Aging-dependent functional alterations of mitochondrial DNA (mtDNA) from human fibroblasts transferred into mtDNA-less cells

To investigate the role that aging-dependent accumulation of mitochondrial DNA (mtDNA) mutations plays in the senescence processes, mitochondria from fibroblasts of 21 normal human individuals between 20 weeks (fetal) and 103 years of age were introduced into human mtDNA-less (ρ0) 206 cells by cytoplast × ρ0 cell fusion, and 7-31 transformant clones were isolated from each fusion. A slight cell donor age-dependent decrease in growth rate was detected in the transformants. Using an O2 consumption rate of 1 fmol/min/cell, which was not observed in any transformant among 158 derived from individuals 20 weeks (fetal) to 37 years of age, as a cut-off to identify respiratory-deficient clones, 11 such clones were found among 198 transformants derived from individuals 39-103 years of age. Furthermore, conventional and nonparametric analysis of the respiratory rates of 356 clones revealed a very significant decrease with donor age. In other analyses, a very significant age-dependent decline in the mtDNA content of the clones was observed, without, however, any significant correlation with the decrease in O2 consumption rate in the defective transformants. These observations clearly indicate the occurrence in the fibroblast-derived transformants of two independent, age-related functional alterations of mtDNA, presumably resulting from structural damage to this genome

Stepping Stones Triple P: The theoretical basis and development of an evidence-based positive parenting program for families with a child who has a disability.

Stepping Stones Triple P is the first in a series of programs based on the Triple P – Positive Parenting Program that has been specifically designed for families who have a child with a disability. This paper presents the rationale, theoretical foundations, historical development and distinguishing features of the program. The multi-level intervention adopts a self-regulation framework in consulting with parents that involves the promotion of parental self-sufficiency, selfefficacy, self-management skills, personal agency and problem-solving skills. This paper describes the key program design features, intervention techniques, model of clinical consultation, its clinical applicability, and empirical base. The 10-session individually administered version of the program, known as Standard Stepping Stones Triple P is described and the important role of training, supervision and agency support in disseminating the program is discussed

Introduction. Traces of Terror, Signs of Trauma

The article introduces a collection of articles about the spatialization processes of memory of war in contemporary Europe. It is divided in three parts. The first part proposes a transdisciplinary perspective, which includes semiotics, to tackle the relations between space, heritage and cultural memory and to analyse memory narratives conveyed by places. An approach based on the investigation of "terrorscapes" (places with a high density of traces) is proposed. The second part delves on the notion of terrorscapes, focusing on the meaning of "terror" and on the shift of paradigm in European politics of memory after 1989. The third part deals with the European space of memory, questioning the possibility of construction of a shared European memory narrative on XX centuries wars. Last paragraph summarizes the contributions of the volume

Life cycle assessment of hydrogen-powered city buses in the High V.LO-City project: integrating vehicle operation and refuelling infrastructure

During the project High V.LO-City, which ended in December 2019, 14 hydrogen fuel cell buses were operated in four European cities. This paper aims at presenting total emissions through the lifetime of fuel cell buses with different hydrogen production options, including the refuelling stations. The environmental assessment of such bus system is carried out using the life cycle assessment methodology. Three hydrogen production pathways are investigated: water electrolysis, chlor-alkali electrolysis and steam methane reforming. Fuel economy during bus operation is around 10.25 KgH2/100 km, and the refuelling station energy demand ranges between 7 and 9 KWh/KgH2. To support the inventory stage, dedicated software tools were developed for collecting and processing a huge amount of bus data and refuelling station performance, for automating data entry and for impacts calculation. The results show that hydrogen-powered buses, compared to a diesel bus, have the potential to reduce emissions during the use phase, if renewables resources are used. On the other hand, impacts from the vehicle production, including battery pack and fuel cell stack, still dominate environmental load. Consequently, improving the emission profile of fuel cell bus system requires to promote clean electricity sources to supply a low-carbon hydrogen and to sharpen policy focus regarding life cycle management and to counter potential setbacks, in particular those related to problem shifting and to grid improvement. For hazardous emissions and resource use, the high energy intensity of mining and refining activities still poses challenges on how to further enhance the environmental advantages of fuel cells and battery packs

Predicting future cancer burden in the United States by artificial neural networks

Aims: To capture the complex relationships between risk factors and cancer incidences in the US and predict future cancer burden. Materials & methods: Two artificial neural network (ANN) algorithms were adopted: a multilayer feed-forward network (MLFFNN) and a nonlinear autoregressive network with eXogenous inputs (NARX). Data on the incidence of the four most common tumors (breast, colorectal, lung and prostate) from 1992 to 2016 (available from National Cancer Institute online datasets) were used for training and validation, and data until 2050 were predicted. Results: The rapid decreasing trend of prostate cancer incidence started in 2010 will continue until 2018–2019; it will then slow down and reach a plateau after 2050, with several differences among ethnicities. The incidence of breast cancer will reach a plateau in 2030, whereas colorectal cancer incidence will reach a minimum value of 35 per 100,000 in 2030. As for lung cancer, the incidence will decrease from 50 per 100,000 (2017) to 31 per 100,000 in 2030 and 26 per 100,000 in 2050. Conclusion: This up-to-date prediction of cancer burden in the US could be a crucial resource for planning and evaluation of cancer-control programs

Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications

Around 80-90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient's response to androgen ablation therapy is variable, and 20-30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs

Involved margins after lumpectomy for breast cancer: Always to be re-excised?

Background: The oncologic benefit of upfront re-excision of involved margins after breast-conserving surgery in the context of current multimodal clinical management of breast cancer is unclear. The aim of the present study was to assess the 5-years locoregional recurrence (LRR)-free and distant metastases (DM)-free survival probabilities in patients not undergoing re-excision of positive margins after lumpectomy for breast cancer. Methods: A cohort of 104 patients with positive margins not undergoing re-excision was matched by propensity score with a cohort of 2006 control patients with clear margins after breast-conserving surgery, treated between 2008 and 2018. A multivariate survival analysis was performed accounting for all variables related to LRR and DM, including adjuvant treatments. Results: After adjusting for potential confounders, avoiding to re-excise a positive margin after lumpectomy had no effect on 5-years LRR-free survival probability (HR 0.98, 95%CI 0.36-2.67, p = 0.96) or 5-years DM-free survival probability (HR 0.37, 95%CI 0.08-1.61, p = 0.18). No correlation was found between occurrence of LRR and number of involved margins (HR 1.28, 95%CI 0.10-12.4, Log-rank p = 0.83), or extension of infiltrating disease (HR 1.21, 95%CI 0.20-7.40, Log-rank p = 0.83), but a trend toward higher LRR probability was found for invasive ductal (HR 6.92, 95%CI 0.7-68.8, Log-rank p = 0.10) and invasive lobular cancer (HR 12.95, 95%CI 0.79-213.6, Log-rank p = 0.07) on positive margins. Conclusions: In the era of multimodal treatment of breast cancer and accurate strategies to reduce the probability of residual disease in the post-lumpectomy cavity, re-excision of positive margins might be omitted in selected patients with low-risk breast cancers

Everolimus Nanoformulation in Biological Nanoparticles Increases Drug Responsiveness in Resistant and Low-Responsive Breast Cancer Cell Lines

Everolimus (Eve) is an FDA approved drug that inhibits mammalian target of rapamycin (mTOR). It is employed in breast cancer treatment even if its responsiveness is controversial. In an attempt to increase Eve effectiveness, we have developed a novel Eve nanoformulation exploiting H-ferritin nanocages (HEve) to improve its subcellular delivery. We took advantage of the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1). Breast cancer cells overexpressing TfR-1 were successfully recognized by H-Ferritin, displaying quick nanocage internalization. HEve has been tested and compared to Eve for in vitro efficacy in sensitive and resistant breast cancer cells. Nanoformulated Eve induced remarkable antiproliferative activity in vitro, making even resistant cell lines sensitive to Eve. Moreover, the antiproliferative activity of HEve is fully in accordance with cytotoxicity observed by cell death assay. Furthermore, the significant increase in anticancer efficacy displayed in HEve-treated samples is due to the improved drug accumulation, as demonstrated by UHPLC-MS/MS quantifications. Our findings suggest that optimizing Eve subcellular delivery, thanks to nanoformulation, determines its improved antitumor activity in a panel of Eve-sensitive or resistant breast cancer cell lines

Unguided low intensity cognitive behaviour therapy for anxiety and depression during the COVID-19 pandemic: A randomised trial.

The COVID-19 pandemic has had a severe impact on mental health worldwide, with increased rates of anxiety and depression widely documented. The aim of this study was to examine unguided low intensity cognitive behaviour therapy for anxiety and depression during the pandemic. A sample of 225 individuals in Australia and the United Kingdom (M age 37.79, SD = 14.02, range 18-80 years; 85% female) were randomised into intervention or waitlist control. The intervention group demonstrated significant decreases in anxiety (d = 0.36 [0.18, 0.54]) and depression (d = 0.28 [0.11, 0.45]) compared to controls. The majority of participants (96%) rated the intervention as useful, and most (83%) reported they spent 30 min or less reading the guide, with 83% agreeing the intervention was easy to read. The results indicate that low intensity cognitive behaviour therapy has efficacy in reducing anxiety and depression during the COVID-19 pandemic. There is an urgent need to disseminate low intensity psychological therapies to improve mental health in this challenging time