tbuckley/cabot-search huggingface dataset:
Estrogen deficiency stimulates B lymphopoiesis in mouse bone marrow.
Authors: T Masuzawa, C Miyaura, Y Onoe, K Kusano, H Ohta, S Nozawa, T Suda
Journal: Journal of Clinical Investigation (1994)

We have found that an estrogen deficiency causes a marked increase in bone marrow cells. To examine the effect of estrogen on hemopoiesis, we characterized the increased population of bone marrow cells after ovariectomy (OVX). In OVX mice, the percentage of myeloid cells and granulocytes was decreased, whereas that of B220-positive B lymphocytes was selectively increased 2-4 wk after surgery. The total number of myeloid cells and granulocytes did not change appreciably, but that of B220-positive cells was greatly increased by OVX. When OVX mice were treated with estrogen, the increased B lymphopoiesis returned to normal. B220-positive cells were classified into two subpopulations, B220low and B220high. The majority of the B220low cells were negative for the IgM mu chain, whereas most of the B220high cells were mu-positive. OVX selectively increased the precursors of B lymphocytes identified by B220low. mu-negative phenotype, suggesting that an estrogen deficiency stimulates accumulation of B lymphocyte precursors. When bone marrow-derived stromal cells (ST2) were pretreated with estrogen then co-cultured with bone marrow cells in the presence of estrogen, the stromal cell-dependent B lymphopoiesis was greatly inhibited. The present study suggests that estrogen plays an important role in the regulation of B lymphocyte development in mouse bone marrow.
The molecular genetics of arrhythmias
Authors: C BEZZINA, A WILDE, D RODEN
Journal: Cardiovascular Research (2005)

It was only ten years ago that mutations in ion channel genes were first described in patients with the long QT syndrome (LQTS) [1].Since then, mutations in a total of eight different sarcolemmal ion channel subunit genes (KCNQ1, KCNH2, KCNE1, KCNE2, SCN5A, KCNJ2, HCN4, CACNA1C), two genes encoding sarcoplasmic reticulum (SR) Ca 2+ handling proteins (RYR2, CASQ2), and an anchoring protein gene (ANK2) have been linked to a range of primary arrhythmia syndromes.The recognition of abnormal function of these genes in the inherited arrhythmia syndromes has provided remarkable insight into mechanisms of arrhythmias not only in these uncommon syndromes, but has also had very important implications for arrhythmia mechanisms and management more generally.It is therefore very opportune that Cardiovascular Research dedicates this spotlight issue to this topic.In this issue, a series of reviews summarizes the current state-ofthe-art, and a number of original papers present new data on various aspects of cardiac arrhythmia genetics.
Anna Cecilia McKee (nee Martin)
Authors: M. M. H. McKee
Journal: BMJ (2008)

The only daughter in a medical family, Anna Cecilia McKee (“Nan”) had hoped to follow her male friends and family (including her future husband) into the armed forces when she qualified in 1941. As her parents made it clear that this was not considered appropriate for a young woman, she spent the remainder of the war in hospitals in Manchester and Birmingham. At the end of the war she returned to Ireland, completing a Diploma in Public Health …
Development of siRNA Payloads to Target <i>KRAS</i>-Mutant Cancer
Authors: Tina L. Yuan, Christof Fellmann, Chih-Shia Lee, Cayde D. Ritchie, Vishal Thapar, Liam C. Lee, Dennis J. Hsu, Danielle Grace, Joseph O. Carver, Johannes Zuber, Ji Luo, Frank McCormick, Scott W. Lowe
Journal: Cancer Discovery (2014)

Abstract RNAi is a powerful tool for target identification and can lead to novel therapies for pharmacologically intractable targets such as KRAS. RNAi therapy must combine potent siRNA payloads with reliable in vivo delivery for efficient target inhibition. We used a functional “Sensor” assay to establish a library of potent siRNAs against RAS pathway genes and to show that they efficiently suppress their targets at low dose. This reduces off-target effects and enables combination gene knockdown. We administered Sensor siRNAs in vitro and in vivo and validated the delivery of KRAS siRNA alone and siRNA targeting the complete RAF effector node (A/B/CRAF) as promising strategies to treat KRAS-mutant colorectal cancer. We further demonstrate that improved therapeutic efficacy is achieved by formulating siRNA payloads that combine both single-gene siRNA and node-targeted siRNAs (KRAS + PIK3CA/B). The customizable nature of Sensor siRNA payloads offers a universal platform for the combination target identification and development of RNAi therapeutics. Significance: To advance RNAi therapy for KRAS-mutant cancer, we developed a validated siRNA library against RAS pathway genes that enables combination gene silencing. Using an in vivo model for real-time siRNA delivery tracking, we show that siRNA-mediated inhibition of KRAS as well as RAF or PI3K combinations can impair KRAS-mutant colorectal cancer in xenograft models. Cancer Discov; 4(10); 1182–97. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 1103
Ethical and practical issues in conducting clinical trials in psoriasis and psoriatic arthritis
Authors: A Kavanaugh
Journal: Annals of the Rheumatic Diseases (2005)

Ethical considerations are inexorably intertwined with the conduct of clinical research. As a result of progress in immunology and biotechnology, several potent novel therapeutics have recently emerged for the treatment of patients with various immunologically driven systemic inflammatory conditions, including psoriasis and psoriatic arthritis. Because of these developments, there is a need to continually assess the design of current and future research studies so that they may be conducted in the optimal and most ethical manner.
Origins of Serum Semicarbazide-Sensitive Amine Oxidase
Authors: Craig M. Stolen, Gennady G. Yegutkin, Riikka Kurkijärvi, Petri Bono, Kari Alitalo, Sirpa Jalkanen
Journal: Circulation Research (2004)

Semicarbazide-sensitive amine oxidases (SSAO) are enzymes that are capable of deaminating primary amines to produce aldehyde, ammonia, and hydrogen peroxide. This activity has been associated with vascular adhesion protein-1 (VAP-1) and is found in the serum, endothelium, adipose, and smooth muscle of mammals. Circulating SSAO activity is increased in congestive heart failure, diabetes, and inflammatory liver diseases. To investigate the origin of circulating SSAO activity, two transgenic mouse models were created with full-length human VAP-1 (hVAP-1) expressed on either endothelial (mTIEhVAP-1) or adipose tissues (aP2hVAP-1), with tie-1 and adipocyte P2 promoters, respectively. Under normal conditions a circulating form of hVAP-1 was found at high levels in the serum of mice with endothelium-specific expression and at low levels in the serum of mice with adipose specific expression. The level of circulating hVAP-1 in the transgenic mice varied with gender, transgene zygosity, diabetes, and fasting. Serum SSAO activity was absent from VAP-1 knockout mice and endothelial cell–specific expression of human VAP-1 restored SSAO activity to the serum of VAP-1 knockout mice. Together, these experiments show that in the mouse VAP-1 is the only source of serum SSAO, that under physiological conditions vascular endothelial cells can be a major source of circulating VAP-1 protein and SSAO, and that serum VAP-1 can originate from both endothelial cells and adipocytes during experimental diabetes. An increased endothelial cell capacity for lymphocyte binding and altered expression of redox-sensitive proteins was also associated with the mTIEhVAP-1 transgene.
Regulation of parathyroid hormone-like peptide in cultured normal human keratinocytes. Effect of growth factors and 1,25 dihydroxyvitamin D3 on gene expression and secretion.
Authors: R Kremer, A C Karaplis, J Henderson, W Gulliver, D Banville, G N Hendy, D Goltzman
Journal: Journal of Clinical Investigation (1991)

We have examined the expression and secretion of endogenous parathyroid hormone-like peptide (PLP) in primary cultures of normal human keratinocytes. In response to growth factors and fetal bovine serum, PLP mRNA expression and immunoreactive PLP release into conditioned medium was rapidly increased (within hours) whereas these effects were inhibited by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. These early responses were not influenced by raising the medium calcium concentration from 0.15 to 1.0 mM. In contrast, increasing the medium calcium concentration to 1.0 mM, addition of 1,25(OH)2D3, or a combination of both, resulted in a delayed augmentation (after several days) in PLP production which was associated with an increase in cellular differentiation as assessed by production of high molecular weight keratin. To investigate whether these factors were acting at the level of transcription of the PLP gene, a series of vectors were prepared by fusing segments of the 5' flanking region of the rat PLP gene to a growth hormone reporter gene. Transient transfection of these constructs into cultured keratinocytes and measurement of immunoreactive growth hormone in the medium showed that a region stimulated by growth factors is located in a 1.9-kb fragment of the 5' flanking region and that a PLP gene promoter region less than 1.2 kb and greater than 0.3 kb upstream of the cap site contains cis-acting elements which respond positively to serum, and negatively to 1,25(OH)2D3. These combined studies demonstrate that, in normal human keratinocytes, growth factors may acutely stimulate PLP mRNA levels and PLP release, whereas 1,25(OH)2D3 inhibits these responses. At least part of these effects are at the level of gene transcription. Additionally, PLP synthesis and release are enhanced under conditions in which keratinocyte differentiation is induced.
VARIATION IN SUSCEPTIBILITY OF A HUMAN LYMPHOID CELL LINE TO IMMUNE LYSIS DURING THE CELL CYCLE
Authors: Michele A. Pellegrino, Soldano Ferrone, Neil R. Cooper, Manfred P. Dierich, Ralph A. Reisfeld
Journal: The Journal of Experimental Medicine (1974)

Cultured human lymphoid cells RPMI 8866 at different stages of their growth cycle vary in their susceptibility to lysis by rabbit, human, and guinea pig complement activated by HL-A antibodies or heterologous antibodies directed to membrane antigens; cells in G(1) phase are the least sensitive to lysis. To investigate the cause of differential susceptibility of cells RPMI 8866 to lysis, the expression of HL-A determinants and the ability of cells to react with complement were investigated. No change was detected in the density of HL-A antigens on RPMI 8866 cells in synchronous growth as determined by quantitative microabsorption assays, isotopic antiglobulin tests and yields of soluble HL-A antigens. Cells did not vary during the growth cycle in their ability to interact with complement components and in their capacity to activate the complement system through the classical or alternate pathway. These data suggest that variability in lytic susceptibility is due to changes in the structure of the cell membrane or in its ability to repair complement induced damage at certain intervals during the cell cycle. Therefore, this cell line constitutes a useful model to investigate the final steps of the cytolytic reaction.
MRI apparent diffusion coefficient reflects histopathologic subtype, axonal disruption, and tumor fraction in diffuse-type grade II gliomas
Authors: I. S. Khayal, S. R. VandenBerg, K. J. Smith, C. P. Cloyd, S. M. Chang, S. Cha, S. J. Nelson, T. R. McKnight
Journal: Neuro-Oncology (2011)

The apparent diffusion coefficient (ADC) determined from MR diffusion tensor imaging (DTI) has shown promise for distinguishing World Health Organization grade II astrocytoma (AS) from the more prognostically favorable grade II oligodendroglioma (OD). Since mixed oligoastrocytomas (OAs) with codeletions in chromosomes 1p and 19q confer prognoses similar to those of OD, we questioned whether a previously determined ADC-based criterion for distinguishing OD and AS would hold on an independent set of gliomas that included OA with codeleted or intact 1p/19q chromosomes. We also questioned whether the ADC is associated with the tumor microstructure. ADC colormaps generated from presurgical DTI scans were used to guide the collection of biopsies from each tumor. The median normalized ADC distinguished OD from AS with 91% sensitivity and 92% specificity. 1p/19q codeleted OAs were always classified as ODs, while 1p/19q intact OAs were always classified as ASs. There were positive associations between the ADC and both the SMI-31 score of axonal disruption and the fraction of tumor cells in the biopsies. The ADC of OD and 1p/19q codeleted OA was more associated with tumor fraction, while the ADC of AS and 1p/19q intact OA was more associated with SMI-31 score. We conclude that our previously determined threshold median ADC can distinguish grade II OD and AS on a new patient cohort and that the distinctions extend to OA with codeleted and intact 1p/19q chromosomes. Further, the ADC in grade II gliomas is associated with the fraction of tumor cells and degree of axonal disruption in tumor subregions.
Doubts about the role of cannabis in causing lung cancer
Authors: R. A. Sewell, A. J. Cohn, M. C. Chawarski
Journal: European Respiratory Journal (2008)

Doubts about the role of cannabis in causing lung cancerTo the Editors:We read with interest the article by ALDINGTON et al.[1] entitled ''Cannabis use and risk of lung cancer: a case-control study''.However, we are concerned that the conclusion stating that ''long-term cannabis use increases the risk of lung cancer in young adults'' is inadequately supported by the data, given the study's several methodological flaws.
Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues
Authors: Keshav K Singh, Mohamed M Desouki, Renty B Franklin, Leslie C Costello
Journal: Molecular Cancer (2006)

Abstract Background In prostate cancer, normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells. m-Aconitase is the critical step involved in this altered citrate metabolism that is essential to prostate malignancy. The limiting m-aconitase activity in prostate epithelial cells could be the result of a decreased level of m-aconitase enzyme and/or the inhibition of existing m-aconitase. Earlier studies identified zinc as an inhibitor of m-aconitase activity in prostate cells; and that the depletion of zinc in malignant cells is an important factor in this metabolic transformation. However, a possibility remains that an altered expression and level of m-aconitase enzyme might also be involved in this metabolic transformation. To address this issue, the in situ level of m-aconitase enzyme was determined by immunohistochemical analysis of prostate cancer tissue sections and malignant prostate cell lines. Results The immunocytochemical procedure successfully identified the presence of m-aconitase localized in the mitochondrial compartment in PC-3, LNCaP, and DU-145 malignant prostate cell lines. The examination of prostate tissue sections from prostate cancer subjects demonstrated that m-aconitase enzyme is present in the glandular epithelium of normal glands, hyperplastic glands, adenocrcinomatous glands, and prostatic intraepithelial neoplastic foci. Quantitative analysis of the relative level of m-aconitase in the glandular epithelium of citrate-producing adenomatous glands versus the citrate-oxidizing adenocarcinomatous glands revealed no significant difference in m-aconitase enzyme levels. This is in contrast to the down-regulation of ZIP1 zinc transporter in the malignant glands versus hyperplastic glands that exists in the same tissue samples. Conclusion The results demonstrate the existence of m-aconitase enzyme in the citrate-producing glandular epithelial cells; so that deficient m-aconitase enzyme is not associated with the limiting m-aconitase activity that prevents citrate oxidation in these cells. The level of m-aconitase is maintained in the malignant cells; so that an altered enzyme level is not associated with the increased m-aconitase activity. Consequently, the elevated zinc level that inhibits m-aconitase enzyme is responsible for the impaired citrate oxidation in normal and hyperplastic prostate glandular epithelial cells. Moreover, the down-regulation of ZIP1 zinc transporter and corresponding depletion of zinc results in the increase in the activity of the existing m-aconitase activity in the malignant prostate cells. The studies now define the mechanism for the metabolic transformation that characterizes the essential transition of normal citrate-producing epithelial cells to malignant citrate-oxidizing cells.
Cancer Screening Practices From National Health Interview Surveys: Past, Present, and Future
Authors: R. A. Hiatt, C. Klabunde, N. Breen, J. Swan, R. Ballard-Barbash
Journal: JNCI Journal of the National Cancer Institute (2002)

The National Health Interview Survey (NHIS) has provided data about health behaviors at the national level since 1957. The 1987 and 1992 Cancer Control Supplements to the NHIS, along with other supplemental surveys administered intermittently on self-reported cancer-related behaviors, have contributed to important research and public health purposes. In this article, we reviewed 73 papers published between 1980 and 2001 that used NHIS data, including the first report from the 1998 NHIS, to examine what has been learned from past surveys. Our goal was to facilitate future analyses of recently released data on cancer screening practices from the Cancer Control Supplement to the 2000 NHIS, which is now known as the Cancer Control Module. We categorized the papers according to which of the following three study approaches they used: trends in screening rates, correlates of these rates with factors that may influence screening, and linkages or comparisons of NHIS data with other surveys or sources of information. We summarize knowledge gained in cancer screening for each of these three categories and identify areas that could benefit from more research. We highlight some of the new information available for the first time on the Cancer Control Module of the 2000 NHIS as fresh opportunities for cancer control research. Finally, we describe how the Cancer Control Supplements to the NHIS are integrated with the objectives of and developments in national cancer surveillance research that have emerged from federal planning efforts and collaborations with national partners in cancer surveillance in recent years.
Kamal Al-Samarraie Behjat Mukhtar Ansari Thomas Leary Kelly John Charles Knox Liselotte (Lilo) Lennhoff Margaret Mary Crawford Louden John Alexander McKinnon Swapna Majumdar Brian Thomas O'Connor Nawal Kishore Prasad Singh Frederick Robert Store William Stanley Sutton David Peter Winder
Authors: A S M Jawad, D P Davies, R. Kelly, B. Corfield, J. Knox, T. Clark, P. Grasty, J. Barnes, C H Y. Smith, B. Majumdar, G A Evans, B. Livesley, F. R. Store, C. Ogilvie, B. C Hovell, I Williams
Journal: BMJ (1999)

FRCOG), d 10 January 1999.He made his specialty popular and attracted enthusiastic staff.He had a special interest in hydatidiform mole and was an expert in surgical reconstruction of the vagina in patients with vaginal atresia.He was obstetrician and gynaecologist to the Iraqi and Jordanian royal families.He
Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells
Authors: Franca Gerosa, Barbara Baldani-Guerra, Lyudmila A. Lyakh, Giovanna Batoni, Semih Esin, Robin T. Winkler-Pickett, Maria Rita Consolaro, Mario De Marchi, Daniela Giachino, Angela Robbiano, Marco Astegiano, Angela Sambataro, Robert A. Kastelein, Giuseppe Carra, Giorgio Trinchieri
Journal: The Journal of Experimental Medicine (2008)

We analyzed interleukin (IL) 12 and IL-23 production by monocyte-derived dendritic cells (mono-DCs). Mycobacterium tuberculosis H37Rv and zymosan preferentially induced IL-23. IL-23 but not IL-12 was efficiently induced by the combination of nucleotide-binding oligodimerization domain and Toll-like receptor (TLR) 2 ligands, which mimics activation by M. tuberculosis, or by the human dectin-1 ligand β-glucan alone or in combination with TLR2 ligands, mimicking induction by zymosan. TLR2 ligands inhibited IL-12 and increased IL-23 production. DC priming with interferon (IFN) γ strongly increased IL-12 production, but was not required for IL-23 production and inhibited IL-23 production induced by β-glucan. The pattern of IL-12 and IL-23 induction was reflected in accumulation of the IL-12p35 and IL-23p19 transcripts, respectively, but not IL-12/23p40. Although IL-23, transforming growth factor β, and IL-6 contained in the supernatants of activated mono-DCs played a role in the induction of IL-17 by human CD4+ T cells, IL-1β, in combination with one or more of those factors, was required for IL-17 production, and its production determined the differential ability of the stimuli used to elicit mono-DCs to produce soluble factors directing IL-17 production. Thus, the differential ability of pathogens to induce antigen-presenting cells to produce cytokines regulates the immune response to infection.
Reactive arthritis following an outbreak of Salmonella typhimurium phage type 193 infection
Authors: T Hannu
Journal: Annals of the Rheumatic Diseases (2002)

Objectives: To determine the occurrence and the clinical picture of reactive arthritis (ReA) following an outbreak of <i>Salmonella typhimurium</i>. Methods: An outbreak of <i>S typhimurium</i> phage type DT 193 occurred in several municipalities in Finland in 1999. A questionnaire which had a specific emphasis on musculoskeletal symptoms was mailed to all 78 subjects with a positive stool culture. Based on the answers, all subjects with recent joint complaints were clinically examined or interviewed by telephone. Results: Sixty three of 78 subjects (81%) returned the questionnaire. Of these 63 subjects, five (8%) fulfilled the criteria for ReA. All the five subjects with ReA were adults with oligo- or polyarthritis. The antigen HLA-B27 was positive in two of the four subjects tested. In two of five subjects with ReA, the duration of acute arthritis was over six months. Subjects who had received antimicrobial drugs developed acute musculoskeletal symptoms significantly (p=0.013) less often than those without such treatment. None of the subjects with ReA had received antimicrobial drugs before the onset of joint symptoms. Conclusions: The occurrence of ReA following an outbreak of <i>S typhimurium</i> was at the same level as in outbreaks due to other salmonella serotypes reported previously by us, indicating that the frequency of ReA after various outbreaks is ∼10%. Early use of antimicrobial drugs may prevent the development of musculoskeletal symptoms.
Lactate and Glucose Exchange across the Forearm, Legs, and Splanchnic Bed during and after Prolonged Leg Exercise
Authors: Gunvor Ahlborg, Philip Felig
Journal: Journal of Clinical Investigation (1982)

The net exchange of glucose and lactate across the leg and the splanchnic bed and the arterialdeep venous (A-DV) differences for these substrates in the forearm were determined in healthy subjects during 3-3.5 h of leg exercise (bicycle ergometer) at 58% maximum O2 uptake and during a 40-min post-exercise recovery period.