tbuckley/cabot-search huggingface dataset:
Expression of Ligand-Activated KIT and Platelet-Derived Growth Factor Receptor β Tyrosine Kinase Receptors in Synovial Sarcoma
Authors: Elena Tamborini, Lorena Bonadiman, Angela Greco, Alessandro Gronchi, Carla Riva, Rossella Bertulli, Paolo G. Casali, Marco A. Pierotti, Silvana Pilotti
Journal: Clinical Cancer Research (2004)

The use of tyrosine kinase receptor inhibitors is increasingly becoming a valuable therapeutic alternative in tumors carrying activated tyrosine kinase receptors. In a previous study, we described a coexpression of KIT and stem cell factor (SCF) mRNA in Synovial sarcomas, (SS) and in a limited number of cases, we demonstrated the presence of an activated receptor. Here, in a wider number of cases, we investigated the expression level and phosphorylation status of two structurally related tyrosine kinase receptors, KIT and platelet-derived growth factor receptor beta (PDGFRbeta), at the light of their role as possible targets of tyrosine kinase receptors inhibitor molecules.Forty-three SS cases were analyzed for KIT and PDGFRbeta expression/activation by immunoprecipitation/Western blotting experiments. The cognate ligands, SCF and PDGFB, were detected by reverse transcription-PCR.KIT was observed in 48 and 41% (45% total) whereas PDGFRbeta in 54 and 33% (45% total) of monophasic and biphasic SS cases, respectively. With respect to the fusion transcript type SYTSSX1 and SYTSSX2, KIT was more expressed in SYTSSX1 carrying cases (48 versus 38%), whereas PDGFRbeta resulted more frequently expressed in SYTSSX2 ones (54 versus 37%). When expressed, the receptors were phosphorylated. Their ligands were detected in all of the activated cases.About 70% of the cases express one of the two activated tyrosine kinase receptors with a mutually exclusive expression trend. Coexpression is not frequent and seems to be restricted to monophasic subtype. These data indicate that a consistent fraction of this tumor type could represent a good candidate for kinase inhibitor molecules effective on KIT and PDGFRbeta where their activation is sustained by an autocrine loop.
Evidence for a shared HLA-A intralocus determinant defined by monoclonal antibody 131.
Authors: B T Spear, J Kornbluth, J L Strominger, D B Wilson
Journal: The Journal of Experimental Medicine (1985)

We describe here a monoclonal antibody, 131, which appears to recognize a determinant shared by HLA-A locus-encoded gene products. Isoelectric focusing analysis demonstrates that 131 reacts with the products of at least seven different HLA-A alleles but none of the five HLA-B allelic products tested. Together with evidence provided by other studies, this finding indicates the existence of A-unique and B-unique determinants, which may have different biological functions. Monoclonal antibody probes, such as the one described here, specific for shared intralocus determinants, may be valuable for assessing these possible functional differences.
Reproducibility and inter-reader agreement of a scoring system for ultrasound evaluation of hip osteoarthritis
Authors: E Qvistgaard, S Torp-Pedersen, R Christensen, H Bliddal
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To evaluate the intra-reader and inter-reader agreements of ultrasonographic assessments of hip joints in patients with hip osteoarthritis. <b>Design:</b> Ultrasonography was performed on 100 patients with hip osteoarthritis at 14 MHz using a 8–15 MHz linear probe. Dynamic sweeps of the hip and representative still images were used for the analysis. A semiquantitative grading score was introduced in the evaluation of the ultrasound pictures and compared with an overall ultrasound evaluation. The evaluation was performed by a specialist in ultrasonography and a rheumatologist trained in musculoskeletal ultrasound examination. Clinical pain assessment and joint aspiration were obtained in parallel with the ultrasonography. <b>Results:</b> Intraobserver agreement represented by intraclass correlation coefficients (ICC) (exact agreement in percentage; unweighted κ values) showed good to excellent correlation, 0.8 with regard to the osteophyte score, 0.78 with regard to the femoral head score, 0.71 with regard to the fluid score and 0.69 with regard to the synovial profile score. Interobserver agreement was fair to good with corresponding ICC 0.65, 0.63, 0.45 and 0.6, respectively. In comparison, the ICC for the global osteoarthritis and synovial assessments were 0.7 and 0.72, respectively, for the intraobserver rating and 0.56 and 0.58, respectively, for the interobserver rating. <b>Conclusions:</b> This study suggests that ultrasound is a reproducible method for the assessment of changes in the osseous surface and synovium-related inflammation. The semiquantitative scoring system presented seemed to match the global assessment of a trained ultrasound investigator and might be used by less-trained investigators.
Prevalence and Costs of Major Depression Among Elderly Claimants With Diabetes
Authors: Eric A. Finkelstein, Jeremy W. Bray, Hong Chen, Mary Jo Larson, Kay Miller, Christopher Tompkins, Allen Keme, Ronald Manderscheid
Journal: Diabetes Care (2003)

OBJECTIVE—To compare the odds of major depression among Medicare claimants with and without diabetes and to test whether annual medical payments are greater for those with both diabetes and major depression than for those with diabetes alone. RESEARCH DESIGN AND METHODS—This retrospective analysis relies on claims data from the 1997 Medicare 5% Standard Analytic Files. Using these data, we statistically determined whether the odds of major depression are greater among elderly claimants with diabetes after controlling for age, race/ethnicity, and sex. We then used regression analysis on a sample of over 220,000 elderly claimants with diabetes to test whether payments for non-mental health-related services are greater for those with both diabetes and major depression (n = 4,203) than for those with diabetes alone. RESULTS—Our findings indicate that the odds of major depression are significantly greater among elderly Medicare claimants with diabetes than among those without diabetes (OR 1.58 ± 0.05). We also found that elderly claimants with both diabetes and major depression seek treatment for more services and spend more time in inpatient facilities, and as a result incur higher medical costs than claimants with diabetes but without major depression. These results hold even after excluding services related to mental health treatment. CONCLUSIONS—This analysis suggests that treatment for major depression among claimants with diabetes may reduce total medical costs if treatment results in a decrease in utilization for general medical services in the future.
Occurrence of Chlamydia trachomatis and Chlamydia pneumoniae in paediatric respiratory infections
Authors: W. C. Webley, Y. Tilahun, K. Lay, K. Patel, E. S. Stuart, C. Andrzejewski, P. S. Salva
Journal: European Respiratory Journal (2008)

An emerging body of evidence suggests that half of asthma in both children and adults is associated with chronic lung infection. The aim of the present study was to determine the frequency of viable Chlamydia pneumoniae (Cp) and C. trachomatis (Ct) in the respiratory tracts of paediatric patients with chronic respiratory diseases. Bronchoalveolar lavage fluid (BALF) samples obtained from 182 children undergoing bronchoscopy for clinical reasons were assayed using PCR analysis, in vitro tissue culture and immunofluorescence staining for the presence of Cp and Ct. Chlamydia-specific DNA was detected by PCR in 124 (68%) out of 182 patients; 79 were positive for Cp, 77 positive for Ct and 32 for both organisms; 75 patients had cultivable Chlamydia. Ct DNA prevalence decreased, whereas Cp positivity generally increased with age. A total of 59 out of 128 asthma patients and 16 out of 54 nonasthmatics were Chlamydia culture positive. When the patients were divided into inflammatory versus noninflammatory airway disease, there were 69 (46%) out of 150 and six (18%) out of 32 BALF samples with cultivable Chlamydia, respectively. Viable Chlamydia pneumoniae and Chlamydia trachomatis occur frequently in children with chronic respiratory diseases and may be more prevalent in asthma patients. To the current authors' knowledge, this is the first report of viable Chlamydia trachomatis in the lungs of children.
Homeobox gene expression in acute myeloid leukemia is linked to typical underlying molecular aberrations
Authors: Karolina Skvarova Kramarzova, Karel Fiser, Ester Mejstrikova, Katerina Rejlova, Marketa Zaliova, Maarten Fornerod, Harry A Drabkin, Marry M van den Heuvel-Eibrink, Jan Stary, Jan Trka, Julia Starkova
Journal: Journal of Hematology & Oncology (2014)

Although distinct patterns of homeobox (HOX) gene expression have been described in defined cytogenetic and molecular subsets of patients with acute myeloid leukemia (AML), it is unknown whether these patterns are the direct result of transcriptional alterations or rather represent the differentiation stage of the leukemic cell.To address this question, we used qPCR to analyze mRNA expression of HOXA and HOXB genes in bone marrow (BM) samples of 46 patients with AML and sorted subpopulations of healthy BM cells. These various stages of myeloid differentiation represent matched counterparts of morphological subgroups of AML. To further study the transcriptional alterations of HOX genes in hematopoiesis, we also analyzed gene expression of epigenetic modifiers in the subpopluations of healthy BM and leukemic cells.Unsupervised hierarchical clustering divided the AMLs into five clusters characterized by the presence of prevalent molecular genetic aberrations. Notably, the impact of genotype on HOX gene expression was significantly more pronounced than that of the differentiation stage of the blasts. This driving role of molecular aberrations was best exemplified by the repressive effect of the PML-RARa fusion gene on HOX gene expression, regardless of the presence of the FLT3/ITD mutation. Furthermore, HOX gene expression was positively correlated with mRNA levels of histone demethylases (JMJD3 and UTX) and negatively correlated with gene expression of DNA methyltranferases. No such relationships were observed in subpopulations of healthy BM cells.Our results demonstrate that specific molecular genetic aberrations, rather than differentiation per se, underlie the observed differences in HOX gene expression in AML. Moreover, the observed correlations between epigenetic modifiers and HOX expression that are specific to malignant hematopoiesis, suggest their potential causal relationships.
Role of ETS Transcription Factors in the Hypoxia-Inducible Factor-2 Target Gene Selection
Authors: Olga Aprelikova, Matthew Wood, Sean Tackett, Gadisetti V.R. Chandramouli, J. Carl Barrett
Journal: Cancer Research (2006)

Abstract Tumor hypoxia often directly correlates with aggressive phenotype, metastasis progression, and resistance to chemotherapy. Two transcription factors [hypoxia-inducible factor-1α (HIF-1α) and HIF-2α] are dramatically induced in hypoxic areas and regulate the expression of genes necessary for tumor adaptation to the conditions of low oxygen; however, the relative contribution of these factors is controversial. We used RNA interference–mediated inactivation of HIF-1α or HIF-2α followed by microarray analysis to identify genes specifically regulated by either HIF-1 or HIF-2 in hypoxia. We found that, in the MCF7 cell line, the vast majority of hypoxia-responsive genes (&amp;gt;80%) were dependent on the presence of HIF-1α. However, a small group of genes were preferentially regulated by HIF-2α. Promoter analysis for this group of genes revealed that all of them have putative binding sites for ETS family transcription factors, and 10 of 11 HIF-2α-dependent genes had at least one potential hypoxia-responsive element (HRE) in proximity to an ETS transcription factor binding site. Knockdown of ELK-1, the most often represented member of ETS family, significantly reduced hypoxic induction of the HIF-2α-dependent genes. Physical and functional interaction between ELK-1 and HIF-2α were supported by coimmunoprecipitation of these two proteins, luciferase reporter assay using CITED2 promoter, and binding of ELK-1 protein to the promoters of CITED2 and WISP2 genes in proximity to a HRE. These data suggest that the choice of the target genes by HIF-1 or HIF-2 depends on availability and cooperation of HIFs with other factors recognizing their cognate elements in the promoters. (Cancer Res 2006; 66(11): 5641-7)
Persistent clinical efficacy and safety of anti-tumour necrosis factor therapy with infliximab in patients with ankylosing spondylitis over 5 years: evidence for different types of response
Authors: J Braun, X Baraliakos, J Listing, C Fritz, R Alten, G Burmester, A Krause, S Schewe, M Schneider, H Sorensen, H Zeidler, J Sieper
Journal: Annals of the Rheumatic Diseases (2007)

There is insufficient evidence for the long-term efficacy and safety of anti-tumour necrosis factor therapy in patients with ankylosing spondylitis (AS). This is the first report on the treatment with infliximab over 5 years.As part of a multicentre randomised trial, 69 patients with active AS at baseline (BL) have been continuously treated with infliximab (5 mg/kg i.v. every 6 weeks)--except for a short discontinuation after 3 years (FU1). The primary outcome of this extension was remission according to the ASsessment in Ankylosing Spondylitis (ASAS) criteria at the end of year 5 of the study (FU2).Of the 43 patients who completed year 3, 42 agreed to continue, 38 of which (90.5%) finished year 5 (55% of 69 initially). Partial clinical remission was achieved in 13 of 38 patients (34.2%) at FU1 and FU2. At FU2, the mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was 2.5+/-1.9 (BL:6.4, FU1:2.5). BASDAI values <4 were seen in 79% of patients at both, FU1 and FU2. ASAS 20% and 40% responses were seen in 32 (84%) and 24 (63%) patients at FU2, respectively. Most patients classified as non-responders at FU2 were part-time responders, as all but one patient achieved an ASAS 20% response at least once within the last 2 years. Three types of responders were identified. No major side effects occurred during years 4 and 5 of infliximab therapy.Infliximab is safe and efficacious in AS patients over 5 years. The majority of the patients remained on treatment and had rather persistent levels of low disease activity. Different response types could be identified.
Antigen-Specific B Cell Memory
Authors: Louise J. McHeyzer-Williams, Melinda Cool, Michael G. McHeyzer-Williams
Journal: The Journal of Experimental Medicine (2000)

The mechanisms that regulate B cell memory and the rapid recall response to antigen remain poorly defined. This study focuses on the rapid expression of B cell memory upon antigen recall in vivo, and the replenishment of quiescent B cell memory that follows. Based on expression of CD138 and B220, we reveal a unique and major subtype of antigen-specific memory B cells (B220−CD138−) that are distinct from antibody-secreting B cells (B220+/−CD138+) and B220+CD138− memory B cells. These nonsecreting somatically mutated B220− memory responders rapidly dominate the splenic response and comprise &amp;gt;95% of antigen-specific memory B cells that migrate to the bone marrow. By day 42 after recall, the predominant quiescent memory B cell population in the spleen (75–85%) and the bone marrow (&amp;gt;95%) expresses the B220− phenotype. Upon adoptive transfer, B220− memory B cells proliferate to a lesser degree but produce greater amounts of antibody than their B220+ counterparts. The pattern of cellular differentiation after transfer indicates that B220− memory B cells act as stable self-replenishing intermediates that arise from B220+ memory B cells and produce antibody-secreting cells on rechallenge with antigen. Cell surface phenotype and Ig isotype expression divide the B220− compartment into two main subsets with distinct patterns of integrin and coreceptor expression. Thus, we identify new cellular components of B cell memory and propose a model for long-term protective immunity that is regulated by a complex balance of committed memory B cells with subspecialized immune function.
Suppression of Amylase Activity by Hypertriglyceridemia
Authors: Ronald W. Fallat
Journal: JAMA (1973)

Patients with clinical acute pancreatitis or abdominal crises possibly indicating surgery, accompanied by lactescent plasma and "normal" serum amylase values, pose a therapeutic dilemma of medical supportive therapy vs prompt surgical intervention. Plasma triglyceride levels in the 500 to 6,000 mg/100 ml range (with grossly turbid plasma) interfere in vitro with determination of amylase activity. In three patients with clinical pancreatitis (normal undiluted serum amylase levels) and lactescent plasma with type V hyperlipoproteinemia, serum amylase level was shown to be elevated after correction for dilution. Serial dilutions of serum with saline solution allow correction to "actual" amylase in hyperlipemic serum, apparently by reducing in vitro interference caused by elevated triglyceride levels.
Evolution of Siglec-11 and Siglec-16 Genes in Hominins
Authors: Xiaoxia Wang, Nivedita Mitra, Pedro Cruz, Liwen Deng, Nissi Varki, Takashi Angata, Eric D. Green, Jim Mullikin, Toshiyuki Hayakawa, Ajit Varki
Journal: Molecular Biology and Evolution (2012)

We previously reported a human-specific gene conversion of SIGLEC11 by an adjacent paralogous pseudogene (SIGLEC16P), generating a uniquely human form of the Siglec-11 protein, which is expressed in the human brain. Here, we show that Siglec-11 is expressed exclusively in microglia in all human brains studied—a finding of potential relevance to brain evolution, as microglia modulate neuronal survival, and Siglec-11 recruits SHP-1, a tyrosine phosphatase that modulates microglial biology. Following the recent finding of a functional SIGLEC16 allele in human populations, further analysis of the human SIGLEC11 and SIGLEC16/P sequences revealed an unusual series of gene conversion events between two loci. Two tandem and likely simultaneous gene conversions occurred from SIGLEC16P to SIGLEC11 with a potentially deleterious intervening short segment happening to be excluded. One of the conversion events also changed the 5′ untranslated sequence, altering predicted transcription factor binding sites. Both of the gene conversions have been dated to ∼1–1.2 Ma, after the emergence of the genus Homo, but prior to the emergence of the common ancestor of Denisovans and modern humans about 800,000 years ago, thus suggesting involvement in later stages of hominin brain evolution. In keeping with this, recombinant soluble Siglec-11 binds ligands in the human brain. We also address a second-round more recent gene conversion from SIGLEC11 to SIGLEC16, with the latter showing an allele frequency of ∼0.1–0.3 in a worldwide population study. Initial pseudogenization of SIGLEC16 was estimated to occur at least 3 Ma, which thus preceded the gene conversion of SIGLEC11 by SIGLEC16P. As gene conversion usually disrupts the converted gene, the fact that ORFs of hSIGLEC11 and hSIGLEC16 have been maintained after an unusual series of very complex gene conversion events suggests that these events may have been subject to hominin-specific selection forces.
Cultures of Diabetic Foot Ulcers Without Clinical Signs of Infection Do Not Predict Outcomes
Authors: Sue E. Gardner, Ambar Haleem, Ying-Ling Jao, Stephen L. Hillis, John E. Femino, Phinit Phisitkul, Kristopher P. Heilmann, Shannon M. Lehman, Carrie L. Franciscus
Journal: Diabetes Care (2014)

OBJECTIVE We examined associations between ulcer bioburden and ulcer outcomes in neuropathic diabetic foot ulcers (DFUs) that lacked clinical signs of infection. RESEARCH DESIGN AND METHODS Three dimensions of bioburden (i.e., microbial load, microbial diversity, and the presence of likely pathogens) were measured at baseline using swab cultures obtained by Levine’s technique. Subjects were assessed every 2 weeks for 26 weeks to determine the rate of healing and development of infection-related complications. Foot ulcers were off-loaded using total-contact casts and routinely debrided. To establish associations between bioburden and rate of healing, Cox proportional hazards and least squares regression were used after adjusting for ulcer depth, surface area, and duration. RESULTS A total of 77 subjects completed the study. Sixty-five (84.4%) had ulcers that healed during follow-up; weeks-to-closure ranged from 2 to 26 (median 4.0). Mean (± SD) percent reduction in surface area/week was 25.0% (± 23.33). Five (6.5%) of the DFUs developed an infection-related complication. None of the bioburden dimensions (i.e., microbial load, microbial diversity, or presence of likely pathogens) was significantly associated with weeks-to-closure or percent reduction in surface area per week. Weeks-to-closure was best predicted by ulcer duration, depth, and surface area (c-statistic = 0.75). CONCLUSIONS Culturing DFUs that showed no clinical signs of infection had no predictive value for outcomes of DFUs managed with total-contact casts and routine debridement. These findings support recommendations of the Infectious Disease Society of America that culturing and antibiotics should be avoided in treating DFUs that show no clinical signs of infection.
Quirks of Human Anatomy: An Evo-Devo Look at the Human Body
Authors: James M. Williams
Journal: JAMA (2010)

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