Deregulation Of Signaling Pathways Research Articles

Effects of siRNA-mediated Silencing of ERBB2, IGF-1R, and ITGB1 in HER2-positive Breast Cancer Cells.

One of the hallmarks of cancer is deregulation of multiple signaling pathways, which can lead to uncontrolled proliferation and migration of cells. Over-expression and mutations in human epidermal growth factor receptor 2 (HER2) can lead to overactivation of these pathways, potentially developing cancer in different tissues, including breast tissue. IGF-1R and ITGB-1 are two receptors that have been linked to cancer development. Therefore, the aim of this study was to investigate the effects of silencing of the corresponding genes using specific siRNAs. Transient silencing of HER2, ITGB-1, and IGF-1R was conducted using siRNAs and expression was quantified by reverse transcription-quantitative polymerase chain reaction. Viability in human breast cancer cells SKBR3, MCF-7, and HCC1954 and cytotoxicity in HeLa cells were tested using WST-1 assay. The use of anti-HER2 siRNAs in a breast cancer cell line over-expressing HER2 (SKBR3) led to a decrease in cell viability. However, silencing of ITGB-1 and IGF-1R in the same cell line had no significant effects. Silencing of any of the genes encoding any of the three receptors in MCF-7, HCC1954, and HeLa had no significant effects. Our results provide evidence towards using siRNAs against HER2-positive breast cancer. Silencing of ITGB-1 and IGF-R1 did not significantly inhibit the growth of SKBR3 cells. Therefore, there is need for testing the effect of silencing ITGB-1 and IGF-R1 in other cancer cell lines over-expressing these biomarkers and explore their potential use in cancer therapy.

Endothelial Differentiation of CCM1 Knockout iPSCs Triggers the Establishment of a Specific Gene Expression Signature.

Cerebral cavernous malformation (CCM) is a neurovascular disease that can lead to seizures and stroke-like symptoms. The familial form is caused by a heterozygous germline mutation in either the CCM1, CCM2, or CCM3 gene. While the importance of a second-hit mechanism in CCM development is well established, it is still unclear whether it immediately triggers CCM development or whether additional external factors are required. We here used RNA sequencing to study differential gene expression in CCM1 knockout induced pluripotent stem cells (CCM1-/- iPSCs), early mesoderm progenitor cells (eMPCs), and endothelial-like cells (ECs). Notably, CRISPR/Cas9-mediated inactivation of CCM1 led to hardly any gene expression differences in iPSCs and eMPCs. However, after differentiation into ECs, we found the significant deregulation of signaling pathways well known to be involved in CCM pathogenesis. These data suggest that a microenvironment of proangiogenic cytokines and growth factors can trigger the establishment of a characteristic gene expression signature upon CCM1 inactivation. Consequently, CCM1-/- precursor cells may exist that remain silent until entering the endothelial lineage. Collectively, not only downstream consequences of CCM1 ablation but also supporting factors must be addressed in CCM therapy development.

KLF regulation of insulin pathway genes.

Alteration in lipid metabolism can result in fat accumulation in adipose tissues, which may lead to two most important human diseases, obesity and diabetes. A shift in lipid metabolism deregulates signaling pathways which regulates obesity and/or diabetes. In this study, we examined the components of insulin/ TGF-β pathways and their genetic interaction with Krüppel-like transcription factors (KLFs). Their role in energy homeostasis were discussed. We separately created klf/daf genes double mutants by carrying out klfs RNAi on daf-2 (e1391), daf-4 (e1364), daf-7 (e1372); dpy-1 (e1), daf-14 (m77), daf-16 (mgDf50) mutants. And then conducted Oil O Red staining to assay the klf/daf RNAi worms for fat deposits and examine genetic interaction between klfs and daf genes. The results showed that worms bearing klf-1, 2, or 3 and daf-2, or daf-4 mutations deposit large, but similar fat levels as individual mutants. The results suggested that they target the same molecular pathway of fat storage. klf-1, 2 or 3 RNAi /daf-7 worms showed higher fat deposits in klf-1, 2, or 3 RNAi/daf-7 worms than klf-1, 2, or 3 RNAi or daf-7 mutants alone, which showed a functional interaction between klfs and daf-7 in perhaps TGF-β-like pathway. Altogether our study suggests a direct role of klfs in insulin signaling pathway.

T-REX17 is a transiently expressed non-coding RNA essential for human endoderm formation.

Long non-coding RNAs (lncRNAs) have emerged as fundamental regulators in various biological processes, including embryonic development and cellular differentiation. Despite much progress over the past decade, the genome-wide annotation of lncRNAs remains incomplete and many known non-coding loci are still poorly characterized. Here, we report the discovery of a previously unannotated lncRNA that is transcribed 230 kb upstream of the SOX17 gene and located within the same topologically associating domain. We termed it T-REX17 (Transcript Regulating Endoderm and activated by soX17) and show that it is induced following SOX17 activation but its expression is more tightly restricted to early definitive endoderm. Loss of T-REX17 affects crucial functions independent of SOX17 and leads to an aberrant endodermal transcriptome, signaling pathway deregulation and epithelial to mesenchymal transition defects. Consequently, cells lacking the lncRNA cannot further differentiate into more mature endodermal cell types. Taken together, our study identified and characterized T-REX17 as a transiently expressed and essential non-coding regulator in early human endoderm differentiation.

The FOXC2 Transcription Factor: A Master Regulator of Chemoresistance in Cancer.

FOXC2, a member of the forkhead box family of transcription factors, is an emerging oncogene that has been linked to several hallmarks of cancer progression. Among its many oncogenic functions is the promotion of drug resistance, with evidence supporting roles for FOXC2 in escape from broad classes of chemotherapeutics across an array of cancer types. In this Mini-Review, we highlight the current understanding of the mechanisms by which FOXC2 drives cancer chemoresistance, including its roles in the promotion of epithelial-mesenchymal transition, induction of multidrug transporters, activation of the oxidative stress response, and deregulation of cell survival signaling pathways. We discuss the clinical implications of these findings, including strategies for modulating FOXC2-associated chemoresistance in cancer. Particular attention is given to ways in which FOXC2 and its downstream gene products and pathways can be targeted to restore chemosensitivity in cancer cells. In addition, the utility of FOXC2 expression as a predictor of patient response to chemotherapy is also highlighted, with emphasis on the value of FOXC2 as a novel biomarker that can be used to guide therapeutic choice towards regimens most likely to achieve clinical benefit during frontline therapy.

Review on lymphoma and deregulated signaling pathways

Since the incidence of cancer is increasing worldwide, there is an urgent need for more successful therapies. Here, we focused on a literature review regarding lymphoma and deregulated pathways that are hallmarks of lymphoma development. Among others, PI3K/AKT, NF-ĸB and JAK/STAT pathways are the most common deregulated ones. These signaling pathways are crucial for numerous cellular processes and possible deregulation can mainly lead to uncontrolled cell division and inhibition of apoptosis. A literature review was performed by using databases including PubMed, PubMed Central and Google Scholar from where the most recent and valuable studies were selected.

Lessons from Using Genetically Engineered Mouse Models of MYC-Induced Lymphoma.

Oncogenic overexpression of MYC leads to the fatal deregulation of signaling pathways, cellular metabolism, and cell growth. MYC rearrangements are found frequently among non-Hodgkin B-cell lymphomas enforcing MYC overexpression. Genetically engineered mouse models (GEMMs) were developed to understand MYC-induced B-cell lymphomagenesis. Here, we highlight the advantages of using Eµ-Myc transgenic mice. We thoroughly compiled the available literature to discuss common challenges when using such mouse models. Furthermore, we give an overview of pathways affected by MYC based on knowledge gained from the use of GEMMs. We identified top regulators of MYC-induced lymphomagenesis, including some candidates that are not pharmacologically targeted yet.

Multifunctional Roles of Betulinic Acid in Cancer Chemoprevention: Spotlight on JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and Non-Coding RNAs in the Inhibition of Carcinogenesis and Metastasis.

The pursual of novel anticancer molecules from natural sources has gained worthwhile appreciation, and a significant fraction of conceptual knowledge has revolutionized our understanding about heterogeneous nature of cancer. Betulinic acid has fascinated interdisciplinary researchers due to its tremendous pharmacological properties. Ground-breaking discoveries have unraveled previously unprecedented empirical proof-of-concept about momentous chemopreventive role of betulinic acid against carcinogenesis and metastasis. Deregulation of cell signaling pathways has been reported to play a linchpin role in cancer progression and colonization of metastatically competent cancer cells to the distant organs for the development of secondary tumors. Importantly, betulinic acid has demonstrated unique properties to mechanistically modulate oncogenic transduction cascades. In this mini-review, we have attempted to provide a sophisticated compendium of regulatory role of betulinic acid in cancer chemoprevention. We have partitioned this multi-component review into different sections in which we summarized landmark research-works which highlighted betulinic acid mediated regulation of JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and ubiquitination pathways in the inhibition of cancer. In parallel, betulinic acid mediated regulation of signaling cascades and non-coding RNAs will be critically analyzed in cell culture and animal model studies. Better comprehension of the pharmaceutical features of betulinic acid and mapping of the existing knowledge gaps will be valuable in the translatability of preclinical studies into rationally designed clinical trials.

Aging-Related Gene Expression Signatures Define Likelihood of Disease Progression in Patients with Lower-Risk Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a heterogeneous clonal bone marrow disorders occurring mostly in the elderly. The Revised International Prognostic System (IPSS-R) groups MDS patients according to the risk of transformation into acute myeloid leukemia. For treatment decision-making, patients are usually divided into two groups: lower- and higher-risk with the cutpoint of 3.5 according to the IPSS-R. However, part of lower-risk MDS patients (LR-MDS) progresses rapidly. Recently, we demonstrated that DNA damage response (DDR) activation and the ensuing senescence form an anti-tumor barrier in CD34+ cells of LR-MDS patients, and that this barrier can be breached by RUNX1 mutations (Kaisrlikova M, et al., Leukemia. 2022; 36:1898). As an extension, we analyzed transcriptomes of LR-MDS patients regardless of their driver mutation, with and without rapid progression (within 2 years of diagnosis), to determine molecular mechanisms underlying the progression. Because MDS is associated with aging, and many anti-tumor barrier mechanisms (DDR, checkpoint activation, senescence) lead to a pro-aging phenotype, we questioned whether aging-related gene expression signatures define the likelihood of disease progression in patients with LR-MDS. We performed RNA-seq on CD34+ cells of 61 LR-MDS diagnostic samples (53 patients without rapid progression (NRP) and 8 patients with rapid progression (RP)) with a median age of 65 years. The differential expression analysis showed 1,701 up- and 1,569 downregulated genes in NRP (FDR<0.01). According to the GO Biological Processes (GO BP) and REACTOME databases, the most significantly upregulated pathways were related to macromolecular metabolic processes such as DNA repair, replication, protein metabolism, cell cycle, chromosome organization, including regulation of gene expression, and telomere organization (Fig. 1). The pathways of rRNA expression regulation, splicing, and RNA metabolism were deregulated as well as the pathways related to apoptosis, cellular senescence and cellular response to stress, immune response, and mitochondrial metabolism. Furthermore, we found deregulation of crucial signaling pathways mediated by NOTCH, RHO GTPases, NF-kB, MAPK, b-catenin, and WNT. Although 1,569 genes were upregulated in RP, only seventeen GO BP terms consisted of regulation of metabolic processes, cytoskeleton organization, phosphorylation, and signal transduction were upregulated. The NRP results are consistent with the hallmarks of aging (López-Otín C, et al., Cell. 2013; 153:1194). In GSEA, 36/37 and 120/143 gene sets were upregulated in NRP for the datasets consisting of gene sets chosen according to the keyword 'aging' and 'stress', respectively (Fig. 2). Among them, gene sets associated with replication stress, DNA damage, oxidative stress and unfolded protein response were significant (FDR<0.1, ІNESІ>1.7). Abnormal splicing is associated with cellular aging. Therefore, we conducted a differential alternative splicing analysis using rMATS. We found significant differences in 1,356 alternative splicing events (FDR<0.05, absolute inclusion level difference>10%) between NRP and RP. Finally, we performed analysis of healthy controls (n=7) and age-matched NRP (NRP-age) (n=13) samples. We observed 70 up- and 209 downregulated genes in NRP-age (FDR<0.05). Only the splicing pathways were upregulated and the immune pathways downregulated. In GSEA, no gene sets were significant (FDR<0.1) for aging and stress datasets. To conclude, these results show increased signatures of aging in CD34+ cells from NRP, which correspond to an increased level of the intrinsic ability of CD34+ cells to suppress malignant progression through anti-tumor barrier activation. This is consistent with the current understanding that most aging phenotypes are known to be the products of DDR and tumor suppression. Based on our data, we hypothesize that the progression of LR-MDS patients represents a cell-autonomously and perhaps also non-cell-autonomously-mediated failure of appropriate cellular stress response mechanisms. Our data also show similarity at the transcriptome level between age-matched NRP and healthy controls. Supported by AZV (NV18-03-00227) and (NU21-03-00565), GA CR (N20-19162S), and MH CZ-DRO (UHKT, 00023736). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Role of Long Intergenic Noncoding RNAs in Cancers with an Overview of MicroRNA Binding.

Long intergenic noncoding RNAs are transcripts originating from the regions without annotated coding genes. They are located mainly in the nucleus and regulate gene expression. Long intergenic noncoding RNAs can be also found in the cytoplasm acting as molecular sponges of certain microRNAs. This is crucial in various biological and signaling pathways. Expression levels of many long intergenic noncoding RNAs are disease related. In this article, we focus on the long intergenic noncoding RNAs and their relation to different types of cancer. Studies showed that abnormal expression of long intergenic noncoding RNA deregulates signaling pathways due to the disrupted free microRNA pool. Hampered signaling pathways leads to abnormal cell proliferation and restricts cell death, thus resulting in oncogenesis. This review highlights promising therapeutic targets and enables the identification of potential biomarkers specific for a certain type of cancer. Moreover, we provide an outline of long intergenic noncoding RNAs/microRNA axes, which might be applied in further detailed experiments broadening our knowledge about the cellular role of those RNA species.

Different Approaches for the Profiling of Cancer Pathway-Related Genes in Glioblastoma Cells.

Deregulation of signalling pathways that regulate cell growth, survival, metabolism, and migration can frequently lead to the progression of cancer. Brain tumours are a large group of malignancies characterised by inter- and intratumoral heterogeneity, with glioblastoma (GBM) being the most aggressive and fatal. The present study aimed to characterise the expression of cancer pathway-related genes (n = 84) in glial tumour cell lines (A172, SW1088, and T98G). The transcriptomic data obtained by the qRT-PCR method were compared to different control groups, and the most appropriate control for subsequent interpretation of the obtained results was chosen. We analysed three widely used control groups (non-glioma cells) in glioblastoma research: Human Dermal Fibroblasts (HDFa), Normal Human Astrocytes (NHA), and commercially available mRNAs extracted from healthy human brain tissues (hRNA). The gene expression profiles of individual glioblastoma cell lines may vary due to the selection of a different control group to correlate with. Moreover, we present the original multicriterial decision making (MCDM) for the possible characterization of gene expression profiles. We observed deregulation of 75 genes out of 78 tested in the A172 cell line, while T98G and SW1088 cells exhibited changes in 72 genes. By comparing the delta cycle threshold value of the tumour groups to the mean value of the three controls, only changes in the expression of 26 genes belonging to the following pathways were identified: angiogenesis FGF2; apoptosis APAF1, CFLAR, XIAP; cellular senescence BM1, ETS2, IGFBP5, IGFBP7, SOD1, TBX2; DNA damage and repair ERCC5, PPP1R15A; epithelial to mesenchymal transition SNAI3, SOX10; hypoxia ADM, ARNT, LDHA; metabolism ATP5A1, COX5A, CPT2, PFKL, UQCRFS1; telomeres and telomerase PINX1, TINF2, TNKS, and TNKS2. We identified a human astrocyte cell line and normal human brain tissue as the appropriate control group for an in vitro model, despite the small sample size. A different method of assessing gene expression levels produced the same disparities, highlighting the need for caution when interpreting the accuracy of tumorigenesis markers.

Insights into functional connectivity in mammalian signal transduction pathways by pairwise comparison of protein interaction partners of critical signaling hubs.

Growth factors and cytokines activate signal transduction pathways and regulate gene expression in eukaryotes. Intracellular domains of activated receptors recruit several protein kinases as well as transcription factors that serve as platforms or hubs for the assembly of multi-protein complexes. The signaling hubs involved in a related biologic function often share common interaction proteins and target genes. This functional connectivity suggests that a pairwise comparison of protein interaction partners of signaling hubs and network analysis of common partners and their expression analysis might lead to the identification of critical nodes in cellular signaling. A pairwise comparison of signaling hubs across several related pathways might reveal novel signaling modules. Analysis of protein interaction connectome by Venn (PIC-Venn) of transcription factors STAT1, STAT3, NFKB1, RELA, FOS, and JUN, and their common interaction network suggested that BRCA1 and TSC22D3 function as critical nodes in immune responses by connecting the signaling hubs into signaling modules. Transcriptional regulation of critical hubs may play a major role in the lung epithelial cells in response to SARS-CoV-2 and in COVID-19 patients. Mutations and differential expression levels of these critical nodes and modules in pathological conditions might deregulate signaling pathways and their target genes involved in inflammation. Biological connectivity emerges from the structural connectivity of interaction networks across several signaling hubs in related pathways. The main objectives of this study are to identify critical hubs, critical nodes, and modules involved in the signal transduction pathways of innate and adaptive immunity. Application of PIC-Venn to several signaling hubs might reveal novel nodes and modules that can be targeted by small regulatory molecules to simultaneously activate or inhibit cell signaling in health and disease.

Peripheral inflammatory markers during an acute bacterial infection in older patients with and without cognitive dysfunction: A case control study

Dementia is a known risk factor for acute bacterial infections which may also play a significant role in promoting or accelerating cognitive impairment. Pneumonia and urinary tract infections are the main cause of hospitalisation of dementia patients and infections are a major precipitant of delirium. It is well established that peripheral immune signals induce a neuroinflammatory response largely mediated by microglial cells which is amplified with advanced age, neurodegenerative disorders and genetic characteristics. Reversely, the innate immune response to acute bacterial infection is tightly regulated by the brain. It remains unclear whether dysfunctional neural circuits affected by dementia and/or delirium could alter systemic innate immune responses at the periphery. The current study aims to determine if dementia and/or delirium are associated with an altered systemic inflammatory response to an acute bacterial infection. We recruited 46 hospitalised older patients with acute bacterial infections. From these, 29 participants had cognitive dysfunction (6 with delirium, 12 with dementia and 11 with delirium superimposed on dementia) and 17 had normal cognition. We also included a control group of 11 patients with dementia but with no current infection matched for age and educational status. Baseline characteristics were tested between groups using Kruskal-Wallis test and pairwise comparisons were subsequently assessed with Bonferroni correction for multiple comparisons for continuous variables. Chi square test was used to assess differences between groups in categorical data and correlations between peripheral inflammatory parameters were assessed with Spearman's test. The 4 groups with infection and the control group with no infection had similar characteristics except for cognitive function and functionality which was higher for the group of infected cognitively healthy participants. Levels of C-reactive protein were similar between the infected groups and higher than the non-infected dementia group. Infected patients with cognitive dysfunction (delirium and/or dementia) had higher serum levels of IL-6, TNF-alpha and IL-1beta. These participants had reduced expression of miR-145 in circulating exosomes which correlated negatively with miR-155 levels (r = −0.411, p = 0.027). Expression of CR1 in circulating CD14+ monocytes was higher in infected participants with cognitive dysfunction and, in this group, PICALM correlated both with TNF-alpha and IL-6. In contrast to what was observed in participants with normal cognition, expression of CR1 did not correlate with DAP12 in infected participants with cognitive dysfunction. Taken together, our findings suggest that cognitive dysfunction is associated with an exaggerated proinflammatory response during acute bacterial infection with deregulation of several molecular signalling pathways in circulating exosomes and in monocytes.

Diverse mutations and structural variations contribute to Notch signaling deregulation in paediatric T-cell lymphoblastic lymphoma.

T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL. Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.

OCT4-mediated transcription confers oncogenic advantage for a subset of gastric tumors with poor clinical outcome.

Deregulated transcription programs and signaling pathways are the critical factors involved in the process of carcinogenesis. Signaling pathway-based classification of tumors is expected to pave the way for the development of targeted therapeutics. We investigated the OCT4-mediated transcription program in the gene expression profiles of 939 gastric tumor samples. A set of 84 genes showing positive correlation with the activation pattern of the available OCT4 gene sets were found to consistently express in diffuse, poorly differentiated, and stage-III gastric tumors with poor prognosis. We also developed stable OCT4-silenced gastric cancer cells and the resultant gene expression changes were investigated by genome-wide mRNA profiling. Functional genomic investigation of the genes downregulated in OCT4-silenced cells and the pathways co-activated with OCT4 gene set across gastric tumors revealed the positive association of dysregulated OCT4 with TGF-β, GLI, PRC2/EzH2, Wnt, KRAS, STK33, and YAP signaling pathways in diffuse subtype gastric tumors. Elevated expression of OCT4 gene set was identified to represent the previously described EMT_UP as well as the GENOMICALLY STABLE subtypes of gastric tumors. Integrative genomic screening of the drug sensitivity of gastric cancer cells in correlation with the expression of OCT4 gene set across drug sensitivity databases revealed the inhibitors of tyrosine kinases, HDAC, and HSP90 to have a negative correlation and needs to be investigated for their potential therapeutic features for the subset of OCT4-activated gastric tumors. Thus, the subset of gastric tumors with OCT4 activation, the associated oncogenic signaling pathways, and potential therapeutic candidates were identified for the development of targeted therapeutic strategies.

Long non-coding RNA signatures and related signaling pathway in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy caused by clonal proliferation of T-cell pre-cursors arising from the thymus. Although the optimized chemotherapy regimen could improve the outcome of such patients, some challenges such as higher risk for induction failure, early relapse and isolated central nervous system (CNS) relapse occurring in T-ALL patients are of great significance, leading to increased mortality rates. Long non-coding RNA (lncRNA) is a key component involved in cell signaling through a variety of mechanisms in regulating gene expression. Oncogenes and tumor suppressors are no exception and their expression can be affected by lncRNAs. In addition, accumulating researches in samples from T-ALL patients as well as pre-clinical studies in mice suggest that the expression profile of lncRNAs in T-ALL could be aberrant, resulting in deregulation of target genes and downstream signaling pathways. In addition, accumulating researches in samples from T-ALL patients as well as pre-clinical studies in mice suggest that the expression profile of lncRNAs in T-ALL could be aberrant, resulting in deregulation of target genes and downstream signaling pathways. These lncRNAs may be determinants of proliferation, apoptosis, and drug resistance observed in T-ALL. Thus, lncRNAs can be a good tool to develop novel strategies against cancer cells in the treatment of relapsed and refractory T-ALL. They can also act as promoting biomarkers in assessing T-ALL and differentiating between patients with poor prognosis and good prognosis.

A systematic review of molecular alterations in invasive non-functioning pituitary adenoma.

Invasive non-functional pituitary adenomas (NFPAs) constitute 35% of NFPAs. Despite a relatively large body of molecular investigations on the invasiveness of NFPA, the underlying molecular mechanisms of invasiveness are yet to be determined. Herein, we aimed to provide an overview of gene/microRNA(miRNAs) expression alterations in invasive NFPA. This article describes a systematic literature review of articles published up to March 23, 2021, on the transcriptional alterations of invasive NFPA. Five digital libraries were searched, and 42 articles in total fulfilled the eligibility criteria. Pathway enrichment was conducted, and protein interactions among the identified deregulated genes were inferred. In total 133 gene/protein transcriptional alterations, comprising 87 increased and 46 decreased expressions, were detected in a collective number of 1001 invasive compared with 1007 non-invasive patients with NFPA. Deregulation of CDH1, PTTG1, CCNB1, SNAI1, SLUG, EZR, and PRKACB, which are associated with epidermal-mesenchymal transition (EMT), was identified. Moreover, six members of the angiogenesis pathway, i.e., VEGFA, FLT1, CCND1, CTNNB1, MYC(c-MYC), and PTTG1, were detected. SLC2A1, FLT1, and VEGFA were also recognized in the hypoxia pathway. Physical interactions of CTNNB1 with FLT1, CCND1, and EZR as well as its indirect interactions with VEGFA, MYC, CCNB1, and PCNA indicate the tight interplay between EMT, angiogenesis, and hypoxia pathways in invasive NFPAs. In addition, Hippo, JAK-STAT, MAPK, Wnt, PI3K-Akt, Ras, TGF-b, VEGF, and ErbB were identified as interwoven signaling pathways. In conclusion, invasive NFPA shares very common deregulated signaling pathways with invasive cancers. A large amount of heterogeneity in the reported deregulations in different studies necessitates the validation of the expressional changes of the suggested biomarkers in a large number of patients with invasive NFPA.

Novel T Follicular Helper-like T-Cell Lymphoma Therapies: From Preclinical Evaluation to Clinical Reality.

Simple SummaryThis work reviews the multiple efforts that have been and are being invested by researchers as well as clinicians to improve the treatment of a specific T-cell lymphoma called follicular helper peripheral T-cell lymphoma. Still, though treatments for B-cell lymphomas have improved, this particular T-cell lymphoma has little to no new therapeutic options that show marked improvements in the survival of the patients compared to treatment with chemotherapy. We report here the evaluation of targeted new therapies for this T-cell lymphoma in new preclinical models for this cancer or in clinical trials with the objective to offer better (combination) treatment options.The classification of peripheral T-cell lymphomas (PTCL) is constantly changing and contains multiple subtypes. Here, we focus on Tfh-like PTCL, to which angioimmunoblastic T-cell lymphoma (AITL) belongs, according to the last WHO classification. The first-line treatment of these malignancies still relies on chemotherapy but gives very unsatisfying results for these patients. Enormous progress in the last decade in terms of understanding the implicated genetic mutations leading to signaling and epigenetic pathway deregulation in Tfh PTCL allowed the research community to propose new therapeutic approaches. These findings point towards new biomarkers and new therapies, including hypomethylating agents, such as azacytidine, and inhibitors of the TCR-hyperactivating molecules in Tfh PTCL. Additionally, metabolic interference, inhibitors of the NF-κB and PI3K-mTOR pathways and possibly novel immunotherapies, such as antibodies and chimeric antigen receptors (CAR) directed against Tfh malignant T-cell surface markers, are discussed in this review among other new treatment options.

AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model.

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA‐binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1‐KO mouse model. Here we show that adeno‐associated viral vector delivery of a modified and FMRP‐independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS‐relevant behavioral phenotypes in the Fmr1‐KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.

From Helicobacter pylori infection to gastric cancer: Current evidence on the immune response.

Gastric cancer (GC) is the result of a multifactorial process whose main components are infection by Helicobacter pylori (H. pylori), bacterial virulence factors, host immune response and environmental factors. The development of the neoplastic microenvironment also depends on genetic and epigenetic changes in oncogenes and tumor suppressor genes, which results in deregulation of cell signaling pathways and apoptosis process. This review summarizes the main aspects of the pathogenesis of GC and the immune response involved in chronic inflammation generated by H. pylori.