tbuckley/cabot-search huggingface dataset:
Building better bugs to deliver biologics in intestinal inflammation
Authors: K. E Barrett
Journal: Gut (2010)

containment. Nevertheless, the work of Steidler and others implies that antiinflammatory biologics, at least, might be supplied directly to the intestinal lumen to affect the outcome of IBD if these limitations could be overcome. Indeed, a preliminary clinical trial using this approach in Crohn’s disease has been reported. 6 The intestinal epithelium is also an appealing target for IBD therapy. Although current thinking about IBD pathogenesis implies that intestinal inflammation arises as an inappropriate immune response to the normal commensal microbiota resident in the gut, the epithelium is also a clear target of, and contributor to, perpetuation of the disease state. 78 The intestinal epithelium is a key barrier that limits interactions between the mucosal immune system and the microbiota, as well as itself responding to luminal micro-organisms, when it is injured, with the production of chemokines and other factors that set up a vicious cycle of inflammation. Moreover, whether the epithelial barrier is compromised as a cause or a consequence of intestinal inflammation, there is now considerable evidence to suggest that restoring its barrier properties can interrupt the natural history of experimental intestinal inflammation, and thus serve as a basis for a lasting therapeutic effect in IBD. Among various strategies, the barrier properties of intestinal epithelial cells can be restored and/or augmented by administration of a variety of peptide growth factors, including epidermal growth factor, transforming growth factor a, and the keratinocyte growth factors (KGFs). Indeed, high doses of recombinant KGF-2, administered systemically, were shown to be effective in ulcerative colitis in shortterm clinical trials, and epidermal growth factor (EGF) and growth hormone have also been shown to exert some therapeutic effects in this setting. 9 Nevertheless, the observations with these growth factors face hurdles in wide-scale translation to therapeutic advances. First, as peptides, they have hitherto required intravenous
Peritubular Capillary Injury during the Progression of Experimental Glomerulonephritis in Rats
Authors: RYUJI OHASHI, HIROSHI KITAMURA, NOBUAKI YAMANAKA
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The functional and morphologic changes occurring in the peritubular capillaries (PTC) of the kidney during the progression of renal disease are not yet completely understood. In this study, the features of PTC disruption observed in a rat anti-glomerular basement membrane-induced glomerulonephritis (GN) model were characterized. Contributions to the progression of the disease made by other interstitial components, including ED-1-positive macrophages and CD3-positive T cells, were also investigated. Within 7 d of inducing GN, severe necrotizing glomerular injuries were observed. Thrombomodulin staining revealed that within 3 to 8 wk, there was a significant ( P &lt; 0.001) decline in the number of PTC, accompanied by a marked accumulation of macrophages, T cells, and fibrotic material. By the end of this period, most PTC were severely damaged or lost, and tubulointerstitial scarring was noted in the affected areas. Furthermore, PTC endothelial cell apoptosis occurred concomitantly, as shown by application of terminal deoxynucleotidyl transferasemediated dUTP-biotin nick end labeling methods and electron microscopy. It was presumed that the PTC injury was mediated possibly by the infiltrating macrophages and T cells, which, together with destruction of the PTC structure, correlated significantly with the impairment of renal function. These findings suggest that PTC disruption and the subsequent regression of the capillary network may contribute to the development of the tubulointerstitial injury largely responsible for the renal dysfunction in progressive GN.
Protection Against Hypertension, Arteriolonecrosis and Death by Hog Renal Extracts in Experimental Malignant Hypertension
Authors: R. O. BURNS, G. E. WAKERLIN
Journal: Circulation Research (1953)

Since hog renin is effective in the treatment and prophylaxis of chronic experimental renal hypertension in the dog, probably through antirenin, a study was made of the prophylactic effect of crude and semipurified hog renins from cortex and from whole kidney on the hypertension, arteriolonecrosis, and course of experimental renal malignant hypertension in the dog. In the absence of medullary protein, protection against the hypertension was found to be well correlated with the antirenin titer. More importantly, the nonrenin fraction of crude hog renin from cortex significantly protected against the arteriolonecrotic lesions and death.
Diagnostic utility of alarm features for colorectal cancer: systematic review and meta-analysis
Authors: A C Ford, S J O Veldhuyzen van Zanten, C C Rodgers, N J Talley, N B Vakil, P Moayyedi
Journal: Gut (2008)

<h3>Objective:</h3> Colorectal cancer is the second most common cause of cancer death in Europe and North America. Alarm features are used to prioritise access to urgent investigation, but there is little information concerning their utility in the diagnosis of colorectal cancer. <h3>Methods:</h3> A systematic review and meta-analysis of the published literature was carried out to assess the diagnostic accuracy of alarm features in predicting colorectal cancer. Primary or secondary care-based studies in unselected cohorts of adult patients with lower gastrointestinal symptoms were identified by searching MEDLINE, EMBASE and CINAHL (up to October 2007). The main outcome measures were accuracy of alarm features or statistical models in predicting the presence of colorectal cancer after investigation. Data were pooled to estimate sensitivity, specificity, and positive and negative likelihood ratios. The quality of the included studies was assessed according to predefined criteria. <h3>Results:</h3> Of 11 169 studies identified, 205 were retrieved for evaluation. Fifteen studies were eligible for inclusion, evaluating 19 443 patients, with a pooled prevalence of colorectal carcinoma of 6% (95% CI 5% to 8%). Pooled sensitivity of alarm features was poor (5% to 64%) but specificity was &gt;95% for dark red rectal bleeding and abdominal mass, suggesting that the presence of either rules the diagnosis of colorectal cancer in. Statistical models had a sensitivity of 90%, but poor specificity. <h3>Conclusions:</h3> Most alarm features had poor sensitivity and specificity for the diagnosis of colorectal carcinoma, whilst statistical models performed better in terms of sensitivity. Future studies should examine the utility of dark red rectal bleeding and abdominal mass, and concentrate on maximising specificity when validating statistical models.
Neck Ecchymosis in Amyloidosis
Authors: Dries Deeren
Journal: Journal of Clinical Oncology (2011)

A 74-year-old man was admitted to the cardiology ward because of heart failure. Echocardiography showed concentric hypertrophy, dense myocardium, and global hypocontractility. Endomyocardial biopsy showed deposition of eosinophilic substance, positive for lambda and negative for kappa, amyloid A, and transthyretin. The bone marrow was invaded with 20% plasma cells with lambda light chain restriction; these cells were responsible for the immunoglobin G lambda paraprotein in the blood. Several vessel walls on the bone marrow biopsy showed amyloid deposition. The patient had amyloidosis that seemed to be the result of myeloma. For the previous 12 months, the patient had noticed ecchymoses on both sides of the neck; these were more pronounced in the morning (Fig 1). There was no history of preceding trauma, and the patient was not receiving anticoagulant or antiplatelet medication. All coagulation tests were normal; factor X activity was 83%. The ecchymoses seemed to be caused by amyloid-induced capillary fragility, which resulted in subcutaneous bleeding even after minor stress, such as lying down to sleep. This phenomenon is known to cause periorbital ecchymosis (so-called raccoon eyes), but in this patient, the skin of the neck was the affected site. Early recognition of amyloidosis-induced ecchymosis may prevent additional myocardial damage.
Myomasp/LRRC39, a Heart- and Muscle-Specific Protein, Is a Novel Component of the Sarcomeric M-Band and Is Involved in Stretch Sensing
Authors: Rainer D. Will, Matthias Eden, Steffen Just, Arne Hansen, Alexandra Eder, Derk Frank, Christian Kuhn, Thalia S. Seeger, Ulrike Oehl, Stefan Wiemann, Bernhard Korn, Manfred Koegl, Wolfgang Rottbauer, Thomas Eschenhagen, Hugo A. Katus, Norbert Frey
Journal: Circulation Research (2010)

Rationale and Objective: The M-band represents a transverse structure in the center of the sarcomeric A-band and provides an anchor for the myosin-containing thick filaments. In contrast to other sarcomeric structures, eg, the Z-disc, only few M-band–specific proteins have been identified to date, and its exact molecular composition remains unclear. Methods and Results: Using a bioinformatic approach to identify novel heart- and muscle-specific genes, we found a leucine rich protein, myomasp ( Myo sin-interacting, M -band- a ssociated s tress-responsive p rotein)/LRRC39. RT-PCR and Northern and Western blot analyses confirmed a cardiac-enriched expression pattern, and immunolocalization of myomasp revealed a strong and specific signal at the sarcomeric M-band. Yeast 2-hybrid screens, as well as coimmunoprecipitation experiments, identified the C terminus of myosin heavy chain (MYH)7 as an interaction partner for myomasp. Knockdown of myomasp in neonatal rat ventricular myocytes (NRVCMs) led to a significant upregulation of the stretch-sensitive genes GDF-15 and BNP. Conversely, the expression of MYH7 and the M-band proteins myomesin-1 and -2 was found to be markedly reduced. Mechanistically, knockdown of myomasp in NRVCM led to a dose-dependent suppression of serum response factor–dependent gene expression, consistent with earlier observations linking the M-band to serum response factor–mediated signaling. Finally, downregulation of myomasp/LRRC39 in spontaneously beating engineered heart tissue constructs resulted in significantly lower force generation and reduced fractional shortening. Likewise, knockdown of the myomasp/LRRC39 ortholog in zebrafish resulted in severely impaired heart function and cardiomyopathy in vivo. Conclusions: These findings reveal myomasp as a previously unrecognized component of an M-band–associated signaling pathway that regulates cardiomyocyte gene expression in response to biomechanical stress.
Electrochemo-gene therapy of cancer: intratumoral delivery of interleukin-12 gene and bleomycin synergistically induced therapeutic immunity and suppressed subcutaneous and metastatic melanomas in mice
Authors: Tsunao Kishida, Hidetsugu Asada, Yoshiki Itokawa, Kakei Yasutomi, Masaharu Shin-Ya, Satoshi Gojo, Feng-De Cui, Yuji Ueda, Hisakazu Yamagishi, Jiro Imanishi, Osam Mazda
Journal: Molecular Therapy (2003)

To treat established melanoma in mice, intratumoral transfer of bleomycin and/or an interleukin (IL)-12 expression vector was performed by means of electroporation. Although either bleomycin alone or the IL12 gene alone significantly suppressed the subcutaneous tumors, the combination therapy drastically improved the therapeutic outcome. Three of eight mice (37.5%) that received both bleomycin and the IL12 gene showed complete remission of the preestablished tumors and rejected subsequent rechallenge with the tumor cells. We also examined whether electrochemo-gene therapy for subcutaneous tumor mass induced suppression of pulmonary metastasis that had been established by intravenous inoculation of the melanoma cells. Although metastatic foci were significantly reduced in number in groups that were given IL12 gene alone or bleomycin plus IL12 gene, it was only the combination therapy that significantly prolonged the mean survival period of the tumor-bearing animals. Natural killer (NK) and cytotoxic T lymphocyte cytolytic activities were markedly enhanced in the mice that received the chemo-gene therapy, while IL12 gene therapy alone partially elevated the NK cytotoxicity. The present study suggests that the electroporation-mediated delivery of the IL12 gene and bleomycin synergistically elicits innate and adaptive anti-melanoma immune responses, resulting in marked suppression of the treated tumors as well as bystander metastatic lesions.
Sex Steroid Actions in Male Bone
Authors: Dirk Vanderschueren, Michaël R. Laurent, Frank Claessens, Evelien Gielen, Marie K. Lagerquist, Liesbeth Vandenput, Anna E. Börjesson, Claes Ohlsson
Journal: Endocrine Reviews (2014)

Sex steroids are chief regulators of gender differences in the skeleton, and male gender is one of the strongest protective factors against osteoporotic fractures. This advantage in bone strength relies mainly on greater cortical bone expansion during pubertal peak bone mass acquisition and superior skeletal maintenance during aging. During both these phases, estrogens acting via estrogen receptor-α in osteoblast lineage cells are crucial for male cortical and trabecular bone, as evident from conditional genetic mouse models, epidemiological studies, rare genetic conditions, genome-wide meta-analyses, and recent interventional trials. Genetic mouse models have also demonstrated a direct role for androgens independent of aromatization on trabecular bone via the androgen receptor in osteoblasts and osteocytes, although the target cell for their key effects on periosteal bone formation remains elusive. Low serum estradiol predicts incident fractures, but the highest risk occurs in men with additionally low T and high SHBG. Still, the possible clinical utility of serum sex steroids for fracture prediction is unknown. It is likely that sex steroid actions on male bone metabolism rely also on extraskeletal mechanisms and cross talk with other signaling pathways. We propose that estrogens influence fracture risk in aging men via direct effects on bone, whereas androgens exert an additional antifracture effect mainly via extraskeletal parameters such as muscle mass and propensity to fall. Given the demographic trends of increased longevity and consequent rise of osteoporosis, an increased understanding of how sex steroids influence male bone health remains a high research priority.
Heterogeneity of liver/kidney microsomal antibody type 1 in autoimmune hepatitis and hepatitis C virus related liver disease.
Authors: L Muratori, M Lenzi, Y Ma, M Cataleta, G Mieli-Vergani, D Vergani, F B Bianchi
Journal: Gut (1995)

Liver/kidney microsomal antibody type 1 (LKM-1), the serological marker of a subset of autoimmune hepatitis, is also present in a proportion of patients with hepatitis C virus (HCV) related chronic liver disease. To characterise further this autoreactivity and to evaluate whether an autoantibody giving an identical immunofluorescence staining, and detected in two different clinical conditions, involves the same antigenic target(s), sera from autoimmune and HCV infected patients were tested with native, recombinant, and synthetic antigens. Sixty five sera were selected on the basis of the typical immunofluorescence pattern: 50 patients had serological markers of HCV infection, the remaining 15 suffered from autoimmune hepatitis. The reactivity of each serum with rat and human microsomal fractions, full length human recombinant CYP2D6, and two synthetic peptides spanning the amino acid regions 257-269 and 373-398 of CYP2D6 was systematically investigated by immunoblotting. Fourteen (93%) sera from autoimmune hepatitis patients and 39 (78%) from HCV infected patients reacted with rat and/or human microsomal polypeptides of 39 kD, 50 kD, 58 kD, and 66 kD in different associations, the 50 kD band being the most frequently observed. Reactivity to CYP2D6 and its amino acid sequence 257-269 was significantly more common in autoimmune hepatitis than in HCV infected patients (p &lt; 0.001 and p &lt; 0.0003, respectively). LKM-1 reactivity is directed against heterogeneous and not entirely defined autoantigens. The main target in autoimmune sera is CYP2D6 and its 257-269 amino acid region, while sera from patients with HCV infection are more likely to recognise other microsomal targets, the molecular identity of which is currently unknown.
Role of Potassium Ions in the Vascular Response to a Brief Tetanus
Authors: DAVID E. MOHRMAN, HARVEY V. SPARKS
Journal: Circulation Research (1974)

Changes in the plasma potassium ion (K + ) concentration in the venous effluent of isolated dog tibialis cranialis and extensor digitorum longus muscles were measured following 1 second of tetanic exercise (32 impulses/sec) during constant-flow perfusion. After a brief delay, venous plasma K + concentration increased to a peak change of 0.23 ± 0.02 mEq/liter and then returned to the control level within 1.5 minutes after the beginning of stimulation, representing a net K + loss of 1.7 µEq/100 g muscle. These experiments indicate a very short period of actual tissue-blood K + transfer, since the time course of the venous efflux can be explained almost entirely by the distribution of vascular transit times. Our best estimate is that a 1-second tetanus produces an immediate 1.3-2.4-mEq/liter increase in interstitial K + concentration which then returns to its control level with a time constant of 6-8 seconds due to rapid cellular reuptake. These K + concentration changes have sufficient magnitude and the correct time course to play a significant role in the production of the vascular response to a brief tetanus.
A proposed system for the nomenclature of hepatitis C viral genotypes
Authors: Peter Simmonds, Alfredo Alberti, Harvey J. Alter, Ferruccio Bonino, Daniel W. Bradley, Christian Brechot, Johannes T. Brouwer, Shiu-Wan Chan, Kazuaki Chayama, Ding-Shinn Chen, Qui-Lim Choo, Massimo Colombo, Theo H.M. Cuypers, Takayasu Date, Geoff M. Dusheiko, Juan I. Esteban, Oscar Fay, S. J. Hadziyannis, Jang Han, Angelos Hatzakis, Eddie C. Holmes, Hak Hotta, Michael Houghton, Bruce Irvine, Michinori Kohara, Janice A. Kolberg, George Kuo, Johnson Y. N. Lau, Nico P. Lelie, Geert Maertens, Fiona McOmish, Tatsuo Miyamura, Masashi Mizokami, Akio Nomoto, Alfred M. Prince, Henk W. Reesink, Charlie Rice, Michael Roggendorf, Solko W. Schalm, Toshio Shikata, Kunitada Shimotohno, Lieven Stuyver, Christian Trépo, Amy Weiner, Peng L. Yap, Mickey S. Urdea
Journal: Hepatology (1994)
Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials
Authors: J. Franklin, A. Pluetschow, M. Paus, L. Specht, A.-P. Anselmo, A. Aviles, G. Biti, T. Bogatyreva, G. Bonadonna, C. Brillant, E. Cavalieri, V. Diehl, H. Eghbali, C. Fermé, M. Henry-Amar, R. Hoppe, S. Howard, R. Meyer, D. Niedzwiecki, S. Pavlovsky, J. Radford, J. Raemaekers, D. Ryder, P. Schiller, S. Shakhtarina, P. Valagussa, J. Wilimas, J. Yahalom
Journal: Annals of Oncology (2006)
CCR7 Deficiency Exacerbates Injury in Acute Nephritis Due to Aberrant Localization of Regulatory T Cells
Authors: Kathrin Eller, Tobias Weber, Monika Pruenster, Anna M. Wolf, Gert Mayer, Alexander R. Rosenkranz, Antal Rot
Journal: Journal of the American Society of Nephrology (2009)

The homing of dendritic cells and T cells to secondary lymphoid organs requires chemokine receptor 7 (CCR7) expression on these cells. T cells mediate the pathogenesis of experimental accelerated nephrotoxic serum nephritis (NTS), including its suppression by regulatory T cells (Tregs), but the contribution of CCR7 to this disease is unknown. Here, we compared the development of NTS in CCR7-knockout (KO) and wild-type (WT) mice. Compared with WT mice, CCR7KO mice developed more severe disease with significantly more inflammatory cells infiltrating the kidney. These cells included FoxP3(+) Tregs, which were virtually absent from WT kidneys. The adoptive transfer of WT Tregs into CCR7KO mice at the time of immunization protected the recipients from disease; these cells homed to secondary lymphoid organs but not to kidneys. Conversely, adoptive transfer of CCR7KO Tregs into WT mice did not inhibit development of NTS. These data suggest that NTS can develop without CCR7 expression, but Treg-mediated disease suppression, which seems to occur in secondary lymphoid organs, requires CCR7.
Growth of epithelial cells in the thymic medulla is under the control of mature T cells.
Authors: C D Surh, B Ernst, J Sprent
Journal: The Journal of Experimental Medicine (1992)

Epithelial cells in the thymic medulla are conspicuous in normal adult mice, but sparse in the early fetal thymus and the thymus of adult T cell-deficient SCID mice. To examine whether growth of medullary epithelial cells (MEC) depends upon local contact with mature T cells, we used the finding that the SCID thymus is unusually permeable to mature T cells entering from the bloodstream. When SCID mice received multiple injections of mature lymph node T cells from birth, the thymus accumulated large numbers of mature TCR+ T cells of resting phenotype, but contained virtually no immature (CD4+8+) cells. The injected T cells localized in the medullary region of the thymus and led to marked regeneration of MEC. These and other data suggest that the growth of MEC is under the control of mature T cells. Placing MEC under T cell control might be a device for regulating the size and integrity of the medulla, especially during the phase of rapid thymic growth. Maintaining the cellular components of the medulla in proper balance could be critical for ensuring efficient self tolerance induction.
LEUKAEMIC RELAPSE FOLLOWING CAMPATH 1 TREATED BONE MARROW TRANSPLANTATION FOR LEUKAEMIA
Authors: C.M. Pollard, R.L. Powles, J.L. Millar, V. Shepherd, S. Milan, A. Lakhani, A. Zuiable, J. Treleaven, G. Helenglass
Journal: The Lancet (1986)
Alterations in Ca2+ cycling proteins and Gαq signaling after left ventricular assist device support in failing human hearts
Authors: Y Takeishi
Journal: Cardiovascular Research (2000)

Objective: Left ventricular assist device support mechanically unloads the failing ventricle with resultant improvement in cardiac geometry and function in patients with end-stage heart failure. Activation of the Gαq signaling pathway, including protein kinase C, appears to be involved in the progression of heart failure. Similarly down-regulation of Ca2+ cycling proteins may contribute to contractile depression in this clinical syndrome. Thus we examined whether protein kinase C activation and decreased Ca2+ cycling protein levels could be reversed by left ventricular assist device support. Methods: Left ventricular myocardial specimens were obtained from seven patients during placement of left ventricular assist device and heart transplantation. We examined changes in protein levels of Gαq, phospholipase C β1, regulators of G protein signaling (RGS), sarcoplasmic reticulum Ca2+ ATPase, phospholamban and translocation of protein kinase C isoforms (α, β1, and β2). Results: The paired pre- and post- left ventricular assist device samples revealed that RGS2, a selective inhibitor of Gαq, was decreased (P<0.01), while the status of Gαq, phospholipase C β1, RGS3 and RGS4 were unchanged after left ventricular assist device implantation. Translocation of protein kinase C isoforms remained unchanged. Left ventricular assist device support increased sarcoplasmic reticulum Ca2+ ATPase protein level (P<0.01), while phospholamban abundance was unchanged. Conclusions: We conclude that altered protein expression and stoichiometry of the major cardiomyocyte Ca2+ cycling proteins rather than reduced phospholipase C β1 activation may contribute to improved mechanical function produced by left ventricular assist device support in human heart failure.