1.Effects of doxorubicin on IL-2 release and LAK activity of human fetal thymocytes
Tihui FU ; Zhirong XIE ; Bifang DENG
Chinese Pharmacological Bulletin 1987;0(02):-
The immunoregulatory effects of some anti-cancer drugs have important role in their anti-tumor mechanisms. Our results showed that doxorubicin (DXR) of 0.04 mg ?L-1 could enhance the interleukin 2 (IL-2) release and induction of lymphokine-activated killer (LAK) activity of human fetal thymocytes(HFT). Higher concentration of this drug (4 mg ?L-1) exhibited inhibition on IL-2 release but no effect on LAK activity. These data suggest that lower concentration of DXR have some immunopotentiation effects on HFT.
2.Treatment of stage Ⅲ-Ⅳa nasopharyngeal carcinoma with late course accelerated hyperfractionation radiotherapy
Jianquan GAO ; Jinxian ZHU ; Zhanghua LEI ; Zhirong DONG ; Bin DENG
Cancer Research and Clinic 2001;0(02):-
0.05). There was no significant difference in radiation reaction and squeal between two groups. Conclusions The clinical results of LCAH radiotherapy may be improve the three year of local control rate than conventional CF in stage Ⅲ~Ⅳa but do not improve the survival rate of three years.The radiation reaction and sequela was similar,is worth further study.
3.Safety, pharmacokinetic and pharmacodynamic studies of batifiban injection following single- and multiple-dose administration to healthy Chinese subjects.
Hui, CHEN ; Jian, QIAO ; Qian, LI ; Jungang, DENG ; Zhirong, TAN ; Tao, GUO ; Weiyong, LI
Journal of Huazhong University of Science and Technology (Medical Sciences) 2009;29(1):12-8
Batifiban, a synthetic cyclic peptide, is a potent platelet glycoprotein GPIIb/IIIa antagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic (inhibition of platelet aggregation) effects, and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55, 110, or 220 microg/kg, or multiple doses of an bolus followed intravenous infusion for 24 h (180 microg/kg plus 2.0 microg/min.kg, and 220 microg/kg plus 2.5 microg/min.kg) in this phase I clinical trial. Plasma levels of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma levels of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner, consistent with its mechanism as a GPIIb/IIIa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.
Injections, Intravenous
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Peptides, Cyclic/*pharmacokinetics
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Peptides, Cyclic/*pharmacology
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Platelet Aggregation Inhibitors/adverse effects
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Platelet Aggregation Inhibitors/*pharmacokinetics
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Platelet Aggregation Inhibitors/*pharmacology
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Platelet Glycoprotein GPIIb-IIIa Complex/*antagonists & inhibitors
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Young Adult
4.Neuronal intranuclear inclusion disease: the clinical features and pathological findings of peripheral tissue biopsy in nine cases with genetic diagnosis
Muliang GU ; Jianwen DENG ; Jiaxi YU ; Jing BAI ; Fan LI ; Wei SUN ; Hong ZHOU ; Qun HU ; Zhirong WAN ; Yining HUANG ; Yun YUAN ; Zhaoxia WANG
Chinese Journal of Neurology 2021;54(3):219-227
Objective:To summarize the clinical features and pathological changes of peripheral tissues from patients with neuronal intranuclear inclusion disease (NIID) diagnosed by genetic tests.Methods:Repeat-primed polymerase chain reaction was used to confirm the GGC repeated expansion in the 5′ untranslated region of the NOTCH2NLC gene in patients with suspected NIID who had visited the Department of Neurology of Peking University First Hospital from January 2018 to February 2020. The clinical data and pathological changes of peripheral tissues from patients with genetically diagnosed NIID were collected retrospectively and analysed. Immunostaining with anti-p62 and anti-ubiquitin antibody was performed on peripheral biopsy specimens.Results:Totally nine patients with NIID who had GGC repeated expansion in the NOTCH2NLC gene were found. Five patients were familial (from three faimilies), and four patients were sporadic. The age of onset was 36-61(51.33±7.12) years. The most common symptoms in this NIID group were episodic emotion and personality change (8/9), paroxysmal disturbance of consciousness (6/9) and intermitant head discomfort (6/9). Other symptoms included cognitive dysfunction, limb weakness, limb sensory disturbance, bladder dysfunction, ataxia, seizures and psychiatric symptoms. Brain magnetic resonance imaging showed high signals along the corticomedullary junction on diffusion-weighted image in eight out of nine patients. Skin biopsied samples from nine patients demonstrated the presence of eosinophilic intranuclear inclusions (IIs), appearing in the nucleus of fibroblasts, fat cells and ductal epithelial cells of sweat glands on hematoxylin-eosin staining. IIs were positive on anti-p62 and anti-ubiquitin immunostaining. Electron microscopy indicated the IIs were composed of a pile of filament materials without membrane. Muscle biopsies from two patients showed no obvious neurogenic or myogenic pathologic changes, except in one patient several rimmed vacuoles fibers were found. In one patient sural nerve biopsy showed severe demyelinating pathological changes. No IIs were found in the muscles and peripheral nerve tissue either by histological examination or by immunohistochemical staining with anti-p62 or anti-ubiquitin, while IIs were found by immunofluorescence staining with both anti-p62 and anti-ubiquitin in three patient′s tissue. Conclusions:The phenotype of this NIID patient group is adult-onset NIID, with episodic encephalopathy as the main clinical manifestation. Skin biopsy has high pathological diagnostic value for NIID. The immunofluorescence staining with anti-p62 and anti-ubiquitin is easier to detect the presence of IIs than histological staining and immumohistochemical staining.
5.Safety, Pharmacokinetic and Pharmacodynamic Studies of Batifiban Injection Following Single- and Multiple-Dose Administration to Healthy Chinese Subjects
CHEN HUI ; QIAO JIAN ; LI QIAN ; DENG JUNGANG ; TAN ZHIRONG ; GUO TAO ; LI WEIYONG
Journal of Huazhong University of Science and Technology (Medical Sciences) 2009;29(1):12-18
Batifiban,a synthetic cyclic peptide,is a potent platelet glycoprotein GPⅡb/Ⅲa an-tagonist which may be useful in the treatment and prevention of acute coronary syndromes. The pharmacokinetics and pharmacodymanic (inhibition of platelet aggregation) effects,and tolerability of batifiban were investigated in healthy subjects following single bolus injection with doses of 55,110,or 220 μg/kg,or multiple doses of an bolus followed intravenous infusion for 24 h (180 μg/kg of batifiban and areas under the curve were found to be proportional to doses. Batifiban was rapidly eliminated with a half-life of approximately 2.5 h. Significant differences were noted for plasma lev-els of batifiban and areas under the curve between males and females. No significant differences in the terminal half-life were found between males and females. Batifiban reversibly inhibited ex vivo platelet aggregation in a dose- and concentration-dependent manner,consistent with its mechanism as a GP Ⅱb/Ⅲa antagonist. Single and multiple intravenous doses of batifiban were found to be safe and well tolerated in healthy subjects. These results support a bolus injection plus intravenous infusion regimen of batifiban for the treatment and prevention of acute coronary syndromes.
6.Genetic analysis in 331 cases of neonatal hyperbilirubinemia with unknown etiology
Ribao LI ; Xia GU ; Guohao WU ; Zhirong DENG ; Jianquan KANG ; Zao LIANG ; Taohan MIAO ; Liuhong QU ; Zhonghe WAN ; Yongxue LU ; Jinyou DENG ; Dongjun LIU ; Wangkai LIU ; Weiben HUANG ; Xin XIAO ; Hu HAO ; Sitao LI
Chinese Journal of Neonatology 2022;37(6):520-524
Objective:To study the genetic profile of neonatal hyperbilirubinemia with unknown etiology in Guangdong Province and the clinical significance of jaundice-related genetic screening.Methods:From July to September, 2021, neonates with hyperbilirubinemia of unknown etiology born in different hospitals in Guangdong Province were studied. 24 neonatal jaundice-related exons were sequenced using targeted capture and high-throughput sequencing technology. The pathogenic variants were analyzed.Results:A total of 331 cases, 139 (42.0%) cases showed positive screening results with five diseases, including 65 (19.6%) cases of Gilbert syndrome, 48 (14.5%) cases of glucose-6-phosphate dehydrogenase (G6PD) deficiency,18 (5.4%) cases of sodium taurocholate cotransporting polypeptide deficiency, 4 (1.2%) cases of Citrin deficiency and 4 (1.2%) cases of Dubin-Johnson syndrome. 149 (45.0%) cases carried one or more genetic variants and 43 (13.0%) cases showed no clinically significant variants. The 8 high-frequency mutation loci (carrier rate >1%) are UGT1A1 gene c.211G>A and c.1091C>T, G6PD gene c.1466G>T and c.1478G>A, SLC10A1 gene c.800C>T, SLC25A13 gene c.852_855del TATG, HBB gene c.126_129delCTTT and c.316-197C>T.Conclusions:Genetic factors are important for neonatal hyperbilirubinemia with unknown etiology in Guangdong. The common pathogenic genes are UGT1A1, G6PD, SLC10A1, and SLC25A13 and the population carries high-frequency mutation loci. Therefore, genetic screening in neonates with hyperbilirubinemia of unknown etiology has important clinical significance.
7.Comprehensive evaluation of salt-alkali tolerance of rice germplasms at germination and seedling stages and analysis of salt-tolerant genes.
Pingyong SUN ; Wuhan ZHANG ; Fu SHU ; Qiang HE ; Li ZHANG ; Zhuhong YANG ; Zhirong PENG ; Yun XIE ; Huafeng DENG
Chinese Journal of Biotechnology 2022;38(1):252-263
Cultivating salt-alkali tolerant rice varieties is one of the important ways to meet the increasing food demand of growing global population. In this study, twenty-one rice germplasms with different salt-alkali tolerance were treated with six salt-alkali concentrations at germination and seedling stages. The germination potential, germination rate, shoot length, root length, root number, fresh weight of shoot and seedlings were measured. The average value of salt damage rate was used to evaluate the salt-alkali tolerance. As the salt-alkali concentration increases, the inhibition on seed germination and growth became more obvious. Upon treatment with 1% NaCl plus 0.25% NaHCO3, the salt damage rate of germination rate has the largest variation, ranging from 0% to 89.80%. The salt damage rate of each trait shows a similar trend at all concentrations. Four germplasm resources with strong salt-alkali tolerance (Dajiugu, Nippobare, Mowanggu and 02428) and 7 sensitive germplasms were screened. The salt-tolerant gene sequence of 4 salt-alkali tolerant varieties and 3 sensitive germplasms were analyzed. OSHAL3 and OsRR22 were identical among the 7 germplasms, but SKC1 and DST showed clear variations between the salt-alkali tolerant and sensitive germplasms. Besides the salt-alkali tolerant germplasm resources, this study can also serve as a reference for mining of genes involved in salt-alkali tolerance and breeding of salt-alkali tolerant rice varieties.
Alkalies
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Germination
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Oryza/genetics*
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Plant Breeding
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Seedlings/genetics*
8.BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models.
Beibei JIANG ; Tong ZHANG ; Minjuan DENG ; Wei JIN ; Yuan HONG ; Xiaotong CHEN ; Xin CHEN ; Jing WANG ; Hongjia HOU ; Yajuan GAO ; Wenfeng GONG ; Xing WANG ; Haiying LI ; Xiaosui ZHOU ; Yingcai FENG ; Bo ZHANG ; Bin JIANG ; Xueping LU ; Lijie ZHANG ; Yang LI ; Weiwei SONG ; Hanzi SUN ; Zuobai WANG ; Xiaomin SONG ; Zhirong SHEN ; Xuesong LIU ; Kang LI ; Lai WANG ; Ye LIU
Frontiers of Medicine 2023;17(6):1170-1185
OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.
Mice
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Animals
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Receptors, Tumor Necrosis Factor/physiology*
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Receptors, OX40
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Membrane Glycoproteins
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Ligands
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Antibodies, Monoclonal/pharmacology*
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Antineoplastic Agents/pharmacology*
9.Fucoidan-functionalized activated platelet-hitchhiking micelles simultaneously track tumor cells and remodel the immunosuppressive microenvironment for efficient metastatic cancer treatment.
Rong GUO ; Miao DENG ; Xuan HE ; Mengmeng LI ; Jiaxin LI ; Penghui HE ; Houqin LIU ; Man LI ; Zhirong ZHANG ; Qin HE
Acta Pharmaceutica Sinica B 2022;12(1):467-482
Tumor metastasis is responsible for most mortality in cancer patients, and remains a challenge in clinical cancer treatment. Platelets can be recruited and activated by tumor cells, then adhere to circulating tumor cells (CTCs) and assist tumor cells extravasate in distant organs. Therefore, nanoparticles specially hitchhiking on activated platelets are considered to have excellent targeting ability for primary tumor, CTCs and metastasis in distant organs. However, the activated tumor-homing platelets will release transforming growth factor-β (TGF-β), which promotes tumor metastasis and forms immunosuppressive microenvironment. Therefore, a multitalent strategy is needed to balance the accurate tumor tracking and alleviate the immunosuppressive signals. In this study, a fucoidan-functionalized micelle (FD/DOX) was constructed, which could efficiently adhere to activated platelets through P-selectin. Compared with the micelle without P-selectin targeting effect, FD/DOX had increased distribution in both tumor tissue and metastasis niche, and exhibited excellent anti-tumor and anti-metastasis efficacy on 4T1 spontaneous metastasis model. In addition, due to the contribution of fucoidan, FD/DOX treatment was confirmed to inhibit the expression of TGF-β, thereby stimulating anti-tumor immune response and reversing the immunosuppressive microenvironment. The fucoidan-functionalized activated platelets-hitchhiking micelle was promising for the metastatic cancer treatment.