tbuckley/cabot-search huggingface dataset:
Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy
Authors: Lex Wunderink, Roeline M. Nieboer, Durk Wiersma, Sjoerd Sytema, Fokko J. Nienhuis
Journal: JAMA Psychiatry (2013)

Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted first-episode psychosis (FEP) showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before.To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction/discontinuation (DR) vs maintenance treatment (MT) trial.Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR.One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million-population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission. PARTICIPANTS After 7 years, 103 patients (80.5%) of 128 patients who were included in the original trial were located and consented to follow-up assessment.After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician.Primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy (MT or DR) was controlled for baseline parameters.The DR patients experienced twice the recovery rate of the MT patients (40.4% vs 17.6%). Logistic regression showed an odds ratio of 3.49 (P = .01). Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates.Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice.isrctn.org Identifier: ISRCTN16228411.
PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma
Authors: Stephen M. Ansell, Alexander M. Lesokhin, Ivan Borrello, Ahmad Halwani, Emma C. Scott, Martin Gutierrez, Stephen J. Schuster, Michael M. Millenson, Deepika Cattry, Gordon J. Freeman, Scott J. Rodig, Bjoern Chapuy, Azra H. Ligon, Lili Zhu, Joseph F. Grosso, Su Young Kim, John M. Timmerman, Margaret A. Shipp, Philippe Armand
Journal: New England Journal of Medicine (2014)

Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).
Metastasis of prostate cancer and melanoma cells in a preclinical in vivo mouse model is enhanced by L-plastin expression and phosphorylation
Authors: Selina M Riplinger, Guido H Wabnitz, Henning Kirchgessner, Beate Jahraus, Felix Lasitschka, Bianca Schulte, Gabri van der Pluijm, Geertje van der Horst, Günter J Hämmerling, Inaam Nakchbandi, Yvonne Samstag
Journal: Molecular Cancer (2014)

Abstract Background Tumor cell migration and metastasis require dynamic rearrangements of the actin cytoskeleton. Interestingly, the F-actin cross-linking and stabilizing protein L-plastin, originally described as a leukocyte specific protein, is aberrantly expressed in several non-hematopoietic malignant tumors. Therefore, it has been discussed as a tumor marker. However, systematic in vivo analyses of the functional relevance of L-plastin for tumor cell metastasis were so far lacking. Methods We investigated the relevance of L-plastin expression and phosphorylation by ectopical expression of L-plastin in human melanoma cells (MV3) and knock-down of endogenous L-plastin in prostate cancer (PC3M). The growth and metastatic potential of tumor cells expressing no L-plastin, phosphorylatable or non-phosphorylatable L-plastin was analyzed in a preclinical mouse model after subcutaneous and intracardial injection of the tumor cells. Results Knock-down of endogenous L-plastin in human prostate carcinoma cells led to reduced tumor cell growth and metastasis. Vice versa, and in line with these findings, ectopic expression of L-plastin in L-plastin negative melanoma cells significantly increased the number of metastases. Strikingly, the metastasis promoting effect of L-plastin was not observed if a non-phosphorylatable L-plastin mutant was expressed. Conclusions Our data provide the first in vivo evidence that expression of L-plastin promotes tumor metastasis and, importantly, that this effect depends on an additionally required phosphorylation of L-plastin. In conclusion, these findings imply that for determining the importance of tumor-associated proteins like L-plastin a characterization of posttranslational modifications is indispensable.
Randomised placebo-controlled trial of rituximab (anti-CD20) in active ulcerative colitis
Authors: K. Leiper, K. Martin, A. Ellis, S. Subramanian, A. J. Watson, S. E. Christmas, D. Howarth, F. Campbell, J. M. Rhodes
Journal: Gut (2011)

To assess the safety and efficacy of the B lymphocyte (anti-CD20) antibody, rituximab, in the treatment of steroid-resistant moderately active ulcerative colitis (UC).A double-blinded, randomised controlled trial with a 2:1 ratio of treatment:placebo (phase II) was carried out in the setting of a University teaching hospital. The subjects comprised 24 patients with moderately active UC who have either failed to respond to conventional corticosteroid therapy or who have relapsed during corticosteroid withdrawal. Five of 8 placebo-treated patients and 12 of 16 rituximab-treated patients were receiving azathioprine, 6-mercaptopurine or methotrexate. Two infusions of rituximab 1 g in 500 ml of 0.9% saline intravenously over 4 h (n=16) or saline placebo (n=8) were given at 0 and 2 weeks. Patients still receiving corticosteroids on entry (placebo group 7/8; rituximab group 14/16) continued a standard steroid tapering regimen. The primary end point was remission (Mayo score ≤ 2) at 4 weeks. Secondary end points included response (Mayo score reduced ≥ 3) at 4 and 12 weeks.Mayo score at entry was higher in rituximab-treated patients (mean 9.19; 95% CI 8.31 to 10.06) than for placebo patients (7.63; 6.63 to 8.62, p=0.03). At week 4 only 1/8 placebo-treated patients and 3/16 rituximab-treated patients were in remission (p=1.0), but 8/16 rituximab-treated patients had responded compared with 2/8 placebo-treated patients, with a median reduction in Mayo score of 2.5 (rituximab) compared with 0 (placebo; p=0.07). This response was only maintained to week 12 in 4/16. Mucosal healing was seen at week 4 in 5/16 rituximab-treated patients and 2/8 placebo-treated patients (non-significant). Rituximab was well tolerated, with one chest infection, three mild infusion reactions plus one case of (probably unrelated) non-fatal pulmonary embolism. CONCLUSIONS Rituximab has no significant effect on inducing remission in moderately active UC not responding to oral steroids. There was a possible short-term response that was not sustained. Rituximab is well tolerated in UC.NCT00261118.
Distinct Clinical and Prognostic Features of Infiltrating Lobular Carcinoma of the Breast: Combined Results of 15 International Breast Cancer Study Group Clinical Trials
Authors: Bernhard C. Pestalozzi, David Zahrieh, Elizabeth Mallon, Barry A. Gusterson, Karen N. Price, Richard D. Gelber, Stig B. Holmberg, Jurij Lindtner, Raymond Snyder, Beat Thürlimann, Elizabeth Murray, Giuseppe Viale, Monica Castiglione-Gertsch, Alan S. Coates, Aron Goldhirsch
Journal: Journal of Clinical Oncology (2008)

To determine how patients with infiltrating lobular carcinoma (ILC) differ from patients with the more common infiltrating ductal carcinoma (IDC) with regard to patient and tumor factors, local treatment, and patterns of recurrence.Twelve thousand two hundred six breast cancer patients entered onto 15 International Breast Cancer Study Group trials between 1978 and 2002 were categorized as having ILC, IDC, or other/mixed types.Seven hundred sixty-seven tumors (6.2%) were classified as ILC, 8,607 (70.5%) were classified as IDC, and 2,832 (23.2%) were classified as other. The analysis is limited to the 9,374 patients categorized as either pure IDC or ILC. The median follow-up time was 13 years. Compared with IDC, ILC was associated with older age; larger, better differentiated, and estrogen receptor (ER)-positive tumors; and less vessel invasion. Mastectomy was used more frequently for ILC (P < .01). There was a significant (P < .01) early advantage in disease-free survival and overall survival for the ILC cohort followed by a significant (P < .01) late advantage for the IDC cohort after 6 and 10 years, respectively. Similar patterns were observed in cohorts defined by ER status. ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (all P < .01).ILC is more than a histologic variant of breast cancer. The diagnosis of ILC carries distinct prognostic and biologic implications.
A Novel FLT3 Inhibitor FI-700 Selectively Suppresses the Growth of Leukemia Cells with FLT3 Mutations
Authors: Hitoshi Kiyoi, Yukimasa Shiotsu, Kazutaka Ozeki, Satomi Yamaji, Hiroshi Kosugi, Hiroshi Umehara, Makiko Shimizu, Hitoshi Arai, Kenichi Ishii, Shiro Akinaga, Tomoki Naoe
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700. Experimental Design: The antileukemia activity of FI-700 was evaluated in human leukemia cell lines, mutant or wild-type (Wt)-FLT3–expressing mouse myeloid precursor cell line, 32D and primary acute myeloid leukemia cells, and in xenograft or syngeneic mouse leukemia models. Results: FI-700 showed a potent IC50 value against FLT3 kinase at 20 nmol/L in an in vitro kinase assay. FI-700 showed selective growth inhibition against mutant FLT3-expressing leukemia cell lines and primary acute myeloid leukemia cells, whereas it did not affect the FLT3 ligand (FL)–driven growth of Wt-FLT3–expressing cells. These antileukemia activities were induced by the significant dephosphorylations of mutant FLT3 and STAT5, which resulted in G1 arrest of the cell cycle. Oral administration of FI-700 induced the regression of tumors in a s.c. tumor xenograft model and increased the survival of mice in an i.v. transplanted model. Furthermore, FI-700 treatment eradicated FLT3/ITD-expressing leukemia cells, both in the peripheral blood and in the bone marrow. In this experiment, the depletion of FLT3/ITD-expressing cells by FI-700 was more significant than that of Ara-C, whereas bone marrow suppression by FI-700 was lower than that by Ara-C. Conclusions: FI-700 is a novel and potent FLT3 inhibitor with promising antileukemia activity.
Race, Ethnicity, Socioeconomic Position, and Quality of Care for Adults With Diabetes Enrolled in Managed Care
Authors: Arleen F. Brown, Edward W. Gregg, Mark R. Stevens, Andrew J. Karter, Morris Weinberger, Monika M. Safford, Tiffany L. Gary, Dorothy A. Caputo, Beth Waitzfelder, Catherine Kim, Gloria L. Beckles
Journal: Diabetes Care (2005)

OBJECTIVE—To examine racial/ethnic and socioeconomic variation in diabetes care in managed-care settings. RESEARCH DESIGN AND METHODS—We studied 7,456 adults enrolled in health plans participating in the Translating Research Into Action for Diabetes study, a six-center cohort study of diabetes in managed care. Cross-sectional analyses using hierarchical regression models assessed processes of care (HbA1c [A1C], lipid, and proteinuria assessment; foot and dilated eye examinations; use or advice to use aspirin; and influenza vaccination) and intermediate health outcomes (A1C, LDL, and blood pressure control). RESULTS—Most quality indicators and intermediate outcomes were comparable across race/ethnicity and socioeconomic position (SEP). Latinos and Asians/Pacific Islanders had similar or better processes and intermediate outcomes than whites with the exception of slightly higher A1C levels. Compared with whites, African Americans had lower rates of A1C and LDL measurement and influenza vaccination, higher rates of foot and dilated eye examinations, and the poorest blood pressure and lipid control. The main SEP difference was lower rates of dilated eye examinations among poorer and less educated individuals. In almost all instances, racial/ethnic minorities or low SEP participants with poor glycemic, blood pressure, and lipid control received similar or more appropriate intensification of therapy relative to whites or those with higher SEP. CONCLUSIONS—In these managed-care settings, minority race/ethnicity was not consistently associated with worse processes or outcomes, and not all differences favored whites. The only notable SEP disparity was in rates of dilated eye examinations. Social disparities in health may be reduced in managed-care settings.
Injuries in West Indies cricket 2003–2004
Authors: A Mansingh, L Harper, S Headley, J King-Mowatt, G Mansingh
Journal: British Journal of Sports Medicine (2006)

To analyse injuries in West Indies Cricket and compare them with those of other cricket playing nations.Injuries between June 2003 and December 2004 were surveyed prospectively in all major matches of the West Indies Cricket Board.Most injuries occurred in the West Indies Test and one day international teams. Mean match injury incidence was 48.7 per 10,000 player-hours in Test cricket, and 40.6 per 10,000 player-hours in one day international cricket, with injury prevalence of 11.3% and 8.1% respectively. In domestic cricket, the match injury incidence was 13.9 per 10,000 player-hours for first class cricket, and 25.4 per 10,000 player-hours in one day domestic competitions. There were more injuries on tour for the West Indies team than at home. The batsmen and fast bowlers sustained 80% of injuries, with many leading to long absence from the game, although many of these injuries were sustained while fielding. Most injuries were of the phalanges (22%) and the lumbar spine (20%) sustained mainly while fielding (including catching) and fast bowling respectively.Injuries in West Indies cricket may be reduced by (a) early detection and management of injuries on tour, (b) attention to fielding and catching techniques, and (c) monitoring of young fast bowlers.
Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial
Authors: Luca Gianni, Urania Dafni, Richard D Gelber, Evandro Azambuja, Susanne Muehlbauer, Aron Goldhirsch, Michael Untch, Ian Smith, José Baselga, Christian Jackisch, David Cameron, Max Mano, José Luiz Pedrini, Andrea Veronesi, Cesar Mendiola, Anna Pluzanska, Vladimir Semiglazov, Eduard Vrdoljak, Michael J Eckart, Zhenzhou Shen, George Skiadopoulos, Marion Procter, Kathleen I Pritchard, Martine J Piccart-Gebhart, Richard Bell
Journal: The Lancet Oncology (2011)
Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors
Authors: Vincenzo Mollace, Carolina Muscoli, Emanuela Masini, Salvatore Cuzzocrea, Daniela Salvemini
Journal: Pharmacological Reviews (2005)

The biosynthesis and release of nitric oxide (NO) and prostaglandins (PGs) share a number of similarities. Two major forms of nitric-oxide synthase (NOS) and cyclooxygenase (COX) enzymes have been identified to date. Under normal circumstances, the constitutive isoforms of these enzymes (constitutive NOS and COX-1) are found in virtually all organs. Their presence accounts for the regulation of several important physiological effects (e.g. antiplatelet activity, vasodilation, and cytoprotection). On the other hand, in inflammatory setting, the inducible isoforms of these enzymes (inducible NOS and COX-2) are detected in a variety of cells, resulting in the production of large amounts of proinflammatory and cytotoxic NO and PGs. The release of NO and PGs by the inducible isoforms of NOS and COX has been associated with the pathological roles of these mediators in disease states as evidenced by the use of selective inhibitors. An important link between the NOS and COX pathways was made in 1993 by Salvemini and coworkers when they demonstrated that the enhanced release of PGs, which follows inflammatory mechanisms, was nearly entirely driven by NO. Such studies raised the possibility that COX enzymes represent important endogenous "receptor" targets for modulating the multifaceted roles of NO. Since then, numerous papers have been published extending the observation across various cellular systems and animal models of disease. Furthermore, other studies have highlighted the importance of such interaction in physiology as well as in the mechanism of action of drugs such as organic nitrates. More importantly, mechanistic studies of how NO switches on/off the PG/COX pathway have been undertaken and additional pathways through which NO modulates prostaglandin production unraveled. On the other hand, NO donors conjugated with COX inhibitors have recently found new interest in the understanding of NO/COX reciprocal interaction and potential clinical use. The purpose of this article is to cover the advances which have occurred over the years, and in particular, to summarize experimental data that outline how the discovery that NO modulates prostaglandin production has impacted and extended our understanding of these two systems in physiopathological events.
Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial
Authors: T N Brooklyn
Journal: Gut (2005)

Pyoderma gangrenosum (PG) is a chronic ulcerating skin condition that often occurs in association with inflammatory bowel disease. There have been a number of reports of PG responding to infliximab, a monoclonal antibody against tumour necrosis factor alpha.In the first randomised placebo controlled trial of any drug for the treatment of PG, we have studied the role of infliximab in this disorder.Patients 18 years of age or older with a clinical diagnosis of PG were invited to take part.Patients were randomised to receive an infusion of infliximab at 5 mg/kg or placebo at week 0. Patients were then assessed at week 2 and non-responders were offered open labelled infliximab. The primary end point was clinical improvement at week 2, with secondary end points being remission and improvement at week 6.Thirty patients were entered into the study. After randomisation, 13 patients received infliximab and 17 patients received placebo. At week 2, significantly more patients in the infliximab group had improved (46% (6/13)) compared with the placebo group (6% (1/17); p = 0.025). Overall, 29 patients received infliximab with 69% (20/29) demonstrating a beneficial clinical response. Remission rate at week 6 was 21% (6/29). There was no response in 31% (9/29) of patients.This study has demonstrated that infliximab at a dose of 5 mg/kg is superior to placebo in the treatment of PG. Open label treatment with infliximab also produced promising results. Infliximab treatment should be considered in patients with PG.
Hapten-specific hemolytic plaque assays usually fail to detect most of the diversity in the anti-hapten response.
Authors: B Merchant, J K Inman
Journal: The Journal of Experimental Medicine (1977)

Immunization of rabbits or mice with a single, chemically defined hapten elicits populations of plaque-forming cells (PFC) detectable not only on sheep erythrocytes (SRBC) bearing the immunizing hapten, but also on SRBC bearing structural analogues of the immunizing hapten. Most of these analogue-reactive PFC preferentially lyse analogue-conjugated SRBC and cannot be detected on erythrocytes bearing the immunizing hapten. Thus, they represent heretofore largely unstudied components of the secretory B-cell response to haptenic immunization, and they have been termed alloreactive PFC. Such alloreactive PFC are detectable using either classical small haptens or tripeptide-enlarged counterparts of these classical haptens. They are present in large numbers both in direct and in indirect PFC assays, and they are elicited in response to both thymic-dependent and thymic-independent antigens. Relatively few alloreactive PFC can be attributed to cells producing hapten-carrier or "bridge area"-specific antibodies. Since the antibodies released by alloreactive PFC can also be detected by passive hemagglutination, their presence does not appear attributable to vagaries of complement activation. Numerous coexisting alloreactive PFC populations are detectable after haptenic immunization. In early direct PFC responses it is not nucommon for a single alloreactive PFC population to outnumber the population of PFC detectable on SRBC bearing the actual immunizing hapten. These alloreactive PFC may be the source of at least some of the new "nonspecific" Ig which is formed at the time of immunization but about which little is known for lack of available techniques. Some possible implications of these findings on the specificity of B precursor cell activation are discussed.