Miracle-dz/UniFAR-FTUs huggingface dataset:
UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation

Simple Summary The use of multi-gene testing platforms to individualize treatment is rapidly expanding into routine oncology practice. UGT1A1, which encodes for the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme, is commonly included on multi-gene molecular testing assays. UGT1A1 polymorphisms may influence drug-induced toxicities of numerous medications used in oncology. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is sparse and can differ depending on the referenced resource. We summarize the literature describing associations between UGT1A1 polymorphisms and toxicity risk with irinotecan, belinostat, pazopanib, and nilotinib. Resources that provide recommendations for UGT1A1-guided drug prescribing are reviewed, and considerations for implementation into patient care are provided. Abstract Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.
Asthma and Chronic Rhinosinusitis: How Similar Are They in Pathogenesis and Treatment Responses?

Severe asthma and rhinosinusitis represent frequent comorbidities, complicating the overall management of the disease. Both asthma and chronic rhinosinusitis (CRS) can be differentiated into endotypes: those with type 2 eosinophilic inflammation and those with a non-type 2 inflammation. A correct definition of phenotype/endotype for these diseases is crucial, taking into account the availability of novel biological therapies. Even though patients suffering from type 2 severe asthma—with or without CRS with nasal polyps—significantly benefit from treatment with biologics, the existence of different levels of patient response has been clearly demonstrated. In fact, in clinical practice, it is a common experience that patients reach a good clinical response for asthma symptoms, but not for CRS. At first glance, a reason for this could be that although asthma and CRS can coexist in the same patient, they can manifest with different degrees of severity; therefore, efficacy may not be equally achieved. Many questions regarding responders and nonresponders, predictors of response, and residual disease after blocking type 2 pathways are still unanswered. In this review, we discuss whether treatment with biological agents is equally effective in controlling both asthma and sinonasal symptoms in patients in which asthma and chronic rhinosinusitis with nasal polyps coexist.
The Effect of Liquid Rubber Addition on the Physicochemical Properties, Cytotoxicity, and Ability to Inhibit Biofilm Formation of Dental Composites

The aim of this study was to evaluate the effect of modification with liquid rubber on the adhesion to tooth tissues (enamel, dentin), wettability and ability to inhibit bacterial biofilm formation of resin-based dental composites. Two commercial composites (Flow-Art–flow type with 60% ceramic filler and Boston–packable type with 78% ceramic filler; both from Arkona Laboratorium Farmakologii Stomatologicznej, Nasutów, Poland) were modified by addition of 5% by weight (of resin) of a liquid methacrylate-terminated polybutadiene. Results showed that modification of the flow type composite significantly (p < 0.05) increased the shear bond strength values by 17% for enamel and by 33% for dentine. Addition of liquid rubber significantly (p < 0.05) reduced also hydrophilicity of the dental materials since the water contact angle was increased from 81–83° to 87–89°. Interestingly, modified packable type material showed improved antibiofilm activity against Steptococcus mutans and Streptococcus sanguinis (quantitative assay with crystal violet), but also cytotoxicity against eukaryotic cells since cell viability was reduced to 37% as proven in a direct-contact WST-8 test. Introduction of the same modification to the flow type material significantly improved its antibiofilm properties (biofilm reduction by approximately 6% compared to the unmodified material, p < 0.05) without cytotoxic effects against human fibroblasts (cell viability near 100%). Thus, modified flow type composite may be considered as a candidate to be used as restorative material since it exhibits both nontoxicity and antibiofilm properties.
High-Protein or Low Glycemic Index Diet—Which Energy-Restricted Diet Is Better to Start a Weight Loss Program?

Background: To date, no crossover studies have compared the effects of high-protein (HP) and low glycemic index (LGI) diets applied as starting energy-restricted diets. Methods: Thirty-five overweight or obese volunteers with sedentary lifestyles aged 41.4 ± 11.0 years, with body mass index (BMI) of 33.6 ± 4.2 kg/m2, without diabetes, completed an 8-week randomized crossover study of an energy-restricted diet (reduction of 30%; approximately 600 kcal/day). The anthropometric parameters, body composition, 24 h blood pressure, and basic metabolic profile were measured at baseline and after completing the two 4-week diets; i.e., the HP (protein at 30% of the daily energy intake) or LGI diet, followed by the opposite diet. All subjects maintained food diaries and attended six counselling sessions with a clinical dietitian. Results: The final weight loss was not significantly different when the HP diet was used first but was associated with a greater loss of fat mass: 4.6 kg (5.8; 3.0 kg) vs. 2.2 (4.5; 0.8); p < 0.025, preserved muscle mass, and reduced LDL-cholesterol. Conclusions: A short-term HP diet applied as a jump-start diet appeared to be more beneficial than an LGI diet, as indicated by the greater fat mass loss, preservation of muscle mass, and better effects on the lipid profile.
Noncoding RNAs in Glioblastoma: Emerging Biological Concepts and Potential Therapeutic Implications

Simple Summary Since the completion of the Human Genome Project, noncoding RNAs (ncRNAs) have emerged as an important class of genetic regulators. Several classes of ncRNAs, which include microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), have been shown to play important roles in controlling developmental and disease processes. In this article, we discuss the potential roles of ncRNAs in regulating glioblastoma (GBM) formation and progression as well as potential strategies to exploit the diagnostic and therapeutic potential of ncRNAs in GBM. Abstract Noncoding RNAs (ncRNAs) have emerged as a novel class of genomic regulators, ushering in a new era in molecular biology. With the advent of advanced genetic sequencing technology, several different classes of ncRNAs have been uncovered, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), which have been linked to many important developmental and disease processes and are being pursued as clinical and therapeutic targets. Molecular phenotyping studies of glioblastoma (GBM), the most common and lethal cancer of the adult brain, revealed that several ncRNAs are frequently dysregulated in its pathogenesis. Additionally, ncRNAs regulate many important aspects of glioma biology including tumour cell proliferation, migration, invasion, apoptosis, angiogenesis, and self-renewal. Here, we present an overview of the biogenesis of the different classes of ncRNAs, discuss their biological roles, as well as their relevance to gliomagenesis. We conclude by discussing potential approaches to therapeutically target the ncRNAs in clinic.
Coffee and Lower Risk of Type 2 Diabetes: Arguments for a Causal Relationship

Prospective epidemiological studies concur in an association between habitual coffee consumption and a lower risk of type 2 diabetes. Several aspects of these studies support a cause–effect relationship. There is a dependency on daily coffee dose. Study outcomes are similar in different regions of the world, show no differences between sexes, between obese versus lean, young versus old, smokers versus nonsmokers, regardless of the number of confounders adjusted for. Randomized controlled intervention trials did not find a consistent impact of drinking coffee on acute metabolic control, except for effects of caffeine. Therefore, lowering of diabetes risk by coffee consumption does not involve an acute effect on the post-meal course of blood glucose, insulin or insulin resistance. Several studies in animals and humans find that the ingestion of coffee phytochemicals induces an adaptive cellular response characterized by upregulation and de novo synthesis of enzymes involved in cell defense and repair. A key regulator is the nuclear factor erythroid 2-related factor 2 (Nrf2) in association with the aryl hydrocarbon receptor, AMP-activated kinase and sirtuins. One major site of coffee actions appears to be the liver, causing improved fat oxidation and lower risk of steatosis. Another major effect of coffee intake is preservation of functional beta cell mass via enhanced mitochondrial function, lower endoplasmic reticulum stress and prevention or clearance of aggregates of misfolded proinsulin or amylin. Long-term preservation of proper liver and beta cell function may account for the association of habitual coffee drinking with a lower risk of type 2 diabetes, rather than acute improvement of metabolic control.
Negative Regulation of the Innate Immune Response through Proteasomal Degradation and Deubiquitination

The rapid and dynamic activation of the innate immune system is achieved through complex signaling networks regulated by post-translational modifications modulating the subcellular localization, activity, and abundance of signaling molecules. Many constitutively expressed signaling molecules are present in the cell in inactive forms, and become functionally activated once they are modified with ubiquitin, and, in turn, inactivated by removal of the same post-translational mark. Moreover, upon infection resolution a rapid remodeling of the proteome needs to occur, ensuring the removal of induced response proteins to prevent hyperactivation. This review discusses the current knowledge on the negative regulation of innate immune signaling pathways by deubiquitinating enzymes, and through degradative ubiquitination. It focusses on spatiotemporal regulation of deubiquitinase and E3 ligase activities, mechanisms for re-establishing proteostasis, and degradation through immune-specific feedback mechanisms vs. general protein quality control pathways.
Realizing Innate Potential: CAR-NK Cell Therapies for Acute Myeloid Leukemia

Simple Summary Infusions of T-cells genetically modified to recognize the protein CD19 (CD19 CAR-T cells) have proven a potent form of cancer therapy for certain cancers arising from B-cells. These treatments, while revolutionary, remain expensive to manufacture using a patients’ own cells and can have considerable side effects. There is great interest in improving upon and expanding the reach of these new treatments to other cancer types. Natural killer (NK) cells are an alternative cell population with unique properties which can also be modified to recognize specific proteins (CAR-NK cells). The properties of CAR-NK cells should allow manufacturing from healthy donor cells with rapid availability and potentially fewer side effects. NK cells have an innate ability to target acute myeloid leukemia (AML). In this review article, we consider the potential that CAR-NK cells possess to enhance this effect and offer a new type of immunotherapy for AML. Abstract Next-generation cellular immunotherapies seek to improve the safety and efficacy of approved CD19 chimeric antigen receptor (CAR) T-cell products or apply their principles across a growing list of targets and diseases. Supported by promising early clinical experiences, CAR modified natural killer (CAR-NK) cell therapies represent a complementary and potentially off-the-shelf, allogeneic solution. While acute myeloid leukemia (AML) represents an intuitive disease in which to investigate CAR based immunotherapies, key biological differences to B-cell malignancies have complicated progress to date. As CAR-T cell trials treating AML are growing in number, several CAR-NK cell approaches are also in development. In this review we explore why CAR-NK cell therapies may be particularly suited to the treatment of AML. First, we examine the established role NK cells play in AML biology and the existing anti-leukemic activity of NK cell adoptive transfer. Next, we appraise potential AML target antigens and consider common and unique challenges posed relative to treating B-cell malignancies. We summarize the current landscape of CAR-NK development in AML, and potential targets to augment CAR-NK cell therapies pharmacologically and through genetic engineering. Finally, we consider the broader landscape of competing immunotherapeutic approaches to AML treatment. In doing so we evaluate the innate potential, status and remaining barriers for CAR-NK based AML immunotherapy.
Transgenic Expression of dsRNA Targeting the Pentalonia nigronervosa acetylcholinesterase Gene in Banana and Plantain Reduces Aphid Populations

The banana aphid, Pentalonia nigronervosa, is the sole insect vector of banana bunchy top virus (BBTV), the causal agent of banana bunchy top disease. The aphid acquires and transmits BBTV while feeding on infected banana plants. RNA interference (RNAi) enables the generation of pest and disease-resistant crops; however, its effectiveness relies on the identification of pivotal gene sequences to target and silence. Acetylcholinesterase (AChE) is an essential enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine in animals. In this study, the AChE gene of the banana aphid was targeted for silencing by RNAi through transgenic expression of AChE dsRNA in banana and plantain plants. The efficacy of dsRNA was first assessed using an artificial feeding assay. In vitro aphid feeding on a diet containing 7.5% sucrose, and sulfate complexes of trace metals supported aphid growth and reproduction. When AChE dsRNA was included in the diet, a dose of 500 ng/μL was lethal to the aphids. Transgenic banana cv. Cavendish Williams and plantain cvs. Gonja Manjaya and Orishele expressing AChE dsRNA were regenerated and assessed for transgene integration and copy number. When aphids were maintained on elite transgenic events, there was a 67.8%, 46.7%, and 75.6% reduction in aphid populations growing on Cavendish Williams, Gonja Manjaya, and Orishele cultivars, respectively, compared to those raised on nontransgenic control plants. These results suggest that RNAi targeting an essential aphid gene could be a useful means of reducing both aphid infestation and potentially the spread of the disease they transmit.
Uptake and distribution of chromium in Saccharomyces cerevisae exposed to Cr(III)-organic compounds

Abstract The present study investigates the influence of different Cr(III)-organic compounds [Cr(III)-citrate and Cr(III)-histidine] in growth-nonsupportive exposure medium on the uptake and localisation of chromium in the cell structure of the yeast Saccharomyces cerevisae. The amount of total accumulated chromium in yeast cells and the distribution of chromium between the yeast cell walls and spheroplasts were determined by atomic absorption spectroscopy. Chromium accumulation potential was shown to depend on treatment time, metal concentration as well as the nature of the bound ligand. Chromium uptake was characterised by a time-dependent increase of total chromium which suggests that the amount of cell-accumulated chromium also tended to increase over time. Cellular chromium accumulation (mg g−1 dry wt) of Cr(III)-histidine is higher than Cr(III)-citrate. The pH dependence pattern of chromium accumulation is similar for both of the Cr(III)-organic compounds: pH 6.5>pH 5>pH 8. Substantial differences were found between the two Cr(III)-organic compounds, in the total chromium accumulation as well as in the distribution in yeast cell walls and spheroplasts.
Kabuki Syndrome—Clinical Review with Molecular Aspects

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.
Stiffness and Aging in Cardiovascular Diseases: The Dangerous Relationship between Force and Senescence

Biological aging is a process associated with a gradual decline in tissues’ homeostasis based on the progressive inability of the cells to self-renew. Cellular senescence is one of the hallmarks of the aging process, characterized by an irreversible cell cycle arrest due to reactive oxygen species (ROS) production, telomeres shortening, chronic inflammatory activation, and chromatin modifications. In this review, we will describe the effects of senescence on tissue structure, extracellular matrix (ECM) organization, and nucleus architecture, and see how these changes affect (are affected by) mechano-transduction. In our view, this is essential for a deeper understanding of the progressive pathological evolution of the cardiovascular system and its relationship with the detrimental effects of risk factors, known to act at an epigenetic level.
Comparison of two freshwater turtle species as monitors of environmental contamination

Two species of turtles that occupy different ecological niches were compared for their usefulness as monitors of contamination in freshwater ecosystems. Trachemvs scrinta (Agassiz) (yellow-bellied slider) and Chelvdra sernentina (Linnaeus) (common snapping turtle) were selected for comparison based on species abundance and differences in food habits and sediment contact. A review of the literature on contaminants in turtles and results of preliminary surveys conducted at the field sites, which are included in this study, were used to direct and focus this research project. White Oak Lake, a settling basin for low-level radioactive and nonradioactive contaminants, and Bearden Creek Embayment, an uncontaminated reference site upriver, were used as study sites in the investigation of turtles as indicators of chemical contamination. Turtles were analyzed for concentrations of strontium-go, cesium-137, cobalt 60, and mercury in specific target tissues, and for single-stranded DNA breaks, a non-specific indicator of possible exposure to genotoxic agents in the environment. Significantly higher concentrations of {sup 90}Sr, {sup 137}Cs, {sup 60}Co, and mercury were detected in turtles from White Oak Lake than in turtles from the reference site. In addition, turtles from White Oak Lake contained a significantly greater amount of DNA damage than those from the reference site. Although this suggests greater exposure of White Oak Lake turtles to genotoxic agents, further studies are needed to establish the cause of the enhanced amount of single-stranded breaks. Interspecific comparisons of the turtles from White Oak Lake indicated that diet may play a significant role in the exposure of turtles to certain contaminants. No difference was detected between the concentrations of {sup 90}Sr, {sup 137}Cs, {sup 60}Co between the two species.
Metabolic Targets of Coenzyme Q10 in Mitochondria

Coenzyme Q10 (CoQ10) is classically viewed as an important endogenous antioxidant and key component of the mitochondrial respiratory chain. For this second function, CoQ molecules seem to be dynamically segmented in a pool attached and engulfed by the super-complexes I + III, and a free pool available for complex II or any other mitochondrial enzyme that uses CoQ as a cofactor. This CoQ-free pool is, therefore, used by enzymes that link the mitochondrial respiratory chain to other pathways, such as the pyrimidine de novo biosynthesis, fatty acid β-oxidation and amino acid catabolism, glycine metabolism, proline, glyoxylate and arginine metabolism, and sulfide oxidation metabolism. Some of these mitochondrial pathways are also connected to metabolic pathways in other compartments of the cell and, consequently, CoQ could indirectly modulate metabolic pathways located outside the mitochondria. Thus, we review the most relevant findings in all these metabolic functions of CoQ and their relations with the pathomechanisms of some metabolic diseases, highlighting some future perspectives and potential therapeutic implications.