Microbiota-induced S100A11-RAGE axis underlies immune evasion in right-sided colon adenomas and is a therapeutic target to boost anti-PD1 efficacy.

BACKGROUND: Tumourigenesis in right-sided and left-sided colons demonstrated distinct features. OBJECTIVE: We aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis. DESIGN: Single-cell and spatial transcriptomic datasets were analysed to reveal alterations between right-sided and left-sided colon ADs. Cells, animal experiments and clinical specimens were used to verify the results. RESULTS: Single-cell analysis revealed that in right-sided ADs, there was a significant reduction of goblet cells, and these goblet cells were dysfunctional with attenuated mucin biosynthesis and defective antigen presentation. An impairment of the mucus barrier led to biofilm formation in crypts and subsequent bacteria invasion into right-sided ADs. The regions spatially surrounding the crypts with biofilm occupation underwent an inflammatory response by lipopolysaccharide (LPS) and an apoptosis process, as revealed by spatial transcriptomics. A distinct S100A11+ epithelial cell population in the right-sided ADs was identified, and its expression level was induced by bacterial LPS and peptidoglycan. S100A11 expression facilitated tumour growth in syngeneic immunocompetent mice with increased myeloid-derived suppressor cells (MDSC) but reduced cytotoxic CD8+ T cells. Targeting S100A11 with well-tolerated antagonists of its receptor for advanced glycation end product (RAGE) (Azeliragon) significantly impaired tumour growth and MDSC infiltration, thereby boosting the efficacy of anti-programmed cell death protein 1 therapy in colon cancer. CONCLUSION: Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer.

DYNLL1 accelerates cell cycle via ILF2/CDK4 axis to promote hepatocellular carcinoma development and palbociclib sensitivity.

BACKGROUND: Disorder of cell cycle represents as a major driver of hepatocarcinogenesis and constitutes an attractive therapeutic target. However, identifying key genes that respond to cell cycle-dependent treatments still facing critical challenges in hepatocellular carcinoma (HCC). Increasing evidence indicates that dynein light chain 1 (DYNLL1) is closely related to cell cycle progression and plays a critical role in tumorigenesis. In this study, we explored the role of DYNLL1 in the regulation of cell cycle progression in HCC. METHODS: We analysed clinical specimens to assess the expression and predictive value of DYNLL1 in HCC. The oncogenic role of DYNLL1 was determined by gain or loss-of-function experiments in vitro, and xenograft tumour, liver orthotopic, and DEN/CCl4-induced mouse models in vivo. Mass spectrometry analysis, RNA sequencing, co-immunoprecipitation assays, and forward and reverse experiments were performed to clarify the mechanism by which DYNLL1 activates the interleukin-2 enhancer-binding factor 2 (ILF2)/CDK4 signalling axis. Finally, the sensitivity of HCC cells to palbociclib and sorafenib was assessed by apoptosis, cell counting kit-8, and colony formation assays in vitro, and xenograft tumour models and liver orthotopic models in vivo. RESULTS: DYNLL1 was significantly higher in HCC tissues than that in normal liver tissues and closely related to the clinicopathological features and prognosis of patients with HCC. Importantly, DYNLL1 was identified as a novel hepatocarcinogenesis gene from both in vitro and in vivo evidence. Mechanistically, DYNLL1 could interact with ILF2 and facilitate the expression of ILF2, then ILF2 could interact with CDK4 mRNA and delay its degradation, which in turn activates downstream G1/S cell cycle target genes CDK4. Furthermore, palbociclib, a selective CDK4/6 inhibitor, represents as a promising therapeutic strategy for DYNLL1-overexpressed HCC, alone or particularly in combination with sorafenib. CONCLUSIONS: Our work uncovers a novel function of DYNLL1 in orchestrating cell cycle to promote HCC development and suggests a potential synergy of CDK4/6 inhibitor and sorafenib for the treatment of HCC patients, especially those with increased DYNLL1.

Neuropilin-1 is a novel host factor modulating the entry of hepatitis B virus.

BACKGROUND & AIMS: Sodium taurocholate cotransporting polypeptide (NTCP) has been identified as the cellular receptor for hepatitis B virus (HBV). However, hepatocytes expressing NTCP exhibit varying susceptibilities to HBV infection. This study aimed to investigate whether other host factors modulate the process of HBV infection. METHODS: Liver biopsy samples obtained from children with hepatitis B were used for single-cell sequencing and susceptibility analysis. Primary human hepatocytes, HepG2-NTCP cells, and human liver chimeric mice were used to analyze the effect of candidate host factors on HBV infection. RESULTS: Single-cell sequencing and susceptibility analysis revealed a positive correlation between neuropilin-1 (NRP1) expression and HBV infection. In the HBV-infected cell model, NRP1 overexpression before HBV inoculation significantly enhanced viral attachment and internalization, and promoted viral infection in the presence of NTCP. Mechanistic studies indicated that NRP1 formed a complex with LHBs and NTCP. The NRP1 b domain mediated its interaction with conserved arginine residues at positions 88 and 92 in the preS1 domain of the HBV envelope protein LHBs. This NRP1-preS1 interaction subsequently promoted the binding of preS1 to NTCP, facilitating viral infection. Moreover, disruption of the NRP1-preS1 interaction by the NRP1 antagonist EG00229 significantly attenuated the binding affinity between NTCP and preS1, thereby inhibiting HBV infection both in vitro and in vivo. CONCLUSIONS: Our findings indicate that NRP1 is a novel host factor for HBV infection, which interacts with preS1 and NTCP to modulate HBV entry into hepatocytes. IMPACT AND IMPLICATIONS: HBV infection is a global public health problem, but the understanding of the early infection process of HBV remains limited. Through single-cell sequencing, we identified a novel host factor, NRP1, which modulates HBV entry by interacting with HBV preS1 and NTCP. Moreover, antagonists targeting NRP1 can inhibit HBV infection both in vitro and in vivo. This study could further advance our comprehension of the early infection process of HBV.

Risk factors for anastomotic leak and postoperative morbidity after right hemicolectomy for colon cancer: results from a prospective, multi-centre, snapshot study in China.

BACKGROUND: Right hemicolectomy is the standard treatment for right-sided colon cancer. There is variation in the technical aspects of performing right hemicolectomy as well as in short-term outcomes. It is therefore necessary to explore best clinical practice following right hemicolectomy in expert centres. METHODS: This snapshot study of right hemicolectomy for colon cancer in China was a prospective, multicentre cohort study in which 52 tertiary hospitals participated. Eligible patients with stage I-III right-sided colon cancer who underwent elective right hemicolectomy were consecutively enrolled in all centres over 10 months. The primary endpoint was the incidence of postoperative 30-day anastomotic leak. RESULTS: Of the 1854 patients, 89.9 per cent underwent laparoscopic surgery and 52.3 per cent underwent D3 lymph node dissection. The overall 30-day morbidity and mortality were 11.7 and 0.2 per cent, respectively. The 30-day anastomotic leak rate was 1.4 per cent. In multivariate analysis, ASA grade > II (P < 0.001), intraoperative blood loss > 50 ml (P = 0.044) and D3 lymph node dissection (P = 0.008) were identified as independent risk factors for postoperative morbidity. Extracorporeal side-to-side anastomosis (P = 0.031), intraoperative blood loss > 50 ml (P = 0.004) and neoadjuvant chemotherapy (P = 0.004) were identified as independent risk factors for anastomotic leak. CONCLUSION: In high-volume expert centres in China, laparoscopic resection with D3 lymph node dissection was performed in most patients with right-sided colon cancer, and overall postoperative morbidity and mortality was low. Further studies are needed to explore the optimal technique for right hemicolectomy in order to improve outcomes further.

Recurrence risk assessment for stage III colorectal cancer based on five methylation biomarkers in plasma cell-free DNA.

For stage III colorectal cancer (CRC) patients with a high risk of recurrence, intensified adjuvant chemotherapy can improve overall survival. We aimed to develop a circulating tumor DNA (ctDNA) methylation marker model for predicting the relapse risk of stage III CRC patients. Differentially methylated markers identified between 53 normal mucosa samples and 165 CRC tissue samples, as well as between plasma samples from 75 stage I/II (early-stage) CRC patients and 55 stage IV (late-stage) CRC patients, were analyzed using Student's t-tests. The overlapping methylation markers shared by plasma and tissue samples were used to establish a methylation marker model to evaluate the tumor burden in the peripheral blood of CRC patients using the random forest method. This model was verified in the validation cohort (n = 44) and then applied to predict recurrence risk in 50 stage III CRC patients and monitor the clinical disease course in serial samples from four CRC patients. We built a five-marker-based ctDNA methylation model that had high sensitivity (84.21%) and specificity (84%) in identifying late-stage CRC in a validation cohort containing 24 stage I/II CRC patients and 20 stage IV CRC patients. The model achieved high sensitivity (87.5%) and specificity (94.12%) in predicting tumor relapse in an independent cohort of 50 stage III CRC patients and could be an independent recurrence risk factor for stage III patients [Hazard ratio (HR), 60.4; 95% confidence interval (CI): 7.68-397; p = 9.73e-5]. Analysis of serial blood samples of CRC showed that the model could monitor disease relapse earlier than imaging examination and serum carcinoembryonic antigen (CEA) and so may provide an opportunity for the early adjustment of therapeutic strategies. Moreover, the model could potentially monitor the clinical course and treatment response dynamically. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Medical image fusion based on machine learning for health diagnosis and monitoring of colorectal cancer.

With the rapid development of medical imaging technology and computer technology, the medical imaging artificial intelligence of computer-aided diagnosis based on machine learning has become an important part of modern medical diagnosis. With the application of medical image security technology, people realize that the difficulty of its development is the inherent defect of advanced image processing technology. This paper introduces the background of colorectal cancer diagnosis and monitoring, and then carries out academic research on the medical imaging artificial intelligence of colorectal cancer diagnosis and monitoring and machine learning, and finally summarizes it with the advanced computational intelligence system for the application of safe medical imaging.In the experimental part, this paper wants to carry out the staging preparation stage. It was concluded that the staging preparation stage of group Y was higher than that of group X and the difference was statistically significant. Then the overall accuracy rate of multimodal medical image fusion was 69.5% through pathological staging comparison. Finally, the diagnostic rate, the number of patients with effective treatment and satisfaction were analyzed. Finally, the average diagnostic rate of the new diagnosis method was 8.75% higher than that of the traditional diagnosis method. With the development of computer science and technology, the application field was expanding constantly. Computer aided diagnosis technology combining computer and medical images has become a research hotspot.

Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.

OBJECTIVE: Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A+ TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. DESIGN: The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. RESULTS: MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8+ T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. CONCLUSION: Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.

GSTZ1-1 Deficiency Activates NRF2/IGF1R Axis in HCC via Accumulation of Oncometabolite Succinylacetone.

The IGF1R signaling is important in the malignant progression of cancer. However, overexpression of IGF1R has not been properly assessed in HCC. Here, we revealed that GSTZ1-1, the enzyme in phenylalanine/tyrosine catabolism, is downregulated in HCC, and its expression was negatively correlated with IGF1R. Mechanistically, GSTZ1-1 deficiency led to succinylacetone accumulation, alkylation modification of KEAP1, and NRF2 activation, thus promoting IGF1R transcription by recruiting SP1 to its promoter. Moreover, inhibition of IGF1R or NRF2 significantly inhibited tumor-promoting effects of GSTZ1 knockout in vivo. These findings establish succinylacetone as an oncometabolite, and GSTZ1-1 as an important tumor suppressor by inhibiting NRF2/IGF1R axis in HCC. Targeting NRF2 or IGF1R may be a promising treatment approach for this subset HCC.

A spacer design strategy for CRISPR-Cas12f1 with single-nucleotide polymorphism mutation resolution capability and its application in the mutations diagnosis of pathogens.

Infectious diseases remain a major global issue in public health. It is important to develop rapid, sensitive, and accurate diagnostic methods to detect pathogens and their mutations. Cas12f1 is an exceptionally compact RNA-guided nuclease and have the potential to fulfill the clinical needs. Based on the interaction between crRNA-SSDNA binary sequence and Cas12f1, here, we addressed the essential features that determine the recognition ability of CRISPR-Cas12f1 single-nucleotide polymorphism (SNP), such as the length of spacer region and the base pairing region that determines the trans-cleavage of ssDNA. A fine-tuning spacer design strategy is also proposed to enhance the SNP recognition capability of CRISPR-Cas12f1. The optimized spacer confers the Cas12f1 system a strong SNP identification capability for viral or bacterial drug-resistance mutations, with a specificity ratio ranging from 19.63 to 110.20 and an admirable sensitivity up to 100  copy/µL. Together, the spacer screening and CRISPR-Cas12f1 based SNP identification method, is sensitive and versatile, and will have a wide application prospect in pathogen DNA mutation diagnosis and other mutation profiling.

TRIM21 promotes ubiquitination of SARS-CoV-2 nucleocapsid protein to regulate innate immunity.

The innate immune response is the first line of host defense against viral infections, but its role in immunity against SARS-CoV-2 remains unclear. By using immunoprecipitation coupled with mass spectroscopy, we observed that the E3 ubiquitin ligase TRIM21 interacted with the SARS-CoV-2 nucleocapsid (N) protein and ubiquitinated it at Lys375 . Upon determining the topology of the TRIM21-mediated polyubiquitination chain on N protein, we then found that polyubiquitination led to tagging of the N protein for degradation by the host cell proteasome. Furthermore, TRIM21 also ubiquitinated the N proteins of SARS-CoV-2 variants of concern, including Alpha, Beta, Gamma, Delta, and Omicron together with SARS-CoV and MERS-CoV variants. Herein, we propose that ubiquitylation and degradation of the SARS-CoV-2 N protein inhibited SARS-CoV-2 viral particle assembly, by which it probably involved in preventing cytokine storm. Eventually, our study has fully revealed the association between the host innate immune system and SARS-CoV-2 N protein, which may aid in developing novel SARS-CoV-2 treatment strategies.

DDX17-regulated alternative splicing that produced an oncogenic isoform of PXN-AS1 to promote HCC metastasis.

BACKGROUND AND AIMS: The mechanism underlying HCC metastasis remains unclear, many oncogenes are known to regulate this process. However, the role of alternative splicing (AS) in pro-metastatic HCC is poorly understood. APPROACH AND RESULTS: By performing RNA sequencing on nine pairs of primary HCC tissues with extrahepatic metastasis (EHMH) and nine pairs of metastasis-free HCC (MFH) tissues, we depicted the AS landscape in HCC and found a higher frequency of AS events in EHMH compared with MFH. Moreover, 28 differentially expressed splicing regulators were identified in EHMH compared with MFH. Among these, DEAD-box RNA helicase 17 (DDX17) was significantly up-regulated in EHMH and was strongly associated with patient outcome. Functional studies indicated that DDX17 knockout inhibited the degradation of the extracellular matrix, and diminished the invasive ability of HCC cells. A significant reduction in lung metastasis induced by DDX17 deficiency was also demonstrated in a diethylnitrosamine-induced DDX17HKO mouse model. Mechanistically, high DDX17 induced intron 3 retention of PXN-AS1 and produced a transcript (termed PXN-AS1-IR3). The transcript PXN-AS1-IR3 acted as an important promoter of HCC metastasis by inducing MYC transcription activation via recruiting the complex of testis expressed 10 and p300 to the MYC enhancer region, which led to transcriptional activation of several metastasis-associated downstream genes. Finally, the PXN-AS1-IR3 level was significantly higher in serum and HCC tissues with extrahepatic metastasis. CONCLUSIONS: DDX17 and PXN-AS1-IR3 act as important metastatic promoters by modulating MYC signaling, suggesting that DDX17 and PXN-AS1-IR3 may be potential prognostic markers for metastatic HCC.

Sphondin efficiently blocks HBsAg production and cccDNA transcription through promoting HBx degradation.

Hepatitis B surface antigen (HBsAg) loss and seroconversion, which is considered as functional cure of chronic Hepatitis B virus (HBV) infection, is rarely achieved even after long-term antiviral treatments. Therefore, new antiviral strategies interfering with other HBV replication steps are required, especially those that could efficiently inhibit HBsAg production. Here, we identified novel anti-HBV compounds that could potently block HBsAg expression from cccDNA by screening a natural compound library derived from Chinese traditional medical plants by a novel screening strategy. The combination of ELISA assay detecting the HBsAg and real-time PCR detecting HBV RNAs as indicator for cccDNA transcriptional activity were used. The antiviral activity of a candidate compound and underlying mechanism were evaluated in HBV-infected cells and a humanized liver mouse model. Herein, we selected a highly effective low-cytotoxic compound sphondin, which could effectively inhibit both intracellular HBsAg production and HBV RNAs levels. Moreover, we found that sphondin markedly inhibited cccDNA transcriptional activity without affecting cccDNA level. Mechanistic study found sphondin preferentially bound to HBx protein by residue Arg72, which led to increased 26S proteasome-mediated degradation of HBx. Sphondin treatment significantly reduced the recruitment of HBx to cccDNA, which subsequently led to inhibition of cccDNA transcription and HBsAg expression. The absence of HBx or R72A mutation potently abrogated the antiviral effect induced by sphondin in HBV-infected cells. Collectively, sphondin may be considered as a novel and natural antiviral agent directly targeting HBx protein, which effectively inhibited cccDNA transcription and HBsAg expression.

Intracorporeal Anastomosis Versus Extracorporeal Anastomosis in Laparoscopic Right Colectomy: An Observational Cohort Study.

BACKGROUND: Current studies did not draw definitive conclusions on comparison of intracorporeal anastomosis (ICA) with extracorporeal anastomosis (ECA) in laparoscopic right colectomy. Whether the intraperitoneal contamination induced by ICA can result in higher risk of postoperative abdominal infection remains unclear. This study was aimed to compare the short-term outcomes, especially the risk of abdominal infection after ICA versus ECA. METHODS: This was an observational cohort study as a secondary analysis of a randomized controlled trial (RCT)-RELARC trial (NCT02619942). The patients enrolled in the RELARC trial were diagnosed with primary colon adenocarcinoma without distant metastasis and underwent radical laparoscopic right colectomy between Jan 2016 and Dec 2019. In our study the patients who converted to open surgery in RELARC trial were excluded. The short-term outcomes were compared between ICA and ECA. The primary endpoint was abdominal infection. The inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) was used for adjusting the potential confounders. RESULTS: This study enrolled 975 patients with 119 patients undergoing ICA and 856 patients undergoing ECA. The incidence of abdominal infection was higher in ICA group (9.2% versus 1.5%, RR from IPTW = 5.7 (95%CI: 2.6-12.6), P < 0.001) as well as the incidence of wound infection (14.3% vs 3.3%, RR from IPTW = 5.0 (95%CI: 2.9-8.6), P < 0.001). ICA was associated with higher incidence of Clavien-Dindo (CD) grade I and II complications (CD-I: 15.1% versus 6.8%, RR from IPTW = 2.4 (95%CI: 1.5-3.9), P < 0.001; CD-II: 26.9% versus 8.2%, RR from IPTW = 3.6 (95%CI: 2.5-5.1), P < 0.001) but similar incidence of CD-III ~ IV complications compared to ECA (3.4% vs 2.1%, RR from IPTW = 1.2 (95%CI: 0.4-4.0), P = 0.73). In ICA group, choosing another incision rather than lengthening main port site decreased the incidence of wound infection although without statistical significance (17.3% (14/81) versus 7.9% (3/38), crude RR = 2.2 (95%CI: 0.7-7.2), P = 0.17). CONCLUSION: ICA is likely to be associated with higher risk of abdominal infection and CD-I ~ II complications.

Microbiota of long-term indwelling hemodialysis catheters during renal transplantation perioperative period: a cross-sectional metagenomic microbial community analysis.

Background: Catheter-related infection (CRI) is a major complication in patients undergoing hemodialysis. The lack of high-throughput research on catheter-related microbiota makes it difficult to predict the occurrence of CRI. Thus, this study aimed to delineate the microbial structure and diversity landscape of hemodialysis catheter tips among patients during the perioperative period of kidney transplantation (KTx) and provide insights into predicting the occurrence of CRI.Methods: Forty patients at the Department of Transplantation undergoing hemodialysis catheter removal were prospectively included. Samples, including catheter tip, catheter outlet skin swab, catheter blood, peripheral blood, oropharynx swab, and midstream urine, from the separate pre- and post-KTx groups were collected and analyzed using metagenomic next-generation sequencing (mNGS). All the catheter tips and blood samples were cultured conventionally.Results: The positive detection rates for bacteria using mNGS and traditional culture were 97.09% (200/206) and 2.65% (3/113), respectively. Low antibiotic-sensitivity biofilms with colonized bacteria were detected at the catheter tip. In asymptomatic patients, no statistically significant difference was observed in the catheter tip microbial composition and diversity between the pre- and post-KTx group. The catheter tip microbial composition and diversity were associated with fasting blood glucose levels. Microorganisms at the catheter tip most likely originated from catheter outlet skin and peripheral blood.Conclusions: The long-term colonization microbiota at the catheter tip is in a relatively stable state and is not readily influenced by KTx. It does not act as the source of infection in all CRIs, but could reflect hematogenous infection to some extent.

Driving forces and variation in water footprint before and after the COVID-19 lockdown in Fujian Province of China.

The COVID-19 outbreak has injured the global industrial supply chain, especially China as the world's largest manufacturing base. Since 2020, China has implemented a rigorous lockdown policy, which has sternly damaged sectoral trade in export-oriented coastal areas. Fujian Province, which mainly processes imported materials, has a more profound influence. Although the COVID-19 lockdown has had some detrimental consequences on the world economy, it also had some favorable benefits on the global ecology. Previous studies have shown that the lockdown has altered the physical water quantity and quality, but the lack of total, virtual, and physical water research that combines water quantity and water quality simultaneously to pinpoint the subject and responsibility of water resources consumption and pollution. This research quantified the physical, virtual, and total water consumption and water pollution among 30 sectors in Fujian Province based on the theory of water footprint and the Economic Input-Output Life Cycle Assessment model. SDA model was then used to investigate the socioeconomic elements that underpin variations in the water footprint. The results show that after the lockdown, the physical water quantity and the physical grey WF in Fujian Province decreased by 2.6 Gm3 (-6.7%) and 0.4 Gm3 (-1.3%) respectively. The virtual water quantity decreased by 2.3 Gm3 (-4.5%), whereas the virtual grey WF rose by 1.5 Gm3 (4.3%). The total water quantity dropped by 3.3 Gm3 (-4.9%), while the grey WF increased by 1.2 Gm3 (2.5%), i.e. the COVID-19 lockdown decreases physical water quantity and improves local water quality. More than 50% of the water comes from virtual water trade outside the province (virtual water is highly dependent on external), and around 60% of the grey WF comes from physical sewage in the province. The COVID-19 lockdown reduced water outsourcing across the province (paid nonlocally decrease) but increased pollution outsourcing (paid nonlocally increase). And gross capital formation's contribution to the growth in water footprint will continue to rise. As a result, this study suggested that Fujian should take advantage of sectoral trade network to enhance the transaction of green water-intensive intermediate products, reduce the physical water consumption of blue water-intensive sectors, and reduce the external dependence on water consumption. Achieving the shared responsibility of upstream and downstream water consumption and reducing the external dependence on water in water-rich regions is crucial to solving the world's water problems. This research provides empirical evidence for the long-term effects of COVID-19 lockdown on the physical and virtual water environment.

Compilation and evaluation of gastrointestinal endoscopy satisfaction scale. / æ¶ˆåŒ–å† é•œè¯Šç–—æ»¡æ„åº¦é‡è¡¨çš„ç¼–åˆ¶åŠè¯„ä»·.

OBJECTIVES: Gastrointestinal endoscopy plays an important role in the diagnosis and treatment of gastrointestinal diseases. The satisfaction degree of gastrointestinal endoscopy can directly affect the patient's compliance and further impact the treating effect. At present, there is no scale to evaluate the satisfaction degree of gastrointestinal endoscopy in China. This study aims to develop a satisfaction scale of gastrointestinal endoscopy suitable for national conditions and to evaluate its reliability and validity, which provides a tool for clinic to evaluate patients' satisfaction with gastrointestinal endoscopy. METHODS: The original gastrointestinal endoscopy satisfaction scale was compiled by literature review, consulting senior endoscopists and experts. Through the first round of survey about 120 patients, the original scale was analyzed and modified according to the results to get the gastrointestinal endoscopy satisfaction scale (formal scale). The formal scale was used to conduct the second round of survey about 200 patients. The reliability and validity of the scale were analyzed and evaluated according to the survey results. RESULTS: The reliability of the original scale was good but the validity was poor. The formal scale had 2 dimensions and 10 items, the Cronbach's alpha and split-half reliability were 0.889 and 0.823. The structure validity index χ2/df was 2.513, root mean square error of approximation (RMSEA) was 0.094, goodness of fit index (GFI) was 0.914, adjusted goodness of fit index (AGFI) was 0.861, comparative fit index (CFI) was 0.946, normed fit index (NFI) was 0.915. The aggregate validity was general, the discriminative validity was good, and the direct score of patients was strongly correlated with the total score of the scale. CONCLUSIONS: The gastrointestinal endoscopy satisfaction scale has good reliability and validity, which can be used as a tool to evaluate patients' satisfaction with gastrointestinal endoscopy in China.

Development and evaluation of acceptance scale for artificial intelligence in digestive endoscopy by subjects. / å—æ£€è€ å¯¹æ¶ˆåŒ–å† é•œäººå·¥æ™ºèƒ½æŽ¥å—åº¦é‡è¡¨çš„ç¼–åˆ¶åŠè¯„ä»·.

OBJECTIVES: Digestive endoscopy is an important diagnostic and therapeutic tool for digestive system diseases. The artificial intelligence (AI)-assisted system in endoscopy (hereinafter referred to as AI in digestive endoscopy) has broad application prospects in the field of digestive endoscopy. The trust and acceptance of endoscopic subjects are the cornerstone of the research, application, and promotion of AI in digestive endoscopy. Currently, the tools for measuring the acceptance of AI in digestive endoscopy by subjects are limited at home and abroad. This study aims to develop a scale for measuring the acceptance of AI in digestive endoscopy by subjects, then to evaluate its reliability and validity. METHODS: By conducting literature research, an item pool and dimensions were constructed, and a preliminary scale was constructed using Delphi method. Through the first stage of the survey on the subjects, the reliability and validity of the scale were tested, and the revised scale was used for the second stage of survey on the subjects to further verify the structural validity of the scale. RESULTS: The acceptance scale for AI in digestive endoscopy included 11 items in 3 dimensions: accuracy, ethics, benefit and willingness. In the first stage of the survey, 351 valid questionnaires were collected, and the Cronbach's α was 0.864. The correlation coefficient between the total score of the scale and the score of the test item was 0.636, and the Kaiser-Meyer-Olkin (KMO) value in exploratory factor analysis was 0.788. In the second stage of the survey, 335 valid questionnaires were collected, and in confirmatory factor analysis, the χ2/df was 3.774, while the root mean squared error of approximation (RMSEA) was 0.091. CONCLUSIONS: Acceptance scale for AI in digestive endoscopy by subjects developed in this study has good reliability and validity.

Distinct immune responses in the early phase to natural SARS-CoV-2 infection or vaccination.

Immune responses elicited by viral infection or vaccination play key roles in the viral elimination and the prevention of reinfection, as well as the protection of healthy persons. As one of the most widely used Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, there have been increasing concerns about the necessity of additional doses of inactivated vaccines, due to the waning immune response several months after vaccination. To further optimize inactivated SARS-CoV-2 vaccines, we compared immune responses to SARS-CoV-2 elicited by natural infection and immunization with inactivated vaccines in the early phase. We observed the lower antibody levels against SARS-CoV-2 spike (S) and nucleocapsid (N) proteins in the early phase of postvaccination with a slow increase, compared to the acute phase of SARS-CoV-2 natural infection. Specifically, IgA antibodies have the most significant differences. Moreover, we further analyzed cytokine expression between these two groups. A wide variety of cytokines presented high expression in the infected individuals, while a few cytokines were elicited by inactivated vaccines. The differences in antibody responses and cytokine levels between natural SARS-CoV-2 infection and vaccination with the inactivated vaccines may provide implications for the optimization of inactivated SARS-CoV-2 vaccines and the additional application of serological tests.

FAM98A promotes resistance to 5-fluorouracil in colorectal cancer by suppressing ferroptosis.

BACKGROUND: FAM98A is a microtubule-associated protein involved in cell proliferation and migration, and is frequently dysregulated in epithelial cancers. But its role in the development of colorectal cancer (CRC) cancer remains unknown. METHODS: Immunohistochemical analysis was performed to examine the expression of FAM98A in CRC samples. We also investigated the effects of abnormal expression on the biological behavior of colorectal cancer cells both in vitro and in vivo. Immunoblotting and immunoprecipitation were used to screen FAM98A-related signalling pathways and downstream factors. RESULTS: FAM98A was upregulated in CRC tissues and CRC cell lines. Overexpression of FAM98A promoted cell proliferation and recovered 5-FU suppressed CRC cell proliferation both in vitro and in vivo. In addition, the Enhanced expression of FAM98A inhibited ferroptosis in CRC cells by activating the translation of xCT in stress granules (SGs). Furthermore, we identified that metformin could reverse FAM98A-mediated 5-FU resistance in CRC cells. CONCLUSIONS: Our results for the first time indicate that FAM98A plays a critical role in promoting CRC progression, which provides a novel target for clinical drug resistance of colorectal cancer. And metformin may sensitize 5-FU in the treatment of colorectal cancer.

Association of circulating tumor cell-white blood cell clusters with survival outcomes in patients with colorectal cancer after curative intent surgery.

BACKGROUND: The analysis of circulating tumor cell-associated white blood cell (CTC-WBC) clusters represented the progress in the liquid biopsy of malignant tumors, however, related research in patients with colorectal cancer is still absent. METHODS: To explore associations between CTC-WBC clusters and the prognosis of these patients, we conducted an independent cohort of 329 colorectal cancer patients after curative intent surgery and pre-operative CTC detection in Nanfang Hospital, Southern Medical University, Guangzhou, China between January 1, 2017, and September 31, 2019. The primary cohort referred to patients with CTC-WBC clusters positive. The control cohort was defined as those with exclusively CTCs positive. CTCs were enriched and distinguished by The CanPatrol™ system (SurExam, China). The Kaplan-Meier curve was used to compare the progressive-free survival (PFS) and overall survival (OS) between two groups. The COX regression model was used to assess the predictive value of CTC-WBC clusters. RESULTS: Sixty three patients presented CTC-WBC clusters positive (CTC-WBC group) and 266 patients showed solely CTCs (CTC group). The number of CTCs was significantly different between two groups (P < 0.001) and the rest of clinical characteristics were not markedly associated with the presence of CTC-WBC clusters. Kaplan-Meier curves of PFS and OS exhibited that the CTC-WBC group had significantly shorter PFS (P = 0.011), while not for OS. The multivariate model further suggested that the CTC-WBC clusters (Hazard Ratio = 1.89, 95% Confidence Interval 1.02-3.51, P = 0.042) was an independent predictor for the PFS of in post-operation CRC patients. CONCLUSION: The CTC-WBC cluster is significantly associated with recurrence after operation in CRC patients. This finding facilitates the evaluation of this indicator in tumor progression.