tbuckley/cabot-search huggingface dataset:
L-BLP25 Vaccine plus Letrozole Induces a TH1 Immune Response and Has Additive Antitumor Activity in MUC1-Expressing Mammary Tumors in Mice
Authors: Neelima R. Mehta, Gregory T. Wurz, Rebekah A. Burich, Brittany E. Greenberg, Stephen Griffey, Audrey Gutierrez, Katie E. Bell, Jamie L. McCall, Michael Wolf, Michael DeGregorio
Journal: Clinical Cancer Research (2012)

In this study, we examine the immunomodulatory effects and antitumor activity of tamoxifen and letrozole when combined with the human epithelial mucin (hMUC1)-specific vaccine, L-BLP25, in the hMUC1-expressing mammary tumor (MMT) mouse model.Dose-finding studies were conducted for both tamoxifen and letrozole. Letrozole and L-BLP25 combination studies used 69 MMT female mice assigned to five groups: untreated, cyclophosphamide + placebo, cyclophosphamide + L-BLP25, letrozole 0.8 mg/kg, and cyclophosphamide + L-BLP25 + letrozole. Tamoxifen and L-BLP25 combination studies used 48 MMT female mice assigned to five treatment groups: untreated, cyclophosphamide + placebo, cyclophosphamide + L-BLP25, tamoxifen 50 mg/kg, and cyclophosphamide + L-BLP25 + tamoxifen 50 mg/kg group. Mice were injected subcutaneously with L-BLP25 (10 μg) weekly for 8 weeks. Serum cytokines were serially measured using a Luminex assay, whereas splenocytes at termination were analyzed by ELISpot to determine T-helper (T(H))1/T(H)2 polarization of immune response.Daily oral doses of 50 and 0.8 mg/kg of tamoxifen and letrozole, respectively, resulted in a significant survival advantage over controls (P < 0.05). A predominant T(H)1-polarized immune response in vaccinated mice was seen with or without tamoxifen or letrozole treatments. In the L-BLP25 plus letrozole treatment group, statistically significant (P < 0.05) additive antitumor activity was observed, whereas tamoxifen plus L-BLP25 was not significantly different (P > 0.05).The results of this study show that hormonal therapy does not interfere with L-BLP25-induced predominant T(H)1 response, and the combination of L-BLP25 with letrozole has additive antitumor activity in the MMT mouse model.
Molecular Genetics of Natural Populations
Authors: A. J. Greenberg
Journal: Molecular Biology and Evolution (2005)

Significant progress in evolutionary genetics has been made by studying, on the one hand, patterns of DNA sequence polymorphism and, on the other, genetic architecture of complex adaptive traits. However, connections between nucleotide variants under selection and adaptively relevant phenotypes are missing. Such connections can be established using precise gene replacement. We review the recent successful introduction of this technique to the analysis of two evolutionarily interesting loci—Odysseus and desaturase2. Both genes have subtle phenotypes that nevertheless could be identified using gene replacement, demonstrating that effects of naturally occurring alleles can be measured in the laboratory. This is an important first step in connecting statistical signatures of selection with adaptation in nature. More candidate genes involved in adaptation, for example, through cloning of genes responsible for reproductive isolation, now need to be identified. Molecular genetic manipulation, DNA polymorphism analysis, and field studies then have to be integrated to provide fresh insights into the mechanisms of evolutionary change.
Carbonic Anhydrase IX Expression Predicts Outcome of Interleukin 2 Therapy for Renal Cancer
Authors: Michael Atkins, Meredith Regan, David McDermott, James Mier, Eric Stanbridge, Amanda Youmans, Philip Febbo, Melissa Upton, Mirna Lechpammer, Sabina Signoretti
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Renal cancer response to interleukin 2 (IL-2) therapy and patient survival has been correlated with tumor histology and carbonic anhydrase IX (CAIX) expression. In an effort to confirm and expand these observations, we examined CAIX expression in pathology specimens from renal cancer patients who had previously received IL-2 therapy. Experimental Design: Paraffin-embedded tissue sections of renal cancer were immunostained with the MN-75 monoclonal antibody to CAIX and expression levels were correlated with histologic findings and clinical outcome. Results: Tissue specimens were obtained from 66 patients; 27 of whom (41%) had responded to IL-2–based therapy. Fifty-eight specimens were assessed as clear cell, with 56, 33, and 4 having alveolar, granular, and papillary features, respectively. Twenty-four (36%), 31 (47%), and 11 (17%) were classified into good, intermediate, and poor prognosis groups according to the Upton pathology model. Forty-one specimens (62%) had high CAIX expression. Twenty-one of 27 (78%) responding patients had high CAIX expressing tumors compared with 20 of 39 (51%) nonresponders (odds ratio, 3.3; P = 0.04). Median survival was prolonged (P = 0.04) and survival &amp;gt;5 years was only seen in high CAIX expressers. In patients with intermediate pathologic prognosis, all nine responders had high CAIX expression versus 11 of 22 nonresponders. A resultant group with good pathologic prognosis alone or with intermediate pathologic prognosis and high CAIX contained 26 of 27 (96%) responders compared with 18 of 39 (46%) nonresponders (odds ratio, 30; P &amp;lt; 0.01) and exhibited longer median survival (P &amp;lt; 0.01). Conclusions: CAIX expression seems to be an important predictor of outcome in renal cell carcinoma patients receiving IL-2–based therapy and may enhance prognostic information obtained from pathology specimens.
Genome-wide association study identifies five loci associated with lung function
Authors: Emmanouela Repapi, Ian Sayers, Louise V Wain, Paul R Burton, Toby Johnson, Ma'en Obeidat, Jing Hua Zhao, Adaikalavan Ramasamy, Guangju Zhai, Veronique Vitart, Jennifer E Huffman, Wilmar Igl, Eva Albrecht, Panos Deloukas, John Henderson, Raquel Granell, Wendy L McArdle, Alicja R Rudnicka, Inês Barroso, Ruth J F Loos, Nicholas J Wareham, Linda Mustelin, Taina Rantanen, Ida Surakka, Medea Imboden, H Erich Wichmann, Ivica Grkovic, Stipan Jankovic, Lina Zgaga, Anna-Liisa Hartikainen, Leena Peltonen, Ulf Gyllensten, Åsa Johansson, Ghazal Zaboli, Harry Campbell, Sarah H Wild, James F Wilson, Sven Gläser, Georg Homuth, Henry Völzke, Massimo Mangino, Nicole Soranzo, Tim D Spector, Ozren Polašek, Igor Rudan, Alan F Wright, Markku Heliövaara, Samuli Ripatti, Anneli Pouta, Åsa Torinsson Naluai, Anna-Carin Olin, Kjell Torén, Matthew N Cooper, Alan L James, Lyle J Palmer, Aroon D Hingorani, S Goya Wannamethee, Peter H Whincup, George Davey Smith, Shah Ebrahim, Tricia M McKeever, Ian D Pavord, Andrew K MacLeod, Andrew D Morris, David J Porteous, Cyrus Cooper, Elaine Dennison, Seif Shaheen, Stefan Karrasch, Eva Schnabel, Holger Schulz, Harald Grallert, Nabila Bouatia-Naji, Jérôme Delplanque, Philippe Froguel, John D Blakey, John R Britton, Richard W Morris, John W Holloway, Debbie A Lawlor, Jennie Hui, Fredrik Nyberg, Marjo-Riitta Jarvelin, Cathy Jackson, Mika Kähönen, Jaakko Kaprio, Nicole M Probst-Hensch, Beate Koch, Caroline Hayward, David M Evans, Paul Elliott, David P Strachan, Ian P Hall, Martin D Tobin
Journal: Nature Genetics (2009)
Use of chaperones in general practice
Authors: Norma O'Flynn, Nicky Britten
Journal: BMJ (2005)

EDITOR—In two separate papers Rosenthal et al and Conway and Harvey studied the use of chaperones in general practice settings.1 2 Conway and Harvey say that chaperones are used for the protection of the doctor rather than the patient. We have found that practitioners who perform vaginal examinations feel that they are juggling competing interests when deciding on …
Disease characteristics, treatment patterns, and outcomes of follicular lymphoma in patients 40 years of age and younger: an analysis from the National Lymphocare Study
Authors: C. Casulo, B. Day, K.L. Dawson, X. Zhou, C.R. Flowers, C.M. Farber, J.D. Hainsworth, J.R. Cerhan, B.K. Link, A.D. Zelenetz, J.W. Friedberg
Journal: Annals of Oncology (2015)
Reduced-Intensity Hematopoietic Stem Cell Transplants for Malignancies: Harnessing the Graft-Versus-Tumor Effect
Authors: Saar Gill, David L. Porter
Journal: Annual Review of Medicine (2012)

Allogeneic hematopoietic cell transplantation combines the power of cytotoxic chemo/radiotherapy with the ability of the new immune system to seek out and destroy tumor cells. However, administration of such myeloablative transplants is fraught with risks, some of which are related to the intensive conditioning regimens. Reductions in the intensity of the administered cytotoxic therapy have demonstrated that under some circumstances, the burden of fighting tumor and enhancing stem cell engraftment can be shouldered mostly by the transplanted immune system. Reduced intensity has allowed a potentially curative therapy for hematologic malignancies to be offered to an expanded patient population. Ongoing research seeks to enhance the safety and power of this form of allogeneic immunotherapy.
Insulin Secretion and Insulin Sensitivity Pattern Is Different in Isolated Impaired Glucose Tolerance and Impaired Fasting Glucose
Authors: Markolf Hanefeld, Carsta Koehler, Katja Fuecker, Elena Henkel, Frank Schaper, Theodora Temelkova-Kurktschiev
Journal: Diabetes Care (2003)

Isolated impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two risk categories for type 2 diabetes. This study compared both categories with respect to the degree of insulin secretion abnormalities and insulin resistance.This is a crossover comparison of a population at high risk for type 2 diabetes. The subjects were recruited from the Risk Factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes (RIAD) study. They underwent a 75-g oral glucose tolerance test, with measurement of specific insulin, C-peptide, proinsulin, and free fatty acids at baseline and every 30 min after load for 2 h. Factor analysis was performed to evaluate the importance of insulin resistance and secretion abnormalities in both categories.All categories of prediabetic hyperglycemia had a higher cardiovascular risk factor level when adjusted for sex, age, and BMI compared to control subjects with normal glucose tolerance. Subjects with isolated IFG were more insulin resistant than those with IGT. By contrast, subjects with isolated IGT exhibited a more severe deficit in early- and late-phase insulin secretion versus IFG subjects. As shown with factor analysis, in IFG the insulin resistance factor explained 28.4% of the variance, whereas in IGT the insulin secretion factor was dominant, explaining 31.1% of the total variance.Our cross-sectional data from the RIAD study demonstrate that isolated IFG and isolated IGT are different with respect to the degree of insulin resistance and anomalies in insulin secretion, and that subjects with IGT exhibit a deficit in the early and late phases of insulin secretion. This finding may be important for a differential approach in primary prevention of type 2 diabetes.
The hepatic venous pressure gradient (HVPG) in patients with chronic hepatitis C is only associated with the extent of fibrosis and the severity of liver disease
Authors: Y. Consigny, A. Plessier, A. Gervais, D. Cazals-Hatem, C. Degott, R. Moreau, D. Valla, D. Lebrec
Journal: Journal of Hepatology (2003)
Scheduling of Fluorouracil: A Forget-Me-Not in the Jungle of Doublets
Authors: Alberto F. Sobrero
Journal: Journal of Clinical Oncology (2003)

The ultimate goal of randomized phase III clinical trials is to help clinicians choose the best treatment for their patients. The large study reported in this issue of the Journal of Clinical Oncology by Goldberg et al [1] achieves this goal. It conveys the message that the FOLFOX regimen (fluorouracil [FU], leucovorin [LV], and oxaliplatin) is more active in response rate and time to progression, more efficacious in overall survival, and less toxic than the IFL regimen (irinotecan, FU, and LV). The IROX regimen (irinotecan and oxaliplatin) is better than IFL as well, but only in terms of overall survival (OS); IROX’s activity is the same and its toxicity is worse with regard to vomiting and paresthesias. The authors conclude that FOLFOX should be an additional first-line standard treatment for advanced colorectal cancer. The findings certainly support this conclusion for the US, where the first-line treatment of advanced colorectal cancer is likely to change. However, the impact of these data will be more limited on the other side of the Atlantic, as few oncologists in continental Europe use IFL because use of oxaliplatin or irinotecan plus infusional FU has been common practice since the year 2000. The background for this difference in practice is illustrated in Figure 1, which summarizes the advancements in the first-line treatment of this disease through randomized trials during the last 20 years. Every vertical arrow indicates a new regimen, with superior efficacy compared with a prior regimen, whereas the horizontal arrows indicate regimens producing longer time to progression (TTP) and response rate, but without significant survival improvement. In addition, the plus or minus symbols refer to the toxicity of the new therapy compared with the previous one. Every regimen reported in the Figure therefore represents a “full” step ahead (vertical) or a “half” step ahead (horizontal) in the treatment of this disease. It is easy to understand that FU was superior to best supportive care, and that FU plus LV was in turn superior to FU, though with more toxicity. IFL [2] was subsequently more efficacious than FU plus LV, again, at the cost of additional toxicity. It is with great enthusiasm that the enhanced efficacy of FOLFOX observed in this trial is finally accompanied by the minus sign as far as toxicity is concerned. The IROX regimen is not included because of its toxicity profile, whereas IFL plus bevacizumab [3], with its very significant prolongation of OS afforded by the angiogenesis inhibitor compared with
Naturally induced auto-anit-idiotypic antibodies. Induction by identical idiotopes in some members of an outbred rabbit family.
Authors: S B Binion, L S Rodkey
Journal: The Journal of Experimental Medicine (1982)

Naturally induced auto-anti-idiotypic (AAI) antibody responses specific for antimicrococcal antibody idiotypes were detected in 42% of the rabbits in a family immunized with Micrococcus lysodeikticus. The natural AAI response of each rabbit recognized only a portion (11-41%) of that individual's total antimicrococcal antibody population. Cross-reactions of idiotypes were observed within the group of rabbits exhibiting natural AAI responses. Examination of the basis for the cross-reactions showed that the natural AAI antisera recognized identical idiotopes on the antimicrococcal F(ab')2 fragments from each rabbit that made an AAI response. The cross-reactive idiotopes were shown to be of paternal origin and were found in the antimicrococcal antibodies of each offspring. The data strongly support the idiotypic network concept that naturally induced AAI responses may occur routinely in outbred normal individuals as a result of antigenic stimulation. Further, the data suggest that the induction of regulatory AAI antibody responses in outbred rabbits may depend on the expression of particular germ line idiotopes.
Systematic Review of Genomic Integration Sites of Human Papillomavirus Genomes in Epithelial Dysplasia and Invasive Cancer of the Female Lower Genital Tract
Authors: Nicolas Wentzensen, Svetlana Vinokurova, Magnus von Knebel Doeberitz
Journal: Cancer Research (2004)

Cancers of the anogenital tract as well as some head and neck cancers are caused by persistent infections with high-risk type human papillomaviruses (HPVs). Two viral oncogenes, E6 and E7, induce severe chromosomal instability associated with centrosome aberrations, anaphase bridges, chromosome lagging, and breaking. This occurs early in preneoplastic lesions, when the viral genome still persists in an episomal state. In most invasive cancers and also in a few high-grade dysplastic lesions, however, integration of high-risk HPV genomes into the host genome is observed. Integration seems to be a direct consequence of chromosomal instability and an important molecular event in the progression of preneoplastic lesions. Disruption or deregulation of defined critical cellular gene functions by insertional mutagenesis by integrated HPV genome fragments has been hypothesized as one major promoting factor in the pathogenesis of HPV-associated cancers. This hypothesis was based on the detection of HPV integration events in the area of tumor-relevant genes in few cases. Here, we reviewed >190 reported integration loci with respect to changes in the viral structure and the targeted genomic locus. This analysis confirms that HPV integration sites are randomly distributed over the whole genome with a clear predilection for genomic fragile sites. No evidence for targeted disruption or functional alteration of critical cellular genes by the integrated viral sequences could be found.
IL1-receptor antagonist anakinra provides long-lasting efficacy in the treatment of refractory adult-onset Still’s disease
Authors: L Naumann, E Feist, A Natusch, S Langen, A Krause, F Buttgereit, G-R Burmester
Journal: Annals of the Rheumatic Diseases (2010)

<h3></h3> Continuous positive airway pressure (CPAP) humidifiers are a potential source of infection, but a literature review yielded no excess incidence of such. However, a 59-year-old white married interior designer with obstructive sleep apnea (BMI 36.6 kg/m<sup>2</sup>) became acutely ill after she used well water in a CPAP humidifier one night in her North Carolina mountain home. Otherwise healthy, she used no tobacco, medications, drugs, or alcohol. A sleep study 6 years earlier showed obstructive sleep apnea, so she used CPAP (6 cm H<sub>2</sub>O) with humidification only by distilled water. One night she slept for 8 hours on her left side using CPAP with well-water humidification and awakened with severe pain in her upper airway. Over the next week, she had increasing dyspnea. Severe coughing disrupted sleep and produced purulent sputum. Her lungs were clear, and she remained afebrile but weak and bed-bound. Azithromycin (250 mg/day) and hydrocodone cough syrup were prescribed by her family physician. After 2 weeks of cough and dyspnea, crackles developed diffusely over the left lung. O<sub>2</sub> saturation was 91%, but chest radiographs were clear. Sputum examination showed 2+ Gram-positive cocci in clusters, but culture yielded only oral flora. No acid-fast or fungal organisms were present on sputum smears, and cultures were negative at 8 weeks. Levofloxacin (750 mg/day for 10 days) yielded no improvement. Methylprednisolone was then given in a tapering dose from 24 mg/day over 6 days followed by prednisone, 10 mg every other day. Crackles and dyspnea decreased during week 5 of the illness, and the patient felt well thereafter except for cough, which persisted through week 8. Repeat O<sub>2</sub> saturation was 98% and plain films remained normal. Well water in 2005 contained nitrates, copper, and trihalomethane at levels &lt; 10% of maximum contaminant goals. Filtration (5- and 2-micron commercial string-wound and carbon filters) was used inside the home. Water used to fill the CPAP humidifier had a pH of 7.4 and showed no microorganisms. Levels of 15 metals, 2 halides, and other standard analytes were normal. <h3>Conclusion</h3> A single use of filtered well water for CPAP humidification was followed by severe tracheobronchial irritation, dyspnea, weakness, left lung crackles, and impaired oxygenation. We suspect that this illness was bronchiolitis due to well-water contents yet to be identified. The patient has used only distilled-water humidification since her illness began.
Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats
Authors: Kohtaro Abe, Hiroaki Shimokawa, Keiko Morikawa, Toyokazu Uwatoku, Keiji Oi, Yasuharu Matsumoto, Tsuyoshi Hattori, Yutaka Nakashima, Kozo Kaibuchi, Katsuo Sueishi, Akira Takeshit
Journal: Circulation Research (2003)

Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase–mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase–mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder.
Developmental features of DNA methylation during activation of the embryonic zebrafish genome
Authors: Ingrid S Andersen, Andrew H Reiner, Håvard Aanes, Peter Aleström, Philippe Collas
Journal: Genome biology (2012)

Abstract Background Zygotic genome activation (ZGA) occurs at the mid-blastula transition (MBT) in zebrafish and is a period of extensive chromatin remodeling. Genome-scale gametic demethylation and remethylation occurs after fertilization, during blastula stages, but how ZGA relates to promoter DNA methylation states is unknown. Using methylated DNA immunoprecipitation coupled to high-density microarray hybridization, we characterize genome-wide promoter DNA methylation dynamics before, during and after ZGA onset, in relation to changes in post-translational histone modifications and gene expression. Results We show methylation of thousands of promoters before ZGA and additional methylation after ZGA, finding more dynamic methylation -1 to 0 kb upstream of the transcription start site than downstream. The MBT is marked by differential methylation of high and low CpG promoters, and we identify hypomethylated promoters that are mostly CG-rich and remain hypomethylated through the MBT. Hypomethylated regions constitute a platform for H3K4me3, whereas H3K9me3 preferentially associates with methylated regions. H3K27me3 associates with either methylation state depending on its coincidence with H3K4me3 or H3K9me3. Cohorts of genes differentially expressed through the MBT period display distinct promoter methylation patterns related to CG content rather than transcriptional fate. Lastly, although a significant proportion of genes methylated in sperm are unmethylated in embryos, over 90% of genes methylated in embryos are also methylated in sperm. Conclusions Our results suggest a pre-patterning of developmental gene expression potential by a combination of DNA hypomethylation and H3K4 trimethylation on CG-rich promoters, and are consistent with a transmission of DNA methylation states from gametes to early embryos.