Objective To investigate the role of cytochrome P450 2E1 (CYP2E1) in trichloroethylene (TCE)-induced skin sensitization and liver damage in guinea pigs, using diallyl sulfide (DAS), a CYP2E1 inhibitor, as an intervention. Methods Specific pathogen-free female guinea pigs were randomly divided into blank control group, solvent control group, positive control (2,4-dinitrochlorobenzene) group, TCE-exposure group, and DAS-intervention group. Skin sensitization experiments were conducted using the guinea pig TCE maximal dose-skin sensitization test. Urinary trichloroacetic acid levels were determined following TCE induction and challenge. At 48 hours after the final challenge, serum liver function markers and inflammatory cytokines levels were detected. Histopathological examination on skin and liver tissues was performed, and hepatic CYP2E1 protein expression and oxidative stress indicators were assessed. Results The sensitization rates of guinea pigs were 100.0%, 75.0%, and 33.3% in the positive control, TCE-exposure, and DAS-intervention groups, respectively, while the blank control and solvent control groups were both 0.0%. Compared with the guinea pigs in TCE-exposure group, those in the DAS-intervention group had lower urinary trichloroacetic acid levels at intradermal induction, local induction, first challenge, and 24 hours after the final challenge time point (all P<0.05). Histopathology of guinea pigs showed dermal inflammatory infiltration and basal keratinocyte necrosis in the TCE-exposure group, whereas only mild dermal inflammation was observed in the DAS-intervention group. The guinea pigs in TCE-exposure group exhibited diffuse hepatocellular necrosis, while hepatic damage in the DAS-intervention group was alleviated, characterized by only mild hepatocellular steatosis and hepatocyte swelling around the central vein. The skin sensitization rate of guinea pigs in the TCE-exposure group increased (all P<0.01), the serum alanine aminotransferase (ALT )activity, the levels of interleukin (IL)-2, IL-17, and tumor necrosis factor-α (TNF- α) increased (all P<0.05), the relative expression of CYP2E1 protein, the activity of superoxide dismutase (SOD), and the level of malondialdehyde in liver tissue increased (all P<0.05), while the activity of catalase decreased (P<0.05), compared with the blank control and solvent control groups. The serum ALT activity and the levels of IL-2, IL-17, and TNF-α of guinea pigs in DAS-intervention group reduced (all P<0.05), as well as CYP2E1 protein expression, SOD activity, and malondialdehyde level in liver tissue reduced (all P<0.05), compared with the TCE-exposure group. Conclusion TCE can induce hepatic CYP2E1 expression, thereby promoting oxidative stress and inflammatory responses, which contributes to skin sensitization and liver damage. DAS alleviates TCE-induced toxic effects on skin and liver by inhibiting CYP2E1 expression.

Objective To investigate the effects of long-term exposure to three new types of light emitting diode (LED) sources on the behavior, learning, and memory of rats. Methods A total of 160 specific pathogen-free SD rats were divided into eight groups as followed, trichromatic fluorescent lamps color temperature control group, violet-chip full-spectrum white LED group, blue-chip white LED group, and blue-chip full-spectrum white LED group based on the light sources types, with color temperature of 4 000 K and 6 500 K groups in each group using the 4×2 factorial design. There were 20 rats in each group, with half of the rats were males and half females. Rats were exposed to artificial lighting, and the illumination was set at 750 lx. The rats in each group were exposed to different lighting environments for 12 hours per day for 24 weeks. The open-field and step-down tests were conducted in rats after 24 weeks exposure, followed by sacrifice of rats and measurement of organ coefficients. Differences in body weight, organ coefficients, and neurobehavioral indexes of rats in different groups were compared. Results The spleen coefficient of female rats decreased in blue-chip white LED of 6 500 K color temperature group, and the liver coefficient of male rats decreased in the violet-chip full-spectrum white LED of 4 000 K color temperature, blue-chip full-spectrum white LED of 4 000 K color temperature, and blue-chip full-spectrum white LED of 6 500 K color temperature groups, compared with the same-sex rats in trichromatic fluorescent lamps with same-color temperature control group (all P<0.05). The result of different types of light sources compared in the open-field test showed that the index of total distance and movement speed of female rats in the blue-chip full-spectrum white LED group were lower than those in the other three groups, and the time cost to the central area was longer than that in the blue-chip white LED group and the violet-chip full-spectrum white LED group (all P<0.05). The total distance and movement speed of male rats in the blue-chip full-spectrum white LED group were longer or higher than those in the violet-chip full-spectrum white LED group (all P<0.05). Based on the comparison of color temperature, the time and total distance of male rats in 6 500 K color temperature group were lower than that in the 4 000 K color temperature group (both P<0.05). In the step-down test, both male and female rats in the blue-chip full-spectrum white LED group made more errors compared with other three groups with the same gender (all P<0.05). Conclusion Based on the experimental conditions of this study, the blue-chip full-spectrum white light LED affects behavior, learning and memory of the rats, and trichromatic fluorescent lamp has the lowest effect on neurobehavior. The color temperature also affects behavior of the rats, and high color temperature has higher risk.

Humans ; Multiple Myeloma/genetics* ; Karyotyping ; Translocation, Genetic/genetics*

{L-End}Objective To explore the feasibility of using positron emission tomography (PET) -computed tomography (CT) to detect brain metabolic abnormalities caused by trimethyltin chloride (TMT) poisoning. {L-End}Methods Specific pathogen free healthy SD rats were randomly divided into model group and control group with six rats in each group. Rats in the model group were intraperitoneally injected with a single dose of 10 mg/kg body mass of TMT solution, and rats in the control group were intraperitoneally injected with a single dose of an equal volume of 0.9% sodium chloride solution. Rats were anaesthetized after three days of modeling and underwent PET-CT brain scanning to detect the standardized uptake value (SUV) of ¹⁸F-2-fluro-D-deoxy-glucose (¹⁸F-FDG). After scanning, rats were sacrificed and brain tissues were collected for brain organ coefficients calculation and brain histopathological analysis. {L-End}Results The rats in the model group showed symptoms of head tremor, limb twitching, irritability and others after TMT modeling. There was no significant difference in the body mass between the two groups of rats on the third day of modeling (P>0.05). The ¹⁸F-FDG uptake in the cerebral cortex, cerebellum and brainstem of the rats in the model group was significantly weakened compared with the control group, with deceased SUV values (all P<0.05). No obvious abnormalities were found in CT images and freshly collected brain tissues of rats of the control and model groups. The brain organ coefficients of rats in the two groups showed no significant difference (P>0.05). The results of hematoxylin-eosin staining of brain tissue showed that the cerebral cortex of rats in the model group had more tiny cavities than that of the control group, and some neuronal cells and a small number of hippocampal vertebral cells were tightly and deeply stained, with the cytoplasm and nucleus poorly demarcated, and pericellular space enlarged. The results of Nissen staining showed that the arrangement of neuronal cells in the model group was slightly disordered, and the interstitial space was slightly enlarged, but no other significant abnormal changes were observed. {L-End}Conclusion PET-CT can be used in detecting the metabolic abnormalities of brain in TMT poisoning rat model, making it a sensitive detection method for TMT poisoning.

Objective:To investigate the efficacy and safety of lenalidomide combined with bortezomib and dexamethasone (RVD) in patients with newly diagnosed multiple myeloma (NDMM).Methods:A total of 100 consecutive NDMM patients treated with RVD from August 2016 to September 2020 at Peking University People′s Hospital were retrospectively analyzed, including response, drug toxicity, follow-up and survival, and subgroup analysis.Results:The median follow-up time was 19.5 (2.0-57.0) months. For patients undergoing autologous stem cell transplantation (ASCT) after RVD regimen, the objective response rate (ORR)/complete response+stringent complete response (CR+sCR)/≥very good partial response (VGPR) rates were 100%, 73.3% (33/45), 95.6% (43/45) respectively. For 54 patients not receiving transplantation, the ORR/CR+sCR/≥VGPR rates were 79.6% (43/54), 18.5% (10/54), 51.9% (28/54) respectively. As to the survival analysis, 2-year progression free survival (PFS) rates were 84.5% and 70.9% in transplant and non-transplant patients respectively ( P=0.102). Two-year overall survival (OS) rates were 100% and 80.8% in transplant and non-transplant patients respectively ( P=0.003). The common hematologic adverse events (AEs) were thrombocytopenia (33%) and neutropenia (25%). Abnormal liver function (43%) and peripheral neuropathy (24%) were recognized more as non-hematologic AEs. Conclusion:RVD as front-line regimen has high efficient response rate and acceptable safety in Chinese NDMM patients.

Objective:To analyze the effect and safety of plerixafor combined with G-CSF mobilization in plasma cell disease.Methods:The clinical baseline data, success rate of collection, and adverse reactions of consecutive cases of plasma cell disease were analyzed retrospectively, where the patients received plerixafor combined with G-CSF for autologous hematopoietic stem cell mobilization in Peking University People's Hospital from January 2018 to December 2019.Results:Forty-nine patients with plasma disease were included, of which 39 (79.6% ) were multiple myeloma, 8 (16.3% ) were amyloidosis, and 2 (4.1% ) were monoclonal gammopathy of renal significance. A total of 16 patients (32.7% ) had renal insufficiency, and 7 patients (14.3% ) had previous collection failure. The median times of apheresis was 1 (1-3) , median days of apheresis was 2 (1-3) days, 47 patients (95.9% ) were successfully collected for once, and the success rate of collection for twice was 100% after using plerixafor for mobilization. In 16 patients with renal insufficiency, collection was successful in 5 patients (31.3% ) on the first day, while aphresis was required in 8 patients (50% ) on the second day and 3 (18.8% ) on the third day. The main adverse reactions were fatigue, insomnia, abdominal pain, diarrhea, dizziness, and arthralgia. A total of 37 patients underwent autologous hematopoietic stem cell transplantation with 11 (8-13) days for neutrophil engraftment, and 11 (9-26) days for platelet engraftment.Conclusions:Plerixafor combined with G-CSF has a high success rate in mobilizaion of autologous hematopoietic stem cells in patients with plasma cell disease with minimum side effects, even in patients with renal insufficiency.

Objective:To investigate the efficacy and safety of daratumumab in relapsed and refractory multiple myeloma (RRMM).Methods:The efficacy and adverse events (AEs) of daratumumab based regimens were retrospectively analyzed in 37 patients with RRMM from Peking University People′s Hospital, Beijing Hospital and Fu Xing Hospital affiliated to Capital Medical University in China. The deadline for inclusion was December, 2019.Results:Among the 37 patients, 35 patients were available for response evaluation. The overall response rate (ORR) was 68.6%, which was better in patients receiving 16 mg/kg daratumumab than in those with fixed doses of 800 mg daratumumab [ORR: 78.3%(18/23) vs. 40.0%(4/10)]. The percentage of infusion related reactions of daratumumab was 27.0%(10/37). The most common hematological AEs were lymphocytopenia and thrombocytopenia, with the incidences of grade 3 or more severe 59.5%(22/37) and 43.2%(16/37) respectively. Pulmonary infections(37.8%, 14/37) were the most common non-hematological AEs. One patient with positive hepatitis B surface antigen (HBsAg) and two patients dependent on dialysis were safely treated with daratumumab.Conclusion:Daratumumab is highly effective in relapsed and refractory multiple myeloma. Adverse reactions are mild and well tolerable.

Objective:To analyze the immunophenotype and cytogenetic characteristics of primary plasma cell leukemia (pPCL), and to evaluate the efficacy of bortezomib and hematopoietic stem cell transplantation as main treatment.Methods:A retrospective cohort study was conducted including 42 pPCL patients admitted to Peking University People′s Hospital from January 1998 to March 2019. All patients were followed up until December 31, 2019. The immunophenotype and cytogenetic characteristics were compared with historical data of multiple myeloma (MM). Thirty-nine patients were divided into bortezomib-based group (29 cases) and non-bortezomib group (10 cases). All patients were also divided into hematopoietic stem cell transplantation (HSCT) group (15 cases) and non-HSCT group (24 cases).Chi-square test was used for efficacy comparison, and Kaplan-Meier method was used for univariate prognostic analysis. Cox proportional hazards model was used for multi-variant analysis.Results:pPCL accounted for 2.6% of the total patients with plasma cell diseases during the same period. There were 22 males and 20 females, with a median age of 50 (30—77) years old at diagnosis. In immunophenotype analysis, tumor cells in pPCL patients also expressed CD38, CD138, CD45, which was similar as patients with MM. However the expression of CXCR4 were more frequently seen in pPCL(73.1% vs. 34.7%, P= 0.000), while intensity of CD9 and CD200 was lower (40.7% vs. 62.5%, P =0.028, 33.3% vs. 58.0%, P=0.021).Overall response rate of bortezomib-based therapy was superior to non-bortezomib therapy (69.0% vs.50.0%). The median survival was 18.2 (0.2—95.7)months, and the 1-and 2-year survival rates were 61.9% and 37.4%, respectively. Multivariate prognostic analysis suggested that age ( P= 0.027) and efficacy( P= 0.035)were significantly correlated with survival.HSCT resulted in superior survival compared with chemotherapy alone(26.8 vs. 8.1 months, P=0.021). Conclusions:Immunophenotypes and cytogenetic abnormalities in patients with pPCL are different from those with multiple myeloma. Bortezomib based regimens improve response rate and survival of pPCL. Hematopoietic stem cell transplantation also predicts survival benefits.

OBJECTIVE: To investigate the chronic toxicity and carcinogenicity of kresoxim-methyl in rats. METHODS: Specific pathogen free SD rats were randomly divided into control group and low-, medium-and high-dose groups according to the body weight of rats, 120 rats in each group with half male and half female rats. The chronic toxicity and carcinogenesis was induced in rats for 104 weeks by oral feeding. The dose of kresoxim-methyl in feed of male and female rats was 0, 75, 300 and 1 200 mg/kg. During the process of experiment, the body weight of rats was weighed. The blood biochemistry, organ coefficient and histopathology were examined at the end of the exposure, and the tumor incidence was calculated. RESULTS: There was no significant difference in mortality of the female or male rats in the four groups(P>0.05). At the 32 nd, 48 th and 56 th week after exposure, the body mass of female rats in the high dose group was lower than that in control group(P<0.05); at the 8 th, 16 th, 24 th and 32 nd week, the body mass of male rats in the high dose group was lower than that in the control group(P<0.05). The organ coefficients of heart and adrenal gland of female rats in the high dose group were higher than those in the control group and the low dose group(P<0.05). The organ coefficient of liver of male rats in the high dose group was lower than that in the control group(P<0.05). The alkaline phosphatase of male rats in the three dose groups was lower than that in the control group(P<0.05). The blood glucose of male rats in the high dose group was higher than that in the control group(P<0.05). The aspartate aminotransferase of male rats in the high dose group was lower than that in the control group(P<0.05). There was no significant difference among the three indexes in female rats(P>0.05). The tumor incidence of the control group and the low, medium and high dose groups were 68.3%, 75.0%, 75.0% and 78.8%, respectively, with no significant difference(P>0.05). The tumor incidence of the female rats was higher than that of the male rats(87.0% vs 61.5%,P<0.01).The tumor multiplicity of the above four groups were 38.3%, 35.8%, 35.0%, 39.8%, respectively, with no significant difference(P>0.05). The tumor multiplicity in female rats was higher than that in male rats(56.9% vs 17.6%,P<0.01). CONCLUSION: The no observed adverse effect level of kresoxim-methyl to female and male SD rats was 24.726 and 20.002 mg/(kg·d), respectively. No carcinogenicity of kresoxim-methyl to SD rats was observed.

OBJECTIVE: To investigate the effects of 1,2-dichloroethane(1,2-DCE) subacute exposure on depression in rats as well as the relevant mechanism of monoamine neurotransmitters. METHODS: The specific pathogen free male SD rats were randomly divided into control group, low-, medium-, and high-dose groups, with 10 rats in each group. The rats in these 4 groups were intra-gastrically administered with 1,2-DCE(diluted in corn oil) at the dose of 0, 20, 40, 80 mg/kg body weight, every other day for 14 times. After exposure, the behavior change of rats was observed by open-field test, sucrose preference test and forced swim test. The levels of the monoamine neurotransmitters including 5-hydroxytryptamine(5-HT), noradrenaline(NA) and dopamine(DA) in prefrontal cortex, hippocampus, and striatum of rats were analyzed by high performance liquid chromatography-electrochemical detection method. RESULTS: The number of rearing, time and distance of central area, sucrose preference index of mice in medium and high dose groups were decreased(P<0.05), while immobility time of forced swim test was increased(P<0.05) when compared with the mice in control group. The levels of 5-HT, NA and DA in prefrontal cortex, hippocampus, and striatum decreased with the increase of 1,2-DCE exposure(P<0.05), showing a dose-effect relationship. The levels of 5-HT, NA and DA in prefrontal cortex, hippocampus, and striatum in the high-dose group were lower than that of control group(P<0.05). CONCLUSION: The subacute exposure of 1,2-DCE can induce depression-like behavior in rats. The mechanism might be related to the reduction of monoamine neurotransmitters in striatum, hippocampus and prefrontal cortex.