Single-cell transcriptome analysis reveals immunosuppressive landscape in overweight and obese colorectal cancer.

BACKGROUND: Overweight and obesity are established risk factors for various types of cancers including colorectal cancer (CRC). However the underlying molecular mechanisms remain unclear. An in-depth understanding of the oncologic characteristics of overweight and obese CRC at the single-cell level can provide valuable insights for the development of more effective treatment strategies for CRC. METHODS: We conducted single-cell RNA sequencing (scRNA-seq) analysis on tumor and adjacent normal colorectal samples from 15 overweight/obese and 15 normal-weight CRC patients. Immunological and metabolic differences between overweight/obese CRC and non-obese CRC were characterized. RESULTS: We obtained single-cell transcriptomics data from a total of 192,785 cells across all samples. By evaluating marker gene expression patterns, we annotated nine main cell types in the CRC ecosystem. Specifically, we found that the cytotoxic function of effector T cells and NK cells was impaired in overweight/obese CRC compared with non-obese CRC, relating to its metabolic dysregulation. CD4+T cells in overweight/obese CRC exhibited higher expression of immune checkpoint molecules. The antigen-presenting ability of DCs and B cells is down-regulated in overweight/obese CRC, which may further aggravate the immunosuppression of overweight/obese CRC. Additionally, dysfunctional stromal cells were identified, potentially promoting invasion and metastasis in overweight/obese CRC. Furthermore, we discovered the up-regulated metabolism of glycolysis and lipids of tumor cells in overweight/obese CRC, which may impact the metabolism and function of immune cells. We also identified inhibitory interactions between tumor cells and T cells in overweight/obese CRC. CONCLUSIONS: The study demonstrated that overweight/obese CRC has a more immunosuppressive microenvironment and distinct metabolic reprogramming characterized by increased of glycolysis and lipid metabolism. These findings may have implications for the development of novel therapeutic strategies for overweight/obese CRC patients.

Evaluation of transrectal ultrasound-guided tru-cut biopsy as a complementary method for predicting pathological complete response in rectal cancer after neoadjuvant treatment: a phase II prospective and diagnostic trial.

IMPORTANCE: Patients with pathological complete response (pCR) of rectal cancer following neoadjuvant treatment had better oncological outcomes. However, reliable methods for accurately predicting pCR remain limited. OBJECTIVE: To evaluate whether transrectal ultrasound-guided tru-cut biopsy (TRUS-TCB) adds diagnostic value to conventional modalities for predicting pathological complete response in patients with rectal cancer after neoadjuvant treatment. DESIGN, SETTING, AND PARTICIPANTS: This study evaluated data of patients with rectal cancer who were treated with neoadjuvant treatment and reassessed using TRUS-TCB and conventional modalities before surgery. This study is registered with ClinicalTrials.gov. MAIN OUTCOMES AND MEASURES: The primary outcome was accuracy, along with secondary outcomes including sensitivity, specificity, negative predictive value, and positive predictive value in predicting tumour residues. Final surgical pathology was used as reference standard. RESULTS: Between June 2021 and June 2022, a total of 74 patients were enroled, with 63 patients ultimately evaluated. Among them, 17 patients (28%) exhibited a complete pathological response. TRUS-TCB demonstrated an accuracy of 0.71 (95% CI, 0.58-0.82) in predicting tumour residues. The combined use of TRUS-TCB and conventional modalities significantly improved diagnostic accuracy compared to conventional modalities alone (0.75 vs. 0.59, P =0.02). Furthermore, TRUS-TCB correctly reclassified 52% of patients erroneously classified as having a complete clinical response by conventional methods. The occurrence of only one mild adverse event was observed. CONCLUSIONS AND RELEVANCE: TRUS-TCB proves to be a safe and accessible tool for reevaluation with minimal complications. The incorporation of TRUS-TCB alongside conventional methods leads to enhanced diagnostic performance.

Preoperative assessment of fistula-in-ano using SonoVue enhancement during three-dimensional transperineal ultrasound.

Background: Accurate preoperative evaluation of fistula-in-ano can guide the choice of surgical procedure and may improve healing rates. This prospective study aimed to evaluate the accuracy of conventional 3D transperineal ultrasound (3D-TPUS) compared with SonoVue (SVE)-enhanced 3D-TPUS for the detection and classification of anal fistula. Methods: In this prospective study, 3D-TPUS reconstructions were performed before and after SVE enhancement in 60 patients with fistula-in-ano who intended to undergo surgery at the Department of Anorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University (P. R. China) between January 2021 and October 2021. Accuracies of anal fistula classification, complexity classification, detection of anal fistula branches, and detection of internal opening between 3D-TPUS and SVE 3D-TPUS were compared based on a reference standard-intraoperative findings. Results: This study enrolled 60 patients (mean age, 37.1 ± 11.4 years; mean follow-up, 9 ± 3 months). Intraoperative findings showed that the fistula type was intersphincteric in 23 patients (38.3%), trans-sphincteric in 35 (58.3%; 12 high and 23 low), and suprasphincteric in 2 (3.3%). Moreover, 68 internal openings were found. Compared with the accuracy of 3D-TPUS, that of SVE 3D-TPUS was similar in fistula classification [95.0% (57/60) vs 96.7% (58/60), P = 0.392], but significantly higher in internal opening evaluation [80.9% (55/68) vs 97.1% (66/68), P = 0.001], complexity classification [85.0% (51/60) vs 98.3% (59/60), P = 0.018], and detection of fistula branches [70.4% (19/27) vs 92.6% (25/27), P = 0.031]. Conclusions: SVE 3D-TPUS may be a useful examination for patients with perianal fistulae because of its high accuracy and consistency with intraoperative findings, especially in complex fistula-in-ano and difficult cases.

Stapled transperineal rectovaginal fistula repair for low- and mid-level rectovaginal fistulas: A comparison study with rectal mucosal advancement flap repair.

BACKGROUND: As an innovative treatment, stapled transperineal rectovaginal fistula repair (STR) for rectovaginal fistula (RVF) has demonstrated effectiveness in preliminary reports. This study aims to compare STR with rectal mucosal advancement flap repair (RAF), a widely utilized surgical procedure, for the surgical outcome of the low- and mid-level RVF. METHODS: In this retrospective cohort study, patients with low- and mid-level RVF who underwent STR or RAF were included from both the Sixth Affiliated Hospital of Sun Yat-sen University and Xi'an Daxing Hospital. Among the 99 total patients, 77 underwent STR and 22 underwent RAF. Patient demographics, operative data, and outcomes were collected and analyzed. Recurrence rate and associated risk factors were evaluated. RESULTS: There were no statistically significant differences among patients in terms of clinical characteristics like age, BMI, aetiology, and fistula features. During the follow-up period of 20 months (interquartile range 3.0-41.8 months), a total of 28 patients relapsed, with a significantly lower recurrence rate in the STR group (20.8 %) than in the RAF group (54.6 %) (P = 0.005). In the multivariate Cox analysis, STR was an independent protective factor against recurrence (HR: 0.37, 95%CI: 0.17-0.79, P = 0.01). Logistic regression indicated that there was no statistically significant difference between these two procedures in terms of surgical complications (OR: 0.53, 95%CI: 0.19-1.48, P = 0.23). CONCLUSION: For low- and mid-level RVF, STR may be an alternative option for treatment modality that offers a lower recurrence rate, without observed disadvantage in terms of surgical complication rates.

Single-cell RNA sequencing reveals cellular dynamics and therapeutic effects of astragaloside IV in slow transit constipation.

The cellular characteristics of intestinal cells involved in the therapeutic effects of astragaloside IV (AS-IV) for treating slow transit constipation (STC) remain unclear. This study aimed to determine the dynamics of colon tissue cells in the STC model and investigate the effects of AS-IV treatment by single-cell RNA sequencing (scRNA-seq). STC mouse models were developed using loperamide, with subsequent treatment using AS-IV. Colon tissues and feces were collected for scRNA-seq and targeted short-chain fatty acid quantification. We integrated scRNA-seq data with network pharmacology to analyze the effect of AS-IV on constipation. AS-IV showed improvement in defecation for STC mice induced by loperamide. Notably, in STC mice, epithelial cells, T cells, B cells, and fibroblasts demonstrated alterations in cell proportions and aberrant functions, which AS-IV partially rectified. AS-IV has the potential to modulate the metabolic pathway of epithelial cells through its interaction with peroxisome proliferator-activated receptor gamma (PPARγ). AS-IV reinstated fecal butyrate levels and improved energy metabolism in epithelial cells. The proportion of naïve CD4+T cells is elevated in STC, and the differentiation of these cells into regulatory T cells (Treg) is regulated by B cells and fibroblasts through the interaction of ligand-receptor pairs. AS-IV treatment can partially alleviate this trend. The status of fibroblasts in STC undergoes alterations, and the FB_C4_Adamdec1 subset, associated with angiogenesis and the Wingless-related integration (Wnt) pathway, emerges. Our comprehensive analysis identifies perturbations of epithelial cells and tissue microenvironment cells in STC and elucidates mechanisms underlying the therapeutic efficacy of AS-IV.

Astragaloside IV improves slow transit constipation by regulating gut microbiota and enterochromaffin cells.

Purpose: Slow transit constipation (STC) is a common gastrointestinal disorder characterized by altered gut microbiota and reduced number of enterochromaffin cells (ECs). Astragaloside IV (AS-IV), a low drug permeability saponin, has showed beneficial effects on patients with STC. However, the specific mechanism by which AS-IV regulates STC remains unclear. In this study, we aimed to investigate the effect of AS-IV on STC and its associated mechanisms involving gut microbiota. Methods: The effect of AS-IV on STC was evaluated on STC mice induced with loperamide. We measured defecation frequency, intestinal mobility, ECs loss, and colonic lesions in STC mice treated with AS-IV. We also analyzed the changes in gut microbiota and metabolites after AS-IV treatment. Moreover, we investigated the relationship between specific gut microbes and altered fecal metabolites, such as 3-bromotyrosine (3-BrY). We also conducted in vitro experiments to investigate the effect of 3-BrY on caspase-dependent apoptosis of ECs and the activation of the p38 MAPK and ERK signaling pathways induced by loperamide. Results: AS-IV treatment promoted defecation, improved intestinal mobility, suppressed ECs loss, and alleviated colonic lesions in STC mice. AS-IV treatment also affected gut microbiota and metabolites, with a significant correlation between specific gut microbes and altered fecal metabolites such as 3-BrY. Furthermore, 3-BrY may potentially reduce caspase-dependent apoptosis of ECs and protect cell survival by inhibiting the activation of the p38 MAPK and ERK signaling pathways induced by loperamide. Conclusion: Our findings suggest that changes in gut microbiota and ECs mediated the therapeutic effect of STC by AS-IV. These results provide a basis for the use of AS-IV as a prebiotic agent for treating STC. The specific mechanism by which AS-IV regulates gut microbiota and ECs warrants further investigation.

A magnetic resonance imaging-based decision-making tool for predicting complex anal fistulas healing in the early postoperative period.

BACKGROUND: Magnetic resonance imaging (MRI) has excellent accuracy in diagnosing preoperative lesions before anal fistula surgery. However, MRI is not good in identifying early recurrent lesions and effective methods for quantitative assessment of fistula healing are still warranted. This retrospective study aimed to develop and validate a specific MRI-based nomogram model to predict fistula healing during the early postoperative period. METHODS: Patients with complex cryptoglandular anal fistulas who underwent surgery between January 2017 and October 2020 were included in this study. MRI features and clinical parameters were analyzed using univariate and multivariate logistic regression analysis. A nomogram for predicting fistula healing was constructed and validated. RESULTS: In total, 200 patients were included, of whom 186 (93%) were male, with a median age of 36 (18-65) years. Of the fistulas, 58.5% were classified as transsphincteric and 19.5% as suprasphincteric. The data were randomly divided into the training cohort and testing cohort at a ratio of 7:3. Logistic analysis revealed that CNR, ADC, alcohol intake history, and suprasphincteric fistula were significantly correlated with fistula healing. These four predictors were used to construct a predictive nomogram model in the training cohort. AUC was 0.880 and 0.847 for the training and testing cohorts, respectively. Moreover, the decision and calibration curves showed high coherence between the predicted and actual probabilities of fistula healing. CONCLUSIONS: We developed a predictive model and constructed a nomogram to predict fistula healing during the early postoperative period. This model showed good performance and may be clinically utilized for the management of anal fistulas.

Corrigendum: Effects of Xiao Chengqi formula on slow transit constipation by assessing gut microbiota and metabolomics analysis in vitro and in vivo.

[This corrects the article DOI: 10.3389/fphar.2022.864598.].

Unveiling mitophagy-mediated molecular heterogeneity and development of a risk signature model for colorectal cancer by integrated scRNA-seq and bulk RNA-seq analysis.

Background: Accumulating researchers have recognized mitophagy as a key player in tumors, but few studies have investigated its role in the tumor microenvironment (TME). Advances in the technology of single-cell RNA sequencing (scRNA-seq) have allowed unveiling the concealed features of the TME at cellular resolution. This study aimed to elucidate the role of mitophagy within the TME of colorectal cancer (CRC) and to establish a mitophagy-mediated risk model. Methods: We assessed mitophagy-related pathway activities at both single-cell and tissue levels. Subsequently, an unsupervised clustering algorithm was employed to identify mitophagy-mediated subtypes. Furthermore, we developed a mitophagy-mediated risk signature (MMRS) using least absolute shrinkage and selection operator (LASSO) Cox analysis and constructed a MMRS model incorporating the risk score and clinical variables. Subsequently, we used quantitative reverse transcription polymerase chain reaction analysis to verify the expression of the screened genes. Results: We retrieved and annotated a total of 14,719 cells from eight samples in the scRNA-seq GSE132465 data set. The activities of mitophagy-related pathways were uniformly upregulated in cancer cells. Integrating with bulk RNA-seq data, we identified two mitophagy-mediated clusters (C1 and C2) with distinct characteristics and prognoses. C2 was identified as a mitophagy-high cluster. Then, we developed a five-gene MMRS via LASSO Cox analysis in The Cancer Genome Atlas (TCGA) cohort. We utilized the GSE39582 cohort to validate the efficacy of our model. The expression of CX3CL1 and INHBB was upregulated in CRC tissues. Conclusions: The present study identified two mitophagy-mediated CRC subtypes with distinct features. Our MMRS may provide potential therapeutic strategies for CRC. The findings of our work offer novel insights into the involvement of mitophagy in CRC.

Cancer-associated fibroblasts undergoing neoadjuvant chemotherapy suppress rectal cancer revealed by single-cell and spatial transcriptomics.

Neoadjuvant chemotherapy (NAC) for rectal cancer (RC) shows promising clinical response. The modulation of the tumor microenvironment (TME) by NAC and its association with therapeutic response remain unclear. Here, we use single-cell RNA sequencing and spatial transcriptome sequencing to examine the cell dynamics in 29 patients with RC, who are sampled pairwise before and after treatment. We construct a high-resolution cellular dynamic landscape remodeled by NAC and their associations with therapeutic response. NAC markedly reshapes the populations of cancer-associated fibroblasts (CAFs), which is strongly associated with therapeutic response. The remodeled CAF subsets regulate the TME through spatial recruitment and crosstalk to activate immunity and suppress tumor progression through multiple cytokines, including CXCL12, SLIT2, and DCN. In contrast, the epithelial-mesenchymal transition of malignant cells is upregulated by CAF_FAP through MIR4435-2HG induction, resulting in worse outcomes. Our study demonstrates that NAC inhibits tumor progression and modulates the TME by remodeling CAFs.

Unraveling dynamic interactions between tumor-associated macrophages and consensus molecular subtypes in colorectal cancer: An integrative analysis of single-cell and bulk RNA transcriptome.

Background: Accumulating research substantiated that tumor-associated macrophages (TAMs) have a significant impact on the tumorigenesis, progression, and distant metastasis, representing a novel target for various cancers. However, the underlying dynamic changes and interactions between TAMs and tumor cells remain largely elusive in colorectal cancer (CRC). Methods: We depicted the dynamic changes of macrophages using sing-cell RNA-seq data and extracted TAM differentiation-related genes. Next, we utilized the weighted gene co-expression network analysis (WGCNA) to acquire CMS-related modular genes using bulk RNA-seq data. Finally, we utilized univariate Cox and Lasso Cox regression analyses to identify TAM differentiation-related biomarkers and established a novel risk signature model. We employed quantitative real-time polymerase chain reaction (qRT-PCR) on CRC tissue samples and used immunohistochemistry (IHC) data frome the HPA database to validate the mRNA and protein expression of prognostic genes. The interaction of TAMs and each consensus molecular subtype (CMS) subpopulation was analyzed at the cellular level. Results: A total of 47,285 cells from single-cell dataset and 1197 CRC patients from bulk dataset were obtained. Among those, 6400 myeloid cells were re-clustered and annotated. RNASE1, F13A1, DAPK1, CLEC10A, RPN2, REG4 and RGS19 were identified as prognostic genes and the risk signature model was established based on the above genes. The qRT-PCR analysis indicated that the expression of RNASE1 and DAPK1 were significantly up-regulated in CRC tumor tissues. The cell-cell communication analysis demonstrated complex interactions between TAMs and CMS malignant cell subpopulations. Conclusion: This study presents an in-depth dissection of the dynamic features of TAMs in the tumor microenvironment and provides promising therapeutic targets for CRC.

A frameshift variant in the SIRPB1 gene confers susceptibility to Crohn's disease in a Chinese population.

Background: Crohn's disease (CD), a chronic gastrointestinal inflammatory disease, is increasing in China. With a focus on Han Chinese families with CD, the aim of this study was to find genetic variations that increase CD susceptibility by genome sequencing, genetic association, expression, and functional research. Materials and methods: We performed family-based genome sequencing (WGS) analysis on 24 patients with CD from 12 families and then filtered shared potential causal variants by incorporating association results from meta-analyses of CD GWAS and immunology genes and in silico variant effect prediction algorithms. Replication analyses were performed in an independent cohort including 381 patients with CD and 381 control subjects. Results: There were 92 genetic variants significantly associated with CD in Chinese individuals. Among them, 61 candidate loci were validated in replication analyses. As a result, patients carrying a rare frameshift variant (c.1143_1144insG; p. Leu381_Leu382fs) in gene SIRPB1 had significantly higher risk to develop CD (p = 0.03, OR 4.59, 95% CI 0.98-21.36, 81.82% vs. 49.53%). The frameshift variation induced tyrosine phosphorylation of Syk, Akt, and Jak2, elevated the expression of SIRPB1 at the mRNA and protein levels, activated DAP12, and controlled the activation of NF-κB in macrophages. Additionally, it promoted the synthesis of the pro-inflammatory cytokines IL-1, TNF-, and IL-6. Conclusion: Our results suggest that the rare gain-of-function frameshift variant in SIRPB1 is associated in Han Chinese patients with CD. The functional mechanism of SIRPB1 and its downstream inflammatory pathways was preliminarily explored in CD.

Percutaneous versus open posterior stabilization and decompression in AOSpine-type A3 thoracolumbar fractures with neurological deficit.

BACKGROUND: This retrospective cohort study aimed to compare the clinical and radiological outcomes between two treatment strategies focusing on non-osteoporotic AOSpine-type A3 fractures of the thoracolumbar spine with neurological deficits at levels T11 to L2. METHODS: In total, 67 patients between 18 and 60 years of age who were treated operatively with either of the two treatment strategies were included. One treatment strategy included open posterior stabilization and decompression, whereas the other was based on percutaneous posterior stabilization and decompression via a tubular retraction system. Demographic data, surgical variables, and further parameters were assessed. Patient-reported outcomes (PROs), including the Visual Analog Scale (VAS), the Oswestry Disability Index (ODI), and the American Spinal Injury Association (ASIA) impairment score, were measured to assess functional outcomes. The regional Cobb angle (CA), the anterior height ratio of the fractured vertebrae (AHRV), and the degree of canal encroachment (DCE) were assessed. The ASIA score was used to assess neurological function recovery. The follow-up period was at least 12 months. RESULTS: Surgical time and postoperative hospital stay were significantly shorter in the minimally invasive surgery (MIS) group. Intraoperative blood loss was significantly less in the MIS group. Regarding radiological outcome, CA and AHRV at the time of follow-up did not show a significant difference. DCE at the time of follow-up was significantly improved in the MIS group. Lower VAS scores and better ODIs were observed in the MIS group at the 6-month follow-up, but similar outcomes were observed at the 12-month follow-up. The ASIA score was similar between both groups at the 12-month follow-up. CONCLUSIONS: Both treatment strategies are safe and effective; however, MIS could provide earlier pain relief and better functional outcomes compared with OS.

Associated Behavioral Factors and Prevalence of the Common Anorectal Disease Among Uyghur Male Adults of China: A Population-Based Crosssectional Study.

Objectives: We investigated the behavioral associated factors and prevalence of common anorectal disease (hemorrhoids, perianal pruritus, anal fistula, and others) among Uyghur male adults in southern Xinjiang. Methods: We conducted a cross-sectional study with a random sampling method from December 2020 to March 2021. Uyghur males aged 18 years and older were selected from Kashgar Prefecture in Xinjiang. The prevalence was evaluated by a bilingual questionnaire (including socio- demographic information, dietary habit, lifestyle, and behavioral habits) and anorectal examinations. The chi-square test was used for categorical variables. Logistic regression analysis was used to identify potential associated factors.Results: A total of 402 Uygur males aged ≥ 18 years were included in the final analysis. Of those, 192 (47.8%) participants were identified with common anorectal disease (CAD). Older age, lower education attainment, being a farmer, having lower personal annual income, having a high level of alcohol consumption, performing less anus-rinsing after defecation, and having less pubic hair removal were significantly associated with CAD. Conclusions: Common anorectal disease is a significant public health concern for the Uygur male population. Anus-rinsing after defecation and pubic hair removal are ethnic-specific behaviors among Uygur and could be preventive strategies for CAD.

Morbidity, Mortality, and Pathologic Outcomes of Transanal Versus Laparoscopic Total Mesorectal Excision for Rectal Cancer Short-term Outcomes From a Multicenter Randomized Controlled Trial.

OBJECTIVE: To determine the morbidity, mortality, and pathologic outcomes of transanal total mesorectal resection (taTME) versus laparoscopic total mesorectal excision (laTME) among patients with rectal cancer with clinical stage I to III rectal cancer below the peritoneal reflection. BACKGROUND: Studies with sufficient numbers of patients allowing clinical acceptance of taTME for rectal cancer are lacking. Thus, we launched a randomized clinical trial to compare the safety and efficacy of taTME versus laTME. METHODS: A randomized, open-label, phase 3, noninferiority trial was performed at 16 different hospitals in 10 Chinese provinces. The primary endpoints were 3-year disease-free survival and 5-year overall survival. The morbidity and mortality within 30 days after surgery, and pathologic outcomes were compared based on a modified intention-to-treat principle; this analysis was preplanned. RESULTS: Between April 13, 2016, and June 1, 2021, 1115 patients were randomized 1:1 to receive taTME or laTME. After exclusion of 26 cases, modified intention-to-treat set of taTME versus laTME groups included 544 versus 545 patients. There were no significant differences between taTME and laTME groups in intraoperative complications [26 (4.8%) vs 33 (6.1%); difference, -1.3%; 95% confidence interval (CI), -4.2% to 1.7%; P =0.42], postoperative morbidity [73 (13.4%) vs 66 (12.1%); difference, 1.2%; 95% CI, -2.8% to 5.2%; P =0.53), or mortality [1 (0.2%) vs 1 (0.2%)]. Successful resection occurred in 538 (98.9%) versus 538 (98.7%) patients in taTME versus laTME groups (difference, 0.2%; 95% CI, -1.9% to 2.2%; P >0.99). CONCLUSIONS: Experienced surgeons can safely perform taTME in selected patients with rectal cancer.

Recurrence Rates and Pharmacological Treatment for Hemorrhoidal Disease: A Systematic Review.

INTRODUCTION: Hemorrhoidal disease (HD) is characterized by prolapse of the inflamed and bleeding vascular tissues of the anal canal. Although HD is associated with a high recurrence rate, there is a lack of understanding around interventions that can reduce recurrence and improve outcomes for patients. As such, a systematic literature review (SLR) was conducted to summarize evidence on epidemiology, recurrence, and efficacy of interventions in HD. METHODS: Real-world evidence (RWE) studies evaluating the incidence, prevalence, or recurrence of HD, as well as SLRs including a meta-analytic component reporting on the efficacy of systemic or topical pharmacological treatments for adults with HD, were included. Systematic searches were conducted in MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Database of Systematic Reviews. RESULTS: The SLR identified 44 eligible publications. Consistent data were limited on the epidemiology of HD or HD recurrence. Specifically, incidence and prevalence reported across geographies were impacted by differences in data collection. Reported risk factors for HD were sedentary behavior, constipation, male gender, and age. Twenty-three RWE studies and one meta-analysis reported HD recurrence rates ranging from 0 to 56.5% following surgery or phlebotonics, with most (n = 19) reporting rates of 20% or less. In addition to time since treatment, risk factors for recurring disease were similar to those for HD in general. With respect to treatment, micronized purified flavonoid fractions significantly improved the main symptoms of HD compared to other pharmacological treatments. CONCLUSION: The SLRs did not identify any RWE studies reporting recurrence in patients receiving systemic or topical treatments, highlighting the need for future research in this area. Further, more studies are needed to understand the optimum duration of medical treatment to prevent recurrence.

Patients with hemorrhoidal disease (HD) can experience recurring disease following a period of improvement or remission. It is not well established how often this might happen, who is at greatest risk, or which treatments can reduce this risk. In this study, a systematic literature review (SLR) was conducted to summarize evidence on the occurrence and recurrence of HD, as well as treatment effectiveness. Several literature databases were searched for articles that described real-world evidence (RWE) studies reporting the epidemiology or recurrence of HD as well as published SLRs that combined the results of multiple studies (meta-analyses) on treatment for adults with HD. Forty of 2037 articles identified by the search were considered relevant, and four others identified by clinicians were also included (total = 44; 39 RWE, 5 meta-analyses). Review of the RWE articles revealed that HD epidemiology was determined differently between studies. Only 23 reported recurrence rates (up to 56.5%) after surgery or treatment with phlebotonic drugs (drugs that improve blood flow in veins). Most (19/23) reported recurrence rates of 20% or less. Risk factors for recurrence were similar to usual HD risk factors (e.g., constipation, male gender, age) in addition to time since treatment. Phlebotonic agents, including those made from plant extracts (micronized purified flavonoid fractions, MPFFs) improved hemorrhoidal symptoms compared with placebo or no treatment. In one meta-analysis, MPFF was the only phlebotonic to significantly reduce recurrence risk versus no treatment or placebo. Overall, more research is needed to compare treatments and determine optimal treatment duration to prevent recurrence. Author-narrated video abstract.

Single-Cell RNA Sequencing Reveals Heterogeneity in the Tumor Microenvironment between Young-Onset and Old-Onset Colorectal Cancer.

BACKGROUND: The incidence of sporadic young-onset colorectal cancer (yCRC) is increasing. Compared with old-onset colorectal cancer (oCRC), yCRC has different clinical and molecular characteristics. However, the difference in the tumor microenvironment (TME) between yCRC and oCRC remains unclear. METHODS: Fourteen untreated CRC tumor samples were subjected to single-cell RNA sequencing analysis. RESULTS: B cells and naïve T cells are enriched in yCRC, while effector T cells and plasma cells are enriched in oCRC. Effector T cells of yCRC show decreased interferon-gamma response and proliferative activity; meanwhile, Treg cells in yCRC show stronger oxidative phosphorylation and TGF-ß signaling than that in oCRC. The down-regulated immune response of T cells in yCRC may be regulated by immune and malignant cells, as we observed a downregulation of antigen presentation and immune activations in B cells, dendritic cells, and macrophages. Finally, we identified malignant cells in yCRC and oCRC with high heterogeneity and revealed their interactions with immune cells in the TME. CONCLUSIONS: Our data reveal significant differences of TME between yCRC and oCRC, of which the TME of yCRC is more immunosuppressive than oCRC. Malignant cells play an essential role in the formation of the suppressive tumor immune microenvironment.

Exploring the mechanism of Tengli Kangliu Decoction in the prevention and treatment of colorectal cancer precancerous based on network pharmacology.

OBJECTIVE: This study aimed to predict the targets and signaling pathways affected by Tengli Kangliu Decoction (TKD) in the treatment of colorectal cancer (CRC) precursor lesions and to determine TKDs mechanism of action based on previous experimental results using network pharmacology techniques and methods. METHODS: Using the traditional Chinese medicine systems pharmacology database (TCMSP) and UniProt database, the active ingredients and potential targets of TKD were identified. Human colorectal adenoma (CRA) targets were analyzed using the GeneCards database, the Online mendelian inheritance in man (OMIM) database, and the NCBI database. The common targets of drug-disease interactions were input into the String database to construct a protein-protein interaction (PPI) network. These data were then used to construct the network diagram. Gene ontology (GO) function analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed on the target genes. Finally, the component-disease-pathway-target network file was imported into Cytoscape 3.8.0 and used to construct the pathway network diagram. RESULTS: Compounds with a drug-likeness (DL) score ≥ 0.18 and an oral bioavailability (OB) ≥ 30% were selected as the active constituents of TKD. Two hundred eighty eight chemical constituents were screened and 305 chemical drug targets were predicted. After further screening, 1942 disease-related targets, which are hypothesized to be the main chemical components of TKD, were obtained. When comparing the targets of action and CRA treatment targets, 172 common targets were identified. Using GO enrichment analysis of common targets of drug diseases, 2550 biological processes (BP) were predicted, 164 items of which were related to molecular functioning (MF), and 67 items related to cell composition. KEGG pathway analysis was performed on the common targets of drug diseases, and a total of 178 signaling pathways were enriched. CONCLUSION: Using network pharmacology research, this study reports on the synergistic effect of the multiple components of TKD on the multi-target, and multiple pathways of colorectal precancerous lesions. These findings lay a theoretical foundation for further colorectal precancerous lesions research.

Impact of Digital Economy Development on Carbon Emission Efficiency: A Spatial Econometric Analysis Based on Chinese Provinces and Cities.

In the realistic context of the development of China's digital economy and carbon peaking and carbon neutrality goals, to efficiently achieve high-quality economic and green and low-carbon transformation, this paper investigates the impact of digital economy development on the carbon emission efficiency of 30 Chinese provinces and cities from 2011-2019. In this paper, firstly, the digital economy development index and carbon emission efficiency are calculated by the entropy method and the Super-SBM-Undesirable Model. Secondly, the Spatial Lag Model (SAR) and the Spatial Durbin Model (SDM) are respectively constructed under the adjacency matrix and the geographic distance matrix to empirically test the spatial impact of the digital economy on carbon emission efficiency. The results show that: the digital economy development and carbon emission efficiency of Chinese provinces and cities both show the spatial distribution characteristics of stronger in the East and weaker in the Middle and West; the digital economy development in Chinese provinces and cities has a significantly positive direct and spatial spillover effect on carbon emission efficiency; there are differences in the direct and spatial spillover effects of various dimensions of the digital economy development on the carbon emission efficiency in Chinese provinces and cities; the direct effect of the digital economy development on the carbon emission efficiency in Chinese provinces and cities has significant regional heterogeneity among eastern, central, and western regions. This paper provides new empirical evidence for developing countries such as China to proactively develop a digital economy to promote energy conservation and emission reduction to realize green and low-carbon transformation.