Long-term safety and efficacy of extended-interval prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) in subjects with haemophilia B

The safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children <12 years) studies of subjects with haemophilia B (≤2 IU/dl). Here, we report interim, long-term safety and efficacy data from B-YOND, the rFIXFc extension study. Eligible subjects who completed B-LONG or Kids B-LONG could enrol in B-YOND. There were four treatment groups: weekly prophylaxis (20–100 IU/kg every 7 days), individualised prophylaxis (100 IU/kg every 8–16 days), modified prophylaxis (further dosing personalisation to optimise prophylaxis), and episodic (on-demand) treatment. Subjects could change treatment groups at any point. Primary endpoint was inhibitor development. One hundred sixteen subjects enrolled in B-YOND. From the start of the parent studies to the B-YOND interim data cut, median duration of rFIXFc treatment was 39.5 months and 21.9 months among adults/adolescents and children, respectively; 68/93 (73.1 %) adults/adolescents and 9/23 (39.1 %) children had ≥100 cumulative rFIXFc exposure days. No inhibitors were observed. Median annualised bleeding rates (ABRs) were low in all prophylaxis regimens: weekly (≥12 years: 2.3; <6 years: 0.0; 6 to <12 years: 2.7), individualised (≥12 years: 2.3; 6 to <12 years: 2.4), and modified (≥12 years: 2.4). One or two infusions were sufficient to control 97 % (adults/adolescents) and 95 % (children) of bleeding episodes. Interim data from B-YOND are consistent with data from B-LONG and Kids B-LONG, and confirm the long-term safety of rFIXFc, absence of inhibitors, and maintenance of low ABRs with prophylactic dosing every 1 to 2 weeks

Swinepox virus vector-based vaccines: attenuation and biosafety assessments following subcutaneous prick inoculation

Abstract Swinepox virus (SPV) has several advantages as a potential clinical vector for a live vector vaccine. In this study, to obtain a safer and more efficient SPV vector, three SPV mutants, Δ003, Δ010, and ΔTK were successfully constructed. A virus replication experiment showed that these SPV mutants had lower replication abilities compared to wtSPV in 10 different host-derived cell lines. Animal experiments with mouse and rabbit models demonstrate that these three mutants and wtSPV did not cause any clinical signs of dermatitis. No fatalities were observed during a peritoneal challenge assay with these mutants and wtSPV in a mouse model. Additionally, the three mutants and wtSPV were not infectious at 60 h after vaccination in rabbit models. Furthermore, we evaluated biosafety, immunogenicity and effectiveness of the three mutants in 65 1-month-old piglets. The results show that there were no clinical signs of dermatitis in the Δ003 and ΔTK vaccination groups. However, mild signs were observed in the Δ010 vaccination groups when virus titres were high, and apparent clinical signs were observed at the sites of inoculation. Samples from all experimental pig groups were assessed by qPCR, and no SPV genomic DNA was found in five organs, faeces or blood. This suggests that the infectious abilities of wtSPV and the SPV mutants were poor and limited. In summary, this study indicates that two mutants of SPV, Δ003 and ΔTK, may be promising candidates for an attenuated viral vector in veterinary medicine

Converse, Focus and Guess -- Towards Multi-Document Driven Dialogue

We propose a novel task, Multi-Document Driven Dialogue (MD3), in which an agent can guess the target document that the user is interested in by leading a dialogue. To benchmark progress, we introduce a new dataset of GuessMovie, which contains 16,881 documents, each describing a movie, and associated 13,434 dialogues. Further, we propose the MD3 model. Keeping guessing the target document in mind, it converses with the user conditioned on both document engagement and user feedback. In order to incorporate large-scale external documents into the dialogue, it pretrains a document representation which is sensitive to attributes it talks about an object. Then it tracks dialogue state by detecting evolvement of document belief and attribute belief, and finally optimizes dialogue policy in principle of entropy decreasing and reward increasing, which is expected to successfully guess the user's target in a minimum number of turns. Experiments show that our method significantly outperforms several strong baseline methods and is very close to human's performance.Comment: Accepted by AAAI202

Fibroblast growth factor-5 promotes spermatogonial stem cell proliferation via ERK and AKT activation

Abstract Background Sertoli cells are the most important somatic cells contributing to the microenvironment (named niche) for spermatogonial stem cells (SSCs). They produce amounts of crucial growth factors and structure proteins that play essential roles in the complex processes of male SSCs survival, proliferation, and differentiation. It has been suggested that Sertoli cell abnormalities could result in spermatogenesis failure, eventually causing azoospermia in humans. However, to the end, the gene expression characteristics and protein functions of human Sertoli cells remained unknown. In this study, we aimed to evaluate the effect of fibroblast growth factor-5 (FGF5), a novel growth factor downregulated in Sertoli cells from Sertoli cell-only syndrome (SCOS) patients compared to Sertoli cells from obstructive azoospermia (OA) patients, on SSCs. Methods We compared the transcriptome between Sertoli cell from SCOS and OA patients. Then, we evaluated the expression of FGF5, a growth factor which is downregulated in SCOS Sertoli cells, in human primary cultured Sertoli cells and testicular tissue. Also, the proliferation effect of FGF5 in mice SSCs was detected using EDU assay and CCK-8 assay. To investigate the mechanism of FGF5, Phospho Explorer Array was performed. And the results were verified using Western blot assay. Results Using RNA-Seq, we found 308 differentially expressed genes (DEGs) between Sertoli cells from SCOS and OA patients. We noted and verified that the expression of fibroblast growth factor-5 (FGF5) was higher in Sertoli cells of OA patients than that of SCOS patients at both transcriptional and translational levels. Proliferation assays showed that rFGF5 enhanced the proliferation of mouse SSCs line C18-4 in a time- and dose-dependent manner. Moreover, we demonstrated that ERK and AKT were activated and the expression of Cyclin A2 and Cyclin E1 was enhanced by rFGF5. Conclusion The distinct RNA profiles between Sertoli cells from SCOS and OA patients were identified using RNA-Seq. Also, FGF5, a growth factor that downregulated in SCOS Sertoli cells, could promote SSCs proliferation via ERK and AKT activation

Exosome Released From Schwann Cells May Be Involved in Microenergy Acoustic Pulse–Associated Cavernous Nerve Regeneration

BackgroundNeurogenic erectile dysfunction (ED) is often refractory to treatment because of insufficient functional nerve recovery after injury or insult. Noninvasive mechano-biological intervention, such as microenergy acoustic pulse (MAP), low-intensity pulsed ultrasound, and low-intensity extracorporeal shockwave treatment, is an optimal approach to stimulate nerve regeneration.AimTo establish a new model in&nbsp;vitro to simulate nerve injury in neurogenic ED and to explore the mechanisms of MAP in&nbsp;vitro.MethodsSprague-Dawley rats were used to isolate Schwann cells (SCs), major pelvic ganglion (MPG), and cavernous nerve with MPG (CN/MPG). SCs were then treated with MAP (0.033&nbsp;mJ/mm2, 1&nbsp;Hz, 100 pulses), and SC exosomes were isolated. The MPG and CN/MPG were treated with MAP (0.033&nbsp;mJ/mm2, 1&nbsp;Hz) at different dosages (25, 50, 100, 200, or 300 pulses) or exosomes derived from MAP-treated SCs in&nbsp;vitro.OutcomesNeurite growth from the MPG fragments and CN was photographed and measured. Expression of neurotropic factors (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) was checked.ResultsNeurite outgrowth from MPG and CN/MPG was enhanced by MAP in a dosage response manner, peaking at 100 pulses. MAP promoted SC proliferation, neurotropic factor (brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) expression, and exosome secretion. SC-derived exosomes significantly enhanced neurite outgrowth from MPG in&nbsp;vitro.Clinical implicationsMAP may have utility in the treatment of neurogenic ED by SC-derived exosomes.Strength &amp; limitationsWe confirmed that MAP enhances penile nerve regeneration through exsomes. Limitations of this study include that our study did not explore the exact mechanisms of how MAP increases SC exosome secretion nor whether MAP modulates the content of exosomes.ConclusionThis study revealed that neurite outgrowth from MPG was enhanced by MAP and by SC-derived exosomes which were isolated after MAP treatment. Our findings indicate that one mechanism by which MAP induces nerve regeneration is by stimulation of SCs to secrete exosomes. Peng D, Reed-Maldonado AB, Zhou F, et&nbsp;al. Exosome Released From Schwann Cells May Be Involved in Microenergy Acoustic Pulse-Associated Cavernous Nerve Regeneration. J Sex Med 2020;17:1618-1628

data for "Selective laser melted Ti-6Al-4V alloy with micron-to-nano-featured surface topography for biomedical applications"

The data available for the manuscript: "Selective laser melted Ti-6Al-4V alloy with micron-to-nano-featured surface topography for biomedical applications" submitted to Journal of Healthcare Engineering

Prognostic nomogram for multiple myeloma early relapse after autologous stem cell transplant in the novel agent era

Abstract Background The present study intended to establish a predictive nomogram for early relapse (ER) ( UNL, and response less than very good partial response (VGPR) after ASCT. The calibration curve showed good fitness between the nomogram predictions and the actual observations and the nomogram was further validated by a clinical decision curve. The nomogram's C‐index achieved 0.75 (95% CI, 0.70–0.80), which was higher than that of the Revised International Staging System (R‐ISS) (0.62), ISS (0.59), and Durie–Salmon (DS) staging system (0.52). The discrimination ability of the nomogram in the validation cohort was superior to that of the other staging systems (C‐index: 0.73 vs. R‐ISS (0.54), ISS (0.55), and DS staging system (0.53)). DCA showed the prediction nomogram adds much more clinical utility. Different scores of the nomogram draw a distinction of OS. Conclusion The present nomogram could serve as a feasible and accurate prediction of ER in novel drug induction transplantation‐eligible MM patients, which could help modify the post‐ASCT strategy for patients at high risk of ER

miR-202-3p Regulates Sertoli Cell Proliferation, Synthesis Function, and Apoptosis by Targeting LRP6 and Cyclin D1 of Wnt/β-Catenin Signaling

MicroRNAs (miRNAs) play important roles in mammalian spermatogenesis, which is highly dependent on Sertoli cells. However, the functions and mechanisms of miRNAs in regulating human Sertoli cells remain largely unknown. Here, we report that hsa-miR-202-3p mediates the proliferation, apoptosis, and synthesis function of human Sertoli cells. miR-202-3p was upregulated in Sertoli cells of Sertoli cell-only syndrome (SCOS) patients compared with obstructive azoospermia (OA) patients with normal spermatogenesis. Overexpression of miR-202-3p induced Sertoli cell apoptosis and inhibited cell proliferation and synthesis, and the effects were opposite when miR-202-3p was knocked down. Lipoprotein receptor-related protein 6 (LRP6) and Cyclin D1 of the Wnt/β-catenin signaling pathway were identified as direct targets of miR-202-3p in Sertoli cells, which were validated by bioinformatics tools and dual-luciferase reporter assay. Differentially expressed LRP6 and Cyclin D1 between OA and SCOS Sertoli cells were also verified. LRP6 small interfering RNA (siRNA) interference not only mimicked the effects of miR-202-3p overexpression, but also antagonized the effects of miR-202-3p inhibition on Sertoli cells. Collectively, miR-202-3p controls the proliferation, apoptosis, and synthesis function of human Sertoli cells via targeting LRP6 and Cyclin D1 of the Wnt/β-catenin signaling pathway. This study thus provides a novel insight into fate determinations of human Sertoli cells and niche of human testis. Keywords: human Sertoli cells, miR-202-3p, proliferation and apoptosis, synthesis, LRP6, Cyclin D1, Wnt/β-cateni