tbuckley/cabot-search huggingface dataset:
Adaptive Clinical Trial Design
Authors: Shein-Chung Chow
Journal: Annual Review of Medicine (2014)

In recent years, the use of adaptive design methods in clinical trials based on accumulated data at interim has received much attention because of its flexibility and efficiency in pharmaceutical/clinical development. In practice, adaptive design may provide the investigators a second chance to modify or redesign the trial while the study is still ongoing. However, it is a concern that a shift in target patient population may occur after significant adaptations are made. In addition, the overall type I error rate may not be preserved. Moreover, the results may not be reliable and hence are difficult to interpret. As indicated by the US Food and Drug Administration draft guidance on adaptive design clinical trials, the adaptive design has to be a prospectively planned opportunity and should be based on information collected within the study, with or without formal statistical hypothesis testing. This article reviews the relative advantages, limitations, and feasibility of commonly considered adaptive designs in clinical trials. Statistical concerns when implementing adaptive designs are also discussed.
Relative acidic compartment volume as a lysosomal storage disorder–associated biomarker
Authors: Danielle te Vruchte, Anneliese O. Speak, Kerri L. Wallom, Nada Al Eisa, David A. Smith, Christian J. Hendriksz, Louise Simmons, Robin H. Lachmann, Alison Cousins, Ralf Hartung, Eugen Mengel, Heiko Runz, Michael Beck, Yasmina Amraoui, Jackie Imrie, Elizabeth Jacklin, Kate Riddick, Nicole M. Yanjanin, Christopher A. Wassif, Arndt Rolfs, Florian Rimmele, Naomi Wright, Clare Taylor, Uma Ramaswami, Timothy M. Cox, Caroline Hastings, Xuntian Jiang, Rohini Sidhu, Daniel S. Ory, Begona Arias, Mylvaganam Jeyakumar, Daniel J. Sillence, James E. Wraith, Forbes D. Porter, Mario Cortina-Borja, Frances M. Platt
Journal: Journal of Clinical Investigation (2014)

Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.
ANTAGONISTIC EFFECTS OF HUMORAL ISOANTIBODIES ON THE IN VITRO CYTOTOXICITY OF IMMUNE LYMPHOID CELLS
Authors: Erna Möller
Journal: The Journal of Experimental Medicine (1965)

The ability of specifically immunized lymphoid cells to kill H-2 incompatible target tumor cells in tissue culture was shown to depend on the source of the lymphoid tissue (spleen versus lymph nodes). Marked cytotoxic effects were obtained with regional lymph node cells 7 to 10 days after primary immunization, whereas spleen cells from the same animals had little or no effect. Hyperimmunization did not decrease the cytotoxic efficiency of lymph node cells. Experiments were performed to test the possibility that the weak effect of spleen cells is a result of humoral antibody production, antagonizing the cell-bound immunity. Humoral antibodies were cytotoxic in vitro in the presence of complement only. Their effect was manifested after 2 hours, whereas immune lymph node cells did not require complement and cytotoxicity was not expressed until 24 to 48 hours' incubation. Tumor cell cultures treated with specific humoral antibodies in the absence of complement became resistant to the cytotoxic effect of subsequently added immune lymph node cells, while no such protection was seen when normal serum was added. Thus, humoral antibodies led to an "efferent" inhibition of cell-bound immunity in vitro, in analogy with previous results in vivo.
Differential Regulation of TCR-mediated Gene Transcription by Vav Family Members
Authors: Shaheen Zakaria, Timothy S. Gomez, Doris N. Savoy, Simon McAdam, Martin Turner, Robert T. Abraham, Daniel D. Billadeau
Journal: The Journal of Experimental Medicine (2004)

Although all three Vav family members are expressed in T lymphocytes, the role that Vav3 plays in T cell activation is poorly defined. Here we show that, like Vav1, Vav3 undergoes rapid tyrosine phosphorylation after T cell receptor (TCR) cross-linkage and interacts with the adaptor molecules SLP76 and 3BP2 in a SH2-dependent manner. However, depletion of Vav1 but not Vav3 protein by RNA interference affects TCR-mediated IL-2 promoter activity. In contrast, Vav3 function is specifically required for coupling TCR stimulation to serum response element–mediated gene transcription. These data indicate that, although both Vav proteins are biochemically coupled to the TCR, they regulate distinct molecular pathways leading to defined gene transcriptional events.
Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin
Authors: Graeme M. Birdsey, Nicola H. Dryden, Valerie Amsellem, Frank Gebhardt, Kapil Sahnan, Dorian O. Haskard, Elisabetta Dejana, Justin C. Mason, Anna M. Randi
Journal: Blood (2008)
Evolutionary adaptation to different thermal environments via transcriptional regulation.
Authors: D L Crawford, D A Powers
Journal: Molecular Biology and Evolution (1992)

Populations of the teleost fish Fundulus heteroclitus are subjected to the clinical variation in environmental temperatures that occurs along the eastern seacoast of North America. In concordance with this change in temperature is the clinal variation in the enzyme concentration of the heart-type lactate dehydrogenase (LDH-B; E.C.1.1.1.27). Previously we have shown that the compensating change in the LDH-B enzyme concentration is due to a change in the amount of LDH-B mRNA, but we did not define whether this was due to differences in mRNA stability or to differences in rate of transcription. The results presented here help clarify the molecular mechanism responsible for the variation in Ldh-B gene expression: the rate of transcription from the Ldh-B locus is significantly different between populations, and this difference is responsible for the compensatory change in LDH-B enzyme concentration.
High Expression Levels of the <i>ETS</i>-Related Gene, <i>ERG</i>, Predict Adverse Outcome and Improve Molecular Risk-Based Classification of Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
Authors: Guido Marcucci, Kati Maharry, Susan P. Whitman, Tamara Vukosavljevic, Peter Paschka, Christian Langer, Krzysztof Mrózek, Claudia D. Baldus, Andrew J. Carroll, Bayard L. Powell, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield
Journal: Journal of Clinical Oncology (2007)

To validate ERG overexpression as an adverse predictor and assess its prognostic value in the context of other molecular markers in cytogenetically normal (CN) -acute myeloid leukemia (AML).Seventy-six adult patients with primary CN-AML, younger than 60 years and treated on Cancer and Leukemia Group B (CALGB) trial 19808, were evaluated for ERG expression by quantitative reverse transcriptase polymerase chain reaction. They were then combined with 72 patients enrolled onto CALGB 9621 for analyses that included other molecular markers.Similar to patients enrolled onto CALGB 9621, high ERG expressers on CALGB 19808 had fewer complete remissions (CRs; P = .03) and worse event-free survival (EFS; P = .016) than low ERG expressers. In the combined set, high expressers (n = 55) had fewer CRs (P = .004) and shorter EFS (P < .001) than low expressers (n = 93). High ERG predicted failure to achieve CR (P = .004) after adjusting for BAALC expression (P = .04) and age (P = .008), and EFS (P = .004) after adjusting for FLT3 internal tandem duplication (ITD; P < .001). Among patients without FLT3-ITD (FLT3-ITD negative), only high ERG predicted shorter EFS (P = .001). Among NPM1-mutated (NPM1 positive) patients, high ERG predicted shorter EFS (P = .003), after adjusting for FLT3-ITD (P < .001). When all three markers were considered together, in the favorable FLT3-ITD-negative/NPM1-positive subset, high ERG was the only factor predicting shorter EFS (P = .002).We validated ERG overexpression as an adverse predictor in CN-AML. Moreover, by using ERG expression levels, we improved the previously proposed molecular-risk classification of CN-AML based on the presence or absence of FLT3-ITD and NPM1 mutations, given that we identified subsets with different outcome among FLT3-ITD-negative, NPM1-positive, and FLT3-ITD-negative/NPM1-positive patients.
Evaluation of the WIDER I system for antimicrobial susceptibility testing of clinical isolates of Haemophilus influenzae and Streptococcus pneumoniae
Authors: F. FernÁAndez-Cuenca, L. Martínez-Martínez, A. Pascual, M. De Cueto, O. Gutiérrez, J. Nieto, E.J. Perea
Journal: Clinical Microbiology and Infection (2003)
Multicenter study of lipoprotein(a) and apolipoprotein(a) phenotypes in patients with end-stage renal disease treated by hemodialysis or continuous ambulatory peritoneal dialysis.
Authors: F Kronenberg, P König, U Neyer, M Auinger, A Pribasnig, U Lang, J Reitinger, G Pinter, G Utermann, H Dieplinger
Journal: Journal of the American Society of Nephrology (1995)

Numerous studies have investigated lipoprotein(a) (Lp(a)) plasma concentrations in patients with ESRD, a patient group with an enormous risk for atherosclerosis. The reported differences in Lp(a) between controls and patients vary from a decrease of 49% to an increase of more than 1,000%. However, data are not consistent, mostly because of problems with statistical analysis, and only limited data are available for patients treated by continuous ambulatory peritoneal dialysis (CAPD). To estimate the significance of Lp(a) in ESRD and to demonstrate the statistical pitfalls concerning Lp(a) in case-control studies, a large multicenter study including 702 patients treated by either hemodialysis (HD) (N = 534) or CAPD (N = 168) was conducted, and results were compared with results from 256 healthy controls. Both patient groups showed significantly elevated Lp(a) levels in comparison with controls: 23.4 +/- 25.0 mg/dL (P < 0.005; HD) and 34.6 +/- 38.4 mg/dL (P < 0.0001; CAPD) versus 18.4 +/- 22.8 mg/dL (controls). CAPD patients showed significantly higher Lp(a) values than did patients treated by HD (P < 0.001). The difference between the two treatment groups possibly reflects an overproduction of Lp(a) to compensate for protein losses in CAPD patients. Both treatment groups included significantly more patients with Lp(a) values greater than the 75th percentile (25.6 mg/dL) of the control group (33.9 and 41.7% for HD and CAPD, respectively; P < 0.005). The higher Lp(a) values in patients were not explained by differences in isoform frequencies and the increase in Lp(a) was apolipoprotein(a) type specific: only patients with high-molecular-weight apolipoprotein(a) isoforms showed a significant elevation in Lp(a) levels. The increased plasma concentrations of Lp(a) may contribute to the high risk for atherosclerosis in ESRD, especially in patients treated by CAPD. Finally, it is believed that small sample sizes are responsible for the diverging results in Lp(a) literature.
MAGNETIC RESONANCE IMAGING ASSESSMENT OF MYOCARDIAL INFLAMMATION IN 132 CONSECUTIVE PATIENTS WITH CLINICAL SUSPICION OF ACUTE OR CHRONIC MYOCARDITIS: ARE WE AS GOOD AS WE THOUGHT?
Authors: Philipp Lurz, Julia Murawski, Julia Steiner, Mahdi Sareban, Ingo Eitel, Steffen Desch, Georg Fuernau, Suzanne de Waha, Matthias Grothoff, Gerhard Schuler, Matthias Gutberlet, Holger Thiele
Journal: Journal of the American College of Cardiology (2011)
BTS guidelines for the management of pleural infection * Authors' reply
Authors: C W H Davies, F V Gleeson, R J O Davies
Journal: Thorax (2004)

We have read the BTS guidelines for the management of pleural infection1 and are concerned about the proposed antibiotic choices for the initial treatment of culture negative or pending pleural infection. Section 2.8 of the text and table 2 detail the antibiotic choices but, in our opinion, leave considerable gaps in antibacterial cover against the likely pathogens. In particular:
Efficacy and Toxicity of Crizotinib for Patients with ALK-Positive Advanced NSCLC
Authors: T. Asao, Y. Honma, K. Suina, K. Muraki, T. Shukuya, R. Ohashi, R. Koyama, N. Shimada, S. Sakuraba, K. Takahashi
Journal: Annals of Oncology (2013)
In Inland China, Rice, Rather than Fish, Is the Major Pathway for Methylmercury Exposure
Authors: Hua Zhang, Xinbin Feng, Thorjørn Larssen, Guangle Qiu, Rolf D. Vogt
Journal: Environmental Health Perspectives (2010)

Fish consumption is considered the primary pathway of methylmercury (MeHg) exposure for most people in the world. However, in the inland regions of China, most of the residents eat little fish, but they live in areas where a significant amount of mercury (Hg) is present in the environment.We assessed concentrations of total Hg and MeHg in samples of water, air, agricultural products, and other exposure media to determine the main exposure pathway of Hg in populations in inland China.We selected Guizhou Province for our study because it is highly contaminated with Hg and therefore is representative of other Hg-contaminated areas in China. We selected four study locations in Guizhou Province: three that represent typical environments with severe Hg pollution [due to Hg mining and smelting (Wanshan), traditional zinc smelting (recently closed; Weining), and heavy coal-based industry (Qingzhen)], and a village in a remote nature reserve (Leigong).The probable daily intake (PDI) of MeHg for an adult population based on 60 kg body weight (bw) was considerably higher in Wanshan than in the other three locations. With an average PDI of 0.096 microg/kg bw/day (range, 0.015-0.45 microg/kg bw/day), approximately 34% of the inhabitants in Wanshan exceeded the reference dose of 0.1 microg/kg bw/day established by the U.S. Environmental Protection Agency. The PDI of MeHg for residents in the three other locations were all well below 0.1 microg/kg bw/day (averages from 0.017 to 0.023 microg/kg bw/day, with a maximum of 0.095 microg/kg bw/day). In all four areas, rice consumption accounted for 94-96% of the PDI of MeHg.We found that rice consumption is by far the most important MeHg exposure route; however, most of the residents (except those in Hg-mining areas) have low PDIs of MeHg.
Acting out our sensory experience
Authors: J. Kevin O'Regan, Alva Noë
Journal: Behavioral and Brain Sciences (2001)

The most important clarification we bring in our reply to commentators concerns the problem of the “explanatory gap”: that is, the gulf that separates physical processes in the brain from the experienced quality of sensations. By adding two concepts (bodiliness and grabbiness) that were not stressed in the target article, we strengthen our claim and clarify why we think we have solved the explanatory gap problem, – not by dismissing qualia, but, on the contrary, by explaining why sensations have a “feel” and why “feels” feel the way they do. We additionally clarify our views on: internal representations (we claim internal representations cannot explain why sensation has a feel), on behaviorism (we are not behaviorists), on perception and action (we believe there can be perception without action), and on the brain (we believe the brain does do something important in perception).
Cardiovascular functional disorder and stress among patients having neck-shoulder symptoms.
Authors: M Gockel, H Lindholm, H Alaranta, A Viljanen, A Lindquist, T Lindholm
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVES--To investigate if autonomic nervous system function, reflected in cardiovascular variables, among patients with neck-shoulder symptoms (tension neck group (T)) differed from that in a symptom free control group (C), and to establish its relation with pain and psychological stress. METHODS--Twelve women with tension neck and nine controls in secretarial jobs were studied. They underwent an orthostatic test, deep breathing test, Valsalva manoeuvre, isometric handgrip test, and muscular endurance test. Pain was measured using visual analogue scales, and psychological stress by the Modified Somatic Perception Questionnaire (MSPQ). Plasma endothelin-1 (ET-1) was measured using high pressure liquid chromatography and radioimmunoassay. RESULTS--Signs of psychological stress were significantly (p &lt; 0.001) more common in group T than in group C. Mean resting heart rate in group T (77.8 (SE 2.9) beats/min; range 64-100) was significantly greater than that in group C (63.8 (3.1) beats/min; range 52-80) (p &lt; 0.01). In the orthostatic test, the overall changes in R-R intervals during the first 40 heart beats after standing up and during seven minutes of testing differed significantly between the groups (p &lt; 0.001, &lt; 0.05, respectively). The increase in diastolic blood pressure in the three minute isometric handgrip test was significantly less in group T (19.4 (3.5) mm Hg; range -5 to 35) than in group C (30 (3.4) mm Hg; range 15-50) (p &lt; 0.05). The MSPQ score in the study group (n = 21) correlated positively with resting heart rate (r = 0.462, p &lt; 0.05) and negatively with increase in diastolic blood pressure (r = -0.514, p &lt; 0.05). Plasma concentrations of ET-1 did not differ between the groups. CONCLUSION--Increased sympathetic activity was found among patients having neck-shoulder symptoms. Local mechanisms may have influenced the cardiovascular changes observed during isometric testing in these patients.
COLICINE K
Authors: Walther F. Goebel, Anne Marie Staub
Journal: The Journal of Experimental Medicine (1965)

1. The immunization of horses with the colicinogenic bacillus E. coli K235 L + O(m) stimulates antibodies which precipitate and neutralize colicine K and neutralize the heterologous colicine I as well. 2. Unlike rabbits, horses evoke predpitating antibodies for the sialic acid-containing polysaccharide colominic acid.
Cutaneous mucinoses and HIV infection
Authors: None Rongioletti, None Ghigliotti, None DE Marchi, None Rebora
Journal: British Journal of Dermatology (1998)

In the last few years cutaneous mucinoses have been reported with increased frequency in HIV patients. We report the occurrence of scleredema, reticular erythematous mucinosis and lichen myxoedematosus in three different HIV‐infected patients, review the literature and discuss the possible relationship between mucin deposits and HIV infection. This is the first report of scleredema and the second of reticular erythematous mucinosis in an HIV‐infected patient. Only the association of HIV infection with lichen myxoedematosus seems to be more than coincidental.
Conditional AC type VI expression in the heart: relevant insights into function of inducible target gene expression
Authors: P MOST, A REMPPIS, H KATUS
Journal: Cardiovascular Research (2002)

See article by Gao et al. [1] ( pages 197 -204) in thisto achieve cardiac-specific conditional gene expression in issue.the heart [30,31].As shown in Fig. 1, this system requires two lines of transgenic mice: one expressing a chimeric Manipulation of the mouse genome by transgenic ap-tet-regulateable transcriptional activator (tTA) in a cardiacproaches is a powerful tool to examine gene function as specific manner, and another carrying the target gene well as interaction of gene products in the intact animal driven by a quiescent minimal cytomegaly virus promoter [2-4].In the past, gain-in-function models were the most (CMV ) which is flanked by multimerized copies of the min
RHEX, a novel regulator of human erythroid progenitor cell expansion and erythroblast development
Authors: Rakesh Verma, Su Su, Donald J. McCrann, Jennifer M. Green, Karen Leu, Peter R. Young, Peter J. Schatz, Jeffrey C. Silva, Matthew P. Stokes, Don M. Wojchowski
Journal: The Journal of Experimental Medicine (2015)

Ligation of erythropoietin (EPO) receptor (EPOR) JAK2 kinase complexes propagates signals within erythroid progenitor cells (EPCs) that are essential for red blood cell production. To reveal hypothesized novel EPOR/JAK2 targets, a phosphotyrosine (PY) phosphoproteomics approach was applied. Beyond known signal transduction factors, 32 new targets of EPO-modulated tyrosine phosphorylation were defined. Molecular adaptors comprised one major set including growth factor receptor-bound protein 2 (GRB2)-associated binding proteins 1-3 (GAB1-3), insulin receptor substrate 2 (IRS2), docking protein 1 (DOK1), Src homology 2 domain containing transforming protein 1 (SHC1), and sprouty homologue 1 (SPRY1) as validating targets, and SPRY2, SH2 domain containing 2A (SH2D2A), and signal transducing adaptor molecule 2 (STAM2) as novel candidate adaptors together with an ORF factor designated as regulator of human erythroid cell expansion (RHEX). RHEX is well conserved in Homo sapiens and primates but absent from mouse, rat, and lower vertebrate genomes. Among tissues and lineages, RHEX was elevated in EPCs, occurred as a plasma membrane protein, was rapidly PY-phosphorylated >20-fold upon EPO exposure, and coimmunoprecipitated with the EPOR. In UT7epo cells, knockdown of RHEX inhibited EPO-dependent growth. This was associated with extracellular signal-regulated kinase 1,2 (ERK1,2) modulation, and RHEX coupling to GRB2. In primary human EPCs, shRNA knockdown studies confirmed RHEX regulation of erythroid progenitor expansion and further revealed roles in promoting the formation of hemoglobinizing erythroblasts. RHEX therefore comprises a new EPO/EPOR target and regulator of human erythroid cell expansion that additionally acts to support late-stage erythroblast development.
Characterization of a rare IL-10–competent B-cell subset in humans that parallels mouse regulatory B10 cells
Authors: Yohei Iwata, Takashi Matsushita, Mayuka Horikawa, David J. DiLillo, Koichi Yanaba, Guglielmo M. Venturi, Paul M. Szabolcs, Steven H. Bernstein, Cynthia M. Magro, Armistead D. Williams, Russell P. Hall, E. William St Clair, Thomas F. Tedder
Journal: Blood (2010)