tbuckley/cabot-search huggingface dataset:
Obesity and Barrett's oesophagus: more than just reflux
Authors: J. A Abrams
Journal: Gut (2009)

The absence of functional peripheral myelin protein 22 (PMP22) is associated with shortened lifespan in rodents and severe peripheral nerve myelin abnormalities in several species including humans. Schwann cells and nerves from PMP22 knock-out (KO) mice show deranged cholesterol distribution and aberrant lipid raft morphology, supporting an unrecognized role for PMP22 in cellular lipid metabolism. To examine the mechanisms underlying these abnormalities, we studied Schwann cells and nerves from male and female PMP22 KO mice. Whole-cell current-clamp recordings in cultured Schwann cells revealed increased membrane capacitance and decreased membrane resistance in the absence of PMP22, which was consistent with a reduction in membrane cholesterol. Nerves from PMP22-deficient mice contained abnormal lipid droplets, with both mRNA and protein levels of apolipoprotein E (apoE) and ATP-binding cassette transporter A1 (ABCA1) being highly upregulated. Despite the upregulation of ABCA1 and apoE, the absence of PMP22 resulted in reduced localization of the transporter to the cell membrane and diminished secretion of apoE. The absence of PMP22 also impaired ABCA1-mediated cholesterol efflux capacity. In nerves from ABCA1 KO mice, the expression of PMP22 was significantly elevated and the subcellular processing of the overproduced protein was aberrant. In wild-type samples, double immunolabeling identified overlapping distribution of PMP22 and ABCA1 at the Schwann cell plasma membrane and the two proteins were coimmunoprecipitated from Schwann cell and nerve lysates. Together, these results reveal a novel role for PMP22 in regulating lipid metabolism and cholesterol trafficking through functional interaction with the cholesterol efflux regulatory protein ABCA1. <b>SIGNIFICANCE STATEMENT</b> Understanding the subcellular events that underlie abnormal myelin formation in hereditary neuropathies is critical for advancing therapy development. Peripheral myelin protein 22 (PMP22) is an essential peripheral myelin protein because its genetic abnormalities account for ∼80% of hereditary neuropathies. Here, we demonstrate that in the absence of PMP22, the cellular and electrophysiological properties of the Schwann cells9 plasma membrane are altered and cholesterol trafficking and lipid homeostasis are perturbed. The molecular mechanisms for these abnormalities involve a functional interplay among PMP22, cholesterol, apolipoprotein E, and the major cholesterol-efflux transporter protein ATP-binding cassette transporter A1 (ABCA1). These findings establish a critical role for PMP22 in the maintenance of cholesterol homeostasis in Schwann cells.
Lysine deacetylation in ischaemic preconditioning: the role of SIRT1
Authors: Sergiy M. Nadtochiy, Emily Redman, Irfan Rahman, Paul S. Brookes
Journal: Cardiovascular Research (2010)

Acute ischaemic preconditioning (IPC) induces protection against cardiac ischaemia-reperfusion (IR) via post-translational modification of key proteins.Lysine (Lys) acetylation is an important regulator of protein function, but this type of modification has not been studied in the context of IPC.We investigated Lys acetylation in IPC and its upstream regulation by SIRT1. Methods and resultsHearts from C57BL/6 mice were Langendorff-perfused and subjected to IPC and IR injury.Mice were exposed to IPC by in vivo coronary artery occlusion.An isolated cardiomyocyte model of IPC was also developed.Lys acetylation was measured by western blotting, and pharmacological modulators of Lys acetylation were tested.More Lys deacetylation was observed in IPC, in the Langendorff, in vivo, and cellular IPC models; this was concurrent with an increase in SIRT1 activity measured by p53 Lys 379 deacetylation.IPC was not accompanied by changes in SIRT1 protein level, but evidence was obtained for SIRT1 modification by Small Ubiquitin-like Modifier (SUMOylation) in IPC.Furthermore, the specific SIRT1 inhibitor splitomicin reversed both IPC-mediated Lys deacetylation and IPC-induced cardioprotection.Inhibition of nicotinamide phosphoribosyltransferase (Nampt, an important enzyme which regulates SIRT1 activity by maintaining availability of the substrate NAD + ) also blocked both IPC-induced deacetylation and cardioprotection. ConclusionLys deacetylation occurs during IPC and an elevation in SIRT1 activity plays a role in this phenomenon.Inhibition of SIRT1, either directly or by restricting the availability of its substrate NAD + , inhibits IPC.Together these data suggest a role for SIRT1-mediated Lys deacetylation in the mechanism of acute IPC.
Clonal analysis of cytotoxic T cell response against human melanoma.
Authors: B Mukherji, T J MacAlister
Journal: The Journal of Experimental Medicine (1983)

We investigated the feasibility of generating cytotoxic T cell clones against autologous human melanoma cells using a melanoma cell line (VIP) and a spontaneously transformed autologous fibroblast line (VIP-F:T). Cytotoxic lymphocytes (CL) generated against the VIP melanoma cells in one-way mixed lymphocyte-tumor cell interactions were expanded in interleukin 2 for 2 wk. The expanded CL were cloned in limiting dilution. Two phenotypically homogeneous clones (3:1 and E.5) were obtained bearing OKT3 phenotype. Both clones expressed cytotoxicity selectively only against the sensitizing autologous target VIP. cytotoxicity assays performed with clone E.5 against the VIP target cells in the presence of autologous unfractionated lymphocytes or serum showed no modulation of autoreactivity of clone E.5. These results indicate that analysis of cellular immune response against autologous tumor cells might be feasible using autoreactive clones generated by the currently available in vitro cloning technology.
Placebos in 19th century medicine: a quantitative analysis of the BMJ
Authors: J. E. Raicek, B. H. Stone, T. J. Kaptchuk
Journal: BMJ (2012)

<b>Objective</b> To provide the first quantitative data on the use of the term “placebo” in the 19th century. <b>Design</b> Computer search of <i>BMJ</i>’s archival database from January 1840 (the first issue) through December 1899 for uses of the words “placebo(s).” Grounded theory was used to categorise the implications of uses of the term. <b>Results</b> 71 citations contained the term “placebo(s).” Of these, 22 (31%) used the term to mean “no effect” or as a general pejorative term, 18 (25%) portrayed placebo treatment as permitting the unfolding of the natural history (the normal waxing and waning of illness), 14 (20%) described placebo as important to satisfy patients, 7 (10%) described it as fulfilling a physician’s performance role, 3 (4%) described its use to buy time, 3 (4%) described its use for financial gain, 2 (3%) used it in a manner similar to a placebo control, and only one implied that placebo could have a clinical effect. Only one citation mentioned telling the patient about his placebo treatment. <b>Conclusion</b> Nineteenth century physicians had diverse a priori assumptions about placebos. These findings remind us that contemporary medicine needs to use rigorous science to separate fact from its own beliefs concerning the “provision of care.” As in previous generations, ethical issues concerning placebos continue to challenge medicine.
Preclinical Toxicity, Toxicokinetics, and Antitumoral Efficacy Studies of DTS-201, a Tumor-Selective Peptidic Prodrug of Doxorubicin
Authors: Denis Ravel, Vincent Dubois, Jérôme Quinonero, Florence Meyer-Losic, JeanPierre Delord, Philippe Rochaix, Céline Nicolazzi, Fabien Ribes, Catherine Mazerolles, Elise Assouly, Karine Vialatte, Inès Hor, Jonathan Kearsey, André Trouet
Journal: Clinical Cancer Research (2008)

There is a clear clinical need for cytotoxic drugs with a lower systemic toxicity. DTS-201 (CPI-0004Na) is a peptidic prodrug of doxorubicin that shows an improved therapeutic index in experimental models. The purpose of the current study was to complete its preclinical characterization before initiation of phase I clinical trials.The preclinical development program consisted of a detailed assessment of the general and cardiac toxicity profiles of DTS-201 in mice, rats, and dogs, together with mass balance and antitumoral efficacy studies in rodents. Neprilysin and thimet oligopeptidase expression, two enzymatic activators of DTS-201, was also characterized in human breast and prostate tumor biopsies.The target organs of DTS-201 toxicity in rodents and dogs are typically those of doxorubicin, albeit at much higher doses. Importantly, chronic treatment with DTS-201 proved to be significantly less cardiotoxic than with doxorubicin at doses up to 8-fold higher in rats. The mass balance study showed that [14C] DTS-201 does not accumulate in the body after intravenous administration. The improved therapeutic index of DTS-201 compared with free doxorubicin was confirmed in three tumor xenograft models of prostate, breast, and lung cancer. Neprilysin and/or thimet oligopeptidase are expressed in all experimental human tumor types thus far tested as well as in a large majority of human breast and prostate tumor biopsies.DTS-201 gave promising results in terms of general toxicity, cardiovascular tolerance, and in vivo efficacy in xenograft mouse models compared with free doxorubicin. Taken together, these results and the confirmation of the presence of activating enzymes in human tumor biopsies provide a strong rationale for a phase I clinical study in cancer patients.
Mutation of the WI-1 gene yields an attenuated Blastomyces dermatitidis strain that induces host resistance
Authors: Marcel Wüthrich, Hanna I. Filutowicz, Bruce S. Klein
Journal: Journal of Clinical Investigation (2000)

Systemic fungal infections are becoming more common and difficult to treat, and vaccine prevention is not available. Pulmonary infection with the dimorphic fungus Blastomyces dermatitidis often progresses and requires treatment to prevent fatality. We recently created a recombinant strain of the fungus lacking the WI-1 adhesin and pathogenicity. We show here that administration of viable yeast of this attenuated strain vaccinates against lethal pulmonary experimental infection due to isogenic and nonisogenic strains from diverse geographic regions. To our knowledge, this is the first example of a recombinant attenuated vaccine against fungi. The vaccine induces delayed-type hypersensitivity and polarized type 1 cytokine responses, which are linked with resistance. A cell-wall/membrane (CW/M) antigen from the vaccine strain also induces polarized and protective immune responses. Lymph node cells and CD4+ T-cell lines raised with CW/M antigen transfer protective immunity when they release type 1 cytokine IFN-γ, but not when they release IL-4, and neutralization of IFN-γ confirmed its role in vivo. Thus, by mutating a pathogenetic locus in a dimorphic fungus, we have created an attenuated vaccine strain and have begun to elucidate fungal and host elements requisite for vaccine immunity.
TCT-478 Effect of different drug-eluting stent design on in-stent restenosis and stent thrombosis
Authors: Oskar Angerås, Per Albertsson, Christian Dworeck, Inger Haraldsson, Dan Ioanes, Berglind Libungan, Göran Matejka, Elmir Omerovic, Petur Petursson, Truls Råmunddal, Wilhelm Ridderstråle, Lotta Robertsson, Jason Stewart, Magnus Wahlin
Journal: Journal of the American College of Cardiology (2013)
TRAIL-Induced Apoptosis Is Preferentially Mediated via TRAIL Receptor 1 in Pancreatic Carcinoma Cells and Profoundly Enhanced by XIAP Inhibitors
Authors: Dominic Stadel, Andrea Mohr, Caroline Ref, Marion MacFarlane, Shaoxia Zhou, Robin Humphreys, Max Bachem, Gerry Cohen, Peter Möller, Ralf M. Zwacka, Klaus-Michael Debatin, Simone Fulda
Journal: Clinical Cancer Research (2010)

We previously reported that small molecule X-linked inhibitor of apoptosis (XIAP) inhibitors synergize with soluble TRAIL to trigger apoptosis in pancreatic carcinoma cells. Because cancers may preferentially signal via 1 of the 2 agonistic TRAIL receptors, we investigated these receptors as a therapeutic target in pancreatic cancer in the present study.We examined TRAIL receptor expression and cytotoxicity of specific monoclonal antibodies to TRAIL-R1 (HGS-ETR1, mapatumumab) or TRAIL-R2 (HGS-ETR2, lexatumumab) and of TRAIL receptor selective mutants alone and in combination with small molecule XIAP inhibitors in pancreatic cancer cell lines, in primary specimens, and in a xenotransplant model in vivo.The majority of primary pancreatic carcinoma samples and all cell lines express one or both agonistic TRAIL receptors. Nine of 13 cell lines are more sensitive to mapatumumab-induced apoptosis, whereas lexatumumab requires cross-linking for maximal activity. Similarly, TRAIL-R1 selective mutants display higher cytotoxicity than TRAIL-R2 selective mutants. Small molecule XIAP inhibitors preferentially act in concert with mapatumumab to trigger caspase activation, caspase-dependent apoptosis, and suppress clonogenic survival. Also, primary cultured pancreatic carcinoma cells are more susceptible to mapatumumab than lexatumumab, which is significantly enhanced by a XIAP inhibitor. Importantly, combined treatment with mapatumumab and a XIAP inhibitor cooperates to suppress tumor growth in vivo.Mapatumumab exerts antitumor activity, especially in combination with XIAP inhibitors against most pancreatic carcinoma cell lines, whereas lexatumumab requires cross-linking for optimal cytotoxicity. These findings have important implications for the design of TRAIL-based protocols for pancreatic cancer.
The role of elevated autophagy on the synaptic plasticity impairment caused by CdSe/ZnS quantum dots
Authors: Liang Chen, Yanyan Miao, Lin Chen, Peipei Jin, Yingying Zha, Yuming Chai, Fang Zheng, Yunjiao Zhang, Wei Zhou, Jigui Zhang, Longping Wen, Ming Wang
Journal: Biomaterials (2013)
Mortality among tuberculosis patients in The Netherlands in the period 1993-1995
Authors: MW Borgdorff, J Veen, NA Kalisvaart, N Nagelkerke
Journal: European Respiratory Journal (1998)

This study aimed to estimate excess mortality among tuberculosis patients in The Netherlands and identify risk factors for tuberculosis-associated mortality. The national tuberculosis register provided data on patients diagnosed in the period 1993-1995. Excess mortality in tuberculosis cases, according to age and sex, was determined by comparison with national mortality rates. Risk factors were identified and adjustment for confounders was carried out using Cox's proportional hazard analysis. Of 4,340 patients alive at diagnosis, 258 died within 1 yr while on treatment. The Kaplan-Meier survival probability after 1 yr was 93%. Tuberculosis patients had a standardized mortality ratio of 8.3. Independent risk factors for mortality were: gender; age; presence of a malignancy or human immunodeficiency virus (HIV) infection; addiction to alcohol or drugs; localization of tuberculosis; and the type of medical officer having made the diagnosis. Of all deaths, 83% occurred in two risk groups comprising 21% of tuberculosis patients: those aged > or =65 yrs and those having HIV infection or a malignancy. Tuberculosis patients in The Netherlands are at a considerably increased risk of death. However, the prognosis is very good for those aged less than 65 yrs and without human immunodeficiency virus infection or a malignancy.
Late-Replicating Domains Have Higher Divergence and Diversity in Drosophila melanogaster
Authors: Claudia C. Weber, Catherine J. Pink, Laurence D. Hurst
Journal: Molecular Biology and Evolution (2011)

Several reports from mammals indicate that an increase in the mutation rate in late-replicating regions may, in part, be responsible for the observed genomic heterogeneity in neutral substitution rates and levels of diversity, although the mechanisms for this remain poorly understood. Recent evidence also suggests that late replication is associated with high mutability in yeast. This then raises the question as to whether a similar effect is operating across all eukaryotes. Limited evidence from one chromosome arm in Drosophila melanogaster suggests the opposite pattern, with regions overlapping early-firing origins showing increased levels of diversity and divergence. Given the availability of genome-wide replication timing profiles for D. melanogaster, we now return to this issue. Consistent with what is seen in other taxa, we find that divergence at synonymous sites in exon cores, as well as divergence at putatively unconstrained intronic sites, is elevated in late-replicating regions. Analysis of genes with low codon usage bias suggests a ∼30% difference in mutation rate between the earliest and the latest replicating sequence. Intronic sequence suggests a more modest difference. We additionally show that an increase in diversity in late-replicating sequences is not owing to replication timing covarying with the local recombination rate. If anything, the effects of recombination mask the impact of replication timing. We conclude that, contrary to prior reports and consistent with what is seen in mammals and yeast, there is indeed a relationship between rates of nucleotide divergence and diversity and replication timing that is consistent with an increase in the mutation rate during late S-phase in D. melanogaster. It is therefore plausible that such an effect might be common among eukaryotes. The result may have implications for the inference of positive selection.
A Comparison of Physician Education in the USSR and the United States
Authors: ROBERT S. DANIELS
Journal: American Journal of Psychiatry (1974)

This paper contains observations of Soviet medicine made by the author during a recent scientific visit. He describes the influence of public policy on Soviet medicine, the emphases in training and practice, the role of women, and the steps in the training of physicians in the USSR. Comparing medicine in the USSR and the United States, the author relates his observations to changes that are taking place in American medicine.
Phase II Study of Belinostat in Patients With Recurrent or Refractory Advanced Thymic Epithelial Tumors
Authors: Giuseppe Giaccone, Arun Rajan, Arlene Berman, Ronan J. Kelly, Eva Szabo, Ariel Lopez-Chavez, Jane Trepel, Min-Jung Lee, Liang Cao, Igor Espinoza-Delgado, John Spittler, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2011)

Thymic epithelial tumors are rare malignancies, and there is no standard treatment for patients with advanced disease in whom chemotherapy has failed. Antitumor activity of histone deacetylase (HDAC) inhibitors in this disease has been documented, including one patient with thymoma treated with the pan-HDAC inhibitor belinostat.
How to measure intracellular [Ca2+] in single cardiac cells with fura-2 or indo-1
Authors: K. R Sipido, G. Callewaert
Journal: Cardiovascular Research (1995)

Journal Article How to measure intracellular [Ca2+] in single cardiac cells with fura-2 or indo-1 Get access Karin R Sipido, Karin R Sipido * Laboratory of Physiology, University of Leuven, Campus Gasthuisberg, Herestraat 49, B3000 Leuven, Belgium *Correspondence to Dr Sipido. Search for other works by this author on: Oxford Academic PubMed Google Scholar Geert Callewaert Geert Callewaert Laboratory of Physiology, University of Leuven, Campus Gasthuisberg, Herestraat 49, B3000 Leuven, Belgium Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 5, May 1995, Pages 717–726, https://doi.org/10.1016/S0008-6363(96)88645-7 Published: 01 May 1995 Article history Received: 05 May 1994 Accepted: 23 January 1995 Published: 01 May 1995
Adhesive Characteristics of Tumor Cell Variants of High and Low Tumorigenic Potential&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: James Varani, William Orr, Peter A. Ward
Journal: JNCI Journal of the National Cancer Institute (1980)

A variant subpopulation of C57BL/6 mouse fibrosarcoma cells that had very low tumorigenic potential was isolated from a highly tumorigenic parent fibrosarcoma cell culture. The adhesive characteristics of parent cells and variant cells were compared. The low-tumorigenic variant cells were released from the surfaces of plastic dishes, from protein-coated dishes, or from monolayers of fibroblasts or endothelial cells by protease treatment much more readily than were the parent cells. There was no difference between the variant cells and the parent cells in EDTA sensitivity or sensitivity to mechanical agitation under the conditions used. Also, no difference existed between the variant cells and the parent cells in rates of attachment to the surfaces of plastic dishes or to monolayers of endothelial cells. The variant cells were characterized by high levels of chymotrypsin-like esterase activity (two to three times increased over parent cell levels), but there was only a slight difference between the variant cells and the parent cells in caseinolytic or fibrinolytic activity.
Targeted Disruption of TGF-β–Smad3 Signaling Leads to Enhanced Neointimal Hyperplasia With Diminished Matrix Deposition in Response to Vascular Injury
Authors: Kazuki Kobayashi, Koutaro Yokote, Masaki Fujimoto, Kimihiro Yamashita, Akemi Sakamoto, Masaki Kitahara, Harukiyo Kawamura, Yoshiro Maezawa, Sunao Asaumi, Takeshi Tokuhisa, Seijiro Mori, Yasushi Saito
Journal: Circulation Research (2005)

The role of transforming growth factor (TGF)-beta and its signal in atherogenesis is not fully understood. Here, we examined mice lacking Smad3, a major downstream mediator of TGF-beta, to clarify the precise role of Smad3-dependent signaling in vascular response to injury. Femoral arteries were injured in wild-type and Smad3-null (null) male mice on C57Bl/6 background. Histopathological evaluation of the arteries 1 to 3 weeks after the injury revealed significant enhancement of neointimal hyperplasia in null compared with wild-type mice. Transplantation of null bone marrow to wild-type mice did not enhance neointimal thickening, suggesting that vascular cells in situ play a major role in the response. Null intima contained more proliferating smooth muscle cells (SMC) with less amount of collagen compared with wild-type intima. TGF-beta caused significant inhibition of cellular proliferation in wild-type aortic SMC, whereas the growth of null SMC was only weakly inhibited by TGF-beta in vitro, indicating a crucial role of Smad3 in the growth inhibitory function. On the other hand, Smad3-deficiency did not attenuate chemotaxis of SMC toward TGF-beta. TGF-beta increased transcript level of alpha2 type I collagen and tissue inhibitor of metalloproteinases-1, and suppressed expression and activity of matrix metalloproteinases in wild-type SMC. However, these effects of TGF-beta were diminished in null SMC. Our findings altogether show that the loss of Smad3 pathway causes enhanced neointimal hyperplasia on injury through modulation of growth and matrix regulation in vascular SMC. These results indicate a vasculoprotective role of endogenous Smad3 in response to injury.