Neoadjuvant chemotherapy is noninferior to chemoradiotherapy for early-onset locally advanced rectal cancer in the FOWARC trial.

BACKGROUND: The early-onset rectal cancer with rapidly increasing incidence is considered to have distinct clinicopathological and molecular profiles with high-risk features. This leads to challenges in developing specific treatment strategies for early-onset rectal cancer patients and questions of whether early-onset locally advanced rectal cancer (LARC) needs aggressive neoadjuvant treatment. METHODS: In this post hoc analysis of FOWARC trial, we investigated the role of preoperative radiation in early-onset LARC by comparing the clinicopathological profiles and short-term and long-term outcomes between the early-onset and late-onset LARCs. RESULTS: We revealed an inter-tumor heterogeneity of clinical profiles and treatment outcomes between the early-onset and late-onset LARCs. The high-risk features were more prevalent in early-onset LARC. The neoadjuvant radiation brought less benefits of tumor response and more risk of complications in early-onset group (pCR: OR = 3.75, 95% CI = 1.37-10.27; complications: HR = 11.35, 95% CI = 1.46-88.31) compared with late-onset group (pCR: OR = 5.33, 95% CI = 1.83-15.58; complications: HR = 5.80, 95% CI = 2.32-14.49). Furthermore, the addition of radiation to neoadjuvant chemotherapy didn't improve long-term OS (HR = 1.37, 95% CI = 0.49-3.87) and DFS (HR = 1.05, 95% CI = 0.58-1.90) for early-onset patients. CONCLUSION: Preoperative radiation plus chemotherapy may not be superior to the chemotherapy alone in the early-onset LARC. Our findings provide insight into the treatment of early-onset LARC by interrogating the aggressive treatment and alternative regimens.

Synthesis of 3-Thiocyanobenzothiophene via Difunctionalization of Active Alkyne Promoted by Electrochemical-Oxidation.

A novel and green method for the synthesis of 3-thiocyanatobenzothiophenes via electrochemical-oxidation promoted difunctionalization of active alkyne has been developed. In this protocol, inexpensive and easily available potassium thiocyanate was chosen as the thiocyanation reagent, 2-alkynylthioanisoles as the substrates, a variety of 3-thiocyanatobenzothiophenes were obtained in moderate to good yields under oxidant- and catalyst-free conditions. Moreover, the continuous flow system has good applicability for this transformation, the use of continuous flow system has overcome the disadvantage of low efficiency in traditional electrochemical amplification, and realized the stable and excellent yields of target products in the scale-up reactions.

Association of mean arterial pressure with 5-year risk of incident diabetes in Chinese adults：a secondary population-based cohort study.

OBJECTIVE: Hypertension predicts the development of diabetes. However, there are still lacking high-quality studies on the correlation between mean arterial pressure (MAP) and incident diabetes. We aimed to explore the relationship between MAP and diabetes in Chinese adults. DESIGN: This is a secondary retrospective cohort study and the data were downloaded from the 'DATADRYAD' database (www.Datadryad.org). PARTICIPANTS: The study included 210 418 adults without diabetes at baseline between 2010 and 2016 across 32 sites and 11 cities in China. SETTING: The target-independent and dependent variables were MAP measured at baseline and diabetes occurred during follow-up. Cox proportional hazards regression was used to explore the relationship between MAP and diabetes. PRIMARY OUTCOME MEASURES: The outcome was incident diabetes, which was defined as fasting blood glucose ≥7.00 mmol/L and/or self-reported diabetes during follow-up. Patients were censored either at the time of the diagnosis or at the last visit, whichever comes first. RESULTS: 3927 participants developed diabetes during a 5-year follow-up. After adjusting covariates, MAP positively correlated with diabetes (HR=1.008, 95% CI 1.005 to 1.011, p<0.001), and the absolute risk difference was 0.02%. E-value analysis and multiple imputations were used to explore the robustness of the results. The relationship between MAP and diabetes was also non-linear, and the inflection point of MAP was 100.333 mm Hg. Subgroup analysis revealed a stronger association between MAP and diabetes in people with age (≥30,<50 years old), fasting plasma glucose <6.1 mmol/L and drinking. Additionally, receiver operating characteristic (ROC) curves showed the predictive performance of MAP for diabetes was similar to systolic blood pressure (SBP) (area under the curve (AUC)=0.694 with MAP vs AUC=0.698 with SBP). CONCLUSIONS: MAP is an independent predictor for a 5-year risk of incident diabetes among Chinese adults. The relationship between MAP and diabetes is also non-linear. When MAP is below 100.333 mm Hg, MAP is closely positively related to diabetes.

Electrochemical-Oxidation-Promoted Direct N-ortho-Selective Difluoromethylation of Heterocyclic N-Oxides.

An efficient and green electrochemical N-ortho-selective difluoromethylation method of various quinoline and isoquinoline N-oxides has been developed. In this method, sodium difluoromethanesulfinate (HCF2SO2Na) was used as the source of the difluoromethyl moiety, and various N-ortho-selective difluoromethylation quinoline and isoquinoline N-oxides were obtained in good to excellent yields under a constant current. In addition, the reaction was easy to scale up and maintained a good yield. Preliminary mechanism studies suggested that the reaction undergoes a free-radical addition and hydrogen elimination pathway.

Variation in physicochemical properties and bioactivities of Morinda citrifolia L. (Noni) polysaccharides at different stages of maturity.

Introduction: Morinda citrifolia L. (Noni) as an evergreen plant is a rich source of natural polysaccharides. Objective: The present work aims to investigate the maturation-related changes in polysaccharides of Morinda citrifolia L. (Noni) at five stages of maturity (stages from the lowest to highest degree - 1, 2, 3, 4, and 5). Methods: The chemical composition (carbohydrate, protein, uronic acid, and sulfate radical) of Noni polysaccharides was determined by different chemical assays. Ion chromatography system was used to analyze the monosaccharide composition, and the molecular weight was measured by HPGPC. The polysaccharides were also analyzed by FT-IR and their radical scavenging effect against DPPH, hydroxyl radicals and ABTS was evaluated. The UV-vis assay and gel electrophoresis assay were performed to investigate the DNA damage protective effect. Results: Results indicated the significant effect of fruit maturities on the extraction yields, molecular weights, uronic acid contents, sugar levels, monosaccharide compositions and proportions, antioxidant capacities, and DNA protective effects of Noni polysaccharides. However, no fruit maturity stage had prominent impact on the sulfuric radical contents and preliminary structure characteristics. Noni polysaccharides extracted at stage 5 (N5) had the largest extraction yield (8.26 ± 0.14%), the highest sugar content (61.94 ± 1.86%) and the most potent scavenging effect on DPPH (IC50: 1.06 mg/mL) and ABTS (IC50: 1.22 mg/mL) radicals. The stronger DPPH and ABTS radical scavenging activities of N5 might be contributed by its higher content of fucose and rhamnose and smaller molecular weight. Noni polysaccharides extracted at stage 4 (N4) showed the highest uronic acid content (4.10 ± 0.12%), and the superior performance in scavenging hydroxyl radicals and protecting DNA. The greater hydroxyl radical scavenging effect of N4 might be attributed to its higher percentage of the low molecular weight counterpart. Moreover, the DNA protective effects of N4 displayed a positive correlation with its hydroxyl radical scavenging ability. Conclusion: Overall, stage 4 and stage 5 could be ideal stages of fruit maturity aiming at high-quality Noni polysaccharides extraction. This study provided valuable information for the selection of suitable Noni polysaccharides to cater for various industrial applications.

Machine Learning for Predicting the 3-Year Risk of Incident Diabetes in Chinese Adults.

Purpose: We aimed to establish and validate a risk assessment system that combines demographic and clinical variables to predict the 3-year risk of incident diabetes in Chinese adults. Methods: A 3-year cohort study was performed on 15,928 Chinese adults without diabetes at baseline. All participants were randomly divided into a training set (n = 7,940) and a validation set (n = 7,988). XGBoost method is an effective machine learning technique used to select the most important variables from candidate variables. And we further established a stepwise model based on the predictors chosen by the XGBoost model. The area under the receiver operating characteristic curve (AUC), decision curve and calibration analysis were used to assess discrimination, clinical use and calibration of the model, respectively. The external validation was performed on a cohort of 11,113 Japanese participants. Result: In the training and validation sets, 148 and 145 incident diabetes cases occurred. XGBoost methods selected the 10 most important variables from 15 candidate variables. Fasting plasma glucose (FPG), body mass index (BMI) and age were the top 3 important variables. And we further established a stepwise model and a prediction nomogram. The AUCs of the stepwise model were 0.933 and 0.910 in the training and validation sets, respectively. The Hosmer-Lemeshow test showed a perfect fit between the predicted diabetes risk and the observed diabetes risk (p = 0.068 for the training set, p = 0.165 for the validation set). Decision curve analysis presented the clinical use of the stepwise model and there was a wide range of alternative threshold probability spectrum. And there were almost no the interactions between these predictors (most P-values for interaction >0.05). Furthermore, the AUC for the external validation set was 0.830, and the Hosmer-Lemeshow test for the external validation set showed no statistically significant difference between the predicted diabetes risk and observed diabetes risk (P = 0.824). Conclusion: We established and validated a risk assessment system for characterizing the 3-year risk of incident diabetes.

Association of hypertension and incident diabetes in Chinese adults: a retrospective cohort study using propensity-score matching.

BACKGROUND: Reliable quantification of the relationship between hypertension and diabetes risk is limited, especially among Chinese people. We aimed to investigate the association between hypertension and the risk of diabetes in a large cohort of the Chinese population. METHODS: This was a retrospective propensity score-matched cohort study among 211,809 Chinese adults without diabetes at baseline between 2010 and 2016. The target independent and dependent variable were hypertension at baseline and incident diabetes during follow-up respectively. The propensity score matching using a non-parsimonious multivariable logistic regression was conducted to balance the confounders between 28,711 hypertensive patients and 28,711 non-hypertensive participants. The doubly robust estimation method was used to investigate the association between hypertension and diabetes. RESULTS: In the propensity-score matching cohort, diabetes risk increased by 11.0% among hypertensive patients (HR = 1.110, 95% confidence interval (CI): 1.031-1.195, P = 0.00539). And diabetes risk dropped to 8.3% among hypertensive subjects after adjusting for the propensity score (HR = 1.083, 95%CI: 1.006-1.166, P = 0.03367). Compared to non-hypertensive participants with low propensity score, the risk of incident diabetes increased by 2.646 times among hypertensive patients with high propensity score (HR = 3.646, 95%CI: 2.635-5.045, P < 0.0001). CONCLUSION: Hypertension was associated with an 11.0% increase in the risk of developing diabetes in Chinese adults. And the figure dropped to 8.3% after adjusting the propensity score. Additionally, compared to non-hypertensive participants with low propensity scores, the risk of incident diabetes increased by 2.646 times among hypertensive patients with high propensity scores.

Applying latent class analysis to risk stratification of incident diabetes among Chinese adults.

OBJECTIVE: To use latent class analysis to identify unobservable subpopulations amongst the heterogeneous population and explore the relationship between subpopulations and incident diabetes among Chinese adults. METHODS: The retrospective study included 32,312 Chinese adults without diabetes at baseline. Latent class indicators included demographic and clinical variables. The outcome was incident diabetes. The relationship between latent class and outcome was evaluated with Cox proportional hazard regression analysis. RESULTS: After screening, the two-class latent class model best fits the population. Participants in class 2 are characterized by higher age, body mass index, systolic and diastolic blood pressure, fasting plasma glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, serum creatinine, serum urea nitrogen, alanine aminotransferase, and a higher proportion of males, ever/current smokers and drinkers, but lower high-density lipoprotein cholesterol and a lower proportion of family history of diabetes. The risk of diabetes in class 2 was 5.451 times (HR: 6.451, 95%CI: 4.179-9.960, P < 0.00001) and 5.264 times (HR: 6.264, 95%CI: 4.680-8.385, P < 0.00001) higher than that in class 1 during 3-year and 5-year follow-up, respectively. CONCLUSIONS: We used latent class analysis to identify two distinct subpopulations with differential risk of diabetes during 3-year and 5-year follow-up.

Oxidant- and Catalyst-Free Synthesis of Sulfonated Benzothiophenes via Electrooxidative Tandem Cyclization.

A green and practical electrochemical method for the synthesis of C-3-sulfonated benzothiophenes from 2-alkynylthioanisoles and sodium sulfinates was developed under oxidant- and catalyst-free conditions. Moderate to good yields of sulfonated benzothiophenes bearing important and useful functional groups have been achieved at a constant current. Preliminary mechanistic studies indicated a tandem radical addition-cyclization pathway. Moreover, the protocol is easy to scale up and exhibits good reaction efficiency.

A prediction nomogram for the 3-year risk of incident diabetes among Chinese adults.

Identifying individuals at high risk for incident diabetes could help achieve targeted delivery of interventional programs. We aimed to develop a personalized diabetes prediction nomogram for the 3-year risk of diabetes among Chinese adults. This retrospective cohort study was among 32,312 participants without diabetes at baseline. All participants were randomly stratified into training cohort (n = 16,219) and validation cohort (n = 16,093). The least absolute shrinkage and selection operator model was used to construct a nomogram and draw a formula for diabetes probability. 500 bootstraps performed the receiver operating characteristic (ROC) curve and decision curve analysis resamples to assess the nomogram's determination and clinical use, respectively. 155 and 141 participants developed diabetes in the training and validation cohort, respectively. The area under curve (AUC) of the nomogram was 0.9125 (95% CI, 0.8887-0.9364) and 0.9030 (95% CI, 0.8747-0.9313) for the training and validation cohort, respectively. We used 12,545 Japanese participants for external validation, its AUC was 0.8488 (95% CI, 0.8126-0.8850). The internal and external validation showed our nomogram had excellent prediction performance. In conclusion, we developed and validated a personalized prediction nomogram for 3-year risk of incident diabetes among Chinese adults, identifying individuals at high risk of developing diabetes.

lncRNA UCA1 Contributes to 5-Fluorouracil Resistance of Colorectal Cancer Cells Through miR-23b-3p/ZNF281 Axis.

PURPOSE: The chemoresistance of 5-fluorouracil (5-FU) limited the application of chemotherapy in colorectal cancer (CRC) treatment. Herein, we aimed to uncover the potential mechanism behind the 5-FU resistance of CRC cells. METHODS: The abundance of long noncoding RNA urothelial carcinoma associated 1 (lncRNA UCA1), microRNA-23b-3p (miR-23b-3p) and zinc finger protein 281 (ZNF281) was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in CRC tissues and cells. Western blot was conducted to examine autophagy-related proteins, apoptosis-associated proteins and ZNF281 in CRC tissues and cells. Cell counting kit-8 (CCK8) assay was performed to detect the viability and inhibitory concentration 50% (IC50) value of 5-FU of CRC cells. The apoptosis of CRC cells was measured by flow cytometry. The binding sites between miR-23b-3p and UCA1 or ZNF281 were predicted by miRcode and Starbase software, respectively, and the combination was confirmed by dual-luciferase reporter assay and RIP assay. Murine xenograft model was established to verify the role of UCA1 on the 5-FU resistance of CRC in vivo. RESULTS: The 5-FU resistance of CRC was positively related to the level of UCA1 and autophagy. UCA1 accelerated the 5-FU resistance of CRC cells through facilitating autophagy and suppressing apoptosis. MiR-23b-3p was a target of UCA1 in 293T and CRC cells. The knockdown of miR-23b-3p reversed the inhibitory effects of UCA1 interference on the 5-FU resistance and autophagy and the promoting impact on the apoptosis of CRC cells. ZNF281 could bind to miR-23b-3p in 293T cells. MiR-23b-3p elevated the 5-FU sensitivity through down-regulating ZNF281 in CRC cells. UCA1 interference enhanced the 5-FU sensitivity of CRC through miR-23b-3p/ZNF281 axis in vivo. CONCLUSION: UCA1 mediated 5-FU resistance of CRC cells through facilitating autophagy and inhibiting apoptosis via miR-23b-3p/ZNF281 axis in vivo and in vitro.

The copper(ii)-catalyzed and oxidant-promoted regioselective C-2 difluoromethylation of indoles and pyrroles.

A novel and efficient approach for the highly selective C-2 difluoromethylation of indole derivatives was developed by using sodium difluoromethylsulfinate (HCF2SO2Na) as the source of difluoromethyl groups and a Cu(ii) complex as the catalyst. Various substrates were well tolerated in this transformation and the desired products were obtained in moderate to good yields. Moreover, the late-stage C-2 difluoromethylation of bioactive molecules containing an indole ring was achieved in good yields. Generally, this reaction features excellent functional group compatibility, broad substrate scope and excellent C-2 selectivity.

The ruthenium-catalyzed meta-selective C-H nitration of various azole ring-substituted arenes.

The efficient ruthenium-catalyzed meta-selective CAr-H nitration of azole ring substituted arenes has been developed. In this work, Ru3(CO)12 was used as the catalyst, AgNO2 as the nitro source, HPcy3+·BF4- as the ligand, pivalic acid as the additive, and DCE as the solvent, and a wide spectrum of arenes bearing thiazole, pyrazolyl or removable oxazoline directing groups were tolerated in this meta-selective CAr-H nitration, affording the nitrated products in moderate to good yields. Moreover, this study reveals a gentler and environmentally friendly way to access meta-nitration arenes compared to the traditional process.

Associations between the cyclooxygenase-2 expression in circulating tumor cells and the clinicopathological features of patients with colorectal cancer.

While previous studies have shown that the number of circulating tumor cells (CTCs) alone is not sufficient to reflect tumor progression and that cyclooxygenase-2 (COX-2) expression is correlated with colorectal cancer (CRC) metastasis, COX-2 expression status and its potential functions in CTCs of CRC patients are unknown. Here, epithelial-mesenchymal transition (EMT) phenotype-based subsets of CTCs and the COX-2 expression status in CTCs were identified and their potential clinical values were assessed in 91 CRC patients. CTCs were enumerated in peripheral blood and subsets of CTCs (epithelial [eCTCs], mesenchymal [mCTCs], and biophenotypic [bCTCs]) and the COX-2 expression status were determined using the RNA in situ hybridization method. CTCs were detected in 80.2% (73 of 91) patients. Neither the total CTC nor eCTC numbers were found to significantly associate with any of the clinicopathological features. However, the number of mCTCs was significantly associated with distance metastasis (P = 0.035) and had a trend of being associated with lymph node metastasis ( P = 0.055). Among the 73 patients enrolled for evaluating COX-2 expression, 52.5% (38 of 73) were found to express COX-2 in CTCs, and COX-2 expression in CTCs was not found to associate with the clinicopathological factors. However, COX-2 expression in mCTCs tended to have a higher rate in patients with metastasis compared with those without metastasis (72.0% vs 42.8%; P = 0.072). Furthermore, COX-2 expression and mCTC marker expression correlated positively ( R = 0.287; P = 0.017). Further studies are required to investigate the clinical value of the expression of COX-2 in mCTCs, especially in CRC patients with the advanced tumor stage and distant metastasis.

Aberrant expression of long noncoding RNA SNHG15 correlates with liver metastasis and poor survival in colorectal cancer.

Long noncoding RNAs (lncRNAs) play a critical role in the initiation and progression of colorectal cancer (CRC), but little is known about the function of lncRNAs in the colorectal liver metastasis (CLM). This study was designed to identify specific lncRNAs correlating to liver metastasis of CRC, and to further assess their clinical value. Seventeen patients with primary CRC lesions, adjacent normal mucosa, and synchronous liver metastases lesions were divided into discovery set (six patients) and test set (11 patients). Transcriptome sequencing (RNAseq) was used to screen differential expression of lncRNAs in the discovery set. Based on bioinformatics data, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to verify the target lncRNA in test set. The relationships between target lncRNA and clinical values were analysed in an expanded validation set of additional 91 patients. 23 upregulated and 14 downregulated lncRNAs were detected for distinguishing synchronous liver metastases, primary CRC lesions from adjacent normal mucosa in the RNAseq set. The expression levels of four lncRNAs in the 37 lncRNA signature were verified by qRT-PCR in the test set. Compared with the paired normal mucosa, high expression levels of lnc-small-nucleolar RNA host gene 15 (SNHG15) were detected not only in primary CRC lesions but also in liver metastases lesions in the test set. Furthermore, in the expanded validation set, high expression of lnc-SNHG15 was significantly associated with lymph-node metastasis and liver metastasis (p < 0.05), and patients displaying high lncRNA-SNHG15 expression exhibited a shorter median overall survival duration than those displaying low expression (30.7 vs. 35.2 months; p = 0.003). Multivariate analyses demonstrated that lncRNA-SNHG15 overexpression may serve as a poor prognostic biomarker for CRC patients (p = 0.049; Cox's regression: 2.731). Lnc-SNHG15 overexpression was significantly associated with CLM and high-expression of lnc-SNHG15 in CRC was an independent predictor of poor survival.

Optical design of a street lamp based on dual-module chip-on-board LED arrays.

We design and propose a compact street lamp based on dual-module chip-on-board LED. The street lamp is composed of six faceted reflectors. It can direct the luminous flux and form uniform illumination on the target area, and it effectively reduces power consumption. We have conducted both simulations and prototype measurements. The test results show good optical performance in that the uniformity of luminance reaches 0.58 for LED lamp zigzag arrangements and 0.60 for LED lamp double-side arrangements. The average luminance can fulfill the requirements in Chinese road lighting Standard CJJ45-2006.

Hybrid daylight/light-emitting diode illumination system for indoor lighting.

A hybrid illumination method using both daylight and light-emitting diodes (LEDs) for indoor lighting is presented in this study. The daylight can be introduced into the indoor space by a panel-integration system. The daylight part and LEDs are combined within a specific luminaire that can provide uniform illumination. The LEDs can be turned on and dimmed through closed-loop control when the daylight illuminance is inadequate. We simulated the illumination and calculated the indoor lighting efficiency of our hybrid daylight and LED lighting system, and compared this with that of LED and fluorescent lighting systems. Simulation results show that the efficiency of the hybrid daylight/LED illumination method is better than that of LED and traditional lighting systems, under the same lighting conditions and lighting time; the method has hybrid lighting average energy savings of T5 66.28%, and that of the LEDs is 41.62%.

Design of an LED-based compound optical system for a driving beam system.

This paper proposes an LED-based compound optical system, which can be involved in the design of the driving beam system in automotive headlamps with high system efficiency and low power consumption. The compound system can meet the requirements announced in the UNECE regulation "Addendum 111: Regulation No. 112 Revision 2." Also, it is composed of a nonspherical reflector, a compound lens, and a two-dimensional diverging lens. Using a single device of high-brightness LED of merely 7.6 W, the specified illumination requirements for the driving beam can be achieved. As we have expected, on the test screen at a distance of 25 m, the simulation results, as well as the testing results for the prototype, can reach the illuminance distribution requirements, including all specified regions and key points. Moreover, this compound system enjoys the features of high compactness, high energy efficiency, and feasibility of manufacturing.

High-energy-efficiency optical system for an LED-based headlamp architecture.

This paper proposes a low-beam system for an LED-based headlamp architecture, which is composed of an elliptical reflector, a baffle, and a faceted reflector. Using a single device with high brightness LED of merely 6.00 W, two devices total 12.00 W. With a low beam 55 W traditional halogen light source compared to 78.18% energy savings, the specified illumination requirements for the headlamp low beam can be achieved, according to the ECE regulation "Addendum 111: Regulation No. 112 Revision 2." As we have expected, on the test screen at a distance of 25 m, the simulation results as well as the testing results for the prototype can reach the illuminance distribution requirements, including all specified regions and key points. Moreover, this faceted low beam system enjoys the features of high compactness, high energy efficiency, and feasibility of manufacturing.

Panel-integration of natural light and the related system of light guiding and illumination.

This Letter proposes an idea of a natural light illumination system by using a light collecting panel. The light collecting panel is coupled with a light guide followed by a specifically designed lens to achieve uniform illumination on a target screen. To assess the system specification, we build a primary model in three-dimensional modeling software and make ray tracing simulation based on a Monte Carlo algorithm. The simulation results show a relatively high efficiency of 41.41% for the entire system and achieve a high uniformity of more than 0.8 within the circular illumination area.