Objective The leptin receptor,encoded by the LEPR gene,is involved in tumorigenesis.A potential functional variant of LEPR,rs1137101(Gln223Arg),has been extensively investigated for its contribution to the risk of digestive system(DS)cancers,but results remain conflicting rather than conclusive.Here,we performed a case-control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk. Methods A total of 1,727 patients with cancer(gastric/liver/colorectal:460/480/787)and 800 healthy controls were recruited.Genotyping of rs1137101 was conducted using a polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP)assay and confirmed using Sanger sequencing.Twenty-four eligible studies were included in the meta-analysis. Results After Bonferroni correction,the case-control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population.The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS,gastric,and liver cancer in the Chinese population. Conclusion The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers(especially liver and gastric cancer)in the Chinese population.

Neuropathic pain(NP) has similar phenotypes but different sequential neuroinflammatory mechanisms in the pathological process. It is of great significance to inhibit the initiation of neuroinflammation, which has become a new direction of NP treatment and drug development in recent years. Mongolian drug Naru-3 is clinically effective in the treatment of trigeminal neuralgia, sciatica, and other NPs in a short time, but its pharmacodynamic characteristics and mechanism of analgesia are still unclear. In this study, a spinal nerve ligation(SNL) model simulating clinical peripheral nerve injury was established and the efficacy and mechanism of Naru-3 in the treatment of NPs was discussed by means of behavioral detection, side effect evaluation, network analysis, and experimental verification. Pharmacodynamic results showed that Naru-3 increased the basic pain sensitivity threshold(mechanical hyperalgesia and thermal radiation hyperalgesia) in the initiation of SNL in animals and relieved spontaneous pain, however, there was no significant effect on the basic pain sensitivity threshold and motor coordination function of normal animals under physiological and pathological conditions. Meanwhile, the results of primary screening of target tissues showed that Naru-3 inhibited the second phase of injury-induced nociceptive response of formalin test in mice and reduced the expression of inflammatory factors in the spinal cord. Network analysis discovered that Naru-3 had synergy in the treatment of NP, and its mechanism was associated with core targets such as matrix metalloproteinase-9(MMP9) and interleukin-1β(IL-1β). The experiment further took the dorsal root ganglion(DRG) and the stage of patho-logical spinal cord as the research objects, focusing on the core targets of inducing microglial neuroinflammation. By means of Western blot, immunofluorescence, agonists, antagonists, behavior, etc., the mechanism of Naru-3 in exerting NP analgesia may be related to the negative regulation of the MMP9/IL-1β signaling pathway-mediated microglia p38/IL-1β inflammatory loop in the activation phase. The relevant research enriches the biological connotation of Naru-3 in the treatment of NP and provides references for clinical rational drug use.
Rats ; Mice ; Animals ; Matrix Metalloproteinase 9/metabolism* ; Rats, Sprague-Dawley ; Neuroinflammatory Diseases ; Interleukin-1beta/metabolism* ; Spinal Cord/metabolism* ; Signal Transduction ; Hyperalgesia/metabolism* ; Neuralgia/metabolism*

Adult ; Atherosclerosis ; Cardiovascular Diseases ; China ; Habits ; Humans ; Lipids

Background::To date, there is no effective medicine to treat coronavirus disease 2019 (COVID-19), and the antiviral efficacy of arbidol in the treatment for COVID-19 remained equivocal and controversial. The purpose of this study was to evaluate the efficacy and safety of arbidol tablets in the treatment of COVID-19.Methods::This was a prospective, open-label, controlled and multicenter investigator-initiated trial involving adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were stratified 1:2 to either standard-of-care (SOC) or SOC plus arbidol tablets (oral administration of 200 mg per time, three times a day for 14 days). The primary endpoint was negative conversion of SARS-CoV-2 within the first week. The rates and 95% confidential intervals were calculated for each variable.Results::A total of 99 patients with laboratory-confirmed SARS-CoV-2 infection were enrolled; 66 were assigned to the SOC plus arbidol tablets group, and 33 to the SOC group. The negative conversion rate of SARS-CoV-2 within the first week in patients receiving arbidol tablets was significantly higher than that of the SOC group (70.3% [45/64] vs. 42.4% [14/33]; difference of conversion rate 27.9%; 95% confidence interval [CI], 7.7%-48.1%; P = 0.008). Compared to those in the SOC group, patients receiving arbidol tablets had a shorter duration of clinical recovery (median 7.0 days vs. 12.0 days; hazard ratio [HR]: 1.877, 95% CI: 1.151-3.060, P = 0.006), symptom of fever (median 3.0 days vs. 12.0 days; HR: 18.990, 95% CI: 5.350-67.410, P < 0.001), as well as hospitalization (median 12.5 days vs. 20.0 days; P < 0.001). Moreover, the addition of arbidol tablets to SOC led to more rapid normalization of declined blood lymphocytes (median 10.0 days vs. 14.5 days; P > 0.05). The most common adverse event in the arbidol tablets group was the elevation of transaminase (5/200, 2.5%), and no one withdrew from the study due to adverse events or disease progression. Conclusions::SOC plus arbidol tablets significantly increase the negative conversion rate of SARS-CoV-2 within the first week and accelerate the recovery of COVID-19 patients. During the treatment with arbidol tablets, we find no significant serious adverse events.Trial registration::Chinese Clinical Trial Registry, NCT04260594, www.clinicaltrials.gov/ct2/show/NCT04260594?term= NCT04260594&draw=2&rank=1

OBJECTIVE: To explore the effects and mechanisms of PKC412 inhibitor on proliferation and apoptosis of HL-60 cell line. METHODS: CCK-8 assay was used to detect the effect of PKC412 on the proliferation of HL-60 cells at different concentrations; Wright-Giemsa staining was used to estimated the effect of PKC412 on the apoptosis of HL-60 cells; the mRNA expression of BCL-2 and P53 genes was detected by qRT-PCR, the expression of BCL-2 and P53 proteins was detected by Western blot. HL-60 cells were injected into mouse caudal vein to construct acute myeloid leukemia model, PKC412 was administered to tail vein for 31.25 nmol/kg, normal saline was injected into the same site of the mice as control group, and the inhibitory effect of PKC412 on HL-60 cells in mice was observed. ELISA assay was used to detect the effect of PKC412 on the inflammatory factors of TNF-α and TGF-β in tumor mice. RESULTS: PKC412 could inhibit the proliferation of HL-60 cell, which was in a dose dependent manner(r=0.9973) (IC50 was 0.31 μmol/L), and induce apoptosis of HL-60 cells. After HL-60 cell was treated by PKC412 for 48 h the expression of BCL-2 gene was down regulated(0.417±0.044 vs 0.933±0.033, t=9.347, P<0.001), the expression of P53 gene was up regulated(1.533±0.145 vs 1.050±0.161, t=2.231, P>0.05) as compared with control group. And the expression of BCL-2 protein was decreased, while the expression of P53 protein was increased. PKC412 could inhibited the growth of HL-60 tumor cells in vivo, the survival rate of mice after administration was 50% and the weight was increased as compared with that in control group(18.02±0.403 g vs 16.44±0.562 g, t=2.272, P=0.0356). The secretion of TNF-α and TGF-β cytokine in serum and spleen cells in PKC412 group was significantly lower than that in control group (P<0.05). CONCLUSION PKC412 can induce apoptosis of HL-60 cells by inhibiting the expression level of BCL-2 gene, PKC412 administration in vivo can inhibit the growth of the tumors.
Animals ; Apoptosis ; Cell Proliferation ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute ; Mice ; Proto-Oncogene Proteins c-bcl-2 ; Staurosporine/analogs & derivatives*

Purpose: This study was performed to establish and validate a nomogram for predicting the overall survival in children with neuroblastoma. Methods: The latest clinical data of neuroblastoma in Surveillance, Epidemiology, and End Results (SEER) database was extracted from 2000 to 2016. The cases included were randomly divided into training and validation cohorts. The survival curves were drawn with a Kaplan-Meier estimator to investigate the influences of certain single factors on overall survival. Also, least absolute shrinkage and selection operator regression was applied to further select the prognostic variables for neuroblastoma. Additionally, receiver operating characteristic (ROC) curves and calibration curves were used to evaluate the accuracy of the nomogram. Results: In total, 1,262 patients were collected and 8 independent prognostic factors were achieved, including patients’ age, sex, race, tumor grade, radiotherapy, chemotherapy, tumor site, and tumor size. Then we constructed a nomogram by using the data of the training cohort with 886 cases. Subsequently, the nomogram was validated internally and externally with 886 and 376 cases, respectively. The internal validation revealed that the area under the curves (AUC) of ROC curves of 1-, 3-, and 5-year overall survival were 0.69, 0.78, and 0.81, respectively. Accordingly, the external validation also showed that the AUC of 1-, 3-, and 5-year overall survival were all ≥0.69. Both methods of validation demonstrated that the predictive calibration curves were consistent with standard curves. Conclusion The nomogram possess the potential to be a new tool in predicting the survival rate of neuroblastoma patients.

Objective:To investigate the effect of blue light combined with albumin treatment on heart, liver and nerve damage in neonatal jaundice.Methods:A total of 120 cases with neonatal jaundice in the Department of Pediatrics of Women's and Children's Hospital of Zhoushan from April 2017 to April 2018 were selected and divided into control group and observation group accorded to the random number method, with 60 cases in each group.The control group received blue light therapy.The observation group was given albumin treatment on the basis of the control group.The serum total bilirubin, bile acid, aspartate aminotransferase(AST), alanine aminotransferase(ALT), glutamyl transpeptidase(GGT), troponin(cTnT), creatine kinase isozyme(CK-MB), -hydroxybutyrate dehydrogenase(HBDH), myoglobin(MYO), S100B, neuron-specific enolase(NSE) and glial fibrillary acidic protein(GFAP) levels were determined.Results:Before treatment, there were no statistically significant differences in serum total bilirubin, bile acid, AST, ALT, GGT, cTnT, CK-MB, HBDH, MYO, S100B, NSE and GFAP levels between the two groups(all P>0.05). After treatment, the serum levels of total bilirubin[(142.67±13.02)μmol/L, (118.62±11.68)μmol/L], bile acid[(15.34±2.42)μmol/L, (7.83±2.07)μmol/L], AST[(32.17±6.34)U/L, (21.04±5.58)U/L], ALT[(25.83±4.16)U/L, (18.37±4.05)U/L], GGT[(55.24±6.37)U/L, (36.17±5.86)U/L], cTnT[(0.16±0.03)×10 -6μg/L, (0.09±0.02)×10 -6μg/L], CK-MB[(4.32±0.85)×10 -6U/L, (2.01±0.72)×10 -6U/L], HBDH[(213.04±43.61)U/L, (137.26±41.61)U/L], MYO[(22.15±3.64)×10 -6μg/L, (14.26±3.27)×10 -6μg/L], S100B[(1.41±0.28)×10 -9μg/L, (0.87±0.22)×10 -9μg/L], NSE[(15.29±2.12)×10 -9μg/L, (15.29±2.12)×10 -9μg/L] and GFAP[(19.34±0.96)×10 -9μg/L, (14.36±0.92)×10 -9μg/L] in the two groups were lower than those before treatment( t=5.214, 8.261; 7.216, 11.524; 4.027, 6.843; 3.248, 5.764; 7.129, 13.654; 6.524, 9.751; 6.854, 9.031; 4.026, 6.204; 4.521, 7.026; 4.276, 5.846; 4.812, 7.023; 7.062, 13.524, all P<0.05). The levels of serum total bilirubin, bile acid, AST, ALT, GGT, cTnT, CK-MB, HBDH, MYO, S100B, NSE and GFAP in the observation group were lower than those in the control group( t=10.651, 18.267, 10.208, 9.953, 17.066, 15.038, 16.063, 9.738, 12.490, 11.747, 17.157, 29.011, all P<0.05). Conclusion:Blue light combined with albumin treatment can alleviate heart, liver and nerve damage in neonatal jaundice.

Objective To characterize a species of the genus Tricula and parasitized trematodes in schistosomiasis-endemic areas of Yunnan Province using a molecular analysis, so as to understand their taxonomic positions. Methods Tricula spp. and Oncomelania snails were collected from Xiangyun County, Yunnan Province, and cercaria parasitizing snails were observed using crushing followed by microscopy. Cercaria parasitizing Tricula snails at various morphologies were sampled using a shedding method. Genomic DNA was extracted from snail soft tissues and cercariae, and the 16S rRNA, COI, 28S rDNA genes in snails and the ND1 and 28S rDNA genes in cercariae were amplified using a PCR assay and sequenced. The species of Tricula snails and their parasitized trematodes was characterized using sequence alignment and phylogenetic analysis. Results Among 382 Tricula snails detected, there were three types of trematode cercariae found, including the non-forked (20.94%, 80/382), double-forked (3.40%, 13/382) and swallow shapes (7.07%, 27/382). Sequence and phylogenetic analyses showed that the 16S rRNA, COI and 28S rDNA gene sequences of this species of Tricula had high homology to those in Delavaya dianchiensis, and were clustered in a branch. Sequencing analysis of the ND1 and 28S rDNA genes revealed that the non-forked cercariae belonged to the family Pleu- rogenidae, the swallow-shaped cercariae belonged to the family Opecoelidae, and the double-forked cercariae belonged to another species of the genus Schistosoma that was different from S. sinensium and S. ovuncatum. Conclusion The species and taxonomy of Triculla spp. and their parasitized trematodes are preliminarily determined in schistosomiasis-endemic areas of Yunnan Province; however, further studies are required to investigate the more definite taxonomy and pathogenicity.

The Lewis lung carcinoma (LLC) metastatic mouse model was used to investigate the effects of gefitinib and Sijunzi Tang (SJZ) on pre-metastatic niche. The experimental protocol was approved by the Ethics Committee which belongs to Cancer Hospital, Chinese Academy of Medical Sciences. To generate spontaneous lung metastatic models, 1×10⁶ luciferase-labeled LLC cells were injected subcutaneously in the shaved right flank of mice. One day after LLC inoculation, the mice were randomly divided into model (saline), gefitinib (50 mg·kg^-1) treatment, SJZ treatment (25.74 g·kg^-1), and co-treatment gefitinib with SJZ groups, with intragastrical administration. After 14 days of continuous administration, tumor size was detected by IVIS^® Spectrum system. The number of monocytes and neutrophils and the expression levels of chemokine receptors (CXCR1, CCR2) and carcinogenic gene (c-Kit), in peripheral blood, spleen and lung tissues of mice were determined by flow cytometry. The contents of interleukin-IL-1α (IL-1α) and interleukin-6 (IL-6) were detected by the enzyme linked immunosorbent assay (ELISA). After 21 days of treatment, tumors were surgically removed, weighed and the tumor volume was measured with vernier caliper and the antitumor effect of co-administration was evaluated. After 45 days of administration, the survival of mice was recorded. The results of flow cytometry showed that the percentage of neutrophils in gefitinib group, SJZ group, and co-treatment group was significantly decreased in the lung tissue compared to the model group (P<0.05 or P<0.01), but there was no significant difference between three treatment groups (P>0.05). In the mouse peripheral blood and lung tissue, compared with the model group, the expression levels of CXCR1, CCR2 and c-Kit on the surface of neutrophils and monocytes in SJZ group and co-treatment group decreased or decreased significantly (P<0.01 or P<0.05). However, there was a significant increase in the expression level of c-Kit on the surface of monocytes (P<0.05). In the mouse spleen tissue, the expression levels of CXCR1, CCR2 and c-Kit in the gefitinib group increased significantly (P<0.05), while decreased significantly in SJZ or co-treatment group (P<0.05). The results of ELISA showed that the content of IL-1α in SJZ group decreased significantly in the plasma of the mice compared with the model group (P<0.01) and the content of IL-6 in co-treatment group decreased significantly (P<0.05). Compared with the gefitinib group, the content of IL-1 in the co-treatment group decreased significantly (P<0.05). In the tumor tissues of mice, compared with the model group, the content of IL-1α in the co-treatment group decreased significantly (P<0.05). Furthermore, the content of IL-1α in co-administrated group and IL-6 in SJZ or co-treatment group decreased significantly compared with the gefitinib group (P<0.05). After 21 days of continuous administration, the tumor inhibition rates of gefitinib group, SJZ group and co-administrated group were 45.7%, 38.4%, and 84.8%, respectively. After 45 days of administration, the survival rate of the model group was 0%, whereas the gefitinib, SJZ or co-treatment group has a survival rate of 40%, 60%, or 60%, respectively. In summary, our study illustrated that Sijunzi Tang could improve the anti-tumor effect of gefitinib by regulating pre-metastatic niche.