tbuckley/cabot-search huggingface dataset:
Real-time polymerase chain reaction analysis of a 3895-bp mitochondrial DNA deletion in epithelial swabs and its use as a quantitative marker for sunlight exposure in human skin
Authors: A. Harbottle, J. Maki, B. Reguly, R. Wittock, K. Robinson, R. Parr, M.A. Birch-Machin
Journal: British Journal of Dermatology (2010)

The use of mitochondrial DNA (mtDNA) damage as a reliable and highly sensitive biomarker of ultraviolet (UV) radiation exposure in both the dermis and epidermis has now been well developed by our group and others. We have previously identified a 3895-bp mtDNA deletion which occurred more frequently and to a higher level in usually sun-exposed skin as opposed to occasionally sun-exposed skin. This work focused on older-aged individuals and, in particular, perilesional, histologically normal skin biopsies taken from patients with skin cancer.To develop novel, less-invasive methods of obtaining skin samples (i.e. epidermis) from volunteers covering a much wider age range and larger number of individuals (n = 239).The 3895-bp deletion was quantified by a specific real-time polymerase chain reaction assay in normal human epidermis samples taken from three body sites with differing sun exposure.The results show a statistical increase of the level of the 3895-bp deletion with increasing sun exposure in the epidermal swabs of human skin (P < 0·001) and with increasing age of the donor in the needle biopsy samples.These data suggest that the upper layers of the epidermis are an accessible and reliable site for assessing mtDNA damage caused by UV exposure.
Metabolism of safingol in human neuroblastoma and ALL leukemia cell lines.
Authors: Hongtao Wang, Guoying Kong, Barry J. Maurer
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2019 

We reported that safingol (L-threo-dihydrosphingosine) synergized the cytotoxicity of the ceramide-generating retinoid, N-(4-hydroxyphenyl)retinamide (fenretinide, 4-HPR) in human cancer cell lines in vitro. The mechanism by which safingol synergized 4-HPR cytotoxicity is not known. Safingol inhibited protein kinase C activity, and D,L-threo-dihydrosphingosine inhibited sphingosine kinase, in platelets, in cell extracts, or in short-term (minutes) drug exposures. However, the significance of these observations to chronic exposure in whole cells is not clear, and in rodent cells, safingol was metabolized to L-threo-ceramide and L-threo-glucosylceramides. Determining safingol metabolism in human cancer cells is crucial to understanding the mechanism of safingol + 4-HPR cytotoxic synergy, and to optimize clinical strategies for safingol administration. Using 3H-safingol, we determined the uptake and metabolism of safingol in human neuroblastoma cell line, CHLA-90, and ALL leukemia cell line, MOLT-4. Safingol and its metabolites were analyzed by thin-layer chromatography and scintillography, cell viability was measured using DIMSCAN analysis. To partially mimic infusional delivery, cells were incubated with 1 uM and 3 uM safingol for 24 hrs. Lipid analysis showed that safingol was acylated to L-threo-dihydroceramide (L-t-(DH)cer) and L-threo-dihydrosphingomyelin (L-t-(DH)SM). No safingol-derived ceramides or glucosylceramide were detected. At +4 hrs in 1 and 3 uM safingol in CHLA-90 cells, free safingol was 47% and 53%, L-t-(DH)cer was 47% and 44%, and L-t-(DH)SM was 6% and 3%, of remaining label, respectively. At +4 hrs in 1 and 3 uM safingol in MOLT-4 cells, free safingol was 20% and 60%, L-t-(DH)cer was 70% and 30%, and L-t-(DH)SM was 10% and 10%, of remaining label, respectively. To mimic a bolus delivery, cells were incubated with 6 uM safingol for 2 hrs and then medium was changed. In CHLA-90, at +4 and +24 hrs after washout, free safingol was 35% and 10%, L-t-(DH)cer was 50% and 30%, and L-t-(DH)SM was 15% and 60%, of remaining label, respectively. In contrast, in MOLT-4, at +4 and +24 hrs after washout, free safingol was 55% and 15%, L-t-(DH)cer was 42% and 75%, and L-t-(DH)SM was 3% and 10% of remaining label, respectively. Short chain L-t-(DH)ceramides (C2, C6 and C8) did not increase 4-HPR cytotoxicity in CHLA-90 and MOLT-4 cells. We conclude that 1) safingol was not metabolized to L-threo-ceramide or L-threo-glucosylceramide in two human cancer cell lines; 2) safingol metabolism differed somewhat in two human cancer cell lines; 3) L-t-(DH)cer most likely does not synergize 4-HPR cytotoxicity; 4) free safingol likely synergizes 4-HPR cytotoxicity; 5) delivery schedule may affect the kinetics of cellular safingol levels. This study has partially clarified the mechanism of safingol + 4-HPR cytotoxic synergy, and provided crucial information to optimize safingol delivery for in vivo efficacy studies.
Abstract P2-05-04: Gene expression associated with poor prognosis of young TNBC patients
Authors: Thomas Karn, Lajos Pusztai, Cornelia Liedtke, Giampaolo Bianchini, Balazs Györffy, Christos Hatzis, Achim Rody, Volkmar Müller, Marcus Schmidt, Uwe Holtrich, Sven Becker
Journal: Cancer Research (2015)

Abstract Background: Among TNBC patients those of very young age (&amp;lt;40 years) display a significantly worse prognosis (Liedtke et al. 2013 Breast Cancer Res Treat). We verified this result in 1161 TNBC samples with full Affymetrix gene expression data of which 845 patients had both detailed age and follow up information. Materials and Methods: We split the full sample set into a finding cohort of 394 TNBC and a validation cohort of 767 TNBC encompassing 309 and 536 samples, respectively, with both age and follow up data. We then used significance analysis of microarrays (SAM) in the finding cohort to look for genes whose expression is associated with young age (&amp;lt;40 years). Identified genes were analyzed for their correlations to known metagenes characteristic for different TNBC subtypes. Subsequently the whole analysis was repeated in the validation cohort. Results: We identified 98 and 222 probesets by SAM in the finding and validation cohort, respectively. Only a subset of identical probesets (19.4%) was re-identified in the validation. However, the gene lists were similarily enriched for correlations to specific metagenes and the respective TNBC subtypes. We found that young age among TNBC is positively correlated with increased proliferation and a basal-like subtype, but negatively correlated with the molecular apocrine phenotype and the claudin-low subtype. We also observed a negative correlation of young age with stromal enrichment and EMT but no difference in lymphocyte infiltration as judged by specific metagenes. However, despite that TNBC of patients &amp;lt;40 years have a poor prognosis (P=0.006) and are clearly enriched in basal-like subtype (70.7% vs 55.3%; P=0.001), still basal-like TNBC do not differ from non-basal-like TNBC in prognosis. Moreover, even within the group of basal-like TNBC the prognostic effect of age&amp;lt;40 was still observed (P=0.008). Interestingly, the changes in expression of single genes and metagenes were observed over a wide age range of 35-85 years. In contrast the difference in prognosis was markedly pronounced at the 40 year age limit. Thus, potential critical differences in gene expression associated with poor prognosis of TNBC &amp;lt;40 years seem to be concealed by many age-associated changes without prognostic value. Citation Format: Thomas Karn, Lajos Pusztai, Cornelia Liedtke, Giampaolo Bianchini, Balazs Györffy, Christos Hatzis, Achim Rody, Volkmar Müller, Marcus Schmidt, Uwe Holtrich, Sven Becker. Gene expression associated with poor prognosis of young TNBC patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-04.
Abstract 15555: Survival of Older Heart Transplant Recipients Bridged with LVAD Support
Authors: Eugene C DePasquale, John A Dodson, Khurram Nasir, Charisse Ward, Daniel L Jacoby
Journal: Circulation (2012)

Background: The association of age with long-term outcomes after heart transplant (HT) is well known. However, age differences among patients bridged with LVAD have not been well-described. We ther...
Principles and Practice of Medical Genetics.
Authors: David E. Comings
Journal: Annals of Internal Medicine (1991)

Part 1 Basic principles: nature and incidence of genetic disease, A.E.Emery gene structure and function in eukaryotic organisms, C.J.Epstein molecular biology in relation to medical genetics, R.F.Mueller mutation in man, F.Vogel chromosomal basis of inheritance, O.J.Miller unifactorial inheritance, R.Skinner Bayesian methods in medical genetics, A.E.Emery segregation analysis, M.A.Spence population genetics, J.A.Sofaer gene mapping, U.Francke analysis of genetic linkage, J.Lalouel multifactoral inheritance, D.T.Bishop twins, J.A.Sofaer teratogenic agents, J.W.Hanson a clinical approach to the dysmorphic child, K.L.Jones. Part 2 Chromosome disorders: human cytogenic nomeclature, H.A.Lubs and P.S.Ing autosomal disorders, J.de Grouchy and C.Turleau sex chromosome abnormalities, A.de la Chapelle. Part 3 System disorders, neurological disorders: x-linked mental retardation and the marker x, H.A.Lubs infertility and recurrent abortion, A.C.Chandley genetics and prevention of neural tube defects, K.M.Laurence the convulsive disorders, G.C.Sutton hereditary disorders of the basal ganglia, R.Eldridge Huntington disease, P.M.Conneally hereditary ataxias and paraplegias, A.E.Harding autonomic and sensory disorders, F.B.Axelrod peripheral neuropathies, P.K.Thomas the phakomatoses, V.Riccardi demyelinating disorders, S.Bundey schizophrenia and major mood disorders, D.K.Kinney the presenile dementias, D.Vassilopoulos addictive disorders, H.W.Goedde mental retardation, H.W.Moser congenital myopathies, J.Z.Heckmatt the muscular dystrophies, A.E.Emery spinal muscular atrophies, J.H.Pearn myotonic dystrophy and related disorders, P.S.Harper myasthenia gravis, G.M.Fenichel motor neuronal diseases, J.Keleman the periodic paralyses, I.Gamstorp congenital blindness, M.Warburg optic atrophy, L.N.Went glaucoma - congenital and later onset, J.R.Henkenlively defects of the cornea, J.Sugar anomalies of the lens, Hans-R.Kock hereditary retinal and choroidal degenerations, J.R.Henkenlively retinoblastoma, D.F.Roberts and G.E.Aherne genetic aspects of strabismus, J.B.Bateman and S.J.Isenberg hereditary deafness, P.Beighton craniofacial disorders, M.Cohen abnormalities of pigmentation, C.J.Witkop Jr ichthyosiform dermatoses, H.P.Baden epidermolysis bullosa, T.Gedde-Dahl, Jr and I.Anton-Lampredth genetic disorders of the skin, L.A.Goldsmith the chandrodysplasias, D.L.Rimoin and R.S.Lachman disorders of bone density, D.O.Sillence. (Part Contents)
The premature ageing syndromes.
Authors: J. J. H. GILKES, D. E. SHARVILL, R. S. WELLS
Journal: British Journal of Dermatology (1974)

Journal Article The premature ageing syndromes: REPORT OF EIGHT CASES AND DESCRIPTION OF A NEW ENTITY NAMED METAGERIA Get access J. J. H. GILKES, J. J. H. GILKES The Department of Dermatology, Guy's Hospital, London, SE1 9RT, The Department of Dermatology, Kent and Canterbury Hospital, Canterbury, and the Department of Genetics, The Institute of Dermatology, St John's Hospital for Diseases of the Skin, Lisle Street, London, WC2H 7BJ *Reprint requests should be addressed to: Dr J. J. H, Gilkes, St Bartholomew's Hospital, London EC1A 7BE. Search for other works by this author on: Oxford Academic Google Scholar D. E. SHARVILL, D. E. SHARVILL The Department of Dermatology, Guy's Hospital, London, SE1 9RT, The Department of Dermatology, Kent and Canterbury Hospital, Canterbury, and the Department of Genetics, The Institute of Dermatology, St John's Hospital for Diseases of the Skin, Lisle Street, London, WC2H 7BJ Search for other works by this author on: Oxford Academic Google Scholar R. S. WELLS R. S. WELLS The Department of Dermatology, Guy's Hospital, London, SE1 9RT, The Department of Dermatology, Kent and Canterbury Hospital, Canterbury, and the Department of Genetics, The Institute of Dermatology, St John's Hospital for Diseases of the Skin, Lisle Street, London, WC2H 7BJ Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 91, Issue 3, 1 September 1974, Pages 243–262, https://doi.org/10.1111/j.1365-2133.1974.tb12893.x Published: 01 September 1974 Article history Accepted: 29 November 1973 Published: 01 September 1974
Human Plasma Protein C
Authors: Walter Kisiel
Journal: Journal of Clinical Investigation (1979)

Protein C is a vitamin K-dependent protein, which exists in bovine plasma as a precursor of a serine protease. In this study, protein C was isolated to homogeneity from human plasma by barium citrate adsorption and elution, ammonium sulfate fractionation, DEAE-Sephadex chromatography, dextran sulfate agarose chromatography, and preparative polyacrylamide gel electrophoresis. Human protein C (Mr = 62,000) contains 23% carbohydrate and is composed of a light chain (Mr = 21,000) and a heavy chain (Mr = 41,000) held together by a disulfide bond(s). The light chain has an amino-terminal sequence of Ala-Asn-Ser-Phe-Leu- and the heavy chain has an aminoterminal sequence of Asp-Pro-Glu-Asp-Gln. The residues that are identical to bovine protein C are underlined. Incubation of human protein C with human α-thrombin at an enzyme to substrate weight ratio of 1:50 resulted in the formation of activated protein C, an enzyme with serine amidase activity. In the activation reaction, the apparent molecular weight of the heavy chain decreased from 41,000 to 40,000 as determined by gel electrophoresis in the presence of sodium dodecyl sulfate. No apparent change in the molecular weight of the light chain was observed in the activation process. The heavy chain of human activated protein C also contains the active-site serine residue as evidenced by its ability to react with radiolabeled diisopropyl fluorophosphate. Human activated protein C markedly prolongs the kaolin-cephalin clotting time of human plasma, but not that of bovine plasma. The amidolytic and anticoagulant activities of human activated protein C were completely obviated by prior incubation of the enzyme with diisopropyl fluorophosphate. These results indicate that human protein C, like its bovine counterpart, exists in plasma as a zymogen and is converted to a serine protease by limited proteolysis with attendant anticoagulant activity.
Research on third generation pill remains unpublished
Authors: Tony Sheldon
Journal: BMJ (2001)

A Dutch radio programme has raised further concerns about the role of unpublished, industry sponsored medical research on the risks of taking the third generation of contraceptive pill.

In its second broadcast in two months on the subject, the investigative programme Argos stated that a new study had been carried out but its results had not yet been published. The study, requested by the European Medicines Evaluation Agency, was carried out by several manufacturers of contraceptive pills, with the company Organon Netherlands acting as the “coordinating sponsor.”

The agency confirmed to the programme makers that the study was complete and that the manufacturers were free to publish the results, but the agency could not release the results …
Identification of a Vav2-dependent mechanism for GDNF/Ret control of mesolimbic DAT trafficking
Authors: Shuyong Zhu, Chengjiang Zhao, Yingying Wu, Qiaoqiao Yang, Aiyun Shao, Tiepeng Wang, Jianfu Wu, Yanqing Yin, Yandong Li, Jincan Hou, Xinhua Zhang, Guomin Zhou, Xiaosong Gu, Xiaomin Wang, Xosé R Bustelo, Jiawei Zhou
Journal: Nature Neuroscience (2015)
Rewriting the blueprint of life by synthetic genomics and genome engineering
Authors: Narayana Annaluru, Sivaprakash Ramalingam, Srinivasan Chandrasegaran
Journal: Genome biology (2015)

Abstract Advances in DNA synthesis and assembly methods over the past decade have made it possible to construct genome-size fragments from oligonucleotides. Early work focused on synthesis of small viral genomes, followed by hierarchical synthesis of wild-type bacterial genomes and subsequently on transplantation of synthesized bacterial genomes into closely related recipient strains. More recently, a synthetic designer version of yeast Saccharomyces cerevisiae chromosome III has been generated, with numerous changes from the wild-type sequence without having an impact on cell fitness and phenotype, suggesting plasticity of the yeast genome. A project to generate the first synthetic yeast genome - the Sc2.0 Project - is currently underway.
Abstract 4089: Histone deacetylase 6 (HDAC6) as a regulator of PD-L1 expression through STAT3 modulation in melanoma
Authors: Maritza Lienlaf, Patricio Perez-Villarroel, Calvin Lee, Fengdong Cheng, Jorge Canales, Tessa Knox, Danay Marante, Amod Sarnaik, Pedro Horna, Ed. Seto, Keiran Smalley, Jeffrey S. Weber, Eduardo M. Sotomayor, Alejandro Villagra
Journal: Cancer Research (2014)

Abstract In spite of the progress made in the understanding of the cell biology, genetics and immunology of melanoma, the outcome for patients with advanced-stage disease has remained poor with a median survival ranging from 2-16 months. Some optimism was recently provided in metastatic melanoma by the improved clinical outcomes observed in patients receiving PD-L1 blocking antibodies. A better understanding of the environmental, genetic and epigenetic factors limiting the efficacy of melanoma immunotherapy will provide appropriate partner(s) for combination with Ipilimumab or PD1/PDL1 antibodies. Among the epigenetic factors, we have found that one member of the histone deacetylase family, HDAC6, plays a critical role not only in the regulation of survival/apoptosis of melanoma cells but also in limiting their immunogenicity and recognition by immune effector cells. Particularly, we found a major role of HDAC6 as a modulator of the immunosuppresive STAT3/IL-10 pathway and down-regulation of tolerogenic PD-L1 molecules in melanoma cells. By analyzing HDAC6 knock-down melanoma cell lines (HDAC6KD) we demonstrated the inactivation of the STAT3 pathway and the subsequent down-regulation of its target genes, including the expression of PD-L1. We also observed that the PD-L1 expression and phosphorylation of STAT3 was decreased in melanoma isolated from xenograph tumor growth models after in vivo treatment with specific HDAC6 inhibitors Fortunately, there are multiple HDAC6-selective inhibitors available to mechanistically study the role of HDAC6 on these processes and provide a viable therapeutic avenue, which may minimize undesirable side effects that are characteristic of pan-HDACi such as SAHA. By building on our understanding of HDAC6 and applying these findings to novel experimental design, we hope to identify innovative therapeutic options to benefit cancer patients. Citation Format: Maritza Lienlaf, Patricio Perez-Villarroel, Calvin Lee, Fengdong Cheng, Jorge Canales, Tessa Knox, Danay Marante, Amod Sarnaik, Pedro Horna, Ed. Seto, Keiran Smalley, Jeffrey S. Weber, Eduardo M. Sotomayor, Alejandro Villagra. Histone deacetylase 6 (HDAC6) as a regulator of PD-L1 expression through STAT3 modulation in melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2014-4089
Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine.
Authors: J. Katz, K. Hancock, V. Veguilla, W. Zhong, X. H. Lu, H. Sun, E. Butler, L. Dong, F. Liu, Z. N. Li, J. DeVos, P. Gargiullo, N. Cox
Journal: MMWR Morbidity and Mortality Weekly Report (2009)
More on HIV-Associated Kaposi's Sarcoma
Authors: Susan E Krown, Jeannette Y Lee, Dirk P Dittmer
Journal: New England Journal of Medicine (2008)

The AIDS Malignancy Consortium, a multicenter cooperative group funded by the National Cancer Institute, has enrolled 442 patients who have human immunodeficiency virus (HIV) infection and measurable Kaposi's sarcoma in a series of therapeutic trials since 1996 (Table 1).
Abstract P174: Increased Cardiovascular Disease Risk Factors in Young Hispanic Women at the High-end of Normal-weight Body Mass Index
Authors: Chantal A Vella, Ximena Burgos-Monzon, Carla J Ellis
Journal: Circulation (2014)

BMI is often used to assess risk of cardiovascular disease (CVD); however, current BMI cutpoints may not be accurate for all ethnicities. Given the high prevalence of obesity and type 2 diabetes in Hispanics, it is important to examine whether current BMI cutpoints accurately identify those at healthy weight and those at risk. We examined whether there was a difference in CVD risk factors within the normal-weight BMI category in young, Hispanic women. We hypothesized that women in the highest tertile of normal-weight would have significantly more CVD risk factors than those in the lowest tertile of normal-weight. Sixty nine normal-weight Hispanic women (20-39 y) were divided into tertiles of normal-weight BMI: 18.5-20.9 kg/m2 (NW low, n=17), 21.0-22.9 kg/m2 (NW mid, n=31) and 23.0-24.9 kg/m2 (NW high, n=21). CVD risk factors measured included waist circumference, blood pressure and fasting glucose, triglycerides and high-density and low-density lipoprotein. Glucose tolerance was measured by a 2h oral glucose tolerance test. Body composition was measured by dual-energy x-ray absorptiometry. Intra-abdominal adipose tissue, an estimate of visceral adiposity, was calculated. Data were analyzed using multivariate ANOVA, with Levine’s test indicating homogeneity of variances among groups, and Kruskal-Wallace test. Post hoc tests included Bonferroni and Mann Whitney. Results indicated the prevalence of women who were risk factor free was 65%, 39% and 24% for NW low, mid and high, respectively. The prevalence of women with one or more CVD risk factors was 35%, 61%, and 76% for NW low, mid and high, respectively. The prevalence of women with two or more CVD risk factors was 0%, 3%, and 29% for NW low, mid and high, respectively. The prevalence of women with three or more CVD risk factors was 0%, 0% and 10% for NW low, mid and high, respectively. Overall the prevalence of CVD risk factors was significantly higher in NW high than NW low (p=0.006) and NW mod (p=0.04) and approached significance between NW mid and NW low (p=0.08). There was a significant increase in percentage body fat (27.6±5.1%, 30.7±4.6%, 36.9±4.6%, respectively), intra-abdominal adipose tissue (24.2±7.9 cm2, 45.6±12.2 cm2, 66.5±19.7 cm2, respectively), and waist circumference (71.2±3.1 cm, 76.6±4.8 cm, 81.0±5.8 cm, respectively) from NW low to NW high (p&lt;0,001). NW high had significantly higher triglyceride levels than NW low (86.4±40.0 mg/dL vs. 58.9±20.6 mg/dL, p=0.04) and significantly higher 2h glucose levels than NW mid (120.0±27.9 mg/dL vs. 99.1±17.3 mg/dL, p=0.003). In conclusion, young, Hispanic women at the upper-end of the normal-weight BMI range had a significantly higher prevalence of CVD risk factors, body fat and central obesity than women in the mid and lower end of normal-weight BMI range. These findings suggest that the normal-weight BMI cutpoint may need to be adjusted for Hispanic women.