tbuckley/cabot-search huggingface dataset:
Prospective Study of Changes in the Metabolomic Profiles of Men during Their First Three Months of Androgen Deprivation Therapy for Prostate Cancer
Authors: Philip J. Saylor, Edward D. Karoly, Matthew R. Smith
Journal: Clinical Cancer Research (2012)

Androgen deprivation therapy (ADT) for prostate cancer causes an increase in fasting insulin and adverse changes in body composition and serum lipid profile. It is unknown what other metabolic alterations are caused by ADT. To better characterize the metabolic effects of ADT, we measured changes in plasma metabolomic profile at baseline and after the first 3 months of therapy.Fasting plasma samples were drawn from 36 subjects at baseline and after 3 months of gonadotropin releasing hormone (GnRH) agonist therapy. Extracted samples were split into equal parts for analysis on the gas chromatography-mass spectrometry and liquid chromatography/tandem mass spectrometry platforms.Of the 292 identified metabolites, 56 changed significantly (P < 0.05) from baseline to 3 months. Notable changes were grouped as follows: (i) Multiple steroids were lower at 3 months, consistent with the effect of therapy on gonadal androgen synthesis. (ii) Most bile acids and their metabolites were higher during treatment. Cholesterol levels changed very little. (iii) Markers of lipid beta-oxidation (acetyl-carnitines and ketone bodies) and omega-oxidation were lower at 3 months. (iv) Two previously identified biomarkers of insulin resistance (2-hydroxybutyrate and branch chain keto-acid dehydrogenase complex products) were stable to lower at 3 months.Unbiased metabolomic analyses revealed expected, novel, and unexpected results. Steroid levels fell, consistent with the effects of ADT. Most bile acids and their metabolites increased during ADT, a novel finding. Biomarkers of lipid metabolism and insulin resistance fell, unexpected given that ADT has been shown to increase fasting insulin.
Myeloid-Derived Suppressor Cells Function as Novel Osteoclast Progenitors Enhancing Bone Loss in Breast Cancer
Authors: Anandi Sawant, Jessy Deshane, Joel Jules, Carnella M. Lee, Brittney A. Harris, Xu Feng, Selvarangan Ponnazhagan
Journal: Cancer Research (2012)

Enhanced bone destruction is a hallmark of various carcinomas such as breast cancer, where osteolytic bone metastasis is associated with increased morbidity and mortality. Immune cells contribute to osteolysis in cancer growth, but the factors contributing to aggressive bone destruction are not well understood. In this study, we show the importance of myeloid-derived suppressor cells (MDSC) in this process at bone metastatic sites. Because MDSC originate from the same myeloid lineage as macrophages, which are osteoclast precursors, we hypothesized that MDSC may undergo osteoclast differentiation and contribute to enhanced bone destruction and tumor growth. Using an immunocompetent mouse model of breast cancer bone metastasis, we confirmed that MDSC isolated from the tumor-bone microenvironment differentiated into functional osteoclasts both in vitro and in vivo. Mechanistic investigations revealed that nitric oxide signaling was critical for differentiation of MDSC into osteoclasts. Remarkably, osteoclast differentiation did not occur in MDSC isolated from control or tumor-bearing mice that lacked bone metastasis, signifying the essential cross-talk between tumor cells and myeloid progenitors in the bone microenvironment as a requirement for osteoclast differentiation of MDSC. Overall, our results identify a wholly new facet to the multifunctionality of MDSC in driving tumor progression, in this case as a novel osteoclast progenitor that specifically drives bone metastasis during cancer progression.
Allelic Variants of Complement Genes Associated with Dense Deposit Disease
Authors: Maria Asuncion Abrera-Abeleda, Carla Nishimura, Kathy Frees, Michael Jones, Tara Maga, Louis M. Katz, Yuzhou Zhang, Richard J.H. Smith
Journal: Journal of the American Society of Nephrology (2011)

The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies.
Circulating allergen-reactive T cells from patients with atopic dermatitis and allergic contact dermatitis express the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen.
Authors: L F Santamaria Babi, L J Picker, M T Perez Soler, K Drzimalla, P Flohr, K Blaser, C Hauser
Journal: The Journal of Experimental Medicine (1995)

The cutaneous lymphocyte-associated antigen (CLA) is the major T cell ligand for the vascular adhesion molecule E-selectin, and it has been proposed to be involved in the selective targeting of memory T cells reactive with skin-associated Ag to cutaneous inflammatory sites. To further investigate the relation of CLA and cutaneous T cell responses, we analyzed the CLA phenotype of circulating memory T cells in patients with allergic contact dermatitis and atopic dermatitis (AD) alone vs in patients manifesting bronchopulmonary atopy (asthma with or without AD) and nonallergic individuals. Significant T cell proliferative responses to Ni, a contact allergen, and to the house dust mite (HDM), an allergen to which sensitization is often observed in AD and/or asthma, was noted only in allergic and atopic individuals, respectively. When the minor circulating CLA+CD3+CD45RO+ subset was separated from the major CLA-CD3+CD45RO+ subpopulation in Ni-sensitive subjects, the Ni-dependent memory T cell response was largely confined to the CLA+ subset. A similar restriction of the T cell proliferative response to the CLA+ memory subset was observed for HDM in patients with AD alone. In HDM-sensitive patients with asthma with or without AD, however, the CLA- subset exhibited a strong antigen-dependent proliferation, in contrast to patients with AD alone, whose CLA- subset proliferated very weakly to HDM. In asthma with or without AD, the HDM-dependent proliferation slightly predominated in the CLA- when compared to the CLA+ subset. The functional linkage between CLA expression and disease-associated T cell effector function in AD was also demonstrated by the finding that the circulating CLA+ T cell subset in AD patients, but not nonatopic controls, selectively showed both evidence of prior activation (human histocompatibility antigen-DR expression) and spontaneous production of interleukin 4 but not interferon-gamma. Taken together, these observations demonstrate the correlation of CLA expression on circulating memory T cells and disease-associated memory T cell responses in cutaneous hypersensitivity, and they suggest the existence of mechanisms capable of sorting particular T cell Ag specificities and lymphokine patterns into homing receptor-defined memory subsets.
Gamma H2Ax and 53Bp1, the Markers of Dna Double Strand Break are Associated with Developing Adenoma and Adenocarcinoma in Colon
Authors: Jeong Ho Kim, Joon Han Jeon, Hye Kang Kim, Hyung Jun Cho, Dae Young Cheung, Jin Il Kim, Hyun Jin Kim, Seong Jin Lee, Hyun Jeong Lee, Se Hyun Cho, Jae Kwang Kim, Soo-Heon Park
Journal: Annals of Oncology (2013)
Effect of -Linolenic Acid-Containing Linseed Oil on Coagulation in Type 2 Diabetes
Authors: Noriaki Tohgi
Journal: Diabetes Care (2004)

Blood coagulation in diabetes is known to be increased (1,2). Because levels of n - 3 and n-6 polyunsaturated fatty acids (PUFAs) influence the parameters of blood coagulation, the aim of this study was to determine the effects of n-3 PUFA supplementation on coagulation and fibrinolytic factors in type 2 diabetic subjects. While it is not clear what the appropriate intake ratio of n-6 to n-3 PUFAs should be for diabetic subjects, it is known that the dietary intake ratio of n-6 to n-3 PUFAs is roughly 4:1 in Japanese subjects (3).

Ten subjects (six women and four men, average age …
GPs have been unfairly attacked, says outgoing NHS chief
Authors: A. O'Dowd
Journal: BMJ (2013)

GPs have been unfairly attacked by politicians and the media, the outgoing chief executive of the NHS in England has told managers.

David Nicholson, who recently announced that he would retire in March 2014,1 told an audience of NHS managers that he had been “incensed” about recent attacks on GPs and accusations—including from the health secretary, Jeremy Hunt—that changes to their out of hours work in the 2004 GP contract had resulted in recent pressure on emergency departments.2

Nicholson gave a frank speech at the NHS Confederation’s annual conference in Liverpool on 6 June, in which he openly criticised politicians of all parties and talked about …
A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment
Authors: Chunxia Wang, Thorsten Maass, Markus Krupp, Florian Thieringer, Susanne Strand, Marcus A. Wörns, Ana-Paula Barreiros, Peter R. Galle, Andreas Teufel
Journal: Journal of Hepatology (2009)
Mitochondrial Genomes of Two Demosponges Provide Insights into An Early Stage of Animal Evolution
Authors: Dennis V. Lavrov, Lise Forget, Michelle Kelly, B. Franz Lang
Journal: Molecular Biology and Evolution (2005)

Mitochondrial DNA (mtDNA) of multicellular animals (Metazoa) is typically a small (∼16 kbp), circular-mapping molecule that encodes 37 tightly packed genes. The structures of mtDNA-encoded transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) are usually highly unorthodox, and proteins are translated with multiple deviations from the standard genetic code. In contrast, mtDNA of the choanoflagellate Monosiga brevicollis, the closest unicellular relative of animals, is four times larger, contains 1.5 times as many genes, and lacks mentioned peculiarities of animal mtDNA. To investigate the evolutionary transition that led to the specific organization of metazoan mtDNA, we determined complete mitochondrial sequences from the demosponges Geodia neptuni and Tethya actinia, two representatives of the most basal animal phylum, the Porifera. We found that poriferan mtDNAs resemble those of other animals in their compact organization, lack of introns, and a well-conserved animal-like gene order. Yet, they contain several extra genes, encode bacterial-like rRNAs and tRNAs, and use a minimally derived genetic code. Our findings suggest that the evolution of the typical metazoan mtDNA has been a multistep process in which the compact genome organization and the reduced gene content were established prior to the reduction of tRNA and rRNA structures and the introduction of multiple changes of the translation code.
Respiratory illness: a complementary perspective
Authors: G. T Lewith
Journal: Thorax (1998)

In the UK there were 13 million visits to practitioners of complementary and alternative medicine (CAM) in 1981, a third of the number of visits made to general practitioners.1 The use of CAM has grown substantially over the last 10 years; between 1986 and 1991 the proportion of Which readers using CAM increased by 70%,2 and a more recent Which survey of 9000 readers in 1995 revealed that 25% had seen a CAM practitioner over the last year with 75% claiming benefit.3 Eisenberg et al noted a similar situation in the United States, estimating that the US public spent $13.7 billion out of pocket in 1990 on CAM,4 a figure no doubt substantially increased by recent interest. Similar data document the rise and importance of CAM in Australia to much the same levels of interest and expenditure as those in the USA and the UK.5 

As yet we have no definite answers as to why people seek CAM. We know that the public perceives these treatments as often being more successful for chronic illness than conventional medicine.6 It also seems that patients who attend CAM practitioners feel more empowered by the process and therefore more in control of their illness.7 8 Thomas et al found that 40% of general practices offered access to at least one complementary therapy.9 

This growing interest in complementary medicine is not confined to the general public; in 1983 80% of trainee general practitioners wished to receive training in CAM,10 and by 1987 this had risen to 92%.11 In 1986 it was reported that 38% of general practitioners in Avon and 31% in Oxfordshire had received training in complementary therapy.12 13 

One area of concern to respiratory physicians is the increased incidence of asthma which …
Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells
Authors: Annabell Bachem, Steffen Güttler, Evelyn Hartung, Frédéric Ebstein, Michael Schaefer, Astrid Tannert, Abdulgabar Salama, Kamran Movassaghi, Corinna Opitz, Hans W. Mages, Volker Henn, Peter-Michael Kloetzel, Stephanie Gurka, Richard A. Kroczek
Journal: The Journal of Experimental Medicine (2010)

In recent years, human dendritic cells (DCs) could be subdivided into CD304+ plasmacytoid DCs (pDCs) and conventional DCs (cDCs), the latter encompassing the CD1c+, CD16+, and CD141+ DC subsets. To date, the low frequency of these DCs in human blood has essentially prevented functional studies defining their specific contribution to antigen presentation. We have established a protocol for an effective isolation of pDC and cDC subsets to high purity. Using this approach, we show that CD141+ DCs are the only cells in human blood that express the chemokine receptor XCR1 and respond to the specific ligand XCL1 by Ca2+ mobilization and potent chemotaxis. More importantly, we demonstrate that CD141+ DCs excel in cross-presentation of soluble or cell-associated antigen to CD8+ T cells when directly compared with CD1c+ DCs, CD16+ DCs, and pDCs from the same donors. Both in their functional XCR1 expression and their effective processing and presentation of exogenous antigen in the context of major histocompatibility complex class I, human CD141+ DCs correspond to mouse CD8+ DCs, a subset known for superior antigen cross-presentation in vivo. These data define CD141+ DCs as professional antigen cross-presenting DCs in the human.
Shaping mycolactone for therapeutic use against inflammatory disorders
Authors: Laure Guenin-Macé, Ludivine Baron, Anne-Caroline Chany, Cédric Tresse, Sarah Saint-Auret, Friederike Jönsson, Fabien Le Chevalier, Pierre Bruhns, Georges Bismuth, Sophie Hidalgo-Lucas, Jean-François Bisson, Nicolas Blanchard, Caroline Demangel
Journal: Science Translational Medicine (2015)

A synthetic mycobacterial macrolide mycolactone decreases skin inflammation and inflammatory pain.
Racial Disparity of Epidermal Growth Factor Receptor Expression in Prostate Cancer
Authors: Brian Shuch, Maryann Mikhail, Jaya Satagopan, Peng Lee, Herman Yee, Caroline Chang, Carlos Cordon-Cardo, Samir S. Taneja, Iman Osman
Journal: Journal of Clinical Oncology (2004)

The epidermal growth factor receptor (EGFR) plays a critical role in prostate cancer (PC) signal transduction and is the target of a novel class of anticancer agents. Despite recent reports of interethnic variation in response to EGFR inhibitors, limited information exists regarding differences in expression of EGFR in PC patients. This has therapeutic relevance because a better understanding of the molecular basis underlying the ethnic variability will help in the design of individualized treatment regimens using EGFR inhibitors.We investigated EGFR expression in a well-characterized cohort of PC patients to determine the association between EGFR expression and race. Tumor tissues from 202 radical prostatectomies performed between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) were studied (142 African Americans, 60 whites; median age, 67 years; stage T2, n = 130; stage > or = T3, n = 72; Gleason score < 7, n = 110; Gleason score > or = 7, n = 92). Membrane-specific EGFR expression was evaluated immunohistochemically.EGFR overexpression, defined as complete membrane staining in more than 10% of tumor cells, was observed in 75 of 202 patients (37%). There was a significant association between EGFR overexpression and African American race (P = .0006), higher pretreatment prostate-specific antigen (PSA; P = .02), and stage (P = .02), but not Gleason score (P = .33). The association between African American race and EGFR overexpression remained significant in a multivariate model after controlling for grade, stage, and pretreatment PSA simultaneously (P = .003).Our data demonstrate that race contributes significantly to variability of EGFR expression in prostate cancer. Racial background may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents.
Fever, rigors and sweats in an immunocompromised male
Authors: G.E. Kapotsis, Z. Daniil, Z. Sardelis, K. Stavrakaki, G. Saroglou, V. Pappa, C. Roussos, S.A. Papiris
Journal: European Respiratory Journal (2003)

This work was supported by a grant from the Thorax Foundation, Athens, Greece.

A 63‐yr-old male presented with a 20‐day history of fever with chills, rigors, sweats and fatigue. He resided in the countryside and there was no history of recent travel to other countries. He had a past medical history of idiopathic pulmonary fibrosis (usual interstitial pneumonia confirmed by surgical biopsy) and the last 2 yrs he was taking daily azathioprine 100 mg per os and methylprednisolone (actually) 12 mg per os .

On physical examination he was pale, with a body temperature of 39.5°C, blood pressure 130/90 mmHg, pulse rate 90 beats per min and respiratory rate 24 breaths per min. There were no skin rashes, petechiae or ecchymoses. The abdomen was soft, without tenderness or rigidity and the spleen was enlarged 3 cm below the costal margin. The auscultation revealed “velcro” rales at the lower lung fields bilaterally. There were no heart murmurs.

Laboratory investigations revealed the following values: haemoglobin 1.271 mM (78 g·L−1); total leukocyte count 1.54×109·L−1, with differential count 56% polymorphonuclears, 39% lymphocytes and 4% monocytes, and 57×109·L−1 platelets. The prothrombin time and activated partial thromboplastin time were within normal range. The blood urea was …
Proteolytic processing activates a viral superantigen.
Authors: D Mix, G M Winslow
Journal: The Journal of Experimental Medicine (1996)

Mouse mammary tumor virus (MMTV) superantigens (vSAg) undergo proteolytic processing at residues that have been demonstrated in vitro to be recognition sites for the endoprotease furin. To examine the role of furin in the presentation of vSAg7 to T cells, the vSAg7 and class II MHC IEk genes were introduced into Chinese Hamster Ovary (CHO) cells (furin-positive) and into a furin-negative CHO variant (FD11). Both transfected cell lines efficiently presented peptide antigen and bacterial superantigens to T cell hybridomas. However, while the furin-positive cells presented vSAg7 well, the furin-negative cells presented poorly. Transient transfection of the furin-negative cells with an expression plasmid containing the furin gene restored the ability to present vSAg7 efficiently. The marginal presentation of vSAg7 observed using the furin-negative transfectants was eliminated after culture with the protease inhibitor leupeptin, suggesting that one or more endoproteases other than furin have a detectable but limited capacity to proteolytically activate vSAg7. Biochemical analyses revealed that vSAg7 was largely unprocessed in the absence of furin. Thus, viral superantigens, unlike bacterial superantigens, require proteolytic processing to activate T cells.
Long-Term Outcomes of Scleroderma Renal Crisis
Authors: Virginia D. Steen
Journal: Annals of Internal Medicine (2000)

Background: Although scleroderma renal crisis, a complication of systemic sclerosis, can be treated with angiotensin-converting enzyme (ACE) inhibitors, its long-term outcomes are not known. Objective: To determine outcomes, natural history, and risk factors in patients with systemic sclerosis and scleroderma renal crisis. Design: Prospective observational cohort study. Setting: University program specializing in scleroderma. Patients: 145 patients with scleroderma renal crisis who received ACE inhibitors and 662 patients with scleroderma who did not have renal crisis. Measurements: Among patients with renal crisis, the four outcomes studied were no dialysis, temporary dialysis, permanent dialysis, and early death. Demographic, clinical, and laboratory data were compared to identify risk factors for specific outcomes. Follow-up was 5 to 10 years. Results: 61% of patients with renal crisis had good outcomes (55 received no dialysis, and 34 received temporary dialysis); only 4 of these (4%) progressed to chronic renal failure and permanent dialysis. More than half of the patients who initially required dialysis could discontinue it 3 to 18 months later. Survival of patients in the good outcome group was similar to that of patients with diffuse scleroderma who did not have renal crisis. Some patients (39%) had bad outcomes (permanent dialysis or early death). Conclusions: Renal crisis can be effectively managed when hypertension is aggressively controlled with ACE inhibitors. Patients should continue taking ACE inhibitors even after beginning dialysis in hopes of discontinuing dialysis.
Megakaryocyte progenitors in the bone marrow and peripheral blood of patients with myeloproliferative diseases
Authors: Alberto Grossi, Alessandro M. Vannucchi, Daniela Rafanelli, Letizia Vannucchi, Pierluigi Rossi Ferrini
Journal: American Journal of Hematology (1987)

Abstract We studied the behavior in culture of megakaryocyte progenitor cells (CFU‐Mk) from peripheral blood (PB) and bone marrow (BM) cells in eight patients with myeloproliferative diseases (MPD). In seven patients we observed megakaryocyte (Mk) colony formation from PB cells, which were generated in the absence of any added stimulator and which did not increase after the addition of a source of Mk‐colony stimulating activity (CSA‐Mk). The number of BM CFU‐Mk was significantly higher in patients than in controls, and in seven out of eight patients the responsiveness to added CSA‐Mk was retained. Plasma obtained from six patients did not stimulate normal donors' BM target cells to form Mk colonies. These data demonstrate an expansion of the CFU‐Mk pool in MPD patients without increased plasma levels of CSA‐Mk, and suggest that PB and BM CFU‐Mk of MPD patients might have different kinetic properties.
Reverse rate dependency is an intrinsic property of canine cardiac preparations
Authors: Tamás Bányász, Balázs Horváth, László Virág, László Bárándi, Norbert Szentandrássy, Gábor Harmati, János Magyar, Stefano Marangoni, Antonio Zaza, András Varró, Péter P. Nánási
Journal: Cardiovascular Research (2009)

AimsClass III antiarrhythmic agents exhibit reverse rate-dependent lengthening of the action potential duration (APD). In spite of the several theories developed so far to explain this reverse rate dependency (RRD), its mechanism has not yet been clarified. The aim of the present work was to further elucidate the mechanisms responsible for reverse rate-dependent drug effects.