Acetylation of ELMO1 correlates with Rac1 activity and colorectal cancer progress.

Acetylation, a critical regulator of diverse cellular processes, holds significant implications in various cancer contexts. Further understanding of the acetylation patterns of key cancer-driven proteins is crucial for advancing therapeutic strategies in cancer treatment. This study aimed to unravel the acetylation patterns of Engulfment and Cell Motility Protein 1 (ELMO1) and its relevance to the pathogenesis of colorectal cancer (CRC). Immunoprecipitation and mass spectrometry precisely identified lysine residue 505 (K505) as a central acetylation site in ELMO1. P300 emerged as the acetyltransferase for ELMO1 K505 acetylation, while SIRT2 was recognized as the deacetylase. Although K505 acetylation minimally affected ELMO1's localization and stability, it played a crucial role in mediating ELMO1-Dock180 interaction, thereby influencing Rac1 activation. Functionally, ELMO1 K505 acetylation proved to be a pivotal factor in CRC progression, exerting its influence on key cellular processes. Clinical analysis of CRC samples unveiled elevated ELMO1 acetylation in primary tumors, indicating a potential association with CRC pathologies. This work provides insights into ELMO1 acetylation and its significance in advancing potentially therapeutic interventions in CRC treatment.

MRI-defined T3, clear mesorectal fascia mid-low rectal cancer: is neoadjuvant treatment necessary?

AIM: Neoadjuvant treatments (nCRT) are becoming the standard treatment for patients with stage II or III mid-low rectal cancer. Recently, some studies have shown that surgery alone may be sufficient for patients with T3 rectal cancer. This raises the question of whether nCRT is necessary for all patients with T3 rectal cancer. Therefore, this study compared the clinical outcomes of patients with MRI-defined T3, clear MRF mid-low rectal cancer treated with surgery alone (TME group) or nCRT followed by surgery (nCRT + TME group). METHODS: A total of 1509 patients were enrolled in this study. After a 1:1 propensity score matching analysis, 480 patients were included in each group. The primary endpoint was 3-year disease-free survival (DFS). The secondary endpoints included the perioperative outcomes, histopathologic outcomes, and other follow-up outcomes. RESULTS: nCRT had advantages in rates of sphincter-preserving surgery and tumor downstaging, but it was accompanied by a higher rate of enterostomies. At 3 years after surgery, local recurrence occurred in 3.3% of patients in the TME group and in 3.5% of patients in the nCRT + TME group (P = 0.914), the DFS rates were 78.3% in the TME group and 75.3% in the nCRT + TME group (P = 0.188), and the overall survival rates were 90.3% in the TME group and 89.9% in the nCRT + TME group (P = 0.776). CONCLUSIONS: Surgery alone versus nCRT followed by surgery may provide similar long-term oncological outcomes for patients with MRI-defined T3, clear MRF, and mid-low rectal cancer. nCRT may cause overtreatment in some patients.

A novel protein encoded by circINSIG1 reprograms cholesterol metabolism by promoting the ubiquitin-dependent degradation of INSIG1 in colorectal cancer.

BACKGROUND: Hypoxia is a hallmark of solid tumors and leads to the metabolic reprogramming of cancer cells. The role of epigenetic regulation between hypoxia and aberrant cholesterol metabolism in colorectal cancer (CRC) remains elusive. METHODS: Hypoxia-responsive circular RNAs (circRNAs) were identified by high throughput RNA sequencing between CRC cells cultured under normoxia or hypoxia. The protein-coding potential of circINSIG1 was identified by polysome profiling and LC-MS. The function of circINSIG1 was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses. RESULTS: A novel hypoxia-responsive circRNA named circINSIG1 was identified, which was upregulated in CRC tissues and correlated with advanced clinical stages and poor survival. Mechanistically, circINSIG1 encoded a 121 amino acid protein circINSIG1-121 to promote K48-linked ubiquitination of the critical cholesterol metabolism regulator INSIG1 at lysine 156 and 158 by recruiting CUL5-ASB6 complex, a ubiquitin E3 ligase complex, thereby inducing cholesterol biosynthesis to promote CRC proliferation and metastasis. The orthotopic xenograft tumor models and patient-derived xenograft models further identified the role of circINSIG1 in CRC progression and potential therapeutic target of CRC. CONCLUSIONS: circINSIG1 presents an epigenetic mechanism which provides insights into the crosstalk between hypoxia and cholesterol metabolism, and provides a promising therapeutic target for the treatment of CRC.

Engulfment and cell motility protein 1 fosters reprogramming of tumor-associated macrophages in colorectal cancer.

Functional reprogramming of tumor-associated macrophages (TAMs) is crucial to their potent tumor-supportive capacity. However, the molecular mechanism behind the reprogramming process remains poorly understood. Here, we identify engulfment and cell motility protein 1 (ELMO1) as a crucial player for TAM reprogramming in colorectal cancer (CRC). The expression of ELMO1 in stromal but not epithelial tumor cells was positively associated with advanced clinical stage and poor disease-free survival in CRC. An increase in ELMO1 expression was specifically found in TAMs, but not in other multiple nonmalignant stromal cells. Gain- and loss-of-function assays indicated ELMO1 reprogrammed macrophages to a TAM-like phenotype through Rac1 activation. In turn, ELMO1-reprogrammed macrophages were shown to not only facilitate the malignant behaviors of CRC cells but exhibited potent phagocytosis of tumor cells. Taken together, our work underscores the importance of ELMO1 in determining functional reprogramming of TAMs and could provide new insights on potential therapeutic strategies against CRC.

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.

Effects of high-heeled shoes on lower extremity biomechanics and balance in females: a systematic review and meta-analysis.

BACKGROUND: High-heeled shoes (HHS) are widely worn by women in daily life. Limited quantitative studies have been conducted to investigate the biomechanical performance between wearing HHS and wearing flat shoes or barefoot. This study aimed to compare spatiotemporal parameters, kinematics, kinetics and muscle function during walking and balance between wearing HHS and flat shoes or barefoot. METHODS: According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, PubMed Medline, Cochrane, EMBASE, CINAHL Complete and Web of Science databases were searched from the earliest record to December 2021. A modified quality index was applied to evaluate the risk of bias, and effect sizes with 95% confidence intervals were calculated as the standardized mean differences (SMD). Potential publication bias was evaluated graphically using funnel plot and the robustness of the overall results was assessed using sensitivity analyses. RESULTS: Eighty-one studies (n = 1501 participants) were included in this study. The reduced area of support requires the body to establish a safer and more stable gait pattern by changing gait characteristics when walking in HHS compared with walking in flats shoes or barefoot. Walking in HHS has a slight effect on hip kinematics, with biomechanical changes and adaptations concentrated in the knee and foot-ankle complex. Females wearing HHS performed greater ground reaction forces earlier, accompanied by an anterior shift in plantar pressure compared with those wearing flat shoes/barefoot. Furthermore, large effect sizes indicate that wearing HHS resulted in poor static and dynamic balance. CONCLUSION: Spatiotemporal, kinematic, kinetic and balance variables are affected by wearing HHS. The effect of specific heel heights on women's biomechanics would benefit from further research.

Validity of IMU measurements on running kinematics in non-rearfoot strike runners across different speeds.

This study aims to determine the validity of the lower extremity joint kinematics measured by inertial measurement units (IMUs) in non-rearfoot strike pattern (NRFS) runners across different speeds. Fifteen NRFS runners completed three 2-min running tests on a treadmill in random order at 8, 10 and 12 km/h, whilst data were synchronously collected using the IMU system and an optical motion capture system. Before the offset was corrected, the validity of the knee angle waveform was higher than that of the hip and ankle; after the offset was corrected, the validity increased in all three joints. The correlation between the touchdown angles in the sagittal plane measured by the two systems was relatively high after the offset was corrected. The running speed influenced the offset-corrected measurements, with higher error values at higher speeds. The IMU system was able to provide measurements of running kinematics in the sagittal plane of NRFS runners at different running speeds but was unable to reliably measure motion in the frontal and horizontal planes. Future research should analyse the 3D gait of NRFS runners under a larger range of speed conditions to provide evidentiary support for the use of IMUs in running analysis outside the laboratory.

Coping response and family communication of cancer risk in men harboring a BRCA mutation: A mixed methods study.

OBJECTIVE: Providing genetic counseling and genetic testing to at-risk blood relatives (cascade screening) is important for improving BRCA cancer outcomes. Intra-familial communication of risk is critical for cascade screening efforts yet relatively little is known about men's role in communicating BRCA risk. We sought to examine men's coping response to their BRCA status and intra-familial communication of risk to inform the development of tailored interventions that could promote cascade screening. METHODS: We employed a sequential mixed-methods design. First, we measured coping response (quantitative) using the Multidimensional Impact of Cancer Risk Assessment (MICRA). MICRA scores were compared between BRCA+ men, BRCA- men and BRCA+ women. Subsequently, we used template analysis to analyze qualitative interviews exploring coping and intra-familial communication of risk. The Theory of Planned Behavior (TPB) served as a guiding framework for identifying intervention targets. RESULTS: BRCA+ men (n = 36) had significantly higher levels of distress (p < 0.001), uncertainty (p < 0.001) and negative experiences (p < 0.05) compared to BRCA- male counterparts (n = 23). BRCA+ men had significantly lower distress (p < 0.001) and uncertainty (p < 0.001) than BRCA+ women (n = 406). Qualitative analysis of in-depth interviews with BRCA+ men (n = 35) identified promoters and barriers to active coping response and intra-familial communication of risk. Mapping results onto the TPB identified targets for tailoring person-centered approaches for men addressing beliefs/attitude, subjective norms, and perceived behavioral control. CONCLUSIONS: Men and women appear to have different coping responses to learning their BRCA status. Developing tailored (sex-based), theory informed interventions may help promote intra-familial communication of BRCA risk and support cascade screening.

Three-year outcomes of transanal total mesorectal excision versus standard laparoscopic total mesorectal excision for mid and low rectal cancer.

INTRODUCTION: Since transanal total mesorectal excision (taTME) was introduced, it has become an important topic in rectal cancer treatment. Many previous studies reported positive relevant short-term results, histopathological results, and associated complications. Recently, concerns regarding the oncological safety of taTME have been raised due to reports showing high local recurrences (LR) rates. Therefore, this study aimed to compare the 3-year outcomes between taTME and laparoscopic total mesorectal excision (laTME) for mid-low rectal cancer. METHODS: A total of 104 patients who underwent taTME were matched with 208 patients treated by laTME. The primary endpoint was 3-year LR rate; secondary endpoints in this matched-cohort study included the perioperative outcomes and histopathological outcomes. RESULTS: taTME was associated with lower permanent ostomy rate (1% vs 13.5%) and lower conversion rate (0% vs 3.4%) compared to laTME. A similar quality of resected specimens was detected for each group. In both groups, the local recurrence rate was 3.8%. Within 3 years after surgery, the disease-free survival (DFS) rates were 78.8% in the taTME group and 76.9% in the laTME group (P = 0.640), while the overall survival (OS) rates were 93.3% in the taTME group and 89.9% in the laTME group (P = 0.327). CONCLUSION: No significant differences regarding 3-year local recurrence rate (3.8%) were observed in the taTME group compared to laTME group.

Enhanced Water Solubility and Anti-Tumor Activity of Oleanolic Acid through Chemical Structure Modification.

Cancer has been a major health problem in the world in the past decades. It is urgent to develop new, effective and safe drugs for the treatment of cancer. There are many pentacyclic triterpenoids with positive anti-tumor activity and safety in nature. Oleanolic acid (OA), as one of the pentacyclic triterpenoids, also has broad biological activities including liver protection, anti-inflammatory, hypoglycemic, antiviral and anti-tumor. Therefore, to investigate its anti-tumor activity and mechanism, many OA derivatives have been developed. Some derivatives are less toxic to normal hepatocytes, which may be due to the strong liver protection ability of OA. However, the poor water solubility of OA is one of the main reasons for the weak anti-tumor activity. It is reported that some OA derivatives could enhance solubility by chemically linking some hydrophilic groups to improve anti-tumor activity. This review not only summarizes the highly water-soluble OA derivatives that can improve anti-tumor activity reported in recent years, but also introduces their possible anti-tumor mechanisms.

A novel NF-κB regulator encoded by circPLCE1 inhibits colorectal carcinoma progression by promoting RPS3 ubiquitin-dependent degradation.

BACKGROUND: Constitutive activation of nuclear factor-κB (NF-κB) signaling plays a key role in the development and progression of colorectal carcinoma (CRC). However, the underlying mechanisms of excessive activation of NF-κB signaling remain largely unknown. METHODS: We used high throughput RNA sequencing to identify differentially expressed circular RNAs (circRNAs) between normal human intestinal epithelial cell lines and CRC cell lines. The identification of protein encoded by circPLCE1 was performed using LC-MS. The function of novel protein was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses. RESULTS: A novel protein circPLCE1-411 encoded by circular RNA circPLCE1 was identified as a crucial player in the NF-κB activation of CRC. Mechanistically, circPLCE1-411 promoted the ubiquitin-dependent degradation of the critical NF-κB regulator RPS3 via directly binding the HSP90α/RPS3 complex to facilitate the dissociation of RPS3 from the complex, thereby reducing NF-κB nuclear translocation in CRC cells. Functionally, circPLCE1 inhibited tumor proliferation and metastasis in CRC cells, as well as patient-derived xenograft and orthotopic xenograft tumor models. Clinically, circPLCE1 was downregulated in CRC tissues and correlated with advanced clinical stages and poor survival. CONCLUSIONS: circPLCE1 presents an epigenetic mechanism which disrupts NF-κB nuclear translocation and serves as a novel and promising therapeutic target and prognostic marker.

Transanal Total Mesorectal Excision in Mid-Low Rectal Cancer: Evaluation of the Learning Curve and Comparison of Short-term Results With Standard Laparoscopic Total Mesorectal Excision.

BACKGROUND: Ever since transanal total mesorectal excision was introduced by Sylla and Lacy in 2010, it has become more popular among colorectal surgeons. However, some surgeons hesitate to use it, because this novel approach differs greatly from laparoscopic total mesorectal excision and requires a long learning curve. OBJECTIVE: This study analyzed the learning curve of transanal total mesorectal excision procedure and compared the different phases of transanal total mesorectal excision with laparoscopic total mesorectal excision. DESIGN: This is retrospective case-control study. SETTINGS: We used data from the approved colorectal cancer database of the Sixth Affiliated Hospital of Sun Yat-sen University. PATIENTS: The patients involved in this study underwent transanal total mesorectal excision performed by a single surgeon (L.K.) or underwent laparoscopic transanal total mesorectal excision performed by experienced surgeons. INTERVENTIONS: Transanal or laparoscopic resection of mid-low rectal cancer was conducted. MAIN OUTCOMES MEASURES: Perioperative complication and resection margin were measured. RESULTS: A total of 342 patients were included in both groups. The learning curve of transanal total mesorectal excision was divided into 3 phases. Data show that demographics and tumor characteristics were not significantly different between the matched groups. Indeed, during phase 1, only operative time was longer than in the laparoscopic group, whereas, during phase 2, results from the transanal group were comparable with the laparoscopic group. Results show that, during phase 3, operative time, intraoperative blood loss, and postoperative hospital stay were all lower than in the laparoscopic group. Local recurrence occurred in 3 patients during phase 1 and in 1 patient during phase 2. LIMITATIONS: This study was a small retrospective study and focused on just 1 surgeon performing transanal total mesorectal excision. CONCLUSIONS: Short-term and histopathologic outcomes are similar compared between a transanal group and matched laparoscopic group. Transanal total mesorectal excision also provided good oncologic outcomes. See Video Abstract at http://links.lww.com/DCR/B450. ESCISIN MESORRECTAL TOTAL TRANSANAL EN EL CNCER DE RECTO MEDIOBAJO EVALUACIN DE LA CURVA DE APRENDIZAJE Y COMPARACIN DE RESULTADOS A CORTO PLAZO CON TME LAPAROSCPICA ESTNDAR: ANTECEDENTES:Desde que Sylla y Lacy introdujeron la escisión mesorrectal total transanal en 2010, se ha vuelto más popular entre los cirujanos colorrectales. Sin embargo, algunos cirujanos dudan en utilizarlo, porque este nuevo método difiere mucho de la escisión mesorrectal total laparoscópica y requiere una larga curva de aprendizaje.OBJETIVO:Este estudio analizó la curva de aprendizaje del procedimiento de escisión mesorrectal total transanal y comparó las diferentes fases de la escisión mesorrectal total transanal con la escisión mesorrectal total laparoscópica.DISEÑO:Este es un estudio retrospectivo de casos y controles.ENTORNO CLINICO:Utilizamos base de datos de cáncer colorrectal aprobada del Sexto Hospital Afiliado de la Universidad Sun Yat-sen (Guangzhou, China).PACIENTES:Los pacientes involucrados en este estudio fueron sometidos a escisión mesorrectal total transanal realizada por un solo cirujano (LK) o se sometieron a escisión mesorrectal total transanal laparoscópica realizada por cirujanos experimentados.INTERVENCIONES:Resección transanal o laparoscópica de cáncer de recto medio-bajo.PRINCIPALES MEDIDAS DE VOLARCION:complicación perioperatoria y margen de resección.RESULTADOS:Se incluyó un total de 342 pacientes en ambos grupos. La curva de aprendizaje de la escisión mesorrectal total transanal se dividió en tres fases. Los datos muestran que las características demográficas y tumorales no fueron significativamente diferentes entre los grupos emparejados. De hecho, durante la fase 1, solo el tiempo operatorio fue más largo que en el grupo laparoscópico. Mientras que durante la fase 2, los resultados del grupo transanal fueron comparables a los del grupo laparoscópico. Los resultados muestran que durante la fase 3, el tiempo operatorio, la pérdida de sangre intraoperatoria y la estancia hospitalaria postoperatoria fueron menores que en el grupo laparoscópico. La recurrencia local ocurrió en 3 pacientes durante la fase 1 y en 1 paciente durante la fase 2.LIMITACIONES:Este estudio fue un estudio retrospectivo pequeño y se centró en un solo cirujano que realizaba la escisión mesorrectal total transanal.CONCLUSIÓN:Los resultados a corto plazo e histopatológicos son similares en comparación entre el grupo transanal y el grupo laparoscópico emparejado. La escisión mesorrectal total transanal también proporcionó buenos resultados oncológicos. Consulte Video Resumen en http://links.lww.com/DCR/B450.

Comparison of pathological outcomes after transanal versus laparoscopic total mesorectal excision: a prospective study using data from randomized control trial.

INTRODUCTION: Total mesorectal excision (TME) is the standard procedure for middle lower rectal cancer, and transanal total mesorectal excision (taTME) was founded as a valid alternative to the open and laparoscopic TME. The quality of the procedure performed is important for prognosis of patients. This study was designed to compare the pathological results of taTME with those of laparoscopic TME (laTME), based on the data from a randomized control trial (RCT: NCT02966483). METHODS: Between April 2016 and November 2018, all rectal cancer patients who underwent taTME or laTME in the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) and enrolled in the RCT were included in this study. The data from all participants were prospectively input in a standardized database. RESULTS: In total 128 patients were included in the taTME group and 133 patients were included in the laTME group. The demographics and tumor characteristics were not significantly different between the two group. T3 or N0 lesions were most common in both groups. The mesorectum specimen was complete or nearly complete in all patients. The positive distal resection margin (DRM) was detected in 2 (1.5%) cases in the laTME group versus no cases in the taTME group (P = 0.498), and the distance between the tumor and DRM in the taTME group (1.4 ± 1.1) may have the longer tendency than that in the laTME group (1.3 ± 0.9) (P = 0.745). The positive circumferential resection margin was detected in 2 cases in each group (P = 0.674). The median number of resected lymph nodes was 15.0 in taTME group versus 16.0 in the laTME group (P = 0.069). CONCLUSION: The pathological outcomes between transanal and laparoscopic total mesorectal excision are similar. The rate of positive resection margin could not be significant decreased, nonetheless the decrease trend could be shown.

Acute effects of athletic taping on arch deformity and plantar pressure in young female adults with flexible flatfoot.

OBJECTIVE: This work aimed to explore the acute effects of athletic taping techniques on foot arch deformity and plantar pressure in young female adults with flexible flatfoot (FFT). METHODS: Twenty young female adults with FFT were recruited in the current study. Each participant was randomly divided into two taping groups, namely, augmented low-dye (ALD) and modified low-dye (MLD). The foot arch deformity and plantar pressure were measured at baseline, after taping and after 20 min of walking. The foot arch deformity was determined based on navicular drop distance (NDD) and resting calcaneal stance position (RCSP). RESULTS: Compared with baseline, the NDD values were significantly lower after taping. After 20 min of walking, ALD taping resulted in a lower NDD value than MLD (p < 0.001). ALD maintained a higher RCSP than baseline after 20 min of walking (p = 0.004). Furthermore, compared with baseline, medial midfoot force-time integration (p = 0.013) and contact area (p = 0.022) increased after taping with MLD, and peak pressure in the medial midfoot increased after walking for 20 min with MLD (p = 0.026). Peak pressure in the second to fifth toes significantly decreased after 20 min of walking with ALD compared with that after taping immediately (p = 0.002). CONCLUSIONS: ALD and MLD taping could improve FFT arch deformity and plantar pressure distribution, prospectively changing peak pressure of the second to fifth toe area and medial midfoot after 20 min of walking, integrated contact area and force-time integration medial midfoot during walking in young female adults. Furthermore, ALD taping could improve FFT deformity more than using MLD after 20 min of walking. Thus, when treating FFT in young female adults, ALD taping should be considered adaptively to guide arch support production and correct midfoot pronation.

Long-term oncological outcomes of transanal versus laparoscopic total mesorectal excision for mid-low rectal cancer: a retrospective analysis of 2502 patients.

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.

circGlis3 promotes ß-cell dysfunction by binding to heterogeneous nuclear ribonucleoprotein F and encoding Glis3-348aa protein.

Circular RNAs (circRNAs) are crucial regulators of ß-cell function and are involved in lipotoxicity-induced ß-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 ß cells. However, the functional role and molecular mechanism of circGlis3 in ß 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 ß-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 ß-cell dysfunction, suggesting that circGlis3 may be a potential therapeutic target for T2DM.

High KRT17 expression in tumour budding indicates immunologically 'hot' tumour budding and predicts good survival in patients with colorectal cancer.

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.

Effects of a multicomponent physical activity programme, Mobility-Fit, compared with a standard care lower limb strengthening programme, to promote safe mobility among older adults in care facilities: protocol for a cluster randomised controlled trial.

INTRODUCTION: Upper limb and core strength training is essential for older adults to safely perform daily activities. However, existing exercise programmes mainly focus on lower limb strength and are not designed or delivered to suit people with different functional capacities. This study describes the design of a two-arm cluster randomised controlled trial to examine the effects of a multicomponent physical activity (PA) programme, Mobility-Fit, on mobility and frailty in older adults living in care facilities. METHODS AND ANALYSIS: 160 older adults from 20 care facilities in Hong Kong will be recruited and randomised by care facilities (1:1) to an intervention or a control group. Participants in the intervention group will attend the Mobility-Fit programme, led by facility-based instructors, three times per week, 45 min per session, for 12 weeks, while the control group will participate in a standard care lower limb strengthening programme offered by the care facility. Participants will then be followed up for 9 months. Mobility-Fit comprises agility, postural coordination, balance and strength training, with suitable dosage based on participant's baseline physical and cognitive function. The primary outcomes encompass upper and lower limb strength, trunk stability, reaction time, mobility function and fall efficacy. Secondary outcomes comprise daily PA level and performance, frailty, cognitive function and quality of life. A repeated measures analysis of variance (ANOVA) and generalised estimating equation (GEE) will be used to examine changes in outcomes over time and between groups. Data will be analysed following the intention-to-treat principles. We will also evaluate programme implementation and health economics throughout the follow-up period. ETHICS AND DISSEMINATION: Ethical approval was acquired in November 2022 from the Joint CUHK-NTEC Clinical Research Ethics Committee in Hong Kong (CREC-2022-459). Informed consent will be obtained from participants. The results of the study will be disseminated through peer-reviewed articles, conference presentations and social media. TRIAL REGISTRATION NUMBER: ChiCTR2300072709.

The relationship of KRAS expression with KRAS status, prognosis, and tumor-infiltrated T lymphocytes in colorectal cancer.

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). Subgroup analysis revealed that high KRAS expression remained indicative of a worse prognosis in the group with mismatch repair-deficient (dMMR) and KRAS mutant type (p < 0.05). Multivariate analysis confirmed KRAS expression as an unfavorable prognostic factor (p < 0.05). However, the significance of KRAS expression was lost in the dMMR and KRAS mutant-type group regarding overall survival (p > 0.05). Notably, KRAS expression showed a negative correlation with the density of CD8+ T lymphocytes in tumor tissue (p < 0.05), a finding also observed in the dMMR group (p < 0.05). Conclusion: No association was found between KRAS expression and KRAS mutation status in CRC. Higher KRAS expression was indicative of poorer prognosis for CRC patients, except for those with proficient mismatch repair and KRAS wild type. In addition, in patients with dMMR, KRAS expression was associated with a lower density of CD8+ T lymphocytes in tumor tissue.

Exploring the link between KRAS gene expression and outcomes in colorectal cancer patients: impact on survival, mutation status, and T lymphocyte levels 1. KRAS gene: A gene that, when mutated, can lead to the development and growth of colorectal cancer. The KRAS gene is part of a family of genes that help control cell growth and death. 2. T lymphocytes: A type of immune cell that plays a crucial role in the body's defense against infections and cancer. They can identify and kill cancer cells. 3. The study found that the level of activity of the KRAS gene in colorectal cancer patients did not change based on whether the KRAS gene was mutated or what type of mutation it had. 4. For patients with a specific type of colorectal cancer (dMMR) and those with mutations in the KRAS gene, high levels of KRAS gene activity were linked to a poorer outlook. Essentially, these patients had a harder time fighting the disease, and KRAS gene activity served as a warning sign for more challenging outcomes. 5. In patients with dMMR colorectal cancer, higher KRAS gene activity was associated with fewer CD8+ T lymphocytes in the tumor. CD8+ T lymphocytes are crucial immune cells that help fight cancer by attacking cancer cells. This means that in these patients, the body's natural defense against the tumor was weaker.

Glycolytic Activation of CD14+ Intestinal Macrophages Contributes to the Inflammatory Responses via Exosomal Membrane Tumor Necrosis Factor in Crohn's Disease.

BACKGROUND: Macrophage (Mφ) activation plays a critical role in the inflammatory response. Activated Mφ go through profound reprogramming of cellular metabolism. However, changes in their intracellular energy metabolism and its effect on inflammatory responses in Crohn's disease (CD) remain currently unclear. The aim of this study is to explore metabolic signatures of CD14+ Mφ and their potential role in CD pathogenesis as well as the underlying mechanisms. METHODS: CD14+ Mφ were isolated from peripheral blood or intestinal tissues of CD patients and control subjects. Real-time flux measurements and enzyme-linked immunosorbent assay were used to determine the inflammatory states of Mφ and metabolic signatures. Multiple metabolic routes were suppressed to determine their relevance to cytokine production. RESULTS: Intestinal CD14+ Mφ in CD patients exhibited activated glycolysis compared with those in control patients. Specifically, macrophagic glycolysis in CD largely induced inflammatory cytokine release. The intestinal inflammatory microenvironment in CD elicited abnormal glycolysis in Mφ. Mechanistically, CD14+ Mφ derived exosomes expressed membrane tumor necrosis factor (TNF), which engaged TNFR2 and triggered glycolytic activation via TNF/nuclear factor κB autocrine and paracrine signaling. Importantly, clinically applicable anti-TNF antibodies effectively prevented exosomal membrane TNF-induced glycolytic activation in CD14+ Mφ. CONCLUSIONS: CD14+ Mφ take part in CD pathogenesis by inducing glycolytic activation via membrane TNF-mediated exosomal autocrine and paracrine signaling. These results provide novel insights into pathogenesis of CD and enhance understanding of the mechanisms of anti-TNF agents.