tbuckley/cabot-search huggingface dataset:
Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis
Authors: Takanori Shouda, Takafumi Yoshida, Toshikatsu Hanada, Toru Wakioka, Masanobu Oishi, Kanta Miyoshi, Setsuro Komiya, Ken-ichiro Kosai, Yasushi Hanakawa, Koji Hashimoto, Kensei Nagata, Akihiko Yoshimura
Journal: Journal of Clinical Investigation (2001)

Immune and inflammatory systems are controlled by multiple cytokines, including ILs and INFs. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. One such cytokine, IL-6, has been proposed to contribute to the development of rheumatoid arthritis (RA). We found that STAT3 was strongly tyrosine phosphorylated in synovial tissue of RA patients, but not those with osteoarthritis. Blockade of the IL-6-gp130-JAK-STAT3–signaling pathway might therefore be beneficial in the treatment of RA. We show here that the mRNA for the endogenous cytokine signaling repressor CIS3/SOCS3 is abundantly expressed in RA patients. To determine whether CIS3 is effective in treating experimental arthritis, a recombinant adenovirus carrying the CIS3 cDNA was injected periarticularly into the ankle joints of mice with antigen-induced arthritis or collagen-induced arthritis (CIA). Periarticular injection of CIS3 adenovirus drastically reduced the severity of arthritis and joint swelling compared with control groups. CIS3 was more effective than a dominant-negative form of STAT3 in the CIA model. Thus, induction of CIS3 could represent a new approach for effective treatment of RA.
Prostaglandin E2 inhibits mast cell–dependent bronchoconstriction in human small airways through the E prostanoid subtype 2 receptor
Authors: Jesper Säfholm, Martijn L. Manson, Johan Bood, Ingrid Delin, Ann-Charlotte Orre, Per Bergman, Mamdoh Al-Ameri, Sven-Erik Dahlén, Mikael Adner
Journal: Journal of Allergy and Clinical Immunology (2015)
Communicating accuracy of tests to general practitioners: a controlled study
Authors: J. Steurer
Journal: BMJ (2002)

To assess the extent to which different forms of summarising diagnostic test information influence general practitioners' ability to estimate disease probabilities.Controlled questionnaire study.Three Swiss conferences in continuous medical education.263 general practitioners.Questionnaire with multiple choice questions about terms of test accuracy and a clinical vignette with the results of a diagnostic test described in three different ways (test result only, test result plus test sensitivity and specificity, test result plus the positive likelihood ratio presented in plain language).Doctors' knowledge and application of terms of test accuracy and estimation of disease probability in the clinical vignette.The correct definitions for sensitivity and predictive value were chosen by 76% and 61% of the doctors respectively, but only 22% chose the correct answer for the post-test probability of a positive screening test. In the clinical vignette doctors given the test result only overestimated its diagnostic value (median attributed likelihood ratio (aLR)=9.0, against 2.54 reported in the literature). Providing the scan's sensitivity and specificity reduced the overestimation (median aLR=6.0) but to a lesser extent than simple wording of the likelihood ratio (median aLR=3.0).Most general practitioners recognised the correct definitions for sensitivity and positive predictive value but did not apply them correctly. Conveying test accuracy information in simple, non-technical language improved their ability to estimate disease probabilities accurately.
Modulation of esophageal peristalsis by vagal efferent stimulation in opossum.
Authors: J S Gidda, B W Cobb, R K Goyal
Journal: Journal of Clinical Investigation (1981)

Experiments were performed on anesthetized opossums to study the influence of vagal efferent stimulation on peristalsis in the esophageal smooth muscle using various stimulus parameters. Current intensity, pulse duration, frequency, and train duration were varied systematically. Electrical and mechanical activities were recorded simultaneously at 5, 3, and 1 cm above the lower esophageal sphincter (LES). Vagal efferent stimulation produced a spike burst and contraction with a latency after the termination of the stimulus. This latency varied at different sites with the same stimulus parameters. For example, a stimulus of 5 mA, 0.5 ms, 10 Hz, and 1-s train produced latencies for the electrical response of 1.48 +/- 0.04, 2.2 +/- 0.12, and 3.5 +/- 0.09 s (+/- SEM) at 5, 3, and 1 cm above LES, respectively. The differences in latency were statistically significant (P less than 0.01). The latency of response at any one site also changed with different stimulus parameters; e.g. at 1 cm above LES, the latency of electrical response at 10 Hz was 3.5 +/- 0.09 s, but at 20 Hz the latency was 2.01 +/- 0.06 s when current intensity, pulse, and train duration remained at 5 mA, 0.5 ms, and 1 s. This decrease in latency with increasing frequency was statistically significant (P less than 0.01). By changing stimulus parameters, antiperistalsis or peristalsis with different speeds of propagation could be induced. Antiperistalsis or simultaneous responses occurred near threshold stimulus parameters. Suprathreshold stimuli produced peristaltic responses. Speed of peristalsis in the distal esophagus was 1.82 +/- 0.08 cm/s with swallowing, which was not different from 1.98 +/- 0.14 cm/s (P greater than 0.05) with vagal stimulation of 5 mA, 0.5 ms, 10 Hz, and 1-s train. These studies suggest that: (a) peristalsis in the smooth muscle part of the esophagus can be explained entirely on the basis of peripheral mechanisms, and (b) the central nervous system may modulate the occurrence, polarity, and speed of propagation by modifying the intensity and frequency of vagal activation.
Cementless Isoelastic RM Total HIP Prosthesis
Authors: Renato Bombelli, Robert Mathys
Journal: Journal of the Royal Society of Medicine (1982)

Some surgeons are beginning to doubt the reliability of bone cement in joint replacements. In 1967 Robert Mathys conceived the idea of an isoelastic prosthesis made of plastic, which would anchor into the bone without cement. He developed the idea by extensive tests in animals and, in 1973, the first human RM cementless hip prosthesis was inserted by E Morscher. In this paper the concept of the cementless isoelastic prosthesis is developed by Robery Mathys, and Professor Bombelli records his experience with the prosthesis between 1977 and 1981.
Generation of a Focused Poly(amino ether) Library: Polymer-mediated Transgene Delivery and Gold-Nanorod based Theranostic Systems
Authors: Lucas Vu, James Ramos, Thrimoorthy Potta, Kaushal Rege
Journal: Theranostics (2012)

A focused library of twenty-one cationic poly(amino ethers) was synthesized following ring-opening polymerization of two diglycidyl ethers by different oligoamines.The polymers were screened in parallel for plasmid DNA (pDNA) delivery, and transgene expression efficacies of individual polymers were compared to those of 25 kDa polyethylenimine (PEI), a current standard for polymer-mediated transgene delivery.Seven lead polymers that demonstrated higher transgene expression than PEI in pancreatic and prostate cancer cells lines were identified from the screen.All seven lead polymers showed highest transgene expression at a polymer:pDNA weight ratio of 5:1 in the MIA PaCa-2 pancreatic cancer cell line.Among the conditions studied, transgene expression efficacy correlated with minimal polymer cytotoxicity but not polyplex sizes.In addition, this study indicated that methylene spacing between amine centers in the monomers, amine content, and molecular weight of the polymers are all significant factors and should be considered when designing polymers for transgene delivery.A lead effective polymer was employed for coating gold nanorods, leading to theranostic nanoassemblies that possess combined transgene delivery and optical imaging capabilities, leading to potential theranostic systems.
Physiotherapy for airway clearance in adults
Authors: JA Pryor
Journal: European Respiratory Journal (1999)

Techniques for augmenting, when necessary, the normal mucociliary and cough clearance mechanisms of the lungs are not new, but, in more recent years, techniques have been developed which are effective, comfortable and can be used independent of an assistant in the majority of adolescents and adults. Postural drainage with chest clapping and chest shaking has, in most parts of the world, been replaced by the more effective techniques of the active cycle of breathing, autogenic drainage, R-C Cornet, Flutter, positive expiratory pressure mask, high-frequency chest wall oscillation and intrapulmonary percussive ventilation. Glossopharyngeal breathing is being considered again and is often a useful technique for increasing the effectiveness of cough in patients with tetraplegia or neuromuscular disorders. The evidence in support of these techniques is variable, and the literature is confusing and conflicting. There may or may not be significant differences among the techniques in the short or long term. Many of the regimens now include the forced expiratory manoeuvre of a "huff" and this has probably increased the effectiveness of airway clearance. If objective differences are small, individual preferences and cultural influences may be significant in increasing adherence to treatment and in the selection of an appropriate regimen or regimens for an individual patient.
The Farnesyltransferase Inhibitor L744832 Potentiates UCN-01–Induced Apoptosis in Human Multiple Myeloma Cells
Authors: Xin-Yan Pei, Yun Dai, Mohamed Rahmani, Weiqun Li, Paul Dent, Steven Grant
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The purpose of this study was to characterize interactions between the farnesyltransferase inhibitor L744832 and the checkpoint abrogator UCN-01 in drug-sensitive and drug-resistant human myeloma cell lines and primary CD138+ multiple myeloma cells. Experimental Design: Wild-type and drug-resistant myeloma cell lines were exposed to UCN-01 ± L744832 for 24 hours, after which mitochondrial injury, caspase activation, apoptosis, and various perturbations in signaling and survival pathways were monitored. Results: Simultaneous exposure of myeloma cells to marginally toxic concentrations of L744832 and UCN-01 resulted in a synergistic induction of mitochondrial damage, caspase activation, and apoptosis, associated with activation of p34cdc2 and c-Jun-NH2-kinase and inactivation of extracellular signal-regulated kinase, Akt, GSK-3, p70S6K, and signal transducers and activators of transcription 3 (STAT3). Enhanced lethality for the combination was also observed in primary CD138+ myeloma cells, but not in their CD138− counterparts. L744832/UCN-01–mediated lethality was not attenuated by conventional resistance mechanisms to cytotoxic drugs (e.g., melphalan or dexamethasone), addition of exogenous interleukin-6 or insulin-like growth factor-I, or the presence of stromal cells. In contrast, enforced activation of STAT3 significantly protected myeloma cells from L744832/UCN-01–induced apoptosis. Conclusions: Coadministration of the farnesyltransferase inhibitor L744832 promotes UCN-01–induced apoptosis in human multiple myeloma cells through a process that may involve perturbations in various survival signaling pathways, including extracellular signal-regulated kinase, Akt, and STAT3, and through a process capable of circumventing conventional modes of myeloma cell resistance, including growth factor– and stromal cell–related mechanisms. They also raise the possibility that combined treatment with farnesyltransferase inhibitors and UCN-01 could represent a novel therapeutic strategy in multiple myeloma.
2003 Nobel Prize in Chemistry
Authors: William G. Couser
Journal: Journal of the American Society of Nephrology (2004)

This month’s Special Commentary articles summarize the careers and research contributions of the two individuals who shared the 2003 Nobel Prize in Chemistry. Dr. Peter Agre, Professor of Biochemistry at Johns Hopkins University (and an ASN member), and Dr. Roderick MacKinnon, Professor and Howard Hughes Investigator at the Rockefeller University, shared the prize for their work on aquaporins and ion channels, respectively. The Nobel Prize is generally recognized as the highest award one can receive in recognition of excellence in a field. Nobel Prizes in medicine or related areas have been awarded to a number of individuals peripherally related to nephrology in the past. Medawar and Burnet in 1960 for their work on immune tolerance; Jerne, Kohler, and Milstein in 1984 for monoclonal antibodies; and Joseph Murray, a surgeon, in 1990 for renal transplantation are examples. But the 2003 Nobels in Chemistry honor work with a direct nephrologic basis. The accomplishments of Agre and MacKinnon provide a vivid illustration of the vitality of our discipline, rooted in the fundamentals of salt and water metabolism since the days of Homer Smith over a half century ago, and they illustrate the remarkable march of that discipline from the traditional tools of whole-organ physiology to modern molecular biology with implications far beyond the kidney. Just as JASN celebrated the receipt of the 2002 Lasker Award by Drs. Kolff and Scribner (JASN 13: 3027–3030, 2003), we celebrate here the receipt of the Nobel Prize by two individuals who are, by interest and contributions, part of the renal community. I want to express sincere appreciation to Drs. Mark Knepper and Soren Nielsen and to Drs. Steve Hebert and Gerhard Giebisch for presenting such lucid summaries of the lives and work of Dr. Peter Agre and Dr. Roderick MacKinnon.
Pain, opioid use, and survival in hospitalized patients with advanced cancer.
Authors: F J Brescia, R K Portenoy, M Ryan, L Krasnoff, G Gray
Journal: Journal of Clinical Oncology (1992)

PURPOSE Pain is a common and feared symptom for patients with incurable cancer. Comprehensive assessment provides the foundation for effective pain management, and data that clarify the relationship between pain and other relevant factors also facilitate this process. The main objective of the study was to develop a clinical data base for advanced cancer patients and to survey data to determine (1) pain severity at admission, (2) opioid use at admission, (3) change in opioid use during the hospital stay, and (4) survival in the hospital. PATIENTS AND METHODS Information was collected prospectively on 1,103 patients admitted and on 1,017 patients who died within 6 months of the study's end. Demographic and clinical data were recorded 72 hours after admission and soon after death or discharge. RESULTS Seventy-three percent of patients had pain at admission. Cancer of the cervix was frequently (68%) associated with severe pain, as were prostate (52%) and rectal/sigmoid tumors (49%). Severe pain was more probable in those with bone metastasis, those admitted from home, and in those younger than 55 years of age. The majority (71.7%) of patients had a stable dosing pattern, and only 4.2% of the patients required dose increases of at least 10% per day. CONCLUSION This study demonstrated the wide variability in opioid doses required. No reliable predictor of opioid requirement was identified, and this lack of predictability of cancer pain severity underscores the need for ongoing assessment.
Hepcidin Regulation in Prostate and Its Disruption in Prostate Cancer
Authors: Lia Tesfay, Kathryn A. Clausen, Jin Woo Kim, Poornima Hegde, Xiaohong Wang, Lance D. Miller, Zhiyong Deng, Nicole Blanchette, Tara Arvedson, Cindy K. Miranti, Jodie L. Babitt, Herbert Y. Lin, Donna M. Peehl, Frank M. Torti, Suzy V. Torti
Journal: Cancer Research (2015)

Abstract Hepcidin is a circulating peptide hormone made by the liver that is a central regulator of systemic iron uptake and recycling. Here, we report that prostate epithelial cells also synthesize hepcidin, and that synthesis and secretion of hepcidin are markedly increased in prostate cancer cells and tissue. Prostatic hepcidin functions as an autocrine hormone, decreasing cell surface ferroportin, an iron exporter, increasing intracellular iron retention, and promoting prostate cancer cell survival. Synthesis of hepcidin in prostate cancer is controlled by a unique intersection of pathways that involves BMP4/7, IL6, Wnt, and the dual BMP and Wnt antagonist, SOSTDC1. Epigenetic silencing of SOSTDC1 through methylation is increased in prostate cancer and is associated with accelerated disease progression in patients with prostate cancer. These results establish a new connection between iron metabolism and prostate cancer, and suggest that prostatic dysregulation of hepcidin contributes to prostate cancer growth and progression. Cancer Res; 75(11); 2254–63. ©2015 AACR.
Selected Methods for Imaging Elastic Properties of Biological Tissues
Authors: James F. Greenleaf, Mostafa Fatemi, Michael Insana
Journal: Annual Review of Biomedical Engineering (2003)

▪ Abstract For millennia, physicians have used palpation as a part of the physical examination to detect pathology. The ubiquitous presence of “stiffer” tissue associated with pathology often represents an early warning sign for disease, as in the cases of breast or prostate cancer. Very often tumors are found at surgery that were occult even with modern imaging instruments. This implies that methods for estimating “hardness” of tissues would add a weapon to the medical armamentarium. To this end, this review discusses several methods of estimating tissue hardness using internal or external means of applying stress (force per unit area) and several associated methods of detecting the resulting strain (fractional length change) in an effort to image a tissue mechanical property, such as Young's modulus (ratio of stress to strain). Some investigators have developed methods of estimating stiffness or modulus, but most methods result in qualitative images of stiffness. Nevertheless, such estimates may add a great deal of information not currently available to the current field of medical imaging.
Proliferation of Transformed Somatotroph Cells Related to Low or Absent Expression of Protein Kinase A Regulatory Subunit 1A Protein
Authors: Andrea G. Lania, Giovanna Mantovani, Stefano Ferrero, Caterina Pellegrini, Sara Bondioni, Erika Peverelli, Paola Braidotti, Marco Locatelli, Mario L. Zavanone, Emanuela Ferrante, Silvano Bosari, Paolo Beck-Peccoz, Anna Spada
Journal: Cancer Research (2004)

Abstract The two regulatory subunits (R1 and R2) of protein kinase A (PKA) are differentially expressed in cancer cell lines and exert diverse roles in growth control. Recently, mutations of the PKA regulatory subunit 1A gene (PRKAR1A) have been identified in patients with Carney complex. The aim of this study was to evaluate the expression of the PKA regulatory subunits R1A, R2A, and R2B in a series of 30 pituitary adenomas and the effects of subunit activation on cell proliferation. In these tumors, neither mutation of PRKAR1A nor loss of heterozygosity was identified. By real-time PCR, mRNA of the three subunits was detected in all of the tumors, R1A being the most represented in the majority of samples. By contrast, immunohistochemistry documented low or absent R1A levels in all tumors, whereas R2A and R2B were highly expressed, thus resulting in an unbalanced R1/R2 ratio. The low levels of R1A were, at least in part, due to proteasome-mediated degradation. The effect of the R1/R2 ratio on proliferation was assessed in GH3 cells, which showed a similar unbalanced pattern of R subunits expression, and in growth hormone-secreting adenomas. The R2-selective cAMP analog 8-Cl cAMP and R1A RNA silencing, stimulated cell proliferation and increased Cyclin D1 expression, respectively, in human and rat adenomatous somatotrophs. These data show that a low R1/R2 ratio promoted proliferation of transformed somatotrophs and are consistent with the Carney complex model in which R1A inactivating mutations further unbalance this ratio in favor of R2 subunits. These results suggest that low expression of R1A protein may favor cAMP-dependent proliferation of transformed somatotrophs.
Pancreatic Proteolytic Enzyme Therapy Compared With Gemcitabine-Based Chemotherapy for the Treatment of Pancreatic Cancer
Authors: John A. Chabot, Wei-Yann Tsai, Robert L. Fine, Chunxia Chen, Carolyn K. Kumah, Karen A. Antman, Victor R. Grann
Journal: Journal of Clinical Oncology (2010)

Purpose Conventional medicine has had little to offer patients with inoperable pancreatic adenocarcinoma; thus, many patients seek alternative treatments. The National Cancer Institute, in 1998, sponsored a randomized, phase III, controlled trial of proteolytic enzyme therapy versus chemotherapy. Because most eligible patients refused random assignment, the trial was changed in 2001 to a controlled, observational study. Methods All patients were seen by one of the investigators at Columbia University, and patients who received enzyme therapy were seen by the participating alternative practitioner. Of 55 patients who had inoperable pancreatic cancer, 23 elected gemcitabine-based chemotherapy, and 32 elected enzyme treatment, which included pancreatic enzymes, nutritional supplements, detoxification, and an organic diet. Primary and secondary outcomes were overall survival and quality of life, respectively. Results At enrollment, the treatment groups had no statistically significant differences in patient characteristics, pathology, quality of life, or clinically meaningful laboratory values. Kaplan-Meier analysis found a 9.7-month difference in median survival between the chemotherapy group (median survival, 14 months) and enzyme treatment groups (median survival, 4.3 months) and found an adjusted-mortality hazard ratio of the enzyme group compared with the chemotherapy group of 6.96 (P &lt; .001). At 1 year, 56% of chemotherapy-group patients were alive, and 16% of enzyme-therapy patients were alive. The quality of life ratings were better in the chemotherapy group than in the enzyme-treated group (P &lt; .01). Conclusion Among patients who have pancreatic cancer, those who chose gemcitabine-based chemotherapy survived more than three times as long (14.0 v 4.3 months) and had better quality of life than those who chose proteolytic enzyme treatment.
The sports concussion note: should SCAT become SCOAT?: Table 1
Authors: Jon Patricios, Robert Collins, Andrew Branfield, Craig Roberts, Ryan Kohler
Journal: British Journal of Sports Medicine (2011)

Sports concussion research and clinical guidelines have evolved rapidly. The most recent concussion consensus statement and guidelines (Zurich, 2008) provided clinicians with the Sports Concussion Assessment Tool version 2 (SCAT2) as a clinical template for the assessment of acute concussion. For the subsequent serial examinations required for the complete assessment of the concussed athlete, SCAT2 may be inadequate. This paper describes the experience and suggestions of South African sports physicians in evolving a more comprehensive clinical evaluation tool and record of patient care, the Sports Concussion Office Assessment Tool.