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The role of hydrogen sulphide (H

To compare the efficacy and safety of induction chemotherapy (IC) followed by intensity‐modulated radiotherapy (IMRT) alone versus concurrent CCRT in locoregionally advanced nasopharyngeal carcinoma (LA‐NPC). Patients with newly diagnosed stage III to IVB nasopharyngeal carcinoma (NPC) were randomized to receive IC plus IMRT (IC+RT arm), or concurrent chemotherapy plus IMRT (CCRT arm), using a random number table. Both treatment arms received the same chemotherapy regimen. The primary endpoint was progression‐free survival (PFS). Secondary end points included overall survival (OS), locoregional recurrence‐free survival (LRRFS), distant metastasis‐free survival (DMFS), treatment response, and acute treatment toxicities. From June 2013 to September 2018, a total of 204 patients histologically diagnosed with LA‐NPC were enrolled in the study, with 102 patients randomly assigned to each arm. After a median follow‐up duration of 45 months (range 4 to 84 months), the 3‐year PFS, OS, LRRFS and DMFS were 72.2%, 87.8%, 92.3%, and 82.7% in the IC+RT arm, compared with 82.6%, 92.8%, 94.7%, and 88.2% in the CCRT arm. No statistical difference for PFS, OS, LRRFS, DMFS, or treatment response was observed between the two arms (p > 0.05). The incidences of leukopenia (p = 0.008) and anemia (p = 0.015) were significantly higher in patients in the CCRT arm than those in the IC+RT arm. Compared to CCRT, IC plus IMRT alone provided similarly favorable treatment outcomes in terms of PFS, OS, LRRFS, and DMFS for patients with LA‐NPC, but resulted in fewer incidences of leukopenia and anemia., Concurrent chemoradiotherapy is the standard modality for locoregionally advanced nasopharyngeal carcinoma, accompanied with non‐negligible toxicities and poor compliance. The authors present comparable favorable treatment results in a randomize trial comparing induction chemotherapy plus IMRT versus CCRT. While induction chemotherapy plus IMRT had fewer incidences of leukopenia and anemia. The authors propose that induction chemotherapy plus IMRT is a promising option for locoregionally advanced nasopharyngeal carcinoma and further investigation to identify favorite individuals is warranted.

miR‐34a‐5p up‐regulates the IL‐1β/COX2/PGE2 inflammation pathway and induces apoptosis and the release of calcitonin gene‐related peptide via inhibition of SIRT1 expression in trigeminal ganglion neurons. This suggests that miR‐34a‐5p may have potential for development into a therapeutic target for the treatment of migraine., Migraine is a debilitating neurological condition, with a global prevalence rate of 10.68% in men and 18.79% in women. Elucidation of the molecular mechanisms underlying migraines is of great importance for improving the quality of life of patients. The release of the neuropeptide calcitonin gene‐related peptide (CGRP) from trigeminal nerve terminals is involved in the pathogenesis of migraine. Recent studies have shown that up‐regulation of miR‐34a‐5p expression is associated with acute migraine attacks. Here, we investigated whether alteration of the expression of miR‐34a‐5p induces the release of the vasoactive peptide CGRP. We isolated primary rat trigeminal ganglion neurons and performed gain‐ and loss‐of‐function assays to alter the expression level of miR‐34a‐5p. Down‐regulation of miR‐34a‐5p inhibited the expression of interleukin‐1β (IL‐1β)/cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2), decreased IL‐1β, PGE2 and CGRP release, and up‐regulated the expression of silencing information regulator 1 (SIRT1) in trigeminal ganglion, whereas overexpression of miR‐34a‐5p enhanced the expression of IL‐1β/COX2/PGE2, increased the release of IL‐1β, PGE2 and CGRP, and decreased the expression of SIRT1 in trigeminal ganglion. In addition, overexpression of miR‐34a‐5p induced apoptosis in primary rat trigeminal neurons. In summary, these findings suggest that miR‐34a‐5p up‐regulates the IL‐1β/COX2/PGE2 inflammation pathway, induces apoptosis and enhances release of CGRP via inhibition of SIRT1 expression in trigeminal ganglion neurons; thus, miR‐34a‐5p may have potential as a therapeutic target for the treatment of migraine.

The amino acid sequence enriched with proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) is a signal-transducing agent providing unique features to its substrate nuclear proteins (PEST-NPs). The PEST motif is responsible for particular posttranslational modifications (PTMs). These PTMs impart distinct properties to PEST-NPs that are responsible for their activation/inhibition, intracellular localization, and stability/degradation. PEST-NPs participate in cancer metabolism, immunity, and protein transcription as oncogenes or as tumor suppressors. Gene-based therapeutics are getting the attention of researchers because of their cell specificity. PEST-NPs are good targets to explore as cancer therapeutics. Insights into PTMs of PEST-NPs demonstrate that these proteins not only interact with each other but also recruit other proteins to/from their active site to promote/inhibit tumors. Thus, the role of PEST-NPs in cancer biology is multivariate. It is hard to obtain therapeutic objectives with single gene therapy. An especially designed combination gene therapy might be a promising strategy in cancer treatment. This review highlights the multifaceted behavior of PEST-NPs in cancer biology. We have summarized a number of studies to address the influence of structure and PEST-mediated PTMs on activation, localization, stability, and protein-protein interactions of PEST-NPs. We also recommend researchers to adopt a pragmatic approach in gene-based cancer therapy.

E-DRS is a novel salvianolic acid A (SAA) analog, which was synthesized from resveratrol (RES) and methyldopate. Its structure is similar to that of SAA, but the 3',4'-dihydroxy-trans-stilbene group and the ester structure in SAA were replaced by the RES structure and an amine group, respectively. E-DRS scavenged free oxygen radicals effectively, including superoxide anion (ascorbic acid > E-DRS > SAA ≥ rutin > RES) and DPPH radical (rutin > E-DRS ≥ ascorbic acid > SAA > RES), and exhibited powerful total antioxidant capacity (ascorbic acid > E-DRS > SAA ≥ rutin > RES) in vitro. Furthermore, oral administration of E-DRS dose-dependently and significantly decreased CCl4 -induced oxidative stress in mice as indicated by the decreased content of hepatic malondialdehyde (MDA). In addition, oral administration of E-DRS also increased the content of nonenzymatic antioxidant glutathione (GSH) and the activity of antioxidant enzymes such as catalase (CAT) and superoxide dismutase (SOD) in the liver of mice. All these results demonstrated that E-DRS had good antioxidant activities both in vitro and in vivo, and could be a potential antioxidant agent after further optimization and evaluation.

Ever reports showed that PCNP is associated with human cancers including neuroblastoma and lung cancer. However, the role and underlying molecular mechanism of PCNP in ovarian cancer have not been plenty elucidated. Herein, we first investigated the expression of PCNP in ovarian cancer tissues and cells, the effects of PCNP in ovarian cancer proliferation, apoptosis, migration and invasion, and determined the molecular mechanism of PCNP in ovarian cancer progression. The results indicated that PCNP was significantly overexpressed in human ovarian cancer tissues and cells, and related to poor prognosis in ovarian cancer patients. In addition, we also detected that PCNP promoted ovarian cancer cells growth, migration and invasion, as well as inhibited ovarian cancer cells apoptosis. Mechanistically, PCNP binding to β‐catenin promoted β‐catenin nuclear translocation and further activated Wnt/β‐catenin signalling pathway. Moreover, PCNP regulated the expression of genes involved in EMT and further triggered EMT occurrence. Conclusionally, PCNP may promote ovarian cancer progression through activating Wnt/β‐catenin signalling pathway and EMT, acting as a novel and promising target for treating ovarian cancer.

OBJECTIVE Equations for predicting body surface area (BSA) produce flawed estimates, especially for individuals with obesity. This study aimed to compare BSA measured by a three-dimensional photonic scanner (3DPS) with BSA predicted by six commonly cited prediction equations and to develop new prediction equations if warranted. METHODS The 3DPS was validated against manual measurements by breadth caliper for body thicknesses measured at three anatomical sites on a mannequin. BSA was derived from 3DPS whole-body scans of 67 males and 201 females, aged 18 to 83 years, with BMI between 17.8 and 77.8 kg/m2 and varied races/ethnicities. RESULTS Width and depth measurements by 3DPS and caliper were within 1%, except for hip, with an error of 1.8%. BSA3DPS differed from BSA predicted by each equation (P

Rural–urban migration is a defining feature of socio‐economic change in contemporary China. It is estimated that internal migrants in China account for 20% of its population of 1.39 billion, providing manpower to the expanding urban industries. Yet internal migrants have long faced barriers to accessing health and other social services in urban destinations, and the migration process may expose them to novel health risks and inequities. Based on the analysis of policy documents and associated material, this article reviews the historical development of health policy in China in relation to internal migrants, identifying elements of continuity and change in the policy agenda and the ways in which migrants have been framed in policy formulations. Against this background, remaining gaps in the current policy framework and implementation challenges are discussed.

Objective To investigate the correlation between acetylcholine receptor antibodies (AChR‐Ab) concentration levels and individualized clinical symptoms in patients with AChR myasthenia gravis (AChR‐MG) in China. Methods ELISA was used to determine the concentration of AChR‐Ab in patients with MG. The Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, Quantitative Myasthenia Gravis (QMG) score, and MG‐specific activities of daily living (MG‐ADL) scoring systems were used to evaluate the clinical status of patients. Spearman correlation analysis was used to determine the correlation between the AChR‐Ab concentration and clinical score. The changes in the antibody concentration and clinical score are shown in MGFA‐antibody concentration–treatment plots. Results Autoantibody detection tests were performed in 67 patients, and their clinical scores were recorded. Forty‐nine patients received immunosuppressive therapy, 17 patients received pyridostigmine only, and 1 patient under thymectomy without any medication. The AChR‐Ab concentration correlated with the MGFA Classification in 5 (29.4%) patients in the pyridostigmine‐only group and 15 (30.6%) patients in the immunosuppressive drug group. The changes in the MGFA Classification preceded the changes in the AChR‐Ab concentration in 4 (23.5%) patients treated with pyridostigmine and 10 (20.4%) patients on immunosuppressive drugs. In patients on oral non‐steroidal immunosuppressants, the AChR‐Ab concentration changed by more than 50%, whereas the MGFA Classification did not increase. The AChR‐Ab concentration decreased in 17/32 (53.1%) patients after thymectomy, and then increased, whereas the AChR‐Ab concentration increased in 15/32 (46.9%) patients and the MGFA Classification decreased in 27/32 (81.8%) patients after thymectomy. The AChR‐Ab concentration presented a slight correlation with the corresponding MGFA, QMG, and MG‐ADL in patients with thymoma. Discussion In the Chinese AChR‐MG population, the Changes in the AChR‐Ab concentration in individuals with AChR‐MG did not consistently correlate with the severity of clinical symptoms., We detected AChR‐Ab concentration at least four times per patient and performed corresponding clinical evaluations on 67 patients, and MGFA‐antibody concentration–treatment plots were drawn for each patient. We found that patients receiving oral glucocorticoid doses greater than 40 mg/d and nonsteroidal immunosuppressive drugs may have increased or decreased AChR‐Ab concentrations, and the clinical symptoms often improved to varying degrees. We did not find a consistent correlation between the changes in individual AChR‐Ab concentrations and the severity of clinical symptoms in patients.

This study aims to discuss the effect of triptolide (TPL) on rheumatoid arthritis (RA) and the mechanism related to osteoclast precursor (OCP) and osteoclast (OC). TNF-transgenic RA mice were treated with different doses of TPL by gavage. After the administration was finished, the curative effects were evaluated and compared, and the OCP apoptosis rates, the OC number, and the OC differentiation ability in vitro were detected. Finally, splenocytes of wild-type mice were cultured in vitro and induced to differentiate into OCP, and the cell apoptosis rate, cIAP2, and apoptotic effectors expression level were detected after cIAP2 overexpression and TPL administration. After TPL administration, the RA symptoms in the TPL groups were all better, the apoptosis rate of OCP was higher, and the amount of OC in vitro were lower than that in the control group (all P < 0.05), and all of the changes in the high-dose group were more obvious than the low-dose group. In splenocytes cells cultured in vitro, cIAP2 overexpression could decrease the apoptosis rate of OCPs and increase the OC number, and TPL treatment could down-regulate the cIAP2 and promote OCP apoptosis and OC reduction. In conclusion, TPL could induce OCP apoptosis and inhibit OC formation to effectively treat RA by mediating cIAP2 degradation.

There is an urgent need to develop new life‐prolonging therapy for pancreatic ductal adenocarcinoma (PDAC). It is demonstrated that improved irinotecan delivery by a lipid bilayer coated mesoporous silica nanoparticle, also known as a silicasome, can improve PDAC survival through a chemo‐immunotherapy response in an orthotopic Kras‐dependent pancreatic cancer model. This discovery is premised on the weak‐basic properties of irinotecan, which neutralizes the acidic lysosomal pH in PDAC cells. This effect triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death (ICD), and programmed death‐ligand 1 (PD‐L1) expression. ICD is characterized by calreticulin expression and high‐mobility group box 1 (HMGB1) release in dying Kras‐induced pancreatic cancer (KPC) cells, which is demonstrated in a vaccination experiment to prevent KPC tumor growth on the contralateral site. The improved delivery of irinotecan by the silicasome is accompanied by robust antitumor immunity, which can be synergistically enhanced by anti‐PD‐1 in the orthotopic model. Immunophenotyping confirms the expression of calreticulin, HMGB1, PD‐L1, and an autophagy marker, in addition to perforin and granzyme B deposition. The chemo‐immunotherapy response elicited by the silicasome is more robust than free or a liposomal drug, Onivyde. The silicasome plus anti‐PD‐1 leads to significantly enhanced survival improvement, and is far superior to anti‐PD‐1 plus either free irinotecan or Onivyde., Improved irinotecan delivery by silicasome can improve pancreatic ductal adenocarcinoma (PDAC) survival through a chemo‐immunotherapy response when combined with anti‐PD‐1 in an orthotopic Kras‐dependent PDAC model. This discovery is premised on the weak‐basic properties of irinotecan, which neutralizes the acidic lysosomal pH and triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death, and PD‐L1 expression.

Background and aim Results obtained from different hepatitis E virus (HEV) tests are usually inconsistent. The detection of serum HEV antigen (Ag) has been suggested to be more sensitive for the diagnosis of genotypes 1 and 3 HEV. Methods We compared the diagnostic accuracies of serum HEV Ag and HEV RNA by using 202 serum samples from patients suspected acute viral hepatitis. Results The HEV Ag assay was 100% specific. The lower detected levels of viremia ranged from 102 to 103 copies/mL. The sensitivity of the HEV Ag test was 90.5%. One of the 42 cases was negative for anti-HEV IgM, but HEV Ag was still detectable. The detectable period of HEV Ag was in concordance with the detectable period of HEV RNA. Serum HEV Ag was persistently detected in two cases of chronic hepatitis E, confirmed by the persistent presence of HEV RNA despite being negative for anti-HEV IgM. HEV Ag demonstrated good consistency with positive HEV RNA (k = 0.938, P 0.095 to predict HEV patients with 95.24% sensitivity and 98.75% specificity, and the area under the curve was 0.9887, which was higher than that of three commercial anti-HEV IgM ELISA tests. Conclusions The presence of HEV Ag has good consistency with HEV RNA in both acute and chronic genotype 4 hepatitis E. HEV Ag is a more promising serum marker to identify active genotype 4 HEV infection than anti-HEV IgM and HEV RNA.

Gefitinib has been widely used in the first-line treatment of advanced EGFR-mutated non-small-cell lung cancer (NSCLC). However, many NSCLC patients will acquire resistance to gefitinib after 9-14 months of treatment. This study revealed that Krüppel-like factor 4 (KLF4) contributes to the formation of gefitinib resistance in c-Met-overexpressing NSCLC cells. We observed that KLF4 was overexpressed in c-Met-overexpressing NSCLC cells and tissues. Knockdown of KLF4 increased tumorigenic properties in gefitinib-resistant NSCLC cell lines without c-Met overexpression, but it reduced tumorigenic properties and increased gefitinib sensitivity in gefitinib-resistant NSCLC cells with c-Met overexpression, whereas overexpression of KLF4 reduced gefitinib sensitivity in gefitinib-sensitive NSCLC cells. Furthermore, Western blot analysis revealed that KLF4 contributed to the formation of gefitinib resistance in c-Met-overexpressing NSCLC cells by inhibiting the expression of apoptosis-related proteins under gefitinib treatment and activating the c-Met/Akt signaling pathway by decreasing the inhibition of β-catenin on phosphorylation of c-Met to prevent blockade by gefitinib. In summary, this study's results suggest that KLF4 is a promising candidate molecular target for both prevention and therapy of NSCLC with c-Met overexpression.

The integration of hypoxia-activated chemotherapy with photodynamic therapy (PDT) has newly become a potent strategy for tumor treatment. Herein, a reactive oxygen species (ROS)-responsive drug carriers (PS@AQ4N/mPEG-b-PSe NPs) are fabricated based on the amphiphilic selenium-containing methoxy poly(ethylene glycol)-polycarbonate (mPEG-b-PSe), the hydrophobic photosensitizer (PS), and hypoxia-activated prodrug Banoxantrone (AQ4N). The obtained nanoparticles are spherical with an average diameter of 100 nm as characterized by transmission electron microscope (TEM) and dynamic laser scattering (DLS) respectively. The encapsulation efficiency of the PS and AQ4N reaches 92.83% and 51.04% at different conditions, respectively, by UV-vis spectrophotometer. It is found that the drug release is accelerated due to the good ROS responsiveness of mPEG-b-PSe and the cumulative release of AQ4N is up to 89% within 30 h. The cell test demonstrates that the nanoparticles dissociate when triggered by the ROS stimuli in the cancer cells, thus the PS is exposed to more oxygen and the ROS generation efficiency is enhanced accordingly. The consumption of oxygen during PDT leads to the increased tumor hypoxia, and subsequently activates AQ4N into cytotoxic counterpart to inhibit tumor growth. Therefore, the synergistic therapeutic efficacy demonstrates this drug delivery has great potential for antitumor therapy.

N6 -methyladenosine (m6 A) modification is an abundant and conservative RNA modification in bacterial and eukaryotic cells. m6 A modification mainly occurs in the 3' untranslated regions (UTRs) and near the stop codons of mRNA. Diverse strategies have been developed for identifying m6 A sites in single nucleotide resolution. Dynamic regulation of m6 A is found in metabolism, embryogenesis, and developmental processes, indicating a possible epigenetic regulation role along RNA processing and exerting biological functions. It has been known that m6 A editing involves in nuclear RNA export, mRNA degradation, protein translation, and RNA splicing. Deficiency of m6 A modification will lead to kinds of diseases, such as obesity, cancer, type 2 diabetes mellitus (T2DM), infertility, and developmental arrest. Some specific inhibitors against methyltransferase and demethylase have been developed to selectively regulate m6 A modification, which may be advantageous for treatment of m6 A related diseases. J. Cell. Biochem. 118: 2534-2543, 2017. © 2017 Wiley Periodicals, Inc.

In this study a mesoporous silica nanoparticle (MSNP) based platform is developed for high-dose loading of a range of activated platinum (Pt) chemo agents that can be attached to the porous interior through the use of electrostatic and coordination chemistry under weak-basic pH conditions. In addition to the design feature for improving drug delivery, the MSNP can also be encapsulated in a coated lipid bilayer (silicasome), to improve the colloidal stability after intravenous (IV) injection. Improved pharmacokinetics and intratumor delivery of encapsulated activated oxaliplatin (1,2-diamminocyclohexane platinum(II) (DACHPt)) over free drug in an orthotopic Kras-derived pancreatic cancer (PDAC) model is demonstrated. Not only does IV injection of the DACHPt silicasome provide more efficacious cytotoxic tumor cell killing, but can also demonstrate that chemotherapy-induced cell death is accompanied by the features of immunogenic cell death (ICD) as well as a dramatic reduction in bone marrow toxicity. The added ICD features are reflected by calreticulin and high-mobility group box 1 expression, along with increased CD8+ /FoxP3+ T-cell ratios and evidence of perforin and granzyme B release at the tumor site. Subsequent performance of a survival experiment, demonstrates that the DACHPt silicasome generates a significant improvement in survival outcome, which can be extended by delayed administration of the anti-PD-1 antibody.

Axially chiral binaphthoic acid (BNA) was studied as a resolving agent for a stereoselective crystallization of 1-(4-chlorophenyl)ethylamine (CPEA). The diastereomeric pair of (R)-BNA/(S)-CPEA crystallizes in methylene chloride, on the other hand, the pair of (S)-BNA/(S)-CPEA crystallizes in acetone. The switch of the solubility of the diastereomeric pair is due to the imine formation with acetone. The very low solubility of the BNA/imine pair appears to be responsible for the fast and complete imine formation. The crystal structure of the BNA part in both crystals of the diastereomers maintains a same feature. Asymmetric chiral channels and pockets composed by intermolecular packing of BNA molecules appear in the crystal structures, and the robustness of them seem to contribute to the recognition of the chirality of CPEA with high selectivity.

The syntheses, structures, and magnetic properties of two series of Cr–Ln heterometallic clusters based on the 2,2′-bipyridine (bipy) ligand are reported; binuclear [LnCr(bipy)2(μ2-OH)2(H2O)6](ClO4)4·2H2O {Ln = Gd (1Gd) or Dy (1Dy)} and trinuclear [LnCr2(bipy)4(μ2-OH)4(H2O)4](ClO4)5·H2O {Ln = Gd (2Gd), Dy (2Dy), or Tb (2Tb)}. Their syntheses could be controlled by the amount of lanthanide perchlorate used. The binuclear [CrLn] clusters could be formed with 24 equivalents of Ln(ClO4)3, whereas 12 equivalents of Ln(ClO4)3 gave the trinuclear [Cr2Ln] species with a CrLnCr core. The Cr3+ and Ln3+ ions are bridged by μ2-OH groups in the two systems, and the [Cr2Ln] cluster is further assembled into a 1D supramolecular architecture by weak intermolecular π–π interactions. Magnetic analyses reveal that the Cr···Gd interactions in 1Gd and 2Gd are both antiferromagnetic.

Background To determine whether periconceptional use of multivitamin supplements containing folic acid increases the occurrence of male births in a Chinese population. Methods A prospective cohort study was carried out in 18 counties in four provinces of China. Participants were naturally and voluntarily divided into an intervention group (who took a multivitamin pill containing folic acid, n = 25 418) and a control group (who did not take any multivitamin, n = 26 580). Multivitamin supplements containing folic acid was ascertained before pregnancy. Pregnant women were followed through the first trimester of pregnancy and the outcome of pregnancy (i.e. livebirth, stillbirth, or fetal death; sex at birth) was recorded. Results A total of 52 043 pregnancies and 51 998 births were recorded between September 2000 and August 2002. The proportion of males born to women who did and did not take the multivitamin were 54.8% (n = 13 935) and 54.0% (n = 11 483), respectively. The male to female sex ratios at birth among women who did and did not take the multivitamin were 117:100 and 121:100, respectively. The risk ratio was 1.03 [95% confidence interval 0.99, 1.06] after adjusting for confounding factors. Conclusions These findings suggest that periconceptional multivitamin supplementation containing folic acid is not associated with an increased likelihood of male births in a Chinese population. However, these results may have been affected by induced abortion or selective termination of pregnancy, and the findings must therefore be cautiously interpreted.