Cytokine release assessment:a good de-risk approach to bi-specific T-cell engagers in non-clinical development / 中国药理学与毒理学杂志

Bi-specific T-cell engagers (BiTEs) show great clinical outcomes for anti-cancer purposes. However, potential cytokine release syndrome (CRS) is notorious to all BiTEs. The mechanism underlying CRS is still not fully known, even though such toxicities are considered to be cytokine release related. Assessment of CRS is a key to non-clinical de-risk programs for BiTEs therapeutic development. In the present review, possible mechanisms are discussed, especially factors contributing to CRS develop?ment. T cell activation may be just an initiation of the CRS cascade, and other cell types can greatly contribute to CRS, such as a chain reaction triggered by downstream B-cells, monocytes, and endothe?lium cells. A non-clinical de-risk program can be designed based on these components in the CRS cascade. Combination of in vitro cytokine release assay, and in vivo mouse and non-human primates studies should be reliable enough to predict and mitigate CRS risk in the clinics. Further more, a good de-risk program should be able to provide ranking for candidates for further development and provide enough confidence to select a first-in-human dose.

Expression of mitochondrial fusion protein-2 in melanoma tissues and its effect on the biological activity of tumor cells / 医学研究生学报

Objective　Melanoma is a malignant tumor with high clinical malignancy, rapid progression, poor prognosis and high mortality. It is of great clinical significance to explore the molecular mechanism of high metastasis of melanoma and find new tumor markers and therapeutic targets. The expression of mitochondrial fusion protein-2 (MFN2) in cutaneous melanoma tissues and peritumoral tissues was studied, and its correlation with clinical parameters was analyzed. The correlation between MFN2 and the biological behavior of melanoma was also discussed.　Methods　Immunohistochemistry was used to detect the expression of Med19 protein in cutaneous melanoma tissues and peritumoral tissues, and to analyze the correlation between MFN2 expression and clinical factors in patients. The lentiviral vector containing MFN2 coding sequence (Lenti-MFN2) infected with melanoma cell B16 was set up as the study group, and the lentivirus with green fluorescent protein gene (Lenti-GFP) as the control group. The mRNA and protein expressions of MFN2 and Ras-Raf1-ERK1/2 signaling pathways in transfected cells were detected by real-time quantitative PCR (qRT-PCR) and Western blot. Flow cytometry was used to detect changes in cell cycle and apoptosis. MTT assay and colony formation assay were used to detect changes in cell viability and proliferation capacity.　Results　The positive expression rate of MFN2 in peritumoral tissues was significantly higher than that in the skin melanoma tissues (83.9% vs 30.6%, P<0.05). MFN2 expression was associated with both lymph node metastasis and TNM staging (P<0.05). Compared with the control group, the proliferation activity and colony forming ability of B16 cells in the study group were significantly inhibited (P<0.05); the proportion of G0/G1 phase cells in B16 cells in the study group significantly increased [(46.3±10.3)% vs (67.9±12.6)%], and the apoptosis rate significantly increased [(12.5±1.6)% vs (57.4±12.6)%], with statistically significant differences (P<0.05). In comparison with the control group, the expression of Ras, Raf, ERK1/2 mRNA and protein in the study group significantly decreased (P<0.05).　Conclusion　MFN2 is down-regulated in melanoma tissues. Up-regulation of MFN2 expression can inhibit melanoma proliferation and promote cell apoptosis, which may be related to the inhibition of Ras-MAPK signaling pathway activity.

Intravascular large B cell lymphoma of thyroid gland and review of literature / 临床与实验病理学杂志

Purpose To investigate the clinical-pathological characteristics of the primary thyroid intravascular large B-cell lymphoma (PT-IVLBCL). Methods The clinical-patho-logical data of the PT-IVLBCL were analyzed retrospective. A comprehensive analysis of the literature on IVLBCL published between 1991-2017 in China were performed. Results A thy-roid mass was identified in a physical examination of a 68-year-old male who initially presented with dyspnea accompanied by intermittent headache for about 1 month. Pathological results showed that large atypical lymphoma-like cells filled the small vessel capillaries in the lesion area. Immunohistochemical staining revealed that the lymphoma-like cells were positive for CD20, Pax-5, BCL-2 and MUM1. The Ki-67 index was estimated to be approximately 85％. Conclusion IVLBCL is a rare and aggressive disease that is easy to be misdiagnosed or missed, because it's clinical presentations are non-specific. The correct diagnosis depends on pathology. IVLBCL is known for its rapid progression and poor prognosis, but timely diagnosis and treatment with chemotherapy can improve patients survival.

Study on clinical efficacy of zhennaoning capsules in treatment of cerebral arteriosclerosis and analysis on its economic benefits / 中国中药杂志

To study clinical efficacy of Zhennaoning capsules in treating cases with cerebral arteriosclerosis, and analyze its economic benefits. Totally 254 cases with cerebral arteriosclerosis were randomly divided into two groups according to their doctor-consulting sequence: the test group (n = 128) that was administered with Zhennaoning capsules, and the control group (n = 126) that was administered with Yangxueqingnao granules. A double-blind parallel-controlled study was conducted for four weeks, in order to observe the clinical efficacy and adverse effects of the two groups, and evaluate their pharmacoeconomics. Additionally, the clinical efficacy and safety of Zhennaoning capsules in treating cerebral arteriosclerosis, as well as its pharmacoeconomics were also discussed. This study showed that Zhennaoning capsules had a better efficacy than its control drug Yangxueqingnao granules in relieving traditional Chinese medicinal syndromes (according to traditional Chinese medicinal syndrome coring, efficacy and cure rate), suggesting a statistical significance (P < 0.01). Despite statistical significance showed from the differences in the remaining indexes and the occurrence rate of adverse effects, the test group displayed a lower cost effectives than the control group (P < 0.01). Zhennaoning capsules have a better clinical efficacy in treating cases with cerebral arteriosclerosis than Yangxueqingnao granules, demonstrating safe clinical application and better economic advantages.

Advance of studies on interaction between active components of natural medicines and lysozymes / 中国中药杂志

Lysozyme (LYSO), as an alkalescent protein micromolecule in living organisms, exhibits important pharmacological actions such as antibiosis, anti-inflammatory, antivirus and enhancing immunity. LYSO can combine with many exogenous and endogenous substances and carry many drugs. This essay summarizes interaction between different kinds of active components of natural medicines and lysozymes, which is significant to comprehensively understand pharmacological mechanism of natural drugs and their transfer and metabolic process in organisms, optimize molecule structures of drugs and increase bioavailability and biological effects of natural drugs.

NADPH oxidase inhibitor apocynin attenuates ischemia/reperfusion induced myocardial injury in rats / 中华心血管病杂志

<p><b>OBJECTIVE</b>To explore the role of NADPH oxidase inhibitor apocynin on ischemia/reperfusion (I/R)-induced myocardial injury.</p><p><b>METHODS</b>Male SD rat hearts were divided into the normal control group; sham group; I/R group (1 h ischemia followed by 3 h reperfusion); I/R + apocynin group (50 mg/kg, administrated at 30 min before reperfusion) and I/R + vehicle group (same volume vehicle administrated at 30 min before reperfusion). At the end of reperfusion, myocardial infarct size, apoptosis, plasma CK activity, myocardial NOX activity, myocardial caspase-3 expression and activity, myocardial mRNA and protein expressions of vascular peroxidase 1 (VPO1) and NOX2 were measured.</p><p><b>RESULTS</b>Infarct size, ratio of cardiomyocyte apoptosis, mRNA and protein expression of VOP1 and NOX2, serum CK, myocardial NOX and caspase-3 activities in the I/R group were all significantly increased compared to those in the sham group (P < 0.01). Above parameters were similar between I/R + vehicle group and I/R group (all P > 0.05). Infarct size, ratio of cardiomyocyte apoptosis, myocardial mRNA and protein expression of VOP1 and NOX2, serum CK, myocardial NOX and caspase-3 activities were significantly lower in I/R + apocynin group compared to those in I/R group (all P < 0.01).</p><p><b>CONCLUSIONS</b>NOX/VPO pathway plays an important role in mediating I/R-induced myocardial oxidative injury. NOX inhibition could reduce I/R-induced myocardial oxidative injury by attenuating myocardial apoptosis in this model.</p>

Clinical study of total glucosides of paeony in patients with systemic lupus erythematosus / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the therapeutic efficacy and adverse reaction of total glucosides of paeony (TGP, extracted from Paeonia lactiflora Pall.) in patients with systemic lupus erythematosus (SLE).</p><p><b>METHODS</b>Clinical data of patients with SLE were analyzed. Those who orally took TGP continuously for five years or more were taken as TGP1 group (29 cases). Those who orally took TGP continuously or intermittently for more than one year but less than five years were taken as TGP2 group (47 cases). Twenty patients matched with the TGP1 group and the TGP2 group in age, affected duration, urine protein, and SLE disease activity index (SLEDAI) were selected as the control group. The average daily dose of prednisone, total cyclophosphamide (CTX) dose, urine protein, SLEDAI score, recurrent case, and episodes of infection were compared among the three groups after five-year treatment.</p><p><b>RESULTS</b>The average daily dose of prednisone, total CTX dose, and SLEDAI score were obviously lower in the TGP1 group than in the control group (P<0.01). The average daily dose of prednisone, total CTX dose, and SLEDAI score were obviously lower in the TGP1 group than in the TGP2 group, Significant difference was shown (P <0. 05). The average daily dose of prednisone and total CTX dose were lower in the TGP2 group than in the control group (P<0.05, P<0.01). There was no statistical difference in the urine protein among the three groups. As for the recurrence, one case occurred in the TGP1 group, nine in the TGP2 group, and seven in the control group. As for episodes of infection, there were three cases in the TGP1 group, seventeen in the TGP2 group, and eighteen in the control group during the five years. No adverse reaction correlated to TGP was found in the three groups.</p><p><b>CONCLUSIONS</b>TGP had definite therapeutic efficacy in treatment of patients with SLE. It could reduce the average daily dose of prednisone and the total CTX dose, lower the recurrent cases and episodes of infection, especially for the medication of more than five years.</p>

Empirical study in the relation of gastric mucosal lesion with gastric emptying and gastric acid secretion / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To study the precise cause and the specific procedure about gastric mucosal lesion in rats with water immersion-restraint stress(WRS).</p><p><b>METHODS</b>One hundred and forty-four Wistar rats were divided into 9 groups randomly: A, B, C, D, E, F, G, H and I group. There were 16 rats in each group. A, B and C groups underwent gastric emptying determination. Emptying rate of gastric fluid was determined with radiate nuclide (99m)Tc. D, E and F groups underwent gastric acid secretion determination after cleaning gastric contents and pylorus ligation. G, H and I groups underwent gastric acid secretion determination after pylorus ligation without cleaning gastric contents. Gastric mucosal lesion ulcer index(UI) was evaluated. The relationship between of gastric mucosal lesion and gastric emptying rate and gastric acid secretion were examined.</p><p><b>RESULTS</b>Gastric emptying rate decreased obviously when the WRS time was prolonged. There were significant differences among B (WRS 2 h), C group (WRS 4 h) and A group (controlled group) (P<0.01). There was also significant difference between B and C group (P<0.01).The rats' gastric acid secretion was inhibited significantly. The differences among E (WRS 2 h), F (WRS 4 h) and D groups (controlled group) were significant (P<0.01). There was no significant difference between F and E groups (P>0.05). The gastric mucosal lesions were aggravated with time of stress. Gastric contents cleaning could effectively prevent gastric mucosal lesions originated by stress .The operation had no influence on this test. There were significant gastric mucosal lesion UI in B and C groups compared with A group (P<0.01). The difference between B and C group was significant (P<0.01).There were no gastric mucosal lesions in A, D, E, F and G groups. However, There was significant difference between I and F group (P<0.01). No significant difference were found among A, D, E, F and G groups (P>0.05). There were significant difference between H and B group and also between I and C group (P<0.01).</p><p><b>CONCLUSIONS</b>WRS can induce gastric emptying disturbance, reduce gastric acid secretion and cause gastric mucosal lesion. As a factor inducing gastric mucosal lesion, acid can damage gastric mucosa as long as it exists without necessary peracid. The prolongation of acid with gastric mucosa contact period and the decrease of gastric mucosa resistance are perhaps the major causes of gastric mucosal lesion. Besides anti-acid, giving facilitative gastric emptying drugs and gastric lavage during stress ulcer prevention and cure should be considered. Acid evacuation in time is also a major cure for gastritis and recurrent ulcer.</p>

Clinical observation of Shuxuetong Injection in treating patients with active rheumatoid arthritis / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the efficacy and adverse reaction of Shuxuetong Injection (SXTI, the extracted liquor from Pheretima and Hirudo) in treating patients with active rheumatoid arthritis (RA).</p><p><b>METHODS</b>Ninety-seven patients with active RA assigned in the SXTI group were treated with high or low dose SXTI (6 mL/d or 8 mL/d) combined with conventional therapy and the 30 in the control group treated with conventional therapy alone. Thompson index, Ritchie index, time of morning stiffness (TMS), erythrocyte sedimentation rate (ESR) and plasma fibrinogen (Fib) in patients were determined before treatment (T0), by the end of the 1st (T1), second (T2) and 4th (T3) week of treatment, respectively, as well as the SXTI associated adverse reaction monitored.</p><p><b>RESULTS</b>Marked improvement of all indexes, including Thompson index, Ritche index, TMS, ESR and Fib, was shown in the SXTI groups at T1 (P < 0.01), but in the control group, it only appeared at T3 (P < 0.01). Compared with the control group, TMS, ESR and Fib at T1, Thompson index and Ritche index at T2 in the SXTI groups were significantly improved (P < 0.01), especially significant in the high dose group (P < 0.01). However, hands edema appeared in 2 patients, foot edema in 1 and fullness sensation of head in 1 in the high dose SXTI group. The dose was forced to redue to 6 mL/d, and then all the symptoms were improved.</p><p><b>CONCLUSION</b>SXTI shows good efficacy with less adverse reaction in treating patients with active RA, and better efficacy was obtained at the dose of 8 mL/d.</p>

Clinical observation on effect of total glucosides of paeony in treating patients with non-systemic involved Sjögren syndrome / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To investigate the efficacy and adverse reaction of total glucosides of paeony (TGP) in treating patients with non-systemic involved Sjögren syndrom (NSI-SS).</p><p><b>METHODS</b>Retrospective study was conducted on 27 patients with NSI-SS who received TGP treatment for over two years as the TGP group, and 20 patients received hydroxychloroquine sulfate (HCQs) for over two years in the HCQs group for positive control. Salivary flow, Schirmer's test and serum gamma-globulin at different time points, i.e. before treatment, and at the end of 1st, 3rd, 6th, 12th and 24th month respectively, were compared between groups, and adverse reactions associated with TGP and HCQ were also observed.</p><p><b>RESULTS</b>In the TGP group, saliva secretion was significantly increased and serum gamma-globulin decreased significantly from the 6th month (P <0.01), Schirmer's test improved significantly after 12 months (P< 0.01). While in the HCQs group serum gamma-globulin was significantly decreased from the 3rd month (P <0.01), saliva secretion and Schirmer's test improved significantly after six months (P<0.01). However, the 3 indexes determined at the end of the 3rd month were insignificantly different from those before treatment. Mild diarrhea occurred in 4 cases in the TGP group, they were improved two weeks later, but one case with severe diarrhea was dropped. While in the HCQs group, 2 patients were dropped, one for the raising of alanine aminotransferase at the 6th month and the other for decreased vision at the 9th month.</p><p><b>CONCLUSION</b>Efficacy of TGP is equivalent to that of HCQs in treating NSI-SS, but with higher safety and the effect initiating time being about 6 - 12 months.</p>

Cloning, expression, purification of protein kinase Cdelta and its preliminary application in drug lead compounds screening / 生物工程学报

Protein kinase Cdelta (PKCdelta) is a member of protein kinase C family, which possess phospholipid-dependent serine and threonine kinase activity. PKCdelta is a potential drug target of diabetes and some cancers. The abnormal activation of PKCdelta can arouse diabetes and some cancers. Therefore the specific inhibitors of PKCdelta can be applied in the research and development of the drug candidate of these diseases. The present aim is to obtain active recombinant PKCdelta from COS1 cells. For cloning of mouse PKCdelta a pair of specific primers were designed based on the published sequence of this gene. The cDNA of full coding region was obtained by RT-PCR. The amplified cDNA was subsequently cloned into FLAG-tagged pcDNA3.0 and its sequence was confirmed by DNA sequencing analysis. FLAG-tagged pcDNA3.0-PKCdelta was transfected into COS1 cells. A cell strain which can stably express PKCdelta was obtained by G418 screening. FLAG-tagged PKCdelta in the supernant of COS1 cells extracts was absorbed by anti-FLAG resin and eluted by FLAG peptide. The purified protein appeared as a single band on both SDS-PAGE and western blotting, indicating that it was chemical and antigenic pure. By kinase assay, the recombinant PKCdelta was active. Positive inhibitor, staurosporine, was used to prove the enzyme could be greatly inhibited. Several compounds have been found to inhibit the enzyme, which indicates the preliminary application in drug lead compounds screening.

Development and application of ultrasound technology for hyperthermia / 中国医疗器械杂志

It has been a long time since ultrasound hyperthermia began to be used in the clinical management of cancers and benign diseases. Numerous biological and clinical investigations have demonstrated that: hyperthermia in the range of 41-45 degrees C can significantly enhance clinical response to radiation therapy and chemotherapy, and high-temperature hyperthermia (greater than 65 degrees C) alone is now being used as an alternative to conventional invasive surgery for selective tissue destruction, causing tumor coagulation and necrosis. As a promising noninvasive and effective local therapy, HIFU has attracted great attention. China is advanced in the clinical applications of HIFU. This article gives an introduction of the development and applications of ultrasound hyperthermia technology, and also provides a general review of a selection of ultrasound hyperthermia systems both in clinical use and under development.

The computer aided-therapy system of tumor thermal-treatment instrument using HIFU technology / 中国医疗器械杂志

Tumor thermal-treatment instrument is a newly developed medical instrument using HIFU technology. On the basis of a brief introduction of the system structure, this paper emphasizes the computer aided-therapy system applying a lot of computer technologies such as digital signal processing, digital signal communication computer aided design, artificial intelligence and database management system. Finally a concise therapy process using computer aided-therapy system is also introduced.