Carriers for metal complexes on tumour cells: the effect of cyclodextrins vs CNTs on the model guest phenanthroline-5,6-dione trithiacyclononane ruthenium(II) chloride

The complex [Ru[9]aneS(3)(pdon)Cl]Cl (pdon = 1,10-phenanthroline-5,6-dione) was readily obtained from the stoichiometric reaction of Ru[9]aneS(3)(dmso)Cl-2 with pdon. Recrystallisation in ethanol using salicylic acid as a co-crystallisation helper afforded single-crystals suitable for the collection of X-ray diffraction data which afforded a reasonable structural description. Two different kinds of molecular carriers were tested as vehicles for this complex: carbon nanotubes (CNTs) and cyclodextrins. CNTs had an insufficient loading rate for the ruthenium complex at CNT concentrations deemed non-cytotoxic on cultured cells. The cyclodextrin (CD) carriers, beta-CD and TRIMEB (standing for permethylated beta-CD), were able to form two adducts, studied by powder X-ray diffraction, thermogravimetric analysis (TGA), C-13{H-1} CP/MAS NMR and FT-IR spectroscopies. The DNA thermal denaturation studies showed that the complex 1 is able to intercalate with DNA. The in vitro cytotoxicity of the free complex [Ru[9]aneS(3)(pdon)Cl]Cl (1) and of its two CD adducts (2 and 3) was assessed on both rodent and human cell lines. By using the mouse K1735-M2 melanoma cell line and the non-tumour rat H9c2 cardiomyoblasts, the results showed that 1 and 2 significantly inhibited the growth of the tumour cell line while displaying a good safety profile on cardiomyoblasts. Compound 3 at 100 mu M inhibited the proliferation of both cell lines, with a higher activity towards the melanoma cell line. The cytotoxicity of the compounds 1-3 was further assessed on human breast cancer cell lines. Against the MDA-MB-231 line, growth inhibition occurred only with 1 and 3 at the incubation time of 96 h, both with approximate inhibition rates of 50 %; against the MCF-7 line, mild cytotoxicity was observed at 48 h of incubation, with IC50 values calculated above 100 mu M for 1, 2 and 3

Genetic models

Genetically altered rat and mouse models have been instrumental in the functional analysis of genes in a physiological context. In particular, studies on the renin-angiotensin system (RAS) have profited from this technology in the past. In this review, we summarize the existing animal models for the protective axis of the RAS consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7)(Ang-(1-7), and its receptor Mas. With the help of models with altered expression of the components of this axis in the brain and cardiovascular organs, its physiological and pathophysiological functions have been elucidated. Thus, novel opportunities for therapeutic interventions in cardiovascular diseases were revealed targeting ACE2 or Mas

Outcomes from elective colorectal cancer surgery during the SARS‐CoV‐2 pandemic

Aim This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic. Method This was an international cohort study of patients undergoing elective resection of colon or rectal cancer without preoperative suspicion of SARS-CoV-2. Centres entered data from their first recorded case of COVID-19 until 19 April 2020. The primary outcome was 30-day mortality. Secondary outcomes included anastomotic leak, postoperative SARS-CoV-2 and a comparison with prepandemic European Society of Coloproctology cohort data. Results From 2073 patients in 40 countries, 1.3% (27/2073) had a defunctioning stoma and 3.0% (63/2073) had an end stoma instead of an anastomosis only. Thirty-day mortality was 1.8% (38/2073), the incidence of postoperative SARS-CoV-2 was 3.8% (78/2073) and the anastomotic leak rate was 4.9% (86/1738). Mortality was lowest in patients without a leak or SARS-CoV-2 (14/1601, 0.9%) and highest in patients with both a leak and SARS-CoV-2 (5/13, 38.5%). Mortality was independently associated with anastomotic leak (adjusted odds ratio 6.01, 95% confidence interval 2.58–14.06), postoperative SARS-CoV-2 (16.90, 7.86–36.38), male sex (2.46, 1.01–5.93), age >70 years (2.87, 1.32–6.20) and advanced cancer stage (3.43, 1.16–10.21). Compared with prepandemic data, there were fewer anastomotic leaks (4.9% versus 7.7%) and an overall shorter length of stay (6 versus 7 days) but higher mortality (1.7% versus 1.1%). Conclusion Surgeons need to further mitigate against both SARS-CoV-2 and anastomotic leak when offering surgery during current and future COVID-19 waves based on patient, operative and organizational risks

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AimThe SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery.MethodsThis was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin.ResultsOverall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P ConclusionOne in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease