tbuckley/cabot-search huggingface dataset:
Prostate cancer's one-two punch
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Tumors can avoid immune destruction despite being invaded by tumor-specific CD8+ T cells. On page 1257, Bronte et al. describe one way that prostate tumors subdue T cells—they make two enzymes that combine forces to cripple T cell signaling components.

Tumors use a variety of tactics to avoid attack by cytotoxic CD8+ T cells; one is to establish an inhospitable environment that inhibits T cell activation. In recent mouse studies, myeloid suppressor cells infiltrated tumors and set up an inhibitory environment, apparently by making two enzymes—arginase and nitric oxide synthase 2 (NOS2).






Figure 

Inducible nitric oxide synthase (NOS2) (brown) helps subdue CD8+ T cells in a human prostate tumor.




Both enzymes can inhibit T cell functions independently. But when expressed together, the enzyme duo triggers a cascade of reactions that culminates in the production of peroxynitrite—an oxidizing agent that nitrates tyrosine residues on proteins. Tyrosine nitration blocks the tyrosine phosphorylation events required for T cell activation and promotes apoptosis.

Increased expression of both arginase and NOS2 in human prostate tumors has been reported, but their affect on tumor-infiltrating T cells has never been directly studied. Bronte and colleagues now show that CD8+ T cells in human prostate tumors failed to up-regulate the activation markers CD25 and CD69 in response to mitogenic stimulation. Activation was restored when both arginase and NOS2 were inhibited. This occurred even without exogenous stimulation, suggesting that the reawakened T cells were responding to in situ–presented tumor antigens.

The need to inhibit both enzymes to reactivate the T cells, and the presence of nitrotyrosine-positive cells in the tumor tissue, pointed to tyrosine nitration as the key to the T cell inhibition in this model. The authors are now trying to understand what triggers the expression of these enzymes in tumors and whether the same mechanisms operate in other human tumors.
Kidney Disease and Cardiovascular Risk
Authors: Marcello Tonelli, Marc A. Pfeffer
Journal: Annual Review of Medicine (2006)

Kidney failure and chronic kidney disease (CKD) are associated with accelerated cardiovascular disease, apparently because of a high burden of traditional vascular risk factors and possibly nontraditional risk factors such as inflammation, chronic volume overload, and abnormal calcium-phosphate metabolism. Although the burden of cardiovascular disease in CKD patients is well documented, potentially beneficial therapies appear to be underused in mild to moderate CKD and are relatively understudied in those with kidney failure. This review describes the epidemiology and pathophysiology of cardiovascular disease in CKD. We also discuss the clinical and public health implications of current knowledge and outline opportunities for further research.
Defective DNA Repair and Increased Genomic Instability in Artemis-deficient Murine Cells
Authors: Sean Rooney, Frederick W. Alt, David Lombard, Scott Whitlow, Mark Eckersdorff, James Fleming, Sebastian Fugmann, David O. Ferguson, David G. Schatz, JoAnn Sekiguchi
Journal: The Journal of Experimental Medicine (2003)

In developing lymphocytes, the recombination activating gene endonuclease cleaves DNA between V, D, or J coding and recombination signal (RS) sequences to form hairpin coding and blunt RS ends, which are fused to form coding and RS joins. Nonhomologous end joining (NHEJ) factors repair DNA double strand breaks including those induced during VDJ recombination. Human radiosensitive severe combined immunodeficiency results from lack of Artemis function, an NHEJ factor with in vitro endonuclease/exonuclease activities. We inactivated Artemis in murine embryonic stem (ES) cells by targeted mutation. Artemis deficiency results in impaired VDJ coding, but not RS, end joining. In addition, Artemis-deficient ES cells are sensitive to a radiomimetic drug, but less sensitive to ionizing radiation. VDJ coding joins from Artemis-deficient ES cells, which surprisingly are distinct from the highly deleted joins consistently obtained from DNA-dependent protein kinase catalytic subunit–deficient ES cells, frequently lack deletions and often display large junctional palindromes, consistent with a hairpin coding end opening defect. Strikingly, Artemis-deficient ES cells have increased chromosomal instability including telomeric fusions. Thus, Artemis appears to be required for a subset of NHEJ reactions that require end processing. Moreover, Artemis functions as a genomic caretaker, most notably in prevention of translocations and telomeric fusions. As Artemis deficiency is compatible with human life, Artemis may also suppress genomic instability in humans.
The Serotonin Syndrome
Authors: Nallini Gnanadesigan, Randall T Espinoza, Rick L Smith
Journal: New England Journal of Medicine (2005)

raises some questions. First, how many features make a diagnosis of the serotonin syndrome? This is especially relevant when a patient presents with nonspecific symptoms (agitation, tachycardia, tremor, diarrhea, or a combination) that are often early and transient side effects of selective serotoninreuptake inhibitors (SSRIs). An overenthusiastic diagnosis of the serotonin syndrome at this stage may actually deprive the patient of the benefits of SSRI treatment for depression. Second, SSRIs and other proserotonergic agents act, by definition, by raising serotonergic activity in the brain. How and when does one decide that this activity is excessive? As Boyer and Shannon rightly point out, “No laboratory tests confirm the diagnosis of the serotonin syndrome.” Hence, the term “serotonin syndrome” might be a misnomer, because we do not know whether it is an excess of serotonin that causes the syndrome, even in its fullblown form. Debasish Basu, M.D.
Investigation of the biological effects of anti-cell adhesive synthetic peptides that inhibit experimental metastasis of B16-F10 murine melanoma cells.
Authors: M J Humphries, K M Yamada, K Olden
Journal: Journal of Clinical Investigation (1988)

The experimental metastasis of B16-F10 murine melanoma cells is blocked by the anti-cell adhesive pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) derived from the central cell-binding domain of fibronectin. In this report, we show that peptide treatment substantially extends the survival time for mice injected intravenously with B16-F10 cells (8/8 vs. 0/8 mice alive at 150 d), thereby demonstrating the potential efficacy of GRGDS treatment in protection against metastatic colonization. We have also examined the specificity of GRGDS activity by testing a series of related homologues for their effects on experimental metastasis. The overall profile of the relative inhibitory activities of these peptides closely matched their previously established capacity to disrupt adhesion in vitro. Lung retention studies with radiolabeled B16-F10 cells revealed an accelerated rate of cell loss from the lung 0-6 h after coinjection with the active peptide GRGDS. This early effect of GRGDS was consistent with its short circulatory half-life, which was found to be 8 min. Taken together, these results suggest that peptide-mediated inhibition of pulmonary colonization is due to interference with B16-F10 cell adhesion to structures in the target organ. Possible peptide interference in tumor cell-blood cell interactions was examined in order to assess (a) possible biological side-effects of peptide treatment and (b) whether such interactions might be an alternative mechanism for GRGDS-mediated inhibition of pulmonary colonization. GRGDS was found to retain full inhibitory activity when coinjected with B16-F10 cells into mice in which platelet function was impaired by acetylsalicylic acid treatment or into thrombocytopenic mice treated with antiplatelet serum (76-93% inhibition of colony formation). These data suggest that platelet involvement in the effects of the peptide is minimal. Similarly, GRGDS was also found to be a potent inhibitor of experimental metastasis in natural killer (NK) cell-deficient beige mice (86% inhibition), thereby discounting the possibility that GRGDS artifactually enhanced NK cell activity. We conclude as a result of these studies that cell-binding fibronectin peptides are specific inhibitors of experimental metastasis that prolong survival, that they appear to function by blocking the adhesion of B16-F10 cells to structures in the target organ, and that they do not appear to act through side effects on certain metastasis-related blood cell functions. In the future, derivatives of fibronectin peptides may be potentially useful prophylactic agents for interfering with the process of metastasis.
A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study.
Authors: A J Wozniak, M K Samson, N T Shah, E D Crawford, C D Ford, S J Altman, R L Stephens, R B Natale, B A Bouroncle, B A Blumenstein
Journal: Journal of Clinical Oncology (1991)

This is a Southwest Oncology Group (SWOG) prospective randomized trial of cisplatin, vinblastine, and bleomycin (PVB) versus vinblastine, cisplatin, and etoposide (VP-16) (VPV) in the treatment of advanced germ cell tumors of the testis. The study objective was to determine what effect the replacement of bleomycin with VP-16 has on complete response (CR), survival, and drug toxicity. One hundred sixty-nine patients were registered and randomized. Of these patients, 160 were assessable for response. All had histologically confirmed disseminated germ cell neoplasms of testicular origin. Forty-six had minimal metastatic disease, and 114 had maximal disease. Seventy-seven were randomized to PVB and 83 to VPV chemotherapy. There was no significant difference in pretreatment characteristics between the two arms with regard to tumor burden, histologic type, and overall performance status. Patients received four courses of induction chemotherapy, either PVB (cisplatin 120 mg/m2 day 3, vinblastine 12 mg/m2 day 1, bleomycin 15 U/m2 twice per week) or VPV (vinblastine 8 mg/m2 day 1, cisplatin 120 mg/m2 day 3, VP-16 50 mg/m2 days 2 to 5). Chemotherapy was given every 3 weeks. Cytoreductive surgery was done postinduction if a chemotherapy CR was not achieved. There was no difference in the percentage of patients achieving a disease-free status between PVB (77%) and VPV (73%). The mean leukocyte nadir was similar for both treatments, but the mean platelet nadir was significantly lower (P = .003) in the VPV arm. All bleomycin-related toxicities (pulmonary, mucositis, skin) were avoided in the VPV arm. We conclude that bleomycin can be replaced in first-line therapy for advanced germ cell tumors without sacrificing efficacy and with the advantage of avoiding unnecessary drug toxicity.
Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies
Authors: C. Lebbé, J.S. Weber, M. Maio, B. Neyns, K. Harmankaya, O. Hamid, S.J. O'Day, C. Konto, L. Cykowski, M.B. McHenry, J.D. Wolchok
Journal: Annals of Oncology (2014)
Pathological features of temporal arteries in patients with giant cell arteritis presenting with permanent visual loss
Authors: D Chatelain, P Duhaut, J Schmidt, R Loire, S Bosshard, M Guernou, H Pellet, J C Piette, H Sevestre, J P Ducroix
Journal: Annals of the Rheumatic Diseases (2008)

Permanent visual loss (PVL) is the most feared complication of giant cell arteritis (GCA), and its risk factors are still unclear.The aim of our study was to assess the pathological features predictive of PVL on temporal artery biopsy (TAB) specimens in patients with GCA.The slides of 391 TAB specimens from patients with GCA were reviewed by two pathologists without clinical information.A total of 29 patients (26 females and 3 males, mean age 78.3 years) presented with unilateral PVL at the onset of the disease, and 362 patients (258 females, 104 males, mean age 74.7 years), did not. The pathological features strongly predictive for PVL were the presence (p = 0.003), number (p = 0.001) and aggregates of giant cells (p = 0.001), presence of plasmocytes (p = 0.002), thickened intima (p = 0.007), neoangiogenesis (p = 0.001) and degree of arterial occlusion (p = 0.006). Presence of neutrophils, eosinophils, parietal necrosis, calcification in the arterial wall and disruption of the internal elastic membrane were similar in both groups. Total obstruction of the arterial lumen by a thrombus, intensity of the inflammatory cells infiltration and inflammation of small vessels, nerves and veins surrounding the temporal artery were not associated with blindness. In multivariate analysis, only giant cells remained significantly associated with PVL.Giant cells are strongly associated with PVL, with a significant gradient between great risk and large number of giant cells. However, PVL was neither associated with the intensity of the inflammatory infiltrate, nor with the presence of arterial thrombosis.
Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia
Authors: Niuscha Yaktapour, Rudolf Übelhart, Julia Schüler, Konrad Aumann, Christine Dierks, Meike Burger, Dietmar Pfeifer, Hassan Jumaa, Hendrik Veelken, Tilman Brummer, Katja Zirlik
Journal: Blood (2013)
Myocyte Volume and Function in Response to Osmotic Stress
Authors: Shinichi Mizutani, Sandip M. Prasad, Angela D. Sellitto, Richard B. Schuessler, Ralph J. Damiano, Jennifer S. Lawton
Journal: Circulation (2005)

Background— Hypothermic hyperkalemic cardioplegia results in significant myocyte swelling and impaired contractility. These detrimental effects may be eliminated by the addition of an adenosine triphosphate-sensitive potassium (K ATP ) channel opener. This study evaluated the hypothesis that a K ATP channel opener (diazoxide) would benefit volume homeostasis by limiting volume and subsequent contractility changes during osmotic stress. Methods and Results— Isolated rabbit ventricular myocyte volume and contractility were evaluated using video microscopy and field stimulation after exposure to osmotic stress at 37°C. Myocytes were exposed to Tyrode’s physiological solution for 20 minutes and test solution for 20 minutes, and then reexposed to Tyrode’s for 20 minutes. Test solutions included control Tyrode’s (1T) and osmotically altered Tyrode’s (2.6T, 0.9T, and 0.6T) solutions with or without the K ATP channel opener diazoxide. Severe osmotic stress (2.6T and 0.6T) resulted in significant cell shrinkage and swelling, respectively. This was unchanged by the addition of diazoxide. Mild hyposmotic stress (0.9T) resulted in significant cell swelling that was eliminated by the addition of diazoxide. Cell swelling was associated with reduced contractility. Conclusions— Cell swelling, but not shrinkage, was detrimental to myocyte contractility. Diazoxide eliminated volume change due to mild hyposmotic stress, similar to that previously noted with hyperkalemic cardioplegia, but did not alter volume change secondary to severe osmotic stress.
Do U.S. Environmental Protection Agency water quality guidelines for recreational waters prevent gastrointestinal illness? A systematic review and meta-analysis.
Authors: Timothy J Wade, Nitika Pai, Joseph N S Eisenberg, John M Colford
Journal: Environmental Health Perspectives (2003)

Despite numerous studies, uncertainty remains about how water quality indicators can best be used in the regulation of recreational water. We conducted a systematic review of this topic with the goal of quantifying the association between microbial indicators of recreational water quality and gastrointestinal (GI) illness. A secondary goal was to evaluate the potential for GI illness below current guidelines. We screened 976 potentially relevant studies and from these identified 27 studies. From the latter, we determined summary relative risks for GI illness in relation to water quality indicator density. Our results support the use of enterococci in marine water at U.S. Environmental Protection Agency guideline levels. In fresh water, (Italic)Escherichia(/Italic) coli was a more consistent predictor of GI illness than are enterococci and other bacterial indicators. A log (base 10) unit increase in enterococci was associated with a 1.34 [95% confidence intervals (CI), 1.00-1.75] increase in relative risk in marine waters, and a log (base 10) unit increase in E. coli was associated with a 2.12 (95% CI, 0.925-4.85) increase in relative risk in fresh water. Indicators of viral contamination were strong predictors of GI illness in both fresh and marine environments. Significant heterogeneity was noted among the studies. In our analysis of heterogeneity, studies that used a nonswimming control group, studies that focused on children, and studies of athletic or other recreational events found elevated relative risks. Future studies should focus on the ability of new, more rapid and specific microbial methods to predict health effects, and estimating the risks of recreational water exposure among susceptible persons.
Osteoarthrosis in a rural South African Negro population.
Authors: L Solomon, P Beighton, J S Lawrence
Journal: Annals of the Rheumatic Diseases (1976)

The prevalence and distribution of osteoarthrosis has been studied in a South African Negro population. One or more joints were affected in 60% of the males and 48% of the females, compared with a prevalence of 55% in males and 63% in females in a comparable English population. Multiple osteoarthrosis was significantly less common in the African than in the English population, the difference here being greatest in females. Clinical Heberden's nodes were also very infrequent in the African population. However, the Tswana males had significantly more osteoarthrosis of the metacarpophalangeal and proximal interphalangeal joints than was encountered in English males. This is attributed to the traumatic effect of hard manual work which is carried on into old age among most African populations.
Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor–induced peritracheal edema
Authors: James Brian Byrd, Ajai Shreevatsa, Pradeep Putlur, Denis Foretia, Laurie McAlexander, Tuhin Sinha, Mark D. Does, Nancy J. Brown
Journal: Journal of Allergy and Clinical Immunology (2007)
Double‐blind, placebo‐controlled food challenge with apple
Authors: K. Skamstrup Hansen, H. Vestergaard, P. Stahl Skov, M. Søndergaard Khinchi, S. Vieths, L. K. Poulsen, C. Bindslev‐Jensen
Journal: Allergy (2001)

The aim of the study was to develop and evaluate different methods of double‐blind, placebo‐controlled food challenge (DBPCFC) with apple. Three different DBPCFC models were evaluated: fresh apple juice, freshly grated apple, and freeze‐dried apple powder. All challenges were performed outside the pollen season and took place from 1997 to 1999. The freeze‐dried apple material was characterized by means of leukocyte histamine release (HR), skin prick test (SPT), and immunoblotting experiments. The study population consisted of birch pollen‐allergic patients with a history of rhinitis in the birch‐pollen season and positive specific IgE to birch. For comparison of the DBPCFC models, 65 patients with a positive open oral challenge with apple were selected. In the characterization of the freeze‐dried apple material, 46 birch pollen‐allergic patients were included. The IgE reactivity to apple was evaluated by measurement of specific IgE, HR, and SPT. Golden Delicious apples were used in all experiments. The results of this study showed that it was possible to perform DBPCFC with apple in birch pollen‐allergic individuals. The model with freshly squeezed apple juice had a low sensitivity and displayed a high frequency of reactions to placebo, probably due to the ingredients used for blinding. The sensitivity of the models with freshly grated apple and freeze‐dried apple powder was 0.74/0.60. An increase in sensitivity is desirable. The freeze‐dried apple powder proved to be useful for SPT, HR, and oral challenges, but further investigation of the stability and the allergenic profile of the material is needed.
A systematic review of health-related quality of life in cutaneous melanoma
Authors: D. Cornish, C. Holterhues, L.V. van de Poll-Franse, J.W. Coebergh, T. Nijsten
Journal: Annals of Oncology (2009)

Melanoma can be considered an emerging chronic disease that may considerably affect patients' lives. The authors systematically reviewed the available literature on health-related quality of life (HRQOL) and melanoma. Of reviews and the selected studies, reference lists were hand-searched. The quality of the eligible studies was appraised based on 14 previously published criteria. Of the 158 abstracts, 44 articles were appraised, resulting in 13 selected studies written in English (published between 2001 and 2008). Most studies assessed patients from specialised centres with varying, but relatively advanced, disease stages. The most commonly used instruments were the SF-36 and EORTC QLQ-C30. Recently, a melanoma-specific HRQOL questionnaire [FACT-Melanoma (FACT-M)] was introduced for clinical trial purposes. It showed that approximately one-third of melanoma patients experienced considerable levels of distress, mostly at the time of diagnosis and following treatment. Systemic therapies affected HRQOL negatively in the short term, but to a lesser extent in the long term. Health status and patients' psychological characteristics are associated with higher levels of HRQOL impairment. The authors found that the impact of melanoma on patients' HRQOL is comparable to that of other cancers. Accurately assessing HRQOL impairment in melanoma patients is pivotal, as it may affect disease management, including therapy and additional counselling, future preventive behaviour and perhaps even prognosis.
Points from Letters: Childhood Autism
Authors: G. L. Davies
Journal: BMJ (1970)

refers I did not comment directly on the case for or against a large increase in number, but was concerned with the evi- dence indicating that the Royal Commission had failed to understand the mathematical basis on which they proposed an exponential expansion, and had thus reached a wholly unjustifiable conclusion about the number of doctors necessary.I also drew attention to the implications of an error of this magnitude, which could require perhaps the provision of 10,000 unnecessary doctors in 10 years, a number equivalent to the output of five new medical schools.As this appears a serious matter, one would expect the mathematical errors in this section of the report to have been ac- knowledged and corrected before now, since it must surely be necessary to prepare a new estimate based on less indefensible grounds.If, however, my conclusions are unjustified, it should be an easy matter to refute them.-Iam, etc.,
Late acute thrombotic occlusion after endovascular brachytherapy and stenting of femoropopliteal arteries
Authors: Robert Bonvini, Iris Baumgartner, Do Dai Do, Mario Alerci, Jeanne-Marie Segatto, Paolo Tutta, Kurt Jäger, Markus Aschwanden, Ernst Schneider, Beatrice Amann-Vesti, Richard Greiner, Felix Mahler, Augusto Gallino
Journal: Journal of the American College of Cardiology (2003)