Citations

Hyperphosphorylation and aggregation of tau are observed in multiple neurodegenerative diseases termed tauopathies. Tau has also been implicated in the pathogenesis of Parkinson's disease (PD) and parkinsonisms. Some PD patients with mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene exhibit tau pathology. Mutations in LRRK2 are a major risk factor for PD, but LRRK2 protein function remains unclear. The most common mutation, G2019S, is located in the kinase domain of LRRK2 and enhances kinase activity in vitro. This suggests that the kinase activity of LRRK2 may underlie its cellular toxicity. Recently, in vitro studies have suggested a direct interaction between tubulin‐bound tau and LRRK2 that results in tau phosphorylation at one identified site. Here we present data suggesting that microtubules (MTs) enhance LRRK2‐mediated tau phosphorylation at three different epitopes. We also explore the effect of divalent cations as catalytic cofactors for G2019S LRRK2‐mediated tau phosphorylation and show that manganese does not support kinase activity but inhibits the efficient ability of magnesium to catalyze LRRK2‐mediated phosphorylation of tau. These results suggest that cofactors such as MTs and cations in the cellular milieu have an important impact on LRRK2‐tau interactions and resultant tau phosphorylation. © 2015 Wiley Periodicals, Inc.

Retraction of ‘N, S co-doped graphene quantum dots from a single source precursor used for photodynamic cancer therapy under two-photon excitation’ by Rijun Gui et al. , Chem. Commun ., DOI: 10.1039/C4CC09280E.

Abstract Background: Although breast cancer (BC) may occur at any age, its prevalence is greater postmenopause. Greater than 75 % of postmenopausal BCs are hormone dependent. Aromatase inhibitors suppress postmenopausal estrogen biosynthesis. Letrozole has demonstrated efficacy against BC in the adjuvant and metastatic setting at the treatment dose of 2.5 mg daily. Its potential role in BC prevention has been inferred from reductions in contralateral BCs. Its side effect profile, similar to other AIs, includes exacerbation of menopausal symptoms that negatively impact quality of life (QOL) and may result in discontinuation of the drug. Both anastrazole and exemestane have been demonstrated to reduce BC in high-risk women. Hypothesis: Lower and intermittent doses of letrozole effectively suppress estrogen in the high-risk postmenopausal woman and provide a better side effect profile. Methods: A randomized, double-blind study comparing the impact of varying letrozole doses (2.5 mg daily, 2.5 mg MWF, 1.0 mg MWF, or 0.25 mg MWF) on estrogen suppression and side effects--lipids, bone resorption, menopause, and QOL-- was conducted. Participants randomized to intermittent dosing received placebo on nontreatment days. Results: 112 participants were enrolled at 2 clinical sites. Mean patient age was 62.8 years, and average BMI was 29.8. Analysis of available data after 24 weeks of therapy revealed statistically significant increase in triglycerides (N=94): 114.67±48.39 to 125.79±54.31 (p<0.01); vasomotor symptoms (N=95): 2.25±1.26 to 2.74±1.67 (p<0.01); and C-telopeptide (N=75): 0.39±0.23 to 0.55±0.28 (p<0.0001). Statistically significant decrease in estradiol (N=68): 5.57±5.19 to 1.26±1.41 (p<0.0001) and estrone (N=68): 22.39±13.02 to 1.64±2.66 (p<0.0001) were observed. No differences in QOL (SF 36) were noted after letrozole treatment. P-values were derived from paired t-test (signed rank test) for the difference between baseline and after 24 weeks of study drug. Conclusions: De-escalating doses of letrozole suppress postmenopausal estrogen effectively and result in statistically significant increases in triglycerides, C-telopeptide and vasomotor symptoms without impact on QOL. Presentation will include unblinded intervention arm outcomes. Citation Format: Ana Maria Lopez, Hsiao Hui Sherry Chow, Denise Frank, Sandhya Puthi, Judy Boughey, Paul Hsu, Jose Guillen, Marjorie Perloff, Michelle Ley, Julie E Lang. De-escalating doses of letrozole in post menopausal women at high risk for breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-12-04.

Abstract Background: I-SPY 2 is a multicenter, phase II neoadjuvant trial in women with high-risk stage II/III breast cancer using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. Primary endpoint is pathologic complete response (pCR). Goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant 300-patient phase III trial defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Experimental regimens may “graduate” in 1 of 10 signatures, with a maximum of 120 patients. We report efficacy results for neratinib (N). Methods: Tumors ≥2.5cm by clinical exam & ≥2cm by imaging are eligible for screening. MP low risk/HR+/HER2- tumors are ineligible for randomization. Patients receive chemotherapy (paclitaxel qwk x 12, doxorubicin and cyclophosphamide q2-3 wk x 4, T->AC). HER2- pts were randomized to N+T->AC vs. T->AC and HER2+ pts to N+T->AC vs. trastuzumab+T->AC. Analysis is intent-to-treat with pts who switch to non-protocol therapy regarded as non-pCRs. We provide estimated pCR rates (95% Bayesian probability intervals), probabilities of superiority of neratinib over control, and Bayesian predictive probabilities of success in an equally randomized phase III trial. Results: Neratinib met the predictive probability criterion in HR-/HER2+, “graduated”, and accrual ceased [115 N patients (65 HER2+), 78 concurrently randomized controls (22 HER2+)]. The table shows results for all 10 signatures. Two patients (1 N and 1 control) withdrew consent and are not included. Conclusion: I-SPY 2's standing trial mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, adaptive randomization successfully identified a biomarker signature (HR-/HER2+) for neratinib's further development. All HER2+ and MP+ tumors may also benefit from this regimen, consistent with preclinical data. Evaluation in I-SPY 3, a phase III registration trial, is planned. SignatureEstimated pCR Rate (95% probability interval)Probability NeratinibIs Superior to ControlPredictive Probability of Success in Phase IIINeratinibControlALL32% (28-36%)23% (19%-28%)92%44%HR+23% (18%-28%)17% (11%-22%)81%40%HR-43% (37%-49%)31% (24%-38%)89%53%HER2+39% (33%-45%)23% (15%-30%)95%73%HER2-26% (21%-32%)24% (18%-29%)63%20%MP+*45% (38%-53%)29% (20%-39%)91%66%HR-/HER2-36% (29%-43%)30% (23%-38%)72%34%HR-/HER2+55% (46%-64%)32% (22%-43%)94%78%HR+/HER2+31% (24%-37%)17% (10%-24%)91%65%HR+/HER2-14% (8%-19%)16% (10%-21%)39%12%* MammaPrint 44K Array Low/High score was adjusted to MammaPrint High1 (MP-) or High2 (MP+), using a pre-defined median cut-point of I-SPY 1 participants, who fit the eligibility criteria of I-SPY 2. Citation Format: John W. Park, Minetta C. Liu, Douglas Yee, Angela DeMichele, Laura van 't Veer, Nola Hylton, Fraser Symmans, Meredith B. Buxton, A. Jo Chien, Amy Wallace, Michelle Melisko, Richard Schwab, Judy Boughey, Debashish Tripathy, Hank Kaplan, Rita Nanda, Stephen Chui, Kathy S. Albain, Stacy Moulder, Anthony Elias, Julie E. Lang, Kirsten Edminston, Donald Northfelt, David Euhus, Qamar Khan, Julia Lyandres, Sarah E. Davis, Christina Yau, Ashish Sanil, Laura J. Esserman, Donald A. Berry. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2014-CT227

Abstract Background: Nulliparity is an established endometrial cancer risk factor, but whether this association is related to infertility is unclear. Although there are many underlying causes of infertility, few studies have assessed risk relationships according to specific causes. Despite concerns that most treatments induce ovulation and that the endometrium is highly hormonally-responsive, previous studies have provided conflicting results on treatment associations. Methods: To address these issues, we conducted a pooled analysis of 8,151 cases and12,471 controls from 2 cohort and 12 case-control studies conducted in 1982 to 2009 (N. America, Europe, Australia, Asia). All studies provided self-reported infertility, causes and treatments, except for 1 study that relied on data from national registries. Study-specific exposures and covariate data were harmonized across studies. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for study, age, interview year, race, parity, oral contraceptive and menopausal hormone use, and body mass index. If data were not reported for a particular variable, that study was excluded from the variable-specific analysis. Results: Nulliparous women had an elevated endometrial cancer risk compared with parous women (adjusted OR=1.73; 95% CI: 1.58-1.90).Women with self-reported infertility also had an increased risk (adjusted OR=1.22; 95% CI: 1.13-1.32) compared with those without infertility issues, even after adjusting for parity; the strongest associations was seen among studies that defined infertility as unsuccessfully trying to conceive for 2+ years (adjusted OR=1.31; 95% CI: 1.07-1.60). Infertility was associated with similar risks among nulliparous (1.22; 1.10-1.48) and parous (1.22; 1.12-1.34) women, although there was no increased risk associated with infertility among those who had given birth to 3+ children. Two infertility causes associated with risk elevation were endometriosis (adjusted OR=2.08; 95% CI: 1.46-2.95 compared with women no infertility problems) and anovulation (adjusted OR=1.40; 95% CI: 1.16-1.70). Based on relatively small numbers, none of the individual treatments (in vitro fertilization, selective estrogen response modulators, gonatropins, progestins, estrogens) were substantially related to risk. Conclusion: Based on mainly self-reported infertility data, we found that parity and infertility independently contribute to endometrial cancer risk, with parity seemingly being the predominant risk predictor. Understanding residual endometrial cancer relationships related to causes of infertility and infertility treatment may benefit from documented medical information on causes of infertility and treatment parameters. Citation Format: Hannah P. Yang, Linda S. Cook, Elisabete Weiderpass, Hans-Olov Adami, Kristin E. Anderson, Hui Cai, James R. Cerhan, Tess Clendenen, Ashley S. Felix, Christine Friedenreich, Montserrat Garcia-Closas, Marc T. Goodman, Xiaolin Liang, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Susan E. McCann, Kristen B. Moysich, Sara H. Olson, Malcolm C. Pike, Silvia Polidoro, Fulvio Ricceri, Harvey Risch, Carlotta Sacerdote, V. Wendy Setiawan, Xiao Ou Shu, Amanda B. Spurdle, Britton Trabert, Penelope M. Webb, Nicolas Wentzensen, Yong-Bing Xiang, Youming Xu, Herbert Yu, Anne Zeleniuch-Jacquotte, Louise A. Brinton. Infertility and risk of incident endometrial carcinoma: a pooled analysis from the Epidemiology of Endometrial Cancer Consortium. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2167. doi:10.1158/1538-7445.AM2014-2167

BackgroundGiven the success of immunotherapeutic approaches in hematologic malignancies, the COG designed a phase I/II study to determine whether the addition of epratuzumab (anti‐CD22) to an established chemotherapy platform improves rates of second remission (CR2) in pediatric patients with B‐lymphoblastic leukemia (B‐ALL) and early bone marrow relapse.ProcedureTherapy consisted of three established blocks of re‐induction chemotherapy. Epratuzumab (360 mg/m2/dose) was combined with chemotherapy on weekly × 4 (B1) and twice weekly × 4 [eight doses] (B2) schedules during the first re‐induction block. Remission rates and minimal residual disease (MRD) status were compared to historical rates observed with the identical chemotherapy platform alone.ResultsCR2 was achieved in 65 and 66%, of the evaluable B1 (n = 54) and B2 patients (n = 60), respectively; unchanged from that observed historically without epratuzumab. Rates of MRD negativity (<0.01%) were 31% in B1 (P = 0.4128) and 39% in B2 patients (P = 0.1731), compared to 25% in historical controls. The addition of epratuzumab was well tolerated, with a similar toxicity profile to that observed with the re‐induction chemotherapy platform regimen alone.ConclusionsEpratuzumab was well tolerated in combination with re‐induction chemotherapy. While CR2 rates were not improved compared to historical controls treated with chemotherapy alone, there was a non‐significant trend towards improvement in MRD response with the addition of epratuzumab (twice weekly for eight doses) to re‐induction chemotherapy. Pediatr Blood Cancer 2015;62:1171–1175. © 2015 Wiley Periodicals, Inc.