tbuckley/cabot-search huggingface dataset:
Correlation Between Myofilament Response to Ca <sup>2+</sup> and Altered Dynamics of Contraction and Relaxation in Transgenic Cardiac Cells That Express β-Tropomyosin
Authors: Beata M. Wolska, Rebecca S. Keller, Christian C. Evans, Kimberly A. Palmiter, Ronald M. Phillips, Mariappan Muthuchamy, James Oehlenschlager, David F. Wieczorek, Pieter P. de Tombe, R. John Solaro
Journal: Circulation Research (1999)

Abstract —We compared the dynamics of the contraction and relaxation of single myocytes isolated from nontransgenic (NTG) mouse hearts and from transgenic (TG-β-Tm) mouse hearts that overexpress the skeletal isoform of tropomyosin (Tm). Compared with NTG controls, TG-β-Tm myocytes showed significantly reduced maximal rates of contraction and relaxation with no change in the extent of shortening. This result indicated that the depression in contraction dynamics determined in TG-β-Tm isolated hearts is intrinsic to the cells. To further investigate the effect of Tm isoform switching on myofilament activity and regulation, we measured myofilament force and ATPase rate as functions of pCa (−log of [Ca 2+ ]). Compared with controls, force generated by myofilaments from TG-β-Tm hearts and myofibrillar ATPase activity were both more sensitive to Ca 2+ . However, the shift in pCa 50 (half-maximally activating pCa) caused by changing sarcomere length from 1.8 to 2.4 μm was not significantly different between NTG and TG-β-Tm fiber preparations. To test directly whether isoform switching affected the economy of contraction, force versus ATPase rate relationships were measured in detergent-extracted fiber bundles. In both NTG and TG-β-Tm preparations, force and ATPase rate were linear and identically correlated, which indicated that crossbridge turnover was unaffected by Tm isoform switching. However, detergent extracted fibers from TG-β-Tm demonstrated significantly less maximum tension and ATPase activity than NTG controls. Our results provide the first evidence that the Tm isoform population modulates the dynamics of contraction and relaxation of single myocytes by a mechanism that does not alter the rate-limiting step of crossbridge detachment. Our results also indicate that differences in sarcomere-length dependence of activation between cardiac and skeletal muscle are not likely due to differences in the isoform population of Tm.
Natural distribution of environmental radon daughters in the different brain areas of an Alzheimer disease victim.
Authors: Berislav Momčilović, Glenn I Lykken, Marvin Cooley
Journal: Molecular Neurodegeneration (2006)

Radon is a ubiquitous noble gas in the environment and a primary source of harmful radiation exposure for humans; it decays in a cascade of daughters (RAD) by releasing the cell damaging high energy alpha particles. We studied natural distribution of RAD 210Po and 210Bi in the different parts of the postmortem brain of 86-year-old woman who had suffered from Alzheimer's disease (AD). A distinct brain map emerged, since RAD distribution was different among the analyzed brain areas. The highest RAD irradiation (mSv·year-1) occurred in the decreasing order of magnitude: amygdale (Amy) >> hippocampus (Hip) > temporal lobe (Tem) ~ frontal lobe (Fro) > occipital lobe (Occ) ~ parietal lobe (Par) > substantia nigra (SN) >> locus ceruleus (LC) ~ nucleus basalis (NB); generally more RAD accumulated in the proteins than lipids of gray and white (gray > white) brain matter. Amy and Hip are particularly vulnerable brain structure targets to significant RAD internal radiation damage in AD (5.98 and 1.82 mSv·year-1, respectively). Next, naturally occurring RAD radiation for Tem and Fro, then Occ and Par, and SN was an order of magnitude higher than that in LC and NB; the later was within RAD we observed previously in the healthy control brains. Naturally occurring environmental RAD exposure may dramatically enhance AD deterioration by selectively targeting brain areas of emotions (Amy) and memory (Hip).
Inhibition of SRC Corrects GM-CSF Hypersensitivity That Underlies Juvenile Myelomonocytic Leukemia
Authors: Severa Bunda, Michelle W. Kang, Stephanie S. Sybingco, Julie Weng, Helene Favre, Danielle H. Shin, Meredith S. Irwin, Mignon L. Loh, Michael Ohh
Journal: Cancer Research (2013)

Abstract Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm in children characterized by the overproduction of monocytic cells that infiltrate the spleen, lung, and liver. JMML remains a disease for which few curative therapies are available other than myeloablative hematopoietic stem cell transplant (HSCT); however, relapse remains a major cause of treatment failure and the long-term morbidities of HSCT for survivors are substantial. A hallmark feature of JMML is acquired hypersensitivity by clonal myeloid progenitor cells to granulocyte macrophage-colony stimulating factor (GM-CSF) via a largely unknown mechanism. Here, we identify c-Cbl (henceforth referred to as Cbl) as a GM-CSF receptor (GMR) adaptor protein that targets Src for ubiquitin-mediated destruction upon GM-CSF stimulation and show that a loss of negative regulation of Src is pivotal in the hyperactivation of GMR signaling in Cbl-mutated JMML cells. Notably, dasatinib, an U.S. Food and Drug Administration–approved multikinase inhibitor that also targets Src family, dramatically attenuated the spontaneous and GM-CSF-induced hypersensitive growth phenotype of mononuclear cells from peripheral blood and bone marrow collected from JMML patients harboring Cbl or other known JMML-associated mutations. These findings reveal Src kinase as a critical oncogenic driver underlying JMML. Cancer Res; 73(8); 2540–50. ©2013 AACR.
Barrett’s oesophagus and colorectal neoplasia: scope for screening?
Authors: RICHARD F A LOGAN, MAEVE M SKELLY
Journal: Gut (1999)

See article on page 867 

Several studies have reported significant positive associations between colorectal cancer (CRC) and Barrett’s oesophagus.1-5 In the initial report, 29 colon tumours, 10 of them malignant, were found in 65 patients with Barrett’s oesophagus.1 The authors suggested that the probability of detecting a similar number of malignant colorectal lesions in an age matched sample of the general population was less than one in a million. The early studies, however, were often hampered by their choice of a “control” group or the complete absence of one. Bias may also have arisen from the discovery of Barrett’s oesophagus during the investigation of patients with gastrointestinal symptoms referable to their presentation of a CRC. In addition, the existence of asymptomatic but prevalent cases of both colon cancer and of Barrett’s oesophagus is now more widely recognised than it was a decade ago.6 Despite reservations about the validity of these studies, the finding that colon tumours seemed to be more common in patients with oesophageal intestinal metaplasia than in patients with functional bowel symptoms or with positive faecal occult blood tests is interesting on two accounts.

Firstly, the implications for a colorectal cancer screening programme of a positive association between the index cancer and Barrett’s oesophagus are considerable. The prevalence of Barrett’s oesophagus in the general population has been reported to be …
Intravenous immunoglobulin contains a broad repertoire of anticarbohydrate antibodies that is not restricted to the IgG2 subclass
Authors: Stephan von Gunten, David F. Smith, Richard D. Cummings, Stefan Riedel, Sylvia Miescher, Alexander Schaub, Robert G. Hamilton, Bruce S. Bochner
Journal: Journal of Allergy and Clinical Immunology (2009)
The Pathogenesis of Acute Pulmonary Viral and Bacterial Infections: Investigations in Animal Models
Authors: Mary F. Lipscomb, Julie Hutt, Julie Lovchik, Terry Wu, C. Rick Lyons
Journal: Annual Review of Pathology Mechanisms of Disease (2009)

Acute viral and bacterial infections in the lower respiratory tract are major causes of morbidity and mortality worldwide. The proper study of pulmonary infections requires interdisciplinary collaboration among physicians and biomedical scientists to develop rational hypotheses based on clinical studies and to test these hypotheses in relevant animal models. Animal models for common lung infections are essential to understand pathogenic mechanisms and to clarify general mechanisms for host protection in pulmonary infections, as well as to develop vaccines and therapeutics. Animal models for uncommon pulmonary infections, such as those that can be caused by category A biothreat agents, are also very important because the infrequency of these infections in humans limits in-depth clinical studies. This review summarizes our understanding of innate and adaptive immune mechanisms in the lower respiratory tract and discusses how animal models for selected pulmonary pathogens can contribute to our understanding of the pathogenesis of lung infections and to the search for new vaccines and therapies.
Expression of Coxsackievirus and Adenovirus Receptor in Hearts of Rats With Experimental Autoimmune Myocarditis
Authors: Masahiro Ito, Makoto Kodama, Masayoshi Masuko, Masayuki Yamaura, Koichi Fuse, Yumiko Uesugi, Satoru Hirono, Yuji Okura, Kiminori Kato, Yuko Hotta, Takao Honda, Ryozo Kuwano, Yoshifusa Aizawa
Journal: Circulation Research (2000)

The expression of coxsackievirus and adenovirus receptor (CAR) was dominant in the brains and hearts of mice until the newborn phase. There is no detailed information concerning the relation between the expression of CAR and development of hearts. It is also uncertain whether CAR is able to be induced in adult hearts after cardiac injury. We demonstrated that CAR was abundant in the hearts of newborn rats but was barely detectable in the hearts of adult rats. The expression of CAR in rat hearts with experimental autoimmune myocarditis, which was induced by immunization of purified cardiac myosin, was serially investigated. Active myocarditis was observed from day 15 after immunization. By immunohistochemistry, cardiomyocytes were strongly stained for CAR antibody from days 24 to 42. CAR mRNA was also detected from days 18 to 30 by using reverse transcription-polymerase chain reaction. In the next experiment, the induction of CAR on isolated cardiomyocytes was investigated. CAR was barely detectable in cultured cardiomyocytes by Western blot analysis after isolation. This molecule gradually appeared along with the creation of clusters and beating of cardiomyocytes. Furthermore, the induction of CAR in cultured cardiomyocytes increased after supplement with conditioned medium of rat splenocytes activated by concanavalin A. In conclusion, rat CAR is expressed strongly in the hearts of newborn rats and is suppressed in those of adult rats. The expression of CAR is enhanced during the active phase of experimental autoimmune myocarditis and is induced by inflammatory mediators. CAR may play a role in cell-to-cell contact and adhesion of cardiomyocytes.
Combined p21-activated kinase and farnesyltransferase inhibitor treatment exhibits enhanced anti-proliferative activity on melanoma, colon and lung cancer cell lines
Authors: Giampiero Porcu, Ainslie B Parsons, Daniele Di Giandomenico, Giuseppe Lucisano, Maria Giovanna Mosca, Charles Boone, Antonella Ragnini-Wilson
Journal: Molecular Cancer (2013)

Abstract Background Farnesyltransferase inhibitors (FTIs) are anticancer agents with a spectrum of activity in Ras-dependent and independent tumor cellular and xenograph models. How inhibition of protein farnesylation by FTIs results in reduced cancer cell proliferation is poorly understood due to the multiplicity of potential FTase targets. The low toxicity and oral availability of FTIs led to their introduction into clinical trials for the treatment of breast cancer, hematopoietic malignancy, advanced solid tumor and pancreatic cancer treatment, and Hutchinson-Gilford Progeria Syndrome. Although their efficacy in combinatorial therapies with conventional anticancer treatment for myeloid malignancy and solid tumors is promising, the overall results of clinical tests are far below expectations. Further exploitation of FTIs in the clinic will strongly rely on understanding how these drugs affect global cellular activity. Methods Using FTase inhibitor I and genome-wide chemical profiling of the yeast barcoded deletion strain collection, we identified genes whose inactivation increases the antiproliferative action of this FTI peptidomimetic. The main findings were validated in a panel of cancer cell lines using FTI-277 in proliferation and biochemical assays paralleled by multiparametric image-based analyses. Results ABC transporter Pdr10 or p-21 activated kinase (PAK) gene deletion increases the antiproliferative action of FTase inhibitor I in yeast cells. Consistent with this, enhanced inhibition of cell proliferation by combining group I PAK inhibition, using IPA3, with FTI-277 was observed in melanoma (A375MM), lung (A549) and colon (HT29), but not in epithelial (HeLa) or breast (MCF7), cancer cell lines. Both HeLa and A375MM cells show changes in the nuclear localization of group 1 PAKs in response to FTI-277, but up-regulation of PAK protein levels is observed only in HeLa cells. Conclusions Our data support the view that group I PAKs are part of a pro-survival pathway activated by FTI treatment, and group I PAK inactivation potentiates the anti-proliferative action of FTIs in yeast as well as in cancer cells. These findings open new perspectives for the use of FTIs in combinatorial strategies with PAK inhibitors in melanoma, lung and colon malignancy.
Fatness Is a Better Predictor of Cardiovascular Disease Risk Factor Profile Than Aerobic Fitness in Healthy Men
Authors: Demetra D. Christou, Christopher L. Gentile, Christopher A. DeSouza, Douglas R. Seals, Phillip E. Gates
Journal: Circulation (2005)

Background— The prevalence of cardiovascular disease (CVD) is partly attributable to an inactive and/or overweight population. However, the independent association of body fatness and aerobic fitness with CVD risk factors is uncertain. We sought to determine whether fatness or fitness better predicted traditional CVD risk factors in men with broad fatness, aerobic fitness, and age ranges using 3 expressions of adiposity. Methods and Results— In 135 carefully screened healthy men, we measured 18 established CVD risk factors, body mass index, total percent body fat, waist circumference, and maximal aerobic capacity. Body mass index, percent body fat, and waist circumference were consistently associated with all metabolic risk factors ( r =−0.44 to 0.51, P &lt;0.05) after partialling out the effects of aerobic fitness and age. Body mass index and waist circumference were also independently associated with selective hemodynamic risk factors ( r =0.20 to 0.30, P ≤0.01). In contrast, aerobic fitness was independently associated with only selective metabolic risk factors ( r =−0.21 to 0.19, P &lt;0.05) and was not associated with any hemodynamic risk factors ( P &gt;0.05). Both aerobic fitness and body fatness were independently associated with selective hemostatic risk factors ( r =−0.22 to −0.26, P ≤0.01; r =−0.32 to 0.48, P &lt;0.05, respectively). Overall, fatness was more strongly and consistently associated with CVD risk factors than aerobic fitness. Conclusions— Body fatness is a better predictor of CVD risk factor profile than aerobic fitness in healthy men. Although habitual physical activity is an effective strategy for preventing CVD, elevated body fatness is associated with an adverse CVD risk factor profile independently of aerobic fitness.
Fluoxetine Administered to Juvenile Monkeys: Effects on the Serotonin Transporter and Behavior
Authors: Stal Saurav Shrestha, Eric E. Nelson, Jeih-San Liow, Robert Gladding, Chul Hyoung Lyoo, Pam L. Noble, Cheryl Morse, Ioline D. Henter, Jeremy Kruger, Bo Zhang, Stephen J. Suomi, Per Svenningsson, Victor W. Pike, James T. Winslow, Ellen Leibenluft, Daniel S. Pine, Robert B. Innis
Journal: American Journal of Psychiatry (2014)

This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth-an animal model of human childhood stress-were also studied.At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N=8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration.Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures.Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo.
Inhibition of CD47 Effectively Targets Pancreatic Cancer Stem Cells via Dual Mechanisms
Authors: Michele Cioffi, Sara Trabulo, Manuel Hidalgo, Eithne Costello, William Greenhalf, Mert Erkan, Joerg Kleeff, Bruno Sainz, Christopher Heeschen
Journal: Clinical Cancer Research (2015)

Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the exocrine pancreas with unmet medical need and is strongly promoted by tumor-associated macrophages (TAM). The presence of TAMs is associated with poor clinical outcome, and their overall role, therefore, appears to be protumorigenic. The "don't eat me" signal CD47 on cancer cells communicates to the signal regulatory protein-α on macrophages and prevents their phagocytosis. Thus, inhibition of CD47 may offer a new opportunity to turn TAMs against PDAC cells, including cancer stem cells (CSC), as the exclusively tumorigenic population.
Therapeutic Efficacy of Bifunctional siRNA Combining TGF-β1 Silencing with RIG-I Activation in Pancreatic Cancer
Authors: Jonathan Ellermeier, Jiwu Wei, Peter Duewell, Sabine Hoves, Mareike R. Stieg, Tina Adunka, Daniel Noerenberg, Hans-Joachim Anders, Doris Mayr, Hendrik Poeck, Gunther Hartmann, Stefan Endres, Max Schnurr
Journal: Cancer Research (2013)

Abstract Deregulated TGF-β signaling in pancreatic cancer promotes tumor growth, invasion, metastasis, and a potent immunosuppressive network. A strategy for disrupting this tumor-promoting pathway is silencing TGF-β by siRNA. By introducing a triphosphate group at the 5′ end of siRNA (ppp-siRNA), gene silencing can be combined with immune activation via the cytosolic helicase retinoic acid-inducible gene I (RIG-I), a ubiquitously expressed receptor recognizing viral RNA. We validated RIG-I as a therapeutic target by showing that activation of RIG-I in pancreatic carcinoma cells induced IRF-3 phosphorylation, production of type I IFN, the chemokine CXCL10, as well as caspase-9–mediated tumor cell apoptosis. Next, we generated a bifunctional ppp-siRNA that combines RIG-I activation with gene silencing of TGF-β1 (ppp-TGF-β) and studied its therapeutic efficacy in the orthotopic Panc02 mouse model of pancreatic cancer. Intravenous injection of ppp-TGF-β reduced systemic and tumor-associated TGF-β levels. In addition, it induced high levels of type I IFN and CXCL10 in serum and tumor tissue, systemic immune cell activation, and profound tumor cell apoptosis in vivo. Treatment of mice with established tumors with ppp-TGF-β significantly prolonged survival as compared with ppp-RNA or TGF-β siRNA alone. Furthermore, we observed the recruitment of activated CD8+ T cells to the tumor and a reduced frequency of CD11b+ Gr-1+ myeloid cells. Therapeutic efficacy was dependent on CD8+ T cells, whereas natural killer cells were dispensable. In conclusion, combing TGF-β gene silencing with RIG-I signaling confers potent antitumor efficacy against pancreatic cancer by breaking tumor-induced CD8+ T cell suppression. Cancer Res; 73(6); 1709–20. ©2013 AACR.
Transcriptional diversity of long-term glioblastoma survivors
Authors: N. K. Gerber, A. Goenka, S. Turcan, M. Reyngold, V. Makarov, K. Kannan, K. Beal, A. Omuro, Y. Yamada, P. Gutin, C. W. Brennan, J. T. Huse, T. A. Chan
Journal: Neuro-Oncology (2014)

Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTSs) may provide important insight into the biology of GBM. We identified 7 patients with GBM, treated at Memorial Sloan-Kettering Cancer Center (MSKCC), with survival >48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTSs in 2 independent cohorts (The Cancer Genome Atlas [TCGA] and NCI Repository for Molecular Brain Neoplasia Data [REMBRANDT]) and analyzed the transcriptomal characteristics of these LTSs. The median overall survival of our cohort was 62.5 months. LTSs were distributed between the proneural (n = 2), neural (n = 2), classical (n = 2), and mesenchymal (n = 1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identities. The majority of the MSKCC LTSs (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutation, and IDH mutation occurred in a minority of the TCGA LTSs as well. A set of 60 genes was found to be differentially expressed in the MSKCC and TCGA LTSs. While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression.