Citations

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

AbstractRecently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBPα transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBPα-p30 isoform, which is produced from the N-terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the microRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBPα-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumorigenic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBPα-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy.

Background We have recently reported that interpositional synovium grafts from tendon sheath have a potential to accelerate tendon healing when implanted at the repair site. The purpose of this study was to investigate the effect of orientation of the synovium after synovium graft transplantation, by comparing the ability of cells from the visceral and parietal surfaces to migrate into the tendon in a canine tissue culture model. Methods The synovium graft was placed within a complete tendon laceration, with either the visceral or parietal surface facing the proximal end of the lacerated tendon. The number of migrating cells was quantified by a cell migration assay. Qualitative immunohistochemistry and confocal laser microscopy were also used at day 10. Results Many labeled synovial cells were observed within the tendon to which the visceral surface of the synovium graft was facing. Migrated cells were also observed on the parietal side, but there were fewer cells compared to visceral surface cells. Migrating cells all expressed α-smooth muscle actin. Conclusion We found that graft orientation affected cell migration. Whether this finding has clinical significance awaits in vivo study.

Abstract Biomarkers are lacking for identifying the switch of transforming growth factor-beta (TGF-β) from tumor-suppressing to tumor-promoting. Mutated p53 (mp53) has been suggested to switch TGF-β to a tumor promoter. However, we found that mp53 does not always promote the oncogenic role of TGF-β. Here, we show that endogenous mp53 knockdown enhanced cell migration and phosphorylation of ERK in DU145 prostate cancer cells. Further, ectopic expression of mp53 in p53-null PC-3 prostate cancer cells enhanced Smad-dependent signaling, but inhibited TGF-β-induced cell migration by downregulating activated ERK. Reactivation of ERK by the expression of its activator, MEK-1, restored TGF-β-induced cell migration. Since TGF-β is known to activate MAPK/ERK pathway through direct phosphorylation of adaptor protein ShcA and MAPK/ERK signaling is pivotal to tumor progression, we investigated whether ShcA contributed to mp53-induced ERK inhibition and the conversion of TGF-β's role during carcinogenesis. We found that mp53 expression led to decrease of phosphorylated p52ShcA/ERK levels and increase of phosphorylated Smad levels in a panel of mp53-expressing cancer cell lines, and in mammary glands and tumors from mp53 knock-in mice. By manipulating ShcA levels to regulate ERK and Smad signaling in human untransformed and cancer cell lines, we show that TGF-β's role in regulating anchorage-dependent and -independent growth, and migration, can be shifted between growth suppression and migration promotion. Thus, our results, for the first time, suggest that mp53 disrupts ShcA's role in balancing Smad-dependent and -independent signaling activity of TGF-β and that ShcA/ERK signaling is a major pathway regulating the tumor-promoting activity of TGF-β. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1069. doi:1538-7445.AM2012-1069

Abstract Background NKTR-102 is a next-generation topoisomerase I inhibitor-polymer conjugate with a markedly reduced Cmax and a continuous exposure profile compared to irinotecan. A phase 2 trial of single-agent NKTR-102 compared a dose of 145 mg/m2 every 2w or every 3w in 3rd-line MBC (Awada et al, ASCO 2011). Overall the ORR was 29% (including 3% CR) with the prior ATC subset demonstrating an ORR of 31%. Dosing every 3w was better tolerated; in this arm, median PFS equaled 5.3m and median OS equaled 13.1m. Trial Design: NKTR-102 will be compared to TPC in an open-label, randomized, parallel, two arm multicenter Phase 3 pivotal study in pts with previously treated locally recurrent or metastatic breast cancer. Key Entry Criteria: Adult females, with ECOG 0 or 1 with adequate liver, kidney and marrow function. All patients must have received prior therapy with an anthracycline (in neo/adjuvant or metastatic setting or both), a taxane (in neo/adjuvant or metastatic setting or both) and capecitabine (in neo/adjuvant or locally advanced/metastatic setting or both) unless not medically appropriate or explicitly contraindicated for the patient. All chemotherapy- and radiation-related toxicities must have resolved to ≤ Grade 1, except for stable sensory neuropathy ≤ Grade 2 and alopecia. Pts with brain metastases may be eligible, if stable for prior 4 weeks without steroids. Pts with Grade ≥ 2 pre-existing diarrhea or receiving chronic anti-diarrheal supportive care are not eligible. Statistical Methods: The primary efficacy endpoint is OS. Secondary endpoints include ORR by RECIST v1.1 and PFS. Pts will be randomized 1:1 to NKTR-102 given IV at 145 mg/m2 over 90-min every 21 days or TPC. Patients randomized to TPC will receive single agent chemotherapy, limited to choice of one of the following 5 agents: eribulin, ixabepilone, vinorelbine, gemcitabine, or a taxane. The investigator must decide which agent will be given to the patient prior to randomization. Pts will be stratified by geographical region and disease characteristics. Target Accrual: Approximately 840 patients (420 pts per treatment arm) will be randomized in order to obtain 615 deaths (alpha = 0.05; power 90% with one interim analysis scheduled when 50% of the deaths have occurred). PK sampling will be performed in a subset of pts and blood and/or tumor samples are planned for potential predictive markers of response and toxicity. Enrollment is expected to remain open until the end of 2013. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-07.

The purpose of this study was to compare two different methods of joining tendons of similar and dissimilar sizes between recipient and donor tendons for flexor tendon grafts. Flexor digitorum profundus (FDP) and peroneus longus (PL) canine tendons were harvested and divided into four groups. The repair technique we compared was a step-cut (SC) suture and a Pulvertaft weave (PW). FDP tendons were significantly larger in diameter than PL tendons ( p < 0.05). The volume of the SC repairs using either FDP or PL tendon as a graft was significantly smaller than PW repairs ( p < 0.05). The ultimate load to failure and repair stiffness in FDP graft tendons significantly increased compared with the PL graft tendons ( p < 0.05). The SC suture can be used as an alternative to the PW, with similar strength and less bulk for repairs using graft tendons of similar diameter. Surgeons should be aware of the effect of graft tendon size and repair method on strength and bulk when performing flexor tendon grafts.

Purpose Evidence has suggested a clinically meaningful relationship between self-reported quality of life (QOL) of a patient with cancer at the time of receiving a cancer diagnosis and overall survival (OS). This study evaluated the prognostic value of QOL assessments with regard to OS in a large cohort of patients with lung cancer. Patients and Methods A total of 2,442 patients with non–small-cell lung cancer were observed between 1997 and 2007 and completed a single-item measure of overall QOL within the first 6 months of receiving a lung cancer diagnosis; these were dichotomized using an a priori definition of a clinically deficient score (CDS; ≤ 50 v > 50). Kaplan-Meier estimates and Cox models were used to evaluate the prognostic importance of QOL on OS alone and in the presence of covariates. Logistic regression modeling was used to identify which clinical and patient characteristics were related to a clinically meaningful deficit in QOL. Results QOL deficits at time of lung cancer diagnosis were significantly associated with OS (hazard ratio [HR], 1.55; P < .001), as were performance status, older age, smoking history, male sex, treatment factors, and stage of disease. The median survival for patients with CDS QOL was 1.6 years versus 5.6 years for patients with non-CDS QOL. After controlling for all these covariates, the indication of a clinically deficient baseline QOL still contributed significantly to the prediction of patient survival (HR, 0.67; P < .001). Conclusion Overall QOL measured by a simple single item at the time of lung cancer diagnosis is a significant and independent prognostic factor for survival in patients with lung cancer.