tbuckley/cabot-search huggingface dataset:
Targeting the BMK1 MAP Kinase Pathway in Cancer Therapy
Authors: Qingkai Yang, Jiing-Dwan Lee
Journal: Clinical Cancer Research (2011)

The big mitogen activated protein kinase 1 (BMK1) pathway is the most recently discovered and least-studied mammalian mitogen-activated protein (MAP) kinase cascade, ubiquitously expressed in all types of cancer cells tested so far. Mitogens and oncogenic signals strongly activate this cellular MAP kinase pathway, thereby passing down proliferative, survival, chemoresistance, invasive, and angiogenic signals in tumor cells. Recently, several pharmacologic small molecule inhibitors of this pathway have been developed. Among them, the BMK1 inhibitor XMD8-92 blocks cellular BMK1 activation and significantly suppresses tumor growth in lung and cervical tumor models and is well tolerated in animals. On the other hand, MEK5 inhibitors, BIX02188, BIX02189, and compound 6, suppress cellular MEK5 activity, but no data exist to date on their effectiveness in animals.
Indoor exposures and respiratory symptoms in a Norwegian community sample
Authors: T Duelien Skorge
Journal: Thorax (2005)

<b>Background:</b> Limited data are available on the effect of a poor indoor climate on the respiratory health of adults. No data are available regarding the contribution of indoor exposures to the burden of respiratory symptoms in the population. <b>Methods:</b> In 1996–7 a community sample of 3181 adults aged 26–82 years was invited to participate in a survey on indoor climate and respiratory health in Hordaland County, Norway. 2401 subjects agreed to take part. Logistic regression was used to examine the relationship between eight markers of indoor exposure and physician diagnosed asthma and five respiratory symptoms, after adjustment for sex, age, smoking, educational level, smoking habits, pack years, and occupational airborne exposure. <b>Results:</b> Mould exposure was associated with all the respiratory symptoms; the adjusted odds ratios (OR) varied from 1.6 (95% confidence interval (CI) 1.0 to 2.4) for cough with phlegm to 2.3 (95% CI 1.4 to 3.9) for grade 2 dyspnoea. Keeping a cat or dog in childhood was associated with grade 2 dyspnoea and attacks of dyspnoea, with adjusted ORs of 1.3 (95% CI 1.0 to 1.7) and 1.4 (95% CI 1.1 to 1.8), respectively. Having a fitted carpet in the bedroom was negatively associated with three of the five respiratory symptoms. 3–5% of the frequency of the respiratory symptoms in the study population could be attributed to exposure to visible moulds. <b>Conclusion:</b> Mould exposure is an independent risk factor for several respiratory symptoms in a general population covering a wide age span, but it makes only a small contribution to the respiratory symptom burden in the population at large.
Positive selection of the peripheral B cell repertoire in gut-associated lymphoid tissues
Authors: Ki-Jong Rhee, Paul J. Jasper, Periannan Sethupathi, Malathy Shanmugam, Dennis Lanning, Katherine L. Knight
Journal: The Journal of Experimental Medicine (2004)

Gut-associated lymphoid tissues (GALTs) interact with intestinal microflora to drive GALT development and diversify the primary antibody repertoire; however, the molecular mechanisms that link these events remain elusive. Alicia rabbits provide an excellent model to investigate the relationship between GALT, intestinal microflora, and modulation of the antibody repertoire. Most B cells in neonatal Alicia rabbits express VHn allotype immunoglobulin (Ig)M. Within weeks, the number of VHn B cells decreases, whereas VHa allotype B cells increase in number and become predominant. We hypothesized that the repertoire shift from VHn to VHa B cells results from interactions between GALT and intestinal microflora. To test this hypothesis, we surgically removed organized GALT from newborn Alicia pups and ligated the appendix to sequester it from intestinal microflora. Flow cytometry and nucleotide sequence analyses revealed that the VHn to VHa repertoire shift did not occur, demonstrating the requirement for interactions between GALT and intestinal microflora in the selective expansion of VHa B cells. By comparing amino acid sequences of VHn and VHa Ig, we identified a putative VH ligand binding site for a bacterial or endogenous B cell superantigen. We propose that interaction of such a superantigen with VHa B cells results in their selective expansion.
Always the Whole and Its Parts
Authors: GABRIEL RICHET
Journal: Journal of the American Society of Nephrology (2000)

We all agree that medicine is a biological science. When our elders understood this fact, they were faced with the difficulties of integrating within the complete organism the functions of its various organs. The relationships between the whole and its parts were therefore open issues at the beginning of modern medicine. They continue to be relevant today. In 1827, Cuvier, the naturalist, prefaced his eulogy of three renowned physicians, Corvisart, the inventor of cardiology, Pinel, one of the founders of psychiatry, and Halle[Combining Acute Accent], who advocated a scientific approach to clinical medicine, with this remark: “Which art is closest to divination?... All (the parts) play endless interactions, acting and reacting continuously with one another and with the whole. The sting of a pin can bring about tetanus; an imperceptible miasma... can spread death in a vast region in but a few days” (1). These words reveal the bewilderment of the founder of paleontology in front of medicine. Since 1950, a reductive analysis has focused on the study of isolated factors, while no comparable attempts were made at establishing links to other normal or pathologic functions. Then, in the laboratory, test tubes had replaced live animals. But everything changed with transgenic mice and rats, leading to a different experimental pathology in which the whole is modified by a specific chemical anomaly of one part, thus revealing unexpected interferences. For those who are smart enough to understand my broken English, I end with this quote from Claude Bernard, who, irritated by the continuous questioning on physiologic regulations by the mathematician Joseph Bertrand, responded, “There is someone who knows much more than you do about integrals. It is the dog now in experimentation” (2).
Methods for Determining the Refractory Period and Excitable Gap During Persistent Atrial Fibrillation in the Goat
Authors: Mattias Duytschaever, Frans Mast, Matthijs Killian, Yuri Blaauw, Maurits Wijffels, Maurits Allessie
Journal: Circulation (2001)

Recently, the temporal excitable gap during atrial fibrillation (AF) has been identified as a vulnerable parameter for cardioversion of AF. In this study, we evaluated 5 methods to measure the refractory period (RP(AF)) and the excitable period (EP(AF)) during persistent AF.In 11 goats instrumented with 83 epicardial atrial electrodes, persistent AF (43+/-34 days) was induced with a median AF cycle length (CL) of 98+/-14 ms. To measure RP(AF), premature stimuli were applied to the center of the electrode array on the right or left atrium. The RP(AF) measured by mapping of premature stimuli was 70+/-12 ms ("gold standard"). The RP(AF) determined during entrainment of AF was 77+/-17 ms (R(2)=0.88, P<0.01). Statistical analysis of the effects of synchronized stimuli (each coupling interval x100) on the AFCL histogram yielded an RP(AF) of 70+/-13 ms (R(2)=0.94, P<0.01). A further simplification was to apply slow fixed-rate pacing (1 Hz) during AF. For each stimulus (n=250 to 500), the paced AFCL was plotted against its coupling interval, and capture was determined by statistical shortening of the AFCL (RP(AF) 71+/-17 ms, R(2)=0.84, P<0.01). The 5th percentile of the AFCL histogram as an index of RP(AF) was 77+/-12 ms (R(2)=0.90, P<0.01).During persistent AF with an AFCL of 98+/-14 ms, the RP(AF) determined by mapping of synchronized premature stimuli (gold standard) was 70+/-12 ms, with an excitable period of 28+/-8 ms. Although the indirect methods to measure RP(AF) all correlated well with the gold standard, slow fixed-rate pacing seems to be the most attractive technique because of the ease of acquiring the data and the clear graphic result.
Pityriasis rubra pilaris and hypothyroidism. Efficacy of thyroid hormone replacement therapy in skin recovery
Authors: V. Orlandini, O. Cogrel, M.S. Doutre, C. Beylot, M. Beylot-Barry
Journal: British Journal of Dermatology (2007)

Journal Article Pityriasis rubra pilaris and hypothyroidism. Efficacy of thyroid hormone replacement therapy in skin recovery Get access V. Orlandini, V. Orlandini Department of Dermatology, Hôpital Haut‐Lévêque, avenue de Magellan, 33604 Pessac, France E‐mail: vincent.orlandini@chu‐bordeaux.fr Search for other works by this author on: Oxford Academic Google Scholar O. Cogrel, O. Cogrel Department of Dermatology, Hôpital Haut‐Lévêque, avenue de Magellan, 33604 Pessac, France E‐mail: vincent.orlandini@chu‐bordeaux.fr Search for other works by this author on: Oxford Academic Google Scholar M.S. Doutre, M.S. Doutre Department of Dermatology, Hôpital Haut‐Lévêque, avenue de Magellan, 33604 Pessac, France E‐mail: vincent.orlandini@chu‐bordeaux.fr Search for other works by this author on: Oxford Academic Google Scholar C. Beylot, C. Beylot Department of Dermatology, Hôpital Haut‐Lévêque, avenue de Magellan, 33604 Pessac, France E‐mail: vincent.orlandini@chu‐bordeaux.fr Search for other works by this author on: Oxford Academic Google Scholar M. Beylot‐Barry M. Beylot‐Barry Department of Dermatology, Hôpital Haut‐Lévêque, avenue de Magellan, 33604 Pessac, France E‐mail: vincent.orlandini@chu‐bordeaux.fr Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 156, Issue 3, 1 March 2007, Pages 606–607, https://doi.org/10.1111/j.1365-2133.2006.07697.x Published: 01 March 2007
Long-Term Beneficial Effect of Islet Transplantation on Diabetic Macro-/Microangiopathy in Type 1 Diabetic Kidney-Transplanted Patients
Authors: Paolo Fiorina, Franco Folli, Federico Bertuzzi, Paola Maffi, Giovanna Finzi, Massimo Venturini, Carlo Socci, Alberto Davalli, Elena Orsenigo, Lucilla Monti, Luca Falqui, Silvia Uccella, Stefano La Rosa, Luciana Usellini, Giuliana Properzi, Valerio Di Carlo, Alessandro Del Maschio, Carlo Capella, Antonio Secchi
Journal: Diabetes Care (2003)

OBJECTIVE—Our aim was to evaluate the long-term effects of transplanted islets on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients. RESEARCH DESIGN AND METHODS—A total of 34 type 1 diabetic kidney-transplanted patients underwent islet transplantation and were divided into two groups: successful islet-kidney transplantation (SI-K; 21 patients, fasting C-peptide serum concentration &amp;gt;0.5 ng/ml for &amp;gt;1 year) and unsuccessful islet-kidney transplantation (UI-K; 13 patients, fasting C-peptide serum concentration &amp;lt;0.5 ng/ml). Patients cumulative survival, cardiovascular death rate, and atherosclerosis progression were compared in the two groups. Skin biopsies, endothelial dependent dilation (EDD), nitric oxide (NO) levels, and atherothrombotic risk factors [von Willebrand factor (vWF) and d-dimer fragment (DDF)] were studied cross-sectionally. RESULTS—The SI-K group showed a significant better patient survival rate (SI-K 100, 100, and 90% vs. UI-K 84, 74, and 51% at 1, 4, and 7 years, respectively, P = 0.04), lower cardiovascular death rate (SI-K 1/21 vs. UI-K 4/13, χ2 = 3.9, P = 0.04), and lower intima-media thickness progression than the UI-K group (SI-K group: Δ1–3 years −13 ± 30 μm vs. UI-K group: Δ1–3 years 245 ± 20 μm, P = 0.03) with decreased signs of endothelial injuring at skin biopsy. Furthermore, the SI-K group showed a higher EDD than the UI-K group (EDD: SI-K 7.8 ± 4.5% vs. UI-K 0.5 ± 2.7%, P = 0.02), higher basal NO (SI-K 42.9 ± 6.5 vs. UI-K 20.2 ± 6.8 μmol/l, P = 0.02), and lower levels of vWF (SI-K 138.6 ± 15.3 vs. UI-K 180.6 ± 7.0%, P = 0.02) and DDF (SI-K 0.61 ± 0.22 vs. UI-K 3.07 ± 0.68 μg/ml, P &amp;lt; 0.01). C-peptide-to-creatinine ratio correlated positively with EDD and NO and negatively with vWF and DDF. CONCLUSIONS—Successful islet transplantation improves survival, cardiovascular, and endothelial function in type 1 diabetic kidney-transplanted patients.
Epigenetics
Authors: Mark E. Cooper, Assam El-Osta
Journal: Circulation Research (2010)

Epigenetic modifications regulate critical functions that underlie chromosome metabolism. Understanding the molecular changes to chromatin structure and the functional relationship with altered signaling pathways is now considered to represent an important conceptual challenge to explain diabetes and the phenomenon of metabolic or hyperglycemic memory. Although it remains unknown as to the specific molecular mechanisms whereby hyperglycemic memory leads to the development of diabetic vascular complications, emerging evidence now indicates that critical gene-activating epigenetic changes may confer future cell memories. Chemical modification of the H3 histone tail of lysine 4 and 9 has recently been identified with gene expression conferred by hyperglycemia. The persistence of these key epigenetic determinants in models of glycemic variability and the development of diabetic complications has been associated with these primary findings. Transient hyperglycemia promotes gene-activating epigenetic changes and signaling events critical in the development and progression of vascular complications. As for the role of specific epigenomic changes, it is postulated that further understanding enzymes involved in writing and erasing chemical changes could transform our understanding of the pathways implicated in diabetic vascular injury providing new therapeutic strategies.
Predictors and Impact of Intensification of Antihyperglycemic Therapy in Type 2 Diabetes
Authors: Laura N. McEwen, Dori Bilik, Susan L. Johnson, Jeffrey B. Halter, Andrew J. Karter, Carol M. Mangione, Usha Subramanian, Beth Waitzfelder, Jesse C. Crosson, William H. Herman
Journal: Diabetes Care (2009)

OBJECTIVE The purpose of this study was to examine the predictors of intensification of antihyperglycemic therapy in patients with type 2 diabetes; its impact on A1C, body weight, symptoms of anxiety/depression, and health status; and patient characteristics associated with improvement in A1C. RESEARCH DESIGN AND METHODS We analyzed survey, medical record, and health plan administrative data collected in Translating Research into Action for Diabetes (TRIAD). We examined patients who were using diet/exercise or oral antihyperglycemic medications at baseline, had A1C &amp;gt;7.2%, and stayed with the same therapy or intensified therapy (initiated or increased the number of classes of oral antihyperglycemic medications or began insulin) over 18 months. RESULTS Of 1,093 patients, 520 intensified therapy with oral medications or insulin. Patients intensifying therapy were aged 58 ± 12 years, had diabetes duration of 11 ± 9 years, and had A1C of 9.1 ± 1.5%. Younger age and higher A1C were associated with therapy intensification. Compared with patients who did not intensify therapy, those who intensified therapy experienced a 0.49% reduction in A1C (P &amp;lt; 0.0001), a 3-pound increase in weight (P = 0.003), and no change in anxiety/depression (P = 0.5) or health status (P = 0.2). Among those who intensified therapy, improvement in A1C was associated with higher baseline A1C, older age, black race/ethnicity, lower income, and more physician visits. CONCLUSIONS Treatment intensification improved glycemic control with no worsening of anxiety/depression or health status, especially in elderly, lower-income, and minority patients with type 2 diabetes. Interventions are needed to overcome clinical inertia when patients might benefit from treatment intensification and improved glycemic control.
Dietary Glycemic Index, Glycemic Load, Cereal Fiber, and Plasma Adiponectin Concentration in Diabetic Men
Authors: Lu Qi, Eric Rimm, Simin Liu, Nader Rifai, Frank B. Hu
Journal: Diabetes Care (2005)

OBJECTIVE—Adiponectin may improve insulin sensitivity, reduce inflammation, and ameliorate glycemic control. However, few studies have evaluated dietary predictors of plasma adiponectin levels, especially among subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS—To examine the associations of dietary glycemic load, glycemic index, and fibers with plasma adiponectin levels, we conducted a cross-sectional analysis in 780 diabetic men from the Health Professionals’ Follow-up Study. Dietary information was obtained in 1986, 1990, and 1994 using semiquantitative food-frequency questionnaires. RESULTS—After adjustment for age, BMI, smoking, alcohol consumption, physical activity, aspirin use, HbA1c, history of hypertension or hypercholesterolemia, and fiber intake, dietary glycemic index and glycemic load were inversely associated with plasma adiponectin in a dose-dependent fashion (P for trend = 0.005 for glycemic index and 0.004 for glycemic load). Adiponectin levels were 13% lower in the highest quintile of dietary glycemic index than in the lowest quintile. For dietary glycemic load, adiponectin levels were 18% lower in the highest quintile than in the lowest. In contrast, high intake of cereal fiber was associated with increased plasma adiponectin levels, adjusting for lifestyle factors and dietary glycemic load (P for trend = 0.003). Adiponectin levels were 19% higher in the highest quintile than in the lowest quintile. Higher magnesium intake was also associated with increased plasma adiponectin. CONCLUSIONS—Diets low in glycemic load and high in fiber may increase plasma adiponectin concentrations in diabetic patients.
Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.
Authors: S Del Prato, R C Bonadonna, E Bonora, G Gulli, A Solini, M Shank, R A DeFronzo
Journal: Journal of Clinical Investigation (1993)

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.
Allogeneic blood cell transplantation following reduced-intensity conditioning is effective therapy for older patients with myelofibrosis with myeloid metaplasia
Authors: Steven M. Devine, Ron Hoffman, Amit Verma, Rajul Shah, Basil A. Bradlow, Wendy Stock, Vera Maynard, Ellen Jessop, David Peace, Marianne Huml, Deana Thomason, Yi-Hsiang Chen, Koen van Besien
Journal: Blood (2002)
Thrombogenic risk factors in patients who suffered a myocardial infarction under the age of 36 years
Authors: Loukianos S. Rallidis, Chrusula I. Belesi, Helen S. Manioudaki, Velsa C. Fakitsa, Vassilis K. Chatziioakimidis, Nikolaos P. Laoutaris, Thomas Apostolou, Evangelos G. Papasteriadis
Journal: Journal of the American College of Cardiology (2002)
Heme Oxygenase-1
Authors: Danielle Morse, Augustine M. K. Choi
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Section:ChooseTop of pageAbstract <<CONTENTSA BRIEF HISTORY OF HEME O...PRODUCTS OF HEME OXYGENAS...HEME OXYGENASE AND NITRIC...HEME OXYGENASE AND THE LU...EXHALED BREATH ANALYSIS O...SUMMARY AND FUTURE DIRECT...ReferencesCITING ARTICLES
Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates γ irradiation–induced thymic lymphoma development
Authors: Verena Labi, Miriam Erlacher, Stephan Kiessling, Claudia Manzl, Anna Frenzel, Lorraine O'Reilly, Andreas Strasser, Andreas Villunger
Journal: The Journal of Experimental Medicine (2008)

Members of the Bcl-2 protein family play crucial roles in the maintenance of tissue homeostasis by regulating apoptosis in response to developmental cues or exogenous stress. Proapoptotic BH3-only members of the Bcl-2 family are essential for initiation of cell death, and they function by activating the proapoptotic Bcl-2 family members Bax and/or Bak, either directly or indirectly through binding to prosurvival Bcl-2 family members. Bax and Bak then elicit the downstream events in apoptosis signaling. Mammals have at least eight BH3-only proteins and they are activated in a stimulus-specific, as well as a cell type–specific, manner. We have generated mice lacking the BH3-only protein Bcl-2–modifying factor (Bmf) to investigate its role in cell death signaling. Our studies reveal that Bmf is dispensable for embryonic development and certain forms of stress-induced apoptosis, including loss of cell attachment (anoikis) or UV irradiation. Remarkably, loss of Bmf protected lymphocytes against apoptosis induced by glucocorticoids or histone deacetylase inhibition. Moreover, bmf−/− mice develop a B cell–restricted lymphadenopathy caused by the abnormal resistance of these cells to a range of apoptotic stimuli. Finally, Bmf-deficiency accelerated the development of γ irradiation–induced thymic lymphomas. Our results demonstrate that Bmf plays a critical role in apoptosis signaling and can function as a tumor suppressor.