tbuckley/cabot-search huggingface dataset:
Systematic biases in DNA copy number originate from isolation procedures
Authors: Sebastiaan van Heesch, Michal Mokry, Veronika Boskova, Wade Junker, Rajdeep Mehon, Pim Toonen, Ewart de Bruijn, James D Shull, Timothy J Aitman, Edwin Cuppen, Victor Guryev
Journal: Genome biology (2013)

Abstract Background The ability to accurately detect DNA copy number variation in both a sensitive and quantitative manner is important in many research areas. However, genome-wide DNA copy number analyses are complicated by variations in detection signal. Results While GC content has been used to correct for this, here we show that coverage biases are tissue-specific and independent of the detection method as demonstrated by next-generation sequencing and array CGH. Moreover, we show that DNA isolation stringency affects the degree of equimolar coverage and that the observed biases coincide with chromatin characteristics like gene expression, genomic isochores, and replication timing. Conclusion These results indicate that chromatin organization is a main determinant for differential DNA retrieval. These findings are highly relevant for germline and somatic DNA copy number variation analyses.
Hypoxia-Inducible Factor-1α Suppresses Squamous Carcinogenic Progression and Epithelial-Mesenchymal Transition
Authors: Marzia Scortegagna, Rebecca J. Martin, Raleigh D. Kladney, Robert G. Neumann, Jeffrey M. Arbeit
Journal: Cancer Research (2009)

Hypoxia-inducible factor-1 (HIF-1) is a known cancer progression factor, promoting growth, spread, and metastasis. However, in selected contexts, HIF-1 is a tumor suppressor coordinating hypoxic cell cycle suppression and apoptosis. Prior studies focused on HIF-1 function in established malignancy; however, little is known about its role during the entire process of carcinogenesis from neoplasia induction to malignancy. Here, we tested HIF-1 gain of function during multistage murine skin chemical carcinogenesis in K14-HIF-1alpha(Pro402A564G) (K14-HIF-1alphaDPM) transgenic mice. Transgenic papillomas appeared earlier and were more numerous (6 +/- 3 transgenic versus 2 +/- 1.5 nontransgenic papillomas per mouse), yet they were more differentiated, their proliferation was lower, and their malignant conversion was profoundly inhibited (7% in transgenic versus 40% in nontransgenic mice). Moreover, transgenic cancers maintained squamous differentiation whereas epithelial-mesenchymal transformation was frequent in nontransgenic malignancies. Transgenic basal keratinocytes up-regulated the HIF-1 target N-myc downstream regulated gene-1, a known tumor suppressor gene in human malignancy, and its expression was maintained in transgenic papillomas and cancer. We also discovered a novel HIF-1 target gene, selenium binding protein-1 (Selenbp1), a gene of unknown function whose expression is lost in human cancer. Thus, HIF-1 can function as a tumor suppressor through transactivation of genes that are themselves targets for negative selection in human cancers.
Topotecan Combination Chemotherapy in Two New Rodent Models of Retinoblastoma
Authors: Nikia A. Laurie, Jonathan K. Gray, Jiakun Zhang, Mark Leggas, Mary Relling, Merrill Egorin, Clinton Stewart, Michael A. Dyer
Journal: Clinical Cancer Research (2005)

Chemotherapy combined with laser therapy and cryotherapy has improved the ocular salvage rate for children with bilateral retinoblastoma. However, children with late-stage disease often experience recurrence shortly after treatment. To improve the vision salvage rate in advanced bilateral retinoblastoma, we have developed and characterized two new rodent models of retinoblastoma for screening chemotherapeutic drug combinations. The first model is an orthotopic xenograft model in which green fluorescent protein- or luciferase-labeled human retinoblastoma cells are injected into the eyes of newborn rats. The second model uses a replication-incompetent retrovirus (LIA-E(E1A)) encoding the E1A oncogene. Clonal, focal tumors arise from mouse retinal progenitor cells when LIA-E(E1A) is injected into the eyes of newborn p53-/- mice. Using these two models combined with pharmacokinetic studies and cell culture experiments, we have tested the efficacy of topotecan combined with carboplatin and of topotecan combined with vincristine for the treatment of retinoblastoma. The combination of topotecan and carboplatin most effectively halted retinoblastoma progression in our rodent models and was superior to the current triple drug therapy using vincristine, carboplatin, and etoposide. Vincristine had the lowest LC50 in culture but did not reduce tumor growth in our preclinical retinoblastoma models. Taken together, these data suggest that topotecan may be a suitable replacement for etoposide in combination chemotherapy for the treatment of retinoblastoma.
Evolving Applications for Patient-Centered Health Status Measures
Authors: John A. Spertus
Journal: Circulation (2008)

Patient-centered health status measures—assessments of patients’ symptoms, function, and quality of life—have matured substantially over the past 2 decades. Currently, valid, reliable, and sensitive disease-specific measures are available for quantifying the health status of patients with cardiovascular disease. This article briefly reviews the concept of health status measures, with a focus on their interpretation. It then discusses both the rationale and potential applications of health status measures in clinical care. Health status measures are not surrogate measures of outcome but rather highly meaningful outcomes of care. As such, they have important emerging roles as outcomes in clinical trials, as tools for monitoring patients in routine clinical care, as a mechanism for operationalizing and evaluating disease management programs, and as tools for quality assessment/improvement. Over time, it is expected that health status measures will also have an increasingly important role in patient-centered medical decision making. By becoming aware of the evolving roles of health status measures, clinicians can help to accelerate the realization of the Institute of Medicine’s vision for a more transparent, evidence-based, patient-centered healthcare system.
MENTAL ILLNESS AMONG NEGRO TROOPS OVERSEAS
Authors: HERBERT S. RIPLEY, STEWART WOLF
Journal: American Journal of Psychiatry (1947)

Data were obtained on the incidence of mental illnesses in Negro troops stationed on an isolated island in the Southwest Pacific and comparisons made with similarly situated white troops. 1. The incidence of psychoneuroses and psychoses was found to be appreciably higher among Negro than among white troops. 2. The Negro appeared less well equipped by virtue of emotional and intellectual resources to adjust to war zone conditions of bodily hazard and isolation from women. 3. The rigors of military discipline, long working hours, and necessarily meager facilities for entertainment in the war zone acted to enhance already existent feelings of maltreatment and racial discrimination among Negroes. 4. Screening out by the induction centers of those unfit for military service because of mental and emotional defects seemed to have been less painstakingly performed among Negroes than among white men and this may have been a factor in the high incidence of psychiatric illness. 5. In many instances the officers were unsuitable to lead Negro troops.
Gene Expression Profiling from Formalin-Fixed Paraffin-Embedded Tumors of Pediatric Glioblastoma
Authors: Takrima Haque, Damien Faury, Steffen Albrecht, Enrique Lopez-Aguilar, Péter Hauser, Miklós Garami, Zoltán Hanzély, László Bognár, Rolando F. Del Maestro, Jeffrey Atkinson, Andre Nantel, Nada Jabado
Journal: Clinical Cancer Research (2007)

Gene expression profiling has proved crucial for understanding the biology of cancer. In rare diseases, including pediatric glioblastoma (pGBM), the lack of readily available fresh frozen (FF) material limits the feasibility of this analysis, as well as its validation, on independent data sets, a step needed to ensure relevance, mandating the use of alternate RNA sources. To overcome the limitation of material number and to validate results we obtained on FF pGBM, we did microarray analysis on RNA extracted from formalin-fixed, paraffin-embedded archival samples from pGBM and control brains, wherein we had no control on the fixation process.RNA from 16 pGBM and 3 control brains was extracted and linearly amplified. Reverse transcription-PCR on housekeeping and formerly identified tumor-associated genes and microarray analysis were done on this RNA source. Results were validated by immunohistochemistry.Despite extensive RNA degradation, microarray analysis was possible on 16 of 19 samples and reproduced the pattern of results obtained on FF pGBM. Gene lists and ontology subgrouping were highly concordant in both sample types. Similar to the findings on FF samples, we were able to identify two subsets of pGBM based on their association/lack of association with evidence consistent with an active Ras pathway.Archival formalin-fixed, paraffin-embedded tissues are an invaluable resource as they are the most widely available materials often accessible in conjunction with clinical and follow-up data. Gene expression profiling on this material is feasible and may represent a significant advance for understanding the biology of rare human diseases.
Identification of previously unknown<i>SERPINB</i>7 splice variants in patients with Nagashima-type palmoplantar keratosis reveals the importance of the CD-loop of SERPINB7
Authors: S. Suzuki, T. Nomura, O. Mizuno, Y. Fujita, H. Shimizu
Journal: British Journal of Dermatology (2015)

Funding sources: This work was supported by Grant‐in‐aid for Young Scientists (B) 25860925 (to T.N.) from the Japan Society for the Promotion of Science. Conflicts of interest: none declared. Dear Editor, Nagashima‐type palmoplantar keratosis (NPPK; MIM #615598) is the most common form of palmoplantar keratoderma (PPK) in Japan (and probably in other East Asian countries) and is inherited in an autosomal recessive fashion.1 NPPK is clinically characterized by hyperkeratosis and erythema on the palms and soles extending to the dorsum of the hands and the feet, the flexor aspects of the wrists and ankles, and the Achilles tendon areas.2 Histological findings include orthokeratotic hyperkeratosis, acanthosis, hypergranulosis and parakeratosis in the lower layers of the stratum corneum.3 In 2013, putative loss‐of‐function mutations in SERPINB7, which encodes a member of the serine protease inhibitor superfamily, were identified as a cause of NPPK.2 To date, seven mutations in SERPINB7 have been reported (Fig. 1).2 3 4 Considering the consensus sequences at the exon–intron boundaries,5 four of the seven mutations are predicted to trigger aberrant splicing of SERPINB7 pre‐mRNA (Fig. 1), whereas the three other mutations are either nonsense or frameshift mutations that result in a premature termination codon (PTC). Given that no phenotype–genotype correlation has been reported in NPPK,2 3 4 mutations in SERPINB7 are considered to be equally pathogenic. However, the consequence of the splice‐site mutations on splicing of SERPINB7 mRNA in patients' skin has not been characterized. Therefore, the pathogenic mechanism by which these mutations lead to NPPK remains unknown. We report here the identification of previously unknown splice variants resulting from two SERPINB7 mutations, c.218_219delinsTAAACTTTACCT and c.455‐1G>A, and a new functional domain of SERPINB7.
The Adaptor Protein AP-3 Is Required for CD1d-Mediated Antigen Presentation of Glycosphingolipids and Development of Vα14<i>i</i> NKT Cells
Authors: Dirk Elewaut, Anna P. Lawton, Niranjana A. Nagarajan, Emanual Maverakis, Archana Khurana, Stefan Höning, Chris A. Benedict, Eli Sercarz, Oddmund Bakke, Mitchell Kronenberg, Theodore I. Prigozy
Journal: The Journal of Experimental Medicine (2003)

Relatively little is known about the pathway leading to the presentation of glycolipids by CD1 molecules. Here we show that the adaptor protein complex 3 (AP-3) is required for the efficient presentation of glycolipid antigens that require internalization and processing. AP-3 interacts with mouse CD1d, and cells from mice deficient for AP-3 have increased cell surface levels of CD1d and decreased expression in late endosomes. Spleen cells from AP-3–deficient mice have a reduced ability to present glycolipids to natural killer T (NKT) cells. Furthermore, AP-3–deficient mice have a significantly reduced NKT cell population, although this is not caused by self-tolerance that might result from increased CD1d surface levels. These data suggest that the generation of the endogenous ligand that selects NKT cells may also be AP-3 dependent. However, the function of MHC class II–reactive CD4+ T lymphocytes is not altered by AP-3 deficiency. Consistent with this divergence from the class II pathway, NKT cell development and antigen presentation by CD1d are not reduced by invariant chain deficiency. These data demonstrate that the AP-3 requirement is a particular attribute of the CD1d pathway in mice and that, although MHC class II molecules and CD1d are both found in late endosomes or lysosomes, different pathways mediate their intracellular trafficking.
Efficacy of Pegfilgrastim and Darbepoetin Alfa As Hematopoietic Support for Dose-Dense Every-2-Week Adjuvant Breast Cancer Chemotherapy
Authors: Harold J. Burstein, Leroy M. Parker, Aparna Keshaviah, Jennifer Doherty, Ann H. Partridge, Lidia Schapira, Paula D. Ryan, Jerry Younger, Lyndsay N. Harris, Beverly Moy, Steven E. Come, Susan T. Schumer, Craig A. Bunnell, Margaret Haldoupis, Rebecca Gelman, Eric P. Winer
Journal: Journal of Clinical Oncology (2005)

Dose-dense, every-2-week adjuvant chemotherapy using doxorubicin/cyclophosphamide (AC; 60/600 mg/m2 every 2 weeks x four cycles) followed by paclitaxel (175 mg/m2 every 2 weeks x four cycles), requiring filgrastim on days 3 through 10 of each cycle has been shown to improve survival compared with every-3-week treatment schedules but is associated with greater risk of RBC transfusion (13%). The role of long-acting hematopoietic growth factors in facilitating every-2-week chemotherapy and minimizing hematologic toxicity has not been established.Women with stage I to III breast cancer received dose-dense AC --> paclitaxel as neoadjuvant or adjuvant chemotherapy. Patients received pegfilgrastim 6 mg subcutaneous (SQ) on day 2 of each cycle. Darbepoetin alfa was initiated at 200 microg SQ every 2 weeks for hemoglobin < or = 12 g/dL, and administered thereafter, according to a preplanned algorithm. The primary end points were to evaluate the percentage of patients with febrile neutropenia and the percentage of patients requiring RBC transfusion.Among 135 women treated on this single arm study, there were two cases of febrile neutropenia (incidence 1.5%). No patients received RBC transfusion. Darbepoetin alfa therapy was initiated in 92% of patients. The modest leukocytosis seen during paclitaxel cycles was attributable, in part, to corticosteroid premedication. Other toxicity and dose-delivery were similar to dose-dense AC --> paclitaxel in Cancer and Leukemia Group B 9741.Pegfilgrastim and darbepoetin alfa are effective and safe in facilitating every-2-week AC --> paclitaxel, minimizing rates of febrile neutropenia and RBC transfusion.
Delivery of Compression Therapy for Venous Leg Ulcers
Authors: Kian Zarchi, Gregor B. E. Jemec
Journal: JAMA Dermatology (2014)

Despite the documented effect of compression therapy in clinical studies and its widespread prescription, treatment of venous leg ulcers is often prolonged and recurrence rates high. Data on provided compression therapy are limited.To assess whether home care nurses achieve adequate subbandage pressure when treating patients with venous leg ulcers and the factors that predict the ability to achieve optimal pressure.We performed a cross-sectional study from March 1, 2011, through March 31, 2012, in home care centers in 2 Danish municipalities. Sixty-eight home care nurses who managed wounds in their everyday practice were included.Participant-masked measurements of subbandage pressure achieved with an elastic, long-stretch, single-component bandage; an inelastic, short-stretch, single-component bandage; and a multilayer, 2-component bandage, as well as, association between achievement of optimal pressure and years in the profession, attendance at wound care educational programs, previous work experience, and confidence in bandaging ability.A substantial variation in the exerted pressure was found: subbandage pressures ranged from 11 mm Hg exerted by an inelastic bandage to 80 mm Hg exerted by a 2-component bandage. The optimal subbandage pressure range, defined as 30 to 50 mm Hg, was achieved by 39 of 62 nurses (63%) applying the 2-component bandage, 28 of 68 nurses (41%) applying the elastic bandage, and 27 of 68 nurses (40%) applying the inelastic bandage. More than half the nurses applying the inelastic (38 [56%]) and elastic (36 [53%]) bandages obtained pressures less than 30 mm Hg. At best, only 17 of 62 nurses (27%) using the 2-component bandage achieved subbandage pressure within the range they aimed for. In this study, none of the investigated factors was associated with the ability to apply a bandage with optimal pressure.This study demonstrates the difficulty of achieving the desired subbandage pressure and indicates that a substantial proportion of patients with venous leg ulcers do not receive adequate compression therapy. Training programs that focus on practical bandaging skills should be implemented to improve management of venous leg ulcers.
Effect of manufacturer-inserted mask leaks on ventilator performance
Authors: B. Louis, K. Leroux, D. Isabey, B. Fauroux, F. Lofaso
Journal: European Respiratory Journal (2009)

Most pressure-support devices use a single circuit with an exhalation port integrated in the mask. The aim of the current study was to compare the effects of masks having different manufacturer-inserted leaks on ventilator performance. We simulated chronic obstructive pulmonary disease and restrictive disease. Four ventilators (VENTImotion (Weinmann, Hamburg, Germany), VPAP III STA (ResMed, Saint Priest, France), Synchrony 2 (Respironics, Nantes, France) and Vivo 40 (Breas, Saint Priest)) were tested with the recommended masks and with the masks having the largest and smallest leaks. Tests were performed with pressure support levels of 10, 15 and 20 cmH(2)O. The in vivo evaluation compared two ventilators using recommended masks opposed in terms of exhaled port resistance. The ventilators were tested with their recommended mask, and after mask exchange. The mask with the largest leak induced auto-triggering and/or increased inspiratory-trigger sensitivity was the VENTImotion under both simulated conditions and VPAP III STA under the simulated obstructive-disease condition. The mask with the smallest leak-increased inspiratory-trigger delay was Synchrony 2 in the simulated obstructive-disease condition and increased rebreathing. The in vivo study confirmed the bench results. When switching to a mask that has a different leak, evaluation is needed to adjust trigger sensitivity and pressurisation level and to check the absence of rebreathing.
Increased Cyclooxygenase-2 Expression and Prostaglandin-Mediated Dilation in Coronary Arterioles of Patients With Diabetes Mellitus
Authors: Tamás Szerafin, Nóra Erdei, Tibor Fülöp, Eniko T. Pasztor, István Édes, Akos Koller, Zsolt Bagi
Journal: Circulation Research (2006)

Based on findings of experimental models of diabetes mellitus (DM) showing increased expression of vascular cyclooxygenase-2 (COX-2), we hypothesized that in patients with DM changes in COX-2-dependent prostaglandin synthesis affect vasomotor responses of coronary arterioles. Arterioles were dissected from the right atrial appendages obtained at the time of cardiac surgery of patient with DM(+) or without documented diabetes DM(-). Isolated arterioles (89+/-15 microm in diameter) were cannulated and pressurized (at 80 mm Hg), and changes in diameter were measured with video microscopy. After spontaneous tone developed [DM(-): 32+/-7%; DM(+): 37+/-5%; P=NS], arteriolar responses to bradykinin were investigated. Dilations to bradykinin (0.1 nmol/L to 1 micromol/L) were significantly (P<0.05) greater in DM(+) than DM(-) patients (10 nmol/L: 77+/-10% versus 38+/-14%). In both groups, dilations were similar to the NO-donor, sodium nitroprusside. In arterioles of DM(+), but not those of DM(-), patients' bradykinin-induced dilations were reduced by the nonselective COX inhibitor indomethacin or by the selective COX-2 inhibitor NS-398 (DM(+) at 10 nmol/L: to 20+/-4% and 29+/-7%, respectively). Correspondingly, a marked COX-2 immunostaining was detected in coronary arterioles of DM(+), but not in those of DM(-) patients. We conclude that in coronary arterioles of diabetic patients bradykinin induces enhanced COX-2-derived prostaglandin-mediated dilation. These findings are the first to show that in humans diabetes mellitus increases COX-2 expression and dilator prostaglandin synthesis in coronary arterioles, which may serve to increase dilator capacity and maintain adequate perfusion of cardiac tissues.
Coupling Freshly Isolated CD44<sup>+</sup>Infrapatellar Fat Pad‐Derived Stromal Cells with a TGF‐β3 Eluting Cartilage ECM‐Derived Scaffold as a Single‐Stage Strategy for Promoting Chondrogenesis
Authors: Henrique V. Almeida, Gráinne M. Cunniffe, Tatiana Vinardell, Conor T. Buckley, Fergal J. O'Brien, Daniel J. Kelly
Journal: Advanced Healthcare Materials (2015)

An alternative strategy to the use of in vitro expanded cells in regenerative medicine is the use of freshly isolated stromal cells, where a bioactive scaffold is used to provide an environment conducive to proliferation and tissue-specific differentiation in vivo. The objective of this study is to develop a cartilage extracellular matrix (ECM)-derived scaffold that could facilitate the rapid proliferation and chondrogenic differentiation of freshly isolated stromal cells. By freeze-drying cryomilled cartilage ECM of differing concentrations, it is possible to produce scaffolds with a range of pore sizes. The migration, proliferation, and chondrogenic differentiation of infrapatellar fat pad-derived stem cells (FPSCs) depend on the concentration/porosity of these scaffolds, with greater sulphated glycosaminoglycan (sGAG) accumulation observed in scaffolds with larger-sized pores. It is then sought to determine if freshly isolated fat pad-derived stromal cells, seeded onto a transforming growth factor (TGF)-β3 eluting ECM-derived scaffold, could promote chondrogenesis in vivo. While a more cartilage-like tissue could be generated using culture expanded FPSCs compared to nonenriched freshly isolated cells, fresh CD44(+) stromal cells are capable of producing a tissue in vivo that stained strongly for sGAGs and type II collagen. These findings open up new possibilities for in-theatre cell-based therapies for joint regeneration.
THE EFFECT OF RO-5-0831/l (MARPLAN) IN DEPRESSIVE STATES
Authors: H. AZIMA, H. DUROST, DOROTHY ARTHURS, A. SILVER
Journal: American Journal of Psychiatry (1959)

1. RO-5-0831/1 is a sufficiently potent anti-depressant to require further study; 2. It should be tried in instances where other anti-depressants have failed; 3. It brings into the therapeutic arsenal of depression the possibility of choice according to the patient responsivity.