Taxane‐based chemotherapy regimens are used as first‐line treatment for breast cancer. Neurotoxicity, mainly taxane‐induced peripheral neuropathy (TIPN), remains the most important dose‐limiting adverse event. Multiple genes may be associated with TIPN; however, the strength and direction of the association remain unclear. For this reason, we systematically reviewed observational studies of TIPN pharmacogenetic markers in breast cancer treatment. We conducted a systematic search of terms alluding to breast cancer, genetic markers, taxanes, and neurotoxicity in Ovid, ProQuest, PubMed, Scopus, Virtual Health, and Web of Science. We assessed the quality of evidence and bias profile. We extracted relevant variables and effect measures. Whenever possible, we performed random‐effects gene meta‐analyses and examined interstudy heterogeneity with meta‐regression models and subgroup analyses. This study follows the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) and STrengthening the REporting of Genetic Association Studies (STREGA) reporting guidance. A total of 42 studies with 19,431 participants were included. These evaluated 262 single‐nucleotide polymorphisms (SNPs) across 121 genes. We conducted meta‐analyses on 23 genes with 60 SNPs (19 studies and 6246 participants). Thirteen individual SNPs (ABCB1‐rs2032582, ABCB1‐rs3213619, BCL6/‐rs1903216, /CAND1‐rs17781082, CYP1B1‐rs1056836, CYP2C8‐rs10509681, CYP2C8‐rs11572080, EPHA5‐rs7349683, EPHA6‐rs301927, FZD3‐rs7001034, GSTP1‐rs1138272, TUBB2A‐rs9501929, and XKR4‐rs4737264) and the overall SNPs' effect in four genes (CYP3A4, EphA5, GSTP1, and SLCO1B1) were statistically significantly associated with TIPN through meta‐analysis. In conclusion, through systematic review and meta‐analysis, we found that polymorphisms, and particularly 13 SNPs, are associated with TIPN, suggesting that genetics does play a role in interindividual predisposition. Further studies could potentially use these findings to develop individual risk profiles and guide decision making.

Age-related macular degeneration (AMD) is the leading cause of central vision loss and severe blindness among the elderly population. Recently, we reported on the association of the SGCD gene (encoding for δ-sarcoglycan) polymorphisms with AMD. However, the functional consequence of Sgcd alterations in retinal degeneration is not known. Herein, we characterized changes in the retina of the Sgcd knocked-out mouse (KO, Sgcd^−/−). At baseline, we analyzed the retina structure of three-month-old wild-type (WT, Sgcd^+/+) and Sgcd^−/− mice by hematoxylin and eosin (H&E) staining, assessed the Sgcd–protein complex (α-, β-, γ-, and ε-sarcoglycan, and sarcospan) by immunofluorescence (IF) and Western blot (WB), and performed electroretinography. Compared to the WT, Sgcd^−/− mice are five times more likely to have retinal ruptures. Additionally, all the retinal layers are significantly thinner, more so in the inner plexiform layer (IPL). In addition, the number of nuclei in the KO versus the WT is ever so slightly increased. WT mice express Sgcd-protein partners in specific retinal layers, and as expected, KO mice have decreased or no protein expression, with a significant increase in the α subunit. At three months of age, there were no significant differences in the scotopic electroretinographic responses, regarding both a- and b-waves. According to our data, Sgcd^−/− has a phenotype that is compatible with retinal degeneration.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Andric C. Perez-Ortiz1, 2, Israel Ramírez1, Juan C. Cruz-López3, *, Cynthia Villarreal-Garza4, *, Alexandra Luna-Angulo5, Esmeralda Lira-Romero1, Salvador Jiménez-Chaidez1, José Díaz-Chávez6, Juan A. Matus-Santos6, Laura Sánchez-Chapul5, Patricia Mendoza-Lorenzo7 and Francisco J. Estrada-Mena1 1Universidad Panamericana, Escuela de Medicina, Mexico City, Mexico 2Yale University School of Public Health, Laboratory of Epidemiology and Public Health, New Haven, CT, USA 3Hospital Regional ISSSTE Puebla and Hospital General Zona Norte SSEP Puebla, Puebla City, Mexico 4Depto. de Investigacion, Instituto Nacional de Cancerologia, Centro de Cancer de Mama, Tecnologico de Monterrey, Monterrey, Nuevo León, Mexico 5Instituto Nacional de Rehabilitación, Mexico City, Mexico 6Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM/Instituto Nacional de Cancerología, Mexico City, Mexico 7División Académica de Ciencias Básicas, Unidad Chontalpa, Universidad Juárez Autónoma de Tabasco, Tabasco, Mexico *These authors contributed equally to this work Correspondence to: Francisco J. Estrada-Mena, email: festrada@up.edu.mx Keywords: pharmacogenetics; paclitaxel; breast cancer; genetic markers; single nucleotide polymorphism Received: July 27, 2017 Accepted: October 27, 2017 Published: November 15, 2017 ABSTRACT Locally advanced breast cancer (LABC) cases have a varying five-year survival rate, mainly influenced by the tumor response to chemotherapy. Paclitaxel activity (response rate) varies across populations from 21.5% to 84%. There are some reports on genetic traits and paclitaxel; however, there is still considerable residual unexplained variability. In this study, we aimed to test the association between eleven novel markers and tumor response to paclitaxel and to explore if any of them influenced tumor protein expression. We studied a cohort of 140 women with LABC. At baseline, we collected a blood sample (for genotyping), fine needle aspirates (for Western blot), and tumor measurements by imaging. After follow-up, we ascertained the response to paclitaxel monotherapy by comparing the percent change in the pre-, post- tumor measurements after treatment. To allocate exposure, we genotyped eleven SNPs with TaqMan probes on RT-PCR and regressed them to tumor response using linear modeling. In addition, we compared protein expression, between breast tumors and healthy controls, of those genes whose genetic markers were significantly associated with tumor response. After adjusting for multiple clinical covariates, SNPs on the LPHN2, ROBO1, SNTG1, and GRIK1 genes were significant independent predictors of poor tumor response (tumor growth) despite paclitaxel treatment. Moreover, proteins encoded by those genes are significantly downregulated in breast tumor samples.

In this study we developed the Disability Beliefs Scale to assess Veterans’ beliefs that engaging in treatment, as well as other behaviors, would affect the likelihood of a Veteran’s being awarded disability-related benefits. We posited that Veterans with stronger beliefs that attending mental health treatment would facilitate a service-connection award would be more likely to attend PTSD treatment before their compensation and pension examinations for PTSD. Electronic health records for 307 post-9/11-era Veterans applying for compensation and pension for service-connected PTSD and engaging in a clinical trial of a treatment-referral intervention were analyzed for PTSD-specific and more general mental health treatment use around the time of their compensation examinations. All participants completed the Disability Beliefs Scale and other baseline assessments. Multilevel models assessed change in treatment use as a function of time relative to the C&P exam, compensation examination status (before or after), and the interaction between examination status and beliefs about treatment benefits. No main effects of time or examination status were observed. As hypothesized, beliefs about treatment benefits moderated the effect of examination status on PTSD treatment use. Veterans believing more strongly that mental health treatment would help a claim differentially attended PTSD treatment before the examination than after. The effect was not observed for general mental health treatment use. The association between Veterans’ use of PTSD treatment and their service-connection examination status was moderated by beliefs that receiving treatment affects the service-connection decision. This suggests that factors reported to motivate seeking service-connection—finances, validation of Veterans’ experiences, and the involvement of significant others—might also help motivate Veterans’ use of effective PTSD treatments. However, the results reflect correlations that could be explained in other ways, and service-connection was one of many factors impacting PTSD treatment engagement.