RESUMEN
Gangliosides play vital biological regulatory roles and are associated with neurological system diseases, malignancies, and immune deficiencies. They have received extensive attention in developing targeted drugs and diagnostic markers. However, it is difficult to obtain enough structurally defined gangliosides and analogs especially at an industrial-relevant scale, which prevent exploring structure-activity relationships and identifying drug ingredients. Here, we report a highly modular chemoenzymatic cascade assembly (MOCECA) strategy for customized and large-scale synthesis of ganglioside analogs with various glycan and ceramide epitopes. We typically accessed five gangliosides with therapeutic promising and systematically prepared ten GM1 analogs with diverse ceramides. Through further process amplification, we achieved industrial production of ganglioside GM1 in the form of modular assembly at hectogram scale. Using MOCECA-synthesized GM1 analogs, we found unique ceramide modifications on GM1 could enhance the ability to promote neurite outgrowth. By comparing the structures with synthetic analogs, we further resolved the problem of contradicting descriptions for GM1 components in different pharmaceutical documents by reinterpreting the exact two-component structures of commercialized GM1 drugs. Because of its applicability and stability, the MOCECA strategy can be extended to prepare other glycosphingolipid structures, which may pave the way for developing new glycolipid drugs.
RESUMEN
Purpose: To assess the efficacy of neoadjuvant chemotherapy plus limb-sparing surgery for osteosarcoma and its impact on long-term quality of life. Methods: Between August 2016 and December 2018, 90 patients with osteosarcoma treated in Nanchong Central Hospital were recruited and divided at a ratio of 1 : 1 to receive limb-sparing surgery (control group) or limb-sparing surgery plus neoadjuvant chemotherapy (study group) by random number table methods. The clinical endpoints were clinical efficacy and long-term quality of life. Results: Limb-sparing surgery plus neoadjuvant chemotherapy was associated with a significantly higher efficacy versus limb-sparing surgery alone. Limb-sparing surgery plus neoadjuvant chemotherapy resulted in a significantly higher Enneking score and a higher good function rating of patients versus limb-sparing surgery. The two groups showed a high but similar 1-year survival rate. Patients given limb-sparing surgery plus neoadjuvant chemotherapy showed significantly higher 2-year and 3-year survival and a longer mean survival versus those receiving limb-sparing surgery alone. Limb-sparing surgery plus neoadjuvant chemotherapy resulted in significantly higher scores of role emotional, mental health, physical function, and social function and a lower bodily pain score than limb-sparing surgery alone. Limb-sparing surgery plus neoadjuvant chemotherapy was associated with significantly lower fatigue, nausea and vomiting, dyspnea, constipation, and diarrhea scores and a significantly higher health status score versus monotherapy of limb-sparing surgery. Conclusion: Neoadjuvant chemotherapy plus limb-sparing surgery improves the postoperative limb function and long-term quality of life of patients with osteosarcoma, which shows great potential for clinical promotion.
RESUMEN
Although cryopreservation of bull semen is widely used commercially in the livestock breeding industry, cryopreservation results in low fertility of bull sperm. As an important regulatory factor, the alteration of small non-coding RNA (sncRNA) profile during cryopreservation of bull sperm is not yet completely known. In the present study, we sequenced sncRNAs of frozen and fresh sperm to study the link of alteration of the sncRNA profiles (particularly in miRNAs and mRNA fragments) with low sperm fertility caused by cryopreservation. We identified 55 miRNAs and 526 mRNA fragments differentially expressed (DE) between frozen and fresh sperm. Subsequently, the functional analysis revealed that targeted genes of DE miRNAs in sperm had roles in the fertilization, ATP, and apoptosis. Instead, targeted genes of DE miRNAs in cow metaphase II oocyte were significantly enriched in the MAPK signaling pathway, autophagy-animal pathway, and mitophagy-animal pathway. Additionally, biological processes of DNA repair, spermatid development, response to temperature stimulus, and cellular response to DNA damage stimulus were enriched by mRNA fragments. In conclusion, we found that DE miRNAs or DE mRNA fragments in cryopreservation may influence the fertility of sperm, these findings will provide the reference to improve the cryopreservation technology of bull semen.
