tbuckley/cabot-search huggingface dataset:
Heterotypy in the N-Terminal Region of Growth/Differentiation Factor 5 (GDF5) Mature Protein during Teleost Evolution
Authors: Koji Fujimura, Yohey Terai, Naoya Ishiguro, Masaki Miya, Mutsumi Nishida, Norihiro Okada
Journal: Molecular Biology and Evolution (2008)

Heterotypy is now recognized as a generative force in the formation of new proteins through modification of existing proteins. We report that heterotypy in the N-terminal region of the mature growth/differentiation factor 5 (GDF5) protein occurred during evolution of teleosts. N-terminal length variation of GDF5 was found among teleost interfamilies and interorders but not within teleost families or among tetrapods. We further show that increase of proline and glutamine to the N-terminal region of mature GDF5 occurred in Eurypterygii, the higher lineage of teleosts. Because the basic amino acids, believed to control diffusion, are conserved in this region across all species examined, we suggest that the N-terminal elongation of the mature GDF5 protein during evolution has altered the protein diffusion in Eurypterygii, leading to high concentrations of the protein in the joint of the pharyngeal skeleton, the location of cartilage formation during development.
New Strategies in Diagnosing Cancer in Thyroid Nodules: Impact of Molecular Markers
Authors: Yuri E. Nikiforov, Linwah Yip, Marina N. Nikiforova
Journal: Clinical Cancer Research (2013)

Thyroid cancer is the most common type of endocrine malignancy, with approximately 55,000 new cases diagnosed in the United States in 2012. However, thyroid nodules are much more prevalent, particularly with increased age, and only a small fraction of those are malignant. Therefore, the major clinical challenge is to reliably differentiate those nodules that are malignant and need to be treated surgically from the majority of nodules that are benign and do not require surgery. The traditional diagnostic approach to this clinical situation is ultrasound-guided fine-needle aspiration (FNA) of the thyroid nodule followed by cytologic examination, which together reliably establish the diagnosis in 70% to 80% of cases. However, in the rest of nodules the presence of cancer cannot be ruled out by FNA cytology, hampering appropriate surgical management and frequently resulting in unnecessary surgical interventions. New approaches to diagnosis of cancer in thyroid nodules are based on mutational and other molecular markers, which can be reliably detected in cells aspirated during the FNA procedure. These markers offer significant improvement in the diagnostic accuracy of FNA cytology and are poised to make a profound effect on the management of patients with thyroid nodules. In addition to the molecular markers that have recently become available for clinical use, rapid development of new sequencing techniques is expected to further improve the accuracy of cancer diagnosis in thyroid nodules and allow for a fully individualized approach to the management of patients with thyroid nodules.
Therapy of Hematogenous Melanoma Brain Metastases with Endostatin
Authors: Matthias Kirsch, Patrick Weigel, Thomas Pinzer, Rona S. Carroll, Peter McL. Black, Hans-Konrad Schackert, Gabriele Schackert
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Cerebral metastases represent the most common type of brain tumors. This study investigated the effects of endogenous endostatin on hematogenous cerebral melanoma metastases. Experimental Design: Murine K1735 melanoma cells were transfected with the mouse endostatin cDNA. Experimental tumors were induced either by s.c. injection, intracerebral implantation, or via injection into the internal carotid artery to simulate hematogenous metastatic spread. The effects of endostatin expression on tumor incidence, growth pattern, and vascularity were analyzed. Results: In vitro secretion of endostatin by 2.5 × 105 cells within 24 hours was 0.12 ± 0.03 ng, 4.35 ± 0.4, and 1.18 ± 0.7 ng/mL for wild type and two endostatin-transfected K1735 clones termed K1735-endo/2 and K1735-endo/8, respectively. Tumor inhibition in vivo correlated with endogenous endostatin production. Within 25 days, growth of s.c. K1735-endo/2 tumors was &amp;lt;20% compared with wild-type controls. Following intracerebral implantation the average survival time of mice was 27.8 ± 2.6 versus 13.3 ± 3.7 days in the K1735-endo/2 versus the wild-type group, respectively. Intracarotid injection of 1 × 105 wild-type cells killed the mice within 24 ± 1.8 days. In contrast, endostatin expression prevented macroscopic metastatic tumor growth in 11 of 12 mice, although viable microscopic tumor pockets were detectable in all animals. Conclusion: Endostatin inhibits tumor progression of multiple cerebral metastases in vivo. Hematogenous micrometastases are more efficiently suppressed than tumors resulting from high focal cell numbers which may be due to a higher angiogenic signaling exerted by massive cell deposits. Endostatin may prevent solid tumor growth more effectively by inhibition of early angiogenesis.
Multicenter Randomized Phase III Trial Comparing Protracted Venous Infusion (PVI) Fluorouracil (5-FU) With PVI 5-FU Plus Mitomycin in Inoperable Pancreatic Cancer
Authors: Nick Maisey, Ian Chau, David Cunningham, Andrew Norman, Matt Seymour, Tamas Hickish, Tim Iveson, Mary O’Brien, Niall Tebbutt, Angela Harrington, Mark Hill
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To compare protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin (MMC) in patients with advanced pancreatic cancer in a multicenter, prospectively randomized study. PATIENTS AND METHODS: Two hundred eight patients were randomized to PVI 5-FU (300 mg/m 2 /d for a maximum of 24 weeks) or PVI 5-FU plus MMC (7 mg/m 2 every 6 weeks for four courses). The major end points were tumor response, survival, toxicity, and quality of life (QOL). RESULTS: The two treatment groups were balanced for baseline demographic factors, and 62% had metastatic disease. The overall response rate was 8.4% (95% confidence interval [CI]) 3.2% to 13.7% for patients treated with PVI 5-FU alone compared with 17.6%; 95% CI 10.3% to 25.1% for PVI 5-FU plus MMC (P = .04). Median failure-free survival was 2.8 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P = .14). Median survival was 5.1 months for PVI 5-FU and 6.5 months for PVI 5-FU plus MMC (P = .34). Toxicities in both arms were mild. There was an increased incidence of neutropenia in the 5-FU plus MMC arm (P &lt; .01), although no differences in infection were seen. No patients developed hemolytic uremic syndrome. Global QOL improved significantly after 24 weeks of treatment compared with baseline for patients receiving 5-FU plus MMC, although there was no statistically significant difference in QOL between arms. CONCLUSION: PVI 5-FU plus MMC resulted in a superior response rate in comparison with PVI 5-FU alone in advanced pancreatic cancer, but this did not translate into a survival advantage. These results emphasize the importance of chemotherapy in this setting and the continuing value of the fluoropyrimidines in pancreatic cancer.
The decline of psychoanalysis. The end of an era, or here we go again
Authors: J. H. Conn
Journal: JAMA (1974)

THE Freudian revolution had achieved all of its goals by 1939, the year that Freud died. An editorial in<i>JAMA</i>of that year, summed up Freud's major contributions and acknowledged that "Psychoanalysis has become firmly established in psychology, education and medicine."<sup>1</sup>As Appel wrote, "It had become a collection of clinical observations, a series of hypotheses, the name of a variety of schools of psychoanalysis, as well as, a cultural phenomenon and a philosophy of life."<sup>2</sup> Here at last was a psychology with clout. It was dynamic, promised to get to the bottom of things, and showed the dark side of the mind. It boasted of many freshly coined concepts, the Castration Complex, Oedipus Conflict, and the Libido. It described a Censor, the Superego, Id, and an amoral, alogical Unconscious, which could overpower one while awake or asleep. What came down to the man-in-the street was that, "All
Primary Central Nervous System Lymphoma: Results of a Pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy
Authors: Hendrik Pels, Ingo G.H. Schmidt-Wolf, Axel Glasmacher, Holger Schulz, Andreas Engert, Volker Diehl, Anton Zellner, Gabriele Schackert, Heinz Reichmann, Frank Kroschinsky, Marlies Vogt-Schaden, Gerlinde Egerer, Udo Bode, Carlo Schaller, Martina Deckert, Rolf Fimmers, Christoph Helmstaedter, Aslihan Atasoy, Thomas Klockgether, Uwe Schlegel
Journal: Journal of Clinical Oncology (2003)

To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy.From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)-based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C.Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%).Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.
Long-Term Lithium Therapy for Bipolar Disorder: Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: John R. Geddes, Sally Burgess, Keith Hawton, Kay Jamison, Guy M. Goodwin
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The authors sought to determine the efficacy and acceptability of lithium for relapse prevention in bipolar disorder. METHOD: A systematic review and meta-analysis of randomized controlled trials comparing lithium with placebo in the long-term treatment of bipolar disorders was conducted. Data were obtained from searching the registers of the Cochrane Collaboration; reviewing reference lists, journals, and conference abstracts; and contacting authors, experts, and pharmaceutical companies. Outcomes investigated included risk of relapse (manic, depressive, and total) as well as risk of specific adverse effects and total withdrawal rates. RESULTS: Five randomized controlled trials (770 participants) were included. Lithium was more effective than placebo in preventing all relapses (random effects relative risk=0.65, 95% CI=0.50 to 0.84) and manic relapses (relative risk=0.62, 95% CI=0.40 to 0.95). The protective effect of lithium on depressive relapses was smaller and was less robust (relative risk=0.72, 95% CI=0.49 to 1.07). CONCLUSIONS: Lithium treatment reduces the risk of relapse in bipolar disorder. The preventive effect is clear for manic episodes, although it is equivocal for depressive episodes.
Chlorine inhalation produces nasal congestion in allergic rhinitics without mast cell degranulation
Authors: D. Shusterman, J. Balmes, P.C. Avila, M.A. Murphy, E. Matovinovic
Journal: European Respiratory Journal (2003)

Seasonal allergic rhinitic (SAR) subjects are more sensitive to nasal irritants than nonrhinitic (NR) subjects; however, the mechanism underlying this difference is unclear. This study sought to determine whether irritant-induced nasal congestion involves mast cell degranulation. Eight SAR and eight NR subjects were exposed to both 1.0 parts per million chlorine and filtered air in separate visits; exposures were via nasal mask and lasted 15 min. Rhinomanometry was performed before, immediately after and 15 min after exposure. Following ≥2 weeks, exposures and symptom reporting were repeated with nasal lavage, rather than rhinomanometry, pre- and postexposure. A separate substudy using rye grass antigen provided a positive control. Mast cell tryptase was measured in nasal lavage fluid from both substudies using an automated fluoroenzyme immunoassay. Chlorine provocation significantly increased nasal airway resistance in SAR but not NR subjects. Conversely, tryptase levels in nasal lavage fluid were unaffected. Nasal allergen challenge significantly increased both nasal obstruction and nasal lavage tryptase in SAR subjects. Irritant-induced nasal congestion is more pronounced among seasonal allergic rhinitic than nonrhinitic subjects. However, unlike nasal allergen challenge, the mechanism of response to chlorine does not appear to involve mast cell degranulation.
Interstitial Vascular Rarefaction and Reduced VEGF-A Expression in Human Diabetic Nephropathy
Authors: Maja T. Lindenmeyer, Matthias Kretzler, Anissa Boucherot, Silvia Berra, Yoshinari Yasuda, Anna Henger, Felix Eichinger, Stefanie Gaiser, Holger Schmid, Maria P. Rastaldi, Robert W. Schrier, Detlef Schlöndorff, Clemens D. Cohen
Journal: Journal of the American Society of Nephrology (2007)

Diabetic nephropathy (DN) is a frequent complication in patients with diabetes. Although the majority of DN models and human studies have focused on glomeruli, tubulointerstitial damage is a major feature of DN and an important predictor of renal dysfunction. This study sought to investigate molecular markers of pathogenic pathways in the renal interstitium of patients with DN. Microdissected tubulointerstitial compartments from biopsies with established DN and control kidneys were subjected to expression profiling. Analysis of candidate genes, potentially involved in DN on the basis of common hypotheses, identified 49 genes with significantly altered expression levels in established DN in comparison with controls. In contrast to some rodent models, the growth factors vascular endothelial growth factor A (VEGF-A) and epidermal growth factor (EGF) showed a decrease in mRNA expression in DN. This was validated on an independent cohort of patients with DN by real-time reverse transcriptase-PCR. Immunohistochemical staining for VEGF-A and EGF also showed a reduced expression in DN. The decrease of renal VEGF-A expression was associated with a reduction in peritubular capillary densities shown by platelet-endothelial cell adhesion molecule-1/CD31 staining. Furthermore, a significant inverse correlation between VEGF-A and proteinuria, as well as EGF and proteinuria, and a positive correlation between VEGF-A and hypoxia-inducible factor-1alpha mRNA was found. Thus, in human DN, a decrease of VEGF-A, rather than the reported increase as described in some rodent models, may contribute to the progressive disease. These findings and the questions about rodent models in DN raise a note of caution regarding the proposal to inhibit VEGF-A to prevent progression of DN.
Hemostatic properties and the role of cell receptor recognition in human hair keratin protein hydrogels
Authors: Luke R. Burnett, Maria B. Rahmany, Jillian R. Richter, Tamer A. Aboushwareb, Daniel Eberli, Catherine L. Ward, Giuseppe Orlando, Roy R. Hantgan, Mark E. Van Dyke
Journal: Biomaterials (2013)
Decoy Receptor 3 Ameliorates an Autoimmune Crescentic Glomerulonephritis Model in Mice
Authors: Shuk-Man Ka, Huey-Kang Sytwu, Deh-Ming Chang, Shie-Liang Hsieh, Pei-Yi Tsai, Ann Chen
Journal: Journal of the American Society of Nephrology (2007)

Autoimmune crescentic glomerulonephritis (ACGN) is a variant of crescentic glomerulonephritis. The outcome of treatment of crescentic glomerulonephritis is poor. Binding of decoy receptor 3 (DCR3) to its ligand is capable of downregulating the alloresponsiveness of T cells. DCR3 has also been shown to benefit an experimental autoimmune model of diabetes. This study tested the hypothesis that a potential immune regulator, DCR3, could prevent the evolution of ACGN. With the use of an established ACGN model in mice, mice were treated with 100 microg/10 g body wt human DCR3 by hydrodynamics-based gene delivery at 14-d intervals. The results showed that the gene therapy resulted in (1) suppression of T and B cell activation and T cell proliferation; (2) a reduction in serum levels of proinflammatory cytokines; (3) improvement of proteinuria and renal dysfunction; (4) prevention of glomerular crescent formation, renal interstitial inflammation, and glomerulosclerosis; (5) a reduction in serum levels of autoantibodies and glomerular immune deposits; (6) inhibition of apoptosis in the spleen and kidney; (7) prevention of T cell and macrophage infiltration of the kidney; and (8) suppression of fibrosis-related gene expression in the kidney compared with empty vector-treated (disease control) ACGN mice. On the basis of these findings, it is proposed that human DCR3 exerts its preventive and protective effects on ACGN through modulation of T cell activation/proliferation, B cell activation, protection against apoptosis, and suppression of mononuclear leukocyte infiltration in the kidney.
Glomerular endothelial cells synthesize collagens but little gelatinase A and B.
Authors: O Lenz, L J Striker, T A Jacot, S J Elliot, P D Killen, G E Striker
Journal: Journal of the American Society of Nephrology (1998)

Mesangial sclerosis is a major feature of progressive renal disease. The mesangium contains mesangial cells and is bounded by the peripheral glomerular basement membrane and endothelial cells. Mesangial cells synthesize and degrade extracellular matrix. Whereas both mesangial and endothelial cells synthesize extracellular matrix components, the degradative pathway, well studied in the former, has not been investigated in endothelial cells. This study examines lines of all three glomerular cell types derived from female B6SJLF1/J mice, as well as mRNA levels for collagens alpha1(I), alpha1(IV), alpha3 (IV), alpha5 (IV), and alpha1 (VI), laminin, tenascin, matrix metalloproteinase-2 (MMP-2), and MMP-9. Type I and IV collagen synthesis was confirmed by enzyme-linked immunosorbent assay. MMP-2 and MMP-9 enzyme activity was measured by zymography. It was found that glomerular endothelial cells are a significant source of collagens, laminin, and tenascin. However, they express only low levels of MMP-2 and no detectable MMP-9. Stimulation with exogenous transforming growth factor-beta1 leads to a significant increase in collagen I, tissue inhibitors of metalloproteinase-1, and MMP-9 in conditioned media. These data suggest that glomerular endothelial cells may play an active role in extracellular matrix remodeling in glomerular disease.
Cardiovascular Risk of NSAIDs: Time to Translate Knowledge into Practice
Authors: K. Srinath Reddy, Ambuj Roy
Journal: PLoS Medicine (2013)

K. Srinath Reddy and Ambuj Roy discuss the Research Article by Patricia McGettigan and David Henry about the continued use of NSAIDs associated with increased risk of cardiovascular disease, including the mechanisms of increased risk, probable reasons for ongoing use, and next steps.
Long-term use of mandibular advancement splints for snoring and obstructive sleep apnoea: a questionnaire survey
Authors: A.D. McGown, H.K. Makker, J.M. Battagel, P.R. L'Estrange, H.R. Grant, S.G. Spiro
Journal: European Respiratory Journal (2001)

A mandibular advancement splint (MAS) may be an alternative treatment for snoring and obstructive sleep apnoea (OSA). However, there is little subjective or objective information concerning long-term effectiveness, compliance and side effects. A retrospective questionnaire was used to survey these issues plus patient satisfaction and maintenance requirements in 166 patients who could have worn a mandibular advancement splint for over a year. One-hundred and twenty-six (76%) subjects returned the questionnaire, (84 with OSA, 42 snorers), of whom 69 (55%) reported still using the splint regularly, 47 (37%) every night. The most common reported reasons for stopping use were discomfort (29/ 57; 52%) of nonusers), and poor perceived efficacy (12 subjects). Users reported more daytime symptoms, and they and their partners were more likely to observe improvements with splint use. Side effects were reported by 49 subjects, more commonly in nonusers. Sixty-five of 67 current users and 23 of 41 nonusers reported less snoring with splint use (p = < 0.001). Long-term mandibular advancement splint usage appeared less satisfactory than previously reported, however, splints were considered effective by 97% of current users and even by over half of those who had stopped use. Reasons for stopping use included side effects, social circumstances, dental treatment, as well as lack of perceived efficacy.
Low Risk of Hepatocellular Carcinoma in Patients With Primary Sclerosing Cholangitis With Cirrhosis
Authors: Roman Zenouzi, Tobias J. Weismüller, Peter Hübener, Kornelius Schulze, Michael Bubenheim, Nadine Pannicke, Christina Weiler–Normann, Henrike Lenzen, Michael P. Manns, Ansgar W. Lohse, Christoph Schramm
Journal: Clinical Gastroenterology and Hepatology (2014)
NATURAL KILLER CELLS IN ANTIVIRAL DEFENSE: Function and Regulation by Innate Cytokines
Authors: Christine A. Biron, Khuong B. Nguyen, Gary C. Pien, Leslie P. Cousens, Thais P. Salazar-Mather
Journal: Annual Review of Immunology (1999)

▪ Abstract Natural killer (NK) cells are populations of lymphocytes that can be activated to mediate significant levels of cytotoxic activity and produce high levels of certain cytokines and chemokines. NK cells respond to and are important in defense against a number of different infectious agents. The first indications for this function came from the observations that virus-induced interferons α/β (IFN-α and -β) are potent inducers of NK cell-mediated cytotoxicity, and that NK cells are important contributors to innate defense against viral infections. In addition to IFN-α/β, a wide range of other innate cytokines can mediate biological functions regulating the NK cell responses of cytotoxicity, proliferation, and gamma interferon (IFN-γ) production. Certain, but not all, viral infections induce interleukin 12 (IL-12) to elicit NK cell IFN-γ production and antiviral mechanisms. However, high levels of IFN-α/β appear to be unique and/or uniquely dominant in the context of viral infections and act to regulate other innate responses, including induction of NK cell proliferation in vivo and overall negative regulation of IL-12 production. A detailed picture is developing of particular innate cytokines activating NK cell responses and their consorted effects in providing unique endogenous milieus promoting downstream adaptive responses, most beneficial in defense against viral infections.