tbuckley/cabot-search huggingface dataset:
Mimicry of a constitutively active pre–B cell receptor in acute lymphoblastic leukemia cells
Authors: Niklas Feldhahn, Florian Klein, Jana L. Mooster, Paul Hadweh, Mieke Sprangers, Maria Wartenberg, Mohamed M. Bekhite, Wolf-Karsten Hofmann, Sebastian Herzog, Hassan Jumaa, Janet D. Rowley, Markus Müschen
Journal: The Journal of Experimental Medicine (2005)

Pre–B cells undergo apoptosis unless they are rescued by pre–B cell receptor–dependent survival signals. We previously showed that the BCR-ABL1 kinase that is expressed in pre–B lymphoblastic leukemia bypasses selection for pre–B cell receptor–dependent survival signals. Investigating possible interference of BCR-ABL1 with pre–B cell receptor signaling, we found that neither SYK nor SLP65 can be phosphorylated in response to pre–B cell receptor engagement. Instead, Bruton's tyrosine kinase (BTK) is constitutively phosphorylated by BCR-ABL1. Activated BTK is essential for survival signals that otherwise would arise from the pre–B cell receptor, including activation of PLCγ1, autonomous Ca2+ signaling, STAT5-phosphorylation, and up-regulation of BCLXL. Inhibition of BTK activity specifically induces apoptosis in BCR-ABL1+ leukemia cells to a similar extent as inhibition of BCR-ABL1 kinase activity itself. However, BCR-ABL1 cannot directly bind to full-length BTK. Instead, BCR-ABL1 induces the expression of a truncated splice variant of BTK that acts as a linker between the two kinases. As opposed to full-length BTK, truncated BTK lacks kinase activity yet can bind to BCR-ABL1 through its SRC-homology domain 3. Acting as a linker, truncated BTK enables BCR-ABL1–dependent activation of full-length BTK, which initiates downstream survival signals and mimics a constitutively active pre–B cell receptor.
<i>AF4p12</i>, a Human Homologue to the <i>furry</i> Gene of <i>Drosophila</i>, as a Novel <i>MLL</i> Fusion Partner
Authors: Sandrine Hayette, Pascale Cornillet-Lefebvre, Isabelle Tigaud, Stéphanie Struski, Stéphanie Forissier, Adrien Berchet, Diane Doll, Lucile Gillot, Wajih Brahim, Eric Delabesse, Jean-Pierre Magaud, Ruth Rimokh
Journal: Cancer Research (2005)

Abstract More than 35 different partner genes with the mixed lineage leukemia (MLL) gene have been cloned from leukemia cells with translocations involving chromosome 11 band q23. In this study, we report on a novel fusion partner of the MLL gene, AF4p12, which we have identified as the human homologue to the furry gene of Drosophila. AF4p12, highly conserved in evolution, encodes a large protein of 3,105 amino acids. The expression of AF4p12 has been preferentially detected in colon, placenta, and brain tissues and in tumor cells of lymphoid origin. We show that the t(4;11)(p12;q23) translocation results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,362 amino acids from the NH2-terminal part of MLL and 712 amino acids from the COOH-terminal part of AF4p12. FLT3 and HOXA9 genes are overexpressed in this leukemia. We found that the COOH-terminal part of AF4p12 fused to MLL contains a leucine zipper motif and exhibits transcriptional activation properties when fused to Gal4 DNA-binding domains in transient transfection assays. The AF4p12 fragment fused to MLL may contribute to the oncogenic activation of MLL, possibly through specific recruitment of the transcriptional machinery.
A Phase I Biodistribution and Pharmacokinetic Trial of Humanized Monoclonal Antibody Hu3s193 in Patients with Advanced Epithelial Cancers that Express the Lewis-Y Antigen
Authors: Andrew M. Scott, Niall Tebbutt, Fook-Thean Lee, Tina Cavicchiolo, Zhanqi Liu, Sanjeev Gill, Aurora M.T. Poon, Wendie Hopkins, Fiona E. Smyth, Carmel Murone, Duncan MacGregor, Anthony T. Papenfuss, Bridget Chappell, Timothy H. Saunder, Martin W. Brechbiel, Ian D. Davis, Roger Murphy, Geoffrey Chong, Eric W. Hoffman, Lloyd J. Old
Journal: Clinical Cancer Research (2007)

Abstract Purpose: We report a first-in-man trial of a humanized antibody (hu3S193) against the Ley antigen. Experimental Design: Patients with advanced Ley-positive cancers received four infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20, and 40 mg/m2). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients. Results: A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1 non–small-cell lung cancer) were entered into the study. Transient grade 1 to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40mg/m2 dose level only. There was one episode of dose-limiting toxicity with self-limiting Common Toxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of 111In-hu3S193 showed no evidence of any consistent normal tissue uptake, and 111In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T1/2β = 189.63 ± 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed. Conclusion: Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Ley-expressing cancers.
Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding
Authors: Alberto Monescillo, Francisco Mart�nez-Lagares, Luis Ruiz-del-Arbol, Angel Sierra, Clemencia Guevara, Elena Jim�nez, Jos� Miguel Marrero, Enrique Buceta, Juan S�nchez, Ana Castellot, M�nica Pe�ate, Ana Cruz, Elena Pe�a
Journal: Hepatology (2004)

Increased portal pressure during variceal bleeding may have an influence on the treatment failure rate, as well as on short- and long-term survival. However, the usefulness of hepatic hemodynamic measurement during the acute episode has not been prospectively validated, and no information exists about the outcome of hemodynamically defined high-risk patients treated with early portal decompression. Hepatic venous pressure gradient (HVPG) measurement was made within the first 24 hours after admission of 116 consecutive patients with cirrhosis with acute variceal bleeding treated with a single session of sclerotherapy injection during urgent endoscopy. Sixty-four patients had an HVPG less than 20 mm Hg (low-risk [LR] group), and 52 patients had an HVPG greater than or equal to 20 mm Hg (high-risk [HR] group). HR patients were randomly allocated into those receiving transjugular intrahepatic portosystemic shunt (TIPS; HR-TIPS group, n = 26) within the first 24 hours after admission and those not receiving TIPS (HR-non-TIPS group). The HR-non-TIPS group had more treatment failures (50% vs. 12%, P =.0001), transfusional requirements (3.7 +/- 2.7 vs. 2.2 +/- 2.3, P =.002), need for intensive care (16% vs. 3%, P <.05), and worse actuarial probability of survival than the LR group. Early TIPS placement reduced treatment failure (12%, P =.003), in-hospital and 1-year mortality (11% and 31%, respectively; P <.05). In conclusion, increased portal pressure estimated by early HVPG measurement is a main determinant of treatment failure and survival in variceal bleeding, and early TIPS placement reduces treatment failure and mortality in high risk patients defined by hemodynamic criteria.
A renaissance of positive inotropic interventions to treat heart failure?
Authors: J Neumann
Journal: Cardiovascular Research (2003)

See article by Kogler et al. [1] (pages 582–592) in this issue. 

Heart failure has a high and increasing prevalence due to the aging population and the better survival rates in other heart diseases (e.g. acute myocardial infarction) in the Western world. Myocardial oxidative stress due to increased production of reactive oxygen free radicals may play an important role in the development and progression of heart failure.

In this issue of Cardiovascular Research , Kogler et al. [1] report on a positive inotropic effect of oxypurinol in a rat model of heart failure. Oxypurinol (plasma half life about 14 h) is the active metabolite of allopurinol (plasma half life about 40 min); both are xanthine oxidase (XO) inhibitors. XO forms free oxygen radicals as it catalyzes the degradation of purines like hypoxanthine and xanthine to uric acid. Increased plasma levels of uric acid lead to gout. Inhibition of XO activity reduces the plasma levels of uric acid as its precursors … 

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Effect of Pitavastatin on Urinary Liver-Type Fatty Acid–Binding Protein Levels in Patients With Early Diabetic Nephropathy
Authors: Tsukasa Nakamura, Takeshi Sugaya, Yasuhiro Kawagoe, Yoshihiko Ueda, Shiwori Osada, Hikaru Koide
Journal: Diabetes Care (2005)

OBJECTIVE—Liver-type fatty acid–binding protein (l-FABP) is expressed in renal proximal tubules and is reported to be a useful marker for progression of chronic glomerulonephritis. The aim of this study was to determine whether urinary l-FABP levels are altered at various stages of diabetic nephropathy and whether pitavastatin affects urinary l-FABP levels in early diabetic nephropathy. RESEARCH DESIGN AND METHODS—Fifty-eight patients with type 2 diabetes (34 men and 24 women, median age 52 years) and 20 healthy, age-matched subjects (group E) were recruited for the study. The diabetic patients included 12 patients without nephropathy (group A), 20 patients with microalbuminuria (group B), 14 patients with macroalbuminuria and normal renal function (group C), and 12 patients with chronic renal failure but not undergoing hemodialysis (blood creatinine &amp;gt;1.2 mg/dl; mean 2.5 mg/dl, group D). Twenty group B patients were randomly assigned to receive 1 mg/day pitavastatin (10 patients, group B1) or placebo (10 patients, group B2). Treatment was continued for 12 months. Urinary l-FABP levels were measured by enzyme-linked immunosorbent assay. Urinary 8-hydroxydeoxyguanosine and serum free fatty acids (FFAs) were also measured in group B. RESULTS—Urinary l-FABP levels in groups A-D were 6.2 ± 4.6 μg/g creatinine, 19.6 ± 13.5 μg/g creatinine, 26.8 ± 20.4 μg/g creatinine, and 52.4 ± 46.8 μg/g creatinine, respectively. Urinary l-FABP levels in groups B-D were significantly higher than those in healthy subjects (group E, 5.8 ± 4.0 μg/g creatinine) (group B, P &amp;lt; 0.05; group C, P &amp;lt; 0.01; group D, P &amp;lt; 0.01). In group B1, urinary albumin excretion (UAE) and urinary l-FABP levels were decreased after pitavastatin treatment (UAE before, 110 ± 74 μg/min; 6 months, 88 ± 60 μg/min, P &amp;lt; 0.05; 12 months, 58 ± 32 μg/min, P &amp;lt; 0.01; l-FABP before, 18.6 ± 12.5 μg/g creatinine; 6 months, 12.2 ± 8.8 μg/g creatinine, P &amp;lt; 0.05; 12 months, 8.8 ± 6.4 μg/g creatinine, P &amp;lt; 0.01). In group B2, UAE and l-FABP levels showed little change during the experimental period. In group B1, urinary 8-hydroxydeoxyguanosine was decreased 12 months after pitavastatin treatment (before 32.5 ± 19.5 ng/mg creatinine, after 18.8 ± 14.5 ng/mg creatinine, P &amp;lt; 0.01), but in group B2, these showed little difference during the experimental period. In both groups B1 and B2, serum FFAs showed little difference during the experimental period. CONCLUSIONS—Urinary l-FABP levels appear to be associated with the progression of diabetic nephropathy, and pitavastatin may be effective in ameliorating tubulointerstitial damage in early diabetic nephropathy.
Patient initiated outpatient follow up in rheumatoid arthritis: six year randomised controlled trial
Authors: Sarah Hewlett, John Kirwan, Jon Pollock, Kathryn Mitchell, Maggie Hehir, Peter S Blair, David Memel, Mark G Perry
Journal: BMJ (2004)

To determine whether direct access to hospital review initiated by patients with rheumatoid arthritis would result in improved clinical and psychological outcome, reduced overall use of healthcare resources, and greater satisfaction with care than seen in patients receiving regular review initiated by a rheumatologist.Two year randomised controlled trial extended to six years.Rheumatology outpatient department in teaching hospital.209 consecutive patients with rheumatoid arthritis for over two years; 68 (65%) in the direct access group and 52 (50%) in the control group completed the study (P = 0.04).pain, disease activity, early morning stiffness, inflammatory indices, disability, grip strength, range of movement in joints, and bone erosion. Psychological status: anxiety, depression, helplessness, self efficacy, satisfaction, and confidence in the system. Number of visits to hospital physician and general practitioner for arthritis.Participants were well matched at baseline. After six years there was only one significant difference between the two groups for the 14 clinical outcomes measured (deterioration in range of movement in elbow was less in direct access patients). There were no significant differences between groups for median change in psychological status. Satisfaction and confidence in the system were significantly higher in the direct access group at two, four, and six years: confidence 9.8 v 8.4, 9.4 v 8.0, 8.7 v 6.9; satisfaction 9.3 v 8.3, 9.3 v 7.7, 8.9 v 7.1 (all P < 0.02). Patients in the direct access group had 38% fewer hospital appointments (median 8 v 13, P < 0.0001).Over six years, patients with rheumatoid arthritis who initiated their reviews through direct access were clinically and psychologically at least as well as patients having traditional reviews initiated by a physician. They requested fewer appointments, found direct access more acceptable, and had more than a third fewer medical appointments. This radical responsive management could be tested in other chronic diseases.
Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events
Authors: Evangelos C. Rizos, Evangelia E. Ntzani, Eftychia Bika, Michael S. Kostapanos, Moses S. Elisaf
Journal: JAMA (2012)

Considerable controversy exists regarding the association of omega-3 polyunsaturated fatty acids (PUFAs) and major cardiovascular end points.To assess the role of omega-3 supplementation on major cardiovascular outcomes.MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through August 2012.Randomized clinical trials evaluating the effect of omega-3 on all-cause mortality, cardiac death, sudden death, myocardial infarction, and stroke.Descriptive and quantitative information was extracted; absolute and relative risk (RR) estimates were synthesized under a random-effects model. Heterogeneity was assessed using the Q statistic and I2. Subgroup analyses were performed for the presence of blinding, the prevention settings, and patients with implantable cardioverter-defibrillators, and meta-regression analyses were performed for the omega-3 dose. A statistical significance threshold of .0063 was assumed after adjustment for multiple comparisons.Of the 3635 citations retrieved, 20 studies of 68,680 patients were included, reporting 7044 deaths, 3993 cardiac deaths, 1150 sudden deaths, 1837 myocardial infarctions, and 1490 strokes. No statistically significant association was observed with all-cause mortality (RR, 0.96; 95% CI, 0.91 to 1.02; risk reduction [RD] -0.004, 95% CI, -0.01 to 0.02), cardiac death (RR, 0.91; 95% CI, 0.85 to 0.98; RD, -0.01; 95% CI, -0.02 to 0.00), sudden death (RR, 0.87; 95% CI, 0.75 to 1.01; RD, -0.003; 95% CI, -0.012 to 0.006), myocardial infarction (RR, 0.89; 95% CI, 0.76 to 1.04; RD, -0.002; 95% CI, -0.007 to 0.002), and stroke (RR, 1.05; 95% CI, 0.93 to 1.18; RD, 0.001; 95% CI, -0.002 to 0.004) when all supplement studies were considered.Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.
Exposure to parental and sibling smoking and the risk of smoking uptake in childhood and adolescence: a systematic review and meta-analysis
Authors: J. Leonardi-Bee, M. L. Jere, J. Britton
Journal: Thorax (2011)

<h3>Background</h3> There is increasing evidence that contact with other smokers, particularly in the family, is a strong determinant of risk of smoking uptake. A systematic review and meta-analysis of the magnitude of these effects is reported. <h3>Methods</h3> Studies were identified by searching four databases to March 2009 and proceedings from international conferences. Meta-analyses were performed using random effects, with results presented as pooled ORs with 95% CIs. <h3>Results</h3> 58 studies were included in the meta-analyses. The relative odds of uptake of smoking in children were increased significantly if at least one parent smoked (OR 1.72, 95% CI 1.59 to 1.86), more so by smoking by the mother (OR 2.19, 95% CI 1.73 to 2.79) than the father (OR 1.66, 95% CI 1.42 to 1.94), and if both parents smoked (OR 2.73, 95% CI 2.28 to 3.28). Smoking by a sibling increased the odds of smoking uptake by 2.30 (95% CI 1.85 to 2.86) and smoking by any household member by 1.92 (95% CI 1.70 to 2.16). After adjusting for overestimation of RRs it is estimated that, in England and Wales, around 17 000 young people take up smoking by the age of 15 each year as a consequence of exposure to household smoking. <h3>Conclusions</h3> Parental and sibling smoking is a strong and significant determinant of the risk of smoking uptake by children and young people and, as such, is a major and entirely avoidable health risk. Children should be protected from exposure to smoking behaviour, especially by family members.
Phosphoinositide-dependent kinase 1 targets protein kinase A in a pathway that regulates interleukin 4
Authors: Ajay Nirula, Mary Ho, Hyewon Phee, Jeroen Roose, Arthur Weiss
Journal: The Journal of Experimental Medicine (2006)

CD28 plays a critical role in T cell immune responses. Although the kinase Akt has been shown to act downstream of CD28 in T helper (Th)1 cytokine induction, it does not induce Th2 cytokines such as interleukin 4 (IL-4). We recently reported that phosphoinositide-dependent kinase 1 (PDK1) partially corrects the defect in IL-4 production present in CD28-deficient T cells, suggesting that PDK1 regulates IL-4 independently of Akt. We now describe a signaling pathway in which PDK1 targets IL-4 in the murine Th2 cell line D10. PDK1-mediated activation of this pathway is dependent on protein kinase A (PKA) and the nuclear factor of activated T cells (NFAT) P1 transcriptional element in the IL-4 promoter. PDK1 localizes to the immune synapse in a phosphatidylinositol 3-kinase–dependent manner, partially colocalizes with PKA at the synapse, and physically interacts with PKA. In RNA interference knockdown experiments, PDK1 is necessary for phosphorylation of PKA in T cells, as well as for activation of the IL-4 NFAT P1 element by the T cell receptor (TCR) and CD28. Phosphorylation of the critical PKA threonine residue is stimulated by engagement of TCR/CD28 via a PDK1-dependent mechanism. These findings together define a pathway linking the kinases PDK1 and PKA in the induction of the Th2 cytokine IL-4.
DERMIS: a computer system for assisting primary-care physicians with dermatological diagnosis
Authors: G.J. BROOKS, R.E. ASHTON, R.J. PETHYBRIDGE
Journal: British Journal of Dermatology (1992)

DERMIS is a computerized skin disease diagnostic prompting system which has been derived from the prospective study of 5203 cases. It has been designed for use by non-dermatologists such as general practitioners. The program produces a list of reasonable diagnoses based on probabilities calculated using Bayes' theorem. Out of 221 precise diagnoses made by the dermatologist in the clinic, 42 groupings were created to encompass the most common or important diseases encountered in general practice. Four 'remainder' or 'send to specialist' groups were included for the 13% of uncommon conditions. The program, when tested by 'one out' analysis on the original cases, placed the correct diagnosis first on 76% of occasions, and within the first three on 95% of occasions. In 76 of 125 cases randomly selected from the data base, a request for diagnostic assistance had been made by the referring general practitioner. It has been estimated that in 54 of these 76 cases the DERMIS system could have provided differential advice with the correct diagnosis appearing at the top of the list. The system has been written in MUMPS and runs on an IBM-compatible desk-top computer. The software allows real time data entry. Arrangements are in hand for performing clinical trials of the system in general practice. If current performance is maintained, and the response to the system's output is favourable, then DERMIS might well enhance performance in medical decision making for the benefit of patients, medical services and budget holders.
Revisiting Li-Fraumeni Syndrome From <i>TP53</i> Mutation Carriers
Authors: Gaëlle Bougeard, Mariette Renaux-Petel, Jean-Michel Flaman, Camille Charbonnier, Pierre Fermey, Muriel Belotti, Marion Gauthier-Villars, Dominique Stoppa-Lyonnet, Emilie Consolino, Laurence Brugières, Olivier Caron, Patrick R. Benusiglio, Brigitte Bressac-de Paillerets, Valérie Bonadona, Catherine Bonaïti-Pellié, Julie Tinat, Stéphanie Baert-Desurmont, Thierry Frebourg
Journal: Journal of Clinical Oncology (2015)

The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity.From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation.The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations.The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.