRNA in ECs increased intracellular Cu and promoted nuclear Atox1, which were rescued by Cu importer CTR1 siRNA or Cu chelator BCS, indicating ATP7A downregulation-induced Cu accumulation is required for Atox1 nuclear translocation. By screening Atox1 target genes, we found that NADPH oxidase p47phox promoter contains Atox1 binding responsible element. p47phox protein expression was significantly increased by wounding or overexpression of nuclear-targeted Atox1, which was markedly decreased in Atox1 KO mice with its downstream VCAM1/ICAM1. Conclusions: Cu chaperone Atox1 functions as a transcription factor by sensing ATP7A downregulation-induced intracellular Cu to upregulate NADPH oxidase p47phox and its downstream redox-sensitive VCAM1/ICAM1 expression in response to injury. This in turn promotes inflammatory cell recruitment and angiogenesis, and thus stimulating wound repair.
A tNOX-based protocol for early detection of lung cancer in smokers and non-smokers
Authors: D. James Morre, Heather Hignite, Brandon Hostetler, Nicole McClain, Joseph Juang, David Gilmartin, Matthew P. Miner, Michael Iannuzzi, Dorothy M. Morre
Journal: Clinical Cancer Research (2006)

A26   Four protocols based on proprietary and/or published detection strategies and reagents have been applied to a cohort of 115 subjects comparing patients with diagnosed lung cancer, smokers not diagnosed with lung cancer and healthy individuals. These protocols were based on measurements of levels of tNOX, a pancancer cancer-specific member of the ECTO-NOX family of growth related cell surface quinol (NADH) oxidases with protein disulfide-thiol interchange activity in plasma or serum. Standard ELISA protocols compared two different polycolonal antibodies and a dot blot ELISA protocol utilized a tNOX-specific single chain variable region fragment (scFv) based on a previously developed tNOX-specific monoclonal antibody (scFv) along with 2-D gel separations with detection using the anti-tNOX scFv. The dot blot ELISA values and the 2-D gels were quantified using computer driven algorithms developed by one of us (MPM) to eliminate operator bias. Use of the dot-blot ELISA and standard ELISAs were restricted to sera. The 2-D gel assay was utilized with plasma and sera. Values of two standard deviations greater than the values for healthy individuals were scored as indicating cancer presence. Circulating tNOX as revealed by 2-D gel analysis was regarded as a definitive indication of lung cancer presence. With 25 healthy individuals, the dot blot ELISA, the standard ELISA and 2-D gel results were uniformly negative. With sera from 65 smokers, 7 gave values both by the dot-blot ELISA and the standard ELISA greater than 2 standard deviations above the average for healthy individuals. Both the dot-blot ELISA and the standard ELISA allow for rapid high-throughput screening of sera of smokers or other groups at risk for lung cancer and yield a low incidence of false positives. For samples yielding positive values, tNOX presence, was confirmed using the specific 2-D gel protocol. Sera or plasma from 25 lung cancer patients contained the tNOX protein whereas tNOX was not detected by this method in any healthy individuals comparing the 25 specimens thus far analyzed in parallel by the 2-D gel protocol and more than 200 specimens analyzed for tNOX presence by other methods.
Diaskintest®- screening method in mass examination of the child population for tuberculosis in Russia
Authors: Valentina Aksenova, Nadezhda Klevno, Tatiana Sevostyanova
Journal: European Respiratory Journal (2014)

In Russia there is a new effective way to identify initial presentation of tuberculosis - Diaskintest® ( DST ), which is a combination of two antigens (ESAT / CFP) presented in virulent strains of mycobacterium tuberculosis and absent in the vaccine strain BCG and non-tuberculous mycobacteria. As opposed to QuantiFERON TB and T- SPOT widely used in other countries, DST injected intradermally and causes specific cutireaction of delayed hyperresponsiveness in people with TB infection. Individuals vaccinated with BCG and noninfected by mycobacterium tuberculosis have no reaction to DST.  The aim of the investigation is to study effectiveness of this test alternatively to skin test with PPDL (Mantoux test with 2TE) in conditions of mass screening for tuberculosis.  The investigation included healthy children (7-14 years) and adolescents (15-17 years). Over 44% of them had positive reactions to tuberculin. All children (n = 1238) were examined by the DST. Positive reactions were noted only in 4%. After X-ray examination 7 patients revealed local tuberculous changes. Thus, as a result of examination all school children and teenagers by the DST, identifying of local tuberculosis was 0.56%.  Conclusion. DST has a high specificity using the secretory proteins ESAT-6 and CFP-10. Introduction into medical practice of new method of tuberculosis diagnosis as a screening method of children examination will allows sharply improve the quality of tuberculosis infection diagnosis, reduce material costs for tuberculosis detection in children and improve the epidemiological situation of tuberculosis in general.
Catecholamines and Neurologic Diseases
Authors: Michael A. Moskowitz, Richard J. Wurtman
Journal: New England Journal of Medicine (1975)

Evidence Relating Brain Catecholamines to Specific Neurologic DiseasesParkinson's DiseaseThe role of catecholamines in Parkinson's disease has been examined more extensively than in any other neurologic disorder. Since several excellent reviews have previously been published on this relation,9,58 59 60 the following discussion provides only a brief outline of the varieties of evidence implicating catecholamines in the pathogenesis of Parkinson's disease. Striatal dopamine content in the postencephalitic, senile-arteriosclerotic, and idiopathic forms of Parkinson's disease is decreased in approximate proportion to the cell loss in the pars compacta of the substantia nigra, and to the akinesia observed premortem. . . .
Abstract 3939: Urine 8-hydroxy-2'-deoxyguanosine as a New Biomarker of Inflammatory Activity in Patients With Cardiac Sarcoidosis
Authors: Takeo Tanaka, Shigeki Kobayashi, Takehisa Susa, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Tomoko Nao, Yasuhiro Yoshiga, Jyutaro Yamada, Syuji Kawamura, Masafumi Yano, Masunori Matsuzaki
Journal: Circulation (2009)

Background: Enhanced production of reactive oxygen species, capable of reducing endogenous defense levels and enhancing inflammation, is suggested to play a crucial role in the pathogenesis of cardiac sarcoidosis (SAR). Here, we investigated whether or not the level of urinary 8-hydroxy-2′-deoxyguanosine (u-8-OHdG), a marker of oxidative DNA damage, correlates with inflammatory activity in SAR. Methods: In a preliminary study, blood sampling from both coronary sinus and artery showed that cardiac tissue produced 8-OHdG in dilated cardiomyopathy (DCM) and SAR. We measured u-8-OHdG in 30 control subjects, 25 patients with DCM (NYHA I/II: 90%, LVEF: 27±15%) and 25 patients with SAR (NYHA I/II: 90%, LVEF: 28±12%). All patients with SAR underwent 18F-FDG PET/CT or 67Ga scintigraphy to evaluate inflammation status for dividing active SAR (n=12) and non-active SAR (n=13). Then, levels of u-8-OHdG were compared between control and all SAR groups as well as between the subgroups of patients with active and non-act...
12 month follow up of emphysema patients treated with endobronchial valves - temporary symptomatic relief
Authors: Simone Boedecker, Thomas Hochgreef, Sabine Grönke, Konrad Frank
Journal: European Respiratory Journal (2014)

In recent years, much effort has been spent in finding non medical therapies for patients with severe emphysema. One way to achieve lung volume reduction are Zephyr®-endobronchial valves.  16 patients were treated with endobronchial valves in unilobular manner. The patients were treated with a median of 5 ± 1 valves per patient. To verify the effectiveness of this treatment, a follow up after 1, 3 ,6 ,9 and 12 months was performed. The follow up included repeating the St. George Respiratory Questionnaire (SGRQ), the 6 Minute-Walk-Test (6-MWT) and pulmonary function test.  In the first follow ups, an improvement in quality of live was observed (SGRQ: total: pre 69.9±3.2 vs. 3-month 63.4±6.6 vs. 6-month 56.4±4.0; activity: pre 87.8±2.7 vs. 3-month 76.8±4.5 vs. 6-month 64.7±1.3; symptoms: pre 75.1±3.3 vs. 3-Mo 75.7±5.7 vs. 6-month 71.3±7.1). Exercise capacity improved as well ( +28% after 1 month, +34% after 3 month, +38% after 6 month).  The initial improvement could no longer be observed after 9 and 12 months. In particular, the symptoms score of SGRQ increased again, while activity scores remained stable (SGRQ total: 12 month 75.9±8.8; symptoms: 12 month 84.5±6.1). Furthermore, initial improvement of the exercise capacity was particularly reversed related to 6 month results: +10% after 9 month and 9% after 12 months. Adverse events after implantation were pneumothorax (n=1), hemoptysis (n=1) and exacerbation (n=4).  Endobronchial valves appear to be a promising treatment for patients with severe emphysema. Improvement in quality of live and exercise capacity could be achieved at least temporarily. However, long term outcome needs additional investigation.
Lesson of the Week: Don't twist my child's head off: iatrogenic cervical dislocation
Authors: A T H Casey, M O'Brien, V Kumar, R D Hayward, H A Crockard
Journal: BMJ (1995)

Excessive rotation of two children's necks while they were undergoing cervical lymph node biopsy probably resulted in their dislocation; delayed diagnosis necessitated complex spinal surgery to correct the deformity. “Wry” neck, a synonym for atlantoaxial rotary subluxation, is a relatively common condition in young children often associated with tonsillitis. It usually resolves spontaneously,1 because the joint surfaces remain in contact. A rotation injury is another possible cause, often following an apparently minor trauma such as heading a football. Iatrogenic torticollis is rarely reported. A complete dislocation of the atlantoaxial joint will not resolve spontaneously and may have important long term effects on the child's facial development. We have treated two otherwise normal children whose necks were dislocated under general anaesthesia while they were undergoing cervical lymph node biopsy. The injury was not appreciated at once and definitive treatment was inevitably delayed.



A 10 year old girl underwent lymph node biopsy from the posterior triangle of her neck. After surgery she awoke with a torticollis, a painful neck, and occipital dysaesthesiae. These symptoms ultimately subsided on conservative treatment but the torticollis persisted. Radiography at that stage showed …
Regulation of Intracellular Iron Metabolism in Human Erythroid Precursors by Internalized Extracellular Ferritin
Authors: E.G. Meyron-Holtz, B. Vaisman, Z.I. Cabantchik, E. Fibach, T.A. Rouault, C. Hershko, A.M. Konijn
Journal: Blood (1999)