tbuckley/cabot-search huggingface dataset:
Rapid Fragile X Carrier Screening and Prenatal Diagnosis Using a Nonradioactive PCR Test
Authors: W. Ted Brown
Journal: JAMA (1993)

To develop a rapid, nonradioactive test using the polymerase chain reaction (PCR) capable of detecting full fragile X mutations, premutations, and resolving normal alleles and to apply this to prenatal diagnosis and carrier screening of pregnant women at risk for fragile X carrier status.Prenatal and blood sample PCR analysis with confirmation by direct Southern blotting and cytogenetic techniques.Samples sent to a DNA diagnostic research laboratory at a tertiary referral center.Pregnant women with a family history of undiagnosed mental retardation or known fragile X syndrome and controls.A rapid, nonradioactive PCR screening protocol for the fragile X mental retardation-1 gene for both normal and mutant alleles was developed. Analysis of 570 control X chromosomes showed a modal number of 30 CGG repeats (range, 12 to 52 repeats) and a calculated heterozygosity of approximately 80%. No excess of homozygosity was found, indicating the test was accurate for normal allele resolution. In addition, 150 unrelated pregnant women were screened. Within known fragile X families, five of 20 pregnant women were diagnosed as carriers. Two new fragile X families were diagnosed among relatives of 130 females with family histories of undiagnosed mental retardation, although no carriers were identified. Prenatal PCR testing of 28 carriers accurately detected nine fetuses with full mutations.This rapid, nonradioactive PCR protocol allows accurate resolution of normal alleles as well as simultaneous detection of carrier alleles and full mutations. With this approach, efficient screening of pregnant women at risk for fragile X carrier status, subsequent genetic counseling of identified carriers, and reliable prenatal diagnosis can be offered.
The Influence of Prostate Volume on Prostate-Specific Antigen Performance: Implications for the Prostate Cancer Prevention Trial Outcomes
Authors: Christopher S. Elliott, Rajesh Shinghal, Joseph C. Presti
Journal: Clinical Cancer Research (2009)

Although showing a 25% reduction in the biopsy prevalence of cancer compared with placebo in the Prostate Cancer Prevention Trial, finasteride was associated with a higher prevalence of high-grade disease. This observation was driven by "for-cause" biopsies. We sought to understand how volume-dependent changes in prostate-specific antigen test performance characteristics may have contributed.A retrospective review was done on 1,304 men referred for initial biopsy with a prostate-specific antigen between 4 and 10 ng/mL or an abnormal digital rectal examination. Receiver-operator curves and positive predictive values were ascertained for prostate-specific antigen stratified by diagnosis and prostate volume.The performance of prostate-specific antigen changed for any and high-grade (Gleason, > or =3 + 4) cancer in a volume-specific manner. For any cancer, the area under the curve (AUC) decreased from 0.758 to 0.629 to 0.520 as prostate volume increased (<30, 30-50, >50 cm(3), respectively). For high-grade cancer, a similar trend was shown (AUC, 0.712, 0.639, and 0.497, respectively). The positive predictive value of a prostate-specific antigen of > or =4 ng/mL was also affected by prostate volume. Trends for Gleason < or = 6 decreased as prostate volume increased (positive predictive value for <30 cm(3), 25.0%; positive predictive value for 30-50 cm(3), 23.8%; and positive predictive value for >50 cm(3), 17.3%). A more significant trend was seen for high-grade cancer (positive predictive value for <30 cm(3), 39.0%; positive predictive value for 30-50 cm(3), 22.3%; and positive predictive value for >50 cm(3), 10.7%).Decreases in prostate volume over time and the resultant change in prostate-specific antigen performance characteristics may have contributed a bias toward the detection of high-grade disease in the finasteride arm of the Prostate Cancer Prevention Trial.
The Effects of Strontium Ranelate on the Risk of Vertebral Fracture in Women with Postmenopausal Osteoporosis
Authors: Pierre J. Meunier, Christian Roux, Ego Seeman, Sergio Ortolani, Janusz E. Badurski, Tim D. Spector, Jorge Cannata, Adam Balogh, Ernst-Martin Lemmel, Stig Pors-Nielsen, René Rizzoli, Harry K. Genant, Jean-Yves Reginster
Journal: New England Journal of Medicine (2004)

Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density.To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months.New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events.Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.
THE DEVELOPMENT OF NEUTROPHILIC POLYMORPHONUCLEAR LEUKOCYTES IN HUMAN BONE MARROW
Authors: Dorothy Ford Bainton, Joan L. Ullyot, Marilyn G. Farquhar
Journal: The Journal of Experimental Medicine (1971)

Neutrophilic leukocytes (PMN) and their precursors from normal human marrow and blood were examined by histochemical staining and by electron microscopy and cytochemistry in order to determine the origin and nature of their cytoplasmic granules. Human neutrophils contain two basic types of granules, azurophils and specifics, which differ in morphology, contents, and time of origin. Azurophils are large and may be spherical or ellipsoid, the latter with a crystalline inclusion. They are produced in the first secretory stage (promyelocyte), contain peroxidase and various lysosomal enzymes, and thus correspond to modified primary lysosomes. Specifics are smaller, may be spherical or elongated, and are formed during a later secretory stage (myelocyte). They lack lysosomal enzymes and contain alkaline phosphatase and basic protein; their contents remain largely undetermined. Specifics outnumber azurophils in the mature PMN because of reduction in numbers of azurophils per cell by cell division in the myelocyte stage. The findings indicate that the situation is basically the same as described previously in the rabbit, insofar as the origin, enzymic activity, and persistence in the mature cell of the two types (azurophil and specific) of granules are concerned. The main difference between PMN of the two species is in the morphology (size, shape, and density) of the granules, especially the azurophils.
Genomic and Expression Profiling of Human Spermatocytic Seminomas: Primary Spermatocyte as Tumorigenic Precursor and<i>DMRT1</i>as Candidate Chromosome 9 Gene
Authors: Leendert H.J. Looijenga, Remko Hersmus, Ad J.M. Gillis, Rolph Pfundt, Hans J. Stoop, Ruud J.H.L.M. van Gurp, Joris Veltman, H. Berna Beverloo, Ellen van Drunen, Ad Geurts van Kessel, Renee Reijo Pera, Dominik T. Schneider, Brenda Summersgill, Janet Shipley, Alan McIntyre, Peter van der Spek, Eric Schoenmakers, J. Wolter Oosterhuis
Journal: Cancer Research (2006)

Abstract Spermatocytic seminomas are solid tumors found solely in the testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and numerical chromosomal changes through conventional karyotyping, spectral karyotyping, and array comparative genomic hybridization using a 32 K genomic tiling-path resolution BAC platform (confirmed by in situ hybridization). Our panel of five spermatocytic seminomas showed a specific pattern of chromosomal imbalances, mainly numerical in nature (range, 3-24 per tumor). Gain of chromosome 9 was the only consistent anomaly, which in one case also involved amplification of the 9p21.3-pter region. Parallel chromosome level expression profiling as well as microarray expression analyses (Affymetrix U133 plus 2.0) was also done. Unsupervised cluster analysis showed that a profile containing transcriptional data on 373 genes (difference of ≥3.0-fold) is suitable for distinguishing these tumors from seminomas/dysgerminomas. The diagnostic markers SSX2-4 and POU5F1 (OCT3/OCT4), previously identified by us, were among the top discriminatory genes, thereby validating the experimental set-up. In addition, novel discriminatory markers suitable for diagnostic purposes were identified, including Deleted in Azospermia (DAZ). Although the seminomas/dysgerminomas were characterized by expression of stem cell–specific genes (e.g., POU5F1, PROM1/CD133, and ZFP42), spermatocytic seminomas expressed multiple cancer testis antigens, including TSP50 and CTCFL (BORIS), as well as genes known to be expressed specifically during prophase meiosis I (TCFL5, CLGN, and LDHc). This is consistent with different cells of origin, the primordial germ cell and primary spermatocyte, respectively. Based on the region of amplification defined on 9p and the associated expression plus confirmatory immunohistochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic seminomas. (Cancer Res 2006; 66(1): 290-302)
The chips are down for Helicobacter pylori
Authors: J C Atherton
Journal: Gut (2002)

Microarrays can be used to demonstrate differences in genetic content between Helicobacter pylori strains, giving a foretaste of how research may be conducted in the near future

The whole genome sequence of Helicobacter pylori strain 26695 was published in 1997 and that of a second strain, J99, in 1999.1, 2 These publications moved H pylori research forward by a quantum leap. Comparing H pylori genes with genes of known function in other bacteria gave immediate insights into H pylori metabolism, structure, adaptive mechanisms, and virulence. Research became more focused in that workers could identify and study genes that were known to be important in other bacteria and appreciate their whole genetic context in H pylori . For example, they could immediately see where an enzyme might fit in a metabolic pathway or what proteins were likely to comprise the H pylori flagella assembly. Now, several groups have taken another quantum leap forward. They have constructed whole genome microarrays—ordered arrays of all identified H pylori genes on glass slides—allowing experiments to be performed on all H pylori genes simultaneously. Such microarrays have already been used to assess differences between H pylori strains3 but the paper by Israel et al shows how they can be applied to research into pathogenesis.

Israel et al took two strains of H pylori , one from a patient with a duodenal ulcer (DU) and one from a patient with a gastric ulcer (GU), and …
Influence of Publication of US and European Prostate Cancer Screening Trials on PSA Testing Practices
Authors: S. B. Zeliadt, R. M. Hoffman, R. Etzioni, J. L. Gore, L. G. Kessler, D. W. Lin
Journal: JNCI Journal of the National Cancer Institute (2011)

In 2009, results from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial indicated no difference in mortality between the screening and the control groups (rate ratio = 1.13, 95% confidence interval = 0.75 to 1.70), whereas those from the European Randomized study of Screening for Prostate Cancer trial indicated a 20% reduction in mortality among the screening group (rate ratio = 0.80, 95% confidence interval = 0.65 to 0.98). In this study, we examined whether prostate-specific antigen (PSA) testing has changed following these publications. The primary outcome measure was the proportion of men seen at least once in a primary care or urology clinic between August 1, 2004, and March 31, 2010, who received a PSA test. Following the publications, PSA use declined slightly—by 3.0 percentage points and 2.7 percentage points among men aged 40–54 and 55–74 years, respectively. PSA testing among men older than 75 years initially declined slightly following the recommendations by the US Preventive Services Task Force in 2008 and continued to decline after the trial publications.
In vitro tubulogenesis of endothelial cells by relaxation of the coupling extracellular matrix-cytoskeleton
Authors: C Deroanne
Journal: Cardiovascular Research (2001)

Objective: This investigation aimed at determining the importance of the rigidity of the adhesive support and the participation of the cytoskeleton in tubulogenesis of endothelial cells in vitro. Methods: The morphotype, biosynthetic phenotype and cytoskeleton organization of human umbilical vein endothelial cells (HUVEC) were analyzed on supports of variable mechanical resistance. Results: Western blot analysis revealed a strong reduction of the expression of actin and focal-adhesion plaque (FAP) proteins in HUVEC organized in tube-like structures (TLS) on soft matrigel or on matrigel co-polymerized with heat-denatured collagen as compared to HUVEC remaining in a monolayer pattern on rigid matrigel-coat or on matrigel co-polymerized with type I collagen. Human skin fibroblasts morphotype was not altered in these culture conditions and the pattern of FAP proteins and actin was not modulated. By using polyacrylamide gels polymerized with various concentrations of bis-acrylamide to modulate the mechanical resistance of the support and cross-linked to a constant amount of gelatin to provide an equal density of attachment sites, it was shown that the less rigid the support, the more endothelial cells switched to a tube-like pattern. Collagen type I-induced tubulogenesis was accompanied by a profound and reversible remodeling of the actin-FAP complex suggesting a weakening of the bridging between extracellular matrix (ECM) and the cytoskeleton. Human skin fibroblasts and smooth muscle cells, used as control cells, adhered strongly to the collagen, did not form TLS and their network of actin stress fibers was not remodeled. The inhibition of collagen type I-induced tubulogenesis by agents altering the actin cytoskeleton-FAP complex including calpain type I inhibitor, orthovanadate, KT5720 and jasplakinolide, further supports the determinant role of mechanical coupling between the cells and the matrix in tubulogenesis. Conclusions: A reduced tension between the endothelial cells and the extracellular matrix, originating in the support or within the cells is sufficient to trigger an intracellular signaling cascade leading to tubulogenesis, an event mimicking one of the last steps of angiogenesis.
Inducible Nitric Oxide Synthase in Long-term Intermittent Hypoxia
Authors: Guanxia Zhan, Polina Fenik, Domenico Pratico, Sigrid C. Veasey
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Long-term intermittent hypoxia (LTIH) exposure in adult mice, modeling oxygenation patterns of moderate-severe obstructive sleep apnea, results in lasting hypersomnolence and is associated with nitration and oxidation injuries in many brain regions, including wake-active regions.We sought to determine if LTIH activates inducible nitric oxide synthase (iNOS) in sleep/wake regions, and if this source of NO contributes to the LTIH-induced proinflammatory gene response, oxidative injury, and wake impairments.Mice with genetic absence of iNOS activity and wild-type control animals were exposed to 6 weeks of long-term hypoxia/reoxygenation before behavioral state recordings, molecular and biochemical assays, and a pharmacologic intervention.Two weeks after recovery from hypoxia/reoxygenation exposures, wild-type mice showed increased iNOS activity in representative wake-active regions, increased sleep times, and shortened sleep latencies. Mutant mice, with higher baseline sleep times, showed no effect of long-term hypoxia/reoxygenation on sleep time latencies and were resistant to hypoxia/reoxygenation increases in lipid peroxidation and proinflammatory gene responses (tumor necrosis factor alpha and cyclooxygenase 2). Inhibition of iNOS after long-term hypoxia/reoxygenation in wild-type mice was effective in reversing the proinflammatory gene response.These data support a critical role for iNOS activity in the development of LTIH wake impairments, lipid peroxidation, and proinflammatory responses in wake-active brain regions, and suggest a potential role for inducible NO inhibition in protection from proinflammatory responses, oxidative injury, and residual hypersomnolence in obstructive sleep apnea.
Circulating mouse Flk1+/c-Kit+/CD45- cells function as endothelial progenitors cells (EPCs) and stimulate the growth of human tumor xenografts
Authors: Jeffery S Russell, J Brown
Journal: Molecular Cancer (2014)

Endothelial progenitor cells (EPCs) have been demonstrated to have stem-cell like as well as mature endothelial functions. However, controversy remains as to their origins, immunophenotypic markings, and contribution to the tumor vascular network and tumor survival. Flow cytometric analysis and sorting was used to isolate Flk-1+/c-Kit+/CD45- cells. Matrigel and methycellulose assays, flow cytometry, and gene array analyses were performed to characterize several murine EPC cell populations. Human tumor xenografts were used to evaluate the impact of EPCs on tumor growth and vascular development. Flk-1+/c-Kit+/CD45- cells were present at low levels in most murine organs with the highest levels in adipose, aorta/vena cava, and lung tissues. Flk-1+/c-Kit+/CD45- cells demonstrated stem cell qualities through colony forming assays and mature endothelial function by expression of CD31, uptake of acLDL, and vascular structure formation in matrigel. High passage EPCs grown in vitro became more differentiated and lost stem-cell markers. EPCs were found to have hemangioblastic properties as demonstrated by the ability to rescue mice given whole body radiation. Systemic injection of EPCs increased the growth of human xenograft tumors and vessel density. Flk-1+/C-Kit+/CD45- cells function as endothelial progenitor cells. EPCs are resident in most murine tissue types and localize to human tumor xenografts. Furthermore, the EPC population demonstrates stem-cell and mature endothelial functions and promoted the growth of tumors through enhanced vascular network formation. Given the involvement of EPCs in tumor development, this unique host-derived population may be an additional target to consider for anti-neoplastic therapy.
Reduced Platelet Thromboxane Formation in Uremia. EVIDENCE FOR A FUNCTIONAL CYCLOOXYGENASE DEFECT
Authors: G. Remuzzi, A. Benigni, P. Dodesini, A. Schieppati, M. Livio, G. De Gaetano, J. S. Day, W. L. Smith, E. Pinca, P. Patrignani, C. Patrono
Journal: Journal of Clinical Investigation (1983)

A qualitative platelet abnormality and a bleeding tendency are frequently associated with renal failure and uremia. We demonstrated previously that uremic patients display an abnormal platelet aggregation to arachidonic acid and reduced malondialdehyde production in response to thrombin and arachidonic acid. The objectives of this investigation were: (a) to compare platelet prostaglandin (PG) and thromboxane (TX) production in whole blood and in platelet-rich plasma (PRP) of 21 uremic patients and 22 healthy subjects; (b) to evaluate the concentration and activity of platelet PG- and TX-forming enzymes; (c) to assess the functional responsiveness of the platelet TXA2/PGH2 receptor; (d) to explore the hemostatic consequences of partially reduced TXA2 production.
BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination
Authors: Laurent Derré, Jean-Paul Rivals, Camilla Jandus, Sonia Pastor, Donata Rimoldi, Pedro Romero, Olivier Michielin, Daniel Olive, Daniel E. Speiser
Journal: Journal of Clinical Investigation (2010)

The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen–specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen–specific effector CD8+ T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen–specific CD8+ T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM–mediated inhibition. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.
Extending the global village: Emotional communication in the online age
Authors: Ross Buck
Journal: Behavioral and Brain Sciences (2014)

Abstract Bentley et al.’s analysis of how human decision-making has changed in the online age does not mention emotion. Although the suggested dimensions involving social influence and transparency are interesting and suggestive, the engines behind the changes wrought by online media are arguably largely emotional, and implications of the communication of specific emotions via online media need to be better understood.
Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases?
Authors: C. Simmons, N. Miller, W. Geddie, D. Gianfelice, M. Oldfield, G. Dranitsaris, M.J. Clemons
Journal: Annals of Oncology (2009)

Decisions about systemic treatment of women with metastatic breast cancer are often based on estrogen receptor (ER), progesterone receptor (PgR), and Her2 status of the primary tumor. This study prospectively investigated concordance in receptor status between primary tumor and distant metastases and assessed the impact of any discordance on patient management.