Simultaneous aortic and renal artery reconstruction: Evolution of an eighteen-year experience

AbstractPurpose: We reviewed an 18-year experience with combined abdominal aortic and renal artery reconstruction (AOR) with a particular focus on patients' clinical risk profile and surgical results in contemporary practice as compared with earlier experience.Methods: One hundred seventy patients underwent AOR during the interval January 1, 1976 to June 30, 1994. To examine parameters representative of current practice, the cohort was divided into group I patients (n = 110) treated before 1990 and group II (n = 60) treated between 1990 and 1994. Median follow-up duration for the entire cohort was 8.4 ± 0.6 years. Renal artery reconstruction patency and patient survival rates were calculated by life-table methods. Logistic and Cox regression analysis were used to determine predictors of perioperative and long-term morbidity/mortality rates.Results: Although demographic features changed little over the review period, the detection (56% vs 73%, p = 0.03) and treatment with percutaneous transluminal coronary angioplasty/coronary artery bypass grafting (11% vs 40%, p = 0.0001) of associated coronary artery disease were more frequent in group II versus group I patients. Alternatively, renal insufficiency was more frequent in group I patients. The operative mortality rate for the entire cohort was 6.5% (group I = 9% vs group II = 2%, p = 0.06). Changing trends of surgical techniques over the review period included (group I vs II, respectively) increased use of bilateral simultaneous renal artery repair (12% vs 25%, p < 0.005) and transaortic endarterectomy as the renal artery reconstruction technique (3% vs 25%, p < 0.0001). Favorable response in blood pressure control was noted in 68% of group II patients. The cumulative 5-year survival rate for all patients was 75% with an initial serum creatinine of 2.0 mg/dl or greater being the only negative predictor of late survival after regression analysis.Conclusion: The current operative mortality rate for AOR is in the range anticipated for aortic surgery alone, and this appears to be related to improved detection and treatment of associated coronary artery disease and intervention before major deterioration in renal function. These findings coupled with currently available natural history data relative to renovascular disease justify an aggressive approach with AOR when significant renal artery stenosis is detected during evaluation of aortic disease. (J VASC SURG 1995;21:916-25.

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals

Background - The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. Methods - We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Results - Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. Conclusions - When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.The workshops that supported the writing of this manuscript were funded by the Swedish Foundation for Strategic Environmental Research “Mistra”. LNV was funded by Award Number K22ES025811 from the National Institute of Environmental Health Sciences of the National Institutes of Health. TJW was funded by The Clarence Heller Foundation (A123547), the Passport Foundation, the Forsythia Foundation, the National Institute of Environmental Health Sciences (grants ES018135 and ESO22841), and U.S. EPA STAR grants (RD83467801 and RD83543301). JT was funded by the Academy of Finland and Sigrid Juselius. UH was funded by the Danish EPA. KAK was funded by the Canada Research Chairs program grant number 950–230607

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Are cystic fibrosis mutation carriers a potentially highly vulnerable group to COVID-19?

Undoubtedly, the new SARS-CoV-2 virus poses a grave health threat, plaguing the health and socio-economic sectors. COVID-19 disease must be treated quickly and effectively as soon as possible. The main axes in this direction are establishing vaccines, drugs, diagnostic tests, as well as identifying the most vulnerable groups. Probably, there is a correlation between COVID-19 and cystic fibrosis. Our interest is focused on cystic fibrosis carriers that, due to limited tests, remain undetectable. There is an activation of the inflammatory response in the carriers, as well as in cystic fibrosis patients. First of all, a striking similarity lies between the inflammatory response in COVID-19 and cystic fibrosis carriers. Notably, ACE-2 plays the same role in both cases and a similar geographical distribution is observed in both diseases. In conclusion, we suggest that cystic fibrosis mutation carriers are potential members of a certain vulnerable group and the detection of such mutations in the population might be vital for the prevention of SARS-CoV-2 virus, and more specifically to limit its serious complications. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley &amp; Sons Ltd

The resistance mechanisms of checkpoint inhibitors in solid tumors

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

The controversial role of autophagy in ewing sarcoma pathogenesis—current treatment options

Ewing Sarcoma (ES) is a rare, aggressive, and highly metastasizing cancer in children and young adults. Most ES cases carry the fusion of the Ewing Sarcoma Breakpoint Region 1 (EWSR1) and FLI1 (Friend leukemia virus integration site 1) genes, leading to an EWS–FLI1 fused protein, which is associated with autophagy, a homeostatic and catabolic mechanism under normal and pathological conditions. Following such interesting and controversial data regarding autophagy in ES, many clinical trials using modulators of autophagy are now underway in this field. In the present review, we summarize current data and clinical trials that associate autophagy with ES. In vitro studies highlight the controversial role of autophagy as a tumor promoter or a tumor suppressor mechanism in ES. Clinical and in vitro studies on ES, together with the autophagy modulators, suggest that caution should be adopted in the application of autophagy as a therapeutic target. Monitoring and targeting autophagy in every ES patient could eliminate the need for targeting multiple pathways in order to achieve the maximum beneficial effect. Future studies are required to focus on which ES patients are affected by autophagy modulators in order to provide novel and more efficient therapeutic protocols for patients with ES based on the current autophagy status of the tumors. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Inhibition of c-MET increases the antitumour activity of PARP inhibitors in gastric cancer models

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Activation of c-MET increases tumour cell survival through the initiation of the DNA damage repair pathway. PARP is an essential key in the DNA damage repair pathway. The primary role of PARP is to detect and initiate an immediate cellular response to single-strand DNA breaks. Tumours suppressor genes such as BRCA1/2 are closely associated with the DNA repair pathway. In BRCA1/2 mutations or deficiency status, cells are more likely to develop additional genetic alterations and chromosomal instability and can lead to cancer. In this study, we investigate the role of c-MET and PARP inhibition in a gastric cancer model. We exploited functional in vitro and in vivo experiments to assess the antitumour potential of co-inhibition of c-MET (SU11274) and PARP (NU1025). This leads to a reduction of gastric cancer cells viability, especially after knockdown of BRCA1/2 through apoptosis and induction of γ-Η2ΑΧ. Moreover, in AGS xenograft models, the combinatorial treatment of NU1025 plus SU11274 reduced tumour growth and triggers apoptosis. Collectively, our data may represent a new therapeutic approach for GC thought co-inhibition of c-MET and PARP, especially for patients with BRCA1/2 deficiency tumours. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley &amp; Sons Lt

The role of the RANKL/RANK axis in the prevention and treatment of breast cancer with immune checkpoint inhibitors and anti-RANKL

The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis. Additionally, the RANKL/RANK axis is a significant mediator of progesterone-driven mammary epithelial cell proliferation, potentially contributing to breast cancer initiation and progression. Moreover, several studies supported the synergistic effect of RANK and epidermal growth factor receptor (EGFR) and described RANK’s involvement in epidermal growth factor receptor 2 (ERBB2)-positive carcinogenesis. Consequently, anti-RANKL treatment has been proposed as a new approach to preventing and treating breast cancer and metastases. Recently, RANKL/RANK signaling pathway inhibition has been shown to modulate the immune environment and enhance the efficacy of anti-CTLA-4 and anti-PD-1 monoclonal antibodies against solid tumors. Clinical and experimental trials have emerged evaluating RANKL inhibition as an enhancer of the immune response, rendering resistant tumors responsive to immune therapies. Trials evaluating the combinatorial effect of immune checkpoint inhibitors and anti-RANKL treatment in double-positive (RANK+/ERBB2+) patients are encouraging. © 2020 by the authors