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Abstract Background Gastric cancer (GC), a molecularly heterogeneous disease, is the third leading cause of cancer death worldwide. The majority of GC cases worldwide occur in East Asia, predominantly China. Mutational Signature Framework offers an elegant approach to identify mutational processes present in tumors. Methods To identify mutational signature patterns, we conducted whole exome sequencing (WES) analysis in Chinese patients with GC. Mutect2 and MutsigCV were used to identify significantly mutated genes in 175 Chinese GC cases using paired tumor-normal tissues. We investigated mutational signatures using Catalogue of Somatic Mutations in Cancer (COSMIC) Version 2 (V2) and Version 3 (V3). Results We identified 104 mutated genes with P

In this paper, a way that using Al2[DK](SO4)3 catalyst to esterify those labile components (such as acids and sugars) in pyrolysis oil into fuel compounds was proposed considering that their presences were the main factor restricting pyrolysis oil's direct use as biofuel. Firstly, various metal sulfates catalysts were screened for producing ethyl levulinate from model compound levoglucosan or for producing ethyl acetate from model compound acetic acid. Secondly, the optimal reaction conditions were investigated for producing esters from the model mixture of levoglucosan and acetic acid over Al2[DK](SO4)3 catalyst. Thirdly, the feasibility of producing esters from the real pyrolysis oil over Al2[DK](SO4)3 catalyst under the optimum reaction conditions was validated. The results showed the formation of significant amounts of esters and acetals accompanying the loss of labile acids, sugars and aldehydes. The esters and acetals accounted for 39.5% of the total GC-MS chromatographic area of the esterified pyrolysis oil. This indicated that Al2[DK](SO4)3 could effectively catalyse the esterification of those labile components in pyrolysis oil to fuel compounds, which could provide reference for producing biofuels from pyrolysis oil..

Summary: Reliable blood-based tests for identifying early-stage breast cancer remain elusive. Employing single-cell transcriptomic sequencing analysis, we illustrate a close correlation between nucleotide metabolism in the breast cancer and activation of regulatory T cells (Tregs) in the tumor microenvironment, which shows distinctions between subtypes of patients with triple-negative breast cancer (TNBC) and non-TNBC, and is likely to impact cancer prognosis through the A2AR-Treg pathway. Combining machine learning with absolute quantitative metabolomics, we have established an effective approach to the early detection of breast cancer, utilizing a four-metabolite panel including inosine and uridine. This metabolomics study, involving 1111 participants, demonstrates high accuracy across the training, test, and independent validation cohorts. Inosine and uridine prove predictive of the response to neoadjuvant chemotherapy (NAC) in patients with TNBC. This study deepens our understanding of nucleotide metabolism in breast cancer development and introduces a promising non-invasive method for early breast cancer detection and predicting NAC response in patients with TNBC.

Abstract Improving cancer therapy by targeting the adverse tumor microenvironment (TME) rather than the cancer cells presents a novel and potentially effective strategy. In this study, we introduced FexMoyS nanoparticles (NPs), which act as sequential bioreactors to manipulate the TME. FexMoyS NPs were synthesized using thermal decomposition and modified with polyethylene glycol (PEG). Their morphology, chemical composition, and photothermal properties were characterized. The capability to produce ROS and deplete GSH was evaluated. Effects on CRC cells, including cell viability, apoptosis, and glycolysis, were tested through various in vitro assays. In vivo efficacy was determined using CRC-bearing mouse models and patient-derived xenograft (PDX) models. The impact on the MAPK signaling pathway and tumor metabolism was also examined. The FexMoyS NPs showed efficient catalytic activity, leading to increased ROS production and GSH depletion, inducing ferroptosis, and suppressing glycolysis in CRC cells. In vivo, the NPs significantly inhibited tumor growth, particularly when combined with NIR light therapy, indicating a synergistic effect of photothermal therapy and chemodynamic therapy. Biosafety assessments revealed no significant toxicity in treated mice. RNA sequencing suggested that the NPs impact metabolism and potentially immune processes within CRC cells. FexMoyS NPs present a promising multifaceted approach for CRC treatment, effectively targeting tumor cells while maintaining biosafety. The nanoparticles exhibit potential for clinical translation, offering a new avenue for cancer therapy.

Abstract Background The clinicopathological features, surgical outcomes, and long-term survival of patients with young-onset colon cancer (≤ 40 years old) remain controversial. Methods The clinicopathologic and follow-up data of patients aged < 40 years with colon cancer between January 2014 and January 2022 were reviewed. The primary objectives were clinical features and surgical outcomes. Long-term survival was investigated as a secondary objective. Results Seventy patients were included in the study, and no significant rising trend (Z=0, P=1) of these patients was observed over the 8-year study period. Stage IV disease was accompanied by more ulcerative or infiltrating type (84.2% vs. 52.9%, P=0.017) and lymphovascular or perineural invasion (64.7% vs. 25.5%, P=0.003) than stage I–III disease. After a median follow-up time of 41 months (range 8–99 months), the 1-, 3-, and 5-year estimated overall survival (OS) rates were 92.6%, 79.5%, and 76.4%, respectively. The 1-, 3-, and 5-year progression-free survival (PFS) rates were 79.6%, 71.7%, and 71.7%, respectively. Multivariate Cox regression showed that M+ stage (hazard ratio [HR], 3.942; 95% confidence interval [CI], 1.176–13.220, P=0.026) was the only independent risk factor affecting OS. Meanwhile, tumor deposits (HR, 4.807; 95% CI, 1.942–15.488, P=0.009), poor differentiation (HR, 2.925; 95% CI, 1.012–8.454, P=0.047), and M+ stage (HR, 3.540; 95% CI, 1.118–11.202, P=0.032) independently affected PFS. Conclusions The differences in the clinical features, surgical outcomes, and long-term survival between young adults and elderly colon cancer patients need further investigation.

Introduction In recent years, the incidence of thyroid cancer has increased manyfold and young adults, who have a greater financial burden and occupational stress, comprise a large number. Previous studies have shown mixed results, even distinct results, on suicide rates among thyroid cancer survivors. As the overdiagnosis and overtreatment of thyroid cancer has gradually become a topical issue, the study aims to summarise the risk of suicide among patients with thyroid cancer to provide robust evidence of the effects of thyroid cancer on suicide.Methods and analysis A total of six databases (MEDLINE, Embase, Web of Science Core Collection, PsycINFO, CINAHL and Google Scholar) will be searched according to MeSH, subheadings, and free words, and the planned search date is 31 Jnauary 2024. The search strategy had three parts, such as suicide, cancer and epidemiological studies, moreover, we will collect the detailed suicide information by reviewers’ extraction. Standard mortality ratio (SMR) was used as the outcome measure, when SMRs were not available, the risk ratio, HR and detailed number of suicides were extracted to calculate the SMRs.Ethics and dissemination The Institutional Review Board of Peking University People’s Hospital provided ethical approval exemption and approved the data collection and subsequent analyses in accordance with the Declaration of Helsinki as revised in 2013.PROSPERO registration number CRD42023445542.

Staplers have been widely used in the clinical treatment of gastrointestinal reconstruction. However, the current titanium (Ti) staple will remain in the human body permanently, resulting in some adverse effects. In this study, we developed a type of biodegradable staple for colonic anastomosis using 0.3 mm diameter magnesium (Mg) alloy wires. The wire surface was modified by micro-arc oxidation treatment (MAO) and then coated with poly-l-lactic acid (PLLA) to achieve a moderate degradation rate matching the tissue healing process. The results of tensile tests on isolated porcine colon tissue anastomosed by Mg and Ti staples showed that the anastomotic property of Mg staples was almost equal to that of Ti staples. The in vitro degradation tests indicated the dual-layer coating effectively enhanced the corrosion resistance and maintained the tensile force of the coated staple stable after 14-day immersion in the simulated colonic fluid (SCF). Furthermore, 24 beagle dogs were employed to conduct a comparison experiment using Mg-based and clinical Ti staples for 90-day implantation by ent-to-side anastomosis of the colon. The integrated structure of Mg-based staples was observed after 7 days and completely degraded after 90 days. All animals did not have anastomotic leakage and stenosis, and 12 dogs with Mg-based staples fully recovered after 90 days without differences in visceral ion levels and other side effects. The favorable performance makes this Mg-based anastomotic staple an ideal candidate for colon reconstruction.

Summary: Transforming growth factor β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of chronic kidney disease (CKD). This study investigated the role of miR-92b-3p in the progression of renal fibrosis in unilateral ureteral occlusion (UUO) and unilateral ischemia-reperfusion injury (uIRI) mouse models, as well as explored its underlying mechanisms in human proximal tubular epithelial (HK2) cells. We found that renal fibrosis increased in UUO mice after miR-92b knockout, while it reduced in miR-92b overexpressing mice. MiR-92b knockout aggravated renal fibrosis in uIRI mice. RNA-sequencing analysis, the luciferase reporter assay, qPCR analysis, and western blotting confirmed that miR-92b-3p directly targeted TGF-β receptor 1, thereby ameliorating renal fibrosis by suppressing the TGF-β signaling pathway. Furthermore, we found that TGF-β suppressed miR-92b transcription through Snail family transcriptional repressors 1 and 2. Our results suggest that miR-92b-3p may serve as a novel therapeutic for mitigating fibrosis in CKD.

Abstract Background The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. Methods A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. Results In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10−8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (P trend = 8.15 × 10−53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. Conclusions In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

Abstract Background PTEN is one of the most frequently mutated genes in human cancer. Although the roles of canonical PTEN protein and PTEN isoforms have been extensively explored, the current understanding of PTEN family members cannot fully illustrate the diversity of their roles in biological processes and tumor development. Notably, the function of noncoding RNAs arising from PTEN has been less elucidated. Methods We searched circBase and circInteractome to analyze the potential of PTEN for generating circRNAs. Then, Sanger sequencing, RNase R and Actinomycin D assays were used to verify the ring structure of circPTEN1. In situ hybridization and qRT-PCR were used to determine the level of circPTEN1 in peritumor and tumor tissues of colorectal cancer (CRC). Furthermore, functional experiments, including Transwell assay, 3D multicellular tumor spheroid invasion assay and metastasis models, were performed using circPTEN1 knockdown and overexpression cell lines in vitro and in vivo to investigate the effects of circPTEN1 on tumor metastasis in CRC. Mechanistically, luciferase reporter assay, fluorescence in situ hybridization, electrophoretic mobility shift assay, RNA immunoprecipitation, RNA pull-down and mass spectrometry were executed. Results We identified a circular RNA generated from the PTEN gene, designated circPTEN1, that is frequently downregulated in colorectal cancer, and decreased expression of circPTEN1 predicts poor survival. Low expression of circPTEN1 promotes metastasis in PDX models in vivo and accelerates cancer cell invasion in vitro, whereas overexpression of circPTEN1 reveals opposite roles. Mechanically, we found that circPTEN1 is capable of binding the MH2 domain of Smad4 to disrupt its physical interaction with Smad2/3, which reduces the formation and subsequent nucleus translocation of Smad complexes and consequently suppresses the expression of its downstream genes associated with epithelial-mesenchymal transition upon TGF-β stimulation. Furthermore, we found that eIF4A3 suppresses the cyclization of circPTEN1 by directly binding to the circPTEN1 flanking region. Conclusions Our study uncovered a novel PTEN gene-generated circRNA with a tumor suppression function, and further revealed the mechanism of circPTEN1 in CRC metastasis mediated by TGF-β. The identification of circPTEN1 provides a new direction for PTEN investigation, and elucidation of circPTEN1/TGF-β/Smad signaling may pave the way for the development of a potential therapeutic strategy for the suppression of cancer progression.

Abstract Background Circular RNAs (circRNAs) have emerged as vital regulators of the initiation and progression of diverse kinds of human cancers. In this study, we explored the role of hsa_circ_0000231 and its downstream pathway in CRC. Methods The expression profile of circRNAs in 5 pairs of CRC tissues and adjacent normal tissues were analyzed by Microarray. Quantitative real-time PCR and in situ hybridization and Base Scope Assay were used to determine the level and prognostic values of hsa_circ_0000231. Then, functional experiments in vitro and in vivo were performed to investigate the effects of hsa_circ_0000231 on cell proliferation. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between hsa_circ_0000231 and IGF2BP3 or has_miR-375. Results We acquired data through circRNA microarray profiles, showing that the expression of hsa_circ_0000231 was upregulated in CRC primary tissues compared to adjacent normal tissues, which was indicated poor prognosis of patients with CRC. Functional analysis indicated that inhibition of hsa_circ_0000231 in CRC cell lines could suppress CRC cell proliferation as well as tumorigenesis in vitro and in vivo. The mechanistic analysis showed that hsa_circ_0000231 might, on the one hand, act as a competing endogenous RNA of miR-375 to promote cyclin D2 (CCND2) and, on the other hand, bind to the IGF2BP3 protein to prevent CCND2 degradation. Conclusions The findings suggested that hsa_circ_0000231 facilitated CRC progression by sponging miR-375 or binding to IGF2BP3 to modulate CCND2, implying that hsa_circ_0000231 might be a potential new diagnostic and therapeutic biomarker of CRC.

Abstract Introduction Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal soft tissue tumor. Clinical diagnosis mainly relies on enhanced CT, endoscopy and endoscopic ultrasound (EUS), but the misdiagnosis rate is still high without fine needle aspiration biopsy. We aim to develop a novel diagnostic model by analyzing the preoperative data of the patients. Methods We used the data of patients who were initially diagnosed as gastric GIST and underwent partial gastrectomy. The patients were randomly divided into training dataset and test dataset at a ratio of 3 to 1. After pre-experimental screening, max depth = 2, eta = 0.1, gamma = 0.5, and nrounds = 200 were defined as the best parameters, and in this way we developed the initial extreme gradient-boosting (XGBoost) model. Based on the importance of the features in the initial model, we improved the model by excluding the hematological features. In this way we obtained the final XGBoost model and underwent validation using the test dataset. Results In the initial XGBoost model, we found that the hematological indicators (including inflammation and nutritional indicators) examined before the surgery had little effect on the outcome, so we subsequently excluded the hematological indicators. Similarly, we also screened the features from enhanced CT and ultrasound gastroscopy, and finally determined the 6 most important predictors for GIST diagnosis, including the ratio of long and short diameter under CT, the CT value of the tumor, the enhancement of the tumor in arterial period and venous period, existence of liquid area and calcific area inside the tumor under EUS. Round or round-like tumors with a CT value of around 30 (25–37) and delayed enhancement, as well as liquid but not calcific area inside the tumor best indicate the diagnosis of GIST. Conclusions We developed a model to further differential diagnose GIST from other tumors in initially clinical diagnosed gastric GIST patients by analyzing the results of clinical examinations that most patients should have completed before surgical resection.

The effect of salinity on biological nitrogen and denitrifying phosphorus removal was investigated in a Modified University of Cape Town (MUCT) system. Removal rates of COD, NH4+-N, NO3−-N, NO2−-N, phosphorus and the sludge characteristics at salt concentrations (0.0, 3.2, 6.4, 11.2 and 16.0 g L−1) were analyzed. With the salt concentration increasing, all the COD, NH4+-N, TN and TP removal rates exhibited a trend of decline, and exhibited an initial reduction and subsequent increase at every stage of salt concentration. NH4+-N, TN and TP removal rates were 92.7%, 51.5% and 67.2% in 16 g L−1 salt concentration, respectively. And they were outperformed the literature reported and acceptable in practical applications. When the salinity of wastewater changed from 0.0 to 16.0 g L−1, the biomass yield coefficients increased from 0.0794 to 0.126 g VSS/g COD. Increased salinity had a detrimental effect on phosphorus-accumulating organisms (PAOs) and denitrifying PAOs (DPAOs) (especially DPAOs). Therefore, phosphorus removal gradually depended on PAO. The simultaneous nitrification and denitrification (SND) rate and nitrogen removal rate (including nitrification rate, denitrification rate, and total nitrogen removal rate) gradually decreased with the increased salinity.

Abstract Increasing evidence has clarified that the tumor microenvironment (TME) is closely related to the prognosis and therapeutic efficacy of cancer. However, there is no reliable TME evaluation system used to accurately predict the prognosis of and therapeutic efficacy in gastric cancer. We evaluated the immune microenvironment score (IMS) of 1422 gastric cancer samples based on 51 immune cell signatures. We explored the relationship between the IMS and prognosis, immune cell infiltration, cancer subtype, and potential immune escape mechanisms. The results show that activation of the stroma and decreased levels of immune infiltration were associated with a low IMS. A high IMS was characterized by Epstein–Barr virus infection, increased mutation load, microsatellite instability, and immune cell infiltration. A high IMS was also related to high expression of immune checkpoint molecules (PD-1/PD-L1). Finally, patients with a high IMS had a better response to PD-1/PD-L1 inhibitors and may be more suitable for immune checkpoint inhibitors (area under the curve = 0.81). In addition, a low IMS may be converted into the immune-infiltrating subtype after romidepsin treatment. Stratification based on the IMS may enable gastric cancer patients to benefit more from immunotherapy and help identify new cancer treatment strategies.

BackgroundColonic gastrointestinal stromal tumor (cGIST) and rectal gastrointestinal stromal tumor (rGIST) are two rare subtypes of gastrointestinal stromal tumor (GIST). The view that colonic and rectal carcinoma are different is generally accepted; however, whether there is a difference between cGIST and rGIST is still unknown. Here, we aimed to provide evidence for future clinical management and research by comparing the differences between the two types of GIST in the above-mentioned aspects.MethodsPatients were enrolled from three medical centers in China and published literature was collected following the inclusion and exclusion criteria. Propensity score matching was used to eliminate differences between cohorts.ResultsBetween cGIST and rGIST patients, significant differences were observed in age, tumor size, mitotic index, NIH risk category, growth pattern, and symptoms. Adjuvant therapy is used in a high proportion of cGIST patients, and neoadjuvant therapy is used in a high proportion of rGIST patients. Although local resection is the main surgical method in both cohorts, the proportion is higher in cGIST patients. The overall survival of rGIST patients was better than that of the cGIST patients before propensity score matching (PSM). Interestingly, no significant differences in prognosis were observed after PSM.ConclusionsAlthough there were significant differences between cGIST and rGIST patients in baseline characteristics, clinicopathological features, treatment choice, and overall survival rate before PSM, no significant differences in long-term survival were observed between the two groups after PSM. In our study, there may be no differences in the tumor entity between cGIST and rGIST.

Colorectal cancer (CRC) is one of the most common cancers of the digestive tract, and patients with advanced-stage cancer have poor survival despite the use of multidrug conventional chemotherapy regimens. Intra-tumor heterogeneity of cancerous cells is the main obstacle in the way to effective cancer treatments. Therefore, we are looking for novel approaches to eliminate just cancer cells including nanoparticles (NPs). PPy@Fe3O4 NPs were successfully synthesized through a portable method. The characterization of transmission electron microscopy (TEM), Fourier-Transformed infrared spectrometer, and X-ray powder diffraction have further proved successful preparation of PPy@Fe3O4 NPs. NIR irradiation was used to test the photothermal properties of NPs and an infrared camera was used to record their temperature. The direct effects of PPy@Fe3O4 NPs on colorectal cancer cell DLD1 were assessed using CCK8, plate clone, transwell, flow cytometry, and western blotting in CRC cell. The effect of PPy@Fe3O4 NPs on neoplasm growth in nude mice was evaluated in vivo. This study demonstrated that PPy@ Fe3O4 NPs significantly inhibit the growth, migration, and invasion and promote ferroptosis to the untreated controls in colorectal cancer cells. Mechanical exploration revealed that PPy@Fe3O4 NPs inhibit the multiplication, migration, and invasion of CRC cells in vitro by modulating the NF-κB signaling pathway. Importantly, Ferroptosis inhibitors Fer-1 can reverse the changes in metastasis-associated proteins caused by NPs treatment. Collectively, our observations revealed that PPy@Fe3O4 NPs were blockers of tumor progression and metastasis in CRC. This study brought new insights into bioactive NPs, with application potential in curing CRC or other human disorders.

Background: Recently, the role of pyroptosis in cancer has attracted people’s attention, but its function in colon cancer remains unclear. This study aimed to construct a pyroptosis-related model that can effectively predict the prognosis of patients with colon cancer and explore the potential functions of pyroptosis-related genes.Methods: We identified 40 differentially expressed PRGs between colon cancer and normal colon tissues. The model was established using the least absolute shrinkage and selection operator (LASSO) Cox regression method, and the patients were divided into high- and low-risk groups. Finally, we verified its biological function in vitro based on three PRGs and demonstrated discrepant expression of PRGs within colon cancer and non-tumor tissues at the protein level with immunohistochemistry.Results: A pyroptosis-related prognosis model was constructed, which divided 446 patients with colon cancer into high- and low-risk groups. Kaplan–Meier analysis results showed that the survival of patients with colon cancer in the high-risk group was worse than that in the low-risk group. Finally, we also confirmed that this score is an independent prognostic factor for colon cancer progression.Conclusion: In summary, the model established by three PRGs was a reliable indicator for predicting prognosis, suggesting that pyroptosis might be a noteworthy therapeutic target in CC.

Abstract Background As the most widespread mRNAs modification, N6‐methyladenosine (m6A) is dynamically and reversibly modulated by methyltransferases and demethylases. ALKBH5 is a major demethylase, and plays vital roles in the progression of cancers. However, the role and mechanisms of ALKBH5 in colorectal cancer (CRC) is unclear. Results Herein, we discovered that in CRC, downregulated ALKBH5 was closely related to poor prognosis of CRC patients. Functionally, our results demonstrated that knockdown of ALKBH5 enhanced the proliferation, migration and invasion of LOVO and RKO in vitro, while overexpression of ALKBH5 inhibited the functions of these cells. The results also demonstrated that knockdown of ALKBH5 promoted subcutaneous tumorigenesis of LOVO in vivo, while overexpression of ALKBH5 suppressed this ability. Mechanistically, results from joint analyses of MeRIP‐seq and RNA‐seq indicated that PHF20 mRNA was a key molecule that was regulated by ALKBH5‐mediated m6A modification. Further experiments indicated that ALKBH5 may inhibit stability of PHF20 mRNA by removing the m6A modification of PHF20 mRNA 3′UTR. Conclusions ALKBH5 suppresses CRC progression by decreasing PHF20 mRNA methylation. ALKBH5‐mediated m6A modification of PHF20 mRNA can serve as a hopeful strategy for the intervention and treatment of CRC.

Accumulating evidence has demonstrated that N6-methyladenosine (m6A) plays important roles in various cancers, making it essential to profile m6A modifications at a transcriptome-wide scale in colorectal cancer (CRC). In the present study, we performed high-throughput sequencing to determine the m6A methylome in CRC. We obtained six pairs of CRC samples and tumour-adjacent normal tissues from Peking University People’s Hospital. We used MeRIP-seq to determine that compared to the tumour-adjacent normal tissues, the CRC samples had 1343 dysregulated m6A peaks, and 625 m6A peaks were significantly upregulated and 718 m6A peaks were significantly downregulated. Genes with altered m6A peaks play critical roles in regulating glucose metabolism, RNA metabolism, and cancer stem cells. Furthermore, we identified 297 hypermethylated m6A peaks and 328 hypomethylated m6A peaks in mRNAs through conjoint analyses of MeRIP-seq and RNA-seq data. After analysing these genes with differentially methylated m6A peaks and synchronously differential expression, we identified four genes (WDR72, SPTBN2, MORC2, and PARM1) that were associated with prognosis of colorectal cancer patients by searching The Cancer Genome Atlas (TCGA). Our study suggests that m6A modifications play important roles in tumour progression and survival of CRC patients. The results also indicate that modulating m6A modifications may represent an alternative strategy to predict the survival of cancer patients and interfere with tumour progression in the future.

Abstract Bacterial culture and drug susceptibility testing are used to identify pathogen infections. Nevertheless, the process requires several days from collection to the identification of bacterial species and drug-resistance patterns. The digital PCR system is a rapidly developing quantitative detection technology widely applied to molecular diagnosis, including copy number variations, single nucleotide variant analysis, cancer biomarker discovery, and pathogen identification. This study aimed to use a droplet digital PCR system to identify bacteria in blood samples and explore its ability to identify pathogen in bacteremia. Then, we designed primers and probes of SWG-9 and COA gene for E. coli and S. aureus to identify in blood samples with the ddPCR system. The system had demonstrated extremely high detection accuracy in blood samples, and the detection rate of E. coli was 13.1–21.4%, and that of S. aureus was 50–88.3%. Finally, blood samples containing both E. coli and S. aureus were tested to evaluate further the accuracy and applicability of this method, indicating the detection rates range from 18.1% to 97%. The ddPCR system is highly promising as a qualitatively and quantitatively screening method for rapidly detecting pathogen.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and has become a serious public health problem worldwide. Dipeptidyl peptidase-4 (DPP4) inhibitors, an emerging drug for the treatment of diabetes, have been found to have renoprotective effects in addition to glucose-lowering effects and therefore have the potential to be a treatment modality for DKD. Lobeliae Chinensis Herba (LCH), a traditional Chinese herb widely used in the treatment of diabetes, has recently been found to have a hypoglycaemic mechanism related to the inhibition of DPP4. Firstly, analysis of single-cell sequencing data from mouse kidneys in the National Center for Biotechnology Information (NCBI) database revealed that DPP4 was specifically upregulated in DKD podocytes and was associated with podocyte proliferation. Subsequently, the network pharmacology approach was applied to the screening of compounds. Twelve LCH active ingredients targeting DPP4 were extracted from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. In addition, these 12 compounds and DPP4 were molecularly docked to predict the probability of them affecting DPP4 activity. In vitro, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin were demonstrated to retard podocyte proliferation by inhibiting DPP4 activity and were the top five compounds predicted by molecular docking to be the most likely to affect DPP4 activity. The half maximal inhibitory concentration (IC50) of the five compounds for DPP4 activity were as follows. Acacetin Log IC50 = −8.349, 95%CI (−9.266, −7.265), Diosmtrin Log IC50 = −8.419, 95%CI (−8.889, −7.950), Log IC50 = −8.349, 95%CI (−9.266, −7.265), Methyl rosmarinate Log IC50 = −8.415, 95%CI (−8.751, −8.085), Kaempferol Log IC50 = −8.297, 95%CI (−9.001, −7.615), Quercetin Log IC50 = −8.864, 95%CI (−9.107, −8.615). Finally, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin qualified for pharmacokinetic and drug similarity screening and have the potential to be the most promising oral agents for the treatment of DKD.

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

Summary: Background: Transanal total mesorectal excision (taTME) is a novel sphincter-preserving procedure for low rectal cancer. This “bottom to up” approach is unfamiliar to colorectal surgeons and the crucial anatomical landmarks also remain unclear. Methods: Two hundred and five cases of pelvic magnetic resonance imaging (MRI) from 2015 to 2016 were reviewed. Curvature of posterior mesorectal fascia, distal mesorectal angle, length of posterior mesorectal fascia, main structures around the mesorectum were measured and analyzed. The landmarks identified on MRI were verified in taTME procedures of five rectal cancer patients. Results: The most of acute angles of posterior mesorectal fascia located at the joint of anococcygeal ligament-coccyx. Degree of distal mesorectal angle was independently correlated with gender and degree of angle of anococcygeal ligament-coccyx. Candidate landmarks evaluated by MRI with verification during taTME procedures included: anterior: seminal vesicle for male while cervix for female. And peritoneal reflection was a substitute landmark when cervix was hardly confirmed in operation; posterior: the joint of anococcygeal ligament-coccyx. The area between the joint of anococcygeal ligament-coccyx and S3S4 was a “transitional zone”, the level of S3S4 could be the as the terminal landmark of transanal posterior dissection during taTME. Conclusions: Preoperative MRI geometrical measurement of mesorectum might play an important role in evaluating the difficulty of taTME procedure before operation, as well as standardizing landmarks during taTME procedure. Keywords: Transanal total mesorectal excision, Landmarks, Anatomy, Image, Standardization

Abstract The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts’ clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

Abnormal expression of RNA binding proteins (RBPs) has been reported across various cancers. However, the potential role of RBPs in colorectal cancer (CRC) remains unclear. In this study, we performed a systematic bioinformatics analysis of RBPs in CRC. We downloaded CRC data from The Cancer Genome Atlas (TCGA) database. Our analysis identified 242 differentially expressed RBPs between tumor and normal tissues, including 200 upregulated and 42 downregulated RBPs. Next, we found eight RBPs (RRS1, PABPC1L, TERT, SMAD6, UPF3B, RP9, NOL3, and PTRH1) related to the prognoses of CRC patients. Among these eight prognosis-related RBPs, four RBPs (NOL3, PTRH1, UPF3B, and SMAD6) were selected to construct a prognostic risk score model. Furthermore, our results indicated that the prognostic risk score model accurately predicted the prognosis of CRC patients [area under the receiver operating characteristic curve (AUC)for 3- and 5-year overall survival (OS) and was 0.645 and 0.672, respectively]. Furthermore, we developed a nomogram based on a prognostic risk score model. The nomogram was able to demonstrate the wonderful performance in predicting 3- and 5-year OS. Additionally, we validated the clinical value of four risk genes in the prognostic risk score model and identified that these risk genes were associated with tumorigenesis, lymph node metastasis, distant metastasis, clinical stage, and prognosis. Finally, we used the TIMER and Human Protein Atlas (HPA)database to validate the expression of four risk genes at the transcriptional and translational levels, respectively, and used a clinical cohort to validate the roles of NOL3 and UPF3B in predicting the prognosis of CRC patients. In summary, our study demonstrated that RBPs have an effect on CRC tumor progression and might be potential prognostic biomarkers for CRC patients.

BackgroundMicroRNAs (miRNAs), such as miR-654-3p, regulate gene expression at the post-transcriptional level affecting malignant tumor behavior. However, the expression levels, function, and mechanism of miR-654-3p in colorectal cancer (CRC) are unknown.MethodsThe expression levels of miR-654-3p and SRC in 103 CRC tissues and matched normal colorectal tissues were detected by a quantitative real-time polymerase chain reaction (qRT-PCR). miR-654-3p was overexpressed by RNA mimics and SRC knockdown by siRNA. Function-based experiments were carried out to detect the proliferation and migration abilities in CRC cell lines. Flow cytometry assay was performed to evaluate the effect of miR-654-3p on cell apoptosis and cycle distribution. Xenograft tumor models in nude mice were utilized to evaluate miR-654-3p functions in vivo. Dual-fluorescence reporter assay was used to verify the direct binding between miR-654-3p and SRC.ResultsmiR-654-3p was downregulated in CRC tissues as compared to matched normal colorectal tissues. The expression levels of miR-654-3p were closely associated with distant metastasis. In addition, elevated expression of miR-654-3p in CRC patients prolonged the overall survival. Upregulated miR-654-3p significantly suppressed the proliferation and migration capacity of CRC cells by enhancing apoptosis and promoting G0/G1 phase arrest. The direct binding between miR-654-3p and SRC was verified by the dual-luciferase reporter gene. Furthermore, the suppression of proliferation and migration capacity by elevated miR-654-3p level could be reversed by overexpressing SRC.ConclusionmiR-654-3p acts as a tumor suppressor through regulating SRC. It might also serve as a diagnostic and prognostic indicator and a novel molecular target for CRC therapy.

BackgroundLong non-coding RNAs (lncRNAs) play pivotal roles in various kinds of human diseases, especially in cancer. However, regulatory role, clinical significance and underlying mechanisms of lncRNAs in colorectal cancer (CRC) liver metastasis still remain largely unknown. This study aimed to report a novel lncRNA, lnc-HSD17B-11:1, and its functional role in CRC progression.Materials and methodsDifferentially expressed lnc-HSD17B11-1:1 was screened and identified from a lncRNA profile microarray. Quantitative real-time PCR was used to determine the expression levels and prognostic values of lncRNA in CRC cohorts. In vitro and in vivo functional experiments were performed to investigate the effects of lnc-HSD17B11-1:1 on tumor growth and metastasis in CRC. Mechanistically, Base Scope, bioinformatics analyses, dual luciferase reporter assay and RNA immunoprecipitation experiments were performed to confirm the association of lnc-HSD17B11-1:1 and miR-338-3p. Dual luciferase reporter assay, qRT-PCR and western blot analysis were performed to assess the relationships among lnc-HSD17B11-1:1, miR-338-3p, and MACC1.ResultsEvidently up-regulation of lnc-HSD17B11-1:1 in CRC primary tissues was correlated with the depth of invasion (p = 0.043), clinical stage (p = 0.027), distant metastasis (p = 0.003) and poor prognosis of patients with CRC. lnc-HSD17B11-1:1 promoted CRC cell proliferation, mobility and invasion in vitro and in vivo. Mechanistic analysis revealed that lnc-HSD17B11-1:1 may act as a competing endogenous RNA (ceRNA) by acting as a sponge for miR-338-3p to upregulate the expression of MACC1.ConclusionThese findings suggest that lnc-HSD17B11-1:1 promotes CRC progression through lnc-HSD17B11-1:1/miR-338-3p/MACC1 axis and this might serve as a new diagnostic marker or target for treatment of CRC.

During the breeding seasons of 2010-2016, we have found seven nests of the Booted Eagle (Hieraaetus pennatus) in Xinjiang, the west of China. We used a method of focal sampling and infrared cameras to continually observe behaviors and nestlings’ growth. Nestling behaviors were different between nestling period and post-nestling period. Attendance at the nests by both adults decreased as the nestling aged. The female brooded significantly more than the male did during daylight hours (P=0.016, F= 8.38, df =1). The daily mean number of food items delivered to the nests by adults was 3.2 times/day in nestling period, and 0.96/day in post-nestling period. Seven orders of wild birds, three orders of mammals and domestic poultry were documented as prey.

Although genome-wide association studies have identified many risk loci associated with colorectal cancer, the molecular basis of these associations are still unclear. We aimed to infer biological insights and highlight candidate genes of interest within GWAS risk loci. We used an in silico pipeline based on functional annotation, quantitative trait loci mapping of cis-acting gene, PubMed text-mining, protein-protein interaction studies, genetic overlaps with cancer somatic mutations and knockout mouse phenotypes, and functional enrichment analysis to prioritize the candidate genes at the colorectal cancer risk loci. Based on these analyses, we observed that these genes were the targets of approved therapies for colorectal cancer, and suggested that drugs approved for other indications may be repurposed for the treatment of colorectal cancer. This study highlights the use of publicly available data as a cost effective solution to derive biological insights, and provides an empirical evidence that the molecular basis of colorectal cancer can provide important leads for the discovery of new drugs.