tbuckley/cabot-search huggingface dataset:
Cholecalciferol Supplementation Alters Calcitriol-Responsive Monocyte Proteins and Decreases Inflammatory Cytokines in ESRD
Authors: Jason R. Stubbs, Arun Idiculla, Joyce Slusser, Rochelle Menard, L. Darryl Quarles
Journal: Journal of the American Society of Nephrology (2009)

In vitro, monocyte 1alpha-hydroxylase converts 25-hydroxyvitamin D [25(OH)D] to 1,25-dihydroxyvitamin D to regulate local innate immune responses, but whether 25(OH)D repletion affects vitamin D-responsive monocyte pathways in vivo is unknown. Here, we identified seven patients who had 25(OH)D insufficiency and were undergoing long-term hemodialysis and assessed changes after cholecalciferol and paricalcitol therapies in both vitamin D-responsive proteins in circulating monocytes and serum levels of inflammatory cytokines. Cholecalciferol therapy increased serum 25(OH)D levels four-fold, monocyte vitamin D receptor expression three-fold, and 24-hydroxylase expression; therapy decreased monocyte 1alpha-hydroxylase levels. The CD16(+) "inflammatory" monocyte subset responded to 25(OH)D repletion the most, demonstrating the greatest increase in vitamin D receptor expression after cholecalciferol. Cholecalciferol therapy reduced circulating levels of inflammatory cytokines, including IL-8, IL-6, and TNF. These data suggest that nutritional vitamin D therapy has a biologic effect on circulating monocytes and associated inflammatory markers in patients with ESRD.
Analysis of the nonfunctional respiratory burst in murine Kupffer cells.
Authors: A Ding, C Nathan
Journal: The Journal of Experimental Medicine (1988)

Murine Kupffer cells (KCs), which constitute one of the largest populations of tissue macrophages, differ from most other cells of the myelomonocytic lineage in lacking the capacity for a respiratory burst. A collagenase perfusion technique followed by adherence to plastic at low temperature yielded pure cultures of KCs uniformly expressing receptors for Fc and C3bi, and containing virtually no morphologically detectable intracytoplasmic debris. Such KCs took up and oxidized glucose via the hexose monophosphate shunt about the same as peritoneal macrophages (PCs). Respiratory burst stimuli failed to enhance the hexose monophosphate shunt in KCs, probably because no H2O2 was produced. Detergent-permeabilized KCs generated no O2- in the presence of 1 mM NADPH, in striking contrast to all PC populations studied. Yet, KCs contained at least one component of the O2(-)-producing oxidase, cytochrome b559, in the same quantities as PCs and neutrophils. Cytochrome b559 was demonstrated by a novel double-reduction spectral technique that eliminated interference from hemoglobin and mitochondrial cytochromes. Consistent with the presence of the oxidase, KCs acquired normal respiratory burst capacity after prolonged incubation in vitro. The defect in triggering the respiratory burst in KCs was selective for the reduction of O2 by NADPH, in that reduction of O2 by endogenous arachidonate was readily demonstrate in response to zymosan. The percent of arachidonate released, the percent oxygenated, and the suppression of prostacyclin and leukotriene C production, as well as the pattern of LFA-1 expression, all resembled the pattern reported with PCs several days after exposure to bacteria. Indeed, exposure of PCs to low numbers of zymosan particles led gradually to complete suppression of respiratory burst capacity and refractoriness to its enhancement by rIFN-gamma, as evident in KCs both before and after their explanation. Thus, the modulation of oxidative metabolism that characterizes KCs probably arises from frequent endocytic encounters. This phenomenon may permit macrophages to act as scavengers without oxidative damage to bystander cells.
Use of proton pump inhibitors after antireflux surgery: a nationwide register-based follow-up study
Authors: Anders Lødrup, Anton Pottegård, Jesper Hallas, Peter Bytzer
Journal: Gut (2014)

<h3>Objective</h3> Antireflux surgery (ARS) has been suggested as an alternative to lifelong use of proton pump inhibitors (PPI) in reflux disease. Data from clinical trials on PPI use after ARS have been conflicting. We investigated PPI use after ARS in the general Danish population using nationwide healthcare registries. <h3>Design</h3> A nationwide retrospective follow-up study of all patients aged ≥18 and undergoing first-time ARS in Denmark during 1996–2010. Two outcome measures were used: redemption of first PPI prescription after ARS (index prescription) and a marker of long-term use, defined by an average PPI use of ≥180 defined daily doses (DDDs) per year. Kaplan–Meier curves and Cox proportional hazards model were used for statistics. <h3>Results</h3> 3465 patients entered the analysis. 12.7% used no PPI in the year before surgery, while 14.2%, 13.4% and 59.7% used 1–89 DDD, 90–179 DDD and ≥180 DDD, respectively. Five-, 10- and 15-year risks of redeeming index PPI prescription were 57.5%, 72.4% and 82.6%, respectively. Similarly, 5-, 10- and 15-year risks of taking up long-term PPI use were 29.4%, 41.1% and 56.6%. Female gender, high age, ARS performed in most recent years, previous use of PPI and use of nonsteroidal anti-inflammatory drugs or antiplatelet therapy significantly increased the risk of PPI use. <h3>Conclusions</h3> Risk of PPI use after ARS was higher than previously reported, and more than 50% of patients became long-term PPI users 10–15 years postsurgery. Patients should be made aware that long-term PPI therapy is often necessary after ARS.
The move toward setting scientific standards for the content of medical review articles
Authors: Edward Huth
Journal: Journal of the Royal Society of Medicine (2009)

In 1987, while Editor of the Annals of Internal Medicine, I wrote and published an editorial with the title ‘Needed: review articles with more scientific rigor’. I was prompted to do this by a paper I had initially rejected but eventually accepted for publication in the Annals with my accompanying editorial commentary. In retrospect, Cynthia Mulrow’s ‘The medical review article: state of the science’ can now be seen as a landmark in medicine’s long road from ‘experience and expertise’ to ‘evidence’ as the justification for particular medical treatments. When and where this road begins will remain a matter for argument: The James Lind Library offers many candidate ‘beginnings’. Despite the growing development during the 18th, 19th and 20th centuries of quantitative data for judgements on treatments, clinicians in these periods continued to rely on ‘expert’ judgements for choices of treatments. The challenge facing doctors who wish to identify evidence relevant to their practice among the plethora of potentially relevant reports was recognized as a problem at least as early as the 18th century. Andrew Duncan’s editorial Introduction to the first issue of Philosophical and Medical Commentaries, published in 1773, has a remarkably familiar ring:
Regulatory T cells influence blood flow recovery in experimental hindlimb ischaemia in an IL-10-dependent manner
Authors: R. Sharir, J. Semo, A. Shaish, N. Landa-Rouben, M. Entin-Meer, G. Keren, J. George
Journal: Cardiovascular Research (2014)

Ischaemic damage is associated with up-regulation of pro-inflammatory cytokines, as well as invasion of leucocytes and lymphocytes to the injured muscle. Regulatory T cells (Tregs) exert suppressive effects on several immune and non-immune cellular elements. We hypothesized that adoptive Treg cell transfer and depletion will influence re-establishment of flow in the hindlimb ischaemia model, and that this effect would be mediated by the cytokine interleukin (IL)-10. To study the functional role of Tregs in hindlimb ischaemia, we either adoptively transferred Tregs or functionally blocked Tregs by antibodies to CD25. Initially, we showed that the number and function of Tregs is altered after the induction of ischaemia. Treg ablation resulted in reduced blood flow by laser Doppler at Day 7 that became more robust at Day 14. Adoptive Treg transfer led to a significant improvement of flow in the ligated limb. Treg-mediated improvement in flow was abolished by employing blocking anti-IL-10 antibodies. These results show that Tregs play an important role in processes that control flow re-establishment after inducible hindlimb ischaemia, and that IL-10 plays a requisite role mediating these effects.
Brawny cutaneous induration and granulomatous panniculitis in large cell non-Hodgkin's (T suppressor/cytotoxic cell) lymphoma
Authors: J. ASWORTH, A.T. COADY, R. GUY, S.M. BREATHNACH
Journal: British Journal of Dermatology (1989)

A 56-year-old lady presented with striking peau d'orange-like, woody, diffuse infiltration of the skin of the upper, inner aspects of both arms and thighs. Initial biopsy specimens showed a granulomatous panniculitis with non-specific lymphohistiocytic infiltration. Clinical deterioration occurred with development of ascites and peripheral oedema; a single axillary node became palpable. Cytology of ascitic fluid, and histology and immunopathology of the axillary node, and of a further skin biopsy, now revealed diagnostic changes of a diffuse large cell lymphocytic lymphoma of T suppressor/cytotoxic type. Granulomatous panniculitis resulting in diffuse cutaneous infiltration may rarely be a presenting sign of malignant lymphoma.
CD8+ Foxp3+ Regulatory T Cells Mediate Immunosuppression in Prostate Cancer
Authors: Yukiko Kiniwa, Yoshihiro Miyahara, Helen Y. Wang, Weiyi Peng, Guangyong Peng, Thomas M. Wheeler, Timothy C. Thompson, Lloyd J. Old, Rong-Fu Wang
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Although elevated proportions of CD4+CD25+ regulatory T (Treg) cells have been shown in several types of cancers, very little is known about the existence and function of CD8+ Treg cells in prostate cancer. In this study, we investigated prostate tumor–derived CD8+ Treg cells and their function. Experimental Design: Tumor-infiltrating lymphocytes (TIL) from fresh tumor specimens of patients with prostate cancer were generated and subjected to phenotypic and suppressive function analyses. In particular, we investigated the role and function CD8+ Treg cells in prostate cancer. Results: We show that high percentages of CD4+CD25+ T cells are probably present in the majority (70%) of prostate TILs. Remarkably, both CD4+ and CD8+ T-cell subpopulations possessed potent suppressive activity. T-cell cloning and fluorescence-activated cell sorting analyses showed the presence of CD8+CD25+ Treg cell clones that expressed FoxP3 and suppressed naïve T-cell proliferation, in addition to the previously known CD4+CD25+ Treg cells. These CD8+ Treg cells suppressed naïve T-cell proliferation mainly through a cell contact–dependent mechanism. Importantly, the suppressive function of CD8+ Treg cells could be reversed by human Toll-like receptor 8 (TLR8) signaling. Conclusion: Our study shows that like CD4+CD25+ Treg cells, CD8+ Foxp3+ Treg cells present in prostate tumor–derived TILs suppress immune responses and that their suppressive function can be regulated by TLR8 ligands, raising the possibility that the manipulation of Treg cell function by TLR8 ligands could improve the efficacy of immunotherapy for prostate cancer patients.
Septicaemia after colonoscopy in patients with cirrhosis.
Authors: J R Thornton, M S Losowsky
Journal: Gut (1991)

Two patients with ulcerative colitis and chronic active hepatitis with cirrhosis, who developed Gram negative septicaemia after colonoscopy are described. These and two similar reported cases indicate that giving prophylactic antibiotics to patients with cirrhosis undergoing colonoscopy should be considered, particularly when the cirrhosis is advanced.
An Intracardiac Manometer: Its Evaluation and Application
Authors: EUGENE J. ELLIS, OTTO H. GAUER, EARL H. WOOD
Journal: Circulation (1951)

The miniature intracardiac manometer supplied a method for recording artefact-free pressure tracings from the heart and great vessels of man and the intact animal. This instrument has been applied to the procedure of cardiac catheterization. It has also been used to demonstrate that if motion artefacts can be minimized, the central pulse can be recorded with reasonable accuracy by means of manometric systems with relatively poor dynamic response. Illustrations of pulse waves within the heart and great vessels of man and dogs and the effects of varying the dynamic response of the recording system are included.
AT receptors and L-type calcium channels: functional coupling in supersensitivity to angiotensin II in diabetic rats
Authors: K ARUN, C KAUL, P RAMARAO
Journal: Cardiovascular Research (2004)

The study was designed to investigate the role of calcium channels in enhanced angiotensin II (Ang II)-induced contraction in thoracic aortic rings from diabetic rats.Ang II-induced isometric tension was studied in thoracic aortic rings isolated from control or streptozotocin-induced (8 weeks) diabetic rats. Saturation binding studies at AT1 receptors and L-type calcium channels were performed using [3H] Ang II and [3H] PN200110, respectively. Ang II-induced calcium influx was studied in fura-2-loaded single vascular smooth muscle cells isolated from thoracic aorta of control and diabetic rats.Ang II did not induce contraction in calcium-free Krebs. In the presence of extracellular calcium, increased Emax (mg/mm2) and pD2 to Ang II was observed in aortic rings from diabetic (795.54+/-38.19; 8.27+/-0.12) compared to control (230.09+/-25.45; 7.68+/-0.22) rats, respectively. Nimodipine but not verapamil or diltiazem dose-dependently blocked the Ang II-induced contractions in a noncompetitive manner and its -log IC50 was significantly lower in aortic rings from diabetic (8.81+/-0.10) compared to control (9.34+/-0.11) rats. The Ang II-induced increase in intracellular calcium levels was significantly enhanced (2.5-fold) in vascular smooth muscle cells from diabetic rats. AT1 receptor saturation binding with [3H] Ang II revealed a significantly higher affinity (nM) and Bmax (pmol/mg protein) in aortic vascular membrane preparation from diabetic (0.31+/-0.04; 64.18+/-2.4) compared to control (0.52+/-0.02; 47.81+/-2.8) rats, respectively, while L-type calcium channel saturation binding with [3H] PN200110 showed a higher affinity (nM) with no change in the Bmax (fmol/mg protein) in diabetic (0.74+/-0.08; 4.52+/-0.40) compared to control (1.49+/-0.32; 5.43+/-0.60) aortic membranes, respectively.Our results suggest that Ang II-induced contraction is dependent on extracellular calcium, and enhanced functional coupling of AT1 receptors and DHP-sensitive L-type calcium channels results in supersensitivity to Ang II in thoracic aorta isolated from diabetic rats.
Phase I Study of Epigenetic Modulation with 5-Azacytidine and Valproic Acid in Patients with Advanced Cancers
Authors: Fadi Braiteh, Andres O. Soriano, Guillermo Garcia-Manero, David Hong, Marcella M. Johnson, Leandro De Padua Silva, Hui Yang, Stefanie Alexander, Johannes Wolff, Razelle Kurzrock
Journal: Clinical Cancer Research (2008)

Abstract Purpose: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers. Experimental Design: 5-AZA was administered s.c. daily for 10 days. Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 μg/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m2 and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1 and 10 of each cycle when patients agreed to provide them. Results: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m2 of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m2 of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed. Conclusion: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m2 for 5-AZA in patients with advanced malignancies.
Accessory left biliary duct draining into the lesser curve of the stomach
Authors: R Mascarenhas
Journal: Gut (2002)

A 32 year old woman presented to a hospital in North America in November 1996 with upper abdominal pain and pyrexia. Liver function tests and ultrasound scan of the abdomen were normal. Gastroscopy demonstrated an abnormal opening on the lesser curve of the stomach which on barium meal investigation appeared as a sinus tract extending superiorly (fig 1A). A computed tomography (CT) scan performed showed minimal aerobilia in the left liver but no other abnormality. At laparoscopy, a well formed tract was identified running from the gastric lesser curve towards the left side of the hilum of the …
Expression, Clinical Significance, and Receptor Identification of the Newest B7 Family Member HHLA2 Protein
Authors: Murali Janakiram, Jordan M. Chinai, Susan Fineberg, Andras Fiser, Cristina Montagna, Ramadevi Medavarapu, Ekaterina Castano, Hyungjun Jeon, Kim C. Ohaegbulam, Ruihua Zhao, Aimin Zhao, Steven C. Almo, Joseph A. Sparano, Xingxing Zang
Journal: Clinical Cancer Research (2014)

Abstract Purpose: HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors. Experimental Design: An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors. Results: HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I–III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2. Conclusions: Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy. Clin Cancer Res; 21(10); 2359–66. ©2014 AACR. See related commentary by Xiao and Freeman, p. 2201
Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma
Authors: D. R. Johnson, D. W. Kimmel, P. A. Burch, T. L. Cascino, C. Giannini, W. Wu, J. C. Buckner
Journal: Neuro-Oncology (2011)

The objective of this phase II study was to evaluate the efficacy and safety of subcutaneous octreotide therapy for the treatment of recurrent meningioma and meningeal hemangiopericytoma. Octreotide is an agonist of somatostatin receptors, which are frequently expressed in meningioma, and reports have suggested that treatment with somatostatin agonists may lead to objective response in meningioma. Patients with recurrent/progressive meningioma or meningeal hemangiopericytoma were eligible for enrollment; those with atypical/anaplastic meningioma or hemangiopericytoma must have experienced disease progression despite radiotherapy or have had a contraindication to radiation. Patients received subcutaneous octreotide with a goal dose of 500 μg 3 times per day, as tolerated. Imaging was performed every 3 months during therapy. The primary outcome measure was radiographic response rate. Eleven patients with meningioma and 1 with meningeal hemangiopericytoma were enrolled during the period 1992–1998. Side effects included diarrhea (grade 1 in 4 patients and grade 2 in 2), nausea or anorexia (grade 1 in 4 patients), and transaminitis (grade 1 in 1 patient). One patient developed extra hepatic cholangiocarcinoma, which was likely unrelated to octreotide therapy. No radiographic responses were observed. Eleven of the 12 patients experienced progression, with a median time to progression of 17 weeks. Two patients experienced long progression-free intervals (30 months and ≥18 years). Eleven patients have died. Median duration of survival was 2.7 years. Immunohistochemical staining of somatostatin receptor Sstr2a expression in a subset of patients did not reveal a correlation between level of expression and length of progression-free survival. Octreotide was well-tolerated but failed to produce objective tumor response, although 2 patients experienced prolonged stability of previously progressive tumors.
Cyclooxygenase-2, Player or Spectator in Cyclooxygenase-2 Inhibitor-Induced Apoptosis in Prostate Cancer Cells
Authors: X. Song
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: The antitumor activity of cyclooxygenase-2 (COX-2) inhibitors is thought to involve COX-2 enzyme inhibition and apoptosis induction, but it is unclear whether COX-2 inhibition is required for apoptosis. Different COX-2 inhibitors have similar IC50 values (concentration for 50% inhibition) for COX-2 inhibition but differ considerably in their abilities to induce apoptosis, suggesting the involvement of a COX-2-independent pathway in apoptosis. To test this hypothesis, we investigated the effect of COX-2 depletion on apoptosis and performed a structure–activity analysis of the COX-2 inhibitor celecoxib in the androgen-independent prostate cancer cell line PC-3. Methods: Tetracycline-inducible (Tet-On) COX-2 antisense clones were isolated to assess the effect of COX-2 expression on cell viability and sensitivity to apoptosis induced by COX-2 inhibitors. Untreated Tet-On clones differentially expressed COX-2, and doxycycline-treated clones were depleted of COX-2. We synthesized and characterized various celecoxib derivatives with various COX-2 inhibitory activities and determined their apoptotic activity in PC-3 cells. Apoptosis was assessed with four tests. Results: In contrast to the effect of COX-2 inhibitors, which induced apoptosis, COX-2 depletion did not induce cell death. Susceptibility to COX-2 inhibitor-induced apoptosis was independent of the level of COX-2 expression. Structure–activity analysis found no correlation between apoptosis induction and COX-2 inhibition. Some celecoxib derivatives that lacked COX-2 inhibitory activity facilitated apoptosis and vice versa. Moreover, celecoxib and apoptosis-active celecoxib derivatives mediated cell death by inhibiting the same pathway. Conclusion: We have dissociated the apoptosis-inducing activity from the COX-2 inhibitory activity by structural modifications of the COX-2 inhibitor celecoxib. This separation of activities may provide a molecular basis for the development of new classes of apoptosis-inducing agents.