tbuckley/cabot-search huggingface dataset:
Involvement of cell calcium and transmembrane potential in control of hepatocyte volume
Authors: Walid E. Khalbuss, Robert Wondergem
Journal: Hepatology (1991)

This study examined the role of hepatocyte calcium and cytoskeleton in activation of hyposmotic stress-induced increases in hepatocyte transmembrane potential and control of cell volume. Hepatocyte transmembrane potential was measured by glass microelectrodes in mouse liver slices before and after exposure to hyposmotic medium. Hepatocytes were loaded with tetramethylammonium by briefly exposing liver slices to nystatin, a cation poreforming antibiotic. Changes in hepatocyte steady-state water volume were determined by changes in intracellular tetramethylammonium activity measured with tetramethylammonium-sensitive, double-barrel microelectrodes 4 min after exposure to hyposmotic medium. Hyposmotic stress of 74% of the control osmolality (˜280 mOsm) hyperpolarized hepatocyte transmembrane potential by 1.83 times the control hepatocyte transmembrane potential, and cell water volume increased by a factor of 1.19. The Ca 2+ channel blocker verapamil (100 μmol/L) completely inhibited hyposmotic stress-induced hyperpolarization of hepatocyte transmembrane potential. This inhibitory effect diminished at doses of 37.5 or 50 μmol/L, but even these hyperpolarizations were decreased significantly compared with control. Hyposmotic stress during added verapamil dosage (50 μmol/L) also resulted in 23% greater cell swelling compared with control. Ca 2+ free medium plus ethylene glycol-bis (β-aminoethylether)-N,N'-tetraacetic acid (5 mmol/L) inhibited hyposmotic stress-induced increases in hepatocyte transmembrane potential and resulted in 16% greater cell swelling compared with control. Calmodulin inhibitors trifluoperazine (100 μmol/L) and promethazine (100 μmol/L) inhibited the hyperpolarization of hepatocyte transmembrane potential caused by hyposmolality, as did 3,4,5-trimethoxybenzoate 8-(N,N-diethylamino)octyl ester) (50 μmol/L), which inhibits mobilization of Ca 2+ from intracellular stores. Cytochalasin B (50 μmol/L), which disrupts microfilaments, also inhibited hyperpolarization of hepatocyte transmembrane potential with osmotic stress. In contrast, colchicine (10 μmol/L) under identical conditions had no effect. These results show that extracellular and intracellular calcium, the calmodulin system and microfilaments are involved in control and activation of hyposmotic stress-induced increases in hepatocyte hepatocyte transmembrane potential. These changes in hepatocyte transmembrane potential play a role in cell volume regulation. (Hepatology 1991;13:962-969.)
On the mechanism underlying the action of D-600 on slow inward current and tension in mammalian myocardium.
Authors: H Nawrath, R E Eick, T F McDonald, W Trautwein
Journal: Circulation Research (1977)

D-600 the methoxy derivative of verapamil, is said to affect the force of cardiac contraction and the slow inward current (LSi) specifically by reducing the membrane conductance for Ca2+ (gsi). However, it is apparent that many effects of D-600 cannot be adequately explained solely by an effect on gsi. We studied the effects of D-600 on membrane current and tension of cat papillary muscle, using a conventional single sucrose gap voltage clamp technique. The results indicate that D-600 not only reduces the maximal Ca conductance but also, depending on concentration and duration of exposure, alters both the kinetics of the Ca-carrying system and the amplitude of the steady state outward current. No changes in the steady state activation and inactivation variables or in the rate of Isi inactivation were found. However, a substantial increase in the time to peak Lsi, as much as 7 times normal, was observed after exposure to D-600 (0.5 X 10(-6) to 2.0 X 10(-6) M) for at least 20 minutes. Because approximately only 75% of the reduction in Lsi induced by D-600 could be attributed to change in the maximum value of gsi (gsi), we conclude that the change in time to peak and about 25% of the reduction in Isi must be due to a change in the activation kinetics of the Ca-carrying system, Calculations suggest that the time to 70% activation of gsi can be prolonged to as much as 10 times normal by prolonged exposure to negatively inotropic concentrations of D-600.
Phosphorylation of CARMA1 Plays a Critical Role in T Cell Receptor-Mediated NF-κB Activation
Authors: Reiko Matsumoto, Donghai Wang, Marzenna Blonska, Hongxiu Li, Masayuki Kobayashi, Bhanu Pappu, Yuhong Chen, Demin Wang, Xin Lin
Journal: Immunity (2005)
Hepatitis C virus treatment for prevention among people who inject drugs: Modeling treatment scale-up in the age of direct-acting antivirals
Authors: Natasha K. Martin, Peter Vickerman, Jason Grebely, Margaret Hellard, Sharon J. Hutchinson, Viviane D. Lima, Graham R. Foster, John F. Dillon, David J. Goldberg, Gregory J. Dore, Matthew Hickman
Journal: Hepatology (2013)

Substantial reductions in hepatitis C virus (HCV) prevalence among people who inject drugs (PWID) cannot be achieved by harm reduction interventions such as needle exchange and opiate substitution therapy (OST) alone. Current HCV treatment is arduous and uptake is low, but new highly effective and tolerable interferon-free direct-acting antiviral (DAA) treatments could facilitate increased uptake. We projected the potential impact of DAA treatments on PWID HCV prevalence in three settings. A dynamic HCV transmission model was parameterized to three chronic HCV prevalence settings: Edinburgh, UK (25%); Melbourne, Australia (50%); and Vancouver, Canada (65%). Using realistic scenarios of future DAAs (90% sustained viral response, 12 weeks duration, available 2015), we projected the treatment rates required to reduce chronic HCV prevalence by half or three-quarters within 15 years. Current HCV treatment rates may have a minimal impact on prevalence in Melbourne and Vancouver (&lt;2% relative reductions) but could reduce prevalence by 26% in 15 years in Edinburgh. Prevalence could halve within 15 years with treatment scale-up to 15, 40, or 76 per 1,000 PWID annually in Edinburgh, Melbourne, or Vancouver, respectively (2-, 13-, and 15-fold increases, respectively). Scale-up to 22, 54, or 98 per 1,000 PWID annually could reduce prevalence by three-quarters within 15 years. Less impact occurs with delayed scale-up, higher baseline prevalence, or shorter average injecting duration. Results are insensitive to risk heterogeneity or restricting treatment to PWID on OST. At existing HCV drug costs, halving chronic prevalence would require annual treatment budgets of US $3.2 million in Edinburgh and approximately $50 million in Melbourne and Vancouver. Conclusion: Interferon-free DAAs could enable increased HCV treatment uptake among PWID, which could have a major preventative impact. However, treatment costs may limit scale-up, and should be addressed. (Hepatology 2013;58:1598–1609)
Effectiveness of the cryosupernatant fraction of plasma in the treatment of refractory thrombotic thrombocytopenic purpura
Authors: John J. Byrnes, Joel L. Moake, Panpit Klug, Phillip Periman
Journal: American Journal of Hematology (1990)

Abstract Many patients with thrombotic thrombocytopenic purpura (TTP) satisfactorily respond to plasma therapy (plasmapheresis and/or plasma infusion). Some, however, respond either not at all or only transiently and incompletely. Evidence indicates that platelets and endothelial cell‐derived unusually large von Willebrand factor (ULvWF) multimers, as well as the largest vWF multimers in plasma, form thrombi which are deposited in the microvascular circulation. Accordingly, platelet transfusions are avoided unless there is intra‐cranial or other life‐threatening hemorrhage. The largest plasma multimers of vWF are, however, replenished by the infusion of large volumes of whole plasma. We postulated that under conditions of massive plasma replacement, plasma depleted of the largest multimers of vWF might be preferable for the treatment of TTP episodes. The largest vWF multimers sediment in the cryoprecipitate, and the cryoprecipitate‐poor fraction of plasma (cryosupernatant) is depleted of these forms. Seven patients responding inadequately to intensive plasma therapy were switched to receive cryosupernatant in place of whole plasma. All patients improved quickly following this change in therapy, and the TTP syndrome resolved in all seven.
Pathways to PTSD, Part I: Children With Burns
Authors: Glenn N. Saxe, Frederick Stoddard, Erin Hall, Neharika Chawla, Carlos Lopez, Robert Sheridan, Daniel King, Lynda King, Rachel Yehuda
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: The goal of this study was to develop a model of risk factors for posttraumatic stress disorder (PTSD) in a group of acutely burned children. METHOD: Seventy-two children between the ages of 7 and 17 who were admitted to the hospital for an acute burn were eligible for study. Members of families who consented completed the Child PTSD Reaction Index, the Multidimensional Anxiety Scale for Children, and other self-report measures of psychopathology and environmental stress both during the hospitalization and 3 months following the burn. A path analytic strategy was used to build a model of risk factors for PTSD. RESULTS: Two pathways to PTSD were discerned: 1) from the size of the burn and level of pain following the burn to the child's level of acute separation anxiety, and then to PTSD, and 2) from the size of the burn to the child's level of acute dissociation following the burn, and then to PTSD. Together these pathways accounted for almost 60% of the variance in PTSD symptoms and constituted a model with excellent fit indices. CONCLUSIONS: These findings support a model of complex etiology for childhood PTSD in which two independent pathways may be mediated by different biobehavioral systems.
Genetic Analysis of Transforming Events That Convert Chronic Myeloproliferative Neoplasms to Leukemias
Authors: Omar Abdel-Wahab, Taghi Manshouri, Jay Patel, Kelly Harris, JinJuan Yao, Cyrus Hedvat, Adriana Heguy, Carlos Bueso-Ramos, Hagop Kantarjian, Ross L. Levine, Srdan Verstovsek
Journal: Cancer Research (2010)

Abstract The oncogenetic events that transform chronic myeloproliferative neoplasms (MPN) to acute myeloid leukemias (AML) are not well characterized. We investigated the role of several genes implicated in leukemic transformation by mutational analysis of 63 patients with AML secondary to a preexisting MPN (sAML). Frequent mutations were identified in TET2 (26.3%), ASXL1 (19.3%), IDH1 (9.5%), and JAK2 (36.8%) mutations in sAML, and all possible mutational combinations of these genes were also observed. Analysis of 14 patients for which paired samples from MPN and sAML were available showed that TET2 mutations were frequently acquired at leukemic transformation [6 of 14 (43%)]. In contrast, ASXL1 mutations were almost always detected in both the MPN and AML clones from individual patients. One case was also observed where TET2 and ASXL1 mutations were found before the patient acquired a JAK2 mutation or developed clinical evidence of MPN. We conclude that mutations in TET2, ASXL1, and IDH1 are common in sAML derived from a preexisting MPN. Although TET2/ASXL1 mutations may precede acquisition of JAK2 mutations by the MPN clone, mutations in TET2, but not ASXL1, are commonly acquired at the time of leukemic transformation. Our findings argue that the mutational order of events in MPN and sAML varies in different patients, and that TET2 and ASXL1 mutations have distinct roles in MPN pathogenesis and leukemic transformation. Given the presence of sAML that have no preexisting JAK2/TET2/ASXL1/IDH1 mutations, our work indicates the existence of other mutations yet to be identified that are necessary for leukemic transformation. Cancer Res; 70(2); 447–52
Identification of differentially expressed genes in cutaneous squamous cell carcinoma by microarray expression profiling.
Authors: Ingo Nindl, Chantip Dang, Tobias Forschner, Ralf J Kuban, Thomas Meyer, Wolfram Sterry, Eggert Stockfleth
Journal: Molecular Cancer (2006)

Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. This study examined and identified differentially expressed genes in cutaneous squamous cell carcinoma (SCC). Three different biopsies of 5 immunosuppressed organ-transplanted recipients each normal skin (all were pooled), actinic keratosis (AK) (two were pooled), and invasive SCC and additionally 5 normal skin tissues from immunocompetent patients were analyzed. Thus, total RNA of 15 specimens were used for hybridization with Affymetrix HG-U133A microarray technology containing 22,283 genes. Data analyses were performed by prediction analysis of microarrays using nearest shrunken centroids with the threshold 3.5 and ANOVA analysis was independently performed in order to identify differentially expressed genes (p < 0.05). Verification of 13 up- or down-regulated genes was performed by quantitative real-time reverse transcription (RT)-PCR and genes were additionally confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes. The majority of identified differentially expressed genes in cutaneous SCC were previously not described.
Selection for Translational Robustness in Buchnera aphidicola, Endosymbiotic Bacteria of Aphids
Authors: C. Toft, M. A. Fares
Journal: Molecular Biology and Evolution (2009)

Its strong intergenerational bottlenecks and effectively asexual reproduction have led Buchnera aphidicola, the endocellular symbiotic bacterium of aphids, to spectacular evolutionary and genomic changes in comparison with its free-living bacterial cousins. These changes summarize into high fixation rates of mildly deleterious destabilizing mutations. This predicts a sharp decline of its fitness and the consequent early demise of this endosymbiotic bacterium. Its survival for hundreds of millions of years casts doubt on genetic drift as the sole evolutionary force and seeks further explanation. We identify in Buchnera selection to increase the robustness of proteins to misfolding translation errors. Translational robustness varies between Buchnera lineages and protein functional categories. Metabolic proteins have been under selection for translational efficiency, whereas evolutionary rates of proteins involved in fundamental cellular processes have been largely determined by selection for translational robustness. We detect the strongest signal of translational robustness in B. aphidicola Cinara cedri with a very similar pattern to that inferred for the most common symbiotic ancestor of Buchnera lineages. This indicates that B. aphidicola Cinara cedri lineage may have probably reached the minimum evolutionary stable gene composition for endosymbiotic lifestyle. The evolutionary patterns from the comparative genomic analyses of these endosymbionts support a paradoxically complex dynamic for apparently simple genomes.
Are Increasing 5-Year Survival Rates Evidence of Success Against Cancer?
Authors: H. Gilbert Welch
Journal: JAMA (2000)

Increased 5-year survival for cancer patients is generally inferred to mean that cancer treatment has improved and that fewer patients die of cancer. Increased 5-year survival, however, may also reflect changes in diagnosis: finding more people with early-stage cancer, including some who would never have become symptomatic from their cancer.To determine the relationship over time between 5-year cancer survival and 2 other measures of cancer burden, mortality and incidence.Using population-based statistics reported by the National Cancer Institute Surveillance, Epidemiology, and End Results Program, we calculated the change in 5-year survival from 1950 to 1995 for the 20 most common solid tumor types. Using the tumor as the unit of analysis, we correlated changes in 5-year survival with changes in mortality and incidence.The association between changes in 5-year survival and changes in mortality and incidence measured using simple correlation coefficients (Pearson and Spearman).From 1950 to 1995, there was an increase in 5-year survival for each of the 20 tumor types. The absolute increase in 5-year survival ranged from 3% (pancreatic cancer) to 50% (prostate cancer). During the same period, mortality rates declined for 12 types of cancer and increased for the remaining 8 types. There was little correlation between the change in 5-year survival for a specific tumor and the change in tumor-related mortality (Pearson r=.00; Spearman r=-.07). On the other hand, the change in 5-year survival was positively correlated with the change in the tumor incidence rate (Pearson r=+. 49; Spearman r=+.37).Although 5-year survival is a valid measure for comparing cancer therapies in a randomized trial, our analysis shows that changes in 5-year survival over time bear little relationship to changes in cancer mortality. Instead, they appear primarily related to changing patterns of diagnosis. JAMA. 2000.
A Human scFv Antibody against TRAIL Receptor 2 Induces Autophagic Cell Death in Both TRAIL-Sensitive and TRAIL-Resistant Cancer Cells
Authors: Kyung-Jin Park, Seung-Hyun Lee, Tae-In Kim, Hae-Won Lee, Chang-Han Lee, Eun-Hee Kim, Ji-Young Jang, Kyeong Sook Choi, Myung-Hee Kwon, Yong-Sung Kim
Journal: Cancer Research (2007)

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptotic cell death in a variety of tumor cells without significant cytotoxicity on normal cells. However, many cancer cells with apoptotic defects are resistant to treatment with TRAIL alone, limiting its potential as an anticancer therapeutic. Here, we report on the tumoricidal activity of a human single-chain fragment variable, HW1, which specifically binds to TRAIL receptor 2 (TR2) without competing with TRAIL for the binding. HW1 treatment as a single agent induces autophagic cell death in a variety of both TRAIL-sensitive and TRAIL-resistant cancer cells, but exhibits much less cytotoxicity on normal cells. The HW1-induced autophagic cell death was inhibited by an autophagy inhibitor, 3-methyladenine, or by RNA interference knockdown of Beclin-1 and Atg7. We also show that the HW1-mediated autophagic cell death occurs predominantly via the c-Jun NH(2)-terminal kinase pathway in a caspase-independent manner. Analysis of the death-inducing signaling complex induced by HW1 binding to TR2 exhibits the recruitment of TNF receptor-associated death domain and TNF receptor-associated factor 2, but not Fas-associated death domain, caspase-8, or receptor-interacting protein, which is distinct from that induced by TRAIL. Our results reveal a novel TR2-mediated signaling pathway triggering autophagic cell death and provides a new strategy for the elimination of cancer cells, including TRAIL-resistant tumors, through nonapoptotic cell death.
Bone Marrow Transplantation for Patients with Myelodysplasia
Authors: Frederick R. Appelbaum, Janet Barrall, Rainer Storb, Lloyd D. Fisher, Gary Schoch, Robert E. Ramberg, Howard Shulman, Claudio Anasetti, Scott I. Bearman, Patrick Beatty, William I. Bensinger, C. Dean Buckner, Reginald A. Clift, John A. Hansen, Paul Martin, Finn B. Petersen, Jean E. Sanders, Jack Singer, Patricia Stewart, Keith M. Sullivan, Robert P. Witherspoon, E. Donnall Thomas
Journal: Annals of Internal Medicine (1990)

Study Objective: To determine the efficacy of allogeneic bone marrow transplantation for severe myelodysplasia, and to identify variables predictive of outcome. Design: Case series study. Setting: A referral-based bone marrow transplant center. Patients: Consecutive series of 59 patients with myelodysplasia or closely related disorders and either life-threatening cytopenia or a progressive increase in marrow blast percentage. Intervention: Patients were treated with high-dose cyclophosphamide and total body irradiation followed by allogeneic bone marrow transplantation from either an HLA-identical (n = 45) or HLA-partially matched (n = 14) donor. Measurements and Main Results: The product-limit estimate for disease-free survival 3 years after transplant is 45% (95% CI, 32% to 59%). The commonest causes of death after transplant were disease recurrence, interstitial pneumonia, and graft-versus-host disease, accounting for eight deaths each. In a univariate analysis, younger patients, those with shorter disease duration, and those whose disease was characterized by an abnormal cytogenetic karyotype had better survival and disease-free survival than the group as a whole. In a multivariate analysis, younger age and abnormal karyotype were independent predictors of improved disease-free survival and overall survival. Patients who received transplants when they had fewer blasts in their bone marrow had a decreased chance for disease recurrence when compared with patients with excess blasts. Conclusions: Bone marrow transplantation offers a potential cure for many patients with myelodysplasia. Best results can be expected in younger patients who receive transplants relatively early in their disease course.
The sinoatrial node, a heterogeneous pacemaker structure
Authors: M Boyett
Journal: Cardiovascular Research (2000)

This article focuses on the regional heterogeneity of the mammalian sinoatrial (SA) node in terms of cell morphology, pacemaker activity, action potential configuration and conduction, densities of ionic currents (iNa, iCa,L, ito, iK,r, iK,s and if), expression of gap junction proteins (Cx40, Cx43 and Cx45), autonomic regulation, and ageing. Experimental studies on the single SA node cell to the whole animal are reviewed. The heterogeneity is considered in terms of the gradient model of the SA node, in which there is gradual change in the intrinsic properties of SA node cells from periphery to centre, and the alternative mosaic model, in which there is a variable mix of atrial and SA node cells from periphery to centre. The heterogeneity is important for the dependable functioning of the SA node as the pacemaker for the heart, because (i) via multiple mechanisms, it allows the SA node to drive the surrounding atrial muscle without being suppressed electrotonically; (ii) via an action potential duration gradient and a conduction block zone, it promotes antegrade propagation of excitation from the SA node to the right atrium and prevents reentry of excitation; and (iii) via pacemaker shift, it allows pacemaking to continue under diverse pathophysiological circumstances.
Glycemic Control in Children With Type 1 Diabetes in Wales
Authors: Malachy O'Hagan, John N. Harvey
Journal: Diabetes Care (2010)

To determine whether glycemic control is improving in diabetic children in Wales and to identify factors associated with improvement.Data were collected in 2001 and 2006.Over time A1C was reduced from 9.08 +/- 1.66 to 8.88 +/- 1.63% (P = 0.012). There were differences among centers (P < 0.001) and differential changes over time (interaction P < 0.001). Since 2001 five centers had appointed a pediatric diabetes specialist nurse (PDSN). A1C improved in these centers from 9.59 +/- 1.88 to 8.72 +/- 1.61% (P < 0.001). Glycemic control was worse in children aged >10 years compared with younger patients (P < 0.001). Improvement occurred in those aged >10 years. Age (P = 0.003) and insulin dose (P < 0.001) were positively and independently associated with A1C. Thus, any influence of PDSNs was not achieved through increased insulin prescription.Improvement in glycemic control has occurred. Worse control is associated with greater prescribed insulin dose in older children. Appointment of PDSNs was associated with improved glycemic control among adolescents.
Preeclampsia: Pathophysiology, Diagnosis, and Management
Authors: M D Lindheimer, A I Katz
Journal: Annual Review of Medicine (1989)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More