tbuckley/cabot-search huggingface dataset:
Differential Selection After Duplication in Mammalian Developmental Genes
Authors: Emmanouil T. Dermitzakis, Andrew G. Clark
Journal: Molecular Biology and Evolution (2001)

Gene duplication provides the opportunity for subsequent refinement of distinct functions of the duplicated copies. Either through changes in coding sequence or changes in regulatory regions, duplicate copies appear to obtain new or tissue-specific functions. If this divergence were driven by natural selection, we would expect duplicated copies to have differentiated patterns of substitutions. We tested this hypothesis using genes that duplicated before the human/mouse split and whose orthologous relations were clear. The null hypothesis is that the number of amino acid changes between humans and mice was distributed similarly across different paralogs. We used a method modified from Tang and Lewontin to detect heterogeneity in the amino acid substitution pattern between those different paralogs. Our results show that many of the paralogous gene pairs appear to be under differential selection in the human/mouse comparison. The properties that led to diversification appear to have arisen before the split of the human and mouse lineages. Further study of the diverged genes revealed insights regarding the patterns of amino acid substitution that resulted in differences in function and/or expression of these genes. This approach has utility in the study of newly identified members of gene families in genomewide data mining and for contrasting the merits of alternative hypotheses for the evolutionary divergence of function of duplicated genes.
Polysomnography for the management of progressive neuromuscular disorders
Authors: F. Lofaso, M.A. Quera-Salva
Journal: European Respiratory Journal (2002)

Invasive mechanical ventilation through a tracheostomy (TMV) is widely used to improve the survival of patients with severe restrictive respiratory disease caused by progressive neuromuscular disorders. For the last 20 yrs, there has been intense interest in noninvasive intermittent positive-pressure ventilation (NIMV) as a means of avoiding tracheostomy in these patients 1. However, there is no evidence that NIMV is beneficial before the development of daytime hypercapnia, and NIMV may even be detrimental by causing a delay in seeking medical advice during acute exacerbations. In keeping with this possibility, a randomized study in which Raphael et al. 2 evaluated the effect of NIMV on patients with Duchenne's muscular dystrophy before the stage of daytime hypercapnia, found an unexpected higher risk of death in the group receiving NIMV. It can be argued that this study did not use appropriate inclusion criteria for selecting the subset of patients most likely to benefit from “preventive” NIMV. Another limitation of this …
Treatment of chronic hepatitis C complicated by mixed cryoglobulinemia with new protease inhibitor, sofosbuvir
Authors: Jonathan G Stine, Scott Cornella, Neeral L Shah
Journal: Annals of the Rheumatic Diseases (2014)

Article citation: Saadoun D, Rigon MR, Thibault V, et al . Peg-IFNα/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Ann Rheum Dis 2014;73:831–7.

The lack of data showing the effective clearance of cryoglobulins with the addition of direct acting antiviral drugs is problematic, where close to 50% of patients with chronic hepatitis C (HCV) have cryoglobulinemia.1 The original article by Saadoun et al .2 is timely and sheds light on this large subset of chronic HCV …
Restoration of Hypoglycemia Awareness After Islet Transplantation
Authors: Cristiane B. Leitão, Thipaporn Tharavanij, Pablo Cure, Antonello Pileggi, David A. Baidal, Camillo Ricordi, Rodolfo Alejandro
Journal: Diabetes Care (2008)

OBJECTIVE—To determine the impact of islet transplantation (ITx) on hypoglycemia awareness in patients with unstable type 1 diabetes and its relation to islet function. RESEARCH DESIGN AND METHODS—A total of 31 ITx recipients were studied. Hypoglycemia unawareness was assessed using the Clarke hypoglycemic score (0 = no hypoglycemia; ≥4 = hypoglycemia unawareness). Subjects were grouped based on graft function: off-insulin (n = 8), graft dysfunction (on-insulin and stimulated C-peptide ≥0.3 ng/ml, n = 13), and graft failure (stimulated C-peptide &amp;lt;0.3 ng/ml, n = 10, evaluated 11.5 ± 14.5 months after graft failure). RESULTS—The hypoglycemia score improved after ITx when compared with baseline values (before vs. after: 5.29 ± 1.51 vs. 1.35 ± 1.92, P &amp;lt; 0.001). This result was sustained even after patient stratification based on islet function (pre vs. post off-insulin: 5.63 ± 2.00 vs. no hypoglycemia reported; graft dysfunction: 5.31 ± 1.49 vs. 1.15 ± 1.63, P &amp;lt; 0.001; and graft failure: 5.00 ± 1.16 vs. 2.70 ± 2.26, P = 0.014). CONCLUSIONS—The improved metabolic control achieved with ITx can restore hypoglycemia awareness in patients with type 1 diabetes, persisting even after islet graft failure.
Strong induction of 4-1BB, a growth and survival promoting costimulatory receptor, in HTLV-1–infected cultured and patients' T cells by the viral Tax oncoprotein
Authors: Klemens Pichler, Tarek Kattan, Juliane Gentzsch, Andrea K. Kress, Graham P. Taylor, Charles R. M. Bangham, Ralph Grassmann
Journal: Blood (2008)
Randomized Phase III Study Comparing Paclitaxel/Cisplatin/ Gemcitabine and Gemcitabine/Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Cancer Without Prior Systemic Therapy: EORTC Intergroup Study 30987
Authors: Joaquim Bellmunt, Hans von der Maase, Graham M. Mead, Iwona Skoneczna, Maria De Santis, Gedske Daugaard, Andreas Boehle, Christine Chevreau, Luis Paz-Ares, Leslie R. Laufman, Eric Winquist, Derek Raghavan, Sandrine Marreaud, Sandra Collette, Richard Sylvester, Ronald de Wit
Journal: Journal of Clinical Oncology (2012)

The combination of gemcitabine plus cisplatin (GC) is a standard regimen in patients with locally advanced or metastatic urothelial cancer. A phase I/II study suggested that a three-drug regimen that included paclitaxel had greater antitumor activity and might improve survival.We conducted a randomized phase III study to compare paclitaxel/cisplatin/gemcitabine (PCG) with GC in patients with locally advanced or metastatic urothelial carcinoma. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate, and toxicity.From 2001 to 2004, 626 patients were randomly assigned; 312 patients were assigned to PCG, and 314 patients were assigned to GC. After a median follow-up of 4.6 years, the median OS was 15.8 months on PCG versus 12.7 months on GC (hazard ratio [HR], 0.85; P = .075). OS in the subgroup of all eligible patients was significantly longer on PCG (3.2 months; HR, 0.82; P = .03), as was the case in patients with bladder primary tumors. PFS was not significantly longer on PCG (HR, 0.87; P = .11). Overall response rate was 55.5% on PCG and 43.6% on GC (P = .0031). Both treatments were well tolerated, with more thrombocytopenia and bleeding on GC than PCG (11.4% v 6.8%, respectively; P = .05) and more febrile neutropenia on PCG than GC (13.2% v 4.3%, respectively; P < .001).The addition of paclitaxel to GC provides a higher response rate and a 3.1-month survival benefit that did not reach statistical significance. Novel approaches will be required to obtain major improvements in survival of incurable urothelial cancer.
Stereotypic Rheumatoid Factors That Are Frequently Expressed in Mucosa‐Associated Lymphoid Tissue–Type Lymphomas Are Rare in the Labial Salivary Glands of Patients With Sjögren's Syndrome
Authors: Richard J. Bende, Linda M. Slot, Robbert Hoogeboom, Thera A. M. Wormhoudt, Akanbi O. Adeoye, Jeroen E. J. Guikema, Carel J. M. van Noesel
Journal: Arthritis & Rheumatology (2014)

Among autoimmune diseases, Sjögren's syndrome (SS) is most strongly associated with the development of malignant B cell lymphoma, in particular mucosa-associated lymphoid tissue (MALT)-type lymphoma. Previously, we have shown that in ∼40% of cases of salivary gland MALT lymphoma, high-affinity stereotypic rheumatoid factor (RF) B cell receptors, specific for IgG-Fc, are expressed. This study was undertaken to investigate whether in the inflamed salivary glands of patients with SS, a similar RF-biased Ig repertoire is present.Extensive analyses of the B cell Ig VH region repertoire were performed on microdissected tissue samples from the labial salivary glands of 4 patients with SS.All SS labial salivary glands harbored expanded B cell clones, of which 1 or 2 were highly expanded and detected in >50% of the microdissected samples. However, among the identified 464 distinct Ig clonotypes, only 3 stereotypic RF-expressing clones were detected. In 2 patients with SS, an RF-expressing clone was detected at low frequency in 1 of the microdissected samples, whereas 1 patient with SS harbored a highly expanded RF-expressing clone that was detected in all microdissected samples and also detected in the peripheral blood. Two years after analysis of this sample, the latter patient developed a diffuse large B cell lymphoma originating from the same RF clone.Inflamed labial salivary glands in patients with SS generally harbor 1 or 2 highly expanded B cell clones. The repertoire strongly biased toward stereotypic RFs in salivary gland MALT lymphomas is not a reflection of a similar repertoire in the inflamed salivary glands of patients with SS; rather, in the latter, the repertoire is based on a strong selection advantage of incidental stereotypic RF-expressing B cells.
Effect of Age on the Risk of Fever and Seizures Following Immunization With Measles-Containing Vaccines in Children
Authors: Ali Rowhani-Rahbar, Bruce Fireman, Edwin Lewis, James Nordin, Allison Naleway, Steven J. Jacobsen, Lisa A. Jackson, Alison Tse, Edward A. Belongia, Simon J. Hambidge, Eric Weintraub, Roger Baxter, Nicola P. Klein
Journal: JAMA Pediatrics (2013)

IMPORTANCE The first dose of live attenuated measles-containing vaccines is associated with an increased risk of febrile seizures 7 to 10 days following immunization among 12- to 23-month-old children. The combination measles, mumps, rubella, and varicella vaccine is associated with a 2-fold increased risk of febrile seizures 7 to 10 days following immunization compared with the separately administered measles, mumps, and rubella and varicella vaccines. It is unknown whether the magnitude of these increased risks depends on age at immunization. OBJECTIVE To examine the potential modifying effect of age on the risk of fever and seizures following immunization with measles-containing vaccines. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 8 Vaccine Safety Datalink sites of a total of 840,348 children 12 to 23 months of age who had received a measles-containing vaccine from 2001 through 2011. EXPOSURES Any measles-containing vaccines and measles-containing vaccines by type. MAIN OUTCOMES AND MEASURES Fever and seizure events occurring during a 42-day postimmunization observation period. RESULTS In the analysis of any measles-containing vaccines, the increased risk of seizures during the 7- to 10-day risk interval, using the remainder of the observation period as the control interval, was significantly greater among older children (relative risk, 6.5; 95% CI, 5.3-8.1; attributable risk, 9.5 excess cases per 10,000 doses; 95% CI, 7.6-11.5) than among younger children (relative risk, 3.4; 95% CI, 3.0-3.9; attributable risk = 4.0 excess cases per 10,000 doses; 95% CI, 3.4-4.6). The relative risk of postimmunization fever was significantly greater among older children than among younger children; however, its attributable risk was not. In the analysis of vaccine type, measles, mumps, rubella, and varicella vaccine was associated with a 1.4-fold increase in the risk of fever and 2-fold increase in the risk of seizures compared with measles, mumps, and rubella vaccine administered with or without varicella vaccine in both younger and older children. CONCLUSIONS AND RELEVANCE Measles-containing vaccines are associated with a lower increased risk of seizures when administered at 12 to 15 months of age. Findings of this study that focused on safety outcomes highlight the importance of timely immunization of children with the first dose of measles-containing vaccines.
C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation
Authors: P CIRILLO, P GOLINO, P CALABRO, G CALI, M RAGNI, S DEROSA, G CIMMINO, M PACILEO, R DEPALMA, L FORTE
Journal: Cardiovascular Research (2005)

Inflammation plays a pivotal role in atherothrombosis. In addition to being a prognostic marker for major cardiovascular events, recent data indicate that C-reactive protein (CRP) might directly promote atherothrombosis by exerting direct effects on vascular cells. The aim of the present study was to determine whether CRP might affect the prothrombotic and proliferative characteristics of endothelial (ECs) and smooth muscle cells (SMCs).Incubation of ECs and SMCs with CRP resulted in a dose-dependent activation of cell proliferation, which was mediated by activation of the p44/42 MAP Kinase (ERK 1/2) pathway. In addition, CRP also induced tissue factor (TF) expression in both cell types in a dose-dependent fashion, exerting its effect at the transcriptional level, as demonstrated by semiquantitative and by real time PCR. Activation of the transcription factor, NF-kappaB, by CRP was demonstrated by EMSA and by suppression of TF expression by the NF-kappaB inhibitor, pyrrolidine-dithio-carbamate ammonium.These data indicate that CRP exerts direct effects on ECs and SMCs by promoting proliferation and TF expression and support the notion that CRP, besides representing a marker of inflammation, is an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the vessel wall.
The Effect of Cyclic AMP and Dibutyryl Cyclic AMP on the Permeability Characteristics of the Renal Tubule
Authors: William B. Lorentz
Journal: Journal of Clinical Investigation (1974)

The effect of adenosine-3',5'-cyclic monophosphate (cyclic AMP) and N(6),O(2)-dibutyryl adenosine-3',5'-cyclic monophosphate (dibutyryl cyclic AMP) on renal tubular permeability was studied by microinjection techniques in anesthetized diuretic rats. Radioactive inulin and mannitol were microinjected simultaneously into superficial proximal and distal convolutions and recovery of the isotopes was measured in the urine.During control conditions, mannitol and inulin recovery was essentially complete. However, during infusion of cyclic AMP or dibutyryl cyclic AMP, mannitol recovery was significantly less than control after early proximal and late proximal microinjections, averaging 79 and 85%, respectively. There was no loss of mannitol from the nephron after microinjection into distal convolutions. Inulin recovery was complete after all microinjections during cyclic AMP or dibutyryl cyclic AMP infusion. Simultaneous clearances of mannitol and inulin as well as peritubular capillary microinjections studies demonstrated bidirectional fluxes of mannitol across the proximal tubular epithelium during infusion of cyclic AMP or dibutyryl cyclic AMP. Intratubular pressures were not different during control and experimental periods. These studies demonstrate a change in the permeability characteristic of the proximal convoluted tubule during infusion of cyclic AMP and dibutyryl cyclic AMP. This change in permeability of the proximal tubule could account for the effects of cyclic AMP on proximal tubular transport processes.
Acute lymphocytic leukemia: Correlation of clinical features with immunocytochemical classification
Authors: Bair‐Her Twu, Chin‐Yang Li, William A. Smithson, H. Clark Hoagland, Gordon W. Dewald
Journal: American Journal of Hematology (1987)

Many immunologic studies of acute lymphocytic leukemia (ALL) during the past decade have demonstrated the close correlation of immunologic phenotypes of ALL subclasses with the clinical presenting features and prognosis. However, the clinical application of conventional immunologic techniques had been very limited because of the requirement of a fresh sample to prepare the mononuclear cell suspensions for study. We studied 81 cases of ALL using immunoperoxidase stain for nuclear terminal deoxynucleotidyl transferase (TdT) and immunoalkaline phosphatase stain for surface markers (using monoclonal antibody J5 for common ALL antigen [CALLA], Leu-1 for pan-T antigen, and B1 for pan-B antigen) on air-dried smears. The cases were classified as common ALL (TdT+, CALLA+, pan-T-, and pan-B-) (41 cases), null-ALL (TdT+, CALLA-, pan-T-, and pan-B-) (19 cases), T-ALL (TdT+, CALLA-, pan-T+, and pan-B-) (nine cases), B-ALL (TdT-, CALLA-, pan-T-, and pan-B+) (six cases), pre-B-ALL (TdT+/-, CALLA+, pan-T-, and pan-B+) (four cases), or pre-T-ALL (TdT+, CALLA+, pan-T+, and pan-B-) (two cases). This subtyping of ALL correlated well with known clinical presenting features, prognosis, chromosome analysis in 35 cases with an abnormal clone, and conventional immunologic typing in 38 cases. The data suggest that these simple and practical immunocytochemical stains can be used for immunologic subclassification of ALL.
Changes in Lung Volume and Ventilation during Surfactant Treatment in Ventilated Preterm Infants
Authors: Martijn Miedema, Frans H. de Jongh, Inez Frerichs, Mariëtte B. van Veenendaal, Anton H. van Kaam
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

The immediate and regional effects of exogenous surfactant in open lung high-frequency oscillatory ventilated (HFOV) preterm infants are unknown.To assess regional changes in lung volume, mechanics, and ventilation during and after surfactant administration in HFOV preterm infants with respiratory distress syndrome (RDS).Using electrical impedance tomography, changes in lung volume were continuously recorded during a stepwise recruitment procedure before, during, and after surfactant administration in 15 preterm infants (gestational age: 28.3 wk; birth weight: 1,000 g). Deflation limbs of the pressure-impedance curve before and after surfactant were mapped and the effect of surfactant on oscillation volumes and ventilation was determined. Data were analyzed for the whole cross-section and the left, right, ventral, and dorsal lung regions.Surfactant increased lung volume by 61 ± 39% within a median time of 241 seconds. The ventral to dorsal ratio in lung volume changed significantly from 1.16 before to 0.81 after surfactant administration. The upper inflection point of the deflation limb after surfactant (10.4 ± 2.4 cm H(2)O) was significantly lower compared with before surfactant (16.4 ± 3.1 cm H(2)O). Surfactant increased maximal compliance of the respiratory system, and this effect was reached at lower airway pressures. Surfactant caused a transient decrease in oscillatory volume but did not alter its regional distribution.Surfactant treatment in HFOV preterm infants with RDS causes a rapid increase and subsequent stabilization of lung volume, which is most prominent in dependent lung regions. It increased maximal compliance, but this effect is only reached at lower airway pressures.
An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential
Authors: Steven M. Jay, Ashwin C. Murthy, Jessica F. Hawkins, Joshua R. Wortzel, Matthew L. Steinhauser, Luis M. Alvarez, Joseph Gannon, Calum A. Macrae, Linda G. Griffith, Richard T. Lee
Journal: Circulation (2013)

Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also proneoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced proneoplastic potential in comparison with the epidermal growth factor-like domain of neuregulin-1β (NRG), an effect mediated by receptor biasing toward ErbB3 homotypic interactions uncommonly formed by native neuregulin-1β. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced proneoplastic effects in comparison with NRG.NN was expressed as a maltose-binding protein fusion in Escherichia coli. As established previously, NN stimulated antineoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated proneoplastic signaling and phenotype. In neonatal rat cardiomyocytes, NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in neonatal rat cardiomyocytes and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7±0.6% versus 50.9±2.6%, P=0.004), whereas native NRG had no significant effect (49.4±3.7% versus 50.9±2.6%, P=0.813).NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced proneoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in patients with cancer receiving anthracyclines.
Frequency analysis of TRBV subfamily sjTRECs to characterize T-cell reconstitution in acute leukemia patients after allogeneic hematopoietic stem cell transplantation
Authors: Xiuli Wu, Kanger Zhu, Xin Du, Shaohua Chen, Lijian Yang, Jufeng Wu, Qifa Liu, Yangqiu Li
Journal: Journal of Hematology & Oncology (2011)

Abstract Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) leads to a prolonged state of immunodeficiency and requires reconstitution of normal T-cell immunity. Signal joint T-cell receptor excision DNA circles (sjTRECs) are markers of developmental proximity to the thymus that have been used to evaluate thymic function related to T-cell immune reconstitution after HSCT. To assess the proliferative history in different T-cell receptor beta variable region (TRBV) subfamilies of T cells after HSCT, expansion of TRBV subfamily-naive T cells was determined by analysis of a series of TRBV-BD1 sjTRECs. Methods sjTRECs levels were detected by real-time quantitative polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMCs) from 43 Chinese acute leukemia patients who underwent allo-HSCT. Twenty-three TRBV-BD1 sjTRECs were amplified by semi-nested PCR. Sixteen age-matched healthy volunteers served as normal controls. Results sjTRECs levels were low or undetectable in the first 6 weeks after allo-HSCT and increased after 8 weeks post HSCT; however, sjTRECs levels at week 20 post-HSCT were still less than normal controls. Frequencies of TRBV subfamily sjTRECs in PBMCs from recipients at week 8 post-HSCT (29.17 ± 20.97%) or at week 16 post-HSCT (38.33 ± 9.03%) were significantly lower than those in donors (47.92 ± 13.82%) or recipients at pre-HSCT (45.83 ± 14.03%). However, frequencies of TRBV subfamily sjTRECs in recipients at week 30 post-HSCT (42.71 ± 21.62%) were similar to those in donors and recipients at pre-HSCT. sjTRECs levels in donors had a positive linear correlation with sjTRECs levels in recipients within 8-12 weeks post-HSCT. Patients with acute graft-versus-host disease (GVHD) or chronic GVHD had profoundly reduced TRECs levels during the first year post-HSCT. Frequencies of BV22-BD1 sjTRECs and BV23-BD1 sjTRECs in patients with GVHD were significantly lower than those in recipients at pre-HSCT, and the frequencies of BV22-BD1 sjTRECs in patients with GVHD were significantly lower than those in donors. Conclusions Reconstitution of thymic output function resulted in a period of immunodeficiency, with low or undetectable TRECs after transplantation, although fludarabine-based dose-reduced conditioning regimens were used. GVHD could affect reconstitution of thymic output function and reduce sjTRECs levels and frequencies of TRBV-BD1 sjTRECs. Low frequency of BV22-BD1 and BV23-BD1 sjTRECs might be associated with GVHD.