Traumatic brain injury (TBI) is induced by immediate physical disruption of brain tissue, and causes death and disability. Studies on experimental TBI animal models show that disruption of the blood-brain barrier (BBB) underlies brain edema and neuroinflammation during the delayed phase of TBI. In neurological disorders, endothelin-1 (ET-1) is involved in BBB dysfunction and brain edema. In this study, the effect of ET antagonists on BBB dysfunction and brain edema were examined in a mouse focal TBI model using lateral fluid percussion injury (FPI). ET-1 and ET receptors were increased at 2-7 days after FPI, which was accompanied by extravasation of Evans blue (EB) and brain edema. Repeated intracerebroventricular administration of BQ788 (15 nmol/day), an ET antagonist, from 2 days after FPI promoted recovery of EB extravasation and brain edema, while FR 139317, an ET antagonist, had no effect. Delayed intravenous administration of BQ788 also promoted recovery from FPI-induced EB extravasation and brain edema. While FPI caused decreases in claudin-5, occludin, and zonula occludens-1 proteins, BQ788 reversed FPI-induced reductions of them. Immunohistochemical observation of the cerebrum after FPI showed that ET receptors are predominantly expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes. BQ788 reduced FPI-induced increases in GFAP-positive astrocytes. GFAP-positive astrocytes produced vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP9). FPI-induced increases in VEGF-A and MMP-9 production were reversed by BQ788. These results suggest that ET receptor antagonism during the delayed phase of focal TBI promotes recovery of BBB function and reduction of brain edema.
A monooxotungsten(iv) benzenedithiolate complex containing two intramolecular NHS hydrogen bonds, (NEt4)2[W(IV)O(1,2-S2-3-t-BuNHCOC6H3)2] (1-W), was synthesized via a ligand-exchange reaction between a new starting complex, (NEt4)2[W(IV)O(SC6F5)4], and a partially deprotonated dithiol. When dithiol was used in solution, the oxo ligand was protonated and removed to afford (NEt4)2[W(IV)(1,2-S2-3-t-BuNHCOC6H3)3]. The trans isomer, trans-1-W, was crystallized, and the molecular structure was determined via X-ray analysis. Trans-1-W was gradually isomerized by heating it in solution and it eventually achieved an approximately 1 : 1 mixture of trans/cis isomers after 48 days. However, a slightly excess amount of trans isomer remained, so the isomerization rate was considerably slower than that of the molybdenum analogue. In the presence of NEt4BH4, deuteration of the NH protons was observed in acetonitrile-d3. The oxidation of both trans- and cis-1-W by Me3NO afforded the corresponding dioxotungsten(vi) complex, (NEt4)2[W(VI)O2(1,2-S2-3-t-BuNHCOC6H3)2] (2-W), as a single isomer. The contributions of the NHS hydrogen bonds to the bond distances, vibrational data, and electrochemical properties are described via comparisons with their molybdenum analogues. The results of this comparative study yielded insights into both tungsten and molybdenum enzymes.
Oligomeric silsesquioxanes (Oligo-SQs) with random structures featuring phenyl (Ph) groups or both Ph and methyl (Me) groups as their substituents were synthesized by the sol–gel method. The ratio of Ph and Me groups controlled the molecular weights and branching in the Oligo-SQs. Branching increased as the molecular weight increased (when the alkaline dissolution rates of all Oligo-SQs adjusted to ∼40 nm s−1). A diazonaphthoquinone (DNQ) derivative was added to the Oligo-SQs to impart positive photosensitivity. A Ph content ratio of over 50 mol% was found to be necessary for the Oligo-SQs to exhibit DNQ compatibility and good patterning performance. Infrared absorption spectroscopy analysis and density functional theory calculations indicated the formation of novel aromatic siloxane DNQ aggregates upon hydrogen bonding between hydroxyl group domains in the Oligo-SQ (formed by hydroxyl groups bonded to Si on adjacent Ph moieties) and the DNQ derivative, which adopts only one of its possible resonance structures.
Background Cancer is the worst prognostic factor for patients with Crohn’s disease (CD). Previous studies of CD-associated colorectal cancer (CRC) have involved only small numbers of patients, and no large series have been reported. The aims of this study are to clarify the prognosis and clinicopathological features of CD-CRC compared with sporadic CRC using a large nationwide database from the Japanese Society for Cancer of the Colon and Rectum. Methods A large nationwide database covering data from 1980 to 2020 was used to identify patients with CD-CRC (n=233) and sporadic CRC (n=129,783). The clinicopathological features, 5-year overall survival (OS), and 5-year recurrence free survival (RFS) for patients with CD-CRC were compared with these outcomes in sporadic CRC. The data were further analyzed based on tumor location in the colon (CC) or anus/rectum (RC). Propensity score (PS) matching was used to account for selection bias. A binomial logistic regression model was used to estimate the PS, using the nine effective covariates: age at cancer diagnosis, sex, CEA, surgical treatment, adjuvant chemotherapy, tumor depth, lymph node metastasis, distant metastasis, and residual tumor. Results Compared with sporadic cases, patients with CD-CRC were younger, more often had RC, multiple lesions, and mucinous adenocarcinoma. R0 resection was less common with CD-CRC (77.43%) vs sporadic CRC (90.99%; P<0.001). Five-year OS was worse with CD-CRC vs sporadic CRC (53.99% vs 71.17%, P<0.001). Evaluation by tumor location showed significantly worse 5-year OS and RFS with CD-RC compared with sporadic RC, whereas 5-year OS and RFS in CD-CC vs sporadic CC was comparable. A higher recurrence was found with CD-RC (39.57%) compared with sporadic RC (21.97%, P<0.001), but the recurrence rates did not differ between CD-CC and sporadic CC. The most frequent sites of recurrence in CD-RC were local. Following PS matching, 5-year RFS with CD-RC was significantly worse than with sporadic RC (52.41% vs 78.74%, P<0.001), but 5-year RFS did not differ between CD-CC and sporadic CC (81.07% vs 82.04%, P=0.900). Conclusion Poor prognosis with CD-CRC is attributable primarily to RC and high local recurrence. Local control is indispensable to improving prognosis.
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