tbuckley/cabot-search huggingface dataset:
Clinical Phenotype and Functional Characterization of <i>CASQ2</i> Mutations Associated With Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Marina Raffaele di Barletta, Serge Viatchenko-Karpinski, Alessandra Nori, Mirella Memmi, Dmitry Terentyev, Federica Turcato, Giorgia Valle, Nicoletta Rizzi, Carlo Napolitano, Sandor Gyorke, Pompeo Volpe, Silvia G. Priori
Journal: Circulation (2006)

Four distinct mutations in the human cardiac calsequestrin gene (CASQ2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). The mechanisms leading to the clinical phenotype are still poorly understood because only 1 CASQ2 mutation has been characterized in vitro.We identified a homozygous 16-bp deletion at position 339 to 354 leading to a frame shift and a stop codon after 5aa (CASQ2(G112+5X)) in a child with stress-induced ventricular tachycardia and cardiac arrest. The same deletion was also identified in association with a novel point mutation (CASQ2(L167H)) in a highly symptomatic CPVT child who is the first CPVT patient carrier of compound heterozygous CASQ2 mutations. We characterized in vitro the properties of CASQ2 mutants: CASQ2(G112+5X) did not bind Ca2+, whereas CASQ2(L167H) had normal calcium-binding properties. When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca2+-storing capacity and reduced the amplitude of I(Ca)-induced Ca2+ transients and of spontaneous Ca2+ sparks in permeabilized myocytes. Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2(G112+5X).CASQ2(L167H) and CASQ2(G112+5X) alter CASQ2 function in cardiac myocytes, which leads to reduction of active sarcoplasmic reticulum Ca2+ release and calcium content. In addition, CASQ2(G112+5X) displays altered calcium-binding properties and leads to delayed afterdepolarizations. We conclude that the 2 CASQ2 mutations identified in CPVT create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias.
Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse
Authors: E Coustan-Smith, A Gajjar, N Hijiya, B I Razzouk, R C Ribeiro, G K Rivera, J E Rubnitz, J T Sandlund, M Andreansky, M L Hancock, C-H Pui, D Campana
Journal: Leukemia (2004)
Agranulocytosis Caused by Chinese Herbal Medicines
Authors: Curt A. Ries
Journal: JAMA (1975)

Four non-Chinese patients, middle-aged or older, developed agranuloctyosis while taking Chinese herbal medicines for relief of arthritis and back pain. All four developed life-threatening infections with bacterial sepsis; one died. The herbal medicines were shown to contain substantial amounts of undeclared aminopyrine and phenylbutazone, drugs that are well-known causes of agranulocytosis. These Chinese herbal medicines are widely available over the counter throughout the United States.
US panel rules that warnings on two birth control pills be strengthened
Authors: J. Lenzer
Journal: BMJ (2011)

Labels on the popular birth control pills Yasmin and Yaz should be strengthened to include more information about the possibility that they could increase the risk of blood clots, an advisory committee to the Food and Drug Administration said on Thursday 8 December.

The panel, which voted 21 to five in favour of changing the labels, stopped short of recommending that the labels should warn that the drugs, whose main active ingredient is drospirenone, are more likely than other contraceptive pills to cause blood clots. Instead the experts suggested that the labels say that the evidence about blood clots is conflicting. The panel also decided by 15-11 that the drug’s benefits outweighed its risks.

The panel reached its decision after reviewing a number of studies of drospirenone, some of which found an increased risk of thromboembolic events.

However, the panel was not shown documents that are at the heart of a report by David Kessler, a former …
Letter: Protection of cytomegalovirus-infected cells by IgG antibody.
Authors: P Diosi, G Herzog
Journal: BMJ (1973)

In Scotland similar immunoglobulin is pre- pared at the Protein Fractionation Gentre and can be obtained by contacting the director of the appropxiate regional blood transfusion centre who will also provide information re- garding the local follow-up arrangements for the recipient.-Iam, etc.,
Distinct regulation of c-myb gene expression by HoxA9, Meis1 and Pbx proteins in normal hematopoietic progenitors and transformed myeloid cells
Authors: E Dassé, G Volpe, D S Walton, N Wilson, W Del Pozzo, L P O'Neill, R K Slany, J Frampton, S Dumon
Journal: Blood Cancer Journal (2012)

The proto-oncogenic protein c-Myb is an essential regulator of hematopoiesis and is frequently deregulated in hematological diseases such as lymphoma and leukemia. To gain insight into the mechanisms underlying the aberrant expression of c-Myb in myeloid leukemia, we analyzed and compared c-myb gene transcriptional regulation using two cell lines modeling normal hematopoietic progenitor cells (HPCs) and transformed myelomonocytic blasts. We report that the transcription factors HoxA9, Meis1, Pbx1 and Pbx2 bind in vivo to the c-myb locus and maintain its expression through different mechanisms in HPCs and leukemic cells. Our analysis also points to a critical role for Pbx2 in deregulating c-myb expression in murine myeloid cells cotransformed by the cooperative activity of HoxA9 and Meis1. This effect is associated with an intronic positioning of epigenetic marks and RNA polymerase II binding in the orthologous region of a previously described alternative promoter for c-myb. Taken together, our results could provide a first hint to explain the abnormal expression of c-myb in leukemic cells.
SAMARIUM (SM) 153 EDTMP IN THE TREATMENT OF PAINFUL BONE METASTASES SECONDARY TO BREAST CANCER
Authors: R. H. Reid, A. R. Dart, F. E. Perrera, V. M. Venkatesant, D Maharaj, M. Kurman
Journal: Clinical Nuclear Medicine (1995)

Reid, R. H.*; Dart, A. R.†; Perrera, F. E.†; Venkatesant, V. M.†; Maharaj, D*; Kurman, M.§ Author Information
German scientists withdraw research paper on cancer vaccine
Authors: A. Tuffs
Journal: BMJ (2003)

More than three years after publishing a research paper in Nature Medicine , 15 German scientists retracted it because of “several incorrect statements and the erroneous presentation of primary data, results and conclusions” ( Nature Medicine 2003;9: 1221 ).

The paper, whose lead author was Alexander Kugler, then senior registrar in the urology department of Gottingen University Hospital, presented a small clinical trial …
Cognitive Behavior Therapy for Pediatric Obsessive-Compulsive Disorder—Reply
Authors: Martin E. Franklin
Journal: JAMA (2012)

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EXERCISE CAPACITY IS AN INDEPENDENT PREDICTOR OF LONG-TERM OUTCOMES IN HYPERTROPHIC CARDIOMYOPATHY PATIENTS THAT UNDERWENT EXERCISE ECHOCARDIOGRAPHY
Authors: Parag Patel, Aditya Bhonsale, Nicholas Smedira, Maran Thamilarasan, Bruce Lytle, Harry Lever, Milind Desai
Journal: Journal of the American College of Cardiology (2012)
Observations on Serum Cholesterol Levels in the Twin Population of Evans County, Georgia
Authors: JOHN R. MCDONOUGH, CURTIS G. HAMES, B. G. GREENBERG, LOUIS H. GRIFFIN, ANDREW J. EDWARDS
Journal: Circulation (1962)

Important factors affecting the variation in cholesterol were found to be the genotype of the individual, age, and type of residence. The effect of genotype is clearly shown in comparing MZ twins with their matched pairs. The difference between MZ twins and their matched pairs was large and statistically significant, while for DZ and UD twins the difference was so small it could easily have been due to chance. In interpreting the significance of the effect of type of residence, we are also comparing two age groups that are almost nonoverlapping, so that adjustment for age by covariance might be questionable, since it involves extrapolating beyond the limits of the data. Thus, it seems that two important sources of variation of cholesterol have been isolated: type of residence or age which is confounded or entangled, and genotype.
Monocyte IL-10 Production during Respiratory Syncytial Virus Bronchiolitis Is Associated with Recurrent Wheezing in a One-Year Follow-up Study
Authors: LOUIS BONT, COBI J. HEIJNEN, ANNEMIEKE KAVELAARS, WIM M. C. van AALDEREN, FRANK BRUS, JOS Th. M. DRAAISMA, SIBYL M. GEELEN, JAN L. L. KIMPEN
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Respiratory syncytial virus (RSV) bronchiolitis is associated with subsequent recurrent wheezing episodes. To determine whether cytokine responses during infection can be of predictive value for the development of recurrent wheezing, we performed a follow-up study in 50 hospitalized children with RSV bronchiolitis. Monocyte and lymphocyte cytokine responses in vitro were studied during the acute phase of disease, and again during the convalescent phase, 3 to 4 wk later. Monocyte cytokine responses, including interleukin-10 (IL-10), were measured in whole blood cultures, stimulated with lipopolysaccharide and interferon- γ (LPS + IFN- γ ). In addition, T-cell cytokine responses, including IFN- γ and IL-4 production, were measured in whole-blood cultures stimulated with phytohemagglutinin (PHA) or α CD2 + α CD28. Cytokine responses were analyzed in relation to the development of recurrent episodes of wheezing, documented by parents in a diary during a 1-yr follow-up period. IL-10 responses during the acute phase of RSV bronchiolitis were comparable to those in healthy control subjects. During the convalescent phase, IL-10 responses were significantly increased in patients as compared with those in healthy control subjects (p < 0.001). At follow-up, 27 children (58%) had recurrent episodes of wheezing. IL-10 levels, measured during the convalescent phase, were significantly higher in patients who developed recurrent wheezing during the year after RSV bronchiolitis than in patients without recurrent episodes of wheezing (p = 0.006). Moreover, IL-10 responses during the convalescent phase correlated significantly with the number of wheezing episodes (r = 0.42, n = 46, p = 0.004). Interestingly, no association was found between IFN- γ responses, IL-4 responses, or IFN γ /IL-4 ratios and recurrent wheezing. We conclude that monocyte IL-10 responses in vitro upon stimulation with nonspecific stimuli may have predictive value for the development of recurrent wheezing after RSV bronchiolitis. Moreover, our results indicate that not only allergen-driven Th2 cytokine responses can lead to asthmatic symptoms but also virus-induced changes in cytokine responses may result in asthmatic symptoms.
Gene Expression Profiles and Molecular Markers To Predict Recurrence of Dukes' B Colon Cancer
Authors: Yixin Wang, Tim Jatkoe, Yi Zhang, Matthew G. Mutch, Dmitri Talantov, John Jiang, Howard L. McLeod, David Atkins
Journal: Journal of Clinical Oncology (2004)

The 5-year survival rate of patients with Dukes' B colon cancer is approximately 75%. Identification of the patients at high risk of recurrence in this group would allow better staging and more informed use of adjuvant chemotherapy. In this study, we used DNA chip technology to systematically identify new prognostic markers for tumor relapse in Dukes' B patients.Using Affymetrix U133a GeneChip containing approximately 22,000 transcripts (Affymetrix, Santa Clara, CA), RNA samples from 74 patients with Dukes' B colon cancer were analyzed. Thirty-one patients developed tumor relapse in less than 3 years, whereas 43 patients remained disease-free for more than 3 years after surgery. Two supervised class prediction approaches were used to identify gene markers that can best discriminate between patients who would experience relapse and patients who would remain disease-free. A multivariate Cox model was built to predict recurrence.Gene expression profiling identified a 23-gene signature that predicts recurrence in Dukes' B patients. This signature was validated in 36 independent patients. The overall performance accuracy was 78%. Thirteen of 18 relapse patients and 15 of 18 disease-free patients were predicted correctly, giving an odds ratio of 13 (95% CI, 2.6 to 65; P =.003). The log-rank test indicated a significant difference in disease-free time between the predicted relapse and disease-free patients (P =.0001).The clinical value of these markers is that the patients at a high predicted risk of relapse (13-fold risk) could be upstaged to receive adjuvant therapy, similar to Dukes' C patients. Our data highlight the feasibility of a prognostic assay that could focus more intensive treatment for localized colon cancer.
IL-12–producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion
Authors: Alexander Rölle, Julia Pollmann, Eva-Maria Ewen, Vu Thuy Khanh Le, Anne Halenius, Hartmut Hengel, Adelheid Cerwenka
Journal: Journal of Clinical Investigation (2014)

Human cytomegalovirus (HCMV) infection is the most common cause of congenital viral infections and a major source of morbidity and mortality after organ transplantation. NK cells are pivotal effector cells in the innate defense against CMV. Recently, hallmarks of adaptive responses, such as memory-like features, have been recognized in NK cells. HCMV infection elicits the expansion of an NK cell subset carrying an activating receptor heterodimer, comprising CD94 and NKG2C (CD94/NKG2C), a response that resembles the clonal expansion of adaptive immune cells. Here, we determined that expansion of this NKG2C(+) subset and general NK cell recovery rely on signals derived from CD14(+) monocytes. In a coculture system, a subset of CD14(+) cells with inflammatory monocyte features produced IL-12 in response to HCMV-infected fibroblasts, and neutralization of IL-12 in this model substantially reduced CD25 upregulation and NKG2C(+) subset expansion. Finally, blockade of CD94/NKG2C on NK cells or silencing of the cognate ligand HLA-E in infected fibroblasts greatly impaired expansion of NKG2C(+) NK cells. Together, our results reveal that IL-12, CD14(+) cells, and the CD94/NKG2C/HLA-E axis are critical for the expansion of NKG2C(+) NK cells in response to HCMV infection. Moreover, strategies targeting the NKG2C(+) NK cell subset have the potential to be exploited in NK cell-based intervention strategies against viral infections and cancer.
Abstract 3790: Loss of BRCA1 regulates autophagy as a cellular stress response in breast and ovarian cancer cells
Authors: Maggie Kei Shuen Tang, Alice Sze Tsai Wong
Journal: Cancer Research (2011)

Abstract Inactivation of cell death is a major step in tumor development. The BRCA1 tumor suppressor, which is frequently mutated in human breast and ovarian cancers, is a critical mediator of cell death. Although the role of BRCA1 gene loss for inhibiting apoptosis is well established, little is known regarding its involvement in other cell survival pathways. Increasing evidence strongly supports that autophagy is a key strategy for cell survival in response to stress. Endoplasmic reticulum (ER) stress and nutrient deprivation are common environmental stresses governing the survival and adaptation of tumor cells in vivo. Here we show that BRCA1 is an important regulator of autophagy, particularly under stress conditions. We found that autophagy could be induced by chemicals that cause ER stress and nutrient deprivation in T47D breast cancer cells and OVCAR-3 ovarian cancer cells with targeted inhibition of endogenous BRCA1 using small interfering RNA. This was characterized by conversion of microtubule-associated protein 1 light chain 3 (LC3) I into LC3 II, punctate green fluorescent protein-labeled LC3 fluorescence, and autophagosomes formation. Treatment of cells with the lysosomal inhibitors, Pepstatin A and E-64d, augmented autophagy, suggesting that autophagosomes were actively produced. In contrast, BRCA1-mediated autophagy that was induced under stress conditions was inhibited by treatment with autophagy inhibitor 3-methyladenine. Similar results were obtained in cells with decreased beclin 1 level by RNA interference. These results reveal a novel link between BRCA1 and autophagy, which may contribute to the survival of BRCA1-deficient cancer cells in their microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3790. doi:10.1158/1538-7445.AM2011-3790
Abstract 2112: CA-microsatellite instability as a factor of branch migration impeding in Holliday junctions
Authors: Natalia Y. Karpechenko, Nina G. Dolinnaya, Vladimir I. Popenko, Marianna G. Yakubovskaya, Victoria K. Gasanova
Journal: Cancer Research (2012)

Abstract The efficient and accurate repair of DNA double-strand breaks is critical for cell survival. HR provides an “error-free” way for the break repair. There is no loss of genetic information when homolog or sister chromatid are used for repair. They are mainly involved in HR and the frequency of non-sister chromatid interaction is greatly lower. However, when recombination occurs between non-sister chromatids, in the half of these cases it leads to loss of heterozygosity (LOH). This genetic alteration represents an important step in multistage carcinogenesis. Recently, the impact of LOH caused by HR in carcinogenesis of inherited cancer has been demonstrated to exceed impacts of point mutagenesis and non-homologous end joining. HR can be modulated by a variety of factors, and deep knowledge of the molecular background of this process is essential to predict and control corresponding genetic rearrangements. Some microsatellites represent “hot-spots” of recombination. In particular, one of the most abundant microsatellites, CA-repeats, enhances recombination between DNA molecules as observed in bacteria and eukaryotes. Previously we described spontaneous DNA-DNA interaction of homologous duplexes via HJ formation, and based on this investigation we elaborated the model system for HJs. We formed several types of HJs using: (1) random fragments restricted from pUC19; (2) fragments of the same sequence but amplified via PCR; (3) restricted fragments of the pE10 plasmid, harboring (CA/TG)31-repeat; (4) corresponding PCR products of the pE10 plasmid. Using different DNA polymerases we demonstrated that PCR amplification caused repetitive unit deletions/insertions in the (CA/TG)31-tract. It leaded to formation in PCR product of the fragment with (CA/TG)31-repeat of heteroduplexes and homoduplexes, differing mainly by one repetitive unit that is in accordance with previously published data. Corresponding restricted fragments with (CA/TG)31-repeats were significantly more stable. Using electron microscopy we showed that the majority of HJs formed by the PCR fragments with (CA/GT)31-repeats had their cross-points at the repetitive region, while the cross points of HJs formed by restricted fragments with (CA/TG)31-repeats and by entirely random sequences were mainly localized at the ends of the fragments. Demonstrated influence of (CA/TG)n-repeat instability on the branch migration is discussed in respect of the role of CA-microsatellites in homologous recombination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2112. doi:1538-7445.AM2012-2112
Abstract PD10-06: CXCL13 mRNA predicts Docetaxel benefit in Triple Negative tumors
Authors: RM Wirtz, M Leinonen, P Bono, J Isola, P-L Kellokumpu-Lehtinen, V Kataja, T Turpeenniemi-Hujanen, S Jyrkkiö, S Eidt, M Schmidt, H Joensuu
Journal: Cancer Research (2012)

Abstract Background: Presence of immune cell infiltrates in tumor may influence outcome of patients with node negative breast cancer (BC) (Schmidt et al 2008). High expression of CXCL13 (B lymphocyte chemoattractant chemokine) was strongly associated with favorable survival in one recent series consisting of BC patients treated with adjuvant chemotherapy (Razis et al. 2012). Here we examined the clinical significance of breast tumor CXCL13 mRNA levels within the context of the FinHer trial, where patients were randomly assigned to receive 3 cycles of either docetaxel or vinorelbine followed by 3 cycles of FEC. Patients with HER2-positive BC had a second randomization for trastuzumab vs. control. Since intratumoral B cells are of particular importance for obtaining response to chemotherapy in triple negative BC (TNBC) and of limited value in luminal BC (Schmidt et al. 2012), and trastuzumab treatment is a confounding factor in HER2+ BC, we focused on TNBC. Methods: RNA was extracted from FFPE tumor tissue of 917 (90.8%) out of the 1010 patients who participated in the FinHer trial. CXCL13 mRNA expression was measured using RT-qPCR. The molecular subtypes (luminal, HER2-enriched and triple-negative) were determined using IHC and central chromogenic in situ hybridization (CISH) testing. Prognostic significance of factors was assessed using univariate and multivariate analyses. Distant disease-free survival (DDFS) between groups was compared using the log-rank test. Results: Tumor CXCL13 mRNA expression showed a bimodal distribution and correlated negatively with tumor ESR1 mRNA levels (r = −0,31; p &amp;lt; 0.0001). 146 (15.9%) out of the 917cancers were classified as TNBC. High tumor CXCL13 mRNA levels above the median were strongly associated with favorable 5-yr DDFS in TNBC compared to low levels (85% vs. 60%; p &amp;lt; 0.0001). The prognostic value of tumor CXCL13 was evident in the subset of women with TNBC treated with vinorelbine (5-year DDFS 90% vs. 40%; p &amp;lt; 0.0001), whereas no significant association was found in the docetaxel arm (5-year DDFS 80% vs. 80%; p = 0.76). When only patients with TNBC and low CXCL13 mRNA levels were assessed, patients treated with docetaxel had better DDFS compared to those treated with vinorelbine (5-year DDFS 80% versus 40%; p &amp;lt; 0.0064). There was no DDFS difference between treatment arms in patients exhibiting high CXCL13 expression. Conclusions: Tumor CXCL13 mRNA expression is a favorable prognostic factor for women with TNBC treated with adjuvant chemotherapy providing further evidence that the host immune response may influence outcome of patients with early BC. The clinical significance of the host B cell immune response may vary substantially pending on the type of chemotherapy administered. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-06.
A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells
Authors: A M Martelli, P L Tazzari, G Tabellini, R Bortul, A M Billi, L Manzoli, A Ruggeri, R Conte, L Cocco
Journal: Leukemia (2003)