Biomarkers in Cerebrospinal Fluid for the Diagnosis and Monitoring of Gliomas.

Gliomas are the most common type of malignant brain tumor and are characterized by a plethora of heterogeneous molecular alterations. Current treatments require the emergence of reliable biomarkers that will aid personalized treatment decisions and increase life expectancy. Glioma tissues are not as easily accessible as other solid tumors; therefore, detecting prominent biomarkers in biological fluids is necessary. Cerebrospinal fluid (CSF) circulates adjacent to the cerebral parenchyma and holds promise for discovering useful prognostic, diagnostic, and predictive biomarkers. In this review, we summarize extensive research regarding the role of circulating DNA, tumor cells, proteins, microRNAs, metabolites, and extracellular vesicles as potential CSF biomarkers for glioma diagnosis, prognosis, and monitoring. Future studies should address discrepancies and issues of specificity regarding CSF biomarkers, as well as the validation of candidate biomarkers.

Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC) Treatment: Quo Vadis?

Lung cancer has been established as the second most common cancer worldwide (most common cancer in men and second most common cancer in women) and as the leading cause of cancer morbidity among neoplasms [...].

Runx2 and Polycystins in Bone Mechanotransduction: Challenges for Therapeutic Opportunities.

Bone mechanotransduction is a critical process during skeletal development in embryogenesis and organogenesis. At the same time, the type and level of mechanical loading regulates bone remodeling throughout the adult life. The aberrant mechanosensing of bone cells has been implicated in the development and progression of bone loss disorders, but also in the bone-specific aspect of other clinical entities, such as the tumorigenesis of solid organs. Novel treatment options have come into sight that exploit the mechanosensitivity of osteoblasts, osteocytes, and chondrocytes to achieve efficient bone regeneration. In this regard, runt-related transcription factor 2 (Runx2) has emerged as a chief skeletal-specific molecule of differentiation, which is prominent to induction by mechanical stimuli. Polycystins represent a family of mechanosensitive proteins that interact with Runx2 in mechano-induced signaling cascades and foster the regulation of alternative effectors of mechanotransuction. In the present narrative review, we employed a PubMed search to extract the literature concerning Runx2, polycystins, and their association from 2000 to March 2024. The keywords stated below were used for the article search. We discuss recent advances regarding the implication of Runx2 and polycystins in bone remodeling and regeneration and elaborate on the targeting strategies that may potentially be applied for the treatment of patients with bone loss diseases.

Mechanotransduction Circuits in Human Pathobiology.

It is widely acknowledged that mechanical forces exerted throughout the human body are critical for cellular and tissue homeostasis [...].

mTOR Signaling: Recent Progress.

In the intricate landscape of human biology, the mechanistic target of rapamycin (mTOR) emerges as a key regulator, orchestrating a vast array of processes in health and disease [...].

Objective Physical Function in the Alzheimer's Disease Continuum: Association with Cerebrospinal Fluid Biomarkers in the ALBION Study.

Cognitive and physical decline, both indicators of aging, seem to be associated with each other. The aim of the present study was to investigate whether physical function parameters (walking time and handgrip strength) are related to cerebrospinal fluid (CSF) biomarkers (amyloid-beta Aß42, Tau, PhTau) in individuals in the Alzheimer's disease (AD) continuum. The sample was drawn from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration study, comprising 163 individuals aged 40-75 years: 112 cognitively normal (CN) and 51 with mild cognitive impairment (MCI). Physical function parameters were measured at baseline, a lumbar puncture was performed the same day and CSF biomarkers were analyzed using automated methods. The association between walking time, handgrip strength and CSF biomarkers was evaluated by linear correlation, followed by multivariate linear regression models adjusted for age, sex, education and APOEe4 genotype. Walking time was inversely related to CSF Aß42 (lower CSF values correspond to increased brain deposition) in all participants (p < 0.05). Subgroup analysis showed that this association was stronger in individuals with MCI and participants older than 60 years old, a result which remained statistically significant after adjustment for the aforementioned confounding factors. These findings may open new perspectives regarding the role of mobility in the AD continuum.

Implication of mTOR Signaling in NSCLC: Mechanisms and Therapeutic Perspectives.

Mechanistic target of the rapamycin (mTOR) signaling pathway represents a central cellular kinase that controls cell survival and metabolism. Increased mTOR activation, along with upregulation of respective upstream and downstream signaling components, have been established as oncogenic features in cancer cells in various tumor types. Nevertheless, mTOR pathway therapeutic targeting has been proven to be quite challenging in various clinical settings. Non-small cell lung cancer (NSCLC) is a frequent type of solid tumor in both genders, where aberrant regulation of the mTOR pathway contributes to the development of oncogenesis, apoptosis resistance, angiogenesis, cancer progression, and metastasis. In this context, the outcome of mTOR pathway targeting in clinical trials still demonstrates unsatisfactory results. Herewith, we discuss recent findings regarding the mechanisms and therapeutic targeting of mTOR signaling networks in NSCLC, as well as future perspectives for the efficient application of treatments against mTOR and related protein molecules.

Deciphering glioma epitranscriptome: focus on RNA modifications.

Gliomas are highly malignant tumors accounting for the majority of brain neoplasms. They are characterized by nuclear atypia, high mitotic rate and cellular polymorphism that often contributes to aggressiveness and resistance to standard therapy. They often associate with challenging treatment approaches and poor outcomes. New treatment strategies or regimens to improve the efficacy of glioma treatment require a deeper understanding of glioma occurrence and development as well as elucidation of their molecular biological characteristics. Recent studies have revealed RNA modifications as a key regulatory mechanism involved in tumorigenesis, tumor progression, immune regulation, and response to therapy. The present review discusses research advances on several RNA modifications involved in glioma progression and tumor microenvironment (TME) immunoregulation as well as in the development of adaptive drug resistance, summarizing current progress on major RNA modification targeting strategies.

Exosomes as Novel Diagnostic Biomarkers and Therapeutic Tools in Gliomas.

Exosomes constitute small extracellular vesicles that contain lipids, proteins, nucleic acids, and glycoconjugates from the secreted cells and are capable of transmitting signals between cells and coordinating cellular communication. By this means, they are ultimately involved in physiology and disease, including development, homeostasis, and immune system regulation, as well as contributing to tumor progression and neurodegenerative diseases pathology. Recent studies have shown that gliomas secrete a panel of exosomes which have been associated with cell invasion and migration, tumor immune tolerance, potential for malignant transformation, neovascularization, and resistance to treatment. Exosomes have therefore emerged as intercellular communicators, which mediate the tumor-microenvironment interactions and exosome-regulated glioma cell stemness and angiogenesis. They may induce tumor proliferation and malignancy in normal cells by carrying pro-migratory modulators from cancer cells as well as many different molecular cancer modifiers, such as oncogenic transcripts, miRNAs, mutant oncoproteins, etc., which promote the communication of cancer cells with the surrounding stromal cells and provide valuable information on the molecular profile of the existing tumor. Moreover, engineered exosomes can provide an alternative system for drug delivery and enable efficient treatment. In the present review, we discuss the latest findings regarding the role of exosomes in glioma pathogenesis, their utility in non-invasive diagnosis, and potential applications to treatment.

Histone H3K9 methyltransferase SETDB1 overexpression correlates with pediatric high-grade gliomas progression and prognosis.

Pediatric high-grade gliomas (pHGGs) are heterogeneous, diffuse, and highly infiltrative tumors with dismal prognosis. Aberrant post-translational histone modifications with elevated histone 3 lysine trimethylation (H3K9me3) have been recently implicated in pHGGs' pathology, conferring to tumor heterogeneity. The present study investigates the potential involvement of H3K9me3 methyltransferase SETDB1 in the cellular function, progression, and clinical significance of pHGG. The bioinformatic analysis detected SETDB1 enrichment in pediatric gliomas compared to the normal brain, as well as positive and negative correlations with a proneural and mesenchymal signature, respectively. In our cohort of pHGGs, SETDB1 expression was significantly increased compared to pLGG and normal brain tissue and correlated with p53 expression, as well as reduced patients' survival. In accordance, H3K9me3 levels were also elevated in pHGG compared to the normal brain and were associated with worse patient survival. Gene silencing of SETDB1 in two patient-derived pHGG cell lines showed a significant reduction in cell viability followed by reduced cell proliferation and increased apoptosis. SETDB1 silencing further reduced cell migration of pHGG cells and the expression of the mesenchymal markers N-cadherin and vimentin. mRNA analysis of epithelial-mesenchymal transition (EMT) markers upon SETDB1 silencing showed a reduction in SNAI1 levels and downregulation of CDH2 along with the EMT regulator gene MARCKS. In addition, SETDB1 silencing significantly increased the bivalent tumor suppressor gene SLC17A7 mRNA levels in both cell lines, indicating its implication in the oncogenic process.Altogether, our findings demonstrate a predominant oncogenic role of SETDB1 in pHGG which along with elevated H3K9me3 levels correlate significantly to tumor progression and inferior patients' survival. There is evidence that targeting SETDB1 may effectively inhibit pHGG progression, providing a novel insight into the therapeutic strategies for pediatric gliomas. KEY MESSAGES: SETDB1 gene expression is enriched in pHGG compared to normal brain. SETDB1 expression is increased in pHGG tissues and associates with reduced patients' survival. Gene silencing of SETDB1 reduces cell viability and migration. SETDB1 silencing affects mesenchymal markers expression. SETDB1 silencing upregulates SLC17A7 levels. SETDB1 has an oncogenic role in pHGG.

Initial Data and a Clinical Diagnosis Transition for the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration (ALBION) Study.

Background and Objectives: This article presents data from the ongoing Aiginition Longitudinal Biomarker Investigation of Neurodegeneration study (ALBION) regarding baseline clinical characterizations and CSF biomarker profiles, as well as preliminary longitudinal data on clinical progression. Materials and Methods: As of March 2022, 138 participants who either were cognitively normal (CN, n = 99) or had a diagnosis of mild cognitive impairment (MCI, n = 39) had been recruited at the specialist cognitive disorders outpatient clinic at Aiginition Hospital. Clinical characteristics at baseline were provided. These patients were followed annually to determine progression from CN to MCI or even dementia. CSF biomarker data (amyloid ß1-42, phosphorylated tau at threonine 181, and total tau) collected using automated Elecsys® assays (Roche Diagnostics) were available for 74 patients. These patients were further sorted based on the AT(N) classification model, as determined by CSF Aß42 (A), CSF pTau (T), and CSF tTau (N). Results: Of the 49 CN patients with CSF biomarker data, 21 (43%) were classified as exhibiting "Alzheimer's pathologic change" (A+Τ− (Ν)−) and 6 (12%) as having "Alzheimer's disease" (A+T−(N)+, A+T+(N)−, or A+T+(N)+). Of the 25 MCI patients, 8 (32%) displayed "Alzheimer's pathologic change", and 6 (24%) had "Alzheimer's disease". A total of 66 individuals had a mean follow-up of 2.1 years (SD = 0.9, min = 0.8, max = 3.9), and 15 of those individuals (22%) showed a clinical progression (defined as a worsening clinical classification, i.e., from CN to MCI or dementia or from MCI to dementia). Overall, participants with the "AD continuum" AT(N) biomarker profile (i.e., A+T−(N)−, A+T−(N)+, A+T+(N)−, and A+T+(N)+) were more likely to clinically progress (p = 0.04). Conclusions: A CSF "AD continuum" AT(N) biomarker profile is associated with an increased risk of future clinical decline in CN or MCI subjects.

Mechanobiology of solid tumors.

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.

New Insights into the Molecular Interplay between Human Herpesviruses and Alzheimer's Disease-A Narrative Review.

Human herpesviruses (HHVs) have been implicated as possible risk factors in Alzheimer's disease (AD) pathogenesis. Persistent lifelong HHVs infections may directly or indirectly contribute to the generation of AD hallmarks: amyloid beta (Aß) plaques, neurofibrillary tangles composed of hyperphosphorylated tau proteins, and synaptic loss. The present review focuses on summarizing current knowledge on the molecular mechanistic links between HHVs and AD that include processes involved in Aß accumulation, tau protein hyperphosphorylation, autophagy, oxidative stress, and neuroinflammation. A PubMed search was performed to collect all the available research data regarding the above mentioned mechanistic links between HHVs and AD pathology. The vast majority of research articles referred to the different pathways exploited by Herpes Simplex Virus 1 that could lead to AD pathology, while a few studies highlighted the emerging role of HHV 6, cytomegalovirus, and Epstein-Barr Virus. The elucidation of such potential links may guide the development of novel diagnostics and therapeutics to counter this devastating neurological disorder that until now remains incurable.

Polycystin-1 regulates cell proliferation and migration through AKT/mTORC2 pathway in a human craniosynostosis cell model.

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.