tbuckley/cabot-search huggingface dataset:
Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature
Authors: K Visser, D van der Heijde
Journal: Annals of the Rheumatic Diseases (2008)

Objectives: To review systematically the available literature on the optimal dosage and route of administration of methotrexate in patients with rheumatoid arthritis (RA), as an evidence base for generating clinical practice recommendations. Methods: A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and American College of Rheumatology/European League Against Rheumatism meeting abstracts, searching for randomised controlled trials evaluating various dosages or routes of administration of methotrexate in RA. Articles that fulfilled predefined inclusion criteria were systematically reviewed and the quality was appraised. Effect sizes and odds ratios for clinical, radiological and toxicity outcomes were calculated and directly or indirectly compared between study groups using methotrexate in different dosages or by different routes. Results: A total of 38 publications out of 1748 identified references was included in the review. Start doses of 25 mg/week or fast escalation with 5 mg/month to 25–30 mg/week were associated with higher clinical effect sizes and more (gastrointestinal) adverse events in comparison with doses of 5–15 mg/week or slow escalation. Starting with 15 mg/week subcutaneous versus oral methotrexate was associated with higher clinical efficacy but more withdrawal due to toxicity in early RA. In longstanding RA, after failure on 15–20 mg/week orally, a switch to 15 mg/week intramuscularly with subsequent dose escalation did not result in increased efficacy. Conclusions: Starting on methotrexate 15 mg/week orally, escalating with 5 mg/month to 25–30 mg/week, or the highest tolerable dose, with a subsequent switch to subcutaneous administration in the case of an insufficient response, seems to be the optimal evidence-based dosing and routing recommendation for methotrexate in RA.
Fate of herpes simplex virus in lymphocytes from inflammatory joint effusions. ii. Mechanisms of non-permissiveness.
Authors: D J Appleford, A M Denman
Journal: Annals of the Rheumatic Diseases (1979)

Mononuclear cells which were isolated from rheumatoid synovial effusions and cultured without prior separation failed to support the growth of herpes simplex virus (HSV). However, subpopulations of T lymphocytes separated on the basis of cell size or receptors for sheep red cells were, in isolation, permissive for this virus. Virus growth in these permissive cells was blocked by cocultivation with the remaining mononuclear cell populations.
Abnormalities of the spleen and liver in patients with hemophilia
Authors: William H. Meyer, Jack Levin, Paul M. Ness, William R. Bell, Kenneth H. Douglass, Edwaldo E. Camargo, William H. Zinkham
Journal: American Journal of Hematology (1983)

Abstract Previous studies have demonstrated functional and histologic abnormalities of the liver, and, more recently, splenomegaly in patients with hemophilia. Since these observations usually were derived from hemophiliacs who had received intensive replacement therapy, the question was posed as to whether the frequency of splenic and hepatic abnormalities was secondary to the amount of therapy utilized. In this study, a variety of tests were employed to evaluate spleen and liver size and function to determine if abnormalities in these organs correlated with the intensity of the transfusion program. The study group was comprised of 25 hemophiliacs (mean factor replacement—18,361 U/year; median factor replacement—12,920 U/year). Over 70% of our patients had elevations of aspartate and alanine aminotransferase. Immunoglobulin and complement levels were normal in most subjects. Ninety‐six percent had evidence of exposure to hepatitis B virus. Liver‐spleen imaging suggested significant hepatic abnormalities in most of the patients as evidenced by inhomogeneity of tracer uptake in the liver in 33% and relatively increased colloid uptake in the spleen in 90%. Splenomegaly (palpable spleen or enlargement on liver‐spleen imaging) was detected in 40% of our patients, and tended to occur in the more frequently transfused patients. These findings indicate that significant abnormalities of the spleen and liver can occur in hemophiliacs who have received moderate amounts of replacement therapy and that liver‐spleen imaging may be a useful method for monitoring the development of hepatic and splenic abnormalities.
Structural differences between the two human complement C4 isotypes affect the humoral immune response.
Authors: O Finco, S Li, M Cuccia, F S Rosen, M C Carroll
Journal: The Journal of Experimental Medicine (1992)

An animal model has been used to address the question of the biological importance of the known structural difference between the two isotypes of human C4, i.e., C4A and C4B. Guinea pigs deficient in C4 were reconstituted transiently with either human C4A or C4B protein and immunized with the bacteriophage phi X174. Results from this study showed that C4A-reconstituted animals made a secondary response, i.e., switch from IgM to IgG; whereas the C4B-reconstituted animals did not.
Proximal cutaneous necrosis in association with chronic renal failure
Authors: L.R. WHITTAM, D.H. MCGIBBON, D.M. MACDONALD
Journal: British Journal of Dermatology (1996)

We report two patients with renal failure who developed painful symmetrical ulceration over the proximal thighs and abdominal wall. Histological examination of the ulcerated areas revealed intravascular calcification. This phenomenon has been termed calciphylaxis and is a rare complication of renal failure. The pathogenesis is poorly understood. However, abnormalities of calcium/phosphate metabolism and of coagulation are important.
Chemokine-dependent T cell migration requires aquaporin-3–mediated hydrogen peroxide uptake
Authors: Mariko Hara-Chikuma, Shunsuke Chikuma, Yoshinori Sugiyama, Kenji Kabashima, Alan S. Verkman, Shintaro Inoue, Yoshiki Miyachi
Journal: The Journal of Experimental Medicine (2012)

Chemokine-dependent trafficking is indispensable for the effector function of antigen-experienced T cells during immune responses. In this study, we report that the water/glycerol channel aquaporin-3 (AQP3) is expressed on T cells and regulates their trafficking in cutaneous immune reactions. T cell migration toward chemokines is dependent on AQP3-mediated hydrogen peroxide (H2O2) uptake but not the canonical water/glycerol transport. AQP3-mediated H2O2 transport is essential for the activation of the Rho family GTPase Cdc42 and the subsequent actin dynamics. Coincidentally, AQP3-deficient mice are defective in the development of hapten-induced contact hypersensitivity, which is attributed to the impaired trafficking of antigen-primed T cells to the hapten-challenged skin. We therefore suggest that AQP3-mediated H2O2 uptake is required for chemokine-dependent T cell migration in sufficient immune response.
Infliximab treatment for rheumatic disease: clinical and radiological efficacy
Authors: E W St Clair
Journal: Annals of the Rheumatic Diseases (2002)

Infliximab is a chimeric anti-tumour necrosis factor α (TNFα) monoclonal antibody with high affinity and binding specificity for human TNFα. Results from several well designed, controlled clinical trials show repeated infusions of infliximab with concomitant methotrexate (MTX) treatment can reduce the signs and symptoms of rheumatoid arthritis (RA). This combination of infliximab and MTX also slows the radiological progression of joint damage, decreases functional disability, and improves qualify of life. These remarkably positive results have led to the investigation of infliximab treatment for other rheumatic diseases. Recently, controlled studies have shown treatment with infliximab can benefit patients with active spondyloarthropathy. TNFα has fast become an important therapeutic target in rheumatology.
Potential Regional Differences for the Tolerability Profiles of Fluoropyrimidines
Authors: Daniel G. Haller, Jim Cassidy, Stephen J. Clarke, David Cunningham, Eric Van Cutsem, Paulo M. Hoff, Mace L. Rothenberg, Leonard B. Saltz, Hans-Joachim Schmoll, Carmen Allegra, Joseph R. Bertino, Jean-Yves Douillard, Bengt G. Gustavsson, Gerard Milano, Michael O'Connell, Youcef Rustum, Josep Tabernero, Frank Gilberg, Florin Sirzén, Chris Twelves
Journal: Journal of Clinical Oncology (2008)

We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability.Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study).In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR.Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.
Origins of Bidirectional Promoters: Computational Analyses of Intergenic Distance in the Human Genome
Authors: D. Takai
Journal: Molecular Biology and Evolution (2003)

We have analyzed intergenic distances and searched for the presence of bidirectional genes using the complete sequences and mapping information of human chromosomes 20, 21, and 22, which contain 2,122 known and predicted genes. Intergenic distances between genes with divergent transcripts were distributed in a biphasic manner with a strong peak of 25 kb and a weak peak of 0.3 kb between the divergent transcripts, suggesting that the genes might share a common promoter. The weak peak was not observed at the transcriptional ends of genes. Seventy-three percent (55/75 pairs of genes, from a total of 150 genes) of these divergent transcripts located within 1 kb of one another were CpG islands. Expression of the divergent transcript genes was not concordant in various human tissues, suggesting that they were independently regulated. Analyses of the frequency of occurrence of interspersed repeats in the intergenic sequences suggested that these repeats are strongly excluded from the regions of transcriptional starts. This exclusion might be responsible for the existence of these divergent transcripts.
Identification of small molecule compounds that inhibit the HIF-1 signaling pathway
Authors: Menghang Xia, Kun Bi, Ruili Huang, Ming-Hsuang Cho, Srilatha Sakamuru, Susanne C Miller, Hua Li, Yi Sun, John Printen, Christopher P Austin, James Inglese
Journal: Molecular Cancer (2009)

Hypoxia-inducible factor-1 (HIF-1) is the major hypoxia-regulated transcription factor that regulates cellular responses to low oxygen environments. HIF-1 is composed of two subunits: hypoxia-inducible HIF-1α and constitutively-expressed HIF-1β. During hypoxic conditions, HIF-1α heterodimerizes with HIF-1β and translocates to the nucleus where the HIF-1 complex binds to the hypoxia-response element (HRE) and activates expression of target genes implicated in cell growth and survival. HIF-1α protein expression is elevated in many solid tumors, including those of the cervix and brain, where cells that are the greatest distance from blood vessels, and therefore the most hypoxic, express the highest levels of HIF-1α. Therapeutic blockade of the HIF-1 signaling pathway in cancer cells therefore provides an attractive strategy for development of anticancer drugs. To identify small molecule inhibitors of the HIF-1 pathway, we have developed a cell-based reporter gene assay and screened a large compound library by using a quantitative high-throughput screening (qHTS) approach. The assay is based upon a β-lactamase reporter under the control of a HRE. We have screened approximate 73,000 compounds by qHTS, with each compound tested over a range of seven to fifteen concentrations. After qHTS we have rapidly identified three novel structural series of HIF-1 pathway Inhibitors. Selected compounds in these series were also confirmed as inhibitors in a HRE β-lactamase reporter gene assay induced by low oxygen and in a VEGF secretion assay. Three of the four selected compounds tested showed significant inhibition of hypoxia-induced HIF-1α accumulation by western blot analysis. The use of β-lactamase reporter gene assays, in combination with qHTS, enabled the rapid identification and prioritization of inhibitors specific to the hypoxia induced signaling pathway.
CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients
Authors: Patrick A. Ott, F. Stephen Hodi, Caroline Robert
Journal: Clinical Cancer Research (2013)

Abstract Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is the first agent associated with a documented improved overall survival benefit in this patient population. A striking attribute of CTLA-4 blockade is the durability of objective responses, leading to speculation of a possible cure for some patients. Many tumor responses achieved with PD-1 and PD-L1 inhibition were durable in the phase I trials and were seen in a higher proportion of patients with melanoma than typically observed with ipilimumab. Biomarker development to identify the subset of patients with melanoma who will achieve durable clinical benefit with checkpoint blockade is critical; tumor PD-L1 expression has been promising in early studies. The contrast between unprecedented response rates but limited durability of responses achieved with BRAF and MEK inhibition in BRAFV600-mutated melanoma and the impressive durability but relatively low rate of response achieved with immune checkpoint blockade is striking. Preclinical data on potential synergies between CTLA-4/PD-1/PD-L1 inhibition and MAPK-targeted therapy is emerging, and combined immune checkpoint blockade and MAPK inhibition are being explored in clinical trials. Other promising approaches to increase the number of patients with melanoma who benefit from durable responses with immune checkpoint blockade include concurrent or sequenced CTLA-4 and PD-1/PD-L1 inhibition and combination with other immunotherapeutic strategies. Clin Cancer Res; 19(19); 5300–9. ©2013 AACR.
Relative impact of radiographic osteoarthritis and pain on quadriceps strength, proprioception, static postural sway and lower limb function
Authors: M C Hall
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To investigate the relative impact of radiographic osteoarthritis (ROA) and current knee pain on lower limb physical function, quadriceps strength, knee joint proprioception, and postural sway. <b>Methods:</b> Using a 2×2 factorial design, 142 community derived subjects aged over 45 were divided into four subgroups based on the presence or absence of ROA (Kellgren &amp; Lawrence &gt;grade 2) and knee pain (as assessed by NHANES questions and a 100 mm visual analogue scale). Maximum isometric contraction of the quadriceps, knee joint proprioceptive acuity, static postural sway, and WOMAC index (both whole and function subscale) were assessed in all subjects. <b>Results:</b> Compared with normal subjects, reported disability was greater for all other subgroups (p&lt;0.01). Subjects with both ROA and knee pain reported the greatest disability, and those with knee pain only had greater disability than those with ROA only. Quadriceps weakness was observed in all groups compared with normal subjects (p&lt;0.01), though they were no significant intergroup differences. Subjects with knee pain had a greater sway area than those without (p&lt;0.05) but the presence of ROA was not associated with increased postural sway. No differences in proprioceptive acuity were observed between groups. <b>Conclusions:</b> The presence of knee pain has a negative association with quadriceps strength, postural sway, and disability compared with ROA. However, the presence of pain-free ROA has a significant negative influence on relative quadriceps strength and reported disability.
Relationship between LAPTM4B gene polymorphism and susceptibility of gastric cancer
Authors: Y. Liu, Q.-Y. Zhang, N. Qian, R.-L. Zhou
Journal: Annals of Oncology (2006)

Background: A novel gene called LAPTM4B (lysosome-associated protein transmembrane 4β) was mapped to 8q22, and contains seven exons. The 2.25-kb messenger RNA of the gene encodes a putative lysosome-associated protein with four transmembrane regions. There are two alleles of the gene, named as LAPTM4B*1 and LAPTM4B*2. Allele *1 differs from allele *2 in that it contains only one copy of a 19-bp sequence in the 5′ untranslated region (UTR), whereas this sequence is duplicated and tandemly arranged in allele *2. Studies showed that the allelic variation of LAPTM4B was associated with the genetic susceptibility of hepatocellular carcinoma but not with that of esophageal squamous cell carcinoma. This study was designed to investigate the possible association between the allelic variation of LAPTM4B and the genetic susceptibility of gastric cancer.Materials and methods: The genotype of LAPTM4B was analyzed in 350 unrelated healthy adult individuals and 214 patients with gastric cancer by utilizing polymerase chain reaction based on specific primers. The genotypic distribution of LAPTM4B was analyzed by χ2 test.Results: The allelic frequencies of the *2 were 33.88% and 24.14% in the gastric cancer group and the healthy control group, respectively, which was significantly different between the two groups (P < 0.001). There was a significant difference in the overall genotypic distribution between the patients and the controls (P = 0.023). The risk of suffering from gastric cancer was increased 1.819 times in the individuals of the *1/2 genotype [95% confidence interval (CI) 1.273–2.601] and 2.387 times in the individuals of the *2/2 genotype of LAPTM4B (95% CI 1.195–4.767) compared with the *1/1 genotype. No association between the genotypic distribution of LAPTM4B and the clinical information on patients of gastric cancer such as age, pathological type, differentiation classification of TNM, and infection of hepatitis B virus was shown.Conclusion: This study indicated that allele *2 of LAPTM4B might be the risk factor of gastric cancer, which could be associated with genetic susceptibility of gastric cancer.
<i>CD44-SLC1A2</i> Gene Fusions in Gastric Cancer
Authors: Jiong Tao, Nian Tao Deng, Kalpana Ramnarayanan, Baohua Huang, Hue Kian Oh, Siew Hong Leong, Seong Soo Lim, Iain Beehuat Tan, Chia Huey Ooi, Jeanie Wu, Minghui Lee, Shenli Zhang, Sun Young Rha, Hyun Cheol Chung, Duane T. Smoot, Hassan Ashktorab, Oi Lian Kon, Valere Cacheux, Celestial Yap, Nallasivam Palanisamy, Patrick Tan
Journal: Science Translational Medicine (2011)

One partner of a fusion gene found in gastric cancer, CD44-SLC1A2 , may contribute to the tumor’s abnormal metabolism.
Long noncoding intronic RNAs are differentially expressed in primary and metastatic pancreatic cancer
Authors: Ana C Tahira, Márcia S Kubrusly, Michele F Faria, Bianca Dazzani, Rogério S Fonseca, Vinicius Maracaja-Coutinho, Sergio Verjovski-Almeida, Marcel CC Machado, Eduardo M Reis
Journal: Molecular Cancer (2011)

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is known by its aggressiveness and lack of effective therapeutic options. Thus, improvement in current knowledge of molecular changes associated with pancreatic cancer is urgently needed to explore novel venues of diagnostics and treatment of this dismal disease. While there is mounting evidence that long noncoding RNAs (lncRNAs) transcribed from intronic and intergenic regions of the human genome may play different roles in the regulation of gene expression in normal and cancer cells, their expression pattern and biological relevance in pancreatic cancer is currently unknown. In the present work we investigated the relative abundance of a collection of lncRNAs in patients' pancreatic tissue samples aiming at identifying gene expression profiles correlated to pancreatic cancer and metastasis. Methods Custom 3,355-element spotted cDNA microarray interrogating protein-coding genes and putative lncRNA were used to obtain expression profiles from 38 clinical samples of tumor and non-tumor pancreatic tissues. Bioinformatics analyses were performed to characterize structure and conservation of lncRNAs expressed in pancreatic tissues, as well as to identify expression signatures correlated to tissue histology. Strand-specific reverse transcription followed by PCR and qRT-PCR were employed to determine strandedness of lncRNAs and to validate microarray results, respectively. Results We show that subsets of intronic/intergenic lncRNAs are expressed across tumor and non-tumor pancreatic tissue samples. Enrichment of promoter-associated chromatin marks and over-representation of conserved DNA elements and stable secondary structure predictions suggest that these transcripts are generated from independent transcriptional units and that at least a fraction is under evolutionary selection, and thus potentially functional. Statistically significant expression signatures comprising protein-coding mRNAs and lncRNAs that correlate to PDAC or to pancreatic cancer metastasis were identified. Interestingly, loci harboring intronic lncRNAs differentially expressed in PDAC metastases were enriched in genes associated to the MAPK pathway. Orientation-specific RT-PCR documented that intronic transcripts are expressed in sense, antisense or both orientations relative to protein-coding mRNAs. Differential expression of a subset of intronic lncRNAs ( PPP3CB , MAP3K14 and DAPK1 loci ) in metastatic samples was confirmed by Real-Time PCR. Conclusion Our findings reveal sets of intronic lncRNAs expressed in pancreatic tissues whose abundance is correlated to PDAC or metastasis, thus pointing to the potential relevance of this class of transcripts in biological processes related to malignant transformation and metastasis in pancreatic cancer.