APC mutations disrupt ß-catenin destruction complex condensates organized by Axin phase separation.

The Wnt/ß-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the ß-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of ß-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the ß-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3ß and CK1α were unsuccessfully recruited, preventing ß-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of ß-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.

Characterization of an imported HIV-1 A1/A7/G recombinant in China.

BACKGROUND: International migration has accelerated the HIV-1 spread across national borders, gradually reducing the restrictions on the geographical distribution of HIV-1 subtypes. Subtypes A and G are globally recognized as the third and sixth most dominant HIV-1 genotypes, mainly prevalent in Africa, but rarely detected in China. Here we reported an imported HIV-1 recombinant which was composed of sub-subtypes A1 and A7 of subtype A and subtype G genes in a Chinese female. This virus was the first HIV-1 recombinant including A7 genes reported in the world. CASE PRESENTATION: The near full-length genome (NFLG) was obtained from the plasma sample of the female in an HIV-1 molecular epidemiological survey with 853 participants in China. Phylogenetic analyses showed that this NFLG sequence contains three A7 segments, four G segments and one A1 segment with seven breakpoints, and all these segments were closely related to HIV-1 references circulating in Africa. The evidence from epidemiological investigation indicated that this female participant had a more-than-two-years heterosexual contact history with a fixed partner from Nigeria, a country in west Africa, which further supported the results of phylogenetic analyses. By the Bayesian phylogenetic analyses, the times of most recent common ancestors (tMRCA) of the partial pol gene (nt2308-3284, A7 region) and full-length vpr-vpu plus partial env gene (nt5534-6858, G region) were estimated around 1989 and 1984, respectively. CONCLUSIONS: In this study, by using the NFLG sequencing, we identified an imported HIV-1 A1/A7/G recombinant which was estimated to originate around 1980s in Africa and introduced into China with international migration. This study highlighted the complexity of the global HIV-1 epidemic, the necessity of using genome sequences to determine HIV-1 genotypes and the importance of real-time monitoring of HIV-1 infection among international migrants and travelers.

Cobalt/Salicylaldehyde-Enabled C-H Alkoxylation of Benzamides with Secondary Alcohols under Solvothermal Conditions.

C-O bond formation via C-H alkoxylation remains a challenge, especially coupling with a secondary alcohol, due to its low activity and sterically encumbered property. Here, we report a general and effective cobalt-catalyzed oxidative cross-coupling of benzamides with secondary alcohols via C-H alkoxylation reaction under solvothermal conditions, enabled by a salicylaldehyde/cobalt complex. The protocol features easy operation without additives, broad substrate scope, and excellent functional tolerance. The applicability is proven by the gram-scale synthesis and modification of natural products.

Salicylaldehyde-Cobalt(II)-Catalyzed C-H Alkoxylation of Indoles with Secondary Alcohols.

A straight and efficient protocol for the synthesis of hindered indole-ethers via C-H alkoxylation of indoles was developed by a cobalt-catalyzed cross-dehydrogenative coupling reaction with secondary alcohols. The selection of the salicylaldehyde-Co(II) catalyst enables the reaction to proceed under conditions without acid or base addition in the presence of limited alcohols. The protocol has broad substrate scope for both indole and secondary alcohols and exhibits good functional tolerance. The synthetic applications are proven by gram-scale reaction and further diversification of the product. Preliminary mechanistic investigations indicate that the activation of C-H bonds is not the rate-determining step of the reaction.

IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP.

BACKGROUND: Pyroptosis is closely related to inflammation. However, the molecular mechanisms and pathologic contributions of pyroptotic epithelial cell are not yet fully understood. OBJECTIVE: This study aimed to explore the function and molecular mechanisms of IL-17A on human nasal epithelial cell (hNEC) pyroptosis. METHODS: The expression of pyroptosis-related biomarkers and IL-17A was assessed in sinonasal mucosa from control individuals, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic rhinosinusitis with nasal polyps (CRSwNP) by using quantitative RT-PCR. Their localization was analyzed via immunohistochemistry and immunofluorescence. The ultrastructural characteristics of IL-17A-induced pyroptosis in hNECs were visualized by using electron microscopy. IL-17A functional assays were performed on hNECs and airway epithelial cell lines. Cytokine levels were quantified via ELISA. The signaling pathways involved in IL-17A-induced pyroptosis were studied via unbiased RNA sequencing and Western blotting. RESULTS: The expression of IL-17A and the pyroptotic biomarkers NOD-like receptor family, pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D, and IL-1ß was increased in nasal mucosa from patients with CRSwNP compared with in those with chronic rhinosinusitis without nasal polyps and the control subjects. IL-17A was positively correlated and colocalized with the pyroptotic biomarkers. IL-17A treatment induced pyroptosis in the hNECs and cell lines analyzed, primarily through the extracellular signal-regulated kinase (ERK)-NLRP3/caspase-1 signaling pathway, and increased IL-1ß and IL-18 secretion in hNECs. Moreover, IL-17A-induced pyroptosis contributed to steroid resistance by affecting glucocorticoid receptor-α and glucocorticoid receptor-ß expression, and the inhibition of pyroptotic proteins partially abolished IL-17A-induced steroid resistance in hNECs. CONCLUSION: Elevated IL-17A level promotes pyroptosis in hNECs through the ERK-NLRP3/caspase-1 signaling pathway and contributes to glucocorticoid resistance by affecting glucocorticoid receptor homeostasis in patients with CRSwNP.

Modeling Approaches to Reimagine Stability (MARS) for Enabling Earlier Access to Critical Drugs for Patients with Unmet Medical Needs.

FDA's experience to date has shown that completion of stability data requirements is one of the most observed challenges for applicants of New Drug Applications (NDAs) with an expedited review designation. Since NDAs submitted under these expedited pathways often have limited available real-time stability data from the primary batches, Modeling Approaches to Reimagine Stability (MARS) have been proposed to support establishment of tentative retest periods of the drug substance and/or expiration dating period (shelf-life) of the drug product. MARS incorporate statistical principles and available tools as a part of the predictive models. In this study, a data mining exercise has been conducted with regulatory submissions of Investigational New Drug (IND) Applications, NDAs, and Abbreviated New Drug Applications (ANDAs) containing MARS data. The case studies presented herein demonstrate how MARS data has been applied to regulatory scenarios involving prediction of retest and/or shelf-life, bridging major development changes, and confirming that no degradation has been observed or predicted. Using the assumption of a linear time trend for those cases that do not display sufficient degradation to conduct MARS for projection of an expiration date, an analysis of covariance (ANCOVA) model is developed and described herein to test the hypothesis of zero slope by a p-value method. Our results show that the application of MARS adequately supported establishment of a tentative commercially viable retest date/shelf-life, thus enabling earlier access to critical drugs for patients with unmet medical needs.

Enhanced function of NR2C/2D-containing NMDA receptor in the nucleus accumbens contributes to peripheral nerve injury-induced neuropathic pain and depression in mice.

N-methyl-d-aspartate receptors (NMDARs) dysfunction in the nucleus accumbens (NAc) participates in regulating many neurological and psychiatric disorders such as drug addiction, chronic pain, and depression. NMDARs are heterotetrameric complexes generally composed of two NR1 and two NR2 subunits (NR2A, NR2B, NR2C and NR2D). Much attention has been focused on the role of NR2A and NR2B-containing NMDARs in a variety of neurological disorders; however, the function of NR2C/2D subunits at NAc in chronic pain remains unknown. In this study, spinal nerve ligation (SNL) induced a persistent sensory abnormity and depressive-like behavior. The whole-cell patch clamp recording on medium spiny neurons (MSNs) in the NAc showed that the amplitude of NMDAR-mediated excitatory postsynaptic currents (EPSCs) was significantly increased when membrane potential held at -40 to 0 mV in mice after 14 days of SNL operation. In addition, selective inhibition of NR2C/2D-containing NMDARs with PPDA caused a larger decrease on peak amplitude of NMDAR-EPSCs in SNL than that in sham-operated mice. Appling of selective potentiator of NR2C/2D, CIQ, markedly enhanced the evoked NMDAR-EPSCs in SNL-operated mice, but no change in sham-operated mice. Finally, intra-NAc injection of PPDA significantly attenuated SNL-induced mechanical allodynia and depressive-like behavior. These results for the first time showed that the functional change of NR2C/2D subunits-containing NMDARs in the NAc might contribute to the sensory and affective components in neuropathic pain.

Discovery of a pyrano[2,3-b]pyridine derivative YX-2102 as a cannabinoid receptor 2 agonist for alleviating lung fibrosis.

BACKGROUND: Pharmacological modulation of cannabinoid 2 receptor (CB2R) is a promising therapeutic strategy for pulmonary fibrosis (PF). Thus, to develop CB2R selective ligands with new chemical space has attracted much research interests. This work aims to discover a novel CB2R agonist from an in-house library, and to evaluate its therapeutic effects on PF model, as well as to disclose the pharmacological mechanism. METHODS: Virtual screening was used to identify the candidate ligand for CB2R from a newly established in-house library. Both in vivo experiments on PF rat model and in vitro experiments on cells were performed to investigate the therapeutic effects of the lead compound and underlying mechanism. RESULTS: A "natural product-like" pyrano[2,3-b]pyridine derivative, YX-2102 was identified that bound to CB2R with high affinity. Intraperitoneal YX-2102 injections significantly ameliorated lung injury, inflammation and fibrosis in a rat model of PF induced by bleomycin (BLM). On one hand, YX-2102 inhibited inflammatory response at least partially through modulating macrophages polarization thereby exerting protective effects. Whereas, on the other hand, YX-2102 significantly upregulated CB2R expression in alveolar epithelial cells in vivo. Its pretreatment inhibited lung alveolar epithelial-to-mesenchymal transition (EMT) in vitro and PF model induced by transforming growth factor beta-1 (TGF-ß1) via a CB2 receptor-dependent pathway. Further studies suggested that the Nrf2-Smad7 pathway might be involved in. CONCLUSION: These findings suggest that CB2R is a potential target for PF treatment and YX-2102 is a promising CB2R agonist with new chemical space.

Pinitol Protects Against Ox-Low-Density Lipoprotein-Induced Endothelial Inflammation and Monocytes Attachment.

ABSTRACT: Atherosclerosis is a cardiovascular disease that affects a majority of people around the world at old age. Atherosclerosis is slow to develop and challenging to treat. Endothelial dysfunction caused by oxidative stress, inflammation, and other pathological factors drives the process of atherogenesis. LOX-1 is one of the main scavenging receptors for oxidized low-density lipoprotein (ox-LDL) and contributes to atherogenesis by inducing overproduction of reactive oxygen species, increased expression of proinflammatory cytokines, and secretion of cellular adhesion molecules. In addition, activation of LOX-1 inhibits the expression of KLF2, a key protective factor against atherosclerosis. In this study, we investigated the effects of pinitol, and naturally occurring cyclic polyol, on endothelial dysfunction induced by ox-LDL. Our findings show that pinitol revealed a good safety profile, as evidenced by reducing lactate dehydrogenase release in human aortic endothelial cells. In our experiments, pinitol reduced the production of reactive oxygen species and expression of IL-6 and monocyte chemoattractant protein-1 induced by ox-LDL. Pinitol also significantly reduced the attachment of THP-1 monocytes to endothelial cells via downregulation of vascular cellular adhesion molecule-1 and E-selectin. Importantly, we found that pinitol reduced the expression of LOX-1 induced by ox-LDL and rescued the expression of KLF2, which is dependent on ERK5 expression. Together, our findings provide notable evidence that pinitol may have potential implication in the prevention and treatment of atherosclerosis.

Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study.

BACKGROUND: The mortality rate remains high among patients with coinfection with Pneumocystis pneumonia (PCP) and HIV. The timing for initiation of antiretroviral therapy (ART) after a diagnosis of moderate to severe PCP remains controversial, however. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS-associated PCP (AIDS/PCP) patients. METHODS: This was a multicenter, observational, prospective clinical trial. Eligible participants were recruited from 14 hospitals in mainland China, and assigned to an Early ART arm (initiation of ART ≤ 14 days after PCP diagnosis) and a Deferred ART arm (initiation of ART > 14 days after PCP diagnosis). The primary outcomes were death and the incidence of AIDS-defining events at week 48. The secondary outcomes were the changes in CD4+ T-cell counts from baseline values at weeks 12, 24, and 48, the virological suppression rate at week 24 and week 48, the rate of development of PCP-associated immune reconstitution inflammatory syndrome (PCP/IRIS), and the rate of adverse events over 48 weeks. RESULTS: The present study was performed using the data of 363 participants, with 169 participants in the Early ART arm, and 194 participants in the Deferred ART arm. Immunological and virological outcomes were found to be similar in both treatment arms. At week 48, there were no significant differences for the incidence of mortality (20 vs. 26, p = 0.860), and AIDS-defining events (17 vs. 26, p = 0.412). Over 48 weeks, the rates of PCP/IRIS (2 vs. 3, p = 1.000), adverse events (70 vs. 72, p = 0.465), and grade 3 or 4 adverse events (28 vs. 34, p = 0.919) did not reach statistical significance. A significant difference observed between two study arms was that 11 participants (55.0%) in the Early ART arm compared to 23 participants (88.5%) in the Deferred ART arm (p = 0.026) succumbed before ART had ever been started. CONCLUSIONS: Early ART initiation results in no increase in mortality, AIDS-defining events, IRIS, adverse events, and immunological or virological outcomes. These results support the early initiation of ART in patients with moderate to severe AIDS/PCP. Clinical trial registration The present trial was registered at Chinese Clinical Trial Registry (ChiCTR1900021195). Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

Polycythemia Vera With Multiple Cerebral Infarctions Complicated By Cerebral Microhemorrhage: A Report of Two Cases.

Polycythemia vera (PV) has multiple vascular risk factors and gradual onset and is an important risk factor for stroke. The first manifestation in some patients with PV is thrombotic cerebrovascular events. However, there are few reports on polycythemia vera with multiple cerebral infarctions and cerebral microhemorrhage. The clinical and imaging features of two PV patients with multiple cerebral infarctions complicated by cerebral microhemorrhage were analyzed retrospectively in order to improve the clinical understanding of the disease.

Multi-omics provide mechanistic insight into the Pb-induced changes in tadpole fitness-related traits and environmental water quality.

Water pollution from lead/Pb2+ poses a significant threat to aquatic ecosystems, and its repercussions on aquatic animals have received considerable attention. Although Pb2+ has been found to affect numerous aspects of animals, including individual fitness, metabolic status, and symbiotic microbiota, few studies have focused on the associations between Pb2+-induced variations in fitness, metabolome, symbiotic microbiome, and environmental parameters in the same system, limiting a comprehensive understanding of ecotoxicological mechanisms from a holistic perspective. Moreover, most ecotoxicological studies neglected the potential contributions of anions to the consequences generated by inorganic lead compounds. We investigated the effects of Pb(NO3)2 at environmentally relevant concentrations on the Rana omeimontis tadpoles and the water quality around them, using blank and NaNO3-treated groups as control. Results showed that Pb(NO3)2 not only induced a rise in water nitrite level, but exposure to this chemical also impaired tadpole fitness-related traits (e.g., growth and development). The impacts on tadpoles were most likely a combination of Pb2+ and NO3-. Tissue metabolomics revealed that Pb(NO3)2 exposure influenced animal substrate (i.e., carbohydrate, lipid, and amino acid) and prostaglandin metabolism. Pb(NO3)2 produced profound shifts in gut microbiota, with increased Proteobacteria impairing Firmicutes, resulting in higher aerobic and possibly pathogenic bacteria. NaNO3 also influenced tadpole metabolome and gut microbiome, in a manner different to that of Pb(NO3)2. The presence of NO3- seemed to counteract some changes caused by Pb2+, particularly on the microbiota. Piecewise structural equation model and correlation analyses demonstrated connections between tissue metabolome and gut microbiome, and the variations in tadpole phenotypic traits and water quality were linked to changes in tissue metabolome and gut microbiome. These findings emphasized the important roles of gut microbiome in mediating the effects of toxin on aquatic ecosystem. Moreover, it is suggested to consider the influences of anions in the risk assessment of heavy metal pollutions.

Correlation study on 18F-FDG PET/CT metabolic characteristics of primary lesion with clinical stage in lung cancer.

BACKGROUND: 18F-FDG PET/CT metabolic characteristics provide the crucial biologic and molecular information for tumors. To explore the relationships between 18F-FDG PET/CT derived parameters such as maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG) of primary tumor and clinical stage in different histopathologic subtypes of lung cancer. METHODS: A total of 97 newly diagnosed lung cancer patients (69 males, 28 females; average age 65.1 years) with pathologically proven were retrospectively analyzed, who had undergone 18F-FDG PET/CT scan before treatment from September 2016 to November 2017. SUVmax, MTV and TLG of primary tumor were measured. Clinical stage was mainly determined by 18F-FDG PET/CT, in conjunction with conventional imaging and endoscopic biopsy. Mann-Whitney U test, χ2 test, Spearman correlation test and ROC curve analysis were used for statistical analysis. RESULTS: There were 53 adenocarcinomas (AC), 28 squamous carcinomas (SCC), 13 small cell carcinomas (SCLC), one adenosquamous carcinoma, one mucoepidermoid carcinoma, and one sarcomatoid carcinoma in 97 patients. Both AC and SCLC revealed more cases in stage IV than in stage I-III (P<0.01). There was no significant difference in four stages of SCC (P>0.05). Metabolic parameters of SCC were higher than AC including SUVmax, MTV and TLG (P<0.01). SCLC showed a higher value than AC in TLG (P<0.05). No significant differences were found between AC and SCLC in SUVmax and MTV, also between SCC and SCLC in SUVmax, MTV and TLG (P>0.05). MTV and TLG except SUVmax were positively correlated with stage in AC (P≤0.001). Only MTV showed a positive correlation with stage in SCC (P<0.05). Whereas there were no definitive relationships between metabolic parameters and stage in SCLC (P>0.05). AC with a higher MTV (MTV≥5.965 cm3) indicated a significantly higher rate of distant metastasis than those with a lower MTV (77.5% (31/40) vs. 30.8% (4/13), χ2=9.553, P<0.01), as well as AC with a higher TLG (TLG≥46.922) than those with a lower TLG (88.5% (23/26) vs. 44.4% (12/27), χ2=11.422, P<0.01). CONCLUSIONS: Histopathologic subtypes have a significant influence on the relationships between MTV/TLG not SUVmax of primary foci and stage in lung cancer. Primary MTV/TLG is related to clinical stage closely in AC, and a higher MTV/TLG results in a higher risk of distant metastasis.

The Association between Interleukin-6 Gene Polymorphisms and Risk of Systemic Lupus Erythematosus: A Meta-analysis with Trial Sequential Analysis.

BACKGROUND: Molecular epidemiological studies have sought associations between interleukin-6 (IL-6) polymorphisms and the risk of systemic lupus erythematosus (SLE); however, the results are controversial. Therefore, we conducted a meta-analysis with trial sequential analysis to evaluate a more accurate estimation of the associations. METHODS: Published literatures reporting the relationships of two IL-6 polymorphisms (G-174C and G-572C) and SLE risk were retrieved from electronic databases such as PubMed and EMBASE. The most appropriate genetic model was chosen for each polymorphism. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Trial sequential analysis (TSA) was introduced to assess the information size and the positive results. RESULTS: With 17 studies (2780 cases and 3100 controls) included, a dominant association (CC+GC vs. GG) was suggested for G-174C polymorphism, and compared with the GG genotype, the CC+GC genotype of G-174C was associated with a decreased SLE risk (OR = 0.71; 95% CI = 0.56-0.88, P =.02). No association was found for G-572C under all genetic models (e.g. OR and 95%CI for CC+GC vs. GG: 0.89, 0.73-1.08, P =.22). Subgroup analyses indicated that SLE risk decreased in G-174C polymorphism by subgroups of Caucasian population, publications after 2010, studies with high quality, and studies complied with Hardy-Weinberg equilibrium (HWE). TSA suggested that the sample sizes used for G-572C were insufficient. CONCLUSION: We found that the minor allele C of IL6G-174C polymorphism is a protective factor in SLE. Further studies with a larger sample size are needed to confirm the null association for G-572C.

Establishment of a novel scoring model for mortality risk prediction in HIV-infected patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) remains a leading cause of death in HIV-infected patients, despite advances in CM diagnostic and therapeutic strategies. This study was performed with the aim to develop and validate a novel scoring model to predict mortality risk in HIV-infected patients with CM (HIV/CM). METHODS: Data on HIV/CM inpatients were obtained from a Multicenter Cohort study in China. Independent risk factors associated with mortality were identified based on data from 2013 to 2017, and a novel scoring model for mortality risk prediction was established. The bootstrapping statistical method was used for internal validation. External validation was performed using data from 2018 to 2020. RESULTS: We found that six predictors, including age, stiff neck, impaired consciousness, intracranial pressure, CD4+ T-cell count, and urea levels, were associated with poor prognosis in HIV/CM patients. The novel scoring model could effectively identify HIV/CM patients at high risk of death on admission (area under curve 0.876; p<0.001). When the cut-off value of 5.5 points or more was applied, the sensitivity and specificity was 74.1 and 83.8%, respectively. Our scoring model showed a good discriminatory ability, with an area under the curve of 0.879 for internal validation via bootstrapping, and an area under the curve of 0.886 for external validation. CONCLUSIONS: Our developed scoring model of six variables is simple, convenient, and accurate for screening high-risk patients with HIV/CM, which may be a useful tool for physicians to assess prognosis in HIV/CM inpatients.

Biogeographic diversification of Mahonia (Berberidaceae): Implications for the origin and evolution of East Asian subtropical evergreen broadleaved forests.

The subtropical evergreen broadleaved forests (EBLFs) inhabit large areas of East Asia and harbor rich biodiversity and high endemism. However, the origin and evolution of biodiversity of East Asian subtropical EBLFs remain poorly understood. Here, we used Mahonia (Berberidaceae), an eastern Asian-western North American disjunct evergreen genus, to obtain new insights into the historical assembly of this biome. We present the most comprehensive phylogenetic analysis of Mahonia do date based on six nuclear and plastid loci. Using the phylogenetic framework, we estimated divergence times, reconstructed ancestral ranges, inferred evolutionary shift of habitats, and estimated diversification rates. Mahonia and each of its two groups (Orientales and Occidentales) are strongly supported as monophyletic. Mahonia originated in western North America during the late Eocene (c. 40.41 Ma) and subsequently dispersed into East Asia prior to the early Oligocene (c. 32.65 Ma). The North Atlantic Land Bridge might have played an important role in population exchanges of Mahonia between East Asia and western North America. The western North American Occidentales began to diversify in summer-dry climates and open landscapes in the early Miocene, whereas the eastern Asian Orientales began to diversify in subtropical EBLFs in the early Miocene and furthermore had a rapid lineage accumulation since the late Miocene. The net diversification rate of Mahonia in eastern Asia appeared to be higher than that in western North America, which is ascribed to lower extinction rates and ecological opportunity. Our findings suggest that western North America is a source of biodiversity of East Asian subtropical EBLFs. This biome in eastern Asia began to rise in the early Miocene and further diversified in the late Miocene, driven by the intensifying East Asian summer monsoon during these two periods.

Induction chemotherapy for the individualised treatment of hypopharyngeal carcinoma with cervical oesophageal invasion: a retrospective cohort study.

BACKGROUND: This study aimed to evaluate the potential of induction chemotherapy as an indicator of the management of advanced hypopharyngeal carcinoma with cervical oesophageal invasion. METHODS: Sixty-eight patients admitted to our hospital between February 2003 and November 2016 with stage IVB hypopharyngeal carcinoma with cervical oesophageal invasion were retrospectively analysed. Patients were divided into two groups according to the treatment they selected following an explanation of the different treatments available. Patients in group A received induction chemotherapy and had (1) complete/partial remission following chemotherapy and radiotherapy/concurrent chemoradiotherapy or (2) stable disease following chemotherapy and surgery. Patients in group B underwent surgery followed by adjuvant radiotherapy/concurrent chemoradiotherapy. Survival analyses were performed using the Kaplan-Meier method, and differences between the groups were evaluated using the log-rank test. Laryngeal and oesophageal retention rates were compared using the cross-tabulation test. RESULTS: The 3- and 5-year overall survival rates were 22.86% and 11.43% in group A and 24.25% and 6.06% in group B, respectively (all P > 0.05). The laryngeal and oesophageal retention rates were 40.0% and 74.3% in group A and 0.0% and 27.3% in group B, respectively (all P < 0.01). There was no statistically significant difference in the incidence of post-operative complications between the two groups (group A 8.6%, group B 12.1%; P > 0.05). CONCLUSIONS: Induction chemotherapy may be an appropriate first choice to ensure laryngeal and oesophageal preservation in the individualised treatment of advanced hypopharyngeal carcinoma with cervical oesophageal invasion.

Association of trimethylamine N-Oxide with cardiovascular and all-cause mortality in hemodialysis patients.

BACKGROUND: Trimethylamine-N-Oxide (TMAO) is a proatherogenic and prothrombotic metabolite. Our study examined the association of plasma TMAO level with cardiovascular and all-cause mortality in hemodialysis (HD) patients. METHODS: Patients who were at least 18 years-old and received HD for at least 6 months were enrolled within 6 months. Patients with coronary heart disease, congestive heart failure, arrhythmia, or stroke within 3 months before study onset were excluded. The primary endpoints were cardiovascular and all-cause death, and the secondary endpoint was cerebrovascular death. RESULTS: We recruited 252 patients and divided them into a high-TMAO group (>4.73 µg/mL) and a low-TMAO group (≤4.73 µg/mL). The median follow-up time was 73.4 months (interquartile range: 42.9, 108). A total of 123 patients died, 39 from cardiovascular disease, 19 from cerebrovascular disease, and 65 from other causes. Kaplan-Meier analysis indicated that the high-TMAO group had a greater incidence of cardiovascular death (Log-Rank: p = 0.006) and all-cause death (Log-Rank: p < 0.001). Cox regression analysis showed that high TMAO level was significantly associated with cardiovascular and all-cause mortality. After adjustment for confounding, this association remained significant for cardiovascular mortality (TMAO as a continuous variable: HR: 1.18, 95%CI: 1.07, 1.294, p < 0.001; TMAO as a dichotomous variable: HR: 3.44, 95%CI: 1.68, 7.08, p < 0.001) and all-cause mortality (TMAO as a continuous variable: HR: 1.14, 95%CI: 1.08, 1.21, p < 0.001; TMAO as a dichotomous variable: HR: 2.54, 95%CI: 1.71, 3.76, p < 0.001). CONCLUSIONS: High plasma TMAO level is significantly and independently associated with cardiovascular and all-cause mortality in HD patients.

Interleukin-17A Expression Correlated with the Prognosis of Chronic Rhinosinusitis with Nasal Polyps and the Anti-Interleukin-17A Effect in a Murine Nasal Polyps Model.

OBJECTIVE: To investigate the expression of interleukin-17A (IL-17A) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and to analyze its effect on prognosis and to explore the role and mechanism of anti-IL-17A effect in vivo by establishing a murine nasal polyps (NP) model. METHODS: Patients with CRSwNP who underwent endoscopic sinus surgery and matched control subjects were collected. We investigated IL-17A expression in human NP tissues using immunohistochemistry and analyzed their clinical features, including Lund-Mackay computed tomography scoring (LMCS) before surgery, Lund-Kennedy endoscopic scoring (LKES) before surgery (LKES B), LKES 6 months after surgery (LKES A), and reduction of LKES (LKES R). Then, after establishing the murine NP model to detect the expression and correlation of IL-17A and matrix metalloproteinase-9 (MMP-9) in nasal tissue, we studied nasal lavage fluid and serum by PCR and enzyme-linked immunosorbent assay in vivo. Anti-IL-17A treatment was administered in the murine NP model to confirm the function of IL-17A during the pathogenic processes. RESULTS: IL-17A expression was upregulated in NP tissues from patients with CRSwNP compared with control subjects (p < 0.001). The number of IL-17A+ cells was significantly negatively correlated with LKES R in patients with CRSwNP (p < 0.01). However, there was no significant correlation between IL-17A and LMCS or LKES B (all p < 0.05). Further, IL-17A and MMP-9 were more abundant in nasal mucosa of the murine NP model compared with that of control mice (all p < 0.05), and severe polypoid lesions were apparently observed in murine NP models. Anti-IL-17A treatment downregulated the mRNA and protein expression of MMP-9 in nasal mucosa and reduced the number of polypoid lesions in the murine NP model (all p < 0.05). CONCLUSION: Our results suggest that IL-17A plays a crucial role and may affect the prognosis of CRSwNP. Anti-IL-17A treatment may reduce the formation of polypoid lesions through inhibition of MMP-9 expression.

Anodic Voltage Dependence of Ti-6Al-4V Substrates and Hydroxyapatite Coating.

Ti-6Al-4V alloys were anodized in a solution containing 0.15 M HF and 2 M H3PO4 for 30 min under different voltages and then coated with hydroxyapatite (HA) by hydrothermal-electrochemical deposition. The effects of anodizing voltage on the morphology and bioactivity of the HA coating and on the bonding strength between the HA coating and the anodized substrates were investigated. Results indicated that highly ordered amorphous TiO2 nanotube arrays formed on the Ti-6Al-4V surface after anodic oxidation. The pore size of the nanotube increased up to approximately 100 nm with increasing anodic voltage until 25 V. The nanotube was damaged at anodic voltages above 25 V. The crystal structure of TiO2 changed from amorphous to anatase when the anodized substrates were heated at 450 °C for 3 h. The contact angle between the Ti-6Al-4V surfaces and the simulated body fluid evidently decreased after anodic oxidation. The roughness increased with increasing anodic voltage, and Ra reached about 0.56 µm under 25 V. The HA coating exhibited layered growth. The deposition of rod-like HA crystals as well as the crystallinity of the HA coating initially increased and then decreased with the further increase of the anodic volatage. The degree of crystallinity reached the maximum of approximately 73% at 25 V. The bonding strength between the coating and the anodized substrates increased and then slightly decreased with increasing voltage. The bonding strength was about 20.0 MPa when titanium substrate was anodized under 25 V. The results of simulated body fluid immersing experiments suggest that the HA coating exhibits promising bioactivity.