tbuckley/cabot-search huggingface dataset:
Human-Specific Hypomethylation of CENPJ, a Key Brain Size Regulator
Authors: Lei Shi, Qiang Lin, Bing Su
Journal: Molecular Biology and Evolution (2013)

Both the enlarged brain and concurrent highly developed cognitive skills are often seen as distinctive characteristics that set humans apart from other primates. Despite this obvious differentiation, the genetic mechanisms that underlie such human-specific traits are not clearly understood. In particular, whether epigenetic regulations may play a key role in human brain evolution remain elusive. In this study, we used bisulfite sequencing to compare the methylation patterns of four known genes that regulate brain size (ASPM, CDK5RAP2, CENPJ, and MCPH1) in the prefrontal cortex among several primate species spanning the major lineages of primates (i.e., humans, great apes, lesser apes, and Old World monkeys). The results showed a human-specific hypomethylation in the 5′ UTR of CENPJ in the brain, where methylation levels among humans are only about one-third of those found among nonhuman primates. Similar methylation patterns were also detected in liver, kidney, and heart tissues, although the between-species differences were much less pronounced than those in the brain. Further in vitro methylation assays indicated that the methylation status of the CENPJ promoter could influence its expression. We also detected a large difference in CENPJ expression in the human and nonhuman primate brains of both adult individuals and throughout the major stages of fetal brain development. The hypomethylation and comparatively high expression of CENPJ in the central nervous system of humans suggest that a human-specific—and likely heritable—epigenetic modification likely occurred during human evolution, potentially leading to a much larger neural progenitor pool during human brain development, which may have eventually contributed to the dramatically enlarged brain and highly developed cognitive abilities associated with humans.
Cyclin A as a Predictive Factor for Chemotherapy Response in Advanced Head and Neck Cancer
Authors: Maria Rodriguez-Pinilla, Jose L. Rodriguez-Peralto, Ricardo Hitt, Jose J. Sanchez, Claudio Ballestin, Ana Diez, Lydia Sanchez-Verde, Francesc Alameda, Montserrat Sanchez-Cespedes
Journal: Clinical Cancer Research (2004)

Overall survival of head and neck squamous cell cancer (HNSCC) patients has not improved despite advances in our understanding of the biology and molecular features of this disease. In particular, patients with advanced HNSCC have the poorest prognosis. To understand more about the contribution of cell cycle alterations to HNSCC development and their possible value in predicting prognosis and response to chemotherapy, we evaluated the levels of proteins involved in cell cycle control in patients diagnosed with advanced HNSCC.A tissue microarray was made with 122 HNSCC specimens obtained from biopsy material. Protein expression was evaluated by immunohistochemistry and correlated with clinical and pathological characteristics.Multiple alterations at various checkpoints of cell cycle progression were observed. Loss of P16 protein was less common in oropharyngeal tumors than at other HNSCC locations (P = 0.02). Evaluation of the simultaneous expression of different proteins highlighted direct correlations (P < 0.05) such as that of the cyclin-dependent kinases with their cyclin-partners, and the Ki-67 protein with cyclin-dependent kinases 1, cyclin A (CA) and cyclin B1. Median overall survival and time-to-progression were longer in patients with CA-expressing tumors (not reached versus 34.4 months, P = 0.02) and (47.3 versus 14.6 months, P = 0.006), respectively. Moreover, expression of CA in tumors predicted a better response to chemotherapy. Positive expression of cyclin E in tumors was also associated with an increased median time-to-progression (14.6 versus 25.8 months, P = 0.04). Finally, patients with cyclin D1-expressing tumors had shorter median overall survival (29.6 months versus not reached, P = 0.05) and shorter median time-to-progression (21.5 months versus not reached, P = 0.06). However, in a multivariate analysis a CA-negative-expressing tumor was the only independent poor prognostic factor in the entire cohort of HNSCC patients [odds ratio, 2.3; 95% confidence interval (CI) = 1.2-4.5; P = 0.01].Our results provide detailed information on the molecular profile of cell cycle components in HNSCCs and identify CA-negative-expressing tumors as an independent marker of tumor progression and poor response to chemotherapy in patients diagnosed with advanced HNSCC.
Remarks on the Pathology of Chorea
Authors: H. C. Bastian
Journal: BMJ (1877)

TEE BRITISH MEDICAL 7OURNAL.was owing to the insensibility of the glottis, or whether the displaced cannula had made an opening into the cesophagus from the pressure of its point against the back of the trachea." It is quite conceivable, no doubt, that the sensibility of the glottis may become impaired, seeing that, so far as respiration is concerned, it is now in a state of disuse ; but there occurs to me still one other possible explanation of, at least, some of the cases.In all the three to which I have referred, the original disease was diphtheria ; and may the passage of liquids into the trachea not be accounted for by the awkwardness of deglutition, which, we know, does exist during this stage, and which often leads to the regurgitation by the nostrils of part, at all events, of the fluids which are swallowed?May it not, indeed, be a paralytic symptom?
B30.2-like domain proteins: update and new insights into a rapidly expanding family of proteins
Authors: J Henry, I H Mather, M F McDermott, P Pontarotti
Journal: Molecular Biology and Evolution (1998)

The B30.2 domain is a conserved region of around 170 amino acids associated with several different protein domains, including the immunoglobulin folds of butyrophilin and the RING finger domain of ret finger protein. We recently reported several novel members of this family as well as previously undescribed protein families possessing the B30.2 domain. Many proteins have subsequently been found to possess this domain, including pyrin/marenostrin and the midline 1 (MID1) protein. Mutations in the B30.2 domain of pyrin/marenostrin are implicated in familial Mediterranean fever, and partial loss of the B30.2 domain of MID1 is responsible for Opitz G/BBB syndrome, characterized by developmental midline defects. In this study, we scrutinized the available sequence data bases for the identification of novel B30.2 domain proteins using highly sensitive database-searching tools. In addition, we discuss the chromosomal localization of genes in the B30.2 family, since the encoded proteins are likely to be involved in other forms of periodic fever, autoimmune, and genetic diseases.
The Nature of the RS-T Segment Displacement as Studied with Esophageal Leads
Authors: AVERY A. SANDBERG, LEONARD SCHERLIS, ARTHUR GRISHMAN, JOSEPH WENER
Journal: Circulation (1950)

The electrocardiographic changes, with particular reference to the RS-T segment and T wave, in surface leads and in esophageal leads reflecting left ventricular cavity potentials, are studied in 7 persons with and without heart disease, before and after the administration of digitoxin. After the administration of digitoxin, the RS-T segment depression in precordial leads and in esophageal leads reflecting the potentials of the posterior surface of the left ventricle, are regularly associated with RS-T segment elevation in esophageal leads reflecting left ventricular cavity potentials. The possible roles played by myocardial involvement due to digitalis, modification of the monophasic curves, and the reduction of the human ventricular gradient are discussed.
Thalidomide Downregulates Angiogenic Genes in Bone Marrow Endothelial Cells of Patients With Active Multiple Myeloma
Authors: Angelo Vacca, Claudio Scavelli, Vittorio Montefusco, Giulia Di Pietro, Antonino Neri, Michela Mattioli, Silvio Bicciato, Beatrice Nico, Domenico Ribatti, Franco Dammacco, Paolo Corradini
Journal: Journal of Clinical Oncology (2005)

Purpose To study the antiangiogenic effect of thalidomide. Patients and Methods The expression of key angiogenic genes was studied in bone marrow endothelial cells (ECs) of patients with active and nonactive multiple myeloma (MM), monoclonal gammopathies unattributed/unassociated (MG[u]), diffuse large B-cell non-Hodgkin's lymphoma, in a Kaposi's sarcoma (KS) cell line, and in healthy human umbilical vein ECs (HUVECs) following exposure to therapeutic doses of thalidomide. Results Thalidomide markedly downregulates the genes in a dose-dependent fashion in active MMECs and KS cell line, but upregulates them or is ineffective in nonactive MMECs, MG(u)ECs, NHL-ECs, and in HUVECs. Secretion of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor also diminishes according to the dose in culture conditioned media (CM) of active MMECs and KS, whereas it does not change in the other CM. Conclusion Inhibition by thalidomide is probably confined to the genes of active MMECs and KS. This would account for its higher efficacy in these diseases.
Pathways of Infant and Childhood Growth That Lead to Type 2 Diabetes
Authors: Johan G. Eriksson, Tom J. Forsen, Clive Osmond, David J.P. Barker
Journal: Diabetes Care (2003)

OBJECTIVE—Although a link between small body size at birth and later type 2 diabetes has been repeatedly documented, less is known about the associations between the disease and growth during infancy. The aim of this study was to explore the pathways of infant and early growth that lead to type 2 diabetes in adult life. RESEARCH DESIGN AND METHODS—We carried out a longitudinal study of 8,760 subjects born in Helsinki from 1934 to 1944. On average, they had 8 measurements of height and weight between birth and 1 year of age and another 10 measurements between 1 and 12 years of age. We identified people with type 2 diabetes using a national register. RESULTS—Among babies whose birth weights were ≤3.5 kg, the rate of infant growth was unrelated to later type 2 diabetes. Among babies with birth weights &amp;gt;3.5 kg, slow growth in length between birth and 3 months of age predicted later disease. Rapid gain in BMI after age 2 years increased the risk of later disease in both groups of babies, but this effect was greatest among children who had slow growth in length between birth and 3 months of age. In children whose Z-scores for length decreased, an SD increase in BMI at age 12 years was associated with an odds ratio (OR) for type 2 diabetes of 1.77 (95% CI 1.50–2.09). The corresponding OR in subjects whose Z-scores for length increased was 1.42 (95% CI 1.20–1.69). Rapid gain in childhood BMI was associated with high maternal BMI and socioeconomic factors (fewer people in the home and lower social class). CONCLUSIONS—Babies with above-average birth weights may develop type 2 diabetes later in life if poor living conditions lead to faltering growth in length in the first few months after birth. We speculate that growth faltering at this time is associated with lifelong impairment of insulin metabolism and inability to meet the challenge of rapid childhood increase in BMI.
Antiatherogenic Effects of Angiotensin Receptor Antagonism in Mild Renal Dysfunction
Authors: Eisuke Suganuma, Yiqin Zuo, Nobuhiko Ayabe, Ji Ma, Vladimir R. Babaev, MacRae F. Linton, Sergio Fazio, Iekuni Ichikawa, Agnes B. Fogo, Valentina Kon
Journal: Journal of the American Society of Nephrology (2005)

Angiotensin II (Ang II) increases atherosclerotic cardiovascular disease. Renal damage that is characterized by activation of Ang II markedly potentiates the risk for atherosclerosis, even in the setting of subtle renal impairment. Therefore, whether antagonism of Ang II actions can modify atherosclerosis in a model of mild renal impairment was examined. Apolipoprotein E-deficient spontaneously hyperlipidemic mice underwent uninephrectomy (UNx) or sham operation (sham) followed by treatment with Ang II receptor antagonist losartan or hydralazine for 12 wk. While UNx did not increase the serum creatinine levels, BP and lipids were higher in UNx mice than in age-matched sham controls with intact kidneys. UNx caused a dramatic increase in the extent and the number of atherosclerotic lesions together with greater macrophage-positive area and more disruption in the elastin component of the extracellular matrix versus sham. Ang II antagonism dramatically decreased the UNx-induced acceleration in atherosclerosis in association with decreased macrophage content, linked to decreased macrophage migration in vitro with losartan but not with hydralazine. Aortae of mice treated with Ang II antagonism had fewer elastin breaks together with less immunostaining for the powerful elastolytic enzyme cathepsin S. None of these benefits was observed in the hydralazine-treated mice despite equivalent reduction in BP. These findings support an important role for endogenous Ang II in accelerated atherosclerosis in renal dysfunction and offer a therapeutic intervention with particular benefit in this setting through mechanisms that include reduced vascular macrophage infiltration and preservation of the elastin component of extracellular matrix.
Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin.
Authors: E Hahn, G Wick, D Pencev, R Timpl
Journal: Gut (1980)

Specific antibodies to collagen type IV, laminin, and fibronectin were used to localise these proteins by indirect immunofluorescence in frozen sections of normal and fibrotic liver. In normal livers distinct staining was found in basement membranes of blood and lymph vessels, of bile ducts and ductules and around nerve axons. Positive reactions for type IV collagen and fibronectin were also observed in the perisinusoidal space, while hepatocytes and most of the interstitial matrix of portal fields remained unstained. Liver specimens obtained from patients with alcoholic liver disease (fatty liver, hepatitis or cirrhosis) and chronic active hepatitis showed a more intense reaction with the antibodies in the perisnusoidal space including now distinct staining for laminin. These patterns were particularly prominent at borders between fibrotic septa and remnants of parenchyma or pseudolobules. Strong reactions were also found for type IV collagen and fibronectin in the periportal interstitium and in large fibrotic areas. The findings support previous electron-microscopical and chemical evidence for increased basement membrane production in human liver fibrosis and demonstrate that this may involve different proteins and occur at different anatomical sites.
Prostaglandin D <sub>2</sub> Inhibits Inducible Nitric Oxide Synthase Expression in Rat Vascular Smooth Muscle Cells
Authors: Hiroshi Nagoshi, Yoshio Uehara, Fumihiko Kanai, Shin Maeda, Tsutomu Ogura, Atsuo Goto, Teruhiko Toyo-oka, Hiroyasu Esumi, Takao Shimizu, Masao Omata
Journal: Circulation Research (1998)

Abstract —Vascular smooth muscle cells (VSMCs) as well as macrophages have been shown to generate a substantial amount of NO in inflammatory vascular lesions. Prostaglandin (PG) D 2 (PGD 2 ) is produced by inflammatory cells, including mast cells and macrophages. We investigated whether PGD 2 modulates NO metabolism in rat VSMCs. PGD 2 at a concentration of 10 –7 mol/L or greater dose-dependently inhibited nitrite accumulation in the medium of cultured VSMCs stimulated with interleukin 1β (IL-1β). In a dose-response analysis of IL-1β and nitrite accumulation, PGD 2 was seen to decrease the maximal ability of VSMCs to generate NO, arguing against competition by PGD 2 at cytokine receptors. Northern analysis showed that PGD 2 suppresses induction of inducible NO synthase (iNOS) mRNA in IL-1β–stimulated VSMCs, with consequent inhibition of iNOS protein expression in Western analysis. A thromboxane A 2 (TXA 2 ) analogue, U46619 (10 –5 mol/L), produced less inhibition of NO generation than did PGD 2 . Neither the PGI 2 analog carbaprostacyclin nor PGE 1 showed any inhibition. PGD 2 dose-dependently inhibited NO generation despite the addition of the TXA 2 antagonist SQ29548. PGJ 2 , Δ 12 -PGJ 2 , and 15-deoxy-Δ 12,14 -PGJ 2 , all metabolites of PGD 2 , were as potent as or slightly stronger than PGD 2 in the inhibition of NO generation. These data suggest that PGD 2 suppresses NO generation in VSMCs by inhibiting iNOS mRNA expression, most likely through the cascade of the PGJ 2 series rather than through the TX receptor or cAMP upregulation. Such action makes it likely that PGD 2 regulates NO metabolism in vascular lesions.
Role of the major histocompatibility complex in T cell activation of B cell subpopulations. A single monoclonal T helper cell population activates different B cell subpopulations by distinct pathways.
Authors: Y Asano, M Shigeta, C G Fathman, A Singer, R J Hodes
Journal: The Journal of Experimental Medicine (1982)

It has recently been demonstrated that the Lyb-5+ and Lyb-5- B cell subpopulations differ in their requirements for major histocompatibility complex (MHC)-restricted activation by T helper (TH) cells. To determine whether these MHC-restricted and -unrestricted pathways of B cell activation result from differences in the participating TH cell populations or reflect differences exclusively in the responding B cell subpopulations, experiments were carried out using cloned TH cells for in vitro antibody responses to trinitrophenyl-keyhole limpet hemocyanin. The same cloned T helper cells were able to activate both CBA/N (Lyb-5-) B cells and CBA/CaHN (Lyb-5+ + Lyb-5-) B cells under different experimental conditions. The activation of Lyb-5-B cells by cloned T helper cells required both MHC-restricted TH cell-B cell interaction and carrier-hapten linkage. In contrast, the activation of Lyb-5+ B cells required only MHC-restricted T helper cell interaction with accessory cells, while T-B interaction was MHC unrestricted and did not require carrier-hapten linkage. Thus, the differences in activation requirements observed for the Lyb-5- and Lyb-5+ B cell subsets do not result from differences in the TH cell populations activating these B cells, but rather reflect differences in the ability of these B cells to respond to signals from the same TH cells.
Increased amount of nitric oxide in exhaled air of asthmatics
Authors: K Alving, E Weitzberg, JM Lundberg
Journal: European Respiratory Journal (1993)

The presence of nitric oxide (NO) in the exhaled air of humans has recently been described. We wanted to assess at what level exhaled NO originates in normal airways, and to determine whether airway inflammation induces changes in the levels of exhaled NO. Exhaled NO was continuously measured by chemiluminescence technique during normal tidal breathing through the nose or mouth, with a detection limit of 1 part per billion (ppb). Twelve control subjects were compared to eight patients with mild atopic asthma and rhinitis caused by occupational allergen. In control subjects, the major part of NO in exhaled air (up to 30 ppb) seemed to originate in the nasal airways, with only minor contribution from the lower airways and the oral cavity. However, in mild asthmatics, the level of exhaled NO during oral breathing, indicating the involvement of the lower airways, was increased 2-3 fold. Since increased production of NO in the lower airways may involve activated macrophages or neutrophils, we suggest that exhaled NO may be used to instantly monitor ongoing bronchial inflammation, at least when involving inducible NO synthase.
Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial
Authors: Katherine MB Ajdukiewicz, Katharine E Cartwright, Matthew Scarborough, James B Mwambene, Patrick Goodson, Malcolm E Molyneux, Eduard E Zijlstra, Neil French, Christopher JM Whitty, David G Lalloo
Journal: The Lancet Infectious Diseases (2011)
Phenotypic correction and long-term expression of factor VIII in hemophilic mice by immunotolerization and nonviral gene transfer using the Sleeping Beauty transposon system
Authors: John R. Ohlfest, Joel L. Frandsen, Sabine Fritz, Paul D. Lobitz, Scott G. Perkinson, Karl J. Clark, Gary Nelsestuen, Nigel S. Key, R. Scott McIvor, Perry B. Hackett, David A. Largaespada
Journal: Blood (2004)
Telomerase activity in human pleural mesothelioma
Authors: K. Dhaene, R. Hubner, S. Kumar-Singh, B. Weyn, E. Van Marck
Journal: Thorax (1998)

Gradual telomere erosion eventually limits the replicative life span of somatic cells and is regarded as an ultimate tumour suppressor mechanism, eliminating cells that have accumulated genetic alterations. Telomerase, which has been found in over 85% of human cancers, elongates telomeres and may be required for tumorigenesis by the process of immortalisation. Malignant mesothelioma is an incurable malignancy with a poor prognosis. The disease becomes symptomatic decades after exposure to carcinogenic asbestos fibres, suggesting the long term survival of pre-malignant cell clones. This study investigated the presence of telomerase in pleural malignant mesothelioma, which may be the target for future anti-telomerase drugs.Telomerase activity was semiquantitatively measured in extracts from 22 primary pleural mesotheliomas, two benign solitary fibrous tumours of the pleura, four mesothelioma cell lines, and six short term mesothelial cell cultures from normal pleura using a non-isotopic dilution assay of the telomeric repeat amplification protocol.Twenty of the 22 primary mesotheliomas (91%) and all tumour derived mesothelioma cell lines were telomerase positive. Different levels of enzyme activity were observed in the tumours of different histological subtypes. Telomerase activity could not be detected in the six normal mesothelial cell cultures or in the two mesotheliomas. Both benign solitary fibrous tumours showed strong telomerase activity.Telomerase activity is found in a high proportion of mesotheliomas and anti-telomerase drugs might therefore be useful clinically. The results are consistent with the hypothesis that telomerase activity may be a feature of carcinogenesis in mesotheliomas and possibly in many other cancers.
845-5 Assessment of microvascular function after acute myocardial infarction by 16-slice computed tomography
Authors: Jonathan Lessick, Robert Dragu, Shmuel Rispler, Rafael Beyar, Haim Hammerman, Michael Kopilevitz, Yoram Agmon, Shimon Reisner, Diab Mutlak, Ahuva Engel
Journal: Journal of the American College of Cardiology (2004)