tbuckley/cabot-search huggingface dataset:
Correlation of <i>CDA, ERCC1</i>, and <i>XPD</i> Polymorphisms with Response and Survival in Gemcitabine/Cisplatin–Treated Advanced Non–Small Cell Lung Cancer Patients
Authors: Carmelo Tibaldi, Elisa Giovannetti, Enrico Vasile, Valentina Mey, Adrie C. Laan, Sara Nannizzi, Roberta Di Marsico, Andrea Antonuzzo, Cinzia Orlandini, Simona Ricciardi, Mario Del Tacca, Godefridus J. Peters, Alfredo Falcone, Romano Danesi
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non–small cell lung cancer (NSCLC). Polymorphisms at the xeroderma pigmentosum group D (XPD), excision repair cross-complementing 1 (ERCC1), and cytidine deaminase (CDA) genes have been associated with alterations in enzymatic activity and may change sensitivity to the widely used cisplatin-gemcitabine regimen. Experimental Design: Analyses of CDA, XPD, and ERCC1 polymorphisms were done on blood samples of 65 chemotherapy-naïve, advanced NSCLC patients treated with cisplatin-gemcitabine. Furthermore, CDA enzymatic activity was evaluated by high-performance liquid chromatography analysis. Association between XPD Asp312Asn and Lys751Gln, ERCC1 C118T, and CDA Lys27Gln polymorphisms and response, clinical benefit, toxicity, time to progression (TTP), and overall survival (OS) was estimated using Pearson's χ2 tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model. Results: The CDA Lys27Lys polymorphism significantly correlated with better clinical benefit (P = 0.04) and grade ≥3 neutropenia and thrombocytopenia, as well as with longer TTP and OS (P = 0.006 and P = 0.002, respectively), whereas no significant associations were found among ERCC1 and XPD polymorphisms and both response and clinical outcome. Finally, the enzymatic activity assay showed a significant lower mean in subjects harboring the CDA Lys27Lys polymorphism. Conclusions: Our data suggested the role of CDA Lys27Lys polymorphism as a possible predictive marker of activity, toxicity, TTP, and OS in advanced NSCLC patients treated with cisplatin and gemcitabine. These results may be explained by the lower enzymatic activity associated with the Lys27Lys CDA and offer a potential new tool for treatment optimization.
Risk factors for a first thrombotic event in antiphospholipid antibody carriers: a prospective multicentre follow-up study
Authors: Amelia Ruffatti, Teresa Del Ross, Manuela Ciprian, Maria T Bertero, Sciascia Salvatore, Salvatore Scarpato, Carlomaurizio Montecucco, Silvia Rossi, Paola Caramaschi, Domenico Biasi, Andrea Doria, Mariaelisa Rampudda, Nuzzo Monica, Fabio Fischetti, Ugo Picillo, Antonio Brucato, Elisa Salvan, Pengo Vittorio, Pierluigi Meroni, Angela Tincani
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To assess risk factors for a first thrombotic event in confirmed antiphospholipid (aPL) antibody carriers and to evaluate the efficacy of prophylactic treatments. Methods Inclusion criteria were age 18–65 years, no history of thrombosis and two consecutive positive aPL results. Demographic, laboratory and clinical parameters were collected at enrolment, once a year during the follow-up and at the time of the thrombotic event, whenever that occurred. Results 258 subjects were prospectively observed between October 2004 and October 2008. The mean±SD follow-up was 35.0±11.9 months (range 1–48). A first thrombotic event (9 venous, 4 arterial and 1 transient ischaemic attack) occurred in 14 subjects (5.4%, annual incidence rate 1.86%). Hypertension and lupus anticoagulant (LA) were significantly predictive of thrombosis (both at p&lt;0.05) and thromboprophylaxis was significantly protective during high-risk periods (p&lt;0.05) according to univariate analysis. Hypertension and LA were identified by multivariate logistic regression analysis as independent risk factors for thrombosis (HR 3.8, 95% CI 1.3 to 11.1, p&lt;0.05, and HR 3.9, 95% CI 1.1 to 14, p&lt;0.05, respectively). Conclusions Hypertension and LA are independent risk factors for thrombosis in aPL carriers. Thromboprophylaxis in these subjects should probably be limited to high-risk situations.
Continuum of Renoprotection with Losartan at All Stages of Type 2 Diabetic Nephropathy
Authors: Giuseppe Remuzzi, Piero Ruggenenti, Annalisa Perna, Borislav D. Dimitrov, Dick de Zeeuw, Darcy A. Hille, Shahnaz Shahinfar, George W. Carides, Barry M. Brenner
Journal: Journal of the American Society of Nephrology (2004)

Renin angiotensin system inhibitor therapy is seldom offered to individuals who have diabetes and advanced chronic kidney disease because of safety concerns. In this post hoc, secondary analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, angiotensin antagonism risk/benefit profile was assessed in 1513 individuals with type 2 diabetes and overt nephropathy. Incidence of ESRD, hospitalizations for heart failure, withdrawals for adverse events, and proteinuria during losartan or conventional treatment were compared within three tertiles of baseline serum creatinine concentration (highest, 2.1 to 3.6 mg/dl; middle, 1.6 to 2.0 mg/dl; lowest, 0.9 to 1.6 mg/dl). Losartan decreased the risk of ESRD by 24.6, 26.3, and 35.3% in highest, middle, and lowest tertiles, respectively. For every 100 patients with serum creatinine >2.0, 1.6 to 2.0, or <1.6 mg/dl, respectively, 4 yr of losartan therapy was estimated to save 18.9, 8.4, and 2.9 ESRD events and US$1,502,855, US$1,021,770, and US$528,591 costs for renal replacement therapy. Losartan also decreased the hospitalizations for heart failure by 50.2 and 45.1, in the highest and middle tertile, respectively. Withdrawals for adverse events other than heart failure were comparable between tertiles and treatment groups. Proteinuria decreased more on losartan than on placebo in all tertiles (highest, 24 versus -8%; middle, 16 versus -8%; lowest, 15 versus -10%). In proteinuric individuals with type 2 diabetes, losartan therapy reduced ESRD and hospitalizations for heart failure and was well tolerated at all levels of renal function. Angiotensin II antagonism is a suitable and well-tolerated treatment for individuals with type 2 diabetes even with GFR levels approaching renal replacement therapy.
Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma1
Authors: Alexandre Carpentier, Florence Laigle-Donadey, Sarah Zohar, Laurent Capelle, Anthony Behin, Annick Tibi, Nadine Martin-Duverneuil, Marc Sanson, Lucette Lacomblez, Sophie Taillibert, Louis Puybasset, Remy Van Effenterre, Jean-Yves Delattre, Antoine F. Carpentier
Journal: Neuro-Oncology (2006)

Neuro-OncologyOligodeoxynucleotides containing CpG motifs (CpG ODNs) display a strong immunostimulating activity and drive the immune response toward the Th1 (T helper type 1) phenotype.These ODNs have shown promising efficacy in preclinical studies when injected locally in several cancer models.We conducted a phase 1 trial to define the safety profile of CpG-28, a phosphorothioate CpG ODN, administered intratumorally by convectionenhanced delivery in patients with recurrent glioblastoma.Cohorts of three to six patients were treated with escalating doses of CpG-28 (0.5-20 mg), and patients were observed for at least four months.Twenty-four patients entered the trial.All patients had previously been treated with radiotherapy, and most patients had received one or several types of chemotherapy.Median
IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis
Authors: Matjaz Rokavec, Meryem Gülfem Öner, Huihui Li, Rene Jackstadt, Longchang Jiang, Dmitri Lodygin, Markus Kaller, David Horst, Paul K. Ziegler, Sarah Schwitalla, Julia Slotta-Huspenina, Franz G. Bader, Florian R. Greten, Heiko Hermeking
Journal: Journal of Clinical Investigation (2014)

Members of the miR-34 family are induced by the tumor suppressor p53 and are known to inhibit epithelial-to-mesenchymal transition (EMT) and therefore presumably suppress the early phases of metastasis. Here, we determined that exposure of human colorectal cancer (CRC) cells to the cytokine IL-6 activates the oncogenic STAT3 transcription factor, which directly represses the MIR34A gene via a conserved STAT3-binding site in the first intron. Repression of MIR34A was required for IL-6–induced EMT and invasion. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6–dependent STAT3 activation, as a conserved, direct miR-34a target. The resulting IL-6R/STAT3/miR-34a feedback loop was present in primary colorectal tumors as well as CRC, breast, and prostate cancer cell lines and associated with a mesenchymal phenotype. An active IL-6R/STAT3/miR-34a loop was necessary for EMT, invasion, and metastasis of CRC cell lines and was associated with nodal and distant metastasis in CRC patient samples. p53 activation in CRC cells interfered with IL-6–induced invasion and migration via miR-34a–dependent downregulation of IL6R expression. In Mir34a-deficient mice, colitis-associated intestinal tumors displayed upregulation of p-STAT3, IL-6R, and SNAIL and progressed to invasive carcinomas, which was not observed in WT animals. Collectively, our data indicate that p53-dependent expression of miR-34a suppresses tumor progression by inhibiting a IL-6R/STAT3/miR-34a feedback loop.
A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657
Authors: Jastinder Sohal, Vernon T. Phan, Philip V. Chan, Elizabeth M. Davis, Bhumi Patel, Louise M. Kelly, Tinya J. Abrams, Anne Marie O'Farrell, D. Gary Gilliland, Michelle M. Le Beau, Scott C. Kogan
Journal: Blood (2003)
Megavitamins for Minimal Brain Dysfunction
Authors: L. Eugene Arnold
Journal: JAMA (1978)

Preliminary to a stimulant comparison study, 31 children with minimal brain dysfunction randomly received either placebo or a megavitamin combination. During a two-week trial, only two children responded so well that stiumlants were not considered necessary; both were in the placebo group. Change scores from pretest to posttest on four blind ratings by teachers and parents did not show a significant difference between the placebo and vitamin groups.
Quartet-Mapping, a Generalization of the Likelihood-Mapping Procedure
Authors: Kay Nieselt-Struwe, Arndt von Haeseler
Journal: Molecular Biology and Evolution (2001)

Likelihood-mapping (LM) was suggested as a method of displaying the phylogenetic content of an alignment. However, statistical properties of the method have not been studied. Here we analyze the special case of a four-species tree generated under a range of evolution models and compare the results with those of a natural extension of the likelihood-mapping approach, geometry-mapping (GM), which is based on the method of statistical geometry in sequence space. The methods are compared in their abilities to indicate the correct topology. The performance of both methods in detecting the star topology is especially explored. Our results show that LM tends to reject a star tree more often than GM. When assumptions about the evolutionary model of the maximum-likelihood reconstruction are not matched by the true process of evolution, then LM shows a tendency to favor one tree, whereas GM correctly detects the star tree except for very short outer branch lengths with a statistical significance of >0.95 for all models. LM, on the other hand, reconstructs the correct bifurcating tree with a probability of >0.95 for most branch length combinations even under models with varying substitution rates. The parameter domain for which GM recovers the true tree is much smaller. When the exterior branch lengths are larger than a (analytically derived) threshold value depending on the tree shape (rather than the evolutionary model), GM reconstructs a star tree rather than the true tree. We suggest a combined approach of LM and GM for the evaluation of starlike trees. This approach offers the possibility of testing for significant positive interior branch lengths without extensive statistical and computational efforts.
The Fbw7 Tumor Suppressor Targets KLF5 for Ubiquitin-Mediated Degradation and Suppresses Breast Cell Proliferation
Authors: Dong Zhao, Han-Qiu Zheng, Zhongmei Zhou, Ceshi Chen
Journal: Cancer Research (2010)

Fbw7 is a tumor suppressor frequently inactivated in cancers. The KLF5 transcription factor promotes breast cell proliferation and tumorigenesis through upregulating FGF-BP. The KLF5 protein degrades rapidly through the ubiquitin proteasome pathway. Here, we show that the Skp1-CUL1-Fbw7 E3 ubiquitin ligase complex (SCF(Fbw7)) targets KLF5 for ubiquitin-mediated degradation in a GSK3beta-mediated KLF5 phosphorylation-dependent manner. Mutation of the critical S303 residue in the KLF5 Cdc4 phospho-degrons motif ((303)SPPSS) abolishes the protein interaction, ubiquitination, and degradation by Fbw7. Inactivation of endogenous Fbw7 remarkably increases the endogenous KLF5 protein abundances. Endogenous Fbw7 suppresses the FGF-BP gene expression and breast cell proliferation through targeting KLF5 for degradation. These findings suggest that Fbw7 inhibits breast cell proliferation at least partially through targeting KLF5 for proteolysis. This new regulatory mechanism of KLF5 degradation may result in useful diagnostic and therapeutic targets for breast cancer and other cancers.
Infection of human thymocytes by Epstein-Barr virus.
Authors: D Watry, J A Hedrick, S Siervo, G Rhodes, J J Lamberti, J D Lambris, C D Tsoukas
Journal: The Journal of Experimental Medicine (1991)

The Epstein-Barr Virus (EBV) causes infectious mononucleosis, and has been strongly associated with certain human cancers. The virus is thought to exclusively bind to B lymphocytes and epithelial cells via receptors (CR2/CD21) that also interact with fragments of the third component of complement (C3). Recent evidence, however, has challenged this belief. We have used two-color immunofluorescence analysis using biotin-conjugated EBV and streptavidin-phycoerythrin along with fluorescein-conjugated anti-T cell antibodies and demonstrated that CD1-positive, CD3-dull (immature) human thymocytes express functional EBV receptors. In four replicate experiments, the binding of EBV to thymocytes ranged between 8 and 18%. This interaction is specific as evidenced by inhibition with nonconjugated virus, anti-CR2 antibodies, aggregated C3, and an antibody to the gp350 viral glycoprotein that the virus uses to bind to CR2. EBV can infect the thymocytes as evaluated by the presence of episomal EBV-DNA in thymocytes that had been incubated with the virus as short as 12 days or as long as 6 weeks. Episomal DNA analysis was performed by Southern blotting with a EBV-DNA probe that hybridizes to the first internal reiteration of the viral DNA. The presence of the EBV genome is also supported by the detection of EBV nuclear antigen 1 in infected thymocytes, assessed by Western blotting with EBV-immune sera. The EBV infection is specific as determined by blocking experiments using anti-CR2 and anti-gp350 antibodies. Finally, virus infection of thymocytes can act synergistically along with interleukin 2 and induce a lymphokine-dependent cellular proliferation. In view of previously reported cases of EBV-positive human T cell lymphomas, the possibility is raised that EBV may be involved in cancers of T lymphocytes that have not been previously appreciated.
When actions speak just as loudly as words
Authors: Gwyn Samuel Williams
Journal: BMJ (2006)

Even if we dislike or have never watched ER or Holby City , few of us could convincingly deny a secret (or not so secret) desire to make a difference in a cardiac arrest or peri-arrest situation. Indeed, medicine would have been an unlikely career choice if this were not so. For those lucky, or unlucky, enough to have been involved in such situations the first time is always the most impressionable.

I remember the first occasion in …
Metabolic Abnormalities in Children with Asthma
Authors: Lesley Cottrell, William A. Neal, Christa Ice, Miriam K. Perez, Giovanni Piedimonte
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. Yet, the relationship between asthma, obesity, and abnormal lipid and glucose metabolism is not well understood, nor has it been adequately explored in children.
Keratin 19: a key role player in the invasion of human hepatocellular carcinomas
Authors: Olivier Govaere, Mina Komuta, Johannes Berkers, Bart Spee, Carl Janssen, Francesca de Luca, Aezam Katoonizadeh, Jasper Wouters, Léon C van Kempen, Anne Durnez, Chris Verslype, Joery De Kock, Vera Rogiers, Leo A van Grunsven, Baki Topal, Jacques Pirenne, Hugo Vankelecom, Frederik Nevens, Joost van den Oord, Massimo Pinzani, Tania Roskams
Journal: Gut (2013)

<h3>Objective</h3> Keratin (K)19, a biliary/hepatic progenitor cell (HPC) marker, is expressed in a subset of hepatocellular carcinomas (HCC) with poor prognosis. The underlying mechanisms driving this phenotype of K19-positive HCC remain elusive. <h3>Design</h3> Clinicopathological value of K19 was compared with EpCAM, and α-fetoprotein, in a Caucasian cohort of 242 consecutive patients (167 surgical specimens, 75 needle biopsies) with different underlying aetiologies. Using microarrays and microRNA profiling the molecular phenotype of K19-positive HCCs was identified. Clinical primary HCC samples were submitted to in vitro invasion assays and to side population analysis. HCC cell lines were transfected with synthetic siRNAs against <i>KRT19</i> and submitted to invasion and cytotoxicity assays. <h3>Results</h3> In the cohort of surgical specimens, K19 expression showed the strongest correlation with increased tumour size (p&lt;0.01), decreased tumour differentiation (p&lt;0.001), metastasis (p&lt;0.05) and microvascular invasion (p&lt;0.001). The prognostic value of K19 was also confirmed in a set of 75 needle biopsies. Profiling showed that K19-positive HCCs highly express invasion-related/metastasis-related markers (eg, <i>VASP</i>, <i>TACSTD2</i>, <i>LAMB1</i>, <i>LAMC2, PDGFRA</i>), biliary/HPC markers (eg, <i>CD133</i>, <i>GSTP1</i>, <i>NOTCH2</i>, <i>JAG1</i>) and members of the miRNA family 200 (eg, miR-141, miR-200c). In vitro, primary human K19-positive tumour cells showed increased invasiveness, and reside in the chemoresistant side population. Functionally, K19/<i>KRT19</i> knockdown results in reduced invasion, loss of invadopodia formation and decreased resistance to doxorubicin, 5-fluorouracil and sorafenib. <h3>Conclusions</h3> Giving the distinct invasive properties, the different molecular profile and the poor prognostic outcome, K19-positive HCCs should be considered as a seperate entity of HCCs.
EDUCATIONAL BACKGROUND AND JOB ADJUSTMENT OF PRIVATE HOSPITAL PSYCHIATRIC AIDES
Authors: JEAN O. LOVE
Journal: American Journal of Psychiatry (1955)

Seventeen educational criteria were examined to see if they differentiated between psychiatric aides whose job adjustments were rated as satisfactory, as opposed to those whose job adjustments were unsatisfactory or partially satisfactory, and those whose job adjustment was above average, as opposed to those who were rated as average or below. It was found that satisfactory aides were distinguished from others on only 3 variables, namely, academic honors in high school or college, participation in literary extracurricular activities in high school or college, and the mean number of extracurricular activities. The above average aides could be differentiated from the average and below average aides by the frequency of psychology or sociology majors if college graduates, by the frequency of having earned academic honors either in high school or college, by the frequency of having taken part in at least one extracurricular group, by the fact of having been members of student government, musical, and social service or religious activities in high school or college, by the average number of years of education, and by average number of extracurricular activities. It is concluded that the consistent evaluation of these educational criteria would assist materially in the selection of applicants who would likely make above average job adjustments as psychiatric aides in the present situation, but that it would be of less value in selecting those whose job adjustments would be at least satisfactory.
Differential Role of Transient Receptor Potential Channels in Ca2+ Entry and Proliferation of Prostate Cancer Epithelial Cells
Authors: Stephanie Thebault, Matthieu Flourakis, Karine Vanoverberghe, Franck Vandermoere, Morad Roudbaraki, V'yacheslav Lehen'kyi, Christian Slomianny, Benjamin Beck, Pascal Mariot, Jean-Louis Bonnal, Brigitte Mauroy, Yaroslav Shuba, Thierry Capiod, Roman Skryma, Natalia Prevarskaya
Journal: Cancer Research (2006)

Abstract One major clinical problem with prostate cancer is the cells' ability to survive and proliferate upon androgen withdrawal. Because Ca2+ is central to growth control, understanding the mechanisms of Ca2+ homeostasis involved in prostate cancer cell proliferation is imperative for new therapeutic strategies. Here, we show that agonist-mediated stimulation of α1-adrenergic receptors (α1-AR) promotes proliferation of the primary human prostate cancer epithelial (hPCE) cells by inducing store-independent Ca2+ entry and subsequent activation of nuclear factor of activated T cells (NFAT) transcription factor. Such an agonist-induced Ca2+ entry (ACE) relied mostly on transient receptor potential canonical 6 (TRPC6) channels, whose silencing by antisense hybrid depletion decreased both hPCE cell proliferation and ACE. In contrast, ACE and related growth arrest associated with purinergic receptors (P2Y-R) stimulation involved neither TRPC6 nor NFAT. Our findings show that α1-AR signaling requires the coupled activation of TRPC6 channels and NFAT to promote proliferation of hPCE cells and thereby suggest TRPC6 as a novel potential therapeutic target. (Cancer Res 2006; 66(4): 2038-47)
“Leukemic” pattern of in vitro growth in a patient with Down syndrome and transient myeloproliferative disorder
Authors: Barry Mendelow, Selma Krawitz, Richard Cohn, Renée Bernstein
Journal: American Journal of Hematology (1984)

Abstract Peripheral blood cells from a female infant with Down syndrome and over 60% circulating myeloblasts were cultured in soft agar. Growth was virtually restricted to cluster formation, and cluster‐forming cells resided almost exclusively in the very light density fraction (SG &lt; 1.062). Morphological assessment of clusters revealed no evidence of cellular differentiation beyond the blast cell stage. Despite receiving no specific chemotherapy, the peripheral blood normalized within 2 months, and there was no evidence of leukemia when the patient died aged 1 year from cardiac pathology. The findings indicate that caution should be exercised when assessing prognosis on the basis of in vitro growth characteristics in such patients.