tbuckley/cabot-search huggingface dataset:
Hypermethylation of 18S and 28S Ribosomal DNAs Predicts Progression-Free Survival in Patients with Ovarian Cancer
Authors: Michael W.Y. Chan, Susan H. Wei, Ping Wen, Zailong Wang, Daniela E. Matei, Joseph C. Liu, Sandya Liyanarachchi, Robert Brown, Kenneth P. Nephew, Pearlly S. Yan, Tim H-M. Huang
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Repetitive ribosomal DNA (rDNA) genes are GC-rich clusters in the human genome. The aim of the study was to determine the methylation status of two rDNA subunits, the 18S and 28S genes, in ovarian tumors and to correlate methylation levels with clinicopathologic features in a cohort of ovarian cancer patients. Experimental Design: 18S and 28S rDNA methylation was examined by quantitative methylation-specific PCR in 74 late-stage ovarian cancers, 9 histologically uninvolved, and 11 normal ovarian surface epithelial samples. In addition, methylation and gene expression levels of 18S and 28S rDNAs in two ovarian cancer cell lines were examined by reverse transcription-PCR before and after treatment with the demethylating drug 5′-aza-2′-deoxycytidine. Results: The methylation level (amount of methylated rDNA/β-actin) of 18S and 28S rDNAs was significantly higher (P &amp;lt; 0.05) in tumors than in normal ovarian surface epithelial samples. Methylation of 18S and 28S rDNA was highly correlated (R2 = 0.842). Multivariate analysis by Cox regression found that rDNA hypermethylation [hazard ratio (HR), 0.25; P &amp;lt; 0.01], but not age (HR, 1.29; P = 0.291) and stage (HR, 1.09; P = 0.709), was independently associated with longer progression-free survival. In ovarian cancer cell lines, methylation levels of rDNA correlated with gene down-regulation and 5′-aza-2′-deoxycytidine treatment resulted in a moderate increase in 18S and 28S rDNA gene expressions. Conclusion: This is the first report of rDNA hypermethylation in ovarian tumors. Furthermore, rDNA methylation levels were higher in patients with long progression-free survival versus patients with short survival. Thus, rDNA methylation as a prognostic marker in ovarian cancer warrants further investigation.
Hepatitis B virus X protein stabilizes amplified in breast cancer 1 protein and cooperates with it to promote human hepatocellular carcinoma cell invasiveness
Authors: Yonghong Liu, Zhangwei Tong, Ting Li, Qiang Chen, Luting Zhuo, Wengang Li, Ray-Chang Wu, Chundong Yu
Journal: Hepatology (2012)

Chronic infection of hepatitis B virus (HBV) is closely associated with the development of human hepatocellular carcinoma (HCC). HBV X protein (HBx) plays a key role in the progression of HCC. We recently found that amplified in breast cancer 1 (AIB1) protein is overexpressed in 68% of human HCC specimens and promotes HCC progression by enhancing cell proliferation and invasiveness. Given that both HBx and AIB1 play important oncogenic roles in HCC, we aimed to determine whether they could cooperatively promote human HCC development. Herein, we show that HBx-positive HCC tissues had a higher level of AIB1 protein, compared to HBx-negative HCC tissues. A positive correlation between HBx protein level and AIB1 protein level was established in HCC specimens. Without affecting its messenger RNA level, HBx induced a significant increase of the protein level of AIB1, which correlated with a significant extension of the half-life of AIB1 protein. Mechanistically, HBx could interact with AIB1 to prevent the interaction between envelope protein 3 ubiquitin ligase F-box and WD repeat domain containing 7 (Fbw7)α and AIB1, then inhibited the Fbw7α-mediated ubiquitination and degradation of AIB1. In addition, reporter assays and chromatin immunoprecipitation assays revealed that both HBx and AIB1 were recruited to matrix metalloproteinase-9 ( MMP-9 ) promoter to enhance MMP-9 promoter activity cooperatively. Consistently, HBx and AIB1 cooperatively enhanced MMP-9 expression in HepG2 cells, which, in turn, increased cell-invasive ability. Conclusion: Our study demonstrates that HBx can stabilize AIB1 protein and cooperate with it to promote human HCC cell invasiveness, highlighting the essential role of the cross-talk between HBx and AIB1 in HBV-related HCC progression.
Aging and Disease as Modifiers of Efficacy of Cell Therapy
Authors: Stefanie Dimmeler, Annarosa Leri
Journal: Circulation Research (2008)

Cell therapy is a promising option for treating ischemic diseases and heart failure. Adult stem and progenitor cells from various sources have experimentally been shown to augment the functional recovery after ischemia, and clinical trials have confirmed that autologous cell therapy using bone marrow—derived or circulating blood–derived progenitor cells is safe and provides beneficial effects. However, aging and risk factors for coronary artery disease affect the functional activity of the endogenous stem/progenitor cell pools, thereby at least partially limiting the therapeutic potential of the applied cells. In addition, age and disease affect the tissue environment, in which the cells are infused or injected. The present review article will summarize current evidence for cell impairment during aging and disease but also discuss novel approaches how to reverse the dysfunction of cells or to refresh the target tissue. Pretreatment of cells or the target tissue by small molecules, polymers, growth factors, or a combination thereof may provide useful approaches for enhancement of cell therapy for cardiovascular diseases.
Roles of BIM Induction and Survivin Down-Regulation in Lapatinib-Induced Apoptosis in Breast Cancer Cells with HER2 Amplification
Authors: J. Tanizaki, I. Okamoto, S. Fumita, W. Okamoto, K. Nakagawa, T. Liu, J. Smeds, A. Östman, J. Bergh, H. Li, G. Kristiansen, M. Holger, U. Eriksson, S. Saji, M. Hirose, F. Sato, S.-i. Hayashi, K. Kuroi, M. Yunokawa, F. Koizumi, K. Tamura, M. Koudaira, K. Yonemori, C. Shimizu, M. Ando, Y. Fujiwara, J. Jo, C. Yoo, J.-E. Kim, J.-H. Ahn, S.-B. Kim, H.-H. Kim, J. H. Cha, H. J. Shin, S.-H. Ahn, B. H. Son, J. W. Lee, H. J. Kim, G. Gong, K. H. Jung, H. Kurihara, M. Kodaira
Journal: Annals of Oncology (2012)
Understanding Differences Between Phylogenetic and Pedigree-Derived mtDNA Mutation Rate: A Model Using Families from the Azores Islands (Portugal)
Authors: Cristina Santos, Rafael Montiel, Blanca Sierra, Conceição Bettencourt, Elisabet Fernandez, Luis Alvarez, Manuela Lima, Augusto Abade, M. Pilar Aluja
Journal: Molecular Biology and Evolution (2005)

We analyzed the control region of the mitochondrial DNA (mtDNA) from maternally related individuals originating from the Azores Islands (Portugal) in order to estimate the mutation rate of mtDNA and to gain insights into the process by which a new mutation arises and segregates into heteroplasmy. Length and/or point heteroplasmies were found at least in one individual of 72% of the studied families. Eleven new point substitutions were found, all of them in heteroplasmy, from which five appear to be somatic mutations and six can be considered germinal, evidencing the high frequency of somatic mutations in mtDNA in healthy young individuals. Different values of the mutation rate according to different assumptions were estimated. When considering all the germinal mutations, the value of the mutation rate obtained is one of the highest reported so far in family studies. However, when corrected for gender (assuming that the mutations present in men have the same evolutionary weight of somatic mutations because they will inevitably be lost) and for the probability of intraindividual fixation, the value for the mutation rate obtained for HVRI and HVRII (0.2415 mutations/site/Myr) was in the upper end of the values provided by phylogenetic estimations. These results indicate that the discrepancy, that has been reported previously, between the human mtDNA mutation rates observed along evolutionary timescales and the estimations obtained using family pedigrees can be minimized when corrections for gender proportions in newborn individuals and for the probability of intraindividual fixation are introduced. The analyses performed support the hypothesis that (1) in a constant, tight bottleneck genetic drift alone can explain different patterns of heteroplasmy segregation and (2) in neutral conditions, the destiny of a new mutation is strictly related to the initial proportion of the new variant. Another important point arising from the data obtained is that, even in the absence of a paternal contribution of mtDNA, recombination may occur between mtDNA molecules present in an individual, which is only observable if it occurs between mtDNA types that differ at two or more positions.
Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing
Authors: Yonghao Zhao, Yunshu Wang, Jiaye Yang, Xin Wang, Yingjun Zhao, Xian Zhang, Yun-wu Zhang
Journal: Molecular Neurodegeneration (2012)

Abstract Background β-site APP cleaving enzyme 1 (BACE1) cleaves β-amyloid precursor protein (APP) to initiate the production of β-amyloid (Aβ), the prime culprit in Alzheimer’s disease (AD). Dysregulation of the intracellular trafficking of BACE1 may affect Aβ generation, contributing to AD pathology. In this study, we investigated whether BACE1 trafficking and BACE1-mediated APP processing/Aβ generation are affected by sorting nexin 12 (SNX12), a member of the sorting nexin (SNX) family that is involved in protein trafficking regulation. Results Herein, we find that SNX12 is widely expressed in brain tissues and is mainly localized in the early endosomes. Overexpression of SNX12 does not affect the steady-state levels of APP, BACE1 or γ-secretase components, but dramatically reduces the levels of Aβ, soluble APPβ and APP β-carboxyl terminal fragments. Downregulation of SNX12 has the opposite effects. Modulation of SNX12 levels does not affect γ-secretase activity or in vitro β-secretase activity. Further studies reveal that SNX12 interacts with BACE1 and downregulation of SNX12 accelerates BACE1 endocytosis and decreases steady-state level of cell surface BACE1. Finally, we find that the SNX12 protein level is dramatically decreased in the brain of AD patients as compared to that of controls. Conclusion This study demonstrates that SNX12 can regulate the endocytosis of BACE1 through their interaction, thereby affecting β-processing of APP for Aβ production. The reduced level of SNX12 in AD brains suggests that an alteration of SNX12 may contribute to AD pathology. Therefore, inhibition of BACE1-mediated β-processing of APP by regulating SNX12 might serve as an alternative strategy in developing an AD intervention.
Raised Circulating Fetuin-A After 28-Day Overfeeding in Healthy Humans
Authors: Dorit Samocha-Bonet, Charmaine S. Tam, Lesley V. Campbell, Leonie Kaye Heilbronn
Journal: Diabetes Care (2013)

Fetuin-A is a liver secretory glycoprotein that has been linked to the development of insulin resistance in animal models (1). Recent work suggests that free fatty acids (FFAs) and fetuin-A interact to induce insulin resistance in animal models (1) and humans (2). However, short-term overfeeding increases peripheral insulin resistance without significant increases in the levels of circulating FFAs in healthy humans (3,4). Thus, short-term overfeeding studies provide an ideal model with which to evaluate the relationships between fetuin-A and insulin resistance, independent of FFAs.

We examined the effects of 28-day overfeeding (1,100 ± 100 kcal/day above baseline energy requirement, increasing mean [±SEM] dietary fat intake from 34 ± 1% to 45 ± 1% of energy intake) on circulating levels of fetuin-A, FFAs, and proinflammatory markers in healthy men and women (BMI 25.6 ± 0.6; age 37 ± 2 years; n = 40 [20 men]). The study protocol was described in detail previously (3 …
Ammonium transport in the kidney
Authors: T D DuBose, D W Good, L L Hamm, S M Wall
Journal: Journal of the American Society of Nephrology (1991)

This article is based on a Basic Science Symposium presented at the 23rd Annual Meeting of the American Society of Nephrology. New information on the segmental transport of ammonium by the proximal tubule, the thick ascending limb of Henle's loop, and the collecting duct is integrated into a thesis that NH4+ excretion is controlled by the rate of production, by diffusion of NH3 along gradients established by proton secretion, and by active transport of NH4+. These new concepts are applied to a novel explanation of the pathogenesis of distal renal tubular acidosis.
N<scp>UTRITIONAL</scp> C<scp>ONSEQUENCES OF THE</scp> A<scp>FRICAN</scp> D<scp>IASPORA</scp>
Authors: Amy Luke, Richard S Cooper, T Elaine Prewitt, Adebowale A Adeyemo, Terrence E Forrester
Journal: Annual Review of Nutrition (2001)

▪ Abstract Along with their foods and dietary customs, Africans were carried into diaspora throughout the Americas as a result of the European slave trade. Their descendants represent populations at varying stages of the nutrition transition. West Africans are in the early stage, where undernutrition and nutrient deficiencies are prevalent. Many Caribbean populations represent the middle stages, with undernutrition and obesity coexisting. African-Americans and black populations in the United Kingdom suffer from the consequences of caloric excess and diets high in fat and animal products. Obesity, non–insulin-dependent diabetes mellitus, hypertension, coronary heart disease, and certain cancers all follow an east-to-west gradient of increasing prevalence. Public health efforts must focus not only on eradicating undernutrition in West Africa and the Caribbean but also on preventing obesity, hypercholesterolemia, and their consequences. Fortunately, a coherent and well-supported set of recommendations exists to promote better nutrition. Implementation of it founders primarily as a result of the influence of commercial and political interests.
Ultrasound for diagnosis of carpal tunnel syndrome: comparison of different methods to determine median nerve volume and value of power Doppler sonography
Authors: Christian Dejaco, Martin Stradner, Dorothea Zauner, Werner Seel, Nicole Elisabeth Simmet, Alexander Klammer, Petra Heitzer, Kerstin Brickmann, Judith Gretler, Florentine C Fürst-Moazedi, Rene Thonhofer, Rusmir Husic, Josef Hermann, Winfried B Graninger, Stefan Quasthoff
Journal: Annals of the Rheumatic Diseases (2012)

Objective To compare ultrasound measurement of median nerve cross-sectional area (CSA) at different anatomical landmarks and to assess the value of power Doppler signals within the median nerve for diagnosis of carpal tunnel syndrome (CTS). Methods A prospective study of 135 consecutive patients with suspected CTS undergoing two visits within 3 months. A final diagnosis of CTS was established by clinical and electrophysiological findings. CSA was sonographically measured at five different levels at forearm and wrist; and CSA wrist to forearm ratios or differences were calculated. Intraneural power Doppler signals were semiquantitatively graded. Diagnostic values of different ultrasound methods were compared by receiver operating characteristic curves using SPSS. Results CTS was diagnosed in 111 (45.5%) wrists; 84 (34.4%) had no CTS and 49 (20.1%) were possible CTS cases. Diagnostic values were comparable for all sonographic methods to determine median nerve swelling, with area under the curves ranging from 0.75 to 0.85. Thresholds of 9.8 and 13.8 mm 2 for the largest CSA of the median nerve yielded a sensitivity of 92% and a specificity of 92%. A power Doppler score of 2 or greater had a specificity of 90% for the diagnosis of CTS. Sonographic median nerve volumetry revealed a good reliability with an intraclass correlation coefficient of 0.90 (95% CI 0.79 to 0.95). Conclusions Sonographic assessment of median nerve swelling and vascularity allows for a reliable diagnosis of CTS. Determination of CSA at its maximal shape offers an easily reproducible tool for CTS classification in daily clinical practice.
Large-scale neocortical dynamics: Some EEG data analysis implications
Authors: Richard E. Greenblatt
Journal: Behavioral and Brain Sciences (2000)

The spatial time-frequency distribution matrix and associated Rényi entropy is proposed as the basis for a method that may be useful for estimating the significance of nonlocal neocortical interactions in the analysis of scalp EEG data. Implications of nonlocal interactions for source estimation are also considered.
Evidence that Increased Circulating 1α,25-Dihydroxyvitamin D is the Probable Cause for Abnormal Calcium Metabolism in Sarcoidosis
Authors: Norman H. Bell, Paula H. Stern, Elizabeth Pantzer, Tushar K. Sinha, Hector F. Deluca
Journal: Journal of Clinical Investigation (1979)

Mean plasma 1α,25-dihydroxyvitamin D[1α,25(OH)2D] was significantly increased and serum parathyroid hormone was suppressed in three patients with sarcoidosis and hypercalcemia. Prednisone lowered the mean plasma 1α,25(OH)2D to normal range and corrected the hypercalcemia. To elucidate the mechanism for the increased sensitivity to vitamin D in this disorder, the effects of orally-administered vitamin D2 were determined in seven normal subjects, four patients with sarcoidosis and normal calcium metabolism and three patients with sarcoidosis and a history of hypercalcemia who were normocalcemic when studied. Serum and urinary calcium, serum 25-hydroxyvitamin D (25-OHD), plasma 1α,25(OH)2D and, in some studies, calcium balance were measured. Vitamin D2, 250 μg a day for 12 d, produced little, if any, change in mean plasma 1α,25(OH)2D and in urinary calcium in the normals and in the patients with normal calcium metabolism. In contrast, vitamin D2 produced increases in plasma 1α,25(OH)2D from concentrations which were within the normal range (20-55 pg/ml) to abnormal values and increased urinary calcium in two patients with abnormal calcium metabolism. In an abbreviated study in the third patient, vitamin D2, 250 μg a day for 4 d, also increased plasma 1α,25(OH)2D abnormally from a normal value. There was a highly significant correlation between plasma 1α,25(OH)2D and urinary calcium. Serum 25-OHD and serum calcium remained within the normal range in all subjects and patients. These findings provide evidence that the defect in calcium metabolism in sarcoidosis probably results from impaired regulation of the production and(or) degradation of 1α,25(OH)2D. Prednisone may act to correct the abnormal calcium metabolism by reducing circulating 1α,25(OH)2D.
One Foot in the Furrow: Linkages Between Agriculture, Plant Pathology, and Public Health
Authors: Karen-Beth G. Scholthof
Journal: Annual Review of Public Health (2003)

▪ Abstract Plant pathology is a field of biology that focuses on understanding the nature of disease in plants as well as on more practical aspects of preventing and controlling plant diseases in crop plants that are important to agriculture. Throughout history, plant diseases have had significant effects on human health and welfare. Several examples, in both historical and contemporary contexts, are presented in this review to show how plant pathogens, biotechnology, and farming practices have affected public health. Specific topics illustrating clear linkages between agriculture and human health include allergens in the environment, food-safety and agricultural practices, mycotoxigenic fungi, agrobioterrorism, and the biological control of plant diseases. The further argument is made that in order to monitor and ensure that good health and safety practices are maintained from “farm to fork,” public health specialists may benefit from the resources and expertise of agricultural scientists. Man does not live by bread alone—but he must have bread. And he must have bread that is truly a staff of life, not a scepter of death ( 44 ).
Intestinal phase of superior mesenteric artery blood flow in man.
Authors: C Sieber, C Beglinger, K Jager, G A Stalder
Journal: Gut (1992)

Duplex ultrasound was used to investigate superior mesenteric artery haemodynamics in humans in order to study the contribution of the small intestine to the postprandial splanchnic hyperaemia, and to determine the relative potencies of the major food components in the postprandial mesenteric flow response. Duplex parameters of vessel diameter, mean velocity, and volume flow were determined serially in the basal state and after stimulation. Flow parameters were significantly (p less than 0.05) increased after liquid and solid oral meals. Modified sham feeding did not alter mesenteric blood flow. Intestinal perfusion of an isocaloric liquid test meal induced flow increases comparable with oral intake. Superior mesenteric artery blood flow also significantly (p less than 0.05) increased after isocaloric and iso-osmolar loads of intraduodenal carbohydrate, fat, and protein meals. Responses were similar after the test meal, fat, and protein, but were significantly (p less than 0.05) less for carbohydrates. Different osmolar loads of saline did not affect flow responses. We conclude that the intestinal phase is the major regulator of the postprandial mesenteric blood flow response in healthy humans and that the chemical nature of food determines the mesenteric response pattern.
Preoperative Chemotherapy Plus Trastuzumab, Lapatinib, or Both in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer: Results of the Randomized Phase II CHER-LOB Study
Authors: Valentina Guarneri, Antonio Frassoldati, Alberto Bottini, Katia Cagossi, Giancarlo Bisagni, Samanta Sarti, Alberto Ravaioli, Luigi Cavanna, Giovanni Giardina, Antonino Musolino, Michael Untch, Laura Orlando, Fabrizio Artioli, Corrado Boni, Daniele Giulio Generali, Patrizia Serra, Michela Bagnalasta, Luca Marini, Federico Piacentini, Roberto D'Amico, PierFranco Conte
Journal: Journal of Clinical Oncology (2012)

This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) -positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes).In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m(2)) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily.A total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019).The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.