tbuckley/cabot-search huggingface dataset:
Analysis of Receptor Tyrosine Kinase ROS1-Positive Tumors in Non–Small Cell Lung Cancer: Identification of a FIG-ROS1 Fusion
Authors: Victoria M. Rimkunas, Katherine E. Crosby, Daiqiang Li, Yerong Hu, Meghan E. Kelly, Ting-Lei Gu, Jennifer S. Mack, Matthew R. Silver, Xinmin Zhou, Herbert Haack
Journal: Clinical Cancer Research (2012)

To deepen our understanding of mutant ROS1 expression, localization, and frequency in non-small cell lung cancer (NSCLC), we developed a highly specific and sensitive immunohistochemistry (IHC)-based assay that is useful for the detection of wild-type and mutant ROS1.We analyzed 556 tumors with the ROS1 D4D6 rabbit monoclonal antibody IHC assay to assess ROS1 expression levels and localization. A subset of tumors was analyzed by FISH to determine the percentage of these tumors harboring ROS1 translocations. Using specific and sensitive IHC assays, we analyzed the expression of anaplastic lymphoma kinase (ALK), EGFR L858R, and EGFR E746-A750del mutations in a subset of lung tumors, including those expressing ROS1.In our NSCLC cohort of Chinese patients, we identified 9 (1.6%) tumors expressing ROS1 and 22 (4.0%) tumors expressing ALK. FISH identified tumors with ALK or ROS1 rearrangements, and IHC alone was capable of detecting all cases with ALK and ROS1 rearrangements. ROS1 fusion partners were determined by reverse transcriptase PCR identifying CD74-ROS1, SLC34A2-ROS1, and FIG-ROS1 fusions. Some of the ALK and ROS1 rearranged tumors may also harbor coexisting EGFR mutations.NSCLC tumors with ROS1 rearrangements are uncommon in the Chinese population and represent a distinct entity of carcinomas. The ROS1 IHC assay described here is a valuable tool for identifying patients expressing mutant ROS1 and could be routinely applied in clinical practice to detect lung cancers that may be responsive to targeted therapies.
Equipoise Lost: Ethics, Costs, and the Regulation of Cancer Clinical Research
Authors: David J. Stewart, Simon N. Whitney, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2010)

Cancer is the leading cause of death in Americans younger than 85 years of age and kills one American every 56 seconds. Advances in understanding of cancer biology have given us the potential to develop new, effective targeted therapies. However, progress is slowed by suboptimal/outdated clinical trial design paradigms and by regulatory complexity and rigidity. For instance, simulations suggest that restricting randomized trials to patients expressing drug target, instead of using unselected patient populations, could substantially reduce patient numbers required to demonstrate efficacy. High response rates that are achievable when patients and drugs are matched on the basis of molecular profiles may also make some randomized trials unnecessary or unjustifiable. Moreover, increasing the regulatory rigidity of clinical trials (regulatory fundamentalism) augments trial complexity and costs while slowing progress without demonstrating meaningful safety benefits. Time from drug discovery to marketing increased from 8 years in 1960 to 12 to 15 years currently. Toxic death rates on phase I trials have decreased from 0.8% in 1979 to 0.5% by 2002, but the estimated cost per life-year gained by tighter regulations is $2,700,000 (far higher than costs of other health measures), and simulations suggest that regulatory delays in development of effective therapies result in tens to hundreds of thousands of life-years lost, whereas stringent regulations save extremely few. Dysregulation is also a major disincentive to patient and clinician participation in clinical research. In summary, current approaches squander research resources and discourage research participation, and the marked imbalance between potential life-years lost versus saved renders the regulatory burden potentially unethical. We outline suggested solutions.
The role of HOX genes in human implantation
Authors: H. S. Taylor
Journal: Human Reproduction Update (2000)

HOXgenes are transcriptional regulators that play an essential role in determining tissue identity during embryonic development. HOXgenes are involved in the development of the Müllerian system and then continue to be expressed in the adult uterus. Two HOX genes have been demonstrated necessary for uterine receptivity in knock-out mice. We have recently elucidated the expression patterns and regulation of HOX genes in the development of the human endometrium during the menstrual cycle. HOX genes are likely key regulators of human implantation. This paper will review the role of HOXgenes in the reproductive tract, specifically the evidence that HOXgenes are important for human endometrial development and receptivity.
Parenteral nutrition-associated liver disease and the role for isolated intestine and intestine/liver transplantation
Authors: Alan L. Buchman, Kishore Iyer, Jonathan Fryer
Journal: Hepatology (2005)

Parenteral nutrition-associated liver disease (PNALD) is the most devastating complication of long-term parenteral nutrition therapy. Because its progression is typically insidious and its long-term consequences are generally underappreciated, PNALD is often recognized too late, when liver injury is irreversible. When end-stage liver disease (ESLD) develops in these patients, most potential interventions are futile and transplantation of both an intestine and a liver becomes the only viable option, despite the relatively poor outcomes associated with this combined procedure. Although likely multifactorial in origin, the etiology of PNALD is poorly understood. Early clinical intervention with a combination of nutritional, medical, hormonal, and surgical therapies can be effective in preventing liver disease progression. If these interventions fail, intestinal transplantation should be performed expeditiously before development of ESLD mandates simultaneous inclusion of a liver graft as well.
Ultrasonographic Screening for Abdominal Aortic Aneurysms
Authors: Frank A. Lederle
Journal: Annals of Internal Medicine (2003)

Abdominal aortic aneurysms (AAAs) occur in 1 of 20 older men, remain asymptomatic for many years, and, if left untreated, cause death from rupture in about one third of patients. Ultrasonography is a suitable screening test for AAA, and elective repair can prevent rupture. Although these features suggest a promising target for a screening program, evidence of benefit from AAA screening has only recently become available. Four randomized trials of ultrasonographic screening involving more than 125 000 men have been reported, and each trial observed a reduction in AAA-related mortality (which was statistically significant in 2 trials), ranging from 21% to 68%. One trial in women found no benefit. Other studies indicate that screening can begin in men older than 65 years of age and does not need to be repeated if results are negative. An AAA larger than 5.5 cm in diameter should be considered for elective open or endovascular repair. Most aneurysms detected at screening are smaller and should be kept under surveillance with periodic imaging measurement. Widespread elective repair of small AAAs could reduce the benefits and increase the costs of screening. No medical treatments have been proven to reduce the enlargement rate. If elective repair is reserved for larger AAAs, one-time ultrasonographic screening for AAA can be recommended for men 65 to 79 years of age who have ever smoked.
Chlamydia heat shock protein 60 decreases expression of endothelial nitric oxide synthase in human and porcine coronary artery endothelial cells
Authors: C. Chen, H. Chai, X. Wang, P. H. Lin, Q. Yao
Journal: Cardiovascular Research (2009)

Clinically, Chlamydia pneumoniae infection and its heat shock protein 60 (cHSP60) may contribute to atherogenesis; however, its underlying mechanisms are largely unknown. The objective of this study was to determine whether cHSP60 could cause endothelial dysfunction in human coronary artery endothelial cells (HCAECs) and porcine coronary arteries. When HCAECs were treated with recombinant cHSP60, endothelial nitric oxide synthase (eNOS) mRNA and protein levels, enzyme activities, cellular NO levels, mRNA stability, and promoter activities were significantly decreased. Superoxide anion production was significantly increased due to the inhibition of mitochondrial membrane potential and catalase and superoxide dismutase (SOD) activities as well as activation of NADPH oxidase. Antioxidant seleno-l-methionine (SeMet) or SOD mimetic MnTBAP effectively blocked cHSP60-induced eNOS downregulation. In addition, cHSP60 activated mitogen-activated protein kinases (MAPKs) including p38, c-Jun-N-terminal kinase/stress-activated protein kinase, and extracellular signal-regulated kinases. Specific chemical inhibitors or their dominant-negative mutant forms of these MAPKs effectively blocked cHSP60-induced eNOS downregulation. cHSP60-induced eNOS downregulation and oxidative stress were also demonstrated in porcine coronary artery rings in vitro. Functionally, endothelium-dependent vasorelaxation was significantly reduced in cHSP60-treated vessels. cHSP60 directly induces eNOS downregulation through oxidative stress and MAPK activation in both HCAECs and porcine coronary arteries, thereby causing endothelial dysfunction.
Genetic CD21 deficiency is associated with hypogammaglobulinemia
Authors: Jens Thiel, Lucas Kimmig, Ulrich Salzer, Magdalena Grudzien, Dirk Lebrecht, Tina Hagena, Ruth Draeger, Nadine Völxen, Astrid Bergbreiter, Stephanie Jennings, Sylvia Gutenberger, Annette Aichem, Harald Illges, Jonathan P. Hannan, Anne-Kathrin Kienzler, Marta Rizzi, Hermann Eibel, Hans-Hartmut Peter, Klaus Warnatz, Bodo Grimbacher, Jörg-Andres Rump, Michael Schlesier
Journal: Journal of Allergy and Clinical Immunology (2011)
Long-term reduction of T-cell intracellular antigens leads to increased beta-actin expression
Authors: Isabel Carrascoso, Carmen Sánchez-Jiménez, José M Izquierdo
Journal: Molecular Cancer (2014)

The permanent down-regulated expression of T-cell intracellular antigen (TIA) proteins in HeLa cells improves cytoskeleton-mediated functions such as cell proliferation and tumor growth.Making use of human and mouse cells with knocked down/out expression of T-cell intracellular antigen 1 (TIA1) and/or TIA1 related/like (TIAR/TIAL1) proteins and classical RNA (e.g. reverse transcription-quantitative polymerase chain reaction, polysomal profiling analysis using sucrose gradients, immunoblotting, immunoprecipitation, electrophoretic mobility shift assays, ultraviolet light crosslinking and poly (A+) test analysis) and cellular (e.g. immunofluorescence microscopy and quimeric mRNA transfections) biology methods, we have analyzed the regulatory role of TIA proteins in the post-transcriptional modulation of beta-actin (ACTB) mRNA.Our observations show that the acquisition of above cellular capacities is concomitant with increased expression levels of the actin beta subunit (ACTB) protein. Regulating TIA abundance does not modify ACTB mRNA levels, however, an increase of ACTB mRNA translation is observed. This regulatory capacity of TIA proteins is linked to the ACTB mRNA 3'-untranslated region (3'-UTR), where these proteins could function as RNA binding proteins. The expression of GFP from a chimeric reporter containing human ΑCΤΒ 3'-UTR recapitulates the translational control found by the endogenous ACTB mRNA in the absence of TIA proteins. Additionally, murine embryonic fibroblasts (MEF) knocked out for TIA1 rise mouse ACTB protein expression compared to the controls. Once again steady-state levels of mouse ACTB mRNA remained unchanged.Collectively, these results suggest that TIA proteins can function as long-term regulators of the ACTB mRNA metabolism in mouse and human cells.
The Effect of Enforcing Tobacco-Sales Laws on Adolescents' Access to Tobacco and Smoking Behavior
Authors: Nancy A. Rigotti, Joseph R. DiFranza, YuChiao Chang, Thelma Tisdale, Becky Kemp, Daniel E. Singer
Journal: New England Journal of Medicine (1997)

Enforcing laws banning tobacco sales to minors is widely advocated as a way to reduce young people's access to tobacco and tobacco use. Whether this approach is successful is not known.
Homozygous <i>SCN5A</i> Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block
Authors: J.M. Lupoglazoff, T. Cheav, G. Baroudi, M. Berthet, I. Denjoy, B. Cauchemez, F. Extramiana, M. Chahine, P. Guicheney
Journal: Circulation Research (2001)

Abstract— Heterozygous mutations in genes encoding cardiac ionic channel subunits KCNQ1 , HERG , SCN5A , KCNE1 , and KCNE2 are causally involved in the dominant form of long-QT syndrome (LQTS) while homozygous mutations in KCNQ1 and KCNE1 cause LQTS with or without congenital deafness. In addition, two homozygous HERG mutations have been associated with severe LQTS with functional atrioventricular conduction anomalies in young children. A 2:1 atrioventricular block (AVB) with a major QTc prolongation (526 ms) was evidenced in a 5-year-old boy referred for syncope and seizure. LQTS was diagnosed and beta-blocking therapy initiated leading to normal atrioventricular conduction. Electrophysiological study provided support that location of the AVB was infra-Hisian. DNA analysis was performed in the proband and in asymptomatic family members. A novel missense mutation, V1777M, in the early C-terminal domain of SCN5A was identified. The proband was homozygous while the parents and two siblings were heterozygous carriers. Homozygote and heterozygote expression of the mutant channels in tsA201 mammalian cells resulted in a persistent inward sodium current of 3.96±0.83% and 1.49±0.47% at −30 mV, respectively, which was dramatically reduced in the presence of tetrodotoxin. This study provides the first evidence for a homozygous missense mutation in SCN5A and suggests that LQTS with functional 2:1 AVB in young children, a severe phenotype associated with bad prognosis, may be caused by homozygous or heterozygous compound mutations not only in HERG but also in SCN5A . The full text of this article is available at http://www.circresaha.org.
Testing the New Animal Phylogeny: First Use of Combined Large-Subunit and Small-Subunit rRNA Gene Sequences to Classify the Protostomes
Authors: Jon Mallatt, Christopher J. Winchell
Journal: Molecular Biology and Evolution (2002)

Although the small-subunit ribosomal RNA (SSU rRNA) gene is widely used in the molecular systematics, few large-subunit (LSU) rRNA gene sequences are known from protostome animals, and the value of the LSU gene for invertebrate systematics has not been explored. The goal of this study is to test whether combined LSU and SSU rRNA gene sequences support the division of protostomes into Ecdysozoa (molting forms) and Lophotrochozoa, as was proposed by Aguinaldo et al. (1997) (Nature 387:489) based on SSU rRNA sequences alone. Nearly complete LSU gene sequences were obtained, and combined LSU + SSU sequences were assembled, for 15 distantly related protostome taxa plus five deuterostome outgroups. When the aligned LSU + SSU sequences were analyzed by tree-building methods (minimum evolution analysis of LogDet-transformed distances, maximum likelihood, and maximum parsimony) and by spectral analysis of LogDet distances, both Ecdysozoa and Lophotrochozoa were indeed strongly supported (e.g., bootstrap values >90%), with higher support than from the SSU sequences alone. Furthermore, with the LogDet-based methods, the LSU + SSU sequences resolved some accepted subgroups within Ecdysozoa and Lophotrochozoa (e.g., the polychaete sequence grouped with the echiuran, and the annelid sequences grouped with the mollusc and lophophorates)-subgroups that SSU-based studies do not reveal. Also, the mollusc sequence grouped with the sequences from lophophorates (brachiopod and phoronid). Like SSU sequences, our LSU + SSU sequences contradict older hypotheses that grouped annelids with arthropods as Articulata, that said flatworms and nematodes were basal bilateralians, and considered lophophorates, nemerteans, and chaetognaths to be deuterostomes. The position of chaetognaths within protostomes remains uncertain: our chaetognath sequence associated with that of an onychophoran, but this was unstable and probably artifactual. Finally, the benefits of combining LSU with SSU sequences for phylogenetic analyses are discussed: LSU adds signal, it can be used at lower taxonomic levels, and its core region is easy to align across distant taxa-but its base frequencies tend to be nonstationary across such taxa. We conclude that molecular systematists should use combined LSU + SSU rRNA genes rather than SSU alone.
Managing patients with mental and physical multimorbidity
Authors: S. W. Mercer, J. Gunn, P. Bower, S. Wyke, B. Guthrie
Journal: BMJ (2012)

Changes are needed in policy, research, and practice

Most people with chronic conditions now have more than one.1 Combinations of illness vary and so do the implications of such multimorbidity. For both patients and professionals, managing a cluster of conditions with synergistic management strategies (concordant conditions such as hypertension, coronary heart disease, and diabetes) is potentially simpler than dealing with conditions with non-synergistic management strategies (discordant conditions such as cardiovascular disease, chronic obstructive pulmonary disease, and arthritis). When the mix of conditions experienced includes both physical and mental health problems, however, the poorly stitched seams of professional care are at their most threadbare. The stigma that surrounds mental ill health may prevent patients with physical conditions from disclosing mental health concerns, which compounds problems of management. For these patients outcomes are usually worse.2

Although the clinical course of multimorbidity is not well understood,3 the relation between mental and physical problems seems to be bidirectional. Patients with severe and enduring mental health problems such as chronic depression, dementia, or psychotic disorder are at high risk of developing long term physical conditions, and the risk of mental health problems increases substantially in …
Transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic variceal ligation in the prevention of variceal rebleeding in patients with cirrhosis: a randomised trial
Authors: G Pomier-Layrargues, J P Villeneuve, M Deschênes, B Bui, P Perreault, D Fenyves, B Willems, D Marleau, M Bilodeau, M Lafortune, M P Dufresne
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> The transjugular intrahepatic portosystemic shunt (TIPS) is a new therapeutic modality for variceal bleeding. In this study we compared the two year survival and rebleeding rates in cirrhotic patients treated by either variceal band ligation or TIPS for variceal bleeding. <h3>METHODS</h3> Eighty cirrhotic patients (Pugh score 7–12) with variceal bleeding were randomly allocated to TIPS (n=41) or ligation (n=39), 24 hours after control of bleeding. <h3>RESULTS</h3> Mean follow up was 581 days in the ligation group and 678 days in the TIPS group. The two year survival rate was 57% in the TIPS group and 56% in the ligation group (NS); the incidence of variceal rebleeding after two years was 18% in the TIPS group and 66% in the ligation group (p&lt;0.001). Uncontrolled rebleeding occurred in 11 patients in the ligation group (eight were rescued by emergency TIPS) but in none of the TIPS group. The incidence of encephalopathy at two years was 47% in the TIPS group and 44% in the ligation group (NS). <h3>CONCLUSIONS</h3> TIPS did not increase the two year survival rate compared with variceal band ligation after variceal bleeding in cirrhotic patients with moderate or severe liver failure. It significantly reduced the incidence of variceal rebleeding without increasing the rate of encephalopathy.
Study of the aetiology of wheezing illness at age 16 in two national British birth cohorts.
Authors: S. Lewis, B. Butland, D. Strachan, J. Bynner, D. Richards, N. Butler, J. Britton
Journal: Thorax (1996)

BACKGROUND: Data from two national British birth cohorts were used to measure the increase in prevalence of wheezing illness at age 16 between 1974 and 1986, and to investigate the role of several potential risk factors in the increase. METHODS: The occurrence of self-reported asthma or wheezy bronchitis within the past year, and the frequency of attacks of wheezing illness at age 16, were compared in 11,262 and 9266 children born in one week of 1958 and 1970, respectively. The effects of several putative risk factors for asthma--including birth weight, maternal age, birth order, breast feeding, maternal smoking in pregnancy, child9s personal smoking, and father9s social class--on the change in occurrence of wheezing illness at age 16 were assessed by multiple logistic regression. RESULTS: The annual period prevalence of asthma or wheezy bronchitis at age 16 increased from 3.8% in 1974 to 6.5% in 1986 (prevalence ratio (PR) = 1.71, 95% CI 1.52 to 1.93). The proportion of children experiencing attacks more than once a week increased from 0.2% to 0.7% (PR = 3.77, 95% CI 2.28 to 6.23). The prevalence of self-reported eczema and hayfever within the past year doubled between 1974 and 1986, suggesting that the increase in asthma was part of a general increase in the prevalence of atopic disease. However, in the complete dataset, after adjustment for the effects of the risk factors studied, the prevalence odds ratio for asthma or wheezy bronchitis in 1986 compared with 1974 was virtually unchanged from the unadjusted value at 1.77 (95% CI 1.46 to 2.15). CONCLUSION: The prevalence of wheezing illness in British teenagers increased by approximately 70% between 1974 and 1986. This increase appears to have occurred in the context of a general increase in atopic disease and was largely unexplained by changes in the distribution of maternal age, birth order, birth weight, infant feeding, maternal smoking, active smoking by the child, or father9s social class.
Analysis of the p53 tumor-suppressor gene in hepatocellular carcinomas from britain
Authors: Christine Challen, John Lunec, William Warren, Jane Collier, Margaret F. Bassendine
Journal: Hepatology (1992)

Human hepatocellular carcinomas from patients in Britain, an area of low prevalence of hepatocellular carcinoma and low dietary exposure to aflatoxin B1, were analyzed for mutations in the p53 tumor-suppressor gene. Abnormalities in the p53 gene were detected in 2 of 19 hepatocellular carcinomas by polymerase chain reaction--single-stranded conformation polymorphism. Direct sequencing of the evolutionarily conserved regions of p53 (exons 5, 6, 7 and 8), where mutations have been commonly found in a variety of tumors, confirmed that only two hepatocellular carcinomas had mutations in p53, one a 6-bp deletion of codons 158 and 159 (exon 5) and the other a G to A transition at codon 286 (exon 8). No mutations were found in any hepatocellular carcinoma in exons 6 and 7; in particular all tumors had wild-type sequence at codon 249, which has been reported to be a mutational hot spot in the p53 gene in hepatocellular carcinomas from high incidence areas such as China and southern Africa. Abnormalities in p53 expression were examined by immunohistochemistry and found in 1 of the 19 hepatocellular carcinomas. These findings show that p53 mutations are infrequently involved in the malignant transformation of hepatocytes in an area of low hepatocellular carcinoma prevalence. They support the suggestion of a possible link between dietary exposure to aflatoxin and selective G to T mutations at codon 249 of the p53 gene. Our observations also indicate that hepatitis B virus infection alone, present in six of the hepatocellular carcinomas examined, does not account for the specificity for codon 249 mutations reported from endemic areas.