PCI-32765,an oral selective and irreversible inhibitor of Bruton tyrosine kinase (BTK),inhibits survival,activation,proliferation and migration of malignant B cells by blocking B cell receptor signaling pathway.PCI-32765 not only acts on malignant B cell,but also prevents resistance to chemical drugs.Therefore,PCI-32765 has broad prospects in the treatment of B cell malignancies.

Objective To investigate the fatigue in patients with type 2 diabetes mellitus (T2DM),and analyze its related factors.Methods A total of 211 patients with type 2 diabetes were investigated with Chinese version of Multidimensional Fatigue Inventory-20 (MFI-20),Medical Outcomes Study Health Status Short Form-Vitality (SF-36-VT) and demographic survey questionnaire.T test,one-way AVOVA and multiple linear regression analysis were used to analyze the data.Results The fatigue incidence of 211cases of patients with type 2 diabetes was 63.5％ (134/211),the mean score of MFI-20 was 54.10±15.63,and women's score (57.89±15.32) was significantly higher than that of men (51.54±15.37)(t=2.949,P ＜ 0.01).Physical fatigue got the highest score of the three dimensions in MFI-20,which was 2.99±1.03,the mental fatigue scored 2.67±0.82.Multiple linear regression analysis showed that fatigue was related to the sports,2hPBG,rest situation,cerebrovascular complications and the number of complications,which could totally explain 30.7％ of the variance.Conclusions More attention should be paid to fatigue of T2DM patients.Effective interventions should be carried out to relieve the fatigue status of T2DM patients and improve their self-management ability and quality of life.

objective To analyze the correlation between the level of serum uric acid and the clinical and pathological features of IgA nephropathy.Methods Totally 148 patients diagnosed as IgA nephropathy by renal biopsy in our hospital from January 2007 to December 2010 were divided into hyperuricaemic group(41 cases)and non-hyperuricaemic group(107 cases)according to the level of serum uric acid.The clinical parameters and renal pathology grade were compared.Results There were significant differences between hyperuricaemic group and non-hyperuricaemic group in the incidences of hypertension(63.4%vs 38.3%),disease duration[(18.90±10.12)months vs(9.46±3.91)months]and body mass index[(22.81±3.60)kg/m2vs(15.32±2.54)kg/m2](all P<0.05),while no differences in age and sex(both P>0.05).The blood urea nitrogen(BUN)[(8.93±4.28)mmol/L vs (5.21±2.18)mmol/L],creatinine(Cr)[(155.96±107.72)μmol/L vs(79.52±40.01)μmol/L],serum triglycerides[(2.11±1.06)mmoVL vs(1.86±1.20)mmol/L]and 24-hour urine protein amount [(4328.16±1434.25)mg/24 h vs(2885.10±1388.15)mg/24 h]were significantly different between the two groups(all P<0.05).The percentage of Lee's grade I+Ⅱin hyperuricaemic group was 12.2%,and IV+V grade was 39.0%,while percentage of Lee's grade I+Ⅱin non-hyperuricaemic group was 25.2%,and IV+V grade was 16.9%(P<0.05).Tubulointerstitial lesions(TIL)gradeⅢ+IV was more in hyperuricaemic group,which was 68.3%,while TIL grade II was more in non-hyperuricaemic group,which was 76.6%.Renal artery damage grade II+Ⅲ was more in hyperuricaemic group.which was 73.2%,while renal artery damage grade 0+1 was more in non-hyperuricaemic group,which was 69.2%.Conclusion The level of serum uric acid was related with 24-hour urine protein amount,blood pressure and kidney function in IgA nephropathy,and Lee's grade,TIL grade and renal artery damage grade were severe in hyperuricaemic group.

Aim To investigate the influences on the aortal structure of rats with long-term high fat forages diet.Methods 14 SD rats were divided into two groups:the control group and the test group. The test rats were fed with high fat forages.12 weeks later, the aortas of the rats were observed with a light microscope, transmission electron microscope(TEM) and scanning electron microscope (SEM).Results In the test group, the aortic tunica intima thickening, endotheliocyte injury and monocyte adhesion were found with a light microscope; the elastic lamina being broken and the smooth muscle cells proliferated. Under TEM, the endothelial cell membrane of the aorta in the test rats was destroyed and appeared to be worm-eclipsed shape.Mitochondria exhibited swelling,vacuole degeneration and its cristae was dissolved, broken or some disappeared.Rough endoplasmic reticula (RER) expanded. The endothelial cell spaces were enlarged and the cell junctions deformed. Monocytes adhering to the endothelial cell stretched out pseudopodia and intruded into the endothelial crevice and the subendothelial layer. Some basement membranes completely sloughed following with endothelial cell. ERE and ribosomes increased in smooth muscle cells. SEM observation showed that the endothelial cells became swelling and the surface of endothelial cell was worm-eclipsed or crater shape. There were deeper crevices between endothelial cells.Conclusions Long-term high fat forages diet can induce injury of the endothelium and elastic lamina, adhesion of the monocytes and its intrusion into endothelial layer and subendothelial layer, proliferation of the subendothelial layer and smooth muscle in the aorta of rats.

Objective To investigate the reversal effect on mdr1 gene mediated multidrug resistance in gastric cancer SGC7901/VCR cells by small interfering RNA(siRNA).Methods Two siRNAs(mdr1si2631 and mdr1si3071) specifically targeting mdr1 gene were designed and synthesized by transcription in vitro.The siRNA duplexes were used to transfect into the gastric cancer SGC7901/VCR cells.The expression levels of mdr1 mRNA and P-gp were detected by RT-PCR and immunohistochemistry respectively.The accumulation of intracellular adriamycin(ADR)was examined by flow cytometry and the cell sensitivity to ADR was demonstrated by MTT.Results The expression level of mdr1 mRNA treated by siRNAs for 48?hours was decreased in the SGC7901/VCR cells.The mdr1 RT-PCR product in the transfected mdr1si2631 SGC7901/VCR cells could hardly been found,similar to its parental SGC7901 cells,the ratio of mdr1 and ?-actin in the control SGC7901/VCR group was 1.05?0.10,the transfected mdr1si3071 group was 0.16?0.03(P0.05).The RT-PCR results showed that the mdr1 mRNA expression level in the mdr1 si2631 group decline more obviously than that in the mdr1si307l group,near by the level in its parental SGC7901 cells.The P-gp immunoreactivity(IR)in brownish-colored granules was located on the cell membrane.The P-gp IR became weaker in the SGC7901/VCR cells treated by siRNAs for 48 hours and the P-gp expression level in both transfected siRNA groups was decreased.The values of adriamycin-specific fluorescence intensity and the positive rates of intracellular ADR in both transfected siRNA groups were increased.The relative reversal efficiency of the SGC7901/VCR cells to ADR detected by MTT was 79.59%in mdr1 si2631 group and 59.98%in mdr1si3071 group respectively.Conclusion siRNA could reverse mdr1 gene mediated multidrug resistance in gastric cancer SGC790l/VCR cells.

OBJECTIVE:To observe clinical efficacy of urinary kallidinogenase in the treatment of acute cerebral watershed in-farct (WSI). METHODS:128 patients with WSI were randomly divided into control group and treatment group,each of the 64 cases. Control group was given Shuxuening 15 ml added into 0.9% Sodium chloride 250 ml,ivgtt,qd;treatment group received urinary kallidinogenase 0.15 PNA added into 0.9% Sodium chloride 100 ml,ivgtt,qd. Both groups were treated for consecutive 14 days. Neurologic impairment score(NIHSS)and clinical efficacy were observed in 2 groups before treatment and 3,7 and 14 days after treatment. The blood specimens were collected after 7 and 14 days treatment,to determine serum levels of TCC. RESULTS:After treatment,NIHSS and total effective rate of treatment group were significantly higher than those of control group,with statis-tical significance(P<0.01). There was no statistical significance in TCC between 2 groups before treatment(P>0.05);7 days af-ter treatment,TCC level of 2 groups increased significantly,to 14 days,and a declive;the treatment group was higher than the control group,with statistical significance (P<0.05). CONCLUSIONS:Urinary kallidinogenase can improve clinical efficacy of WSI significantly,and promote neurologic impairment symptom and TCC levels.

Objective:To investigate the in vitro effect of arsenic trioxide (As2O3) alone and in combination with dexamethasone (DXM), etoposide (VP-16), methotrexate (MTX), bortezomib (BTZ), and suberoylanilide hydroxamic acid (SAHA) on the growth of human cutaneous T cell lymphoma (CTCL) cells Hut-78 and Hut-102. Methods:Hut-78 and Hut-102 cells were cultured with different concentrations of As2O3, DXM, VP-16, MTX, BTZ, and SAHA alone and As2O3 in combination with DXM, VP-16, MTX, BTZ, or SAHA for 48 h. The effects of the different samples on Hut-78 and Hut-102 cell proliferation were determined by MTT assay. Analyses using CalcuSyn software were performed to determine whether the combination of As2O3 with DXM, VP-16, MTX, BTZ, or SAHA in-duced synergistic cytoxicity. Results:As2O3, DXM, VP-16, MTX, BTZ, and SAHA alone significantly inhibited the growth of Hut-78 and Hut-102 cells in a dose-dependent manner, with a 50%inhibiting concentration of 5μmol/L, 500μg/mL, 2.5μg/mL, 1μg/mL, 10μmol/L, and 2.5μmol/L individually after 48 h of culture. As2O3 with DXM, VP-16, MTX, BTZ, or SAHA showed remarkable antitu-mor efficacy compared with that of individual applications. Conclusion:As2O3 alone or combined with DXM, VP-16, MTX, BTZ, or SAHA significantly inhibited Hut-78 and Hut-102 cell growth in vitro. This study demonstrated that As2O3 with DXM, VP-16, MTX, BTZ, or SAHA presents synergistic antitumor effects on CTCL cells and may be an optimal regimen in clinical trials of CTCL.

Objective:To detect the inhibitory effects of CAL-101, a selective inhibitor of phosphoinostitide-3'-kinase delta (PI3Kδ), on Burkitt's lymphoma cell line Raji and diffused large B-cell lymphoma cell line SUDHL-10 and elucidate its relative mechanism. Methods:Raji and SUDHL-10 cells were treated with various concentrations of CAL-101. Methyl thiazolyl tetrazolium (MTT) assay was performed to determine the inhibitory effect of CAL-101 on lymphoma cells, and cell apoptosis was measured by Annexin V/PI and DAPI staining. Migration assays were performed with transwell to detect the migration of lymphoma cells derived from the stromal cell line HK. Western blot was used to detect the phosphorylation status of the ERK pathway. MTT and CalcuSyn software analyses were preformed to detect whether or not combining CAL-101 with bortezomib induces synergistic cytoxicity. Results:CAL-101 at con-centrations of 5, 10, 15, and 20μmol/L inhibited cell proliferation in a dose-dependent manner. The proliferation rates of the Raji cells treated with 5, 10, 15, and 20μmol/L for 48 h were 29.17%± 1.23%, 38.15%± 1.51%, 46.46%± 1.78%, and 55.8%± 2.01%, respec-tively, which were significantly higher (P<0.05) than that of the control group (1.15% ± 0.02%). Similar results were found in the SUDHL-10 cells after treatment with CAL-101 (P<0.05). CAL-101 also exerted an apoptotic effect on the lymphoma cells. The apop-totic rates of the Raji cells treated with CAL-101 for 21 h were 22.69%± 3.83%and 49.96%± 7.36%, respectively, which were signifi-cantly higher (P<0.05) than that of the control group (5.23%± 2.04%). Similar results were found in the SUDHL-10 cells (P<0.05). Treatment with 5 and 10 μmol/L CAL-101 dose-dependently inhibited the migration activity of lymphoma cells to stromal cells (P<0.05). Western blot analysis showed that the expression level of ERK phosphorylation protein was significantly downregulated in the cells treated with CAL-101. A synergistic effect between CAL-101 and bortezomib was verified. That is, these two drugs can signifi-cantly inhibit the proliferation of lymphoma cells with CI values less than 1. Conclusion:The PI3Kδ-specific inhibitor CAL-101 sup-pressed the proliferation of Raji and SUDHL-10 cells, induced apoptosis, and inhibited stromal cell-derived migration. This inhibitory effect may be induced by blocking the ERK pathway. Overall, our study indicated that CAL-101 is a novel and potential agent in the therapeutic strategy against aggressive B-cell lymphoma.

Objective To construct a risk prediction model of post-traumatic stress disorder(PTSD)after hypertensive intracerebral hemorrhage in elderly patients and analyze the correla-tion of PTSD with rs806377 polymorphism of cannabinoid receptor 1(CNR1)gene.Methods A total of 215 elderly patients with hypertensive cerebral hemorrhage admitted to the Department of Neurology of Geriatric Hospital of Hainan and Department of Neurosurgery of the First Affiliated Hospital of Hainan Medical University from January 2020 to August 2022 were enrolled in this study.According to the results of PTSD scale(scoring＞50 or 0～50)after surgical treatment,they were divided into PTSD group(43 cases)and non-PTSD group(172 cases).The rs806377 polymorphism of CNR1 gene was detected in both groups by gene sequencing.Univariate and mul-tivariate logistic regression analyses were used to analyze the susceptibility to PTSD among the elderly after hypertensive intracerebral hemorrhage.Another 103 elderly patients with hyperten-sive intracerebral hemorrhage during the same period were also subjected and served as verifica-tion set.A prediction model was constructed.Results There were significant differences in age,family annual income,blood loss amount,psychological resilience score and social support score between the PTSD group and non-PTSD group(P＜0.05,P＜0.01).The PTSD group had obvi-ously larger proportion of TT genotype carriers and higher T allele frequency than the non-PTSD group(P＜0.05,P＜0.01).Logistic regression analysis showed that age(OR=2.020,95％CI:1.115-3.658),family annual income(OR=1.799,95％CI:1.232-2.626),blood loss(OR=1.507,95％CI:1.243-1.826),psychological resilience score(OR=2.059,95％CI:1.068-3.969),social support score(OR=1.664,95％CI:1.122-2.467),rs806377 TT genotype(OR=1.861,95％CI:1.485-2.331)and rs806377 T allele(OR=3.777,95％CI:2.049-6.962)were the influencing fac-tors of postoperative PTSD in these patients(P＜0.05,P＜0.01).ROC curve analysis indicated that the sensitivity was 69.57％,the specificity was 71.25％,and the AUC value was 0.762(95％CI:0.708-0.813)in the verification group,indicating a certain accuracy of our model.Conclusion CNR1 gene rs806377 locus polymorphism is an influencing factor for PTSD susceptibility,and rs806377 TT genotype and rs806377 T allele can predict PTSD in elderly patients after hyperten-sive intracerebral hemorrhage.

OBJECTIVETo investigate the effect of CAL-101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL-2 and Jeko-1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma.

METHODSMTT assay was applied to detect the inhibitory effects of CAL-101 and bortezomib either alone or combined on Z138, HBL-2 and Jeko-1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expression of PI3K-p110σ and p-Akt, Akt, p-ERK and ERK proteins after the cells were exposed to different concentrations of CAL-101. Flow cytometry was employed to assess the apoptosis rate. NF-κB kit was used to determine the changes of location of NF-κB P65, and Western blot was applied to detect the level of caswpase-3 and the phosphorylation of Akt in different groups.

RESULTSCAL-101 and BTZ inhibited the proliferation of Z138, HBL-2 and Jeko-1 cells in a dose- and time-dependent manner. CAL-101/BTZ combination induced significantly synergistic cytotoxicity in the MCL cells. The results of Western blot assay showed that CAL-101 significantly blocked the phosphorylation of Akt and ERK in the MCL cell lines. In addition, CAL-101 combined with BTZ induced pronounced apoptosis (P < 0.01). For example, after the Z138 cells exposed to the drugs for 48 h, the apoptosis rates of the control, CAL-101, BTZ and CAL-101 + BTZ groups were: (2.6 ± 1.8)%, (40.0 ± 3.0)%, (34.0 ± 1.0)%, and (67.4 ± 1.0)%, respectively; and when drug treatment was given to HBL-2 cells over 96 h, the apoptosis rates of these four cell groups were (7.4 ± 0.6)%, (30.7 ± 5.7)%, (12.0 ± 1.0)%, and (85.0 ± 4.0)%, respectively. The combination therapy contributed to the enhanced inactivity of nuclear factor-κB (NF-κB) and Akt inactivation in the MCL cell lines (P < 0.05), however, the casepase-3 activity was up-regulated.

CONCLUSIONSThe combination of CAL-101 and bortezomib is muchmore effective in inhibiting proliferation and promoting apoptosis of mantle cell lymphoma cell lines (Z138, HBL-2 and Jeko-1), which may be mediated through inhibiting PI3K/Akt signaling pathway and the transcription of NF-κB.

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