tbuckley/cabot-search huggingface dataset:
Soluble IGF2 Receptor Rescues <i>Apc</i> <i>Min/</i>+ Intestinal Adenoma Progression Induced by <i>Igf2</i> Loss of Imprinting
Authors: James Harper, Jason L. Burns, Emily J. Foulstone, Massimo Pignatelli, Silvio Zaina, A. Bassim Hassan
Journal: Cancer Research (2006)

Abstract The potent growth-promoting activity of insulin-like growth factor-II (IGF-II) is highly regulated during development but frequently up-regulated in tumors. Increased expression of the normally monoallelic (paternally expressed) mouse (Igf2) and human (IGF2) genes modify progression of intestinal adenoma in the ApcMin/+ mouse and correlate with a high relative risk of human colorectal cancer susceptibility, respectively. We examined the functional consequence of Igf2 allelic dosage (null, monoallelic, and biallelic) on intestinal adenoma development in the ApcMin/+ by breeding with mice with either disruption of Igf2 paternal allele or H19 maternal allele and used these models to evaluate an IGF-II–specific therapeutic intervention. Increased allelic Igf2 expression led to elongation of intestinal crypts, increased adenoma growth independent of systemic growth, and increased adenoma nuclear β-catenin staining. By introducing a transgene expressing a soluble form of the full-length IGF-II/mannose 6-phosphate receptor (sIGF2R) in the intestine, which acts as a specific inhibitor of IGF-II ligand bioavailability (ligand trap), we show rescue of the Igf2-dependent intestinal and adenoma phenotype. This evidence shows the functional potency of allelic dosage of an epigenetically regulated gene in cancer and supports the application of an IGF-II ligand–specific therapeutic intervention in colorectal cancer. (Cancer Res 2006; 66(4): 1940-8)
Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules.
Authors: O Mandelboim, H T Reyburn, M Valés-Gómez, L Pazmany, M Colonna, G Borsellino, J L Strominger
Journal: The Journal of Experimental Medicine (1996)

Recognition of major histocompatibility complex class I molecules by natural killer (NR) cells leads to inhibition of target cell lysis. Based on the capacity of different human histocompatibility leukocyte antigen (HLA)-C and HLA-B molecules to inhibit target cell lysis by NK lines and clones, three NK allospecificities have been defined: NK1 and NK2 cells are inhibited by different HLA-C allotypes and NK3 cells by some HLA-B allotypes. The NK1 and NK2 inhibitory ligands on target cells correspond to a dimorphism of HLA-C at residues 77 and 80 in the alpha 1 helix: Asn77-Lys80 in NK1 and Ser77-Asn80 in NK2 inhibitory ligands. It has been reported that protection from NK1 killers depended on the presence of the Lys residue at position 80, an upward pointing residue near the end of the alpha 1 helix (and not on Asn77), whereas inhibition of NK2 effector cells required Ser77, a residue deep in the F pocket and interacting with the peptide (and not Asn80). As part of ongoing experiments to investigate the structural requirements for NK cell inhibition by HLA-C locus alleles, we also examined the effects of mutations at residues 77 and 80 on the ability of HLA-C alleles to confer protection from NK lysis. We present data confirming that the NK1 specificity depended on Lys80 (and not on Asn77); however recognition of NK2 ligands by NK cells was also controlled by the amino acid at position 80 (Asn), and mutation of Ser77 had no effect. Furthermore, bound peptide was shown to be unnecessary for the inhibition of NK cell-mediated lysis since HLA-C molecules assembled in the absence of peptide in RMA-S cells at 26 degrees C were fully competent to inhibit NK cells specifically. The implications of these data for peptide-independent recognition of HLA-C by NK receptors are discussed.
bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages.
Authors: E Lagasse, I L Weissman
Journal: The Journal of Experimental Medicine (1994)

Neutrophils, the most common inflammatory leukocytes, have the most limited life span of all blood cells. After they undergo apoptosis, they are recognized and engulfed by macrophages. bcl-2, a proto-oncogene rearranged and deregulated in B cell lymphomas bearing the t(14;18) translocation, is known to inhibit programmed death. bcl-2 expression is localized in early myeloid cells of the bone marrow but is absent in mature neutrophils. Transgenic mice that expressed bcl-2 in mature neutrophils showed that bcl-2 blocked neutrophil apoptosis. Despite this, homeostasis of neutrophil population is essentially unaffected. In fact, macrophage uptake of neutrophils expressing bcl-2 still occurred. This transgenic model indicates that the mechanism that triggers phagocytosis of aging neutrophils operates independently of the process of apoptosis regulated by bcl-2.
International Atomic Energy Agency Randomized Phase III Study of Radiation Therapy in Elderly and/or Frail Patients With Newly Diagnosed Glioblastoma Multiforme
Authors: Wilson Roa, Lucyna Kepka, Narendra Kumar, Valery Sinaika, Juliana Matiello, Darejan Lomidze, Dalenda Hentati, Douglas Guedes de Castro, Katarzyna Dyttus-Cebulok, Suzanne Drodge, Sunita Ghosh, Branislav Jeremić, Eduardo Rosenblatt, Elena Fidarova
Journal: Journal of Clinical Oncology (2015)

Purpose The optimal radiotherapy regimen for elderly and/or frail patients with newly diagnosed glioblastoma remains to be established. This study compared two radiotherapy regimens on the outcome of these patients. Patients and Methods Between 2010 and 2013, 98 patients (frail = age ≥ 50 years and Karnofsky performance status [KPS] of 50% to 70%; elderly and frail = age ≥ 65 years and KPS of 50% to 70%; elderly = age ≥ 65 years and KPS of 80% to 100%) were prospectively randomly assigned to two arms in a 1:1 ratio, stratified by age (&lt; and ≥ 65 years old), KPS, and extent of surgical resection. Arm 1 received short-course radiotherapy (25 Gy in five daily fractions over 1 week), and arm 2 received commonly used radiotherapy (40 Gy in 15 daily fractions over 3 weeks). Results The short-course radiotherapy was noninferior to commonly used radiotherapy. The median overall survival time was 7.9 months (95% CI, 6.3 to 9.6 months) in arm 1 and 6.4 months (95% CI, 5.1 to 7.6 months) in arm 2 (P = .988). Median progression-free survival time was 4.2 months (95% CI, 2.5 to 5.9) in arm 1 and 4.2 months (95% CI, 2.6 to 5.7) in arm B (P = .716). With a median follow-up time of 6.3 months, the quality of life between both arms at 4 weeks after treatment and 8 weeks after treatment was not different. Conclusion There were no differences in overall survival time, progression-free survival time, and quality of life between patients receiving the two radiotherapy regimens. In view of the reduced treatment time, the short 1-week radiotherapy regimen may be recommended as a treatment option for elderly and/or frail patients with newly diagnosed glioblastoma.
Unconscious semantic access: A case against a hyperpowerful unconscious
Authors: Daniel Holender, Katia Duscherer
Journal: Behavioral and Brain Sciences (2002)

We analyze some of the recent evidence for unconscious semantic access stemming from tasks that, although based on a priming procedure, generate semantic congruity effects because of response competition, not semantic priming effects. We argue that such effects cannot occur without at least some glimpses of awareness about the identity and the meaning of a significant proportion of the primes.
Refractory SLE patients respond to the proteasome inhibitor bortezomib
Authors: F Hiepe, T Alexander, R Peukert, A Rubbert, J Rech, T Braun, G Schott, M Wiesener, K U Eckardt, M Baeuerle, A Reisch, B Hoyer, A Taddeo, G Burmester, G Schett, A Radbruch, R E Voll
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> Long-lived memory plasma cells secreting pathogenic autoantibodies are resistant to conventional immunosuppression and B cell targeting therapies. Bortezomib, an approved drug for relapsing multiple myeloma, efficiently depletes short- and long-lived plasma cells and ameliorates nephritis in murine lupus models. Therefore, the authors studied the efficacy of bortezomib in refractory SLE patients in a case series. <h3>Materials and methods</h3> At three university centers, 13 SLE patients refractory or intolerant to cyclophosphamide, MMF and/or rituximab were treated with bortezomib intravenously at a dose of 1.3 mg/m2 body surface area on days 1, 4, and 8 and, in some cases, on day 11. Most patients received 20mg of dexamethasone together with bortezomib. Treatment cycles were repeated up to four times with an interruption of usually 10 to 14 days between cycles. The following clinical and laboratory parameters were monitored: SLEDAI disease activity score, 24 h proteinuria, creatinine clearance, circulating plasma cells, complement C3 and C4, IgG, IgA, IgM, antibodies to dsDNA and ENA, and vaccine titers. <h3>Results</h3> SLEDAI and antibody levels significantly decreased under bortezomib while complement levels increased. In seven patients with active nephritis, proteinuria declined within 6 weeks of treatment, and normalised after four months in one case. Anti-dsDNA antibodies decreased by up to 90%, anti-ENA and protective vaccine titers by up to 50%, and immunoglobulin levels by up to 30%. Circulating plasmablasts dropped substantially. Serious side effects were not observed. One patient experienced myalgia, fever and headache 1 day after the first 3 bortezomib doses. Three of five patients treated with four bortezomib injections per cycle developed polyneuropathies, which were reversible upon discontinuation of treatment. One patient developed reversible thrombocytopenia after four treatment cycles. <h3>Conclusions</h3> The proteasome inhibitor bortezomib may effectively reduce disease activity in refractory SLE patients by depleting plasma cells. The data encourage initiation of clinical trials with bortezomib in refractory SLE and support the relevance of plasma cells in the pathogenesis of this autoimmune disease.
Cholesterol emboli presenting as acute allograft dysfunction after renal transplantation.
Authors: I Singh, P D Killen, A B Leichtman
Journal: Journal of the American Society of Nephrology (1995)

Cholesterol emboli are a common complication of atherosclerotic vascular disease. A 40-yr-old renal transplant recipient who developed acute allograft dysfunction 1 day after the initiation of cyclosporine therapy and 6 days after transplantation is described. A renal allograft biopsy revealed cholesterol emboli in interlobular arteries and in glomeruli. Four previously reported cases of cholesterol emboli in renal allografts are described, and the cause and pathogenesis of atheroembolic disease are reviewed. Atheroemboli causing injury to the renal allograft may arise from either donor or recipient vessels. Vigilance for the occurrence of these emboli needs to be maintained when donor or recipient vessels demonstrate evidence of significant atherosclerotic vascular disease.
Iron Metabolism Is Associated With Adipocyte Insulin Resistance and Plasma Adiponectin
Authors: Nick Wlazlo, Marleen M.J. van Greevenbroek, Isabel Ferreira, Eugene H.J.M. Jansen, Edith J.M. Feskens, Carla J.H. van der Kallen, Casper G. Schalkwijk, Bert Bravenboer, Coen D.A. Stehouwer
Journal: Diabetes Care (2012)

Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron metabolism-related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin.Serum ferritin, transferrin, total iron, non-transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 individuals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers.Serum ferritin (β = 1.00% increase in adipocyte IR per 10 μg/L [95% CI 0.66-1.34]), transferrin (4.18% per 0.1 g/L [2.88-5.50]), total iron (1.36% per μmol/L [0.61-2.12]), and NTBI (5.14% per μmol/L [1.88-8.52]) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P < 0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P < 0.01).The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM.
Recombinant adeno-associated virus vectors induce functionally impaired transgene product–specific CD8+ T cells in mice
Authors: Shih-Wen Lin, Scott E. Hensley, Nia Tatsis, Marcio O. Lasaro, Hildegund C.J. Ertl
Journal: Journal of Clinical Investigation (2007)

Recombinant adeno-associated virus (rAAV) vectors were used in human trials as carriers of vaccines for HIV-1 after encouraging preclinical results. However, the clinical trials yielded disappointing results. Here we demonstrated that in mice, rAAV vectors expressing the gene encoding HIV-1 gag stimulated gag-specific CD8+ T cells, but these T cells failed to expand after a booster immunization with a replication-defective adenoviral (Ad) vector also expressing gag. We tested rAAV vectors of different serotypes expressing HIV-1 gag for induction of transgene product–specific CD8+ T cells and found that the immunoinhibitory effect of rAAV priming observed with different AAV serotypes was transgene product specific, was independent of the interval between prime and boost, and extended to boosts with vaccine modalities other than Ad vectors. rAAV vector–induced CD8+ T cells proliferated poorly, produced low levels of IFN-γ in response to gag stimulation, and upregulated immunoinhibitory molecules. These T cells did not protect efficiently against challenge with a surrogate pathogen. Finally, we showed that the impaired proliferative capacity of the T cells was caused by persistence of the antigen-encoding rAAV vectors and could be reversed by placing the CD8+ T cells in an antigen-free environment. Our data suggest that rAAV vectors induce functionally impaired T cells and could dampen the immune response to a natural infection.
Dehydration, a clue to neglect in care homes
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2015)

The challenge to the sustainability of the NHS is unlikely to fade. With an increasingly elderly population, and accompanying multiple morbidity, the pressures to deliver a high-quality, high-value service will outlast the current efficiency drive. Any five-year forward view requires to be mindful of demographic changes beyond the next five years. Do the answers lie in expensive high-tech solutions or low-cost simple interventions?

Research can help guide future policy but research is a time-consuming enterprise and rarely offers up a quick answer. Policy makers favour rapid evaluations that often don’t stand methodological scrutiny and are designed to best serve political timelines. The balance between producing evidence quickly and ensuring it is rigorous is a difficult one. The best research available may not be the most ideal research, but it can be a starting point for a serious debate on questions that are hard to study. Let’s take residential care homes for instance. We know already that health professionals have concerns about the quality of care in such homes in the UK. Elderly people may be neglected by health services in comparison with elderly people living in their own homes.

With this in mind, Anthony Wolff et al. focus on dehydration, exploring the association between hypernatraemia and residence in care homes.1 Data are scarce, and this month’s study based in one NHS Trust in London is the most robust evidence we have on this controversial topic. Worryingly but perhaps unsurprisingly, Wolff et al. find that patients admitted to hospitals from care homes have a 10-fold higher prevalence of hypernatraemia than those admitted from their own homes. Further still, these patients also have double the risk of in-hospital mortality.

The authors argue that a follow-up intervention study is required, involving education and active encouragement of water intake in care homes. The benefits from such an intervention, both for patients’ well-being and healthcare costs, might be considerable. In our 4G-Internet-of-Things-World we strive for expensive high-tech solutions to even the most minor clinical problems. The welfare of patients is generally better served by investing in simple preventative measures.
Atherogenic diet increases cholesteryl ester transfer protein messenger RNA levels in rabbit liver.
Authors: E M Quinet, L B Agellon, P A Kroon, Y L Marcel, Y C Lee, M E Whitlock, A R Tall
Journal: Journal of Clinical Investigation (1990)

Cholesteryl ester transfer activity is increased in plasma of cholesterol-fed rabbits. To investigate the mechanisms leading to changes in activity, we measured cholesteryl ester transfer protein (CETP) mass by RIA and CETP mRNA abundance by Northern and slot blot analysis using a human CETP cDNA probe in control (n = 8) and cholesterol-fed rabbits (n = 10). Cholesterol feeding (chow plus 0.5% cholesterol, 10% corn oil) for 30 d increased CETP mass in plasma 3.2-fold in the cholesterol-fed rabbits (12.45 +/- 0.82 micrograms/ml) compared with controls (3.86 +/- 0.38 micrograms/ml). In the hypercholesterolemic rabbit, liver CETP mRNA levels were increased 2.8 times control mRNA levels. Actin, apo E, lecithin-cholesterol acyltransferase, and albumin mRNA abundances were unchanged. In contrast to the widespread tissue distribution in humans, CETP mRNA was not detected in extrahepatic tissues of either control or cholesterol-fed animals. Using a sensitive RNase protection assay, the increase in liver CETP mRNA was detectable within 3 d of beginning the high cholesterol diet. Thus, in response to the atherogenic diet there is an early increase in liver CETP mRNA, probably causing increased CETP synthesis and secretion, and increased plasma CETP. The results indicate that the CETP gene may be regulated by diet-induced changes in lipid metabolism.
A thriathlete with acute onset of dyspnea and hemoptysis
Authors: Karin Pintscher, Marianne Hubner, Meinhard Kneussl
Journal: European Respiratory Journal (2014)

INTRODUCTION:  The etiology of swimming induced pulmonary edema (SIPE) is a peripheral vasoconstriction, centralization and finally an increase of the preload and afterload, which leads to an elevation of the transmural pressure of the capillaries and finally to an influx of fluid into the alveoli.  THE CASE:  During the swimming competition of a thriatlon a 50 year old healthy man developed symptoms like dyspnea and hemoptysis.  Lab tests showed no signs of infection: D-Dimer, Troponin I, NT-proBNP and kidney function were normal. Oxygen saturation on room air was 90 %. The chest X ray revealed an alveolar infiltration in the right upper lobe as well as signs of left heart failure. A thromboembolic event could be excluded by CT angiography. Although the patient did not receive any specific treatment he was free of symptoms 48 hours later.  At the follow-up, echocardiography, pulmonary function test (PFT) including diffusion capacity were normal. The chest X ray revealed a complete remission of the pathological lesions.  In summary, we assume that the rapid reversibility of the pulmonary alterations, as well as the clinical course with a spontaneous recovery of symptoms within 48 hours correlate with a swimming induced pulmonary edema which is a rare case of a non-cardiac pulmonary edema.  DISCUSSION:  SIPE is associated with physical stress and shows a spontaneous remission. The pulmonary capillary stress  failure leads to a peripheral constriction of the vessels with an increase of preload and afterload. The exceeding pressure during physical exertion causes loss of the integrity of the capillary barrier. The only therapy of SIPE is supplementary oxygen. Diuretics are of no benefit, based on the pathophysiological mechanism.
Chromosome 6p22 Locus Associated with Clinically Aggressive Neuroblastoma
Authors: John M. Maris, Yael P. Mosse, Jonathan P. Bradfield, Cuiping Hou, Stefano Monni, Richard H. Scott, Shahab Asgharzadeh, Edward F. Attiyeh, Sharon J. Diskin, Marci Laudenslager, Cynthia Winter, Kristina A. Cole, Joseph T. Glessner, Cecilia Kim, Edward C. Frackelton, Tracy Casalunovo, Andrew W. Eckert, Mario Capasso, Eric F. Rappaport, Carmel McConville, Wendy B. London, Robert C. Seeger, Nazneen Rahman, Marcella Devoto, Struan F.A. Grant, Hongzhe Li, Hakon Hakonarson
Journal: New England Journal of Medicine (2008)

Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known.