Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA.

Breast cancer exhibits various epigenetic abnormalities that regulate gene expression and contribute to tumor characteristics. Epigenetic alterations play a significant role in cancer development and progression, and epigenetic-targeting drugs such as DNA methyltransferase inhibitors, histone-modifying enzymes, and mRNA regulators (such as miRNA mimics and antagomiRs) can reverse these alterations. Therefore, these epigenetic-targeting drugs are promising candidates for cancer treatment. However, there is currently no effective epi-drug monotherapy for breast cancer. Combining epigenetic drugs with conventional therapies has yielded positive outcomes and may be a promising strategy for breast cancer therapy. DNA methyltransferase inhibitors, such as azacitidine, and histone deacetylase inhibitors, such as vorinostat, have been used in combination with chemotherapy to treat breast cancer. miRNA regulators, such as miRNA mimics and antagomiRs, can alter the expression of specific genes involved in cancer development. miRNA mimics, such as miR-34, have been used to inhibit tumor growth, while antagomiRs, such as anti-miR-10b, have been used to inhibit metastasis. The development of epi-drugs that target specific epigenetic changes may lead to more effective monotherapy options in the future.

COVID-19 vaccination in healthcare workers: Long-term benefits and protection.

Introduction: This study aimed to evaluate the long-term effectiveness of COVID-19 vaccination in healthcare workers by analyzing the population's response to the vaccine after two years, based on anti-SARS-CoV-2 protein S antibody levels. Additionally, the study aimed to assess the impact of basic factors on antibody levels. Material and methods: A total of 4,090 healthcare workers were included in the study, and their antibody levels were measured using ELISA to detect anti-SARS-CoV-2 immunoglobulin G (IgG). Statistical analysis was conducted to examine the influence of COVID-19 infection, vaccination status, and number of vaccine doses on antibody concentrations. Results and Conclusion: The majority of participants (85.1%) received the Pfizer/BioNTech vaccine, while a smaller percentage chose vector vaccines such as AstraZeneca and Johnson & Johnson. The incidence of COVID-19 among vaccinated individuals was relatively low for all vaccines, confirming their effectiveness in preventing symptomatic SARS-CoV-2 infection. The study observed variations in IgG antibody levels within the study population, with only 0.46% of individuals testing negative for the presence of antibodies. The average anti-SARS-CoV-2 IgG values showed significant differences across consecutive 3-month periods following infection or vaccination, with a gradual decrease over time. Notably, the most significant changes in antibody levels were observed within the first 6 months (mean values ranged from 3647.11 BAU/ml to 2601.49 BAU/ml). Subsequently, minor fluctuations were observed, with mean antibody values hovering around 2000 BAU/ml. The differences between average anti-SARS-CoV-2 IgG values between consecutive 3-month periods from disease onset were statistically significant.

Characteristic of the Ascorbate Oxidase Gene Family in Beta vulgaris and Analysis of the Role of AAO in Response to Salinity and Drought in Beet.

Ascorbate oxidase, which is known to play a key role in regulating the redox state in the apoplast, cell wall metabolism, cell expansion and abiotic stress response in plants, oxidizes apo-plastic ascorbic acid (AA) to dehydroascorbic acid (DHA). However, there is little information about the AAO genes and their functions in beets under abiotic stress. The term salt or drought stress refers to the treatment of plants with slow and gradual salinity/drought. Contrastingly, salt shock consists of exposing plants to high salt levels instantaneously and drought shock occurs under fast drought progression. In the present work, we have subjected plants to salinity or drought treatments to elicit either stress or shock and carried out a genome-wide analysis of ascorbate oxidase (AAO) genes in sugar beet (B. vulgaris cv. Huzar) and its halophytic ancestor (B. maritima). Here, conserved domain analyses showed the existence of twelve BvAAO gene family members in the genome of sugar beet. The BvAAO_1-12 genes are located on chromosomes 4, 5, 6, 8 and 9. The phylogenetic tree exhibited the close relationships between BvAAO_1-12 and AAO genes of Spinacia oleracea and Chenopodium quinoa. In both beet genotypes, downregulation of AAO gene expression with the duration of salt stress or drought treatment was observed. This correlated with a decrease in AAO enzyme activity under defined experimental setup. Under salinity, the key downregulated gene was BvAAO_10 in Beta maritima and under drought the BvAAO_3 gene in both beets. This phenomenon may be involved in determining the high tolerance of beet to salinity and drought.

The Effect of Platelet-Rich Plasma on the Intra-Articular Microenvironment in Knee Osteoarthritis.

Knee osteoarthritis (KOA) represents a clinical challenge due to poor potential for spontaneous healing of cartilage lesions. Several treatment options are available for KOA, including oral nonsteroidal anti-inflammatory drugs, physical therapy, braces, activity modification, and finally operative treatment. Intra-articular (IA) injections are usually used when the non-operative treatment is not effective, and when the surgery is not yet indicated. More and more studies suggesting that IA injections are as or even more efficient and safe than NSAIDs. Recently, research to improve intra-articular homeostasis has focused on biologic adjuncts, such as platelet-rich plasma (PRP). The catabolic and inflammatory intra-articular processes that exists in knee osteoarthritis (KOA) may be influenced by the administration of PRP and its derivatives. PRP can induce a regenerative response and lead to the improvement of metabolic functions of damaged structures. However, the positive effect on chondrogenesis and proliferation of mesenchymal stem cells (MSC) is still highly controversial. Recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, significant progress has been made in understanding the mechanism of PRP action. In this review, we will discuss mechanisms related to inflammation and chondrogenesis in cartilage repair and regenerative processes after PRP administration in in vitro and animal studies. Furthermore, we review clinical trials of PRP efficiency in changing the OA biomarkers in knee joint.

Genetics in Cartilage Lesions: Basic Science and Therapy Approaches.

Cartilage lesions have a multifactorial nature, and genetic factors are their strongest determinants. As biochemical and genetic studies have dramatically progressed over the past decade, the molecular basis of cartilage pathologies has become clearer. Several homeostasis abnormalities within cartilaginous tissue have been found, including various structural changes, differential gene expression patterns, as well as altered epigenetic regulation. However, the efficient treatment of cartilage pathologies represents a substantial challenge. Understanding the complex genetic background pertaining to cartilage pathologies is useful primarily in the context of seeking new pathways leading to disease progression as well as in developing new targeted therapies. A technology utilizing gene transfer to deliver therapeutic genes to the site of injury is quickly becoming an emerging approach in cartilage renewal. The goal of this work is to provide an overview of the genetic basis of chondral lesions and the different approaches of the most recent systems exploiting therapeutic gene transfer in cartilage repair. The integration of tissue engineering with viral gene vectors is a novel and active area of research. However, despite promising preclinical data, this therapeutic concept needs to be supported by the growing body of clinical trials.

Genomic and transcriptomic profiles and in vitro resistance to mitoxantrone and idarubicin in pediatric acute leukemias.

BACKGROUND: A major problem in the treatment of leukemia is the development of drug resistance to chemotherapeutic agents. METHODS: To determine the ex vivo drug resistance profile to anthracyclines, an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) cytotoxicity assay was performed on mononuclear cells obtained from 155 patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML). Gene expression profiles (for 51 patients with ALL and 16 with AML) were prepared on the basis of cRNA hybridization to oligonucleotide arrays of the human genome (Affymetrix). Hierarchical clustering, assignment location and biological function were investigated during the correlation analysis for identified probe sets. Comparative genomic hybridization (CGH) array profiles (34 patients with ALL and 12 with AML) were prepared on the basis of DNA hybridization to oligonucleotide arrays of the human genome (Agilent). The validation of the array results was performed by a quantitative reverse transcriptase polymerase chain reaction. RESULTS: The collected expression and CGH microarray experiment results indicate that the ITGB2, SCL6A7, CASP1 and DUSP genes may comprise a resistance marker for acute leukemia cells correlated with anthracyclines. Moreover, there were also identified chromosome rearrangements associated with drug resistance, such as del5q32-35.3 and amp8p12-p11.21. Precise genes, as well as genome aberrations, might be classified as targets in therapy. CONCLUSIONS: In AML, the resistance of blasts to idarubicin and mitoxantrone may reflect an impaired integrin pathway. In ALL, the development of resistance is caused by the inhibition of B and T cell activation. Copyright © 2016 John Wiley & Sons, Ltd.

An analysis of the expression of collagen I and III genes in the fascia of obese patients.

BACKGROUND: The etiology of incisional hernias in the population of morbidly obese patients remains unclear. Most likely, factors other than purely mechanical are at play; it has been ascertained that nonobese patients suffering from inguinal and incisional hernias display alterations in the architecture of the connective tissue. The goal of this study has been to evaluate and compare the relative expression of collagen type I and III genes in the rectus abdominis muscle sheath (RMS) of obese and nonobese individuals to investigate their possible influence on the quality of the connective tissue. MATERIALS AND METHODS: RMS specimens were harvested in the early stages of either bariatric or non-bariatric laparotomies; total RNA was isolated and enzymatically purified from the tissue samples. The resulting material was subjected to a quantitative and qualitative analysis; reverse transcription reactions were then performed and the resulting complementary DNA was used in real-time reverse transcription polymerase chain reactions. The biopsy specimens were also examined by scanning electron microscopy. RESULTS: The real-time reverse transcription polymerase chain reactions, performed on complementary DNA, provided specific amplicons for individual genes. The efficacy of the reactions was rather low. An almost twofold decrease of the relative expression level for type I and III collagen was observed between the two patient groups; the results did not reach statistical significance. Scanning electron microscope photographs have documented a marked difference in the ultrastructure of the RMS in both groups. CONCLUSIONS: The authors have shown that changes in messenger RNA levels for collagen type I and III genes may be related to the pathogenesis of incisional hernia through alterations in the ultrastructure of the RMS fascia. Our report should be considered preliminary; the results should be verified on a larger group of patients.

Analysis of relative expression level of VEGF ( vascular endothelial growth factor ), HIF-1α ( hypoxia inducible factor 1α ) and CTGF ( connective tissue growth factor ) genes in chronic glomerulonephritis (CGN) patients.

BACKGROUND/AIMS: Analysis of gene expression in renal tissue is considered to be a diagnostic tool predicting the clinical course of glomerulonephritis. The present study quantified the relative transcript levels of VEGF, CTGF and HIF-1α in renal tissue to establish their relationship with some clinical variables in patients suffering from chronic glomerulonephritis (CGN). METHODS: 28 patients (6F and 22M, mean age 51.2±15.0) with CGN were enrolled. Type of CNG recognized by kidney biopsy (histopatological evaluation) was as follows: minimal change disease (MCD)-3pts, IgA nephropathy-5pts, FSGS-3pts, membranous nephropathy-4pts, mesangio-proliferative glomerulonephritis-3pts; MPGN-1pts, lupus nephritis-6pts, granulomatosis with polyangitis-2 pts; hypertensive nephropathy- 3pts. Renal tissue from 3 individuals with normal eGFR and histology was taken as control. Mean clinical follow-up of patients was 12 months after biopsy eGFR and daily urinary protein excretion (DPE) was assessed at the time of biopsy and then in 6 months intervals. Real-time PCR was used to determine relative gene expression. The housekeeping gene GAPDH was used as normalization control. RESULTS: At the time of the biopsy relative expression of 3 analyzed genes was diminished in comparison to control. There were statistically significant differences in VEGF gene relative expression level in patients which varied according to eGFR and tendency in patients which varied according to DPE. HIF-alfa and CTGF gene showed only a tendency. CONCLUSIONS: Overexpression of the VEGF gene in subjects with DPE>3,5 g may point to insufficient oxygen supply in renal tissue which may result in tubulointerstitial fibrosis with further functional renal impairment and decline of eGFR.

Array comparative genomic hybridization in pediatric acute leukemias.

Array comparative genomic hybridization has proven to be a very powerful tool in searching for new biomarkers which can find an application in clinical practise. CGH-array technology is satisfying in almost every possible way. It is highly specific, sensitive, simple, and relatively cheap. Thus, this modern method meets the demands of clinical application. An increasing knowledge about molecular pathways and pathologic genome alterations in acute leukemias enable to define unequivocal diagnosis, prognosis and to predict a response to individual compatible therapy. This review shows a various application of CGH-array in pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

MicroRNA-Mediated Regulation of Histone-Modifying Enzymes in Cancer: Mechanisms and Therapeutic Implications.

In the past decade, significant advances in molecular research have provided a deeper understanding of the intricate regulatory mechanisms involved in carcinogenesis. MicroRNAs, short non-coding RNA sequences, exert substantial influence on gene expression by repressing translation or inducing mRNA degradation. In the context of cancer, miRNA dysregulation is prevalent and closely associated with various stages of carcinogenesis, including initiation, progression, and metastasis. One crucial aspect of the cancer phenotype is the activity of histone-modifying enzymes that govern chromatin accessibility for transcription factors, thus impacting gene expression. Recent studies have revealed that miRNAs play a significant role in modulating these histone-modifying enzymes, leading to significant implications for genes related to proliferation, differentiation, and apoptosis in cancer cells. This article provides an overview of current research on the mechanisms by which miRNAs regulate the activity of histone-modifying enzymes in the context of cancer. Both direct and indirect mechanisms through which miRNAs influence enzyme expression are discussed. Additionally, potential therapeutic implications arising from miRNA manipulation to selectively impact histone-modifying enzyme activity are presented. The insights from this analysis hold significant therapeutic promise, suggesting the utility of miRNAs as tools for the precise regulation of chromatin-related processes and gene expression. A contemporary focus on molecular regulatory mechanisms opens therapeutic pathways that can effectively influence the control of tumor cell growth and dissemination.

Identification of the genes expression profile associated with the ex vivo resistance to etoposide in childhood acute leukemias.

INTRODUCTION: Drug resistance and the gene expression profiles might discriminate the therapy outcome, and indicate the subgroup of patients with poor prognosis. In this study we analyzed the gene expression profile in correlation with the profile of ex vivo resistance to etoposide in children with acute leukemias. METHODS: The ex vivo drug resistance profile was determined by the MTT cytotoxicity assay performed on leukemic blasts of 56 patients. Gene expression profiles were obtained from the results of hybridization of cRNA to Human Genome U133A 2.0 ologonucleotide arrays. The following analyses were performed: correlation analysis, hierarchical clustering, the assignment of location and function. Verification of data for four selected genes (MNDA, GH1, NUDT21, RHOG) was performed by quantitative real time polymerase chain reaction in the studied population and in an independent group of 54 leukemic patients. RESULTS: Using the permutation Spearman correlation test, a set of 233 probes/209 genes was selected. The global test confirmed the significance of the correlation of gene expression profile and resistance to etoposide (p<0.001). The NUDT21 (nudix, nucleoside diphosphate linked moiety X-type, motif 21) gene showed the strongest correlation with resistance to etoposide (FDR<0.0001%). CONCLUSIONS: Profiling of transcriptome may help in assessing the sensitivity to drugs used in chemotherapy. Resistance to etoposide is possibly associated with a change of expression of a large number of biologically important genes that influence several cellular mechanisms.

MicroRNA as a Potential Therapeutic Molecule in Cancer.

Small noncoding RNAs, as post-translational regulators of many target genes, are not only markers of neoplastic disease initiation and progression, but also markers of response to anticancer therapy. Hundreds of miRNAs have been identified as biomarkers of drug resistance, and many have demonstrated the potential to sensitize cancer cells to therapy. Their properties of modulating the response of cells to therapy have made them a promising target for overcoming drug resistance. Several methods have been developed for the delivery of miRNAs to cancer cells, including introducing synthetic miRNA mimics, DNA plasmids containing miRNAs, and small molecules that epigenetically alter endogenous miRNA expression. The results of studies in animal models and preclinical studies for solid cancers and hematological malignancies have confirmed the effectiveness of treatment protocols using microRNA. Nevertheless, the use of miRNAs in anticancer therapy is not without limitations, including the development of a stable nanoconstruct, delivery method choices, and biodistribution. The aim of this review was to summarize the role of miRNAs in cancer treatment and to present new therapeutic concepts for these molecules. Supporting anticancer therapy with microRNA molecules has been verified in numerous clinical trials, which shows great potential in the treatment of cancer.

The Dynamics of Changes in the Concentration of IgG against the S1 Subunit in Polish Healthcare Workers in the Period from 1 to 12 Months after Injection, Including Four COVID-19 Vaccines.

BACKGROUND: The presented research made it possible to obtain the characteristics of changes in anti-SARS-CoV-2 IgG within one year of vaccination in healthcare workers. MATERIALS AND METHODS: The research group consisted of 18,610 participants represented by medical and administration staff. IgG antibody concentrations were determined by ELISA. RESULTS: At 5-8 months after full vaccination, the levels of anti-SARS-CoV-2 IgG with equal vaccines were similar. The exception was JNJ-78436735, for which IgG levels were significantly lower. In the 9th month after vaccination, an increase in the anti-SARS-CoV-2 IgG level, suggesting asymptomatic infection, was observed in a large group of participants. Significantly higher levels of anti-SARS-CoV-2 IgG antibodies were observed after the booster dose compared to the second dose. The increase in antibodies was observed already around the 5th day after the injection of the booster dose, and was maximized at approximately the 14th day. CONCLUSION: The cut-off date for protection against the disease seems to be the period 8-9 months from the vaccination for mRNA vaccines and 5-6 months for vector vaccines. The introduction of a booster dose was the right decision, which could have a real impact on restricting the further transmission of the virus.

Analysis of profibrogenic microRNAs (miRNAs) expression in urine and serum of chronic kidney disease (CKD) stage 1-4 patients and their relationship with proteinuria and kidney function.

PURPOSE: Besides conventional kidney diseases diagnostics, micro RNAs (miRNAs) assessment in urine and serum is considered to be a promising non-invasive method of diagnostics of renal parenchymal diseases and valuable therapeutic target also. The purpose of the study was to investigate the role of several miRNAs as a markers of kidney damage. METHODS: Assessment of 45 chronic kidney disease (CKD) patients stage 1-4 and 17 healthy control. Sample of urine and blood was taken from each participant for molecular analysis using Real Time PCR method to identify such micro-RNAs as: hsa-miR-155-5p, hsa-miR-214-3p, hsa-miR-200a-5p, hsa-miR-29a-5p, hsa-miR-21-5p, hsa-miR-93-5p, and hsa-miR-196a-5p. Basic biochemical test was done. Analysis was performed in CKD patients group and subgroup with chronic glomerulonephritis (CGN) confirmed by kidney biopsy. Moreover, analysis was performed in subgroup with different estimated glomerular filtration rate (eGFR) (according to CKD-EPI equation: eGFR < 60 ml/min, eGFR > 60 ml/min) and different daily protein excretion (DPE): (DPE < 3.5 g; DPE > 3.5 g). RESULTS: Increased relative expression of hsa-miR-29-5p, hsa-miR-21-5p, and hsa-miR-196a-5p and decreased expression of hsa-miR-155-5p, hsa-miR-214-5p, hsa-miR-200a-5p, and hsa-miR-93-5p was demonstrated in urine of analyzed CKD patients. In subpopulation of chronic glomerulonephritis (CGN) patients, there was higher level of expression in urine of hsa-miR-155-5p, hsa-miR 214-3p, hsa-miR-93-5p, and hsa-miR-196a-5p in CGN with DPE < 3.5 g. CGN patients with eGFR < 60 ml/min showed higher expression level of miRNAs such as hsa-miR-214-3p, hsa-miR-29-5p, hsa-miR-93-5p, and hsa-miR-196-5p in urine. There was increase in hsa-miR 155-5p, hsa-miR-214-3p, and hsa-miR-200a-5p serum expression level in CKD population and reduction of hsa-miR-29a-5p, hsa-miR-21-5p, and hsa-miR-93-5p expression. Increased level of expression of hsa-miR-155-5p; hsa-miR-214-3p, hsa-miR-200a-5p, and hsa-miR-29-5p was found in CGN patients with eGFR > 60 ml/min. CONCLUSION: Increased relative expression of profibrogenic miRNAs in urine or serum of CKD patients with eGFR > 60 ml/min and DPE < 3.5 g may indicate higher degree of fibrosis at early CKD stages.

Anti-SARS-CoV-2 IgG against the S Protein: A Comparison of BNT162b2, mRNA-1273, ChAdOx1 nCoV-2019 and Ad26.COV2.S Vaccines.

BACKGROUND: COVID-19 vaccines induce a differentiated humoral and cellular response, and one of the comparable parameters of the vaccine response is the determination of IgG antibodies. MATERIALS AND METHODS: Concentrations of IgG anti-SARS-CoV-2 antibodies were analyzed at three time points (at the beginning of May, at the end of June and at the end of September). Serum samples were obtained from 954 employees of the Nicolaus Copernicus University in Torun (a total of three samples each were obtained from 511 vaccinated participants). IgG antibody concentrations were determined by enzyme immunoassay. The statistical analysis included comparisons between vaccines, between convalescents and COVID-19 non-patients, between individual measurements and included the gender, age and blood groups of participants. RESULTS: There were significant differences in antibody levels between mRNA and vector vaccines. People vaccinated with mRNA-1273 achieved the highest levels of antibodies, regardless of the time since full vaccination. People vaccinated with ChAdOx1 nCoV-2019 produced several times lower antibody levels compared to the mRNA vaccines, while the antibody levels were more stable. In the case of each of the vaccines, the factor having the strongest impact on the level and stability of the IgG antibody titers was previous SARS-CoV-2 infection. There were no significant correlations with age, gender and blood type. SUMMARY: mRNA vaccines induce a stronger humoral response of the immune system with the fastest loss of antibodies over time.

Salt stress and salt shock differently affect DNA methylation in salt-responsive genes in sugar beet and its wild, halophytic ancestor.

Here we determined the impact of salt shock and salt stress on the level of DNA methylation in selected CpG islands localized in promoters or first exons of sixteen salt-responsive genes in beets. Two subspecies differing in salt tolerance were subjected for analysis, a moderately salt-tolerant sugar beet Beta vulgaris ssp. vulgaris cv. Huzar and a halophytic beet, Beta vulgaris ssp. maritima. The CpG island methylation status was determined. All target sequences were hyper- or hypomethylated under salt shock and/or salt stress in one or both beet subspecies. It was revealed that the genomic regions analyzed were highly methylated in both, the salt treated plants and untreated controls. Methylation of the target sequences changed in a salt-dependent manner, being affected by either one or both treatments. Under both shock and stress, the hypomethylation was a predominant response in sugar beet. In Beta vulgaris ssp. maritima, the hypermethylation occurred with higher frequency than hypomethylation, especially under salt stress and in the promoter-located CpG sites. Conversely, the hypomethylation of the promoter-located CpG sites predominated in sugar beet plants subjected to salt stress. This findings suggest that DNA methylation may be involved in salt-tolerance and transcriptomic response to salinity in beets.

Differences in the Concentration of Anti-SARS-CoV-2 IgG Antibodies Post-COVID-19 Recovery or Post-Vaccination.

At the end of 2020, population-based vaccination programs with new generation mRNA-based vaccines began almost all over the world. The aim of the study was to evaluate the titer of anti-SARS-CoV-2 IgG antibodies against the S1 subunit of the virus's spike protein as a marker of the humoral response in 477 patients and the concentration of interferon-gamma as an indicator of cellular response in 28 individuals. In our studies, we used serological enzyme-linked immunosorbent assays. IgG was measured in weeks 2 and 3 after the first dose and 1-5 weeks after the second dose of an mRNA vaccine in seropositive and seronegative individuals as well as in symptomatic and asymptomatic convalescents. High levels of antibodies were observed in 98% of our vaccinated cohort, and the presence of protective T cells was confirmed in the blood samples of all participants. The humoral immune response is diversified and is visible as early as 2-3 weeks after the first dose of the mRNA vaccine. The level of protection increased significantly after the second dose, with the increase being much greater in pre-vaccine healthy subjects and less in convalescents. In the second and third weeks after the second dose, the concentration of IgG antibodies was the highest, and in the following weeks, it decreased gradually. Regular serological measurements on eight subjects show that antibody titers are lower four months after vaccination than before the second dose.

[Action of type III IFNs and their roles in immune responses]. / Dzialanie interferonów typu III i ich rola w odpowiedziach immunologicznych.

Type III interferons, also known as IFN-lambda or IL-28/29, are a recently discovered family of IFNs related to both the type I IFNs and interleukin-10 family members. Interferon-lambda is functionally an interferon but structurally it is related to the interleukin-10 family. These novel cytokines are directly induced during viral infection like type-I interferons and signal through a similar JAK-STAT signaling pathway as type I IFN to activate the transcription of a similar set of IFN-stimulated genes (ISG) but use a separate receptor complex. ISG product induced by the type III family of IFNs are associated with immunomodulatory ability, antiviral activity and other effects. The antiviral and immunomodulatory effects of type III interferons make them interesting therapeutics for clinical use. In this review, we summarize the current state of knowledge about the biology of IFN-lambdas and their roles in immune responses via immunomodulatory and antiviral activity.

Role of microRNA dysregulation in childhood acute leukemias: Diagnostics, monitoring and therapeutics: A comprehensive review.

MicroRNAs (miRNAs) are short noncoding RNAs that regulate the expression of genes by sequence-specific binding to mRNA to either promote or block its translation; they can also act as tumor suppressors (e.g., let-7b, miR-29a, miR-99, mir-100, miR-155, and miR-181) and/or oncogenes (e.g., miR-29a, miR-125b, miR-143-p3, mir-155, miR-181, miR-183, miR-196b, and miR-223) in childhood acute leukemia (AL). Differentially expressed miRNAs are important factors associated with the initiation and progression of AL. As shown in many studies, they can be used as noninvasive diagnostic and prognostic biomarkers, which are useful in monitoring early stages of AL development or during therapy (e.g., miR-125b, miR-146b, miR-181c, and miR-4786), accurate classification of different cellular or molecular AL subgroups (e.g., let-7b, miR-98, miR-100, miR-128b, and miR-223), and identification and development of new therapeutic agents (e.g., mir-10, miR-125b, miR-203, miR-210, miR-335). Specific miRNA patterns have also been described for commonly used AL therapy drugs (e.g., miR-125b and miR-223 for doxorubicin, miR-335 and miR-1208 for prednisolone, and miR-203 for imatinib), uncovering miRNAs that are associated with treatment response. In the current review, the role of miRNAs in the development, progression, and therapy monitoring of pediatric ALs will be presented and discussed.

Comparative Analysis of the Liver Transcriptome among Cattle Breeds Using RNA-seq.

Global gene expression in liver transcriptome varies among cattle breeds. The present investigation was aimed to identify the differentially expressed genes (DEGs), metabolic gene networks and metabolic pathways in bovine liver transcriptome of young bulls. In this study, we comparatively analyzed the bovine liver transcriptome of dairy (Polish Holstein Friesian (HF); n = 6), beef (Hereford; n = 6), and dual purpose (Polish-Red; n = 6) cattle breeds. This study identified 895, 338, and 571 significant (p < 0.01) differentially expressed (DE) gene-transcripts represented as 745, 265, and 498 hepatic DE genes through the Polish-Red versus Hereford, Polish-HF versus Hereford, and Polish-HF versus Polish-Red breeds comparisons, respectively. By combining all breeds comparisons, 75 hepatic DE genes (p < 0.01) were identified as commonly shared among all the three breed comparisons; 70, 160, and 38 hepatic DE genes were commonly shared between the following comparisons: (i) Polish-Red versus Hereford and Polish-HF versus Hereford; (ii) Polish-Red versus Hereford and Polish-HF versus Polish-Red; and (iii) Polish-HF versus Hereford and Polish-HF versus Polish-Red, respectively. A total of 440, 82, and 225 hepatic DE genes were uniquely observed for the Polish-Red versus Hereford, Polish-HF versus Hereford, and Polish-Red versus Polish-HF comparisons, respectively. Gene ontology (GO) analysis identified top-ranked enriched GO terms (p < 0.01) including 17, 16, and 31 functional groups and 151, 61, and 140 gene functions that were DE in all three breed liver transcriptome comparisons. Gene network analysis identified several potential metabolic pathways involved in glutamine family amino-acid, triglyceride synthesis, gluconeogenesis, p38MAPK cascade regulation, cholesterol biosynthesis (Polish-Red versus Hereford); IGF-receptor signaling, catecholamine transport, lipoprotein lipase, tyrosine kinase binding receptor (Polish-HF versus Hereford), and PGF-receptor binding, (Polish-HF versus Polish-Red). Validation results showed that the relative expression values were consistent to those obtained by RNA-seq, and significantly correlated between the quantitative reverse transcription PCR (RT-qPCR) and RNA-seq (Pearson's r > 0.90). Our results provide new insights on bovine liver gene expressions among dairy versus dual versus beef breeds by identifying the large numbers of DEGs markers submitted to NCBI gene expression omnibus (GEO) accession number GSE114233, which can serve as useful genetic tools to develop the gene assays for trait-associated studies as well as, to effectively implement in genomics selection (GS) cattle breeding programs in Poland.