tbuckley/cabot-search huggingface dataset:
Epidermal Growth Factor Receptor Expression in Pretreatment Biopsies From Head and Neck Squamous Cell Carcinoma As a Predictive Factor for a Benefit From Accelerated Radiation Therapy in a Randomized Controlled Trial
Authors: Søren M. Bentzen, Beste M. Atasoy, Frances M. Daley, Stanley Dische, Paul I. Richman, Michele I. Saunders, Klaus R. Trott, George D. Wilson
Journal: Journal of Clinical Oncology (2005)

Purpose Accelerated repopulation is a main reason for locoregional failure after fractionated radiotherapy for head and neck squamous cell carcinoma (HNSCC). Epidermal growth factor receptor (EGFR) is a key controller of cellular proliferation in HNSCC, which stimulated the current study to look for a direct link between EGFR status and a possible clinical advantage of accelerated radiotherapy. Patients and Methods Immunohistochemical staining for EGFR was performed in 304 patients with available pretreatment tumor biopsy material among 918 patients randomized to receive continuous hyperfractionated accelerated radiotherapy versus conventionally fractionated radiotherapy. The EGFR index was estimated as the proportion of tumor cells with EGFR membrane staining. Results Significant benefit in locoregional tumor control from continuous hyperfractionated accelerated radiotherapy was seen in patients with HNSCC with high EGFR expression (2P = .010) but not in those with low EGFR expression (2P = .85). EGFR status had no significant effect on survival or rate of distant metastases. The EGFR index was significantly associated with histologic grade and microvessel density. There was moderate support for an association between EGFR status and subsite within the head and neck region but no significant association with Ki-67 index, Ki-67 pattern, p53 index, p53 intensity, bcl-2 expression, or cyclin D1 index. Conclusion This study indicates a key role for the EGFR receptor in determining the proliferative cellular response to fractionated radiotherapy in HNSCC. It also shows that we can select the dose-fractionation regime that has the greatest chance of benefiting the patient. These results also encourage further development of EGFR targeting combined with fractionated radiotherapy in HNSCC.
Dialysis survival in a large inner-city facility
Authors: J C Stivelman, J M Soucie, E S Hall, E J Macon
Journal: Journal of the American Society of Nephrology (1995)

Impoverished patients may represent a high-risk population with poor survival. With 1993 U.S. Renal Data System survival tables (to adjust the risk of death for differences in age, race, and ESRD diagnosis), the mortality rates of patients over 3 yr in a large inner-city dialysis facility using high-flux technique were compared with national averages. At least 93.7% of patients were African-American, 50% had incomes below $7,000 per year, and employment was 5% or less. Observed and expected deaths (the latter derived from the U.S. Renal Data System tables) were used to calculate a standardized mortality ratio (observed deaths/expected deaths); the U.S. average is 1.0. The standardized mortality ratio at this facility for each year was < 0.600 and was significantly lower than the U.S. average in 1991, in 1992 (P < 0.05), and for all 3 yr (P < .001). Over all 3 yr, it was lower for females (0.540, P < 0.05), males (0.620, P < 0.05), patients with diabetes (0.593, P < 0.05), and glomerulonephritis (0.318, P < 0.05). For the 3 yr, a Cox regression analysis revealed independent associations between mortality and age (P = 0.004), serum albumin (P = 0.02), Kt/V (P = 0.02), and dialysis for more than 2 yr (P = 0.01). Patients with economic hardship can attain survival significantly better than the national average with the provision of adequate dialysis, nutrition, and support services.
A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis
Authors: Toru Atsumi, Katsuhiko Ishihara, Daisuke Kamimura, Hideto Ikushima, Takuya Ohtani, Seiichi Hirota, Hideyuki Kobayashi, Sung-Joo Park, Yukihiko Saeki, Yukihiko Kitamura, Toshio Hirano
Journal: The Journal of Experimental Medicine (2002)

We generated a mouse line in which the src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130F759/F759). The gp130F759/F759 mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130F759/F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease.
738 HIGHEST RATES OF RESPONSE AT WEEK 72 OF THE NEPTUNE STUDY ARE ACHIEVED WITH PEGINTERFERON ALFA-2A 180 μG FOR 48 WEEKS
Authors: P. Marcellin, Q. Xie, J. Sung, T. Tanwandee, K. Han, C. Wat, C.-W. Hsu, J. Jia
Journal: Journal of Hepatology (2011)
Identification of Novel Kinase Targets for the Treatment of Estrogen Receptor–Negative Breast Cancer
Authors: Corey Speers, Anna Tsimelzon, Krystal Sexton, Ashley M. Herrick, Carolina Gutierrez, Aedin Culhane, John Quackenbush, Susan Hilsenbeck, Jenny Chang, Powel Brown
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Previous gene expression profiling studies of breast cancer have focused on the entire genome to identify genes differentially expressed between estrogen receptor (ER) α–positive and ER-α–negative cancers. Experimental Design: Here, we used gene expression microarray profiling to identify a distinct kinase gene expression profile that identifies ER-negative breast tumors and subsets ER-negative breast tumors into four distinct subtypes. Results: Based on the types of kinases expressed in these clusters, we identify a cell cycle regulatory subset, a S6 kinase pathway cluster, an immunomodulatory kinase–expressing cluster, and a mitogen-activated protein kinase pathway cluster. Furthermore, we show that this specific kinase profile is validated using independent sets of human tumors and is also seen in a panel of breast cancer cell lines. Kinase expression knockdown studies show that many of these kinases are essential for the growth of ER-negative, but not ER-positive, breast cancer cell lines. Finally, survival analysis of patients with breast cancer shows that the S6 kinase pathway signature subtype of ER-negative cancers confers an extremely poor prognosis, whereas patients whose tumors express high levels of immunomodulatory kinases have a significantly better prognosis. Conclusions: This study identifies a list of kinases that are prognostic and may serve as druggable targets for the treatment of ER-negative breast cancer. (Clin Cancer Res 2009;15(20):6327–40)
Low Serum Level of the Endogenous Secretory Receptor for Advanced Glycation End Products (esRAGE) Is a Risk Factor for Prevalent Vertebral Fractures Independent of Bone Mineral Density in Patients With Type 2 Diabetes
Authors: Masahiro Yamamoto, Toru Yamaguchi, Mika Yamauchi, Toshitsugu Sugimoto
Journal: Diabetes Care (2009)

OBJECTIVE Patients with type 2 diabetes are known to have an increased risk for fracture compared with non–type 2 diabetic control subjects, despite having higher bone mineral density (BMD). We previously showed that serum pentosidine, one of the advanced glycation end products (AGEs), was associated with prevalent vertebral fractures (VFs) in those with type 2 diabetes. The involvement of the endogenous secretory receptor for AGEs (esRAGE) in VFs in those with type 2 diabetes, however, is still unknown. RESEARCH DESIGN AND METHODS We compared parameters including esRAGE, pentosidine, and BMD in Japanese type 2 diabetic patients (137 men &amp;gt;50 years old and 140 postmenopausal women) with and without VFs. RESULTS The esRAGE-to-pentosidine ratio in type 2 diabetic patients with VFs was significantly lower than in those without VFs (men: 7.1 ± 2.8 vs. 9.4 ± 6.2, P = 0.013, respectively; women: 4.7 ± 2.7 vs. 8.2 ± 5.4, P &amp;lt; 0.001, respectively). Multivariate logistic regression analysis adjusted for age, BMI, A1C, serum creatinine, duration of diabetes, therapeutic agents, diabetes complications, osteoporotic risk factors, and lumbar BMD identified the serum esRAGE level and esRAGE-to-pentosidine ratio as factors associated with the presence of VFs, independent of BMD in men (odds ratio [OR] 0.46 [95% CI 0.25–0.84], P = 0.012; and OR 0.34 [0.15–0.76], P = 0.009, respectively) and in women (OR 0.32 [0.16–0.67], P = 0.002; and OR 0.14 [0.04–0.43], P = 0.001, respectively). CONCLUSIONS These results show that serum esRAGE level and esRAGE-to-pentosidine ratio are more useful than BMD for assessing the risk of VFs in type 2 diabetic patients.
Characterization of X-Linked SNP genotypic variation in globally distributed human populations
Authors: Amanda M Casto, Jun Z Li, Devin Absher, Richard Myers, Sohini Ramachandran, Marcus W Feldman
Journal: Genome biology (2010)

Abstract Background The transmission pattern of the human X chromosome reduces its population size relative to the autosomes, subjects it to disproportionate influence by female demography, and leaves X-linked mutations exposed to selection in males. As a result, the analysis of X-linked genomic variation can provide insights into the influence of demography and selection on the human genome. Here we characterize the genomic variation represented by 16,297 X-linked SNPs genotyped in the CEPH human genome diversity project samples. Results We found that X chromosomes tend to be more differentiated between human populations than autosomes, with several notable exceptions. Comparisons between genetically distant populations also showed an excess of X-linked SNPs with large allele frequency differences. Combining information about these SNPs with results from tests designed to detect selective sweeps, we identified two regions that were clear outliers from the rest of the X chromosome for haplotype structure and allele frequency distribution. We were also able to more precisely define the geographical extent of some previously described X-linked selective sweeps. Conclusions The relationship between male and female demographic histories is likely to be complex as evidence supporting different conclusions can be found in the same dataset. Although demography may have contributed to the excess of SNPs with large allele frequency differences observed on the X chromosome, we believe that selection is at least partially responsible. Finally, our results reveal the geographical complexities of selective sweeps on the X chromosome and argue for the use of diverse populations in studies of selection.
Biomarkers of Lead Exposure and DNA Methylation within Retrotransposons
Authors: Robert O. Wright, Joel Schwartz, Rosalind J. Wright, Valentina Bollati, Letizia Tarantini, Sung Kyun Park, Howard Hu, David Sparrow, Pantel Vokonas, Andrea Baccarelli
Journal: Environmental Health Perspectives (2010)

DNA methylation is an epigenetic mark that regulates gene expression. Changes in DNA methylation within white blood cells may result from cumulative exposure to environmental metals such as lead. Bone lead, a marker of cumulative exposure, may therefore better predict DNA methylation than does blood lead.In this study we compared associations between lead biomarkers and DNA methylation.We measured global methylation in participants of the Normative Aging Study (all men) who had archived DNA samples. We measured patella and tibia lead levels by K-X-Ray fluorescence and blood lead by atomic absorption spectrophotometry. DNA samples from blood were used to determine global methylation averages within CpG islands of long interspersed nuclear elements-1 (LINE-1) and Alu retrotransposons. A mixed-effects model using repeated measures of Alu or LINE-1 as the dependent variable and blood/bone lead (tibia or patella in separate models) as the primary exposure marker was fit to the data.Overall mean global methylation (+/- SD) was 26.3 +/- 1.0 as measured by Alu and 76.8 +/- 1.9 as measured by LINE-1. In the mixed-effects model, patella lead levels were inversely associated with LINE-1 (beta = -0.25; p < 0.01) but not Alu (beta = -0.03; p = 0.4). Tibia lead and blood lead did not predict global methylation for either Alu or LINE-1.Patella lead levels predicted reduced global DNA methylation within LINE-1 elements. The association between lead exposure and LINE-1 DNA methylation may have implications for the mechanisms of action of lead on health outcomes, and also suggests that changes in DNA methylation may represent a biomarker of past lead exposure.
<i>Thorax</i>editorial by Jenkins and Beasley related to tiotropium respimat
Authors: Norbert Metzdorf, Christoph Hallmann, Bernd Disse
Journal: Thorax (2013)

We thank Drs Jenkins and Beasley for their comments in the recent editorial regarding tiotropium (SPIRIVA).1 Preceding the Singh et al 2 analysis cited by the authors, Boehringer Ingelheim (BI) had analysed both the tiotropium HandiHaler and Respimat pooled datasets using patient-level data on-treatment as well as including vital status. The results showed a nominally statistically significant reduction for tiotropium HandiHaler and a numerical increase with tiotropium Respimat compared with the respective placebo group for all-cause mortality.

These results are adequately reflected in the local SPIRIVA product information (http://www.medicines.org.uk/EMC/searchresults.aspx?term=spiriva&searchtype=QuickSearch) …
IL-17 produced by Paneth cells drives TNF-induced shock
Authors: Nozomi Takahashi, Ineke Vanlaere, Riet de Rycke, Anje Cauwels, Leo A.B Joosten, Erik Lubberts, Wim B. van den Berg, Claude Libert
Journal: The Journal of Experimental Medicine (2008)

Tumor necrosis factor (TNF) has very potent antitumor activity, but it also provokes a systemic inflammatory response syndrome that leads to shock, organ failure, and death. Here, we demonstrate that interleukin (IL)-17, a proinflammatory cytokine known to be produced mainly by activated T cells, has a critical role in this process. Antiserum against IL-17 or deletion of Il17r protected mice against a lethal TNF challenge. Serum levels of TNF-induced IL-6 and nitric oxide metabolites were significantly reduced in mice deficient in the IL-17R. TNF-induced leukocyte influx in the small intestine was reduced, and there was no injury to the small intestine. Surprisingly, electron microscopy showed that IL-17 was constitutively present in Paneth cells of the crypts. Upon TNF challenge, the intracellular pool of IL-17 in these cells was drastically reduced, suggesting rapid release of IL-17 from the granules of Paneth cells. Our findings assign a novel role for IL-17 in an acute inflammation and identify Paneth cells as a source of the IL-17 that plays a role in this process. These data indicate that innate immune cytokine responses in the local mucosa may participate in rapidly amplifying responses to systemic inflammatory challenges.
Comparative Pathology of Nerve Sheath Tumors in Mouse Models and Humans
Authors: Anat O. Stemmer-Rachamimov, David N. Louis, Gunnlaugur P. Nielsen, Cristina R. Antonescu, Alexander D. Borowsky, Roderick T. Bronson, Dennis K. Burns, Pascale Cervera, Margaret E. McLaughlin, Guido Reifenberger, Michael C. Schmale, Mia MacCollin, Richard C. Chao, Karen Cichowski, Michel Kalamarides, Shanta M. Messerli, Andrea I. McClatchey, Michiko Niwa-Kawakita, Nancy Ratner, Karlyne M. Reilly, Yuan Zhu, Marco Giovannini
Journal: Cancer Research (2004)

Abstract Despite the progress made in our understanding of the biology of neurofibromatosis (NF), the long-term clinical outcome for affected patients has not changed significantly in the past decades, and both NF1 and NF2 are still associated with a significant morbidity and a decreased life span. A number of NF1 and NF2 murine models have been generated to aid in the study of NF tumor biology and in the development of targeted therapies for NF patients. A single, universal pathological classification of the lesions generated in these murine models is essential for the validation of the models, for their analysis and comparison with other models, and for their future effective use in preclinical treatment trials. For the formulation of a pathological classification of these lesions, the WHO classification of human tumors was used as a reference. However, it was not adopted for the classification of the GEM lesions because of some important differences between the human and murine lesions. A novel classification scheme for peripheral nerve sheath tumors in murine models was therefore devised.
Preliminary results of early clinical trials with the fully human anti-TNFalpha monoclonal antibody D2E7
Authors: J. Kempeni
Journal: Annals of the Rheumatic Diseases (1999)

Preliminary results of early clinical trials with the fully human anti-TNF monoclonal antibody D2E7 Joachim KempeniCurrent pharmacological treatments for rheumatoid arthritis (RA), including non-steroidal anti-inflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs (DMARDs), and corticosteroids, have been moderately successful in alleviating the discomforts associated with swollen, painful joints.However, conventional medical approaches to treatment have had little or no impact on the disease course of RA. 1 Innovative strategies, particularly those based on new concepts in the immunobiology of RA, are being developed to target cellular inflammatory mechanisms and potentially prevent disease progression.The more promising of these treatments seem to be those that block the eVects of tumour necrosis factor (TNF) , because this proinflammatory cytokine seems to play a central part in the immunopathogenesis of RA. 2 3
Apoptosis Induction in Human Melanoma Cells by Inhibition of MEK Is Caspase-Independent and Mediated by the Bcl-2 Family Members PUMA, Bim, and Mcl-1
Authors: Yu Fang Wang, Chen Chen Jiang, Kelly Anne Kiejda, Susan Gillespie, Xu Dong Zhang, Peter Hersey
Journal: Clinical Cancer Research (2007)

Given that inhibitors of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) are being introduced into treatment for melanoma, the present study was carried out to better understand the mechanism by which they may induce apoptosis of melanoma cells.A panel of human melanoma cell lines and fresh melanoma isolates was assessed for their sensitivity to apoptosis induced by the MEK inhibitor U0126. The apoptotic pathways and regulatory mechanisms involved were examined by use of the inhibitor and small interfering RNA (siRNA) techniques.Inhibition of MEK induced apoptosis in the majority of melanoma cell lines through a mitochondrial pathway that was associated with the activation of Bax and Bak, release of mitochondrial apoptogenic proteins, and activation of caspase-3. However, apoptosis was independent of caspases and instead was associated with mitochondrial release of AIF as shown by the inhibition of apoptosis when AIF was knocked down by siRNA. Inhibition of MEK resulted in the up-regulation of the BH3-only proteins PUMA and Bim and down-regulation of the antiapoptotic protein Mcl-1. These changes were critical for the induction of apoptosis by U0126 as siRNA knockdown of PUMA or Bim inhibited apoptosis, whereas siRNA knockdown of Mcl-1 increased apoptosis particularly in the apoptosis-resistant cell lines.Apoptosis of melanoma cells induced by the inhibition of the MEK/ERK pathway is mediated by the up-regulation/activation of PUMA and Bim and down-regulation of Mcl-1. Release of AIF rather than the activation of caspases seems to be the mediator of apoptosis. Our results suggest that cotargeting Mcl-1 and the MEK/ERK pathway may further improve treatment results in melanoma.
Comparison of Tzanck Smear, Viral Culture, and DNA Diagnostic Methods in Detection of Herpes Simplex and Varicella-Zoster Infection
Authors: George T. Nahass
Journal: JAMA (1992)

To compare Tzanck smears, viral cultures, and DNA diagnostic methods using the polymerase chain reaction (PCR) in detection of herpes simplex virus (HSV) or varicella-zoster virus (VZV) infection in clinically suspected cases.A 12-month trial comparing PCR with viral cultures and Tzanck smears in patients with clinically suspected HSV or VZV infection.Both ambulatory and hospitalized patients were recruited from a tertiary referral center and the Miami (Fla) Veterans Affairs Medical Center.Convenience samples of patients clinically suspected to have HSV (n = 48) or VZV (n = 35). To be included in the final analysis patients needed to have a positive Tzanck smear, viral culture, or PCR result. Patients who were clinically suspected to have HSV but had VZV by viral culture or PCR were analyzed in the VZV group. Similarly, patients who were clinically suspected to have VZV, but had HSV by viral culture or PCR were analyzed in the HSV group. Seventy-seven patients were available for final analysis: HSV (n = 30), VZV (n = 32), and 15 control cases who did not have evidence of viral infection.For HSV, PCR detected HSV DNA sequences in 73% of stained smears and 83% of unstained smears. For VZV infection, VZV DNA sequences were detected in 88% of stained smears and 97% of unstained smears. Viral DNA sequences were not detected in the 15 control cases. Viral cultures were positive in 83% and 44% of HSV and VZV cases, respectively. The Tzanck smear was positive in 60% and 75% of HSV and VZV cases, respectively.PCR is a reliable method for detecting HSV and VZV DNA sequences from single stained and unstained Tzanck smears. It is clearly superior to viral culture in identifying VZV infection and is equivalent to conventional culture techniques in identifying cases of HSV.
Effectiveness of Routine Visits and Routine Tests in Detecting Isolated Locoregional Recurrences After Treatment for Early-Stage Invasive Breast Cancer: A Meta-Analysis and Systematic Review
Authors: G.H. de Bock, J. Bonnema, J. van Der Hage, J. Kievit, C.J.H. van de Velde
Journal: Journal of Clinical Oncology (2004)

To review the effectiveness of routine visits and routine tests in detecting isolated locoregional recurrences in asymptomatic patients after treatment for early-stage invasive breast cancer.Systematic review and meta-analysis. The proportion of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients was compared with the proportion of isolated locoregional recurrences in symptomatic patients.Twelve studies that involved a total of 5,045 patients and 378 isolated locoregional recurrences were identified. Pooling data showed an overall estimate of 40% of isolated locoregional recurrences diagnosed during routine visits or routine tests in asymptomatic patients (95% CI, 35 to 45). Of these, 47% (95% CI, 39 to 54) were diagnosed after mastectomy, and 36% (95% CI, 28 to 43) were diagnosed after breast-conserving therapy (relative risk, 1.327; 95% CI, 1.014 to 1.738). Apart from differences in therapy, we have not been able to discern subgroups of patients for whom results were different.Approximately 40% of isolated locoregional recurrences are diagnosed during routine visits and routine tests in asymptomatic patients treated for early-stage invasive breast cancer. We could not assess whether these were detected by either physical examination or other tests, nor if the detection of asymptomatic isolated recurrences had any influence on potential for cure or quality of life. As the overall quality of the included studies and the overall incidence of isolated locoregional recurrences are low, this systematic review highlights the need for prospective comparative studies on cost-effective strategies for the follow-up of patients after a diagnosis of breast cancer.