tbuckley/cabot-search huggingface dataset:
Melanocortin ligands: 30 years of structure–activity relationship (SAR) studies
Authors: Jerry Ryan Holder, Carrie Haskell‐Luevano
Journal: Medicinal Research Reviews (2004)

Abstract The challenge of peptide and peptidomimetic research is the development of methods and techniques to improve the biological properties of native peptides and to convert peptide ligands into non‐peptide compounds. Improved biological properties of peptides includes enhancement of stability, potency, and receptor selectivity, for both in vivo and in vitro applications. The design of a ligand with specific activity and desired biological properties is a complex task, and, to accomplish this objective, knowledge about putative interactions between a ligand and the corresponding receptor will be valuable. This includes interactions for both the binding and signal transduction processes. Structure–activity relationship (SAR) studies involve systematic modification of a lead peptide and are designed to provide insight into potential interactions involved in the formation of the ligand–receptor complex. It is desirable to have knowledge about both favorable and unfavorable processes that may occur in putative ligand–receptor interactions that result in either receptor stimulation or inhibition. Herein, we discuss various SAR studies that have involved melanocortin peptides over three decades and the information these studies have provided to the melanocortin field. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 3, 325–356, 2004
To TOE or not to TOE? That is the question in patients with portal hypertension and varices: Table 1
Authors: Christopher Leung, Sern Wei Yeoh, Lucy Y Lim, Ray Boyapati, Adam G Testro, Rhys Vaughan, Kaye Marion, Louise M Burrell, Peter W Angus
Journal: Gut (2012)

We read with interest your recently published review by Cardenas and Gines on patients with cirrhosis, awaiting liver transplantation,1 with an emphasis on the high morbidity and mortality with variceal bleeding. Such patients may require a transoesophageal echocardiogram (TOE) to assess cardiorespiratory abnormalities potentially precluding a transplant, as well as for intraoperative haemodynamic monitoring and for investigation for endocarditis. However, the safety of performing a TOE in such patients is debated by clinicians due to the perceived risk of postprocedural bleeding.2 Three small studies have analysed post-TOE bleeding complications in patients with varices, having reported no bleeding in 26, 14 and 23 patients.3–5 We hypothesised that direct external trauma by the echocardiographic probe is unlikely to cause significant bleeding, as variceal bleeding is primarily caused by wall tension, a function of increasing variceal diameter and internal pressure.6 We therefore audited post-TOE bleeding rates at an Australian liver transplant referral centre in patients who had both varices or portal hypertension and a TOE based on International Classification of Diseases 10 coding from 1995 …
Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I
Authors: William J. Zinnanti, Jelena Lazovic, Cathy Housman, Kathryn LaNoue, James P. O’Callaghan, Ian Simpson, Michael Woontner, Stephen I. Goodman, James R. Connor, Russell E. Jacobs, Keith C. Cheng
Journal: Journal of Clinical Investigation (2007)

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I.
Structural characteristics of the variable regions of immunoglobulin genes encoding a pathogenic autoantibody in murine lupus.
Authors: B P Tsao, F M Ebling, C Roman, N Panosian-Sahakian, K Calame, B H Hahn
Journal: Journal of Clinical Investigation (1990)

We have studied several monoclonal anti-double-stranded (ds) DNA antibodies for their ability to accelerate lupus nephritis in young NZB X NZW F1 female mice and to induce it in BALB/c mice. Two identified as pathogens in both strains have characteristics previously associated with nephritogenicity: expression of IgG2a isotype and IdGN2 idiotype. Both pathogenic antibodies used the combination of genes from the VHJ558 and VK9 subfamilies. Two weak pathogens failed to accelerate nephritis in young BW mice, but induced lupus nephritis in BALB/c mice. They both express IdGN2; one is cationic and an IgG3, the other is an IgG2a. Additional MAbs (some IgG2a, one IdGN2-positive) did not accelerate or induce nephritis. We have cloned and sequenced the variable regions of the immunoglobulin genes of one pathogenic autoantibody. No unique V, D, or J gene segments and no evidence of unusual mechanisms in generating diversity were used to construct this antibody. These data argue against use of unique abnormal Ig genes by systemic lupus erythematosus individuals to construct pathogenic autoantibody subsets. Instead, the major abnormality may be immunoregulatory.
Hormonal Control of DNA Synthesis: Altered Responsiveness of Hyperplastic Alveolar Nodules of Mouse Mammary Gland&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: M. R. Banerjee
Journal: JNCI Journal of the National Cancer Institute (1969)

The effect of ovariectomy on DNA synthesis in two types of outgrowths of hyperplastic alveolar nodules (HAN) of C3H and BALB/c mouse mammary gland was determined by autoradiography. DNA synthesis in normal mammary-gland cells of both C3H and BALB/c virgin hosts was virtually stopped after bilateral ovariectomy. DNA synthesis in the outgrowths of mammary-tumor-virus-induced HAN of C3H mice could continue in castrated hosts, and its extent remained essentially unaltered. But DNA synthesis in outgrowths of hormone-induced HAN of BALB/c females was markedly reduced after removal of the ovaries. Results strongly indicate that DNA synthesis in C3H-HAN tissue is independent of the ovaries, whereas in BALB/c-HAN outgrowths, the ovaries are essential to maintain the comparatively high tritiated thymidine labeling index. Data on the average number of silver grains per nucleus in C3H-HAN and BALB/c-HAN outgrowths remained essentially unaltered after ovariectomy. Thus the decreased labeling index in BALB/c-HAN after castration might be due to the inability of the cells to enter the S phase rather than a failure of the DNA replication process itself. It has been suggested that the sustained DNA synthesis in C3H-HAN might be the result of alterations of some precursor steps of DNA synthesis which are normally under host hormonal control.
Effects of cyclo-oxygenase inhibition on vasodilatory response to acetylcholine in patients with type 1 diabetes and nondiabetic subjects.
Authors: D R Meeking, D L Browne, S Allard, J Munday, P J Chowienczyck, K M Shaw, M H Cummings
Journal: Diabetes Care (2000)

Studies examining vasodilatory responses to acetylcholine (ACh) and its derivatives have been conflicting. Enhanced activation of the cyclo-oxygenase pathway and increased availability of vasodilatory prostanoids may occur in type 1 diabetes, and this may compensate for the observed reduction in nitric oxide (NO) activity We examined the role of cyclo-oxygenase inhibition on vasodilatory responses in 12 healthy normotensive type 1 diabetic adults and 12 nondiabetic control subjects of similar age, sex, and BMI.Forearm blood flow was measured using a venous occlusion plethysmography technique at baseline and after brachial artery infusions of ACh (7.5, 15, and 30 microg/min). Forearm blood flow at baseline and after ACh was then reexamined after local intra-arterial infusion of indomethacin (0.3 mg/100 ml forearm volume), a cyclo-oxygenase inhibitor.Baseline blood flow in the diabetic and control groups were similar (2.65 +/- 0.26 vs. 2.59 +/- 0.20 ml/min per 100 ml, respectively; P = 0.4). After indomethacin infusion, the vasodilatory responses to all doses of ACh were reduced in both the diabetic (by 25.30 +/- 4.90%) and control group (by 11.23 +/- 5.45%). However, the reduction in blood flow response to ACh after indomethacin was greater in diabetic patients compared with control subjects (P = 0.03).Our findings suggest that vasodilatory, prostanoids are important in determining endothelial response to ACh in diabetic and nondiabetic subjects. Increased prostaglandin-mediated vasodilation may compensate for attenuated responses to NO previously reported in diabetic subjects. These findings may partly explain the conflicting reports of endothelial dysfunction in patients with type 1 diabetes.
ApoE genotype, past adult lead exposure, and neurobehavioral function.
Authors: Walter F Stewart, Brian S Schwartz, David Simon, Karl Kelsey, Andrew C Todd
Journal: Environmental Health Perspectives (2002)

Our objective in this study was to determine if the known relation between tibia bone lead levels and neurobehavioral test scores are influenced by the apolipoprotein E (ApoE) genotype. We collected data on 20 neurobehavioral tests in 529 former organolead workers who had an average of 16 years since last occupational exposure to lead. We used linear regression to model the relations between each of 20 neurobehavioral test scores and tibia lead, a binary variable for ApoE genotype (i.e., at least one Epsilon4 allele vs. none), and an interaction term between tibia lead and the binary term for ApoE genotype. At the time of testing, former lead workers were an average of 57.6 years of age; 82% were younger than 65 years. In regression analysis, we observed one statistically significant and one borderline significant coefficient for ApoE genotype alone. Coefficients for the ApoE and tibia lead interaction term were negative in 19 of the 20 regression models. This indicates that the slope for the relation between tibia lead and each neurobehavioral test was more negative for individuals with at least one Epsilon4 allele than for those who did not have an Epsilon4 allele. Four of 19 negative coefficients for the interaction term were statistically significant (digit symbol, Purdue pegboard assembly, Purdue pegboard-dominant hand, complex reaction time); another three of the remaining 16 coefficients (symbol digit, trail-making A, Stroop) were borderline significant (i.e., p < 0.10). This study suggests that individuals may vary in susceptibility to the long-term effects of lead on the central nervous system (CNS). In particular, the persistent CNS effect of lead may be more toxic in individuals who have at least one ApoE-Epsilon4 allele.
Mycobacterium tuberculosis Induces Interleukin-32 Production through a Caspase- 1/IL-18/Interferon-γ-Dependent Mechanism
Authors: Mihai G Netea, Tania Azam, Eli C Lewis, Leo A. B Joosten, Maorong Wang, Dennis Langenberg, Xianzhong Meng, Edward D Chan, Do-Young Yoon, Tom Ottenhoff, Soo-Hyun Kim, Charles A Dinarello
Journal: PLoS Medicine (2006)

Background Interleukin (IL)–32 is a newly described proinflammatory cytokine that seems likely to play a role in inflammation and host defense. Little is known about the regulation of IL-32 production by primary cells of the immune system. Methods and Findings In the present study, freshly obtained human peripheral blood mononuclear cells were stimulated with different Toll-like receptor (TLR) agonists, and gene expression and synthesis of IL-32 was determined. We demonstrate that the TLR4 agonist lipopolysaccharide induces moderate (4-fold) production of IL-32, whereas agonists of TLR2, TLR3, TLR5, or TLR9, each of which strongly induced tumor necrosis factor α and IL-6, did not stimulate IL-32 production. However, the greatest amount of IL-32 was induced by the mycobacteria Mycobacterium tuberculosis and M. bovis BCG (20-fold over unstimulated cells). IL-32-induced synthesis by either lipopolysaccharide or mycobacteria remains entirely cell-associated in monocytes; moreover, steady-state mRNA levels are present in unstimulated monocytes without translation into IL-32 protein, similar to other cytokines lacking a signal peptide. IL-32 production induced by M. tuberculosis is dependent on endogenous interferon-γ (IFNγ); endogenous IFNγ is, in turn, dependent on M. tuberculosis–induced IL-18 via caspase-1. Conclusions In conclusion, IL-32 is a cell-associated proinflammatory cytokine, which is specifically stimulated by mycobacteria through a caspase-1- and IL-18-dependent production of IFNγ.
LMO2 Protein Expression Predicts Survival in Patients With Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Based Chemotherapy With and Without Rituximab
Authors: Yasodha Natkunam, Pedro Farinha, Eric D. Hsi, Christine P. Hans, Robert Tibshirani, Laurie H. Sehn, Joseph M. Connors, Dita Gratzinger, Manuel Rosado, Shuchun Zhao, Brad Pohlman, Nicholas Wongchaowart, Martin Bast, Abraham Avigdor, Ginette Schiby, Arnon Nagler, Gerald E. Byrne, Ronald Levy, Randy D. Gascoyne, Izidore S. Lossos
Journal: Journal of Clinical Oncology (2007)

The heterogeneity of diffuse large B-cell lymphoma (DLBCL) has prompted the search for new markers that can accurately separate prognostic risk groups. We previously showed in a multivariate model that LMO2 mRNA was a strong predictor of superior outcome in DLBCL patients. Here, we tested the prognostic impact of LMO2 protein expression in DLBCL patients treated with anthracycline-based chemotherapy with or without rituximab.DLBCL patients treated with anthracycline-based chemotherapy alone (263 patients) or with the addition of rituximab (80 patients) were studied using immunohistochemistry for LMO2 on tissue microarrays of original biopsies. Staining results were correlated with outcome.In anthracycline-treated patients, LMO2 protein expression was significantly correlated with improved overall survival (OS) and progression-free survival (PFS) in univariate analyses (OS, P = .018; PFS, P = .010) and was a significant predictor independent of the clinical International Prognostic Index (IPI) in multivariate analysis. Similarly, in patients treated with the combination of anthracycline-containing regimens and rituximab, LMO2 protein expression was also significantly correlated with improved OS and PFS (OS, P = .005; PFS, P = .009) and was a significant predictor independent of the IPI in multivariate analysis.We conclude that LMO2 protein expression is a prognostic marker in DLBCL patients treated with anthracycline-based regimens alone or in combination with rituximab. After further validation, immunohistologic analysis of LMO2 protein expression may become a practical assay for newly diagnosed DLBCL patients to optimize their clinical management.
Remission of Type 2 Diabetes Mellitus in Patients After Different Types of Bariatric Surgery
Authors: Jan Peter Yska, Eric N. van Roon, Anthonius de Boer, Hubert G. M. Leufkens, Bob Wilffert, Loek J. M. de Heide, Frank de Vries, Arief Lalmohamed
Journal: JAMA Surgery (2015)

To our knowledge, an observational study on the remission of type 2 diabetes mellitus (T2DM) after different types of bariatric surgery based on data from general practice has not been carried out.To assess the effect of different types of bariatric surgery in patients with T2DM on diabetes remission compared with matched control patients, and the effect of the type of bariatric surgery on improvement of glycemic control and related clinical parameters.A retrospective cohort study conducted from May 2013 to May 2014 within the Clinical Practice Research Datalink involving 2978 patients with a record of bariatric surgery (2005-2012) and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or greater. We identified 569 patients with T2DM and matched them to 1881 patients with diabetes without bariatric surgery. Data on the use of medication and laboratory results were evaluated.Bariatric surgery, stratified by type of surgery (gastric banding, Roux-en-Y gastric bypass, sleeve gastrectomy, or other/unknown).Remission of T2DM (complete discontinuation of glycemic therapy, accompanied with a subsequently recorded hemoglobin A1c level<6.0%).Among patients undergoing bariatric surgery, we found a prevalence of 19.1% for T2DM. Per 1000 person-years, 94.5 diabetes mellitus remissions were found in patients who underwent bariatric surgery compared with 4.9 diabetes mellitus remissions in matched control patients. Patients with diabetes who underwent bariatric surgery had an 18-fold increased chance for T2DM remission (adjusted relative rate [RR], 17.8; 95% CI, 11.2-28.4) compared with matched control patients. The greatest effect size was observed for gastric bypass (adjusted RR, 43.1; 95% CI, 19.7-94.5), followed by sleeve gastrectomy (adjusted RR, 16.6; 95% CI, 4.7-58.4) and gastric banding (adjusted RR, 6.9; 95% CI, 3.1-15.2). Body mass index and triglyceride, blood glucose, and hemoglobin A1c levels sharply decreased during the first 2 years after bariatric surgery.Population-based data show that bariatric surgery strongly increases the chance for remission of T2DM. Gastric bypass and sleeve gastrectomy have a greater effect than gastric banding. Although the risks and possible adverse effects of surgery should be weighed against its benefits, bariatric surgery and, in particular, gastric bypass or sleeve gastrectomy may be considered as new treatment options for T2DM.
Sleep-disordered Breathing in Newborn Mice Heterozygous for the Transcription Factor Phox2b
Authors: Estelle Durand, Stéphane Dauger, Alexandre Pattyn, Claude Gaultier, Christo Goridis, Jorge Gallego
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Central congenital hypoventilation syndrome (CCHS) is a rare autosomal dominant syndrome present from birth, and characterized by depressed ventilation during sleep. Heterozygous mutations of the homeobox gene Phox2b were recently found in a very high proportion of patients.To determine whether newborn mice with heterozygous targeted deletion of the transcription factor Phox2b would display sleep-disordered breathing.We measured breathing pattern using whole-body plethysmography in wild-type and mutant 5-day-old mice, and we classified sleep-wake states using nuchal EMG and behavioral scores.We found that sleep apnea total time was approximately six times longer (8.9 +/- 12 vs. 1.5 +/- 2.2 seconds, p < 0.0015), and ventilation during active sleep was 21% lower (18.4 +/- 5.1 vs. 23.3 +/- 5.5 ml/g/second, p < 0.006) in mutant than in wild-type pups. During wakefulness, apnea time and ventilation were not significantly different between mutant and wild-type pups. Mutant and wild-type pups showed highly similar sleep-wake states.Although their respiratory phenotype was much less severe than CCHS, the Phox2b(+/-) mutant mice showed sleep-disordered breathing, which partially modeled the key feature of CCHS.
MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion
Authors: Antonella Spinazzola, Carlo Viscomi, Erika Fernandez-Vizarra, Franco Carrara, Pio D'Adamo, Sarah Calvo, René Massimiliano Marsano, Claudia Donnini, Hans Weiher, Pietro Strisciuglio, Rossella Parini, Emmanuelle Sarzi, Alicia Chan, Salvatore DiMauro, Agnes Rötig, Paolo Gasparini, Iliana Ferrero, Vamsi K Mootha, Valeria Tiranti, Massimo Zeviani
Journal: Nature Genetics (2006)
Differences in the antibody response to a mucosal bacterial antigen between allergic and non-allergic subjectsSmoke-free legislation reduces exposure in children
Authors: B J Hales, L J Pearce, M M H Kusel, P G Holt, P D Sly, W R Thomas
Journal: Thorax (2007)

The immune response to bacterial antigens on mucosal surfaces may be modified in individuals allergic to aeroallergens due to a maturational or genetic difference or from the interaction between inhaled allergens and bacteria at the mucosa.Plasma from children and adults allergic (n = 97) and non-allergic (n = 54) to aeroallergens were initially tested for IgG1 (Th1) and IgG4 (Th2) reactivity to P6, a conserved outer membrane protein of Haemophilus influenzae. IgE binding was measured for some allergic donors. The development of the antibody responses to P6 was subsequently examined in the plasma from 35 children aged 1, 2 and 5 years taken from a prospective birth cohort.IgG4 antibodies to P6 were more readily detected in allergic subjects than in non-allergic subjects (p<0.001), with a strong bias to the male gender. Some allergic subjects (35%) also had IgE antibody (1-10 ng/ml) that was not associated with IgG4 or gender. In the cohort study of infants, subjects who developed skin prick test positivity to mite allergens by 5 years of age had an 85% reduction in the IgG1 anti-P6 antibody at year 2 (p<0.05) and, unlike skin test negative infants, this group had IgG4 anti-P6 antibodies at 5 years of age.The antibodies of subjects allergic to a bacterial antigen included IgE and IgG4 (particularly for males) compared with the almost exclusive IgG1 response of non-allergic subjects. The IgG1 responses of 2-year-old children who became skin test positive was markedly reduced and P6-specific IgG4 became detectable at 5 years of age.
Risk Factors for Mortality Among Patients With Diabetes
Authors: Laura N. McEwen, Catherine Kim, Andrew J. Karter, Mary N. Haan, Debashis Ghosh, Paula M. Lantz, Carol M. Mangione, Theodore J. Thompson, William H. Herman
Journal: Diabetes Care (2007)

We sought to examine demographic, socioeconomic, and biological predictors of all-cause, cardiovascular, and noncardiovascular mortality in patients with diabetes.Survey, medical record, and administrative data were obtained from 8,733 participants in the Translating Research Into Action for Diabetes Study, a multicenter, prospective, observational study of diabetes care in managed care. Data on deaths (n = 791) and cause of death were obtained from the National Death Index after 4 years. Predictors examined included age, sex, race, education, income, duration, and treatment of diabetes, BMI, smoking, microvascular and macrovascular complications, and comorbidities.Predictors of adjusted all-cause mortality included older age (hazard ratio [HR] 1.04 [95% CI 1.03-1.05]), male sex (1.57 [1.35-1.83]), lower income (< $15,000 vs. > $75,000, HR 1.82 [1.30-2.54]; $15,000-$40,000 vs. > $75,000, HR 1.58 [1.15-2.17]), longer duration of diabetes (> or = 9 years vs. < 9 years, HR 1.20 [1.02-1.41]), lower BMI (< 26 vs. 26-30 kg/m2, HR 1.43 [1.13-1.69]), smoking (1.44 [1.20-1.74]), nephropathy (1.46 [1.23-2.73]), macrovascular disease (1.46 [1.23-1.74]), and greater Charlson index (> or = 2-3 vs. < 1, HR 2.01 [1.04-3.90]; > or = 3 vs. < 1, HR 4.38 [2.26-8.47]). The predictors of cardiovascular and noncardiovascular mortality were different. Macrovascular disease predicted cardiovascular but not noncardiovascular mortality.Among people with diabetes and access to medical care, older age, male sex, smoking, and renal disease are important predictors of mortality. Even within an insured population, socioeconomic circumstance is an important independent predictor of health.