tbuckley/cabot-search huggingface dataset:
Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2
Authors: Uwe Kornak, Ellen Reynders, Aikaterini Dimopoulou, Jeroen Van Reeuwijk, Bjoern Fischer, Anna Rajab, Birgit Budde, Peter Nürnberg, Francois Foulquier, William B. Dobyns, Dulce Quelhas, Laura Vilarinho, Elisa Leao-Teles, Marie Greally, Eva Seemanova, Martina Simandlova, Mustafa Salih, Arti Nanda, Lina Basel-Vanagaite, Hulya Kayserili, Memmune Yuksel-Apak, Marc Larregue, Jacqueline Vigneron, Sanda Giurgea, Dirk Lefeber, Zsolt Urban, Stephanie Gruenewald, Wim Annaert, Han G. Brunner, Hans Van Bokhoven, Ron Wevers, Eva Morava, Gert Matthijs, Lionel Van Maldergem, Stefan Mundlos
Journal: Nature Genetics (2007)
Mediterranean diet and telomere length in Nurses' Health Study: population based cohort study
Authors: M. Crous-Bou, T. T. Fung, J. Prescott, B. Julin, M. Du, Q. Sun, K. M. Rexrode, F. B. Hu, I. De Vivo
Journal: BMJ (2014)

<b>Objective</b> To examine whether adherence to the Mediterranean diet was associated with longer telomere length, a biomarker of aging. <b>Design</b> Population based cohort study. <b>Setting</b> Nurses’ Health Study, an ongoing prospective cohort study of 121 700 nurses enrolled in 1976; in 1989-90 a subset of 32 825 women provided blood samples. <b>Participants</b> 4676 disease-free women from nested case-control studies within the Nurses’ Health Study with telomere length measured who also completed food frequency questionnaires. <b>Main outcome measure</b> Association between relative telomere lengths in peripheral blood leukocytes measured by quantitative real time polymerase chain reaction and Alternate Mediterranean Diet score calculated from self reported dietary data. <b>Results</b> Greater adherence to the Mediterranean diet was associated with longer telomeres after adjustment for potential confounders. Least squares mean telomere length z scores were −0.038 (SE 0.035) for the lowest Mediterranean diet score groups and 0.072 (0.030) for the highest group (P for trend=0.004). <b>Conclusion</b> In this large study, greater adherence to the Mediterranean diet was associated with longer telomeres. These results further support the benefits of adherence to the Mediterranean diet for promoting health and longevity.
A rapid quantitation of platelet‐associated igg by nephelometry
Authors: Bernard S. Morse, Dennis Giuliani, Murray Nussbaum
Journal: American Journal of Hematology (1982)

Abstract Platelet‐associated IgG (PAIgG) was measured by a simple rapid nephelometric technique using washed solubilized platelets and commercially available, prestandardized reagents. Normal subjects with normal platelet counts had PAIgG levels of 2.1–6.7 fg/platelet. Subjects with idiopathic immune thrombocytopenic purpura (ITP) had levels of 7.2–43.3 fg/platelet. Ninety percent of ITP patients had values exceeding 2 SD units of the mean of normal subjects. Elevated values were also found in 17% of patients with recovered ITP, patients with SLE with and without thrombocytopenia, patients with thrombocytopenia occurring during septicemia, and patients with IgG myeloma. Results can be obtained within several hours of receipt of blood specimen, and are similar to the reports that used more complex techniques.
Ambulatory Blood Pressure and Left Ventricular Mass in Normotensive Patients with Autosomal Dominant Polycystic Kidney Disease
Authors: F. ALFREDO VALERO, ALBERTO MARTINEZ-VEA, ALFREDO BARDAJÍ, CRISTINA GUTIERREZ, CARMEN GARCIA, CRISTOBAL RICHART, JESUS A. OLIVER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Higher left ventricular mass (LVM) has been found in early stages of autosomal dominant polycystic kidney disease (ADPKD). The mechanisms involved in the increase of LVM are unknown. To investigate whether LVM in ADPKD may be influenced by abnormal diurnal BP variations, the 24-h ambulatory BP profile was analyzed in a group of young normotensive ADPKD patients. Ambulatory BP monitoring and two-dimensional echocardiography were performed in 26 young normotensive ADPKD with normal renal function and in 26 healthy control subjects. LVM index was higher in ADPKD patients than in controls (90.8 ± 19.6 g/m 2 versus 73.9 ± 16.1 g/m 2 , P = 0.001). Average 24-h and daytime systolic, diastolic, and mean BP were similar in both groups. Nighttime diastolic and mean BP, but not systolic BP, were greater in ADPKD patients. The average and percent nocturnal decrease of systolic BP was lower in ADPKD patients than in control subjects (10.0 mmHg [-3 to 24] versus 15.5 mmHg [-4 to 31], P = 0.009, and 9.0% [-2 to 22] versus 14.2% [-2 to 25], P = 0.016, respectively). On the basis of their profile BP patterns, 54% of ADPKD subjects and 31% of controls were classified as nondippers ( P = 0.092). There were no differences between dippers and nondippers in left ventricular wall thickness, chamber dimensions, and mass indexes. In ADPKD patients, simple regression analysis showed that LVM index was correlated with 24-h, daytime, and nighttime systolic BP. On multiple regression analysis, the 24-h systolic BP was the only variable linked to LVM index. It is concluded that young normotensive ADPKD patients have higher LVM that is closely related to the ambulatory systolic BP. The nocturnal fall in BP is attenuated in these patients, although it is not associated with the higher LVH that they present.
Effect of Age on the Changes of Extracranial Circulation During Hypoxia
Authors: ERNST SIMONSON
Journal: Circulation Research (1961)

In 68 healthy older men (mean age 59.5 years), the peak amplitude of impedance plethysmographic pulse tracings from the forehead increased significantly during hypoxia (breathing a 10 per cent O 2 , 90 per cent nitrogen mixture), while there was no significant change in a group of 58 healthy young men (mean age 23.4 years). The height of the dicrotic notch increased in the older men and decreased in the younger men. In both groups, the cycle length decreased, and the relative peak time increased significantly during hypoxia. The absolute peak time decreased in the older group and did not change in the younger group. The amplitude changes in hypoxia were related to the decrease of arterial oxygen saturation in the older, but not in the younger, men. It is suggested that hypoxia is a stronger stimulus for the reaction of extracranial circulation in older subjects.
Blockade of the Bcr-Abl Kinase Activity Induces Apoptosis of Chronic Myelogenous Leukemia Cells by Suppressing Signal Transducer and Activator of Transcription 5–Dependent Expression of Bcl-XL
Authors: Machiko Horita, Enrique Jose Andreu, Adalberto Benito, Cristina Arbona, Cristina Sanz, Isana Benet, Felipe Prosper, Jose Luis Fernandez-Luna
Journal: The Journal of Experimental Medicine (2000)

Bcr-Abl–expressing leukemic cells are highly resistant to apoptosis induced by chemotherapeutic drugs. Although a number of signaling molecules have been shown to be activated by the Bcr-Abl kinase, the antiapoptotic pathway triggered by this oncogene has not been elucidated. Here, we show that the interleukin 3-independent expression of the antiapoptotic protein, Bcl-xL, is induced by Bcr-Abl through activation of signal transducer and activator of transcription (Stat)5. Inhibition of the Bcr-Abl kinase activity in Bcr-Abl–expressing cell lines and CD34+ cells from chronic myelogenous leukemia (CML) patients induces apoptosis by suppressing the capacity of Stat5 to interact with the bcl-x promoter. Interestingly, after inhibition of the Bcr-Abl kinase, the expression of Bcl-xL is downregulated more rapidly in chronic phase than in blast crisis CML cells, suggesting an involvement of this protein in disease progression. Overall, we describe a novel antiapoptotic pathway triggered by Bcr-Abl that may contribute to the resistance of CML cells to undergo apoptosis.
There is no association between polymyalgia rheumatica and acute parvovirus B19 infection
Authors: A. HEMAUER, S. MODROW, J. GEORGI, K. HELMKE, P. VAITH, B. LANG, J. SCHOLMERICH, R. H STRAUB
Journal: Annals of the Rheumatic Diseases (1999)

Cladribine in the treatment of systemic lupus erythematosus nephritisSystemic lupus erythematosus (SLE) nephritis often requires treatment with cyclophosphamide, which carries the risk of major side eVects including infection, ovarian failure and bladder malignancy.Therapeutic strategies that would specifically target lymphocytes are appealing.Following the first report of the use of the purine nucleoside analogue cladribine (2-chloro-2'deoxyadenosine), a selective lymphocyte depleting agent, in the treatment of lupus nephritis, 1 we report our experience in two patients with severe renal involvement.
Transcriptional induction of slit diaphragm genes by Lmx1b is required in podocyte differentiation
Authors: Jeffrey H. Miner, Roy Morello, Kaya L. Andrews, Cong Li, Corinne Antignac, Andrey S. Shaw, Brendan Lee
Journal: Journal of Clinical Investigation (2002)

LMX1B encodes a LIM-homeodomain transcription factor. Mutations in LMX1B cause nail-patella syndrome (NPS), an autosomal dominant disease with skeletal abnormalities, nail hypoplasia, and nephropathy. Expression of glomerular basement membrane (GBM) collagens is reduced in Lmx1b–/– mice, suggesting one basis for NPS nephropathy. Here, we show that Lmx1b–/– podocytes have reduced numbers of foot processes, are dysplastic, and lack typical slit diaphragms, indicating an arrest in development. Using antibodies to podocyte proteins important for podocyte function, we found that Lmx1b–/– podocytes express near-normal levels of nephrin, synaptopodin, ZO-1, α3 integrin, and GBM laminins. However, mRNA and protein levels for CD2AP and podocin were greatly reduced, suggesting a cooperative role for these molecules in foot process and slit diaphragm formation. We identified several LMX1B binding sites in the putative regulatory regions of both CD2AP and NPHS2 (podocin) and demonstrated that LMX1B binds to these sequences in vitro and can activate transcription through them in cotransfection assays. Thus, LMX1B regulates the expression of multiple podocyte genes critical for podocyte differentiation and function. Our results indicate that reduced levels of proteins associated with foot processes and the glomerular slit diaphragm likely contribute, along with reduced levels of GBM collagens, to the nephropathy associated with NPS.
Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis
Authors: Wolfgang Hueber, Dhavalkumar D. Patel, Thaddeus Dryja, Andrew M. Wright, Irina Koroleva, Gerard Bruin, Christian Antoni, Zoe Draelos, Michael H. Gold, Patrick Durez, Paul P. Tak, Juan J. Gomez-Reino, C. Stephen Foster, Rosa Y. Kim, C. Michael Samson, Naomi S. Falk, David S. Chu, David Callanan, Quan Dong Nguyen, Kristine Rose, Asifa Haider, Franco Di Padova
Journal: Science Translational Medicine (2010)

A human antibody to interleukin-17A is well tolerated and may be effective in the treatment of psoriasis, rheumatoid arthritis, and noninfectious uveitis.
Inducible Expression of BNIP3 Provokes Mitochondrial Defects and Hypoxia-Mediated Cell Death of Ventricular Myocytes
Authors: Kelly M. Regula, Karen Ens, Lorrie A. Kirshenbaum
Journal: Circulation Research (2002)

In this study, we provide evidence for the operation of BNIP3 as a key regulator of mitochondrial function and cell death of ventricular myocytes during hypoxia. In contrast to normoxic cells, a 5.6-fold increase ( P &lt;0.05) in myocyte death was observed in cells subjected to hypoxia. Moreover, a significant increase in BNIP3 expression was detected in postnatal ventricular myocytes and adult rat hearts subjected to hypoxia. An increase in BNIP3 expression was detected in adult rat hearts in vivo with chronic heart failure. Subcellular fractionation experiments indicated that endogenous BNIP3 was integrated into the mitochondrial membranes during hypoxia. Adenovirus-mediated delivery of full-length BNIP3 to myocytes was toxic and provoked an 8.3-fold increase ( P &lt;0.05) in myocyte death with features typical of apoptosis. Mitochondrial defects consistent with opening of the permeability transition pore (PT pore) were observed in cells expressing BNIP3 but not in cells expressing BNIP3 missing the carboxyl-terminal transmembrane domain (BNIP3ΔTM), necessary for mitochondrial insertion. The pan-caspase inhibitor z-VAD-fmk (25 to 100 μmol/L) suppressed BNIP3-induced cell death of ventricular myocytes in a dose-dependent manner. Bongkrekic acid (50 μmol/L), an inhibitor of the PT pore, prevented BNIP3-induced mitochondrial defects and cell death. Expression of BNIP3ΔTM suppressed the hypoxia-induced integration of the endogenous BNIP3 protein and cell death of ventricular myocytes. To our knowledge, the data provide the first evidence for the involvement of BNIP3 as an inducible factor that provokes mitochondrial defects and cell death of ventricular myocytes during hypoxia.
A nucleoside anticancer drug, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106), sensitizes cells to radiation by suppressing BRCA2 expression
Authors: Shunsuke Meike, Tohru Yamamori, Hironobu Yasui, Masato Eitaki, Akira Matsuda, Masami Morimatsu, Masakazu Fukushima, Yasundo Yamasaki, Osamu Inanami
Journal: Molecular Cancer (2011)

A novel anticancer drug 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)cytosine (ECyd, TAS106) has been shown to radiosensitize tumor cells and to improve the therapeutic efficiency of X-irradiation. However, the effect of TAS106 on cellular DNA repair capacity has not been elucidated. Our aim in this study was to examine whether TAS106 modified the repair capacity of DNA double-strand breaks (DSBs) in tumor cells.Various cultured cell lines treated with TAS106 were irradiated and then survival fraction was examined by the clonogenic survival assays. Repair of sublethal damage (SLD), which indicates DSBs repair capacity, was measured as an increase of surviving cells after split dose irradiation with an interval of incubation. To assess the effect of TAS106 on the DSBs repair activity, the time courses of γ-H2AX and 53BP1 foci formation were examined by using immunocytochemistry. The expression of DNA-repair-related proteins was also examined by Western blot analysis and semi-quantitative RT-PCR analysis.In clonogenic survival assays, pretreatment of TAS106 showed radiosensitizing effects in various cell lines. TAS106 inhibited SLD repair and delayed the disappearance of γ-H2AX and 53BP1 foci, suggesting that DSB repair occurred in A549 cells. Western blot analysis demonstrated that TAS106 down-regulated the expression of BRCA2 and Rad51, which are known as keys among DNA repair proteins in the homologous recombination (HR) pathway. Although a significant radiosensitizing effect of TAS106 was observed in the parental V79 cells, pretreatment with TAS106 did not induce any radiosensitizing effects in BRCA2-deficient V-C8 cells.Our results indicate that TAS106 induces the down-regulation of BRCA2 and the subsequent abrogation of the HR pathway, leading to a radiosensitizing effect. Therefore, this study suggests that inhibition of the HR pathway may be useful to improve the therapeutic efficiency of radiotherapy for solid tumors.
Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation
Authors: M Vivinus-Nébot, G Frin-Mathy, H Bzioueche, R Dainese, G Bernard, R Anty, J Filippi, M C Saint-Paul, M K Tulic, V Verhasselt, X Hébuterne, T Piche
Journal: Gut (2013)

<h3>Objective</h3> To determine the role of colonic barrier defects and low-grade inflammation in irritable bowel syndrome (IBS)-like symptoms in quiescent inflammatory bowel disease (IBD). <h3>Design</h3> Caecal biopsies were collected from 51 IBS, 49 quiescent IBD (31 Crohn9s disease (CD) and 18 ulcerative colitis (UC)) patients and 27 controls. IBS was assessed using the Rome III criteria and the IBS severity score. Epithelial barrier integrity was evaluated by determining the paracellular permeability of biopsies mounted in Ussing chambers and the mRNA expression of tight junction proteins (ZO-1, α-catenin and occludin). Low-grade inflammation was evaluated by counting cells, including intraepithelial lymphocytes (IELs), eosinophils and mast cells, and by determining the mRNA and protein expression of tumour necrosis factor (TNF)-α in biopsies and culture supernatants. <h3>Results</h3> IBS-like symptoms were present in 35.4 and 38% of CD and UC patients, respectively. Paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms (p&lt;0.01, respectively) or controls (p&lt;0.01, respectively). Significantly lower expression of ZO-1 and α-catenin was detected in IBS and quiescent IBD with IBS-like symptoms. IELs and TNF-α were significantly increased in quiescent IBD with IBS-like symptoms, but not in IBS. <h3>Conclusions</h3> In quiescent IBD, IBS-like symptoms related to persistent subclinical inflammation associated with increased colonic paracellular permeability. A persistent increase in TNF-α in colonic mucosa may contribute to the epithelial barrier defects associated with abdominal pain in quiescent IBD, but not in IBS. Optimisation of anti-inflammatory therapy may be considered in quiescent IBD with IBS-like symptoms.
TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis
Authors: A Tefferi, A Pardanani, K-H Lim, O Abdel-Wahab, T L Lasho, J Patel, N Gangat, C M Finke, S Schwager, A Mullally, C-Y Li, C A Hanson, R Mesa, O Bernard, F Delhommeau, W Vainchenker, D G Gilliland, R L Levine
Journal: Leukemia (2009)
Phase II Study of Daily Sunitinib in FDG-PET–Positive, Iodine-Refractory Differentiated Thyroid Cancer and Metastatic Medullary Carcinoma of the Thyroid with Functional Imaging Correlation
Authors: Laurie L. Carr, David A. Mankoff, Bernardo H. Goulart, Keith D. Eaton, Peter T. Capell, Elizabeth M. Kell, Julie E. Bauman, Renato G. Martins
Journal: Clinical Cancer Research (2010)

We conducted a phase II study to assess the efficacy of continuous dosing of sunitinib in patients with flurodeoxyglucose positron emission tomography (FDG-PET)-avid, iodine-refractory well-differentiated thyroid carcinoma (WDTC) and medullary thyroid cancer (MTC) and to assess for early response per FDG-PET.Patients had metastatic, iodine-refractory WDTC or MTC with FDG-PET-avid disease. Sunitinib was administered at 37.5 mg daily on a continuous basis. The primary end point was response rate per Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included toxicity, overall survival, and time to progression. We conducted an exploratory analysis of FDG-PET response after 7 days of treatment.Thirty-five patients were enrolled (7 MTC, 28 WDTC), and 33 patients were evaluable for disease response. The primary end point, objective response rate per RECIST, was 11 patients (31%; 95% confidence interval, 16-47%). There were 1 complete response (3%), 10 partial responses (28%), and 16 patients (46%) with stable disease. Progressive disease was seen in 6 patients (17%). The median time to progression was 12.8 months (95% confidence interval, 8.9 months-not reached). Repeat FDG-PET was done on 22 patients. The median percent change in average standardized uptake values was -11.7%, -13.9%, and 8.6% for patients with RECIST response, stable disease, and progressive disease, respectively. Differences between response categories were statistically significant (P = 0.03). The most common toxicities seen included fatigue (11%), neutropenia (34%), hand/foot syndrome (17%), diarrhea (17%), and leukopenia (31%). One patient on anticoagulation died of gastrointestinal bleeding.Continuous administration of sunitinib was effective in patients with iodine-refractory WDTC and MTC. Further study is warranted.
The association of pemphigus with thymoma or malignancy: a critical review
Authors: LAWRENCE S. KRAIN
Journal: British Journal of Dermatology (2006)

In order to determine the relationship between all forms of pemphigus and malignancy or thymoma, a search of the world literature was carried out. Fifty‐nine case reports or isolated citations for pemphigus with malignancies or thymomas were noted, including twenty‐one reports published before the histological separation by Lever of pemphigus and bullous pemphigoid in 1953. Of these cases, twenty‐six were acceptable for analysis. In approximately 54% of patients surveyed with these associations, the malignancy involved the lymphoid or reticuloendothelial systems. Approximately 48% of the patients with pemphigus and malignancy or thymoma had associated autoimmune diseases. Pemphigus with malignancies or thymomas may be related through some intervening variables such as immuno‐suppressive therapy or the antigenic and cross‐reacting nature of the primary tumour, or through an immunological consequence of associated autoimmune disease.
Comment on: International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma
Authors: Michael E. Wechsler, Gerard P. Cox
Journal: European Respiratory Journal (2014)

We commend CHUNG et al. [1] for their effort on consolidating recommendations for severe asthma in the European Respiratory Society/American Thoracic Society guidelines on the definition, evaluation and treatment of severe asthma.However, we were concerned by the recommendation that bronchial thermoplasty be performed ''only in the context of an Institutional Review Board-approved independent systemic registry or a clinical study'' [1].In addition to the positive benefits observed in our patients, bronchial thermoplasty has been demonstrated to be effective in several studies, including the pivotal AIR2 (Asthma Intervention Research 2) trial which resulted in this therapy's approval by the US Food and Drug Administration in 2010 [2,3].It has been shown to improve asthma-related quality of life and reduce exacerbations, emergency room visits and hospitalisations.Furthermore, these benefits have been sustained for .5 years with no significant safety concerns [4,5].We agree that it is important to monitor the efficacy and safety of this and other new therapies in the real world, and that studies to better understand phenotypes of responding patients are warranted.However, mandating that this therapy be limited to the research setting will prevent many patients suffering from severe asthma with ongoing unmet needs from gaining access to bronchial thermoplasty and gaining better control of their disease.Given the demonstrated long-term efficacy (.5 years) and safety of this therapy, and since the therapeutic options for patients with severe asthma are currently limited, we feel that it is important to include bronchial thermoplasty for consideration as an effective treatment option for patients with severe refractory asthma.Bronchial thermoplasty is a safe and effective therapy for patients with severe, refractory asthma http://ow.
Quantitative proteomics analysis reveals similar release profiles following specific PAR-1 or PAR-4 stimulation of platelets
Authors: Thijs C. van Holten, Onno B. Bleijerveld, Patrick Wijten, Philip G. de Groot, Albert J.R. Heck, Arjan D. Barendrecht, Tesy H. Merkx, Arjen Scholten, Mark Roest
Journal: Cardiovascular Research (2014)

AimsPlatelets are a natural source of growth factors, cytokines and chemokines, that regulate angiogenesis and inflammation. It has been suggested that differential release of pro- and anti-angiogenic growth factors from platelet α-granules by protease-activated receptors (PAR) 1 and 4 may be important for the regulation of angiogenesis. We aimed to compare the releasates of unstimulated platelets with PAR-1- and PAR-4-stimulated platelets.