Vascular reconstruction provides short-term and long-term survival benefits for patients with hilar cholangiocarcinoma: A retrospective, multicenter study.

BACKGROUND: In patients with hilar cholangiocarcinoma (HCCA), radical resection can be achieved by resection and reconstruction of the vasculature. However, whether vascular reconstruction (VR) improves long-term and short-term prognosis has not been demonstrated comprehensively. METHODS: This was a retrospective multicenter study of patients who received surgery for HCCA with or without VR. Variables associated with overall survival (OS) and recurrence-free survival (RFS) were identified based on Cox regression. Kaplan-Meier curves were used to explore the impact of VR. Restricted mean survival time (RMST) was used for comparisons of short-term survival between the groups. Patients' intraoperative and postoperative characteristics were compared. RESULTS: Totally 447 patients were enrolled. We divided these patients into 3 groups: VR with radical resections (n = 84); non-VR radical resections (n = 309) and non-radical resection (we pooled VR-nonradical and non-VR nonradical together, n = 54). Cox regression revealed that carbohydrate antigen 242 (CA242), vascular invasion, lymph node metastasis and poor differentiation were independent risk factors for OS and RFS. There was no significant difference of RMST between the VR and non-VR radical groups within 12 months after surgery (10.18 vs. 10.76 mon, P = 0.179), although the 5-year OS (P < 0.001) and RFS (P < 0.001) were worse in the VR radical group. The incidences of most complications were not significantly different, but those of bile leakage (P < 0.001) and postoperative infection (P = 0.009) were higher in the VR radical group than in the non-VR radical group. Additionally, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) up to 7 days after surgery tended to decrease in all groups. There was no significant difference in the incidence of postoperative liver failure between the VR and non-VR radical groups. CONCLUSIONS: Radical resection can be achieved with VR to improve the survival rate without worsening short-term survival compared with resection with non-VR. After adequate assessment of the patient's general condition, VR can be considered in the resection.

MethHC 2.0: information repository of DNA methylation and gene expression in human cancer.

DNA methylation is an important epigenetic regulator in gene expression and has several roles in cancer and disease progression. MethHC version 2.0 (MethHC 2.0) is an integrated and web-based resource focusing on the aberrant methylomes of human diseases, specifically cancer. This paper presents an updated implementation of MethHC 2.0 by incorporating additional DNA methylomes and transcriptomes from several public repositories, including 33 human cancers, over 50 118 microarray and RNA sequencing data from TCGA and GEO, and accumulating up to 3586 manually curated data from >7000 collected published literature with experimental evidence. MethHC 2.0 has also been equipped with enhanced data annotation functionality and a user-friendly web interface for data presentation, search, and visualization. Provided features include clinical-pathological data, mutation and copy number variation, multiplicity of information (gene regions, enhancer regions, and CGI regions), and circulating tumor DNA methylation profiles, available for research such as biomarker panel design, cancer comparison, diagnosis, prognosis, therapy study and identifying potential epigenetic biomarkers. MethHC 2.0 is now available at http://awi.cuhk.edu.cn/∼MethHC.

Paraburkholderia phosphatilytica sp. nov., a phosphate-solubilizing bacterium isolated from forest soil.

A novel Gram-stain-negative, aerobic, non-spore-forming, non-motile and rod-shaped bacterial strain, 7QSK02T, was isolated from forest soil of Dinghushan Biosphere Reserve, Guangdong Province, China. It grew at 12-37 °C, at pH 4.0-7.5 and in the presence of 0-1.0 % (w/v) NaCl on R2A agar medium, with optimum growth at 28 °C, pH 5.5 and 0 % NaCl. Strain 7QSK02T was closely related to members of the genus Paraburkholderia: P. acidipaludis NBRC 101816T (98.1 % 16S rRNA gene sequence similarity), P. piptadeniae STM 7183T (97.6 %), P. kururiensis JCM 10599T (97.3 %), P. caballeronis TNe-841T (97.3 %) and P. diazotrophica JPY461T (97.1 %). 16S rRNA gene sequence analysis showed that strain 7QSK02T and two closely strains, P. kururiensis JCM 10599T and P. caballeronis TNe-841T, formed a clade within the genus Paraburkholderia, but was clearly separated from the established species. The genomic G+C content of strain 7QSK02T was 64.9 mol% based on total genome calculations. The average nucleotide identity and digital DNA-DNA hybridization value for the complete genomes were 79.2-81.5 and 23.2-24.9 % between strain 7QSK02T and its closely related species listed above. Strain 7QSK02T contained ubiquinone 8 as the major respiratory quinone. Major fatty acids were C16 : 0, C17 : 0 cyclo and C19 : 0 cyclo ω8c. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylmethylethanolamine, one unidentified aminophospholipid, aminolipid and polar lipid. The phenotypic, chemotaxonomic and phylogenetic properties, and genome analysis suggest that strain 7QSK02T represents a novel species of the genus Paraburkholderia, for which the name Paraburkholderia phosphatilytica sp. nov. is proposed. The type strain is 7QSK02T (=GDMCC 1.1283T=CGMCC 1.15470T=KCTC 62473T).

Dyella halodurans sp. nov., isolated from lower subtropical forest soil.

A Gram-stain-negative, aerobic, non-endospore-forming, motile by a polar flagellum, rod-shaped bacterium, designated strain DHOG02T, which produced yellow-pigmented colonies, was isolated from a soil sample collected from the lower subtropical forest of the Dinghushan Biosphere Reserve, Guangdong Province, PR China. Strain DHOG02T grew at 12-37 °C, pH 4-9 and 0-4 % (w/v) NaCl, with optima at 28 °C, pH 6-7 and 0.5 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that this strain formed a clade with Dyella lipolytica DHOB07T and Dyella jejuensis JP1T, with sequence similarities of 98.0 and 97.4 %, respectively. The result of the concatenated partial gyrB, lepA and recA gene sequence analysis confirmed that strain DHOG02T belongs to the genus Dyella, but is distinct from all currently known species of the genus. The G+C content of the genomic DNA was 62 mol%. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified aminophospholipid and phospholipid. Ubiquinone-8 was the only respiratory quinone detected, and iso-C15 : 0, iso-C17 : 1ω9c and summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c) were the major fatty acids, all of which supported the affiliation of strain DHOG02T to the genus Dyella. On the basis of the evidence presented here, strain DHOG02T represents a novel species of the genus Dyella, for which the name Dyella halodurans sp. nov. is proposed. The type strain is DHOG02T (=NBRC 111474T=CGMCC 1.15435T).

Programmable co-delivery of the immune checkpoint inhibitor NLG919 and chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric prodrug carrier.

To achieve synergistic therapeutic efficacy and prevent cancer relapse, chemotherapy and immunotherapy have been combined as a new modality for tumor treatment. In this work, we designed a redox-responsive immunostimulatory polymeric prodrug carrier, PSSN10, for programmable co-delivery of an immune checkpoint inhibitor NLG919 (NLG) and a chemotherapeutic doxorubicin (DOX). NLG-containing PSSN10 prodrug polymers were self-assembled into nano-sized micelles that served as a carrier to load DOX (DOX/PSSN10 micelles). DOX/PSSN10 micelles displayed spherical morphology with a size of ∼170 nm. DOX was effectively loaded into PSSN10 micelles with a loading efficiency of 84.0%. In vitro DOX release studies showed that rapid drug release could be achieved in the highly redox environment after intracellular uptake by tumor cells. In 4T1.2 tumor-bearing mice, DOX/PSSN10 micelles exhibited greater accumulation of DOX and NLG in the tumor tissues compared with other organs. The PSSN10 carrier dose-dependently enhanced T-cell immune responses in the lymphocyte-Panc02 co-culture experiments, and significantly inhibited tumor growth in vivo. DOX/PSSN10 micelles showed potent cytotoxicity in vitro against 4T1.2 mouse breast cancer cells and PC-3 human prostate cancer cells comparable to that of DOX. In 4T1.2 tumor-bearing mice, DOX/PSSN10 mixed micelles (5 mg DOX/kg, iv) was more effective than DOXIL (a clinical formulation of liposomal DOX) or free DOX in inhibiting the tumor growth and prolonging the survival of the treated mice. In addition, a more immunoactive tumor microenvironment was observed in the mice treated with PSSN10 or DOX/PSSN10 micelles compared with the other treatment groups. In conclusion, systemic delivery of DOX via PSSN10 nanocarrier results in synergistic anti-tumor activity.

Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson's disease: linking to Akt/GSK3ß signaling pathway.

Higher plasma urate level is reported to be associated with a reduced risk and slower progression of Parkinson's disease (PD). In this study, we explored the effects of urate on dopaminergic neurons in nigrostriatal pathway in the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats. Uric acid (UA), when given twice daily at 200 mg/kg intraperitoneally for 10 consecutive days, elevated urate (the anionic form of UA) in plasma and striatum by 55% and 36.8%, respectively, as compared with vehicle group. This regimen of UA was found to ameliorate the behavioral deficits, dopaminergic neuron loss as well as dopamine depletion in the nigrostriatal system. Moreover, UA administration was capable of increasing glutathione level and superoxide dismutase activity while decreasing malondialdehyde accumulation in striatum. In addition, the phosphorylation of both protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3ß) in the lesioned striata of 6-OHDA-lesioned rats was dramatically reduced as compared with sham-operated rats. This reduction was attenuated in the Parkinsonian rats receiving UA treatment. Similarly, in vitro findings showed that UA alleviated the decrease in Akt activation and the increase in GSK3ß activity caused by 6-OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3ß phosphorylation at Ser9 was found to be abolished in the presence of PI3K inhibitor. Therefore, our findings demonstrated that urate was able to protect dopaminergic neurons in rat nigrostriatal pathway against the neurotoxicity of 6-OHDA, and showed that its beneficial effects may be related to its regulation on Akt/GSK3ß signaling.

Association of Decreased Serum BDNF With Restless Legs Syndrome in Parkinson's Disease Patients.

Objective: To objective of the study was to investigate whether serum brain-derived neurotrophic factor (BDNF) levels are associated with the severity of restless legs syndrome (RLS) in Parkinson's disease (PD). Methods: A total of 249 PD patients with (n = 53) and without RLS (n = 196) and 326 age-matched controls were included in this study. All the serum BDNF levels of the participants were measured. The International Restless Legs Syndrome Study Group Rating Scale (IRLSSG-RS) was administered for the severity of RLS. The severity of PD patients were assessed by the Unified PD Rating Scale (UPDRS) and the Hoehn and Yahr (H-Y) stage. Results: The prevalence of RLS was significantly higher in PD patients (21.3%) than in the controls group (7.4%) (p < 0.05). The IRLSSG-RS score in PD patients with RLS (16.25 ± 5.24) was significantly increased than in controls with RLS (12.08 ± 3.99) (p < 0.01). The serum BDNF levels were significantly decreased in PD patients with RLS than in PD patients without RLS, controls without RLS, and controls with RLS (p < 0.001). BDNF levels were negatively associated with IRLSSG-RS in both PD patients with RLS and controls with RLS group (both p < 0.01). Multiple regression analysis confirmed that in either PD with RLS or controls with RLS group, BDNF was an independent contributor to IRLSSG-RS (both p < 0.01). Conclusions: Decreased serum BDNF levels may be involved in the pathophysiology of RLS in PD, suggesting that it may serve as a potential blood biomarker of diagnostic value for RLS in PD.

An enantioselective convergent route to pamamycin 621A.

An effective approach to the total synthesis of natural antibiotic pamamycin 621A is described, in which the stereogenic centers at the C-13 and C-15 were taken from a chiral building block derived from the inexpensive D-glucolactone while all others (except the C-10) were installed via chiral auxiliary-induced asymmetric Evans/Crimmins aldol reactions. In the synthesis of the smaller/lower fragment, an antiselective Evans aldol condensation was found to occur only if a stoichiometric (rather than catalytic as reported in the literature) amount of magnesium chloride was present. A previously unknown effect of the steric bulkiness of the pyridine base employed on the stereochemical outcome of the formation of the THF ring in the presence of a chiral auxiliary was also observed. The THF rings in the larger/upper fragment were similarly synthesized with a high level of stereoselectivity from a linear precursor carrying a chiral auxiliary via intramolecular O-alkylations, most notably even under acidic conditions. The basic dimethylamino functionality at the C-15 was installed at the final stage of the whole synthesis, with those otherwise unavoidable side reactions in the conversion of the azido group effectively circumvented through using a very mild yet largely forgotten tributyltin reduction protocol.

CSC counteracts l-DOPA-induced overactivity of the corticostriatal synaptic ultrastructure and function in 6-OHDA-lesioned rats.

l-DOPA remains the gold-standard treatment for Parkinson's disease (PD). However, the emergence of l-DOPA-induced dyskinesia (LID) and motor fluctuations represents a major clinical problem in PD. The selective localization of adenosine A(2A) receptors to the basal ganglia and specifically to the indirect output pathway appear to be crucial both in the pathogenesis of PD and in the development of LID. In this study, we investigated the effects of a 3-week treatment with l-DOPA (50mg/kg/day+benserazide 12.5mg/kg/day, twice daily, i.p.) alone or combined with adenosine A(2A) receptor antagonist 8-(3-Chlorostyryl)caffeine (CSC) (5mg/kg/day, twice daily), on the rotational motor response duration, abnormal involuntary movements (AIM) and the associated striatal expression of adenosine A(2A) receptor in rats with a nigrostriatal lesion. CSC treatment ameliorated the shortening of the rotational motor response duration, partly attenuated dyskinesia and reduced striatal expression of adenosine A(2A) receptor induced by l-DOPA. Electron microscopy technique results showed that the postsynapse density depth was much thicker, synapse cleft width was narrower and the ratio of perforated synapses significantly increased in the l-DOPA-treated rats, while systemic coadministration of CSC with l-DOPA attenuated the overactivity of corticostriatal synaptic ultrastructure and function induced by l-DOPA. In conclusion, CSC by means of its dual action as A(2A) receptor antagonist and MAO-B inhibitor ameliorated the changed behavior, expression of adenosine A(2A) receptor and postsynaptic effects, observed in the 6-OHDA-lesioned rats, pointing out to its potential benefit for the treatment of LID.