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Polypharmacy poses a significant risk for adverse reactions. While there are clinical decision support tools to assist clinicians in medication management, pharmacogenetic testing to identify potential drug–gene or drug–drug–gene interactions is not widely implemented in the clinical setting. A PRISMA-compliant scoping review was performed to determine if pharmacogenetic testing for absorption, distribution, metabolism, and excretion (ADME)-related genetic variants is associated with improved clinical outcomes in patients with polypharmacy. Six studies were reviewed. Five reported improved clinical outcomes, reduced side effects, reduction in the number of drugs used, or reduced healthcare utilization. The reviewed studies varied in methodological quality, risk of bias, and outcome measures. Age, diet, disease state, and treatment adherence also influence drug response, and may confound the relationship between genetic polymorphisms and treatment outcomes. Further studies using a randomized control design are needed. We conclude that pharmacogenetic testing represents an opportunity to improve health outcomes in patients exposed to polypharmacy, particularly in patients with psychiatric disorders and the elderly.

Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from <50 kb to >9 Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8 Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS.

BackgroundProstate-specific membrane antigen (PSMA) is a transmembrane glycosylated homodimer overexpressed in >80% of prostate cancers. PSMA expression is increased in advanced stages of the disease, making it an attractive therapeutic target. Clinically, autologous anti-PSMA αβ CAR T cells have shown initial efficacy with significant CRS-like dose-limiting toxicities. Compared to αβ T cells and other innate cells, γδ T cells are associated with multifunctional innate and adaptive targeting and differentiated biodistribution into tumor-associated tissues. Additionally, γδ CAR T cells have demonstrated enhanced tumoricidal activity and tailored activation-induced cytokine profiles that may decrease toxicities associated with CRS. We characterized γδ T cells modified from a set of novel scFv-based CARs targeting PSMA for prostate cancer.MethodsWe used phage panning to identify a library of anti-PSMA scFv sequences, which were reformatted into CARs in VH-VL and VL-VH orientations and screened in Jurkat-Lucia™ NFAT cells to assess CAR expression and activation in the context of target cell-based stimulation. We transduced a set of functional CARs into Vδ1 T cells, a primarily tissue-resident subset, activated and expanded from healthy donor PBMCs. We performed in vitro cell-based cytotoxicity assays and phenotypic assessments of CAR Vδ1 T cells using flow cytometry. Potency was also assessed in NSG mice bearing subcutaneous PSMA-expressing xenografts.ResultsAnti-PSMA scFvs ranged in apparent affinities from the low nanomolar to the sub-micromolar range. CAR-expressing Jurkat cells showed target-specific NFAT activation and low tonicity. CAR-engineered Vδ1 T cells demonstrated robust expansion, in vitro cytotoxicity and antigen-specific proliferation against PSMA+ cell lines in a manner comparable to, or greater than, J591 scFv-based Vδ1 CAR. In vitro potency correlated with the release of multiple effector cytokines. Notably, IL-6 and IL-10 production by anti-PSMA Vδ1 CAR T cells was negligible, while TNFα production was low, further supporting the potential of the γδ CAR T platform to demonstrate a favorable cytokine-associated safety profile. Anti-PSMA Vδ1 CAR T cells were also found to be predominantly naïve, with low levels of exhaustion marker expression. Additionally, in vitro (figure 1) and in vivo (figure 2) potency of anti-PSMA Vδ1 CAR T cells was investigated upon co-expression of dominant negative TGFβRII (dnTGFβRII). In xenograft models, anti-PSMA Vδ1 CAR T cells demonstrated potent anti-tumor efficacy.ConclusionsWe have engineered, screened and demonstrated preclinical efficacy for “off-the-shelf” PSMA-targeting γδ CAR T cells. Resulting γδ CAR T constructs identified here are candidates for further preclinical and clinical development in the context of armoring technologies.Ethics ApprovalAll mouse experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals and followed all institutional and national guidelines with appropriate protocol review and approval.Abstract 203 Figure 1In vitro cytotoxicity of PSMA-targeting Vδ1 CAR-T cellsDemonstration of in vitro potency at 1:1 E:T ratio of PSMA-targeting Vδ1 CAR-T cells (including CAR A co-expressing dnTGFβRII) when co-cultured with PSMA-expressing target cell lines, 22Rv1 (left) and TGFβ-secreting PC3 cells engineered to express PSMA (right)[Figure omitted. See PDF]Abstract 203 Figure 2in vivo potency of Vδ1 CAR-T cells in 22Rv1 PCa modelDemonstration of in vivo potency in a 22Rv1 PCa xenograft model (low, heterogenous PSMA expression) with PSMA-targeting Vδ1 CAR-T cells. Schematic outlines the study design (top panel). Graphs detail tumor volumes determined for the entire study duration (bottom, left panel) as well as statistical comparison of treatment groups relative to the untreated tumor alone control at study termination (bottom, right panel).[Figure omitted. See PDF]

Objective: The purpose of the study was to determine if sexual behaviors, orgasm, tampon use, and douching during menstruation modify the risk of endometriosis. Methods: A case-control study was conducted. Subjects (n = 2,012) consisted of members of the Endometriosis Association and friends not affiliated with the organization who completed mailed surveys. Data were analyzed using χ 2 , Fisher’s exact test, t test, and regression analyses. Results: There was no difference between study groups concerning douching practices. However, cases were less likely than controls to report sometimes or often engaging in sexual behaviors during menstruation (p = 0.002, OR = 1.5), and sexual behaviors during menstruation that included orgasm (p = 0.001, OR = 1.5). Cases were also less likely than controls to report using only tampons (p < 0.0001, OR = 2.6). Conclusion: Sexual activity, orgasm, and tampon use during menstruation may confer protection against endometriosis.

Retrograde menstruation, the backward flow of menstrual debris, is generally considered an etiologic factor in the development of endometriosis. It was hypothesized that certain activities may enhance the degree of retrograde flow, and increase the risk of disease development. A case-control study of 2012 survey respondents was performed to determine if sexual behaviors, orgasm, tampon use, and douching during menstruation modify the risk of endometriosis. There was no difference between study groups concerning douching practices. However, cases were less likely than controls to report sometimes or often engaging in sexual behaviors during menstruation (p =.002, OR = 1.5), and sexual behaviors during menstruation that included orgasm (p =.001, OR = 1.5). Cases were also less likely than controls to report using only tampons (p$<$ .0001, OR = 2.6). Sexual activity, orgasm, and tampon use during menstruation may confer protection against endometriosis. Recommendations for future studies are discussed.