Rapid identification of components in Wuzhuyu Decoction using UHPLC Q-Exactive Orbitrap MS~n and molecular network technology / 中国中药杂志

Wuzhuyu Decoction, the classical formula recorded in the Treatise on Febrile Diseases(Shang Han Lun), has been included in the Catalogue of Ancient Classic Prescriptions(the First Batch). Consisting of Euodiae Fructus, Ginseng Radix et Rhizoma, Zingiberis Rhizoma Recens, and Jujubae Fructus, it is effective in warming the middle, tonifying deficiency, dispelling cold, and descending adverse Qi, and is widely applied clinically with remarkable efficacies. For a classical formula, the chemical composition is the material basis and an important premise for quantity value transfer. This study aimed to establish a rapid identification method of chemical components in Wuzhuyu Decoction by high-resolution mass spectrometry(HR-MS) and molecular network. AQUITY UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 μm) was used for sample separation, and acetonitrile-0.1% formic acid in water was used as mobile phases for gradient elution. Q-Exactive Orbitrap MS data were collected in positive and negative ion modes, and GNPS molecular network was plotted according to the similarity of MS/MS fragmentation modes. Cytoscape 3.6.1 was used to screen molecular clusters with similar structures. Finally, the chemical components of Wuzhuyu Decoction were rapidly identified according to the controls, as well as the information of retention time, accurate relative molecular weight of HR-MS, and MS/MS multistage fragments. A total of 105 chemical components were identified in Wuzhuyu Decoction. This study can provide data for the follow-up quality control, standard substance research, and pharmacodynamic material research on Wuzhuyu Decoction, as well as references for the rapid qualitative analysis of the chemical components of Chinese medicine.

Chinese Medicine Treatment Prolonged Survival in Small Cell Lung Cancer Patients: A Clinical Observation / 中国结合医学杂志

OBJECTIVE@#To evaluate the effect of Chinese medicine (CM) treatment on survival time and quality of life (QOL) in patients with small cell lung cancer (SCLC).@*METHODS@#This was an exploratory and prospective clinical observation. Patients diagnosed with SCLC receiving CM treatment were included and followed up every 3 months. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS) and QOL.@*RESULTS@#A total of 136 patients including 65 limited-stage SCLC (LS-SCLC) patients and 71 extensive-stage SCLC (ES-SCLC) patients were analyzed. The median OS of ES-SCLC patients was 17.27 months, and the median OS of LS-SCLC was 40.07 months. The survival time was 16.27 months for SCLC patients with brain metastasis, 9.83 months for liver metastasis, 13.43 months for bone metastasis, and 18.13 months for lung metastasis. Advanced age, pleural fluid, liver and brain metastasis were risk factors, while longer CM treatment duration was a protective factor. QOL assessment indicated that after 6 months of CM treatment, scores increased in function domains and decreased in symptom domains.@*CONCLUSION@#CM treatment might help prolong OS of SCLC patients. Moreover, CM treatment brought the trend of symptom amelioration and QOL improvement. These results provide preliminary evidence for applying CM in SCLC multi-disciplinary treatment.

Identification of Chemical Constituents in Coptis chinensis Inflorescence by UPLC-Q-Orbitrap HRMS / 中国实验方剂学杂志

Objective:An ultra-high performance liquid chromatography coupled with quadrupole-orbitrap high resolution mass spectrometry （UPLC-Q-Orbitrap HRMS） was developed to analyze and identify the chemical constituents in <italic>Coptis chinensis</italic> inflorescence. Method:The chromatographic separation was performed on ACQUITY UPLC BEH C₁₈ column （2.1 mm×100 mm， 1.7 μm） with the mobile phase of 0.1% formic acid aqueous solution （A）-acetonitrile （B） for gradient elution （0-15 min， 10%-22%B； 15-20 min， 22%B； 20-25 min， 22%-44%B； 25-35 min， 44%-50%B； 35-40 min， 50%-60%B； 40-55 min， 60%-85%B）， the flow rate was 0.15 mL·min^-1， the injection volume was 3 μL and the column temperature was 30 ℃. HRMS was equipped with electrospray ionization （ESI） and scanned in positive and negative ion modes by means of full scan/data dependent secondary scan （Full MS/dd-MS²）. Compound Discoverer 3.0 software combined with mzCloud， mzVault， ChemSpider databases and HRMS database of components in traditional Chinese medicine were used to analyze and identify the collected data by HRMS， based on accurate relative molecular mass， retention time and characteristic ion fragmentation of the compounds， as well as literature information and relevant reference materials. Result:A total of 51 chemical constituents were identified in <italic>C</italic>.<italic> chinensis</italic> inflorescence， including 16 alkaloids， 14 flavonoids， 7 phenylpropanoids， 7 organic acids and 7 others. Among them， 10 components ［berberine， palmatine， coptidine， rutin， quercetin， isoquercitrin， chlorogenic acid， cryptochlorogenic acid，<italic> D</italic>-（-） quinic acid and <italic>D</italic>-proline］ were unambiguously identified by comparing with reference standards. Conclusion:The established UPLC-Q-Orbitrap HRMS can be used to accurately analyze and identify chemical constituents of <italic>C. chinensis</italic> inflorescence. A total of 41 chemical constituents are reported from <italic>C. chinensis</italic> inflorescence for the first time and 6 alkaloids are found from the <italic>C. chinensis</italic> for the first time. These findings can provide methodological reference and experimental basis for the basic research of quality evaluation and efficacy materials of <italic>C. chinensis</italic> inflorescence， and lay a foundation for its further development and utilization.

Research progress of chimeric antigen receptor natural killer cells in hematological malignancies / 国际生物医学工程杂志

Chimeric antigen receptor natural killer cell (CAR-NK) is a new promising immunotherapy. NK cell can derive from peripheral blood cells, cord blood cells, NK-92 cell line and iPSC cells. CAR-NK cells can recognize target antigens non-specifically and are not restricted by human leukocyte antigens. Allogeneic infusion of CAR-NK cells does not cause graft-versus-host disease. It has a strong effect on primary cells of leukemia, lymphoma and multiple myeloma, thus making animal models have strong anti-tumor effect. Therefore, as a "off-the-shelf" product, CAR-NK cells have a wide range of clinical applications. In this paper, the construction of CAR-NK vector and its preliminary clinical application in hematological tumors and the challenges were reviewed.

Development of a biomechanical model for dynamic occlusal stress analysis / 国际口腔科学杂志·英文版

The use of traditional finite element method (FEM) in occlusal stress analysis is limited due to the complexity of musculature simulation. The present purpose was to develop a displacement boundary condition (DBC)-FEM, which evaded the muscle factor, to predict the dynamic occlusal stress. The geometry of the DBC-FEM was developed based on the scanned plastic casts obtained from a volunteer. The electrognathographic and video recorded jaw positional messages were adopted to analyze the dynamic occlusal stress. The volunteer exhibited asymmetrical lateral movements, so that the occlusal stress was further analyzed by using the parameters obtained from the right-side eccentric movement, which was 6.9 mm long, in the stress task of the left-side eccentric movement, which was 4.1 mm long. Further, virtual occlusion modification was performed by using the carving tool software aiming to improve the occlusal morphology at the loading sites. T-Scan Occlusal System was used as a control of the in vivo detection for the location and strength of the occlusal contacts. Data obtained from the calculation using the present developed DBC-FEM indicated that the stress distribution on the dental surface changed dynamically with the occlusal contacts. Consistent with the T-Scan recordings, the right-side molars always showed contacts and higher levels of stress. Replacing the left-side eccentric movement trace by the right-side one enhanced the simulated stress on the right-side molars while modification of the right-side molars reduced the simulated stress. The present DBC-FEM offers a creative approach for pragmatic occlusion stress prediction.

Systematic evaluation of efficacy and safety of Huangqi Guizhi Wuwu Decoction for preventing oxaliplatin-induced peripheral neurotoxicity / 国际生物医学工程杂志

Objective:To evaluate the efficacy and safety of Huangqi Guizhi Wuwu Decoction for preventing oxaliplatin-induced peripheral neurotoxicity(OIPN).Methods:PubMed, ScienceDirect, EMbase, VIP, CNKI and WanFang Data were searched to collect the randomized controlled trials(RCTs) of Huangqi Guizhi Wuwu Decoction for OIPN from the date of establishment until July 2019. Two reviewers independently evaluated the quality of literature and extracted data. RevMan5.3 software was used for Meta-analysis.Results:Fifteen RCTs (849 patients) were included. The results of Meta-analyses showed statistically significant differences in favor of Huangqi Guizhi Wuwu Decoction group compared with control group for all incidence of OIPN [ RR=0.57, 95% CI(0.40, 0.81), P=0.002] and incidence of serious OIPN [ RR=0.35, 95% CI(0.25, 0.48), P<0.000 01]. No differences were observed in disease control rates between two groups. There was statistically significant differences between Huangqi Guizhi Wuwu Decoction group and mecobalamine group for all incidence of OIPN [ RR=0.51, 95% CI(0.39, 0.66), P<0.000 01] and incidence of serious OIPN [ RR=0.37, 95% CI(0.19, 0.70), P=0.002]. Conclusions:Huangqi Guizhi Wuwu Decoction is more safety and effective than mecobalamine on the prevention of OIPN and did not affect the efficacy of chemotherapy. So Huangqi Guzhi Wuwu decoction can be widely extended to clinical applications.

A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis / 中华医学杂志(英文版)

BACKGROUND@#Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.@*METHODS@#We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician's global assessment (sPGA) at week 12.@*RESULTS@#The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported.@*CONCLUSION@#During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.@*TRIAL REGISTRATION@#Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.

PD-1 expression, mRNA level and cytotoxicity changes in CD19CAR-T cells / 中华血液学杂志

Objective@#To observe the changes of PD-1 expression, mRNA level and cytotoxic activity of CD19 CAR-T cells during the culture process of CAR-T cells.@*Methods@#The peripheral blood T cells of 6 lymphoma patients with high expression of PD-1 and 6 healthy volunteers were the source of CAR-T cells. The expression of PD-1 was analyzed by flow cytometry. The mRNA level of PD-1 was analyzed by PCR. The cell proliferation was analyzed by CCK-8 assay. The cytotoxicity was analyzed by LDH assay.@*Results@#①The transfection efficiency of high PD-1 expression T cells and healthy volunteer T cells were as the same (P>0.05) . ②The cell proliferation capacity of CD19 CAR-T cells from high PD-1 expression T cells or healthy volunteer T cells, with or without PD-1 inhibitor were as the same (P>0.05) . ③The cytotoxicity to lymphoma cells of high PD-1 expression T cells and CAR-T cells were lower than that of these two T cells combined with PD-1 inhibitor and the CAR-T cells from healthy volunteer T cells (P<0.001) . There was no difference of the cytotoxicity between the CAR-T cells from high PD-1 expression T cells combined with PD-1 inhibitor and the CAR-T cells from healthy volunteer (P>0.05) . ④There was no difference of the expression of PD-1 in all CAR-T cell groups during the culture process (P>0.05) . There was no difference of mRNA level of PD-1 in all groups during the culture process (P>0.05) . ⑤The PD-1 expression of CAR-T cells increased by the time of culture after contacting with lymphoma cells (P<0.001) . The PD-1 inhibitors could antagonize this effect. There was no difference of mRNA level of PD-1 in all groups after contacting with lymphoma cells (P>0.05) .@*Conclusion@#The PD-1 expression of CAR-T cells from high PD-1 expression T cells increased by the time of culture after contacting with lymphoma cells. However, the mRNA level of PD-1 of all groups did not change, even if PD-1 inhibitor was applied.

In vitro and in vivo cytotoxic activity of humanized CD19 CAR-T cells against Raji cell line / 中华微生物学和免疫学杂志

Objective@#To investigate the different functions of humanized and murinized CD19 chimeric antigen receptor (CAR)-T cells against Raji cell line in vitro and in vivo.@*Methods@#Peripheral blood samples were collected from eight patients with lymphoma who were going to receive CD19 CAR-T cell therapy and used for the preparation of peripheral blood mononuclear cells (PBMC) as well as humanized and murinized CAR-T cells. Cell proliferation and cytotoxicity were detected with CCK-8 and LDH assays, respectively. A tumor-bearing mouse model was established by injecting BALB/c female nude mice with fluorescent Raji cells. Changes in tumor volume in these mice were observed by in vivo imaging technology. The transfection efficiency and amount of CAR-T cells in the mice were detected with flow cytometry.@*Results@#No statistical difference in transfection efficiency was found between humanized and murinized CAR-T cells, nor in cell proliferation at 24 h of culture in vitro(P=0.104). The proliferation of humanized CAR-T cells showed a significant increase compared with that of murinized CAR-T cells at 48 h of culture (P=0.009). Similarly, the cytotoxicity of the two types of CAR-T cells against Raji cells showed no significant difference at 24 h at any effector/target (E/T) ratio (1∶1 or 4∶1), and that of humanized CAR-T cells was higher than that of murinized CAR-T cells at both E/T ratios at 48 h (E/T ratio=1∶1, P=0.005; E/T ratio=4∶1, P=0.008). Moreover, the cytotoxicity of CAR-T cells was higher than that of PBMC in any case. Tumor volumes in mice were reduced 14 d after humanized or murinized CAR-T cell therapy, while the mice in the PBMC control group suffered tumor progression. Tumor volume began to increase in mice 21 d after murinized CAR-T cell therapy, while no significant change was observed in the mice treated with humanized CAR-T cells. All of the mice died 25 d after murinized CAR-T cell therapy, while the deaths among those under humanized CAR-T cell therapy occurred on 31 d. The proportion of CAR-T cells in mice reached the peak 7 d after receiving humanized or murinized CAR-T cell therapy, while that in the humanized group was significantly higher than that in the murinized group at any time point (P4 d=0.001, P7 d=0.000, P14 d=0.003). Murinized CAR-T cells became undetectable on 21 d, while humanized CAR-T cells on 35 d. The maximum survival time for mice in the PBMC and murinized and humanized CAR-T cell groups was 20 d, 25 d and 53 d, respectively.@*Conclusions@#Compared with murinized CD19 CAR-T cells, humanized CD19 CAR-T cells showed stronger proliferation potential and cytotoxicity and remained in vivo detectable for a longer period of time. This study indicated that humanized CD19 CAR-T cells were superior to murinized CD19 CAR-T cells for the treatment of B cell lymphoma.

The evaluation of modified cell infusion method to reduce febrile non-hemolytic transfusion reaction in CD19 chimeric antigen receptor T cell threapy / 中华内科杂志

Objective@#To retrospectively analyze the efficacy and safety of modified cell infusion method in reducing the incidence of febrile non-hemolytic transfusion reaction (FNHTR).@*Methods@#A total of 69 patients were enrolled in the clinical trial of CD19 chimeric antigen receptor T (CAR-T) cell treatment from February 2017 to October 2018. Study group received the modified cell infusion method, that 1×106 CAR-T cells were re-suspended in 2 mg human serum albumin with total volume of 20 ml and injected intravenously. The control group was intravenously administrated with CAR-T cell in 100 ml normal saline. The incidence of FNHTR, cytokine releasing syndrome (CRS) grade, cytokine level and efficacy were compared.@*Results@#(1)The incidence of FNHTR in the study group was 21.1%, significantly lower than that in the control group (71%)(P=0.000). (2)There was no statistical difference in cell proliferation between the study group and the control group on day 4, 7, 14 and 21 after CAR-T cell infusion (P=10.223, 3.254, 5.551, 7.605). (3)There was no statistical difference in CRS grading between the study group and the control group (P=0.767). There was no statistical difference in the levels of interleukin 2 receptor (IL-2R), IL-6, tumor necrosis factor (TNF)-α between the two groups. (4)The C-reaction protein (CRP) level of the study group was lower than that of the control group on day 4 and 7 (P=0.026, 0.007). (5)There was no statistical difference of response rates in acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL) patients between the two groups (PALL=0.842; PNHL=0.866).@*Conclusion@#The modified cell infusion method in CD19 CAR-T cell treatment reduces the incidence of treatment-related FNHTR. It does not affect the proliferation of CAR-T cells in vivo, the grading of CRS and the response rates.

In vitro and in vivo cytotoxic activity of humanized CD19 CAR-T cells against Raji cell line / 中华微生物学和免疫学杂志

Objective To investigate the different functions of humanized and murinized CD19 chimeric antigen receptor ( CAR)-T cells against Raji cell line in vitro and in vivo. Methods Peripheral blood samples were collected from eight patients with lymphoma who were going to receive CD19 CAR-T cell therapy and used for the preparation of peripheral blood mononuclear cells ( PBMC) as well as humanized and murinized CAR-T cells. Cell proliferation and cytotoxicity were detected with CCK-8 and LDH assays, respectively. A tumor-bearing mouse model was established by injecting BALB/c female nude mice with flu-orescent Raji cells. Changes in tumor volume in these mice were observed by in vivo imaging technology. The transfection efficiency and amount of CAR-T cells in the mice were detected with flow cytometry. Re-sults No statistical difference in transfection efficiency was found between humanized and murinized CAR-T cells, nor in cell proliferation at 24 h of culture in vitro(P=0. 104). The proliferation of humanized CAR-T cells showed a significant increase compared with that of murinized CAR-T cells at 48 h of culture ( P=0. 009). Similarly, the cytotoxicity of the two types of CAR-T cells against Raji cells showed no significant difference at 24 h at any effector/target (E/T) ratio (1 : 1 or 4 : 1), and that of humanized CAR-T cells was higher than that of murinized CAR-T cells at both E/T ratios at 48 h (E/T ratio=1 : 1, P=0. 005;E/T ratio=4 : 1, P=0. 008). Moreover, the cytotoxicity of CAR-T cells was higher than that of PBMC in any case. Tumor volumes in mice were reduced 14 d after humanized or murinized CAR-T cell therapy, while the mice in the PBMC control group suffered tumor progression. Tumor volume began to increase in mice 21 d after murinized CAR-T cell therapy, while no significant change was observed in the mice treated with hu-manized CAR-T cells. All of the mice died 25 d after murinized CAR-T cell therapy, while the deaths among those under humanized CAR-T cell therapy occurred on 31 d. The proportion of CAR-T cells in mice reached the peak 7 d after receiving humanized or murinized CAR-T cell therapy, while that in the humanized group was significantly higher than that in the murinized group at any time point (P4 d=0. 001, P7 d=0. 000, P14 d=0. 003). Murinized CAR-T cells became undetectable on 21 d, while humanized CAR-T cells on 35 d. The maximum survival time for mice in the PBMC and murinized and humanized CAR-T cell groups was 20 d, 25 d and 53 d, respectively. Conclusions Compared with murinized CD19 CAR-T cells, humanized CD19 CAR-T cells showed stronger proliferation potential and cytotoxicity and remained in vivo detectable for a longer period of time. This study indicated that humanized CD19 CAR-T cells were superior to murinized CD19 CAR-T cells for the treatment of B cell lymphoma.

Effects of Clostridium butyricum on the function of intestinal mucosal barrier and flora in acute necrotizing pancreatitis rats with intra-abdominal hypertension / 中华胰腺病杂志

Objective To explore the effect of Clostridium butyricum ( C. butyricum ) and its metabolite butyrate on the function of intestinal mucosal barrier and intestinal flora in acute necrotizing pancreatitis ( ANP) rats with intra-abdominal hypertension ( IAH) . Methods Eighty SD rats were randomly divided into normal control group (A group, n=20), ANP with IAH group(B group, n=20), ANP with IAH and C. butyricum treated group ( C group, n=20 ) , ANP with IAH and sodium butyrate treated group ( D group, n=20). Rats of C and D group were given intragastric administration of C. butyricum 1 × 109 CFU once a day or 100 mg/kg sodium butyrate once a day from 10 days before modeling. Sodium taurocholate injection method via pancreatobiliary ducts was used to establish ANP with IAH rat model, and the intra-abdominal pressure was measured by direct puncture of left lower belly 24 h after modeling. Blood samples were collected for detecting serum amylase(AMY), tumor necrosis factor alpha (TNF-α), diamine oxidase( DAO ) , lipopolysaccharide ( LPS ) and D-Lactate, and the pathological changes of terminal ileum was observed. Real-time quantitative PCR was used to detect the populations of 6 bacteria in ileum mucosa. Results The levels of AMY, TNF-α, LPS,DAO, D-Lactate and ileum mucosa score were obviously higher in B, C and D group than those in A group, but the number of piobiotic flora in ileum mucosa was lower than that in A group, while the number of pathogenic bacteria was higher than that in A group. The levels of LPS, DAO, D-Lactate and ileum mucosa pathological score were lower in C group and D group than those in B group, but the number of piobiotic flora in ileum mucosa was lower than that in B group, while the number of pathogenic bacteria was higher than that in B group. All the differences above were statistically different (P<0.05). Conclusions C. butyricum and butyrate can maintain the function of intestinal mucosal barrier in ANP rats with IAH, and also readjust the imbalance of intestinal flora.

Immunophenotypic characteristics of CD19 chimeric antigen receptor( CAR)-transfected Nalm-6 cells / 中华微生物学和免疫学杂志

Objective To investigate the immunophenotypic characteristics of potential leukemia cells transfected with CD19 antigen receptor( CAR) during CAR-T cell preparation. Methods Morphological chan-ges in CD19 CAR-transfected cells were observed under inverted microscope. The transfection rate and immuno-phenotype of transfected Nalm-6 cells were analyzed by flow cytometry. Secretion of cytokines in the culture sys-tem was detected by chemiluminescence. Results The transfection rate of Nalm-6 cells by CD19 CAR was (46. 50±3. 78) ％ and that of KG1a cells was (15. 70±1. 22) ％. CD19 CAR-transfected Nalm-6 cells prolifer-ated more rapidly than Nalm-6 cells ( P values on 0 d, 4 d, 7 d and 12 d were 6. 339, 3. 447, 0. 012 and 0. 009). In the culture of CD19 CAR-transfected Nalm-6 cells, cell aggregation and adhesion were observed and they gradually gathered into a group. The rate of CD19 expression was only 1. 19％ in the CD19 CAR-transfect-ed Nalm-6 cell culture system with the transfection rate of (46. 50±3. 78) ％. After increasing the proportion of Nalm-6 cells in the culture system, CD19 expression was gradually increased, while the expression of CD22 re-mained stable. CD19 expressed by Nalm-6 cells cultured in the supernatant of CD19 CAR-transfected Nalm-6 cell culture system was decreased gradually. The levels of IL-10 and TNF-αsecreted by CD19 CAR-transfected Nalm-6 cells were higher than those by Nalm-6 cells. Conclusions Results of the immunophenotypic analysis of CD19 CAR-transfected leukemia cells suggested that CD22 CAR-T cell therapy could be used as a rescue or combination therapy for CD19 CAR transfection into leukemia cells.

Mucormycosis in patients with hematological diseases: seven cases reports and literature review / 中华血液学杂志

Objective@#To explore the clinical characteristics, diagnosis, treatment and prognosis of patients with hematological diseases that complicated by mucormycosis, and to improve the understanding and clinical diagnosis and treatment of the disease.@*Methods@#The clinical data of 7 patients suffering from mucormycosis during September 2012 and September 2018 were retrospectively analyzed, and their clinical characteristics, treatment process and prognosis were analyzed.@*Results@#Of 7 patients, there were 4 males and 3 females, with a median age of 36 (19-79) years old. Two patients were diagnosed as acute myeloid leukemia as the underlying disease, the other 5 patients suffered from acute B lymphoblastic leukemia, peripheral T cell lymphoma, chronic myelocytic leukemia in blastic phase, myeloproliferative neoplasm and severe aplastic anemia after transplantation, respectively. Among them, disease types of mucormycosis were pulmonary in 4 patients, rhino-orbital-cerebral in 1 patient, cutaneous in 1 patient and disseminated in 1 patient. All the cases were confirmed by biopsy histopathology. The treatment drugs were amphotericin B or liposomal amphotericin B, and posaconazole. Surgical treatment was performed in 4 patients, 3 out of 4 achieved radical debridement, and the other one had local debridement. Two patients were cured, 1 patient was improved and 4 patients died.@*Conclusions@#The clinical manifestation and image feature of mucormycosis in patients with hematological diseases were diverse, and the mortality rate is high, diagnosis mainly depends on histopathology. Early diagnosis, control of underlying disease, improvement of immunosuppressive status, timely effective antifungal therapy and radical surgical debridement are the key points for improving the survival rate of patients with hematological diseases complicated by mucormycosis.

Effects of anesthesia on neurodevelopment assessment in preschool children / 解放军医学杂志

Objective To investigate the effects of anesthesia on neurodevelopment of preschool children. Methods A total of 445 children, scheduled to undergo surgery in the Fourth Medical Center of Chinese PLA General Hospital from 1st May 2017 to 1st May 2018, were enrolled and, according to different test purpose, grouped as follows: (1) 120 children (GA group) who underwent surgery before Denver Developmental Screening Test (DDST) were matched to 325 unexposed children (Non-GA group). Meanwhile, 168 children (Naive group) were measured as blank control. (2) According to the number of anesthesia that children had undergone, those in GA group were assigned to three subgroups: single, twice and multiple groups. (3) Subgroup analyses was performed based on the time of cumulative duration of anesthesia exposures (less than 3 and greater than or equal to 3h). Data were collected with a questionnaire to evaluate the children's physical development, DDST results were recorded, and the effects were evaluated of the number of anesthesia and the time of cumulative duration of anesthesia exposures on the DDST results. Results For the children aged 0 to 6 yr, the DDST positive rates in Naive, Non-GA and GA groups were 6.0%, 6.5% and 12.5%, respectively. No significant difference existed in DDST positive rate between Naive group and Non-GA group (P=0.825). Compared with Non-GA group, the DDST positive rate increased in GA group (6.5% vs. 12.5%) with significant difference (P=0.038). Compared among the four domains of DDST separately, statistical difference was found only in terms of personal-social, those in GA group showed poor performance than in Non-GA group (P=0.025). For the children aged less than 3 yr, the DDST positive rates in GA group and Non-GA group were 18.6% and 3.9%, respectively, showing significant differences (P=0.019), but no statistical difference was found on DDST positive rate among the three groups of children aged 3 to 6 yr (P>0.05). In GA group, there was no increase in odds of early developmental vulnerability with increasing frequency of anesthesia exposure (P=0.784). However, the DDST positive rate was significantly higher with longer cumulative duration of anesthesia exposure (≥3h) than that of <3h (18.7% vs. 2.2%, P=0.008). Conclusions Exposure to anesthesia is an increased risk for the later neurodevelopment of preschool children, especially before 3 years old. The time of cumulative duration of anesthesia may be positively correlated to the children's neurodevelopment disabilities.

The evaluation of modified cell infusion method to reduce febrile non?hemolytic transfusion reaction in CD19 chimeric antigen receptor T cell threapy / 中华内科杂志

To retrospectively analyze the efficacy and safety of modified cell infusion method in reducing the incidence of febrile non?hemolytic transfusion reaction (FNHTR). Methods A total of 69 patients were enrolled in the clinical trial of CD19 chimeric antigen receptor T (CAR?T) cell treatment from February 2017 to October 2018. Study group received the modified cell infusion method, that 1×106 CAR?T cells were re?suspended in 2 mg human serum albumin with total volume of 20 ml and injected intravenously. The control group was intravenously administrated with CAR?T cell in 100 ml normal saline. The incidence of FNHTR, cytokine releasing syndrome (CRS) grade, cytokine level and efficacy were compared. Results (1)The incidence of FNHTR in the study group was 21.1%, significantly lower than that in the control group (71%)(P=0.000). (2)There was no statistical difference in cell proliferation between the study group and the control group on day 4, 7, 14 and 21 after CAR?T cell infusion (P=10.223, 3.254, 5.551, 7.605). (3)There was no statistical difference in CRS grading between the study group and the control group (P=0.767). There was no statistical difference in the levels of interleukin 2 receptor (IL?2R), IL?6, tumor necrosis factor (TNF)?α between the two groups. (4)The C?reaction protein (CRP) level of the study group was lower than that of the control group on day 4 and 7 (P=0.026, 0.007). (5)There was no statistical difference of response rates in acute lymphocytic leukemia (ALL) and non?Hodgkin lymphoma (NHL) patients between the two groups (PALL=0.842; PNHL=0.866). Conclusion The modified cell infusion method in CD19 CAR?T cell treatment reduces the incidence of treatment?related FNHTR. It does not affect the proliferation of CAR?T cells in vivo, the grading of CRS and the response rates.

Retrospective analysis of 185 inpatients with acute urticaria / 中华皮肤科杂志

Objective To analyze the precipitating factors for,clinical manifestations of,laboratory findings in and therapeutic effect on acute urticaria.Methods Clinical data were collected from 185 inpatients with acute urticaria in Shanxi Dayi Hospital from January 2013 to December 2016.Clinical features,laboratory examination results,treatment,prognosis and adverse reactions were analyzed retrospectively.Statistical analysis was carried out by chi-square test.Results There were 63 male patients and 122 female patients in this study,with an average age at onset of 32.87 ± 14.18 years.Of the 185 patients,78 (42.2％) were able to report the aetiological agents accurately,33 (17.8％) were induced by infection or drug therapy following infection,and 82 (44.3％) had fever.Blood cell analysis showed increased white blood cell count in 132 (71.4％) cases and increased proportion of neutrophils in 128 (69.2％) cases.The level of C reactive protein increased in 118 (69％) of 171 cases.A total of 185 patients received routine anti-anaphylactic treatment.Of 183 cured patients,153 (83.6％) were treated with antibiotics,26(14.2％)with antibiotics alone,and 24(13.1％) with azithromycin.There were 127 (69.4％) patients receiving combined treatment with glucocorticoids,antibiotics,and so on,and the antibiotic used in 111 (60.7％) cases was azithromycin.Of 88 cured patients with simultaneous signs of infection,85 (96.6％) showed increased levels of part or all of infection markers (including the white blood cell count,proportion of neutrophils and level of C reactive protein),and 69 (78.4％) were treated with azithromycin.Of 95 cured patients without signs of infection,83 (87.4％) showed increased levels of infection markers,and 61 (64.2％) were treated with azithromycin.Moreover,there were significant differences in the proportion of patients with increased levels of infection markers and that of patients treated with azithromycin between the cured patients with and without signs of infection (x2 =5.164,4.476,both P ＜ 0.05).Conclusions Infection is a common cause of acute urticaria,and laboratory examinations including white blood cell count,proportion of neutrophils and level of C reactive protein are of important reference value to the diagnosis of infection in patients with acute urticaria.Patients with signs of infection or increased levels of infection markers need to be treated with combined anti-infective therapy,and in the cured patients,the proportion of patients administrating azithromycin was higher than that of those administrating other antibiotics for the treatment of acute infectious urticaria.

Analysis of patients suffering from fungemia of Candida parapsilosis adimitted in geriatric intensive care unit / 中国中西医结合急救杂志

Objective To observe the clinical features of senile patients suffering from fungemia of Candida parapsilosis, and the effect and safety of antifungal therapy in treatment of this disease in geriatric intensive care unit (GICU). Methods The clinical data of patients with fungi positive either in peripheral blood culture or catheter culture admitted to the GICU of Tianjin Medical University General Hospital from November 2012 to June 2015 were retrospectively analyzed, of them 45 cases were of infection of Candida parapsilosis (parapsilosis group) and 15 cases infection of non-Candida parapsilosis (non-parapsilosis group). The clinical features of the two groups were collected, such as sex, age, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score, sequential organ failure assessment (SOFA) score, timing of antifungal therapy, number of patients mechanical ventilation, concomitant disease, catheter-related infection, method of catheter-indwelling, levels of creatinine (Cr), hemoglobin (Hb), platelet count (PLT), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc.; the differences in above indicators were compared between the two groups; multifactor Cox-regression-analysis was used to analyze the risk factors that could affect the patients' prognosis; the patients' survival rates on 7, 14 and 28-day were calculated and compared between the two groups, and the therapeutic effects of different anti-fungal drugs on patients' survival rates and liver function damage were recorded and compared. Results The non-parapsilosis group had a higher rate in mechanical ventilation than parapsilosis group [73.3% (11/15) vs. 33.3% (15/45), P < 0.05], and in the comparisons of other clinical features, there were no statistical significant differences between the two groups (all P > 0.05). There were no statistical significant differences in survival rates in the duration of 7, 14 and 28 days between the two groups[7 days: 82.2% (37/45) vs. 66.7% (10/15), 14 days: 75.6% (34/45) vs. 60.0% (9/15), 28 days: 66.7% (30/45) vs. 46.7% (7/15), all P > 0.05]. When the patients in parapsilosis group treated with echinocinomycin were compared with those treated with azolol, no statistical significant differences were found between the 2 types of therapy in the survival rates in the duration of 7, 14, and 28 days after treatment [7 days: 100.0% (23/23) vs. 82.4% (14/17), 14 days: 91.3% (21/23) vs. 76.5% (13/17), 28 days: 78.3% (18/23) vs. 70.6% (12/17), all P > 0.05]. Multifactor Cox-regression-analyses showed:diabetes [odds ratio (OR) = 0.268, 95% confidence interval (95%CI) = 0.077 - 0.928, P = 0.038), infection of Candida parapsilosis (OR = 0.260, 95%CI = 0.072 - 0.946, P = 0.041), APACHE Ⅱ score (OR = 1.241, 95%CI = 1.051 - 1.466, P = 0.011) and SOFA score (OR = 1.405, 95%CI = 1.005 - 1.966, P = 0.047) were the risk factors affecting the prognosis of the patients. When the patients in parapsilosis group treated with echinocinomycin were compared with those treated with azolol, there were no statistical significant differences in incidences of aggravation of liver damage and newly developed liver damage (aggravation of liver damage: 18.8% vs. 21.0%, newly developed liver damage: 6.2% vs. 10.5%, both P > 0.05). Conclusion The patients with fungemia in GICU are mainly the infection of Candida parapsilosis, and diabetes, infection of parapsilosis, APACHE Ⅱ score and SOFA score are the risk factors affecting the prognosis of the patients.

Effect of PD-1 inhibitor Nivolumab on the proliferation and cytotoxicity of anti-CD19 chimeric antigen receptor T cells / 中华血液学杂志

Objective@#To Evaluation the effect of PD-1 inhibitor Nivolumab on the proliferation and cytotoxicity of anti-CD19 chimeric antigen receptor T cells (CD19-CAR-T) in vitro.@*Methods@#Five patients with high PD-1 expression in peripheral blood and five healthy volunteers were selected. These peripheral blood mononuclear cells were used as the source of T cells to prepare CD19-CAR-T cells. Different doses (72, 36, 18 μg/ml) of Nivolumab was added on day 8 to the culture medium. Patient T cells incubated with 72 μg/ml Nivolumab and CD19-CAR-T cells of healthy volunteers were used as controls. CCK-8, lactate dehydrogenase (LDH) cytotoxicity assay and ELASA were used to detect the proliferation capacity, the specific cytotoxicity and the inflammatory factor secretion.@*Results@#①T cells from patients with high expression of PD-1 as the source of CD19-CAR-T cells did not affect transfection rate compared with that of healthy volunteers [(32.80±7.22)% vs (35.10±5.84)%, t=-0.554, P=0.593]. ②Incubation of CD19-CAR-T cells with 72 μg/ml Nivolumab did not affect CD19-CAR-T cell proliferation, but its cytotoxicity was significantly higher than that of CD19-CAR-T cells alone or patients’ T cells +72 μg/ml Nivolumab (all P<0.001), there was no significant difference in the killing activity between the 72 μg/ml and 36 μg/ml Nivolumab treated CD19-CAR-T cells on Pfeiffer cells (P=0.281, 0.267, respectively), and they were all higher than those of 18 μg/ml Nivolumab treated CD19-CAR-T cells (all P<0.001). ③Different doses of PD-1 inhibitor Nivolumab combined with CD19-CAR-T cells does not affect the secretion of IFN-γ and IFN-α (all P>0.05).@*Conclusion@#Combination of 36 μg/ml PD-1 inhibitor and CD19-CAR-T cells could reduce the drug toxicity and enhance the cytotoxicity.

New Carrier Materials for Particles Drug Delivery System of Irinotecan Hydrochloride / 中国药学杂志

OBJECTIVE: To prepare micelle drug delivery system of irinotecan hydrochloride, which could reduce its side effects and improve the therapeutic effects. METHODS: Firstly, the irinotecan hydrochloride was prepared as phospholipid compound to improve the lipophilicity. The synthesized polycaprolactone-polyethylene glycol copolymer was used as carrier material, then the phospholipid complex of irinotecan hydrochloride was wrapped to prepare a polymer micelle drug delivery system. The optimum prescription and preparation process of micelle drug delivery system of irinotecan hydrochloride were screened by the method of single factor combined with orthogonal test. RESULTS: The liposoluble of phospholipid compound of irinotecan hydrochloride was obviously increased compared with active compound. The irinotecan hydrochloride micelle was spherical and its particle size distribution was uniform. The average entrapment efficiency was 61.32%, and the average drug loading was 2.88%. CONCLUSION: Through this method, the particle size of irinotecan hydrochloride is small and the quality is controllable, and it is hopeful to increase the drug concentration at the target site.