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Objective: To reduce the risk of locoregional recurrence, the addition of neoadjuvant concurrent chemoradiotherapy (CCRT) is recommended before surgical management for rectal cancer patients. However, despite identical tumor histology, individual patient response to neoadjuvant CCRT varies greatly. Accordingly, a comprehensive molecular characterization that is used to predict CCRT efficacy is instantly needed. Methods: Pearson's chi-squared test was utilized to correlate dehydrogenase/reductase 9 (DHRS9) expression with clinicopathological features. Survival curves were created applying the Kaplan-Meier method, and the log-rank test was conducted to compare prognostic utility between high and low DHRS9 expression groups. Multivariate Cox proportional hazards regression analysis was applied to identify independent prognostic biomarkers based on variables with prognostic utility at the univariate level. Results: Utilizing a public transcriptome dataset, we identified that the DHRS9 gene is the most considerably upregulated gene related to epithelial cell differentiation (GO: 0030855) among rectal cancer patients with CCRT resistance. Employing immunohistochemical staining, we also demonstrated that high DHRS9 immunoexpression is considerably associated with an aggressive clinical course and CCRT resistance in our rectal cancer cohort. Among all variables with prognostic utility at the univariate level, only high DHRS9 immunoexpression was independently unfavorably prognostic of all three endpoints (all p ≤ 0.048) in the multivariate analysis. In addition, applying bioinformatic analysis, we also linked DHRS9 with unrevealed functions, such as keratan sulfate and mucin synthesis which may be implicated in CCRT resistance. Conclusion: Altogether, DHRS9 expression may serve as a helpful predictive and prognostic biomarker and assist decision-making for rectal cancer patients who underwent neoadjuvant CCRT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Hsu, Lee, Yang, Tian, Kuo, Li, Tsai, Wu, Yeh, Chou and Lai.)

Background: Chimeric antigen receptor-engineered T cell (CAR-T) therapy has shown promising potential for anti-cancer treatment. However, for pancreatic ductal adenocarcinoma (PDAC), the lack of infiltrative ability of these CAR-T cells leads to sub-optimal treatment outcome., Methods: Chemokine (C-C motif) ligand 19 (CCL19), the expression of which is regulated by the nuclear factor of activated T cell pathway, was transfected into targeting mesothelin CAR-T cells (mesoCAR-N19) using NFAT regulating element. It was expressed in activated CAR-T cells by OKT3 or mesothelin+ tumor cells but not in inactive cells. The migratory ability of these CAR-T cells was then measured. Subsequently, functional identification of these CAR-T cells was performed in vivo . In addition, the tumor lytic activity and proliferation of the CAR-T cells were measured in vitro . The degree of CAR-T cell infiltration and distribution into the PDAC tumors was examined using the immunohistochemical staining of hCD3 and the detection of CAR gene copy number by quantitative PCR. Finally, the functional assessment of chemokine (C-C motif) receptor 7 knock-out was performed in the CAR-T cells., Results: Through in vitro Transwell assays, it was demonstrated that mesoCAR-N19 can be specifically expressed in CAR-T cells activated by tumor cells compared with conventional mesothelin CAR-T (mesoCAR) cells. We also observed that upregulating the expression of CCL19 can increase the recruitment of additional T cells. In vivo studies subsequently revealed that this highly specific recruitment of T cell infiltration is associated with enhanced tumor-suppressive activities downstream., Conclusion: Induced expression of CCL19 can promote the anti-tumor ability of CAR-T cells by increasing their infiltrative ability. This study potentially uncovered novel method of activating CAR-T cells to enhance their infiltrative capacities, which offers a novel direction for PDAC treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Wang, Liao, Chen, Kang, Lin, Lin, Huang, Tian and Chen.)

Background: Colorectal cancer is one of the leading cancers worldwide. This study aimed to investigate the mortality differences between 2 primary tumor locations, the proximal/distal colon and rectosigmoid junction (RSJ)/rectum, after adjusting for comorbidities., Methods: The Taiwan Cancer Registry linked with Taiwan's National Health Insurance Research Database was used to estimate the 5-year mortality rate among patients with colorectal cancer. A total of 73 769 individuals were enrolled in the study, which included 44 234 patients with proximal and distal colon cancers and 29 535 patients with RSJ and rectal cancers. Potential mortality risk was calculated using Cox regression analysis., Results: The mortality rates due to the location of the cancer in the proximal/distal colon and RSJ/rectum were 45.27% and 42.20%, respectively. After adjustment for age, sex, comorbidities, and clinical stages, the proximal/distal colon had a 1.03-fold higher 5-year overall mortality rate than RSJ/rectal cancer (95% confidence interval = 1.00-1.05). Proximal and distal colon cancers had a worse prognosis and survival than RSJ and rectal colon cancers in women and older patients (⩾70 years). Comorbidities had different effects on mortality in the proximal/distal colon and RSJ/rectum., Conclusions: Tumor location is associated with the prognosis of patients with colorectal cancer. It is important to treat patients beyond their cancer treatment, and to manage their comorbidities., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

An artificial "salt-in-polymer" SEI, composed of poly-(1,3-dioxolane) and high-modulus fluorinated products generated from the in situ decomposition of Li salts, was constructed on the surface of Li-MSiO x particles. This LiF-rich SEI helps to maintain the structural integrity of Li-MSiO x particles and improves the Li storage reversibility of the Li-MSiO x anode.

A total of 8 bHLH transcription factors were cloned from Panax quinquefolius and the response of them to methyl jasmonate(MeJA) was studied.To be specific, based on the preliminary transcriptome screening, 8 bHLH transcription factors were cloned with seedlings which had been cultured for 3 weeks.The content of ginsenosides Rg_1, Re, and Rb_1, and total saponins in the adventitious roots of P.quinquefolius was determined at different time of MeJA treatment by high performance liquid chromatography(HPLC) and spectrophotometry.Real-time quantitative polymerase chain reaction(PCR) was used to detect the relative expression of 8 transcription factors after MeJA treatment.The correlation between the relative expression of the 8 transcription factors and the saponin content after MeJA treatment was checked by Pearson's correlation analysis.The results showed that the PCR products(Pq-bHLH21-Pq-bHLH28) of the 8 bHLH transcription factors were 762-2 013 bp in length.They were submitted to NCBI to obtain the Genbank access numbers.The proteins yielded from Pq-bHLH21-Pq-bHLH28 showed amino acid sequence identity of 24.90%, and each amino acid sequence had the bHLH(Basic Helix-loop-helix) conserved domain and belonged to the bHLH family.The 5 amino acid sequences of Pq-bHLH22 and Pq-bHLH24-Pq-bHLH27 contained the bHLH-MYC N domain, which belonged to the MYC transcription factors.Pq-bHLH21-Pq-bHLH28 responded to MeJA within 48 h of treatment.At 72 h, the expression of Pq-bHLH24 reached 106.53 folds the highest in the treatment group.Pq-bHLH25, Pq-bHLH27, and Pq-bHLH28 showed synergic expression.Pq-bHLH21 may re-gulate the biosynthetic pathway of ginsenoside Rb_1, while Pq-bHLH22, Pq-bHLH25, and Pq-bHLH28 were in significantly positive correlation with the biosynthetic pathway of ginsenoside Re.The result lays a foundation for further verifying the regulation of ginsenoside biosynthesis by bHLH transcription factors.

The carbon-coated silicon monoxide (SiO x @C) has been considered as one of the most promising high-capacity anodes for the next-generation high-energy-density lithium-ion batteries (LIBs). However, the relatively low initial Coulombic efficiency (ICE) and the still existing huge volume expansion during repeated lithiation/delithiation cycling remain the greatest challenges to its practical application. Here, we developed a lithium and boron (Li/B) co-doping strategy to efficiently enhance the ICE and alleviate the volume expansion or pulverization of SiO x @C anodes. The in situ generated Li silicates (Li x SiO y ) by Li doping will reduce the active Li loss during the initial cycling and enhance the ICE of SiO x @C anodes. Meanwhile, B doping works to promote the Li + diffusion and strengthen the internal bonding networks within SiO x @C, enhancing its resistance to cracking and pulverization during cycling. As a result, the enhanced ICE (83.28%), suppressed volume expansion, and greatly improved cycling (85.4% capacity retention after 200 cycles) and rate performance could be achieved for the Li/B co-doped SiO x @C (Li/B-SiO x @C) anodes. Especially, the Li/B-SiO x @C and graphite composite anodes with a capacity of 531.5 mA h g -1 were demonstrated to show an ICE of 90.1% and superior cycling stability (90.1% capacity retention after 250 cycles), which is significant for the practical application of high-energy-density LIBs.

Patients with deep burns are prone to suffer cicatrix hyperplasia or contracture, leading to problems including dysfunction in limbs, which impacts patients' life quality and makes it difficult for them to return to society. Thereby, the rehabilitation treatment after deep burns is particularly important. Currently, exercise therapy plays an important role in burn rehabilitation, which is mainly based on therapies such as continuous manual assistance training and manual stretching practice to provide patients with physical exercise to limbs and to correct the functional dysfunction of limbs in patients. With the continuous progress in technology, functional training robots have been developed to meet the needs. The emergence of functional training robots saves manpower and provides patients refined and standardized functional exercise treatment. From the aspects of production technology and multi-technology integration, this paper mainly introduces the recent innovation and development of functional training robots and the advantages of the application of functional training robots in the field of burn rehabilitation.

Serine/arginine-rich splicing factor 3 (SRSF3) regulates mRNA alternative splicing of more than 90% of protein-coding genes, providing an essential source for biological versatility. This study finds that SRSF3 expression is associated with drug resistance and poor prognosis in pancreatic cancer. We also find that SRSF3 regulates ANRIL splicing and m6A modification of ANRIL in pancreatic cancer cells. More importantly, we demonstrate that m6A methylation on lncRNA ANRIL is essential for the splicing. Moreover, our results show that SRSF3 promotes gemcitabine resistance by regulating ANRIL's splicing and ANRIL-208 (one of the ANRIL spliceosomes) can enhance DNA homologous recombination repair (HR) capacity by forming a complex with Ring1b and EZH2. In conclusion, this study establishes a link between SRSF3, m6A modification, lncRNA splicing, and DNA HR in pancreatic cancer and demonstrates that abnormal alternative splicing and m6A modification are closely related to chemotherapy resistance in pancreatic cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the clinical efficacy and safety of acupuncture combined with moxibustion on allergic rhinitis., Methods: Using the random number table, 80 patients with allergic rhinitis were divided into a medication group and an acupuncture combined with moxibustion (acu-mox) group, 40 cases in each one. In the medication group, ioratadine tables were prescribed for oral administration, one tablet daily for 10 days as 1 session , 3 sessions of treatment were required. In the acupuncture combined with moxibustion group, bilateral Yingxiang (LI20), Yintang (EX-HN3), bilateral Hegu (LI4) and bilateral Shenshu (BL23) were selected as the main points and stimulated with acupuncture and moxibustion; and the acupoint prescription was modified according to symptoms. This combined treatment was given once every day, stimulating for 30 min each time, and 10 treatments made 1 course, for 3 courses of treatment totally. Before and after treatment, the scores for symptoms and physical signs, as well as the score of rhino-conjunctivitis related quality of life scale (R-QOL) were evaluated separately. The sample of the inferior turbinate mucosa tissue was collected and the distribution of eosinophil (EOS) was scored using HE staining and Sheldeny evaluation. Using enzyme-linked immunosorbent assay (ELISA), the contents of serum immunoglobulin E (IgE), retinoic-acid-receptor-related orphan nuclear receptor γt (RORγt), forkhead box protein P3 (Foxp3), interleukin-17 (IL-17), IL-27 and IL-33 were determined. The clinical efficacy was evaluated in the patients with allergic rhinitis of two groups and all the adverse reactions were recorded during treatment., Results: The scores of symptoms and physical signs as well as the score of R-QOL, and EOS distribution score and the contents of serum IgE, RORγt, IL-17 and IL-33 were all reduced as compared with those before treatment in each group ( P <0.05), and the contents of serum Foxp3 and IL-27 were increased as compared with those before treatment in each group ( P <0.05). After treatment, the scores of symptoms and physical signs as well as the score of R-QOL, and the contents of serum IgE, RORγt and IL-33 in the acu-mox group were lower than those in the medication group ( P <0.05), and the contents of serum Foxp3 and IL-27 were higher than those of the medication group ( P <0.05). The total effective rate of the acu-mox group was 100.0% (40/40), significantly higher than 82.5% (33/40) in the medication group ( P <0.05). No ob-vious adverse reaction was found in either group during and after treatment., Conclusion: Acupuncture combined with moxibustion is significantly effective and safe in treatment of allergic rhinitis. Its effect mechanism may be related to the balance modulation of Th1/Th2 and Th17/Treg cells mediated by naive CD4 + T cells.

Background: Chemoresistance of pancreatic cancer is the main reason for the poor treatment effect of pancreatic cancer patients. Exploring chemotherapy resistance-related genes has been a difficult and hot topic of oncology. Numerous studies implicate the key roles of circular RNAs (circRNAs) in the development of pancreatic cancer. However, the regulation of circRNAs in the process of pancreatic ductal adenocarcinoma (PDAC) chemotherapy resistance is not yet fully clear., Methods: Based on the cross-analysis of the Gene Expression Omnibus (GEO) database and the data of our center, we explored a new molecule, hsa&#95;circ&#95;0078297 (circ-MTHFD1L), related to chemotherapy resistance. QRT-PCR was used to detect the expression of circRNAs, miRNAs, and mRNAs in human PDAC tissues and their matched normal tissues. The interaction between circ-MTHFD1L and miR-615-3p/RPN6 signal axis was confirmed by a series of experiments such as Dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) RNA immunoprecipitation (RIP) assays., Results: Circ-MTHFD1L was significantly increased in PDAC tissues and cells. And in PDAC patients, the higher the expression level of circ-MTHFD1L, the worse the prognosis. Mechanism analysis showed that circ-MTHFD1L, as an endogenous miR-615-3p sponge, upregulates the expression of RPN6, thereby promoting DNA damage repair and exerting its effect on enhancing gemcitabine chemotherapy resistance. More importantly, we also found that Silencing circ-MTHFD1L combined with olaparib can increase the sensitivity of pancreatic cancer to gemcitabine., Conclusion: Circ-MTHFD1L maintains PDAC gemcitabine resistance through the miR-615-3p/RPN6 signal axis. Circ-MTHFD1L may be a molecular marker for the effective treatment of PDAC., (© 2022. The Author(s).)

In recent years, micrometer-sized Si-based anode materials have attracted intensive attention in the pursuit of energy-storage systems with high energy and low cost. However, the significant volume variation during repeated electrochemical (de)alloying processes will seriously damage the bulk structure of SiO x microparticles, resulting in rapid performance fade. This work proposes to address the challenge by preparing in situ magnesium-doped SiO x (SiMg y O x ) microparticles with stable structural evolution against Li uptake/release. The homogeneous distribution of magnesium silicate in SiMg y O x contributes to building a bonding network inside the particle so that it raises the modulus of lithiated state and restrains the internal cracks due to electrochemical agglomeration of nano-Si. The prepared micrometer-sized SiMg y O x anode shows high reversible capacities, stable cycling performance, and low electrode expansion at high areal mass loading. A 21700 cylindrical-type cell based on the SiMg y O x -graphite anode and LiNi 0.8 Co 0.15 Al 0.05 O 2 cathode demonstrates a 1000-cycle operation life using industry-recognized electrochemical test procedures, which meets the practical storage requirements for consumer electronics and electric vehicles. This work provides insights on the reasonable structural design of micrometer-sized alloying anode materials toward realization of high-performance Li-ion batteries., (© 2022 Wiley-VCH GmbH.)

Most new cases and the highest mortality rates of breast cancer occur among middle-aged and old women. The recurrence rate of early-stage invasive ductal carcinoma (IDC) among women aged ≥ 50 years and receiving different treatments remains unclear. Therefore, this study was conducted to determine these rates. We used Surveillance, Epidemiology, and End Results (SEER) data for this nationwide population-based cohort study. All women aged ≥ 50 years and diagnosed with early-stage IDC between 2000 and 2015 were identified and divided into three treatment groups, namely, breast conservation therapy (BCT), mastectomy alone (MAS), and mastectomy with radiation therapy (MAS + RT). The recurrence rates of IDC among these groups were then compared. The BCT group had a lower short-term recurrence risk than the MAS and MAS + RT groups (hazard ratio [HR]: 1.00 vs. 2.90 [95% CI 1.36-2.66] vs. 2.07 [95% CI 0.97-4.44]); however, the BCT group also had a higher long-term recurrence risk than MAS and MAS + RT groups (HR 1.00 vs. 0.30 [95% CI 0.26-0.35] vs. 0.43 [95% CI 0.30-0.63]). The high long-term recurrence rate of the BCT group was especially prominent at the 10- and 15-year follow-ups. The results provide valuable evidence of the most reliable treatment strategy for this population. Further studies including more variables and validation in other countries are warranted to confirm our findings., (© 2022. The Author(s).)

Objective: To understand the epidemiological characteristics of COVID-19 epidemic in Ejina banner, Inner Mongolia, in October 2021 and provide evidence for the improvement of COVID-19 prevention and control. Methods: The information about the time, area and population distributions of COVID-19 cases in Ejina before November 13, 2021 and the gene sequencing result of the isolates were collected for a statistical descriptive analysis. Results: The first COVID-19 case in Ejina occurred on 7 October, 2021. A total of 164 COVID-19 cases were reported from October 19 to November 12. Most cases were distributed in 6 communities in Darahub (156 cases, 95.12%). The result of full gene sequencing of the isolates indicted that the pathogen was Delta variant (B.1.617.2). The male to female ratio of the cases was 1.3∶1. The age of cases ranged from 1 to 85 years, and the cases aged 20-59 years accounted for 78.66%. The main clinical symptoms were sore throat (91 cases, 91.92%), cough (49 cases, 49.49%) and fever (23 cases, 23.23%). Most cases were ordinary ones (81 cases, 49.39%) and mild ones (68 cases, 41.46%). The cases were mainly detected at the isolation points (84 cases, 51.22%) and through population based nucleic acid testing (62 cases, 37.80%). The basic reproduction number ( R 0 ) of COVID-19 was 5.3, the average incubation period was 3.9 days. The local government rapidly started Ⅳ level emergency response and conducted 10 rounds of nucleic acid tests. The transferring of travelers reduced the risk for the further spread of COVID-19 in Ejina. Conclusions: The epidemic of COVID-19 in Ejina characterized by strong transmission, short incubation period, herd susceptibility and case clustering. Delta variant (B.1.617.2) was the pathogen, which might be imported from Zeke port. Comprehensive prevention and control measures, such as closed-loop management and vaccination, should be continued. The successful transferring of the patients and travelers provided evidence for the effective and precise prevention and control of COVID-19 in a routine manner.

Background: Globally, gastric cancer is ranked 4th and 3rd in terms of incidence and mortality rate among all cancer types. This study aimed to examine the relationship between G protein-coupled receptor kinase 3 (GRK3) and gastric cancer prognosis and investigate the role of GRK3 in gastric cancer carcinogenesis. Methods: GRK3 level in gastric tissues and cells were determined using immunohistochemistry and immunoblotting. Kaplan-Meier analysis with the log-rank test was employed to evaluate the relationship between GRK3 expression and gastric cancer prognosis. RNAi technology was applied to examine the effects of GRK3 inhibition on gastric cancer proliferation and spread. Results: GRK3 overexpression was correlated significantly with lymphatic metastasis (P = 0.0011), distant metastasis (P < 0.0001), TNM stage (P = 0.0035), and vascular invasion (P = 0.0025). Kaplan-Meier survival analysis showed that the disease-free survival and overall survival of patients with high GRK3 expression were significantly shorter than those of patients with low GRK3 expression. Multivariate Cox regression analysis also showed that the overexpression of GRK3 was an independent prognostic biomarker of gastric cancer (P = 0.029). In cultured gastric cancer cells, GRK3 knockdown inhibited cell proliferation, migration, and invasion. Further analysis revealed that more GRK3-knockdown cells were in G0/G1 phase and few cells were in S phase, thereby inhibiting cell proliferation. Conclusions: GRK3 overexpression can be a candidate biomarker for gastric cancer prognosis. GRK3 is also a potential therapeutic target for gastric cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Chemokine (C-C motif) ligand 5 (CCL5) and CCR5, one of its receptors have been reported to be highly expressed in white adipose tissue (WAT) and are associated with the progression of inflammation and the development of insulin resistance in obese humans and mice. However, the role of CCL5/CCR5 signaling in obesity-associated dysregulation of energy metabolism remains unclear. Here, we demonstrate that global CCL5/CCR5 double knockout (DKO) mice have higher cold stress-induced energy expenditure and thermogenic function in brown adipose tissue (BAT) than wildtype (WT) mice. DKO mice have higher cold stress-induced energy expenditure and thermogenic function in BAT than WT mice. KEGG pathway analysis indicated that deletion of CCL5/CCR5 further facilitated the cold-induced expression of genes related to oxidative phosphorylation (OxPhos) and lipid metabolic pathways. In primary brown adipocytes of DKO mice, the augmentation of CL-316243-stimulated thermogenic and lipolysis responses was reversed by co-treatment with AMPKα1 and α2 short interfering RNA (siRNA). Overexpression of BAT CCL5/CCR5 genes by local lentivirus injection in WT mice suppressed cold stress-induced lipolytic processes and thermogenic activities. In contrast, knockdown of BAT CCL5/CCR5 signaling further up-regulated AMPK phosphorylation as well as thermogenic and lipolysis responses to chronic adrenergic stimuli and subsequently decreased level of body weight gain. Chronic knockdown of BAT CCL5/CCR5 signaling improved high-fat diet (HFD)-induced insulin resistance in WT mice. It is suggested that obesity-induced augmentation of adipose tissue (AT) CCL5/CCR5 signaling could, at least in part, suppress energy expenditure and adaptive thermogenesis by inhibiting AMPK-mediated lipolysis and oxidative metabolism in thermogenic AT to exacerbate the development of obesity and insulin resistance., (© 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Immune checkpoint inhibitor (ICI) therapy continues to revolutionize melanoma treatment, but only a subset of patients respond. Major efforts are underway to develop minimally invasive predictive assays of ICI response. Using single-cell transcriptomics, we discovered a unique CD8 T cell blood/tumor-shared subpopulation in melanoma patients with high levels of oxidative phosphorylation (OXPHOS), the ectonucleotidases CD38 and CD39, and both exhaustion and cytotoxicity markers. We called this population with high levels of OXPHOS "CD8+ TOXPHOS cells." We validated that higher levels of OXPHOS in tumor- and peripheral blood-derived CD8+ TOXPHOS cells correlated with ICI resistance in melanoma patients. We then developed an ICI therapy response predictive model using a transcriptomic profile of CD8+ TOXPHOS cells. This model is capable of discerning responders from nonresponders using either tumor or peripheral blood CD8 T cells with high accuracy in multiple validation cohorts. In sum, CD8+ TOXPHOS cells represent a critical immune population to assess ICI response with the potential to be a new target to improve outcomes in melanoma patients., Competing Interests: Disclosures: P. Funchain reported grants from Pfizer and Bristol Myers Squibb and personal fees from Eisai outside the submitted work. A. Rodriguez reported non-financial support from Lipid Genomics during the conduct of the study and non-financial support from Lipid Genomics outside the submitted work; in addition, A. Rodriguez had a patent to LAG3 issued (Lipid Genomics). No other disclosures were reported., (© 2021 Li et al.)

Purpose: Several studies have investigated the association between gastroesophageal reflux disease (GERD) and colorectal cancer (CRC) risk, but the presented scientific results are highly debatable. This study examined the longitudinal association between GERD and CRC in an Asian population., Methods: A retrospective cohort study was performed using the National Health Insurance Research Database of Taiwan. The study cohort comprised 45,828 individuals with newly diagnosed GERD (the GERD cohort) and 229,140 age, sex, and date of enrollment-matched patients without GERD (the comparison cohort) from 2000 to 2006. The primary outcome was the incidence of CRC. To estimate the effect of GERD on the risk of CRC, the Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: There were 785 newly diagnosed CRC patients in the 45,828 patients with GERD. Relatively, there were 2375 incident CRC cases in 229,140 patients without GERD. The incidence rate of CRC for the GERD cohort (17.60 per 10,000 person-years) was significantly higher than the corresponding incidence rate for the comparison cohort (10.22 per 10,000 person-years). After adjustment for confounders, GERD was associated with a significantly increased risk of CRC (adjusted HR,1.76; 95% CI, 1.62-2.90). Of note, a significant association between GERD and CRC risk was evident in both genders., Conclusions: In conclusion, this nationwide population-based cohort study supports the hypothesis that GERD was associated with a significantly increased risk of CRC. Our findings warrant still further investigation of the underlying mechanisms related to carcinogenic effect of GERD on colorectal carcinoma., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Breast cancer and stroke were leading cause of cancer-related mortality in the world. Stroke is the second leading cause of death. Previous studies showed that patients with breast cancer had a relatively higher risk of sleep disorders. Sleep disorders increased the risk of stroke. The aim of our study was to examine the risk of stroke after a breast cancer with sleep disorder among women in Taiwan. The Taiwan Cancer Registry was used to identify patients with breast cancer. Patients with new-onset breast cancer from January 2007 to December 2015 were selected for this study and followed until December 31, 2017. Patients who were diagnosed with sleep disorders were set as the case group, and the controls were those without sleep disorders. We enrolled 5256 patients with sleep disorders and 10,512 patients without sleep disorders. There were 121 (2.30%) patients with ischemic stroke among the breast cancer patients with sleep disorders. The mean time from the diagnosis of breast cancer to the occurrence of ischemic stroke was 6.29±2.59 years for breast cancer patients with sleep disorders and 6.00±2.76 years for those without sleep disorders (p < 0.0001). After matching by age and index year, breast patients with sleep disorders had a 1.31-fold higher risk (95% confidence interval: 1.03-1.66; p-value=0.026) of ischemic stroke than those without sleep disorders, after adjustment for comorbidities, cancer clinical stage, and treatment types. In conclusion, Breast cancer patients with sleep disorders have an increased risk of stroke., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Rectal cancer patients can conceivably obtain relief from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before resection, but the stratification of risk and clinical outcomes remains challenging. Therefore, identifying effective predictive biomarkers offers clinicians the opportunity to individually tailor early interventions, which would help optimize therapy., Methods: Using a public rectal cancer transcriptome dataset (GSE35452), we focused on cytoskeletal protein binding (GO: 0008092)-related genes and identified FERM domain containing 3 (FRMD3) as the most significant differentially expressed gene associated with CCRT resistance. We gathered 172 tumor samples from rectal cancer patients treated with neoadjuvant CCRT accompanied by curative resection and estimated the expression level of FRMD3 using immunohistochemistry., Results: The results revealed that high FRMD3 immunoexpression was remarkably associated with advanced pre-CCRT and post-CCRT tumor status (p = 0.004 and p < 0.001), pre-CCRT and post-CCRT lymph node metastasis (both p < 0.001), more perineurial invasion (p = 0.023), and a smaller extent of tumor regression (p = 0.018). High FRMD3 immunoexpression was remarkably correlated with inferior disease-specific survival (DSS) (p = 0.0001), local recurrence-free survival (LRFS) (p = 0.0003), and metastasis-free survival (MeFS) (p = 0.0023) at the univariate level. Furthermore, in multivariate analysis, high FRMD3 immunoexpression remained independently predictive of inferior DSS (p = 0.002), LRFS (p = 0.005), and MeFS (p = 0.015)., Conclusion: These results suggest that high FRMD3 expression is related to advanced clinicopathological features and inferior therapeutic responses in rectal cancer patients treated with CCRT, validating the promising prognostic value of FRMD3 expression., (© 2021. Japan Society of Clinical Oncology.)

Rechargeable lithium-metal batteries with a cell-level specific energy of >400 Wh kg -1 are highly desired for next-generation storage applications, yet the research has been retarded by poor electrolyte-electrode compatibility and rigorous safety concerns. We demonstrate that by simply formulating the composition of conventional electrolytes, a hybrid electrolyte was constructed to ensure high (electro)chemical and thermal stability with both the Li-metal anode and the nickel-rich layered oxide cathodes. By employing the new electrolyte, Li∥LiNi 0.6 Co 0.2 Mn 0.2 O 2 cells show favorable cycling and rate performance, and a 10 Ah Li∥LiNi 0.8 Co 0.1 Mn 0.1 O 2 pouch cell demonstrates a practical specific energy of >450 Wh kg -1 . Our findings shed light on reasonable design principles for electrolyte and electrode/electrolyte interfaces toward practical realization of high-energy rechargeable batteries., (© 2021 Wiley-VCH GmbH.)

For locally advanced rectal cancer patients, introducing neoadjuvant concurrent chemoradiotherapy (CCRT) before radical resection allows tumor downstaging and increases the rate of anus retention. Since accurate staging before surgery and sensitivity prediction to CCRT remain challenging, a more precise genetic biomarker is urgently needed to enhance the management of such situations. The epithelial mucous barrier can protect the gut lumen, but aberrant mucin synthesis may defend against drug penetration. In this study, we focused on genes related to maintenance of gastrointestinal epithelium (GO: 0030277) and identified mucin 2 ( MUC2 ) as the most significantly upregulated gene correlated with CCRT resistance through a public rectal cancer transcriptome dataset (GSE35452). We retrieved 172 records of rectal cancer patients undergoing CCRT accompanied by radical resection from our biobank. We also assessed the expression level of MUC2 using immunohistochemistry. The results showed that upregulated MUC2 immunoexpression was considerably correlated with the pre-CCRT and post-CCRT positive nodal status ( p = 0.001 and p < 0.001), advanced pre-CCRT and post-CCRT tumor status ( p = 0.022 and p < 0.001), vascular invasion ( p = 0.015), and no or little response to CCRT ( p = 0.006). Upregulated MUC2 immunoexpression was adversely prognostic for all three endpoints, disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS) (all p < 0.0001), at the univariate level. Moreover, upregulated MUC2 immunoexpression was an independent prognostic factor for worse DSS ( p < 0.001), LRFS ( p = 0.008), and MeFS ( p = 0.003) at the multivariate level. Collectively, these results imply that upregulated MUC2 expression is characterized by a more advanced clinical course and treatment resistance in rectal cancer patients undergoing CCRT, revealing the potential prognostic utility of MUC2 expression.

The introduction of preoperative concurrent chemoradiotherapy (CCRT) increases the rate of anal preservation and allows tumor downstaging for clinical stage T3/T4 or node-positive rectal cancer patients. However, there is no precise predictive tool to verify the presence of residual tumor apart from surgical resection. The gastrointestinal (GI) tract not only digests nutrients but also coordinates immune responses. As the outermost layer of the GI tract, mucus plays a key role in mediating the interaction between the digestive and immune systems, and aberrant mucus mesh formation may cause chemoresistance by impeding drug delivery. However, the correlations among digestion-related genes, mucin synthesis, and chemoresistance remain poorly understood. In the present study, we evaluated genes related to digestion (GO: 0007586) and identified cathepsin E ( CTSE ), which is involved in immune regulation, as the most significantly upregulated gene associated with CCRT resistance in rectal cancer in a public transcriptome dataset (GSE35452). We recovered 172 records of rectal cancer patients receiving CCRT followed by surgical resection from our biobank and evaluated the expression level of CTSE using immunohistochemistry. The results revealed that tumors with CTSE overexpression were significantly correlated with pre-CCRT and post-CCRT positive nodal status (both p < 0.001), advanced pre-CCRT and post-CCRT tumor status ( p < 0.001 and p = 0.002), perineural invasion ( p = 0.023), vascular invasion ( p < 0.001), and a lesser degree of tumor regression ( p = 0.003). At the univariate level, CTSE overexpression was an adverse prognostic factor for all three endpoints: disease-specific survival (DSS), metastasis-free survival (MeFS) (both p < 0.0001), and local recurrence-free survival (LRFS) ( p = 0.0001). At the multivariate level, CTSE overexpression remained an independent prognostic factor for poor DSS, MeFS (both p = 0.005), and LRFS ( p = 0.019). Through bioinformatics analysis, we speculated that CTSE overexpression may confer CCRT resistance by forming a defensive mucous barrier. Taken together, these results suggest that CTSE overexpression is related to CCRT resistance and inferior survival in rectal cancer patients, highlighting the potential predictive and prognostic value of CTSE expression.

Background: Patients with rectal cancer can prospectively be favored for neoadjuvant concurrent chemoradiotherapy (CCRT) to downstage before a radical proctectomy, but the risk stratification and clinical outcomes remain disappointing., Methods: From a published rectal cancer transcriptome dataset (GSE35452), we highlighted extracellular matrix (ECM)-linked genes and identified the serine protease inhibitor Kazal-type 4 (SPINK4) gene as the most relevant among the top 10 differentially expressed genes associated with CCRT resistance. We accumulated the cases of 172 rectal cancer patients who received neoadjuvant CCRT followed by surgery and collected tumor specimens for the evaluation of the expression of SPINK4 using immunohistochemistry., Results: The results revealed that high SPINK4 immunoexpression was significantly related to advanced pre-CCRT and post-CCRT tumor status (both p < 0.001), post-CCRT lymph node metastasis ( p = 0.001), more vascular and perineurial invasion ( p = 0.015 and p = 0.023), and a lower degree of tumor regression ( p = 0.001). In univariate analyses, high SPINK4 immunoexpression was remarkably correlated with worse disease-specific survival (DSS) ( p < 0.0001), local recurrence-free survival (LRFS) ( p = 0.0017), and metastasis-free survival (MeFS) ( p < 0.0001). Furthermore, in multivariate analyses, high SPINK4 immunoexpression remained independently prognostic of inferior DSS and MeFS ( p = 0.004 and p = 0.002)., Conclusion: These results imply that high SPINK4 expression is associated with advanced clinicopathological features and a poor therapeutic response among rectal cancer patients undergoing CCRT, thus validating the prospective prognostic value of SPINK4 for those patients.

Gastric cancer (GC) is one of the most common malignant tumors worldwide and has high rates of morbidity and mortality. This study investigated the role of Krüppel-like factor 16 (KLF16) in GC. Real-time polymerase chain reaction, Western blotting, and immunohistochemistry were used to examine the expression of KLF16 in gastric cells and tissues. Gene overexpression and silencing were applied to study the involvement of KLF16 in GC cell growth and metastasis along with its underlying mechanism. The results indicate that KLF16 overexpression is significantly associated with nodal status, distant metastasis, staging, degree of differentiation, vascular invasion, and patient survival. Multivariate Cox proportional hazards regression model analysis revealed that the overexpression of KLF16 is an independent prognostic biomarker of GC. The in vitro study revealed that up-regulated KLF16 accelerates cell growth and metastasis, whereas the inhibition of KLF16 suppresses these cellular activities. The results of an animal study also indicated that the overexpression and silencing of KLF16 accelerate and repress xenograft proliferation and metastasis. Further studies of affected cell growth and metastasis revealed that KLF16 modulates the cell cycle and epithelial-mesenchymal transition through transcriptional regulation of microfibrillar-associated protein 5. Collectively, these results reveal that KLF16 overexpression is a potential prognostic biomarker and therapeutic target for the treatment of GC., Competing Interests: None., (AJCR Copyright © 2021.)

Objectives: Diabetes is a risk factor for poor COVID-19 prognosis. The analysis of related prognostic factors in diabetic patients with COVID-19 would be helpful for further treatment of such patients. Methods: This retrospective study involved 3623 patients with COVID-19 (325 with diabetes). Clinical characteristics and laboratory tests were collected and compared between the diabetic group and the non-diabetic group. Binary logistic regression analysis was applied to explore risk factors associated in diabetic patients with COVID-19. A prediction model was built based on these risk factors. Results: The risk factors for higher mortality in diabetic patients with COVID-19 were dyspnea, lung disease, cardiovascular diseases, neutrophil, PLT count, and CKMB. Similarly, dyspnea, cardiovascular diseases, neutrophil, PLT count, and CKMB were risk factors related to the severity of diabetes with COVID-19. Based on these factors, a risk score was built to predict the severity of disease in diabetic patients with COVID-19. Patients with a score of 7 or higher had an odds ratio of 7.616. Conclusions: Dyspnea is a critical clinical manifestation that is closely related to the severity of disease in diabetic patients with COVID-19. Attention should also be paid to the neutrophil, PLT count and CKMB levels after admission., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Xiao, He, Xu, Liu, Lin, Li, Xu, Hu, Ren, Zhang, Zhang, Duan, Tian, Li, Wu, Song, Liu and Yang.)

Background/aims: Pancreatic ductal adenocarcinoma (PDAC) can occur in different parts of the pancreas. This study aimed to identify clinicopathological characteristics independently correlated with the prognosis of PDAC of the pancreatic head/uncinate (PHC) or body-tail (PBTC), and to develop novel nomograms for predicting cancer-specific survival (CSS) according to different primary cancer locations., Methods: 1160 PDAC patients were retrospectively enrolled and assigned to training and test sets with each set divided into PHC and PBTC groups. Comparative analysis of clinicopathologic characteristics, survival analysis, and multivariate analysis were performed. Independent factors were identified and used for constructing nomograms. The performance of the nomograms was validated in the test set., Results: Primary tumor location was an independent risk factor for prognosis of PDAC after surgery. Specially, gender, fasting blood glucose, and preoperative cancer antigen 19-9 were significantly associated with prognosis of PHC, whereas age, body mass index, and lymph nodes were significantly correlated with the prognosis of PBTC. A significant difference in prognosis was found between PHC and PBTC in stage Ia and stage III. Three nomograms were established for predicting the prognosis for PDAC, PHC, and PBTC. Notably, these nomograms were calibrated modestly (c-indexes of 0.690 for PDAC, 0.669 for PHC, and 0.704 for PBTC), presented better accuracy and reliability than the 8 th AJCC staging system, and achieved clinical validity., Conclusions: PHC and PBTC share the differential clinical-pathological characteristics and survival. The nomograms show good performance for predicting prognosis in PHC and PBTC. Therefore, these nomograms hold potential as novel approaches for predicting survival of PHC and PBTC patients after surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Liao, Chen, Huang, Yang, Tian, Wang, Du, Zhan, Chen and Chen.)

Background: Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear., Methods: RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5 250-Ser (SRSF5 250-Ser ) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14 exon10 (METTL14 exon10 ) and Cyclin L2 exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14 exon 10 and Cyclin L2 exon6.3 skipping were surveyed., Results: CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5 250-Ser , which inhibited METTL14 exon10 skipping while promoted Cyclin L2 exon6.3 skipping. In addition, aberrant METTL14 exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2 exon6.3 promoted proliferation of PDAC cells., Conclusions: The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients.

O-GlcNAcylation is important in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The glycosyltransferase EGF domain-specific O-linked GlcNAc transferase (EOGT) acts as a key participant in glycosylating NOTCH1. High-throughput sequencing of specimens from 30 advanced PDAC patients identified SHCBP1 and EOGT as factors of poor prognosis. We hypothesized that they could mediate PDAC progression by influencing NOTCH1 O-GlcNAcylation. Thus, 186 PDAC tissue specimens were immunostained for EOGT and SHCBP1. Pancreatic cancer cell lines and nude mouse models were used for in vitro and in vivo experiments. Respectively, The protein expression of EOGT and SHCBP1 was significantly elevated and correlated with worse prognosis in PDAC patients. In vitro, SHCBP1 overexpression promoted pancreatic cancer cell proliferation, migration and invasion, while knocking down SHCBP1 and EOGT inhibited these malignant processes. In vivo data showed that SHCBP1 overexpression promoted xenograft growth and lung metastasis and shortened survival in mice, whereas knocking down either EOGT or SHCBP1 expression suppressed xenograft growth and metastasis and prolonged survival. We further clarified the molecular mechanisms by which EOGT and SHCBP1 enhance the O-GlcNAcylation of NOTCH1, Subsequently promoting the nuclear localization of the Notch intracellular domain (NICD) and inhibiting the transcription of E-cadherin and P21 in pancreatic cancer cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The association of exertional heat stroke (EHS) and testicular morphological changes affecting sperm quality, as well as the association of EHS and hypothalamic changes affecting sexual behavior, has yet to be elucidated. This study aimed to elucidate the effects of EHS on fertility, erectile function, and testicular morphology in male rats. Animals were exercised at higher room temperature (36 ℃ relative humidity 50%) to induce EHS, characterized by excessive hyperthermia, neurobehavioral deficits, hypothalamic cell damage, systemic inflammation, coagulopathy, and multiple organ injury. In particular, EHS animals had erectile dysfunction (as determined by measuring the changes of intracavernosal pressure and mean arterial pressure in response to electrical stimulation of cavernous nerves). Rats also displayed testicular temperature disruption, poorly differentiated seminiferous tubules, impaired sperm quality, and atrophy of interstitial Leydig cells, Sertoli cells, and peri-tubular cells in the testicular tissues accompanied by no spermatozoa and broken cells with pyknosis in their seminal vesicle and prostatitis. These EHS effects were still observed after 3 days following EHS onset, at least. Our findings provide a greater understanding of the effect of experimentally induced EHS on masculine sexual behavior, fertility, stress hormones, and morphology of both testis and prostate.

Obesity is closely linked with type 2 diabetes and the effective therapies on obesity-associated diabetes are under development. The aim of this study was undertaken to investigate whether the inhibition of the augmented CCR5-mediated signaling could be a common target for treatment of obesity-associated insulin resistance and impairment of pancreatic insulin secretion in high-fat diet (HFD) fed rats and CCR5 knockout mice and also in isolated islets and RIN-m5F cells. Conducted with SD rats, HFD-induced body weight gain was significantly decreased in those combined with Maraviroc treatment, but food intake remained similar compared to control. Maraviroc also significantly improved the impaired oral glucose tolerance test (OGTT). As compared with wild-type mice, CCR5 deletion significantly attenuated the HFD-induced increases in glucose area under curve of OGTT and the value of HOMA-IR as well as plasma lipid profile. It also reversed the HFD-suppressed gene expressions of GLUT4 and IRS-1 in adipose tissue. On the other hand, the HFD-associated islet macrophage and T-cell infiltration were significantly decreased in CCR5 KO mice. H 2 O 2 significantly suppressed glucose-stimulated insulin secretion (GSIS) is isolated islets, which were significantly reversed in those cotreated with CCR5 mAb. H 2 O 2 failed to change GSIS in those of CCR5 KO mice. The palmitate-induced reactive oxygen species production was significantly decreased in those cotreated with CCR5 antagonist in RIN-m5F cells. Collectively, it is suggested that targeting inhibition of the CCR5 mediated inflammatory pathway could not only improve obesity-associated insulin resistance but also directly alleviate pancreatic β-cell dysfunction., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Carbon monoxide (CO) is a toxic gas and an endogenous signaling molecule. Some studies involving cell lines have revealed the potential antibreast cancer effects of CO. Data on such effects in humans, however, are limited. Thus, we conducted a study on patients with CO poisoning (COP) to evaluate the effects of CO on the risk of breast cancer. We identified female patients who were diagnosed with COP over the period of 2002 and 2009 from the Nationwide Poisoning Database of Taiwan. For comparison, we selected females without COP from the National Health Insurance Research Database. Participants in the COP and comparison cohorts were matched on the index year, age, monthly income, and geographic region of residence at a 1:6 ratio. We followed up the two cohorts until the end of 2014 and compared their risks of developing breast cancer. We included 7053 participants with COP and 42,318 participants without COP. Participants with COP were at a lower risk of developing breast cancer than those without COP (0.7% vs. 1.0%, p < 0.001). Cox proportional hazard regression analyses revealed that COP was associated with a hazard ratio of 0.67 (95% confidence interval [95% CI] 0.50-0.90) for breast cancer after we adjusted for age, monthly income, geographic region, and comorbidities of hypertension, diabetes, and hyperlipidemia. Our result provides evidence for the potential protective effects of CO against breast cancer in humans. Further studies that directly evaluate the potential effects are warranted.

The aim of this study was to investigate the relationship between textbook outcome and survival in patients with surgically treated colon cancer. A total of 804 surgical cases were enrolled between June 1, 2010 and December 31, 2014. Textbook outcome was defined as patients who had colon cancer surgery and met the six healthcare parameters of surgery within 6 weeks, radical resection, lymph node (LN) yield ≥12, no ostomy, no adverse outcome and colonoscopy before/after surgery within 6 months. The effect of textbook outcome on 5-year disease-specific survival (DSS) was calculated using the Kaplan-Meier method. A Cox regression model was used to find significant independent variables and stratified analysis used to determine whether text-book outcome had a survival benefit. A textbook outcome was achieved in 59.5% of patients undergoing colon cancer surgery. Important obstacles to achieving textbook outcome were no stomy, no adverse outcome and LN yield ≥12. Patients with text-book outcome had statistically significant better 5-year DSS compared to those with-out (80.1% vs. 58.3%). Multivariate analyses indicated that colon cancer patients with textbook outcome had better 5-year DSS after adjusting for various confounders ([aHR], 0.44; 95% CI, 0.34-0.57). Thus, besides being an index of short-term quality of care, textbook outcomes could be used as a prognosticator of long-term outcomes, such as 5-year survival rates.

Carbon-coated SiO x microparticles (SiO x /C) demonstrate attractive potential for anode use in high-energy-density lithium-ion batteries due to high capacity and proper cycling stability. However, the excessive irreversible consumption of Li ions during the initial cycling remains a serious challenge arising from the limited lithium in full cells. Here, we endow SiO x /C anode with high initial Coulombic efficiency using the chemical pre-lithiation strategy. The lithium silicate is uniformly pregenerated in SiO x /C microparticles, which could effectively counteract the irreversible consumption of Li ions and avoid the complicated pre-lithiation process. Moreover, this strategy guarantees the structural integrity and processability of anode materials because of the homogeneous Li-organic complex solution pre-lithiation and high-temperature calcination process. The obtained SiO x /C microparticles can be applied as anode materials by directly mixing with commercial graphite, which demonstrates proper specific capacity, high initial Coulombic efficiency, and excellent cycling performance. Furthermore, the pouch cells using LiNi 0.8 Co 0.1 Mn 0.1 O 2 cathodes and the as-prepared anodes exhibit high energy density (301 Wh kg -1 ) and satisfactory cycling stability (93.3% capacity retention after 100 cycles).

Stressful life events induce abnormalities in emotional and cognitive behaviour. The endogenous opioid system plays an essential role in stress adaptation and coping strategies. In particular, the µ-opioid receptor (μR), one of the major opioid receptors, strongly influences memory processing in that alterations in μR signalling are associated with various neuropsychiatric disorders. However, it remains unclear whether μR signalling contributes to memory impairments induced by acute stress. Here, we utilized pharmacological methods and cell-type-selective/non-cell-type-selective μR depletion approaches combined with behavioural tests, biochemical analyses, and in vitro electrophysiological recordings to investigate the role of hippocampal μR signalling in memory-retrieval impairment induced by acute elevated platform (EP) stress in mice. Biochemical and molecular analyses revealed that hippocampal μRs were significantly activated during acute stress. Blockage of hippocampal μRs, non-selective deletion of μRs or selective deletion of μRs on GABAergic neurons (μR GABA ) reversed EP-stress-induced impairment of memory retrieval, with no effect on the elevation of serum corticosterone after stress. Electrophysiological results demonstrated that stress depressed hippocampal GABAergic synaptic transmission to CA1 pyramidal neurons, thereby leading to excitation/inhibition (E/I) imbalance in a μR GABA -dependent manner. Pharmaceutically enhancing hippocampal GABA A receptor-mediated inhibitory currents in stressed mice restored their memory retrieval, whereas inhibiting those currents in the unstressed mice mimicked the stress-induced impairment of memory retrieval. Our findings reveal a novel pathway in which endogenous opioids recruited by acute stress predominantly activate μR GABA to depress GABAergic inhibitory effects on CA1 pyramidal neurons, which subsequently alters the E/I balance in the hippocampus and results in impairment of memory retrieval.

Objective: Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is now the standard care for patients with advanced rectal cancer. Because a certain proportion of these patients have poor response to CCRT, the risk stratification of survival outcomes needs to be investigated. DNA repair responses in tumor cells can regulate malignant potential and therapy resistance. In this study, we analyzed the clinical significance of principal DNA repair effectors in patients with rectal cancer., Methods: We applied data mining for DNA repair pathways in a published transcriptome for rectal cancer cases, and identified that tumors with BRCA2 downregulation correlated with poor response to CCRT. We next examined BRCA2 expression by using immunohistochemistry staining in tumor tissues of 172 patients with rectal cancer. The correlation between BRCA2 expression levels and clinical variables was further analyzed in this rectal cancer cohort., Results: Among clinical and pathological factors, low BRCA2-expression was significantly correlated with higher pre-treatment (Tx) tumor status (P = .013), post-Tx tumor (P < .001) and nodal status (P = .044), vascular invasion (P = .008), and poor tumor regression grades (P < .001). In analyses of survival outcomes, patients with low BRCA2-expression were associated with shorter local recurrence-free survival (LRFS; P = .0005) and disease-specific survival (P = .0269). Multivariate analyses confirmed the independent prognostic value of low BRCA2-expression for shorter LRFS (P = .045, hazard ratio = 4.695)., Conclusion: Low BRCA2-expression is a significant predictor for tumors in advanced stages, poor response to CCRT, and shorter survivals in patients with rectal cancer. Poly (adenosine diphosphate-ribose) polymerase inhibitors targeting DNA repair response in cells have demonstrated clinical efficacy in BRCA2-mutated patients with cancer. Further studies evaluating the efficacy of CCRT combined with these inhibitors in low BRCA2-expressing rectal cancers are encouraged., Competing Interests: Declaration of Competing Interest The authors indicate that they have no potential conflicts of interest., (Copyright © 2020. Published by Elsevier GmbH.)

Exosomes are endogenous vesicles of cells, and can be used as important biomarkers for cancers. In this work, we developed a sensitive and reliable SERS sensor for simultaneous detection of multiple cancer-related exosomes. The SERS detection probes were made of bimetallic SERS-active nanotags, gold-silver-silver core-shell-shell nanotrepangs (GSSNTs), which were composed of bumpy surface nanorod (gold nanotrepang, GNT) cores and bilayer silver shells, and decorated with linker DNAs, which were complementary to the aptamer targeting exosomes. Three kinds of SERS detection probes were designed via the adoption of different Raman reporter molecules and linker DNAs. The capture probes were prepared by modifying specific aptamers of the target exosomes on magnetic beads (MBs). In the absence of target exosomes, SERS detection probes were coupled with MBs via specific DNA hybridization for use as aptamer-based SERS sensors. In the presence of target exosomes, the aptamer specifically recognized and captured the exosomes, and GSSNTs were subsequently released into the supernatant. Therefore, attenuated SERS signals were detected on the MBs, indicating the presence of target exosomes. The proposed aptamer-based SERS sensor is expected to be a facile and sensitive method for the multiplex detection of cancer biomarkers and has potential future applications in clinical diagnosis.

Objective: To evaluate the postoperatively hidden blood loss of elderly intertrochanteric fracture patients fixed with combined external fixator, and to explore the correlation between hidden blood loss and age. Methods: A retrospective analysis was conducted on 60 elderly intertrochanteric fracture patients who were admitted to the Department of Orthopedics of Hebei Provincial Hospital from January 2016 to May 2019. All the fractures were fixed with combined external fixators. The patients were divided into two groups according to the age: there were 31 cases in group A (60-80 years old) and 29 cases in group B (≥80 years old). The Gross equation and the Nandler formula were used to evaluate the amount of hidden blood loss based on changes in hematocrit (Hct) at the day preoperatively, 3 days postoperatively and the weight. The data were compared between the two groups by independent-sample t test. Results: The decreased Hct, hemoglobin(Hb) and the dominant blood loss and hidden blood loss in group A and B was 3.4%±1.7%, (13±7) g/L, (25±6) ml, (186±7) ml and 3.8%±1.2%, (13±3) g/L, (24±8) ml, (194±7) ml, respectively. There was no significant differences in the dominant and hidden blood loss between the groups ( t= 0.309, 0.883, both P> 0.05). Conclusion: The age doesn't affect the hidden blood loss in elderly intertrochanteric fracture patients fixed with combined external fixator, which indicated that the operation is safe and reliable for such patients.

Background: Epidemiological studies on the obstructive sleep apnea (OSA) and cancer relationship in humans are inconsistent. Furthermore, there are limited prospective studies on the association between OSA and the risk of colorectal cancer (CRC). This retrospective cohort study examined the longitudinal relationship between OSA and CRC in a nationwide population-based cohort., Methods: We identified 4180 individuals newly diagnosed with OSA (the exposed cohort) and randomly selected 16,720 age- and sex-matched subjects without OSA (the nonexposed cohort) between 2000 and 2008 from Taiwan's National Health Insurance Research Database (NHIRD). The Kaplan-Meier method was used for calculating the cumulative incidence of CRC in each cohort. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and the accompanying 95% confidence intervals (CIs) for the association between OSA and CRC., Results: After adjusting for potential confounders, patients with OSA were associated with a significantly higher risk of CRC than those without OSA (adjusted HR, 1.80; 95% CI, 1.28-2.52). The cumulative incidence of CRC was significantly higher in the OSA cohort than in the comparison cohort (log-rank test, p < 0.001). Furthermore, the association between OSA and CRC appeared to be enhanced with increasing frequency of OSA medical visits (adjusted HR [95% CI] was 1.61 [0.97-2.66] and 1.86 [1.26-2.75] for one visit and two or more visits, respectively)., Conclusion: This population-based cohort study demonstrated that OSA was associated with an increased risk of CRC. Further large-scale prospective studies are needed to confirm our results., (Copyright © 2019. Published by Elsevier B.V.)

To investigate the antipyretic effect of active components of Mahuang Decoction in febrile rats, and explore its correlation with pharmacokinetics at different time points. The feverished rat models were induced by dry yeast, and intragastrically administered with the effective components of Mahuang Decoction with different orthogonal compatibility ratios. At different time points after administration, body temperature was measured; blood was taken from orbital vena plexus, and the contents of interleukin-6(IL-6), interleukin-1β(IL-1β), and tumor necrosis factor-α(TNF-α) in rat serum were determined with the kits. Combined with the pharmacokinetic data of the seven effective components in Mahuang Decoction, PK-PD(pharmacokinetics-pharmacodynamics) data fitting was conducted by using the analysis method of non-atrioventricular model, and then the pharmacodynamic parameters were calculated to determine the optimal binding model. The results showed that the effective components of Mahuang Decoction inhibited the release of heat-causing factors IL-6, IL-1β and TNF-α, and reduced the increase of body temperature. There was a significant lag between drug effect and blood drug concentration, which was consistent with Sigmoid-E&#95;(max) model. The model fitting value showed a good correlation with mea-sured data, which could be used to evaluate and predict the correlation between PK and PD in Mahuang Decoction, and further applied to the multiple-indicator and multiple-effect study of PK-PD in other compound traditional Chinese medicines.

The role of atopic dermatitis (AD) in the development of colorectal cancer (CRC) has been a matter of scientific debate with mixed results. We conducted a nationwide cohort study to assess the association between AD and risk of CRC. Drawing on Taiwan's National Health Insurance Research Database, 46,703 patients with AD (the AD cohort) and 186,812 sex, age, and index year-matched patients without AD (the non-AD cohort) were identified in the period between 2000 and 2008. Follow-up time was calculated from the date of entry in the cohort until the occurrence of a first CRC diagnosis, death, or the end of the observation period (December 31, 2013), whichever occurred first. Hazards ratios (HRs) and accompanying 95% confidence intervals (CIs) derived from the Fine-Gray competing risk model were used to estimate the association between AD and CRC risk. After multivariable adjustment, AD was associated with an increased risk of CRC (adjusted HR, 1.26; 95% CI, 1.14-1.40). Of note, a significant positive association between AD and CRC risk was evident in both men and women and in all age groups. In summary, this population-based cohort study revealed that AD was associated with an increased risk of CRC in an Asian population. It will be of interest for cohort studies with prediagnostic specimens to evaluate the potential relationship between AD and CRC using biomarkers for allergy status.

Background/aim: A great proportion of patients with rectal cancer initially present with locally advanced disease and can potentially benefit from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before surgery. However, risk and clinical outcome stratification remain a great challenge. We aimed to find the potential biomarker to predict the effect of neoadjuvant CCRT on rectal cancer., Methods: We identified epiregulin (EREG) as the most significant predictive marker for neoadjuvant CCRT response from the published rectal cancer transcriptome data set GSE35452. We collected 172 biopsy specimens from rectal cancer patients who received neoadjuvant CCRT followed by radical proctectomy, performed EREG immunohistochemistry, and analyzed the H-scores. We further examined the correlations between the expression level of EREG and clinicopathological features, tumor regression grade, and survival, including disease-specific survival (DSS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MeFS)., Results: High EREG expression was significantly related to early pretreatment (pre-Tx) and posttreatment (post-Tx) tumor status (T1, T2, p = 0.047 and p < 0.001), pre-Tx and post-Tx negative nodal status (N0, p < 0.001 and p = 0.004), less vascular and perineurial invasion (p = 0.015 and p = 0.023), and higher tumor regression grade (p < 0.001). In the survival analysis, high EREG expression was significantly associated with better DSS (p < 0.0001), LRFS (p = 0.0004), and MeFS (p < 0.0001). In the multivariate analysis, high EREG expression remained prognostically significant for better DSS (p = 0.003; hazard ratio: 5.599)., Conclusion: These data suggest that EREG is a potential predictive marker and therapeutic target in rectal cancer patients receiving neoadjuvant CCRT., (© 2020 S. Karger AG, Basel.)

Glioma is one of the most common and aggressive malignant primary brain tumors with high recurrence rate and mortality rate and heavily depends on the angiogenesis. LncRNA H19 has many diverse biological functions, including the regulation of cell proliferation, differentiation and metabolism. Here, we aimed to investigate the molecular mechanism of lncRNA H19 affecting angiogenesis in glioma, which could help to uncover potential target for glioma therapy. RT-qPCR analysis was performed to detect the expression of lncRNA H19 and miR-138 in HEB, U87, A172 and U373 cell lines. MTT assay was used to evaluate the cell viability. To evaluate the migration and invasion after lncRNA H19 knockdown, Transwell and wound healing assay were employed. After lncRNA H19 knockdown, protein expression of HIF 1α and VEGF was detected by western blot and tube formation was assessed. For the prediction and validation of the interaction between lncRNA H19 and miR-138, bioinformatics and luciferase assay were performed. We investigated the regulatory roles and downstream molecular mechanisms of lncRNA H19 in glioma by knockdown H19, which inhibited the proliferation, migration and angiogenesis of glioma cells. Moreover, miR-138 acted as a target of H19 as detected by luciferase reporter assays. Meanwhile, HIF-1α was also a target of miR-138 and miR-138 could also regulate the proliferation, migration and angiogenesis of glioma cells by targeting HIF-1α and affecting the expression of VEGF in turn. Our findings identified an upregulated lncRNA H19 in glioma cells, which could promote proliferation, migration, invasion and angiogenesis via miR-138/HIF-1α axis as a ceRNA. This study provided a new opportunity to advance our understanding in the potential mechanism of lncRNA in glioma angiogenesis.

Our study aims to estimate the incidence of metachronous second primary lung cancer(SPLC) in initial primary lung cancer(IPLC) survivors and to determine whether radiotherapy affects the risk of metachronous SPLC in the first five years after the diagnosis of lung cancer. Incidence data of IPLC individuals who survived ≥2 years were obtained from SEER-18 database in 2004-2007. Joinpoint regression analysis and competing risk analysis were used to calculate the incidence of metachronous SPLC. Propensity score matching and decision analysis were available to estimate the effect of radiotherapy on metachronous SPLC. 264 of 11657 IPLC survivors with radiotherapy and 1090 of 24499 IPLC survivors without radiotherapy developed metachronous SPLC during 5-year follow-up, respectively. In joinpoint regression analysis, the 5-year incidence of metachronous SPLC in the radiotherapy group was lower than that in the nonradiotherapy group(2385 per 100,000 vs 4748 per 100,000, HR = 0.43,95% CI:0.39-0.47). Competing risk analysis showed that the survivors with radiotherapy were associated with the lower 5 year incidence of metachronous SPLC compared with those without radiotherapy(2.28% vs 4.47%, HR = 0.49,95% CI:0.43-0.57). Through propensity score matching, 4077 pairs of survivors were available to further study that radiotherapy potentially decreased the risk of developing metachronous SPLC with the adjustment of various factors(2.5% vs 3.3%, HR = 0.72, 95% CI:0.55-0.96). Decision analysis suggested that radiotherapy was a negative independent risk factor of metachronous SPLC with clinical net benefit in a range of risk thresholds (2% to 5%). Survivors of IPLC with radiotherapy likely had a low risk of metachronous SPLC during the first five years follow-up, especially non-small cell lung cancer.

Background: Kidney transplantation (KT) correlates with an increased risk of developing several malignancies; however, the risk of colorectal cancer (CRC) after KT remains debatable and has been marginally explored. Hence, in this nationwide, retrospective, population-based cohort study, we aimed to examine the correlation between KT and CRC in a large-scale population-based Chinese cohort., Methods: We identified a total of 3739 regular hemodialysis patients undergoing KT (exposed cohort) and 42,324 hemodialysis patients not undergoing KT (non-exposed cohort) between 2000 and 2008 from Taiwan's National Health Insurance Research Database (NHIRD). Both cohorts were followed up from January 1, 2000, to the date of CRC diagnosis, death, or the end of 2013. Using Kaplan-Meier method, we measured the cumulative incidence of CRC in each cohort. Furthermore, Cox proportional hazards models were used to compute hazards ratios (HRs) and 95% confidence intervals (CIs) to estimate the correlation between KT and CRC in hemodialysis patients., Results: The Kaplan-Meier analysis revealed that the cumulative incidence of CRC was significantly higher in the exposed cohort than in the non-exposed cohort (log-rank test, P < 0.001). After adjusting for potential confounders, the exposed cohort exhibited a significantly increased risk of CRC compared with the non-exposed cohort (adjusted HR, 1.34; 95% CI, 1.11-1.62)., Conclusions: Hemodialysis patients undergoing KT have a significantly higher risk of CRC than those not undergoing KT. Cancer should continue to be a primary focus of prevention during KT.

Background: The role of Helicobacter pylori (H. pylori) infection in the development of colorectal neoplasia has been a matter of scientific debate with controversial findings., Aims: This study examined the association between H. pylori infection and colorectal cancer (CRC) in a nationwide population-based Chinese cohort study., Methods: A total of approximately 3936 individuals with newly diagnosed H. pylori infection (the H. pylori-infected cohort) and 15 744 age- and sex-matched patients with diagnoses absence of H. pylori infection (the comparison cohort) from 2000 to 2005 were identified from Taiwan's National Health Insurance Research Database. The Kaplan-Meier method was used for measuring the cumulative incidence of CRC in each cohort. Cox proportional hazards models were used to compute hazard ratios (HRs) and accompanying 95% confidence intervals (CIs) for the estimation of the association between H. pylori infection and CRC., Results: The cumulative incidence of CRC was higher in H. pylori-infected cohort than that in the comparison cohort (log-rank test, P < 0.001). After adjustment for potential confounders, H. pylori infection was associated with a significantly increased risk of CRC (adjusted HR 1.87; 95% CI 1.37-2.57). In addition, the HR of CRC appeared to increase with increasing frequency of clinical visits for H. pylori infection., Conclusions: Our study demonstrated that H. pylori infection was associated with an increased risk of CRC, which warrants confirmation and exploration of the underlying biologic mechanisms by future studies., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We synthesized a novel and sensitive Au/Ag bimetallic SERS-active nanotag, Au-Ag-Ag core-shell-shell nanorod (Au@AgAgNR). The Au@AgAgNR nanotag exhibited a strong SERS signal and was easily assembled from bilayer silver shells on an Au nanorod (AuNR) core with embedded Raman reporter molecules in the core-shell-shell gaps. The SERS activity of the nanotags was investigated with 2-mercaptopyridine (2-Mpy) as a Raman reporter, which could form pyridine/Ag + coordination complexes to mediate the formation of silver shells. Specific enhancement of Raman signals was observed in the following order: AuNR < Au@AgNR < Au@AgAgNR. Then, Au@AgAgNR nanotags were coupled with magnetic beads (MBs) via specific DNA hybridization as a SERS sensor with a detection limit of 1 fM for a segment of the gene HPV-16. Factors affecting sensitivity and selectivity were investigated, including Raman dye concentration, silver nitrate dosage and the response to similar oligonucleotides. The proposed SERS sensor is expected to be a facile and sensitive method for specific gene detection.

In the present paper,after the febrile rat model was prepared by injecting yeast,orthogonally compatible effective components from prescription drugs of Mahuang Decoction( Ephedra sinica total alkaloids,Cinnamomum cassia essential oil,amygdalin,Glycyrrhiza uralensis total flavonoids+G. uralensis total saponins) with nine different dosage ratios were given by gavage administration.The plasma concentrations of main active ingredients including ephedrine hydrochloride,pseudoephedrine hydrochloride,methylephedrine hydrochloride,cinnamic acid,amygdalin,liquritin and glycyrrhizin at different time points were analyzed by liquid chromatograph mass spectrometer( LC-MS). Based on the pharmacokinetic parameters of non-compartmental model,the area under curve of total quantum( AUCt) and the mean chromatographic retention time of total quantum( MRTt) were further calculated,in order to evaluate the effect of compatibility on the total statistical moment parameters. The results showed that the pharmacokinetic characteristics of main active components in febrile rats were significantly different after treatment with orthogonally compatibility of E. sinica total alkaloids,C.cassia essential oil,amygdalin,G. uralensis total flavonoids and G. uralensis total saponins. Orthogonal analysis confirmed that different compatibility components had different effects on the total statistical moment parameters. The contribution of effective components of Mahuang Decoction to AUCtwas as follows in a descending order: E. sinica total alkaloids>C. cassia essential oil>amygdalin>G. uralensis total flavonoids+G. uralensis total saponin,while the contribution to MRTtwas: E. sinica total alkaloids >G. uralensis total flavonoids+G. uralensis total saponin>amygdalin>C. cassia essential oil. The E. sinica total alkaloid had the greatest effects on both of the above parameters,and the optimal combination was A&#95;3B&#95;3C&#95;2D&#95;1 for AUCt,and A&#95;1B&#95;1C&#95;1D&#95;1 for MRTt.

Background: Metabolic adaptation in cancer cells is important for cancer cell survival. Alternation in cellular metabolism getting more energy to support cell proliferation played a critical role in disease progression. We initially analyzed the public transcriptome of urothelial carcinoma in Gene Expression Omnibus database (GSE31684) with particular focus on genes associated with carbohydrate metabolism, and found that Chitinase 3-like-1 (CHI3L1) was a significantly up-regulated gene associated with advanced disease status. This study was aimed to evaluate the expression and prognostic significance of CHI3L1 in upper urinary tract urothelial carcinoma (UTUC) and urinary bladder urothelial carcinoma (UBUC)., Materials and Methods: We performed immunohistochemical study to evaluate CHI3L1 expression in 2 well-defined cohorts of urothelial carcinoma, including UTUC (n = 340) and UBUC (n = 295). CHI3L1 expression level was determined by H-score method. The associations between CHI3L1 expression and clinicopathological features, disease-specific survival (DSS) and metastasis-free survival (MFS) were analyzed., Results: High expression of CHI3L1 was significantly associated with adverse clinicopathological features in UTUC or UBUC, including advanced tumor status (pT), nodal metastasis, high histological grade, vascular invasion, perineural invasion, and high mitotic activity (all P < 0.05). Kaplan-Meier survival analysis revealed that patients with high CHI3L1 expression had shorter DSS and MFS in both UTUC and UBUC (all P < 0.05). In multivariate survival analyses, high expression of CHI3L1 acted as an independent prognostic factor for worse DSS (P < 0.001 in UTUC and P = 0.036 in UBUC) and MFS (P = 0.002 in UTUC and P = 0.003 in UBUC) in both UTUC and UBUC groups., Conclusions: High expression of CHI3L1 was significantly associated with aggressive clinicopathological features and acted as an independent prognostic factor for worse outcome in urothelial carcinoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)