Autophagy in Cancer Therapy—Molecular Mechanisms and Current Clinical Advances

Autophagy is a crucial general survival tactic of mammalian cells. It describes the capability of cells to disassemble and partially recycle cellular components (e.g., mitochondria) in case they are damaged and pose a risk to cell survival or simply if their resources are urgently needed elsewhere at the time. Autophagy-associated pathomechanisms have been increasingly recognized as important disease mechanisms in non-malignant (neurodegeneration, diffuse parenchymal lung disease) and malignant conditions alike. However, the overall consequences of autophagy for the organism depend particularly on the greater context in which autophagy occurs, such as the cell type or whether the cell is proliferating. In cancer, autophagy sustains cancer cell survival under challenging, i.e., resource-depleted, conditions. However, this leads to situations in which cancer cells are completely dependent on autophagy. Accordingly, autophagy represents a promising yet complex target in cancer treatment with therapeutically induced increase and decrease of autophagic flux as important therapeutic principles.

Relations between UN Sustainable Development Goals and societal security. Part 2

Sustainable development goals constitute the main measures of risk-oriented sustainable development. The article presents the results of a literature study on the relationship between these objectives and universal security, which indeed refers to the most important utilitarian values. In the second part, attention is drawn to seven goals: ‘accessible and clean energy’, ‘economic growth and decent work’, ‘innovation, industry, infrastructure’, ‘less inequality’, ‘sustainable cities and communities’, ‘responsible consumption and production’, and ‘climate action’. As a result of the review of the Web of Science® Data Collection database, 46 articles were selected to serve as a basis for a literature survey. In the second part of the presentation of obtained research results, we proved that issues related to general survival and social development indirectly shape universal security in sustainable development, especially in the contexts of threats to human life and health, their social nature, promptness in responding to threats, and characteristics of threats. All identified relationships can be used to improve the link between universal security and sustainable development, increasing the potential to protect core utilitarian values in light of contemporary global development strategies.

Ordering results for smallest claim amounts from two portfolios of risks with dependent heterogeneous exponentiated location-scale claims

Let $\{Y_{1},\ldots ,Y_{n}\}$ be a collection of interdependent nonnegative random variables, with $Y_{i}$ having an exponentiated location-scale model with location parameter $\mu _i$ , scale parameter $\delta _i$ and shape (skewness) parameter $\beta _i$ , for $i\in \mathbb {I}_{n}=\{1,\ldots ,n\}$ . Furthermore, let $\{L_1^{*},\ldots ,L_n^{*}\}$ be a set of independent Bernoulli random variables, independently of $Y_{i}$ 's, with $E(L_{i}^{*})=p_{i}^{*}$ , for $i\in \mathbb {I}_{n}.$ Under this setup, the portfolio of risks is the collection $\{T_{1}^{*}=L_{1}^{*}Y_{1},\ldots ,T_{n}^{*}=L_{n}^{*}Y_{n}\}$ , wherein $T_{i}^{*}=L_{i}^{*}Y_{i}$ represents the $i$ th claim amount. This article then presents several sufficient conditions, under which the smallest claim amounts are compared in terms of the usual stochastic and hazard rate orders. The comparison results are obtained when the dependence structure among the claim severities are modeled by (i) an Archimedean survival copula and (ii) a general survival copula. Several examples are also presented to illustrate the established results.

Effects of immunosuppressive therapy reduction and early post-infection graft function in kidney transplant recipients with COVID-19

Kidney transplant (KT) recipients with COVID-19 are at high risk of poor outcomes because of comorbidities and long-term immunosuppressive therapy (IST). There are little data on the effect of IST reduction and early graft function after COVID-19. We conducted a retrospective study on 45 consecutive KT recipients followed at the University Hospital of Modena who tested positive for COVID-19 by RT-PCR analysis. We detailed clinical management and outcomes of these patients. Median age of patients was 56.1 (interquartile range, [IQR] 47.3-61.1) years with a predominance of male (64.4%) and patients of Caucasian origin (91.1%). Kidney transplantation vintage was 10.1 (2.7-16) years, and more than half (55.6%) was on triple IST. Therapeutic management included antimetabolite (62.8%) and calcineurin inhibitor withdrawal (22.2%), and suspension of IST in severely ill patients. Of the 45 patients, 88.9% became symptomatic and 40% required hospitalization. Overall mortality accounted for 17.8% (n=8). There were no differences in outcomes between full- and reduced-dose IST at the end of follow-up. Overall, early graft function after COVID-19 showed a stable and unmodified kidney function in 95% of survivors. Risk factors for death were age (odds ratio [OR]: 1.19; 95% CI: 1.01-1.39), and years spent on immunosuppression (OR: 1.96; 95% CI: 0.38-10.03-4.9). One patient experienced symptomatic reinfection with COVID-19 after primary infection and anti-SARS-CoV-2 mRNA vaccine. COVID-19 impacted the graft and general survival of KT recipients. Short-term graft outcome after COVID-19 was favorable in most survivors. Age and transplantation vintage are independent predictors of death in our patients.

Post-Cryo Survival of Rat Testicular Interstitial Cells in Hydroxyethyl Starch-Based Media

The development of cryoprotective serum-free or xeno-free media is required for safe use of cryopreserved testicular material for transplantation. In this study, the solutions containing 10% fetal bovine serum (FBS) or 5 mg/ml bovine serum albumin (BSA) did not significantly enhance the general survival of interstitial cells (ICs) after cryopreservation but increase their metabolic activity and steroid producing cell (HSD+-cells) survival. The use of 50 and 100 mg/ml hydroxyethyl starch (HES) in DMSO-based cryoprotective solutions instead of BSA or FBS enabled the improvement of the IC general survival and the survival of HSD+-cells. The use of HES supplemented media allowed to decrease the dimethyl sulfoxide (DMSO) concentration from 1.4 to 0.7 M and to preserve the amount and metabolic activity of ICs. Thus, designing cryoprotective media containing DMSO and HES can facilitate the formulation of serum-free solutions for cryopreservation that in turn paves a way for implementation of the use of cryopreserved material for practical medicine.

Salt-Laden Winter Runoff and Freshwater Mussels; Assessing the Effect on Early Life Stages in the Laboratory and Wild Mussel Populations in Receiving Waters

The widespread use of road salt for winter road maintenance has led to an increase in the salinity of surface water in many seasonally cold areas. Freshwater mussels have a heightened sensitivity to salt, which is a concern, because many Canadian mussel species at risk have ranges limited to southern Ontario, Canada’s most road-dense region. This study examined the effect of winter road runoff on freshwater mussels. The impact of two bridges that span mussel habitat in the Thames River watershed (Ontario, Canada), the second most species-rich watershed for mussels in Canada, were studied. During a winter melt event, bridge runoff, as well as creek surface water surrounding the bridges were collected. Chloride concentrations in samples from bridge deck and tile drains varied (99–8250 mg/L). In general, survival of Lampsilis fasciola glochidia exposed to those samples reflected chloride levels (e.g. 84% at 99 mg/L; 0% at 8250 mg/L), although potassium (60 mg/L) may have at least contributed to toxicity in one sample. Serial dilution exposures with the two most toxic runoff samples revealed 48-h glochidia EC50s of 44% (McGregor Creek Tile Drain) and 26% (Baptiste Creek Deck Drain). During the melt event, the chloride concentrations in creek surface waters downstream of the bridges ranged from 69 to 179 mg Cl−/L; effects on glochidia (viability 77–91%) exposed to those waters was minimal. There were no live mussels surrounding one bridge (Baptiste Creek), likely due to poor habitat. At the other targeted bridge (McGregor Creek), fewer mussels were found close (< 100 m up- or downstream) to the bridge than further (> 200 m) away. However, other contributing factors, including agriculture, were present at both study areas.

Memory shapes microbial populations

Correct decision making is fundamental for all living organisms to thrive under environmental changes. The patterns of environmental variation and the quality of available information define the most favourable strategy among multiple options, including sensing and reacting to environmental cues or randomly adopting a phenotypic state. Memory – a phenomenon often associated with, but not restricted to, higher multicellular organisms – can help when temporal correlations exist. How does memory manifest itself in unicellular organisms? Through a combination of deterministic modelling and stochastic simulations, we describe the population-wide fitness consequences of phenotypic memory in microbial populations. Moving beyond binary switching models, our work highlights the need to consider a broader range of switching behaviours when describing microbial adaptive strategies. We show that multiple cellular states capture the empirical observations of lag time distributions, overshoots, and ultimately the phenomenon of phenotypic heterogeneity. We emphasise the implications of our work in understanding antibiotic tolerance, and, in general, survival under fluctuating environments.

Is it important to maintain the reverse remodeling?

Background Consistent advances in Heart Failure (HF) treatment have generated a new phenotype: reverse remodelling (RR). These patients have better outcomes than those who don't achieve the RR, however little is known about the long-term remodelling maintenance and its predictors or about a new worsening on ejection fraction (EF). Purpose To analyze the difference between patients who maintain the RR, those who can not maintain it and those who have not improved. Methods Observational study that analyzed features in outpatients with HF and initial EF lower than 40%, an intermediary EF, and last EF in 2014, 2015 and 2016, with a minimal interval of 6 months. Patients were divided into 3 groups: Negative RR (NRR - All EF &lt;40%); non-maintained RR (NMRR – 2nd EF &gt;40% and 3rd EF&lt;40%) and Maintained RR (MRR – 2nd and 3rd EF &gt;40%). Comparisons were made by Kruskal-Wallis test and the survival was analyzed by Kaplan Meyer and Log-Rank tests. Results 1762 medical records were analyzed and 1484 were included. 993 patients had NRR, 201 patients had NMRR and 290 patients had MRR. The initial EF was lower in the NRR group. In the first 3 years, the groups NMRR and MRR improve the EF by 16.4% (±1.2) and 18.1% (±1.1), respectively. During the next 3 years, the NMRR group lost this improvement (−16.1% ±1.1), while the MRR group maintained it (0.7% ±1.4). The MRR group had more hypertension (0.75±0.05) as comorbidity, while the NMRR had more myocardial infarction (0.39±0.07) and myocardial revascularization (0.17±0.05). Chagasic and alcoholic aetiologies predominated in the NRR group (0.05±0.01 and 0.19±0.02) and these patients had less valvar cause (0.04±0.01). The NMRR group had more ischemic aetiology (0.41±0.07), and the MRR had more hypertensive (0.22±0.05). General survival was different between the three groups (p&lt;0.001) major in MRR, NMRR and NRR group, respectively. Survival after the last EF also was significantly different between the groups (p&lt;0.001) with the same pattern. Conclusion Achieving RR is important, but maintaining it can bring better outcomes and prognosis. Therefore, it is important to identify factors and therapeutic goals for the RR maintenance. Figure 1 Funding Acknowledgement Type of funding source: None