tbuckley/cabot-search huggingface dataset:
The pre-ligand binding assembly domain: a potential target of inhibition of tumour necrosis factor receptor function
Authors: F. K.-M. Chan
Journal: Annals of the Rheumatic Diseases (2000)

Signalling by the tumour necrosis factor receptors (TNFR) is thought to be mediated by the binding of the trimeric ligand TNF to three monomeric subunits of the receptor. This ligand induced trimerisation model of TNFR signalling is mainly supported by crystallographic data of the p60 TNFR-1 and TNFβ complex in which the trimeric ligand interdigitates between the individual receptor chains and prevents the receptor subunits from interacting with each other. Recently, a domain NH<sub>2</sub>-terminal to the ligand binding domain in the extracellular region of p60 TNFR-1, p80 TNFR-2 and Fas was identified that mediates receptor self association before ligand binding. This pre-ligand binding assembly domain or PLAD is critical for assembly of functional receptor complexes on the cell surface and may provide a potential target in the design of future novel therapeutics against diseases mediated by members of the TNFR family of receptors.
Bortezomib Added to R-CVP Is Safe and Effective for Previously Untreated Advanced-Stage Follicular Lymphoma: A Phase II Study by the National Cancer Institute of Canada Clinical Trials Group
Authors: Laurie H. Sehn, David MacDonald, Sheldon Rubin, Guy Cantin, Morel Rubinger, Bernard Lemieux, Sanraj Basi, Kevin Imrie, Randy D. Gascoyne, Jonathan Sussman, Bingshu E. Chen, Marina Djurfeldt, Lois Shepherd, Stephen Couban, Michael Crump
Journal: Journal of Clinical Oncology (2011)

Purpose Bortezomib has demonstrated promising activity in patients with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of bortezomib added to rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in previously untreated advanced-stage FL. Patients and Methods This is a phase II multicenter trial adding bortezomib (1.3 mg/m 2 days 1 and 8) to standard-dose R-CVP (BR-CVP) for up to eight cycles in patients with newly diagnosed stage III/IV FL requiring therapy. Two co-primary end points, complete response rate (complete response [CR]/CR unconfirmed [CRu]) and incidence of grade 3 or 4 neurotoxicity, were assessed. Results Between December 2006 and March 2009, 94 patients were treated with BR-CVP. Median patient age was 57 years (range, 29 to 84 years), and the majority had a high (47%) or intermediate (43%) Follicular Lymphoma International Prognostic Index score. BR-CVP was extremely well tolerated, with 90% of patients completing the intended eight cycles. No patients developed grade 4 neurotoxicity, and only five of 94 patients (5%; 95% CI, 0.8% to 9.9%) developed grade 3 neurotoxicity, which was largely reversible. On the basis of an intention-to-treat analysis, 46 of 94 patients (49%; 95% CI, 38.8% to 59.0%) achieved a CR/CRu, and 32 of 94 patients (34%) achieved a partial response, for an overall response rate of 83% (95% CI, 75.4% to 90.6%). Conclusion The addition of bortezomib to standard-dose R-CVP for advanced-stage FL is feasible and well tolerated with minimal additional toxicity. The complete response rate in this high-risk population compares favorably to historical results of patients receiving R-CVP. Given these results, a phase III trial comparing BR-CVP with R-CVP is planned.
Suppression of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification
Authors: Walter P Maksymowych, Nathalie Morency, Barbara Conner-Spady, Robert G Lambert
Journal: Annals of the Rheumatic Diseases (2012)

Although MRI data supports a link between spinal inflammation and formation of new bone in ankylosing spondylitis, anti-tumour necrosis factor α therapies have not been shown to prevent new bone formation. The authors aimed to demonstrate that while acute lesions resolve completely, more advanced lesions, characterised by evidence of reparation, are associated with new bone formation.MRI scans were performed at baseline, 12 and 52 weeks in 76 ankylosing spondylitis patients recruited to a placebo-controlled trial of adalimumab therapy. New syndesmophytes were assessed on lateral radiographs of the cervical and lumbar spine at baseline and 104 weeks. Anonymised MRI scans were read independently by two readers who recorded the presence/absence of acute (type A) and advanced (type B) vertebral corner inflammatory lesions (CIL) and fat lesions. The authors used generalised linear latent and mixed models analysis to adjust for the extent of syndesmophytes/ankylosis at baseline.New syndesmophytes developed significantly more frequently from type B CIL (16.7%) compared with type A CIL (2.9%) (p=0.002) or no CIL (2.5%) (p<0.0001). This was also observed for both baseline and new vertebral corner fat lesions evolving over 52 weeks (11.1% (p<0.001) and 6.8% (p=0.03), respectively). The association with type B CIL (OR (95% CI 3.88, 1.20 to -12.57) and fat (OR 95% CI 4.83, 2.38- to 9.80), p<0.0001) was significant after adjustment for the extent of syndesmophytes/ankylosis at baseline.Our data supports the hypothesis that new bone formation is more likely in advanced inflammatory lesions and proceeds through a process of fat metaplasia, supporting a window of opportunity for disease modification.
Recurrent Focal Copy-Number Changes and Loss of Heterozygosity Implicate Two Noncoding RNAs and One Tumor Suppressor Gene at Chromosome 3q13.31 in Osteosarcoma
Authors: Ivan Pasic, Adam Shlien, Adam D. Durbin, Dimitrios J. Stavropoulos, Berivan Baskin, Peter N. Ray, Ana Novokmet, David Malkin
Journal: Cancer Research (2010)

Osteosarcomas are copy number alteration (CNA)-rich malignant bone tumors. Using microarrays, fluorescence in situ hybridization, and quantitative PCR, we characterize a focal region of chr3q13.31 (osteo3q13.31) harboring CNAs in 80% of osteosarcomas. As such, osteo3q13.31 is the most altered region in osteosarcoma and contests the view that CNAs in osteosarcoma are nonrecurrent. Most (67%) osteo3q13.31 CNAs are deletions, with 75% of these monoallelic and frequently accompanied by loss of heterozygosity (LOH) in flanking DNA. Notably, these CNAs often involve the noncoding RNAs LOC285194 and BC040587 and, in some cases, a tumor suppressor gene that encodes the limbic system-associated membrane protein (LSAMP). Ubiquitous changes occur in these genes in osteosarcoma, usually involving loss of expression. Underscoring their functional significance, expression of these genes is correlated with the presence of osteo3q13.31 CNAs. Focal osteo3q13.31 CNAs and LOH are also common in cell lines from other cancers, identifying osteo3q13.31 as a generalized candidate region for tumor suppressor genes. Osteo3q13.31 genes may function as a unit, given significant correlation in their expression despite the great genetic distances between them. In support of this notion, depleting either LSAMP or LOC285194 promoted proliferation of normal osteoblasts by regulation of apoptotic and cell-cycle transcripts and also VEGF receptor 1. Moreover, genetic deletions of LOC285194 or BC040587 were also associated with poor survival of osteosarcoma patients. Our findings identify osteo3q13.31 as a novel region of cooperatively acting tumor suppressor genes.
Immunochemotherapy With Rituximab and Overall Survival in Patients With Indolent or Mantle Cell Lymphoma: A Systematic Review and Meta-analysis
Authors: H. Schulz, J. F. Bohlius, S. Trelle, N. Skoetz, M. Reiser, T. Kober, G. Schwarzer, M. Herold, M. Dreyling, M. Hallek, A. Engert
Journal: JNCI Journal of the National Cancer Institute (2007)

Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy (R-chemo) has been shown to improve response rates and progression-free survival in patients with indolent or mantle cell lymphoma. However, the impact of R-chemo on overall survival is unclear. We performed a comprehensive systematic review and meta-analysis to examine the efficacy of combined immunochemotherapy using R-chemo compared with the identical chemotherapy alone with respect to overall survival in patients with advanced indolent lymphoma or mantle cell lymphoma. Medical databases and conference proceedings were searched for randomized controlled trials published from January 1990 through December 2005 that compared R-chemo with chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma or mantle cell lymphoma. We included full-text and abstract publications. Endpoints were overall survival, disease control, overall response, and toxicity. A fixed-effects model was assumed in all meta-analyses. For binary data, the relative risk was used as an indicator of treatment effect, and the Mantel–Haenszel method was used to pool relative risks. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided. Seven randomized controlled trials involving 1943 patients with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas were included in the meta-analysis. Five studies were published as full-text articles, and two were in abstract form. Patients treated with R-chemo had better overall survival (hazard ratio [HR] for mortality = 0.65; 95% confidence interval [CI] = 0.54 to 0.78), overall response (relative risk of tumor response = 1.21; 95% CI = 1.16 to 1.27), and disease control (HR of disease event = 0.62; 95% CI = 0.55 to 0.71) than patients treated with chemotherapy alone. R-chemo improved overall survival in patients with follicular lymphoma (HR for mortality = 0.63; 95% CI = 0.51 to 0.79) and in patients with mantle cell lymphoma (HR for mortality = 0.60; 95% CI = 0.37 to 0.98). However, in the latter case, there was heterogeneity among the trials ( P = .07), making the survival benefit less reliable. In patients with indolent or mantle cell lymphoma, R-chemo is superior to chemotherapy alone with respect to overall survival.
Mechanism of malignant hypercalcaemia in carcinoma of the breast.
Authors: R C Percival, A J Yates, R E Gray, J Galloway, K Rogers, F E Neal, J A Kanis
Journal: BMJ (1985)

To investigate the mechanisms of hypercalcaemia in carcinoma of the breast, 22 patients with hypercalcaemia due to metastatic carcinoma were studied and the findings compared with those obtained in normal subjects and patients with benign and malignant breast disease without hypercalcaemia. As expected, patients with metastases of bone showed biochemical evidence of increased bone resorption. Whereas all patients with hypercalcaemia had skeletal metastases, not all patients with skeletal metastases had hypercalcaemia despite considerable degrees of bone resorption. The presence of hypercalcaemia was associated with a significant increase in renal tubular reabsorption of calcium (p less than 0.001) and decreased reabsorption of phosphate (p less than 0.001) despite adequate rehydration of patients. These studies suggest that increased renal tubular reabsorption of calcium, possibly mediated by a humoral factor with activity similar to that of parathyroid hormone, contributes appreciably to the hypercalcaemia of malignant breast disease.
Transduction of E2F-1 TAT fusion proteins represses expression of hTERT in primary ductal breast carcinoma cell lines
Authors: Kimberly A Elliott, Lee F Rickords, J Marcelete Labrum
Journal: Molecular Cancer (2008)

Abstract Background Telomerase expression is detectable in 81–95% of breast carcinomas and may serve as a therapeutic target. The objective of this study was to investigate repression of telomerase activity in primary ductal breast cancer cells through transcriptional regulation of the catalytic subunit hTERT. We hypothesized that inhibition of telomerase expression could be achieved via Tat mediated protein transduction of the repressor protein E2F-1. Methods Protein purification techniques were refined to yield biologically active Tat fusion proteins (TFPs) capable of transducing the breast cancer cell lines HCC1937 and HCC1599. Cell lines were treated with wildtype E2F-1 (E2F-1/TatHA), mutant E2F-1 (E132/TatHA) and a control Tat peptide (TatHA) for 24 hours. Total RNA was isolated from treated cells, reverse transcribed and fold changes in gene expression for hTERT determined via real-time RT-qPCR. Results Significant repression of the catalytic subunit of telomerase (hTERT) was present in both HCC1937 and HCC1599 cells following treatment with E2F-1/TatHA. In HCC1937 cells, hTERT was repressed 3.5-fold by E2F-1/TatHA in comparison to E132/TatHA (p &lt; 0.0012) and the TatHA peptide controls (p &lt; 0.0024). In HCC1599 cells, hTERT was also repressed with E2F-1/TatHA treatment by 4.0-fold when compared to the E132/TatHA control (p &lt; 0.0001). A slightly lower hTERT repression of 3.3-fold was observed with E2F-1/TatHA in the HCC1599 cells when compared to the TatHA control (p &lt; 0.0001). Conclusion These results suggest that transduction of E2F-1/TatHA fusion proteins in vitro is an effective repressor of hTERT expression in the primary ductal breast cancer cell lines HCC1937 and HCC1599.
Proportions of activities in a climbing gym
Authors: David Humphries
Journal: British Journal of Sports Medicine (2001)

Editor,—I refer to the paper on indoor rock climbing by Wright et al .1 Firstly, thanks to the authors for adding some valuable information to the under researched area of indoor climbing injuries (particularly given the popularity of this activity world wide).

While I have no doubt that many of your participants put leading or bouldering as the activity that they spent most time doing while in the gym, I would have significant doubts that that is actually the case, particularly in lower grade climbers. I suspect that the participants in …
No problem for Aristotle's subject and predicate
Authors: Guy Politzer
Journal: Behavioral and Brain Sciences (2003)

It is argued that, in the traditional subject-predicate sentence, two interpretations of the subject term coexist, one intensional and the other extensional, which explains the superficial difference between the traditional S-P relation and the predication of predicate logic. Data from psychological studies of syllogistic reasoning support the view that the contrast between predicate and argument is carried over to the traditional S-P sentence.
Response to Comment on Heianza et al. Effect of Postmenopausal Status and Age at Menopause on Type 2 Diabetes and Prediabetes in Japanese Individuals: Toranomon Hospital Health Management Center Study 17 (TOPICS 17). Diabetes Care 2013;36:4007–4014
Authors: Yoriko Heianza, Hirohito Sone
Journal: Diabetes Care (2014)

We thank Akter et al. (1) for their interest in our study (2). While we agree that the mean age was higher in the postmenopausal women than in the premenopausal women, results of our additional analysis of the 10,878 women showed that independently of older age (≥50 years) and demographic and metabolic factors (BMI, parental history of diabetes, physical activity habit, smoking habit, hypertension, log-transformed triglycerides, and HDL cholesterol) the postmenopausal state was associated with a 1.50 (95% CI 1.30–1.74) higher probability of the presence of dysglycemia (either type 2 diabetes or prediabetes) compared with premenopausal women. Admittedly, and as Akter et al. suggested, the association was attenuated (odds …
Metabonomics adds a new dimension to fragile × syndrome
Authors: Inge Heulens, Sien Braat, R Frank Kooy
Journal: Genome Medicine (2011)

Fragile X syndrome is the most common cause of inherited intellectual disability, but the underlying pathophysiology is complex and effective treatments are lacking. In a recent study of fragile X mental retardation 1 (Fmr1) knockout mice, the metabolic profile of the fragile X brain was determined using proton high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. This analysis revealed deficiencies in four metabolic categories: neurotransmission, osmoregulation, energy metabolism and oxidative stress response. Abnormalities in the metabolic phenotype were linked to the fragile X mental retardation protein using an integrated metabolome and interactome mapping approach, allowing a global picture of the disorder to emerge.
Malignant histiocytosis and encephalomyeloradiculopathy complicating coeliac disease.
Authors: M Camilleri, T Krausz, P D Lewis, H J Hodgson, C A Pallis, V S Chadwick
Journal: Gut (1983)

A 62 year old Irish woman with an eight year history of probable coeliac disease developed brain stem signs, unilateral facial numbness and weakness, wasting and anaesthesia in both lower limbs. Over the next two years, a progressive deterioration in neurological function and in intestinal absorption, and the development of anaemia led to a suspicion of malignancy. Bone marrow biopsy revealed malignant histiocytosis. Treatment with cytotoxic drugs led to a transient, marked improvement in intestinal structure and function, and in power of the lower limbs. Relapse was associated with bone marrow failure, resulting in overwhelming infection. Post mortem examination confirmed the presence of an unusual demyelinating encephalomyelopathy affecting the brain stem and the posterior columns of the spinal cord.
Genome-wide Profiling of AP-1–Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer
Authors: Chunyan Zhao, Yichun Qiao, Philip Jonsson, Jian Wang, Li Xu, Pegah Rouhi, Indranil Sinha, Yihai Cao, Cecilia Williams, Karin Dahlman-Wright
Journal: Cancer Research (2014)

Triple-negative breast cancer (TNBC) is an aggressive clinical subtype accounting for up to 20% of all breast cancers, but its malignant determinants remain largely undefined. Here, we show that in TNBC the overexpression of Fra-1, a component of the transcription factor AP-1, offers prognostic potential. Fra-1 depletion or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes of TNBC cells in vitro. Similarly, RNAi-mediated attenuation of Fra-1 or c-Jun reduced cellular invasion in vivo in a zebrafish tumor xenograft model. Exploring the AP-1 cistrome and the AP-1-regulated transcriptome, we obtained insights into the transcriptional regulatory networks of AP-1 in TNBC cells. Among the direct targets identified for Fra-1/c-Jun involved in proliferation, adhesion, and cell-cell contact, we found that AP-1 repressed the expression of E-cadherin by transcriptional upregulation of ZEB2 to stimulate cell invasion. Overall, this work illuminates the pathways through which TNBC cells acquire invasive and proliferative properties.
Targeting ABL1-Mediated Oxidative Stress Adaptation in Fumarate Hydratase-Deficient Cancer
Authors: Carole Sourbier, Christopher J. Ricketts, Shingo Matsumoto, Daniel R. Crooks, Pei-Jyun Liao, Philip Z. Mannes, Youfeng Yang, Ming-Hui Wei, Gaurav Srivastava, Sanchari Ghosh, Viola Chen, Cathy D. Vocke, Maria Merino, Ramaprasad Srinivasan, Murali C. Krishna, James B. Mitchell, Ann Marie Pendergast, Tracey A. Rouault, Len Neckers, W. Marston Linehan
Journal: Cancer Cell (2014)
Flat Adenomas in a Colon Cancer-Prone Kindred1
Authors: H. T. Lynch, T. Smyrk, S. J. Lanspa, J. N. Marcus, M. Kriegler, J. F. Lynch, H. D. Appelman
Journal: JNCI Journal of the National Cancer Institute (1988)

We describe new pathologic findings in a hereditary nonpolyposis colorectal cancer family. Affected family members developed multiple small adenomas with right-sided predominance; many adenomas had an unusual appearance featuring slightly elevated lesions with adenomatous changes confined to the upper regions of the colonic crypts. We have adopted the previously established term "flat adenoma" for these lesions. This phenotype may be a morphologic marker for at least one subset of hereditary nonpolyposis colorectal cancer. [J Natl Cancer Inst 1988;80:278–282]
Next-Generation Sequencing for the Identification of Targetable Molecular Alterations in Cancer
Authors: Martin F. Dietrich, Robert H. Collins, David E. Gerber
Journal: JAMA Oncology (2015)

This diagnostic challenge describes a patient who presented with progressive inguinal lymphadenopathy and a leukocytosis of 144 000/µL with 97% lymphocytes who eventually achieved complete remission but experienced disease recurrence 6 months later.
A transgenic rabbit model for human hypertrophic cardiomyopathy
Authors: Ali J. Marian, Yun Wu, Do-Sun Lim, Meghan McCluggage, Keith Youker, Qun-tao Yu, Ramon Brugada, Francesco DeMayo, Miguel Quinones, Robert Roberts
Journal: Journal of Clinical Investigation (1999)

Certain mutations in genes for sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). We have developed a transgenic rabbit model for HCM caused by a common point mutation in the β-myosin heavy chain (MyHC) gene, R400Q. Wild-type and mutant human β-MyHC cDNAs were cloned 3′ to a 7-kb murine β-MyHC promoter. We injected purified transgenes into fertilized zygotes to generate two lines each of the wild-type and mutant transgenic rabbits. Expression of transgene mRNA and protein were confirmed by Northern blotting and 2-dimensional gel electrophoresis followed by immunoblotting, respectively. Animals carrying the mutant transgene showed substantial myocyte disarray and a 3-fold increase in interstitial collagen expression in their myocardia. Mean septal thicknesses were comparable between rabbits carrying the wild type transgene and their nontransgenic littermates (NLMs) but were significantly increased in the mutant transgenic animals. Posterior wall thickness and left ventricular mass were also increased, but dimensions and systolic function were normal. Premature death was more common in mutant than in wild-type transgenic rabbits or in NLMs. Thus, cardiac expression of β-MyHC-Q403 in transgenic rabbits induced hypertrophy, myocyte and myofibrillar disarray, interstitial fibrosis, and premature death, phenotypes observed in humans patients with HCM due to β-MyHC-Q403.
The sickly Stuarts
Authors: E D Myers
Journal: Journal of the Royal Society of Medicine (2004)

Neither in Milo Keynes' review of Professor Holmes' book The Sickly Stuarts—the Medical Downfall of a Dynasty (June 2004 JRSM1) nor in Graham Brack's comments on the review (August 2004 JRSM2) is mention made of Holmes' view of the hypothesis that James VI/I suffered from familial porphyria. Having described the renal findings at the necropsy of James VI/I, Holmes writes 'this finding negates and lays to rest the presumption of Dr Ida Macalpine and her colleagues that James and his mother had acute intermittent porphyria... unfortunately this idea has had a life of its own....' Having cited publications opposing the porphyria hypothesis, Holmes concludes 'James did not have porphyria. Nor, for that matter, did any of the Stuarts or Hanoverians'. In the subsequent paragraph, he states 'The clinical description of de Mayerne and the autopsy report of Walton provide a clear description of chronic kidney stone disease'.3

Although Macalpine and Hunter4 are supported by Rohl, Warren and Hunt,5 Holmes' contrary view needs to be made known to a wider readership than those who have read his book.
Applications of Codon and Rate Variation Models in Molecular Phylogeny
Authors: Eric E. Schadt, Janet S. Sinsheimer, Kenneth Lange
Journal: Molecular Biology and Evolution (2002)

Abstract The current article illustrates the practical advantages of some new models and statistical algorithms for codon substitution and spatial rate variation in molecular phylogeny. Our companion paper in this issue discusses at length the mathematical properties of these models for nucleotide and codon substitution, for site-to-site and branch-to-branch heterogeneity in rates of evolution, and for spatial correlation in the assignment of rates. In this study we summarize the theoretical background and apply the models and algorithms to data on β-globin, the complete HIV genome, and the mitochondrial genome. Our complex but realistic models enhance biological interpretation of sequence data and show substantial improvements in model fit over existing models. All the new statistical algorithms applied are incorporated in our phylogeny software LINNAEUS, which is tuned for performance and modeling flexibility.