Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Similar effects of fatigue induced by a repetitive pointing task on local and remote light touch and pain perception in men and women.

BackgroundWomen involved in repetitive, fatiguing, jobs develop more neck and/or shoulder musculoskeletal disorders than men. Sex differences in the pain response to exercise could contribute to the higher prevalence of neck/shoulder musculoskeletal disorders in women. The objective of this study was to assess sex differences in pain sensitivity following a fatiguing upper limb task. Relationships between measures of fatigue and of the sensitivity to nociceptive and to non-nociceptive stimulations were also explored.MethodsThirty healthy adults (15 women) performed a fatiguing repetitive pointing task with their dominant arm. Upper limb electromyography was recorded from the dominant upper trapezius, anterior deltoid and bicep brachii and from the contralateral tibialis anterior. Before and immediately after the repetitive pointing task, pressure pain and light touch sensitivity thresholds were measured over the same muscles.ResultsElectromyographic signs of fatigue were observed only in the anterior deltoid and biceps brachii muscles. Pressure pain thresholds over both muscles increased slightly (effect size ≤ 0.34), but no changes occurred over the upper trapezius and the tibialis anterior. Light touch thresholds increased moderately to importantly after the repetitive pointing task over all four muscles (effect sizes = 0.58 to 0.87). No sex differences were observed in any sensory variable. Moreover, no or weak correlations (r = -0.27 to 0.39) were observed between electromyographical signs of fatigue, light touch threshold and pressure pain threshold variables.ConclusionsWe observed sex-independent effects of a repetitive upper limb task on the sensitivity to painful and to nonpainful stimuli. Moreover, the hypoalgesia induced by the repetitive pointing task was weak and localized, and did not directly correlate with the induced muscle fatigue. Results suggest that fatigue-related changes in the sensitivity to noxious and innocuous stimuli could not explain women's greater prevalence of neck/shoulder musculoskeletal disorders

Personal non-commercial use only. The Journal of Rheumatology erosive damage

ABSTRACT. Objective. To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking, PTPN22 R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA). Methods. Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage. Results. Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28-1.90, p = 8.5 × 10 -6 ), carriage of at least 1 of the PTPN22 risk alleles (OR 1.50, 95% CI 1.13-2.00, p = 5.5 × 10 -3 ) and both ever smoking and carriage of at least 1 of the PTPN22 risk alleles (OR 2.22, 95% CI 1.69-2.91, p = 8.3 × 10 -9 ). There was no evidence of an association between presence of erosive damage and smoking status or carriage of PTPN22 risk alleles when analyzed overall or separately by ACPA status. Conclusion. This metaanalysis indicates that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction between PTPN22 and smoking with erosive damage, despite evidence that ACPA positivity is associated wit

Metaanalysis of the association of smoking and PTPN22 R620W genotype on autoantibody status and radiological erosions in rheumatoid arthritis

Objective.To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking,PTPN22R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA).Methods.Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage.Results.Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28–1.90, p = 8.5 × 10−6), carriage of at least 1 of thePTPN22risk alleles (OR 1.50, 95% CI 1.13–2.00, p = 5.5 × 10−3) and both ever smoking and carriage of at least 1 of thePTPN22risk alleles (OR 2.22, 95% CI 1.69–2.91, p = 8.3 × 10−9). There was no evidence of an association between presence of erosive damage and smoking status or carriage ofPTPN22risk alleles when analyzed overall or separately by ACPA status.Conclusion.This metaanalysis indicates that both smoking and thePTPN22risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction betweenPTPN22and smoking with erosive damage, despite evidence that ACPA positivity is associated with erosive damage.</jats:sec

40:7; Personal non-commercial use only

ABSTRACT. Objective. To investigate the interrelationships among smoking, protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W (rs2476601) genotype, and anticitrullinated peptide antibody (ACPA) status; and among smoking, PTPN22 R620W genotype, and presence of bone erosions overall and separately by ACPA status in patients with rheumatoid arthritis (RA). Methods. Six studies totaling 2680 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating ACPA status and up to 8 studies totaling 3172 patients with RA were included in a Mantel-Haenszel fixed-effects metaanalysis investigating presence of erosive damage. Results. Evidence was found for an increase in the odds of ACPA positivity for ever smoking (OR 1.56, 95% CI 1.28-1.90, p = 8.5 × 10 -6 ), carriage of at least 1 of the PTPN22 risk alleles (OR 1.50, 95% CI 1.13-2.00, p = 5.5 × 10 -3 ) and both ever smoking and carriage of at least 1 of the PTPN22 risk alleles (OR 2.22, 95% CI 1.69-2.91, p = 8.3 × 10 -9 ). There was no evidence of an association between presence of erosive damage and smoking status or carriage of PTPN22 risk alleles when analyzed overall or separately by ACPA status. Conclusion. This metaanalysis indicates that both smoking and the PTPN22 risk allele are associated with the risk of ACPA positivity. There was insufficient evidence to establish a relationship in either direction between PTPN22 and smoking with erosive damage, despite evidence that ACPA positivity is associated with erosive damage. (First Release May 1 2013

RECOVER: Researching COVID to Enhance Recovery

HOW WILL RECOVER ACHIEVE ITS GOALS? NIH has selected health care institutions across the nation, including MaineHealth , to conduct this study, which is anticipated to enroll a total of 15,000 participants who have or had SARS CoV 2 infection and 2,680 control participants without a SARS CoV 2 infection.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2022/1020/thumbnail.jp

BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers

Complete loss of BRCA1 or BRCA2 function is associated with sensitivity to DNA damaging agents. However, not all BRCA1 and BRCA2 germline mutation-associated tumors respond. Herein we report analyses of 160 BRCA1 and BRCA2 germline mutation-associated breast and ovarian tumors. Retention of the normal BRCA1 or BRCA2 allele (absence of locus-specific loss of heterozygosity (LOH)) is observed in 7% of BRCA1 ovarian, 16% of BRCA2 ovarian, 10% of BRCA1 breast, and 46% of BRCA2 breast tumors. These tumors have equivalent homologous recombination deficiency scores to sporadic tumors, significantly lower than scores in tumors with locus-specific LOH (ovarian, P = 0.0004; breast P &lt; 0.0001, two-tailed Student's t-test). Absence of locus-specific LOH is associated with decreased overall survival in ovarian cancer patients treated with platinum chemotherapy (P = 0.01, log-rank test). Locus-specific LOH may be a clinically useful biomarker to predict primary resistance to DNA damaging agents in patients with germline BRCA1 and BRCA2 mutations.Most tumours associated with germline BRCA1/BRCA2 loss of function mutations respond to DNA damaging agents, however, some do not. Herein, the authors identify that a subset of breast/ovarian tumors retain a normal allele, which is associated with decreased overall survival after DNA damage-inducing platinum chemotherapy