tbuckley/cabot-search huggingface dataset:
Cancer Biomarkers: Can We Turn Recent Failures into Success?
Authors: E. P. Diamandis
Journal: JNCI Journal of the National Cancer Institute (2010)

Disease biomarkers are used widely in medicine. But very few biomarkers are useful for cancer diagnosis and monitoring. Over the past 15 years, major investments have been made to discover and validate cancer biomarkers. Despite such investments, no new major cancer biomarkers have been approved for clinical use for at least 25 years. In the last decade, many reports have described new cancer biomarkers that promised to revolutionize the diagnosis of cancer and the management of cancer patients. However, many initially promising biomarkers have not been validated for clinical use. In this commentary, a plethora of parameters before sample analysis, during sample analysis, and after sample analysis that can complicate biomarker discovery and validation and lead to "false discovery" are discussed. Several examples of biomarker discoveries that were published in high-profile journals are also presented, as well as why they were not validated and the lessons learned from these false discoveries, so that similar mistakes can be avoided in the future.
Compensatory Evolution in RNA Secondary Structures Increases Substitution Rate Variation among Sites
Authors: J. L. Knies, K. K. Dang, T. J. Vision, N. G. Hoffman, R. Swanstrom, C. L. Burch
Journal: Molecular Biology and Evolution (2008)

There is growing evidence that interactions between biological molecules (e.g., RNA–RNA, protein–protein, RNA–protein) place limits on the rate and trajectory of molecular evolution. Here, by extending Kimura's model of compensatory evolution at interacting sites, we show that the ratio of transition to transversion substitutions (κ) at interacting sites should be equal to the square of the ratio at independent sites. Because transition mutations generally occur at a higher rate than transversions, the model predicts that κ should be higher at interacting sites than at independent sites. We tested this prediction in 10 RNA secondary structures by comparing phylogenetically derived estimates of κ in paired sites within stems (κp) and unpaired sites within loops (κu). Eight of the 10 structures showed an excellent match to the quantitative predictions of the model, and 9 of the 10 structures matched the qualitative prediction κp > κu. Only the Rev response element from the human immunovirus (HIV) genome showed the reverse pattern, with κp < κu. Although a variety of evolutionary forces could produce quantitative deviations from the model predictions, the reversal in magnitude of κp and κu could be achieved only by violating the model assumption that the underlying transition (or transversion) mutation rates were identical in paired and unpaired regions of the molecule. We explore the ability of the APOBEC3 enzymes, host defense mechanisms against retroviruses, which induce transition mutations preferentially in single-stranded regions of the HIV genome, to explain this exception to the rule. Taken as a whole, our findings suggest that κ may have utility as a simple diagnostic to evaluate proposed secondary structures.
Anterior cruciate ligament rupture: is osteoarthritis inevitable?
Authors: J Feller
Journal: British Journal of Sports Medicine (2004)

Anterior cruciate ligament rupture, whether treated surgically or not, is associated with an increase in osteoarthritis in former soccer players

Alarming is the word Von Parat, Roos, and Roos choose to describe their findings of significant knee osteoarthritis in middle aged former soccer players who had sustained a rupture of the anterior cruciate ligament more than a decade previously.1 Not only was there a high incidence of osteoarthritis in these former players, but reconstruction of the anterior cruciate ligament did not appear to provide protection from degenerative change in the knee.

In a 14 year follow up of subjects who had formed the basis of an earlier study,2 the authors identified 238 male soccer players who were diagnosed with anterior cruciate ligament injuries in 1986. They were able to contact 205 of the players. Of these, 154 answered questionnaires and a further subgroup of 122 consented to have knee radiographs.

In just over half of the 95 subjects with radiographic changes, there was osteoarthritis equivalent to Kellgren-Lawrence grade 2 or higher. Of the subjects who answered questionnaires, 58% had undergone anterior cruciate ligament reconstruction. Interestingly, and perhaps surprisingly, there was no difference in radiographic outcome between those that had been treated with anterior cruciate ligament reconstruction and those who had not undergone reconstructive surgery. On the other hand, subjects who had sustained a meniscal tear had an increased prevalence of osteoarthritis, but the severity of radiographic changes was similar to those who did not have meniscal pathology associated with their anterior cruciate ligament rupture. …
Systemic Deletion of the Myelin-Associated Outgrowth Inhibitor Nogo-A Improves Regenerative and Plastic Responses after Spinal Cord Injury
Authors: Marjo Simonen, Vera Pedersen, Oliver Weinmann, Lisa Schnell, Armin Buss, Birgit Ledermann, Franziska Christ, Gilles Sansig, Herman van der Putten, Martin E Schwab
Journal: Neuron (2003)
Antifibroblast antibodies from systemic sclerosis patients bind to α-enolase and are associated with interstitial lung disease
Authors: B Terrier, M C Tamby, L Camoin, P Guilpain, A Bérezné, N Tamas, C Broussard, F Hotellier, M Humbert, G Simonneau, L Guillevin, L Mouthon
Journal: Annals of the Rheumatic Diseases (2009)

Objective: To identify target antigens of antifibroblast antibodies (AFA) in systemic sclerosis (SSc) patients. Patients and Methods: In the first part, sera from 24 SSc patients (12 with pulmonary arterial hypertension (PAH) and 12 without) and 36 idiopathic PAH patients, tested in pooled sera for groups of three, were compared with a sera pool from 14 healthy controls (HC). Serum IgG reactivity was analysed by the use of a two-dimensional electrophoresis and immunoblotting technique with normal human fibroblasts antigens. In the second part, serum IgG reactivity for two groups: 158 SSc, 67 idiopathic PAH and 100 HC; and 35 SSc and 50 HC was tested against α-enolase from Saccharomyces cerevisiae and recombinant human (rHu) α-enolase, respectively, on ELISA. Results: In the first part, α-enolase was identified as a main target antigen of AFA from SSc patients. In the second part, 37/158 (23%) SSc patients, 6/67 (9%) idiopathic PAH patients and 4/100 (4%) HC (p&lt;0.001) had anti- S cerevisiae α-enolase antibodies; 12/35 (34%) SSc patients and 3/50 (6%) HC had anti-rHu α-enolase antibodies (p = 0.001). In SSc, the presence of anti- S cerevisiae α-enolase antibodies was associated with interstitial lung disease (ILD), decreased total lung capacity (73.2% vs 89.7%; p&lt;0.001) and diffusion capacity for carbon monoxide (47.4% vs 62.3%; p&lt;0.001), and antitopoisomerase 1 antibodies (46% vs 21%; p = 0.005) but not anticentromere antibodies (11% vs 34%; p = 0.006). Results were similar with rHu α-enolase testing. Conclusion: In SSc, AFA recognise α-enolase and are associated with ILD and antitopoisomerase antibodies.
Evidence for negative association of the chemokine receptor CCR5 d32 polymorphism with rheumatoid arthritis
Authors: V Pokorny
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> Ligands of chemokine receptor CCR5, including MIP-1α, MIP-1β, and RANTES, have been implicated in rheumatoid arthritis. <b>Objective:</b> To test whether CCR5 d32 polymorphism has a negative association with rheumatoid arthritis in a New Zealand cohort. <b>Methods:</b> 516 white patients with rheumatoid arthritis and 985 healthy controls were investigated by PCR amplification of the region flanking the known CCR5 d32 deletion, and the frequencies of <i>CCR5 d32</i> compared. An early rheumatoid arthritis (ERA) cohort of 92 patients was followed prospectively for two years; disease severity and outcome were correlated with <i>CCR5 d32</i> status. <b>Results:</b> 12 control subjects (1.2%) were homozygous for d32; no d32 homozygous rheumatoid patients were detected (p = 0.012); 56 patients (10.9%) were heterozygous for the d32 polymorphism (d32/wt), compared with 169 controls (17.2%) (p = 0.0011). The CCR5 d32 allele frequency was lower in the rheumatoid patients than in the controls (frequencies of 0.054 and 0.098, respectively; p = 3.7×10<sup>−5</sup>). The frequency of <i>CCR5 d32</i> did not differ significantly according to disease severity or outcome in the prospective ERA cohort, nor with HLA-DRB1 status. <b>Conclusions:</b> This study provides further evidence for a protective effect of the CCR5 d32 variant on rheumatoid arthritis, consistent with a role for CCR5 and its ligands in disease pathogenesis.
Functional analysis of the antigen binding site on the T cell receptor alpha chain.
Authors: E A Nalefski, S Kasibhatla, A Rao
Journal: The Journal of Experimental Medicine (1992)

We have identified residues on a T cell receptor (TCR) alpha chain that are important for interaction with antigen/major histocompatibility complex (MHC). Using site-directed mutagenesis, we modified DNA encoding the postulated antigen/MHC binding loops on the TCR alpha chain expressed by the T cell clone D5, which recognizes p-azobenzenearsonate-conjugated antigens presented by cells bearing I-Ad. These variant TCR alpha chains were expressed in conjunction with the wild-type D5 TCR beta chain on the surface of hybridoma cells, and were tested for the ability to recognize hapten-conjugated antigens presented by I-Ad. Individual amino acid substitutions in each of the three antigen binding loops (alpha 1, alpha 2, alpha 3) of the D5 TCR alpha chain affected antigen recognition, demonstrating that all three loops are important in recognition of antigen/MHC. A subset of the single amino acid substitutions completely eliminated antigen recognition, thus identifying the residues that are particularly important in the recognition of antigenic peptide/MHC by the D5 TCR. Because the wild-type D5 TCR recognizes arsonate and certain structural analogues of arsonate conjugated to a variety of protein antigens, we were able to test whether the TCR substitutions affected the specificity of the D5 TCR for hapten or carrier antigen. One substitution introduced into antigen binding loop alpha 3 markedly altered the pattern of carrier recognition. Together, these results verify the Ig model for the TCR and are consistent with the proposition that residues forming the first and second antigen binding loops of the TCR contact the MHC, while those forming the third loop contact mainly antigenic peptides.
Mobilization/transplantation of Ph1-negative blood progenitor cells in chronic myelogenous leukaemia
Authors: A.M. Carella, M. Podestà, E. Lerma, A. Dejana, E. Prencipe, F. Vassallo, C. Crescenti, M. Soracco, F. Benvenuto, F. Chimirri, P. Carlier, G. Florio, M. Valbonesi, F. Frassoni
Journal: Annals of Oncology (1996)
Quantification of stratum corneum ceramides and lipid envelope ceramides in the hereditary ichthyoses
Authors: D.G. PAIGE, N. MORSE-FISHER, J.I. HARPER
Journal: British Journal of Dermatology (1994)

Summary Ceramides (sphingolipids) are the main polar lipids of the stratum corneum and play an important role in skin barrier function, cell adhesion and epidermal differentiation. In view of the function of ceramides in normal skin, this study aimed to assess their levels in patients with various types of hereditary ichthyosis, in which epidermal homeostasis is markedly abnormal. Stratum corneum samples were collected from 80 patients and 23 normal controls, and the intercellular and lipid envelope ceramides were analysed by high-performance thin-layer chromatography. The covalently bound ceramides (ceramides A and B) of the lipid envelope were present in all patients studied, and showed no significant differences from control samples. Total ceramides (ceramides 1–6) were decreased in bullous ichthyosiform erythroderma, which is presumably a secondary phenomenon similar to that seen in patients with atopic dermatitis. Patients with non-erythrodermic lamellar ichthyosis showed a marked decrease in levels of the important acylceramide, ceramide 1, whereas those with other types of autosomal recessive ichthyosis (limited lamellar ichthyosis and non-bullous ichthyosiform erythroderma) had mean levels similar to the controls. Ceramide 1 deficiency may therefore define a subgroup within the autosomal recessive ichthyoses. Sjögren-Larsson syndrome (SLS) shows a deficiency of both acyl-ceramides (ceramides 1 and 6), which would seem likely to disrupt the normal skin barrier function. Furthermore, glucosyl-ceramides (cerebrosides) are known to be deficient in the neural tissue of patients with SLS. The relationship of these ceramide abnormalities to the underlying fatty alcohol oxidoreductase defect remains uncertain, but they may provide an interesting link between the nerve damage and cutaneous abnormalities seen in this rare neurodermatosis.
Differences in Cardiovascular Risk Profile of Diabetic Subjects Discordantly Classified by Diagnostic Criteria Based on Glycated Hemoglobin and Oral Glucose Tolerance Test
Authors: Mauro Boronat, Pedro Saavedra, Laura López-Ríos, Marta Riaño, Ana M. Wägner, Francisco J. Nóvoa
Journal: Diabetes Care (2010)

To characterize the cardiovascular risk profile of subjects categorized differently by A1C- and oral glucose tolerance test (OGTT)-based diagnostic criteria for diabetes according to the recommendations of the American Diabetes Association (ADA).An OGTT, A1C, and several cardiovascular risk factors were assessed in 964 individuals without known diabetes participating in a cross-sectional epidemiological survey in Gran Canaria, Spain.Taking the OGTT as the gold standard, the sensitivity and specificity of an A1C value ≥ 6.5% were 38.7 and 99.6%, respectively. Subjects who fulfilled A1C-based criterion presented greater measures of BMI and waist circumference, lower values for HDL cholesterol, and higher values for fasting plasma glucose, homeostasis model assessment of insulin resistance, and fibrinogen than subjects with diabetic OGTT but A1C <6.5%.Newly diagnosed diabetic individuals who fulfill A1C-based diagnostic criterion for the disease display a more unfavorable cardiovascular risk profile than individuals who only meet the glucose-based criteria.
Mutations in the Epidermal Growth Factor Receptor and in KRAS Are Predictive and Prognostic Indicators in Patients With Non–Small-Cell Lung Cancer Treated With Chemotherapy Alone and in Combination With Erlotinib
Authors: David A. Eberhard, Bruce E. Johnson, Lukas C. Amler, Audrey D. Goddard, Sherry L. Heldens, Roy S. Herbst, William L. Ince, Pasi A. Jänne, Thomas Januario, David H. Johnson, Pam Klein, Vincent A. Miller, Michael A. Ostland, David A. Ramies, Dragan Sebisanovic, Jeremy A. Stinson, Yu R. Zhang, Somasekar Seshagiri, Kenneth J. Hillan
Journal: Journal of Clinical Oncology (2005)

Purpose Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non–small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described. Patients and Methods Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses. Results EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P &lt; .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P &lt; .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy–treated patients. Conclusion EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.
Structure and Function of Myelin Protein Genes
Authors: K Mikoshiba, H Okano, T A Tamura, K Ikenaka
Journal: Annual Review of Neuroscience (1991)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Hypertriglyceridemia in the Genomic Era: A New Paradigm
Authors: Gary F. Lewis, Changting Xiao, Robert A. Hegele
Journal: Endocrine Reviews (2015)

Hypertriglyceridemia (HTG) is a highly prevalent condition that is associated with increased cardiovascular disease risk. HTG may arise as a result of defective metabolism of triglyceride-rich lipoproteins and their remnants, ie, impaired clearance, or increased production, or both. Current categorization of HTG segregates primary and secondary cases, implying genetic and nongenetic causes for each category. Many common and rare variants of the genes encoding factors involved in these pathways have been identified. Although monogenic forms of HTG do occur, most cases are polygenic and often coexist with nongenetic conditions. Cumulative, multiple genetic variants can increase the risks for HTG, whereas environmental and lifestyle factors can force expression of a dyslipidemic phenotype in a genetically susceptible person. HTG states are therefore best viewed as a complex phenotype resulting from the interaction of cumulated multiple susceptibility genes and environmental stressors. In view of the heterogeneity of the HTG states, the absence of a unifying metabolic or genetic abnormality, overlap with the metabolic syndrome and other features of insulin resistance, and evidence in some patients that accumulation of numerous small-effect genetic variants determines whether an individual is susceptible to HTG only or to HTG plus elevated low-density lipoprotein cholesterol, we propose that the diagnosis of primary HTG and further delineation of familial combined hyperlipidemia from familial HTG is neither feasible nor clinically relevant at the present time. The hope is that with greater understanding of genetic and environmental causes and their interaction, therapy can be intelligently targeted in the future.
Relative risk analysis of angiographic predictors of restenosis within the coronary Wallstent.
Authors: B H Strauss, P W Serruys, I K de Scheerder, J G Tijssen, M E Bertrand, J Puel, B Meier, U Kaufmann, J C Stauffer, A F Rickards
Journal: Circulation (1991)

BACKGROUND Late angiographic narrowing has been observed following coronary implantation of the Wallstent. To identify the angiographic variables that predict restenosis within the stented segment, a retrospective study of data from the European Wallstent core laboratory was performed. METHODS AND RESULTS Follow-up angiograms (excluding patients with in-hospital occlusions) were analyzed for 214 lesions in 176 patients (78% restudy rate). The incidence of restenosis within the stented segment was 35% by lesion and 35% by patient for criterion 1 (greater than or equal to 0.72 mm loss in minimal luminal diameter) and 24% by lesion and 24% by patient for criterion 2 (diameter stenosis greater than or equal to 50% at follow-up). The association between 16 variables and restenosis was determined by a relative risk ratio assessment. Variables with significant risk ratios for restenosis with criterion 1 were use of multiple stents/lesion (relative risk, 1.56; 95% confidence interval [CI], 1.08-2.25) and oversized (unconstrained stent diameter exceeding reference diameter greater than 0.7 mm) stents (relative risk, 1.64; 95% CI, 1.10-2.45), and for criterion 2, oversizing by more than 0.70 mm (relative risk, 1.93; 95% CI, 1.13-3.31), bypass grafts (relative risk, 1.62; 95% CI, 0.98-2.66), use of multiple stents/lesion (relative risk, 1.61; 95% CI, 0.97-2.67) and residual diameter stenosis more than 20% post stenting (relative risk, 1.51; 95% CI, 0.91-2.50). CONCLUSIONS It is concluded that several angiographic variables are significantly associated with late angiographic narrowing after stenting in the coronary arteries. We suggest that stent operators avoid excessive oversizing in the selection of stent diameter and the use of multiple stents per lesion to lessen the risk of late restenosis.
Evidence for Archaic Asian Ancestry on the Human X Chromosome
Authors: Daniel Garrigan, Zahra Mobasher, Tesa Severson, Jason A. Wilder, Michael F. Hammer
Journal: Molecular Biology and Evolution (2004)

The human RRM2P4 pseudogene has a pattern of nucleotide polymorphism that is unlike any locus published to date. A gene tree constructed from a 2.4-kb fragment of the RRM2P4 locus sequenced in a sample of 41 worldwide humans clearly roots in East Asia and has a most-recent common ancestor approximately 2 Myr before present. The presence of this basal lineage exclusively in Asia results in higher nucleotide diversity among non-Africans than among Africans. A global survey of a single-nucleotide polymorphism that is diagnostic for the basal, Asian lineage in 570 individuals shows that it occurs at frequencies up to 53% in south China, whereas only one of 177 surveyed Africans carries this archaic lineage. We suggest that this ancient lineage is a remnant of introgressive hybridization between expanding anatomically modern humans emerging from Africa and archaic populations in Eurasia.