tbuckley/cabot-search huggingface dataset:
Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome.
Authors: A Dunaif, J Xia, C B Book, E Schenker, Z Tang
Journal: Journal of Clinical Investigation (1995)

We investigated the cellular mechanisms of the unique disorder of insulin action found in the polycystic ovary syndrome (PCOS). Approximately 50% of PCOS women (PCOS-Ser) had a significant increase in insulin-independent beta-subunit [32P]phosphate incorporation (3.7-fold, P < 0.05 vs other groups) in skin fibroblast insulin receptors that was present in serine residues while insulin-induced tyrosine phosphorylation was decreased (both P < 0.05 vs other groups). PCOS skeletal muscle insulin receptors had the same abnormal phosphorylation pattern. The remaining PCOS women (PCOS-n1) had basal and insulin-stimulated receptor autophosphorylation similar to control. Phosphorylation of the artificial substrate poly GLU4:TYR1 by the PCOS-Ser insulin receptors was significantly decreased (P < 0.05) compared to control and PCOS-n1 receptors. The factor responsible for excessive serine phosphorylation appeared to be extrinsic to the receptor since no insulin receptor gene mutations were identified, immunoprecipitation before autophosphorylation corrected the phosphorylation defect and control insulin receptors mixed with lectin eluates from affected PCOS fibroblasts displayed increased serine phosphorylation. Our findings suggest that increased insulin receptor serine phosphorylation decreases its protein tyrosine kinase activity and is one mechanism for the post-binding defect in insulin action characteristic of PCOS.
Do Glycemic Index, Glycemic Load, and Fiber Play a Role in Insulin Sensitivity, Disposition Index, and Type 2 Diabetes?
Authors: Xavier Pi-Sunyer
Journal: Diabetes Care (2005)

In this issue of Diabetes Care , Liese et al. (1) report on the relation of dietary glycemic index, glycemic load, carbohydrate, and fiber intake to measures of insulin sensitivity, insulin secretion, and adiposity in the Insulin Resistance Atherosclerosis Study (IRAS). The evaluation was confined to those with normal or impaired glucose tolerance and did not include diabetic individuals. As the authors state, there has been no previous large epidemiologic study relating glycemic index and glycemic load to direct measures of insulin sensitivity and insulin secretion, whose dysfunction are the two hallmarks leading to type 2 diabetes.

There are some caveats to this study that must be pointed out. First, it is a cross-sectional study looking at one point in time. Longitudinal studies are certainly preferable. Second, it is an observational study and interventional studies are more valuable, though much more difficult and expensive to carry out. Third, the food frequency questionnaire used in this study was not specifically designed to test for glycemic index and glycemic load. While it has been validated as an overall instrument, it has not been validated for reproducibility and reliability as an appropriate glycemic index instrument, and this needs to be done by the IRAS group. This field has been dogged by the inaccuracy of dietary records and the difficulty in calculating dietary glycemic index and glycemic load levels of individuals from their reported intake of foods. Validation of experimental instruments is crucial. Fourth, the minimal model was instituted using 30 plasma samples to calculate insulin sensitivity (2). This study used 12. While this seems reasonable in a large epidemiological study, the reliability is likely to …
Phase I Evaluation of Prolonged-Infusion Gemcitabine With Mitoxantrone for Relapsed or Refractory Acute Leukemia
Authors: David A. Rizzieri, Adam J. Bass, Gary L. Rosner, Jon P. Gockerman, Carlos M. DeCastro, William P. Petros, David J. Adams, Mary J. Laughlin, Patti Davis, Traci Foster, Robert Jacobson, Herbert Hurwitz, Joseph O. Moore
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m2/min in combination with mitoxantrone at 12 mg/m2 daily for 3 days in the treatment of acute leukemia. PATIENTS AND METHODS: Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m2 daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m2/min with the duration adjusted by following a continuous reassessment model. RESULTS: Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m2). The mean steady-state concentration of gemcitabine was 24.72 μmol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively. CONCLUSION: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m2/min for 12 hours with 12 mg/m2/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.
Dietary Fat and Prostate Cancer: Current Status
Authors: L. N. Kolonel, A. M. Y. Nomura, R. V. Cooney
Journal: JNCI Journal of the National Cancer Institute (1999)

Efforts to elucidate the causes of prostate cancer have met with little success to date. All that is known with certainty is that the incidence increases exponentially with age, varies by geography and by race or ethnicity, and is higher among men whose father or brother had the disease. Because the incidence changes in migrants and their offspring, exogenous factors certainly contribute to the risk of prostate cancer. Early epidemiologic studies implicated dietary fat asa likely causal factor for this cancer. However, scientific support for such an association has diminished in recent years as more epidemiologic evidence has accrued. Accordingly, we reviewed the relevant English language literature on this topic, including epidemiologic and animal studies, as well as current concepts regarding the involvement of fat in carcinogenesis to re-examine the fat-prostate cancer hypothesis. We conclude that dietary fat may indeed be related to prostate cancer risk, although the specific fat components that are responsible are not yet clear. Given the diverse effects of fatty acids on cellular biology and chemistry, it seems likely that the relationship is complex, involving the interplay of fat with other dietary factors, such as antioxidant vitamins and minerals, or with genetic factors that influence susceptibility. Some suggestions for further research are offered.
Comparison of two dose and three dose human papillomavirus vaccine schedules: cost effectiveness analysis based on transmission model
Authors: M. Jit, M. Brisson, J.-F. Laprise, Y. H. Choi
Journal: BMJ (2015)

<b>Objective</b> To investigate the incremental cost effectiveness of two dose human papillomavirus vaccination and of additionally giving a third dose. <b>Design</b> Cost effectiveness study based on a transmission dynamic model of human papillomavirus vaccination. Two dose schedules for bivalent or quadrivalent human papillomavirus vaccines were assumed to provide 10, 20, or 30 years' vaccine type protection and cross protection or lifelong vaccine type protection without cross protection. Three dose schedules were assumed to give lifelong vaccine type and cross protection. <b>Setting</b> United Kingdom. <b>Population</b> Males and females aged 12-74 years. <b>Interventions</b> No, two, or three doses of human papillomavirus vaccine given routinely to 12 year old girls, with an initial catch-up campaign to 18 years. <b>Main outcome measure</b> Costs (from the healthcare provider's perspective), health related utilities, and incremental cost effectiveness ratios. <b>Results</b> Giving at least two doses of vaccine seems to be highly cost effective across the entire range of scenarios considered at the quadrivalent vaccine list price of £86.50 (€109.23; $136.00) per dose. If two doses give only 10 years' protection but adding a third dose extends this to lifetime protection, then the third dose also seems to be cost effective at £86.50 per dose (median incremental cost effectiveness ratio £17 000, interquartile range £11 700-£25 800). If two doses protect for more than 20 years, then the third dose will have to be priced substantially lower (median threshold price £31, interquartile range £28-£35) to be cost effective. Results are similar for a bivalent vaccine priced at £80.50 per dose and when the same scenarios are explored by parameterising a Canadian model (HPV-ADVISE) with economic data from the United Kingdom. <b>Conclusions</b> Two dose human papillomavirus vaccine schedules are likely to be the most cost effective option provided protection lasts for at least 20 years. As the precise duration of two dose schedules may not be known for decades, cohorts given two doses should be closely monitored.
Novel Oncogenic <i>PDGFRA</i> Mutations in Pediatric High-Grade Gliomas
Authors: Barbara S. Paugh, Xiaoyan Zhu, Chunxu Qu, Raelene Endersby, Alexander K. Diaz, Junyuan Zhang, Dorine A. Bax, Diana Carvalho, Rui M. Reis, Arzu Onar-Thomas, Alberto Broniscer, Cynthia Wetmore, Jinghui Zhang, Chris Jones, David W. Ellison, Suzanne J. Baker
Journal: Cancer Research (2013)

Abstract The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. Cancer Res; 73(20); 6219–29. ©2013 AACR.
Abnormal computed tomography brain scans in children with acute lymphoblastic leukemia: serial long-term follow-up.
Authors: R Riccardi, P Brouwers, G Di Chiro, D G Poplack
Journal: Journal of Clinical Oncology (1985)

In a previous study we reported the occurrence of computed tomographic (CT) brain-scan abnormalities in a group of asymptomatic children with acute lymphoblastic leukemia (ALL) who had received prophylactic cranial irradiation and maintenance intrathecal chemotherapy. One or more of four types of CT-scan abnormalities were observed: ventricular dilatation (VD), subarachnoid space dilatation (SAD), areas of parenchymal decreased attenuation coefficient (DAC), and intracerebral calcifications (CALs). To study the natural history of these findings, serial CT scans were obtained on 24 of the original 32 patients who were available for long-term follow-up. CT scanning was performed for a minimum of seven years from the initiation of CNS preventive therapy. Review of the CT scans showed that VD (n = 5) and SAD (n = 7) were stable over the time of follow-up. DAC, originally observed in two patients, was no longer present on follow-up scans. In contrast, five patients developed CALS from five to seven years after initiation of CNS preventive therapy. All occurred in children who were less than 8 years of age at the time of diagnosis (P less than .01). These data indicate that CALs may develop many years after the cessation of CNS preventive therapy and suggest that long-term CT-scan follow-up should be considered in children who have received CNS preventive therapy.
Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial
Authors: D Wayne Taylor, Henry JM Barnett, R Brian Haynes, Gary G Ferguson, David L Sackett, Kevin E Thorpe, Denis Simard, Frank L Silver, Vladimir Hachinski, G Patrick Clagett, R Barnes, J David Spence
Journal: The Lancet (1999)
Bradykinin Production Associated with Oxygenation of the Fetal Lamb
Authors: MICHAEL A. HEYMANN, ABRAHAM M. RUDOLPH, ALAN S. NIES, KENNETH L. MELMON
Journal: Circulation Research (1969)

Previous studies showed that synthetic bradykinin produced in-vitro constriction of the ductus arteriosus of the fetal lamb and guinea pig, constriction of isolated human and lamb umbilical vessels, and pulmonary vasodilatation in the fetal lamb. The present study showed that bradykinin precursor, kininogen, is present in arterial blood of the fetal lamb by 61 days of gestation and that its concentration increases toward term. We studied the bradykinin-generating system in 6 exteriorized fetal lambs. Kininogen concentrations in left atrial blood decreased within 1 to 2 minutes after beginning ventilation with O 2 , and free bradykinin was detected in left atrial blood. Pulmonary arterial blood kininogen concentration was not significantly altered. Kininogen concentration in left atrial blood did not fall in 4 other lambs ventilated with N 2 but did fall after subsequent ventilation with O 2 . To study the effects of increased oxygenation in utero without lung expansion, 6 pregnant ewes were exposed to hyperbaric O 2 at 3.63 atmospheres absolute. Associated with a mean increase in brachial arterial blood Po 2 to 44 mm Hg, a value equivalent to that in the ventilated exteriorized fetus, kininogen concentration fell, and free bradykinin was detected in the brachial arterial blood of 3 of the 6 fetuses. In 4 other exteriorized lambs we measured kininogen concentration in brachial arterial and right ventricular blood at frequent intervals up to 30 minutes after ventilation with O 2 . The concentration in brachial arterial blood fell before that in right ventricular blood. The hypothesis is presented diat bradykinin is produced from kininogen in the lungs of the fetal lamb when oxygenated, and that the maximal rate of production occurs during the first few minutes after expansion of the lungs or exposure of the ewe and fetus to hyperbaric O 2 .
Rapid Functional Divergence of a Newly Evolved Polyubiquitin Gene in Drosophila and Its Role in the Trade-off between Male Fecundity and Lifespan
Authors: Z. Zhan, Y. Ding, R. Zhao, Y. Zhang, H. Yu, Q. Zhou, S. Yang, H. Xiang, W. Wang
Journal: Molecular Biology and Evolution (2011)

The cost of reproduction is a pivotal trade-off with various biological processes during the evolution of organisms. However, the genes and molecular mechanisms underlying the evolution of balancing reproductive capacity and its cost are still largely unknown. Here, we present a comprehensive study on the evolution, expression, and biological functions of a newly evolved pair of X-linked polyubiquitin tandemly duplicated genes, CG32744 and CG11700, of which the duplication event occurred in Drosophila melanogaster lineage after the split from D. simulans clade. We found that CG32744 retains conserved polyubiquitin-coding sequences across Drosophila species and is ubiquitously expressed, whereas CG11700 has accumulated numerous amino acid changes and shows a male-specific expression pattern. Null mutants of CG11700 have a higher male fecundity but shorter lifespan, whereas its overexpression decreases male fecundity. In contrast, the null mutants of the peptide-conserved CG32744 do not exhibit such phenotypes. These results suggest that CG11700 might have experienced neofunctionalization and evolved important functions in the trade-off between male fecundity and lifespan and that CG32744 likely has retained the ancestral function.
Lifelines: Living Longer, Growing Frail, Taking Heart
Authors: S. J. Olshansky
Journal: JAMA (2000)

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Morphology of sporadic colorectal cancer with DNA replication errors
Authors: J R Jass, K-A Do, L A Simms, H Iino, C Wynter, S P Pillay, J Searle, G Radford-Smith, J Young, B Leggett
Journal: Gut (1998)

Background —Up to 15% of colorectal cancers are characterised by DNA microsatellite instability (MIN), shown by the presence of DNA replication errors (RERs). Aims —To identify pathological features that are discriminating for colorectal cancer (CRC) showing extensive MIN. Subjects —A prospective series of 303 patients with CRC and no family history of either familial adenomatous polyposis or hereditary non-polyposis colorectal cancer. Methods —DNA was extracted from fresh tissue samples and the presence of MIN was studied at nine loci that included TGFβRII, IGFIIR, and BAX. The 61 cases showing RERs were compared with 63 RER negative cases with respect to a comprehensive set of clinical and pathological variables. Predictive utility of the variables was tested by decision tree analysis. Results —Twenty seven patients with CRC showed extensive RERs (three loci or more) (RER+) and 34 had limited RERs only (28 = one locus; 6 = two loci) (RER+/−), yielding a bimodal distribution. RER+ cancers differed from RER− and RER+/− cases. Tumour type (adenocarcinoma, mucinous carcinoma, and undifferentiated carcinoma) (p=0.001), tumour infiltrating lymphocytes (p=0.001), and anatomical site (p=0.001) were the most significant of the discriminating variables. Algorithms developed by decision tree analysis allowed cases to be assigned to RER+ versus RER− and +/− status with a global sensitivity of 81.5%, specificity of 96%, and overall accuracy of 93%. Conclusion —Pathological examination of CRC allows assignment of RER+ status; assignment is specific and relatively sensitive. Conversely RER− and RER+/− CRC are indistinguishable.
Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac–derived macrophages
Authors: Guillaume Hoeffel, Yilin Wang, Melanie Greter, Peter See, Pearline Teo, Benoit Malleret, Marylène Leboeuf, Donovan Low, Guillaume Oller, Francisca Almeida, Sharon H.Y. Choy, Marcos Grisotto, Laurent Renia, Simon J. Conway, E. Richard Stanley, Jerry K.Y. Chan, Lai Guan Ng, Igor M. Samokhvalov, Miriam Merad, Florent Ginhoux
Journal: The Journal of Experimental Medicine (2012)

Langerhans cells (LCs) are the dendritic cells (DCs) of the epidermis, forming one of the first hematopoietic lines of defense against skin pathogens. In contrast to other DCs, LCs arise from hematopoietic precursors that seed the skin before birth. However, the origin of these embryonic precursors remains unclear. Using in vivo lineage tracing, we identify a first wave of yolk sac (YS)-derived primitive myeloid progenitors that seed the skin before the onset of fetal liver hematopoiesis. YS progenitors migrate to the embryo proper, including the prospective skin, where they give rise to LC precursors, and the brain rudiment, where they give rise to microglial cells. However, in contrast to microglia, which remain of YS origin throughout life, YS-derived LC precursors are largely replaced by fetal liver monocytes during late embryogenesis. Consequently, adult LCs derive predominantly from fetal liver monocyte-derived cells with a minor contribution of YS-derived cells. Altogether, we establish that adult LCs have a dual origin, bridging early embryonic and late fetal myeloid development.
Gliomas display a microRNA expression profile reminiscent of neural precursor cells
Authors: Iris Lavon, Daniel Zrihan, Avital Granit, Ofira Einstein, Nina Fainstein, Malkiel A. Cohen, Mikhal A. Cohen, Bracha Zelikovitch, Yigal Shoshan, Sergei Spektor, Benjamin E. Reubinoff, Yakov Felig, Offer Gerlitz, Tamir Ben-Hur, Yohav Smith, Tali Siegal
Journal: Neuro-Oncology (2010)

Gliomas express many genes that play a role in neural precursor cells (NPCs), but no direct comparison between glioma and stem cell (SC) gene expression profiles has been performed. To investigate the similarities and differences between gliomas and SCs, we compared the microRNA (miRNA) expression signatures of glial tumors, embryonic SCs (ESCs), NPCs, and normal adult brains from both human and mouse tissues. We demonstrated that both human gliomas (regardless of their grade) and methylcholanthrene-induced mouse glioma shared an miRNA expression profile that is reminiscent of NPCs. About half of the miRNAs expressed in the shared profile clustered in seven genomic regions susceptible to genetic/epigenetic alterations in various cancers. These clusters comprised the miR17 family, mir183-182, and the SC-specific clusters mir367-302 and mir371-373, which are upregulated in gliomas, ESCs, and NPCs. The bipartite cluster of 7 + 46 miRNAs on chromosome 14q32.31, which might represent the largest tumor suppressor miRNA cluster, was downregulated in the shared expression profile. This study provides the first evidence for association between these clusters and gliomas. Despite the broad similarity in the miRNA expression profiles, 15 miRNAs showed disparate expression between SC and gliomas. Ten miRNAs belong to the 2 SC-specific clusters and the remaining (mir135b, mir141, mir205, mir200C, and mir301a) have been previously shown to associate with malignancies. Our finding showed that all gliomas displayed NPC-like miRNA signatures, which may have implications for studies of glioma origins. Furthermore, careful study of the 15 miRNAs that differ in expression between SCs and gliomas, particularly those 5 that are not SC-specific, may enhance our understanding of gliomagenesis.