tbuckley/cabot-search huggingface dataset:
Cytosolic phospholipase A2α–deficient mice are resistant to experimental autoimmune encephalomyelitis
Authors: Suzana Marusic, Michael W. Leach, Jeffrey W. Pelker, Mihai L. Azoitei, Naonori Uozumi, Junqing Cui, Marina W.H. Shen, Charlene M. DeClercq, Joy S. Miyashiro, Brenda A. Carito, Paresh Thakker, David L. Simmons, John P. Leonard, Takao Shimizu, James D. Clark
Journal: The Journal of Experimental Medicine (2005)

Experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the central nervous system (CNS), is a model of human multiple sclerosis. Cytosolic phospholipase A2α (cPLA2α), which initiates production of prostaglandins, leukotrienes, and platelet-activating factor, is present in EAE lesions. Using myelin oligodendrocyte glycoprotein (MOG) immunization, as well as an adoptive transfer model, we showed that cPLA2α−/− mice are resistant to EAE. Histologic examination of the CNS from MOG-immunized mice revealed extensive inflammatory lesions in the cPLA2α+/− mice, whereas the lesions in cPLA2α−/− mice were reduced greatly or completely absent. MOG-specific T cells generated from WT mice induced less severe EAE in cPLA2α−/− mice compared with cPLA2α+/− mice, which indicates that cPLA2α plays a role in the effector phase of EAE. Additionally, MOG-specific T cells from cPLA2α−/− mice, transferred into WT mice, induced EAE with delayed onset and lower severity compared with EAE that was induced by control cells; this indicates that cPLA2α also plays a role in the induction phase of EAE. MOG-specific T cells from cPLA2α−/− mice were deficient in production of Th1-type cytokines. Consistent with this deficiency, in vivo administration of IL-12 rendered cPLA2α−/− mice susceptible to EAE. Our data indicate that cPLA2α plays an important role in EAE development and facilitates differentiation of T cells toward the Th1 phenotype.
Effects of Gut-Targeted 15-LOX-1 Transgene Expression on Colonic Tumorigenesis in Mice
Authors: Xiangsheng Zuo, Zhanglong Peng, Yuanqing Wu, Micheline J. Moussalli, Xiu L. Yang, Yan Wang, Jan Parker-Thornburg, Jeffrey S. Morris, Russell R. Broaddus, Susan M. Fischer, Imad Shureiqi
Journal: JNCI Journal of the National Cancer Institute (2012)

Expression of 15-lipoxygenase-1 (15-LOX-1) is decreased in many human cancers; however, the mechanistic significance of its decreased expression has been difficult to determine because its mouse homolog 12/15-LOX has opposing functions. We generated a mouse model in which expression of a human 15-LOX-1 transgene was targeted to the intestinal epithelium via the villin promoter. Targeted expression was confirmed by real-time reverse transcription–polymerase chain reaction and immunoblotting. When the 15-LOX-1 transgene was expressed in colonic epithelial cells of two independent mouse lines (B6 and FVB), azoxymethane-inducible colonic tumorigenesis was suppressed (mean number of tumors: wild type [WT] = 8.2, 15-LOX-1+/− = 4.91, 15-LOX-1+/+ = 3.57; WT vs 15-LOX-1+/− two-sided P = .003, WT vs 15-LOX-1+/+ two-sided P < .001; n = 10–14 mice per group). 15-LOX-1 transgene expression was always decreased in the tumors that did develop. In the presence of expression of the 15-LOX-1 transgene, expression of tumor necrosis factor alpha and its target inducible nitric oxide synthase were decreased and activation of nuclear factor-kappa B in colonic epithelial cells was inhibited.
Spatial Nonuniformity of Excitation–Contraction Coupling Causes Arrhythmogenic Ca <sup>2+</sup> Waves in Rat Cardiac Muscle
Authors: Yuji Wakayama, Masahito Miura, Bruno D. Stuyvers, Penelope A. Boyden, Henk E.D.J. ter Keurs
Journal: Circulation Research (2005)

Ca 2+ waves underlying triggered propagated contractions (TPCs) are initiated in damaged regions in cardiac muscle and cause arrhythmias. We studied Ca 2+ waves underlying TPCs in rat cardiac trabeculae under experimental conditions that simulate the functional nonuniformity caused by local mechanical or ischemic local damage of myocardium. A mechanical discontinuity along the trabeculae was created by exposing the preparation to a small jet of solution with a composition that reduces excitation–contraction coupling (ECC) in myocytes within that segment. The jet solution contained either caffeine (5 mmol/L), 2,3-butanedione monoxime (BDM; 20 mmol/L), or low Ca 2+ concentration ([Ca 2+ ]; 0.2 mmol/L). Force was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques in 15 trabeculae. Simultaneously, [Ca 2+ ] i was measured locally using epifluorescence of Fura-2. The jet of solution was applied perpendicularly to a small muscle region (200 to 300 μm) at constant flow. When the jet contained caffeine, BDM, or low [Ca 2+ ], during the stimulated twitch, muscle-twitch force decreased and the sarcomeres in the exposed segment were stretched by shortening normal regions outside the jet. Typical protocols for TPC induction (7.5 s-2.5 Hz stimulus trains at 23°C; [Ca 2+ ] o =2.0 mmol/L) reproducibly generated Ca 2+ waves that arose from the border between shortening and stretched regions. Such Ca 2+ waves started during force-relaxation of the last stimulated twitch of the train and propagated (0.2 to 2.8 mm/sec) into segments both inside and outside of the jet. Arrhythmias, in the form of nondriven rhythmic activity, were induced when the amplitude of the Ca 2+ -wave was increased by raising [Ca 2+ ] o . Arrhythmias disappeared rapidly when uniformity of ECC throughout the muscle was restored by turning the jet off. These results show, for the first time, that nonuniform ECC can cause Ca 2+ waves underlying TPCs and suggest that Ca 2+ dissociated from myofilaments plays an important role in the initiation of Ca 2+ waves.
Towards an understanding of organic anion transporters: Structure-function relationships
Authors: Guofeng You
Journal: Medicinal Research Reviews (2004)

Organic anion transporters (OAT) play essential roles in the body disposition of clinically important anionic drugs, including anti-viral drugs, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. The activities of OATs are directly linked to drug toxicity and drug-drug interactions. So far, four members of the OAT family have been identified: OAT1, OAT2, OAT3, and OAT4. These transporters share several common structural features including 12 transmembrane domains, multiple glycosylation sites localized in the first extracellular loop between transmembrane domains 1 and 2, and multiple phosphorylation sites present in the intracellular loop between transmembrane domains 6 and 7, and in the carboxyl terminus. The impact of these structural features on the function of these transporters has just begun to be explored. In the present review, the author will summarize recent progress made from her laboratory as well as from others, on the molecular characterization of the structure-function relationships of OATs, including particular amino acid residues/regions of the transporter protein ("molecular domains") that potentially determine transport characteristics.
Experimental Ascorbic Acid Deficiency
Authors: J. D. Andrew
Journal: BMJ (1949)

MRDIIRNA 1273 organs and may affect any part of any organ of the body.Difficulty in diagnosis arises if the possibility of malaria is not thought of, and examination of the blood (if necessary, repeated examinations) is essential for a definite diagnosis.Early detection and immediate specific treatment will save many lives: one cannot afford to wait long under such critical conditions.
NH2-Terminal Probrain Natriuretic Peptide Is Associated With Diabetes Complications in the EURODIAB Prospective Complications Study
Authors: Gabriella Gruden, Federica Barutta, Nish Chaturvedi, Casper Schalkwijk, Coen D. Stehouwer, Silvia Pinach, Maria Manzo, Maria Loiacono, Marinella Tricarico, Giulio Mengozzi, Daniel R. Witte, John H. Fuller, Paolo Cavallo Perin, Graziella Bruno
Journal: Diabetes Care (2012)

Circulating levels of NH(2)-terminal probrain natriuretic peptide (NT-proBNP), a marker of acute heart failure, are associated with increased risk of cardiovascular disease (CVD) in the general population. However, there is little information on the potential role of NT-proBNP as a biomarker of vascular complications in type 1 diabetic patients. We investigated whether serum NT-proBNP levels were associated with micro- and macrovascular disease in type 1 diabetic subjects.A cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 507 type 1 diabetic patients was performed. Case subjects (n = 345) were defined as those with one or more complications of diabetes; control subjects (n = 162) were those with no evidence of any complication. We measured NT-proBNP levels by a two-site sandwich electrochemiluminescence immunoassay and investigated their associations with complications.Mean NT-proBNP levels were significantly higher in case than in control subjects. In logistic regression analyses, NT-proBNP values >26.46 pg/mL were independently associated with a 2.56-fold increased risk of all complications. Odds ratios of CVD (3.95 [95% CI 1.26-12.35]), nephropathy (4.38 [1.30-14.76]), and distal symmetrical polyneuropathy (4.32 [1.41-13.23]) were significantly increased in patients with NT-proBNP values in the highest quartile (>84.71 pg/mL), independently of renal function and known risk factors. These associations were no longer significant after inclusion of TNF-α into the model.In this large cohort of type 1 diabetic subjects, we found an association between NT-proBNP and diabetic micro- and macrovascular complications. Our results suggest that the inflammatory cytokine TNF-α may be involved in this association.
The Impact of Insurance Status on Tumor Characteristics and Treatment Selection in Contemporary Patients With Prostate Cancer
Authors: Nicola Fossati, Daniel P. Nguyen, Quoc-Dien Trinh, Jesse Sammon, Akshay Sood, Alessandro Larcher, Giorgio Guazzoni, Francesco Montorsi, Alberto Briganti, Mani Menon, Firas Abdollah
Journal: Journal of the National Comprehensive Cancer Network (2015)

Approximately 15% of the US population does not have health insurance. The objective of this study was to evaluate the impact of insurance status on tumor characteristics and treatment selection in patients with prostate cancer.We identified 20,393 patients younger than 65 years with prostate cancer in the 2010-2011 SEER database. Multivariable logistic regression analysis tested the relationship between insurance status and 2 end points: (1) presenting with low-risk prostate cancer at diagnosis and (2) receiving local treatment of the prostate. Locally weighted scatterplot smoothing methods were used to graphically explore the interaction among insurance status, use of local treatment, and baseline risk of cancer recurrence. The latter was defined using the Stephenson nomogram and CAPRA score.Overall, 18,993 patients (93%) were insured, 849 (4.2%) had Medicaid coverage, and 551 (2.7%) were uninsured. At multivariable analysis, Medicaid coverage (odds ratio [OR], 0.67; 95% CI, 0.57, 0.80; P<.0001) and uninsured status (OR, 0.57; 95% CI, 0.46, 0.71; P<.0001) were independent predictors of a lower probability of presenting with low-risk disease. Likewise, Medicaid coverage (OR, 0.72; 95% CI, 0.60, 0.86; P=.0003) and uninsured status (OR, 0.45; 95% CI, 0.37, 0.55; P<.0001) were independent predictors of a lower probability of receiving local treatment. In uninsured patients, treatment disparities became more pronounced as the baseline cancer recurrence risk increased (10% in low-risk patients vs 20% in high-risk patients).Medicaid beneficiaries and uninsured patients are diagnosed with higher-risk disease and are undertreated. The latter is more accentuated for patients with high-risk prostate cancer. This may seriously compromise the survival of these individuals.
Heterogeneous CD52 Expression among Hematologic Neoplasms: Implications for the Use of Alemtuzumab (CAMPATH-1H)
Authors: Scott J. Rodig, Jeremy S. Abramson, Geraldine S. Pinkus, Steven P. Treon, David M. Dorfman, Henry Y. Dong, Margaret A. Shipp, Jeffery L. Kutok
Journal: Clinical Cancer Research (2006)

Abstract Purpose: CD52 is a GPI-linked glycoprotein expressed by B cells, T cells, monocytes, and macrophages. The humanized monoclonal antibody alemtuzumab (CAMPATH-1H) is specific for CD52 and is Food and Drug Administration–approved for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL). The utility of CAMPATH in the treatment of other hematologic neoplasms has been explored; however, a comprehensive survey of CD52 expression among a broad spectrum of WHO-defined tumor types has not been completed. Experimental Design: We evaluated 294 hematologic neoplasms for the presence of CD52 using standard immunohistochemical techniques on paraffin-embedded biopsy specimens fixed with formalin, B-Plus, Zenker's acetic acid, or B5-formalin. Results: The vast majority of low-grade B cell lymphoproliferative disorders (CLL/small lymphocytic leukemia, follicular lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, and mucosa-associated lymphoid tissue lymphomas) express CD52. In addition, we found that the majority of precursor B cell acute lymphoblastic leukemia/lymphomas express this antigen. In contrast, there is surprising heterogeneity in CD52 expression among more aggressive B cell lymphomas, with 25% of cases of diffuse large B cell lymphoma and Burkitt lymphoma demonstrating no detectable CD52. In addition, the majority of neoplasms of the T cell lineage are negative for the antigen, including most cases of precursor T cell acute lymphoblastic leukemia/lymphoma, anaplastic large cell lymphoma, and peripheral T cell lymphoma, not otherwise specified. Finally, the vast majority of cases of acute myeloid leukemia, Hodgkin lymphoma, and multiple myeloma are negative for CD52 expression. Conclusion: In contrast with CLL, the variable expression of CD52 among other hematologic malignancies suggests that target validation on a case-by-case basis will likely be necessary to guide the rational analysis of CAMPATH therapy.
Gender Influences [Ca <sup>2+</sup> ] <sub>i</sub> During Metabolic Inhibition in Myocytes Overexpressing the Na <sup>+</sup> -Ca <sup>2+</sup> Exchanger
Authors: Kazuro Sugishita, Zhi Su, Fenghua Li, Kenneth D. Philipson, William H. Barry
Journal: Circulation (2001)

Background The Na + -Ca 2+ exchanger (NCX) may contribute to Ca 2+ overload and injury in ischemic cardiomyocytes. Recently, NCX overexpression was reported to increase ischemia/reperfusion injury in male and oophorectomized female but not in female mice. We therefore measured the effects of gender and estrogen on [Ca 2+ ] i and [Na + ] i during metabolic inhibition (MI) in myocytes from wild-type (WT) and transgenic (TG) mice overexpressing NCX. Methods and Results Flow cytometry was used with fluo 3 for [Ca 2+ ] i and sodium green for [Na + ] i measurements. Male TG mouse myocytes had higher [Ca 2+ ] i after 30 minutes of MI (1086±160 nmol/L, n=8) than male WT (688±104 nmol/L, n=9, P =0.01). The increase in [Ca 2+ ] i during MI induced by NCX overexpression in female myocytes was not significant, however (TG 552±62 nmol/L, n=9; WT 426±44 nmol/L, n=7). The magnitude of rise in [Ca 2+ ] i during MI was greater in male than female myocytes. KB-R7943, an NCX inhibitor, abolished the effect of NCX overexpression but did not totally eliminate the effect of gender on [Ca 2+ ] i during MI. NCX current density and basal Na + pump function were not influenced by gender. The rise in [Na + ] i during MI was greater in male than in female myocytes. Estrogen attenuated the increase in [Ca 2+ ] i and [Na + ] i in male myocytes during MI and abolished the gender difference in [Na + ] i during MI. Conclusions Increased expression of NCX results in a more marked rise in [Ca 2+ ] i during MI in male than in female mouse myocytes. This gender difference appears to be mediated in part by an inhibitory effect of estrogen on the rise in [Na + ] i , an NCX modifier, during MI.
Out of the Water: Origin and Diversification of the LBD Gene Family
Authors: Andre S. Chanderbali, Fengmei He, Pamela S. Soltis, Douglas E. Soltis
Journal: Molecular Biology and Evolution (2015)

LBD (LATERAL ORGAN BOUNDARIES DOMAIN) genes are essential to the developmental programs of many fundamental plant organs and function in some of the basic metabolic pathways of plants. However, our historical perspective on the roles of LBD genes during plant evolution has, heretofore, been fragmentary. Here, we show that the LBD gene family underwent an initial radiation that established five gene lineages in the ancestral genome of most charophyte algae and land plants. By inference, the LBD gene family originated after the emergence of the green plants (Viridiplantae), but prior to the diversification of most extant streptophytes. After this initial radiation, we find limited instances of gene family diversification in land plants until successive rounds of expansion in the ancestors of seed plants and flowering plants. The most dynamic phases of LBD gene evolution, therefore, trace to the aquatic ancestors of embryophytes followed by relatively recent lineage-specific expansions on land.
LYRIC/AEG-1 Is Targeted to Different Subcellular Compartments by Ubiquitinylation and Intrinsic Nuclear Localization Signals
Authors: Hayley J. Thirkettle, Joanne Girling, Anne Y. Warren, Ian G. Mills, Kanagasabai Sahadevan, Hing Leung, Freddie Hamdy, Hayley C. Whitaker, David E. Neal
Journal: Clinical Cancer Research (2009)

LYRIC/AEG-1 has been reported to influence breast cancer survival and metastases, and its altered expression has been found in a number of cancers. The cellular function of LYRIC/AEG-1 has previously been related to its subcellular distribution in cell lines. LYRIC/AEG-1 contains three uncharacterized nuclear localization signals (NLS), which may regulate its distribution and, ultimately, function in cells.Immunohistochemistry of a human prostate tissue microarray composed of 179 prostate cancer and 24 benign samples was used to assess LYRIC/AEG-1 distribution. Green fluorescent protein-NLS fusion proteins and deletion constructs were used to show the ability of LYRIC/AEG-1 NLS to target green fluorescent protein from the cytoplasm to the nucleus. Immunoprecipitation and Western blotting were used to show posttranslational modification of LYRIC/AEG-1 NLS regions.Using a prostate tissue microarray, significant changes in the distribution of LYRIC/AEG-1 were observed in prostate cancer as an increased cytoplasmic distribution in tumors compared with benign tissue. These differences were most marked in high grade and aggressive prostate cancers and were associated with decreased survival. The COOH-terminal extended NLS-3 (amino acids 546-582) is the predominant regulator of nuclear localization, whereas extended NLS-1 (amino acids 78-130) regulates its nucleolar localization. Within the extended NLS-2 region (amino acids 415-486), LYRIC/AEG-1 can be modified by ubiquitin almost exclusively within the cytoplasm.Changes in LYRIC/AEG-1 subcellular distribution can predict Gleason grade and survival. Two lysine-rich regions (NLS-1 and NLS-3) can target LYRIC/AEG-1 to subcellular compartments whereas NLS-2 is modified by ubiquitin in the cytoplasm.
Interobserver agreement for endosonography in the diagnosis of pancreatic cysts
Authors: K. de Jong, T. Verlaan, M. Dijkgraaf, J. Poley, H. van Dullemen, M. Bruno, P. Fockens
Journal: Endoscopy (2011)

See also: Commentaire de travail de K. de Jong et al., pp. 579Endoscopy 2011; 43(07): 647-647DOI: 10.1055/s-0031-1291782
Dysautonomias: Clinical Disorders of the Autonomic Nervous System
Authors: David S. Goldstein
Journal: Annals of Internal Medicine (2002)

The term dysautonomia refers to a change in autonomic nervous system function that adversely affects health. The changes range from transient, occasional episodes of neurally mediated hypotension to progressive neurodegenerative diseases; from disorders in which altered autonomic function plays a primary pathophysiologic role to disorders in which it worsens an independent pathologic state; and from mechanistically straightforward to mysterious and controversial entities. In chronic autonomic failure (pure autonomic failure, multiple system atrophy, or autonomic failure in Parkinson disease), orthostatic hypotension reflects sympathetic neurocirculatory failure from sympathetic denervation or deranged reflexive regulation of sympathetic outflows. Chronic orthostatic intolerance associated with postural tachycardia can arise from cardiac sympathetic activation after “patchy” autonomic impairment or blood volume depletion or, as highlighted in this discussion, from a primary abnormality that augments delivery of the sympathetic neurotransmitter norepinephrine to its receptors in the heart. Increased sympathetic nerve traffic to the heart and kidneys seems to occur as essential hypertension develops. Acute panic can evoke coronary spasm that is associated with sympathoneural and adrenomedullary excitation. In congestive heart failure, compensatory cardiac sympathetic activation may chronically worsen myocardial function, which rationalizes treatment with β-adrenoceptor blockers. A high frequency of positive results on tilt-table testing has confirmed an association between the chronic fatigue syndrome and orthostatic intolerance; however, treatment with the salt-retaining steroid fludrocortisone, which is usually beneficial in primary chronic autonomic failure, does not seem to be beneficial in the chronic fatigue syndrome. Dysautonomias are an important subject in clinical neurocardiology.
Arrhythmogenic Mutation-Linked Defects in Ryanodine Receptor Autoregulation Reveal a Novel Mechanism of Ca <sup>2+</sup> Release Channel Dysfunction
Authors: Christopher H. George, Hala Jundi, Nicola Walters, N. Lowri Thomas, Robert R. West, F. Anthony Lai
Journal: Circulation Research (2005)

Arrhythmogenic cardiac ryanodine receptor (RyR2) mutations are associated with stress-induced malignant tachycardia, frequently leading to sudden cardiac death (SCD). The causative mechanisms of RyR2 Ca2+ release dysregulation are complex and remain controversial. We investigated the functional impact of clinically-severe RyR2 mutations occurring in the central domain, and the C-terminal I domain, a key locus of RyR2 autoregulation, on interdomain interactions and Ca2+ release in living cells. Using high-resolution confocal microscopy and fluorescence resonance energy transfer (FRET) analysis of interaction between fusion proteins corresponding to amino- (N-) and carboxyl- (C-) terminal RyR2 domains, we determined that in resting cells, RyR2 interdomain interaction remained unaltered after introduction of SCD-linked mutations and normal Ca2+ regulation was maintained. In contrast, after channel activation, the abnormal Ca2+ release via mutant RyR2 was intrinsically linked to altered interdomain interaction that was equivalent with all mutations and exhibited threshold characteristics (caffeine >2.5 mmol/L; Ca2+ >150 nmol/L). Noise analysis revealed that I domain mutations introduced a distinct pattern of conformational instability in Ca2+ handling and interdomain interaction after channel activation that was absent in signals obtained from the central domain mutation. I domain-linked channel instability also occurred in intact RyR2 expressed in CHO cells and in HL-1 cardiomyocytes. These new insights highlight a critical role for mutation-linked defects in channel autoregulation, and may contribute to a molecular explanation for the augmented Ca2+ release following RyR2 channel activation. Our findings also suggest that the mutational locus may be an important mechanistic determinant of Ca2+ release channel dysfunction in arrhythmia and SCD.