Blood parameters of adult marsh frogs Pelophylax ridibundus (Amphibia: Ranidae) in rice paddies subjected to intense agrochemical use.

We present the results of an in situ study of a set of blood parameters in adult marsh frogs (Pelophylax ridibundus (Pallas 1771) from populations inhabiting the largest system of rice fields in Bulgaria, the Tsalapitsa rice fields (TRF), under chronic stress conditions. This study was conducted in spring 2022 to assess the health status of TRF frogs compared to that of frogs occupying a reference site (RS). Furthermore, this study also compared the results obtained for the TRF population with those obtained in a study conducted at the exact same location with P. ridibundus individuals in 2013 (Zhelev et al. 2018). This comparison highlights the potential effects of persistent use of agrochemicals (pesticides and fertilizers) on the marsh frogs of later generations. Our results suggest that the general health of marsh frogs in the polluted site (PS) in southern Bulgaria has severely deteriorated. Frogs of both sexes were anemic with weakened immune systems compared to those living in the RS. The long-term use of agrochemicals in the PS affected males to a greater extent than it did females. Statistically significant hypochromia was observed in males, combined with general leukopenia, neutrophilia, lymphopenia, monocytosis, eosinophilia, and higher neutrophil/lymphocyte (N/L) ratios.

Remote monitoring for long-term physical health conditions: an evidence and gap map.

Background: Remote monitoring involves the measurement of an aspect of a patient's health without that person being seen face to face. It could benefit the individual and aid the efficient provision of health services. However, remote monitoring can be used to monitor different aspects of health in different ways. This evidence map allows users to find evidence on different forms of remote monitoring for different conditions easily to support the commissioning and implementation of interventions. Objectives: The aim of this map was to provide an overview of the volume, diversity and nature of recent systematic reviews on the effectiveness, acceptability and implementation of remote monitoring for adults with long-term physical health conditions. Data sources: We searched MEDLINE, nine further databases and Epistemonikos for systematic reviews published between 2018 and March 2022, PROSPERO for continuing reviews, and completed citation chasing on included studies. Review methods: (Study selection and Study appraisal): Included systematic reviews focused on adult populations with a long-term physical health condition and reported on the effectiveness, acceptability or implementation of remote monitoring. All forms of remote monitoring where data were passed to a healthcare professional as part of the intervention were included. Data were extracted on the characteristics of the remote monitoring intervention and outcomes assessed in the review. AMSTAR 2 was used to assess quality. Results were presented in an interactive evidence and gap map and summarised narratively. Stakeholder and public and patient involvement groups provided feedback throughout the project. Results: We included 72 systematic reviews. Of these, 61 focus on the effectiveness of remote monitoring and 24 on its acceptability and/or implementation, with some reviews reporting on both. The majority contained studies from North America and Europe (38 included studies from the United Kingdom). Patients with cardiovascular disease, diabetes and respiratory conditions were the most studied populations. Data were collected predominantly using common devices such as blood pressure monitors and transmitted via applications, websites, e-mail or patient portals, feedback provided via telephone call and by nurses. In terms of outcomes, most reviews focused on physical health, mental health and well-being, health service use, acceptability or implementation. Few reviews reported on less common conditions or on the views of carers or healthcare professionals. Most reviews were of low or critically low quality. Limitations: Many terms are used to describe remote monitoring; we searched as widely as possible but may have missed some relevant reviews. Poor reporting of remote monitoring interventions may mean some included reviews contain interventions that do not meet our definition, while relevant reviews might have been excluded. This also made the interpretation of results difficult. Conclusions and future work: The map provides an interactive, visual representation of evidence on the effectiveness of remote monitoring and its acceptability and successful implementation. This evidence could support the commissioning and delivery of remote monitoring interventions, while the limitations and gaps could inform further research and technological development. Future reviews should follow the guidelines for conducting and reporting systematic reviews and investigate the application of remote monitoring in less common conditions. Review registration: A protocol was registered on the OSF registry (https://doi.org/10.17605/OSF.IO/6Q7P4). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Services and Delivery Research programme (NIHR award ref: NIHR135450) as part of a series of evidence syntheses under award NIHR130538. For more information, visit https://fundingawards.nihr.ac.uk/award/NIHR135450 and https://fundingawards.nihr.ac.uk/award/NIHR130538. The report is published in full in Health and Social Care Delivery Research; Vol. 11, No. 22. See the NIHR Funding and Awards website for further project information.

Remote monitoring is when an aspect of a patient's health, such as blood pressure, is measured at home, and this information is passed to a healthcare professional. We created an evidence and gap map for remote monitoring in adults with long-term physical health conditions. The map is presented as an interactive online table, which can be used to find the number and quality of systematic reviews that address specific questions (e.g. remote monitoring in diabetes). The map does not summarise findings from the reviews (e.g. whether remote monitoring works or not). We found 72 reviews investigating whether remote monitoring works and/or how to implement it, including whether it is acceptable to patients, carers and healthcare professionals. Thirty-seven reviews included studies from the United Kingdom. The most common health conditions were heart disease, diabetes and lung conditions. There was little or no evidence for some health conditions (e.g. epilepsy). Data from patients were collected mainly using common devices (e.g. heart rate monitors) and passed to healthcare providers using computer applications, websites and telephone calls. Most feedback received by patients was motivational/educational. There was evidence about the acceptability of remote monitoring for patients, but little for carers and healthcare professionals. Reviews focused on whether remote monitoring affected physical and mental health, health service use, acceptability or implementation. More than half the included reviews were judged to be low quality; however, they may still include high-quality studies. The map could help to design and deliver remote monitoring programmes and guide further research and technology development. Stakeholder and public and patient representatives provided feedback throughout the project. The map contains reviews published between 2018 and March 2022.

Tolerable treatment of glioblastoma with redox-cycling 'mitocans': a comparative study in vivo.

Objectives: The present study describes a pharmacological strategy for the treatment of glioblastoma by redoxcycling 'mitocans' such as quinone/ascorbate combination drugs, based on their tumor-selective redox-modulating effects and tolerance to normal cells and tissues.Methods: Experiments were performed on glioblastoma mice (orthotopic model) treated with coenzyme Q0/ascorbate (Q0/A). The drug was injected intracranially in a single dose. The following parameters were analyzed in vivo using MRI orex vivo using conventional assays: tumor growth, survival, cerebral and tumor perfusion, tumor cell density, tissue redox-state, and expression of tumor-associated NADH oxidase (tNOX).Results: Q0/A markedly suppressed tumor growth and significantly increased survival of glioblastoma mice. This was accompanied by increased oxidative stress in the tumor but not in non-cancerous tissues, increased tumor blood flow, and downregulation of tNOX. The redox-modulating and anticancer effects of Q0/A were more pronounced than those of menadione/ascorbate (M/A) obtained in our previous study. No adverse drug-related side-effects were observed in glioblastoma mice treated with Q0/A.Discussion: Q0/A differentiated cancer cells and tissues, particularly glioblastoma, from normal ones by redox targeting, causing a severe oxidative stress in the tumor but not in non-cancerous tissues. Q0/A had a pronounced anticancer activity and could be considered safe for the organism within certain concentration limits. The results suggest that the rate of tumor resorption and metabolism of toxic residues must be controlled and maintained within tolerable limits to achieve longer survival, especially at intracranial drug administration.

Redox-Cycling "Mitocans" as Effective New Developments in Anticancer Therapy.

Our study proposes a pharmacological strategy to target cancerous mitochondria via redox-cycling "mitocans" such as quinone/ascorbate (Q/A) redox-pairs, which makes cancer cells fragile and sensitive without adverse effects on normal cells and tissues. Eleven Q/A redox-pairs were tested on cultured cells and cancer-bearing mice. The following parameters were analyzed: cell proliferation/viability, mitochondrial superoxide, steady-state ATP, tissue redox-state, tumor-associated NADH oxidase (tNOX) expression, tumor growth, and survival. Q/A redox-pairs containing unprenylated quinones exhibited strong dose-dependent antiproliferative and cytotoxic effects on cancer cells, accompanied by overproduction of mitochondrial superoxide and accelerated ATP depletion. In normal cells, the same redox-pairs did not significantly affect the viability and energy homeostasis, but induced mild mitochondrial oxidative stress, which is well tolerated. Benzoquinone/ascorbate redox-pairs were more effective than naphthoquinone/ascorbate, with coenzyme Q0/ascorbate exhibiting the most pronounced anticancer effects in vitro and in vivo. Targeted anticancer effects of Q/A redox-pairs and their tolerance to normal cells and tissues are attributed to: (i) downregulation of quinone prenylation in cancer, leading to increased mitochondrial production of semiquinone and, consequently, superoxide; (ii) specific and accelerated redox-cycling of unprenylated quinones and ascorbate mainly in the impaired cancerous mitochondria due to their redox imbalance; and (iii) downregulation of tNOX.

Health technology assessment of diagnostic tests: a state of the art review of methods guidance from international organizations.

OBJECTIVES: To identify which international health technology assessment (HTA) agencies are undertaking evaluations of medical tests, summarize commonalities and differences in methodological approach, and highlight examples of good practice. METHODS: A methodological review incorporating: systematic identification of HTA guidance documents mentioning evaluation of tests; identification of key contributing organizations and abstraction of approaches to all essential HTA steps; summary of similarities and differences between organizations; and identification of important emergent themes which define the current state of the art and frontiers where further development is needed. RESULTS: Seven key organizations were identified from 216 screened. The main themes were: elucidation of claims of test benefits; attitude to direct and indirect evidence of clinical effectiveness (including evidence linkage); searching; quality assessment; and health economic evaluation. With the exception of dealing with test accuracy data, approaches were largely based on general approaches to HTA with few test-specific modifications. Elucidation of test claims and attitude to direct and indirect evidence are where we identified the biggest dissimilarities in approach. CONCLUSIONS: There is consensus on some aspects of HTA of tests, such as dealing with test accuracy, and examples of good practice which HTA organizations new to test evaluation can emulate. The focus on test accuracy contrasts with universal acknowledgment that it is not a sufficient evidence base for test evaluation. There are frontiers where methodological development is urgently required, notably integrating direct and indirect evidence and standardizing approaches to evidence linkage.

Docosahexaenoic Acid Potentiates the Anticancer Effect of the Menadione/Ascorbate Redox Couple by Increasing Mitochondrial Superoxide and Accelerating ATP Depletion.

BACKGROUND/AIM: Mitochondria-targeted anticancer drugs ("mitocans") of natural origin are attractive candidates as adjuvants in cancer therapy. The redox couple menadione/ascorbate (M/A), which belongs to the "mitocans" family, induces selective oxidative stress in cancerous mitochondria and cells, respectively. DHA has also been found to regulate the mevalonate pathway, which is closely related to the prenylation of the cytotoxic menadione to the non-cytotoxic menaquinone. The aim of this study was to elucidate the ability of docosahexaenoic acid (DHA) to potentiate the anticancer effect of M/A by increasing ROS production, as well as affecting steady-state ATP levels in cancer cells. MATERIALS AND METHODS: The experiments were performed on leukemic lymphocyte Jurkat. Cells were treated with DHA, M/A, and their combination (M/A/DHA) and four parameters were examined using the following assays: cell viability and proliferation, steady-state ATP, mitochondrial superoxide, intracellular hydroperoxides. Three independent experiments with two or six parallel measurements were performed for each parameter. RESULTS: The triple combination M/A/DHA was characterized by much higher antiproliferative activity and cytotoxicity than M/A and DHA administered alone. DHA significantly accelerated M/A-induced ATP depletion in cells, which was accompanied by an additional increase in mitochondrial superoxide compared to cells treated with M/A or DHA alone. CONCLUSION: DHA significantly enhanced M/A-induced cytotoxicity in leukemic lymphocytes by inducing severe mitochondrial oxidative stress and accelerated ATP depletion. Selective DHA-mediated suppression of cholesterol synthesis in cancer cells (involved in the prenylation of cytotoxic menadione to the less cytotoxic phylloquinone), as well as DHA-mediated inhibition of superoxide dismutase are suggested to underlie the potentiation of the anticancer effect of M/A.

Redox-mediated Anticancer Activity of Anti-parasitic Drug Fenbendazole in Triple-negative Breast Cancer Cells.

BACKGROUND/AIM: An increasing number of studies are reporting anticancer activity of widely used antiparasitic drugs and particularly benzimidazoles. Fenbendazole is considered safe and tolerable in most animal species at the effective doses as an anthelmintic. Little is known about the redox-modulating properties of fenbendazole and the molecular mechanisms of its antiproliferative effects. Our study aimed to investigate the possibility of selective redox-mediated treatment of triple-negative breast cancer cells by fenbendazole without affecting the viability and redox status of normal breast epithelial cells. MATERIALS AND METHODS: The experiments were performed on three cell lines: normal breast epithelial cells (MCF-10A) and cancer breast epithelial cells (MCF7 - luminal adenocarcinoma, low metastatic; MDA-MB-231 - triple-negative adenocarcinoma, highly metastatic). Cells were treated with fenbendazole for 48-h and three parameters were analyzed using conventional assays: cell viability and proliferation, level of intracellular superoxide, and level of hydroperoxides. RESULTS: The data demonstrated that MDA-MB-231 cells were more vulnerable to fenbendazole-induced oxidative stress than MCF-7 cells. In normal breast epithelial cells MCF-10A, fenbendazole significantly suppressed oxidative stress compared to untreated controls. These data correlate with the effect of fenbendazole on cell viability and the IC50 values, which is indirect evidence of the potential targeting anticancer effect of the drug, especially in MDA-MB-231 cells. CONCLUSION: The difference in the levels of oxidative stress induced by fenbendazole in MDA-MB-231 and MCF-7 indicates that the two types of breast cancer respond to the drug through different redox-related mechanisms.

Test accuracy of artificial intelligence-based grading of fundus images in diabetic retinopathy screening: A systematic review.

OBJECTIVES: To systematically review the accuracy of artificial intelligence (AI)-based systems for grading of fundus images in diabetic retinopathy (DR) screening. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library and the ClinicalTrials.gov from 1st January 2000 to 27th August 2021. Accuracy studies published in English were included if they met the pre-specified inclusion criteria. Selection of studies for inclusion, data extraction and quality assessment were conducted by one author with a second reviewer independently screening and checking 20% of titles. Results were analysed narratively. RESULTS: Forty-three studies evaluating 15 deep learning (DL) and 4 machine learning (ML) systems were included. Nine systems were evaluated in a single study each. Most studies were judged to be at high or unclear risk of bias in at least one QUADAS-2 domain. Sensitivity for referable DR and higher grades was ≥85% while specificity varied and was <80% for all ML systems and in 6/31 studies evaluating DL systems. Studies reported high accuracy for detection of ungradable images, but the latter were analysed and reported inconsistently. Seven studies reported that AI was more sensitive but less specific than human graders. CONCLUSIONS: AI-based systems are more sensitive than human graders and could be safe to use in clinical practice but have variable specificity. However, for many systems evidence is limited, at high risk of bias and may not generalise across settings. Therefore, pre-implementation assessment in the target clinical pathway is essential to obtain reliable and applicable accuracy estimates.

Serial high-sensitivity cardiac troponin testing for the diagnosis of myocardial infarction: a scoping review.

OBJECTIVES: We aimed to assess the diversity and practices of existing studies on several assays and algorithms for serial measurements of high-sensitivity cardiac troponin (hs-cTn) for risk stratification and the diagnosis of myocardial infarction (MI) and 30-day outcomes in patients suspected of having non-ST-segment elevation MI (NSTEMI). METHODS: We searched multiple databases including MEDLINE, EMBASE, Science Citation Index, the Cochrane Database of Systematic Reviews and the CENTRAL databases for studies published between January 2006 and November 2021. Studies that assessed the diagnostic accuracy of serial hs-cTn testing in patients suspected of having NSTEMI in the emergency department (ED) were eligible. Data were analysed using the scoping review method. RESULTS: We included 86 publications, mainly from research centres in Europe, North America and Australasia. Two hs-cTn assays, manufactured by Abbott (43/86) and Roche (53/86), dominated the evaluations. The studies most commonly measured the concentrations of hs-cTn at two time points, at presentation and a few hours thereafter, to assess the two-strata or three-strata algorithm for diagnosing or ruling out MI. Although data from 83 studies (97%) were prospectively collected, 0%-90% of the eligible patients were excluded from the analysis due to missing blood samples or the lack of a final diagnosis in 53 studies (62%) that reported relevant data. Only 19 studies (22%) reported on head-to-head comparisons of alternative assays. CONCLUSION: Evidence on the accuracy of serial hs-cTn testing was largely derived from selected research institutions and relied on two specific assays. The proportions of the eligible patients excluded from the study raise concerns about directly applying the study findings to clinical practice in frontline EDs. PROSPERO REGISTRATION NUMBER: CRD42018106379.

Electroporation, electrochemotherapy and electro-assisted drug delivery in cancer. A state-of-the-art review.

This review focuses on electrochemotherapy that consists in the delivery of anti-cancer drugs using high-voltage electrical pulses. Technical issues, choice of drugs, and protocol of drug delivery are still under investigation and no consensus has been achieved yet. The different aspects of electrochemotherapy are discussed in the present paper. It includes interrogations about the choice of the preferred anti-cancer drug and dose to be delivered on the solid tumors. Another promising area is related to the electro-assisted release of nanoparticles (quantum dots) in xenografted solid tumors. Molecular mechanisms of enhanced drug delivery are discussed in terms of high cholesterol level and large fraction of lipid rafts in cancer cells. Electrochemotherapy is a paradigmatic example of cooperation between physicists, biophysicists, chemists, technicians, manufacturers, biologists, clinicians, and patients to improve a very promising treatment delivery in line with the conception of personalized medicine.

Cellular redox imbalance on the crossroad between mitochondrial dysfunction, senescence, and proliferation.

Recent studies demonstrate that redox imbalance of NAD+/NADH and NADP+/NADPH pairs due to impaired respiration may trigger two "hidden" metabolic pathways on the crossroad between mitochondrial dysfunction, senescence, and proliferation: "ß-oxidation shuttle" and "hydride transfer complex (HTC) cycle". The "ß-oxidation shuttle" induces NAD+/NADH redox imbalance in mitochondria, while HTC cycle maintains the redox balance of cytosolic NAD+/NADH, increasing the redox disbalance of NADP+/NADPH. Senescence appears to depend on high cytoplasmic NADH but low NADPH, while proliferation depends on high cytoplasmic NAD+ and NADPH that are under mitochondrial control. Thus, activating or deactivating the HTC cycle can be crucial to cell fate - senescence or proliferation. These pathways are a source of enormous cataplerosis. They support the production of large amounts of NADPH and intermediates for lipid synthesis and membrane biogenesis, as well as for DNA synthesis.

Are there correlations between the levels of fluctuating asymmetry in Pelophylax ridibundus (Anura: Ranidae) meristic morphological traits and morphological parameters used for assessing their physical fitness (health status)?

The degree of developmental stability of individuals and populations is most often estimated by their level of fluctuating asymmetry (FA) - the random deviations from perfect symmetry. In our previous work, we recorded high levels of FA (FAMI index: frequency of asymmetric manifestation of an individual) in Pelophylax ridibundus populations that inhabit biotopes at Sazliyka River, south Bulgaria with high levels of anthropogenic pollution (domestic sewage pollution). At the same time, in the biotopes located in the upper reaches of the river (less disrupted habitats), the populations showed low levels of FA. Currently, we present the results of the study of the values of several morphological parameters: snout-vent length (SVL), body weight (BW), and body condition factor (CF) in the same populations of P. ridibundus. In addition, we evaluate the correlation between the values of these morphological parameters and the values of fluctuating asymmetry (the FAMI index), using the Kendall rank correlation analysis. The analysis of the relationships between the parameters characterizing the physical fitness of frogs and the indicator of developmental stability - the FAMI index - did not establish statistically significant correlations in the analyses in the whole groups of P. ridibundus from each site and in the correlations between sexes. We believe that the approaches to the study of developmental stability (analysis of fluctuating asymmetry levels) and those related to the assessment of physical fitness (health status) of frogs should be applied independently of each other.

A "Weird" Mitochondrial Fatty Acid Oxidation as a Metabolic "Secret" of Cancer.

Cancer metabolism is an extensively studied field since the discovery of the Warburg effect about 100 years ago and continues to be increasingly intriguing and enigmatic so far. It has become clear that glycolysis is not the only abnormally activated metabolic pathway in the cancer cells, but the same is true for the fatty acid synthesis (FAS) and mevalonate pathway. In the last decade, a lot of data have been accumulated on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. In this article, we discuss how mFAO can escape normal regulation under certain conditions and be overactivated. Such abnormal activation of mitochondrial ß-oxidation can also be combined with mutations in certain enzymes of the Krebs cycle that are common in cancer. If overactivated ß-oxidation is combined with other common cancer conditions, such as dysfunctions in the electron transport complexes, and/or hypoxia, this may alter the redox state of the mitochondrial matrix. We propose the idea that the altered mitochondrial redox state and/or inhibited Krebs cycle at certain segments may link mitochondrial ß-oxidation to the citrate-malate shuttle instead to the Krebs cycle. We call this abnormal metabolic condition "ß-oxidation shuttle". It is unconventional mFAO, a separate metabolic pathway, unexplored so far as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and ultimately a source of proliferation. It is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathway.

Targeting Glioblastoma via Selective Alteration of Mitochondrial Redox State.

Glioblastoma is one of the most aggressive brain tumors, characterized by a pronounced redox imbalance, expressed in a high oxidative capacity of cancer cells due to their elevated glycolytic and mitochondrial oxidative metabolism. The assessment and modulation of the redox state of glioblastoma are crucial factors that can provide highly specific targeting and treatment. Our study describes a pharmacological strategy for targeting glioblastoma using a redox-active combination drug. The experiments were conducted in vivo on glioblastoma mice (intracranial model) and in vitro on cell lines (cancer and normal) treated with the redox cycling pair menadione/ascorbate (M/A). The following parameters were analyzed in vivo using MRI or ex vivo on tissue and blood specimens: tumor growth, survival, cerebral perfusion, cellular density, tissue redox state, expression of tumor-associated NADH oxidase (tNOX) and transforming growth factor-beta 1 (TGF-ß1). Dose-dependent effects of M/A on cell viability, mitochondrial functionality, and redox homeostasis were evaluated in vitro. M/A treatment suppressed tumor growth and significantly increased survival without adverse side effects. This was accompanied by increased oxidative stress, decreased reducing capacity, and decreased cellular density in the tumor only, as well as increased cerebral perfusion and down-regulation of tNOX and TGF-ß1. M/A induced selective cytotoxicity and overproduction of mitochondrial superoxide in isolated glioblastoma cells, but not in normal microglial cells. This was accompanied by a significant decrease in the over-reduced state of cancer cells and impairment of their "pro-oncogenic" functionality, assessed by dose-dependent decreases in: NADH, NAD+, succinate, glutathione, cellular reducing capacity, mitochondrial potential, steady-state ATP, and tNOX expression. The safety of M/A on normal cells was compromised by treatment with cerivastatin, a non-specific prenyltransferase inhibitor. In conclusion, M/A differentiates glioblastoma cells and tissues from normal cells and tissues by redox targeting, causing severe oxidative stress only in the tumor. The mechanism is complex and most likely involves prenylation of menadione in normal cells, but not in cancer cells, modulation of the immune response, a decrease in drug resistance, and a potential role in sensitizing glioblastoma to conventional chemotherapy.

Over-Reduced State of Mitochondria as a Trigger of "ß-Oxidation Shuttle" in Cancer Cells.

A considerable amount of data have accumulated in the last decade on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. As a result, mFAO was found to coexist with abnormally activated fatty acid synthesis (FAS) and the mevalonate pathway. Recent studies have demonstrated that overactivated mitochondrial ß-oxidation may aggravate the impaired mitochondrial redox state and vice versa. Furthermore, the impaired redox state of cancerous mitochondria can ensure the continuous operation of ß-oxidation by disconnecting it from the Krebs cycle and connecting it to the citrate-malate shuttle. This could create a new metabolic state/pathway in cancer cells, which we have called the "ß-oxidation-citrate-malate shuttle", or "ß-oxidation shuttle" for short, which forces them to proliferate. The calculation of the phosphate/oxygen ratio indicates that it is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathways. The "ß-oxidation shuttle" is an unconventional mFAO, a separate metabolic pathway that has not yet been explored as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and, ultimately, a source of proliferation. The role of the "ß-oxidation shuttle" and its contribution to redox-altered cancer metabolism provides a new direction for the development of future anticancer strategies. This may represent the metabolic "secret" of cancer underlying hypoxia and genomic instability.

A Unified Approach to Analysis of Body Condition in Green Toads.

Body condition is increasingly used to assess the status of populations and as a proxy for individual fitness. A common, quick and non-invasive approach is to estimate condition from the relation between body length and mass. Among the methods developed for this purpose, the Scaled Mass Index (SMI) appears best suited for comparisons among populations. We assembled data from 17 populations of European green toads (Bufotes viridis) with the aim of devising a standard formula applicable for monitoring this species. The mean value of the exponents describing length-mass allometry in these samples was 3.0047. Hence, we propose using 3 as a scaling coefficient for calculating the SMI in green toads. From the contrast of SMI values for both sexes within populations, estimated with either the population-specific or the standard coefficient, we conclude that applying the standard formula not only facilitates comparisons among populations but may also help to avoid misinterpretation of variation within populations.

Effect of Alpha-tocopheryl Succinate on the Cytotoxicity of Anticancer Drugs Towards Leukemia Lymphocytes.

BACKGROUND/AIM: This study analysed the effect of α-tocopheryl succinate (α-TS) on the redox-state of leukemia and normal lymphocytes, as well as their sensitization to fifteen anticancer drugs. MATERIALS AND METHODS: Cell viability was analyzed by trypan blue staining and automated counting of live and dead cells. Apoptosis was analyzed by FITC-Annexin V test. Oxidative stress was evaluated by the intracellular levels of reactive oxygen species (ROS) and protein-carbonyl products. RESULTS: Most combinations (α-TS plus anticancer drug) exerted additive or antagonistic effects on the proliferation and viability of leukemia lymphocytes. α-TS combined with barasertib, bortezomib or lonafarnib showed a strong synergistic cytotoxic effect, which was best expressed in the case of barasestib. It was accompanied by impressive induction of apoptosis and increased production of ROS, but insignificant changes in protein-carbonyl levels. α-TS plus barasertib did not alter the viability and did not induce oxidative stress and apoptosis in normal lymphocytes. CONCLUSION: α-TS could be a promising adjuvant in second-line anticancer therapy, particularly in acute lymphoblastic leukemia, to reduce the therapeutic doses of barasertib, bortezomib, and lonafarnib, increasing their effectiveness and minimizing their side effects.

It was not easy to identify the study design from the title and abstract of articles indexed as diagnostic (test) accuracy studies in EMBASE in 2012 and 2019.

OBJECTIVE: To quantify use of shorthand description of research design in the titles and abstracts of diagnostic test accuracy studies, comparing 2012 and 2019. STUDY DESIGN AND SETTING: Joint examination, using pre-specified criteria, by two investigators of 320 randomly sampled articles indexed as "diagnostic (test) accuracy studies" in EMBASE in 2012 and 2019. RESULTS: The percentage of abstracts with shorthand descriptions of study design was 11% in 2012 and 15% in 2019, a difference of 4% (95% CI -3, 12). Although use of the term accuracy in the abstract did increase (58% in 2012 to 74% in 2019, difference 16% (95% CI 5, 26)), accuracy was only used to convey purpose or design in 49% (95% CI 43, 56) of abstracts where accuracy appeared (2012+2019). CONCLUSION: It is difficult to identify the study design of test evaluations from information in the title and abstract. This is important because bias is associated with different study designs. Developing a limited number of standardised, widely understood study design descriptions could greatly improve clarity of the only freely available information on many pieces of medical research. It may be helpful that the fact that a study addresses test accuracy be part of shorthand descriptions.

Nitroxyl Radical as a Theranostic Contrast Agent in Magnetic Resonance Redox Imaging.

Significance:In vivo assessment of paramagnetic and diamagnetic conversions of nitroxyl radicals based on cyclic redox mechanism can be an index of tissue redox status. The redox mechanism of nitroxyl radicals, which enables their use as a normal tissue-selective radioprotector, is seen as being attractive on planning radiation therapy. Recent Advances:In vivo redox imaging using nitroxyl radicals as redox-sensitive contrast agents has been developed to assess tissue redox status. Chemical and biological behaviors depending on chemical structures of nitroxyl radical compounds have been understood in detail. Polymer types of nitroxyl radical contrast agents and/or nitroxyl radical-labeled drugs were designed for approaching theranostics. Critical Issues: Nitroxyl radicals as magnetic resonance imaging (MRI) contrast agents have several advantages compared with those used in electron paramagnetic resonance (EPR) imaging, while support by EPR spectroscopy is important to understand information from MRI. Redox-sensitive paramagnetic contrast agents having a medicinal benefit, that is, nitroxyl-labeled drug, have been developed and proposed. Future Directions: A development of suitable nitroxyl contrast agent for translational theranostic applications with high reaction specificity and low normal tissue toxicity is under progress. Nitroxyl radicals as redox-sensitive magnetic resonance contrast agents can be a useful tool to detect an abnormal tissue redox status such as disordered oxidative stress. Antioxid. Redox Signal. 36, 95-121.