Remodeled eX vivo muscle engineered tissue improves heart function after chronic myocardial ischemia

: The adult heart displays poor reparative capacities after injury. Cell transplantation and tissue engineering approaches have emerged as possible therapeutic options. Several stem cell populations have been largely used to treat the infarcted myocardium. Nevertheless, transplanted cells displayed limited ability to establish functional connections with the host cardiomyocytes. In this study, we provide a new experimental tool, named 3D eX vivo muscle engineered tissue (X-MET), to define the contribution of mechanical stimuli in triggering functional remodeling and to rescue cardiac ischemia. We revealed that mechanical stimuli trigger a functional remodeling of the 3D skeletal muscle system toward a cardiac muscle-like structure. This was supported by molecular and functional analyses, demonstrating that remodeled X-MET expresses relevant markers of functional cardiomyocytes, compared to unstimulated and to 2D- skeletal muscle culture system. Interestingly, transplanted remodeled X-MET preserved heart function in a murine model of chronic myocardial ischemia and increased survival of transplanted injured mice. X-MET implantation resulted in repression of pro-inflammatory cytokines, induction of anti-inflammatory cytokines, and reduction in collagen deposition. Altogether, our findings indicate that biomechanical stimulation induced a cardiac functional remodeling of X-MET, which showed promising seminal results as a therapeutic product for the development of novel strategies for regenerative medicine

Modelling three‐dimensional cancer‐associated cachexia and therapy: The molecular basis and therapeutic potential of interleukin‐6 transignalling blockade

Abstract Background Causes and mechanisms underlying cancer cachexia are not fully understood, and currently, no therapeutic approaches are available to completely reverse the cachectic phenotype. Interleukin‐6 (IL‐6) has been extensively described as a key factor in skeletal muscle physiopathology, exerting opposite roles through different signalling pathways. Methods We employed a three‐dimensional ex vivo muscle engineered tissue (X‐MET) to model cancer‐associated cachexia and to study the effectiveness of selective inhibition of IL‐6 transignalling in counteracting the cachectic phenotype. Conditioned medium (CM) derived from C26 adenocarcinoma cells was used as a source of soluble factors contributing to the establishment of cancer cachexia in the X‐MET model. A dose of 1.2 ng/mL of glycoprotein‐130 fused chimaera (gp130Fc) was added to cachectic culture medium to neutralize IL‐6 transignalling. Results C26‐conditioned medium induced a cachectic‐like phenotype in the X‐MET, leading to a decline of muscle mass (−60%; P < 0.001), a reduction in myosin expression (−92.4%; P < 0.005) and a reduction of the contraction frequency spectrum (−94%). C26‐conditioned medium contains elevated amounts of IL‐6 (8.61 ± 4.09 pg/mL) and IL6R (56.85 ± 10.96 pg/mL). These released factors activated the signal transducer and activator of transcription 3 (STAT3) signalling in the C26_CM X‐MET system (phosphorylated STAT3/TOTAL +54.6%; P < 0.005), which in turn promote an enhancement of Il‐6 (+69.2%; P < 0.05) and Il6r (+43%; P < 0.05) gene expression, suggesting the induction of a feed‐forward loop. The selective neutralization of IL‐6 transignalling, by gp130Fc, in C26_CM X‐MET prevented the hyperactivation of STAT3 (−55.8%; P < 0.005), countered the reduction of cross‐sectional area (+28.2%; P < 0.05) and reduced the expression of proteolytic factors including muscle ring finger‐1 (−88%; P < 0.005) and ATROGIN1 (−92%; P < 0.05), thus preserving the robustness and increasing the contractile force (+20%) of the three‐dimensional muscle system. Interestingly, the selective inhibition of IL‐6 transignalling modulated gene regulatory networks involved in myogenesis and apoptosis, normalizing the expression of pro‐apoptotic miRNAs, including miR‐31 (−53.2%; P < 0.05) and miR‐34c (−65%; P < 0.005), and resulting in the reduction of apoptotic pathways highlighted by the sensible reduction of cleaved caspase 3 (−92.5%; P < 0.005) in gp130Fc‐treated C26_CM X‐MET. Conclusions IL‐6 transignalling appeared as a promising target to counter cancer cachexia‐related alterations. The X‐MET model has proven to be a reliable drug‐screening tool to identify novel therapeutic approaches and to test them in preclinical studies, significantly reducing the use of animal models

International Variations in Surgical Morbidity and Mortality Post Gynaecological Oncology Surgery: A Global Gynaecological Oncology Surgical Outcomes Collaborative Led Study (GO SOAR1)

Simple Summary Little is known about factors contributing to early post-operative morbidity and mortality in low and middle income countries with a paucity of data limiting global efforts to improve gynaecological cancer care. In this multicentre, international prospective cohort study of women undergoing gynaecological oncology surgery, we show that low and middle versus high income countries were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention.Abstract Gynaecological malignancies affect women in low and middle income countries (LMICs) at disproportionately higher rates compared with high income countries (HICs) with little known about variations in access, quality, and outcomes in global cancer care. Our study aims to evaluate international variation in post-operative morbidity and mortality following gynaecological oncology surgery between HIC and LMIC settings. Study design consisted of a multicentre, international prospective cohort study of women undergoing surgery for gynaecological malignancies (NCT04579861). Multilevel logistic regression determined relationships within three-level nested-models of patients within hospitals/countries. We enrolled 1820 patients from 73 hospitals in 27 countries. Minor morbidity (Clavien-Dindo I-II) was 26.5% (178/672) and 26.5% (267/1009), whilst major morbidity (Clavien-Dindo III-V) was 8.2% (55/672) and 7% (71/1009) for LMICs/HICs, respectively. Higher minor morbidity was associated with pre-operative mechanical bowel preparation (OR = 1.474, 95%CI = 1.054-2.061, p = 0.023), longer surgeries (OR = 1.253, 95%CI = 1.066-1.472, p = 0.006), greater blood loss (OR = 1.274, 95%CI = 1.081-1.502, p = 0.004). Higher major morbidity was associated with longer surgeries (OR = 1.37, 95%CI = 1.128-1.664, p = 0.002), greater blood loss (OR = 1.398, 95%CI = 1.175-1.664, p <= 0.001), and seniority of lead surgeon, with junior surgeons three times more likely to have a major complication (OR = 2.982, 95%CI = 1.509-5.894, p = 0.002). Of all surgeries, 50% versus 25% were performed by junior surgeons in LMICs/HICs, respectively. We conclude that LMICs and HICs were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention

Pancreatic surgery outcomes: multicentre prospective snapshot study in 67 countries

Background: Pancreatic surgery remains associated with high morbidity rates. Although postoperative mortality appears to have improved with specialization, the outcomes reported in the literature reflect the activity of highly specialized centres. The aim of this study was to evaluate the outcomes following pancreatic surgery worldwide.Methods: This was an international, prospective, multicentre, cross-sectional snapshot study of consecutive patients undergoing pancreatic operations worldwide in a 3-month interval in 2021. The primary outcome was postoperative mortality within 90 days of surgery. Multivariable logistic regression was used to explore relationships with Human Development Index (HDI) and other parameters.Results: A total of 4223 patients from 67 countries were analysed. A complication of any severity was detected in 68.7 percent of patients (2901 of 4223). Major complication rates (Clavien-Dindo grade at least IIIa) were 24, 18, and 27 percent, and mortality rates were 10, 5, and 5 per cent in low-to-middle-, high-, and very high-HDI countries respectively. The 90-day postoperative mortality rate was 5.4 per cent (229 of 4223) overall, but was significantly higher in the low-to-middle-HDI group (adjusted OR 2.88, 95 per cent c.i. 1.80 to 4.48). The overall failure-to-rescue rate was 21 percent; however, it was 41 per cent in low-to-middle-compared with 19 per cent in very high-HDI countries.Conclusion: Excess mortality in low-to-middle-HDI countries could be attributable to failure to rescue of patients from severe complications. The authors call for a collaborative response from international and regional associations of pancreatic surgeons to address management related to death from postoperative complications to tackle the global disparities in the outcomes of pancreatic surgery (NCT04652271; ISRCTN95140761)