tbuckley/cabot-search huggingface dataset:
Relationship Between Hypoglycemic Episodes and Ventricular Arrhythmias in Patients With Type 2 Diabetes and Cardiovascular Diseases: Silent Hypoglycemias and Silent Arrhythmias
Authors: Annett Stahn, Frank Pistrosch, Xenia Ganz, Madlen Teige, Carsta Koehler, Stefan Bornstein, Markolf Hanefeld
Journal: Diabetes Care (2013)

In patients with type 2 diabetes and cardiovascular diseases (CVDs), intensive treatment with insulin and/or sulfonylurea (SU) may be associated with excessive increased risk of hypoglycemic episodes. To evaluate the risk of critical arrhythmias related to glycemic variability, we carried out an observational study in type 2 diabetes patients with CVD.Thirty patients with type 2 diabetes and documented CVD who had been treated with insulin and/or SU underwent 5 days of monitoring with a continuous glucose measurement system along with parallel electrocardiogram recording for monitoring of ventricular arrhythmias. Twelve age-matched patients with documented CVD who received treatment with metformin and/or dipeptidyl peptidase-4 inhibitor served as the control group. Patients were receiving stable treatment, and were instructed to notice symptoms of arrhythmias and hypoglycemia, respectively.We observed a high incidence of asymptomatic severe episodes of hypoglycemia (<3.1 mmol/L) in patients receiving treatment with insulin and/or SU, whereas severe hypoglycemia did not develop in any of the control subjects. Patients with severe hypoglycemia (n = 12) had a higher number of severe ventricular arrhythmias (patients with versus without severe hypoglycemia, respectively: ventricular couplets 41.7 ± 81.8 vs. 5.5 ± 16.7; ventricular tachycardia 1.0 ± 1.9 vs. 0.1 ± 0.3). No direct correlation could be found among different variables of glucose profile, corrected QT interval, and ventricular arrhythmias.Our results suggest that severe episodes of hypoglycemia are associated with an increased risk of severe ventricular arrhythmias.
A cloned major histocompatibility complex-restricted trinitrophenyl-reactive human helper T cell line that activates B cell subsets via two distinct pathways.
Authors: M A Principato, G S Thompson, S M Friedman
Journal: The Journal of Experimental Medicine (1983)

A cloned, trinitrophenyl (TNP)-specific helper T cell line (TCL), termed E-11, has been established in long-term, interleukin 2-dependent culture and used to study human T helper (Th)-B cell collaboration. Co-culture of E-11 with TNP-modified, but not unmodified or FITC-modified, autologous B cells results in a vigorous, polyclonally plaque-forming cell (PFC) response. E-11 helper activity is not constitutive, but requires antigen-specific, major histocompatibility complex-restricted activation of the TCL cells by interaction with TNP-modified autologous or DR 5+ allogeneic macrophages. Using B cell subsets isolated by discontinuous density gradient cengrifugation as responder populations, we determined that E-11 activates B cell subsets via two distinct mechanisms: (a) E-11 polyclonally activates large B cells in an unrestricted and nonspecific manner; and (b) E-11 preferentially induces a PFC response by TNP-modified small B cells. These results suggest that the large B cell subset is activated by helper signals generated during the Th-antigen-presenting cell interaction, while small B cells require an additional stimulus that is provided by antigen-specific Th-B cell contact.
Concanavalin A potentiates syngeneic response in murine lymphocytes.
Authors: K Ozato, J D Ebert
Journal: The Journal of Experimental Medicine (1976)

In an attempt to modulate the recognition processes that occur on lymphocyte membranes in mixed lymphocyte culture, responding cortisone resistant thymocytes or stimulating spleen cells (treated with mitomycin C) were pretreated with native concanavalin A (N-Con A) or succinyl-Con A (S-Con A). Highly significant cell proliferation was observed in syngeneic combinations when either the responding cells or the stimulating cells were so treated with Con A, although Con A pretreatment alone was never mitogenic. In allogeneic combinations the proliferative response with Con A pretreatment of either partner on day 3 was five to seven times higher than in the normal mixed lymphocyte reactions. The triggering of proliferation was dependent on two factors: (a) The presence of spleen cells as the stimulating cells (thymocytes were much less effective). (b) The binding of Con A molecules to either one of the partners, the effect being abrogated by the specific inhibitor of Con A, alpha-mannopyranoside. The optimal concentration of S-Con A was about twice that of N-Con A. Even more striking was the observation that cultures in which either one of the partners was pretreated with Con A in allogeneic combinations showed a strong suppression (60-80% inhibition) in the subsequent generation of the cytotoxic lymphocytes (CL). The Con A concentration required to trigger a proliferative response corresponded to that for suppressing the generation of CL. Con A pretreatment did not result in a cytotoxic activity toward syngeneic tumor cells.
Pulmonary manifestation of systemic mast cell disease
Authors: M. Schmidt, C. Dercken, O. Loke, S Reimann, S Diederich, S Blasius, S. Heidenreich
Journal: European Respiratory Journal (2000)

Systemic mast cell disease is a rare disease of unknown aetiology. Systemic infiltration and proliferation of mast cells in skin, bone marrow, gastrointestinum and lymph nodes is the central pathological feature. This study reports a patient with mastocytosis of the skin (urticaria pigmentosa) for 10 yrs. The patient was referred to hospital for dyspnoea. Chest radiograph showed moderate reticular infiltration of both lungs, computerized tomography revealed multiple lymph nodes of the mediastinum and faint nodular lesions of middle and upper areas of lungs. Transbronchial biopsy demonstrated mast cell infiltration of the lung with formation of mast cell granuloma. According to the current literature, systemic mast cell disease with pulmonary involvement is a very rare entity. After a treatment with interferon alpha-2a over 6 months, the patient9s condition and particularly dyspnoea showed improvement in parallel with an amelioration of the lesions as demonstrated by thorax computed tomography.
Gene Expression Profiles in Peripheral Blood Mononuclear Cells Can Distinguish Patients with Non–Small Cell Lung Cancer from Patients with Nonmalignant Lung Disease
Authors: Michael K. Showe, Anil Vachani, Andrew V. Kossenkov, Malik Yousef, Calen Nichols, Elena V. Nikonova, Celia Chang, John Kucharczuk, Bao Tran, Elliot Wakeam, Ting An Yie, David Speicher, William N. Rom, Steven Albelda, Louise C. Showe
Journal: Cancer Research (2009)

Early diagnosis of lung cancer followed by surgery presently is the most effective treatment for non-small cell lung cancer (NSCLC). An accurate, minimally invasive test that could detect early disease would permit timely intervention and potentially reduce mortality. Recent studies have shown that the peripheral blood can carry information related to the presence of disease, including prognostic information and information on therapeutic response. We have analyzed gene expression in peripheral blood mononuclear cell samples including 137 patients with NSCLC tumors and 91 patient controls with nonmalignant lung conditions, including histologically diagnosed benign nodules. Subjects were primarily smokers and former smokers. We have identified a 29-gene signature that separates these two patient classes with 86% accuracy (91% sensitivity, 80% specificity). Accuracy in an independent validation set, including samples from a new location, was 78% (sensitivity of 76% and specificity of 82%). An analysis of this NSCLC gene signature in 18 NSCLCs taken presurgery, with matched samples from 2 to 5 months postsurgery, showed that in 78% of cases, the signature was reduced postsurgery and disappeared entirely in 33%. Our results show the feasibility of using peripheral blood gene expression signatures to identify early-stage NSCLC in at-risk populations.
Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor–Driven Lung Adenocarcinoma
Authors: Tapan K. Maity, Abhilash Venugopalan, Ilona Linnoila, Constance M. Cultraro, Andreas Giannakou, Roxanne Nemati, Xu Zhang, Joshua D. Webster, Daniel Ritt, Sarani Ghosal, Heinz Hoschuetzky, R. Mark Simpson, Romi Biswas, Katerina Politi, Deborah K. Morrison, Harold E. Varmus, Udayan Guha
Journal: Cancer Discovery (2015)

Abstract Somatic mutations in the EGFR kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here, we demonstrate that MIG6 is a tumor suppressor for the initiation and progression of mutant EGFR–driven lung adenocarcinoma in mouse models. Mutant EGFR–induced lung tumor formation was accelerated in Mig6-deficient mice, even with Mig6 haploinsufficiency. We demonstrate that constitutive phosphorylation of MIG6 at Y394/Y395 in EGFR-mutant human lung adenocarcinoma cell lines is associated with an increased interaction of MIG6 with mutant EGFR, which may stabilize EGFR protein. MIG6 also fails to promote mutant EGFR degradation. We propose a model whereby increased tyrosine phosphorylation of MIG6 decreases its capacity to inhibit mutant EGFR. Nonetheless, the residual inhibition is sufficient for MIG6 to delay mutant EGFR–driven tumor initiation and progression in mouse models. Significance: This study demonstrates that MIG6 is a potent tumor suppressor for mutant EGFR–driven lung tumor initiation and progression in mice and provides a possible mechanism by which mutant EGFR can partially circumvent this tumor suppressor in human lung adenocarcinoma. Cancer Discov; 5(5); 534–49. ©2015 AACR. See related commentary by Izumchenko and Sidransky, p. 472. This article is highlighted in the In This Issue feature, p. 453
Genetic Variation in APOL1 Associates with Younger Age at Hemodialysis Initiation
Authors: Zahra Kanji, Camille E. Powe, Julia B. Wenger, Chunmei Huang, Elizabeth Ankers, Dorothy A. Sullivan, Gina Collerone, Neil R. Powe, Marcello Tonelli, Ishir Bhan, Andrea J. Bernhardy, Salvatore DiBartolo, David Friedman, Giulio Genovese, Martin R. Pollak, Ravi Thadhani
Journal: Journal of the American Society of Nephrology (2011)

African Americans have a markedly higher incidence of ESRD compared with other racial groups. Two variants in the APOL1 gene, to date observed only among individuals of recent African ancestry, associate with increased risk for renal disease among African Americans. Here, we investigated whether these risk alleles also associate with age at initiation of chronic hemodialysis. We performed a cross-sectional study of 407 nondiabetic African Americans with ESRD who participated in the Accelerated Mortality on Renal Replacement (ArMORR) study, a prospective cohort of incident chronic hemodialysis patients. African Americans carrying two copies of the G1 risk allele initiated chronic hemodialysis at a mean age of 49.0 ± 14.9 years, which was significantly younger than both subjects with one copy of the G1 allele (55.9 ± 16.7 years; P = 0.014) and subjects without either risk allele (61.8 ± 17.1 years; P = 6.2 × 10(-7)). The association between the presence of the G1 allele and age at initiation of hemodialysis remained statistically significant after adjusting for sociodemographic and other potential confounders. We did not detect an association between the G2 risk allele and age at initiation of hemodialysis, but the sample size was limited. In conclusion, genetic variations in APOL1 identify African Americans that initiate chronic hemodialysis at a younger age. Early interventions to prevent progression of kidney disease may benefit this high-risk population.
A Neutral Envelope‐Type Nanoparticle Containing pH‐Responsive and SS‐Cleavable Lipid‐Like Material as a Carrier for Plasmid DNA
Authors: Hidetaka Akita, Ryohei Ishiba, Hiroto Hatakeyama, Hiroki Tanaka, Yusuke Sato, Kota Tange, Masaya Arai, Kazuhiro Kubo, Hideyoshi Harashima
Journal: Advanced Healthcare Materials (2013)

SS-cleavable proton-activated lipid-like material (ssPalm) functions as a key element in a lipid nanoparticle in which pDNA is encapsulated. The ssPalm contains dual sensing motifs that can respond to the intracellular environment; a proton-sponge unit (tertiary amines) that functions in response to an acidic environment (endosome/lysosome), and disulfide bonding that can be cleaved in a reducing environment (cytosol).
Protective effect of ambroxol against heat- and hydrogen peroxide-induced damage to lung lipids in mice
Authors: D Nowak, A Antczak, T Pietras, P Bialasiewicz, M Krol
Journal: European Respiratory Journal (1994)

We wanted to determine whether ambroxol, a drug which stimulates the release of surfactant by type II pneumocytes, can protect lung lipids from peroxidative damage in mice. Animals were injected intraperitoneally with ambroxol, 0.169 mmol.kg-1, or 1 ml buffer once a day for three consecutive days. Lipid peroxidation was then induced in lung homogenates either by means of heat, 50 degrees C, or H2O2, 10 mmol.l-1. The lung homogenates from ambroxol-treated animals revealed decreased lipid peroxidation in response to both stimuli. The heat- and H2O2-induced generation of conjugated dienes (a first lipid peroxidation product) in ambroxol-treated lung homogenates was 3.7 and 3.1 fold lower than in the lungs from buffer-injected mice. Ambroxol, as an inhibitor of heat- and H2O2-induced lipid peroxidation, was equipotent to and stronger than the two antioxidants, N-acetylcysteine and methionine, respectively. Ambroxol was not able to protect heart and liver lipids. These results suggest that ambroxol can sufficiently enhance the antioxidant defence in lung tissue and can act as a lung lipid antioxidant.
Evaluating Survivorship Care Plans: Results of a Randomized, Clinical Trial of Patients With Breast Cancer
Authors: Eva Grunfeld, Jim A. Julian, Gregory Pond, Elizabeth Maunsell, Douglas Coyle, Amy Folkes, Anil A. Joy, Louise Provencher, Daniel Rayson, Dorianne E. Rheaume, Geoffrey A. Porter, Lawrence F. Paszat, Kathleen I. Pritchard, André Robidoux, Sally Smith, Jonathan Sussman, Susan Dent, Jeffrey Sisler, Jennifer Wiernikowski, Mark N. Levine
Journal: Journal of Clinical Oncology (2011)

An Institute of Medicine report recommends that patients with cancer receive a survivorship care plan (SCP). The trial objective was to determine if an SCP for breast cancer survivors improves patient-reported outcomes.Women with early-stage breast cancer who completed primary treatment at least 3 months previously were eligible. Consenting patients were allocated within two strata: less than 24 months and ≥ 24 months since diagnosis. All patients were transferred to their own primary care physician (PCP) for follow-up. In addition to a discharge visit, the intervention group received an SCP, which was reviewed during a 30-minute educational session with a nurse, and their PCP received the SCP and guideline on follow-up. The primary outcome was cancer-related distress at 12 months, assessed by the Impact of Event Scale (IES). Secondary outcomes included quality of life, patient satisfaction, continuity/coordination of care, and health service measures.Overall, 408 survivors were enrolled through nine tertiary cancer centers. There were no differences between groups on cancer-related distress or on any of the patient-reported secondary outcomes, and there were no differences when the two strata were analyzed separately. More patients in the intervention than control group correctly identify their PCP as primarily responsible for follow-up (98.7% v 89.1%; difference, 9.6%; 95% CI, 3.9 to 15.9; P = .005).The results do not support the hypothesis that SCPs are beneficial for improving patient-reported outcomes. Transferring follow-up to PCPs is considered an important strategy to meet the demand for scarce oncology resources. SCPs were no better than a standard discharge visit with the oncologist to facilitate transfer.
A recombinant Leishmania antigen that stimulates human peripheral blood mononuclear cells to express a Th1-type cytokine profile and to produce interleukin 12.
Authors: Y A Skeiky, J A Guderian, D R Benson, O Bacelar, E M Carvalho, M Kubin, R Badaro, G Trinchieri, S G Reed
Journal: The Journal of Experimental Medicine (1995)

Leishmania braziliensis causes cutaneous and mucosal leishmaniasis in humans. Most patients with cutaneous leishmaniasis heal spontaneously and may therefore have developed protective immunity. There appears to be a mixed cytokine profile associated with active cutaneous or mucosal disease, and a dominant T helper (Th)1-type response associated with healing. Leishmanial antigens that elicit these potent proliferative and cytokine responses from peripheral blood mononuclear cells (PBMC) are now being identified. Herein, we report on the cloning and expression of a L. braziliensis gene homologous to the eukaryotic ribosomal protein eIF4A (LeIF) and patient PBMC responses to rLeIF. Patients with mucosal and self-healing cutaneous disease had significantly higher proliferative responses than those with cutaneous lesions. Whereas the parasite lysate stimulated patient PBMC to produce a mixed Th1/Th2-type cytokine profile, LeIF stimulated the production of interferon gamma (IFN-gamma), interleukin 2 (IL-2), and tumor necrosis factor alpha but not IL-4 or IL-10. Recombinant LeIF (rLeIF) downregulated both IL-10 mRNA in the "resting" PBMC of leishmaniasis patients and LPS-induced IL-10 production by patient PBMC. rLeIF also stimulated the production of IL-12 in cultured PBMC from both patients and uninfected individuals. The production of IFN-gamma by patient PBMC stimulated with either rLeIF or parasite lysate was IL-12 dependent, whereas anti-IFN-gamma monoclonal antibody only partially blocked the LeIF-induced production of IL-12. In vitro production of both IFN-gamma and IL-12 was abrogated by exogenous human recombinant IL-10. Therefore, we have identified a recombinant leishmanial antigen that elicits IL-12 production and Th1-type responses in patients as well as IL-12 production in normal human PBMC.
A phase II study of cisplatin, etoposide and gemcitabine in an unfavourable group of patients with carcinoma of unknown primary site
Authors: C. Balaña, J.-L. Manzano, I. Moreno, B. Cirauqui, A. Abad, A. Font, J.-L. Mate, R. Rosell
Journal: Annals of Oncology (2003)

BackgroundThe aim of this phase II study was to determine toxicity, response rate, time to progression, and overall survival of cisplatin, etoposide and gemcitabine in patients with carcinoma of unknown primary tumour site.Patients and methodsThirty patients with no previous chemotherapy and not belonging to a treatable group were treated with cisplatin 70 mg/m2 on day 1, etoposide 70 mg/m2 on days 1 and 2, and gemcitabine 700 mg m2 on days 1 and 8, administered every 3 weeks. Stable or responding patients received a maximum of eight cycles. Twenty patients (67%) had more than three affected sites, and 25 patients (84%) had adenocarcinomas.ResultsOverall response rate was 36.6% (11 patients), including four complete responses (13.3%) and seven partial responses (23.3%), with a 95% confidence interval of 19.9–56. Median survival was 7.21 months and eight patients remained alive for >1 year. Myelosuppression was the most important toxicity, with grade 3–4 neutropenia in 18 patients (60%) in 32% of the cycles: eight patients had neutropenic fever and 10 patients had thrombopenia in 11% of cycles. No non-haematological grade 4 toxicity occurred.ConclusionsCisplatin, etoposide and gemcitabine is an active combination, inducing objective responses in a subset of heavily advanced disease patients with carcinoma of unknown primary site. The role of adding gemcitabine to cisplatin and etoposide remains to be resolved as to the best schedule to diminish toxicity for the three-drug combination.
A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA)
Authors: Dudley J. Pennell, John B. Porter, Antonio Piga, Yongrong Lai, Amal El-Beshlawy, Khawla M. Belhoul, Mohsen Elalfy, Akif Yesilipek, Yurdanur Kilinç, Tomasz Lawniczek, Dany Habr, Marianne Weisskopf, Yiyun Zhang, Yesim Aydinok
Journal: Blood (2014)
A p70 killer cell inhibitory receptor specific for several HLA-B allotypes discriminates among peptides bound to HLA-B*2705.
Authors: M Peruzzi, N Wagtmann, E O Long
Journal: The Journal of Experimental Medicine (1996)

Natural killer (NK) cells express a repertoire of killer cell inhibitory receptors (KIR) for major histocompatibility complex (MHC) class I molecules. KIR specificity for MHC class I can be broad, as in the case of a single p70 KIR that can recognize several HLA-B allotypes, including HLA-B*2705. On the other hand, recognition of MHC class I can also be highly specific, as in the case of NK clones that recognize HLA-B*2705 in a peptide-specific manner. Most NK cells express multiple KIR sequences. To determine whether the broad and specific types of HLA-B recognition by NK cells reflect the use of different receptors or a property of a single KIR we analyzed the recognition of HLA-B*2705 by the p70 KIR-11, known to recognize several HLA-B allotypes. Vaccinia virus-mediated expression of KIR-11 in NK clones resulted in inhibition by HLA-B*2705 molecules on wild type but not on target cells deficient in the transporter for antigen presentation (TAP). Two peptides (FRYNGLIHR and RRSKEITVR) loaded onto HLA-B*2705 molecules on TAP-deficient cells provided protection from lysis by NK cells expressing KIR-11 but three other B27-specific peptides did not. As the five peptides bound to HLA-B*2705 with similar stability, these data demonstrate that a single KIR specific for several HLA-B allotypes recognizes a subset of peptides bound to HLA-B*2705.
Phylogenetic Substitution Models for Detecting Heterotachy during Plastid Evolution
Authors: S. Whelan, B. P. Blackburne, M. Spencer
Journal: Molecular Biology and Evolution (2010)

There is widespread evidence of lineage-specific rate variation, known as heterotachy, during protein evolution. Changes in the structural and functional constraints acting on a protein can lead to heterotachy, and it is plausible that such changes, known as covarion shifts, may affect many amino acids at once. Several previous attempts to model heterotachy have used covarion models, where the sequence undergoes covarion drift, whereby each site may switch independently among a set of discrete classes having different substitution rates. However, such independent switching may not capture biologically important events where the selective forces acting on a protein affect many sites at once. We describe a new class of models that allow the rates of substitution and switching to vary among branches of a phylogenetic tree. Such models are better able to handle covarion shifts. We apply these models to a set of genes occurring in nonphotosynthetic bacteria, cyanobacteria, and the plastids of green and red algae. We find that 4/5 genes show evidence of some form of rate switching and that 3/5 genes show evidence that the relative switching rate differs among taxonomic groups. We conclude that covarion shifts may be frequent during the deep evolution of plastid genes and that our methodology may provide a powerful new tool for investigating such shifts in other systems.
Genome-wide association study of lung function phenotypes in a founder population
Authors: Tsung-Chieh Yao, Gaixin Du, Lide Han, Ying Sun, Donglei Hu, James J Yang, Rasika Mathias, Lindsey A Roth, Nicholas Rafaels, Emma E Thompson, Dagan A Loisel, Rebecca Anderson, Celeste Eng, Maitane Arruabarrena Orbegozo, Melody Young, James M Klocksieben, Elizabeth Anderson, Kathleen Shanovich, Lucille A Lester, L Keoki Williams, Kathleen C Barnes, Esteban G Burchard, Dan L Nicolae, Mark Abney, Carole Ober
Journal: Journal of Allergy and Clinical Immunology (2013)