tbuckley/cabot-search huggingface dataset:
Heterogeneity of single cell cytokine gene expression in clonal T cell populations.
Authors: R P Bucy, A Panoskaltsis-Mortari, G Q Huang, J Li, L Karr, M Ross, J H Russell, K M Murphy, C T Weaver
Journal: The Journal of Experimental Medicine (1994)

T helper type 0 (Th0), Th1, and Th2 CD4+ T cell clones derived from a T cell receptor alpha/beta (TCR-alpha/beta) transgenic mouse were activated by antigen presented on "artificial" antigen-presenting cells that expressed or lacked the costimulatory molecule B7-1, and were analyzed for single cell cytokine mRNA expression by in situ hybridization. There was significant heterogeneity in the frequency of T cells that expressed individual cytokine mRNAs within each clonal population, suggesting that transcriptional control of each of the cytokine genes was not coordinate within an individual cell. The majority of antigen-stimulated Th1 cells expressed mRNA for interferon gamma (IFN-gamma), but far fewer cells in the same population expressed interleukin 2 (IL-2). Similarly, the frequency of IL-4-expressing cells was greater than that of IL-5- or IL-10-expressing cells in the same Th2 population, but the difference in expression frequencies was more variable between clones. The expression frequencies of each of the cytokines was quite heterogeneous in the antigen-activated Th0 population. The principal effect of increased antigen on the activation of individual cytokine genes in each of the clonal populations was to increase recruitment of mRNA-positive cells, with little or no effect on the level of cytokine mRNA expression in individual positive cells. The effects of B7 costimulation were variable depending on the cytokine gene analyzed. B7 costimulation markedly increased the frequency and the level of IL-2 mRNA expression in individual positive cells in the Th1 and Th0 populations, with less effect on the recruitment and single cell expression level of IFN-gamma. IL-4 frequencies were modestly increased by B7 costimulation of the Th2 clones, but there was no detectable increase in single cell IL-4 expression level. The observed patterns of cytokine mRNA expression favor a model of T cell activation in which all-or-none, rather than graded, responses of cytokine genes are dominant.
PPM1D Is a Potential Therapeutic Target in Ovarian Clear Cell Carcinomas
Authors: David S.P. Tan, Maryou B.K. Lambros, Sydonia Rayter, Rachael Natrajan, Radost Vatcheva, Qiong Gao, Caterina Marchiò, Felipe C. Geyer, Kay Savage, Suzanne Parry, Kerry Fenwick, Narinder Tamber, Alan Mackay, Tim Dexter, Charles Jameson, W. Glenn McCluggage, Alistair Williams, Ashley Graham, Dana Faratian, Mona El-Bahrawy, Adam J. Paige, Hani Gabra, Martin E. Gore, Marketa Zvelebil, Christopher J. Lord, Stanley B. Kaye, Alan Ashworth, Jorge S. Reis-Filho
Journal: Clinical Cancer Research (2009)

To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer.Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of PPM1D amplification and mRNA expression was determined using chromogenic in situ hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers.Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. PPM1D had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. PPM1D amplification was significantly associated with ovarian clear cell carcinoma histology (P = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with PPM1D gene amplification in primary ovarian clear cell carcinomas.Our data provide strong circumstantial evidence that PPM1D is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.
The renin-angiotensin-aldosterone system in rabbits with congestive heart failure produced by aortic constriction.
Authors: B J Morris, J O Davis, M L Zatzman, G M Williams
Journal: Circulation Research (1977)

Severe constriction of the suprarenal abdominal aorta of 3-kg rabbits to 3.7+/-0.2 mm2 and maintenance of a daily sodium intake of 10 mE q by infusion of 0.9% sodium chloride resulted in a progressive increase in central ear arterial pressure to 106+/-3 (SEM) mm Hg (control=79+/-1). This was accompanied by a progressive increase in left ventricular end-diastolic pressure to 22+/-2 mm Hg (control=3+/-1), plasma renin activity to 21+/-5 ng of angiotensin/hour per ml (control=5+/-1), plasma aldosterone concentration to 99+/-23 pg/ml (control=14+/-4), and plasma sodium concentration to 142+/-1 mEq/liter (control=136+/-1). Urinary excretion of sodium decreased to 3.9+/-0.7 mEq/day and marked fluid retention occurred. We also found that these changes were accompanied by a decrease in hematocrit to 24+/-2% (control=40+/-1), formation of 36+/-9 ml of fluid in the thoracic cavity, 33+/-9 ml of ascites, pulmonary congestion and edema, hepatic congestion, and enlargement and hypertrophy of both the left and right ventricles. All rabbits died of ventricular failure at a time that was partly related to the degree of aortic constriction and that ranged from 2 to 12 days. The model we have established is chronic, highly reproducible, easy to produce, and inexpensive, and resembles the clinical syndrome of right and left congestive heart failure in man. Furthermore, the studies provide evidence for an important role of the renin-angiotensin-aldosterone system in the fluid retention that leads to pulmonary and systemic venous congestion after suprarenal aortic constriction.
Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice
Authors: Mohammed Qatanani, Nava R. Szwergold, David R. Greaves, Rexford S. Ahima, Mitchell A. Lazar
Journal: Journal of Clinical Investigation (2009)

Resistin is an adipokine that contributes to insulin resistance in mice. In humans, however, studies investigating the link between resistin and metabolic disease are conflicting. Further complicating the matter, human resistin is produced mainly by macrophages rather than adipocytes. To address this important issue, we generated mice that lack adipocyte-derived mouse resistin but produce human resistin in a pattern similar to that found in humans, i.e., in macrophages (humanized resistin mice). When placed on a high-fat diet, the humanized resistin mice rapidly developed accelerated white adipose tissue (WAT) inflammation, leading to increased lipolysis and increased serum free fatty acids. Over time, these mice accumulated lipids, including diacylglycerols, in muscle. We found that this resulted in increased Pkcq pathway activity, leading to increased serine phosphorylation of Irs-1 and insulin resistance. Thus, although the site of resistin production differs between species, human resistin exacerbates WAT inflammation and contributes to insulin resistance.
Magnetic Resonance Metabolomics of Intact Tissue: A Biotechnological Tool in Cancer Diagnostics and Treatment Evaluation
Authors: Tone F. Bathen, Beathe Sitter, Torill E. Sjøbakk, May-Britt Tessem, Ingrid S. Gribbestad
Journal: Cancer Research (2010)

Personalized medicine is increasingly important in cancer treatment for its role in staging and its potential to improve stratification of patients. Different types of molecules, genes, proteins, and metabolites are being extensively explored as potential biomarkers. This review discusses the major findings and potential of tissue metabolites determined by high-resolution magic angle spinning magnetic resonance spectroscopy for cancer detection, characterization, and treatment monitoring.
Short- and Long-Term Effects of Real-Time Continuous Glucose Monitoring in Patients With Type 2 Diabetes
Authors: Robert A. Vigersky, Stephanie J. Fonda, Mary Chellappa, M. Susan Walker, Nicole M. Ehrhardt
Journal: Diabetes Care (2011)

OBJECTIVE To determine whether short-time, real-time continuous glucose monitoring (RT-CGM) has long-term salutary glycemic effects in patients with type 2 diabetes who are not on prandial insulin. RESEARCH DESIGN AND METHODS This was a randomized controlled trial of 100 adults with type 2 diabetes who were not on prandial insulin. This study compared the effects of 12 weeks of intermittent RT-CGM with self-monitoring of blood glucose (SMBG) on glycemic control over a 40-week follow-up period. Subjects received diabetes care from their regular provider without therapeutic intervention from the study team. RESULTS There was a significant difference in A1C at the end of the 3-month active intervention that was sustained during the follow-up period. The mean, unadjusted A1C decreased by 1.0, 1.2, 0.8, and 0.8% in the RT-CGM group vs. 0.5, 0.5, 0.5, and 0.2% in the SMBG group at 12, 24, 38, and 52 weeks, respectively (P = 0.04). There was a significantly greater decline in A1C over the course of the study for the RT-CGM group than for the SMBG group, after adjusting for covariates (P &amp;lt; 0.0001). The subjects who used RT-CGM per protocol (≥48 days) improved the most (P &amp;lt; 0.0001). The improvement in the RT-CGM group occurred without a greater intensification of medication compared with those in the SMBG group. CONCLUSIONS Subjects with type 2 diabetes not on prandial insulin who used RT-CGM intermittently for 12 weeks significantly improved glycemic control at 12 weeks and sustained the improvement without RT-CGM during the 40-week follow-up period, compared with those who used only SMBG.
Impact of nurse-led outpatient management of children with asthma on healthcare resource utilisation and costs
Authors: A.W.A. Kamps, R.J. Roorda, J.L.L. Kimpen, A.W. Overgoor-van de Groes, L.C.J.A.M. van Helsdingen-Peek, P.L.P. Brand
Journal: European Respiratory Journal (2003)

The high burden of asthma on healthcare utilisation and costs warrants economic appraisal of management approaches. The authors previously demonstrated that the efficacy of nurse-led outpatient management of childhood asthma was comparable to management by a paediatrician and now report on the healthcare utilisation and costs of both management approaches. A total of 74 newly referred children with asthma were randomly assigned to a 1‐yr follow-up by paediatricians or asthma nurse. Healthcare utilisation was recorded and associated costs calculated for both management approaches. There were no significant differences in healthcare utilisation except for the total time spent on patient contact (136(n=14) versus 187(n=41) min, for patients followed-up by paediatrician and an asthma nurse repectively). Costs within the healthcare sector were reduced by 7.2% in favour of nurse-led care. The reduction in costs was solely attributable to a 17.5% reduction in the costs of outpatient visits. Nurse-led care appeared to be cost-saving even if the duration of follow-up visits would be twice that of doctor's visits. Overall healthcare costs (within and outside the healthcare sector) were 4.1% lower for nurse-led outpatient management compared to traditional medical care. Nurse-led outpatient management of childhood asthma can be provided at a lower cost than medical care by paediatricians.
Recent advances: Palliative care
Authors: J A. Billings
Journal: BMJ (2000)

Palliative care is defined as comprehensive, interdisciplinary care of patients and families facing a terminal illness, focusing primarily on comfort and support. 1 Key aspects include meticulous symptom control; psychosocial and spiritual care; a personalised management plan that maximises patient-determined quality of life; family oriented care that extends through the time of bereavement; and delivery of coordinated services, especially in the home but also in hospital, extended care facilities, day care centres, and specialised units.In this article I introduce current concepts about palliative care and review advances in this subject over the past five years, highlighting developments of particular interest to generalists. MethodsMy choice of topics derives from my familiarity with patterns of medical practice, particularly in the United States; presentations at meetings; review of current textbooks; and monitoring of general medical journals, selected specialty journals on pain and cancer, and nine palliative care journals (see extra box on the BMJ 's website).
Advances and Challenges in Treatment of Locally Advanced Rectal Cancer
Authors: J. Joshua Smith, Julio Garcia-Aguilar
Journal: Journal of Clinical Oncology (2015)

Dramatic improvements in the outcomes of patients with rectal cancer have occurred over the past 30 years. Advances in surgical pathology, refinements in surgical techniques and instrumentation, new imaging modalities, and the widespread use of neoadjuvant therapy have all contributed to these improvements. Several questions emerge as we learn of the benefits or lack thereof for components of the current multimodality treatment in subgroups of patients with nonmetastatic locally advanced rectal cancer (LARC). What is the optimal surgical technique for distal rectal cancers? Do all patients need postoperative chemotherapy? Do all patients need radiation? Do all patients need surgery, or is a nonoperative, organ-preserving approach warranted in selected patients? Answering these questions will lead to more precise treatment regimens, based on patient and tumor characteristics, that will improve outcomes while preserving quality of life. However, the idea of shifting the treatment paradigm (chemoradiotherapy, total mesorectal excision, and adjuvant therapy) currently applied to all patients with LARC to a more individually tailored approach is controversial. The paradigm shift toward organ preservation in highly selected patients whose tumors demonstrate clinical complete response to neoadjuvant treatment is also controversial. Herein, we highlight many of the advances and resultant controversies that are likely to dominate the research agenda for LARC in the modern era.
Primary Cutaneous T-Cell Lymphomas Show a Deletion or Translocation Affecting <i>NAV3</i>, the Human <i>UNC-53</i> Homologue
Authors: Leena Karenko, Sonja Hahtola, Suvi Päivinen, Ritva Karhu, Sanna Syrjä, Marketta Kähkönen, Boguslaw Nedoszytko, Soili Kytölä, Ying Zhou, Vesna Blazevic, Maria Pesonen, Hanna Nevala, Nina Nupponen, Harri Sihto, Inge Krebs, Annemarie Poustka, Jadwiga Roszkiewicz, Kalle Saksela, Pärt Peterson, Tapio Visakorpi, Annamari Ranki
Journal: Cancer Research (2005)

Abstract Multicolor fluorescent in situ hybridization (FISH) was used to identify acquired chromosomal aberrations in 12 patients with mycosis fungoides or Sézary syndrome, the most common forms of primary cutaneous T-cell lymphoma (CTCL). The most frequently affected chromosome was 12, which showed clonal deletions or translocations with a break point in 12q21 or 12q22 in five of seven consecutive Sézary syndrome patients and a clonal monosomy in the sixth patient. The break point of a balanced translocation t(12;18)(q21;q21.2), mapped in the minimal common region of two deletions, fine mapped to 12q2. By locus-specific FISH, the translocation disrupted one gene, NAV3 (POMFIL1), a human homologue of unc-53 in Caenorhabditis elegans. A missense mutation in the remaining NAV3 allele was found in one of six cases with a deletion or translocation. With locus-specific FISH, NAV3 deletions were found in the skin lesions of four of eight (50%) patients with early mycosis fungoides (stages IA-IIA) and in the skin or lymph node of 11 of 13 (85%) patients with advanced mycosis fungoides or Sézary syndrome. Preliminary functional studies with lentiviral small interfering RNA-based NAV3 silencing in Jurkat cells and in primary lymphocytes showed enhanced interleukin 2 expression (but not CD25 expression). Thus, NAV3 may contribute to the growth, differentiation, and apoptosis of CTCL cells as well as to the skewing from Th1-type to Th2-type phenotype during disease progression. NAV3, a novel putative haploinsufficient tumor suppressor gene, is disrupted in most cases of the commonest types of CTCL and may thus provide a new diagnostic tool.
Oxidative stress: an important phenomenon with pathogenetic significance in the progression of acute pancreatitis
Authors: K Tsai, S-S Wang, T-S Chen, C-W Kong, F-Y Chang, S-D Lee, F-J Lu
Journal: Gut (1998)

Background —Reactive oxygen species and related oxidative damage have been implicated in the initiation of acute pancreatitis. Changes in these parameters during disease progression merit further investigation. Aims —To evaluate changes and the clinical relevance of superoxide radicals, endogenous antioxidants, and lipid peroxidation during the course of acute pancreatitis. Patients and methods —Superoxide radicals (measured as lucigenin amplified chemiluminescence), ascorbic acid, dehydroascorbic acid, α tocopherol, and lipid peroxidation (measured as thiobarbiturate reactive substances) were analysed in blood samples from 56 healthy subjects, 30 patients with mild acute pancreatitis, and 23 patients with severe acute pancreatitis. The association with grades of disease severity was analysed. Measurements were repeated one and two weeks after onset of pancreatitis. Results —In the blood from patients with acute pancreatitis, there were increased levels of the superoxide radical as well as lipid peroxides. There was notable depletion of ascorbic acid and an increased fraction of dehydroascorbic acid. Changes in α tocopherol were not great except in one case with poor prognosis. Differences between severe and mild acute pancreatitis were significant (p&lt;0.01). Variable but significant correlations with disease severity scores were found for most of these markers. The normalisation of these indexes postdated clinical recovery one or two weeks after onset of disease. Conclusions —Heightened oxidative stress appears early in the course of acute pancreatitis and lasts longer than the clinical manifestations. The dependence of disease severity on the imbalance between oxidants and natural defences suggests that oxidative stress may have a pivotal role in the progression of pancreatitis and may provide a target for treatment.
5-Aminolevulinic acid photodynamic therapy versus argon plasma coagulation for ablation of Barrett's oesophagus: a randomised trial
Authors: M Hage
Journal: Gut (2004)

<b>Background:</b> Photochemical and thermal methods are used for ablating Barrett’s oesophagus (BO). The aim of this study was to compare 5-aminolevulinic acid induced photodynamic therapy (ALA-PDT) with argon plasma coagulation (APC) with respect to complete reversal of BO. <b>Methods:</b> Patients with BO (32 no dysplasia and eight low grade dysplasia) were randomised to one of three treatments: (a) ALA-PDT as a single dose of 100 J/cm<sup>2</sup> at four hours (PDT100; n = 13); (b) ALA-PDT as a fractionated dose of 20 and 100 J/cm<sup>2</sup> at one and four hours, respectively (PDT20+100; n = 13); or (c) APC at a power setting of 65 W in two sessions (APC; n = 14). If complete elimination of BO was not achieved by the designated treatment, the remaining BO was treated by a maximum of two sessions of APC. <b>Results:</b> Mean endoscopic reduction of BO at six weeks was 51% (range 20–100%) in the PDT100 group, 86% (range 0–100%) in the PDT20+100 group, and 93% (range 40–100%) in the APC group (PDT100 <i>v</i> PDT20+100, p&lt;0.005; PDT100 <i>v</i> APC, p&lt;0.005; and PDT20+100 <i>v</i> APC, NS) with histologically complete ablation in 1/13 (8%) patients in the PDT100 group, 4/12 (33%) in the PDT20+100 group, and 5/14 (36%) in the APC group (NS). Remaining BO was additionally treated with APC in 23/40 (58%) patients. Histological examination at 12 months revealed complete ablation in 9/11 (82%) patients in the PDT100 group, in 9/10 (90%) patients in the PDT20+100 group, and in 8/12 (67%) patients in the APC group (NS). At 12 months, no dysplasia was detected. Side effects (that is, pain (p&lt;0.01), and nausea and vomiting (p&lt;0.05)) and elevated liver transaminases (p&lt;0.01) were more common after PDT than APC therapy. One patient died three days after treatment with PDT, presumably from cardiac arrhythmia. <b>Conclusion:</b> APC alone or ALA-PDT in combination with APC can lead to complete reversal of Barrett’s epithelium in at least two thirds of patients when administered in multiple treatment sessions. As the goal of treatment should be complete reversal of Barrett’s epithelium, we do not recommend these techniques for the prophylactic ablation of BO.
Extracellular K <sup>+</sup> Is a Prerequisite for the Function and Plasma Membrane Stability of HERG Channels
Authors: Hamid Massaeli, Jun Guo, Jianmin Xu, Shetuan Zhang
Journal: Circulation Research (2010)

The human ether-a-go-go-related gene (HERG) encodes the pore-forming subunits of the rapidly activating delayed rectifier potassium channel (I(Kr)) that is important for cardiac repolarization. Dysfunction of HERG causes long QT syndrome (LQTS) which can lead to sudden cardiac death. We previously showed that a reduction in extracellular K(+) concentration ([K(+)](o)) prolongs QT intervals in intact rabbits, and decreases the cell surface density of I(Kr) in rabbit ventricular myocytes and of the HERG channel expressed in human embryonic kidney (HEK) cells.The goal of the present study was to gain insights into the mechanisms for low [K(+)](o) induced reduction in HERG expression levels.Using patch clamp, Western blot and confocal imaging methods, we demonstrated that at low [K(+)](o), the HERG channel entered a novel nonconducting state. Furthermore, this novel functional state triggered rapid internalization and degradation of the cell surface HERG channels. Thus, our data demonstrated for the first time a direct link between a gating state and the plasma membrane stability of an ion channel, HERG. Using HERG-permeant cations and site-directed mutagenesis, we identified the sites in the channel which are involved in the K(+)(o) dependence of HERG channels.Extracellular K(+) is a prerequisite for HERG function and membrane stability.