Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1
) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which ...suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg
(also known as Ercc5
) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1
mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1
mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1
mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.
Within this work, we demonstrate a method for the etch-less, additive microfabrication of TiO2 thin film layers on top of the medical implant material titanium grade 23. A combination of common ...UV-lithographic microfabrication and a subsequent anodic oxidation process allows the direct additive fabrication of microstructured oxide layers on top of the bulk base material without the use of any additional preparation or etching step. Titanium grade 23 samples were firstly prepared by grinding and polishing to achieve an adequate surface finish for UV lithography. Photoresist was applied to the samples and lithographically structured using line patterns with lateral sizes ranging from 1.5 up to 50 µm. The samples were then anodically oxidized within a H2SO4 containing electrolyte and the resist patterns could successfully be copied into the resulting oxide layers. The presented method allows cost-effective and fast microfabrication of structured oxide thin film layers while protecting the underlying bulk material from hazardous etching media, often containing hydrofluoric acid, enabling novel implant coating designs and fabrication concepts for future works.
Abstract
The purpose of this work was to demonstrate the technical feasibility for the fabrication of microgrooves or micropits on dental implants or dental implant abutment surfaces using a novel ...fabrication method derived from common UV-lithographic microfabrication. Instead of using a flat and rigid chromium/glass mask to structure a photoresist layer on a small cylindrical part, a flexible chromium-coated polymer mask was introduced into the lithographic setup. Through an elastic deformation of the polymer mask, it was possible to achieve lateral resolutions as small as 1.5
µ
m on small cylinders and to structure conical parts. By subsequent controlled under-etching of the structured photoresist layer, microgrooves of different cross-sectional geometries can be generated and applied to the implant or implant abutment surface. Such structures can be used for contact guidance of human gingival fibroblasts or endothelia cells to enhance the wound healing process and the overall soft-tissue integration.
We develop a unifying theory of hypoxia tolerance based on information from two cell level models (brain cortical cells and isolated hepatocytes) from the highly anoxia tolerant aquatic turtle and ...from other more hypoxia sensitive systems. We propose that the response of hypoxia tolerant systems to oxygen lack occurs in two phases (defense and rescue). The first lines of defense against hypoxia include a balanced suppression of ATP-demand and ATP-supply pathways; this regulation stabilizes (adenylates) at new steady-state levels even while ATP turnover rates greatly decline. The ATP demands of ion pumping are down-regulated by generalized ``channel'' arrest in hepatocytes and by ``spike'' arrest in neurons. Hypoxic ATP demands of protein synthesis are down-regulated probably by translational arrest. In hypoxia sensitive cells this translational arrest seems irreversible, but hypoxia-tolerant systems activate ``rescue'' mechanisms if the period of oxygen lack is extended by preferentially regulating the expression of several proteins. In these cells, a cascade of processes underpinning hypoxia rescue and defense begins with an oxygen sensor (a heme protein) and a signal-transduction pathway, which leads to significant gene-based metabolic reprogramming--the rescue process--with maintained down-regulation of energy-demand and energy-supply pathways in metabolism throughout the hypoxic period. This recent work begins to clarify how normoxic maintenance ATP turnover rates can be drastically (10-fold) down-regulated to a new hypometabolic steady state, which is prerequisite for surviving prolonged hypoxia or anoxia. The implications of these developments are extensive in biology and medicine.
Within this work we demonstrate the fabrication of silicon nanopillar arrays for advanced cell/surface interaction studies and the results of the bacterial interaction of Escherichia coli with such ...highly ordered nanostructures. By combination of Electron Beam Lithography and Reactive Ion Etching a powerful and highly precise method for the fabrication of nanopillars with different diameters in the sub 100 nm region and high aspect ratios is available. The fabrication method allows building highly ordered nanotopographies which can help to increase the understanding of cell/substrate interaction. The biological results indicate that the adhesion of E. coli correlates to the available discrete adhesion bond points on top of the pillars and additionally that the cells align with the nanostructures to maximize their contact to the surface. The research of such structures will lead to the development of novel materials which might reduce biomaterial associated infections.
With increasing availability of different treatments for chronic obstructive pulmonary disease (COPD), we sought to understand patient preferences for COPD treatment in the UK, USA, and Germany using ...a discrete choice experiment (DCE).
Qualitative research identified six attributes associated with COPD maintenance treatments: ease of inhaler use, exacerbation frequency, frequency of inhaler use, number of different inhalers used, side effect frequency, and out-of-pocket costs. A DCE using these attributes, with three levels each, was designed and tested through cognitive interviews and piloting. It comprised 18 choice sets, selected using a D-efficient experimental design. Demographics and disease history were collected and the final DCE survey was completed online by participants recruited from panels in the UK, USA and Germany. Responses were analyzed using mixed logit models, with results expressed as odds ratios (ORs).
Overall, 450 participants (150 per country) completed the DCE; most (UK and Germany, 97.3%; USA, 98.0%) were included in the final analysis. Based on relative attribute importance, avoidance of side effects was found to be most important (UK: OR 11.65; USA: OR 7.17; Germany: OR 11.45; all
<0.0001), followed by the likelihood of fewer exacerbations (UK: OR 2.22; USA: OR 1.63; Germany: OR 2.54; all
<0.0001) and increased ease of use (UK: OR 1.84; USA: OR 1.84; Germany: OR 1.60; all
<0.0001). Number of inhalers, out-of-pocket costs, and frequency of inhaler use were found to be less important. Preferences were relatively consistent across the three countries. All participants required a reduction in exacerbations to accept more frequent inhaler use or use of more inhalers.
When selecting COPD treatment, individuals assigned the highest value to the avoidance of side effects, experiencing fewer exacerbations, and ease of inhaler use. Ensuring that patients' preferences are considered may encourage treatment compliance.
The Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) convened virtually on 4 November 2021. The WCGCCC is an interactive multi-disciplinary conference attended by health care ...professionals, including surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals from across four Western Canadian provinces, British Columbia, Alberta, Saskatchewan, and Manitoba, who are involved in the care of patients with gastrointestinal cancer. They participated in presentation and discussion sessions for the purpose of developing recommendations on the role of systemic therapy and its optimal sequence in patients with resectable metastatic colorectal cancer.
Gastric, esophageal and gastro-esophageal junction cancers are associated with inferior outcomes. For early-stage disease, perioperative chemotherapy or chemoradiation followed by surgery is the ...standard treatment. For most patients with advanced upper gastrointestinal tract cancers, platinum-based chemotherapy remains a standard treatment. Recently, several randomized clinical trials have demonstrated the benefit of immunotherapy involving checkpoint inhibitors alone or in combination with chemotherapy in patients with gastro-esophageal cancer and have changed the treatment landscape. The Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC), involving experts from four Western Canadian provinces, convened virtually on 16 June 2021 and developed the recommendations on the role of immunotherapy in patients with gastro-esophageal cancer.
The Western Canadian Gastrointestinal Cancer Consensus Conference (WC-5) convened virtually on 10 February 2021. The WC-5 is an interactive multidisciplinary conference attended by health care ...professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of hepatocellular cancer (HCC). Recommendations have been made for the transition from local to systemic therapy and the optimal sequencing of systemic regimens in the management of HCC.
The 21st annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Calgary, Alberta, 20-21 September 2019. The WCGCCC is an interactive multi-disciplinary conference ...attended by health care professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists, pathologists, radiologists, and allied health care professionals such as dietitians and nurses participated in presentation and discussion sessions to develop the recommendations presented here. This consensus statement addresses current issues in the management of hepato-pancreato-biliary (HPB) cancers.
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