tbuckley/cabot-search huggingface dataset:
Molecular Interactions with Mercury in the Kidney
Authors: R K Zalups
Journal: Pharmacological Reviews (2000)

Mercury is unique among the heavy metals in that it can exist in several physical and chemical forms, including elemental mercury, which is a liquid at room temperature. All forms of mercury have toxic effects in a number of organs, especially in the kidneys. Within the kidney, the pars recta of the proximal tubule is the most vulnerable segment of the nephron to the toxic effects of mercury. The biological and toxicological activity of mercurous and mercuric ions in the kidney can be defined largely by the molecular interactions that occur at critical nucleophilic sites in and around target cells. Because of the high bonding affinity between mercury and sulfur, there is particular interest in the interactions that occur between mercuric ions and the thiol group(s) of proteins, peptides and amino acids. Molecular interactions with sulfhydryl groups in molecules of albumin, metallothionein, glutathione, and cysteine have been implicated in mechanisms involved in the proximal tubular uptake, accumulation, transport, and toxicity of mercuric ions. In addition, the susceptibility of target cells in the kidneys to the injurious effects of mercury is modified by a number of intracellular and extracellular factors relating to several thiol-containing molecules. These very factors are the theoretical basis for most of the currently employed therapeutic strategies. This review provides an update on the current body of knowledge regarding the molecular interactions that occur between mercury and various thiol-containing molecules with respect to the mechanisms involved in the renal cellular uptake, accumulation, elimination, and toxicity of mercury.
The adult respiratory distress syndrome bronchogenic pulmonary tuberculosis.
Authors: R A Dyer, P D Potgieter
Journal: Thorax (1984)

In three cases of pulmonary tuberculosis associated with the adult respiratory distress syndrome the clinical features, which were similar to those of patients with miliary tuberculosis and adult respiratory distress syndrome, included a history of cough, fever, and dyspnoea on effort, and the physical signs of fever, tachypnoea, pulmonary adventitious sounds, tachycardia, and hepatomegaly. In these cases the radiological features, though suggestive of diffuse pulmonary oedema, were more prominent on the side in which the cavitatory lesion appeared. The diagnosis of tuberculosis was made easily from direct examination of sputum. Despite early ventilatory support and antituberculous therapy, two of the three patients died. Postmortem examination of the lungs in these cases showed evidence of acute alveolar damage (loss of type 1 pneumocytes and the presence of hyaline membranes within alveolar ducts) and of chronic alveolar damage (interstitial and alveolar fibrosis).
THE LOCALIZATION OF SKIN-SENSITIZING ANTIBODY IN THE SERA OF RAGWEED-SENSITIVE INDIVIDUALS BY ELECTROPHORESIS
Authors: Alec H. Sehon, John G. Harter, Bram Rose
Journal: The Journal of Experimental Medicine (1956)

Starch electrophoresis was used to separate allergic sera into electrophoretically distinct albumin, alpha-, beta-, and gamma-globulin fractions. The identity of the various fractions was established by free and paper electrophoresis. The gamma-globulin fractions were also characterized by ultracentrifugation. The serum skin-sensitizing antibody to ragweed pollen was shown to be associated with the gamma-globulins in fourteen allergic sera by means of passive transfer technique. The mobility of the skin-sensitizing antibody corresponded to that of gamma-1 and/or gamma-2 globulins. All the other serum fractions were devoid of reaginic activity. Reaginic activity per se was not directly related to protein concentration. The discrepancies between these results, and those obtained by others and ourselves previously are discussed.
The Isopeptidase USP2a Protects Human Prostate Cancer from Apoptosis
Authors: Carmen Priolo, Dan Tang, Mohan Brahamandan, Barbara Benassi, Ewa Sicinska, Shuji Ogino, Antonella Farsetti, Alessandro Porrello, Stephen Finn, Johann Zimmermann, Phillip Febbo, Massimo Loda
Journal: Cancer Research (2006)

Abstract Deubiquitinating enzymes can prevent the destruction of protein substrates prior to proteasomal degradation. The ubiquitin-specific protease 2a (USP2a) deubiquitinates the antiapoptotic proteins Fatty Acid Synthase and Mdm2. Here, we show that when USP2a is overexpressed in nontransformed cells, it exhibits oncogenic behavior both in vitro and in vivo and prevents apoptosis induced by chemotherapeutic agents. Notably, USP2a silencing in several human cancer cell lines results in apoptosis. Gene set enrichment analysis, which focuses on groups of genes sharing biological function or regulatory pathways, was done on microarray expression data from human prostate cancers. The cell death–related gene set, as well as a selected cluster of validated p53 target genes, were significantly enriched in the low USP2a expression group of tumors. Conversely, genes implicated in fatty acid metabolism were significantly associated with tumors expressing high USP2a (44%). The expression profile analysis is consistent with the effects of USP2a on its known targets, i.e., Fatty Acid Synthase and Mdm2, defining a subset of prostate tumors resistant to apoptosis. USP2a thus represents a therapeutic target in prostate cancer. (Cancer Res 2006; 66(17): 8625-32)
The Natural Killer T (NKT) Cell Ligand α-Galactosylceramide Demonstrates Its Immunopotentiating Effect by Inducing Interleukin (IL)-12 Production by Dendritic Cells and IL-12 Receptor Expression on NKT Cells
Authors: Hidemitsu Kitamura, Kenji Iwakabe, Takashi Yahata, Shin-ichiro Nishimura, Akio Ohta, Yasushi Ohmi, Marimo Sato, Kazuyoshi Takeda, Ko Okumura, Luc Van Kaer, Tetsu Kawano, Masaru Taniguchi, Takashi Nishimura
Journal: The Journal of Experimental Medicine (1999)

The natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of α-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by α-GalCer. We first established, using purified subsets of various lymphocyte populations, that α-GalCer selectively activates NKT cells for production of interferon (IFN)-γ. Production of IFN-γ by NKT cells in response to α-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, α-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1−/− or Vα14−/− mice. This effect of α-GalCer required the production of IFN-γ by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of α-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-γ production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by α-GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.
GDC-0449 in patients with advanced chondrosarcomas: a French Sarcoma Group/US and French National Cancer Institute Single-Arm Phase II Collaborative Study
Authors: A. Italiano, A. Le Cesne, C. Bellera, S. Piperno-Neumann, F. Duffaud, N. Penel, P. Cassier, J. Domont, N. Takebe, M. Kind, J.-M. Coindre, J.-Y. Blay, B. Bui
Journal: Annals of Oncology (2013)
T cell immune abnormalities in immune thrombocytopenia
Authors: Xuebin Ji, Liping Zhang, Jun Peng, Ming Hou
Journal: Journal of Hematology & Oncology (2014)

Immune thrombocytopenia is an autoimmune disease with abnormal T cell immunity. Cytotoxic T cells, abnormal T regulatory cells, helper T cell imbalance, megakaryocyte maturation abnormalities and abnormal T cell anergy are involved in the pathogenesis of this condition. The loss of T cell-mediated immune tolerance to platelet auto-antigens plays a crucial role in immune thrombocytopenia. The induction of T cell tolerance is an important mechanism by which the pathogenesis and treatment of immune thrombocytopenia can be studied. Studies regarding the roles of the new inducible costimulator signal transduction pathway, the ubiquitin proteasome pathway, and the nuclear factor kappa B signal transduction pathway in the induction of T cell tolerance can help improve our understanding of immune theory and may provide a new theoretical basis for studying the pathogenesis and treatment of immune thrombocytopenia.
Tendinopathy: no longer a 'one size fits all' diagnosis
Authors: Jill Cook
Journal: British Journal of Sports Medicine (2011)

<h3>ABSTRACT</h3> We analyzed age-specific and sex-specific morbidity and mortality data from SARS-COV-2 pandemic in China and Republic of Korea (ROK). Data from China exhibit a standard Gaussian distribution with peak morbidity in the 50-59 years cohort, while the ROK data have a bimodal distribution with highest morbidity in the 20-29 years cohort.
Assessment of exposure to environmental tobacco smoke
Authors: MS Jaakkola, JJ Jaakkola
Journal: European Respiratory Journal (1997)

We present a theoretical framework for assessment of exposure to environmental tobacco smoke (ETS), and review current methods in order to provide guidelines for different types of studies. Exposure assessment should include both a quantitative dimension and consideration of time-specificity of exposure. The ultimate aim is to measure the concentrations of ETS encountered by an individual for different time periods in various microenvironments. The first step is to identify an indicator of ETS. Personal monitoring of air nicotine and respirable suspended particulates (RSPs) are the most direct assessment methods. Indirect assessment methods include stationary measurements of tobacco smoke constituents in different microenvironments and/or questionnaire-derived information, modelled with time-activity information. Biomarkers, such as nicotine and/or cotinine in body fluids or hair, can be used as surrogate measures of dose, although they are usually affected by individual processes in the body after exposure. The best approach to assess ETS exposure will depend on the aim of the study, the health outcome, and the resources. Personal monitoring of nicotine or RSPs is the best method in studies of short-term health effects with small study samples. Stationary measurements of indoor air nicotine or RSPs are suitable for overall monitoring of ETS in different microenvironments over time. Questionnaires and interviews are suitable when studying health outcomes with a long latency period and rare diseases requiring large study populations. Cotinine in body fluids and nicotine concentration in hair can be used to assess cumulative exposure over days or months, respectively. A combination of different methods is often the best approach.
Extracellular superoxide dismutase in the airways of transgenic mice reduces inflammation and attenuates lung toxicity following hyperoxia
Authors: Rodney J. Folz, Amir M. Abushamaa, Hagir B. Suliman
Journal: Journal of Clinical Investigation (1999)

Extracellular superoxide dismutase (EC-SOD, or SOD3) is the major extracellular antioxidant enzyme in the lung. To study the biologic role of EC-SOD in hyperoxic-induced pulmonary disease, we created transgenic (Tg) mice that specifically target overexpression of human EC-SOD (hEC-SOD) to alveolar type II and nonciliated bronchial epithelial cells. Mice heterozygous for the hEC-SOD transgene showed threefold higher EC-SOD levels in the lung compared with wild-type (Wt) littermate controls. A significant amount of hEC-SOD was present in the epithelial lining fluid layer. Both Tg and Wt mice were exposed to normobaric hyperoxia (>99% oxygen) for 48, 72, and 84 hours. Mice overexpressing hEC-SOD in the airways attenuated the hyperoxic lung injury response, showed decreased morphologic evidence of lung damage, had reduced numbers of recruited inflammatory cells, and had a reduced lung wet/dry ratio. To evaluate whether reduced numbers of neutrophil infiltration were directly responsible for the tolerance to oxygen toxicity observed in the Tg mice, we made Wt and Tg mice neutropenic using anti-neutrophil antibodies and subsequently exposed them to 72 hours of hyperoxia. Both Wt and Tg neutrophil-depleted (ND) mice have less severe lung injury compared with non-ND animals, thus providing direct evidence that neutrophils recruited to the lung during hyperoxia play a distinct role in the resultant acute lung injury. We conclude that oxidative and inflammatory processes in the extracellular lung compartment contribute to hyperoxic-induced lung damage and that overexpression of hEC-SOD mediates a protective response to hyperoxia, at least in part, by attenuating the neutrophil inflammatory response.
The risk of future cardiovascular diseases in the patients with OSAS is dependently or independently associated with obstructive sleep apnoea
Authors: S. Teramoto, H. Kume, T. Matsuse, Y. Fukuchi
Journal: European Respiratory Journal (2001)

To the Editor: 

In the recent issue of European Respiratory Journal , Kiely and McNicolas have sophisticatedly demonstrated that the increased risk of future cardiovascular diseases is independent of obstructive sleep apnoea (OSA) in patients with obstructive sleep apnoea syndrome (OSAS) 1. Although many investigators have reported that there is a significant link between OSA and the cardiovascular events, they insisted that the patients with OSAS are at high risk of future cardiovascular diseases from factors, i.e. diabetes mellitus, hypertension, …
Heat Shock Protein 90 Inhibitor Is Synergistic with JAK2 Inhibitor and Overcomes Resistance to JAK2-TKI in Human Myeloproliferative Neoplasm Cells
Authors: Warren Fiskus, Srdan Verstovsek, Taghi Manshouri, Rekha Rao, Ramesh Balusu, Sreedhar Venkannagari, Nalabothula Narasimha Rao, Kyungsoo Ha, Jacqueline E. Smith, Stacey L. Hembruff, Sunil Abhyankar, Joseph McGuirk, Kapil N. Bhalla
Journal: Clinical Cancer Research (2011)

Abstract Purpose: We determined the activity of hsp90 inhibitor, and/or Janus-activated kinase 2 (JAK2) tyrosine kinase inhibitor (TKI), against JAK2-V617F–expressing cultured mouse (Ba/F3-JAK2-V617F) and human (HEL92.1.7 and UKE-1) or primary human CD34+ myeloproliferative neoplasm (MPN) cells. Experimental Design: Following exposure to the hsp90 inhibitor AUY922 and/or JAK2-TKI TG101209, the levels of JAK2-V617F, its downstream signaling proteins, as well as apoptosis were determined. Results: Treatment with AUY922 induced proteasomal degradation and depletion of JAK2-V617F as well as attenuated the signaling proteins downstream of JAK2-V617F, that is, phospho (p)-STAT5, p-AKT, and p-ERK1/2. AUY922 treatment also induced apoptosis of HEL92.1.7, UKE-1, and Ba/F3-hJAK2-V617F cells. Combined treatment with AUY922 and TG101209 caused greater depletion of the signaling proteins than either agent alone and synergistically induced apoptosis of HEL92.1.7 and UKE-1 cells. Cotreatment with AUY922 and TG101209 also induced significantly more apoptosis of human CD34+ MPN than normal hematopoietic progenitor cells. As compared with the sensitive controls, JAK2-TKI–resistant HEL/TGR and UKE-1/TGR cells exhibited significantly higher IC50 values for JAK2-TKI (P &amp;lt; 0.001), which was associated with higher expression of p-JAK2, p-STAT5, p-AKT, and Bcl-xL, but reduced levels of BIM. Unlike the sensitive controls, HEL/TGR and UKE/TGR cells were collaterally sensitive to the hsp90 inhibitors AUY922 and 17-AAG, accompanied by marked reduction in p-JAK2, p-STAT5, p-AKT, and Bcl-xL, with concomitant induction of BIM. Conclusions: Findings presented here show that cotreatment with hsp90 inhibitor and JAK2-TKI exerts synergistic activity against cultured and primary MPN cells. In addition, treatment with hsp90 inhibitor may overcome resistance to JAK2-TKI in human MPN cells. Clin Cancer Res; 17(23); 7347–58. ©2011 AACR.
X-Linked Lymphoproliferative Disease
Authors: Silvia Parolini, Cristina Bottino, Michela Falco, Raffaella Augugliaro, Silvia Giliani, Roberta Franceschini, Hans D. Ochs, Hermann Wolf, Jean-Yves Bonnefoy, Roberto Biassoni, Lorenzo Moretta, Luigi D. Notarangelo, Alessandro Moretta
Journal: The Journal of Experimental Medicine (2000)

2B4 is a surface molecule involved in activation of the natural killer (NK) cell–mediated cytotoxicity. It binds a protein termed Src homology 2 domain–containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV+ B cell lines. Remarkably, NK cells from XLP patients could not kill EBV+ B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4–CD48 interaction restored lysis of EBV+ target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I+) EBV+ lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4–CD48 and NK receptor–HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain–containing phosphatase 1.
Nonresponsiveness to Hepatitis B Vaccine in Health Care Workers
Authors: DONALD E. CRAVEN
Journal: Annals of Internal Medicine (1986)

Twenty-eight health care workers who had a poor antibody response when initially vaccinated with hepatitis B vaccine were revaccinated with three additional 20-µg doses. Eight of the twenty nonresponders, who had levels of antibody to hepatitis B surface antigen (anti-HBs) of less than 8 estimated radioimmunoassay (RIA) units, and all 8 of the hyporesponders, who had anti-HBs levels of 8 or 16 RIA units, attained anti-HBs levels of 36 RIA units or more after revaccination. Tests for HLA-A, B, C, and DR; for complement proteins C2, C4A, C4B, and BF; and for the erythrocyte enzyme glyoxalase I were done in 17 nonresponders and 3 hyporesponders. Nine (45%) had HLA-DR7 and 8 (40%) had HLA-DR3, compared with an expected rate of 23% in the general population. At least one of two extended haplotypes (B44, DR7, FC31 or B8, DR3, SCOl) were detected in 6 of the 9 who did not respond to revaccination, compared with 2 of 11 who responded to a second course of vaccine. Poor responders to vaccine may benefit from revaccination, and genetic factors may modulate the immune response to vaccination.
The evolving biology and treatment of prostate cancer
Authors: Russel S. Taichman, Robert D. Loberg, Rohit Mehra, Kenneth J. Pienta
Journal: Journal of Clinical Investigation (2007)

Since the effectiveness of androgen deprivation for treatment of advanced prostate cancer was first demonstrated, prevention strategies and medical therapies for prostate cancer have been based on understanding the biologic underpinnings of the disease. Prostate cancer treatment is one of the best examples of a systematic therapeutic approach to target not only the cancer cells themselves, but the microenvironment in which they are proliferating. As the population ages and prostate cancer prevalence increases, challenges remain in the diagnosis of clinically relevant prostate cancer as well as the management of the metastatic and androgen-independent metastatic disease states.
Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma
Authors: S. Miller, H. A. Rogers, P. Lyon, V. Rand, M. Adamowicz-Brice, S. C. Clifford, J. T. Hayden, S. Dyer, S. Pfister, A. Korshunov, M.-A. Brundler, J. Lowe, B. Coyle, R. G. Grundy
Journal: Neuro-Oncology (2011)

Central nervous system primitive neuroectodermal tumor (CNS PNET) and pineoblastoma are highly malignant embryonal brain tumors with poor prognoses. Current therapies are based on the treatment of pediatric medulloblastoma, even though these tumors are distinct at both the anatomical and molecular level. CNS PNET and pineoblastoma have a worse clinical outcome than medulloblastoma; thus, improved therapies based on an understanding of the underlying biology of CNS PNET and pineoblastoma are needed. To this end, we characterized the genomic alterations of 36 pediatric CNS PNETs and 8 pineoblastomas using Affymetrix single nucleotide polymorphism arrays. Overall, the majority of CNS PNETs contained a greater degree of genomic imbalance than pineoblastomas, with gain of 19p (8 [27.6%] of 29), 2p (7 [24.1%] of 29), and 1q (6 [20.7%] of 29) common events in primary CNS PNETs. Novel gene copy number alterations were identified and corroborated by Genomic Identification of Significant Targets In Cancer (GISTIC) analysis: gain of PCDHGA3, 5q31.3 in 62.1% of primary CNS PNETs and all primary pineoblastomas and FAM129A, 1q25 in 55.2% of primary CNS PNETs and 50% of primary pineoblastomas. Comparison of our GISTIC data with publically available data for medulloblastoma confirmed these CNS PNET–specific copy number alterations. With use of the collection of 5 primary and recurrent CNS PNET pairs, we found that gain of 2p21 was maintained at relapse in 80% of cases. Novel gene copy number losses included OR4C12, 11p11.12 in 48.2% of primary CNS PNETs and 50% of primary pineoblastomas. Loss of CDKN2A/B (9p21.3) was identified in 14% of primary CNS PNETs and was significantly associated with older age among children (P = .05). CADPS, 3p14.2 was lost in 27.6% of primary CNS PNETs and was associated with poor prognosis (P = .043). This genome-wide analysis revealed the marked molecular heterogeneity of CNS PNETs and enabled the identification of novel genes and clinical associations potentially involved in the pathogenesis of these tumors.