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Background: Transanal total mesorectal excision has emerged as a potential solution to certain limitations associated with laparoscopic total mesorectal excision in rectal cancer patients. Differences in surgical approaches have raised questions regarding their impact on the risk of postoperative urinary retention, with limited data available from large scale randomized clinical study. Objective: To report incidence of postoperative urinary retention and evaluate the associated risk factors for transanal total mesorectal excision. Design: In this randomized controlled trial (ClinicalTrials. gov NCT06147492), we retrieved 524 patients who received total mesorectal excision (TME) for stage I–III rectal cancer between June 2019 and April 2022, and the patients were randomly assigned in a 1:1 ratio to undergo either taTME or laTME. Patients: We enrolled 524 patients who underwent total mesorectal excision for stage I–III rectal cancer between June 2019 and April 2022. Main outcome measures: The incidence of postoperative urinary retention. Results: Among the 524 enrolled patients, 261 were randomized to the laTME group, while 263 were were randomized the taTME group. The median age was 58 years, and 340 participants (64.8 %) were male. Notably, 37 individuals (7.0 %) experienced postoperative urinary retention during the follow-up period, with no significant disparity was observed between the taTME and laTME groups (6.8 % and 7.2 %, respectively, P = 0.98). Risk factors associated with PUR in patients following taTME encompassed early removal of the urinary catheter (P = 0.006), net infusion rate >4.09 ml kg−1.h−1 (P = 0.006), and an age surpassing 65 years (P = 0.0321). Limitations: The generalizability of the findings outside specialist rectal cancer centers may be limited. Conclusions: Transanal total mesorectal excision was not found to heighten the risk of postoperative urinary retention. Nonetheless, it is advisable removing postoperative catheter beyond the initial day and exercising caution in the administration of intravenous fluids in clinical practice for taTME procedures.

Abstract Circular RNAs (circRNAs) play important roles in gastric cancer progression but the regulatory role of circRNAs in controlling macrophage function remains elusive. Exosomes serve as cargo for circRNAs and play a crucial role as mediators in facilitating communication between cancer cells and the tumor microenvironment. In this study, we found that circATP8A1, a previously unreported circular RNA, is highly expressed in both gastric cancer tissues and exosomes derived from plasma. Increased circATP8A1 was associated with advanced TNM stage and worse prognosis in patients with gastric cancer. We showed that the circATP8A1 knockdown significantly inhibited gastric cancer proliferation and invasion in vitro and in vivo. Functionally, exosome circATP8A1 induced the M2 polarization of macrophages through the STAT6 pathway instead of the STAT3 pathway. Mechanistically, circATP8A1 was shown to activate the STAT6 pathway through competitive binding to miR-1-3p, as confirmed by Fluorescence In Situ Hybridization (FISH), RNA immunoprecipitation, RNA pulldown, and Luciferase reporter assays. The reversal of circATP8A1-induced STAT6 pathway activation and macrophage polarization was observed upon blocking miR-1-3p. Macrophages treated with exosomes from gastric cancer cells overexpressing circATP8A1 were able to promote gastric cancer migration, while knockdown of circATP8A1 reversed these effects in vivo. In summary, exosome-derived circATP8A1 from gastric cancer cells induce macrophages M2 polarization via the circATP8A1/miR-1-3p/STAT6 axis, and tumor progression. Our results highlight circATP8A1 as a potential prognostic biomarker and therapeutic target in gastric cancer.

Abstract Background Adenosquamous carcinoma is a rare sub-type of colorectal cancer with a poor prognosis. Little is known about its clinicopathological and molecular characteristics in Asian populations. This study aimed to investigate these features in a cohort of patients with adenosquamous carcinoma in the colorectum. Methods Tumor cases pathologically diagnosed with colorectal adenosquamous carcinoma were retrieved from the Sixth Affiliated Hospital, Sun Yat-sen University tissue archive between December 2012 and June 2020. Clinicopathological features, molecular characteristics, and oncology outcomes were analyzed. Results Among 18,139 cases of colorectal cancer, 11 were diagnosed with adenosquamous carcinoma, providing an incidence rate of 0.061%. The median overall survival (OS) was 14 months, and the expected 3-year OS rate was 29.6%. As of October 14, 2022, four cases had local recurrence and five had distant metastasis. KRAS gene mutations were found in four of seven patients (57.1%), and three out of eleven (27.3%) patients had mismatch repair-deficient (dMMR) tumors. Conclusions Adenosquamous carcinoma is associated with a poor prognosis. Compared to other sub-types of colorectal cancer, a higher proportion of patients with dMMR and KRAS mutations were observed. These findings suggested that more patients with adenosquamous carcinoma could benefit from targeted therapies, such as immunotherapy.

Abstract Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.

Background: The significance of Kirsten rat sarcoma viral oncogene (KRAS) mutation in colorectal cancer (CRC) is well established; yet, its association with KRAS expression and prognosis warrants further investigation. While high KRAS expression is commonly linked with poorer prognosis in other cancers, its role in CRC remains relatively understudied. Objective: To explore the correlation between KRAS expression, KRAS status, prognosis, and tumor-infiltrating T lymphocyte density in CRC. Design: Single-center retrospective study. Methods: Conducted between 2010 and 2020, this study utilized tumor samples to assess KRAS expression and quantify CD3+/CD8+ T lymphocytes. The Cox proportional hazards model and linear regression analysis were employed to examine the relationship between KRAS expression, prognosis, and tumor-infiltrating T lymphocytes. Results: This study included 265 CRC patients who underwent radical surgery. No significant association was observed between KRAS expression and KRAS status ( p > 0.05). High KRAS expression was associated with poorer overall survival and disease-free survival ( p 0.05). Notably, KRAS expression showed a negative correlation with the density of CD8+ T lymphocytes in tumor tissue ( p

Summary: Circular RNAs (circRNAs) are crucial regulators of β-cell function and are involved in lipotoxicity-induced β-cell damage in type 2 diabetes mellitus (T2DM). We previously identified that circGlis3, a circRNA derived from exon 4 of the diabetes susceptibility gene Glis3, was upregulated in lipotoxic β cells. However, the functional role and molecular mechanism of circGlis3 in β cells remain largely unknown. Here, we revealed that the splicing factor CUGBP Elav-Like Family Member 1 (CELF1) facilitated the biogenesis of circGlis3. Moreover, we established a transgenic mouse model and confirmed that the overexpression of circGlis3 impaired β-cell function. Mechanistically, circGlis3 bound to heterogeneous nuclear ribonucleoprotein F (hnRNPF) and blocked its nuclear translocation, thereby reducing Sirt1 levels. Additionally, circGlis3 encoded a 348aa protein that interacted with GLIS3 and inhibited its transcriptional activity. Our data uncover a critical role of circGlis3 in β-cell dysfunction, suggesting that circGlis3 may be a potential therapeutic target for T2DM.

Abstract Objectives Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T‐lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically ‘hot’ TB remain poorly understood. Methods We quantified the number of TB by haematoxylin–eosin (H&E) sections and the densities of CD3+ and CD8+ T‐lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T‐lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB‐positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed. Results In a CRC cohort of 351 cases, low‐grade TB was associated with high CD3+ and CD8+ T‐cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB‐grade and T‐lymphocyte infiltration. In 278 TB‐positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low‐grade TB and positively associated with high CD3+ and CD8+ T‐cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease‐free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T‐lymphocyte infiltration. Conclusions KRT17 can be employed as a new indicator for distinguishing different immunological TBs.

Abstract The Fe–Sn-based kagome compounds attract intensive attention due to its attractive topological transport and rich magnetic properties. Combining experimental data, first-principles calculations, and Calphad assessment, thermodynamic and topological transport properties of the Fe–Sn system were investigated. Density functional theory (DFT) calculations were performed to evaluate the intermetallics’ finite-temperature heat capacity (C p ). A consistent thermodynamic assessment of the Fe–Sn phase diagram was achieved by using the experimental and DFT results, together with all available data from previous publications. Here, we report that the metastable phase Fe3Sn was introduced into the current metastable phase diagram, and corrected phase locations of Fe5Sn3 and Fe3Sn2 under the newly measured corrected temperature ranges. Furthermore, the anomalous Hall conductivity and anomalous Nernst conductivity of Fe3Sn were calculated, with magnetization directions and doping considered as perturbations to tune such transport properties. It was observed that the enhanced anomalous Hall and Nernst conductivities originate from the combination of nodal lines and small gap areas that can be tuned by doping Mn at Fe sites and varying magnetization direction.

The Au-28Ge (at%) eutectic alloy is a high-performance solder with a melting point of 361 °C. However, the brittle interfacial reaction products layer formed between the Au–Ge solder and substrate (Cu or Ni) is always the weak region. Hence, the joint fails at a relatively low shear strength (∼53 MPa). Here, the Cu–Ni alloys (Ni content is 20, 50, or 70 at%) are designed as the substrates to connect with the Au–Ge eutectic at 400 °C. A classic example is represented by the Au–Ge/Cu20Ni joint, which achieves a shear strength of above 100 MPa after soldering at 400 °C for 10–20 min. Microstructure characterization reveals that a face-centered cubic structured solid solution (FCC) layer forms at the Au–Ge/Cu20Ni joint. In contrast, it is mainly the NiGe or Ni2Ge layer in the Au–Ge/Cu50Ni and Au–Ge/Cu70Ni joints. On the one hand, compared to the brittle intermetallic compound products layer, the FCC layer shows adequate ductility, releasing the local strain incompatibility via pronounced local plastic deformation. On the other hand, the fine NiGe and Ni2Ge precipitation and fine grains make the FCC layer stronger than the solder matrix. Therefore, this products layer is no longer the weak region in the solder joint. As a result, the Au–Ge/Cu20Ni joint achieves outstanding shear strength. This study enriches our fundamental understanding of producing ductile phases to enhance the shear strength of the solder joints by designing alloy substrates.

Abstract High lymphocyte infiltration and immunosuppression characterize the tumor microenvironment (TME) in renal cell carcinoma (RCC). There is an urgent need to elucidate how tumor cells escape the immune attack and to develop novel therapeutic targets to enhance the efficacy of immune checkpoint blockade (ICB) in RCC. Overactivated IFN‐γ‐induced JAK/STAT signaling involves in such TME, but the underlying mechanisms remain elusive. Here, EH domain‐binding protein 1‐like protein 1 (EHBP1L1) is identified as a crucial mediator of IFN‐γ/JAK1/STAT1/PD‐L1 signaling in RCC. EHBP1L1 is highly expressed in RCC, and high EHBP1L1 expression levels are correlated with poor prognosis and resistance to ICB. EHBP1L1 depletion significantly inhibits tumor growth, which is attributed to enhanced CD8+ T cell‐mediated antitumor immunity. Mechanistically, EHBP1L1 interacts with and stabilizes JAK1. By competing with SOCS1, EHBP1L1 protects JAK1 from proteasomal degradation, which leads to elevated JAK1 protein levels and JAK1/STAT1/PD‐L1 signaling activity, thereby forming an immunosuppressive TME. Furthermore, the combination of EHBP1L1 inhibition and ICB reprograms the immunosuppressive TME and prevents tumor immune evasion, thus significantly reinforcing the therapeutic efficacy of ICB in RCC patient‐derived xenograft (PDX) models. These findings reveal the vital role of EHBP1L1 in immune evasion in RCC, which may be a potential complement for ICB therapy.

Abstract The roles of oncogenic KRAS in tumor immune evasion remain poorly understood. Here, mutant KRAS is identified as a key driver of tumor immune evasion in colorectal cancer (CRC). In human CRC specimens, a significant reduction in cytotoxic CD8+ T‐cell tumor infiltration is found in patients with mutant versus wild type KRAS. This phenomenon is confirmed by preclinical models of CRC, and further study showed KRAS mutant tumors exhibited poor response to anti‐PD‐1 and adoptive T‐cell therapies. Mechanistic analysis revealed lactic acid derived from mutant KRAS‐expressing tumor cells sensitized tumor‐specific cytotoxic CD8+ T‐cells to activation‐induced cell death via NF‐κB inactivation; this may underlie the inverse association between intratumoral cytotoxic CD8+ T‐cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by inhibiting KRAS or blocking lactic acid production. Together, this work suggests the KRAS‐mediated immune program is an exploitable therapeutic approach for the treatment of patients with KRAS mutant CRC.

Background: Approximately 15–30% of locally advanced rectal cancer (LARC) patients achieved pathological complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) and total mesorectal excision, but the clinical significance of adjuvant chemotherapy (ACT) for pCR patients remains unclear. Objectives: To determine whether LARC pCR patients can benefit from the administration of ACT. Design: Single center retrospective study. Methods: This study retrospectively included 280 LARC patients who achieved pCR after CRT and surgery from 2011 to 2019. The information of patients was recorded. Main outcome measures included 5-year disease-free survival (DFS) and 5-year overall survival. Subgroup analysis was conducted on whether pCR patients with acellular mucin pools received ACT or not. Results: A total of 74/280 (26.4%) patients were identified with acellular mucin pools. Disease recurrence occurred in 38/280 (13.6%) patients, and in the subgroup of patients with acellular mucin pools, 15/74 (20.3%) patients developed distant metastases. The existence of acellular mucin pools was associated with worse DFS (79.7% versus 88.8%, P = 0.037). Among pCR patients with acellular mucin pools, 9/25 (36.0%) of non-ACT patients occurred recurrence, and ACT was beneficial for improving DFS (hazard ratio: 0.245; 95% confidence interval: 0.084–0.719; P = 0.010). Conclusions: The existence of acellular mucin pools may represent a sign of invasive tumor biology, which indicated a negative prognosis. ACT can improve the prognosis of patient with acellular mucin pools, so ACT should be considered for them.

Background: Deficient mismatch repair (dMMR) or microsatellite instability is one of the well-established molecular biomarkers in colorectal cancer (CRC). The efficiency of neoadjuvant chemotherapy (NAC) in locally advanced colorectal cancer (LACC) patients with dMMR is unclear. Objectives: We assessed the tumor response and clinical outcome in LACC patients with dMMR received NAC. Design: Retrospective, single-center analysis. Methods: From 2013 to 2018, a total of 577 LACC patients with dMMR who underwent radical surgery were identified. Among them, 109 patients who received adjuvant chemotherapy were further screened out for analysis. According to whether receiving NAC or not, 109 patients were divided into two groups with the purpose of retrospectively analyzing their characteristics, treatment, and survival results, especially the 5-year disease-free survival (DFS) and 5-year overall survival. Results: Baseline characteristics were matched between the two groups. One of 40 patients in NAC group recurred, while 13 of 69 patients in non-NAC group recurred. Univariate and multivariate analyses showed that NAC (hazard ratio: 0.115; 95% confidence interval: 0.015–0.897; p = 0.039) was independent influence factor for DFS. In NAC group, there were 13/40 (32.5%) patients for tumor regression grade 1 and 27/40 (67.5%) patients converted clinical positive N-stage into negative N-stage. Conclusion: In this study, NAC was associated with better tumor downstaging and longer 5-year DFS in LACC patients with dMMR. Consequently, NAC might be an additional treatment choice when it comes to such patients in the future.

Adipose‐derived stem cells (ADSCs) play a vital role in colorectal cancer (CRC) progression, but the mechanism remains largely unknown. Herein, we found that ADSCs isolated from CRC patients produced more cysteine‐rich 61 (Cyr61) than those from healthy donors, and the elevated serum Cyr61 levels were associated with advanced TNM stages. Moreover, serum Cyr61 displayed a better diagnostic value for CRC compared to carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19‐9). Mechanistically, integrin αVβ5 was identified as the functional receptor by which Cyr61 promotes CRC cell metastasis in vitro and in vivo by activating the αVβ5/FAK/NF‐κB signaling pathway. In addition, Cyr61 promotes vasculogenic mimicry (VM) formation, thereby promoting tumor growth and metastasis through a αVβ5/FAK/HIF‐1α/STAT3/MMP2 signaling cascade. Histologically, xenografts and clinical samples of CRC both exhibited VM, which was correlated with HIF‐1α and MMP2 activation. Notably, we demonstrated the synergistic effect of combined anti‐VM therapy (integrin αVβ5 inhibitor) and anti‐VEGF therapy (bevacizumab) in patient‐derived xenograft models. Further investigation showed that CRC cell‐derived exosomal STAT3 promoted Cyr61 transcription in ADSCs. These findings indicate that Cyr61 derived from ADSCs plays a critical role in promoting CRC progression via integrin αVβ5 and provides a novel antitumor strategy by targeting Cyr61/αVβ5.

Background. Since Sylla and Lacy successfully reported the transanal total mesorectal excision in 2010, taTME was considered to have the potential to overcome some problematic laparoscopic cases in male, low advanced rectal cancer. However, the evidence is still lacking. This study compared the short and long outcomes of taTME with laTME in these “challenging” patients to explore the advantages of taTME among the patients. Method. After propensity score matching analysis, 106 patients were included in each group from 325 patients who met the including standard. Statistical analysis was used to compare the differences of perioperative outcomes, histopathological results, and survival results between taTME and laTME groups. Results. The mean time of pelvic operation in the taTME group was significantly shorter than in the laTME group (62.2±14.2 mins vs 81.1±18.9 mins, P=0.003). The complication incidence rate and the rate of protective loop ileostomy in the taTME group were significantly lower than those in the laTME group (19.8% vs 38.7%, P=0.003 and 70.8% vs 92.5%, P

Background: Transanal total mesorectal resection (taTME) has recently emerged as a promising surgical approach for the treatment of mid-low rectal cancer. However, there is limited evidence on the long-term survival outcomes associated with taTME. This retrospective study aimed to compare the overall survival (OS), disease-free survival (DFS), and cancer-specific survival of taTME and laparoscopic TME (laTME) in patients with mid-low rectal cancer. Materials and Methods: From July 2014 to June 2022, a total of 3627 patients were identified from two prospective cohorts: the laparoscopic rectal surgery cohort and the CNTAES cohort. To balance the baseline characteristics between the taTME and laTME groups, propensity score matching (PSM) was performed. Results: A total of 2502 patients were included in the study. Prior to PSM, the laTME group comprised 1853 patients, while the taTME group comprised 649 patients. The 5-year OS (82.9% vs. 80.4%, P=0.202) and 5-year DFS (74.4% vs. 72.5%, P=0.167) were comparable between the taTME and laTME groups. After PSM, the taTME group showed no statistically significant difference in the 5-year OS (83.1% vs. 79.2%, P=0.101) and 5-year DFS (74.8% vs. 72.1%, P=0.135) compared to the laTME group. Subgroup analysis further suggested that taTME may potentially reduce the risk of death [hazard ratio 0.652; (95% CI, 0.452-0.939)] and disease recurrence [hazard ratio 0.736; (95% CI, 0.562-0.965)] specifically in patients with low rectal cancer. Conclusion: In this study, taTME demonstrated comparable oncologic safety to laTME in patients with mid-low rectal cancer. Moreover, the results indicate that taTME may confer potential survival benefits for patients with low rectal cancer. [ABSTRACT FROM AUTHOR]

Background: Transanal total mesorectal excision (taTME) is a novel approach to radical surgery for low rectal cancer; however, it is not clear whether taTME causes a more severe inflammatory stress response than laparoscopic total mesorectal excision (laTME). Therefore, the authors conducted this study to address this question, with the secondary objective of analyzing the predictive effect of inflammatory indexes on postoperative infective complications between laTME and taTME. Methods: A total of 545 cases of laTME and 544 cases of taTME from the TaLaR randomized controlled trial were included. Inflammatory stress response was assessed via C-reactive protein (CRP), white blood cell count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, and prognostic nutritional index. Inflammatory indexes were measured and calculated preoperatively (t1) and on postoperative days one (t2) and seven (t3). The accuracy of inflammatory indexes as predictor of infective complications was evaluated by areas under the receiver operating characteristic curve. Results: Preoperative blood parameters were comparable between the two surgical methods. There were no significant differences in CRP, white blood cell count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, or prognostic nutritional index between the two surgical methods at any time point (P>0.05). Among the inflammatory indexes at three time points, CRP on the first postoperative day was the most accurate predictor of infective complications, which is suitable for two surgical methods. The AUC was 0.7671 (P <0.0001) with a cutoff of 39.84 mg/l, yielding 94% sensitivity and 47% specificity. Conclusions: Compared with laTME, taTME surgery has no obvious disadvantage with respect to the postoperative inflammatory stress response. In addition, inflammatory indexes were favorable in predicting infective complications, with the best results for CRP on the first postoperative day. Defining the specific predictors for laTME and taTME is unnecessary. [ABSTRACT FROM AUTHOR]