tbuckley/cabot-search huggingface dataset:
Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas
Authors: Jennifer Barrow, Martyna Adamowicz-Brice, Maria Cartmill, Donald MacArthur, James Lowe, Keith Robson, Marie-Anne Brundler, David A. Walker, Beth Coyle, Richard Grundy
Journal: Neuro-Oncology (2010)

Overall, pediatric high-grade glioma (pHGG) has a poor prognosis, in part due to the lack of understanding of the underlying biology. High-resolution 244 K oligo array comparative genomic hybridization (CGH) was used to analyze DNA from 38 formalin-fixed paraffin-embedded predominantly pretreatment pHGG samples, including 13 diffuse intrinsic pontine gliomas (DIPGs). The patterns of gains and losses were distinct from those seen in HGG arising in adults. In particular, we found 1q gain in up to 27% of our cohort compared with 9% reported in adults. A total of 13% had a balanced genetic profile with no large-scale copy number alterations. Homozygous loss at 8p12 was seen in 6 of 38 (16%) cases of pHGG. This novel deletion, which includes the ADAM3A gene, was confirmed by quantitative real-time PCR (qPCR). Loss of CDKN2A/CDKN2B in 4 of 38 (10%) samples by oligo array CGH was confirmed by fluorescent in situ hybridization on tissue microarrays and was restricted to supratentorial tumors. Only ∼50% of supratentorial tumors were positive for CDKN2B expression by immunohistochemistry (IHC), while ∼75% of infratentorial tumors were positive for CDKN2B expression (P = 0.03). Amplification of the 4q11–13 region was detected in 8% of cases and included PDGFRA and KIT, and subsequent qPCR analysis was consistent with the amplification of PDGFRA. MYCN amplification was seen in 5% of samples being significantly associated with anaplastic astrocytomas (P= 0.03). Overall, DIPG shared similar spectrum of changes to supratentorial HGG with some notable differences, including high-frequency loss of 17p and 14q and lack of CDKN2A/CDKN2B deletion. Informative genetic data providing insight into the underlying biology and potential therapeutic possibilities can be generated from archival tissue and typically small biopsies from DIPG. Our findings highlight the importance of obtaining pretreatment samples.
IgH sequences in common variable immune deficiency reveal altered B cell development and selection
Authors: Krishna M. Roskin, Noa Simchoni, Yi Liu, Ji-Yeun Lee, Katie Seo, Ramona A. Hoh, Tho Pham, Joon H. Park, David Furman, Cornelia L. Dekker, Mark M. Davis, Judith A. James, Kari C. Nadeau, Charlotte Cunningham-Rundles, Scott D. Boyd
Journal: Science Translational Medicine (2015)

Deep sequence analysis of the IgH repertoires of common variable immune deficiency patients highlights phenotypic features of the disorder and potential disease mechanisms.
Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial
Authors: Michaela Diamant, Luc Van Gaal, Bruno Guerci, Stephen Stranks, Jenny Han, Jaret Malloy, Marilyn K Boardman, Michael E Trautmann
Journal: The Lancet Diabetes & Endocrinology (2014)
Integration of gefitinib (G), into a concurrent chemoradiation (CRT) regimen followed by G adjuvant therapy in patients with locally advanced head and neck cancer (HNC) - a Phase II Trial
Authors: E. E. W. Cohen, D. J. Haraf, K. M. Stenson, E. Blair, B. E. Brockstein, A. M. Mauer, A. Dekker, R. Williams, E. Lester, E. E. Vokes
Journal: Journal of Clinical Oncology (2005)

5506 Background: This study was undertaken to evaluate the tolerability and efficacy of substituting G for paclitaxel into a well-described CRT regimen (Clin Cancer Res 9: 5936; JCO 21: 320) and then continuing G as adjuvant therapy. Endpoints included complete response (CR) rate to CRT, progression-free and overall survival, and local and distant control rates. Methods: Previously untreated subjects with stage III, IVa, or IVb HNC were enrolled and were required to have squamous cell or poorly differentiated carcinomas, or lymphoepithelioma. Organ sparing prior surgical therapy was allowed. Subjects received 2 cycles of induction chemotherapy (carboplatin and paclitaxel) followed by CRT consisting of G (250mg PO OD), 5FU, hydroxyurea, and twice daily radiation on a week on/week off schedule repeated every 14 days. G (250mg PO OD) was continued for at total of 2 years from the start of CRT. Results: From 2/03 to 10/04, 69 subjects were accrued. Characteristics included 52 males; median age 55; ECOG performance status 0 in 49, 1 in 19, and 2 in 1; and stage IV disease in 63 (91%). With a current median follow-up of 294 days and 42 subjects evaluable for response to CRT we have observed 37 CR (88%). Non-evaluable subjects withdrew consent and never received G (3), underwent surgery prior to CRT (6), expired prior to evaluation (2), or have not yet been evaluated (16). Thus far there have been 2 subjects with progressive disease (1 distant and 1 local) and four deaths (1 disease progression, 1 Listeria sepsis, 1 cardiac failure, 1 post-op complication). Grade 3 and 4 toxicity has been consistent with previous CRT or single-agent G trials, including mucositis (73% and 10%), radiation dermatitis (29% and 2%), pustulo-papular rash (6% and 0%), and diarrhea (2% and 0%). 80% of eligible subjects continue to adhere to maintenance G therapy. Conclusions: The addition of G to concurrent CRT after induction chemotherapy and its administration as adjuvant therapy appears tolerable and feasible. High rates of CR and few recurrences seen thus far suggest that this is a promising regimen for patients with locally advanced HNC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer AstraZeneca, Bristol-Myers Squibb
Under-use of the Ross operation—a lost opportunity
Authors: Magdi H Yacoub, Ismail El-Hamamsy, Hans-Hinrich Sievers, Blase A Carabello, Robert O Bonow, Paul Stelzer, Francisco D A da Costa, Hans J Schäfers, Peter Skillington, Efstratios I Charitos, Giovanni Battista Luciani, Johanna J M Takkenberg
Journal: The Lancet (2014)
Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis.
Authors: B H Strauss, R J Chisholm, F W Keeley, A I Gotlieb, R A Logan, P W Armstrong
Journal: Circulation Research (1994)

Remodeling of the vessel wall after balloon angioplasty injury is incompletely understood, and in particular, the role of extracellular matrix synthesis in restenosis has received little attention. The objective of the present study was to determine the sequence of changes in collagen, elastin, and proteoglycan synthesis and content after balloon injury and to relate these changes to growth of the intimal lesions and extent of cell proliferation. In a double-injury non-cholesterol-fed model, right iliac arterial lesions in 43 rabbits were treated with balloon angioplasty, and the rabbits were killed at five time points ranging from immediate to 12 weeks. Vessel wall collagen and elastin content and synthesis were measured after incubation with 14C-proline and separation with a cyanogen bromide extraction procedure. Sulfated glycosaminoglycan synthesis was measured after incubation with [35S]sulfate, papain digestion, and ethanol precipitation. Continuous in vivo infusion of bromodeoxyuridine (96 hours) was used to assess cell proliferation. The intimal area significantly increased from 0.27 +/- 0.08 to 0.73 +/- 0.11 mm2 between 0 and 12 weeks. Intimal and medial cell proliferation were modest and peaked at 1 week (labeling indexes of 4.8% and 3.0%, respectively) and then markedly declined by 2 weeks. Significant increases in collagen, elastin, and proteoglycan synthesis, up to 4 to 10 times above control nondamaged contralateral iliac arteries, were noted at 1, 2, and 4 weeks. These increases in synthesis were accompanied by significant increases in collagen and elastin content (by approximately 35%) that coincided with the temporal increase in cross-sectional area.(ABSTRACT TRUNCATED AT 250 WORDS)
The Mentally Retarded in Penal and Correctional Institutions
Authors: BERTRAM S. BROWN, THOMAS F. COURTLESS
Journal: American Journal of Psychiatry (1968)

Rapidly expanding interest in the many facets of mental retardation has not, until recently, included the varied problems posed by mentally retarded offenders. The authors report on the results of a nationwide survey to determine the extent of retardation in prison populations, the criminal offenses committed by retardates, and the problems encountered by those responsible for dealing with the incarcerated retardate. An intensive case study also revealed significant data regarding crimino-legal issues and problems.
Potentiation of the Effect of Erlotinib by Genistein in Pancreatic Cancer: The Role of Akt and Nuclear Factor-κB
Authors: Basil F. El-Rayes, Shadan Ali, Ifrah F. Ali, Philip A. Philip, James Abbruzzese, Fazlul H. Sarkar
Journal: Cancer Research (2006)

Abstract The epidermal growth factor receptor (EGFR) is a target of new therapies in most nonhematologic cancers. EGFR blockade alone may not be sufficient for the control of growth and invasion of human pancreas cancer because of the independent activation of Akt and nuclear factor-κB (NF-κB). The expression of EGFR, Akt, and NF-κB was determined in six human pancreatic cancer cell lines. Selected cells for specific expression were treated with erlotinib, genistein, gemcitabine, or the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. EGFR, phosphorylated EGFR, phosphorylated Akt, and survivin expressions were determined by immunoblotting. Electrophoretic mobility shift assay was used to evaluate the DNA binding activity of NF-κB. Genistein significantly increased (P &amp;lt; 0.05) erlotinib-induced growth inhibition and apoptosis in BxPC-3, CAPAN-2, and AsPC-1 cells. In the BxPC-3 cell line, significant down-regulation of EGFR, phosphorylated Akt, NF-κB activation, and survivin was observed in the cells treated with the combination compared with the erlotinib-treated cells. In the HPAC and MIAPaCa cell line, no potentiation of the effects of erlotinib by genistein on cell growth or inhibition of the EGFR/Akt/NF-κB was observed. Genistein potentiated growth inhibition and apoptosis of the gemcitabine and erlotinib combination in COLO-357 cell line. Genistein potentiates the growth inhibition and apoptosis induced by erlotinib and gemcitabine in certain pancreatic cancer cells. Akt and NF-κB inhibition represents one of the mechanisms for the potentiation of erlotinib- and gemcitabine-induced cell death by genistein. (Cancer Res 2006; 66(21): 10553-9)
Adenosine A <sub>1</sub> Stimulation Activates δ-Protein Kinase C in Rat Ventricular Myocytes
Authors: Patrick Henry, Sophie Demolombe, Michel Pucéat, Denis Escande
Journal: Circulation Research (1996)

Abstract By making use of immunoblotting and immunocytochemical analysis, we explored whether stimulation of adenosine A 1 receptors would promote the activation of δ-protein kinase C (δ-PKC) immunolabeled with a polyclonal antibody. Immunoblot analysis of Triton X-100–soluble cell membrane and cytosolic fractions revealed the presence of a specific 75-kD band reactive to the δ-PKC polyclonal antibody. In freshly isolated rat cardiac myocytes, 28% of the total immunoreactive δ-PKC was associated with the membrane fraction, whereas 72% was associated with the soluble fraction. Under stimulation with the tumor-promoting phorbol 12-myristate 13-acetate (PMA, 500 nmol/L) used as a positive control, δ-PKC translocated to the cell membrane, with the membrane fraction representing 88% and the cytosolic fraction representing 12% of the total immunoreactive δ-PKC. Transverse optical sections performed with confocal laser microscopy showed that immunostaining with anti–δ-PKC antibody was distributed in the cytosol of unstimulated cells but accumulated in the cell membrane under PMA stimulation. In the membrane fraction of cells pretreated with adenosine (100 μmol/L) or with the adenosine A 1 agonist (−)- N 6 -(2-phenylisopropyl)-adenosine (R-PIA, 1 μmol/L), the 75-kD band corresponding to δ-PKC increased by 57% and 66%, respectively, when compared with nonstimulated cells processed under the same experimental conditions. In cells exposed to either of the purine agonists, specific fluorescence staining decorated the cell membrane, a pattern that was not observed in control cells. Activation of membrane δ-PKC produced either by adenosine itself or by its analogue R-PIA was fully antagonized by the specific A 1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (1 μmol/L). From these data, we conclude that adenosine A 1 stimulation activates δ-PKC in freshly isolated rat ventricular myocytes.
Alarmin IL-33 Acts as an Immunoadjuvant to Enhance Antigen-Specific Tumor Immunity
Authors: Daniel O. Villarreal, Megan C. Wise, Jewell N. Walters, Emma L. Reuschel, Min Joung Choi, Nyamekye Obeng-Adjei, Jian Yan, Matthew P. Morrow, David B. Weiner
Journal: Cancer Research (2014)

Studies of interleukin (IL)-33 reveal a number of pleiotropic properties. Here, we report that IL-33 has immunoadjuvant effects in a human papilloma virus (HPV)-associated model for cancer immunotherapy where cell-mediated immunity is critical for protection. Two biologically active isoforms of IL-33 exist that are full-length or mature, but the ability of either isoform to function as a vaccine adjuvant that influences CD4 T helper 1 or CD8 T-cell immune responses is not defined. We showed that both IL-33 isoforms are capable of enhancing potent antigen-specific effector and memory T-cell immunity in vivo in a DNA vaccine setting. In addition, although both IL-33 isoforms drove robust IFN-γ responses, neither elevated secretion of IL-4 or immunoglobulin E levels. Further, both isoforms augmented vaccine-induced antigen-specific polyfunctional CD4(+) and CD8(+) T-cell responses, with a large proportion of CD8(+) T cells undergoing plurifunctional cytolytic degranulation. Therapeutic studies indicated that vaccination with either IL-33 isoform in conjunction with an HPV DNA vaccine caused rapid and complete regressions in vivo. Moreover, IL-33 could expand the magnitude of antigen-specific CD8(+) T-cell responses and elicit effector-memory CD8(+) T cells. Taken together, our results support the development of these IL-33 isoforms as immunoadjuvants in vaccinations against pathogens, including in the context of antitumor immunotherapy.
Regulation of brain-derived neurotrophic factor (BDNF) during sleep apnoea treatment
Authors: R Staats
Journal: Thorax (2005)

<b>Background:</b> Patients with obstructive sleep apnoea syndrome (OSAS) often display persistent cognitive dysfunction despite effective treatment with continuous positive airway pressure (CPAP). Brain-derived neurotrophic factor (BDNF) is a key mediator of memory and cognition, but its regulation in OSAS and during CPAP treatment is unknown. <b>Methods:</b> Serum and plasma BDNF concentrations, BDNF secretion by peripheral blood mononuclear cells, and overnight polysomnography were evaluated in 17 men with newly diagnosed OSAS (as defined by a respiratory disturbance index of &gt;10/hour with &gt;70% obstructive events and corresponding daytime symptoms) and 12 healthy control men. In the patients all the parameters were monitored after 1 night and 3 months of CPAP treatment. <b>Results:</b> There was no significant difference in baseline serum BDNF, plasma BDNF, or spontaneous BDNF secretion by peripheral blood mononuclear cells between untreated patients and controls. After 1 night of CPAP treatment there was a steep fall in median serum BDNF (from 18.0 ng/ml to 4.1 ng/ml) and plasma BDNF (from 58.7 pg/ml to 22.0 pg/ml) concentrations. Following 3 months of treatment BDNF concentrations did not return to baseline. In contrast, BDNF secretion was not suppressed by CPAP treatment. <b>Conclusions:</b> Patients with untreated OSAS have normal serum and plasma BDNF levels. CPAP treatment is associated with a rapid decrease in serum and plasma BDNF levels which may reflect enhanced neuronal demand for BDNF in this condition.
Sequential Increases in Proliferating Cell Nuclear Antigen Expression in Head and Neck Tumorigenesis: A Potential Biomarker
Authors: D. M. Shin, N. Voravud, J. Y. Ro, J. S. Lee, W. K. Hong, W. N. Hittelman
Journal: JNCI Journal of the National Cancer Institute (1993)

Proliferating cell nuclear antigen (PCNA) is a 36-kd nuclear protein whose expression is associated with DNA synthesis and cell proliferation. Tumorigenesis in head and neck squamous cell carcinoma is proposed to be a multistep process; dysregulation of proliferation is a potential marker of this process. Purpose : PCNA dysregulation was analyzed in squamous cell carcinoma tissue samples containing premalignant lesions (hyperplasia and/or dysplasia) and in adjacent normal epithelium to better understand proliferative changes during head and neck tumor development. Methods : Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded sections by using a monoclonal anti-PCNA antibody. PCNA expression was analyzed in 33 head and neck squamous cell carcinomas and in their adjacent premalignant lesions from different sites and compared with that in the control samples, which had never been exposed to first-hand tobacco smoke. PCNA expression was assessed by semiquantitative scoring (scale 0–3) in three epithelial layers (basal, parabasal, and superficial). The labeling index and the weighted mean index of PCNA expression were calculated. Results : Normal epithelium adjacent to the tumor had much more proliferative activity than the controls: The weighted mean index of PCNA expression was fourfold higher in the basal layer and sixfold higher in the parabasal layer. PCNA expression increased as tissues progressed from adjacent normal epithelium to hyperplasia ( P <.001), hyperplasia to dysplasia ( P <.001), and dysplasia to squamous cell carcinoma ( P = .065); the total increase in PCNA expression ranged from fourfold to 10fold from adjacent normal epithelium to squamous cell carcinoma. PCNA expression was higher in the parabasal than in the basal layer at all premalignant stages (23 of 25 samples in adjacent normal epithelium, 12 of 13 in hyperplasia, and 17 of 22 in dysplasia). As the tissue progressed from normal through premalignant stages to squamous cell carcinomas, we observed not only incremental increases in the labeling index, but also incremental increases in PCNA expression per labeled cells. Conclusions : These results indicate that PCNA could be a useful biomarker for multistep carcinogenesis in head and neck cancer and may serve as an intermediate end point in chemopreventive trials. [J Natl Cancer Inst 85: 971–978, 1993]
Cutis Verticis Gyrata in Association With Vemurafenib and Whole-Brain Radiotherapy
Authors: James J. Harding, Christopher A. Barker, Richard D. Carvajal, Jedd D. Wolchok, Paul B. Chapman, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2014)

Vemurafenib and Whole-Brain Radiotherapy Case Report 1A 33-year-old man presented to an outside hospital with a 2-month history of lower back pain, fever, chills, and anorexia.Physical examination revealed subcutaneous nodules on the chest, abdomen, and back.Cross-sectional imaging demonstrated multiple masses throughout the paraspinal tissue, vertebrae, liver, and subcutis.A magnetic resonance imaging scan of the brain showed four brain metastases ranging from 2 to 12 mm in size.An excisional biopsy of a subcutaneous lesion revealed metastatic melanoma characterized by a BRAF V600E mutation.
Pollen‐derived adenosine is a necessary cofactor for ragweed allergy
Authors: M. Wimmer, F. Alessandrini, S. Gilles, U. Frank, S. Oeder, M. Hauser, J. Ring, F. Ferreira, D. Ernst, J. B. Winkler, P. Schmitt‐Kopplin, C. Ohnmacht, H. Behrendt, C. Schmidt‐Weber, C. Traidl‐Hoffmann, J. Gutermuth
Journal: Allergy (2015)

Abstract Background Ragweed ( Ambrosia artemisiifolia ) is a strong elicitor of allergic airway inflammation with worldwide increasing prevalence. Various components of ragweed pollen are thought to play a role in the development of allergic responses. The aim of this study was to identify critical factors for allergenicity of ragweed pollen in a physiological model of allergic airway inflammation. Methods Aqueous ragweed pollen extract, the low molecular weight fraction or the major allergen Amb a 1 was instilled intranasally on 1–11 consecutive days, and allergic airway inflammation was evaluated by bronchoalveolar lavage, lung histology, serology, gene expression in lung tissue, and measurement of lung function. Pollen‐derived adenosine was removed from the extract enzymatically to analyze its role in ragweed‐induced allergy. Migration of human neutrophils and eosinophils toward supernatants of ragweed‐stimulated bronchial epithelial cells was analyzed. Results Instillation of ragweed pollen extract, but not of the major allergen or the low molecular weight fraction, induced specific IgG 1 , pulmonary infiltration with inflammatory cells, a Th2‐associated cytokine signature in pulmonary tissue, and impaired lung function. Adenosine aggravated ragweed‐induced allergic lung inflammation. In vitro , human neutrophils and eosinophils migrated toward supernatants of bronchial epithelial cells stimulated with ragweed extract only if adenosine was present. Conclusions Pollen‐derived adenosine is a critical factor in ragweed‐pollen‐induced allergic airway inflammation. Future studies aim at therapeutic strategies to control these allergen‐independent pathways.
Diabetes Mellitus Worsens Diastolic Left Ventricular Dysfunction in Aortic Stenosis Through Altered Myocardial Structure and Cardiomyocyte Stiffness
Authors: Inês Falcão-Pires, Nazha Hamdani, Attila Borbély, Cristina Gavina, Casper G. Schalkwijk, Jolanda van der Velden, Loek van Heerebeek, Ger J.M. Stienen, Hans W.M. Niessen, Adelino F. Leite-Moreira, Walter J. Paulus
Journal: Circulation (2011)

Background— Aortic stenosis (AS) and diabetes mellitus (DM) are frequent comorbidities in aging populations. In heart failure, DM worsens diastolic left ventricular (LV) dysfunction, thereby adversely affecting symptoms and prognosis. Effects of DM on diastolic LV function were therefore assessed in aortic stenosis, and underlying myocardial mechanisms were identified. Methods and Results— Patients referred for aortic valve replacement were subdivided into patients with AS and no DM (AS; n=46) and patients with AS and DM (AS-DM; n=16). Preoperative Doppler echocardiography and hemodynamics were implemented with perioperative LV biopsies. Histomorphometry and immunohistochemistry quantified myocardial collagen volume fraction and myocardial advanced glycation end product deposition. Isolated cardiomyocytes were stretched to 2.2-μm sarcomere length to measure resting tension (F passive ). Expression and phosphorylation of titin isoforms were analyzed with gel electrophoresis with ProQ Diamond and SYPRO Ruby stains. Reduced LV end-diastolic distensibility in AS-DM was evident from higher LV end-diastolic pressure (21±1 mm Hg for AS versus 28±4 mm Hg for AS-DM; P =0.04) at comparable LV end-diastolic volume index and attributed to higher myocardial collagen volume fraction (AS, 12.9±1.1% versus AS-DM, 18.2±2.6%; P &lt;0.001), more advanced glycation end product deposition in arterioles, venules, and capillaries (AS, 14.4±2.1 score per 1 mm 2 versus AS-DM, 31.4±6.1 score per 1 mm 2 ; P =0.03), and higher F passive (AS, 3.5±1.7 kN/m 2 versus AS-DM, 5.1±0.7 kN/m 2 ; P =0.04). Significant hypophosphorylation of the stiff N2B titin isoform in AS-DM explained the higher F passive and normalization of F passive after in vitro treatment with protein kinase A. Conclusions— Worse diastolic LV dysfunction in AS-DM predisposes to heart failure and results from more myocardial fibrosis, more intramyocardial vascular advanced glycation end product deposition, and higher cardiomyocyte F passive , which was related to hypophosphorylation of the N2B titin isoform.