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Background and ObjectivesAging is characterized by a functional shift of the immune system toward a proinflammatory phenotype. This derangement has been associated with cognitive decline and has been implicated in the pathogenesis of dementia. Diet can modulate systemic inflammation; thus, it may be a valuable tool to counteract the associated risk for cognitive impairment and dementia. The present study aimed to explore the associations between the inflammatory potential of diet, assessed with an easily applicable, population-based, biomarker-validated diet inflammatory index (DII), and the risk for dementia in community-dwelling older adults.MethodsIndividuals from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present cohort study. Participants were recruited through random population sampling and were followed up for a mean of 3.05 (standard deviation 0.85) years. Dementia diagnosis was based on standard clinical criteria. Those with baseline dementia or missing cognitive follow-up data were excluded from the analyses. The inflammatory potential of diet was assessed through a DII score that considers literature-derived associations of 45 food parameters with levels of proinflammatory and anti-inflammatory cytokines in the blood; higher values indicated a more proinflammatory diet. Consumption frequencies were derived from a detailed food frequency questionnaire and were standardized to representative dietary intake normative data from 11 different countries. Analysis of dementia incidence as a function of baseline DII scores was performed by Cox proportional hazards models.ResultsAnalyses included 1,059 individuals (mean age 73.1 years, 40.3% male, mean education 8.2 years), 62 of whom developed incident dementia. Each additional unit of DII score was associated with a 21% increase in the risk for dementia incidence (hazard ratio 1.21 [95% confidence interval 1.03–1.42]; p = 0.023). Compared to participants in the lowest DII score tertile, participants in the highest one (maximal proinflammatory diet potential) were 3 (95% confidence interval 1.2–7.3; p = 0.014) times more likely to develop incident dementia. The test for trend was also significant, indicating a potential dose-response relationship (p = 0.014).DiscussionIn the present study, higher DII scores (indicating greater proinflammatory diet potential) were associated with an increased risk for incident dementia. These findings might avail the development of primary dementia preventive strategies through tailored and precise dietary interventions.

Alterations in global histone methylation regulate gene expression and participate in cancer onset and progression. The profile of histone methylation marks in pediatric astrocytomas is currently understudied with limited data on their distribution among grades. The global expression patterns of repressive histone marks H3K9me3, H3K27me3, and H4K20me3 and active H3K4me3 and H3K36me3 along with their writers SUV39H1, SETDB1, EZH2, MLL2, and SETD2 were investigated in 46 pediatric astrocytomas and normal brain tissues. Associations between histone marks and modifying enzymes with clinicopathological characteristics and disease-specific survival were studied along with their functional impact in proliferation and migration of pediatric astrocytoma cell lines using selective inhibitors in vitro. Upregulation of histone methyltransferase gene expression and deregulation of histone code were detected in astrocytomas compared to normal brain tissues, with higher levels of SUV39H1, SETDB1, and SETD2 as well as H4K20me3 and H3K4me3 histone marks. Pilocytic astrocytomas exhibited lower MLL2 levels compared to diffusely infiltrating tumors indicating a differential pattern of epigenetic regulator expression between the two types of astrocytic neoplasms. Moreover, higher H3K9me3, H3K36me3, and SETDB1 expression was detected in grade IIΙ/IV compared to grade II astrocytomas. In univariate analysis, elevated H3K9me3 and MLL2 and diminished SUV39H1 expression adversely affected survival. Upon multivariate survival analysis, only SUV39H1 expression was revealed as an independent prognostic factor of adverse significance. Treatment of pediatric astrocytoma cell lines with SUV39H1 inhibitor reduced proliferation and cell migration. Our data implicate H3K9me3 and SUV39H1 in the pathobiology of pediatric astrocytomas, with SUV39H1 yielding prognostic information independent of other clinicopathologic variables. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01090-x.

Mechanical features of cancer cells emerge as a distinct trait during development and progression of solid tumors. Herein, we discuss recent key findings regarding the impact of various types of mechanical stresses on cancer cell properties. Data suggest that different mechanical forces, alterations of matrix rigidity and tumor microenvironment facilitate cancer hallmarks, especially invasion and metastasis. Moreover, a subset of mechanosensory proteins are responsible for mediating mechanically induced oncogenic signaling and response to chemotherapy. Delineating cancer dynamics and decoding of respective signal transduction mechanisms will provide new therapeutic strategies against solid tumors in the future.

Craniosynostosis refers to the premature fusion of one or more cranial sutures leading to skull shape deformities and brain growth restriction. Among the many factors that contribute to abnormal suture fusion, mechanical forces seem to play a major role. Nevertheless, the underlying mechanobiology‐related mechanisms of craniosynostosis still remain unknown. Understanding how aberrant mechanosensation and mechanotransduction drive premature suture fusion will offer important insights into the pathophysiology of craniosynostosis and result in the development of new therapies, which can be used to intervene at an early stage and prevent premature suture fusion. Herein, we provide evidence for the first time on the role of polycystin‐1 (PC1), a key protein in cellular mechanosensitivity, in craniosynostosis, using primary cranial suture cells isolated from patients with trigonocephaly and dolichocephaly, two common types of craniosynostosis. Initially, we showed that PC1 is expressed at the mRNA and protein level in both trigonocephaly and dolichocephaly cranial suture cells. Followingly, by utilizing an antibody against the mechanosensing extracellular N‐terminal domain of PC1, we demonstrated that PC1 regulates runt‐related transcription factor 2 (RUNX2) activation and osteocalcin gene expression via extracellular signal–regulated kinase (ERK) signalling in our human craniosynostosis cell model. Altogether, our study reveals a novel mechanotransduction signalling axis, PC1‐ERK‐RUNX2, which affects osteoblastic differentiation in cranial suture cells from trigonocephaly and dolichocephaly patients.

In the present study we investigated the expression and the functional role of mechanosensitive polycystins in renal cell carcinoma (RCC). In 115 RCC patients we evaluated the protein expression of polycystin-1 (PC1), polycystin-2 (PC2), VEGF and protein components of the PI3K/Akt/mTOR pathway, which have been implicated both in RCC and polycystic kidney disease. PC1 and PC2 demonstrated reduced expression throughout the RCC tissue compared to the adjacent normal tissue. PC1 and PC2 revealed high expression when they were associated with higher grade and decreased 5-year survival respectively. PC1 and PC2 were positively correlated with p110γ subunit of PI3K and high PC1 expressing cells tended to display activation/phosphorylation of Akt. There was also a positive association between PC1 and VEGF expression, whereas PC1 augmented the tumor's microvascular network in stage IV carcinomas. In human RCC cells, functional inhibition of PC1 resulted in upregulation of the PI3K/Akt/mTOR pathway, enhanced cell proliferation and led to inhibition of cell migration. Conclusively, aberrant PC1 regulation is associated with increased angiogenesis and features of advanced disease in RCC tissues.

Craniosynostosis is the premature fusion of skull sutures and has a severe pathological impact on childrens' life. Mechanical forces are capable of triggering biological responses in bone cells and regulate osteoblastogenesis in cranial sutures, leading to premature closure. The mechanosensitive proteins polycystin-1 (PC1) and polycystin-2 (PC2) have been documented to play an important role in craniofacial proliferation and development. Herein, we investigated the contribution of PC1 to the pathogenesis of non-syndromic craniosynostosis and the associated molecular mechanisms. Protein expression of PC1 and PC2 was detected in bone fragments derived from craniosynostosis patients via immunohistochemistry. To explore the modulatory role of PC1 in primary cranial suture cells, we further abrogated the function of PC1 extracellular mechanosensing domain using a specific anti-PC1 IgPKD1 antibody. Effect of IgPKD1 treatment was evaluated with cell proliferation and migration assays. Activation of PI3K/AKT/mTOR pathway components was further detected via Western blot in primary cranial suture cells following IgPKD1 treatment. PC1 and PC2 are expressed in human tissues of craniosynostosis. PC1 functional inhibition resulted in elevated proliferation and migration of primary cranial suture cells. PC1 inhibition also induced activation of AKT, exhibiting elevated phospho (p)-AKT (Ser473) levels, but not 4EBP1 or p70S6K activation. Our findings indicate that PC1 may act as a mechanosensing molecule in cranial sutures by modulating osteoblastic cell proliferation and migration through the PC1/AKT/mTORC2 cascade with a potential impact on the development of non-syndromic craniosynostosis.

The mechanobiological aspects of glioblastoma (GBM) pathogenesis are largely unknown. Polycystin-1 (PC1) is a key mechanosensitive protein which perceives extracellular mechanical cues and transforms them into intracellular biochemical signals that elicit a change in cell behaviour. The aim of the present study was to investigate if and how PC1 participates in GBM pathogenesis under a mechanically induced microenvironment. Therefore, we subjected T98G GBM cells to continuous hydrostatic pressure (HP) and/or PC1 blockade and evaluated their effect on cell behaviour, the activity of signalling pathways and the expression of mechano-induced transcriptional regulators and markers associated with properties of cancer cells. According to our data, PC1 and HP affect GBM cell proliferation, clonogenicity and migration; the diameter of GBM spheroids; the phosphorylation of mechanistic target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK); the protein expression of transcription cofactors YES-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ); and the mRNA expression of markers related to anti-apoptosis, apoptosis, angiogenesis, epithelial to mesenchymal transition (EMT) and proliferation. Together, our in vitro results suggest that PC1 plays an important role in GBM mechanobiology.

Anti-SARS-CoV-2 spike RBD (receptor-binding domain) IgG antibody levels were monitored in 1643 volunteer healthcare workers of Eginition, Evangelismos, and Konstantopoulio General Hospitals (Athens, Greece), who underwent vaccination with two doses of COVID-19 BNT162b2 mRNA vaccine (Pfizer) and had no history of SARS-CoV-2 infection. Venous blood was collected 20–30 days after the second vaccine dose and anti-RBD IgG levels were determined using CMIA SARS-CoV-2 IgG II Quant (Abbott) on ARCHITECT i System or ADVIA Centaur SARS-CoV-2 IgG (Siemens) on Centaur XP platform. From the total population of 1643 vaccinees (533 M/1110 F; median age = 49; interquartile range-IQR = 40–56), 1636 (99.6%) had anti-SARS-CoV-2 IgG titers above the positivity threshold of the assay used. One-Way ANOVA Kruskal-Wallis H test showed a statistically significant difference in the median of antibody titers between the different age groups (p < 0.0001). Consistently, Spearman’s correlation coefficient (r) for IgGs and age as continuous variables was −0.2380 (p = 1.98 × 10−17). Moreover, antibody titers were slightly higher by 1.2-mean fold (p = 3 × 10−6) in the total female population of the three hospitals (median = 1594; IQR = 875–2584) as compared to males (median = 1292; IQR = 671.9–2188). The present study supports that BNT162b2 vaccine is particularly effective in producing high anti-SARS-CoV-2 IgG levels in healthy individuals, and this humoral response is age- and gender-dependent.

Polycystic Kidney Disease (PKD), which is attributable to mutations in the PKD1 and PKD2 genes encoding polycystin‐1 (PC1) and polycystin‐2 (PC2) respectively, shares common cellular defects with cancer, such as uncontrolled cell proliferation, abnormal differentiation and increased apoptosis. Interestingly, PC1 regulates many signalling pathways including Jak/STAT, mTOR, Wnt, AP‐1 and calcineurin‐NFAT which are also used by cancer cells for sending signals that will allow them to acquire and maintain malignant phenotypes. Nevertheless, the molecular relationship between polycystins and cancer is unknown. In this study, we investigated the role of PC1 in cancer biology using glioblastoma (GOS3), prostate (PC3), breast (MCF7), lung (A549) and colorectal (HT29) cancer cell lines. Our in vitro results propose that PC1 promotes cell migration in GOS3 cells and suppresses cell migration in A549 cells. In addition, PC1 enhances cell proliferation in GOS3 cells but inhibits it in MCF7, A549 and HT29 cells. We also found that PC1 up‐regulates mTOR signalling and down‐regulates Jak signalling in GOS3 cells, while it up‐regulates mTOR signalling in PC3 and HT29 cells. Together, our study suggests that PC1 modulates cell proliferation and migration and interacts with mTOR and Jak signalling pathways in different cancer cell lines. Understanding the molecular details of how polycystins are associated with cancer may lead to the identification of new players in this devastating disease.

Distorted mechanotransduction represents the molecular hallmark of disease mechanobiology and is displayed with common features during the development of various pathophysiologies. Polycystins constitute a family of mechanosensitive proteins that facilitate pathogenic signal transduction mechanisms. The main representatives of the family are polycystin-1 (PC1) and polycystin-2 (PC2), which function as a mechano-induced membrane receptor and a calcium-permeable ion channel, respectively. PC1 and PC2 mediate extracellular mechanical stimulation, induce intracellular molecular signaling and evoke corresponding gene transcription. Recent reports reveal that polycystin-mediated signaling does not occur in polycystic kidney disease only, where it is most prominently studied. It is also present during the development of clinical entities such as endothelial dysfunction and atheromatosis, deregulation of osteoblast differentiation, cancer development, and psoriasis. In this study, we highlight emerging data that support the overall contribution of polycystins to disease mechanobiology and suggest further exploration of this protein family in diseases generated from force-bearing tissue structures.

Psoriatic plaques tend to localize to the knees and elbows, areas that are particularly subject to mechanical stress resulting from bending and friction. Moreover, plaques often develop at sites of mechanical trauma or injury (Koebner phenomenon). Nevertheless, mechanotransduction has never been linked to psoriasis. Polycystins (polycystin-1, PC1; polycystin-2, PC2) are mechanosensitive molecules that function as key regulators of cellular mechanosensitivity and mechanotransduction. The aim of this in vitro study was to investigate the role of polycystins in the development of psoriasis. We showed that PC1 knockdown in HaCaT cells led to an elevated mRNA expression of psoriasis-related biomarkers Ki-67, IL-6, TNF-α, VEGF and Bcl-2, while PC1 functional inhibition was accompanied by increased cell proliferation and migration of HaCaT cells. In addition, PC1 knockdown via siRNA in HaCaT cells was followed by activation of critical molecules of the mTOR and MAPK pathways and this mTOR pathway activation was ERK-dependent. Furthermore, loss of PC1 protein expression and elevated levels of activated mTOR substrates were also observed in human samples of psoriatic plaques. Overall, our study suggests that the PC1/ERK/mTOR signaling axis represents a novel potential mechanism in psoriasis pathogenesis.

Background To investigate the association between frailty, Parkinson’s disease (PD), and the probability of prodromal Parkinson’s disease (prodromal PD) in Greek community-dwelling older individuals. Methods Parkinson’s disease diagnosis was reached through standard clinical research procedures. Probability of prodromal PD was calculated according to the International Parkinson and Movement Disorder Society’s research criteria for PD-free participants. Frailty was evaluated according to definitions of the phenotypic and multidomain approach. Logistic and linear regression models were performed to investigate associations between frailty (predictor) and the probability of prodromal PD, either continuous or dichotomous (≥30% probability score), or PD (outcome). Results Data from 1765 participants aged 65 and older were included in the present analysis. Parkinson’s disease and prodromal PD prevalence were 1.9% and 3.0%, respectively. Compared to nonfrail participants, those who were frail, as identified with either the Fried frailty phenotype or Frailty Index had approximately 4 (odds ratio [OR] 4.09, 95% confidence interval [CI] 1.54–10.89) and 12 times (OR 12.16, 95% CI 5.46–27.09) higher odds of having a PD diagnosis, respectively. Moreover, compared to the nonfrail, frail participants as identified with either the Fried frailty phenotype or Frailty Index had 2.8 (OR 2.83, 95% CI 1.09–7.37) and 8.3 times (OR 8.39, 95% CI 4.56–15.42) higher odds of having possible/probable prodromal PD, respectively. Conclusions Frailty status was associated with prodromal PD and PD, suggesting common characteristics or underlying mechanisms of these conditions. Although prospective studies are warranted, acknowledging the possible association of frailty, PD, and prodromal PD may improve their clinical management.

Background: Glioma is a heterogeneous, highly complicated central nervous system (CNS) tumor with uncertain mechanism of initiation and progression, resulting in an unfavorable outcome. An extended network of cytokines is recognized as a major regulator of glioma pathogenesis, either promoting or inhibiting glioma progression based on their type and specificity. Interleukin-8 (IL-8) has been revealed as a critical regulator of CNS function and development with participation in many CNS disorders including gliomas. Objective: The aim of the present review is to address the role of IL-8 in glioma pathogenesis focusing on the implicated molecular pathways as well as on its potential targeting for glioma therapy. Methods and Results: PubMed-Medline, SCOPUS, and Google Scholar databases were searched for pre-clinical and clinical studies related to IL-8 implication in gliomagenesis and IL-8 targeting strategies for gliomas. Literature data indicate that IL-8 participates in glioma angiogenesis and cell migration and it can serve as a potential biomarker, for early diagnosis, follow-up and response to therapy. Conclusion: Several promising approaches that target directly or indirectly IL-8 effects in gliomas are currently in progress while more-in-depth studies are needed to validate its biomarker role and elucidate the underlying molecular mechanisms.

Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet and STAT3 inhibitors have not reached the clinic in everyday practice. In the present article, we review the STAT3 signaling network in CRC and highlight the current notion for the design of STAT3-focused treatment approaches. We also discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, therefore providing a new perception for the clinical application of STAT3 in CRC.

Alterations in the process of mechanotransduction have been implicated in the pathogenesis of several diseases such as genetic diseases, osteoporosis, cardiovascular anomalies, and cancer. Several studies over the past twenty years have demonstrated that polycystins (polycystin-1, PC1; and polycystin-2, PC2) respond to changes of extracellular mechanical cues, and mediate pathogenic mechanotransduction and cyst formation in kidney cells. However, recent reports reveal the emergence of polycystins as key proteins that facilitate the transduction of mechano-induced signals in various clinical entities besides polycystic kidney disease, such as cancer, cardiovascular defects, bone loss, and deformations, as well as inflammatory processes like psoriasis. Herewith, we discuss data from recent studies that establish this role with potential clinical utility.

Endothelial dysfunction involves deregulation of the key extracellular matrix (ECM) enzyme lysyl oxidase (LOX) and the vasoconstrictor protein, endothelin-1 (ET-1), whose gene expression can be modulated by the transcriptional activators nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1). Advanced glycation end products (AGEs) present an aggravating factor of endothelial dysfunction which upon engagement to their receptor RAGE induce upregulation of mitogen-activated protein kinases (MAPKs), leading to NF-κB and AP-1 potentiation. We hypothesized that AGEs could induce NF-κΒ- and AP-1-dependent regulation of LOX and ET-1 expression via the AGE/RAGE/MAPK signaling axis. Western blot, real-time qRT-PCR, FACS analysis and electrophoretic mobility-shift assays were employed in human aortic endothelial cells (HAECs) following treatment with AGE-bovine serum albumin (AGE-BSA) to investigate the signaling pathway towards this hypothesis. Furthermore, immunohistochemical analysis of AGEs, RAGE, LOX and ET-1 expression was conducted in aortic endothelium of a rat experimental model exposed to high- or low-AGE content diet. HAECs exposed to AGE-BSA for various time points exhibited upregulation of LOX and ET-1 mRNA levels in a dose- and time-dependent manner. Exposure of HAECs to AGE-BSA also showed specific elevation of phospho(p)-ERK1/2 and p-JNK levels in a dose- and time-dependent fashion. AGE administration significantly increased NF-κΒ- and AP-1-binding activity to both LOX and ET-1 cognate promoter regions. Moreover, LOX and ET-1 overexpression in rat aortic endothelium upon high-AGE content diet confirmed the functional interrelation of these molecules. Our findings demonstrate that AGEs trigger NF-κΒ- and AP-1-mediated upregulation of LOX and ET-1 via the AGE/RAGE/MAPK signaling cascade in human endothelial cells, thus contributing to distorted endothelial homeostasis by impairing endothelial barrier function, altering ECM biomechanical properties and cell proliferation.

Cancer mechanics have lately emerged as a distinct tumor feature that promotes tumor development, invasion, and metastasis. Tumor mechanosensing involves a mechanical interplay between cancer cells, extracellular matrix, and cells of the surrounding stroma. Mechanoreceptors sense alterations of the extracellular mechanical cues and activate signaling molecules, which mediate oncogenic transcription in favor of cancer initiation, survival, growth, and metastasis. Furthermore, alterations of the matrix rigidity and activation of mechano-induced transcriptional regulators has been strongly associated with resistance to anti-cancer agents. In this context, new mechanosensitive molecules arise as potential therapeutic targets. Therefore, tumor mechanosignaling represents a promising field that can potentially offer new combination regimens to overcome drug resistance, but also suggest novel targeting strategies.

Membrane receptors constitute novel targets during current treatment of metastatic colorectal cancer (CRC) due to the fact that their aberrant expression/activity favors cancer cell properties. Protein trafficking is responsible for the correct targeting of membrane receptors to the apical and basolateral surfaces, as well as to the adherent and tight junctions of the cell. Impaired availability or distribution of these receptors along the plasma membrane is not only associated with defective cellular homeostasis and tumor progression, but also to emerging mechanisms of resistance to CRC-targeted therapy. The present review describes how protein trafficking facilitates invasion and metastasis of CRC cells and focuses on receptor tyrosine kinases (RTKs) endocytic transport, providing thoughts for surpassing RTKs-centered mechanisms of resistance.

The polycystins PC1 and PC2 are emerging as major players in mechanotransduction, a process that influences all steps of the invasion/metastasis cascade. We hypothesized that PC1 and PC2 facilitate cancer aggressiveness. Immunoblotting, RT-PCR, semi-quantitative and quantitative real-time PCR and FACS analyses were employed to investigate the effect of polycystin overexpression in colorectal cancer (CRC) cells. The impact of PC1 inhibition on cancer-cell proliferation was evaluated through an MTT assay. In vitro data were analyzed by Student's t-test. HT29 human xenografts were treated with anti-PC1 (extracellular domain) inhibitory antibody and analyzed via immunohistochemistry to determine the in vivo role of PC1 in CRC. Clinical significance was assessed by examining PC1 and PC2 protein expression in CRC patients (immunohistochemistry). In vivo and clinical data were analyzed by non-parametric tests, Kaplan-Meier curves, log-rank test and Cox model. All statistical tests were two-sided. PC1 overexpression promotes epithelial-to-mesenchymal transition (EMT) in HCT116 cells, while PC2 overexpression results in upregulation of the mTOR pathway in SW480 cells. PC1 inhibition causes reduced cell proliferation in CRC cells inducing tumor necrosis and suppressing EMT in HT29 tumor xenografts. In clinical study, PC1 and PC2 overexpression associates with adverse pathological parameters, including invasiveness and mucinous carcinomas. Moreover, PC1 overexpression appears as an independent prognostic factor of reduced recurrence-free survival (HR = 1.016, p = 0.03) and lowers overall survival probability, while aberrant PC2 expression predicts poor overall survival (p = 0.0468). These results support, for the first time, a direct link between mechanosensing polycystins (PC1 and PC2) and CRC progression.

Dynamic changes in the colorectal cancer (CRC) signalome and tumor genetic heterogeneity underlie acquired drug resistance. Improving treatment-related decisions is facilitated by an emerging consensus in the classification of tumor subtypes as well as by real-time monitoring of predictive biomarkers in circulating tumor cells and DNA.

BACKGROUND Pediatric brain tumors are characterized by altered epigenetic profiles and deregulated chromatin remodelling that affects gene expression. Histone lysine methylation has emerged as important chromatin function regulator, with potential role in glioma formation. Τhis study investigates the expression of histone lysine methyltransferases (SETDB1, SUV39H1, EZH2, MLL2, SETD2) and their corresponding methylation marks (H3K9me3, H3K27me3, H3K4me2/3, H3K36me3) in pediatric astrocytomas. MATERIAL AND METHODS Thirty-four (34) archival pediatric astrocytomas [27 low grade (I/II) and 7 high grade (III/IV) tumors; 21 males, 13 females; 1–15 years old] and 5 postmortem normal brain samples were studied. Methyltransferases expression and histone marks were detected by immunohistochemistry as H-score (intensity multiplied with cell percentage, 0–300) and validated by western blot. RESULTS Elevated nuclear SETD2 and SETDB1 staining was observed in all astrocytomas (median H-score:165 and 110, respectively). SETDB1 and SETD2 expression levels were positively associated (p=0.004), being higher in high grade compared to lower grade tumors (p=0.001, p=0.027, respectively). Furthermore, SETDB1 staining was significantly increased in male children (p=0.051) and negatively associated with patients age (p=0.028). A moderate nuclear and cytoplasmic staining was obtained for MLL2 at low grade (median H-score:84) compared to high grade tumors (median H-score:144). In accordance, lower SUV39H1 nuclear and cytoplasmic expression was detected in low grade tissues (median H score:85) compared to high grade (median H-score:160). EZH2 presented no significant nuclear expression. Increased nuclear staining of H3K9me3 and H4K20me3 repressive marks was observed in astrocytomas (median H-score:297 and 270, respectively), being positively associated (p=0.02). Elevated nuclear staining of H3K4me3 active mark (median H-score:210) was detected in astrocytomas, being significantly higher in high grade tumors (p=0.025) and in male children (p=0.036). CONCLUSION SETDB1, SETD2, SUV39H1 and MLL2 may play a significant role in modulating gene expression in pediatric astrocytomas. Increased presence of H3K9me3, H4K20me3 and H3K4me3 histone marks signifies their possible participation in gliomagenesis. Larger cohort studies need to elucidate the functional significance and underlying molecular mechanisms of these chromatin-modifying enzymes and respective histone changes in pediatric astrocytomas.

Src has been one of the most studied proto-oncogenes. The cellular Src (c-Src) holds a critical role in several human malignancies and has emerged as a key factor that promotes tumor progression during the multistep process of colorectal cancer (CRC) pathogenesis. The robust activation of Src in CRC of aggressive phenotype and poor prognosis seems to be a subsequent event of a strong link between its deregulated activity and the tumor's cell adhesion properties, invasiveness and metastatic potential. The rarely detected genetic defects drive interest in signaling networks that control Src kinase activity and integrate the association of Src with receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). Therefore, a dynamic crosstalk is being formed with oncogenic capacity and therapeutic applications, because Src inhibition seems to sensitize previously unresponsive cancer cells to chemotherapy and anti-EGFR inhibitors. The present review explores the molecular basis behind Src inhibition in colorectal carcinomas. Furthermore, preclinical studies and clinical trials of Src inhibitors and combination regimens are discussed, providing new insights for further investigation and new therapeutic strategies.

MicroRNAs (miRNAs) are small, non-coding RNAs, that function as post-transcriptional regulators of gene expression. Recent studies now predict that numerous miRNA molecules regulate a large proportion of the human transcriptome, thus creating a whole new research field that utilizes their potential impact on gene expression in favor of diagnosis, prognosis and drug development. MiRNAs are generated from transcription of respective genes into primary structures that usually follow a two-step maturation process in the cell nucleus and cytoplasm. Active miRNA folds downregulate protein expression either via direct repression of targeted messenger RNA (mRNA) or mRNA cleavage. They are critical factors that control human development and organogenesis and reemerge as key-molecules that profoundly influence adult cells and tissues under stress-responsive conditions. Therefore, several miRNAs exhibit dysregulated functions in almost all aspects of human pathology such as cancer, cardiovascular diseases, metabolic disorders, genetic and neurodegenerative diseases, forming tissue-specific molecular profiles that further define salient pathologic features. The present article offers an overview on miRNAs biogenesis and functional processes, major aspects of their participation in human development and milestones regarding their contribution in human diseases. Furthermore, their utility as extracellular biomarkers and the rationale behind miRNA inhibition or miRNA delivery are being discussed.

Mechanotransduction is a key process by which cells perceive extracellular mechanical cues/intercellular physical interactions and transform them into intracellular biochemical signals. This physiological process is crucial during bone development and bone remodeling throughout childhood and adult life, whereas several aberrations during this process have emerged as a distinct pathogenic molecular entity in bone maladies and tumor formation. The present review focuses on recent advances regarding the mechanobiology of osteosarcoma, the most common type of bone cancer. Special emphasis is given on the mechano-responsive signal transduction pathways underlying osteosarcoma pathology and on specific mechanosensitive molecules engaged in osteosarcoma development. J. Cell. Biochem. 118: 232-236, 2017. © 2016 Wiley Periodicals, Inc.

Polycystin-1 (PC1) has been proposed as a chief mechanosensing molecule implicated in skeletogenesis and bone remodeling. Mechanotransduction via PC1 involves proteolytic cleavage of its cytoplasmic tail (CT) and interaction with intracellular pathways and transcription factors to regulate cell function. Here we demonstrate the interaction of PC1-CT with JAK2/STAT3 signaling axis in mechanically stimulated human osteoblastic cells, leading to transcriptional induction of Runx2 gene, a master regulator of osteoblastic differentiation. Primary osteoblast-like PC1-expressing cells subjected to mechanical-stretching exhibited a PC1-dependent increase of the phosphorylated(p)/active form of JAK2. Specific interaction of PC1-CT with pJAK2 was observed after stretching while pre-treatment of cells with PC1 (anti-IgPKD1) and JAK2 inhibitors abolished JAK2 activation. Consistently, mechanostimulation triggered PC1-mediated phosphorylation and nuclear translocation of STAT3. The nuclear phosphorylated(p)/DNA-binding competent pSTAT3 levels were augmented after stretching followed by elevated DNA-binding activity. Pre-treatment with a STAT3 inhibitor either alone or in combination with anti-IgPKD1 abrogated this effect. Moreover, PC1-mediated mechanostimulation induced elevation of Runx2 mRNA levels. ChIP assays revealed direct regulation of Runx2 promoter activity by STAT3/Runx2 after mechanical-stretching that was PC1-dependent. Our findings show that mechanical load upregulates expression of Runx2 gene via potentiation of PC1-JAK2/STAT3 signaling axis, culminating to possibly control osteoblastic differentiation and ultimately bone formation.

Osteosarcoma is the most frequent type of primary bone tumors among children and adolescents. During the past years, little progress has been made regarding prognosis of osteosarcoma patients, especially for those with metastatic disease. Genomic instability and gene alterations are common, but current data do not reveal a consistent and repeatable pattern of osteosarcoma development, thus paralleling the tumor's high heterogeneity. Critical signal transduction pathways have been implicated in osteosarcoma pathobiology and are being evaluated as therapeutic targets, including receptor activator for nuclear factor-κB (RANK), Wnt, Notch, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, and mechanotransduction pathways. Herein, we recapitulate and discuss recent advances in the context of molecular mechanisms and signaling networks that contribute to osteosarcoma progression and metastasis, towards patient-tailored and novel-targeted treatments.