tbuckley/cabot-search huggingface dataset:
A Double-Blind, Delayed-Start Trial of Rasagiline in Parkinson's Disease
Authors: C. Warren Olanow, Olivier Rascol, Robert Hauser, Paul D. Feigin, Joseph Jankovic, Anthony Lang, William Langston, Eldad Melamed, Werner Poewe, Fabrizio Stocchi, Eduardo Tolosa
Journal: New England Journal of Medicine (2009)

A therapy that slows disease progression is the major unmet need in Parkinson's disease.In this double-blind trial, we examined the possibility that rasagiline has disease-modifying effects in Parkinson's disease. A total of 1176 subjects with untreated Parkinson's disease were randomly assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72 weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To determine a positive result with either dose, the early-start treatment group had to meet each of three hierarchical end points of the primary analysis based on the Unified Parkinson's Disease Rating Scale (UPDRS, a 176-point scale, with higher numbers indicating more severe disease): superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36, superiority to delayed-start treatment in the change in the score between baseline and week 72, and noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72.Early-start treatment with rasagiline at a dose of 1 mg per day met all end points in the primary analysis: a smaller mean (+/-SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36 (0.09+/-0.02 points per week in the early-start group vs. 0.14+/-0.01 points per week in the placebo group, P=0.01), less worsening in the score between baseline and week 72 (2.82+/-0.53 points in the early-start group vs. 4.52+/-0.56 points in the delayed-start group, P=0.02), and noninferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085+/-0.02 points per week in the early-start group vs. 0.085+/-0.02 points per week in the delayed-start group, P<0.001). All three end points were not met with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score between baseline and week 72 was not significantly different in the two groups (3.47+/-0.50 points in the early-start group and 3.11+/-0.50 points in the delayed-start group, P=0.60).Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution. (ClinicalTrials.gov number, NCT00256204.)
Randomized Phase III Trial of Marimastat Versus Placebo in Patients With Metastatic Breast Cancer Who Have Responding or Stable Disease After First-Line Chemotherapy: Eastern Cooperative Oncology Group Trial E2196
Authors: Joseph A. Sparano, Patricia Bernardo, Patricia Stephenson, William J. Gradishar, James N. Ingle, Stanley Zucker, Nancy E. Davidson
Journal: Journal of Clinical Oncology (2004)

To determine whether a matrix metalloproteinase inhibitor improves progression-free survival (PFS) in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy.One hundred seventy-nine eligible patients were randomly assigned to receive oral marimastat (10 mg bid; n = 114) or a placebo (n = 65) within 3 to 6 weeks of completing six to eight cycles of first-line doxorubicin- and/or taxane-containing chemotherapy for metastatic disease. Patients were evaluated every 3 months until disease progression.When comparing placebo with marimastat, there was no significant difference in PFS (median, 3.1 months v 4.7 months, respectively; hazard ratio, 1.26; 95% CI, 0.91 to 1.74; P = .16) or overall survival (median, 26.6 months v 24.7 months, respectively; hazard ratio, 1.03; 95% CI, 0.73 to 1.46; P = .86). Patients treated with marimastat were more likely to develop grade 2 or 3 musculoskeletal toxicity (MST), a known complication of the drug indicative of achieving a biologic effect, compared with patients administered placebo (63% v 22%, respectively; P < .0001). Patients with grade 2 or 3 MST had significantly inferior survival compared with patients who had grade 0 or 1 MST (median, 22.5 months v 28.2 months; P = .04). In addition, patients who had a marimastat plasma concentration of at least 10 ng/mL at month 1 and/or 3 were significantly more likely to have grade 2 to 3 MST (P < .0001).Marimastat does not prolong PFS when used after first-line chemotherapy for metastatic breast cancer. Patients with higher marimastat levels exhibited MST, and MST was associated with inferior survival.
Lineage-specific Requirement for Signal Transducer and Activator of Transcription (Stat)4 in Interferon γ Production from CD4+ Versus CD8+ T Cells
Authors: Laura L. Carter, Kenneth M. Murphy
Journal: The Journal of Experimental Medicine (1999)

CD4+ and CD8+ T cells exhibit important differences in their major effector functions. CD8+ T cells provide protection against pathogens through cytolytic activity, whereas CD4+ T cells exert important regulatory activity through production of cytokines. However, both lineages can produce interferon (IFN)-γ, which can contribute to protective immunity. Here we show that CD4+ and CD8+ T cells differ in their regulation of IFN-γ production. Both lineages require signal transducer and activator of transcription (Stat)4 activation for IFN-γ induced by interleukin (IL)-12/IL-18 signaling, but only CD4+ T cells require Stat4 for IFN-γ induction via the TCR pathway. In response to antigen, CD8+ T cells can produce IFN-γ independently of IL-12, whereas CD4+ T cells require IL-12 and Stat4 activation. Thus, there is a lineage-specific requirement for Stat4 activation in antigen-induced IFN-γ production based on differences in TCR signaling between CD4+ and CD8+ T cells.
Conversion Analysis for Mutation Detection in &lt;EMPH&gt;MLH1&lt;/EMPH&gt; and &lt;EMPH&gt;MSH2&lt;/EMPH&gt; in Patients With Colorectal Cancer
Authors: Graham Casey
Journal: JAMA (2005)

The accurate identification and interpretation of germline mutations in mismatch repair genes in colorectal cancer cases is critical for clinical management. Current data suggest that mismatch repair mutations are highly heterogeneous and that many mutations are not detected when conventional DNA sequencing alone is used.To evaluate the potential of conversion analysis compared with DNA sequencing alone to detect heterogeneous germline mutations in MLH1, MSH2, and MSH6 in colorectal cancer patients.Multicenter study with patients who participate in the Colon Cancer Family Registry. Mutation analyses were performed in participant samples determined to have a high probability of carrying mismatch repair germline mutations. Samples from a total of 64 hereditary nonpolyposis colorectal cancer cases, 8 hereditary nonpolyposis colorectal cancer-like cases, and 17 cases diagnosed prior to age 50 years were analyzed from June 2002 to June 2003.Classification of family members as carriers or noncarriers of germline mutations in MLH1, MSH2, or MSH6; mutation data from conversion analysis compared with genomic DNA sequencing.Genomic DNA sequencing identified 28 likely deleterious exon mutations, 4 in-frame deletion mutations, 16 missense changes, and 22 putative splice site mutations. Conversion analysis identified all mutations detected by genomic DNA sequencing--plus an additional exon mutation, 12 large genomic deletions, and 1 exon duplication mutation--yielding an increase of 33% (14/42) in diagnostic yield of deleterious mutations. Conversion analysis also showed that 4 of 16 missense changes resulted in exon skipping in transcripts and that 17 of 22 putative splice site mutations affected splicing or mRNA transcript stability. Conversion analysis provided an increase of 56% (35/63) in the diagnostic yield of genetic testing compared with genomic DNA sequencing alone.The data confirm the heterogeneity of mismatch repair mutations and reveal that many mutations in colorectal cancer cases would be missed using conventional genomic DNA sequencing alone. Conversion analysis substantially increases the diagnostic yield of genetic testing for mismatch repair mutations in patients diagnosed as having colorectal cancer.
Sphingosine-1-Phosphate and Lymphocyte Egress from Lymphoid Organs
Authors: Jason G. Cyster, Susan R. Schwab
Journal: Annual Review of Immunology (2012)

Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.
Different types of smooth muscle antibodies in chronic active hepatitis and primary biliary cirrhosis: their diagnostic and prognostic significance.
Authors: P Kurki, A Miettinen, E Linder, P Pikkarainen, M Vuoristo, M P Salaspuro
Journal: Gut (1980)

The diagnostic and prognostic significance of the different types of serum smooth muscle antibodies (SMA) were investigated in sera of 24 patients with chronic active hepatitis (CAH) and 15 patients with primary biliary cirrhosis (PBC). SMA of IgG class were found in 92% of sera from patients with CAH but in only 20% of sera from PBC patients, whereas the incidence of IgM-SMA was higher in PBC (67%) than in CAH (38%). All six patients with the atypical cholestatic form of CAH has SMA of IgM class, whereas other CAH patients had SMA of mainly IgG class. SMA reacting with rabbit liver (bile canaliculus antibodies, BCA) and with rat glomeruli (glomerulus antibodies) were of anti-actin specificity and were more common in CAH than in PBC. Organ specific BCA or glomerulus antibodies were not found. Anti-actin antibodies were detected in the majority of the investigated sera by an immunoenzymatic anti-actin assay. The results suggest that the determination of SMA titres with heavy chain specific antisera may help in the assessment of diagnosis and prognosis of chronic hepatitis.
The role of high-energy phosphate in norepinephrine-induced acute renal failure in the dog.
Authors: T D Sinsteden, T J O'Neil, S Hill, M D Lifschitz, J H Stein
Journal: Circulation Research (1986)

Previous studies have demonstrated that pretreatment with mannitol, furosemide, or bradykinin can attenuate the severity of norepinephrine-induced renal functional impairment. The present studies were designed to evaluate the possibility that these agents are protective, in part, by preserving cellular metabolic integrity. The renal cortex was repetitively biopsied during the course of this study, and high-pressure liquid chromatography was used to analyze the tissue content of adenine nucleotides (expressed in nanomoles per gram of wet tissue). The adenine nucleotide charge ratio (CR) and total adenine nucleotide (TAN) content were calculated as indices of cellular metabolic integrity. In addition to the above-established protective agents, phenoxybenzamine was used to evaluate a direct toxic effect of norepinephrine on renal tissue. Inulin clearance at 3 hours post infusion (expressed as a percent of control) was 7% with norepinephrine alone and, in the protected groups, 36% with bradykinin, 61% with furosemide, 51% with mannitol, and 100% with phenoxybenzamine. There was no change in CR or TAN with phenoxybenzamine. In contrast, during norepinephrine administration CR fell significantly in all other groups. Three hours after stopping norepinephrine, CR had returned toward control values and the level of CR was significantly better in all protected groups when compared with norepinephrine alone. Similarly, the levels of TAN were significantly diminished in the norepinephrine-alone group when compared to all protected groups, and there was significantly more tubular necrosis as well. The maintenance of higher levels of TAN and the preserved ability to regenerate adenosine triphosphate in the protected groups, when compared to the norepinephrine-alone group, support the contention that these agents offer protection, at least in part, by preserving cellular metabolic integrity.
Complex History of a Chromosomal Paralogy Region: Insights from Amphioxus Aromatic Amino Acid Hydroxylase Genes and Insulin -Related Genes
Authors: S J Patton, G N Luke, P W Holland
Journal: Molecular Biology and Evolution (1998)

Aromatic amino acid hydroxylase (AAAH) genes and insulin-like genes form part of an extensive paralogy region shared by human chromosomes 11 and 12, thought to have arisen by tetraploidy in early vertebrate evolution. Cloning of a complementary DNA (cDNA) for an amphioxus (Branchiostoma floridae) hydroxylase gene (AmphiPAH) allowed us to investigate the ancestry of the human chromosome 11/12 paralogy region. Molecular phylogenetic evidence reveals that AmphiPAH is orthologous to vertebrate phenylalanine (PAH) genes; the implication is that all three vertebrate AAAH genes arose early in metazoan evolution, predating vertebrates. In contrast, our phylogenetic analysis of amphioxus and vertebrate insulin-related gene sequences is consistent with duplication of these genes during early chordate ancestry. The conclusion is that two tightly linked gene families on human chromosomes 11 and 12 were not duplicated coincidentally. We rationalize this paradox by invoking gene loss in the AAAH gene family and conclude that paralogous genes shared by paralogous chromosomes need not have identical evolutionary histories.
Obesity among over 65s in UK reflects "lifetime of gaining weight"
Authors: A. Gulland
Journal: BMJ (2010)

The prevalence of obesity among elderly people in the United Kingdom is higher than among young people, with almost three quarters of those aged between 65 and 74 years classed as obese or overweight.

The 40th edition of Social Trends , published by the Office for National Statistics, shows that in 2008 in England more than three quarters (77.1%) of adults aged between 65 and 74 were obese or overweight, whereas a third (33.5%) of those aged 16 to 24 were. In Scotland and Wales in 2008 those aged between 55 and 64 were most likely to be overweight or obese, standing at 79% and 68% respectively. However, in Scotland almost four in 10 (38%) …
Fragile Histidine Triad Expression in Oral Squamous Cell Carcinoma and Precursor Lesions
Authors: Omar Kujan, Richard Oliver, Luca Roz, Gabriella Sozzi, Noel Ribeiro, Robert Woodwards, Nalin Thakker, Philip Sloan
Journal: Clinical Cancer Research (2006)

Abstract Pupose: Fragile histidine triad (FHIT) expression in precursor oral lesions (POL) and oral squamous cell carcinomas (OSCC) was studied with regard to (a) the frequency of loss of FHIT expression, (b) whether loss of FHIT expression correlates with degree of dysplasia in POLs, (c) whether FHIT loss predicts high-risk POLs that are more likely to transform, and (d) whether FHIT loss in OSCCs correlates with survival. Experimental Design: Ninety-four POLs and 86 OSCCs were immunostained for FHIT. Survival analysis was done for cases with validated clinical outcomes. Results: By optimizing the immunostaining protocol, we found that FHIT is expressed in a distinctive strong nuclear and weak cytoplasmic pattern in oral tissues. Loss of FHIT expression was found in 42 of 94 (45%) POLs and in 66 of 86 (77%) OSCCs. We observed a statistically significant positive correlation between frequency of FHIT loss and increasing grade of dysplasia (χ2 = 13.8; degrees of freedom = 4; P = 0.008). Loss of FHIT expression in POLs that progressed to malignancy was more frequent than in those that did not [17 of 25 (68%) versus 12 of 29 (41.4%), respectively]. This difference was statistically significant (χ2 = 3.8; degrees of freedom = 1; P = 0.046). In OSCCs, loss of FHIT staining indicated a worse prognosis (survival rate, 36.2%) than when positive FHIT staining was observed (survival rate, 50%), but the difference was not statistically significant (P = 0.546, Kaplan-Meier, log-rank). Conclusions: FHIT seems to localize to both nuclear and cytoplasmic domains. FHIT inactivation occurs early in oral carcinogenesis and may be useful molecular marker for progressive dysplastic oral lesions.
Visual Acuity in Infants after Vitrectomy for Severe Retinopathy of Prematurity
Authors: Graham E. Quinn, Velma Dobson, Charles C. Barr, Barry R. Davis, John T. Flynn, Earl A. Palmer, Joseph Robertson, Michael T. Trese
Journal: Ophthalmology (1991)

During the course of the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP), 98 infants (129 eyes) from the randomized segment of the trial developed total retinal detachment from retinopathy of prematurity (ROP) before the 1-year examination. The authors report as a case series the results of acuity card assessment of monocular grating acuity at 1 year in 53 infants (71 eyes) postvitrectomy and in 45 infants (58 eyes) who had retinal detachments but who did not undergo retinal reattachment surgery. The decision to undertake and the surgical technique used for a retinal reattachment procedure was not part of the randomized CRYO-ROP trial. Two eyes of one infant had pattern vision at the lowest measurable threshold after vitrectomy. None of the remaining eyes that had undergone vitrectomy and none of the eyes that did not undergo vitrectomy showed evidence of pattern vision. The relatively poor visual outcomes in this case series suggest that efforts are well-spent in attempting to prevent retinal detachment in ROP.
Benefits of the Intermittent Use of 6-Mercaptopurine and Methotrexate in Maintenance Treatment for Low-Risk Acute Lymphoblastic Leukemia in Children: Randomized Trial From the Brazilian Childhood Cooperative Group—Protocol ALL-99
Authors: Silvia R. Brandalise, Vitória R. Pinheiro, Simone S. Aguiar, Eduardo I. Matsuda, Rosemary Otubo, José A. Yunes, Waldir V. Pereira, Eny G. Carvalho, Lilian M. Cristofani, Marcelo S. Souza, Maria L. Lee, Jane A. Dobbin, Maria S. Pombo-de-Oliveira, Luiz F. Lopes, Katharina N.T. Melnikoff, Algemir L. Brunetto, Luiz G. Tone, Carlos A. Scrideli, Vera L.L. Morais, Marcos B. Viana
Journal: Journal of Clinical Oncology (2010)

PURPOSE To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. PATIENTS AND METHODS Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MTX (200 mg/m(2) every 3 weeks; group 2, n = 272). RESULTS The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P = .28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2). CONCLUSION The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.
Loss of the Notch effector RBPJ promotes tumorigenesis
Authors: Iva Kulic, Gordon Robertson, Linda Chang, Jennifer H.E. Baker, William W. Lockwood, Winnie Mok, Megan Fuller, Michèle Fournier, Nelson Wong, Vennie Chou, Mark D. Robinson, Hye-Jung Chun, Blake Gilks, Bettina Kempkes, Thomas A. Thomson, Martin Hirst, Andrew I. Minchinton, Wan L. Lam, Steven Jones, Marco Marra, Aly Karsan
Journal: The Journal of Experimental Medicine (2014)

Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJ-depleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-κB and MYC were essential for survival of RBPJ-depleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notch-independent activation by alternate transcription factors that promote tumorigenesis.