PABPN1 gene therapy for oculopharyngeal muscular dystrophy

International audienceOculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment

A Clinical N of 1 Time Series on the Efficacy of Internal Family Systems and Christian Inner Healing Prayer with Adult Survivors of Childhood Trauma

Internal Family Systems (IFS) is a non-pathologizing psychospiritual therapeutic model in which “all parts are welcome.” Christian Inner Healing Prayer (CIHP) is an intervention that invites an authentic experience with the Divine to address inner wounds. Both methods are touted as beneficial to clients with trauma histories. However, IFS is an evidenced based treatment while only preliminary research on CIHP has been done. Several efforts to create a Christian cultural accommodation of IFS have been authored; two implicitly reference CIHP. None have been researched. This study is an N of 1 time series study of the efficacy of IFS with CIHP religious accommodation on symptoms of post-traumatic stress, anxiety, and depression. Additionally, effects to hope, forgiveness, Self access, Self leadership, Self qualities, love of self, and love of God were investigated utilizing multiple psycho-metric instruments and measures. The study’s results demonstrated IFS/eCIHP significantly correlated with a decrease in post-traumatic stress, anxiety, and depression symptoms in a small group of N-of-1 Christian clients with histories of childhood trauma. Simultaneously, increases in Self access, Self-leadership, Self-qualities, hope, love of self, and love of God were documented in that same group of participants after eight sessions of treatment. However, IFS/eCIHP did not correlate with evidenced increased forgiveness for the participants. Future research recommendations are made

Release of reactive selenium species from phthalic selenoanhydride in the presence of hydrogen sulfide and glutathione with implications for cancer research

The last decade has witnessed a renewed interest in selenium (Se) as an element able to prevent a range of illnesses in humans, mainly through supplementation. However, such supplementation relies on species such as sodium selenite or selenomethionine, which proved to have limited solubility and bioavailability, thus leading to limited activity. To overcome this limitation, other selenium species need to be explored, such as phthalic selenoanhydride (R-Se), which is soluble in physiological media. R-Se releases various reactive selenium species (RSeS), including hydrogen selenide (HSe), that can interact with cellular components, such as glutathione (GSH) and hydrogen sulfide (HS). This interplay between R-Se and the cellular components provides a sophisticated biochemical release mechanism that could be behind the noteworthy biological activities observed for this compound. In order to investigate the interactions of phthalic chalcogen anhydrides with HS or GSH, we have employed UV-vis spectrophotometry, electron paramagnetic resonance spectroscopy (EPR) and plasmid DNA (pDNA) cleavage assay. We found that apart from R-Se, the other analogues do not have the ability to scavenge the cPTIO radical or to cleave pDNA on their own. In contrast, the scavenging potency for the cPTIO radical and for the O radical exerted by R-Se and its sulfur analogue (R-S) significantly increased when they were evaluated in the presence of HS. However, GSH only changed the radical scavenging activity of R-Se. These new discoveries may explain some of the biological activities associated with this class of compounds and open a new approach to ascertain the possible mechanisms underlying their biological actions.This research was funded by the Slovak Research & Development Agency, grant numbers APVV-15-0371, 15-0565 and 17-0384, and the Scientific Grant Agency of the Slovak Republic, grant numbers VEGA 1/0026/18, 2/0079/19, 2/0014/17 and 2/0053/19. The authors would also like to acknowledge the financial support of the Agencia Estatal Consejo Superior de Investigaciones Científicas (Spain, project 201780I027) and of the University of Saarland (through the Landesforschungsfo¨rderungsprogramm (LFPP) of the state of Saarland, Grant No. WT/2-LFFP 16/01). We also acknowledge the INTERREG-VA GR program (BIOVAL, Grant No. 4-09-21) and the NutRedOx (COST Project CA16112), as well as the support of the Erasmus+ program. We also thank Prof. Dr Anna K. H. Hirsch and Dr Eleonora Diamanti from Helmholtz Institute for Pharmaceutical Research in Saarland (HIPS) for helping with MS spectra measurementsWe acknowledge support of the publication fee by the CSIC Open Access Support Initiative through its Unit of Information Resources for Research (URICI)Peer Reviewe

Utilization of genomic signatures to identify high-efficacy candidate drugs for chemorefractory endometrial cancers Cancer Cell Biology

Endometrial cancer, one of the most common gynecologic malignancies, is increasing in Japan, nearly doubling over the last decade. High-grade disease patients are often resistant to conventional chemotherapy with platinum agents; therefore, discovery of efficacious new drugs in this setting is required to benefit chemorefractory cases. The 50% growth-inhibitory (GI50) concentration of 27 clinically relevant drugs was measured in the NCI60 panel of cell lines. Gene expression data were analyzed using Bayesian binary regression, to first generate a response signature for each drug and then to calculate individual susceptibility scores using in vivo endometrial cancer data (GSE2109; http://www.ncbi.nlm.nih.gov/geo) and in vitro data (GSE25458), as well as to identify candidate drugs for chemorefractory cases. Using these candidates, cell proliferation, apoptosis and caspase assays were performed in vitro. The tumor growth-inhibitory effect of the candidate was also assessed in vivo using nude mice. Through microarray analysis, fludarabine and temsirolimus showed higher susceptibility scores in high-grade cases compared to cisplatin, doxorubicin and paclitaxel. Fludarabine significantly inhibited cell proliferation and increased apoptosis in the cisplatin-resistant endometrial cancer cell line, HEC1A, relative to HEC50B (p < 0.001). Fludarabine treatment also enhanced caspase-3/7 activity in HEC1A relative to HEC50B cells (p < 0.001), and inhibited the growth of HEC1A xenograft tumors relative to cisplatin (p < 0.05). These results support that identification and use of genomic signatures can lead to identification of new therapeutic candidates that may prove beneficial to chemoresistant cases. Fludarabine may be useful in targeting high-grade, chemorefractory endometrial cancer. Endometrial cancer is the leading cause of gynecologic malignancy with 43,470 estimated cases diagnosed per year and 7,950 annual death in the United States, respectively, consisting of 6% of new cancer cases and 3% of all cancer deaths, and disease incidence has been steadily increasing. 1,2 The majority of endometrial cancers, more than 80%, are diagnosed at an early stage with the disease located within the uterus. When diagnosed at an early stage, primary surgery is frequently curative enough to be associated with a favorable prognosis. In contrast, extrauterine spread of cancer cells profoundly impacts patient prognosis as previous studies revealed high hazard ratios for Stage III and Stage IV compared to Stage I disease. 2 Clear cell and papillary serous carcinomas of the uterus are associated with aggressive behaviors, even at an early stage, with 5-year survival between 60 and 66%. 5 With the objective of improving the prognosis of those with high-risk disease, it is essential to identify candidate cytotoxic agents that are effective against patients with resistance to conventional chemotherapies (chemorefractory tumors) or supportive agents that increase sensitivity to primary chemotherapies