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Introduction The process of approval for flibanserin (trade name Addyi) has been associated with controversy since before its approval on August 18, 2015. This argument centered on challenges to the validity of the diagnosis of hypoactive sexual desire disorder in women and the safety and efficacy of the drug. Aim To explore the process of Food and Drug Administration (FDA) approval for flibanserin and delve further into the research, concerns, and various roadblocks to its approval. Methods A literature review was undertaken using the terms flibanserin and hypoactive sexual desire disorder and relevant commentary from supporters and critics regarding the medication and difficulties leading up to approval. Main Outcome Measures Review of the process of FDA approval of a medication to treat hypoactive sexual desire disorder and research published exploring the efficacy and safety of flibanserin. Results Before flibanserin, there were no drugs approved to treat hypoactive sexual desire disorder, which has a reported estimated incidence of 10% of women. For studying the effectiveness of flibanserin, the FDA required satisfying sexual events as the primary end point, although this end point does not measure level of desire or the associated distress. The satisfying sexual event measurement was significant across all three flibanserin trials in premenopausal women, as was an increase in desire according to the Female Sexual Function Index desire domain and a decrease in distress as recorded with the Female Sexual Distress Scale–Revised, Item 13. Safety concerns centered on the incidence of sedation, syncope, hypotension, and the interaction of flibanserin with alcohol and CYP3A4 inhibitors. Additional targeted challenge studies were mandated by the FDA. Conclusion The process of approval of flibanserin was lengthy. This was due in part to it being the first drug in its class and one with no clear guidance on study design from the FDA or roadmap for development and approval. Dooley EM, Miller MK, Clayton AH. Flibanserin: From Bench to Bedside. Sex Med Rev 2017;5:461–469.

Female sexual dysfunction (FSD) is a highly prevalent, yet commonly underdiagnosed and undertreated condition. This paper reviews the diagnostic terminology for FSD, and basic sexual physiology in women. The Food and Drug Administration (FDA) approved drugs for FSD are discussed, followed by investigational drugs for FSD currently in phase 2 or 3 clinical trials, reasons for failure of drug development, and potential future drug targets. Areas covered: A literature review was conducted for available treatments for FSD: flibanserin, estrogen, ospemifene and prasterone. Potential treatments are assessed, as was the Pharmaprojects database which includes clinical trial information. Testosterone, bremelanotide, bupropion-trazodone, PDE-5 inhibitors, prostaglandins, tibolone and combination therapies, and the theoretical basis of potential drug targets are discussed. Expert opinion: The lack of established endpoints for phase 3 studies of FSD has impeded approval of new treatments, and required additional studies for validation, resulting in proposed changes to the FDA draft guidance for FSD clinical trials in October 2016. Current DSM-5 diagnostic nosology also fails to capture the full range of symptomology. Several promising compounds have shown no movement for several years limiting women's options. Overcoming socio-cultural bias against women's sexual and reproductive health will be critical in the approval of new treatments for FSD.

Every heart beat is not equal. As physiological demands of the cardiovascular system change, cardiac myocytes modulate contractile parameters including the rate and force of contraction. Adaptive responses require the sensing of biomechanical signals involving the interface between the contractile cytoskeleton (myofibrils) and the sarcolemma at specialized cell–cell junctions (intercalated discs) and cell–substrate adhesion complexes (costameres). Recent studies have shed insight into how protein complexes within cardiac myocytes sense biomechanical signals, processes required for normal adaptive or pathological responses. This new evidence suggests that complexes associated with the giant, myofibrillar protein titin sense myocyte stretch. Here, we discuss evidence supporting titin being an ideal biomechanical sensor.

CARP, ankrd-2/Arpp, and DARP, are three members of a conserved gene family, referred to here as MARPs (muscle ankyrin repeat proteins). The expression of MARPs is induced upon injury and hypertrophy (CARP), stretch or denervation (ankrd2/Arpp), and during recovery following starvation (DARP), suggesting that they are involved in muscle stress response pathways. Here, we show that MARP family members contain within their ankyrin repeat region a binding site for the myofibrillar elastic protein titin. Within the myofibril, MARPs, myopalladin, and the calpain protease p94 appear to be components of a titin N2A-based signaling complex. Ultrastructural studies demonstrated that all three endogenous MARP proteins co-localize with I-band titin N2A epitopes in adult heart muscle tissues. In cultured fetal rat cardiac myocytes, passive stretch induced differential distribution patterns of CARP and DARP: staining for both proteins was increased in the nucleus and at the I-band region of myofibrils, while DARP staining also increased at intercalated discs. We speculate that the myofibrillar MARPs are regulated by stretch, and that this links titin-N2A-based myofibrillar stress/strain signals to a MARP-based regulation of muscle gene expression.

Overexpression of the HER-2 (neu, erb B-2) receptor results in cellular transformation and is associated with a variety of human cancers. Multiple mechanisms, including gene amplification and transcriptional, post-transcriptional, and translational controls contribute to the regulation of HER-2 expression. One of the components of these regulatory mechanisms is a short upstream open reading frame (uORF) in the HER-2 mRNA that represses downstream translation in a variety of cell types. Here we explore the mechanism by which this uORF exerts its inhibitory effect. As judged by comparisons of protein and mRNA abundance and by polysomal distribution analyses, the uORF represses translation of the HER-2 cistron or of a heterologous reporter gene. Despite its conservation among mammalian species, the peptide sequence of the uORF is not required for this inhibitory effect. Rather, the majority of ribosomes that load on the HER-2 mRNA most likely translate the uORF and are then unable to reinitiate at the downstream AUG codon, in part due to the short intercistronic spacing. A minority of ribosomes gain access to the HER-2 initiation codon either by leaky scanning past the upstream AUG codon or by reinitiating after having translated the uORF despite the short intercistronic region. These results suggest that the HER-2 uORF controls synthesis of this oncoprotein by limiting ribosomal access to downstream initiation sites.

The mammalian heart expresses two myosin heavy chain (MYH) genes (Myh6 and Myh7), which are major components of the thick filaments of the sarcomere. We have determined that a third MYH, MYH7B, is also expressed in the myocardium. Developmental analysis shows Myh7b expression in cardiac and skeletal muscle of Xenopus, chick and mouse embryos, and in smooth muscle tissues during later stages of mouse embryogenesis. Myh7b is also expressed in the adult human heart. The promoter region of the Myh7b gene shows remarkable similarity between diverse species, suggesting that transcriptional control mechanisms have been conserved. Using luciferase reporter analysis in rat cardiomyocytes, it can be shown that MEF2, GATA, and E-box regulatory elements are essential for efficient expression of the Myh7b gene. In addition two conserved elements that do not correspond to consensus binding sites for known transcription factors are also essential for full transcriptional activity of the Myh7b reporter. Finally, the Myh7b gene shows a transcriptional response similar to Myh6 in response to cardiac hypertrophy. © 2012 Wiley Periodicals, Inc

Overexpression of the HER-2 oncogene occurs in a variety of human tumors, including 25-30% of breast carcinomas, and has been associated with an adverse prognosis. Amplification of the HER-2 gene is frequently detected in tumors, but by itself may not fully account for HER-2 overexpression since transcriptional and post-transcriptional mechanisms also regulate HER-2 protein synthesis. Our studies reveal that the efficiency of HER-2 translation differs between primary and transformed cells. In primary human fibroblasts and human mammary epithelial cells, the HER-2 mRNA is associated with monosome and small polysome fractions. In contrast, in BT474 and MCF-7 human breast cancer cell lines and in COS-7 cells the mRNA co-sedimented with larger polysomes, indicating that it is more efficiently translated in these transformed cells. Northern analysis revealed no detectable mRNA size difference, and nuclease S1 protection and sequence analyses showed no differences between the HER-2 transcript leader in primary cells compared to transformed human cells. The transcript leader in all cell types contains a short upstream open reading frame that is also conserved in other mammalian species. Transient transfection assays revealed that the HER-2 transcript leader repressed downstream translation approximately five-fold in both primary and transformed cells and mutation of the upstream initiation codon alleviated most of the inhibitory effect. These results indicate that HER2 expression is translationally controlled both by a short upstream open reading frame that represses HER-2 translation in a cell type-independent manner, and by a distinct cell type-dependent mechanism that increases translational efficiency of HER-2 in transformed cells.