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

Epstein-Barr virus(EBV)is a double-stranded DNA herpes virus that is universally susceptible to human populations worldwide.It mainly infects B cells and epithelial cells and has the characteristics of incubation and transformation.The innate immune response is the first line of defense against EBV.In particular, the immune response of type Ⅰ interferons and the direct cell-killing effects of innate cytotoxic lymphocyte are essential for initial control of viral infection and subsequent activation of adaptive immune responses.There is a delicate balance between innate immune response and immune escape of EBV, and the breakdown of the balance is related to the occurrence and prognosis of EBV-related diseases.A better understanding of this balance mechanism will guide the prevention and targeted therapy of EBV-related diseases.This article reviews the role of innate immune cells(epithelial cells, mononuclear/dendritic cells, NK cells, γδT cells, NKT cells)and type Ⅰ interferon in EBV infection and the immune escape mechanism of EBV.

Objective:To explore the protective effect of α-lipoic acid (LA) on radiation damage of mice cochlear ribbon synapses.Methods:Mice were divided into five groups: control group, radiation 3 d group, radiation 3 d+ LA group, radiation 14 d group and radiation 14 d+ LA group. The radiation groups were irradiated with 16 Gy, the radiation+ LA groups were given LA once a day after radiation, the control group was given the same amount of normal saline. The auditory brainstem response (ABR) of mice were measured before irradiation and sacrifice. The number of ribbon synapses were observed with immunofluorescently labeled protein ctBP2. Western blot assay was performed to obtain the semi-quantitative expression levels of otoferlin and AP-2 protein.Results:Compared with the control group, the ABR threshold of radiation groups were significantly higher ( P<0.05) with the highest value at 14 d after irradiation ( P<0.05), and the ABR threshold of the radiation+ LA groups were significantly lower ( P<0.05). The ABR threshold shifts of 12 kHz, 24 kHz at 3 d and 14 d groups had no significant difference with 8 kHz threshold shift ( P>0.05). The 32 kHz threshold shift was significantly higher than 8 kHz threshold shift ( t=-2.38, -5.48, P<0.05). The number of ribbon synapses in the radiation groups was significantly lower than that of control group ( P<0.05), with the lowest value in the radiation 14 d group. LA treatment increased the ABR value significantly ( P<0.05). AP-2 and otoferlin protein levels were significantly reduced after irradiation, especially in the radiation 14 d groups, and they were increased by the LA treatment. Conclusions:LA has protective effect on the ribbon synapses of cochlear hair cells.

Objective:To study the quality of life and postoperative complications in patients after laparoscopic cholecystectomy (LC).Methods:The data from 319 patients who were admitted to Nanjing First Hospital Affiliated to Nanjing Medical University and underwent LC from October 2013 to October 2017 were reviewed. These patients were assessed by a questionnaire which was based on the Gastrointestinal Quality of Life Index (GIQLI) before and after surgery.Results:The GIQLI scores on conscious symptoms, physiological function were significantly lower after surgery. The main postoperative complications were diarrhea (53.9%), decline in physical strength (30.1%), abdominal distension (25.4%), fatigue (26.9%) and abdominal pain (11.0%). Among patients with decline in physical strength, fatigue, and abdominal pain, 60.4%, 55.8%, and 51.4% of each of the groups, respectively, were associated with diarrhea. The incidences of severe diarrhea was 0.9%, severe fatigue was 0.3%, severe decline in physical strength 0% and severe abdominal pain 0%.Conclusions:The quality of life of patients declined after LC. The main postoperative complications were diarrhea, decline in physical strength, abdominal distension, fatigue and abdominal pain. However, the incidence of serious complications was small.

Objective: To investigate the breakthrough incidence of invasive fungal disease(IFD) and side effects of posaconazole as primary prophylaxis during induction chemotherapy for acute myeloid leukemia(AML). Methods: A total of 206 newly diagnosed AML patients admitted to our department during January 2016 and December 2018 were enrolled in the study. Exclusive criteria were as followings including patients diagnosed as acute promyelocytic leukemia; those who received intravenous antifungal therapy after admission or had history of IFD one month before induction chemotherapy, or those with functional insufficiency of vital organs and those older than 65. Forty-seven patients received posaconazole (posaconazole group), 61 cases received voriconazole (voriconazole group) and 98 cases did not receive any prophylaxis (control group) during induction chemotherapy. Prophylactic efficacy and safety between posaconazole and voriconazole were compared. Results: During induction chemotherapy, five possible cases of IFD occurred in posaconazole group (10.6%); while 11 cases (18.0%) were in voriconazole group including 7 possible, 3 probable and 1 proven. Thirty-five cases (35.7%) in control group were diagnosed as IFD including 19 possible, 11 probable and 5 proven ones. The incidences of IFD in posaconazole and voriconazole group were significantly lower than that in control group (P<0.05). The difference of posaconazole group and voriconazole group was not significant (P>0.05). The reported adverse events in posaconazole group were significantly lower than those in voriconazole group [12.8%(6/47) vs. 32.8%(20/61), P<0.05]. Conclusions Posaconazole and voriconazole decrease IFD as primary prophylaxis during induction chemotherapy in patients with AML. The prophylactic effect of IFD with posaconazole is similar as voriconazole, but posaconazole shows better safety.

Objective To analyze the prognostic impact of Ikaros family zinc finger 1(IKZF1)mutation on adult Philadelphia chromosome (Ph1) positive acute lymphoblastic leukemia (ALL) patients.Methods IKZF1 mutation was detected in 63 adult Phi positive ALL patients at diagnosis using capillary electrophoresis.Recruited patients were treated in our center and other three hospitals in Ningbo from January 2014 to January 2017.Clinical data were collected and retrospectively analyzed.Results Thirty-nine (61.9％) patients were positive IKZF1 mutation in this cohort.The white blood cell (WBC) count in IKZF1 mutation group was significantly higher than that of mutation negative group [(64.6±11.3)× 109/L vs.(33.7±5.6)×109/L,P＜0.05].Patients with WBC count over 30×109/L accounted for 56.4％ in IKZF1 mutation group.Complete remission (CR) rate in the IKZF1 mutation group was also lower than that of negative group after induction chemotherapy (64.1％ vs.75.0％,P＞0.05).IKZF1 was a negative prognostic factor but not independent factor for survival by univariate and multivariate analyses.Patients were divided into chemotherapy and allogeneic transplantation groups.The 3-year overall survival (OS) rate and 3-year leukemia-free survival (LFS) rate in IKZF1 mutation group were significantly lower than those of negative group in both transplantation group (42.3％ vs.59.3％;31.2％ vs.50.0％;respectively,both P＜0.05) and chemotherapy group (24.8％ vs.40.0％;19.0％ vs.34.3％;respectively,both P＜0.05).Conclusion IKZF1 mutation is a poor prognostic factor for adult Ph1 positive ALL patients.

Objective: To investigate the impact of FLT3-ITD and DNMT3A R882 double mutations to the prognosis of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: FLT3-ITD, DNMT3A, C-kit, CEBPA, FLT3-TKD and NPM1 mutations were detected in 206 newly diagnosed AML patients by Sanger sequencing (M₃ and those received FLT3 inhibitor were excluded). Clinical data of AML patients were retrospectively analyzed to compare the prognosis of each gene mutation group. Results: ①Of 206 patients, 104 were male and 102 female with a median age of 38 (3-63) years, including 6 cases of M₀, 24 cases of M₁, 56 cases of M₂, 39 cases of M₄, 63 cases of M₅, 6 cases of M₆ and 12 unclassified cases. ②All 206 patients were divided into four groups according to the mutation gene at the time of diagnosis: FLT3-ITD⁺ DNMT3A R882⁺ group (group A), FLT3-ITD⁺ DNMT3A R882^- group (group B), FLT3-ITD^- DNMT3A R882⁺ group (group C) and FLT3-ITD^- DNMT3A R882^- groups (group D). Gender, leukocyte count at diagnosis, chromosome karyotype, the median age, FAB classification, disease status prior to transplantation, type of donor, conditioning regimen and GVHD were not significantly different between four groups (P>0.05). ③The 2-year cumulative recurrence rate (CIR) of group A was significantly higher than that of other groups [group A (72.2±2.6)%, group B (38.6±0.6)%, group C (36.8±1.6)%, group D (27.8±0.1)%, respectively, P<0.05], while the 2-year overall survival (OS) rate and 2-year leukocyte-free survival (LFS) rate were lower than those of other groups [group A (30.9±13.3)%, (11.3±10.2)%; group B (67.5±7.8)%, (47.9±8.4)%; group C (61.4±12.4)%, (56.8±12.5)%; group D (80.1±3.7)%, (79.7±3.6)%, respectively, P<0.05]. Conclusion AML patients with FLT3-ITD and DNMT3A R882 double mutations had a very high CIR and low OS, LFS after transplantation.

Objective: A second generation CAR-NK-92 cell line expressing CD19 was constructed to investigate its specific killing effect on CD19 positive non-Hodgkin lymphoma cells. Methods: First, build CD19-CAR gene expression vector and packaged slow virus particles, then the infection rate was detected by flow cytometry after infected NK-92 cells and positive cells were further separated. Finally, detected the expression of CD19-CAR in NK-92 cells by Western blotting. U-266 with CD19 negative myeloma cells,ARH77 and HS-Sultan with CD19 positive non-Hodgkin’s lymphoma cells as target cells, and CD19CAR-NK-92 as effector cells, then the killing rate was calculated by the absolute number of tumor cells alive in the cell killing experiment. Results: Construct lentivirus vector pLVX-CD19-CAR and packaged virus particles successfully, the purity of CD19-CAR-NK-92 cells also was over 90% after infected with NK-92 cells; and Western blotting analysis showed that CD19-CAR had been successfully expressed in NK-92 cell. The killing effect of CD19CAR-NK-92 onARH-77 ([70.10±1.86]% vs [1.95±0.63]%, P<0.01) and HS-Sultan ([74.98±1.60]% vs [0.58±1.49]%, P< 0.01) cells was significantly higher than the empty vector control group of ZsGreen-NK-92, but there was no difference in killing U266 (P>0.05). Conclusion: The NK-92 cell lines expressing CD19CAR were successfully constructed, and also has specific killing effects on CD19 positive non-Hodgkin lymphoma cells.

Objective To observe the clinical effect of sequential therapy with micafungin and reduced -dose voriconazole in prevention of invasive fungal infections in patients received allogeneic hematopoietic stem cell transplantion (Allo -HSCT).Methods 28 patients received the treatments for prevention of fungal infection with micafungin 50 mg per day from pretreatment to 30 days,then oral voriconazole at a dose of 1 00 mg two times per day until 90 days after Allo -HSCT.The occurrence of invasive fungal infection and the side effects of both medicine were observed during 1 80 days after Allo -HSCT.Results 8 patients(28.6%)developed above grade 2 acute graft verse host disease(GVHD),2 patients developed grade 3 GVHD among the 8 patients.Two case with GVHD were cured by voriconazole with the therapeutic dose who occurred probably pulmonary invasive fungal infection at two months after Allo -HSCT.There were no other patients diagnosed fungal infection.No toxic efect were observed during the clinical observation during treatment with micafungin.5 patients appeared mild liver function abnormalities during treatment with voriconazole,and liver dysfunction were improved by symptomatic treatment.2 cases developed transient auditory hallucination and visual impairment induced by voriconazole.Conclusion Micafungin and reduced -dose voricon-azole are effective and safe prophylaxis in prevention early invasive fungal infection after HSCT.

Objective This study was designed to investigate the expression and potential role of the protein phosphatase 1 (PP1) impairment in D -galactose-induced inner ear aging mouse model .Methods Forty Kunming mice were randomly divided into two groups :the control group and D -galactose group ,20 mice for each .The D-galactose group mice were treated with a daily subcutaneous injection of the D -galactose solutions (800 mg · kg -1 · d-1 ) or an equal volume of normal saline(for the control group) in the nape back for 8 weeks .Eight weeks after D-galactose administration ,the effects of were measured by total Superoxide Dismutase (SOD) activity and Malon-dialdehyde (MDA) level in plasma .Immunofluoresence was performed to detect the location of the PP1 expression in the cochlea .Real-time PCR was performed to detect the level of PP1 mRNA in cochlea .A Western blot analysis was performed to analyze the protein levels of protein phosphates 1 nuclear targeting subunit (PNUTS) ,PP1 and caspase-3 in the inner ear .Results The MDA level was more significantly increased in the D -galactose group than in the control group ;however ,the total SOD activity was significantly decreased in the plasma of D -galactose- induced aging mice(P<0 .01) .The results showed that PP1 was predominantly localized in the nucleus and cyto-plasm of the hair cell ,spiral ganglion cell and stria vascularis cell .And the protein levels of PP1 and caspase-3 sig-nificantly increased ,and the level of PNUTS was decreased in the cochlea of the D -galactose group when compared to the control group .Conclusion PP1 contributes to the development of D -galactose-induced aging mice .