Short-term exposure to gossypol causes reversible reproductive toxicity and nephrotoxicity in mice / 南方医科大学学报

OBJECTIVE@#To study the toxic effects of short-term exposure to gossypol on the testis and kidney in mice and whether these effects are reversible.@*METHODS@#Twenty 7 to 8-week-old male mice were randomized into blank control group, solvent control group, gossypol treatment group and drug withdrawal group. In the former 3 groups, the mice were subjected to daily intragastric administration of 0.3 mL of purified water, 1% sodium carboxymethylcellulose solution, and 30 mg/mL gossypol solution for 14 days, respectively; In the drug withdrawal group, the mice were treated with gossypol solution in the same manner for 14 days followed by treatment with purified water for another 14 days. After the last administration, the mice were euthanized and tissue samples were collected. The testicular tissue was weighed and observed microscopically with HE and PAS staining; the kidney tissue was stained with HE and examined for mitochondrial ATPase activity.@*RESULTS@#Compared with those in the control group, the mice with gossypol exposure showed reduced testicular seminiferous epithelial cells with rounded seminiferous tubules, enlarged space between the seminiferous tubules, interstitium atrophy of the testis, and incomplete differentiation of the spermatogonia. The gossypol-treated mice also presented with complete, non-elongated spermatids, a large number of cells in the state of round spermatids, and negativity for acrosome PAS reaction; diffuse renal mesangial cell hyperplasia, increased mesangial matrix, and adhesion of the mesangium to the wall of the renal capsule were observed, with significantly shrinkage or even absence of the lumens of the renal capsules and reduced kidney mitochondrial ATPase activity. Compared with the gossypol-treated mice, the mice in the drug withdrawal group showed obvious recovery of morphologies of the testis and the kidney, acrosome PAS reaction and mitochondrial ATPase activity.@*CONCLUSIONS@#Shortterm treatment with gossypol can cause reproductive toxicity and nephrotoxicity in mice, but these toxic effects can be reversed after drug withdrawal.

Efficacy and safety of VRD regimen of autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma / 中华内科杂志

Objective: To explore the stem cell collection rate and efficacy and safety of patients aged 70 and below with newly diagnosed multiple myeloma (MM) treated with the VRD (bortezomib, lenalidomide and dexamethasone) regimen followed by autologous stem cell transplantation (ASCT). Methods: Retrospective case series study. The clinical data of 123 patients with newly diagnosed MM from August 1, 2018, to June 30, 2020, at the First Affiliated Hospital of Soochow University and Suzhou Hopes Hematology Hospital, who were eligible for VRD regimen sequential ASCT, were collected. The clinical characteristics, efficacy after induction therapy, mobilization regimen of autologous stem cells, autologous stem cell collection rate, and side effects and efficacy of ASCT were retrospectively analyzed. Results: Of the 123 patients, 67 were males. The median patient age was 56 (range: 31-70) years. Patients with IgG, IgA, IgD, and light-chain types accounted for 47.2% (58/123), 23.6% (29/123), 3.2% (4/123), and 26.0% (32/123) of patients, respectively. In addition, 25.2% (31/123) of patients had renal insufficiency (creatinine clearance rate<40 ml/min). Patients with Revised-International Staging System (R-ISS) Ⅲ accounted for 18.2% (22/121) of patients. After induction therapy, the rates of partial response and above, very-good partial response (VGPR) and above, and complete response (CR)+stringent CR were 82.1% (101/123), 75.6% (93/123), and 45.5% (56/123), respectively. Overall, 90.3% (84/93) of patients were mobilized with cyclophosphamide+granulocyte colony-stimulating factor (G-CSF) and 8 patients with G-CSF or G-CSF+plerixafor due to creatinine clearance rate<30 ml/min and one of them was mobilized with DECP (cisplatin, etoposide, cyclophosphamide and dexamethasone)+G-CSF for progressive disease. The rate of autologous stem cell collection (CD34+cells≥2×106/kg) after four courses of VRD regimen was 89.1% (82/92), and the rate of collection (CD34+cells≥5×106/kg) was 56.5% (52/92). Seventy-seven patients treated with the VRD regimen sequential ASCT. All patients had grade 4 neutropenia and thrombocytopenia. Among the nonhematologic adverse events during ASCT, the highest incidence was observed for gastrointestinal reactions (76.6%, 59/77), followed by oral mucositis (46.8%, 36/77), elevated aminotransferases (44.2%, 34/77), fever (37.7%, 29/77), infection (16.9%, 13/77) and heart-related adverse events (11.7%, 9/77). Among the adverse events, grade 3 adverse events included nausea (6.5%, 5/77), oral mucositis (5.2%, 4/77), vomiting (3.9%, 3/77), infection (2.6%, 2/77), elevated blood pressure after infusion (2.6%, 2/77), elevated alanine transaminase (1.3%, 1/77), and perianal mucositis (1.3%, 1/77); there were no grade 4 or above nonhematologic adverse events. The proportion of patients who achieved VGPR and above after VRD sequential ASCT was 100% (75/75), and the proportion of patients who were minimal residual disease-negative (<10-4 level) was 82.7% (62/75). Conclusion: In patients aged 70 and below with newly diagnosed MM treated with VRD induction therapy, the collection rate of autologous stem cells was good, and good efficacy and tolerability were noted after follow-up ASCT.

Demographic characteristics and associated influencing factors in treated patients with chronic hepatitis B with hypoviremia : a single-center retrospective cross-sectional study / 中华肝脏病杂志

Objective: To investigate the demographic characteristics and clinical influencing factors which associates with the occurrence probability of persistent or intermittent hypoviremia (LLV) in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs). Methods: A single-center retrospective analysis was performed on patients with CHB who received outpatient NAs therapy for≥48 ± 2 weeks. According to the serum hepatitis B virus (HBV) DNA load at 48±2 weeks treatment, the study groups were divided into LLV (HBV DNA < 20 IU/ml and < 2 000 IU/ml) and MVR group (sustained virological response, HBV DNA < 20 IU/ml). Demographic characteristics and clinical data at the start of NAs treatment (considered as baseline) were retrospectively collected for both patient groups. The differences in the reduction of HBV DNA load during treatment was compared between the two groups. Correlation and multivariate analysis were further conducted to analyze the associated factors influencing the LLV occurrence. Statistical analysis was performed using the independent samples t-test, c2 test, Spearman analysis, multivariate logistic regression analysis, or area under the receiver operating characteristic curve. Results: A total of 509 cases were enrolled, with 189 and 320 in the LLV and MVR groups, respectively. Compared to patients with MVR group at baseline: (1) the demographics characteristics of patients showed that LLV group was younger in age (39.1 years, P = 0.027), had a stronger family history (60.3%, P = 0.001), 61.9% received ETV treatment, and higher proportion of compensated cirrhosis (20.6%, P = 0.025) at baseline; (2) the serum virological characteristics of patients showed that LLV group had higher HBV DNA load, qHBsAg level, qHBeAg level, HBeAg positive rate, and the proportion of genotype C HBV infection but decreased HBV DNA during treatment (P < 0.001) at baseline; (3) the biochemical characteristics of patients showed that LLV group had lower serum ALT levels (P = 0.007) at baseline; (4) the noninvasive fibrosis markers of patients showed that LLV group were characterized by high aspartate aminotransferase platelet ratio index (APRI) (P = 0.02) and FIB-4 (P = 0.027) at baseline. HBV DNA, qHBsAg and qHBeAg were positively correlated with LLV occurrence (r = 0.559, 0.344, 0.435, respectively), while age and HBV DNA reduction were negatively correlated (r = -0.098, -0.876, respectively). Logistic regression analysis showed that ETV treatment history, high HBV DNA load at baseline, high qHBsAg level, high qHBeAg level, HBeAg positive, low ALT and HBV DNA level were independent risk factors for patients with CHB who developed LLV with NAs treatment. Multivariate prediction model had a good predictive value for LLV occurrence [AUC 0.922 (95%CI: 0.897 ~ 0.946)]. Conclusion: In this study, 37.1% of CHB patients treated with first-line NAs has LLV. The formation of LLV is influenced by various factors. HBeAg positivity, genotype C HBV infection, high baseline HBV DNA load, high qHBsAg level, high qHBeAg level, high APRI or FIB-4 value, low baseline ALT level, reduced HBV DNA during treatment, concomitant family history, metabolic liver disease history, and age < 40 years old are potential risk factors for developing LLV in patients with CHB during the therapeutic process.

Study on the current situation and influencing factors of job involvement for employed nurses in military hospital / 中华劳动卫生职业病杂志

Objective: To investigate the current situation of job involvement of nurses in military hospitals in Henan Province and analyze the influencing factors, so as to provide reference for improving the level of job involvement of military nurses. Methods: In February 2022, the employed nurses of 4 military hospitals in Henan Province were investigated by convenient sampling method. A total of 663 questionnaires were collected, including 632 valid questionnaires, with an effective recovery rate of 95.32%. The self-designed questionnaire was used to investigate the basic information of nurses, the Job Involvement Scale was used to investigate the job involvement of nurses, the Emotional Labor Scale for Nurses was used to investigate nurses' emotions, and the Work-Family Conflict Scale was used to investigate the work-family conflict of nurses. Independent sample t-test and univariate analysis of variance were used to compare the job involvement of military employed nurses with different demographic characteristics, Pearson correlation analysis was used to explore the correlation between emotional labor, work-family conflict and job involvement, and hierarchical regression analysis was used to explore the impact of relevant variables on the job involvement of military employed nurses. Results: The total average score of job involvement of military employed nurses was (3.68±1.13), and the scores of vitality, dedication and focus were (3.64±1.15), (3.74±1.25) and (3.67±1.21) respectively. The total score of emotional labor of nurses was 33-80 (62.95±8.12), with an average score of (3.93±0.51). The total score of work-family conflict was 18-94 (55.16±13.53), with an average score of (3.06±0.75). Professional emotional regulation, patient-centered emotional inhibition and standardized emotional play were positively related to the job involvement (r=0.46, 0.41, 0.22, P<0.01). Time-based conflict, stress-based conflict and behavior-based conflict had negative correlation with the job involvement (r=-0.12, -0.23, -0.20, P<0.01). In hierarchical regression analysis, after controlling demographic variables, emotional labor and work-family conflict accounted for 17.2% and 4.2% of the variation of job involvement. Conclusion: The job involvement of military employed nurses tends to be at a moderate level. Emotional labor and work-family conflict can significantly affect their job involvement.

Fibrocartilaginous mesenchymoma: a clinicopathological analysis of four cases / 中华病理学杂志

Objective: To investigate the clinical, radiological, histological and molecular features and the differential diagnosis of fibrocartilaginous mesenchymoma (FM). Methods: Four cases of FM diagnosed in the Department of Pathology, the Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine from 2020 to 2022 were analyzed. Related literature was also reviewed. Results: Case 1 was a 10-year-old girl with bone destruction in the sacrum and L5 articular processes revealed by CT scan. Case 2 was a 7-year-old girl with an aggressive lesion in her right distal ulna. Case 3 was an 11-year-old boy with a lesion in the metaphysis of his left proximal tibia. Case 4 was an 11-year-old boy with bone destruction in the distal portion of a radius. Microscopically, the four tumors all consisted of numerous spindle cells, hyaline cartilage nodules, and bone trabeculae. The hypocellular to moderately cellular spindle cell component contained elongated cells with slightly hyperchromatic, mildly atypical nuclei arranged in bundles or intersecting fascicles. Benign-appearing cartilaginous nodules of various sizes and shapes were scattered throughout the tumors. There were areas mimicking epiphyseal growth-plate characterized by chondrocytes arranged in parallel columns and areas of enchondral ossification. The stroma was rich in mucus in case 1. Mutation of GNAS and IDH1/IDH2 and amplification of MDM2 gene were not found in any of the three tested cases. Conclusions: FM is very rare and tends to affect young patients. It most frequently occurs in the metaphysis of long tubular bones, followed by the iliac-pubic bones and vertebrae. FM is characterized by a mixed population of spindle cells, hyaline cartilage nodules and trabeculae of bone, without specific immunophenotypes and molecular alternations. As a borderline, locally aggressive neoplasm, surgical removal with a wide margin is generally the treatment of choice for FM.

Design, synthesis and evaluation of phenoxyacetic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for type 2 diabetes. Phosphotyrosine (pTyr) mimetics still dominate the currently available PTP1B inhibitors. The phenoxyacetic acid moiety was taken as a pTyr mimetic herein and phenoxyacetic acid-based compounds 2a-2g and 3a-3c were designed. Among them, compounds 2a-2g exhibited potent inhibition against PTP1B, and compound 2g showed an IC50 of 0.42 μmol·L-1 against PTP1B. Compound 2f exhibited pharmacological profiles similar to that of rosiglitazone, and could improve the insulin sensitivity and the serum total cholesterol level. The results suggest that PTP1B inhibitors might be effective in treating type 2 diabetes as well as associated metabolic syndromes.

Efficacy of total oral regimens containing ixazomib in patients with relapsed and refractory multiple myeloma / 中华内科杂志

To investigate the efficacy and safety of total oral regimen containing ixazomib in multidrug-resistant relapsed and refractory multiple myeloma(RRMM). A total of 38 patients were retrospectively analyzed from August 2018 to January 2020 in the First Affiliated Hospital of Soochow University. The overall response rate (ORR)was 36.8%. Among them, the very good partial response (VGPR) or better rate was 23.7%, and the complete response (CR) rate was 5.3%. The ORR was 41.7% in patients receiving ixazomib-lenalidomide-dexamethasone (IRD) regimen. Median PFS was 5 months and median OS was 7.5 months. The ORR was 50% after second-line therapy, 40% after third-line therapy and 12.5% after forth-line therapy or more. The ORR was 29.0% in bortezomib-refractory patients, 38.0% in lenalidomide-refractory patients, 21.4% in bortezmoib & lenalidomide dual refractory patients. Grade 3-4 hematological adverse events (AEs) were reported in 21% patients. Common hematological AEs included lymphopenia, neutropenia, thrombocytopenia. Other usual AEs were fatigue and diarrhea. No grade 3-4 peripheral neuropathy was recorded. In the treatment of relapsed/refractory multiple myeloma patients with multidrug resistance, the total oral regimens containing ixazomib demonstrate reliable efficacy and safety. Early administration of ixazomib at first or second relapse is suggested for more favorable clinical outcome.

The Role of Whole Body DWI in the Evaluation of Bone Disease in Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To explore the characteristics of ADC value changes in DWI of newly diagnosed symptomatic MM patients and its correlation with R-ISS stage.@*METHODS@#The data of 148 newly diagnosed symptomatic MM patients treated by whole-body DWI scan at The First Affiliated Hospital of Soochow University from June 2016 to June 2019 were selected and retrospectively analyzed and 30 cases of age-matched healthy people were selected as controls. The differences of ADC values between the patients in normal control group, DWI- group and DWI+ group were compared, and the relationship between ADC values and R-ISS stage in MM patients was compared.@*RESULTS@#The plasma cell percentage of the patients in DWI+ group was higher than those in DWI- group. ADC values of vertebra, sternum, rib, pectoral girdle, pelvic girdle of the patients in DWI+ group were significantly higher than those in DWI- group and normal control group. The ADC values of each part of the patients in DWI- group were higher than those in normal control group. ADC values of sternum, rib and pectoral girdle in the patients at R-ISS stage III were higher than those at R-ISS stage I and II, while, there was no statistical difference between R-ISS stage I and II groups. And there was no significant difference in ADC values of other bone parts such as vertebra and pelvic girdle in patients at R-ISS stage Ⅰ-Ⅲ.@*CONCLUSION@#DWI+ in MM patients is related to higher tumor invasion. The ADC values of the DWI+ group are higher than those of the DWI- group; the bone ADC values of the DWI- patients are still higher than the normal ones. And there is a certain relationship between ADC value and R-ISS stage.

A clinical retrospective analysis of newly diagnosed multiple myeloma patients with systemic light chain amyloidosis / 中华血液学杂志

Objective: To analyze the clinical characteristics, treatment response, and prognosis of newly diagnosed symptomatic multiple myeloma (MM) patients with systemic light chain amyloidosis (AL) . Methods: The clinical data of 160 patients with newly diagnosed MM treated at the First Affiliated Hospital of Soochow University from January 1, 2017 to October 31, 2018, were retrospectively analyzed. According to the histopathological biopsy results of bone marrow, skin, and other tissues, the patients were divided into two groups according to whether amyloidosis was combined or not, namely, the MM+AL group and the MM group. The clinical characteristics and treatment responses of the two groups were compared. Results: Among the 160 patients with newly diagnosed MM, there were 42 cases in the MM+AL group and 118 cases in the MM group. In terms of clinical features, the involved light chain and non-involved light chain (dFLC) in the MM+AL group was significantly higher than that in the MM group (P=0.039) . After induction treatment, the MM+AL group had a higher overall response rate (85.7%vs 79.7%, P<0.05) and higher excellent partial response (76.2%vs 55.1%, P<0.05) . After a median follow-up of 26 (0.25-41) months, there was no significant difference in the progression free survival and overall survival (OS) between the two groups (P>0.05) . The OS of patients in autologous hematopoietic stem cell transplantation group was better than that in non transplantation group (P<0.05) .The prognosis of patients with cardiac involvement in the MM+AL group was significantly worse than that in the MM group and MM+AL group without cardiac involvement (P<0.001) , with a median OS of only 13 months. Conclusion: The differential diagnosis between the MM+AL and MM groups requires histopathology, particularly for patients with significantly increased dFLC. The overall remission rate of patients in MM+AL group after 4 courses of induction chemotherapy was higher than that in MM group. The prognosis of patients with cardiac involvement in MM+AL group was poor.

Mechanism of Fangji Fulingtang for Treating Acute Kidney Injury Induced by Ischemia-reperfusion Based on Network Pharmacology and Molecular Docking Verification / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Fangji Fulingtang in the treatment of acute kidney injury （AKI） induced by ischemia-reperfusion based on network pharmacology and experimental verification. MethodActive components of Fangji Fulingtang were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） and previous report and targets of these components were predicted by SwissTargetPrediction. The targets of AKI were searched from GeneCards， Online Mendelian Inheritance in Man （OMIM）， the database of gene-disease associations （DisGeNET）， and Therapeutic Target Database （TTD）. Protein-protein interaction （PPI） network was constructed by STRING. Metascape was used for Gene Ontology （GO） term enrichment and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment of core targets. Cytoscape was employed to construct the "medicinal-active component-target-disease" network and “active component-target-pathway” network. AutoDock was applied for molecular docking. Finally， animal experiment was carried out to validate the mechanism of Fangji Fulingtang in treatment of AKI. ResultA total of 137 active components and 858 targets of Fangji Fulingtang， 1 294 targets of AKI， and 267 targets of Fangji Fulingtang in the treatment of AKI were screened out. Phosphoinositide-3-kinase regulatory subunit 1 （PIK3R1）， phosphatidylinositol-4，5-bisphosphate 3-kinase catalytic subunit alpha （PIK3CA）， proto-oncogene tyrosine protein kinase （SRC）， protein kinase B1 （Akt1）， and mitogen-activated protein kinase 3 （MAPK3） were the key anti-AKI targets of Fangji Fulingtang， which were involved in 1 609 GO terms， particularly cell response to lipids， membrane rafts， and protein kinase activity， and 140 KEGG pathways such as PI3K/Akt signaling pathway， chemokine signaling pathway， and Toll-like receptor signaling pathway. Molecular docking showed that the core active components had strong binding affinity to the key targets. The hematoxylin and eosin （HE） staining results indicated that Fangji Fulingtang can significantly improve the pathological state and the serological results suggested that the levels of serum creatinine （SCr） and blood urea nitrogen （BUN） were significantly reduced. ConclusionThis study clarified the mechanism of Fangji Fulingtang in the treatment of AKI and found that Fangji Fulingtang had the multi-component， multi-target， and multi-pathway characteristics in the treatment of AKI. The result lays a foundation for further study of its specific mechanism.

Data mining-based analysis of formulation rules for prescriptions containing herbal pair Acori Tatarinowii Rhizoma-Polygalae Radix / 中国中药杂志

By the in-depth excavation of prescriptions containing herbal pair Acori Tatarinowii Rhizoma-Polygalae Radix in the Dictionary of Traditional Chinese Medicine Prescriptions, this study analyzed their formulation rules, so as to provide reference for their clinical application and new drug development. First, the prescriptions containing Acori Tatarinowii Rhizoma-Polygalae Radix were collected from the Dictionary of Traditional Chinese Medicine Prescriptions, and their indications, herbal compatibility, and dosage forms were analyzed statistically using the Traditional Chinese Medicine Inheritance Support System(TCMISS). Meanwhile, the formulation rules and common dosage forms for the top four indications(amnesia, palpitation, mania, and epilepsy) sorted by frequency were analyzed with Apriori algorithm. A total of 507 prescriptions containing Acori Tatarinowii Rhizoma-Polygalae Radix were screened out, involving 15 indications(frequency>10) like amnesia, palpitation, mania, and epilepsy. There were 30 commonly used Chinese herbs(frequency≥60), with the Qi-tonifying herbs(Ginseng Radix et Rhizoma and Glycyrrhizae Radix et Rhizome), mind-tranquilizing herbs(Poria and Poria cum Radix Pini), and Yin-nourishing herbs(Angelicae Sinensis Radix and Ophiopogonis Radix) being the core ones. The commonly used dosage forms were honey pill, paste pill, decoction, and powder. These have indicated that the herbal pair Acori Tatarinowii Rhizoma-Polygalae Radix is often combined with Qi-tonifying, Yin-nourishing, and mind-tranquilizing herbs for the treatment of "heart or brain diseases" caused by phlegm production due to spleen deficiency, Qi and blood deficiency, and phlegm-turbidity blocking orifice. In the treatment of amnesia, supplementing essence and replenishing marrow are considered on the basis of tonifying Qi, nourishing Yin, and tranquilizing mind. In the treatment of palpitation and mania, tranquilizing mind is emphasized. In the treatment of epilepsy, the emphasis is placed on resolving phlegm, extinguishing wind, and stopping convulsion.

Effect of Huanglian Jiedutang on Learning and Memory Ability and Cholinergic System in AD Rats Induced by Aβ1-42 / 中国实验方剂学杂志

Objective:To investigate the effects of Huanglian Jiedutang on learning and memory ability and the cholinergic system in Alzheimer's disease（AD） rats induced by amyloid <italic>β</italic>-protein（A<italic>β</italic>）_1-42. Method:Sixty male SD rats were divided into normal group， model group， huperzine A group （2.1×10^-5 g·kg^-1）， high-， medium- and low dose of Huanglian Jiedutang groups （6，3，1.5 g·kg^-1）. AD rat model was replicated by hippocampal injection of A<italic>β</italic>_1-42. After 4 weeks of treatment， Morris water maze test was performed. Hematoxylineosin （HE） staining was used to observe the pathological changes of rat hippocampus. Sampling blood from abdominal aorta was taken. Acetylcholine （ACh）， acetylcholinesterase （AchE） and choline acetyltransferase （ChAT） in serum and hippocampus were detected by enzyme-linked immunosorbent assay （ELISA）. The expression of hippocampal <italic>α</italic>7 nicotinic acetylcholine receptor （<italic>α</italic>7nAChR） protein was detected by Western blot. The expression of hippocampal <italic>α</italic>7nAChR mRNA was detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. Result:Compared with the normal group， there were obvious pathological changes in the model group，such as neuron necrosis in the cerebral cortex，pyramidal cell or granular cell necrosis in the hippocampus，disorder of arrangement and inflammatory cell infiltration，prolonged escape latency，decreased escape platform times，decreased residence time in the effective area and swimming path in the effective area （<italic>P<</italic>0.05，<italic>P<</italic>0.01）. The contents of <italic>α</italic>7nAChR mRNA，ACh，AchE，ChAT，<italic>α</italic>7nAChR in the hippocampus decreased （<italic>P<</italic>0.01）. Compared with the model group，the escape latency of the middle dose group was shorter （<italic>P<</italic>0.05）， the escape platform times，the swimming path in the effective area and the residence time in the effective area increased （<italic>P<</italic>0.05，<italic>P<</italic>0.01）， the contents of serum ACh，ChAT， hippocampal AchE，ChAT and <italic>α</italic>7nAChR increased （<italic>P<</italic>0.05，）. The expression of hippocampal <italic>α</italic>7nAChR protein significantly increased （<italic>P<</italic>0.01）， the residence time of effective area in high dose group was prolonged （<italic>P<</italic>0.01）， the times of escape platform increased，and the contents of serum ACh，ChAT and hippocampal ACh，AchE，<italic>α</italic>7nAChR protein and <italic>α</italic>7nAChR mRNA increased （<italic>P<</italic>0.05）. Conclusion:Huanglian Jiedutang can significantly improve the learning and memory ability of AD rats induced by A<italic>β</italic>_1-42，and its mechanism may be related to the improvement of cholinergic system damage and enhancement of cholinergic system function induced by A<italic>β</italic>_1-42.

The Effects of Chidamide Combined with Anti-myeloma Drugs on the Proliferation and Apoptosis of Myeloma Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of chidamide combined with anti-myeloma drugs on the proliferation and apoptosis of myeloma cells.@*METHODS@#The proliferation inhibition of the cells was detected by CCK-8 method, and flow cytometry was used to detected the apoptosis of the cells.@*RESULTS@#Chidamide could inhibit the proliferation of myeloma cells and promote the apoptosis of primary myeloma plasma cells in a time- and dose-dependent manner (P<0.05). In NCI-H929 cell line, chidamide combined with low-dose bortezomib and lenalidomide showed synergistic effect, while combined with dexamethasone and pomalidomide showed additive effect. In MM.1s cell line, chidamide combined with bortezomib, dexamethasone, lenalidomide and pomalidomide all showed synergistic effects.@*CONCLUSION@#Chidamide inhibits proliferation of myeloma cells in a time- and dose-dependent manner and promotes apoptosis of primary myeloma plasma cells. Furthermore, it can enhance the inhibitory effect of anti-myeloma drugs.

The anti-hyperuricemic effects of compound CC18022 targeting xanthine oxidase / 药学学报

Hyperuricemia is not only the biochemical basis of gout, but also closely related to the development of metabolic syndrome, cardiovascular diseases, chronic kidney disease, etc. Xanthine oxidase (XOD) is the key catalytic enzyme for uric acid biosynthesis, therefore the vital target for anti-hyperuricemic drugs. In this study, compound CC18022 was designed and synthesized specifically targeting to XOD. Molecular docking analysis indicated a fairly tight binding between CC18022 and XOD. In the in vitro study, CC18022 significantly inhibited XOD activity with a half maximal inhibitory concentration (IC50) value in the order of nmol·L-1, which is relative to the XOD inhibitor febuxostat. By using both acute and chronic hyperuricemic mice model, compound CC18022 was found to have serum uric acid-lowering effect in a dose-dependent manner in vivo. The animal welfare and experimental processes were in accordance with the provisions of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. In the acute hyperuricemic mice, CC18022 significantly inhibited serum XOD activity, and also the XOD activity in intestine and liver, which were related to purine absorption and metabolism. Therefore, the novel compound CC18022 exhibited significant inhibition on XOD activity and anti-hyperuricemic effects, making it a favorable candidate for further research.

Application of Conditioning Regimen with Busulfan and Cyclophosphamide in Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To evaluate the safety and efficacy of BUCY (busulfan and cyclophosphamide) conditioning regimen for autologous hematopoietic stem cell transplantation (ASCT) in patients with multiple myeloma (MM).@*METHODS@#The clinical data of 72 MM patients received transplantation in the Hematology Department of the First Affiliated Hospital of Soochow University from May 2012 to June 2015 were retrospectively analyzed. Among them, 36 patients received BUCY conditioning regimen while the others received high-dose melphalan (HDM) conditioning regimen. The complication, post-transplantation hematopoietic reconstitution and efficacy between the two groups were compared.@*RESULTS@#There were no significant differences in sex, age, isotype, stage, induction therapy, mobilization method and proportion of conditioning regimen with Bortezomib between the two groups. The median time of neutrophil engraftment for the patients in BUCY and HDM groups was 10 (8-17) and 10 (9-13) d (P=0.046), and the median time of platelet engraftment was 10 (8-18) and 11 (9-47) d (P=0.017), respectively. The transplant related mortality of the patients in both groups was 2.7%. The CR rates of the patients after ASCT (38.9% and 50.0%) were higher than those before ASCT (27.8% and 19.4%) in the two groups. For the patients in BUCY group, the median follow-up time was 45 (0-61) months. Fifteen patients (41.7%) achieved disease progression. While for the patients in HDM group, the median follow-up time was 52(0-75) months. Twenty-two patients (61.1%) achieved disease progression.@*CONCLUSION@#The BUCY conditioning regimen is a safe and effective therapy for ASCT in patients with MM. Besides, in terms of safety and efficacy, BUCY regimen is not inferior to HDM regimen. BUCY regimen may replace HDM regimen as a standard conditioning regimen for ASCT in MM.

How autoantibodies interfere with the identification of alloantibodies / 中国输血杂志

【Objective】 To explore a method to accurately identify the specificity of alloantibodies or autoantibodies in autoimmune hemolytic anemia (AIHA)patients with both warm and cold antibodies, so as to provide guidance for the selection of blood components. 【Methods】 Blood samples of AIHA patients with both warm and cold antibodies were screened by the direct antiglobulin testing (DAT). The plasma of patients were treated with dilution or adsorption method and the erythrocyte was dispersed for specificity identification of alloantibodies or autoantibodies.According to the results of antibody identification, appropriate phenotype of red blood cells(RBCs) were transfused to patients, and the incidence of adverse reactions and efficacy of transfusion were observed. 【Results】 Alloantibodies or specific autoantibodies were detected in serum or elution in 14 of the 16 patients. 10 patients underwent blood transfusion during hospitalization, and all of them received RBCs with the same or compatible ABO/Rh (D) type as the patients and without any reaction to the alloantibodies and specific warm autoantibodies. No hemolytic reaction occurred, and anemia symptoms were improved after blood transfusion. 【Conclusion】 The selection of appropriate methods could eliminate the influence of autoantibodies on the identification of alloantibodies in AIHA patients with both warm and cold antibodies. Therefore, the selection of blood from compatible donors for transfusion could effectively avoid the occurrence of hemolytic reaction.

A three-microRNA panel in serum as novel biomarker for papillary thyroid carcinoma diagnosis / 中华医学杂志(英文版)

BACKGROUND@#Accumulating evidence has revealed that circulating microRNAs (miRNAs) can serve as non-invasive biomarkers for cancer diagnosis. This study aimed to identify differentially expressed miRNAs in serum which might become potential biomarkers for non-invasive diagnosis of papillary thyroid carcinoma (PTC).@*METHODS@#The experiment was carried out between 2015 and 2017. In the screening stage, the Exiqon miRNA quantitative real-time polymerase chain reaction (qPCR) panel was applied to select candidate miRNAs. In the following training, testing, and external validation stages, the serum samples of 100 patients and 96 healthy controls (HCs) were analyzed to compare the expression levels of the identified miRNAs. The areas under the receiver operating characteristic curves (AUCs) were calculated to assess the diagnostic value of the identified signature.@*RESULTS@#Three miRNAs (miR-25-3p, miR-296-5p, and miR-92a-3p) in serum were consistently up-regulated in PTC patients compared with HCs. A three-miRNA panel was constructed by logistic regression analysis and showed better diagnostic performance than a single miRNA for PTC detection. The AUCs of the panel were 0.727, 0.771, and 0.862 for the training, testing, and external validation stage, respectively. Meanwhile, the panel showed stable capability in differentiating PTC patients from patients with benign goiters, with an AUC as high as 0.969. For further exploration, the three identified miRNAs were analyzed in tissue samples (23 PTC vs. 23 HCs) and serum-derived exosomes samples (24 PTC vs. 24 HCs), and the altered expression in the tumor also indicated their close relationship with PTC disease.@*CONCLUSION@#We identify a three-miRNA panel in serum which might serve as a promising biomarker for PTC diagnosis.

Clinical value of serum isoform -2 proprostate-specific antigen and its derivatives in predicting aggressive prostate cancer / 北京大学学报(医学版)

OBJECTIVE@#To explore the clinical value of serum isoform [-2] proprostate-specific antigen (p2PSA) and its derivatives %p2PSA and prostate health index (PHI) in predicting aggressive prostate cancer (PCa).@*METHODS@#The pre-operation serum and basic clinical data of 322 patients with PCa (including 143 patients diagnosed with PCa by transrectal ultrasound-guided prostate biopsy and 179 patients undergoing radical prostatectomy) in Peking University First Hospital were collected from August 2015 to May 2018. Serum total prostate-specific antigen (tPSA), free prostate antigen (fPSA) and fPSA/tPSA (f/t) and the p2PSA level of all these patients were measured on automatic immune analyzers DxI800, and then %p2PSA and PHI were calculated. The prostate pathologic result was considered as the gold standard to evaluate the Gleason score of the patients with PCa. Receiver operator curves (ROC) were used to assess the ability of p2PSA, %p2PSA and PHI to predict aggressive PCa (pathologic Gleason score≥7) compared with those traditional markers tPSA, fPSA and f/t.@*RESULTS@#Among these patients, the p2PSA, %p2PSA and PHI median levels were significantly higher in patients with pathologic Gleason score≥7 than those with Gleason score<7 (p2PSA: 30.22 ng/L vs. 18.33 ng/L; %p2PSA: 2.50 vs. 1.27; PHI: 91.81 vs. 35.44; all P<0.01). The area under curve (AUC) of %p2PSA and PHI (0.770, 0.760) in predicting Gleason score≥7 were higher than those of the traditional indicators tPSA, fPSA and f/t (AUC were 0.648, 0.536 and 0.693, respectively). Among those patients diagnosed with PCa by transrectal ultrasound-guided prostate biopsy, the AUC of %p2PSA and PHI (AUC were 0.808 and 0.801, respectively) in predicting Gleason score≥7 were higher than those of the traditional indicators tPSA, fPSA and f/t (AUC were 0.729, 0.655 and 0.665 respectively). Among those patients undergoing radical prostatectomy, PHI and %p2PSA also had the trend of higher predictive value than those of the traditional indicators. The AUC of %p2PSA and PHI were 0.798 and 0.744, respectively while the AUC of tPSA, fPSA and f/t were 0.625, 0.507 and 0.697, respectively.@*CONCLUSION@#Compared with traditional markers tPSA, fPSA and f/t, %p2PSA and PHI had much higher predictive value for aggressive PCa, which may help clinicians to evaluate the therapeutic regime and make more appropriate management plan for the patients.

Based on PI3K/Akt/mTOR Signaling Pathway to Explore Mechanism of Zhigancao Tang Against MIRI-induced Ventricular Tachycardia and Ventricular Fibrillation in Rats / 中国实验方剂学杂志

Objective:Through phosphatidylinositol 3-kinase（PI3K）/protein kinase B （Akt）/mammalian rapamycin target protein （mTOR） signaling pathway， explore the effect of Zhigancao Tang on myocardial ischemia-reperfusion injury（MIRI）The role and mechanism of arrhythmia（ventricular tachycardia and ventricular fibrillation）. Method:The 72 SD rats were randomly divided into sham operation group，model group， Zhigancao Tang low，medium and high dose group（11.43，22.86，45.72 g·kg-1），Wenxin granule group（2.43 g·kg-1），continuous drug intervention for 10 days. Two hours after the last administration，the MIRI model of rat was prepared by ligating the left anterior descending coronary artery，and the changes of electrocardiogram were recorded. After successful modeling，blood and heart tissue were collected to detect the content of creatine creatine（CK），lactate dehydrogenase（LDH）and aspartate aminotransferase（AST）in the serum, the enzyme-linked immunoassay（ELISA） method was used to detect cardiac troponin（CtnI）content, immunohistochemical detection of myocardial PI3K，Akt，mTOR expression. Western blot was used to detect the myocardial autophagy-related protein microtubule-associated protein 1 light chain 3（LC-3），autophagy markers Beclin1 and PI3K/Akt/mTOR signaling pathway related protein expression and phosphorylated p-PI3K，p-Akt，p-mTOR levels. Result:In model group， 100% of ventricular tachycardia and 91.67% of ventricular fibrillation occurred. Compared with sham operation group， the serum levels of CK，LDH，AST，and CtnI in the model group were significantly increased（P<0.01），PI3K，Akt，mTOR AOD values in myocardial tissue were significantly increased （P<0.01），the relative expression of the ratio of LC3-Ⅱ/LC3-Ⅰ and Beclin1 was significantly increased（P<0.01），p-PI3K/PI3K，p-Akt/Akt，and p-mTOR/mTOR were significantly reduced （P<0.01）. Compared with model group， the incidence of ventricular tachycardia and ventricular fibrillation in the high-dose Zhigancao Tang group was significantly reduced （P<0.01），and the duration was the shortest compared with other administration groups（P<0.01）， CK，LDH，AST level and CtnI content were significantly reduced（P<0.01）， the expression of PI3K，Akt and mTOR of Zhigancao Tang group was significantly decreased with increasing dose（P<0.01）， the expression of LC-3 and Beclin1 was accompanied by Zhigancao Tang increase of each dose group of soup had different degrees of decrease （P<0.01），while the expression ratio of PI3K/Akt/mTOR-related protein was significantly increased （P<0.05，P<0.01）. Conclusion:Pretreatment of Zhigancao Tang can reduce the abusually elevated cardiac enzymes CK, LDH, AST and CtnI, inhibit excessive autophagy of cells, and up-regulate the expression of PI3K, Akt and mTOR, indicating that the anti-MIRI arrhythmia effect of Zhigancao Tang may be related to the PI3K/Akt/mTOR signaling pathway.

Design, synthesis and biological evaluation of inhibitors of urate transporter 1 (URAT1) / 药学学报

Urate transporter 1 (URAT1) is a validated target for the treatment of hyperuricemia. Based on the structure of URC-102, which is currently under a phase Ⅱ clinical trial, fourteen novel analogs were designed and synthesized. Among them, four compounds (9b, 9c, 10e and 10g) exhibited substantial inhibitory effect against URAT1. The most active compound 9b showed an IC50 value of 0.061 μmol·L-1, which is significantly more potent than Lesinurad and Benzbromarone. Preliminary SAR was drawn, providing clues for further structural optimization.