tbuckley/cabot-search huggingface dataset:
TR-10 * AUTOPHAGY INHIBITION REVERSES RESISTANCE TO TARGETED BRAF THERAPY IN PEDIATRIC CNS TUMORS
Authors: S. Zahedi, A. Griesinger, M. Handler, N. Foreman, A. Thorburn, J. M. Levy
Journal: Neuro-Oncology (2015)

Autophagy inhibition is a potential therapeutic strategy in cancer. We have previously shown that autophagy-dependent tumors, such as those with BRAFV600E, there may be broad potential application of autophagy inhibition. Targeted inhibition against the BRAFV600E mutation (BRAFi) has been identified as important in pediatric CNS tumors and is being more broadly provided to these patients. Patients treated with BRAFi will develop resistance mechanisms and new approaches to reversing this resistance are needed. Our findings suggest that pediatric CNS tumors with BRAFV600E are autophagy-dependent in parental tumors and those with inherent or acquired BRAFi resistance. Autophagy was evaluated by flow cytometry and Western blot. Autophagy was inhibited by clinically available chloroquine and BRAFi was provided by vemurafenib. Cell survival was evaluated using a variety of techniques. Ex vivo organotypic culture of resistant tumor was used to verify in vitro findings. We found that mutant (but not WT) cells display high rates of induced autophagy, and these levels remain similar in BRAFi resistant cells. Both parental and resistant cells are sensitive to autophagy inhibition and display synergy when chloroquine was combined with BRAFi. We also demonstrate chloroquine can improve vemurafenib sensitivity in a resistant ex vivo primary culture. Autophagy inhibition decreases the ratio of pERK:ERK levels when used in combination with BRAFi in resistant tumor cells, suggesting a potential mechanism for improved response in combination treatment. Importantly, chloroquine improved vemurafenib sensitivity in a patient with acquired BRAFi resistance and improved clinical outcomes. These data highlight an exciting possibility for identifying genetic markers, such as BRAFV600E, which sensitize tumors to autophagy inhibition combination therapy. Synergy was identified in both parental and resistant cells suggesting that autophagy-dependence is driven by its underlying mutations. Therefore, in autophagy-dependent BRAFV600E tumors there may be broad potential application of autophagy inhibition in both BRAFi naive and resistant patients.
Points: The Mandwa experiment
Authors: J. Chakrabarti
Journal: BMJ (1986)

August, p 395) make an important point which deserves highlighting.Fracture dislocation of the cervical spine complicating near drowning is a rare event in Britain but is seen more commonly in Australia, where body surfing is a popular sport.The advice given to rescuers in Britain is that any unconscious patient found in standing depth water should be handled as though he or she had suffered fracture dislocation of the neck.It is possible on occasions to ventilate adequately without extending the neck, but if this is not the case then the rescuer has no alternative but to tilt the head back.
Neonatal Herpes Simplex Infection and the Three Musketeers
Authors: Anne A. Gershon
Journal: New England Journal of Medicine (2011)

Metaphorically, the Three Musketeers can represent our defenses against viral pathogens. Actually, there were four Musketeers; the hero D'Artagnan was an add-on. In Dumas's novel, the Musketeers' motto, “one for all and all for one,” indicated a synergistic approach. Our four antiviral defenses include specific and nonspecific antiviral therapy, passive immunization, and, finally, active immunization, represented by D'Artagnan. We do not have all these defenses for every pathogen. Although active and passive immunization and nonspecific treatment (vitamin A)1 are available for measles, it would be better if a specific therapy existed, particularly now, when some parents are not vaccinating their . . .
A short history of pharmaceutical marketing
Authors: R. Ferner
Journal: BMJ (2012)

Thomas Gainsborough’s painting Peasants Going to Market: Early Morning suggests these peasants have a fairly straightforward plan to sell their meagre baskets of produce, which they will not expect to make them wealthy. Ironically, the canvas was one of a collection amassed by Thomas Holloway, who made a fortune from patent medicines, adroitly using newspapers both for explicit advertising and as a vehicle for news stories of astounding cures.1 Unsurprisingly, he advocated the “Hollowayian System of Medicine,” encapsulated in the slogan, …
Detection of cytokine producing cells in the synovial membrane from patients with rheumatoid arthritis.
Authors: A.K Ulfgren, S Lindblad, L Klareskog, J Andersson, U Andersson
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVES--To develop and evaluate a new immunohistochemical method to study the localisation and phenotype of individual cytokine producing cells in synovial biopsy specimens in rheumatoid arthritis. METHODS--Cryopreserved sections of synovial tissue from nine patients with rheumatoid arthritis were incubated with carefully selected cytokine specific antibodies detecting 19 different cytokines, after fixation of the specimens with paraformaldehyde and using saponin to permeabilise the cell membranes. RESULTS--The immunohistochemical method yielded reproducible and distinct staining patterns, in which the cytokines accumulated mainly in the Golgi apparatus of producer cells, indicating that the method preferentially detected local synthesis rather than cytokine uptake. The cytokine production patterns varied considerably between biopsy specimens from different patients. CONCLUSION--The present modified immunohistochemical method may provide a simple and rapid way to determine the local production of a wide array of cytokines in the synovium. The data obtained with this method also indicated that more T cell derived cytokines than previously recognised were present in active synovitis, as located and sampled by arthroscopy.
Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Has Nuclear Localization Signal–Like Sequences for Nuclear Import Mediated by Major Vault Protein
Authors: Ji-Hyun Chung, Margaret E. Ginn-Pease, Charis Eng
Journal: Cancer Research (2005)

Although phosphatase and tensin homologue deleted on chromosome 10 (PTEN) localization in the nucleus and cytoplasm is established, the mechanism is unknown. PTEN is a tumor suppressor phosphatase that causes cell cycle arrest and/or apoptosis. Nuclear-cytoplasmic compartmentalization may be a novel mechanism in regulating these events. PTEN does not contain a traditional nuclear localization sequence (NLS); however, we identified putative NLS-like sequences, which we analyzed by site-directed mutagenesis and localization studies in MCF-7 cells. Two double site mutations exhibited nuclear localization defects. Furthermore, unlike wild-type PTEN, double NLS mutant PTEN did not interact with major vault protein (MVP), a previously hypothesized nuclear-cytoplasmic transport protein. We conclude that these two NLS-like sequences are required for PTEN nuclear import that is mediated by MVP. Further, we show that this MVP-mediated nuclear import is independent of PTEN phosphorylation and of the lipid and protein phosphatase activities of PTEN.
Preconditioning of the distal tubular epithelium of the human kidney precedes nephrocalcinosis
Authors: Anja Verhulst, Marino Asselman, Stephanie De Naeyer, Benjamin A. Vervaet, Michael Mengel, Wilfried Gwinner, Patrick C. D'Haese, Carl F. Verkoelen, Marc E. De Broe
Journal: Kidney International (2005)
Stem cells in liver diseases and cancer: Recent advances on the path to new therapies
Authors: C. Bart Rountree, Lopa Mishra, Holger Willenbring
Journal: Hepatology (2011)

Stem cells have potential for therapy of liver diseases, but may also be involved in the formation of liver cancer. Recently, the American Association for the Study of Liver Diseases Henry M. and Lillian Stratton Basic Research Single Topic Conference "Stem Cells in Liver Diseases and Cancer: Discovery and Promise" brought together a diverse group of investigators to define the status of research on stem cells and cancer stem cells in the liver and identify problems and solutions on the path to clinical translation. This report summarizes the outcomes of the conference and provides an update on recent research advances. Progress in liver stem cell research includes isolation of primary liver progenitor cells (LPCs), directed hepatocyte differentiation of primary LPCs and pluripotent stem cells, findings of transdifferentiation, disease-specific considerations for establishing a therapeutically effective cell mass, and disease modeling in cell culture. Tumor-initiating stem-like cells (TISCs) that emerge during chronic liver injury share the expression of signaling pathways, including those organized around transforming growth factor beta and β-catenin, and surface markers with normal LPCs. Recent investigations of the role of TISCs in hepatocellular carcinoma have provided insight into the transcriptional and post-transcriptional regulation of hepatocarcinogenesis. Targeted chemotherapies for TISC are in development as a means to overcome cellular resistance and mechanisms driving disease progression in liver cancer.
The association of particulate air metal concentrations with heart rate variability.
Authors: Shannon R Magari, Joel Schwartz, Paige L Williams, Russ Hauser, Thomas J Smith, David C Christiani
Journal: Environmental Health Perspectives (2002)

Numerous studies show an association between particulate air pollution and adverse health effects. Particulate matter is a complex mixture of elemental carbon, ammonium, sulfates, nitrates, organic components, and metals. The mechanisms of action of particulate matter less than or equal to 2.5 micro m in mean aerodynamic diameter (PM(2.5)), as well as the constituents responsible for the observed cardiopulmonary health effects, have not been identified. In this study we focused on the association between the metallic component of PM(2.5) and cardiac autonomic function based on standard heart rate variability (HRV) measures in an epidemiologic study of boilermakers. Thirty-nine male boilermakers were monitored throughout a work shift. Each subject wore an ambulatory electrocardiogram (Holter) monitor and a personal monitor to measure PM(2.5). We used mixed-effects models to regress heart rate and SDNN index (standard deviation of the normal-to-normal) on PM(2.5) and six metals (vanadium, nickel, chromium, lead, copper, and manganese). There were statistically significant mean increases in the SDNN index of 11.30 msec and 3.98 msec for every 1 micro g/m(3) increase in the lead and vanadium concentrations, respectively, after adjusting for mean heart rate, age, and smoking status. Small changes in mean heart rate were seen with all exposure metrics. The results of this study suggest an association between exposure to airborne metals and significant alterations in cardiac autonomic function. These results extend our understanding of the adverse health effects of the metals component of ambient PM(2.5).
The Hemolytic–Uremic Syndrome — Toxin, Thrombin, and Thrombosis
Authors: Eric F. Grabowski
Journal: New England Journal of Medicine (2002)

The term “hemolytic–uremic syndrome” was coined by Gasser et al. in 19551 to describe a devastating illness consisting of acute renal failure accompanied by nonimmune hemolytic anemia and thrombocytopenia. Although it may be seen in adolescents and adults, the hemolytic–uremic syndrome most frequently occurs in young children (under the age of five years) after a prodromal period of bloody diarrhea caused by Shiga toxin from Escherichia coli (especially serotype O157:H7). Multiorgan failure involving the central nervous system, pancreas, heart, or other systems or organs may accompany this disease. The differential diagnosis includes, not surprisingly, disseminated intravascular coagulation, primary hemolytic anemia, . . .
Physicians and Their Patients' Suicides-Reply
Authors: Steven Miles
Journal: JAMA (1994)

<h3>In Reply.</h3> —Dr Grisolia's proposal to legalize physician-assisted suicide in a couple of test states will probably occur as a result of referendum, possibly as early as this fall. The larger infrastructure of suicide specialists, whom he euphemistically calls terminal care specialists, would be costly and a poor career choice until there was strong social approval and reimbursement for assisted suicide. The institutionalization of specialists in physician-assisted suicide that Grisolia proposes is another form of the "all or nothing" we both lament and the overspecialization that has fragmented and encumbered primary patient care. A middle ground may lie in fundamentally restructuring primary care systems for the common event of end-of-life care. We could assure universal access to hospice benefits to give patients a choice. We could minimize legal controls on narcotics for terminally ill persons to improve pain control, promote autonomy, decrease fear of loss of control, and empower nonmedical
Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk
Authors: Hyacinth I. Hyacinth, Robert J. Adams, Jenifer H. Voeks, Jacqueline M. Hibbert, Beatrice E. Gee
Journal: American Journal of Hematology (2013)

Stroke is one of the most disabling complications of sickle cell anemia (SCA). The molecular mechanisms leading to stroke in SCA or by which packed red blood cell (PRBC) transfusion prevents strokes are not understood. We investigated the effects of PRBC transfusion on serum biomarkers in children with SCA who were at high‐risk for stroke. Serum samples from 80 subjects were analyzed, including baseline, study exit time point and 1 year after study exit. Forty of the 80 samples were from subjects randomized to standard care and 40 from transfusion arm. Samples were assayed for levels of BDNF, sVCAM‐1, sICAM‐1, MPO, Cathepsin‐D, PDGF‐AA, PDGF‐AB/BB, RANTES (CCL5), tPAI‐1, and NCAM‐1 using antibody immobilized bead assay. Significantly lower mean serum levels of sVCAM‐1 (2.2 × 10 6 ± 0.8 × 10 6 pg/mL vs. 3.1 × 10 6 ± 0.9 × 10 6 pg/mL, P &lt; 0.0001), Cathepsin‐D (0.5 × 10 6 ± 0.1 × 10 6 pg/mL vs. 0.7 × 10 6 ± 0.2 × 10 6 pg/mL, P &lt; 0.0001), PDGF‐AA (10556 ± 4033 pg/mL vs. 14173 ± 4631 pg/mL, P = 0.0008), RANTES (0.1 × 10 6 ± 0.07 × 10 6 pg/mL vs. 0.2 × 10 6 ± 0.06 × 10 6 pg/mL, P &lt; 0.006), and NCAM‐1 (0.7 × 10 6 ± 0.2 × 10 6 pg/mL vs. 0.8 × 10 6 ± 0.1 × 10 6 pg/mL, P &lt; 0.0006) were observed among participants who received PRBC transfusion, compared to those who received standard care. Twenty or more PRBC transfusion over 4 years was associated with lower serum levels of sVCAM‐1 ( P &lt; 0.001), PDGF‐AA ( P = 0.025), and RANTES ( P = 0.048). Low baseline level of BDNF ( P = 0.025), sVCAM‐1 ( P = 0.025), PDGF‐AA ( P = 0.01), t‐PAI‐1 ( P = 0.025) and sICAM‐1 ( P = 0.022) was associated with higher probability of stroke free survival. Beyond improving hemoglobin levels, our results suggest that the protective effects of PRBC transfusion on reducing stroke in SCD may result from reduced thrombogenesis and vascular remodeling. Am. J. Hematol. 89:47–51, 2014. © 2013 Wiley Periodicals, Inc.
Diagnosis and Management of Infective Endocarditis and Its Complications
Authors: Arnold S. Bayer, Ann F. Bolger, Kathryn A. Taubert, Walter Wilson, James Steckelberg, Adolph W. Karchmer, Matthew Levison, Henry F. Chambers, Adnan S. Dajani, Michael H. Gewitz, Jane W. Newburger, Michael A. Gerber, Stanford T. Shulman, Thomas J. Pallasch, Tommy W. Gage, Patricia Ferrieri
Journal: Circulation (1998)

HomeCirculationVol. 98, No. 25Diagnosis and Management of Infective Endocarditis and Its Complications
HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion
Authors: Kristina E. Hoot, Masako Oka, Gangwen Han, Erwin Bottinger, Qinghong Zhang, Xiao-Jing Wang
Journal: Journal of Clinical Investigation (2010)

TGF-β signaling can promote tumor formation and development or suppress it, depending on the cellular context and tumor stage. A potential target of this dual effect of TGF-β is HGF, as TGF-β can inhibit or promote its expression, although the mechanisms underlying this are largely unknown. In the present study, we found that mice with keratinocyte-specific deletion of the TGF-β signaling mediator Smad2 (referred to herein as K5.Smad2(-/-) mice), which have increased susceptibility to squamous cell carcinomas (SCCs), exhibited angiogenesis associated with epithelial overexpression of HGF and endothelial activation of the HGF receptor c-Met. Application of a c-Met inhibitor abrogated angiogenesis, suggesting that HGF overexpression plays a major role in angiogenesis associated with epithelial Smad2 loss. On the Hgf promoter, Smad2 was mainly associated with transcriptional corepressors, whereas Smad4 was mainly associated with the transcriptional coactivator CREB-binding protein (CBP/p300). Smad2 loss caused increased binding of Smad4 and CBP/p300 to the Hgf promoter. Consistent with this, knocking down Smad2 in human keratinocytes caused increased levels of HGF, which were abrogated by concomitant knockdown of Smad3 and Smad4. Importantly, the incidence of HGF-positive human SCC was high in cases with Smad2 loss and lower when Smad4 was also lost. We therefore conclude that Smad2 loss causes HGF upregulation via loss of Smad2-mediated transcriptional repression and enhanced Smad3/4-mediated transactivation. Since Smad2 is often downregulated in human SCCs, our data suggest a therapeutic strategy of blocking HGF/c-Met activation for Smad2-deficient SCCs.
Mechanisms of regulation of cell-mediated immunity. IV. Azobenzenearsonate-specific suppressor factor(s) bear cross-reactive idiotypic determinants the expression of which is linked to the heavy-chain allotype linkage group of genes.
Authors: B A Bach, M I Greene, B Benacerraf, A Nisonoff
Journal: The Journal of Experimental Medicine (1979)

T-cell derived suppressor factor(s) (SF) specific for azobenzenearsonate (ABA) were prepared by the mechanical disruption of suppressor cells. Such suppressor factors were adsorbed to and recovered from immunoadsorbents prepared from the F(ab')2 fragments of rabbit immunoglobulin directed against the cross-reactive idiotype of A/J anti-ABA antibodies. These ABA-suppressor factors were not retained on Sepharose 4B immunoadsorbent columns which had been coupled with F(ab')2 fragments or normal rabbit immunoglobulins prepared from prebleeds of rabbits used to make anti-idiotypic antiserum. The specificity of the F(ab')2 rabbit anti-idiotypic serum was established by direct idiotypic-binding assays and by affinity purification over an immunoadsorbent consisting of CRI+ anti-ABA immunoglobulin from A/J mice. ABA-suppressor factors were shown to be specifically absorbed and eluted from F(ab')2 anti-idiotypic columns. Futhermore, the eluted suppressor factor can be specifically reabsorbed and recovered from a second anti-idiotypic immunoadsorbent. The concordance between antigen-binding specificity and the presence of idiotypic determinants was demonstrated by adsorbing ABA SF to antigen columns and then fractionating the ABA-specific factor on anti-idiotypic immunoadsorbents. ABA-suppressor factors were shown to be specifically retained on immunoadsorbents directed against major histocompatibility complex (MHC) determinants. Factor eluted from anti-MHC columns could then be specifically adsorbed to anti-idiotypic immunoadsorbents. This suggests that the same molecular complex that is recognized by the H-2 alloantiserum is specifically adsorbed to an anti-idiotypic immunoadsorbent. Genetic analysis of the expression of CRI+ suppressor factor was performed using the C.AL-20 mouse strain which has the AL/N allotype and produces CRI+ anti-ABA immunoglobulins. The implication of these findings to the nature of T-cell-derived regulatory molecules is discussed.
Spontaneous Rupture of a Choledochal Cyst and the Role of Hepatobiliary Scintigraphy
Authors: Ashwani Sood, M S. Senthilnathan, Satyawati Deswal, Prasant Kumar Pradhan, B K. Das, Rakesh Kumar
Journal: Clinical Nuclear Medicine (2004)

A 2-year-old girl presented with jaundice of 2 weeks’ duration. Ultrasonography of the abdomen revealed ascites and a dilated common bile duct suggestive of a choledochal cyst. Tc-99m mebrofenin hepatobiliary imaging demonstrated findings consistent with a diagnosis of spontaneous rupture of a choledochal cyst. Timely surgical intervention yielded excellent results. A follow-up hepatobiliary scan 4-months after surgery revealed no abnormality.
Osteoporosis and arthritis.
Authors: J Dequeker, P Geusens
Journal: Annals of the Rheumatic Diseases (1990)

Osteoporosis and arthritisIf hypertension is a silent killer, osteoporosis is a silent thief.It insidiously robs the skeleton of its banked resources, often for decades, until the bone ultimately becomes weak enough to sustain a spontaneous fracture.'Recently, the field of metabolic bone disease has received prominent recognition because of the increased public awareness of the prevalence and problems associated with osteoporosis.Because of the enormous disability and health care costs resulting from this disease, attempts have been made to try to identify subjects at risk or those who have established disease for either preventive or therapeutic interventions.
Cutaneous Responses to Insects
Authors: James H. Barnard
Journal: JAMA (1966)

In this discussion concerning the cutaneous effects of insects on human beings, it is necessary to emphasize that, due to the great variety of insects involved and the large number of clinical responses they may produce, only a summary of available data can be given. Sabrosky<sup>1</sup>estimated that the number of kinds or species of insects throughout the world which had been named and described by the end of 1948 was nearly 700,000. It was suggested that this number might reach 1 1/2 million at some later time. To make it more local, the state of New York had over 15,000 species tabulated, including 3,600 kinds of flies. The orders, their common names, and number of species per order are shown in Table 1.<sup>1</sup> The effects on the skin, as well as on other tissues of the body, are most commonly considered to result from the insects' bite
Inorganic Arsenic and Human Prostate Cancer
Authors: Lamia Benbrahim-Tallaa, Michael P. Waalkes
Journal: Environmental Health Perspectives (2007)

ObjectiveWe critically evaluated the etiologic role of inorganic arsenic in human prostate cancer.Data sourcesWe assessed data from relevant epidemiologic studies concerning environmental inorganic arsenic exposure. Whole animal studies were evaluated as were in vitro model systems of inorganic arsenic carcinogenesis in the prostate.Data synthesisMultiple studies in humans reveal an association between environmental inorganic arsenic exposure and prostate cancer mortality or incidence. Many of these human studies provide clear evidence of a dose–response relationship. Relevant whole animal models showing a relationship between inorganic arsenic and prostate cancer are not available. However, cellular model systems indicate arsenic can induce malignant transformation of human prostate epithelial cells in vitro. Arsenic also appears to impact prostate cancer cell progression by precipitating events leading to androgen independence in vitro.ConclusionAvailable evidence in human populations and human cells in vitro indicates that the prostate is a target for inorganic arsenic carcinogenesis. A role for this common environmental contaminant in human prostate cancer initiation and/or progression would be very important.