Rho/SRF Inhibitor Modulates Mitochondrial Functions.

CCG-1423 is a Rho A pathway inhibitor that has been reported to inhibit Rho/SRF-mediated transcriptional regulation. Serum response factor and its cofactors, which include ternary complex factors and myocardin-related transcription factors, regulate various cellular functions. In this study, we observed that CCG-1423 modulates the mitochondrial functions. The effect of this small molecule drug was determined by measuring mitochondrial function using an XFe96 Analyzer and an Oxygraph 2k (O2k) high-resolution respirometer. CCG-1423 treatment significantly reduced oxidative phosphorylation in a dose-dependent manner. However, CCG-1423 increased the glycolytic rate. We also observed that histone 4 at lysine-16 underwent hyperacetylation with the treatment of this drug. Immunolabeling with F-actin and MitoTracker revealed the alteration in the actin cytoskeleton and mitochondria. Taken together, our findings highlight a critical role of CCG-1423 in inhibiting the transcription of SRF/p49 and PGC-1α, ß, resulting in the downregulation of mitochondrial genes, leading to the repression of mitochondrial oxidative phosphorylation and overall ATP reduction. This study provides a better understanding of the effects of CCG-1423 on mitochondria, which may be useful for the assessment of the potential clinical application of CCG-1423 and its derivatives.

Complete mesocolic excision versus conventional surgery for colon cancer: A systematic review and meta-analysis.

AIM: Complete mesocolic excision (CME) lacks consistent data advocating operative superiority compared to conventional surgery for colon cancer. We performed a systematic review and meta-analysis, analysing population characteristics and perioperative, pathological and oncological outcomes. METHODS: D3 extended lymphadenectomy dissection was considered comparable to CME, and D2 and D1 dissection to be comparable to conventional surgery. Outcomes reviewed included lymph node yield, R1 resection, overall complications, overall survival and disease-free survival. RESULTS: In all, 3039 citations were identified; 148 studies underwent full-text reviews and 31 matched inclusion criteria: total cohort 26 640 patients (13 830 CME/D3 vs. 12 810 conventional). Overall 3- and 5-year survival was higher in the CME/D3 group compared with conventional surgery: relative risk (RR) 0.69 (95% CI 0.51-0.93, P = 0.016) and RR 0.78 (95% CI 0.64-0.95, P = 0.011) respectively. Five-year disease-free survival also demonstrated CME/D3 superiority (RR 0.67, 95% CI 0.52-0.86, P < 0.001), with similar findings at 1 and 3 years. There were no statistically significant differences between the CME/D3 and conventional group in overall complications (RR 1.06, 95% CI 0.97-1.14, P = 0.483) or anastomotic leak (RR 1.02, 95% CI 0.81-1.29, P = 0.647). CONCLUSIONS: Meta-analysis suggests CME/D3 may have a better overall and disease-free survival compared to conventional surgery, with no difference in perioperative complications. Quality of evidence regarding survival is low, and randomized control trials are required to strengthen the evidence base.

Risk and consequences of dehydration following colorectal cancer resection with diverting ileostomy. A systematic review and meta-analysis.

AIM: This systematic review aims to assess dehydration prevalence and dehydration-related morbidity from diverting ileostomy compared to resections without ileostomy formation in adults undergoing colorectal resection for cancer. METHOD: MEDLINE, Embase, CENTRAL and ClinicalTrials.gov were searched for studies of any design that reported dehydration, renal function and dehydration-related morbidity in adult colorectal cancer patients with diverting ileostomy (last search 12 August 2020). Bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomized trials and the Risk of Bias in Non-randomized Studies of Interventions tool. RESULTS: Of 1927 screened papers, 22 studies were included (21 cohort studies and one randomized trial) with a total of 19 485 patients (12 209 with ileostomy). The prevalence of dehydration was 9.00% (95% CI 5.31-13.45, P < 0.001). The relative risk of dehydration following diverting ileostomy was 3.37 (95% CI 2.30-4.95, P < 0.001). Three studies assessing long-term trends in renal function demonstrated progressive renal impairment persisting beyond the initial insult. Consequences identified included unplanned readmission, delay or non-commencement of adjuvant chemotherapy, and development of chronic kidney disease. DISCUSSION: Significant dehydration is common following diverting ileostomy; it is linked to acute kidney injury and has a long-term impact on renal function. This study suggests that ileostomy confers significant morbidity particularly related to dehydration and renal impairment.

Convulsant Effects of Abused Synthetic Cannabinoids JWH-018 and 5F-AB-PINACA Are Mediated by Agonist Actions at CB1 Receptors in Mice.

Convulsant effects of abused synthetic cannabinoid (SCB) drugs have been reported in humans and laboratory animals, but the mechanism of these effects is not known. We compared convulsant effects of partial CB1R agonist ∆9-tetrahydrocannabinol (THC), full CB1R agonist SCBs JWH-018 and 5F-AB-PINACA, and classic chemical convulsant pentylenetetrazol (PTZ) using an observational rating scale in mice. THC did not elicit convulsions, but both SCBs did so as effectively as and more potently than PTZ. SCB-elicited convulsions were attenuated by the CB1R antagonist rimonabant or by THC, or by dose regimens of THC and JWH-018, which downregulate and desensitize CB1Rs. None of these treatments altered the convulsant effects of PTZ, although diazepam attenuated PTZ-elicited convulsions without altering SCB-induced convulsant effects. Repeated administration of a subthreshold dose of PTZ kindled convulsant effects, but this was not observed with the SCBs, and no cross-kindling was observed. Repeated administration of the SCBs resulted in tolerance to convulsant effects, but no cross-tolerance to PTZ was observed. Inhibition on Phase I metabolism via nonselective inhibition of CYP450s with 1-aminobenzotriazole potentiated the hypothermic effects of the SCBs and protected against the convulsant effects of JWH-018, but not those of 5F-AB-PINACA or PTZ. Incubation of human liver microsomes with the SCBs showed that JWH-018 is eliminated via oxidation, whereas 5F-AB-PINACA is not. These studies suggest that SCB-elicited convulsions are mediated by high intrinsic efficacy at CB1Rs and that benzodiazepines may not be effective treatments. Finally, drug metabolism may dramatically modulate the convulsant effects of some, but not all, SCBs.

Relationship between the m-FI 11 score and 2-year survival in octogenarians undergoing colorectal cancer resection.

Introduction: The modified Frailty Index (m-FI) offers a simple scoring tool, predicting short-term outcomes in elderly colorectal cancer (CRC) patients. However, links between m-FI scores and 2-year postoperative mortality in octogenarian CRC resection patients remain underexplored. A streamlined frailty index can aid in preoperative assessments to identify elderly patients who are likely to live longer after curative resection surgery to then tailor postoperative care. Our study aims to assess the association between m-FI scores and 2-year postoperative mortality in elderly CRC surgery patients. Methods: A retrospective analysis was conducted on a cohort of consecutive patients aged older than or equal to 80 years who underwent colorectal cancer resection at a tertiary referral centre between 2010 and 2017. The m-FI-11 scores less than or equal to two denoted the non-frail category, whereas m-FI scores equal to or exceeding 3 were categorised as frail. The primary outcome measure was defined as 2-year all-cause mortality. Results: A total of 337 patients were studied. The 2-year overall survival rate was 83% with an overall median survival time of 84 months (95% CI: 74-94 months). Patients with m-FI scores less than or equal to 2 had a 2-year survival rate of 85% and a median survival time of 94 months (95% CI: 84-104 months). Conversely, patients with m-FI scores greater than or equal to 3 had a 2-year survival rate of 72% and a median survival time of 69 months (95% CI: 59-79 months). An m-FI score greater than or equal to 3 showed a hazard ratio of 1.73 (95% CI: 0.92-3.26, P=0.092) for 2-year mortality compared to an m-FI score less than or equal to 2. Conclusion: Higher m-FI scores significantly correlate with an increased 2-year mortality risk among octogenarian CRC resection patients. This highlights the potential of the m-FI as a preoperative tool for identifying patients likely to survive longer post-surgery. Its integration aids in tailored postoperative care strategies, ensuring efficient recovery to functional baselines in this cohort.

Compartment syndrome: a rare complication following laparoscopic colorectal surgery.

We present a 71-year-old man who developed left calf pain after an elective laparoscopic assisted anterior resection. A clinical picture with a raised creatine kinase and negative Doppler ultrasound was suggestive of compartment syndrome. Successful surgical management was performed with two incisional fasciotomies to release all four compartments of the left leg. The patient recovered well postoperatively. The lateral incision was closed primarily while the medial incision required vacuum-assisted closure dressings and healed by secondary intention. Neither wound required skin grafts. The patient recovered well but had an extended hospital stay due to extensive physiotherapy requirements and mild foot drop. This report is intended as a guide for clinicians when considering differentials in calf pain following surgery and to keep in mind the small risk of developing compartment syndrome after pelvic surgery.

Perforated gallbladder in a parastomal hernia.

We present an 87-year-old woman who presented to the emergency department with a 7-day history of severe abdominal pain at her ileostomy parastomal hernia site. Prior to presentation, her general practitioner had started her on a reducing steroid dose for suspected Crohn's disease exacerbation. On examination, she had a distended abdomen with localised guarding and tenderness over her hernia site. A CT scan demonstrated an incarcerated perforated gallbladder within her parastomal hernia. Successful surgical management was performed involving an enterotomy, refashioning her ileostomy and an open cholecystectomy. The patient recovered well with a short postoperative stay. This report is intended as a guide for clinicians in the differential diagnoses for acute abdominal pain and an unusual presentation of a gallbladder perforation.

Lumbar hernia diagnosed after laparoscopic hiatal hernia surgery.

The presence of a new lumbar swelling or pain in the postoperative period following laparoscopic surgery should raise the suspicion of a lumbar hernia. Cross-sectional imaging can be used to establish an early diagnosis to enable successful management.

Minimizing the hidden dangers of cholecystectomy in vascular Ehlers-Danlos syndrome through a multidisciplinary approach.

Ehlers-Danlos syndrome, specifically EDS4, can be a dangerous condition. Clinicians should be aware of this when referring such patients for any interventional procedure. An MDT approach should be adopted to help plan perioperative treatment and care.