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Receptor tyrosine kinases (RTKs) are key cell surface receptors involved in cell communication and signal transduction, with great importance in cell growth, differentiation, survival, and metabolism. Dysregulation of RTKs, such as EGFR, VEGFR, HER2 or ROR, could lead to various diseases, particularly cancers. ROR1 has emerged as a promising target in hematological malignancies. The development of ROR1 targeted therapies is continuously growing leading to remarkable novel therapeutical approaches using mAbs, antibody-drug conjugates, several small molecules or CAR T cells which have shown encouraging preclinical results. In the hematological field, mAbs, small molecules, BiTEs or CAR T cell therapies displayed promising outcomes with the clinical trials data encouraging the use of anti-ROR1 therapies. This paper aims to offer a comprehensive analysis of the current landscape of ROR1-targeted therapies in hematological malignancies marking the innovative approaches with promising preclinical and clinical. Offering a better understanding of structural and functional aspects of ROR1 could lead to new perspectives in targeting a wide spectrum of malignancies., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The study of different processing techniques, such as sprouting, cooking and fermentation, can help to develop new products for human health. In this work, raw, cooked and fermented seeds and germinated seeds of Chenopodium quinoa Willd. var. Tunkahuan and Amaranthus caudatus L. var. Alegrìa were compared for the content of antioxidant molecules, total antioxidant capacity and mineral elements. Fermentation was induced spontaneously, with the yeast Saccharomyces cerevisiae , with the bacterium Lactobacillus plantarum and with both microorganisms, for 24 and 48 h. The increase in antioxidant molecules and antioxidant activity was induced by germination, by 24 h of spontaneous fermentation (polyphenols and flavonoids) and by 24 h of L. plantarum fermentation (total antioxidant activity) for both species. Germinated seeds of the two plants showed higher values in respect to seeds of macroelements and microelements. No genotoxic but rather protective effects were determined for seed and germinated seed extracts using the D7 strain of S. cerevisiae , a good tool for the evaluation of protection from oxidative damage induced by radical oxygen species (ROS) in cells and tissues. Therefore, the two varieties could be very suitable for their use in human diet and in supplements, especially as germinated seeds or as fermented foods.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes., (© 2024. The Author(s).)

Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ- miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL -encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity., Competing Interests: Competing interests statement:The authors declare no competing interest.

Nucleoli are large nuclear sub-compartments where vital processes, such as ribosome assembly, take place. Technical obstacles still limit our understanding of the biological functions of nucleolar proteins in cell homeostasis and cancer pathogenesis. Since most nucleolar proteins are essential, their abrogation cannot be achieved through conventional approaches. Additionally, the biological activities of many nucleolar proteins are connected to their physiological concentration. Thus, artificial overexpression might not fully recapitulate their endogenous functions. Proteolysis-based approaches, such as the Auxin Inducible Degron (AID) system paired with CRISPR/Cas9 knock-in gene-editing, have the potential to overcome these limitations, providing unprecedented characterization of the biological activities of endogenous nucleolar proteins. We applied this system to endogenous nucleolin (NCL), one of the most abundant nucleolar proteins, and characterized the impact of its acute depletion on Triple-Negative Breast Cancer (TNBC) cell behavior. Abrogation of endogenous NCL reduced proliferation and caused defective cytokinesis, resulting in bi-nucleated tetraploid cells. Bioinformatic analysis of patient data, and quantitative proteomics using our experimental NCL-depleted model, indicated that NCL levels are correlated with the abundance of proteins involved in chromosomal segregation. In conjunction with its effects on sister chromatid dynamics, NCL abrogation enhanced the anti-proliferative effects of chemical inhibitors of mitotic modulators such as the Anaphase Promoting Complex. In summary, using the AID system in combination with CRISPR/Cas9 for endogenous gene editing, our findings indicate a novel role for NCL in supporting the completion of the cell division in TNBC models, and that its abrogation could enhance the therapeutic activity of mitotic-progression inhibitors., Competing Interests: Conflict of Interest Statement DP and CMC are inventors of the patent application WO2017011411A1 (methods and compositions relating to anti-NCL recombinant immunoagents). DP and TJM are consultants and own equity Koru Biopharma, which is developing anti-NCL agents.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and - 140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Despite the many beneficial properties of legume plants, their use in diets for poultry is limited by the presence of antinutritional factors. The aim of the study was to determine the activity of DT-diaphorase, ethoxycoumarin O-deethylase, and catalase, and the concentration of malondialdehyde in liver tissue, as well as the activity of SOD and CAT in the serum of Hy-line Brown hens fed a diet supplemented with various doses of Lupinus angustifolius seeds. The results indicate that the use of large amounts of lupin in the diet resulted in an increase in MDA concentration in the liver and the lipid vacuolization of hepatocytes. A significant increase in DTD activity was observed in chickens receiving 15% lupin. Regardless of lupin dose, no increase in SOD activity was observed in chicken serum after 33 days of the experiment. From the 66th day of the experiment, an increase in catalase activity in the serum of laying hens was observed, while low activity of this enzyme was found in the liver. It can be concluded that the short-term use of lupin in the diet of laying hens does not affect the activity of antioxidant enzymes and, therefore, does not affect the oxidative-antioxidant balance of their body.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC. Here, we identified the transcription factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically, we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR, modulated the autophagic flux and sustained PDAC growth in nutrient deprivation. In a genetic mouse model, Mir15a KO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC., (© 2024. The Author(s).)

Fos-related antigen-2 (Fra-2) is the most recently discovered member of the Fos family and, by dimerizing with Jun proteins, forms the activator protein 1 (AP-1) transcription factor. By inducing or repressing the transcription of several target genes, Fra-2 is critically involved in the modulation of cell response to a variety of extracellular stimuli, stressors and intracellular changes. In physiological conditions, Fra-2 has been found to be ubiquitously expressed in human cells, regulating differentiation and homeostasis of bone, muscle, nervous, lymphoid and other tissues. While other AP-1 members, like Jun and Fos, are well characterized, studies of Fra-2 functions in cancer are still at an early stage. Due to the lack of a trans-activating domain, which is present in other Fos proteins, it has been suggested that Fra-2 might inhibit cell transformation, eventually exerting an anti-tumor effect. In human malignancies, however, Fra-2 activity is enhanced (or induced) by dysregulation of microRNAs, oncogenes and extracellular signaling, suggesting a multifaceted role. Therefore, Fra-2 can promote or prevent transformation, proliferation, migration, epithelial-mesenchymal transition, drug resistance and metastasis formation in a tumor- and context-dependent manner. Intriguingly, recent data reports that Fra-2 is also expressed in cancer associated cells, contributing to the intricate crosstalk between neoplastic and non-neoplastic cells, that leads to the evolution and remodeling of the tumor microenvironment. In this review we summarize three decades of research on Fra-2, focusing on its oncogenic and anti-oncogenic effects in tumor progression and dissemination., (© 2023. The Author(s).)

tRNA-derived ncRNAs are a heterogeneous class of non-coding RNAs recently proposed to be active regulators of gene expression and be involved in many diseases, including cancer. Consequently, several online resources on tRNA-derived ncRNAs have been released. Although interesting, such resources present only basic features and do not adequately exploit the wealth of knowledge available about tRNA-derived ncRNAs. Therefore, we introduce tRFUniverse , a novel online resource for the analysis of tRNA-derived ncRNAs in human cancer. tRFUniverse presents an extensive collection of classes of tRNA-derived ncRNAs analyzed across all the TCGA and TARGET tumor cohorts, NCI-60 cell lines, and biological fluids. Moreover, public AGO CLASH/CLIP-Seq data were analyzed to identify the molecular interactions between tRNA-derived ncRNAs and other transcripts. Importantly, tRFUniverse combines in a single resource a comprehensive set of features that we believe may be helpful to investigate the involvement of tRNA-derived ncRNAs in cancer biology., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

MiRNAs play crucial roles in a broad spectrum of biological processes, both physiological and pathological. Different reports implicate miR-205 in the control of breast stem cell properties. Differential miR-205 expression has been observed in different stages of mammary gland development and maturation. However, a functional role in this process has not been clearly demonstrated. We generated an miR-205 knockout in the FVB/N mouse strain, which is viable and characterized by enhanced mammary gland development. Indeed, mammary glands of miR-205 -/- female mice at different ages (1.5 and 5.5 months) show increased outgrowth and branching. This evidence is consistent with our previously reported data demonstrating the direct miR-205-mediated targeting of HER3, a master regulator of mammary gland development, and the oncosuppressive activity of this microRNA in different types of breast cancer.

Objective: To evaluate snacking and diet quality among US adolescents., Design: Cross-sectional analysis examined snack frequency (snacks/day), size (kcal/snack) and energy density (kcal/g/snack) as predictors of diet quality using the mean of two 24-h dietary recalls. Diet quality was assessed using the Healthy Eating Index (HEI-2015, 0-100), a mean adequacy ratio (MAR, 0-100) for under-consumed nutrients (potassium, fibre, Ca, vitamin D) and mean percentage of recommended limits for over-consumed nutrients (added sugar, saturated fat, Na). Linear regression models examined total snacks, food only snacks and beverage only snacks, as predictors of diet quality adjusting for demographic characteristics and estimated energy reporting accuracy., Setting: 2007-2018 National Health and Nutrition Examination Survey., Participants: Adolescents 12-19 years ( n 4985)., Results: Snack frequency was associated with higher HEI-2015 ( β = 0·7 (0·3), P < 0·05) but also with higher intake of over-consumed nutrients ( β = 3·0 (0·8), P ≤ 0·001). Snack size was associated with lower HEI ( β = -0·005 (0·001), P ≤ 0·001) and MAR ( β = -0·005 (0·002), P < 0·05) and higher intake of over-consumed nutrients ( β = 0·03 (0·005), P ≤ 0·001). Associations differed for food only and beverage only snacks. Food only snack frequency was associated with higher HEI-2015 ( β = 1·7 (0·03), P ≤ 0·001), while food only snack size ( β = -0·006 (0·0009), P ≤ 0·001) and food only snack energy density ( β = -1·1 (0·2), P ≤ 0·001) were associated with lower HEI-2015. Conversely, beverage only snack frequency ( β = 4·4 (2·1) P < 0·05) and beverage only snack size ( β = 0·03 (0·01), P ≤ 0·001) were associated with higher intake of over-consumed nutrients., Conclusions: Smaller, frequent, less energy-dense food only snacks are associated with higher diet quality in adolescents; beverages consumed as snacks are associated with greater intake of over-consumed nutrients.

Chronic lymphocytic leukemia (CLL) is one of the most diagnosed forms of leukemia worldwide and it is usually classified into two forms: indolent and aggressive. These two forms are characterized by distinct molecular features that drive different responses to treatment and clinical outcomes. In this context, a better understanding of the molecular landscape of the CLL forms may potentially lead to the development of new drugs or the identification of novel biomarkers. Human endogenous retroviruses (HERVs) are a class of transposable elements that have been associated with the development of different human cancers, including different forms of leukemias. However, no studies about HERVs in CLL have ever been reported so far. Here, we present the first locus-specific profiling of HERV expression in both the aggressive and indolent forms of CLL. Our analyses revealed several dysregulations in HERV expression occurring in CLL and some of them were specific for either the aggressive or indolent form of CLL. Such results were also validated by analyzing an external cohort of CLL patients and by RT-qPCR. Moreover, in silico analyses have shown relevant signaling pathways associated with them suggesting a potential involvement of the dysregulated HERVs in these pathways and consequently in CLL development.

Dysregulated apoptosis and proliferation are fundamental properties of cancer, and microRNAs (miRNA) are critical regulators of these processes. Loss of miR-15a/16-1 at chromosome 13q14 is the most common genomic aberration in chronic lymphocytic leukemia (CLL). Correspondingly, the deletion of either murine miR-15a/16-1 or miR-15b/16-2 locus in mice is linked to B cell lymphoproliferative malignancies. However, unexpectedly, when both miR-15/16 clusters are eliminated, most double knockout (DKO) mice develop acute myeloid leukemia (AML). Moreover, in patients with CLL, significantly reduced expression of miR-15a, miR-15b, and miR-16 associates with progression of myelodysplastic syndrome to AML, as well as blast crisis in chronic myeloid leukemia. Thus, the miR-15/16 clusters have a biological relevance for myeloid neoplasms. Here, we demonstrate that the myeloproliferative phenotype in DKO mice correlates with an increase of hematopoietic stem and progenitor cells (HSPC) early in life. Using single-cell transcriptomic analyses, we presented the molecular underpinning of increased myeloid output in the HSPC of DKO mice with gene signatures suggestive of dysregulated hematopoiesis, metabolic activities, and cell cycle stages. Functionally, we found that multipotent progenitors (MPP) of DKO mice have increased self-renewing capacities and give rise to significantly more progeny in the granulocytic compartment. Moreover, a unique transcriptomic signature of DKO MPP correlates with poor outcome in patients with AML. Together, these data point to a unique regulatory role for miR-15/16 during the early stages of hematopoiesis and to a potentially useful biomarker for the pathogenesis of myeloid neoplasms.

The discrimination of protein biological functions in different phases of the cell cycle is limited by the lack of experimental approaches that do not require pre-treatment with compounds affecting the cell cycle progression. Therefore, potential cycle-specific biological functions of a protein of interest could be biased by the effects of cell treatments. The OsTIR1/auxin-inducible degron (AID) system allows "on demand" selective and reversible protein degradation upon exposure to the phytohormone auxin. In the current format, this technology does not allow to study the effect of acute protein depletion selectively in one phase of the cell cycle, as auxin similarly affects all the treated cells irrespectively of their proliferation status. Therefore, the AID system requires coupling with cell synchronization techniques, which can alter the basal biological status of the studied cell population, as with previously available approaches. Here, we introduce a new AID system to Regulate OsTIR1 Levels based on the Cell Cycle Status (ROLECCS system), which induces proteolysis of both exogenously transfected and endogenous gene-edited targets in specific phases of the cell cycle. We validated the ROLECCS technology by down regulating the protein levels of TP53, one of the most studied tumor suppressor genes, with a widely known role in cell cycle progression. By using our novel tool, we observed that TP53 degradation is associated with increased number of micronuclei, and this phenotype is specifically achieved when TP53 is lost in S/G 2 /M phases of the cell cycle, but not in G 1 . Therefore, we propose the use of the ROLECCS system as a new improved way of studying the differential roles that target proteins may have in specific phases of the cell cycle., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Background: Snacking is nearly universal and contributes significant energy to U.S. children's diets. Little is known, however, about where and when snacking intake occurs and if such patterns change with age. This research evaluated age-related differences in eating location, food source location, and timing of snacking among U.S. children aged 1-19 years (y)., Methods: A cross-sectional analysis of snacking among 14,666 children in the 2007-2018 U.S. National Health and Nutrition Examination Survey was conducted using a single 24-hour dietary recall. Snacking was participant-defined and included all eating occasions outside of meals. Linear regression and analysis of covariance were used to examine the effects of age (toddler 1-2 y, preschooler 3-5 y, school-age 6-11 y, adolescent 12-19 y) on the percentage of daily snack energy consumed by eating location (at home vs. away from home), food source location (grocery store, convenience store, school/childcare, restaurant, from someone else (i.e. "socially"), and other), and time of day (morning, 6am-12pm; early afternoon, 12pm-3pm; late afternoon/afterschool 3pm-6pm; evening 6pm-9pm, late-night 9pm-12am, and overnight 12am-6am)., Results: On average, U.S. children consumed most of their daily snacking energy at home (71%), from foods and beverages obtained from grocery stores (75%), and in the late afternoon/afterschool (31%). Toddlers and preschoolers consumed a greater percentage of their daily snack energy during the morning hours compared to school-age children and adolescents (both p < 0.001); school-age children consumed the most in the evening (27%, p < 0.001), and adolescents consumed the most in the late-night period (22%, p < 0.001). Age-related increases were seen in the percentage of daily snacking energy eaten outside the home (p < 0.001), and obtained socially (p < 0.001), from restaurants (p < 0.001), and convenience stores (p < 0.001)., Conclusion: Findings reveal age-related differences in eating location, food source location, and timing of snack intake among U.S. children aged 1-19 y. Younger children consume a greater percentage of snacking calories in the morning and at home relative to older children. School-age children and adolescents show greater snacking in the evening and at night and from foods obtained and eaten outside the home. Efforts to promote healthy snacking behaviors among children should consider developmental differences in snacking patterns., (© 2023. The Author(s).)

Snacking starts early in childhood, yet little is known about child versus family influences on snacking during infancy and toddlerhood. This secondary analysis of baseline data examined associations of child characteristics (e.g., appetitive traits, temperament), caregiver feeding decisions, and sociodemographic characteristics with the mean frequency of (times/day) and mean energy from (kcal/day) child snack food intake. Caregivers and their children (ages 9-15 months) were recruited in Buffalo, NY from 2017 to 2019. Caregivers reported on sociodemographics, child appetitive traits (Baby Eating Behaviour Questionnaire), and child temperament (Infant Behavior Questionnaire-Revised). Three 24-h dietary recalls were collected, and USDA food categories were used to categorize snack foods (e.g., cookies, chips, and puffs). Hierarchical multiple linear regression models examined associations of child characteristics (Step 1: age, sex, baseline weight-for-length z-score, appetitive traits, and temperament), caregiver feeding decisions (Step 2: breastfeeding duration and age of solid food introduction), and caregiver sociodemographic characteristics (Step 3: caregiver age, prepregnancy BMI, education, and household size) with mean child snack food intake. Caregivers (n = 141) were on average 32.6 years of age, predominantly white (89.1%), and college-educated (84.2%). Age of solid food introduction (B = -0.21, p = 0.03), prepregnancy BMI (B = 0.03, p = 0.04), and household size (B = 0.23, p = 0.02) were significantly associated with the mean frequency of (times/day) snack food intake, over and above other variables of interest. Child age (B = 15.96, p = 0.002) was significantly associated with mean energy from (kcal/day) snack food intake. Household size (B = 28.51, p = 0.006) was significantly associated with mean energy from (kcal/day) snack food intake, over and above other variables of interest. There were no significant associations of other child characteristics with snack food intake. Findings show that child snack food intake is more closely associated with caregiver feeding decisions and sociodemographic characteristics than child characteristics. TRIAL REGISTRATION: National Institute on Child Health and Human Development, Grant/Award Number R01HD087082-01., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

As a type of short noncoding RNAs, microRNA (miRNA) undoubtedly plays a crucial role in cancer development. Since the discovery of the identity and clinical functions of miRNAs, over the past few decades, the roles of miRNAs in cancer have been actively investigated. Numerous pieces of evidence indicate that miRNAs are pivotal factors in most types of cancer. Recent cancer research focused on miRNAs has identified and characterized a large cohort of miRNAs commonly dysregulated in cancer or exclusively dysregulated in specific types of cancer. These studies have suggested the potential of miRNAs as biomarkers in the diagnosis and prognostication of cancer. Moreover, many of these miRNAs have oncogenic or tumor-suppressive functions. MiRNAs have been the focus of research given their potential clinical applications as therapeutic targets. Currently, various oncology clinical trials using miRNAs in screening, diagnosis, and drug testing are underway. Although clinical trials studying miRNAs in various diseases have been reviewed before, there have been fewer clinical trials related to miRNAs in cancer. Furthermore, updated results of recent preclinical studies and clinical trials of miRNA biomarkers and drugs in cancer are needed. Therefore, this review aims to provide up-to-date information on miRNAs as biomarkers and cancer drugs in clinical trials., (© 2023. The Author(s).)

Recently, green microalgae have gained importance due to their nutritional and bioactive compounds, which makes them some of the most promising and innovative functional foods. The aim of this study was to evaluate the chemical profile and the in vitro antioxidant, antimicrobial and antimutagenic activity of an aqueous extract of the green microalga Ettlia pseudoalveolaris , obtained from the freshwater lakes of the Ecuadorian Highlands. Human microvascular endothelial cells (HMEC-1) were used to determine the ability of the microalga to reduce the endothelial damage caused by hydrogen peroxide-induced oxidative stress. Furthermore, the eukaryotic system Saccharomyces cerevisiae was used to evaluate the possible cytotoxic, mutagenic and antimutagenic effect of E. pseudoalveolaris . The extract showed a notable antioxidant capacity and a moderate antibacterial activity mostly due to the high content in polyphenolic compounds. It is likely that the antioxidant compounds present in the extract were also responsible for the observed reduction in endothelial damage of HMEC-1 cells. An antimutagenic effect through a direct antioxidant mechanism was also found. Based on the results of in vitro assays, E. pseudoalveolaris proved to be a good source of bioactive compounds and antioxidant, antibacterial and antimutagenic capacities making it a potential functional food.

Soft-tissue sarcomas (STS) are a rare and heterogeneous group of tumors that arise from connective tissue and can occur anywhere in the body. Among the plethora of over 50 different STS types, liposarcoma (LPS) is one of the most common. The subtypes of STS are characterized by distinct differences in tumor biology that drive responses to pharmacologic therapy and disparate oncologic outcomes. Small non-coding RNAs (sncRNA) are a heterogeneous class of regulatory RNAs involved in the regulation of gene expression by targeting mRNAs. Among the several types of sncRNAs, miRNAs and tRNA-derived ncRNAs are the most studied in the context of tumor biology, and we are learning more about the role of these molecules as important regulators of STS tumorigenesis and differentiation. However, challenges remain in translating these findings and no biomarkers or therapeutic approaches targeting sncRNAs have been developed for clinical use. In this review, we summarize the current landscape of sncRNAs in the context of STS with an emphasis on LPS, including the role of sncRNAs in the tumorigenesis and differentiation of these rare malignancies and their potential as novel biomarkers and therapeutic targets. Finally, we provide an appraisal of published studies and outline future directions to study sncRNAs in STS, including tRNA-derived ncRNAs., (©2023 American Association for Cancer Research.)

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% decrease in ESCC incidence vs. Zn-untreated controls. Zn treatment eliminated ESCCs by affecting a spectrum of biological processes that included downregulation of expression of the two miRs and miR-31-controlled inflammatory pathway, stimulation of miR-21-PDCD4 axis apoptosis, and reversal of the ESCC metabolome: with decrease in putrescine, increase in glucose, accompanied by downregulation of metabolite enzymes ODC and HK2. Thus, Zn treatment or miR-31/21 silencing are effective therapeutic strategies for ESCC in this rodent model and should be examined in the human counterpart exhibiting the same biological processes.

tRNA fragments (tRNA derived fragments or tRFs) are small single stranded RNA molecules derived from pre-tRNAs and mature tRNAs. tRFs have been known for a number of years, but previously they were believed to be not important products of tRNA degradation. tRFs can be unique, like tRF-1 s, or redundant, like tRF-3 s and tRF-5 s. Scientific interest in tRFs has drastically increased in the last 5 years. Many studies have found that tRFs are differentially expressed in many normal cellular processes as well as in transformed cancer cells. Dysregulation of tRFs expression have been reported in multiple major types of cancer including solid cancers and lymphoid malignancies. However the exact molecular role of these molecules is not entirely clear. A number of studies proposed that tRFs can work as microRNAs by targeting gene expression. Here we discuss recent studies showing differential expression of tRFs in many cancers as well as what is currently known about tRFs biological functions in cancer cells., (© 2022. The International CCN Society.)

Background: Snacking (ie, eating between meals) is common among US preschool-aged children, but associations with weight status are unclear., Objective: This research evaluated associations of snack frequency, size, and energy density as well as the percent of daily energy from snacking with weight status and sociodemographic characteristics among US children aged 2 to 5 years., Design: Cross-sectional analysis of 2007-2018 National Health and Nutrition Examination Survey data using two, caregiver proxy, 24-hour dietary recalls., Participants/setting: US children aged 2 to 5 years (n = 3,313) with at least one snack occasion over 2 days of intake., Main Outcome Measures: Snacking parameters included frequency (number of occasions per day), size (kilocalories per occasion), and energy density (kilocalories per gram per occasion) as well as percent of daily energy from snacking., Statistical Analyses: Generalized linear regression models evaluated associations of snacking with child weight status (ie, normal weight and overweight/obesity), adjusting for survey weights, energy misreporting, mean meal size, and sociodemographic covariates., Results: Children with overweight/obesity consumed more frequent snacks (2.8 [0.06] vs 2.5 [0.03] snacks/day, respectively; P < 0.001), larger snacks (188 [4] vs 162 [23] kcal/occasion, respectively; P < 0.001), and a greater percent of daily energy from snacking (29.80% [1.00%] vs 26.09% [0.40%], respectively; P < 0.001) than children with normal weight. Mean snack frequency and size as well as percentage of daily energy from snacking varied with child age, gender, and head of household education. Associations of snacking with child race and ethnicity were less consistent., Conclusions: These nationally representative findings provide evidence that the consumption of larger, more frequent snacks is associated with overweight/obesity among US children aged 2 to 5 years and snacking varies by sociodemographic characteristics., (Copyright © 2023 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to evaluate snack food-group composition by weight status among United States adolescents., Methods: Cross-sectional analysis of adolescent food-group-component intake from snacking occasions using two 24-hour dietary recalls from the 2007 through 2018 National Health and Nutrition Examination Survey (NHANES; n = 5264; 12-19 years) was conducted. ANCOVA models evaluated food intakes by BMI percentile (BMI%; normal weight [NW]: <85th BMI%; overweight [OW]: 85th-95th BMI%; and obesity [OB]: ≥95th BMI%), adjusting for energy misreporting and key covariates., Results: Adolescents with OB consumed greater total daily energy from snacks (mean [SE]: NW = 424 [10] kcal; OW = 527 [16] kcal; OB = 603 [22] kcal; p < 0.001) than adolescents with OW and NW. Adolescents with OW or OB consumed higher amounts of refined grains, dairy, protein, oil, solid fat, and added sugar from snacks than adolescents with NW (p < 0.05-0.001)., Conclusions: Adolescents with OW or OB consume more calories and higher levels of overconsumed dietary components, i.e., added sugar, solid fats, and refined grains, from snacks than adolescents with NW. Age-specific snacking recommendations to inform dietary guidance are needed to prevent excess intake of overconsumed nutrients and calories., (© 2022 The Obesity Society.)

Epitranscriptomic studies of miRNAs have added a new layer of complexity to the cancer field. Although there is fast-growing interest in adenosine-to-inosine (A-to-I) miRNA editing and alternative cleavage that shifts miRNA isoforms, simultaneous evaluation of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modification types, including A-to-I miRNA editing and shifted miRNA isoforms, in &gt;13,000 adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments data sets. The differences between canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint were investigated. The combination of canonical miRNAs and modified miRNAs boosted the quality of clustering results, outlining unique clinicopathologic features among cohorts. Certain modified miRNAs showed opposite expression from their canonical counterparts in cancer, potentially impacting their targets and function. Finally, a shifted and edited miRNA isoform was experimentally validated to directly bind and suppress a unique target. These findings outline the importance of going beyond the well-established paradigm of one mature miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression., Significance: Modified miRNAs may act as cancer biomarkers and function as allies or antagonists of their canonical counterparts in gene regulation, suggesting the concurrent consideration of canonical and modified miRNAs can boost patient stratification., (©2022 The Authors; Published by the American Association for Cancer Research.)

Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths worldwide. Among its subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the most common, accounting for more than 85% of lung cancer diagnoses. Despite the incredible efforts and recent advances in lung cancer treatments, patients affected by this condition still have a poor prognosis. Therefore, novel diagnostic biomarkers are needed. Recently, a class of transposable elements called human endogenous retroviruses (HERVs) has been found to be implicated in cancer development and later employed as novel biomarkers for several tumor types. In this study, we first ever characterized the expression of HERVs at genomic locus-specific resolution in both LUAD and LUSC cohorts available in The Cancer Genome Atlas (TCGA). Precisely, (i) we profiled the expression of HERVs in TCGA-LUAD and TCGA-LUSC cohorts; (ii) we identified the dysregulated HERVs in both lung cancer subtypes; (iii) we evaluated the impact of the dysregulated HERVs on signaling pathways using neural network-based predictions; and (iv) we assessed their association with overall survival (OS) and relapse-free survival (RFS). In conclusion, we believe this study may help elucidate another layer of dysregulation that occurs in lung cancer involving HERVs, paving the way for identifying novel lung cancer biomarkers.

EVs have emerged as an important component in tumour initiation, progression and metastasis. Although notable progresses have been made, the detection of EV cargoes remain significantly challenging for researchers to practically use; faster and more convenient methods are required to validate the EV cargoes, especially as biomarkers. Here we show, the possibility of examining embedded EVs as substrates to be used for detecting DNA amplification through ultrasensitive in situ hybridization (ISH). This methodology allows the visualization of DNA targets in a more direct manner, without time consuming optimization steps or particular expertise. Additionally, formalin-fixed paraffin-embedded (FFPE) blocks of EVs allows long-term preservation of samples, permitting future studies. We report here: (i) the successful isolation of EVs from liposarcoma tissues; (ii) the EV embedding in FFPE blocks (iii) the successful selective, specific ultrasensitive ISH examination of EVs derived from tissues, cell line, and sera; (iv) and the detection of MDM2 DNA amplification in EVs from liposarcoma tissues, cell lines and sera. Ultrasensitive ISH on EVs would enable cargo study while the application of ISH to serum EVs, could represent a possible novel methodology for diagnostic confirmation. Modification of probes may enable researchers to detect targets and specific DNA alterations directly in tumour EVs, thereby facilitating detection, diagnosis, and improved understanding of tumour biology relevant to many cancer types., (© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)

Herein we characterized the bioactive metabolites of the aqueous extract of Kavolì®, a commercial product composed of a mixture of Brassica oleracea leaves, and assessed its potential ameliorating effects in a rat model of non-alcoholic fatty liver disease (NAFLD). Kavolì® extract showed high levels of bioactive compounds and strong in vitro antioxidant activities. Chlorogenic and neochlorogenic acids were identified as the most representative polyphenols. The administration of brassica extract to steatotic rats significantly ameliorated the levels of blood lipids and transaminases, and lipid content and inflammatory markers in liver. Oxidative stress parameters were significantly improved in both liver and brain of steatotic rats. Moreover, plasma and feces levels of short chain fatty acids (SCFAs) were bring back close to control values by Kavolì® treatment, in spite of high fat diet/streptozotocin (HFD/STZ)-induced alterations. The efficacy of Kavolì® in treating hypercholesterolemia, reducing the level of inflammation and cardiovascular disease biomarkers, steatosis and oxidative stress parameters, as well as the ability in modulating SCFAs levels is probably related to the bioactive compounds of the water extract administered to the rat model of NAFLD. In particular, the ameliorating effects are largely attributable to the high content in polyphenols observed in our study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Current dietary guidelines recommend avoiding foods and beverages with added sugars and higher sodium before age 2 years., Objective: The aim was to describe daily snack food intake (frequency and total energy) and the associations with overconsumed nutrients (added sugars, sodium, and saturated fats) and child weight-for-length z scores., Design: A cross-sectional, secondary analysis of baseline data from an ongoing longitudinal intervention was conducted., Participants and Setting: A sample of 141 caregivers with infants (aged 9 to 11 months) and toddlers (aged 12 to 15 months) was recruited in Buffalo, NY, between 2017 and 2019., Main Outcome Measures: Three 24-hour dietary recalls were used to categorize 'sweet and salty snack foods' or 'commercial baby snack foods' based on the US Department of Agriculture What We Eat in America food group classifications and estimate nutrient intakes. Child recumbent length and weight were measured by trained researchers., Statistical Analysis: Daily frequency (times/day), energy (kcal/day), and overconsumed nutrients from snack food intake were calculated. Multivariable regression models examined associations between the frequency of and energy from snack food intake with overconsumed nutrients and child weight-for-length z scores., Results: Infants consumed snack foods on average 1.2 times/day contributing 5.6% of total daily energy, 19.6% of added sugars, and 6.8% of sodium. Toddlers consumed snack foods on average 1.4 times/day contributing 8.9% of total daily energy, 40.0% of added sugars, and 7.2% of sodium. In adjusted models including all children, greater frequency of sweet and salty snack food intake, but not commercial baby snack foods, was associated with higher weight-for-length z scores., Conclusions: Snack foods are frequently consumed by infants and toddlers and contribute to the intake of overconsumed nutrients such as added sugars and sodium. Given the current guidelines to avoid added sugars and higher sodium before age 2 years, additional recommendations related to nutrient-dense snack intake may be beneficial., (Copyright © 2022 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are small noncoding RNAs that act as endogenous regulatory molecules targeting specific mRNAs for translational repression. Studies of breast cancer genomics indicate that breast cancer subtypes are distinguished and regulated by specific sets of miRNAs which affect activities such as tumor initiation, progression, and even drug response. Polo-like Kinase 1 (PLK1) is widely considered to be a proto-oncogene due to its increased expression in multiple tumor types, as well as its crucial role in regulating mitosis. Pharmacological inhibition of PLK1 can reduce tumor volume and induce tumor cell death in solid and hematologic malignancies. This prompted us to investigate how PLK1 inhibition with the target-specific inhibitor NMS-P937 would impact breast cancer cells, and how miRNAs may influence the overall response of these cells to this inhibition. We found that miR-183-5p targets PLK1 gene, effectively reducing its protein expression. Such miRNA-driven regulation of PLK1 expression sensitizes breast cancer cells to NMS-P937, resulting in synergistically increased apoptosis. We also show that the miRNA-regulated reduction of PLK1 influences the expression of apoptosis-related key proteins and possibly inducing further indirect PLK1 downmodulation through a DNMT1-p53 axis. These results suggest a potential biologically significant link between the expression of miR-183-5p and the efficacy of PLK1-specific inhibitors in breast cancer cells. Our work further elucidates how miR-183-5p regulates PLK1 gene while also enhancing NMS-P937 effect in breast cancer. Future studies assessing the role of miR-183-5p as a novel biomarker for anti-PLK1 chemotherapy agents are warranted., (© 2021. The Author(s).)

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is characterized by chromosomal aberrations including 13q, 11q, and 17p deletions and a trisomy of chromosome 12 (T12). 13q deletions are often associated with 11q and 17p deletions in aggressive cases. Conversely, T12 CLLs show a variable prognosis, and association with 13q deletions is uncommon. The miR-15a/16-1 cluster is the functional target of 13q deletions, leading to BCL2 overexpression. Chromosomal aberrations in CLL are associated with prognosis, and their identification is carried out by fluorescence in situ hybridization (FISH). Since standard FISH only detects large deletions, we investigated the presence of undetected microdeletions targeting miR-15a/16-1 in CLL cases. We found that ∼34% of CLL samples show an unreported loss of the miR-15a/16-1 locus regardless of their cytogenetic profile. Interestingly, 15 out of 39 (∼39%) of all CLLs with T12, carry microdeletions of miR-15a/16-1 , indicating that, in patients with T12, miR-15a/16-1 are mostly inactivated by microdeletions. In addition, ∼40% of CLL cases bearing T12, 17p - , and 11q - showed unidentified microdeletions of miR-15a/16-1 , suggesting that miR-15a/16-1 loss cooperates with such chromosomal alterations in CLL. These data may have clinical relevance for the successful stratification of patients for treatment., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

In 2020, more than 60,500 people were diagnosed with leukemia in the USA, and more than 23,000 died. The incidence of leukemia is still rising, and drug resistance development is a serious concern for patients' wellbeing and survival. In the past two decades, small non-coding RNAs have been studied to evaluate their functions and possible role in cancer pathogenesis. Small non-coding RNAs are short RNA molecules involved in several cellular processes by regulating the expression of genes. An increasing body of evidence collected by many independent studies shows that the expression of these molecules is tissue specific, and that their dysregulation alters the expression of genes involved in tumor development, progression and drug response. Indeed, small non-coding RNAs play a pivotal role in the onset, staging, relapse and drug response of hematological malignancies and cancers in general. These findings strongly suggest that small non-coding RNAs could function as biomarkers and possible targets for therapy. Thus, in this review, we summarize the regulatory mechanisms of small non-coding RNA expression in different types of leukemia and assess their potential clinical implications.