Increasing Chemical Diversity of B2 N2 Anthracene Derivatives by Introducing Continuous Multiple Boron-Nitrogen Units.

Increasing the chemical diversity of organic semiconductors is essential to develop efficient electronic devices. In particular, the replacement of carbon-carbon (C-C) bonds with isoelectronic boron-nitrogen (B-N) bonds allows precise modulation of the electronic properties of semiconductors without significant structural changes. Although some researchers have reported the preparation of B2 N2 anthracene derivatives with two B-N bonds, no compounds with continuous multiple BN units have been prepared yet. Herein, we report the synthesis and characterization of a B2 N2 anthracene derivative with a BNBN unit formed by converting the BOBN unit at the zigzag edge. Compared to the all-carbon analogue 2-phenylanthracene, BNBN anthracene exhibits significant variations in the C-C bond length and a larger highest occupied molecular orbital-lowest unoccupied molecular orbital energy gap. The experimentally determined bond lengths and electronic properties of BNBN anthracene are confirmed through theoretical calculations. The BOBN anthracene organic light-emitting diode, used as a blue host, exhibits a low driving voltage. The findings of this study may facilitate the development of larger acenes with multiple BN units and potential applications in organic electronics.

PN-Doped tetraphenylnaphthalene: a straightforward synthetic strategy analogous to BN-annulation.

Compared to BN heterocycles, few studies on PN heterocycles have been reported to date. Herein, we developed an efficient synthetic strategy analogous to BN-annulation to simultaneously incorporate a PN bond and a halogen group into the naphthalene core. Subsequently, we prepared PN-containing tetraphenylnaphthalene using this method, followed by palladium-catalyzed cross-coupling and reduction reactions. The prepared molecule was characterized via X-ray crystallography, NMR spectroscopy, UV-vis spectroscopy, and cyclic voltammetry.

Persistent status of metabolic syndrome and risk of cholangiocarcinoma: A Korean nationwide population-based cohort study.

OBJECTIVE: It is unknown whether persistent metabolic syndrome (MetS) is associated with an increased risk of cholangiocarcinoma (CCA). Therefore, we investigated the risk of CCA according to changes in MetS status. RESEARCH DESIGN AND METHODS: This nationwide cohort study included 8,581,407 adults who underwent anthropometric measurements and laboratory tests in two consecutive national health screenings during 2009-2012 and observed the subjects until 2017. Individuals with cancer, or follow-up duration <1 year were excluded (n = 377,915). Subjects were classified into the MetS-free, MetS-developed, MetS-improved, and MetS-persistent groups. The outcome was the incidence of CCA, identified using the claims database. Multivariable Cox proportional hazards regression models were used. RESULTS: Among the 8,203,492 subjects (mean age 48.9 ± 12.8 years; 56.7% male), 7506 CCA patients were newly identified during a median follow-up of 5.1 years. The probability of CCA was consistently higher in the MetS-persistent group than in the MetS-free group (P < 0.001). MetS-persistent status was significantly associated with an increased risk of CCA compared with the MetS-free status (unadjusted hazard ratio [HR] 2.8, 95% confidence interval [CI] 2.66-2.95), even after adjusting for multiple covariates (adjusted HR 1.07, 95% CI 1.01-1.13). Improved or newly developed MetS was not associated with CCA risk in the fully adjusted model (aHR 1.02, 95% CI 0.94-1.10 and aHR 0.99, 95% CI 0.92-1.06, respectively). CONCLUSIONS: MetS was associated with an increased risk of CCA if it persisted for ≥2 years. Our finding suggests that MetS may be a potentially modifiable risk factor for CCA.

An aza-Diels-Alder approach to chlorinated quinolines, benzoquinolines, and polybenzoquinolines.

Quinolines and quinoline-containing macromolecules are renowned for their valuable biological activities and excellent materials properties. Herein, we validate a general strategy for the synthesis of chloro-containing quinoline, benzoquinoline and polybenzoquinoline variants via the aza-Diels-Alder reaction. The described findings could be ultimately implemented in other synthetic pathways and may open new opportunities for analogous quinoline-derived materials.

Unveiling 79-Year-Old Ixene and Its BN-Doped Derivative.

Polycyclic aromatic hydrocarbons (PAHs) are key components of organic electronics. The electronic properties of these carbon-rich materials can be controlled through doping with heteroatoms such as B and N, however, few convenient syntheses of BN-doped PAHs have been reported. Described herein is the rationally designed, two-step syntheses of previously unknown ixene and BN-doped ixene (B2 N2 -ixene), and their characterizations. Compared to ixene, B2 N2 -ixene absorbs longer-wavelength light and has a smaller electrochemical energy gap. In addition to its single-crystal structure, scanning tunneling microscopy revealed that B2 N2 -ixene adopts a nonplanar geometry on a Au(111) surface. The experimentally obtained electronic structure of B2 N2 -ixene and the effect of BN-doping were confirmed by DFT calculations. This synthesis enables the efficient and convenient construction of BN-doped systems with extended π-conjugation that can be used in versatile organic electronics applications.

Toll-like receptor distribution in colonic epithelium and lamina propria is disrupted in HIV viremic, immune success, and failure.

DESIGN: Since intestinal immunity and the microbiome are disrupted in HIV disease, we studied the abundance of innate immune sensors, Toll-like receptors (TLRs), in the mucosa of participants with viremia, prior to antiretroviral therapy (ART), immune success (>500 CD4 T cells/µl after 2 years of ART; suppressed viremia), and immune failure (<350 CD4 T cells/µl after 2 years of ART; suppressed viremia). We hypothesized that disruption of intestinal TLR abundance and location provides a mechanism behind persistent inflammation. METHODS: Immunofluorescence for TLR3, TLR4, and TLR9 on paraffin embedded biopsies from uninfected, viremic, immune success, and immune failure colons was imaged by deconvolution microscopy and quantified with MetaMorph software. Plasma levels of C-reactive protein, IL-6, and intestinal fatty-acid binding protein (I-FABP) were correlated with TLR expression. RESULTS: Viremic participants have significantly higher levels of TLR3 and TLR9 on surface epithelium and in crypts when compared with uninfected controls. TLR3 is further elevated in immune failure and immune success. TLR9 abundance remains elevated in immune failure and is normalized in immune success. TLR9 expression in the crypt and lamina propria positively associates with C-reactive protein and IL-6 and negatively with I-FABP. TLR4 is significantly lower on surface epithelium and higher in crypts in viremic. Its expression in the lamina propria positively correlates with IL-6 and negatively correlates with I-FABP. CONCLUSION: Mucosal TLR imbalance and deregulation, and the resulting mucosal TLR desensitization and hypervigilance, remain after suppressive ART, in the presence or absence of T-cell recovery, likely contributing to chronic systemic inflammation.

Impact of sphingosine and acetylsphingosines on the aggregation and toxicity of metal-free and metal-treated amyloid-ß.

Pathophysiological shifts in the cerebral levels of sphingolipids in Alzheimer's disease (AD) patients suggest a link between sphingolipid metabolism and the disease pathology. Sphingosine (SP), a structural backbone of sphingolipids, is an amphiphilic molecule that is able to undergo aggregation into micelles and micellar aggregates. Considering its structural properties and cellular localization, we hypothesized that SP potentially interacts with amyloid-ß (Aß) and metal ions that are found as pathological components in AD-affected brains, with manifesting its reactivity towards metal-free Aß and metal-bound Aß (metal-Aß). Herein, we report, for the first time, that SP is capable of interacting with both Aß and metal ions and consequently affects the aggregation of metal-free Aß and metal-Aß. Moreover, incubation of SP with Aß in the absence and presence of metal ions results in the aggravation of toxicity induced by metal-free Aß and metal-Aß in living cells. As the simplest acyl derivatives of SP, N-acetylsphingosine and 3-O-acetylsphingosine also influence metal-free Aß and metal-Aß aggregation to different degrees, compared to SP. Such slight structural modifications of SP neutralize its ability to exacerbate the cytotoxicity triggered by metal-free Aß and metal-Aß. Notably, the reactivity of SP and the acetylsphingosines towards metal-free Aß and metal-Aß is determined to be dependent on their formation of micelles and micellar aggregates. Our overall studies demonstrate that SP and its derivatives could directly interact with pathological factors in AD and modify their pathogenic properties at concentrations below and above critical aggregation concentrations.

National study of the nutritional status of Korean older adults with dementia who are living in long-term care settings.

AIM: To evaluate the nutritional status of older adults with dementia who were living in long-term care settings. METHODS: As a secondary analysis, this study used the data from the Nationwide Survey on Dementia Care in Korea that was conducted between December 1, 2010, and August 31, 2011, which surveyed 3472 older adults with dementia, aged ≥60 years (mean age: 81.24 years), who were residing in 248 randomly selected long-term care settings in South Korea. Twenty-three different variables that related to the participants' demographics, diseases, and functional and nutritional characteristics were selected. The nutritional status was assessed by using the Mini Nutritional Assessment (MNA). Descriptive statistics, an ANOVA, and a chi-squared test were used to analyze the data. RESULTS: The mean MNA score of the participants was 17.90. The malnutrition rate was 38.4% (n = 1333), with 54.7% (n = 1900) of the participants at risk for malnutrition. The largest population with malnutrition resided in long-term care hospitals (47.9%), followed by nursing homes (34.1%), and group homes (25.9%). Being older and female, while exhibiting higher cognitive impairment, more neuropsychiatric symptoms, higher functional dependency, and a higher number of disabilities, were associated with poor nutritional status. CONCLUSION: The nutritional status of older adults with dementia who were living in long-term care settings in South Korea was poor and associated with multiple factors. Paying special attention to recognizing, assessing, preventing, and treating malnutrition in this population is necessary.

Dalotuzumab in chemorefractory KRAS exon 2 mutant colorectal cancer: Results from a randomised phase II/III trial.

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p < 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.

Comparison of Endoscopic Vacuum Therapy and Endoscopic Stent Implantation With Self-Expandable Metal Stent in Treating Postsurgical Gastroesophageal Leakage.

The aim of the present study was to evaluate the more effective therapy for the postsurgical gastroesophageal leakage by a head-to-head comparison of endoscopic vacuum therapy (EVT) and endoscopic stent implantation with self-expandable metal stent (E-SEMS). In this hospital-based, retrospective, observative study, the patients were classified into 2 groups. Those treated with EVT were assigned to the EVT group (n = 7), and those treated with E-SMS were assigned to the E-SEMS group (n = 11). We evaluated the clinical characteristics and treatment outcomes between the 2 groups. All 7 patients (100%) were treated with EVT, but only 7 of 11 patients (63.6%) in the stenting group were treated successfully. The median time to clinical success was 19.5 (5-21) days in the EVT group and 27.0 (3-84) days in the E-SEMS group. The median hospital stay was 37.1 (13-128) days in the EVT group and 87.3 (17-366) days in the E-SEMS group. The complicaion rate was lower in the EVT group (0/7, 0.0%) than that in the E-SEMS group (6/11, 54.5%) with statistically significant difference (P = 0.042). EVT is more effective and has fewer adverse effects than E-SMS therapy as a treatment for postsurgical gastroesophageal leakage.

Synthesis of Nitrogen-Containing Rubicene and Tetrabenzopentacene Derivatives.

Carbon-based materials, such as acenes, fullerenes, and graphene nanoribbons, are viewed as the potential successors to silicon in the next generation of electronics. Although a number of methodologies provide access to these materials' all-carbon variants, relatively fewer strategies readily furnish their nitrogen-doped analogues. Herein, we report the rational design, preparation, and characterization of nitrogen-containing rubicenes and tetrabenzopentacenes, which can be viewed either as acene derivatives or as molecular fragments of fullerenes and graphene nanoribbons. The reported findings may prove valuable for the development of electron transporting organic semiconductors and for the eventual construction of larger carbonaceous systems.

An Aza-Diels-Alder Approach to Crowded Benzoquinolines.

Graphene nanoribbons (GNRs) are promising candidate materials for the next generation of nanoscale electronics. Described herein is the synthesis of 2,4,6-substituted benzoquinolines, which constitute building blocks for nitrogen-doped GNRs. The presented facile and modular aza-Diels-Alder chemistry accommodates the installation of diverse functionalities at the crowded benzoquinolines' 2 positions. Given the general utility of the benzoquinoline motif, these findings hold relevance not only for carbon-based electronics but also for a range of chemical disciplines.

A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory, KRAS Wild-Type, Metastatic Colorectal Cancer.

BACKGROUND: Insulin-like growth factor type 1 receptor (IGF-1R) mediates resistance to epidermal growth factor receptor (EGFR) inhibition and may represent a therapeutic target. We conducted a multicenter, randomized, double blind, phase II/III trial of dalotuzumab, an anti-IGF-1R monoclonal antibody, with standard therapy in chemo-refractory, KRAS wild-type metastatic colorectal cancer. METHODS: Eligible patients were randomly assigned to dalotuzumab 10mg/kg weekly (arm A), dalotuzumab 7.5mg/kg every alternate week (arm B), or placebo (arm C) in combination with cetuximab and irinotecan. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included exploratory biomarker analyses. All statistical tests were two-sided. RESULTS: The trial was prematurely discontinued for futility after 344 eligible KRAS wild-type patients were included in the primary efficacy population (arm A = 116, arm B = 117, arm C = 111). Median PFS was 3.9 months in arm A (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 0.98 to 1.83, P = .07) and 5.4 months in arm B (HR = 1.13, 95% CI = 0.83 to 1.55, P = .44) compared with 5.6 months in arm C. Median OS was 10.8 months in arm A (HR = 1.41, 95% CI = 0.99 to 2.00, P = .06) and 11.6 months in arm B (HR = 1.26, 95% CI = 0.89 to 1.79, P = .18) compared with 14.0 months in arm C. Grade 3 or higher asthenia and hyperglycaemia occurred more frequently with dalotuzumab compared with placebo. In exploratory biomarker analyses, patients with high IGF-1 mRNA tumors in arm A had numerically better PFS (5.6 vs 3.6 months, HR = 0.59, 95% CI = 0.28 to 1.23, P = .16) and OS (17.9 vs 9.4 months, HR = 0.67, 95% CI = 0.31 to 1.45, P = .31) compared with those with high IGF-1 mRNA tumors in arm C. In contrast, in arm C high IGF-1 mRNA expression predicted lower response rate (17.6% vs 37.3%, P = .04), shorter PFS (3.6 vs 6.6 months, HR = 2.15, 95% CI = 1.15 to 4.02, P = .02), and shorter OS (9.4 vs 15.5 months, HR = 2.42, 95% CI = 1.21 to 4.82, P = .01). CONCLUSIONS: Adding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome. IGF-1R ligands are promising biomarkers for differential response to anti-EGFR and anti-IGF-1R therapies.

Surface-Effect-Induced Optical Bandgap Shrinkage in GaN Nanotubes.

We investigate nontrivial surface effects on the optical properties of self-assembled crystalline GaN nanotubes grown on Si substrates. The excitonic emission is observed to redshift by ∼100 meV with respect to that of bulk GaN. We find that the conduction band edge is mainly dominated by surface atoms, and that a larger number of surface atoms for the tube is likely to increase the bandwidth, thus reducing the optical bandgap. The experimental findings can have important impacts in the understanding of the role of surfaces in nanostructured semiconductors with an enhanced surface/volume ratio.

Synthesis of polybenzoquinolines as precursors for nitrogen-doped graphene nanoribbons.

Graphene nanoribbons (GNRs) represent promising materials for the next generation of nanoscale electronics. However, despite substantial progress towards the bottom-up synthesis of chemically and structurally well-defined all-carbon GNRs, strategies for the preparation of their nitrogen-doped analogs remain at a nascent stage. This scarce literature precedent is surprising given the established use of substitutional doping for tuning the properties of electronic materials. Herein, we report the synthesis of a previously unknown class of polybenzoquinoline-based materials, which have potential as GNR precursors. Our scalable and facile approach employs few synthetic steps, inexpensive commercial starting materials, and straightforward reaction conditions. Moreover, due to the importance of quinoline derivatives for a variety of applications, the reported findings may hold implications across a diverse range of chemical and physical disciplines.

Ultimate eradication rate of Helicobacter pylori after first, second, or third-line therapy in Korea.

BACKGROUND AND AIMS: Resistance rates of Helicobacter pylori to clarithromycin, metronidazole, and quinolone are over 30% in South Korea. The aim of this prospective study was to evaluate the ultimate eradication rate of H. pylori after first, second, or third-line therapy in Korea. METHODS: A cohort of 2202 patients with H. pylori was treated with proton pump inhibitor (PPI)-based triple therapy for seven days. In case of treatment failure or recurrence, moxifloxacin-based triple therapy (MA) or bismuth-based quadruple therapy (QUAD) was randomly given. When the second-line treatment failed or H. pylori recurred, the unused MA or QUAD was used as a third-line treatment. RESULTS: Eighty-six patients had recurrence at least once during consecutive lines of treatments. Among 2116 patients (intention-to-treat [ITT]) without recurrence, 1644 (77.7%, per-protocol [PP]) completely followed our treatment flow. The ITT and PP rates of first-line treatment were 69.8% and 89.3%. After second line, they reached 78.4% (ITT) and 98.4% (PP). The "final" eradication rate up to third line treatment were 80.0% (1692/2116) and 99.8% (1641/1644), respectively. Resistance to clarithromycin showed significantly lower eradication rate (OR 0.358, P < 0.001) than those with susceptible strains in multivariate analysis. However in PP analysis, there was no significant difference in ultimate success rate regarding resistance pattern. CONCLUSION: Final success rate of PP was high, 99.8% in Korea in spite of high antibiotic resistance rates. However, high rate of refusal of further treatment and follow-up loss made ITT eradication rate low. Proper strategy to improve the treatment adherence is needed.

A magnetic resonance imaging technique to evaluate tumor-brain adhesion in meningioma: brain-surface motion imaging.

OBJECTIVE: We examined the effectiveness of a newly developed magnetic resonance imaging (MRI) technique, brain surface motion imaging (BSMI), in the preoperative evaluation of tumor-brain adhesion in meningioma surgery. METHODS: Cine phase-contrast MRI was used to measure cerebrospinal fluid (CSF) pulsations and heart rates at 2 different time points to create a subtraction image in meningioma patients who underwent BSMI. With no tumor-brain adhesion, a gap was observed in the tumor-brain movements, resulting in an outline of the tumor in BSMI. If adhesion was evident, no outline was observed. Cases were evaluated as exact if the presence or absence of edema in T2-weighted MRI, BSMI findings, and intraoperative findings all matched; as effected when only BSMI findings and intraoperative images matched; and as false when BSMI findings and intraoperative findings did not match. RESULTS: BSMI judged 27 patients as adhesion (+) and 33 as adhesion (-), whereas surgical findings evaluated 22 as adhesion (+) and 38 as adhesion (-). The sensitivity and specificity were both high, at 95.5% and 84.2%, respectively. Forty-one of 60 patients were evaluated as exact, 12 as effected, and 7 as false. World Health Organization tumor grade assessment of effected subjects included 16.7% in grade 1 and 36.4% in grade 2. CONCLUSIONS: BSMI was shown to be effective in evaluating adhesion between the meningioma and the brain, allowing safe and effective removal planning to be carried out preoperatively.

Adaptation of international guidelines for metastatic colorectal cancer: an asian consensus.

Colorectal cancer (CRC) is among the most common cancers worldwide, but marked epidemiological differences exist between Asian and non-Asian populations. Hence, a consensus meeting was held in Hong Kong in December 2012 to develop Asia-specific guidelines for the management of metastatic CRC (mCRC). A multidisciplinary expert panel, consisting of 23 participants from 10 Asian and 2 European countries, discussed current guidelines for colon or rectal cancer and developed recommendations for adapting these guidelines to Asian clinical practice. Participants agreed that mCRC management in Asia largely follows international guidelines, but they proposed a number of recommendations based on regional 'real-world' experience. In general, participants agreed that 5-fluorouracil (5-FU) infusion regimens in doublets can be substituted with UFT (capecitabine, tegafur-uracil) and S1 (tegafur, 5-chloro-2,4-dihydroxypyridine and oxonic acid), and that the monoclonal antibodies cetuximab and panitumumab are recommended for KRAS wild type tumors. For KRAS mutant tumors, bevacizumab is the preferred biological therapy. FOLFOX (folinic acid, 5-FU, and oxaliplatin) is preferred for initial therapy in Asian patients. The management of mCRC is evolving, and it must be emphasized that the recommendations presented here reflect current treatment practices and thus might change as more data become available.

Polymerization of tellurophene derivatives by microwave-assisted palladium-catalyzed ipso-arylative polymerization.

We report the synthesis of a tellurophene-containing low-bandgap polymer, PDPPTe2T, by microwave-assisted palladium-catalyzed ipso-arylative polymerization of 2,5-bis[(α-hydroxy-α,α-diphenyl)methyl]tellurophene with a diketopyrrolopyrrole (DPP) monomer. Compared with the corresponding thiophene analog, PDPPTe2T absorbs light of longer wavelengths and has a smaller bandgap. Bulk heterojunction solar cells prepared from PDPPTe2T and PC71 BM show PCE values of up to 4.4%. External quantum efficiency measurements show that PDPPTe2T produces photocurrent at wavelengths up to 1 µm. DFT calculations suggest that the atomic substitution from sulfur to tellurium increases electronic coupling to decrease the length of the carbon-carbon bonds between the tellurophene and thiophene rings, which results in the red-shift in absorption upon substitution of tellurium for sulfur.

Controlling ferromagnetic easy axis in a layered MoS2 single crystal.

We report the effective methods to induce weak ferromagnetism in pristine MoS2 persisting up to room temperature with the improved transport property, which would lead to new spintronics devices. The hydrogenation of MoS2 by heating at 300 °C for 1 h leads to the easy axis out of plane, while the irradiation of proton with a dose of 1 × 10(13) P/cm(2) leads to the easy axis in plane. The theoretical modeling supports such magnetic easy axes.