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Background: Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ., Methods: Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors., Results: TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma., Conclusion: Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8 + T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients., (© 2024. The Author(s).)

Objective: To explore characteristics of tongue pressure changes in nasopharyngeal carcinoma (NPC) patients with dysphagia after radiotherapy using a novel system with multisite flexible sensors., Design: Prospective observational study., Setting: Inpatient rehabilitation centers and community dwellings., Participants: Nineteen patients with dysphagia after radiotherapy for NPC and 19 healthy participants were recruited for this study (N=38)., Intervention: Not applicable., Main Outcome Measures: A new 9-site (3 × 3) flexible tongue pressure sensor was used to measure tongue-to-palate pressure across different parts of the tongue. The oral tongue was divided into 3 parts: anterior tongue region (TAR), central tongue region (TCR), and posterior tongue region (TPR); 3 sensors were placed on each part. The mean tongue pressure and endurance time at the 3 sites in the TAR, TCR, and TPR were analyzed. The ratios of the mean TAR, TCR, and TPR values were calculated., Results: Pressures of TAR, TCR, and TPR in NPC patients with dysphagia were significantly lower than those in healthy participants (P<.05). The pressure in TPR decreased most significantly, followed by that in TCR. The endurance times of TAR and TCR were longer than those of healthy participants (P<.05). The endurance time of TPR was not significantly different between the patients and healthy participants (P>.05). Ratios of pressure between TAR and TCR and TAR and TPR in patients were lower than that in healthy participants (P<.05). There was no significant difference in the TCR to TPR pressure ratio between patients and healthy participants (P>.05)., Conclusions: Tongue pressure significantly decreased in NPC patients with dysphagia, and the drop in pressure was most pronounced in the TPR area. The results of our study indicate that we should pay attention to the pressure training of the TPR during treatments. The endurance time of the TAR and TCR increased significantly, which may be due to bolus transport compensation. Therefore, clinical rehabilitation strategies should aim to increase the endurance time training in NPC patients after radiotherapy to help increase the effectiveness of the swallowing process in patients., (Copyright © 2023 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is a highly lethal cancer characterized by dominant driver mutations, including p53. Consequently, there is an urgent need to search for novel therapeutic agents to treat HCC. Andrographolide (Andro), a clinically available anti-inflammatory phytochemical agent, has shown inhibitory effects against various types of cancer, including HCC. However, the underlying molecular mechanisms of its action remain poorly understood., Purpose: This study aims to investigate the molecular mechanisms by which p53 and p62 collectively affect Andro-induced HCC cell death, using both in vitro and in vivo models., Methods: In vitro cellular experiments were conducted to examine the effects of Andro on cell viability and elucidate its mechanisms of action. In vivo xenograft experiments further validated the anti-cancer effects of Andro., Results: Andro induced dose- and time-dependent HCC cell death while sparing normal HL-7702 hepatocytes. Furthermore, Andro caused DNA damage through the generation of reactive oxygen species (ROS), a critical event leading to cell death. Notably, HCC cells expressing p53 exhibited greater resistance to Andro-induced cell death compared to p53-deficient cells, likely due to the ability of p53 to induce G2/M cell cycle arrest. Additionally, Andro-induced p62 aggregation led to the proteasomal degradation of RAD51 and 53BP1, two key proteins involved in DNA damage repair. Consequently, silencing or knocking out p62 facilitated DNA damage repair and protected HCC cells. Importantly, disruption of either p53 or p62 did not affect the expression of the other protein. These findings were further supported by the observation that xenograft tumors formed by p62-knockout HCC cells displayed increased resistance to Andro treatment., Conclusion: This study elucidates the mechanistic basis of Andro-induced HCC cell death. It provides valuable insights for repurposing Andro for the treatment of HCC, regardless of the presence of functional p53., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Objective: To observe the effect of acupoint catgut embedding (CE) on Nod-like receptor protein 3 (NLRP3)/Caspase-1 signaling pathway in "deficiency-stasis" syndrome type ulcerative colitis (UC) rats, so as to explore its mechanisms underlying improvement of UC., Methods: A total of 58 male SD rats were randomly divided into control group (10 rats) and model group (48 rats). The "deficiency-stasis" type UC model was established by gavage of adenine and folium sennae solution for 4 weeks, followed by clycter of mixture solution of 5% trinitro-benzene-sulfonic acid and 50% ethanol. A total of 44 UC rats were randomized into model, salicylazosulfapyridine (SASP), non-acupoint CE, and acupoint CE groups (11 rats in each group). The catgut embedment was applied to bilateral "Zusanli"(ST36), "Shenshu"(BL23), "Pishu"(BL20), "Dachangshu"(BL25), "Geshu" (BL17) and "Tianshu"(ST25), or non-acupoints (the fat muscles of the buttocks), separately, once every two weeks, 3 times altogether. Rats of the SASP group received gavage of SASP solution, and those of the other groups received gavage of same amount of normal saline, once daily for 42 days. The rat's general conditions and the colon length were recorded, the disease activity index (DAI, 0 to 4 points) and colonic mucosal damage index (CMDI, 0 to 5 points) were calculated. Histopathological changes of the colonic mucosa tissue were observed after HE staining, and the tissue damage index (TDI, 0 to 6 points) was given. The levels of serum NLRP3, interleukin (IL)-1β and IL-18 were measured by ELISA, and the expression levels of NLRP3, Caspase-1, apoptosis-associated speck-like protein (ASC), IL-1β and IL-18 mRNAs were measured by fluorescence quantitative PCR. The expression levels of NLRP3 and Caspase-1 proteins in the colon tissues were measured by Western blot, and the immunoactivity of colonic ASC was detected by immunohistochemistry., Results: Compared with the control group, the rats' body mass and colonic length were significantly decreased ( P <0.01), and DAI score, CMDI score, TDI score, contents of serum NLRP3, IL-1β and IL-18, expression levels of colonic NLRP3, ASC, Caspase-1, IL-1β and IL-18 mRNAs, and NLRP3 and Caspase -1 proteins as well as colonic ASC immunoactivity were significantly up-regulated in the model group ( P <0.01). Compared with the model group, both SASP and acupoint CE groups had a significant increase in body mass and colonic length ( P <0.01), and a marked decrease in DAI score, CMDI score, TDI score, contents of serum NLRP3, IL-1β and IL-18, expression levels of NLRP3, ASC, Caspase-1, IL-1β and IL-18 mRNAs and NLRP3 and Caspase-1 proteins and ASC immunoactivity ( P <0.01). The above indexes were improved in the acupoint CE group in relevant to those of the non-acupoint CE group ( P <0.01). HE staining of colonic mucosal tissue showed obvious ulcerative surface, destroyed recess, disordered arrangement of glands, mucosal edema and congestion, infiltration of a large number of inflammatory cells in the model group, which was obviously milder in both SASP and acupoint CE groups., Conclusion: Acupoint embedding can alleviate colonic injury and inhibit inflammatory reaction in rats with "deficiency-stasis" type UC by down-regulating colonic NLRP3/Caspase-1 signaling.

To improve the water solubility of anti-human immunodeficiency virus (HIV) agent DB02, an excellent non-nucleoside reverse-transcriptase inhibitor (NNRTI) obtained in our previous efforts, we designed and synthesized four phosphate derivatives of DB02 based on the molecular model of DB02 with RT. Here, the antiviral activity of these four derivatives was detected, leading to the discovery of compound P-2, which possessed a superior potency to the lead compound DB02 against wild-type HIV-1 and a variety of HIV-resistant mutant viruses significantly. Furthermore, the water solubility of P-2 was nearly 17 times higher than that of DB02, and the pharmacokinetic test in rats showed that P-2 demonstrate significantly improved oral bioavailablity of 14.6%. Our study showed that the introduction of a phosphate ester group at the end of the C-2 side chain of DB02 was beneficial to the improvement of its antiviral activity and pharmacokinetic properties, which provided a promising lead for the further development of S-DACOs type of NNRTIs., (© 2023 Wiley Periodicals LLC.)

Objective: To evaluate the effect of intensive oropharyngeal functional training on swallowing in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma., Methods: Fourteen patients with nasopharyngeal carcinomas and dysphagia after radiotherapy received intensive oropharyngeal training for two weeks. The Functional Oral Intake Scale (FOIS) and videofluoroscopic swallowing studies (VFSS) were used to evaluate swallowing function before and after intensive oropharyngeal training. Spatiotemporal parameters of the VFSS were analyzed using a digital image analysis system., Results: After training, the FOIS, Rosenbek penetration-aspiration score, DIGEST, normalized residue ratio scale, and spatiotemporal parameters of VFSS were significantly improved (P < 0.05)., Conclusions: This study indicated that intensive oropharyngeal training improves swallowing function after radiotherapy in patients with nasopharyngeal carcinoma., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: More than half of post-stroke patients develop dysphagia, which manifests as delayed swallowing and is associated with a high risk of aspiration. In this study, we aimed to investigate the immediate effect of neuromuscular electrical stimulation (NMES) on swallowing initiation in post-stroke patients using videofluoroscopic swallowing study (VFSS) data., Materials and Methods: This randomized, self-controlled crossover study included 35 patients with post-stroke dysphagia. All selected patients received real and sham NMES while swallowing 5 ml of thin liquid. Participants completed the conditions in random order, with a 10-min interval between conditions. The primary evaluation indicators included the Modified Barium Swallow Impairment Profile-6 (MBSImp-6) and Penetration-Aspiration Scale (PAS). Secondary indicators included oral transit time (OTT), pharyngeal transit time (PTT), and laryngeal closure duration (LCD)., Results: Modified Barium Swallow Impairment Profile-6 ( P = 0.008) and PAS ( P < 0.001) scores were significantly lower in the Real-NMES condition than in the Sham-NMES condition. OTT ( P < 0.001) was also significantly shorter during Real-NMES than during Sham-NMES. However, LCD ( P = 0.225) and PTT ( P = 0.161) did not significantly differ between the two conditions., Conclusion: Neuromuscular electrical stimulation may represent a supplementary approach for promoting early feeding training in patients with post-stroke dysphagia., Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [ChiCTR2100052464]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Dou, Zhao, Xie, Shi, Yang, Wan, Wen, Chen and Tang.)

Zika virus (ZIKV), a mosquito-borne flavivirus, is a global health concern because of its association with severe neurological disorders such as neonatal microcephaly and adult Guillain-Barre syndrome. Although many efforts have been made to combat ZIKV infection, there is currently no approved vaccines or antiviral drugs available and there is an urgent need to develop effective anti-ZIKV agents. In this study, 26 acetylarylamine- S -DACOs derivatives were prepared, and eight of them were found to have inhibitory activity against Zika virus. Among these substances, 2-[(4-cyclohexyl-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio]-N-(3,5-difluorophenyl)acetamide ( 4w ) with the best anti-ZIKV activity was selected for in-depth study of antiviral activity and mechanism of action. Here, we discovered 4w targeted on the ZIKV NS5 RNA -dependent RNA polymerase (RdRp), which exhibited good in vitro antiviral activity without cell species specificity, both at the protein level and at the RNA level can significantly inhibit ZIKV replication. Preliminary molecular docking studies showed that 4w preferentially binds to the palm region of NS5A RdRp through hydrogen bonding with residues such as LYS468, PHE466, GLU465, and GLY467. ZIKV NS5 RdRp enzyme activity experiment showed that 4w could directly inhibit ZIKV RdRp activity with EC 50 = 11.38 ± 0.51 μM. In antiviral activity studies, 4w was found to inhibit ZIKV RNA replication with EC 50 = 6.87 ± 1.21 μM. ZIKV-induced plaque formation was inhibited with EC 50 = 7.65 ± 0.31 μM. In conclusion, our study disclosed that acetylarylamine- S -DACOs is a new active scaffolds against ZIKV, among which compound 4w was proved to be a potent novel anti-ZIKV compound target ZIKV RdRp protein. These promising results provide a future prospective for the development of ZIKV RdRp inhibitors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Xie, Xue, Wang, Yang, Zheng, Luo, Yang, Chen, Yang, Wang, Zhang, He and Zheng.)

Objective: To investigate the effects and mechanism of diammonium glycyrrhizinate (DG) on liver injury in severely scalded rats. Methods: The experimental research method was used. Fifty-four female Sprague-Dawley rats aged 7-9 weeks were divided into sham injury group with simulated injury on the back, and simple scald group and scald+DG group with scald of 30% total body surface area on the back, with 18 rats in each group. Rats in sham injury group were not specially treated after injury, and rats in simple scald group and scald+DG group were rehydrated for antishock. Besides, rats in scald+DG group were injected intraperitoneally with 50 mg/kg DG at post injury hour (PIH) 1, 25, and 49. Rats in the three groups were collected, the serum content of liver function injury related indexes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), total protein, and albumin was measured by automatic biochemical assay analyzer, and serum content of ornithine carbamoyl transferase (OCT) was measured by enzyme-linked immunosorbent assay method at PIH 24, 48, and 72; hepatic histopathological changes at PIH 72 were observed by hematoxylin-eosin staining; the mRNA expressions of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), glucose regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), and protein kinase R-like endoplasmic reticulum kinase (PERK) in liver tissue were detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction at PIH 24, 48, and 72. The protein expressions of Bcl-2, Bax, GRP78, PERK, and ATF4 in liver tissue were detected by Western blotting at PIH 72 in sham injury group and PIH 24, 48, and 72 in simple scald group and scald+DG group. The number of samples was 6 in each group at each time point. Data were statistically analyzed with analysis of variance for factorial design, one-way analysis of variance, and Bonferroni test. Results: Compared with that in sham injury group, the serum content of AST, ALT, and LDH was significantly increased ( P <0.01), and the serum content of total protein and albumin was significantly decreased ( P <0.05 or P <0.01) of rats in simple scald group at all post-injury time points. Compared with those in simple scald group, the serum AST content of rats in scald+DG group at PIH 24 was decreased significantly ( P <0.05); the serum AST, ALT, and LDH content of rats in scald+DG group at PIH 48 was decreased significantly ( P <0.01), and the serum total protein content was increased significantly ( P <0.01); the serum AST, ALT, and LDH content of rats in scald+DG group at PIH 72 was decreased significantly ( P <0.01), and the serum total protein and albumin content was increased significantly ( P <0.01). At PIH 24, 48, and 72, the serum OCT content of rats in simple scald group was (48.5±3.9), (40.8±2.4), and (38.7±2.0) U/L, which was significantly higher than (15.1±2.5), (15.7±2.6), and (16.4±3.7) U/L in sham injury group ( P <0.01), and (39.0±4.5), (31.8±2.0), and (22.1±2.6) U/L in scald+DG group ( P <0.05 or P <0.01). At PIH 72, the cells in liver tissue of rats in sham injury group had normal morphology and regular arrangement, with no obvious inflammatory cell infiltration; the cells in liver tissue of rats in simple scald group had disordered arrangement, diffuse steatosis, and moderate inflammatory cell infiltration; the cells in liver tissue of rats in scald+DG group arranged regularly, with scattered steatosis and a small amount of inflammatory cell infiltration. Compared with those in sham injury group, the Bcl-2 mRNA ( P <0.05 or P <0.01) and protein expressions of liver tissue were significantly decreased, and the mRNA ( P <0.01) and protein expressions of Bax were significantly increased in rats in simple scald group at PIH 24, 48, and 72. Compared with those in simple scald group, the mRNA ( P <0.05) and protein expressions of Bax in liver tissue of rats in scald+DG group were decreased significantly at PIH 48; the mRNA ( P <0.01) and protein expressions of Bax in liver tissue of rats in scald+DG group were significantly decreased, and the mRNA ( P <0.01) and protein expressions of Bcl-2 were significantly increased at PIH 72. Compared with those in sham injury group, the mRNA ( P <0.05 or P <0.01) and protein expressions of ATF4, GRP78, and PERK in liver tissue were significantly increased in rats in simple scald group at all post-injury time points. Compared with those in simple scald group, the mRNA ( P <0.01) and protein expressions of ATF4 in liver tissue of rats in scald+DG group at PIH 48 were significantly decreased, and the mRNA ( P <0.05 or P <0.01) and protein expressions of ATF4, GRP78, and PERK were significantly decreased in liver tissue of rats in scald+DG group at PIH 72. Conclusions: DG can effectively reduce the degree of liver injury in rats after severe scald, and the mechanism may involve alleviating endoplasmic reticulum stress and mitigating mitochondrial damage.

Objective: To investigate the effects and molecular mechanism of exogenous L-carnitine on hepatic pyroptosis mediated by excessive endoplasmic reticulum stress in severely scald rats. Methods: The experimental research method was adopted. According to the random number table (the same group method below), fifteen female Sprague Dawley rats aged 6-8 weeks were divided into sham-injury group, scald alone group, and scald+carnitine group (with 5 rats in each group), and full-thickness scald of 30% total body surface area were made on the back of rats in scald alone group and scald+carnitine group, and rats in scald+carnitine group were additionally given intraperitoneal injection of L-carnitine. At post injury hour (PIH) 72, The levels of aspartate aminotransferase (AST) and alanine dehydrogenase (ALT) of biochemical indicators of liver injury were detected by automatic biochemical analyzer with the sample number of 5. At PIH 72, liver tissue damage was detected by hematoxylin-eosin staining. At PIH 72, The mRNA levels of nucleotide-binding oligomerization domain-containing protein-like receptor family pyrin domain containing 3 (NLRP3), cysteine aspartic acid specific protease 1 (caspase-1), gasderminD (GSDMD), and interleukin 1β(IL-1β) in liver tissue as pyroptosis-related markers and glucose regulatory protein 78 (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP) in liver tissue as endoplasmic reticulum stress-related markers were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-qPCR). Protein expression levels of GRP78, CHOP, NLRP3, caspase-1, caspase-1/p20, GSDMD-N, and cleaved IL-1β in liver tissue were detected by Western blotting, and the sample numbers were all 5. HepG2 cells as human liver cancer cells were divided into dimethyl sulfoxide (DMSO) group, 0.1 μmol/L tunicamycin (TM) group, 0.2 μmol/L TM group, 0.4 μmol/L TM group, and 0.8 μmol/L TM group and were treated accordingly. After 24 h of culture, cell viability was detected by cell counting kit 8, and the intervention concentration of TM was screened, and the sample number was 5. HepG2 cells were divided into DMSO group, TM alone group, and TM+carnitine group, and treated accordingly. After 24 h of culture, the protein expression levels of GRP78, CHOP, NLRP3, caspase-1, caspase-1/p20, GSDMD-N, and cleaved IL-1β in cells were detected by Western blotting, and the sample numbers were all 3. Data were statistically analyzed with one-way analysis of variance and least significant difference- t test. Results: At PIH 72, the AST and ALT levels of serum in scald alone group were (640±22) and (157±8) U/L, which were significantly higher than (106±13) and (42±6) U/L in sham-injury group, respectively, with t values of -46.78 and -25.98, respectively, P <0.01. The AST and ALT levels of serum in scald+carnitine group were (519±50) and (121±10) U/L, which were significantly lower than those in scald alone group, respectively, with t values of 4.93 and 6.06, respectively, P <0.01. At PIH 72, the morphology of liver tissue of rats in sham-injury group were basically normal with no obvious inflammatory cell infiltration; compared with those in sham-injury group, the liver tissue of rats in scald alone group showed a large number of inflammatory cell infiltration and disturbed cell arrangement; compared with that in scald alone group, the liver tissue of rats in scald+carnitine group showed a small amount of inflammatory cell infiltration. At PIH 72, the mRNA expression on levels of NLRP3, caspase-1, GSDMD, and IL-1β in liver tissue of rats in scald alone group were significantly higher than those in sham-injury group (with t values of 34.42, 41.93, 30.17, and 15.68, respectively, P <0.01); the mRNA levels of NLRP3, caspase-1, GSDMD, and IL-1β in liver tissue of rats in scald+carnitine group were significantly lower than those in scald alone group (with t values of 34.40, 37.20, 19.95, and 7.88, respectively, P <0.01). At PIH 72, the protein expression levels of NLRP3, caspase-1, caspase-1/p20, GSDMD-N, and cleaved IL-1β in liver tissue of rats in scald alone group were significantly higher than those in sham-injury group (with t values of 12.28, 26.92, 5.20, 10.02, and 24.78, respectively, P <0.01); compared with those in scald alone group, the protein expression levels of NLRP3, caspase-1, caspase-1/p20, GSDMD-N, and cleaved IL-1β in liver tissue of rats in scald+carnitine group were significantly decreased (with t values of 10.99, 27.96, 12.69, 8.96, and 12.27, respectively, P <0.01). At PIH 72, the mRNA levels of GRP78 and CHOP in liver tissue of rats in scald alone group were significantly higher than those in sham-injury group (with t values of 21.00 and 16.52, respectively, P <0.01), and the mRNA levels of GRP78 and CHOP in liver tissue of rats in scald+carnitine group were significantly lower than those in scald alone group (with t values of 8.92 and 8.21, respectively, P <0.01); the protein expression levels of GRP78 and CHOP in liver tissue of rats in scald alone group were significantly higher than those in sham-injury group (with t values of 22.50 and 14.29, respectively, P <0.01), and the protein expression levels of GRP78 and CHOP in liver tissue of rats in scald+carnitine group were significantly lower than those in scald alone group (with t values of 14.29 and 5.33 respectively, P <0.01). After 24 h of culture, the cell survival rates of 0.1 μmol/L TM group, 0.2 μmol/L TM group, 0.4 μmol/L TM group, and 0.8 μmol/L TM group were significantly decreased than that in DMSO group (with t values of 4.90, 9.35, 18.64, and 25.09, respectively, P <0.01). Then 0.8 μmol/L was selected as the intervention concentration of TM. After 24 h of culture, compared with that in DMSO group, the protein expression levels of GRP78 and CHOP in cells in TM alone group were significantly increased (with t values of 10.48 and 17.67, respectively, P <0.01), and the protein expression levels of GRP78 and CHOP in TM+carnitine group were significantly lower than those in TM alone group (with t values of 8.08 and 13.23, respectively, P <0.05 or P <0.01). After 24 h of culture, compared with those in DMSO group, the protein expression levels of NLRP3 and GSDMD-N in cells in TM alone group were significantly increased (with t values of 13.44 and 27.51, respectively, P <0.01), but the protein expression levels of caspase-1, caspase-1/p20, and cleaved IL-1β in cells were not significantly changed ( P >0.05); compared with that in TM alone group, the protein expression levels of NLRP3 and GSDMD-N in cells in TM+carnitine group were significantly decreased (with t values of 20.49 and 21.95, respectively, P <0.01), but the protein expression levels of caspase-1, caspase-1/p20, and cleaved IL-1β in cells were not significantly changed ( P >0.05). Conclusions: In severely scald rats, exogenous L-carnitine may play a protective role against liver injury by inhibiting the pathways related to excessive endoplasmic reticulum stress-mediated pyroptosis.

Qingluoyin (QLY) is a representative herbal formula prescribed for hot symptom-related rheumatoid arthritis treatment. Among its derivatives, Xiaoyao-Qingluoyin (XYQLY) attracts increasing attention due to the notable clinical efficacy. In this study, we compared its effects with QLY on adjuvant-induced arthritis (AIA) in rats and partially elucidated the antirheumatic mechanism using a network pharmacology-based strategy. After continuous oral treatments, clinical outcomes were systematically evaluated by radiographic, histological, immunohistochemical, and serological analyses. Possibly altered pathways were predicted based on reported interactions between the related chemicals and proteins/genes. The obtained conclusion was further validated by experiments in vitro . QLY and XYQLY eased polyarthritis in AIA rats after repeated doses, which reflected in reduced inflammation and bone degradation and downregulated p-p65, MMP3, and TLR4 expressions in joints. Meanwhile, they restored oxidative stress (MDA, SOD, GSH, T-AOC, and NO) and inflammatory indicators (TNF- α and CO) in serum. Synovium-based immunoblotting assay revealed that QLY and XYQLY were similarly effective in downregulating MMP3 and COX-2, but XYQLY treatment exhibited notable merit in suppressing p-p65 expression. Network pharmacology analysis hinted that XYQLY should exert greater impacts on LPS signaling and the downstream. Based on results from LC-MS analysis, we treated AIA rat-derived peripheral blood mononuclear cells with either QLY or XYQLY-based chemical combinations and confirmed that XYQLY had the better potential in inhibiting TLR4/NF- κ B-controlled IL-6 production. Consequently, it led to a more profound decrease in Th17 cells counts. Overall evidence demonstrated that XYQLY was especially effective in regulating innate immunity and, therefore, improved immune environment in AIA rats as a whole., Competing Interests: The authors declare that there are no conflicts of interest related to this work., (Copyright © 2022 Dan-Feng Li et al.)

Gynura procumbens is a traditional herb and food extensively cultivated in China and Southeast Asian countries. In this work, the crude extract (CE) of G. procumbens was purified with macroporous resin to obtain the refined fraction, and its anti-inflammatory activity was compared with that of CE. Moreover, the detailed mechanisms of anti-inflammatory activity were also investigated for the first time. The results indicated that CE was more effective in anti-inflammatory activity and it could reduce the secretion of NO, TNF- α , and PGE2 via decreasing the iNOS, TNF- α , and COX-2 genes transcription and related proteins translation, which were associated with the inhibition of AP-1 and NF- κ B nuclear translocation and downregulation of PI3K/Akt and MAPK signaling pathways. In conclusion, the extract of G. procumbens has a promising potential in inflammation-related disorders alleviation, and these findings could provide the basis for the comprehensive utilization of G. procumbens and the new functional food development., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Ming-Yuan Cao et al.)

Objective: Asymmetrical cortical vein sign (ACVS) shown on susceptibility-weighted imaging (SWI) can reflect regional hypoperfusion. We investigated if ACVS could predict the cerebral collateral circulation (CC) as assessed by digital subtraction angiography (DSA) in acute ischemic stroke patients with ipsilateral severe stenosis/occlusion of the anterior circulation. Methods: Clinical data and imaging data of 62 acute ischemic stroke patients with ipsilateral severe stenosis or occlusion of the anterior circulation confirmed by DSA were collected retrospectively. Participants underwent magnetic resonance imaging, including an SWI sequence. ACVS was defined as more and/or larger venous signals in the cerebral cortex of one side of SWI than that in the contralateral side. ACVS was measured using the Alberta Stroke Program Early Computed Tomography score based on SWI. The grading of the cerebral CC was judged using DSA. Results: Of the 62 patients, 30 patients (48.4%) had moderate-to-severe ACVS. According to DSA assessment, 19 patients (30.6%) had a good CC (grade 3-4), and 43 (69.4%) patients had a poor-to-moderate CC (grade 0-2). Among the 30 patients with moderate-to-severe ACVS, only three (10%) patients had a good CC, and 27 (90%) patients had a poor-to-moderate CC; among the 32 patients with none or mild ACVS, 16 (50%) of them had a good CC, and the other 50% had a moderate-to-severe CC. We constructed two logistic regression models with ACVS grading and none or mild ACVS entered into the models, respectively, together with age and large-artery occlusion. In model 1, no ACVS (compared with severe ACVS; OR = 40.329, 95%CI = 2.817-577.422, P = 0.006), mild ACVS (compared with severe ACVS; OR = 17.186, 1.735-170.224, 0.015) and large-artery occlusion (OR = 45.645, 4.603-452.592, 0.001) correlated with a good CC. In model 2, none or mild ACVS (OR = 36.848, 95%CI = 5.516-246.171, P < 0.001) was significantly associated with a good CC as judged by DSA, adjusted by age and large-artery occlusion. Conclusions: Cortical venous changes in SWI may be a useful indicator for the cerebral CC as confirmed by DSA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhan, Chen, Li, Luo, Wu, Liu, Xiao, Hu and Xie.)

Purpose: We aimed to develop an accurate prognostic model to identify suitable candidates for definitive radiation therapy (DRT) in addition to palliative chemotherapy (PCT) among patients with de novo metastatic nasopharyngeal carcinoma (mNPC)., Methods and Materials: Patients with de novo mNPC who received first-line PCT with or without DRT were included. Overall survival for patients who received PCT alone versus PCT plus DRT was estimated using inverse probability of treatment weighting-adjusted survival analyses. We developed and validated a prognostic model to predict survival and stratify risks in de novo mNPC. A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores obtained from the prognostic model and to identify suitable DRT candidates. Dominance analysis was used to determine the relative importance of each predictor of receiving DRT., Results: A total of 460 patients were enrolled; 244 received PCT plus DRT and 216 received PCT alone. The 6-month conditional landmark, inverse probability of treatment weighting-adjusted Cox regression analysis showed that PCT plus DRT was associated with a significant survival benefit (hazard ratio: 0.516; 95% confidence interval, 0.403-0.660; P < .001). A prognostic model based on 5 independent prognostic factors, including serum lactate dehydrogenase, number of metastatic sites, presence of liver metastasis, posttreatment Epstein-Barr virus DNA level, and response of metastases to chemotherapy was developed and subsequently validated. Prognostic scores obtained from the prognostic model were used for risk stratification and efficacy estimation. High-risk patients identified using the proposed model would not benefit from additional DRT, whereas low-risk patients experienced significant survival benefits. Socioeconomic factors, including insurance status and education level, played an important role in receipt of DRT., Conclusions: Additional DRT after PCT was associated with increased overall survival in patients with de novo mNPC, especially low-risk patients identified with a newly developed prognostic model., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The intumescent flame retardant (IFR) with ammonium polyphosphate (APP) as the main component has many defects in practical applications, more than that, APP can be traced to non-renewable phosphate rock resources. For the foregoing reasons, the melamine phytate supramolecular nanosheet flame retardant incorporating manganese ion (PAMA-Mn) was successfully prepared with a facile and environmental friendly hydrothermal procedure based on renewable bio-based material phytic acid (PA). The flame retardant polypropylene composite (PPI) with 13.5 wt% APP and 4.5 wt% pentaerythritol (PER) failed to the UL-94 test, and its limiting oxygen index (LOI) value was only 26.5%. After 33 wt% of APP was replaced by PAMA-Mn, the PPMn33 incorporating only 18 wt% flame retardant additives passed the UL-94 V-0 rating, and its LOI value was increased to 31.9%. Compared with PP, pHRR and pSPR values of PPMn33 were reduced by 56% and 23%, respectively. The fire retardant mechanism of PPMn33 was thoroughly discussed via a variety of characterization methods. It was found that the peak of the Gram-Schmidt curve of PPMn33 was drastically reduced by 49% relative to that of PPI, indicating a remarkably decrease of combustible volatile products owing to the incorporation of PAMA-Mn, thereby rapidly reducing the fire hazard risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale: Very severe aplastic anemia (vSAA) with active infections is always fatal. Adequate infection control before hematopoietic stem cell transplantation is recommended., Patient Concerns: A 38-year-old woman with vSAA suffered from acute perforated appendicitis and invasive pulmonary fungal infection, and she failed to respond to intense antimicrobial therapies., Diagnosis: She was diagnosed with refractory vSAA with stubborn acute perforated appendicitis and invasive pulmonary fungal infection., Interventions: We successfully completed an emergent reduced intensity conditioning-matched unrelated donor (MUD)-peripheral blood stem cell transplantation (PBSCT) as a salvage therapy in the presence of active infections. The conditioning regimens consisted of reduced cyclophosphamide 30 mg/kg/day from day-5 to day-3, fludarabine 30 mg/m/day from day-5 to day-3 and porcine-antilymphocyte immunoglobulin 15 mg/kg/day from day-4 to day-2 without total body irradiation. Cyclosporin A, mycophenolate mofetil and short-term methotrexate were administered as graft-versus-host disease (GVHD) prophylaxis. Neutrophils and platelets were engrafted on day+15 and day+21. Appendiceal abscess and severe pneumonia developed after neutrophil engraftment, which were successfully managed with intense antimicrobial therapy and surgical intervention., Outcomes: Only limited cutaneous chronic GVHD was observed 5 months after transplantation. The patient still lives in a good quality of life 2 years after transplantation., Lessons: Active infections may be no longer a contraindication to hematopoietic stem cell transplantation for some patients with vSAA.

Laser induced plasmas (LIPs) method is a highly regarded approach to evaluate the chemical composition of materials. But the strong self-absorption of the radiation seriously affects its accuracy. Meanwhile, the model based on self-absorption phenomenon makes its application very difficult. In this work, a self-absorption internal standard (SAIS) model is proposed for detection of the multi-element concentrations of complex constituent material with a single emission line of the element in laser plasmas. A typical LIPs experiment system is set up to generate plasmas, and the soil is selected as a test sample. The average electron temperature (0.975 eV) and electron density (1.44×10 18 cm -3 ) are determined by the Boltzmann plot and emission lines Stark broadening, respectively. The plasmas are diagnosed as in local thermodynamic equilibrium condition. The emission lines selected to calculate the concentration of sample contain a wide set of kt values (0.575×10 -30 ∼37.2×10 -30 m 3 ). Then, the concentrations of some elements are calculated by the model using single emission line of each element. It is found that the concentrations of the five elements (Ti, Fe, Mg, Al, Si) calculated by SAIS model are relatively consistent with the results of the traditional chemical testing methods. This indicated that the SAIS model is an effective and neat method for multi-element concentrations detection of complex constituent materials.

Growing data have indicated that the miR-17-92 cluster is implicated in inflammatory response and rheumatoid arthritis (RA). This study was aimed to investigate the effects of miR-92a on the proliferation and migration of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). Our results showed that miR-92a was significantly down-regulated in RA synovial tissue and RA-FLSs, whereas the protein level of AKT2 is increased. Restoration of miR-92a suppressed the proliferation and migration of RA-FLSs. Down-regulation of miR-92a promotes proliferation and migration of normal human FLSs. Dual luciferase reporter gene assay showed that miR-92a could specifically bind with the 30UTR of AKT2 and significantly repressed the luciferase activity. Down-regulation or up-regulation of miR-92a significantly increased or decreased the protein and phosphorylation levels of AKT2. siRNA-mediated down-regulation of AKT2 significantly prevented cell proliferation and migration of RA-FLSs, which were similar to the effects induced by overexpression of miR-92a. Moreover, AKT2 overexpression rescued miR-92a-mediated suppressive effect on proliferation and migration of RA-FLS. Thus, miR-92a could inhibit the proliferation and migration of RA-FLSs through regulation of AKT2 expression.

Background: Green tea ( Camelliasinensis [L.] Kuntze) belongs to the plant family Theaceae and is mainly distributed in East Asia, the Indian subcontinent and Southeast Asia. This plant has been proven to be beneficial to human health, and green tea is the second most consumed beverage in the world after water. However, until now, the effect of green tea aqueous extract (GTE) upon postmenopausal osteoporosis has remained unclear. In this study, we investigated the therapeutic effects of GTE on estrogen deficiency-induced osteoporosis and explored the possible mechanisms in vivo and in vitro ., Materials and Methods: Ovariectomized (OVX) female rats were orally administered with GTE at doses of 60, 120, and 370 mg kg -1 for 13 consecutive weeks. The biochemical parameters, bone gla protein, alkaline phosphatase, acid phosphatase, estrogen, interleukin-1β, and interleukin-6 in blood samples were detected, and histological change in bones was analyzed by hematoxylin and eosin staining. Meanwhile, the mechanisms of GTE on osteoclast formation were explored in RAW 264.7 cells induced by receptor activation of the nuclear factor kappa B ligand (RANKL)., Results: The results showed that GTE could increase bone mass and inhibit trabecular bone loss in OVX rats. Furthermore, real-time quantitative reverse transcription polymerase chain reaction analysis from in vitro experiments also showed that GTE reduced the mRNA expression of osteoclast-associated genes such as cathepsin K (cath-K), c-Fos , matrix metalloproteinase 9 , nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and tartrate-resistant acid phosphatase . In addition, GTE caused a reduction in the protein levels of NFATc1, c-Fos, c-src and cath-K., Conclusion: Evidence from both animal models and in vitro experiments suggested that GTE might effectively ameliorate the symptoms of osteoporosis in OVX rats and inhibit RANKL-induced osteoclast-specific gene and protein expression., Competing Interests: There are no conflicts of interest to declare.

Liquid metal (LM)-based flexible sensors, which utilize advanced liquid conductive materials to serve as sensitive elements, are emerging as a promising solution to measure large deformations. Nowadays, one of the biggest challenges for precise control of soft robots is the detection of their real-time positions. Existing fabrication methods are unable to fabricate flexible sensors that match the shape of soft robots. In this report, we first described a novel 3D printed multifunction inductance flexible and stretchable sensor with LMs, which is capable of measuring both axial tension and curvature. This sensor is fabricated with a developed coaxial LM 3D printer by coprinting of silicone rubber and LMs. Because of the solenoid shape, this sensor can be easily installed on snakelike soft robots and can accurately distinguish different degrees of tensile and bending deformations. We determined the structural parameters of the sensor and proved its excellent stability and reliability. As a demonstration, we used this sensor to measure the curvature of a finger and feedback the position of an endoscope, a typical snakelike structure. Because of its bending deformation form consistent with the actual working status of the soft robot and unique shape, this sensor has better practical application prospects in the pose detection.

Accurate knowledge of electrical conductivity and thermal conductivity temperature dependence plays a crucial role in the design of a thermometer. Here, by using a two-beam laser direct writing system, an individual silver nanowire (AgNW) with well-defined dimensions is fabricated on a polyethylene terephthalate (PET) substrate. The temperature dependence of the resistivity of the fabricated AgNW is measured ranging from 10 to 300 K, and fitted with the Bloch-Grüneisen formula. The residual resistivity ((1.62 ± 0.20) × 10 -7 Ω m) of the AgNW is larger than that of the bulk material (1 × 10 -11 Ω m). The electron-phonon coupling constant of the AgNW is (1.08 ± 0.13) × 10 -7 Ω m, which is larger than that of the bulk silver (5.24 × 10 -8 Ω m). Moreover, the Debye temperature of the AgNW is 199.30 K and is lower than that of the bulk silver (235 K). The Lorenz number of the fabricated AgNW is found to decrease as the temperature increases. Besides, the Lorenz number (2.66 × 10 -7 W Ω K -2 ) is larger than the Sommerfeld value (2.44 × 10 -8 W Ω K -2 ) at room temperature. The measurement results allow one to design a thermometer in the temperature range 40-300 K. The flexibility of the AgNW is also excellent, and the resistance increase of the AgNW is only 2.58% when the AgNW bending about 1000 times with a bending radius of 1 mm., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Osteoarthritis is a type of joint disease that may lead to other joint diseases. Previous research has demonstrated that tumor necrosis factor (TNF)‑α is associated with osteoarthritis activity and pathology. The possible mechanisms of the TNF‑α‑mediated signaling pathway have not been clearly elaborated in synovial fibroblasts. The present study aimed to investigate the potential mechanisms of TNF‑α in a mouse model of iodoacetate‑induced osteoarthritis. Reverse transcription‑quantitative polymerase chain reaction, ELISA, western blotting and immunohistochemistry were performed to evaluate the role of TNF‑α in the progression of osteoarthritis. The results revealed that the serum levels of TNF‑α, interleukin (IL)‑1β, IL‑4 and IL‑6 were significantly upregulated in a mouse model of iodoacetate‑induced osteoarthritis compared with healthy mice (P<0.01). TNF‑α, IL‑1β, IL‑4 and IL‑6 mRNA and protein levels were also significantly upregulated in synovial fibroblasts in the experimental mice (P<0.01). It was demonstrated that TNF‑α increased pro‑inflammation factors matrix metalloproteinase (MMP)‑3, MMP‑9, nuclear factor (NF)‑κB and receptor activator of NF‑κB ligand (RANKL) in synovial fibroblasts. It was also observed that the toll‑like receptor (TLR)‑3 was significantly upregulated and extracellular signal‑regulated kinase (ERK) and protein kinase B (AKT) were significantly downregulated in synovial fibroblasts in osteoarthritis mice (P<0.01). An in vitro assay demonstrated that TNF‑α inhibitor decreased mRNA and protein levels of IL‑1β, IL‑4 and IL‑6 in synovial fibroblasts. The knockdown of TLR‑3 abolished the TNF‑α upregulated mRNA and protein levels of IL‑1β, IL‑4 and IL‑6 in synovial fibroblasts. In addition, the knockdown of TLR‑3 also reversed TNF‑α‑upregulated ERK and AKT expression in synovial fibroblasts. In vivo assays demonstrated that TNF‑α inhibitor significantly decreased the deposition of IL‑1β, IL‑4 and IL‑6 as well as bone destruction and significantly increased the body weight and osteoarthritis score for osteoarthritic mice (P<0.01). TNF‑α inhibitor decreased TLR‑3 and significantly increased the expression and phosphorylation of ERK and AKT in articular cartilage (P<0.01). In conclusion the results of the present study indicate that TNF‑α serves an essential role in synovial fibroblasts in osteoarthritis, suggesting that inhibition of TNF‑α may decrease inflammation via the TLR‑3‑mediated ERK/AKT signaling pathway in a mouse model of monosodium iodoacetate‑induced osteoarthritis.

Background: MicroRNAs (miRs) play an important role in osteoclastogenesis. However, no study has investigated the underlying molecular mechanisms of miR-145 in this process. The purpose of the present study was to investigate the role of miR-145 and its post-transcriptional mechanism in the progression of osteoclast differentiation., Methods: Macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kB ligand (RANKL) were used to induce osteoclastogenesis originated from bone marrow-derived macrophages (BMMs). Female C57BL/6J mice were divided into sham, OVX, OVX + NC-agomir and OVX + miR-145-agomir groups. Tartrate-resistant acid phosphatase (TRAP) staining was performed to identify osteoclasts in-vitro and in-vivo. The mRNA and protein levels in osteoclast and tibia were assayed by qRT-PCR and western blotting, respectively., Results: miR-145 expression was inhibited in RANKL-induced osteoclastogenesis, whereas overexpression of miR-145 attenuated it. We further found that Smad3 is a direct target gene of miR-145 by binding with its 3'-UTR. Overexpression of miR-145 significantly suppressed Smad3 mRNA and protein expression. In-vivo, miR-145 agomir treatment inhibited osteoclast activity in OVX mice by inhibiting Smad3 expression., Conclusion: We provide the evidence that over-expression of miR-145 could inhibit osteoclast differentiation, at least partially, by decreasing Smad3 expression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: Dendrobium candidum (DC) and black tea, are traditional chinese drinks, which contain multiple active ingredients. However, whether or not the combination of these two ingredients can improve osteoporosis remains unknown. This study therefore aimed to examine the effects of the combination of DC and black tea extract (BTE) on osteoporosis., Main Methods: Ovariectomy (OVX)-induced osteoporosis in vivo as well as receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in vitro was selected., Key Findings: Results showed that OVX rats that were treated orally with a DC and BTE combination for 12 weeks maintained their calcium (Ca) and phosphorus (P) homeostasis and exhibited significantly enhanced estradiol (E 2 ) and OPG levels. This combination treatment also simultaneously reduced levels of interleukin (IL)-1β, IL-6 and improved the organ coefficients of the uterus and femur as well as BMD and BMC in OVX rats. In addition, this DC and BTE combination suppressed osteoclast differentiation in the RANKL-stimulated osteoclastogenesis of RAW 264.7 cells and effectively inhibited the expression of osteoclast-associated genes and proteins. The results of this study further highlight the fact that a combination of DC and BTE improved ovariectomy-induced osteoporosis in rats and suppressed RANKL-stimulated osteoclastogenesis in RAW 264.7 cells., Significance: This combination also significantly alleviated osteoporosis when compared to the alternative sole treatments above, due to synergistic effects among components. One partial mechanism of this combination might be the inhibition of osteoclast proliferation and the regulation of NFATC1/c-Fos expression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Whether the waiting time for radical radiotherapy (WRT) detrimentally impacts nasopharyngeal carcinoma (NPC) prognosis is unclear. We estimated the influence of WRT on overall survival (OS) and disease-specific survival (DSS) of NPC., Patients and Methods: Patients were identified from prospectively maintained database. WRT was calculated from histological diagnosis to initiation of radiotherapy (RT). Survival analysis was estimated using Weibull parametric model and propensity score analysis (PSA). Recursive partitioning analysis (RPA) identified optimal WRT threshold via conditional inference trees to estimate the greatest survival differences based on randomly selected training and validation sets, and this process was repeated 1000 times to ensure threshold robustness. Sensitivity analysis estimated effects of potential unmeasured confounders., Results: A total of 9896 patients were included. In multivariate analysis, WRT of 31-60°d, of 61-90°d and of greater than 90°d independently increased mortality risk compared to less than 30°d. Upon RPA, ranges of 30-35°d with the peak of 30°d were confirmed with 89% of simulations validating optimal thresholds. In threshold-based groups, adjusted hazard ratios (HRs) for WRT of greater than 30°d by both Weibull model and PSA were significantly higher than for WRT of less than 30°d [OS: HR = 1.13, 95% confidence interval (CI) 1.04-1.23, P = 0.003; DSS: HR = 1.15, 95% CI 1.05-1.26, P = 0.002]. Sensitivity analysis revealed robustness of results., Conclusions: WRT independently affects survival. Increasing WRT beyond 30°d was most consistently detrimental to survival. WRT of NPC should be as short as reasonably achievable (ASARA)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aphasia is an acquired language disorder that is a common consequence of stroke. The pathogenesis of the disease is not fully understood, and as a result, current treatment options are not satisfactory. Here, we used blood oxygenation level-dependent functional magnetic resonance imaging to evaluate the activation of bilateral cortices in patients with Broca's aphasia 1 to 3 months after stroke. Our results showed that language expression was associated with multiple brain regions in which the right hemisphere participated in the generation of language. The activation areas in the left hemisphere of aphasia patients were significantly smaller compared with those in healthy adults. The activation frequency, volumes, and intensity in the regions related to language, such as the left inferior frontal gyrus (Broca's area), the left superior temporal gyrus, and the right inferior frontal gyrus (the mirror region of Broca's area), were lower in patients compared with healthy adults. In contrast, activation in the right superior temporal gyrus, the bilateral superior parietal lobule, and the left inferior temporal gyrus was stronger in patients compared with healthy controls. These results suggest that the right inferior frontal gyrus plays a role in the recovery of language function in the subacute stage of stroke-related aphasia by increasing the engagement of related brain areas., Competing Interests: Conflicts of interest: None declared.

Multidrug resistance (MDR) is a major obstacle in the effective chemotherapeutic treatment of cancers. Triptolide (TPL) is a diterpenoid isolated from Tripterygium wilfordii Hook. f., a traditional Chinese medicine. It was demonstrated in our previous study that TPL exerts anti-MDR cancers on various MDR cell lines (including A549/Taxol, MCF-7/ADR and Bel7402/5-Fu). The present study was designed to investigate its anti-proliferative activity on A549/Taxol cells, and explore the underlying mechanism of action. The anti-proliferative activity of TPL on A549/Taxol cells was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Its pro-apoptosis and cell cycle arrest activities were analyzed by flow cytometry. Western blot assay was employed to investigate the levels of mitogen-activated protein kinases (MAPKs) and apoptosis-related proteins in cells. TPL efficiently suppressed the proliferation of A549/Taxol cells. Co-treatment with MAPK inhibitors in the MTT assay indicated that the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways were involved in the process. Upregulation of p-p38, p-ERK, p-GSK-3β, Bax and cleaved caspases-3 and -9, and downregulation of p-JNK, p-Akt and Bcl-2 were observed upon treatment with TPL in the A549/Taxol cells. The results from flow cytometry assay revealed that TPL induced apoptosis and S-phase arrest in A549/Taxol cells. This occurred as a result of the upregulation of p-ERK and p-GSK-3β, and the downregulation of p-JNK and p-Akt, and was responsible for the subsequent anti-proliferative activity.

Determination of color values on tomato leaves stressed by the high temperature using hyperspectral imaging technique was studied in this paper. Hyperspectral images of sixty healthy and sixty unhealthy tomato leaves in the wavelengths of 380-1023 nm were acquired by the hyperspectral imaging system. Simultaneously, three color parameters (L*, a* and b*) were measured by a colorimeter. Reflectance of all pixels in the region of interest (ROI) was extracted from the corrected hyperspectral image. Partial Least Squares (PLS) models were established based on different preprocessing methods. Successive Projections Algorithm (SPA) was identified to select effective wavelengths. Finally, Partial Least Squares-Discriminant Analysis (PLS-DA) models were built to classify different types of samples. The results showed that the determination coefficient (R²) were 0. 818, 0. 109 and 0. 896 in the prediction sets of PLS modes; 0.591, 0.244 and 0.673 in the prediction sets of SPA-PLS models. The overall classification accuracy in the prediction sets of PLS-DA models were over 77.50%. It demonstrated that it is feasible to measure color values on tomato leaves and identify different types of samples using hyperspectral imaging technique.

Objective: To study the effects of browning inhibitors on Changium smyrnioides suspension cells growth and secondary metabolites production., Methods: Different concentrations of V(C), AC, AHC, Na2S2O3 and PVP were added to the light brown suspension cells, and the contents of phenols, total coumarins, bergaptol and bergapten were determined by UV-Vis and HPLC., Results: PVP with low concentration and V(C) improved the growth of the suspension cells in different degrees. It was showed that the content of phenols in the suspension cells was related to the kinds of browning inhibitors. The addition of V(C) in the medium increased the content of total coumarins significantly. After using 2 mg/mL of V(C), the gross increase rate of total coumarins was 51.53%, which was 4.8 times than that of the control group. The browning phenomenon caused by salicylic acid were inhibited by adding 2 mg/mL of V(C) into suspension culture system (with salicylic acid as the inducer). At the same time, the content of bergaptol and bergapten was increased 25.96% and 33.33%, respectively., Conclusion: V(C) is the best anti-browning agent in this study. It can inhibit browning, and promote cell growth and accumulation of secondary metabolites in Changium smyrnioides suspension cells.

In order to explore the feasibility of prediction soluble solid contents (SSC) in sugarcane stalks by using near infrared hyperspectral imaging techniques, two hundred and forty sugarcane stalks which come from three different varieties were studied. After obtaining the raw hyperspectral images of sugarcane stalks, the spectral information and textural features were discussed respectively. The prediction models were established by using partial least squares regression (PLSR), principal components regression (PCR) and least squares support vector machines (LS-SVM) algorithms. Besides, three different selected wavelengths algorithms such as successive projection (SPA) algorithms, intervals partial least squares (iPLS) algorithms and uninformation variables elimination (UVE) algorithm were analyzed after building partial least squares regression model. The results indicate that partial least squares regression model based on spectral features can be an steady model to predict SSC and the correlation coefficient (R2) of calibration sets and prediction sets are 0.879, 0.843. The root mean square errors of calibration sets and prediction sets are 0.644, 0.742 respectively. The obtained 105 wavelengths which were selected by UVE algorithm are effective spectral features. The R2 results of calibration sets and prediction sets of its PLSR model are 0.860, 0.813. The root mean square errors of calibration sets and prediction sets are 0.693, 0.810 respectively

Compared with the traditional chemical methods and the subjective visual ways for measuring plant physiology information indicators, the assessments of crop canopy information through spectral radiometer are more simple, rapid and accurate. The applications of different types of spectral radiometer, especially for international general used Cropscan multispectral radiometer, for predicting crop canopy leaf area index under different growth stage, biomass, nitrogen, chlorophyll and yield, and monitoring plant diseases and insect pests were summarized based on crop group information acquisition methods in recent years. The varity of vegetation indices (VIs) were concluded after comparing regression coefficients of related models among different crops. In general, the correlation coefficients of mathematical models were high and it can realize the crop detection of various kinds of physiological information. Besides, the combination of multispectral radiometer and other sensors can provide useful information to evaluate the status of crops growth, which is very important in practice.

Background: In order to shed light on the regenerative mechanism of mesenchymal stem cells (MSCs) in vivo, the bio-distribution profile of implanted cells using a stable and long-term tracking method is needed. We herein investigated the bio-distribution of human placental deciduas basalis derived MSCs (termed as PDB-MSCs) in nude mice after intravenous injection by carbon radioisotope labeling thymidine ((14)C-TdR), which is able to incorporate into new DNA strands during cell replication., Results: The proliferation rate and radioactive emission of human PDB-MSCs after labeled with different concentrations of (14)C-TdR were measured. PDB-MSCs labeled with 1 μCi possessed high radioactivity, and the biological characteristics (i.e. morphology, colony forming ability, differentiation capabilities, karyotype and cell cycle) showed no significant changes after labeling. Thus, 1 μCi was the optimal concentration in this experimental design. In nude mice, 1 × 10(6) (14)C-TdR-labeled PDB-MSCs were injected intravenously and the organs were collected at days 1, 2, 3, 5, 30 and 180 after injection, respectively. Radiolabeled PDB-MSCs were found mainly in the lung, liver, spleen, stomach and left femur of the recipient nude mice at the whole observation period., Conclusions: This work provided solid evidence that (14)C-TdR labeling did not alter the biological characteristics of human placental MSCs, and that this labeling method has potential to decrease the signal from non-infused or dead cells for cell tracking. Therefore, this labeling technique can be utilized to quantify the infused cells after long-term follow-up in pre-clinical studies.

In this study, based on a 4 hm2 stem-mapping plot, we analyzed spatial distributions of Abies georgei var. smithii, the dominant species in forest of Sygera Mountains in southeast Tibet, China. Pair-correlation function was used to characterize univariate spatial point patterns of three size classes of the population and bivariate spatial patterns between those and different sizes of dead wood. A. georgei var. smithii population was characterized by reverse J-shaped DBH distribution, indicating an increasing population. Saplings of the population were spatially obviously aggregated at the small scales (0-7 m), and mid-sized trees and large-sized trees of the population were randomly or uniformly distributed. The aggregation intensities of A. georgei var. smithii decreased with the increasing diameter classes and spatial scales. Saplings and mid-sized trees were significantly and negatively associated with large-sized trees at the small scales (0-35 and 0-30 m), but the associations reversed at the large scales (45-100 and 80-100 m). In addition, with the increasing age difference between diameter classes of the population, the intensities of positive or negative correlations increased. Spatial associations between saplings and dead large-sized trees, and between mid-sized trees and dead large-sized trees were negative at the small scales (0-34 and 5-27 m), but positive at the large scales (49-100 and 73-100 m). This suggested that released niche space due to dead large-sized trees is not enough to weaken their negative impacts on saplings. We concluded that self-thinning effect and Janzen-Connell hypothesis may be the main mechanisms for the spatial pattern formation of A. georgei var. smithii population.

Based on relevant statistical yearbook and with an integrated method, the ecological footprint and ecological carrying capacity of farmers and herdsmen during the period from 2000 to 2012 in Tibet Autonomous Region, China were studied. The results showed that the ecological status of farmers and herdsmen were in a surplus state during the study period, but the surplus amount exhibited a decreasing tendency. The ecological capacity decreased from 7.49 hm2 in 2000 to 6.35 hm2 in 2012, with a decrease of 15.3%, while the ecological footprint increased gradually from 1.03 hm2 in 2000 to 1.26 hm2 in 2012.

Identification of early blight on tomato leaves by using hyperspectral imaging technique based on different effective wavelengths selection methods (successive projections algorithm, SPA; x-loading weights, x-LW; gram-schmidt orthogonaliza-tion, GSO) was studied in the present paper. Hyperspectral images of seventy healthy and seventy infected tomato leaves were obtained by hyperspectral imaging system across the wavelength range of 380-1023 nm. Reflectance of all pixels in region of interest (ROI) was extracted by ENVI 4. 7 software. Least squares-support vector machine (LS-SVM) model was established based on the full spectral wavelengths. It obtained an excellent result with the highest identification accuracy (100%) in both calibration and prediction sets. Then, EW-LS-SVM and EW-LDA models were established based on the selected wavelengths suggested by SPA, x-LW and GSO, respectively. The results showed that all of the EW-LS-SVM and EW-LDA models performed well with the identification accuracy of 100% in EW-LS-SVM model and 100%, 100% and 97. 83% in EW-LDA model, respectively. Moreover, the number of input wavelengths of SPA-LS-SVM, x-LW-LS-SVM and GSO-LS-SVM models were four (492, 550, 633 and 680 nm), three (631, 719 and 747 nm) and two (533 and 657 nm), respectively. Fewer input variables were beneficial for the development of identification instrument. It demonstrated that it is feasible to identify early blight on tomato leaves by using hyperspectral imaging, and SPA, x-LW and GSO were effective wavelengths selection methods.

Purpose: To describe our technique and experience with retroperitoneoscopic upper pole nephroureterectomy in duplex kidney, focusing on the role of dilated upper ureter., Materials and Methods: From November 2004 to August 2011, retroperitoneoscopic upper pole nephroureterectomy was performed in 31 patients with a duplex kidney by a single, experienced laparoscopic surgeon. We developed our own surgical technique to suit this technically challenging procedure. Follow-up studies were performed using renal ultrasonography, intravenous urography (IVU) and/or dimercaptosuccinic acid (DMSA) renal scan in all patients at 3 months postoperatively and annually thereafter., Results: All procedures were completed laparoscopically without conversion to open surgery and blood transfusion. The mean operative time was 106 (90-157) min. The estimated blood loss was < 50 mL in all cases. The mean postoperative hospital stay was 4.2 (3-7) days. Perioperative complications were limited to 1 case of peritoneal tear during a procedure and 1 case of transient postoperative fever. No major intraoperative and postoperative complication occurred. With the mean follow-up period of 41 months (range 3 to 80), no case was observed to have functional loss of the remaining lower moiety on postoperative IVU or DMSA renal scan., Conclusion: Retroperitoneoscopic upper pole nephroureterectomy using our technique is safe and effective.

An efficient C(sp)-CH(2)CF(3) bond-forming reaction via Pd-catalyzed 2,2,2-trifluoroethylation of aryl and alkyl terminal alkynes has been developed. This protocol proceeds under mild conditions using the readily available and cheap reagent CF(3)CH(2)I as the source of the CH(2)CF(3) group. Various terminal aryl alkynes as well as alkylacetylenes can be transformed into the corresponding trifluoroethylated products in good-to-excellent yields. The method is tolerant of carbonyl, nitro, ester, cyano, and even formyl groups.

Objective: To present our experience of combining transperitoneal mini-laparoscopic pyeloplasty (mini-LP) and concomitant ureteroscopy-assisted pyelolithotomy (U-P) for ureteropelvic junction obstruction (UPJO) complicated by renal caliceal stones in the same session., Methods: Between May 2007 and December 2011, mini-LP and concomitant U-P was performed in nine patients with UPJO and ipsilateral renal caliceal stones. Stone location and burden were preoperatively assessed. After pyelotomy with appropriate length (about 4 mm), a 16-Fr catheter sheath replaced the uppermost or lowermost laparoscopic trocar and was introduced directly into the renal pelvis under the guidance of a guide wire and laparoscopic vision. A 7.5F rigid ureteroscopy passed through the catheter sheath into the plevis. Intracorporeal lithotripsy and/or pressure irrigation via a pump was used for caliceal stone removal. Subsequently, laparoscopic pyeloplasty was performed in a standard fashion. Postoperative imaging was assessed., Results: The calculi sizes ranged from 2 to 11 mm (mean, 7.1 mm) and an average of 3 stones per patient was removed (range, 1 to 6 stones). Complete stone clearance confirmed by postoperative imaging was achieved in all patients. Mean operative time was 210 minutes, and estimated blood loss was 20 mL. Mean hospital stay was 5 days (4-7). Stent was removed after 4-8 weeks. No intraoperative or postoperative complications were noted during a mean follow-up of 18.5 months (range, 6 to 24 months)., Conclusions: Mini-LP and concomitant U-P are simple and effective alternatives for the simultaneous management of UPJO complicated by coexisting ipsilateral renal caliceal stones.

New couple: The Cu-promoted trifluoromethylation of primary and secondary alkylboronic acids with TMSCF(3) extends the scope of transition-metal-catalyzed trifluoromethylation reactions to sp(3)-hybridized carbon centers. It also represents one of the first examples for Cu-catalyzed C-C cross-coupling reactions of alkylboronic acid derivatives., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hyperspectral imaging feature of chlorophyll content (SPAD) in tomato leaves stressed by grey mold was studied in the present paper. Hyperspectral imagings of healthy and infected tomato leaves were obtained by hyperspectral imaging system from 380 to 1 030 nm and diffuse spectral response of region of interest (ROI) from hyperspectral imaging was extracted by EN-VI software, then different preprocessing methods were used including smoothing and normalization etc. The partial least squares regress (PLSR) and principal component regress (PCR) models were developed for the prediction of SPAD value in tomato leaves based on normalization preprocessing method, then the back-propagation neural network (BPNN) and least squares-support vector machine (LS-SVM) models were built based on the four variables suggested by PLSR model. Among the four models, LS-SVM model was the best to predict SPAD value and the coefficient of determination (R2) was 0.901 8 with the root mean square error of prediction (RMSEP) of 2.599 2. It was demonstrated that chlorophyll content (SPAD) in healthy and infected tomato leaves can be effectively detected by the hyperspectral imaging technique.

A 53-year-old man presented with a 6-month history of intermittent right flank pain. Radiological imaging confirmed the diagnosis of retrocaval ureter (RCU) and ureteral calculus. Retroperitoneal laparoendoscopic single-site surgery (LESS) ureterolithotomy and ureteroureterostomy was successfully performed. The operative time was 185 min and the blood loss was approximately 20 ml. The patient's postoperative course was uneventful. Postoperative analgesia was not needed. The patient was discharged on the third postoperative day. The drain and double-J stent were respectively removed at 1 and 8 weeks postoperatively. At the 3-month follow-up, nuclear scan showed no evidence of obstruction of the right kidney and the patient also remained symptom free. It may be concluded that retroperitoneal LESS repair for RCU is a feasible and safe procedure, which can be considered as a option for the management of RCU even if it is complicated by the presence of a ureteral calculus.

Objective: To retrospectively review our experience with respect to evaluating the feasibility and safety of laparoendoscopic single-site (LESS) dismembered pyeloplasty for ureteropelvic junction obstruction (UPJO) through a retroperitoneal approach., Patients and Methods: Between March 2011 and January 2012, 10 consecutive patients underwent LESS retroperitoneoscopic dismembered pyeloplasty performed by one experienced laparoscopic surgeon at our institution. A single-port access was inserted through a 2.5-cm transverse skin incision below the 12th rib along the midaxillary line. Standard steps of the multisite retroperitoneoscopic Anderson-Hynes dismembered pyeloplasty technique using conventional instruments or a combination of conventional and bent laparoscopic instruments were performed. Follow-up studies were conducted by intravenous urography (IVU), diuretic renal scan, and renal ultrasonography., Results: LESS retroperitoneoscopic dismembered pyeloplasty was successful in 9 patients, whereas 1 required four-port retroperitoneoscopic conversion because of difficulties in remaining in the retroperitoneal space due to a peritoneal tear during the procedure. The mean operative time was 148.4 minutes (range, 103-210 minutes). The mean estimated blood loss was 31 mL (range, 10-70 mL), and the mean postoperative hospital stay was 5.7 days (range, 3-13 days). Intraoperative complications were limited to the one case of peritoneal tear. An aberrant crossing vessel was noted in 4 patients, and transposition was not required in these patients. Urine leakage occurred in 1 patient postoperatively and was successfully treated by conservative management. The mean follow-up period was 6.2 months (range, 5-10 months). Satisfactory drainage with decreased hydronephrosis on IVU, diuretic renal scan, and renal ultrasonography was observed in all cases at the 3-month imaging studies., Conclusions: In experienced hands, LESS retroperitoneoscopic dismembered pyeloplasty is a feasible and safe alternative for correcting UPJO, although it remains technically challenging. The long-term outcome awaits further studies.

Purpose: To present our early experience with retroperitoneal laparoendoscopic single-site (LESS) simple nephrectomy., Patients and Methods: A total of 16 patients with benign nonfunctioning kidney underwent retroperitoneal LESS nephrectomy by one experienced laparoscopic surgeon. A single-port access was inserted through an approximately 3-cm lumbar incision made below the 12th rib along the midaxillary line. Standard steps of multisite retroperitoneoscopic nephrectomy technique with a combination of conventional and bent laparoscopic instruments were performed., Results: Retroperitoneal LESS nephrectomy was performed in 15 cases successfully. The procedure of one patient (genitourinary tuberculosis) needed conversion to open surgery because of the severe adhesions surrounding the kidney, which resulted in failure to progress. Overall, the mean operative time was 85 (75-140) minutes, and estimated blood loss was 56 (20-110) mL. The mean time to resume oral diet was 1.5 days. The mean postoperative hospital stay was 4 (3-5) days. Perioperative complications were limited to one case of transient postoperative fever. No major intraoperative and postoperative complication occurred., Conclusions: Retroperitoneal LESS nephrectomy performed by an experienced laparoscopic surgeon is feasible and safe, offering improved cosmesis, although it remains technically challenging. Retroperitoneal LESS nephrectomy should be selectively used in terms of patients' specific conditions.

Duck hepatitis virus type 1 (DHV-1) causes a highly contagious disease in ducklings and is often associated with liver necrosis, hemorrhages, and high mortality. In the current study, the expression levels of gene transcripts encoding proinflammatory cytokines and the virus were measured by quantitative reverse-transcription PCR in duck livers after infection with a DHV-1 JX isolate obtained from natural cases in Hubei Province, China. In addition, sera IL-1β, IL-6, and alanine aminotransferase levels were quantified. Liver histopathology was examined following DHV-1 infection. The ducklings died within 1 to 2 d postinfection (d.p.i.) because of typical liver degeneration, hemorrhage, necrosis, and bile-duct epithelial cell proliferation. Transcripts of the cytokines IFN-α, IL-6, TNF-α, and IL-10 decreased by 0.5 d.p.i. and then gradually increased at 1 d.p.i. Similarly, DHV-1 JX 3D gene levels in the liver sharply increased at 1 d.p.i. and then maintained a high level. In contrast, liver TNF-α and IL-1β transcripts showed no increased expression of the cytokine gene postinfection and significantly decreased compared with the expression at 0.25 d.p.i., only the expression of IFN-α transcripts increased 128-fold by 1 d.p.i. Changes in the serum IL-6 level remained relatively stable postinfection and not significantly different compared with that of the control (P > 0.05), whereas serum levels of IL-1β significantly decreased at 0.5 d.p.i. and increased from 1 d.p.i. onwards (P < 0.05). Serum alanine aminotransferase levels significantly increased 2 d.p.i. compared with that of the control group (P < 0.01), which seemed to keep with the number of dead ducks. The cytokines exhibited a biphasic pattern following DHV-1 JX infection. Taken together, the data indicated that duckling liver inflammatory responses were produced following experimental DHV-1 JX infection involving multiple cytokines.

To establish a potential resource for cell therapy and a developmental model for human diseases, we had isolated three Chinese human embryonic stem cell lines from the inner cell mass of human blastocysts in 2002. All the three cell lines were grown on mouse embryonic fibroblasts as feeder cells; one of these cell lines, chHES-3, has maintained its normal karyotype even after being cultured in vitro for more than 100 passages, after the standardization of mouse feeder preparation. Each hES cell line has been completely characterized. All the three cell lines expressed hES-specific markers and pluripotency-related genes. These cells maintained their normal karyotype during long-term culture and displayed a high telomerase activity. When differentiated in vivo and in vitro, the derivatives representing the three germ layers could be observed. Human leukocyte antigen, ABO blood type, and DNA fingerprinting were also performed to provide a unique identity to each cell line. By establishing these hES cell lines, we provide an appropriate in vitro model to study human development and regeneration. All the three cell lines can be obtained for research purposes by placing a request at our website at www.hescbank.cn.