tbuckley/cabot-search huggingface dataset:
A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC
Authors: Dhruv K. Sethi, David A. Schubert, Anne-Kathrin Anders, Annie Heroux, Daniel A. Bonsor, Chantz P. Thomas, Eric J. Sundberg, Jason Pyrdol, Kai W. Wucherpfennig
Journal: The Journal of Experimental Medicine (2011)

Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-α chain with the MHC class II β chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3β loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3α loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand.
Encephalitogenic T cell clones specific for myelin basic protein. An unusual bias in antigen recognition.
Authors: S S Zamvil, P A Nelson, D J Mitchell, R L Knobler, R B Fritz, L Steinman
Journal: The Journal of Experimental Medicine (1985)

Class II-restricted T cell clones specific for myelin basic protein (MBP) have been generated from PL/J and (PL/J X SJL/J)F1 [((PLSJ)F1] mice following sensitization to rat MBP. Of 17 T cell clones generated from (PLSJ)F1 mice, 5 are I-Au(A alpha uA beta u) restricted, one is restricted to I-As(A alpha sA beta s), 10 are restricted to hybrid I-A(u X s)F1 (A alpha sA beta u) determinants, and one clone is restricted to hybrid I-E(u X s) (E alpha uE beta s) molecules. Thus, of 16 I-A-restricted T cell clones generated from (PLSJ)F1 mice, only one is I-As-restricted, reflecting a lack of priming to MBP in association with I-As. T cell clones restricted to I-Au and to I-E (E alpha u E beta s) molecules recognize mouse (self) MBP. Furthermore, only the five T cell clones restricted to I-Au molecules recognize a determinant in common with mouse (self) MBP within the encephalitogenic N-terminal peptide. Three such I-Au restricted T cell clones, derived independently, cause paralysis in 100% of (PL/J X SJL/J)F1 mice tested. Acute, chronic unremitting, and chronic relapsing paralysis are all induced following injection of these clones. Administration of greater numbers of cloned T cells causes acute and fatal experimental allergic encephalomyelitis, while administration of lower numbers of cloned T cells is associated with chronic unremitting and relapsing paralysis. Paralysis induced with T cell clones shares many clinical, immunologic, and histologic aspects with human demyelinating diseases such as multiple sclerosis. Histopathology reveals perivascular lymphocytic infiltration, demyelination, and remyelination. These studies demonstrate the utility of T cell clones for analyzing the association between class II major histocompatibility complex molecules and disease susceptibility.
Long-Term Dynamics of Bone Mineral Density During Intermittent Androgen Deprivation for Men With Nonmetastatic, Hormone-Sensitive Prostate Cancer
Authors: Evan Y. Yu, Kevin F. Kuo, Roman Gulati, Shu Chen, Teresa E. Gambol, Suzanne P. Hall, Peter Y. Jiang, Peggy Pitzel, Celestia S. Higano
Journal: Journal of Clinical Oncology (2012)

Purpose To investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer. Patients and Methods Men with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period. Results Fifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was −3.4% (P &lt; .001) for the spine and −1.2% (P = .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7+ years), BMD recovery at the spine was significant, with an average percentage change of +1.4% (P = .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8+) years on trial, one patient (1.8%) had a compression fracture associated with trauma. Conclusion Patients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare.
The Endomorphin System and Its Evolving Neurophysiological Role
Authors: Jakub Fichna, Anna Janecka, Jean Costentin, Jean-Claude Do Rego
Journal: Pharmacological Reviews (2007)

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH<sub>2</sub>) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH<sub>2</sub>) are two endogenous opioid peptides with high affinity and remarkable selectivity for the μ-opioid receptor. The neuroanatomical distribution of endomorphins reflects their potential endogenous role in many major physiological processes, which include perception of pain, responses related to stress, and complex functions such as reward, arousal, and vigilance, as well as autonomic, cognitive, neuroendocrine, and limbic homeostasis. In this review we discuss the biological effects of endomorphin-1 and endomorphin-2 in relation to their distribution in the central and peripheral nervous systems. We describe the relationship between these two μ-opioid receptor-selective peptides and endogenous neurohormones and neurotransmitters. We also evaluate the role of endomorphins from the physiological point of view and report selectively on the most important findings in their pharmacology.
ENZYMATIC ACTIVITY OF THE ISOLATED GLOMERULUS IN NORMAL AND NEPHROTIC RATS*
Authors: Ulrich C. Dubach, Lillian Recant
Journal: Journal of Clinical Investigation (1960)

Recent studies of the nephrotic kidney have implicated the glomerulus as the primary anatomic site of injury.Using the electron microscope, Farquhar, Vernier and Good (1) and other in- vestigators have demonstrated that the most con- sistent and striking alteration is a lesion in the foot process of the glomerular epithelial cell.Hjelt, Stjernvall and Hallman (2), in a study of con- genital nephrosis, found imperfectly formed or absent foot processes.Vernier, Papenmaster and Good (3), and Harkin and Recant (4) have de- scribed similar lesions of the foot process in experi- mental nephrosis induced by the aminonucleoside of Puromycin, and Piel (5) has made similar observations in nephrosis produced by antikidney serum.In the experimentally induced lesion, glomerular injury is found prior to tubular changes (4).With the recognition that relatively specific anatomic changes occur in the glomerulus in nephrosis, it seemed pertinent to determine if alterations occur in glomerular enzyme activities.The application of quantitative histochemical tech- niques seemed to be the most promising approach for such a study.Previous histochemical studies of kidney utiliz- ing staining techniques have been "qualitative" in nature in that they demonstrated the presence or absence of enzyme, but could not quantify these enzymes.In addition, such studies have given most attention to the renal tubule rather than to the glomerulus.
TCT-630 ENERGY 1'000 Subject Registry with a Thin Strut Bare Metal Stent with Passive Coating Presenting one Year MACE Data on Pre-Specified Subgroups
Authors: Raimund Erbel, Holger Eggebrecht, Ariel Roguin, Erwin Schroeder, Thomas Heitzer, Sebastian Philipp, Oded Ayzenberg, Harald Schwacke, Antonio Serra, Ton Slagboom
Journal: Journal of the American College of Cardiology (2012)
Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer
Authors: H. Borghaei, L. Paz-Ares, L. Horn, D. R. Spigel, M. Steins, N. E. Ready, L. Q. Chow, E. E. Vokes, E. Felip, E. Holgado, F. Barlesi, M. Kohlhufl, O. Arrieta, M. A. Burgio, J. Fayette, H. Lena, E. Poddubskaya, D. E. Gerber, S. N. Gettinger, C. M. Rudin, N. Rizvi, L. Crina, G. R. Blumenschein, S. J. Antonia, C. Dorange, C. T. Harbison, F. Graf Finckenstein, J. R. Brahmer
Journal: New England Journal of Medicine (2015)

Nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, disrupts PD-1-mediated signaling and may restore antitumor immunity.
ABC of ENT: Vertigo.
Authors: H Ludman
Journal: BMJ (1981)

Vertigo is an illusion of movement, when a patient wrongly believes that -' he or the environment is moving.It is not a synonym for imbalance; n .. L tvertigo is always associated with imbalance but imbalance is not always due to vertigo.C ,(>9 .~~~~~Correct balance requires (a) accurate sensory information from the eyes, proprioceptive receptors, and the vestibular labyrinth; (b) accurate co-ordination of this information within the brain; and (c) a functioning motor output from the central nervous system to a normal musculoskeletal system.A defect in any of these systems will impair balance.Vertigo occurs when the information from vestibular sources confficts with that from other sensory systems or when a disordered central integration system cannot coherently assess the body's movements from vestibular information.Vertigo is always a symptom of a vestibular defect.The defect may lie in the peripheral labyrinth or in its connections within 4 ' '-J -s4 XX-R 8 t; .-. sio.?-- thebrinthe brain stem, the cerebeflum, or the temporalobcrtx 'When severe it is usually accompanied by nausea and vomiting.Vertigo is caused by: (a) peripheral vestibular (labyrinthine) disorders; U a -: \ .\ -(b) central vestibular disorders, due to multiple sclerosis, tumours, infarcts, abscesses; and (c) external influences on the vestibular system; external influences include drugs, anaemia, hypoglycaemia, hypotension, viral infection, syphilis, and most important, becuase of its potential danger, erosion of the bony walls of the labyrinth by destructive middle ear disease.
Gene Dosage–limiting Role of<i>Aire</i>in Thymic Expression, Clonal Deletion, and Organ-specific Autoimmunity
Authors: Adrian Liston, Daniel H.D. Gray, Sylvie Lesage, Anne L. Fletcher, Judith Wilson, Kylie E. Webster, Hamish S. Scott, Richard L. Boyd, Leena Peltonen, Christopher C. Goodnow
Journal: The Journal of Experimental Medicine (2004)

Inactivation of the autoimmune regulator (Aire) gene causes a rare recessive disorder, autoimmune polyendocrine syndrome 1 (APS1), but it is not known if Aire-dependent tolerance mechanisms are susceptible to the quantitative genetic changes thought to underlie more common autoimmune diseases. In mice with a targeted mutation, complete loss of Aire abolished expression of an insulin promoter transgene in thymic epithelium, but had no effect in pancreatic islets or the testes. Loss of one copy of Aire diminished thymic expression of the endogenous insulin gene and the transgene, resulting in a 300% increase in islet-reactive CD4 T cells escaping thymic deletion in T cell receptor transgenic mice, and dramatically increased progression to diabetes. Thymic deletion induced by antigen under control of the thyroglobulin promoter was abolished in Aire homozygotes and less efficient in heterozygotes, providing an explanation for thyroid autoimmunity in APS1. In contrast, Aire deficiency had no effect on thymic deletion to antigen controlled by a systemic H-2K promoter. The sensitivity of Aire-dependent thymic deletion to small reductions in function makes this pathway a prime candidate for more subtle autoimmune quantitative trait loci, and suggests that methods to increase Aire activity would be a potent strategy to lower the incidence of organ-specific autoimmunity.
DNA Demethylating Agents Synergize with Oncolytic HSV1 against Malignant Gliomas
Authors: Kazuo Okemoto, Kazue Kasai, Benjamin Wagner, Amy Haseley, Hans Meisen, Chelsea Bolyard, Xiaokui Mo, Allison Wehr, Amy Lehman, Soledad Fernandez, Balveen Kaur, E. Antonio Chiocca
Journal: Clinical Cancer Research (2013)

Oncolytic viruses (OV) based on herpes simplex virus type 1 (HSV1) are being used in clinical trials for a variety of cancers. The OV, rQNestin34.5, uses a nestin promoter/enhancer to selectively drive robust viral replication in malignant glioma cells. We have discovered that this promoter becomes extensively methylated in infected glioma cells, reducing OV efficacy.We used demethylating drugs [5-azacytidine (5-Aza)], decitabine, or valproic acid (VPA) in both in vitro and in vivo malignant glioma models to determine if they improved the efficacy of rQNestin34.5 therapy.The use of demethylating agents, such as 5-Aza, improved OV replication and tumor cell lysis in vitro and, in fact, synergized pharmacologically on Chou-Talalay analysis. In vivo, the combination of the demethylating agents, 5-Aza or decitabine, with rQNestin34.5 significantly prolonged the survivorship of athymic mice harboring intracranial human glioma xenografts over single agent alone.These results, thus, provide further justification for the exploration of demethylating agents when combined with the OV, rQNestin34.5, in preclinical therapeutics and, possibly, clinical trials for malignant glioma.
Effect of Meal on Retinal Blood Flow in IDDM Patients
Authors: Paul M Sullivan, Vernon J Parfitt, Roger Jagoe, Richard Newsom, Eva M Kohner
Journal: Diabetes Care (1991)

Objective The effect of postprandial hyperglycemia on retinal blood flow was examined in 11 adults with insulin-dependent diabetes mellitus (IDDM) and 9 nondiabetic subjects. Research Design And Methods Retinal blood flow was measured with bidirectional laser Doppler velocimetry before and 60 and 120 min after a 50-g carbohydrate breakfast. Diabetic subjects were studied twice, being randomized to take their usual insulin (isoglycemic study) or to omit their morning short-acting insulin (hyperglycemic study). Nondiabetic subjects were studied once and received no insulin. Results Plasma glucose rose significantly (from 11.5 ± 5.2 to 22.1 ± 5.5 mM, P &amp;lt; 0.001) during the hyperglycemic study but not during the isoglycemic or nondiabetic studies. There were no significant changes in blood pressure or retinal blood flow in any of the groups studied. Conclusions Short-term hyperglycemia does not increase retinal blood flow.
High-Risk Medulloblastoma: A Pediatric Oncology Group Randomized Trial of Chemotherapy Before or After Radiation Therapy (POG 9031)
Authors: Nancy J. Tarbell, Henry Friedman, William R. Polkinghorn, Torunn Yock, Tianni Zhou, Zhengjia Chen, Peter Burger, Patrick Barnes, Larry Kun
Journal: Journal of Clinical Oncology (2013)

Purpose To compare event-free survival (EFS) in children with high-risk medulloblastoma randomly assigned to receive either chemotherapy before radiation or chemotherapy after radiation. Patients and Methods One hundred twelve patients were randomly assigned to each arm. Criteria used to categorize patients as high risk included M1-4 disease by modified Chang staging classification, T3b/T4 disease, or greater than 1.5 cm 3 of residual tumor after surgery. Postoperatively, children with high-risk medulloblastoma were randomly assigned to two arms, either chemotherapy entailing three cycles of cisplatin and etoposide before radiation (chemotherapy first [CT1]) or the same chemotherapy regimen after radiation (radiation therapy first [RT1]). Both groups received consolidation chemotherapy consisting of vincristine and cyclophosphamide. Results The median follow-up time was 6.4 years. Five-year EFS was 66.0% in the CT1 arm and 70.0% in the RT1 arm (P = .54), and 5-year overall survival in the two groups was 73.1% and 76.1%, respectively (P = .47). In the CT1 arm, 40 of the 62 patients with residual disease achieved either complete or partial remission. Conclusion Five-year EFS did not differ significantly whether, after surgery, patients received chemotherapy before or after radiotherapy.
Elevated Plasma Fibrinogen Associated with Reduced Pulmonary Function and Increased Risk of Chronic Obstructive Pulmonary Disease
Authors: MORTEN DAHL, ANNE TYBJŒRG-HANSEN, JØRGEN VESTBO, PETER LANGE, BØRGE G. NORDESTGAARD
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

We tested whether increased concentrations of the acute-phase reactant fibrinogen correlate with pulmonary function and rate of chronic obstructive pulmonary disease (COPD) hospitalization. We measured plasma fibrinogen and forced expiratory volume in 1 s (FEV1), and assessed prospectively COPD hospitalizations in 8,955 adults from the Danish general population. Smokers with plasma fibrinogen in the upper and middle tertile ( > 3.3 and 2.7–3.3 g/L) had 7% (95% confidence interval [CI]: 5–8%) and 2% (0–3%) lower percentage predicted FEV1 than smokers with fibrinogen in the lower tertile ( < 2.7 g/L). The equivalent decreases in nonsmokers were 6% (4–7%) and 0% ( − 1–2%), respectively. Individuals with plasma fibrinogen in the upper and middle tertile had COPD hospitalization rates of 93 and 60 compared with 52 per 10,000 person-years in individuals with fibrinogen in the lower tertile (log-rank: p < 0.001 and p = 0.31). After adjusting for age, body mass index, sex, pack-years, and recent respiratory infections, relative risks for COPD hospitalization were 1.7 (95% CI: 1.1–2.6) and 1.4 (0.9–2.1) in individuals with fibrinogen in the upper and middle versus lower tertile. In conclusion, elevated plasma fibrinogen was associated with reduced FEV1 and increased risk of COPD. This could not be explained by smoking alone.Keywords: fibrinogen; pulmonary function; epidemiology; airway inflammation; COPD
A 71-yr-old male with increasing dyspnoea, cough and an intrathoracic mass
Authors: E. Seebus, B. Vrugt, R.S. de Jong, R. Aalbers
Journal: European Respiratory Journal (2003)

A 71‐year-old White male was referred to the Martini Hospital for evaluation of progressive shortness of breath, tiredness, a nonproductive cough and night sweats. Until the beginning of his complaints a few weeks before, he felt healthy and skated 40 km per week. His appetite was good, he had not lost weight, had no skin or joint disorders and no thoracic pain.

His medical history revealed a partial gastrectomy and duodenectomy for persistent ulcers and bronchitis in his childhood. Exposure to asbestos was uncertain. There were no family related diseases. He did not use any medication, but had smoked over 50 pack-yrs and drank alcohol occasionally. He had been a cook in the navy and a swimming instructor.

Routine physical examination showed a vital, healthy-looking man with finger clubbing, decreased breathing sounds and dullness to percussion at the dorsal inferior part of the right hemithorax. There were no palpable lymph nodes, no signs of osteoarthropathy and the liver was not enlarged.

Routine laboratory findings and arterial blood-gas analysis showed no abnormalities, except for the blood sedimentation rate of 71 mm·h−1 (normal <10 mm·h−1), C‐reactive protein of 32 mg·mL−1 (normal <8 mg·mL−1), alkaline phosphatase of 260 U·L−1 (normal <130 U·L−1) and γ‐glutamyl transpeptidase of 85 U·L−1 (normal <50 U·L−1). The electrocardiogram was normal.

A chest radiograph (fig. 1⇓) was taken, followed by a bronchoscopy, which showed no abnormalities. Further investigation included ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) of the thorax (fig. 2⇓) and angiography.



Fig. 1.— 
Chest radiograph: frontal projection.





Fig. 2.— 
Magnetic resonance imaging of the thorax.



Spirography demonstrated a total lung volume capacity …
Vascular Risk Factors and Markers of Endothelial Function as Determinants of Inflammatory Markers in Type 1 Diabetes
Authors: Miranda T. Schram, Nish Chaturvedi, Casper Schalkwijk, Francesco Giorgino, Pertti Ebeling, John H. Fuller, Coen D. Stehouwer
Journal: Diabetes Care (2003)

OBJECTIVE—Inflammatory activity is increased in type 1 diabetes and may predispose to vascular disease. Its origin is not clear. We therefore investigated determinants of inflammation in type 1 diabetes. RESEARCH DESIGN AND METHODS—We performed a nested case-control study from the EURODIAB Prospective Complications Study of 543 European individuals having type 1 diabetes (278 men), diagnosed at &amp;lt;36 years of age. Case subjects (n = 348) were those with one or more complications of diabetes; control subjects (n = 195) were all those with no evidence of any complication. We determined levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α, combined them in a “general score of inflammatory markers,” and investigated their associations with vascular risk factors and markers of endothelial dysfunction by use of multiple linear regression analysis. RESULTS—Measures of inflammation were associated with sex, diabetes duration, glycemic control, the advanced glycation end product pentosidine, BMI, HDL cholesterol, triglycerides, and systolic blood pressure (standardized βs with the general score of inflammatory markers 0.15 [P = 0.002], 0.15 [P = 0.006], 0.18 [P &amp;lt; 0.0001], 0.12 [P = 0.005], 0.10 [P = 0.057], −0.15 [P = 0.001], 0.16 [P &amp;lt; 0.0001], and 0.09 [P = 0.042], respectively). In addition, measures of inflammation were strongly associated with markers of endothelial dysfunction, soluble vascular cell adhesion molecule-1, and soluble E-selectin (standardized βs with the general score of inflammatory markers 0.28 [P &amp;lt; 0.0001] and 0.19 [P &amp;lt; 0.0001]). CONCLUSIONS—We have shown that conventional risk factors for vascular disease and endothelial adhesion molecules are important determinants of inflammation in type 1 diabetic individuals, suggesting that strategies to decrease inflammatory activity in type 1 diabetes should focus not only on control of conventional risk factors, but also on improvement of endothelial function.