Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe dose-limiting adverse event of chemotherapy. Presently, the mechanism underlying the induction of CIPN remains unclear, and no effective treatment is available. In this study, through metabolomics analyses, we found that nab-paclitaxel therapy markedly increased serum serotonin [5-hydroxtryptamine (5-HT)] levels in both cancer patients and mice compared to the respective controls. Furthermore, nab-paclitaxel-treated enterochromaffin (EC) cells showed increased 5-HT synthesis, and serotonin-treated Schwann cells showed damage, as indicated by the activation of CREB3L3/MMP3/FAS signaling. Venlafaxine, an inhibitor of serotonin and norepinephrine reuptake, was found to protect against nerve injury by suppressing the activation of CREB3L3/MMP3/FAS signaling in Schwann cells. Remarkably, venlafaxine was found to significantly alleviate nab-paclitaxel-induced CIPN in patients without affecting the clinical efficacy of chemotherapy. In summary, our study reveals that EC cell-derived 5-HT plays a critical role in nab-paclitaxel-related neurotoxic lesions, and venlafaxine co-administration represents a novel approach to treating chronic cumulative neurotoxicity commonly reported in nab-paclitaxel-based chemotherapy.
Paclitaxel/toxicity* ; Animals ; Albumins/adverse effects* ; Serotonin/metabolism* ; Mice ; Humans ; Male ; Female ; Venlafaxine Hydrochloride/therapeutic use* ; Neurotoxicity Syndromes/metabolism* ; Middle Aged ; Schwann Cells/metabolism* ; Peripheral Nervous System Diseases/drug therapy* ; Antineoplastic Agents

The inhibition of cyclin-dependent kinases (CDKs) is considered a promising strategy for cancer treatment due to their role in cell cycle regulation. However, CDK inhibitors with no selectivity among CDK families have not been approved. A CDK inhibitor with high selectivity for CDK4/6 exhibited significant treatment effects on breast cancer and has become a heavy bomb on the market. Subsequently, resistance gradually decreased the efficacy of selective CDK4/6 inhibitors in breast cancer treatment. In this review, we first introduce the development of selective CDK4/6 inhibitors and then explain the role of CDK2 activation in inducing resistance to CDK4/6 inhibitors. Moreover, we focused on the development of CDK2/4/6 inhibitors and selective CDK2 inhibitors, which will aid in the discovery of novel CDK inhibitors targeting the cell cycle in the future.
Humans ; Cell Cycle/drug effects* ; Protein Kinase Inhibitors/chemistry* ; Cyclin-Dependent Kinases/metabolism* ; Neoplasms/genetics* ; Antineoplastic Agents/pharmacology* ; Animals ; Breast Neoplasms/enzymology* ; Cyclin-Dependent Kinase 4/metabolism*

Porcine deltacoronavirus(PDCoV),a newly discovered virus in recent years,can cause severe diarrhea,vomiting,dehydration and even death in piglets.S protein is an important structur-al protein of PDCoV,which determines the host or tissue tropism of the virus,and is an important target for the development of PDCoV vaccines and detection methods.In order to prepare mono-clonal antibody(MAb)against the S protein of PDCoV,the recombinant plasmid of S protein was constructed based on the extracellular domain sequence of S protein of PDCoV epidemic strain in China and transformed into DH10Bac competent cells.The recombinant bacmid was identified by blue-white spot screening and PCR.BALB/c mice were immunized with S protein,and the spleen cells of immunized mice were fused with myeloma cells.The positive hybridoma cells that secreted stable antibodies were screened by indirect ELISA and subcloning.Five hybridoma cell superna-tants(MAb)specifically recognizing S protein(2E5,4D5,5D10,2F7 and 5A9)were identified by Western blot and immunofluorescence assay(IFA).Subsequently,the neutralization test showed that three of the monoclonal antibodies(2E5,4D5 and 5D10)could neutralize the virus to varying degrees.The S protein was successfully expressed and 5 monoclonal antibodies that can stably se-crete and specifically bind to PDCoV and S protein were prepared,which laid an important founda-tion for further research on the structure and function of S protein,the development of detection methods for PDCoV infection,and the prevention or treatment of PDCoV infection.

Objective:To cultivate human-derived prostate cancer (PCa) cells via conditional reprogramming cell (CRC) technology, and establish individualized cell bank for PCa research in vitro.Methods:We obtained three fresh PCa tissue samples from different patients between January 2019 and April 2019. Then each sample was divided into two parts. One was used for cancer nature confirmation by intraoperative biopsy. Another part was sent to the laboratory and digested into single primary cancer cells with 0.25% EDTA enzyme for CRC technology. The details were described as followed: 1. The primary PCa cells were co-cultured with 3T3-J2 cells irradiated by 30 Gy (feeder cells) in conditioned medium, and observed for the growth of cell clones, 2. The feeder cells were removed by 0.25% EDTA trypsin for 1 minute before primary PCa cells digested for passage. All primary PCa cells were validated by multiple experiments such as immunofluorescence, immunohistochemistry, immunoblotting and fluorescence in situ hybridization (FISH).Results:Total three cases of human-derived PCa cell lines were successfully established during 15days through CRC technology. All those primary PCa cells could be steadily and continuously passaged, which also expressed AR, CK5, CK18, P504s and PSA. FISH demonstrated that each cell line harbored≥1.6% TMPRSS2/ERG fusion and conformed to the features of PCa.Conclusion:CRC technology can be used for stable and continuous PCa cell culture in vitro.

Objective To investigate the mechanisms of paeoniflorin in protection of retinal ischemia injury.Methods Fifty-four male specefic pathogen free (SPF) degree Wistar rats were randomly divided into normal control group,model control group and paeoniflorin group.Retinal ischemia injury was induced by raising the intraocular pressure of right eyes of rats to 110 mmHg for 30 minutes.The rats of paeoniflorin group were administrated through intraperitoneal injection of 5 mg/kg paeoniflorin each day for 14 days.OCT and electroretinogram (ERG) were performed to detect the thickness of retinal nerve fiber layer+retinal ganglion cell layer+inner plexiform layer (NGI)and electrophysiological changes of retina,respectively.Retrograde labelling of retinal ganglion cells (RGCs) was used to evaluate the survival number of RGCs.Western blot analysis was used to detect NLRP3,apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC),cleaved caspase 1 (c-caspase 1),IL-18,and IL-1β expression.The use and care of animals complied with the statement of the Association for Research in Vision and Ophthalmology (ARVO) and Regulations for the Administration of Affair Concerning Experimental Animals by State Science and Technology Commission.Results The thickness of retinal NGI in model control group was (58.2 ± 1.7) μm,which was significantly lower than (84.8 ± 1.9) μm in normal control group and (71.1 ±2.4) μm in paeoniflorin group (both at P＜0.05).The amplitudes of A and B waves in paeoniflorin group and normal control group were significantly higher than those in model control group (both at P＜0.05).The number of RGC in model control group was significantly lower than that in paeoniflorin group and normal control group (both at P＜0.05).The relative expressions of NLRP3,ASC,c-caspase 1,IL-18 and IL-1β in model control group were significantly higher than those in normal control group and paeoniflorin group (all at P＜0.05).Conclusions The paeoniflorin can prevent retinal ischemia induced injury of the retina through NLRP3 inflammasomes pathway,which provides a new treatment strategy for clinical therapy.

Objective To investigate the mechanisms of paeoniflorin in protection of retinal ischemia injury. Methods Fifty.four male specefic pathogen free ( SPF) degree Wistar rats were randomly divided into normal control group,model control group and paeoniflorin group. Retinal ischemia injury was induced by raising the intraocular pressure of right eyes of rats to 110 mmHg for 30 minutes. The rats of paeoniflorin group were administrated through intraperitoneal injection of 5 mg/kg paeoniflorin each day for 14 days. OCT and electroretinogram ( ERG ) were performed to detect the thickness of retinal nerve fiber layer+retinal ganglion cell layer+inner plexiform layer ( NGI) and electrophysiological changes of retina, respectively. Retrograde labelling of retinal ganglion cells ( RGCs ) was used to evaluate the survival number of RGCs. Western blot analysis was used to detect NLRP3,apoptosis.associated speck.like protein containing a caspase activation and recruitment domain (ASC),cleaved caspase 1 (c.caspase 1), IL.18,and IL.1β expression. The use and care of animals complied with the statement of the Association for Research in Vision and Ophthalmology ( ARVO ) and Regulations for the Administration of Affair Concerning Experimental Animals by State Science and Technology Commission. Results The thickness of retinal NGI in model control group was ( 58. 2 ± 1. 7)μm, which was significantly lower than ( 84. 8 ± 1. 9)μm in normal control group and(71. 1±2. 4)μm in paeoniflorin group (both at P<0. 05). The amplitudes of A and B waves in paeoniflorin group and normal control group were significantly higher than those in model control group ( both at P<0. 05 ) . The number of RGC in model control group was significantly lower than that in paeoniflorin group and normal control group ( both at P<0. 05). The relative expressions of NLRP3,ASC,c.caspase 1,IL.18 and IL.1β in model control group were significantly higher than those in normal control group and paeoniflorin group (all at P<0. 05). Conclusions The paeoniflorin can prevent retinal ischemia induced injury of the retina through NLRP3 inflammasomes pathway,which provides a new treatment strategy for clinical therapy.

Patient satisfaction is an important index of hospital quality evaluation and performance evaluation.This study established multi-attribute patient satisfaction index system based on the theory of customer satisfaction index,determined the index weight by combination weighting approach,and graded the hospitals and adjusted the weights by the RSR method.A set of comprehensive evaluation scheme is initially formed,which is suitable for patient satisfaction evaluation and performance evaluation.

Objective Examination and evaluation of employee satisfaction index in the hospital performance evaluation.Methods Stratified sampling,field survey and telephone survey were used in customizing a questionnaire for two surveys in July and December 201 5 respectively.Results The standardized score of employee satisfaction was 86.252±1 5.1 53,and the lowest score was found in the canteen environment and food quality.Conclusion Employee satisfaction is found as good overall,and targeted measures are recommended to improve insufficiencies for better employee satisfaction.

Objective To explore the effect of salmon calcitonin on osteoporosis induced by spinal cord injury. Methods 100 patients with osteoporosis induced by spinal cord injury from September 2011 to September 2014 in our department were included. They were randomly divided into control group (n=50) and observation group (n=50). The control group received vitamin D3 only, while the observation group received vitamin D3 combined with salmon calcitonin on the basis of rehabilitation physiotherapy, for 6 months. Visual Analogue Scale (VAS) of pain was evaluated in different periods. The bone mineral density (BMD) of lumbar spine and femoral neck, the parathyroid hormone (PTH), bone gla protein (BGP) and 1,25- dihydroxy vitamin D3 (1,25-(OH)2D3) were tested and recorded. Results The VAS score was lower in the observation group than in the control group 1, 2, 3 and 6 months after treatment (P<0.001). The BMD of lumbar spine and femoral neck was significantly higher, the PTH and BGP were significantly lower and the 1,25-(OH)2D3 was significantly higher in the observation group than in the control group after treatment (P<0.001). Conclusion Combination of salmon calcitonin can effectively reduce the bone pain and improve the BMD in patients with osteoporosis induced by spinal cord injury.