[Progress on clinical trials of common gastrointestinal cancer drugs in China from 2012 to 2021].

Objective: Systematically summarize the research progress of clinical trials of gastric cancer oncology drugs and the overview of marketed drugs in China from 2012 to 2021, providing data and decision-making evidence for relevant departments. Methods: Based on the registration database of the drug clinical trial registration and information disclosure platform of Food and Drug Administration of China and the data query system of domestic and imported drugs, the information on gastric cancer drug clinical trials, investigational drugs and marketed drugs from January 1, 2012 to December 31, 2021 was analyzed, and the differences between Chinese and foreign enterprises in terms of trial scope, trial phase, treatment lines and drug type, effect and mechanism studies were compared. Results: A total of 114 drug clinical trials related to gastric tumor were registered in China from 2012 to 2021, accounting for 3.7% (114/3 041) of all anticancer drug clinical trials in the same period, the registration number showed a significant growth rate after 2016 and reached its peak with 32 trials in 2020. Among them, 85 (74.6%, 85/114) trials were initiated by Chinese pharmaceutical enterprise. Compared with foreign pharmaceutical enterprise, Chinese pharmaceutical enterprise had higher rates of phase I trials (35.3% vs 6.9%, P=0.001), but the rate of international multicenter trials (11.9% vs 67.9%, P<0.001) was relatively low. There were 76 different drugs involved in relevant clinical trials, of which 65 (85.5%) were targeted drugs. For targeted drugs, HER2 is the most common one (14 types), followed by PD-1 and multi-target VEGER. In the past ten years, 3 of 4 marketed drugs for gastric cancer treatment were domestic and included in the national medical insurance directory. Conclusions: From 2012 to 2021, China has made some progress in drug research and development for gastric carcinoma. However, compared with the serious disease burden, it is still insufficient. Targeted strengthening of research and development of investment in many aspects of gastric cancer drugs, such as new target discovery, matured target excavating, combination drug development and early line therapy promotion, is the key work in the future, especially for domestic companies.

Prognostic value of the pretreatment albumin:globulin ratio combined with adult comorbidity evaluation 27 and TMN staging in patients with squamous cell carcinoma of the maxillary sinus.

The albumin:globulin (A:G) ratio, adult comorbidity evaluation 27 (ACE-27), and TMN staging have been shown to be strong predictive indicators of the survival of patients with many types of tumours. We have investigated the prognostic value of pretreatment based on the A:G ratio combined with TMN staging and ACE-27 in patients with squamous cell carcinoma (SCC) of the maxillary sinus. We studied 196 patients, and the prognostic value was explored by univariate and multivariate Cox's hazards analysis. Multivariate analyses suggested that pretreatment A:G ratio was independently associated with overall survival (hazard ratio (HR) 1.542, 95% CI 1.219 to 1.991, p=0.002); disease-specific survival, (HR 1.499, 95% CI 1.197 to 1.842, p=0.001); and disease-free survival (HR 1.452, 95% CI 1.207 to 1.834, p<0.001). Additional prognostic factors shown in the survival analyses included ACE-27, pathological T stage, and pathological N stage. Pretreatment A:G ratio combined with ACE-27 and TMN staging were powerful prognostic indicators of outcome in patients with SCC of the maxillary sinus, which has potentially important ramifications for stratification of the disease in the future.

[A case of craniopharyngioma presenting as cavernous sinus space occupying].

SummaryA 37-year-old female patient has the symptoms of recurrent headache for 2 years and worse for 1 month. The skull CT and MRI show a space-occupying lesion in the right of the cavernous sinus region. The patient underwent the resection of the tumor by the nasal endoscopy. The pathological biopsy showed the craniopharyngioma. This paper reports a case of craniopharyngioma in the cavernous sinus region and reviews the literature in order to increase the understanding of the disease and reduce misdiagnosis and missed diagnosis.

[Expression and role of IL-18 in chronic rhinosinusitis].

Objective:To study the expression and role of interleukin-18 (IL-18) in different clinical phenotypes of chronic rhinosinusitis(CRS)and in different subtypes of CRS with nasal polyps (CRSwNP).Method:During nasal endoscopic surgery, inferior turbinates were obtained from 13 patients with nasal septum deviation (control group),uncinate processes were obtained from 10 patients with chronic rhinosinusitis without nasal polyps (CRSsNP) and nasal polyp tissues were obtained from 36 patients with CRSwNP, respectively. IL-5 expression in CRSwNP was detected by ELISA, and the expression of IL-18 mRNA and protein in different subtypes of CRS were assessed by real-time PCR, ELISA and immunohistochemistr.Result:CRSwNP was divided into 12 cases of IL-5 positive nasal polyps (IL-5+NP)group and 24 cases of IL-5 negative nasal polyps (IL-5-NP)group. The expression of IL-18 mRNA and protein in all CRSsNP,IL-5+NP and IL-5-NP groups were higher than that in control group (P<0.01 or P<0.05),but no significant difference existed between IL-5+NP and IL-5-NP (P>0.05) group. IL-18 also expresses in epithelial cells of normal nasal mucosa.Conclusion:CRSwNP can be divided into two main subtypes: IL-5+NP and IL-5-NP. The increasing expression of IL-18 in CRSsNP, IL-5+NP and IL-5-NP compared with control group indicates that IL-18 may play a key role in the pathogenesis of CRS, and IL-18 expression in nasal polyps is not affected by the type of inflammation. The possible presence of balance between IL-18 and IL-18 binding protein in normal nasal mucosa provides a new way for research and treatment of CRS.

[Effect of intratympanic injection of budesonide for otitis media with effusion in adolescents and adults].

Objective:To assess the longitudinal curative effect and improvement of subjective symptoms by using intratympanic injection of budesonide (BUD) for OME patients over 12 years old and adults.Method:One hundred and eighty patients who were diagnosed as OME were recruited. A single-blind, randomized, parallel-control prospective study was performed. Dexamethasone (DEX) and sodium chloride (NS) were served as controls. The patients were randomly assigned into three groups, which respectively received intratympanic injection of BUD (0.5 mg/ml), DEX (5 mg/ml) or 0.9% NS solution (1 ml) once a week. Survival analysis was applied to compare the longitudinal curative effect among the three groups. Meanwhile, seven main subjective symptoms were scored by 10-point visual scale (VAS) and physician's evaluations were preformed during treatment and follow-up.Result:After adjustement for course of disease, volume and characters of effusion, the relative risk (RR) of BUD was 0.131 (95%CI: 0.053-0.354) when compared with NS. Survival curve showed, in BUD group, about 96.6%(57/59) of patients maintained effectiveness more than 3 months, 83.1%(49/59) were more than 1 year, and 81.4%(48/59) of the patients could sustain longer than 3 years. In DEX group, 73.2%(41/56) of patients showed effectiveness more than 3 months, 46.4%(26/56) were more than 1 year, and 42.9%(24/56) of the patients could sustain longer than 3 years. While in NS group, 50.8%(33/65) of the patients showed effectiveness more than 3 months, 26.2% (17/65) were more than 1 year, and 20.0%(13/65) of the patients could sustain longer than 3 years. Survival curve demonstrated that the rank of longitudinal therapeutic efficacy was BUD, DEX and NS (P< 0.05). Both BUD and DEX showed improvements in subjective symptoms and quality of life (except for mental stress) compared with NS (P< 0.05). In the aspect of improving the symptom of stuffy ear, BUD showed advantage over both DEX and NS. During and after treatment, no serious complications or sequelae were observed.Conclusion:Intratympanic injection with BUD for OME patients showed advantages in improving long-term therapeutic efficacy, it was a safe as well as effective intervention for children over age of 12 and adults suffering from OME.

[The inflammatory pattern and the characteristics of mucous remodeling in different immune type of nasal polyps].

Objective:The aim of this study is to study the different immune-type of polyps and valuate mucosal inflammatory pattern and remodeling features between in IL-5 positive vs.IL-17 positive nasal polyps.Method:Nasal polyp or nasal turbinate tissue was obtained from 88 CRSwNP patients during endonasal sinus surgery or 18 non-atopic control subjects during septoplasty,respectively.Assessment of pro-inflammatory cytokines and mediators by ELISA.Additionally,the distribution of IL-5 positive or IL-17 positive cells and inflammatory cells(eosinophil,neutrophil,etc.) were examined using immunohistochemistry(IHC).Result:Overall more than half amount of polyp tissue did not express any TH cells key cytokine.However there are 21% polyp present IL-5 positive and 16% of IL-17 positive as well as 9% of IFN-γ positives.Amount of them that IL-17 positive polyps by synthesis of mediators promoting neutrophilic inflammation[myeloperoxidase(MPO),IL-1ß,IL-6 and IL-8)] and staining infiltration of MPO positive with IL-17 positive cells,whereas IL-5 positive nasal polyps were characterized by synthesis of mediators promoting eosinophilic inflammation(IL-5,ECP,TIgE,and SAE-IgE) and infiltrating of eosinophils and IL-5 positive cells.Meanwhile TGF-ß1 and MMP7 protein levels enhanced in IL-17 positive polyps and decreased in IL-5 positive than control.Conclusion:Nasal polyps presenting as different immune types and there were characterized with different inflammatory and remodeling patterns.Amount of them that IL-17 positive polyps presenting as a neutrophilic inflammation with remodeling biased.Whereas IL-5 positive nasal polyps were characterized by eosinophilic inflammation and absence of remodeling tendency.

MicroRNA-200 family members are weakly expressed in the neurosensory epithelia of the developing zebrafish (Danio rerio) inner ear.

MicroRNA-200 family members are expressed in the developing mouse inner ear and in zebrafish (Danio rerio) olfactory epithelia, taste buds, and neuromasts, and have also been shown to be associated with differentiation of olfactory and taste buds. However, the role of the miR-200 family in the inner ear of zebrafish had not been studied. We investigated the expression and function of the miR-200 family in the zebrafish inner ear via in situ hybridization and loss-of-function methods. Expression of the miR-200 family was weak and dispersed throughout the developing zebrafish inner ear. After knockdown of miR-200 family members in the developing inner ear, no significant differences in development were observed compared to the controls. Otic vesicles, otoliths, and semicircular canals appeared normal. Compared with less differentiated olfactory filaments in olfactory epithelia, the development of hair cells and statoacoustic ganglion neurons were normal. The kinocilia and stereocilia of hair cells, the innervation of hair cells, and the formation of ribbon synapses were also unaffected. Overall, we conclude that the miR-200 family has a negligible role in the development of zebrafish inner ear; the functions of the miR- 200 family may be organ-specific.

MicroRNA-23b promotes tolerogenic properties of dendritic cells in vitro through inhibiting Notch1/NF-κB signalling pathways.

BACKGROUND: MicroRNAs (miRNAs) are known to regulate the inflammatory response in various cell types. However, the ability of miRNAs to modulate dendritic cells (DCs) function for allergen immunotherapy is unclear. OBJECTIVE: To assess the role of miR-23b in the regulation of ovalbumin (OVA)-induced DC differentiation and function and to investigate the related molecular mechanisms. METHODS: Bone marrow-derived dendritic cells (BMDCs) were generated from murine bone marrow progenitor cells and subsequently stimulated with OVA to examine the profile of miRNA expression. After transfection with miR-23b reagents, DCs were evaluated for endocytic ability, surface marker expression, cytokine secretion and CD4+ T-cell differentiation. The possible roles of the Notch and NF-κB signalling pathways were also evaluated. Human monocyte-derived dendritic cells (MDDCs) were similarly evaluated as well. RESULTS: Significant upregulation of miR-23b was observed in BMDCs pulsed with OVA. Following miR-23b transfection, BMDCs showed decreased OVA uptake, increased IL-10 production, decreased IL-12 production and an enhanced capacity to promote FoxP3+ CD4+ T regulatory cells (Tregs) differentiation. In addition, inactivation of the Notch1 and NF-κB signalling pathways were observed. Conversely, inhibition of miR-23b in BMDCs resulted in the opposite effects. In human MDDCs, miRNA23b transfection similarly increased IL-10 and decreased IL-12 production, and that treated human MDDCs induced increased FoxP3+ CD4+ T cells. CONCLUSION: Our findings provide evidence that miR-23b is capable of inducing tolerogenic DC activity and Treg responses in vitro through the inhibition of the Notch1 and NF-κB signalling pathways; thus, miR-23b might represent a therapeutic target for the management of allergic diseases.

Concise preparation of N(alpha)-Fmoc-N(epsilon)-(Boc, methyl)-lysine and its application in the synthesis of site-specifically lysine monomethylated peptide.

A concise preparation of N(alpha)-Fmoc-N(epsilon)-(Boc, methyl)-lysine and its application in the synthesis of site-specifically lysine monomethylated peptide is described. N (alpha)-Fmoc-N(epsilon)-(Boc, methyl)-lysine is obtained, via consecutive reductive benzylation and reductive methylation in a one-pot reaction, followed by debenzylation through catalytic hydrogenolysis and Boc protection in another one-pot reaction. A peptide containing monomethylated lysine is successfully synthesized by incorporating N(alpha)-Fmoc-N(epsilon)-(Boc, methyl)-lysine as a building block via solid-phase peptide synthesis.

Sex differences in arachidonate cyclo-oxygenase products in elicited rat peritoneal macrophages.

Peritoneal macrophages were elicited by Freund's incomplete adjuvant from adult male and female Fisher 344 rats. The release of prostaglandin E2 and thromboxane B2 from these macrophages was determined by radioimmunoassay. The basal release of these products was the same for males and females. The macrophages of the female rats released, in a dose-dependent manner, significantly more prostaglandin E2 and thromboxane B2 than macrophages from the male, following challenge with either a particulate stimulus, zymosan (25-150 micrograms/ml) or a soluble stimulus, calcium ionophore A23187 (1 X 10(-7) -1 X 10(-6) M). These results may relate to gender differences in immune responses.

Human peritoneal macrophages synthesize leukotrienes B4 and C4.

Macrophages were isolated from the dialysis fluid of patients undergoing continuous ambulatory peritoneal dialysis and separated by gradient centrifugation and purification on 50% Percoll. The cells were prelabeled with [14C]arachidonic acid for 1.5 h. The labeled cells were then incubated with calcium ionophore A23187 (1 microM), serum-treated zymosan (200 micrograms/ml), and a lipoxygenase inhibitor, nordihydroguairetic acid (1 X 10(-5) M). The arachidonate metabolites in the medium were separated on Sep-Pak columns, and finally purified by reverse-phase high-pressure liquid chromatography (HPLC). The labeled products co-chromatographed with authentic leukotriene B4 and leukotriene C4 standards. Serum-treated zymosan and A23187 significantly stimulated and nordihydroguairetic acid significantly inhibited leukotriene synthesis. Leukotriene D4 was not detected, which suggests that these cells contain low gamma-glutamyltranspeptidase or high dipeptidase activity. These results establish, for the first time, that human peritoneal macrophages synthesize the lipoxygenase products, leukotriene B4 and leukotriene C4.

Biochemical alterations in livers of rats exposed to vinyl chloride.

Sprague-Dawley rats were exposed to vinyl chloride to determine the earliest sequential biochemical changes occurring with liver injury before anglosarcoma development. Activity of glucose-6-phosphatase, a key gluconeogenic enzyme in the liver microsomal fraction, decreased 25% with respect to controls after 70 h of exposure. Glucose-6-phosphate dehydrogenase activity increased twofold after more than 100 h of exposure. Nonprotein sulfhydryl levels (glutathione and/or cysteine) showed a slight but progressive elevation, whereas glutathione reductase activity increased 50-60% during exposure to vinyl chloride.NADPH-cytochrome c reductase and mixed function oxidase were unchanged in the same microsomal fraction. There markers of liver mitochondrial, cytosol, and microsomal function. No significant histological changes were found on light microscopic examination during this exposure period. However, with electron microscopy, dilation of rough endoplasmic reticulum was seen in the animals exposed for more than 137 h. These enzymatic changes are considered to reflect early hepatocellular adaptation to vinyl chloride exposure with very mild or limited hepatocellular injury in its earliest stage.