tbuckley/cabot-search huggingface dataset:
“TODAY” Reflects on the Changing “Faces” of Type 2 Diabetes
Authors: William T. Cefalu
Journal: Diabetes Care (2013)

The diabetes landscape has seen unprecedented changes over the recent past. On the one hand, there have been consistent and impressive advancements in clinical care, which include new therapeutic agents, novel dietary approaches, technical advances in glycemic monitoring and closed-loop technology, and a heightened awareness of individuals at risk. The tools required to treat and halt the progression of diabetes complications and the clinical evidence in support of effective management strategies have been established. On the other hand, the need for these developments has never been greater given the global burden of the diabetes epidemic. A particularly disturbing observation is that the “faces” of those who develop type 2 diabetes are becoming younger by the year as evidenced by the reports demonstrating the increased frequency of both type 1 and type 2 diabetes in youth (1–3). Until recent data were made available, it was really not known how adolescents would respond to therapies normally reserved for the adult population. We also had no evidence regarding the rate and severity of the complications in this age-group or the prevalence and progression of other risk factors. In this regard, the TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) study has succeeded in filling a major gap in knowledge (4–10). Thus, given the importance of the problem of type 2 diabetes in youth and the need to effectively disseminate the information, our editorial team has elected to feature the TODAY study in this issue of Diabetes Care . Specifically, articles from the TODAY study researchers featured in this issue provide new data on the efficacy and safety of clinical treatment and longitudinal observations of specific risk factors and complications for the new “faces” of the type 2 diabetes epidemic—namely, adolescents!

As I reflect on the problem …
Scleroderma Autoantigens Are Uniquely Fragmented by Metal-catalyzed Oxidation Reactions: Implications for Pathogenesis
Authors: Livia Casciola-Rosen, Fredrick Wigley, Antony Rosen
Journal: The Journal of Experimental Medicine (1997)

The observation that revelation of immunocryptic epitopes in self antigens may initiate the autoimmune response has prompted the search for processes which induce novel fragmentation of autoantigens as potential initiators of autoimmunity. The reversible ischemia reperfusion which characterizes scleroderma has focused attention on reactive oxygen species as molecules which might induce autoantigen fragmentation. We demonstrate that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by reactive oxygen species, in a metal-dependent manner. Multiple features of the fragmentation reaction and its inhibition indicate that these autoantigens possess metal-binding sites, which focus metal-catalyzed oxidation reactions (and consequent fragmentation) to specific regions of the antigens. These data suggest that the autoantibody response in scleroderma is the immune marker of unique protein fragmentation, induced by ischemia reperfusion in the presence of appropriate metals, and focus attention on abnormal metal status as a potential pathogenic principle in this disease.
Interferon: Immunobiology and Clinical Significance
Authors: E. RICHARD STIEHM
Journal: Annals of Internal Medicine (1982)

Interferons are proteins elaborated by infected cells that protect noninfected cells from viral infection. These proteins produce a temporary "antiviral state" by altering nucleotide metabolism and cytoplasmic enzyme induction. Interferons appear early after viral infection locally and systematically to limit spread of viral infection; they also affect cell differentiation, growth, surface, antigen expression, morphologic findings, and immunoregulation. Several human disorders have diminished interferon production. Newborns have normal interferon alpha but deficient interferon gamma production. Infants with congenital infections may also have defects in interferon production. Immunosuppressed patients receiving transplants (marrow, heart, of kidney) have diminished interferon production, particularly immediately after transplant. Deficiencies of interferon have also been noted in Down's syndrome, cellular immunodeficiencies, uremia, malnutrition, and hematopoietic malignancy. Leukocyte interferon has been of therapeutic value in herpes zoster infections, in patients with cancer, and in patients with hepatitis B infection. Interferon has not been proved to help children with congenital cytomegalovirus or rubella. Interferon can shrink lymphoid tumors, particularly non-Hodgkin's lymphoma.
The trunk muscles of elite oarsmen
Authors: A H McGregor, L Anderton, W M W Gedroyc
Journal: British Journal of Sports Medicine (2002)

To investigate the trunk strength of elite rowers and the impact of low back pain on these measures in order to determine if asymmetries or weakness were present.Twenty two elite rowers were recruited: 13 reported previous low back pain, five current low back pain, and the remainder had no history of low back pain. All subjects were scanned during simulated rowing in an interventional open magnetic resonance imaging scanner. In each simulated rowing position, axial scans were obtained at the level of the L4-5 and L5-S1 disc interspace to determine the cross sectional area of the posterior trunk muscles.Considerable differences were observed between the three groups of rowers. In contrast with expectations and previous literature, the trunk muscles of rowers with low back pain had significantly larger cross sectional areas (p<0.001). No left/right asymmetries were observed and no differences between oarside and non-oarside in terms of muscle cross sectional area.These findings suggest that low back pain in rowers does not arise as a result of muscle weakness.
PRENATAL DIAGNOSIS AND CARRIER DETECTION OF DUCHENNE MUSCULAR DYSTROPHY WITH CLOSELY LINKED RFLPs
Authors: E Bakker, N Goor, K Wrogemann, L.M Kunkel, W.A Fenton, D Majoor-Krakauer, M.G.J Jahoda, G.J.B.Van Ommen, M.H Hofker, J.L Mandel, K.E Davies, H.F Willard, L Sandkuyl, A.J.V Essen, E.S Sachs, P.L Pearson
Journal: The Lancet (1985)
A possible change in the rate-limiting step for cardiac norepinephrine synthesis in the cardiomyopathic Syrian hamster.
Authors: M J Sole, A B Kamble, M N Hussain
Journal: Circulation Research (1977)

The development of heart failure in the cardiomyopathic hamster is associated with a decrease in norepinephrine stores and parallel increases in cardiac sympathetic tone and tyrosine hydroxylase activity. Despite the increase in tyrosine hydroxylase, cardiac norepinephrine synthesis does not increase in heart failure. In this study, we have shown that an accumulation of cardiac dopamine accompanies the decline of cardiac norepinephrine. The abnormal content of norepinephrine and of dopamine in the decompensating hamster heart is restored to normal by peripheral ganglionic blockade. The acute increase in cardiac sympathetic tone induced by immobilization stress in control hamsters mimics the alterations in cardiac catecholamine distribution found in heart failure. Other investigators have demonstrated similar alterations in the catecholamine content of the rat submaxillary gland and adrenal medulla following an increase in sympathetic input to these organs. We conclude that the increase in cardiac sympathetic tone in the late stages of hamster cardiomyopathy appears to lead to a shift in the rate-limiting step for norepinephrine synthesis from the hydroxylation of tyrosine to the hydroxylation of dopamine. There is evidence that this shift which results in an accumulation of dopamine in the noradrenergic nerve terminals of the heart is a general manifestaion of augmented sympathetic nerve traffic rather than a peculiarity of hamster cardiomyopathy.
Protein Kinase Cθ in T Cell Activation
Authors: Noah Isakov, Amnon Altman
Journal: Annual Review of Immunology (2002)

The novel protein kinase C (PKC) isoform, PKCθ, is selectively expressed in T lymphocytes and is a sine qua non for T cell antigen receptor (TCR)-triggered activation of mature T cells. Productive engagement of T cells by antigen-presenting cells (APCs) results in recruitment of PKCθ to the T cell–APC contact area—the immunological synapse—where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and IL-2 production. The transcription factors NF-κB and AP-1 are the primary physiological targets of PKCθ, and efficient activation of these transcription factors by PKCθ requires integration of TCR and CD28 costimulatory signals. PKCθ cooperates with the protein Ser/Thr phosphatase, calcineurin, in transducing signals leading to activation of JNK, NFAT, and the IL-2 gene. PKCθ also promotes T cell cycle progression and regulates programmed T cell death. The exact mode of regulation and immediate downstream substrates of PKCθ are still largely unknown. Identification of these molecules and determination of their mode of operation with respect to the function of PKCθ will provide essential information on the mechanism of T cell activation. The selective expression of PKCθ in T cells and its essential role in mature T cell activation establish it as an attractive drug target for immunosuppression in transplantation and autoimmune diseases.
Identification of a Tibetan-Specific Mutation in the Hypoxic Gene EGLN1 and Its Contribution to High-Altitude Adaptation
Authors: Kun Xiang, None Ouzhuluobu, Yi Peng, Zhaohui Yang, Xiaoming Zhang, Chaoying Cui, Hui Zhang, Ming Li, Yanfeng Zhang, None Bianba, None Gonggalanzi, None Basang, None Ciwangsangbu, Tianyi Wu, Hua Chen, Hong Shi, Xuebin Qi, Bing Su
Journal: Molecular Biology and Evolution (2013)

Tibetans are well adapted to high-altitude hypoxic conditions, and in recent genome-wide scans, many candidate genes have been reported involved in the physiological response to hypoxic conditions. However, the limited sequence variations analyzed in previous studies would not be sufficient to identify causal mutations. Here we conducted resequencing of the entire genomic region (59.4 kb) of the hypoxic gene EGLN1 (one of the top candidates from the genome-wide scans) in Tibetans and identified 185 sequence variations, including 13 novel variations (12 substitutions and 1 insertion or deletion). There is a nonsynonymous mutation (rs186996510, D4E) showing surprisingly deep divergence between Tibetans and lowlander populations (Fst = 0.709 between Tibetans and Han Chinese). It is highly prevalent in Tibetans (70.9% on average) but extremely rare in Han Chinese, Japanese, Europeans, and Africans (0.56-2.27%), suggesting that it might be the causal mutation of EGLN1 contributing to high-altitude hypoxic adaptation. Neutrality test confirmed the signal of Darwinian positive selection on EGLN1 in Tibetans. Haplotype network analysis revealed a Tibetan-specific haplotype, which is absent in other world populations. The estimated selective intensity (0.029 for the C allele of rs186996510) puts EGLN1 among the known genes that have undergone the strongest selection in human populations, and the onset of selection was estimated to have started at the early Neolithic (∼8,400 years ago). Finally, we detected a significant association between rs186996510 and hemoglobin levels in Tibetans, suggesting that EGLN1 contributes to the adaptively low hemoglobin level of Tibetans compared with acclimatized lowlanders at high altitude.
Adrenomedullin refines mortality prediction by the BODE index in COPD: the "BODE-A" index
Authors: Daiana Stolz, Kostantinos Kostikas, Francesco Blasi, Wim Boersma, Branislava Milenkovic, Alicia Lacoma, Renaud Louis, Joachim G. Aerts, Tobias Welte, Antoni Torres, Gernot G.U. Rohde, Lucas Boeck, Janko Rakic, Andreas Scherr, Sabine Hertel, Sven Giersdorf, Michael Tamm
Journal: European Respiratory Journal (2013)

The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index is well-validated for mortality prediction in chronic obstructive pulmonary disease (COPD). Concentrations of plasma pro-adrenomedullin, a surrogate for mature adrenomedullin, independently predicted 2-year mortality among inpatients with COPD exacerbation. We compared accuracy of initial pro-adrenomedullin level, BODE and BODE components, alone or combined, in predicting 1-year or 2-year all-cause mortality in a multicentre, multinational observational cohort with stable, moderate to very severe COPD. Pro-adrenomedullin was significantly associated (p&lt;0.001) with 1-year mortality (4.7%) and 2-year mortality (7.8%) and comparably predictive to BODE regarding both (C statistics 0.691 versus 0.745 and 0.635 versus 0.679, respectively). Relative to using BODE alone, adding pro-adrenomedullin significantly improved 1-year and 2-year mortality prognostication (C statistics 0.750 and 0.818, respectively; both p&lt;0.001). Pro-adrenomedullin plus BOD was more predictive than the original BODE including 6-min walk distance. In multivariable analysis, pro-adrenomedullin (likelihood ratio Chi-squared 13.0, p&lt;0.001), body mass index (8.5, p=0.004) and 6-min walk distance (7.5, p=0.006) independently foretold 2-year survival, but modified Medical Research Council dyspnoea score (2.2, p=0.14) and forced expiratory volume in 1 s % predicted (0.3, p=0.60) did not. Pro-adrenomedullin plus BODE better predicts mortality in COPD patients than does BODE alone; pro-adrenomedullin may substitute for 6-min walk distance in BODE when 6-min walk testing is unavailable.
Nomogram to Predict Subsequent Brain Metastasis in Patients With Metastatic Breast Cancer
Authors: Olivier Graesslin, Bassam S. Abdulkarim, Charles Coutant, Florence Huguet, Zsolt Gabos, Limin Hsu, Olivier Marpeau, Serge Uzan, Lajos Pusztai, Eric A. Strom, Gabriel N. Hortobagyi, Roman Rouzier, Nuhad K. Ibrahim
Journal: Journal of Clinical Oncology (2010)

PURPOSE Brain metastasis is usually a fatal event in patients with stage IV breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of enriched patient populations for prevention trials. PATIENTS AND METHODS Electronic medical records of patients with metastatic breast cancer were retrospectively reviewed for the period between January 2000 and February 2007 under a study approved by the institutional review board. A multivariate logistic regression analysis of selected prognostic features was done. A nomogram to predict brain metastasis was constructed and validated in a cohort of 128 patients with brain metastasis treated at the Cross Cancer Institute (Edmonton, Alberta, Canada). Results Of 2,136 patients with breast cancer, 362 developed subsequent brain metastasis. Age, grade, negative status of estrogen receptor and human epidermal growth factor receptor 2, number of metastatic sites (one v > one), and short disease-free survival were significantly and independently associated with subsequent brain metastasis. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.68 (95% CI, 0.66 to 0.69) in the training set. The validation set showed a good discrimination with an AUC of 0.74 (95% CI, 0.70 to 0.79). The nomogram was well calibrated, with no significant difference between the predicted and the observed probabilities. CONCLUSION We have developed a robust tool that is able to predict subsequent brain metastasis in patients with breast cancer with nonbrain metastatic disease. Selection of an enriched patient population at high risk for brain metastasis will facilitate the design of trials aiming at its prevention.
Coevolution Reveals a Network of Human Proteins Originating with Multicellularity
Authors: A. Bezginov, G. W. Clark, R. L. Charlebois, V.-u.-N. Dar, E. R. M. Tillier
Journal: Molecular Biology and Evolution (2012)

Protein interaction networks play central roles in biological systems, from simple metabolic pathways through complex programs permitting the development of organisms. Multicellularity could only have arisen from a careful orchestration of cellular and molecular roles and responsibilities, all properly controlled and regulated. Disease reflects a breakdown of this organismal homeostasis. To better understand the evolution of interactions whose dysfunction may be contributing factors to disease, we derived the human protein coevolution network using our MatrixMatchMaker algorithm and using the Orthologous MAtrix project (OMA) database as a source for protein orthologs from 103 eukaryotic genomes. We annotated the coevolution network using protein–protein interaction data, many functional data sources, and we explored the evolutionary rates and dates of emergence of the proteins in our data set. Strikingly, clustering based only on the topology of the coevolution network partitions it into two subnetworks, one generally representing ancient eukaryotic functions and the other functions more recently acquired during animal evolution. That latter subnetwork is enriched for proteins with roles in cell–cell communication, the control of cell division, and related multicellular functions. Further annotation using data from genetic disease databases and cancer genome sequences strongly implicates these proteins in both ciliopathies and cancer. The enrichment for such disease markers in the animal network suggests a functional link between these coevolving proteins. Genetic validation corroborates the recruitment of ancient cilia in the evolution of multicellularity.
Therapeutic vaccines for cancer: an overview of clinical trials
Authors: Ignacio Melero, Gustav Gaudernack, Winald Gerritsen, Christoph Huber, Giorgio Parmiani, Suzy Scholl, Nicholas Thatcher, John Wagstaff, Christoph Zielinski, Ian Faulkner, Håkan Mellstedt
Journal: Nature Reviews Clinical Oncology (2014)
Activated Epidermal Growth Factor Receptor–Stat-3 Signaling Promotes Tumor Survival<i>In vivo</i>in Non–Small Cell Lung Cancer
Authors: Eric B. Haura, Zhong Zheng, Lanxi Song, Alan Cantor, Gerold Bepler
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Signal transducers and activators of transcription 3 (Stat3), a member of the STAT family of transcription factors, regulates multiple oncogenic pathways, including pathways regulating tumor cell survival. We evaluated Stat3 activation in early stage non–small cell lung cancers (NSCLC) and how this relates to upstream epidermal growth factor receptor (EGFR) activation, tumor apoptosis, and prognosis. Experimental Design: High-density tissue microarrays using tissues from 176 surgically resected NSCLC were evaluated for expression of phosphorylated Stat3 (pStat3) and epidermal growth factor receptor (pEGFR) along with tumor apoptosis. Using NSCLC cell lines, we evaluated how pStat3 expression relates to EGFR mutations and sensitivity of cells to gefitinib. Results: We identified nuclear pStat3 expression in 54% of tumors. pStat3 expression was correlated with smaller tumors (P &amp;lt; 0.0001) and with limited smoking history (P = 0.02). We identified a trend toward higher pStat3 expression in adenocarcinomas compared with other tumor histology (P = 0.09). No relationship was found between pStat3 and prognosis following surgical resection. Importantly, we found a strong positive correlation between pEGFR expression and pStat3 expression (P &amp;lt;0.0001) and an inverse correlation between pStat3 and apoptosis (P = 0.01) consistent with less apoptosis in tumors expressing high amounts of pStat3. Cell lines with mutant EGFR have increased levels of pStat3 compared with cell lines without mutant EGFR and this correlates with their sensitivity to gefitinib. Finally, antisense-mediated knockdown of Stat3 induces apoptosis in EGFR mutant lung cancer cells. Conclusions: Early-stage NSCLC tumors have activated EGFR-Stat3 signaling with low apoptosis. Our findings suggest that pStat3 expression may be helpful in identifying patients appropriate for treatment with EGFR tyrosine kinase inhibitors.
Effect of cimetidine and sodium bicarbonate on pancreatic replacement therapy in cystic fibrosis.
Authors: P R Durie, L Bell, W Linton, M L Corey, G G Forstner
Journal: Gut (1980)

Fifteen patients with cystic fibrosis and pancreatic insufficiency were studied during four randomised seven day treatment periods in which they received only pancreatic supplement (Pancrelipase, 27 capsules per day) or supplement plus cimetidine (20 mg/kg body weight/24 h) or sodium bicarbonate (15 g/m2/24 h) alone or in combination. Dietary intake was not fixed but was restricted to foods of known fat and nitrogen content from which daily intakes could be computed. Faecal fat and nitrogen were calculated as g/24 h and percentage of intake. Addition of either cimetidine or bicarbonate resulted in significant improvement in fat and nitrogen excretion, which was not greater with the combination of both drugs. Cimetidine and sodium bicarbonate in these doses are therefore sufficient to produce maximal improvement in digestive activity of pancreatic supplements. Fat excretion per gram of intake fell with cimetidine and bicarbonate from 12 times the normal level, to normal, in patients consuming less than 120 g fat daily. Above this intake the dose of pancreatic supplement appeared to be inadequate. Faecal nitrogen excretion increased with nitrogen intake in all four periods, but, in contrast with fat excretion, the response to cimetidine and bicarbonate was not affected by the level of intake. Dietary intake appears to be a significant factor in determining the faecal output of fat and nitrogen in patients with pancreatic insufficiency and should be considered when determining the optimum amount of pancreatic supplementation.
Darier's disease with peri-follicular depigmentation
Authors: J. BERTH-JONES, P.E. HUTCHINSON
Journal: British Journal of Dermatology (1989)

Journal Article Darier's disease with peri‐follicular depigmentation Get access J. BERTH‐JONES, J. BERTH‐JONES Department of Dermatology, Leicester Royal Infirmary, Leicester LE1 5WW, U.K. Dr J.Berth‐Jones. Search for other works by this author on: Oxford Academic Google Scholar P.E. HUTCHINSON P.E. HUTCHINSON Department of Dermatology, Leicester Royal Infirmary, Leicester LE1 5WW, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 120, Issue 6, 1 June 1989, Pages 827–830, https://doi.org/10.1111/j.1365-2133.1989.tb01381.x Published: 01 June 1989
Modifiable Behavioral Factors as Causes of Death
Authors: M Nawal Lutfiyya, Eric Henley
Journal: JAMA (2004)

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