tbuckley/cabot-search huggingface dataset:
Thymidylate Synthase Protein Expression in Primary Colorectal Cancer: Lack of Correlation With Outcome and Response to Fluorouracil in Metastatic Disease Sites
Authors: Patrick G. Johnston, Al B. Benson, Paul Catalano, M. Sambasiva Rao, Peter J. O’Dwyer, Carmen J. Allegra
Journal: Journal of Clinical Oncology (2003)

The aim of this study was to investigate the utility of quantitating thymidylate synthase (TS) in the primary tumor as a surrogate for metastatic disease sites to predict the likelihood of response and outcome to fluorouracil (FU) treatment in patients with metastatic colorectal cancer.TS protein expression was evaluated using the TS 106 antibody and the avidin biotin labeling immunohistochemical technique in primary tumor samples from 219 patients with metastatic colorectal cancer. The patients were a representative sample of those patients enrolled into the Eastern Cooperative Oncology Group E2290 protocol that evaluated five separate FU-containing regimens in patients with metastatic residual or recurrent colorectal carcinoma.Our retrospective analysis found that the level and extent of TS protein expression in the primary tumor did not correlate with overall survival in patients with metastatic or recurrent colorectal cancer. A trend toward a direct correlation between the level of TS protein expression and response was noted in tumors that expressed high TS levels. This response advantage for patients expressing high TS levels in the primary tumor was apparent regardless of what FU-based treatment the patient received but was most apparent in the subgroup treated with leucovorin, in which the level of TS expression and response to FU and leucovorin reached statistical significance (P =.034). No significant interaction could be detected between the addition of leucovorin to FU and the level of TS expression in the primary tumor.This study demonstrated that measurement of TS protein levels in the primary tumor tissue does not aid in predicting outcome or response to FU in a metastatic disease site. These assays must be performed on biopsy tissue from the metastatic disease site that is used to radiologically assess response and outcome to treatment.
Can we justify spermatid microinjection for severe male factor infertility?
Authors: I Aslam
Journal: Human Reproduction Update (1998)

During 1995 and 1996 the first spermatid pregnancies were announced with both round spermatid ROSI) and elongated spermatid ELSI) injections. These publications were flanked by live births from ROSI in a number of animal species, with resulting offspring appearing normal, healthy and fertile. However, the live births in humans heralded a scientific and ethical debate on the clinical use of this technology; and in a number of countries nationwide moratoria prohibiting spermatid microinjection were enjoined. Concerns surrounded the biological condition of spermatids and clinical implications of utilizing an immature spermatozoan for conception. Nevertheless, case reports and a few scientific studies on human spermatid conception have been published in recent years, and further polemic on testicular histopathology and prognosis has ensued. This paper reviews the current arguments on the clinical use of ROSI and ELSI, and evaluates the biology of the main contributory components of a spermatozoan to the subsequent embryo, namely the genetic material, the microtubular organizing complex and the putative oocyte activating factor. We also consider the relevant testicular histopathology and likely outcome in the context of the current birth rate from ROSI and ICSI. We conclude by considering the way forward for infertile men who require this technology to become genetic fathers, and whether the time is now appropriate to consider clinical trials.
Fungal Hydrogenosomes Contain Mitochondrial Heat-Shock Proteins
Authors: M. van der Giezen
Journal: Molecular Biology and Evolution (2003)

At least three groups of anaerobic eukaryotes lack mitochondria and instead contain hydrogenosomes, peculiar organelles that make energy and excrete hydrogen. Published data indicate that ciliate and trichomonad hydrogenosomes share common ancestry with mitochondria, but the evolutionary origins of fungal hydrogenosomes have been controversial. We have now isolated full-length genes for heat shock proteins 60 and 70 from the anaerobic fungus Neocallimastix patriciarum, which phylogenetic analyses reveal share common ancestry with mitochondrial orthologues. In aerobic organisms these proteins function in mitochondrial import and protein folding. Homologous antibodies demonstrated the localization of both proteins to fungal hydrogenosomes. Moreover, both sequences contain amino-terminal extensions that in heterologous targeting experiments were shown to be necessary and sufficient to locate both proteins and green fluorescent protein to the mitochondria of mammalian cells. This finding, that fungal hydrogenosomes use mitochondrial targeting signals to import two proteins of mitochondrial ancestry that play key roles in aerobic mitochondria, provides further strong evidence that the fungal organelle is also of mitochondrial ancestry. The extraordinary capacity of eukaryotes to repeatedly evolve hydrogen-producing organelles apparently reflects a general ability to modify the biochemistry of the mitochondrial compartment.
Phase I/II Study of Biweekly Paclitaxel and Radiation in Androgen-Ablated Locally Advanced Prostate Cancer
Authors: Nicholas J. Sanfilippo, Samir S. Taneja, Abraham Chachoua, Herbert Lepor, Silvia C. Formenti
Journal: Journal of Clinical Oncology (2008)

To determine the maximum-tolerated dose (MTD) of concurrent paclitaxel and radiation therapy (RT) in patients with locally advanced prostate cancer.Eligible patients had T2-4 tumors with Gleason scores greater than 7 and/or PSA levels greater than 10 ng/mL and/or had tumors with pathologic stage TxN1. Hormonal ablation was initiated 3 months before RT and was given for 9 months. RT was delivered daily (1.8 Gy) with concurrent twice-weekly paclitaxel (30 mg/m(2)). The whole pelvis was irradiated to 39.6 Gy. The radiation dose was escalated as follows: 63 Gy, 66.6 Gy, 70.2 Gy, and 73.8 Gy. The last RT dose level was fixed at 73.8 Gy.Between January 2000 and October 2006, 22 patients were enrolled. The median age was 59 years (range, 48 to 72 years); the median PSA level was 22.4 ng/mL (range, 2.8 to 113 ng/mL). The number of patients per stage was as follows: three with T1, eight with T2, 11 with T3, and five with pN1 = 5. No grade 3 toxicities occurred at 63 Gy. Grade 3 diarrhea occurred in three patients at 66.6 Gy. The protocol then was amended to treat the prostate volume first followed by the whole pelvis. No grade 3 toxicities were observed at 70.2 Gy. One patient experienced grade 3 diarrhea at 73.8 Gy. Five additional patients were treated to 73.8 Gy without grade 3 toxicity, which established the MTD for combined paclitaxel and RT at 73.8 Gy. At 38 months median follow-up (range, 9 to 87 months), 21 (95%) of 22 patients are alive. Six (27%) of 22 experienced recurrence.Concurrent biweekly paclitaxel with RT is feasible, with an MTD of 73.8 Gy. Recovery of gonadal function occurs in the majority of patients. These results encourage testing in a phase III setting.
Sex-specific Effects of Asthma on Pulmonary Function in Children
Authors: KIROS BERHANE, ROB McCONNELL, FRANK GILLILAND, TALAT ISLAM, W. JAMES GAUDERMAN, EDWARD AVOL, STEPHANIE J. LONDON, ED RAPPAPORT, HELENE G. MARGOLIS, JOHN M. PETERS
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

To evaluate the effects on lung function of asthma, time since diagnosis of asthma, and age at diagnosis of asthma, we examined school children in a cohort of 2,277 fourth- and seventh-graders at least twice during a 4-yr follow-up period. Sex-specific models for each lung function were fitted through mixed-effects models that used regression splines and captured age-dependent trends in the effect of asthma on lung function. In males, a history of asthma was associated with large and statistically significant deficits in maximum midexpiratory flow (MMEF) ( − 4.89%) and forced expiratory flow at 75% of expired FVC (FEF75) ( − 6.62%), whereas in females these deficits were smaller ( − 1.93% and − 2.45%, respectively) and were not statistically significant. However, larger deficits were seen in both males and females with longer time since diagnosis. In males with more than 6 yr since diagnosis, there were significant deficits in FEV1 ( − 3.91%), MMEF ( − 7.39%), FEF75 ( − 8.12%), and peak expiratory flow rate (PEFR) ( − 4.65%) as compared with children with less than 3 yr since diagnosis. There were fewer females with more than 6 yr since diagnosis, but deficits were similar to those of males for FEV1 ( − 2.52%), MMEF ( − 9.26%), and FEF75 ( − 14.28%). Large deficits in flow rates in both large and small airways were observed in males and females for whom asthma was reported to have been diagnosed before age 3 yr. There was little evidence that lung growth in children with asthma "catches up" at older ages. Therefore, because a constant percent deficit in lung function implies an increasingly large absolute deficit in older children with larger lungs, these results are consistent with prior evidence that lung function deficits in children with asthma persist into adulthood. We also suggest that in children, commonly observed differences between sexes in the impact of asthma on lung function may reflect differences in the duration and age of onset of asthma in males and females.
Risk Stratification of Colon Carcinogenesis through Enhanced Backscattering Spectroscopy Analysis of the Uninvolved Colonic Mucosa
Authors: Hemant K. Roy, Young L. Kim, Yang Liu, Ramesh K. Wali, Michael J. Goldberg, Vladimir Turzhitsky, Jonathan Horwitz, Vadim Backman
Journal: Clinical Cancer Research (2006)

Our group has been interested in applying advances in biomedical optics to colorectal cancer risk stratification. Through a recent technological breakthrough, we have been able to harness information from enhanced backscattering spectroscopy, an optics phenomenon that allows quantitative, depth-selective analysis of the epithelial microscale/nanoscale architecture. In the present study, we investigated the ability of enhanced backscattering analysis of the preneoplastic mucosa to predict risk of colon carcinogenesis.Enhanced backscattering analysis was done on intestinal mucosa at preneoplastic time points from two experimental models of colorectal cancer: the azoxymethane-treated rat and the multiple intestinal neoplasia (MIN) mouse. Data were analyzed using two previously validated spectral markers: spectral slope and principle components. We then did a pilot study on mucosal biopsies from 63 subjects undergoing screening colonoscopy.In the azoxymethane-treated rat, when compared with saline-treated controls, significant changes in the enhanced backscattering markers were observed as early as 2 weeks after azoxymethane treatment (before the development of aberrant crypt foci and adenomas). Enhanced backscattering markers continued to progress over time in a manner consonant with future neoplasia. These data were replicated in the preneoplastic MIN mouse mucosa. In humans, spectral slopes in the endoscopically normal cecum, midtransverse colon, and rectum were markedly reduced in patients harboring adenomas when compared with those who were neoplasia free.We show, for the first time, that enhanced backscattering analysis of an aliquot of uninvolved mucosa has the potential for predicting neoplastic risk throughout the colon in both experimental colorectal cancer models and humans.
Double blind randomised controlled trial of two different breathing techniques in the management of asthma
Authors: C A Slader
Journal: Thorax (2006)

<b>Background:</b> Previous studies have shown that breathing techniques reduce short acting β<sub>2</sub> agonist use and improve quality of life (QoL) in asthma. The primary aim of this double blind study was to compare the effects of breathing exercises focusing on shallow nasal breathing with those of non-specific upper body exercises on asthma symptoms, QoL, other measures of disease control, and inhaled corticosteroid (ICS) dose. This study also assessed the effect of peak flow monitoring on outcomes in patients using breathing techniques. <b>Methods:</b> After a 2 week run in period, 57 subjects were randomised to one of two breathing techniques learned from instructional videos. During the following 30 weeks subjects practised their exercises twice daily and as needed for relief of symptoms. After week 16, two successive ICS downtitration steps were attempted. The primary outcome variables were QoL score and daily symptom score at week 12. <b>Results:</b> Overall there were no clinically important differences between the groups in primary or secondary outcomes at weeks 12 or 28. The QoL score remained unchanged (0.7 at baseline <i>v</i> 0.5 at week 28, p = 0.11 both groups combined), as did lung function and airway responsiveness. However, across both groups, reliever use decreased by 86% (p&lt;0.0001) and ICS dose was reduced by 50% (p&lt;0.0001; p&gt;0.10 between groups). Peak flow monitoring did not have a detrimental effect on asthma outcomes. <b>Conclusion:</b> Breathing techniques may be useful in the management of patients with mild asthma symptoms who use a reliever frequently, but there is no evidence to favour shallow nasal breathing over non-specific upper body exercises.
Biochemical and biological characterization of exosomes containing prominin-1/CD133
Authors: Germana Rappa, Javier Mercapide, Fabio Anzanello, Robert M Pope, Aurelio Lorico
Journal: Molecular Cancer (2013)

Abstract Exosomes can be viewed as complex “messages” packaged to survive trips to other cells in the local microenvironment and, through body fluids, to distant sites. A large body of evidence indicates a pro-metastatic role for certain types of cancer exosomes. We previously reported that prominin-1 had a pro-metastatic role in melanoma cells and that microvesicles released from metastatic melanoma cells expressed high levels of prominin-1. With the goal to explore the mechanisms that govern proteo-lipidic-microRNA sorting in cancer exosomes and their potential contribution(s) to the metastatic phenotype, we here employed prominin-1-based immunomagnetic separation in combination with filtration and ultracentrifugation to purify prominin-1-expressing exosomes (prom1-exo) from melanoma and colon carcinoma cells. Prom1-exo contained 154 proteins, including all of the 14 proteins most frequently expressed in exosomes, and multiple pro-metastatic proteins, including CD44, MAPK4K, GTP-binding proteins, ADAM10 and Annexin A2. Their lipid composition resembled that of raft microdomains, with a great enrichment in lyso-phosphatidylcholine, lyso-phosphatidyl-ethanolamine and sphingomyelin. The abundance of tetraspanins and of tetraspanin-associated proteins, together with the high levels of sphingomyelin, suggests that proteolipidic assemblies, probably tetraspanin webs, might be the essential structural determinant in the release process of prominin-1 of stem and cancer stem cells. Micro-RNA profiling revealed 49 species of micro-RNA present at higher concentrations in prom1-exo than in parental cells, including 20 with cancer-related function. Extensive accumulation of prom1-exo was observed 3 h after their addition to cultures of melanoma and bone marrow-derived stromal cells (MSC). Short-term co-culture of melanoma cells and MSC resulted in heterologous prominin-1 transfer. Exposure of MSC to prom1-exo increased their invasiveness. Our study supports the concept that specific populations of cancer exosomes contain multiple determinants of the metastatic potential of the cells from which they are derived.
Comparative Virulence and Immunogenicity of the Towne Strain and a Nonattenuated Strain of Cytomegalovirus
Authors: GERALD V. QUINNAN
Journal: Annals of Internal Medicine (1984)

The Towne strain cytomegalovirus and a low-passage strain, Toledo-1, were compared for virulence and immunogenicity in healthy adult male subjects to determine the suitability of the Towne strain for vaccination. Five seropositive subjects who received the Toledo-1 strain developed infections ranging in severity from laboratory abnormalities to mild mononucleosis syndromes (mean incubation, 4.7 weeks). None of the four seronegative subjects receiving the Towne strain developed systemic infection, but all developed delayed local reactions at the injection sites. All subjects developed cytotoxic lymphocyte responses specific to cytomegalovirus, usually HLA-restricted, but these were of greater magnitude and duration in the Toledo-1 recipients. The latter also developed natural killer cell and interferon responses, atypical lymphocytosis, inversion of helper/suppressor cell ratios, and depressed responses to T-cell mitogens, none of which occurred in Towne strain recipients. The results further substantiate the avirulence and immunogenicity of the Towne strain cytomegalovirus.
Lymphocytes are important in early atherosclerosis
Authors: Li Song, Cynthia Leung, Christian Schindler
Journal: Journal of Clinical Investigation (2001)

Lymphocytes represent a potentially important proinflammatory cell that localizes to atherosclerotic lesions. To determine whether they contribute to lesion development, atherosclerosis-prone (LDLR–/–) mice were crossed with lymphocyte-deficient (RAG1–/–) mice to generate double knockout progeny. After 8 weeks on a Western-type diet (WTD), lesion development was reduced by 54% in double knockout mice, as compared with matched LDLR–/– controls. However, these significant differences in lesion area gradually subsided as the WTD was continued for 12 and 16 weeks. Consistent with this observation, histological studies determined that lesion initiation and early progression were delayed in RAG1/LDL-R double knockout mice. Differences in lesion area did not correlate with any significant alterations in plasma lipid levels. These studies suggest that lymphocytes play an important role early in atherogenesis.
Foetal nicotine exposure causes PKCε gene repression by promoter methylation in rat hearts
Authors: Jennifer Lawrence, Man Chen, Fuxia Xiong, Daliao Xiao, Haitao Zhang, John N. Buchholz, Lubo Zhang
Journal: Cardiovascular Research (2010)

Foetal nicotine exposure results in decreased protein kinase C epsilon (PKCε) expression and increased cardiac vulnerability to ischaemia and reperfusion injury in adult rat offspring. The present study tested the hypothesis that maternal nicotine administration causes increased promoter methylation of the PKCε gene resulting in PKCε repression in the heart. Nicotine treatment of pregnant rats starting at day 4 of gestation increased the methylation of the Egr-1 binding site at the PKCε gene promoter and decreased PKCε protein and mRNA abundance in near-term foetal hearts. Methylation of the Egr-1 binding site reduced Egr-1 binding to the PKCε promoter in the heart. Site-specific deletion of the Egr-1 binding site significantly decreased PKCε promoter activity. The effects of nicotine were sustained in the heart of adult offspring. Ex vivo studies found no direct effect of nicotine on PKCε gene expression. However, maternal nicotine administration increased norepinephrine content in the foetal heart. Treatment of isolated foetal hearts with norepinephrine resulted in the same effects of increased methylation of the Egr-1 binding site and PKCε gene repression in the heart. 5-Aza-2′-deoxycytidine inhibited the norepinephrine-induced increase in methylation of the Egr-1 binding site and restored Egr-1 binding and PKCε gene expression to the control levels. This study demonstrates that prolonged nicotine exposure increases the sympathetic neurotransmitter release in the foetal heart and causes programming of PKCε gene repression through promoter methylation, linking maternal smoking to pathophysiological consequences in the offspring heart.
Different Patterns of Insulin Resistance in Relatives of Type 1 Diabetic Patients With Retinopathy or Nephropathy
Authors: Samy Hadjadj, Franck Péan, Yves Gallois, Philippe Passa, Robert Aubert, Laurent Weekers, Vincent Rigalleau, Bernard Bauduceau, Amine Bekherraz, Ronan Roussel, Bernard Dussol, Michel Rodier, Richard Marechaud, Pierre J. Lefebvre, Michel Marre
Journal: Diabetes Care (2004)

OBJECTIVE—Insulin resistance may be a risk factor for diabetic microangiopathy, which may have a familial component. We carried out a family-based study to determine which components of the insulin resistance syndrome are associated with diabetic retinopathy and nephropathy in type 1 diabetes. RESEARCH DESIGN AND METHODS—The Genesis France-Belgium Study is a multicenter binational study designed to investigate the genetic factors involved in the microvascular complications of type 1 diabetes using a family-based design. Probands were type 1 diabetic patients with diabetic retinopathy (classified as background, preproliferative, or proliferative) and possibly diabetic nephropathy (absent, incipient, established, or advanced). The insulin resistance score of their first-degree relatives was calculated according to their BMI and history of arterial hypertension, lipid disorders, and type 2 diabetes. RESULTS—The insulin resistance score of relatives was positively correlated with the albumin excretion rate (P = 0.0009) and fasting plasma glucose (P = 0.0003) and HbA1c (P &amp;lt; 0.0001) concentrations. This score was higher in the relatives of probands with than in those without diabetic nephropathy (P = 0.0370). Similarly, it was higher in relatives of subjects with proliferative diabetic retinopathy than in those of probands without, even after controlling for subjects with versus without diabetic nephropathy (P = 0.0379). However, the components of the insulin resistance score in relatives differed according to the severity of diabetic retinopathy or nephropathy in the probands. Obesity and history of arterial hypertension were most common in relatives of probands with proliferative diabetic retinopathy, whereas obesity and history of lipid disorders were most common in the relatives of probands with diabetic nephropathy. CONCLUSIONS—Familial insulin resistance segregates with diabetic complications: lipid disorders and obesity segregate with diabetic nephropathy, whereas arterial hypertension and obesity segregate with diabetic retinopathy.