Practical differences between luteinizing hormone-releasing hormone agonists in prostate cancer: perspectives across the spectrum of care

Background:Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists is well established for the treatment of men with metastatic prostate cancer. As clear differences in efficacy, safety, or tolerability between the available LHRH agonists are lacking, the healthcare management team needs to look to practical differences between the formulations when selecting therapy for their patients. Moreover, as the economic burden of prostate cancer rises alongside earlier diagnosis and improved survival, the possibility for cost savings by using products with specific features is growing in importance.Methods:A review was conducted to summarize the information on the different LHRH agonist formulations currently available and offer insight into their relative benefits and disadvantages from the perspectives of physicians, a pharmacist, and a nurse.Results:The leuprorelin acetate and goserelin acetate solid implants have the advantage of being ready to use with no requirement for refrigeration, whereas powder and microsphere formulations have to be reconstituted and have specific storage or handling constraints. The single-step administration of solid implants, therefore, has potential to reduce labor time and associated costs. Dosing frequency is another key consideration, as administering the injection provides an opportunity for face-to-face interaction between the patient and healthcare professionals to ensure therapy is optimized and give reassurance to patients. Prostate cancer patients are reported to prefer 3- or 6-monthly dosing, which aligns with the monitoring frequency recommended in European Association of Urology guidelines and has been shown to result in reduced annual costs compared with 1-month formulations.Conclusions:A number of practical differences exist between the different LHRH agonist preparations available, which may impact on clinical practice. It is important for healthcare providers to be aware and carefully consider these differences when selecting treatments for their prostate cancer patients.Peer reviewe

Association of unicuspid unicommissural aortic valve and complex congenital heart disease depicted by cardiac magnetic resonance

A 12-year-old male child was referred for follow-up cardiac magnetic resonance (CMR) of complex congenital heart disease, characterized by aortic decoarctation, interventricular and interatrial septal defects (VSD and ASD) closure and bicuspid aortic valve.peer-reviewe

The Dually Acylated NH2-terminal Domain of Gi1α Is Sufficient to Target a Green Fluorescent Protein Reporter to Caveolin-enriched Plasma Membrane Domains: PALMITOYLATION OF CAVEOLIN-1 IS REQUIRED FOR THE RECOGNITION OF DUALLY ACYLATED G-PROTEIN α SUBUNITS IN VIVO

Here we investigate the molecular mechanisms that govern the targeting of G-protein α subunits to the plasma membrane. For this purpose, we used Gi1α as a model dually acylated G-protein. We fused full-length Gi1α or its extreme NH2-terminal domain (residues 1–32 or 1–122) to green fluorescent protein (GFP) and analyzed the subcellular localization of these fusion proteins. We show that the first 32 amino acids of Gi1α are sufficient to target GFP to caveolin-enriched domains of the plasma membrane in vivo, as demonstrated by co-fractionation and co-immunoprecipitation with caveolin-1. Interestingly, when dual acylation of this 32-amino acid domain was blocked by specific point mutations (G2A or C3S), the resulting GFP fusion proteins were localized to the cytoplasm and excluded from caveolin-rich regions. The myristoylated but nonpalmitoylated (C3S) chimera only partially partitioned into caveolin-containing fractions. However, both nonacylated GFP fusions (G2A and C3S) no longer co-immunoprecipitated with caveolin-1. Taken together, these results indicate that lipid modification of the NH2-terminal of Gi1α is essential for targeting to its correct destination and interaction with caveolin-1. Also, a caveolin-1 mutant lacking all three palmitoylation sites (C133S, C143S, and C156S) was unable to co-immunoprecipitate these dually acylated GFP-G-protein fusions. Thus, dual acylation of the NH2-terminal domain of Gi1α and palmitoylation of caveolin-1 are both required to stabilize and perhaps regulate this reciprocal interaction at the plasma membrane in vivo. Our results provide the first demonstration of a functional role for caveolin-1 palmitoylation in its interaction with signaling molecules

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Testosterone suppression with a unique form of leuprorelin acetate as a solid biodegradable implant in patients with advanced prostate cancer: results from four trials and comparison with the traditional leuprorelin acetate microspheres formulation

Background: There are two slow-release ready-to-use forms of leuprorelin acetate (1-month and 3-month) that are available as solid, biodegradable implants for the treatment of advanced, hormone-sensitive prostate cancer. These implants have been shown to be as effective as traditional leuprorelin acetate microspheres for achieving successful testosterone suppression (⩽0.5 ng/ml) and lowering prostate-specific antigen (PSA) levels. Here we further evaluate testosterone suppression levels from four clinical trials evaluating the 3-month leuprorelin implant, including analysis below the European Association of Urology (EAU) castration level (3 months. In both long-term, single-arm studies with the leuprorelin implant, median values of testosterone ⩽0.2 ng/ml were achieved at Week 4 and maintained until study completion (6 and 8 months); PSA decrease was also observed versus baseline. Conclusions: Long-lasting steady serum levels of testosterone, comparable with orchiectomy and consistent with the EAU-recommended castration level (<0.2 ng/ml), were achieved at Week 4 and maintained up to 8 months in men with advanced prostate cancer who received the leuprorelin implant

Treatment costs for advanced prostate cancer using luteinizing hormone-releasing hormone agonists: a solid biodegradable leuprorelin implant versus other formulations

Aim: To compare treatment costs with alternative luteinizing hormone-releasing hormone (LHRH) agonist preparations and determine whether a leuprorelin solid implant is associated with potential cost savings. Patients & methods: A hypothetical population of 1000 prostate cancer patients was apportioned between the three most commonly-prescribed LHRH agonist preparations. Differentiated annual costs for 1- and 3-monthly formulations were calculated for France, Germany, Italy, Spain, the UK (EU5) and Sweden, and compared with the leuprorelin solid implant. Results: Compared with alternative formulations, leuprorelin solid implants had potential annual cost savings/1000 patients of Euro353,000 (EU5) and Euro699,000 (Sweden; 1-month formulations), and Euro259,000 (EU5) and Euro300,000 (Sweden; 3-month formulations). Conclusion: The leuprorelin solid implant was associated with potential cost savings compared with the most commonly used LHRH agonist preparations

Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates

<p>Abstract</p> <p>Background</p> <p>Progressive diversification of paralogs after gene expansion is essential to increase their functional specialization. However, mode and tempo of this divergence remain mostly unclear. Here we report the comparative analysis of PRDM genes, a family of putative transcriptional regulators involved in human tumorigenesis.</p> <p>Results</p> <p>Our analysis assessed that the PRDM genes originated in metazoans, expanded in vertebrates and further duplicated in primates. We experimentally showed that fast-evolving paralogs are poorly expressed, and that the most recent duplicates, such as primate-specific <it>PRDM7</it>, acquire tissue-specificity. <it>PRDM7 </it>underwent major structural rearrangements that decreased the number of encoded Zn-Fingers and modified gene splicing. Through internal duplication and activation of a non-canonical splice site (GC-AG), <it>PRDM7 </it>can acquire a novel intron. We also detected an alternative isoform that can retain the intron in the mature transcript and that is predominantly expressed in human melanocytes.</p> <p>Conclusion</p> <p>Our findings show that (a) molecular evolution of paralogs correlates with their expression pattern; (b) gene diversification is obtained through massive genomic rearrangements; and (c) splicing modification contributes to the functional specialization of novel genes.</p

Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates-1

<p><b>Copyright information:</b></p><p>Taken from "Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates"</p><p>http://www.biomedcentral.com/1471-2148/7/187</p><p>BMC Evolutionary Biology 2007;7():187-187.</p><p>Published online 4 Oct 2007</p><p>PMCID:PMC2082429.</p><p></p>yan. and are represented as grey blocks. The chromosome number in the corresponding genome is provided. Dashed lines correspond to regions of break of synteny. Abbreviations: , Homo sapiens; , Pan troglodytes; , Macaca mulatta; , Mus musculus; , Rattus norvegicus; , Gallus gallus. . Since for chimp and macaque no mRNA sequences are available, the human and were used as templates for gene predictions. In chimp, the intron putatively gained by is composed of eight repeats. In the genomic regions corresponding to chimp , there are four additional Zn-Fingers, which are reported in black because there is no evidence for their transcription. The dashed lines represent regions of gaps in the genome assembly. In rodents, the last intron is longer and not in scale; the corresponding length is reported in brackets. . The grey lines represent the genomic regions of segmental duplication. The corresponding chromosome number, chromosomal coordinates and direction of transcription are given. For , the splicing variants present in the database are shown. For , both the database transcripts and the isoforms detected in this study are reported together with an in-silico gene prediction obtained by using the PRDM9 long isoform as template

Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates-0

<p><b>Copyright information:</b></p><p>Taken from "Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebrates"</p><p>http://www.biomedcentral.com/1471-2148/7/187</p><p>BMC Evolutionary Biology 2007;7():187-187.</p><p>Published online 4 Oct 2007</p><p>PMCID:PMC2082429.</p><p></p>are shown in grey. On main bifurcations, the corresponding posterior probability from Bayesian inference is reported (see Methods). Different colours associated to tree branches correspond to the main subfamilies. For each subfamily, the gene structure of human PRDM ortholog is depicted. The scale refers to exons only. The tree image was produced using iTOL [44]. . PRDM genes are ordered by increasing evolutionary divergence, calculated as cumulative branch lengths from the tip to the root of the phylogenetic tree. The expression data were measured as the mean values of different assays for each gene (see Methods). The upper limit of the 2values was set to 10. For original values see Additional file