tbuckley/cabot-search huggingface dataset:
Clinical and Translational Studies of a Phase II Trial of the Novel Oral Akt Inhibitor Perifosine in Relapsed or Relapsed/Refractory Waldenström's Macroglobulinemia
Authors: Irene M. Ghobrial, Aldo Roccaro, Fangxin Hong, Edie Weller, Nancy Rubin, Renee Leduc, Meghan Rourke, Stacey Chuma, Antonio Sacco, Xiaoying Jia, Feda Azab, Abdel Kareem Azab, Scott Rodig, Diane Warren, Brianna Harris, Lyuba Varticovski, Peter Sportelli, Xavier Leleu, Kenneth C. Anderson, Paul G. Richardson
Journal: Clinical Cancer Research (2010)

Waldenström's macroglobulinemia (WM) is a rare, low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM.Thirty-seven patients were treated with oral perifosine (150 mg daily) for six cycles. Stable or responding patients were allowed to continue therapy until progression.The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, beta2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor kappaB activity.Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM.
Translational Selection Frequently Overcomes Genetic Drift in Shaping Synonymous Codon Usage Patterns in Vertebrates
Authors: Aoife Doherty, James O. McInerney
Journal: Molecular Biology and Evolution (2013)

Synonymous codon usage patterns are shaped by a balance between mutation, drift, and natural selection. To date, detection of translational selection in vertebrates has proven to be a challenging task, obscured by small long-term effective population sizes in larger animals and the existence of isochores in some species. The consensus is that, in such species, natural selection is either completely ineffective at overcoming mutational pressures and genetic drift or perhaps is effective but so weak that it is not detectable. The aim of this research is to understand the interplay between mutation, selection, and genetic drift in vertebrates. We observe that although variation in mutational bias is undoubtedly the dominant force influencing codon usage, translational selection acts as a weak additional factor influencing synonymous codon usage. These observations indicate that translational selection is a widespread phenomenon in vertebrates and is not limited to a few species.
Low dose N, N-dimethylsphingosine is cardioprotective and activates cytosolic sphingosine kinase by a PKCε dependent mechanism
Authors: Z JIN, J KARLINER
Journal: Cardiovascular Research (2006)

Objective:N, N-Dimethylsphingosine (DMS) is recognized as an inhibitor of sphingosine kinase (SphK), a key enzyme responsible for the formation of sphingosine-1-phosphate (S1P). We previously showed that S1P was cardioprotective and that SphK was critical for myocardial ischemic preconditioning. Although DMS is an endogenous sphingolipid, its effect on cardiac function and cardioprotection at low concentration has not been studied.
Exploring the rice dispensable genome using a metagenome-like assembly strategy
Authors: Wen Yao, Guangwei Li, Hu Zhao, Gongwei Wang, Xingming Lian, Weibo Xie
Journal: Genome biology (2015)

The dispensable genome of a species, consisting of the dispensable sequences present only in a subset of individuals, is believed to play important roles in phenotypic variation and genome evolution. However, construction of the dispensable genome is costly and labor-intensive at present, and so the influence of the dispensable genome in genetic and functional genomic studies has not been fully explored. We construct the dispensable genome of rice through a metagenome-like de novo assembly strategy based on low-coverage (1–3×) sequencing data of 1483 cultivated rice (Oryza sativa L.) accessions. Thousands of protein-coding genes are successfully assembled, including most of the known agronomically important genes absent from the Nipponbare rice reference genome. We develop an integration approach based on alignment and linkage disequilibrium, which is able to assign genomic positions relative to the reference genome for more than 78.2 % of the dispensable sequences. We carry out association mapping studies for rice grain width and 840 metabolic traits using 0.46 million polymorphisms between the dispensable sequences of different rice accessions. About 23.5 % of metabolic traits have more significant association signals with polymorphisms from dispensable sequences than with SNPs from the reference genome, and 41.6 % of trait-associated SNPs have concordant genomic locations with associated dispensable sequences. Our results suggest the feasibility of building a species' dispensable genome using low-coverage population sequencing data. The constructed sequences will be helpful for understanding the rice dispensable genome and are complementary to the reference genome for identifying candidate genes associated with phenotypic variation.
Scottish doctors will have to register financial links to drug companies
Authors: B. Christie
Journal: BMJ (2004)

Doctors in Scotland are to be required to declare any financial or personal links they have with drug companies on official registers that will be made available for public inspection. The move is part of an agreement between the NHS and the drugs industry on joint working that aims to reduce potential conflicts of interest and improve openness and transparency.

The agreement is the first of its kind in the United Kingdom and may lead to pressure for similar action elsewhere. Joe Collier, editor …
Phase I Clinical Trial of Oral Curcumin
Authors: Ricky A. Sharma, Stephanie A. Euden, Sharon L. Platton, Darren N. Cooke, Aisha Shafayat, Heather R. Hewitt, Timothy H. Marczylo, Bruno Morgan, David Hemingway, Simon M. Plummer, Munir Pirmohamed, Andreas J. Gescher, William P. Steward
Journal: Clinical Cancer Research (2004)

Abstract Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E2 (PGE2) production, or suppression of oxidative DNA adduct (M1G) formation. We designed a dose-escalation study to explore the pharmacology of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 months. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liquid chromatography and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclinical models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M1G, and PGE2 production induced ex vivo. Dose-limiting toxicity was not observed. Curcumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE2 production in blood samples taken 1 hour after dose on days 1 and 29, respectively, of treatment compared with levels observed immediately predose (P &amp;lt; 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE2 production in blood and target tissue may indicate biological activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.
Cell Death Independent of Caspases: A Review
Authors: Linda E. Bröker, Frank A.E. Kruyt, Giuseppe Giaccone
Journal: Clinical Cancer Research (2005)

Abstract Patterns of cell death have been divided into apoptosis, which is actively executed by specific proteases, the caspases, and accidental necrosis. However, there is now accumulating evidence indicating that cell death can occur in a programmed fashion but in complete absence and independent of caspase activation. Alternative models of programmed cell death (PCD) have therefore been proposed, including autophagy, paraptosis, mitotic catastrophe, and the descriptive model of apoptosis-like and necrosis-like PCD. Caspase-independent cell death pathways are important safeguard mechanisms to protect the organism against unwanted and potential harmful cells when caspase-mediated routes fail but can also be triggered in response to cytotoxic agents or other death stimuli. As in apoptosis, the mitochondrion can play a key role but also other organelles such as lysosomes and the endoplasmic reticulum have an important function in the release and activation of death factors such as cathepsins, calpains, and other proteases. Here we review the various models of PCD and their death pathways at molecular and organelle level and discuss the relevance of the growing knowledge of caspase-independent cell death pathways for cancer.
Genetic ancestry of participants in the National Children’s Study
Authors: Erin N Smith, Kristen Jepsen, Angelo D Arias, Peter J Shepard, Christina D Chambers, Kelly A Frazer
Journal: Genome biology (2014)

The National Children's Study (NCS) is a prospective epidemiological study in the USA tasked with identifying a nationally representative sample of 100,000 children, and following them from their gestation until they are 21 years of age. The objective of the study is to measure environmental and genetic influences on growth, development, and health. Determination of the ancestry of these NCS participants is important for assessing the diversity of study participants and for examining the effect of ancestry on various health outcomes. We estimated the genetic ancestry of a convenience sample of 641 parents enrolled at the 7 original NCS Vanguard sites, by analyzing 30,000 markers on exome arrays, using the 1000 Genomes Project superpopulations as reference populations, and compared this with the measures of self-reported ethnicity and race. For 99% of the individuals, self-reported ethnicity and race agreed with the predicted superpopulation. NCS individuals self-reporting as Asian had genetic ancestry of either South Asian or East Asian groups, while those reporting as either Hispanic White or Hispanic Other had similar genetic ancestry. Of the 33 individuals who self-reported as Multiracial or Non-Hispanic Other, 33% matched the South Asian or East Asian groups, while these groups represented only 4.4% of the other reported categories. Our data suggest that self-reported ethnicity and race have some limitations in accurately capturing Hispanic and South Asian populations. Overall, however, our data indicate that despite the complexity of the US population, individuals know their ancestral origins, and that self-reported ethnicity and race is a reliable indicator of genetic ancestry.
Variation within 3′-UTRs of Base Excision Repair Genes and Response to Therapy in Colorectal Cancer Patients: A Potential Modulation of microRNAs Binding
Authors: Barbara Pardini, Fabio Rosa, Elisa Barone, Cornelia Di Gaetano, Jana Slyskova, Jan Novotny, Miroslav Levy, Sonia Garritano, Ludmila Vodickova, Tomas Buchler, Federica Gemignani, Stefano Landi, Pavel Vodicka, Alessio Naccarati
Journal: Clinical Cancer Research (2013)

Colorectal cancer is routinely treated with a 5-fluorouracil (5-FU)-based chemotherapy. 5-FU incorporates into DNA, and the base excision repair (BER) pathway specifically recognizes such damage. We investigated the association of single-nucleotide polymorphisms (SNP) in the 3'-untranslated regions (UTR) of BER genes, and potentially affecting the microRNA (miRNA) binding, on the risk of colorectal cancer, its progression, and prognosis. SNPs in miRNA-binding sites may modulate the posttranscriptional regulation of gene expression operated by miRNAs and explain interindividual variability in BER capacity and response to 5-FU.We tested 12 SNPs in the 3'-UTRs of five BER genes for colorectal cancer susceptibility in a case-control study (1,098 cases and 1,459 healthy controls). Subsequently, we analyzed the role of these SNPs on clinical outcomes of patients (866 in the Training set and 232 in the Replication set).SNPs in the SMUG1 and NEIL2 genes were associated with overall survival. In particular, SMUG1 rs2233921 TT carriers showed increased survival compared with those with GT/GG genotypes [HR, 0.54; 95% confidence interval (CI), 0.36-0.81; P = 0.003] in the Training set and after pooling results from the Replication set. The association was more significant following stratification for 5-FU-based chemotherapy (P = 5.6 × 10(-5)). A reduced expression of the reporter gene for the T allele of rs2233921 was observed when compared with the common G allele by in vitro assay. None of the genotyped BER polymorphisms were associated with colorectal cancer risk.We provide the first evidence that variations in miRNA-binding sites in BER genes 3'-UTR may modulate colorectal cancer prognosis and therapy response.
Survival after progression in patients with follicular lymphoma: analysis of prognostic factors
Authors: S. Montoto, A. López-Guillermo, A. Ferrer, M. Camós, A. Álvarez-Larrán, F. Bosch, J. Bladé, F. Cervantes, J. Esteve, F. Cobo, D. Colomer, E. Campo, E. Montserrat
Journal: Annals of Oncology (2002)
Abstract P437: Children First Study II: How An Educational Program In Cardiovascular Prevention At School Can Improve Children Recreational Inactivity
Authors: Cristiano J Pinto, Silvia M Oyama, Maria Manoela D Rodrigues, Taciana Davanço, Bruno Caramelli, Luciana S Fornari
Journal: Circulation (2014)

Objective: Evaluate the improvement in recreational inactivity (tv/internet/vieogames) in school age children after a multidisciplinary educational program in cardiovascular prevention (CVP) at school. Methods: Students aging 6 to 10 years old were exposed to two different approaches at two public schools in Sao Paulo, Brazil. For the control school we delivered written educational material (EM) for their parents during the year of 2012 about healthy lifestyle. The intervention school students received the same EM for their parents and the children were exposed to a weekly educational program in CVP with a multidisciplinary heath team during the year 2012. This intervention tried to teach to these children concepts of healthy nutrition, avoidance of tobacco and physical activity. Both at the inclusion in the study and one year later we collect data of parents and their children, including a questionnarie about the time children spent in tv, computes and videogames during the day (recreational inactivity). Results: We studied 262 children. The control group had 136 children (mean age of 8 years) and the intervention group had 126 children (mean age of 8 years). In the intervention group 79.4% of children (100 children) had a reacreational inactivity time (RIT) &gt; 2 hours/day, and in the control group 80.1% of children (109 children) had a RIT &gt; 2 hours/day. After one year of educational intervention 87 children (69.0%) of the intervention group and 107 children (78.6%) of the control group still had a RIT &gt;2 hours/day, p= 0.03923 (Fisher's Exact test Mid p). This represents a 13% reduction in the intervention group and a 1,8% reduction in the control group. Conclusion: An educational program in cardiovascular prevention directed to children at school age can improve recreational inactivity in children contributing for the reduction of obesity and cardiovascular risk.
Cloning of Vascular Adhesion Protein 1 Reveals a Novel Multifunctional Adhesion Molecule
Authors: David J. Smith, Marko Salmi, Petri Bono, Jukka Hellman, Taina Leu, Sirpa Jalkanen
Journal: The Journal of Experimental Medicine (1998)

Vascular adhesion protein 1 (VAP-1) is a human endothelial sialoglycoprotein whose cell surface expression is induced under inflammatory conditions. It has been shown previously to participate in lymphocyte recirculation by mediating the binding of lymphocytes to peripheral lymph node vascular endothelial cells in an L-selectin–independent fashion. We report here that the VAP-1 cDNA encodes a type II transmembrane protein of 84.6 kD with a single transmembrane domain located at the NH2-terminal end of the molecule and six potential N-glycosylation sites in the extracellular domain. In vivo, the protein exists predominantly as a homodimer of 170–180 kD. Ax endothelial cells transfected with a VAP-1 cDNA express VAP-1 on their cell surface and bind lymphocytes, and the binding can be partially inhibited with anti–VAP-1 mAbs. VAP-1 has no similarity to any currently known adhesion molecules, but has significant identity to the copper-containing amine oxidase family and has a monoamine oxidase activity. We propose that VAP-1 is a novel type of adhesion molecule with dual function. With the appropriate glycosylation and in the correct inflammatory setting, its expression on the lumenal endothelial cell surface allows it to mediate lymphocyte adhesion and to function as an adhesion receptor involved in lymphocyte recirculation. Its primary function in other locations where it is expressed, such as smooth muscle, may depend on its inherent monoamine oxidase activity.
Thromboembolic Complications and Prophylaxis Patterns in Colorectal Surgery
Authors: Daniel W. Nelson, Vlad V. Simianu, Amir L. Bastawrous, Richard P. Billingham, Alessandro Fichera, Michael G. Florence, Eric K. Johnson, Morris G. Johnson, Richard C. Thirlby, David R. Flum, Scott R. Steele
Journal: JAMA Surgery (2015)

Translation Network (SCOAP-CERTAIN) Collaborative V enous thromboembolism (VTE) prevention in hospitalized patients has been promoted as a patient safety priority by a multitude of agencies. 1Despite the fact that colorectal surgery is one of the most commonly performed procedures, the American College of Chest Physicians' revised evidence-based guidelines regarding strategies to reduce VTE among hospitalized surgical patients do not offer comprehensive recommendations for patients undergoing colorectal surgery. 2,3General strategies recommended in the American College of Chest Physicians' guidelines regarding abdominal surgery, as well as the American Society of Clinical Oncology's guidelines for VTE prevention in cancer, 4 may be extrapolated and applied to patients with colorectal cancer.How-ever, these patients represent a diverse population with an array of patient-related and procedure-associated factors that place them at particularly high risk of VTE.6][7][8] In addition, lithotomy positioning, prolonged operative times, and pelvic dissection are procedure-specific risk factors associated with VTE. 9 In the absence of appropriate prophylaxis, rates of radiologically and clinically diagnosed VTE, including deep vein thrombosis (DVT) and pulmonary embolism, have been as high as 40% and 5%, respectively, following colorectal surgery. 9Among patients undergoing colorectal procedures who receive guidelinerecommended chemoprophylaxis, VTE rates are as high as IMPORTANCE Venous thromboembolism (VTE) is an important complication of colorectal surgery, but its incidence is unclear in the era of VTE prophylaxis.OBJECTIVE To describe the incidence of and risk factors associated with thromboembolic complications and contemporary VTE prophylaxis patterns following colorectal surgery.
P217 Current Practise in Considering Early Life Factors in Respiratory Disease: A British Thoracic Society Survey: Abstract P217 Table 1
Authors: CE Bolton, A Bush, JR Hurst, S Kotecha, LP McGarvey, J Stocks, M Walshaw
Journal: Thorax (2012)

<h3>Background</h3> Despite an 8% UK preterm birth rate and the improved survival of very preterm infants into adulthood, we hypothesised that the longer term impact of early life factors on respiratory health and disease is not routinely considered by respiratory specialists. We surveyed BTS members to determine their practise. <h3>Methods</h3> Using a survey link, an email was sent twice, 4 weeks apart, to clinically active BTS members, enquiring whether they asked their patients about birth-weight, being born preterm, pregnancy and postnatal complications, and time in a neonatal unit; whether patients’ knew this information, and also whether members believed their patients had airflow limitation due to prematurity or low birth-weight. <h3>Results</h3> There was good geographical spread of the 123 replies (61% consultants, 21% doctors in training, 15% nursing profession, 2% GPs and 1% SAS doctors). 93% worked in the secondary care sector (55% in teaching hospitals), and only 13 dealt predominantly with children (12 in hospital, 1 community). <h3>Results</h3> are summarised in the Table. Only a small minority (mainly hospital paediatricians) ask “most respiratory patients” about early life factors. In those who do ask, there is a wide variation in patient knowledge, this being greatest for children, in whom parental recall or use of the “red book” assisted. Although 47% thought some of their patients were born preterm or had a low birth-weight, 46% were unaware and 7% thought there were none. <h3>Discussion</h3> Given evidence suggesting early life factors do impact on respiratory health, the survey suggests little current consideration is given to these in adult medicine. Limited retrospective recall may preclude accurate assessment. To develop a greater understanding of the potential impact of early life influences on chronic respiratory disease requires a new approach, for example accessing early medical records, recall by a living parent of the patient or via a preterm registry. In tandem, training needs to address the gaps in history taking.