Targeting AQP9 enhanced the anti-TNF therapy response in Crohn's disease by inhibiting LPA-hippo pathway.

Although anti-TNF antibodies are extensively used to treat Crohn's disease (CD), a significant proportion of patients, up to 40%, exhibit an inadequate response to this therapy. Our objective was to identify potential targets that could improve the effectiveness of anti-TNF therapy in CD. Through the integration and analysis of transcriptomic data from various CD databases, we found that the expression of AQP9 was significantly increased in anti-TNF therapy-resistant specimens. The response to anti-TNF therapy in the CD mouse model was significantly enhanced by specifically inhibiting AQP9. Further experiments found that the blockade of AQP9, which is dominantly expressed in macrophages, decreased inflamed macrophage functions and cytokine expression. Mechanistic studies revealed that AQP9 transported glycerol into macrophages, where it was metabolized to LPA, which was further metabolized to LPA, resulting in the activation of the LPAR2 receptor and downstream hippo pathway, finally promoting the expression of cytokines, especially IL23 and IL1ß⊡ Taken together, the expansion of AQP9+ macrophages is associated with resistance to anti-TNF therapy in Crohn's disease. These findings indicated that AQP9 could be a potential target for enhancing anti-TNF therapy in Crohn's disease.

Local Excision Versus Radical Resection for Grade 2 Rectal Neuroendocrine Tumors: A Multicenter Propensity Score-Matched Analysis.

BACKGROUND: Studies on grade 2 rectal neuroendocrine tumors are limited, and the optimal treatment for these tumors is not well established. OBJECTIVE: We aimed to compare the oncologic results of local excision versus radical resection for the treatment of grade 2 rectal neuroendocrine tumors. DESIGN: Retrospective multicenter propensity score-matched study to minimize heterogeneity between groups and focus on the differences between surgery strategies. SETTINGS: Seventeen large-scale Chinese medical centers participated in this study. PATIENTS: A total of 144 patients with pathologically confirmed grade 2 rectal neuroendocrine tumors were retrospectively analyzed. MAIN OUTCOME MEASURES: Cancer-specific survival and relapse-free survival were assessed to compare surgery strategies. RESULTS: A total of 144 patients with grade 2 rectal neuroendocrine tumors were enrolled in this study. Twenty-seven patients underwent endoscopic resection, 55 underwent transanal excision, 50 underwent radical resection, and 12 underwent palliative surgery or biopsy for distant metastasis. Of the 50 patients who underwent radical resection, 30 (60.0%) had clinically positive lymph nodes on the basis of the histopathology results. The optimal cutoff value for tumor size to predict cancer-specific survival was 1.5 cm. In patients with grade 2 rectal neuroendocrine tumors of ≤1.5-cm size, there were no significant differences in cancer-specific survival and relapse-free survival between local excision and radical resection groups ( p > 0.05). In patients with grade 2 rectal neuroendocrine tumors of >1.5-cm size, relapse-free survival was significantly lower in the local excision group than in the radical resection group ( p = 0.04). LIMITATIONS: The nature of retrospective reviews and a relatively short follow-up period are limitations of this study. CONCLUSIONS: Grade 2 rectal neuroendocrine tumors have a nonnegligible rate of lymph node metastasis. Local excision is a feasible choice for tumors of ≤1.5 cm size without metastasis, whereas radical resection is more beneficial in those of >1.5 cm size. See Video Abstract . ESCISIN LOCAL VERSUS RESECCIN RADICAL PARA TUMORES NEUROENDOCRINOS RECTALES GRADO ANLISIS MULTICNTRICO CON PUNTUACIN DE PROPENSIN COINCIDENTE: ANTECEDENTES:Los estudios sobre los tumores neuroendocrinos rectales de grado 2 son limitados y el tratamiento óptimo para estos tumores no está bien establecido.OBJETIVO:Comparar los resultados oncológicos de la escisión local versus la resección radical para el tratamiento de tumores neuroendocrinos rectales grado 2.DISEÑO:Estudio multicéntrico retrospectivo emparejado por puntuación de propensión para minimizar la heterogeneidad entre grupos y centrarse en la diferencia entre estrategias quirúrgicas.ESCENARIO:Diecisiete centros médicos chinos de gran tamaño participaron en este estudio.PACIENTES:Se analizaron retrospectivamente un total de 144 pacientes con tumores neuroendocrinos rectales grado 2 patológicamente confirmados.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron la supervivencia específica del cáncer y la supervivencia libre de recaída para comparar las estrategias quirúrgicas.RESULTADOS:En este estudio se inscribieron un total de 144 pacientes con tumores neuroendocrinos rectales grado 2. Veintisiete pacientes se sometieron a resección endoscópica, 55 a escisión transanal, 50 a resección radical y 12 a cirugía paliativa o biopsia por metástasis a distancia. De los 50 pacientes que se sometieron a resección radical, 30 (60,0%) tenían ganglios linfáticos clínicamente positivos según los resultados histopatológicos. El valor de corte óptimo para el tamaño del tumor para predecir la supervivencia específica del cáncer fue de 1,5 cm. En pacientes con tumores neuroendocrinos rectales grado 2 ≤ 1,5 cm, no hubo diferencias significativas en la supervivencia específica del cáncer y la supervivencia libre de recaída entre los grupos de escisión local y resección radical ( p >0,05). En pacientes con tumores neuroendocrinos rectales grado 2 > 1,5 cm, la supervivencia libre de recaída fue significativamente menor en el grupo de escisión local que en el grupo de resección radical ( p = 0,04).LIMITACIONES:La naturaleza de la revisión retrospectiva y el período de seguimiento relativamente corto son limitaciones de este estudio.CONCLUSIONES:Los tumores neuroendocrinos rectales grado 2 tienen una tasa no despreciable de metástasis en los ganglios linfáticos. La escisión local es una opción factible para tumores ≤ 1,5 cm sin metástasis, mientras que la resección radical es más beneficiosa en aquellos > 1,5 cm. (Traducción-Dr. Felipe Bellolio ).

Lymph node ratio and hematological parameters predict relapse-free survival in patients with high grade rectal neuroendocrine neoplasms after radical resection: a multicenter prognostic study.

BACKGROUND: The prognostic nutritional index (PNI), alkaline phosphatase (ALP), and lymph node ratio (LNR) are reportedly related to prognosis. The aim of this study was to elucidate the clinical importance of the LNR and hematological parameters in patients with high grade rectal neuroendocrine neoplasms (HG-RNENs) who were undergoing radical resection. METHODS: We reviewed the medical records of patients with HG-RNENs from 17 large-scale medical centers in China (January 1, 2010-April 30, 2022). A nomogram was constructed by using a proportional hazard model. Bootstrap method was used to draw calibration plots to validate the reproducibility of the model. Concordance index (C-Index), decision curve analysis (DCA), and time-dependent area under the receiver operating characteristic curve (TD-AUC) analysis were used to compare the prognostic predictive power of the new model with American Joint Committee on Cancer (AJCC) TNM staging and European Neuroendocrine Tumor Society (ENETS) TNM staging. RESULTS: A total of 85 patients with HG-RNENs were enrolled in this study. In the 45 patients with HG-RNENs who underwent radical resection, PNI ≤ 49.13 (HR: 3.997, 95% CI: 1.379-11.581, P = 0.011), ALP > 100.0 U/L (HR: 3.051, 95% CI: 1.011-9.205, P = 0.048), and LNR > 0.40 (HR: 6.639, 95% CI: 2.224-19.817, P = 0.0007) were independent predictors of relapse-free survival. The calibration plots suggested that the nomogram constructed based on the three aforementioned factors had good reproducibility. The novel nomogram revealed a C-index superior to AJCC TNM staging (0.782 vs 0.712) and ENETS TNM staging (0.782 vs 0.657). Also, the new model performed better compared to AJCC TNM staging and ENETS TNM staging in DCA and TD-AUC analyses. CONCLUSIONS: LNR, ALP, and PNI were independent prognostic factors in patients with HG-RNENs after radical resection, and the combined indicator had better predictive efficacy compared with AJCC TNM staging and ENETS TNM staging.

Mesenchymal Stem Cells Versus Placebo for Perianal Fistulizing Crohn's Disease: A Systemic Review and Meta-Analysis.

BACKGROUND: Mesenchymal stem cells (MSCs)-based therapy for perianal fistulizing Crohn's disease (pfCD) has been extensively studies in the past decade. Its efficacy and safety had been preliminarily confirmed in some phase 2 or phase 3 clinical trials. This meta-analysis is performed to evaluate the efficacy and safety of MSCs-based therapy for pfCD. METHODS: Electronic databases (Pubmed, Cochrane Library, Embase) were searched for studies that reported the efficacy and safety of MSCs. And RevMan were used to assess the efficacy and safety. RESULTS: After screening, 5 randomized controlled trials (RCTs) were included in this meta-analysis. RevMan 5.4 for meta-analysis showed that: [Efficacy] Patients had definite remission after MSCs treatment, with an odds ratio (OR) of 2.06 (P < .0001, 95%CI 1.46, 2.89) vs controls. [Safety] The incidence of the most frequently reported TEAEs (treatment-emergent adverse events, TEAEs), perianal abscess and proctalgia, did not significantly increase due to the use of MSCs, with an OR of 1.07 in perianal abscess (P = .87, 95%CI 0.67, 1.72) vs controls, and an OR of 1.10 in proctalgia (P = .47, 95%CI 0.63, 1.92) vs controls. CONCLUSIONS: MSCs seem to be an effective and safe therapy for pfCD. MSCs based therapy has the potential to be used in combination with traditional therapies.

SIRT1 induces the accumulation of TAMs at colorectal cancer tumor sites via the CXCR4/CXCL12 axis.

Our previous work suggested that high SIRT1 expression by cancer cells predicted a poor colorectal cancer (CRC) prognosis, but its role in the tumor microenvironment was unclear. Here, we examined tumor-infiltrating lymphocytes (TILs) in CRC expressing different levels of SIRT1. We also established a co-culture system with monocytes, CD8+ T cells and patient-derived tumor organoids (PDOs) to study the relationships between immune cells and cancer cells. The percentage of CD8+ T cells was decreased and the percentage of macrophages was increased in SIRT1-high (SIRT1-hi) CRC. Co-culture results showed that tumor-associated macrophages (TAMs) from SIRT1-hi CRC inhibited the proliferation and anti-tumor activity of CD8+ T cells. Importantly, SIRT1-hi CRC were shown to modulate the migration and the activity of TAMs. RNA sequencing revealed that CD14+ monocytes in SIRT1-hi patients expressed higher levels of CXCR4. Mechanistically, SIRT1 expression was shown to promote CXCL12 expression by inhibiting the acetylation of p53. Our findings indicate that SIRT1 in CRC induces TAM migration through the CXCR4/CXCL12 pathway, and inhibits the proliferation and activity of CD8+ T cells, resulting in promotion of CRC progression.

MIN score predicts primary response to infliximab/adalimumab and vedolizumab therapy in patients with inflammatory bowel diseases.

Infliximab/adalimumab (IFX/ADA) and vedolizumab (VDZ) are the most widely used biologics in inflammatory bowel diseases. Current models used to predict their efficacies are restricted to either Crohn's disease or ulcerative colitis or to only one type of biologic, which makes them limited in external validation. We therefore designed a comprehensive comparison among these models to identify the most meaningful predictors for patient responses. Several biomarkers and models were compared for their abilities to predict both IFX/ADA and VDZ responses by receiver operating characteristic curves. Least absolute shrinkage and selection operator regression was adopted to determine a simplified gene signature. Verification was performed in biopsy samples by immunohistochemical staining. The GIMATS module (based on counts of IgG plasma cells, inflammatory monocytes, activated T cells, and stromal cells) had the best overall performance for response prediction in both biologics (IFX/ADA, AUC = 0.720-0.853; VDZ, AUC = 0.661-0.728). Based on this module, patients were equally divided into 3 groups: M type (GIMATS-low, metabolism), with a preference for IFX/ADA; I type (GIMATS-high, immune), with a preference for VDZ; and N type (GIMATS-medium, normal), with no preference for either treatment. Furthermore, to improve clinical utility, a simplified 6-gene model, MIN score, was established to determine the baseline expression of G0S2, S100A9, SELE, CHI3L1, MMP1 and CXCL13 and function as a substitute for GIMATS module. Our study suggested that the classification of metabolic or immune type by MIN score was valuable for IBD diagnosis to assist with selection of IFX/ADA and VDZ.

Intracorporeal reinforcement with barbed suture is associated with low anastomotic leakage rates after laparoscopic low anterior resection for rectal cancer: a retrospective study.

BACKGROUND: Anastomotic leakage (AL) is one of most severe postoperative complications following low anterior resection (LAR) for rectal cancer, and has an adverse impact on postoperative recovery. The occurence of AL is associated with several factors, while few studies explored the role of intracorporeal barbed suture reinforcement in it. METHODS: Consecutive cases underwent laparoscopic LAR for rectal cancer from Mar. 2018 to Feb. 2021 in our center were retrospectively collected. Cases were classified into the intracorporeal barbed suture reinforcement group and the control group according to whether performing intracorporeal reinforcement with barbed suture, and AL incidences were compared between two groups. Propensity score matching (PSM) was then performed based on identified risk factors to reduce biases from covariates between two groups. AL incidences in the matched cohort were compared. RESULTS: A total of 292 cases entered into the study, and AL incidences were significantly lower in the intracorporeal barbed suture reinforcement group compared with the control group (10.00% vs 2.82%, P = 0.024). Sex, BMI, preoperative adjuvant chemoradiotherapy and anastomotic level were chose for PSM analyses based on previous studies. In the matched cohort, the AL incidences were still significantly lower in the intracorporeal barbed suture reinforcement group (10.57% vs 2.44%, SD = 0.334). CONCLUSIONS: Intracorporeal barbed suture reinforcement is associated with low AL incidences after laparoscopic LAR for rectal cancer, which is a potential procedure for reducing AL and worthy of application clinically.

D3 Versus D2 Lymphadenectomy in Right Hemicolectomy: A Systematic Review and Meta-analysis.

PURPOSE: D3 lymphadenectomy for right colon cancer improves oncological outcomes. This meta-analysis aimed to compare operation data, histopathological characteristics, perioperative conditions, and long-term survival after D3 and D2 lymphadenectomy in right hemicolectomy. METHODS: We searched PubMed, Embase, and the Cochrane Library for relevant articles (up to March 31, 2020). Random-effects and fixed-effects meta-analysis models were used. Review Manager (RevMan) version 5.3 and Stata version 15.1 were used for pooled estimates. RESULTS: After screening 714 articles, 7 articles with a total of 1368 patients were eligible for inclusion. Compared with D2, D3 lymphadenectomy improves results in terms of blood loss (weighted mean difference [WMD] = -20.63, 95% confidence interval [CI] -28.19 to -13.16, P < .01), harvested lymph nodes (WMD = 8.86, 95% CI 7.74 to 9.98, P < .01), 3-year overall survival (OS) (hazard ratio [HR] = 2.03, 95% CI 1.20 to 3.43, P < .01), 5-year OS (HR = 2.22, 95% CI 1.15 to 4.30, P = .02), and 5-year disease-free survival (DFS) (HR = 2.16, 95% CI 1.19 to 3.90, P = .01). There was no significant difference regarding operation time, anastomosis leakage, wound infection, overall morbidity, postoperative hospital stay, mortality, length of dissected colon, and 3-year DFS (P >= .05). CONCLUSIONS: It is suggested in this review that D3 lymphadenectomy is superior to D2 lymphadenectomy in terms of blood loss, harvested lymph nodes, 3-year OS, 5-year OS, and 5-year DFS. The conclusion must be drawn with caution due to the limited number of included studies. Further RCTs are needed for stronger evidence.

GPR126 regulates colorectal cancer cell proliferation by mediating HDAC2 and GLI2 expression.

The G-protein-coupled receptor 126 (GPR126) may play an important role in tumor development, although its role remains poorly understood. We found that GPR126 had higher expression in most colorectal cancer cell lines than in normal colon epithelial cell lines, and higher expression levels in colorectal cancer tissues than in normal adjacent colon tissues. GPR126 knockdown induced by shRNA inhibited cell viability and colony formation in HT-29, HCT116, and LoVo cells, decreased BrdU incorporation into newly synthesized proliferating HT-29 cells, led to an arrest of cell cycle progression at the G1 phase in HCT-116 and HT-29 cells, and suppressed tumorigenesis of HT-29, HCT116, and LoVo cells in nude mouse xenograft models. GPR126 knockdown engendered decreased transcription and translation of histone deacetylase 2 (HDAC2), previously implicated in the activation of GLI1 and GLI2 in the Hedgehog signaling pathway. Ectopic expression of HDAC2 in GPR126-silenced cells restored cell viability and proliferation, GLI2 luciferase reporter activity, partially recovered GLI2 expression, and reduced the cell cycle arrest. HDAC2 regulated GLI2 expression and, along with GLI2, it bound to the PTCH1 promoter, as evidenced by a chip assay with HT-29 cells. Purmorphamine, a hedgehog agonist, largely restored the cell viability and expression of GLI2 proteins in GPR126-silenced HT-29 cells, whereas GANT61, a hedgehog inhibitor, further enhanced the GPR126 knockdown-induced inhibitory effects. Our findings demonstrate that GPR126 regulates colorectal cancer cell proliferation by mediating the expression of HDAC2 and GLI2, therefore it may represent a suitable therapeutic target for colorectal cancer treatment.

Comparative study of oncologic efficacy of cephalomedial to lateral dissection versus medial to lateral dissection in laparoscopic total mesorectal excision for rectal cancer: An RCT study.

BACKGROUND AND OBJECTIVES: We compared the 3-year overall survival between cephalomedial-to-lateral approach proctectomy (CEMP) and medial-to-lateral approach proctectomy (MAP) in patients undergoing laparoscopic total mesorectal excision for rectal cancer. The advantages of CEMP and the clinical value of No. 253 lymph nodes resection have not been objectively analyzed in literature. METHODS: This was a prospective, two-arm, multicenter, single-blinded, randomized trial. The primary endpoint was 3-year overall survival, and secondary endpoints included safety, feasibility, oncological radicality (including number of No. 253 lymph nodes harvested), short-term outcome, 3-year disease-free survival, rate of postoperative complications, mortality, and rate of recurrence. RESULTS: From May 2016 to July 2020, 506 patients were enrolled-256 in the CEMP group and 250 in the MAP group. Comparison of overall survival and disease-free survival showed that there was treatment benefit in the CEMP group (28.22 ± 12.12 vs. 27.44 ± 13.06, p = 0.485; 27.24 ± 12.01 vs. 26.42 ± 12.81; p = 0.457). More No. 253 lymph nodes were harvested in the CEMP group, and cases with positive No. 253 lymph nodes had worse prognosis in stage III. Surgical safety was equal for both approaches. CONCLUSIONS: Dissection of No. 253 lymph nodes may be important to improve clinical prognosis, but further studies with larger samples are needed to confirm this finding.

Non-energy devices to dissect recurrent laryngeal nerve lymph nodes of non-small cell lung cancer under video-assisted thoracic surgery.

BACKGROUND: Systematic nodal dissection plays a crucial role in improving survival and staging in resectable non-small cell lung cancer (NSCLC) patients but at the cost of increasing the occurrence of recurrent laryngeal nerve injury. Technology should be improved to protect the recurrent laryngeal nerve (RLN) during surgery. METHODS: NSCLC patients who underwent video-assisted thoracic surgery (VATS) surgical treatment by the same surgeon at our hospital from January 2016 to December 2017 were included as the research subjects and were divided into an energy-device group and a non-energy-device group. Their procedures included anatomic pulmonary resection, normative N1 dissection, and systemic N2 dissection. RESULTS: The rate of metastatically involved recurrent laryngeal nerve lymph nodes (RLNLNs) was 5.19% (39/752). Dissection device, side of primary, FEV1, operative time and BMI were independent predictors of recurrent laryngeal nerve injury (RLNI) (hazard ratio (HR) = 3.576, 95% confidence interval (CI): 1.490-8.583, P = 0.004; HR = 0.175, 95% CI: 0.072-0.424, P = < 0.001; HR = 3.008, 95% CI: 1.30-6.927, P = 0.010; HR = 0.328, 95% CI: 0.136-0.794, P = 0.013; HR = 0.344, 95%CI: 0.147-0.801, P = 0.013, respectively). Patients in the non-energy-device group had significantly less RLNI than the energy-device group (P = 0.016) and nearly half of the non-thermal RLNI recovered in 2 weeks (P = 0.025) whereas most thermal RLNI required 3 months for recovery. CONCLUSIONS: Every station of RLNLN had some degree of cancer metastasis in NSCLC patients and when dissecting RLNLNs, dissection device was an independent and artificially controlled predictor of RLNI. Using a non-energy device is a feasible method to protect the RLN as well as an improved recovery time of RLNI.

Rab27A promotes cellular apoptosis and ROS production by regulating the miRNA-124-3p/STAT3/RelA signalling pathway in ulcerative colitis.

Ulcerative colitis (UC) is a multifactorial inflammatory disease, and increasing evidence has demonstrated that the mechanism of UC pathogenesis is associated with excessive cellular apoptosis and reactive oxygen species (ROS) production. However, their function and molecular mechanisms related to UC remain unknown. In this study, Rab27A mRNA and protein were proven to be overexpressed in intestinal epithelial cells of UC patients and DSS-induced colitis mice, compared with control (P < 0.05). And Rab27A silencing inhibits inflammatory process in DSS-induced colitis mice (P < 0.05). Then, it was shown that knockdown of Rab27A suppressed apoptosis and ROS production through modulation of miR-124-3p, whereas overexpression of Rab27A promoted apoptosis and ROS production in LPS-induced colonic cells. In addition, enhanced expression of miR-124-3p attenuated apoptosis and ROS production by targeting regulation of STAT3 in LPS-induced colonic cells. Mechanistically, we found Rab27A reduced the expression and activity of miR-124-3p to activate STAT3/RelA signalling pathway and promote apoptosis and ROS production in LPS-induced colonic cells, whereas overexpression of miR-124-3p abrogated these effects of Rab27A. More importantly, animal experiments illustrated that ectopic expression of Rab27A promoted the inflammatory process, whereas overexpression of miR-124-3p might interfere with the inflammatory effect in DSS-induced colitis mice. In summary, Rab27A might modulate the miR-124-3p/STAT3/RelA axis to promote apoptosis and ROS production in inflammatory colonic cells, suggesting that Rab27A as a novel therapeutic target for the prevention and treatment of UC patients.

Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages.

BACKGROUND/AIMS: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion. METHODS: The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed. RESULTS: ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice. CONCLUSION: ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers.

Increased epoxyeicosatrienoic acids may be part of a protective mechanism in human ulcerative colitis, with increased CYP2J2 and reduced soluble epoxide hydrolase expression.

BACKGROUND: Previous preclinical evidence has suggested that the elevation of epoxyeicosatrienoic acids (EETs) derived from the cytochrome P450 (CYP) epoxygenases-dependent metabolism of arachidonic acid has important anti-inflammatory effects. However, the levels of EETs and their synthetic and metabolic enzymes in human ulcerative colitis has not been evaluated. METHOD: To evaluate EETs and the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), tissue biopsies were collected from 16 pairs of ulcerative colitis patients' tissues and matched with adjacent non-inflamed tissues. EETs were extracted from tissue homogenates and analyzed by liquid chromatography coupled with tandem mass spectrometry. RESULTS: The concentration of EETs was higher in ulcerative colitis tissues compared with matched adjacent non-inflamed tissues (1.91 ±â€¯0.98 ng/mg vs. 0.96 ±â€¯0.77 ng/mg, mean ±â€¯SD, P < 0.01). As shown by immunohistochemistry, sEH was present in the cytoplasm and intestinal mucosa and showed a decline in ulcerative colitis tissues compared with matched adjacent non-inflamed tissues. Western blot analyses showed reduced sEH expression in ulcerative colitis tissues compared with matched adjacent non-inflamed tissues, whereas CYP2J2 increased in ulcerative colitis tissues (P < 0.05). However, there was no statistically significant difference observed in CYP2C8 and CYP2C9 protein expression between them (P > 0.05). CONCLUSION: Our data suggest that the increase in EET levels may be part of a protective mechanism in ulcerative colitis. Furthermore, the concentration of EETs could be a key factor for drug therapy for ulcerative colitis.

Perineural invasion in colorectal cancer: mechanisms of action and clinical relevance.

BACKGROUND: In recent years, the significance of the nervous system in the tumor microenvironment has gained increasing attention. The bidirectional communication between nerves and cancer cells plays a critical role in tumor initiation and progression. Perineural invasion (PNI) occurs when tumor cells invade the nerve sheath and/or encircle more than 33% of the nerve circumference. PNI is a common feature in various malignancies and is associated with tumor invasion, metastasis, cancer-related pain, and unfavorable clinical outcomes. The colon and rectum are highly innervated organs, and accumulating studies support PNI as a histopathologic feature of colorectal cancer (CRC). Therefore, it is essential to investigate the role of nerves in CRC and comprehend the mechanisms of PNI to impede tumor progression and improve patient survival. CONCLUSION: This review elucidates the clinical significance of PNI, summarizes the underlying cellular and molecular mechanisms, introduces various experimental models suitable for studying PNI, and discusses the therapeutic potential of targeting this phenomenon. By delving into the intricate interactions between nerves and tumor cells, we hope this review can provide valuable insights for the future development of CRC treatments.

Long-term outcomes of 1-2 cm rectal neuroendocrine tumors after local excision or radical resection: A population-based multicenter study.

Objectives: Studies on rectal neuroendocrine tumors (R-NETs) that are 1-2 cm in size are limited, and the optimal treatment for these tumors is not well established. Methods: Data from patients with primary localized R-NETs 1-2 cm in size were retrospectively collected from 17 large-scale referral medical centers in China. Long-term prognosis, quality of life (QOL), and fecal incontinence were evaluated, and the effects of local excision (LE) or radical resection (RR) were elucidated using propensity score matching (PSM). Results: A total of 272 patients were included in this study; 233 underwent LE, and the remaining 39 underwent RR. Patients in the LE group showed lower tumor location, fewer postoperative Clavien-Dindo III-V complications, more G1 tumors, and lower tumor stage. There were no significant differences in the relapse-free survival or overall survival (OS) between the LE and RR groups after PSM. Patients in the LE group reported superior physical, role, emotional, social, and cognitive functions, global QOL, and Wexner fecal incontinence scores compared with those in the RR group (all P < 0.050). Eighteen (6.6%) patients had lymph node metastases. Multivariable analysis revealed that tumor location (odds ratio [OR] = 3.19, 95% confidence interval [CI] 1.04-10.07, P = 0.010), neutrophil-to-lymphocyte ratio (NLR) > 1.80 (OR = 4.50, 1.46-15.89, P = 0.012), and T3-T4 (OR = 36.31, 95% CI 7.85-208.62, P < 0.001) were independent risk factor for lymph node metastasis. Conclusions: R-NETs measuring 1-2 cm generally have a favorable prognosis, and there is no difference in postoperative survival between LE and RR. For patients without lymph node metastasis, LE should be the preferred choice; however, for patients with a higher tumor location, preoperative NLR >1.8 or T3/T4 tumors, RR should be considered.

The impact of indirect notification of a cancer diagnosis and a risk model based on it to predict the prognosis of postoperative stage T3 esophageal cancer patients.

Chinese doctors are required to inform patients' direct relatives of a cancer diagnosis rather than the patients themselves. The disease may be hidden from patients by their family members, which could result in severe outcomes. We selected postoperative T3 esophageal cancer (EsC) patients hospitalized from June 2015 to December 2019 as research subjects. The patients were divided into a direct-notification group and an indirect-notification group. Several variables were used to evaluate both groups' 36-month progress-free survival (PFS). A risk prediction model of prognosis based on the risk score was established, which was assessed using the area under the curve (AUC) of the receiver operating characteristic curve. One hundred and thirteen patients were enrolled in the training group and forty-eight in the validation group. Cox multivariate regression analysis revealed that males, late stage, poor pathological differentiation, and indirect notification were independent worse risk factors for postoperative T3 stage EsC patients at 36-month PFS (hazard ratio (HR) = 0.454, 95% confidence interval (CI): 0.254-0.812, P = .008; HR = 1.560, 95% CI: 1.006-2.420, P = .047; HR = 0.595, 95% CI: 0.378-0.936, P = .025; HR = 2.686, 95% CI: 1.679-4.297, P < 0.001, respectively). The type of notification was the best correlation factor. The risk score was calculated as follows: risk score = 0.988 × cancer notification (indirect = 1, direct = 0)-0.790 × sex (female = 1, Male = 0) + 0.445 × stage (IIIB = 1, IIA + IIB = 0)-0.519 × pathological differentiation (moderately + well = 1, poorly = 0). The model had a sensitivity of 64.8% and specificity of 81.8%, with the AUC at 0.717 (95% CI: 0.614-0.810) in internal verification, and a sensitivity of 56.8% and specificity of 100%, with the AUC at 0.705 (95% CI: 0.651-0.849) in external validation. The model had good internal and external stability. The model showed a Brier score of 0.18. Indirect notification of a cancer diagnosis was an important negative predictor of postoperative EsC patients' PFS. The model displayed good accuracy and stability in the prediction of risk for cancer progression.

Fungal dysbiosis facilitates inflammatory bowel disease by enhancing CD4+ T cell glutaminolysis.

The fungal microbiota is an important component of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation. However, how fungi regulate inflammatory bowel disease (IBD) is poorly understood. This study found that intestinal fungi regulate immune responses in IBD. Antibiotic-mediated depletion of fungi facilitated the development of IBD. Fungi greatly enhanced oxidative phosphorylation (OXPHOS) by enhancing glutaminolysis. Mechanistically, we found that fungi could activate the dectin-1-Syk- NF-κB signaling pathway to promote the expression of key enzymes and transporters involved in glutaminolysis. In summary, our findings reveal that fungal interactions in the human gut could be a promising therapeutic target for IBD.

LncRNA CACClnc promotes chemoresistance of colorectal cancer by modulating alternative splicing of RAD51.

Long non-coding RNAs (lncRNAs) play important roles in carcinogenesis. However, the effect of lncRNA on chemoresistance and RNA alternative splicing remains largely unknown. In this study, we identified a novel lncRNA, CACClnc, which was upregulated and associated with chemoresistance and poor prognosis in colorectal cancer (CRC). CACClnc promoted CRC resistance to chemotherapy via promoting DNA repair and enhancing homologous recombination in vitro and in vivo. Mechanistically, CACClnc specifically bound to Y-box binding protein 1 (YB1, a splicing factor) and U2AF65 (a subunit of U2AF splicing factor), promoting the interaction between YB1 and U2AF65, and then modulated alternative splicing (AS) of RAD51 mRNA, and consequently altered CRC cell biology. In addition, expression of exosomal CACClnc in peripheral plasma of CRC patients can effectively predict the chemotherapy effect of patients before treatment. Thus, measuring and targeting CACClnc and its associated pathway could yield valuable insight into clinical management and might ameliorate CRC patients' outcomes.

Nerve Dependence in Colorectal Cancer.

Cancerous invasion of nerves has been reported in a list of malignant tumors as a high-risk pathological feature and marker of poor disease outcome especially in neurotrophic cancers (such as in pancreas and prostate), indicating that although once neglected, nerves could have played a pivotal role in tumorigenesis and cancer progression. In colorectal cancer, perineural invasion, a specific form of tumor-nerve interaction referring to the identification of tumor cells in proximity to the nerve, has been recognized as a strong and independent prognosis predictor; denervation of autonomic nerves and enteric nerves have shown that the existence of these nerves in the gut are accompanied by promoted cancer proliferation, further supporting that nerve is a potential accomplice to shield and nurture tumor cells. However, the precise role of nerve in CRC and the pattern of interaction between CRC cells and nerve has not been unveiled yet. Here we aim to review some basic knowledge of the importance of nerves in CRC and attempt to depict a mechanistic view of tumor-nerve interaction during CRC development.