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Ferroptosis, a lipid peroxidation- and iron-mediated type of regulated cell death, relates to both neuroinflammation, which is common in relapsing-remitting multiple sclerosis (RRMS), and neurodegeneration, which is prevalent in progressive (P)MS. Currently, findings related to the molecular markers proposed in this paper in patients are scarce. We analyzed circulatory molecular indicators of the main ferroptosis-related processes, comprising lipid peroxidation (malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and hexanoyl–lysine adduct (HEL)), glutathione-related antioxidant defense (total glutathione (reduced (GSH) and oxidized (GSSG)) and glutathione peroxidase 4 (GPX4)), and iron metabolism (iron, transferrin and ferritin) to estimate their contributions to the clinical manifestation of MS and differences between RRMS and PMS disease course. In 153 patients with RRMS and 69 with PMS, plasma/serum lipid peroxidation indicators and glutathione were quantified using ELISA and colorimetric reactions, respectively. Iron serum concentrations were determined using spectrophotometry, and transferrin and ferritin were determined using immunoturbidimetry. Compared to those with RRMS, patients with PMS had decreased 4-HNE (median, 1368.42 vs. 1580.17 pg/mL; p = 0.03). Interactive effects of MS course (RRMS/PMS) and disease-modifying therapy status on MDA (p = 0.009) and HEL (p = 0.02) levels were detected. In addition, the interaction of disease course and self-reported fatigue revealed significant impacts on 4-HNE levels (p = 0.01) and the GSH/GSSG ratio (p = 0.04). The results also show an association of MS course (p = 0.03) and EDSS (p = 0.04) with GSH levels. No significant changes were observed in the serum concentrations of iron metabolism indicators between the two patient groups (p > 0.05). We suggest circulatory 4-HNE as an important parameter related to differences between RRMS and PMS. Significant interactions of MS course and other clinically relevant parameters with changes in redox processes associated with ferroptosis support the further investigation of MS with a larger sample while taking into account both circulatory and central nervous system estimation. [ABSTRACT FROM AUTHOR]

Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion. [ABSTRACT FROM AUTHOR]

Effective management of chronic kidney disease (CKD), a major health problem worldwide, requires accurate and timely diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for evaluating specific aspects of CKD have been proposed in the literature, many of which are based on a small number of samples. Based on the evidence presented in relevant studies, a comprehensive overview of the different biomarkers applicable for clinical implementation is lacking. This review aims to compile information on the non-invasive diagnostic, prognostic, and predictive biomarkers currently available for the management of CKD and provide guidance on the application of these biomarkers. We specifically focus on biomarkers that have demonstrated added value in prospective studies or those based on prospectively collected samples including at least 100 subjects. Published data demonstrate that several valid non-invasive biomarkers of potential value in the management of CKD are currently available. [ABSTRACT FROM AUTHOR]

Known as a diverse collection of neoplastic diseases, breast cancer (BC) can be hyperbolically characterized as a dynamic pseudo-organ, a living organism able to build a complex, open, hierarchically organized, self-sustainable, and self-renewable tumor system, a population, a species, a local community, a biocenosis, or an evolving dynamical ecosystem (i.e., immune or metabolic ecosystem) that emphasizes both developmental continuity and spatio-temporal change. Moreover, a cancer cell community, also known as an oncobiota, has been described as non-sexually reproducing species, as well as a migratory or invasive species that expresses intelligent behavior, or an endangered or parasite species that fights to survive, to optimize its features inside the host's ecosystem, or that is able to exploit or to disrupt its host circadian cycle for improving the own proliferation and spreading. BC tumorigenesis has also been compared with the early embryo and placenta development that may suggest new strategies for research and therapy. Furthermore, BC has also been characterized as an environmental disease or as an ecological disorder. Many mechanisms of cancer progression have been explained by principles of ecology, developmental biology, and evolutionary paradigms. Many authors have discussed ecological, developmental, and evolutionary strategies for more successful anti-cancer therapies, or for understanding the ecological, developmental, and evolutionary bases of BC exploitable vulnerabilities. Herein, we used the integrated framework of three well known ecological theories: the Bronfenbrenner's theory of human development, the Vannote's River Continuum Concept (RCC), and the Ecological Evolutionary Developmental Biology (Eco-Evo-Devo) theory, to explain and understand several eco-evo-devo-based principles that govern BC progression. Multi-omics fields, taken together as onco-breastomics, offer better opportunities to integrate, analyze, and interpret large amounts of complex heterogeneous data, such as various and big-omics data obtained by multiple investigative modalities, for understanding the eco-evo-devo-based principles that drive BC progression and treatment. These integrative eco-evo-devo theories can help clinicians better diagnose and treat BC, for example, by using non-invasive biomarkers in liquid-biopsies that have emerged from integrated omics-based data that accurately reflect the biomolecular landscape of the primary tumor in order to avoid mutilating preventive surgery, like bilateral mastectomy. From the perspective of preventive, personalized, and participatory medicine, these hypotheses may help patients to think about this disease as a process governed by natural rules, to understand the possible causes of the disease, and to gain control on their own health. [ABSTRACT FROM AUTHOR]

The progression of idiopathic pulmonary fibrosis (IPF) is diverse and unpredictable. We identified and validated a new biomarker for IPF progression. To identify a candidate gene to predict progression, we assessed differentially expressed genes in patients with advanced IPF compared with early IPF and controls in three lung sample cohorts. Candidate gene expression was confirmed using immunohistochemistry and Western blotting of lung tissue samples from an independent IPF clinical cohort. Biomarker potential was assessed using an enzyme-linked immunosorbent assay of serum samples from the retrospective validation cohort. We verified that the final candidate gene reflected the progression of IPF in a prospective validation cohort. In the RNA-seq comparative analysis of lung tissues, CD276, COL7A1, CTSB, GLI2, PIK3R2, PRAF2, IGF2BP3, and NUPR1 were up-regulated, and ADAMTS8 was down-regulated in the samples of advanced IPF. Only CTSB showed significant differences in expression based on Western blotting (n = 12; p < 0.001) and immunohistochemistry between the three groups of the independent IPF cohort. In the retrospective validation cohort (n = 78), serum CTSB levels were higher in the progressive group (n = 25) than in the control (n = 29, mean 7.37 ng/mL vs. 2.70 ng/mL, p < 0.001) and nonprogressive groups (n = 24, mean 7.37 ng/mL vs. 2.56 ng/mL, p < 0.001). In the prospective validation cohort (n = 129), serum CTSB levels were higher in the progressive group than in the nonprogressive group (mean 8.30 ng/mL vs. 3.00 ng/mL, p < 0.001). After adjusting for baseline FVC, we found that CTSB was independently associated with IPF progression (adjusted OR = 2.61, p < 0.001). Serum CTSB levels significantly predicted IPF progression (AUC = 0.944, p < 0.001). Serum CTSB level significantly distinguished the progression of IPF from the non-progression of IPF or healthy control. [ABSTRACT FROM AUTHOR]

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate–glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83–13.94] and HR: 2.44, [CI 95%: 1.10–5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) remains one of the most common malignancies among women worldwide. Breast cancer shows metastatic heterogeneity with priority to different organs, which leads to differences in prognosis and response to therapy among patients. The main targets for metastasis in BC are the bone, lung, liver and brain. The molecular mechanism of BC organ-specificity is still under investigation. In recent years, the appearance of new genomic approaches has led to unprecedented changes in the understanding of breast cancer metastasis organ-specificity and has provided a new platform for the development of more effective therapeutic agents. This review summarises recent data on molecular organ-specific markers of metastasis as the basis of a possible therapeutic approach in order to improve the diagnosis and prognosis of patients with metastatically heterogeneous breast cancer. [ABSTRACT FROM AUTHOR]

Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion.

Effective management of chronic kidney disease (CKD), a major health problem worldwide, requires accurate and timely diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for evaluating specific aspects of CKD have been proposed in the literature, many of which are based on a small number of samples. Based on the evidence presented in relevant studies, a comprehensive overview of the different biomarkers applicable for clinical implementation is lacking. This review aims to compile information on the non-invasive diagnostic, prognostic, and predictive biomarkers currently available for the management of CKD and provide guidance on the application of these biomarkers. We specifically focus on biomarkers that have demonstrated added value in prospective studies or those based on prospectively collected samples including at least 100 subjects. Published data demonstrate that several valid non-invasive biomarkers of potential value in the management of CKD are currently available.

The metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tumor proliferation and development. However, the precise role and function of SHMT2 in gastric cancer (GC) remain poorly understood. In this study, we presented evidence that SHMT2 was necessary for hypoxia-inducible factor-1α (HIF1α) stability and contributed to GC cells' hypoxic adaptation. The analysis of datasets retrieved from The Cancer Genome Atlas and the experimentation with human cell lines revealed a marked increase in SHMT2 expression in GC. The SHMT2 knockdown in MGC803, SGC7901, and HGC27 cell lines inhibited cell proliferation, colony formation, invasion, and migration. Notably, SHMT2 depletion disrupted redox homeostasis and caused glycolytic function loss in GC cells under hypoxic circumstances. Mechanistically, we discovered SHMT2 modulated HIF1α stability, which acted as a master regulator of hypoxia-inducible genes under hypoxic conditions. This, in turn, regulated the downstream VEGF and STAT3 pathways. The in vivo xenograft experiments showed that SHMT2 knockdown markedly reduced GC growth. Our results elucidate the novel function of SHMT2 in stabilizing HIF1α under hypoxic conditions, thus providing a potential therapeutic strategy for GC treatment. [ABSTRACT FROM AUTHOR]

Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent years, with the aid of next-generation sequencing (NGS), an increasing number of molecular aberrations were discovered, such as recurrent mutations in FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1 genes. During MDS progression to leukemia, the order of gene mutation acquisition is not random and is important when considering the prognostic impact. Moreover, the co-occurrence of certain gene mutations is not random; some of the combinations of gene mutations seem to have a high frequency (ASXL1 and U2AF1), while the co-occurrence of mutations in splicing factor genes is rarely observed. Recent progress in the understanding of molecular events has led to MDS transformation into AML and unraveling the genetic signature has paved the way for developing novel targeted and personalized treatments. This article reviews the genetic abnormalities that increase the risk of MDS transformation to AML, and the impact of genetic changes on evolution. Selected therapies for MDS and MDS progression to AML are also discussed. [ABSTRACT FROM AUTHOR]

Despite extensive research into the pathophysiology of multiple sclerosis (MS) and recent developments in potent disease-modifying therapies (DMTs), two-thirds of relapsing-remitting MS patients transition to progressive MS (PMS). The main pathogenic mechanism in PMS is represented not by inflammation but by neurodegeneration, which leads to irreversible neurological disability. For this reason, this transition represents a critical factor for the long-term prognosis. Currently, the diagnosis of PMS can only be established retrospectively based on the progressive worsening of the disability over a period of at least 6 months. In some cases, the diagnosis of PMS is delayed for up to 3 years. With the approval of highly effective DMTs, some with proven effects on neurodegeneration, there is an urgent need for reliable biomarkers to identify this transition phase early and to select patients at a high risk of conversion to PMS. The purpose of this review is to discuss the progress made in the last decade in an attempt to find such a biomarker in the molecular field (serum and cerebrospinal fluid) between the magnetic resonance imaging parameters and optical coherence tomography measures. [ABSTRACT FROM AUTHOR]

Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial–mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression. [ABSTRACT FROM AUTHOR]

The progression of idiopathic pulmonary fibrosis (IPF) is diverse and unpredictable. We identified and validated a new biomarker for IPF progression. To identify a candidate gene to predict progression, we assessed differentially expressed genes in patients with advanced IPF compared with early IPF and controls in three lung sample cohorts. Candidate gene expression was confirmed using immunohistochemistry and Western blotting of lung tissue samples from an independent IPF clinical cohort. Biomarker potential was assessed using an enzyme-linked immunosorbent assay of serum samples from the retrospective validation cohort. We verified that the final candidate gene reflected the progression of IPF in a prospective validation cohort. In the RNA-seq comparative analysis of lung tissues, CD276, COL7A1, CTSB, GLI2, PIK3R2, PRAF2, IGF2BP3, and NUPR1 were up-regulated, and ADAMTS8 was down-regulated in the samples of advanced IPF. Only CTSB showed significant differences in expression based on Western blotting (n = 12; p < 0.001) and immunohistochemistry between the three groups of the independent IPF cohort. In the retrospective validation cohort (n = 78), serum CTSB levels were higher in the progressive group (n = 25) than in the control (n = 29, mean 7.37 ng/mL vs. 2.70 ng/mL, p < 0.001) and nonprogressive groups (n = 24, mean 7.37 ng/mL vs. 2.56 ng/mL, p < 0.001). In the prospective validation cohort (n = 129), serum CTSB levels were higher in the progressive group than in the nonprogressive group (mean 8.30 ng/mL vs. 3.00 ng/mL, p < 0.001). After adjusting for baseline FVC, we found that CTSB was independently associated with IPF progression (adjusted OR = 2.61, p < 0.001). Serum CTSB levels significantly predicted IPF progression (AUC = 0.944, p < 0.001). Serum CTSB level significantly distinguished the progression of IPF from the non-progression of IPF or healthy control.

Known as a diverse collection of neoplastic diseases, breast cancer (BC) can be hyperbolically characterized as a dynamic pseudo-organ, a living organism able to build a complex, open, hierarchically organized, self-sustainable, and self-renewable tumor system, a population, a species, a local community, a biocenosis, or an evolving dynamical ecosystem (i.e., immune or metabolic ecosystem) that emphasizes both developmental continuity and spatio-temporal change. Moreover, a cancer cell community, also known as an oncobiota, has been described as non-sexually reproducing species, as well as a migratory or invasive species that expresses intelligent behavior, or an endangered or parasite species that fights to survive, to optimize its features inside the host’s ecosystem, or that is able to exploit or to disrupt its host circadian cycle for improving the own proliferation and spreading. BC tumorigenesis has also been compared with the early embryo and placenta development that may suggest new strategies for research and therapy. Furthermore, BC has also been characterized as an environmental disease or as an ecological disorder. Many mechanisms of cancer progression have been explained by principles of ecology, developmental biology, and evolutionary paradigms. Many authors have discussed ecological, developmental, and evolutionary strategies for more successful anti-cancer therapies, or for understanding the ecological, developmental, and evolutionary bases of BC exploitable vulnerabilities. Herein, we used the integrated framework of three well known ecological theories: the Bronfenbrenner’s theory of human development, the Vannote’s River Continuum Concept (RCC), and the Ecological Evolutionary Developmental Biology (Eco-Evo-Devo) theory, to explain and understand several eco-evo-devo-based principles that govern BC progression. Multi-omics fields, taken together as onco-breastomics, offer better opportunities to integrate, analyze, and interpret large amounts of complex heterogeneous data, such as various and big-omics data obtained by multiple investigative modalities, for understanding the eco-evo-devo-based principles that drive BC progression and treatment. These integrative eco-evo-devo theories can help clinicians better diagnose and treat BC, for example, by using non-invasive biomarkers in liquid-biopsies that have emerged from integrated omics-based data that accurately reflect the biomolecular landscape of the primary tumor in order to avoid mutilating preventive surgery, like bilateral mastectomy. From the perspective of preventive, personalized, and participatory medicine, these hypotheses may help patients to think about this disease as a process governed by natural rules, to understand the possible causes of the disease, and to gain control on their own health.

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate–glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83–13.94] and HR: 2.44, [CI 95%: 1.10–5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies.

Remyelination therapies, which are currently under development, have a great potential to delay, prevent or even reverse disability in multiple sclerosis patients. Several models are available to study the effectiveness of novel compounds in vivo, among which is the cuprizone model. This model is characterized by toxin-induced demyelination, followed by endogenous remyelination after cessation of the intoxication. Due to its high reproducibility and ease of use, this model enjoys high popularity among various research and industrial groups. In this review article, we will summarize recent findings using this model and discuss the potential of some of the identified compounds to promote remyelination in multiple sclerosis patients. [ABSTRACT FROM AUTHOR]

To evaluate the utility of different risk assessments in non-muscle-invasive bladder cancer (NMIBC) patients, a total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the molecular signature-based subtype predictor (MSP888) and risk calculators based on clinicopathological factors (EORTC, CUETO and 2021 EAU risk scores) was compared. Of the 178 patients, 49 were newly analyzed by the RNA-sequencing, and their MSP888 subtype was evaluated. The ability of the EORTC, MSP888 and two molecular subtyping systems of bladder cancer (Lund and UROMOL subtypes) to predict progression of 460 NMIBC patients from the UROMOL project was assessed. Cox regression analyses showed that the MSP888 was an independent predictor of NMIBC progression in the CBNUH cohort (p = 0.043). Particularly in patients without an intravesical BCG immunotherapy, MSP888 significantly linked with risk of disease recurrence and progression (both p < 0.05). However, the EORTC, CUETO and 2021 EAU risk scores showed disappointing results with respect to estimating the NMIBC prognosis. In the UROMOL cohort, the MSP888, Lund and UROMOL subtypes demonstrated a similar capacity to predict NMIBC progression (all p < 0.05). Conclusively, the MSP888 is favorable for stratifying patients to facilitate optimal treatment. [ABSTRACT FROM AUTHOR]

Long noncoding (lnc)RNAs are reported to be key regulators of tumor progression, including hepatocellular carcinoma (HCC). The lncRNA long intergenic noncoding RNA 00673 (LINC00673) was indicated to play an important role in HCC progression, but the impacts of genetic variants (single-nucleotide polymorphisms, SNPs) of LINC00673 on HCC remain unclear. A TaqMan allelic discrimination assay was performed to analyze the genotypes of three tagging SNPs, viz., rs9914618 G > A, rs6501551 A > G, and rs11655237 C > T, of LINC00673 in 783 HCC patients and 1197 healthy subjects. Associations of functional SNPs of LINC00673 with HCC susceptibility and clinicopathologic variables were analyzed by logistic regression models. After stratification by confounding factor, we observed that elderly patients (≥60 years) with the LINC00673 rs9914618 A allele had an increased risk of developing HCC under a codominant model (p = 0.025) and dominant model (p = 0.047). Moreover, elderly patients carrying the GA + AA genotype of rs9914618 exhibited a higher risk of having lymph node metastasis compared to those who were homozygous for the major allele (p = 0.013). Genotype screening of rs9914618 in HCC cell lines showed that cells carrying the AA genotype expressed higher LINC00673 levels compared to the cells carrying the GG genotype. Further analyses of clinical datasets from the Cancer Genome Atlas (TCGA) showed that LINC00673 expressions were upregulated in HCC tissues compared to normal tissues, and were correlated with advanced clinical stages and poorer prognoses. In conclusions, our results suggested that the LINC00673 rs9914618 polymorphism may be a promising HCC biomarker, especially in elderly populations. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) remains one of the most common malignancies among women worldwide. Breast cancer shows metastatic heterogeneity with priority to different organs, which leads to differences in prognosis and response to therapy among patients. The main targets for metastasis in BC are the bone, lung, liver and brain. The molecular mechanism of BC organ-specificity is still under investigation. In recent years, the appearance of new genomic approaches has led to unprecedented changes in the understanding of breast cancer metastasis organ-specificity and has provided a new platform for the development of more effective therapeutic agents. This review summarises recent data on molecular organ-specific markers of metastasis as the basis of a possible therapeutic approach in order to improve the diagnosis and prognosis of patients with metastatically heterogeneous breast cancer.

The standard clinical management of locally advanced rectal cancer (LARC) patients includes neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) followed by mesorectal excision. MicroRNA (miR)-19b expression levels in LARC biopsies obtained from initial colonoscopy have recently been identified as independent predictors of both patient outcome and pathological response to preoperative CRT in this disease. Moreover, it has been discovered that this miR increases its expression in 5-FU resistant colon cancer cells after 5-FU exposure. Despite the fact that these observations suggest a functional role of miR-19b modulating 5-FU response of LARC cells, this issue still remains to be clarified. Here, we show that downregulation of miR-19b enhances the antitumor effects of 5-FU treatment. Moreover, ectopic miR-19b modulation was able to restore sensitivity to 5-FU treatment using an acquired resistant model to this compound. Notably, we also evaluated the potential clinical impact of miR-19b as a predictive marker of disease progression after tumor surgery resection in LARC patients, observing that miR-19b overexpression significantly anticipates patient recurrence in our cohort (p = 0.002). Altogether, our findings demonstrate the functional role of miR-19b in the progressively decreasing sensitivity to 5-FU treatment and its potential usefulness as a therapeutic target to overcome 5-FU resistance, as well as its clinical impact as predictor of tumor progression and relapse. [ABSTRACT FROM AUTHOR]

Meningiomas are mostly benign tumors that, at times, can behave aggressively, displaying recurrence despite gross-total resection (GTR) and progression to overt malignancy. Such cases represent a clinical challenge, particularly because they are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription factor with a key role in stem cell maintenance and has been associated with tumorigenesis in a variety of cancers. The purpose of the present work was to dissect the role of SOX2 in predicting the aggressiveness of meningioma. We analyzed progressive/recurrent WHO grade 1–2 meningiomas and WHO grade 3 meningiomas; as controls, non-recurring WHO grade 1 and grade 2 meningioma patients were enrolled. SOX2 expression was evaluated using both immunohistochemistry (IHC) and RT-PCR. The final analysis included 87 patients. IHC was able to reliably assess SOX2 expression, as shown by the good correlation with mRNA levels (Spearman R = 0.0398, p = 0.001, AUC 0.87). SOX2 expression was an intrinsic characteristic of any single tumor and did not change following recurrence or progression. Importantly, SOX2 expression at first surgery was strongly related to meningioma clinical behavior, histological grade and risk of recurrence. Finally, survival data suggest a prognostic role of SOX2 expression in the whole series, both for overall and for recurrence-free survival (p < 0.0001 and p = 0.0001, respectively). Thus, SOX2 assessment could be of great help to clinicians in informing adjuvant treatments during follow-up. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the central nervous system's white and grey matter. Especially during the progressive phases of the disease, immunomodulatory treatment strategies lose their effectiveness. To develop novel progressive MS treatment options, pre-clinical animal models are indispensable. Among the various different models, the cuprizone de- and remyelination model is frequently used. While most studies determine tissue damage and repair at the histological and ultrastructural level, functional readouts are less commonly applied. Among the various overt functional deficits, gait and coordination abnormalities are commonly observed in MS patients. Motor behavior is mediated by a complex neural network that originates in the cortex and terminates in the skeletal muscles. Several methods exist to determine gait abnormalities in small rodents, including the rotarod testing paradigm. In this review article, we provide an overview of the validity and characteristics of the rotarod test in cuprizone-intoxicated mice. [ABSTRACT FROM AUTHOR]

Various enzymes in the one-carbon metabolic pathway are closely related to the development of tumors, and they can all be potential targets for cancer therapy. Serine hydroxymethyltransferase2 (SHMT2), a key metabolic enzyme, is very important for the proliferation and growth of cancer cells. However, the function and mechanism of SHMT2 in head and neck cancer (HNC) are not clear. An analysis of The Cancer Genome Atlas (TCGA) data showed that the expression of SHMT2 was higher in tumor tissue than in normal tissue, and its expression was significantly associated with male sex, aggressive histological grade, lymph node metastasis, distant metastasis, advanced TNM stage, and lymphovascular invasion in HNC. SHMT2 knockdown in FADU and SNU1041 cell lines significantly inhibited cell proliferation, colony formation, migration, and invasion. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using TCGA data revealed that SHMT2 was closely related to cancer stem cell regulation and maintenance. Furthermore, we found that silencing SHMT2 inhibited the expression of stemness markers and tumor spheroid formation compared with a control group. On the contrary, stemness markers were significantly increased after SHMT2 overexpression in HEP-2 cells. Interestingly, we found that knocking down SHMT2 reduced the expression of genes related to the Notch and Wnt pathways. Finally, silencing SHMT2 significantly reduced tumor growth and decreased stemness markers in a xenograft model. Taken together, our study suggests that targeting SHMT2 may play an important role in inhibiting HNC progression. [ABSTRACT FROM AUTHOR]

Tumor cell infiltrative ability into surrounding brain tissue is a characteristic of diffusely infiltrative astrocytoma and is strongly associated with extracellular matrix (ECM) stiffness. Collagens are the most abundant ECM scaffolding proteins and contribute to matrix organization and stiffness. LOX family members, copper-dependent amine oxidases, participate in the collagen and elastin crosslinking that determine ECM tensile strength. Common IDH mutations in lower-grade gliomas (LGG) impact prognosis and have been associated with ECM stiffness. We analyzed the expression levels of LOX family members and matrisome-associated genes in astrocytoma stratified by malignancy grade and IDH mutation status. A progressive increase in expression of all five LOX family members according to malignancy grade was found. LOX, LOXL1, and LOXL3 expression correlated with matrisome gene expressions. LOXL1 correlations were detected in LGG with IDH mutation (IDHmut), LOXL3 correlations in LGG with IDH wild type (IDHwt) and strong LOX correlations in glioblastoma (GBM) were found. These increasing correlations may explain the increment of ECM stiffness and tumor aggressiveness from LGG-IDHmut and LGG-IDHwt through to GBM. The expression of the mechanosensitive transcription factor, β-catenin, also increased with malignancy grade and was correlated with LOXL1 and LOXL3 expression, suggesting involvement of this factor in the outside–in signaling pathway. [ABSTRACT FROM AUTHOR]

Cancer suppression through the inhibition of N-acetyltransferase 10 (NAT10) by its specific inhibitor Remodelin has been demonstrated in a variety of human cancers. Here, we report the inhibitory effects of Remodelin on prostate cancer (PCa) cells and the possible associated mechanisms. The prostate cancer cell lines VCaP, LNCaP, PC3, and DU145 were used. The in vitro proliferation, migration, and invasion of cells were measured by a cell proliferation assay, colony formation, wound healing, and Transwell assays, respectively. In vivo tumor growth was analyzed by transplantation into nude mice. The inhibition of NAT10 by Remodelin not only suppressed growth, migration, and invasion in vitro, but also the in vivo cancer growth of prostate cancer cells. The involvement of NAT10 in DNA replication was assessed by EdU labeling, DNA spreading, iPOND, and ChIP-PCR assays. The inhibition of NAT10 by Remodelin slowed DNA replication. NAT10 was detected in the prereplication complex, and it could also bind to DNA replication origins. Furthermore, the interaction between NAT10 and CDC6 was analyzed by Co-IP. The altered expression of NAT10 was measured by immunofluorescence staining and Western blotting. Remodelin markedly reduced the levels of CDC6 and AR. The expression of NAT10 could be altered under either castration or noncastration conditions, and Remodelin still suppressed the growth of in vitro-induced castration-resistant prostate cancers. The analysis of a TCGA database revealed that the overexpression of NAT10, CDC6, and MCM7 in prostate cancers were correlated with the Gleason score and node metastasis. Our data demonstrated that Remodelin, an inhibitor of NAT10, effectively inhibits the growth of prostate cancer cells under either no castration or castration conditions, likely by impairing DNA replication. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is the inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide. In the last decade, a new era was heralded in by a new phenotypic classification, a new diagnostic protocol and the first ever therapeutic guideline, making personalized medicine the aim of MS management. However, despite this great evolution, there are still many aspects of the disease that are unknown and need to be further researched. A hallmark of these research are molecular biomarkers that could help in the diagnosis, differential diagnosis, therapy and prognosis of the disease. Proteomics, a rapidly evolving discipline of molecular biology may fulfill this dire need for the discovery of molecular biomarkers. In this review, we aimed to give a comprehensive summary on the utility of proteomics in the field of MS research. We reviewed the published results of the method in case of the pathogenesis of the disease and for biomarkers of diagnosis, differential diagnosis, conversion of disease courses, disease activity, progression and immunological therapy. We found proteomics to be a highly effective emerging tool that has been providing important findings in the research of MS. [ABSTRACT FROM AUTHOR]

The metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tumor proliferation and development. However, the precise role and function of SHMT2 in gastric cancer (GC) remain poorly understood. In this study, we presented evidence that SHMT2 was necessary for hypoxia-inducible factor-1α (HIF1α) stability and contributed to GC cells’ hypoxic adaptation. The analysis of datasets retrieved from The Cancer Genome Atlas and the experimentation with human cell lines revealed a marked increase in SHMT2 expression in GC. The SHMT2 knockdown in MGC803, SGC7901, and HGC27 cell lines inhibited cell proliferation, colony formation, invasion, and migration. Notably, SHMT2 depletion disrupted redox homeostasis and caused glycolytic function loss in GC cells under hypoxic circumstances. Mechanistically, we discovered SHMT2 modulated HIF1α stability, which acted as a master regulator of hypoxia-inducible genes under hypoxic conditions. This, in turn, regulated the downstream VEGF and STAT3 pathways. The in vivo xenograft experiments showed that SHMT2 knockdown markedly reduced GC growth. Our results elucidate the novel function of SHMT2 in stabilizing HIF1α under hypoxic conditions, thus providing a potential therapeutic strategy for GC treatment.

Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent years, with the aid of next-generation sequencing (NGS), an increasing number of molecular aberrations were discovered, such as recurrent mutations in FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1 genes. During MDS progression to leukemia, the order of gene mutation acquisition is not random and is important when considering the prognostic impact. Moreover, the co-occurrence of certain gene mutations is not random; some of the combinations of gene mutations seem to have a high frequency (ASXL1 and U2AF1), while the co-occurrence of mutations in splicing factor genes is rarely observed. Recent progress in the understanding of molecular events has led to MDS transformation into AML and unraveling the genetic signature has paved the way for developing novel targeted and personalized treatments. This article reviews the genetic abnormalities that increase the risk of MDS transformation to AML, and the impact of genetic changes on evolution. Selected therapies for MDS and MDS progression to AML are also discussed.

Despite extensive research into the pathophysiology of multiple sclerosis (MS) and recent developments in potent disease-modifying therapies (DMTs), two-thirds of relapsing-remitting MS patients transition to progressive MS (PMS). The main pathogenic mechanism in PMS is represented not by inflammation but by neurodegeneration, which leads to irreversible neurological disability. For this reason, this transition represents a critical factor for the long-term prognosis. Currently, the diagnosis of PMS can only be established retrospectively based on the progressive worsening of the disability over a period of at least 6 months. In some cases, the diagnosis of PMS is delayed for up to 3 years. With the approval of highly effective DMTs, some with proven effects on neurodegeneration, there is an urgent need for reliable biomarkers to identify this transition phase early and to select patients at a high risk of conversion to PMS. The purpose of this review is to discuss the progress made in the last decade in an attempt to find such a biomarker in the molecular field (serum and cerebrospinal fluid) between the magnetic resonance imaging parameters and optical coherence tomography measures.

Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial–mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression.

Breast cancer (BC) is one of the most devastating cancers, with high morbidity and mortality, among the female population worldwide. In BC, mesenchymal stem cells (MSCs), as pluripotent stromal stem cells, play a significant role in TME formation and tumor progression. Recently, an increasing number of studies have demonstrated that extracellular vesicles (EVs) are essential for the crosstalk between MSCs and BC cells. MSC-derived EVs (MSC-EVs) can deliver a diversity of molecules, including lipids, proteins, and nucleic acids, etc., to target cells, and produce corresponding effects. Studies have demonstrated that MSC-EVs exert both inhibitory and promotive effects in different situations and different stages of BC. Meanwhile, MSC-EVs provide novel therapeutic options for BC, such as EVs as carriers for drug delivery. Therefore, in this review, we summarize the role of MSC-EVs in BC progression and application in clinical treatment, in the hope of providing a basis for further research. [ABSTRACT FROM AUTHOR]

Remyelination therapies, which are currently under development, have a great potential to delay, prevent or even reverse disability in multiple sclerosis patients. Several models are available to study the effectiveness of novel compounds in vivo, among which is the cuprizone model. This model is characterized by toxin-induced demyelination, followed by endogenous remyelination after cessation of the intoxication. Due to its high reproducibility and ease of use, this model enjoys high popularity among various research and industrial groups. In this review article, we will summarize recent findings using this model and discuss the potential of some of the identified compounds to promote remyelination in multiple sclerosis patients.

To evaluate the utility of different risk assessments in non-muscle-invasive bladder cancer (NMIBC) patients, a total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the molecular signature-based subtype predictor (MSP888) and risk calculators based on clinicopathological factors (EORTC, CUETO and 2021 EAU risk scores) was compared. Of the 178 patients, 49 were newly analyzed by the RNA-sequencing, and their MSP888 subtype was evaluated. The ability of the EORTC, MSP888 and two molecular subtyping systems of bladder cancer (Lund and UROMOL subtypes) to predict progression of 460 NMIBC patients from the UROMOL project was assessed. Cox regression analyses showed that the MSP888 was an independent predictor of NMIBC progression in the CBNUH cohort (p = 0.043). Particularly in patients without an intravesical BCG immunotherapy, MSP888 significantly linked with risk of disease recurrence and progression (both p < 0.05). However, the EORTC, CUETO and 2021 EAU risk scores showed disappointing results with respect to estimating the NMIBC prognosis. In the UROMOL cohort, the MSP888, Lund and UROMOL subtypes demonstrated a similar capacity to predict NMIBC progression (all p < 0.05). Conclusively, the MSP888 is favorable for stratifying patients to facilitate optimal treatment.

Long noncoding (lnc)RNAs are reported to be key regulators of tumor progression, including hepatocellular carcinoma (HCC). The lncRNA long intergenic noncoding RNA 00673 (LINC00673) was indicated to play an important role in HCC progression, but the impacts of genetic variants (single-nucleotide polymorphisms, SNPs) of LINC00673 on HCC remain unclear. A TaqMan allelic discrimination assay was performed to analyze the genotypes of three tagging SNPs, viz., rs9914618 G > A, rs6501551 A > G, and rs11655237 C > T, of LINC00673 in 783 HCC patients and 1197 healthy subjects. Associations of functional SNPs of LINC00673 with HCC susceptibility and clinicopathologic variables were analyzed by logistic regression models. After stratification by confounding factor, we observed that elderly patients (≥60 years) with the LINC00673 rs9914618 A allele had an increased risk of developing HCC under a codominant model (p = 0.025) and dominant model (p = 0.047). Moreover, elderly patients carrying the GA + AA genotype of rs9914618 exhibited a higher risk of having lymph node metastasis compared to those who were homozygous for the major allele (p = 0.013). Genotype screening of rs9914618 in HCC cell lines showed that cells carrying the AA genotype expressed higher LINC00673 levels compared to the cells carrying the GG genotype. Further analyses of clinical datasets from the Cancer Genome Atlas (TCGA) showed that LINC00673 expressions were upregulated in HCC tissues compared to normal tissues, and were correlated with advanced clinical stages and poorer prognoses. In conclusions, our results suggested that the LINC00673 rs9914618 polymorphism may be a promising HCC biomarker, especially in elderly populations.

The standard clinical management of locally advanced rectal cancer (LARC) patients includes neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) followed by mesorectal excision. MicroRNA (miR)-19b expression levels in LARC biopsies obtained from initial colonoscopy have recently been identified as independent predictors of both patient outcome and pathological response to preoperative CRT in this disease. Moreover, it has been discovered that this miR increases its expression in 5-FU resistant colon cancer cells after 5-FU exposure. Despite the fact that these observations suggest a functional role of miR-19b modulating 5-FU response of LARC cells, this issue still remains to be clarified. Here, we show that downregulation of miR-19b enhances the antitumor effects of 5-FU treatment. Moreover, ectopic miR-19b modulation was able to restore sensitivity to 5-FU treatment using an acquired resistant model to this compound. Notably, we also evaluated the potential clinical impact of miR-19b as a predictive marker of disease progression after tumor surgery resection in LARC patients, observing that miR-19b overexpression significantly anticipates patient recurrence in our cohort (p = 0.002). Altogether, our findings demonstrate the functional role of miR-19b in the progressively decreasing sensitivity to 5-FU treatment and its potential usefulness as a therapeutic target to overcome 5-FU resistance, as well as its clinical impact as predictor of tumor progression and relapse.

Meningiomas are mostly benign tumors that, at times, can behave aggressively, displaying recurrence despite gross-total resection (GTR) and progression to overt malignancy. Such cases represent a clinical challenge, particularly because they are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription factor with a key role in stem cell maintenance and has been associated with tumorigenesis in a variety of cancers. The purpose of the present work was to dissect the role of SOX2 in predicting the aggressiveness of meningioma. We analyzed progressive/recurrent WHO grade 1–2 meningiomas and WHO grade 3 meningiomas; as controls, non-recurring WHO grade 1 and grade 2 meningioma patients were enrolled. SOX2 expression was evaluated using both immunohistochemistry (IHC) and RT-PCR. The final analysis included 87 patients. IHC was able to reliably assess SOX2 expression, as shown by the good correlation with mRNA levels (Spearman R = 0.0398, p = 0.001, AUC 0.87). SOX2 expression was an intrinsic characteristic of any single tumor and did not change following recurrence or progression. Importantly, SOX2 expression at first surgery was strongly related to meningioma clinical behavior, histological grade and risk of recurrence. Finally, survival data suggest a prognostic role of SOX2 expression in the whole series, both for overall and for recurrence-free survival (p < 0.0001 and p = 0.0001, respectively). Thus, SOX2 assessment could be of great help to clinicians in informing adjuvant treatments during follow-up.

Multiple Sclerosis (MS) is a neuroinflammatory disorder, which is histopathologically characterized by multifocal inflammatory demyelinating lesions affecting both the central nervous system’s white and grey matter. Especially during the progressive phases of the disease, immunomodulatory treatment strategies lose their effectiveness. To develop novel progressive MS treatment options, pre-clinical animal models are indispensable. Among the various different models, the cuprizone de- and remyelination model is frequently used. While most studies determine tissue damage and repair at the histological and ultrastructural level, functional readouts are less commonly applied. Among the various overt functional deficits, gait and coordination abnormalities are commonly observed in MS patients. Motor behavior is mediated by a complex neural network that originates in the cortex and terminates in the skeletal muscles. Several methods exist to determine gait abnormalities in small rodents, including the rotarod testing paradigm. In this review article, we provide an overview of the validity and characteristics of the rotarod test in cuprizone-intoxicated mice.

Tumor cell infiltrative ability into surrounding brain tissue is a characteristic of diffusely infiltrative astrocytoma and is strongly associated with extracellular matrix (ECM) stiffness. Collagens are the most abundant ECM scaffolding proteins and contribute to matrix organization and stiffness. LOX family members, copper-dependent amine oxidases, participate in the collagen and elastin crosslinking that determine ECM tensile strength. Common IDH mutations in lower-grade gliomas (LGG) impact prognosis and have been associated with ECM stiffness. We analyzed the expression levels of LOX family members and matrisome-associated genes in astrocytoma stratified by malignancy grade and IDH mutation status. A progressive increase in expression of all five LOX family members according to malignancy grade was found. LOX, LOXL1, and LOXL3 expression correlated with matrisome gene expressions. LOXL1 correlations were detected in LGG with IDH mutation (IDHmut), LOXL3 correlations in LGG with IDH wild type (IDHwt) and strong LOX correlations in glioblastoma (GBM) were found. These increasing correlations may explain the increment of ECM stiffness and tumor aggressiveness from LGG-IDHmut and LGG-IDHwt through to GBM. The expression of the mechanosensitive transcription factor, β-catenin, also increased with malignancy grade and was correlated with LOXL1 and LOXL3 expression, suggesting involvement of this factor in the outside–in signaling pathway.

Various enzymes in the one-carbon metabolic pathway are closely related to the development of tumors, and they can all be potential targets for cancer therapy. Serine hydroxymethyltransferase2 (SHMT2), a key metabolic enzyme, is very important for the proliferation and growth of cancer cells. However, the function and mechanism of SHMT2 in head and neck cancer (HNC) are not clear. An analysis of The Cancer Genome Atlas (TCGA) data showed that the expression of SHMT2 was higher in tumor tissue than in normal tissue, and its expression was significantly associated with male sex, aggressive histological grade, lymph node metastasis, distant metastasis, advanced TNM stage, and lymphovascular invasion in HNC. SHMT2 knockdown in FADU and SNU1041 cell lines significantly inhibited cell proliferation, colony formation, migration, and invasion. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using TCGA data revealed that SHMT2 was closely related to cancer stem cell regulation and maintenance. Furthermore, we found that silencing SHMT2 inhibited the expression of stemness markers and tumor spheroid formation compared with a control group. On the contrary, stemness markers were significantly increased after SHMT2 overexpression in HEP-2 cells. Interestingly, we found that knocking down SHMT2 reduced the expression of genes related to the Notch and Wnt pathways. Finally, silencing SHMT2 significantly reduced tumor growth and decreased stemness markers in a xenograft model. Taken together, our study suggests that targeting SHMT2 may play an important role in inhibiting HNC progression.

Cancer suppression through the inhibition of N-acetyltransferase 10 (NAT10) by its specific inhibitor Remodelin has been demonstrated in a variety of human cancers. Here, we report the inhibitory effects of Remodelin on prostate cancer (PCa) cells and the possible associated mechanisms. The prostate cancer cell lines VCaP, LNCaP, PC3, and DU145 were used. The in vitro proliferation, migration, and invasion of cells were measured by a cell proliferation assay, colony formation, wound healing, and Transwell assays, respectively. In vivo tumor growth was analyzed by transplantation into nude mice. The inhibition of NAT10 by Remodelin not only suppressed growth, migration, and invasion in vitro, but also the in vivo cancer growth of prostate cancer cells. The involvement of NAT10 in DNA replication was assessed by EdU labeling, DNA spreading, iPOND, and ChIP-PCR assays. The inhibition of NAT10 by Remodelin slowed DNA replication. NAT10 was detected in the prereplication complex, and it could also bind to DNA replication origins. Furthermore, the interaction between NAT10 and CDC6 was analyzed by Co-IP. The altered expression of NAT10 was measured by immunofluorescence staining and Western blotting. Remodelin markedly reduced the levels of CDC6 and AR. The expression of NAT10 could be altered under either castration or noncastration conditions, and Remodelin still suppressed the growth of in vitro-induced castration-resistant prostate cancers. The analysis of a TCGA database revealed that the overexpression of NAT10, CDC6, and MCM7 in prostate cancers were correlated with the Gleason score and node metastasis. Our data demonstrated that Remodelin, an inhibitor of NAT10, effectively inhibits the growth of prostate cancer cells under either no castration or castration conditions, likely by impairing DNA replication.

Multiple sclerosis (MS) is the inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) that affects approximately 2.8 million people worldwide. In the last decade, a new era was heralded in by a new phenotypic classification, a new diagnostic protocol and the first ever therapeutic guideline, making personalized medicine the aim of MS management. However, despite this great evolution, there are still many aspects of the disease that are unknown and need to be further researched. A hallmark of these research are molecular biomarkers that could help in the diagnosis, differential diagnosis, therapy and prognosis of the disease. Proteomics, a rapidly evolving discipline of molecular biology may fulfill this dire need for the discovery of molecular biomarkers. In this review, we aimed to give a comprehensive summary on the utility of proteomics in the field of MS research. We reviewed the published results of the method in case of the pathogenesis of the disease and for biomarkers of diagnosis, differential diagnosis, conversion of disease courses, disease activity, progression and immunological therapy. We found proteomics to be a highly effective emerging tool that has been providing important findings in the research of MS.

Breast cancer (BC) is one of the most devastating cancers, with high morbidity and mortality, among the female population worldwide. In BC, mesenchymal stem cells (MSCs), as pluripotent stromal stem cells, play a significant role in TME formation and tumor progression. Recently, an increasing number of studies have demonstrated that extracellular vesicles (EVs) are essential for the crosstalk between MSCs and BC cells. MSC-derived EVs (MSC-EVs) can deliver a diversity of molecules, including lipids, proteins, and nucleic acids, etc., to target cells, and produce corresponding effects. Studies have demonstrated that MSC-EVs exert both inhibitory and promotive effects in different situations and different stages of BC. Meanwhile, MSC-EVs provide novel therapeutic options for BC, such as EVs as carriers for drug delivery. Therefore, in this review, we summarize the role of MSC-EVs in BC progression and application in clinical treatment, in the hope of providing a basis for further research.

Calcium signaling plays important roles in physiological and pathological conditions, including cutaneous melanoma, the most lethal type of skin cancer. Intracellular calcium concentration ([Ca2+]i), cell membrane calcium channels, calcium related proteins (S100 family, E-cadherin, and calpain), and Wnt/Ca2+ pathways are related to melanogenesis and melanoma tumorigenesis and progression. Calcium signaling influences the melanoma microenvironment, including immune cells, extracellular matrix (ECM), the vascular network, and chemical and physical surroundings. Other ionic channels, such as sodium and potassium channels, are engaged in calcium-mediated pathways in melanoma. Calcium signaling serves as a promising pharmacological target in melanoma treatment, and its dysregulation might serve as a marker for melanoma prediction. We documented calcium-dependent endoplasmic reticulum (ER) stress and mitochondria dysfunction, by targeting calcium channels and influencing [Ca2+]i and calcium homeostasis, and attenuated drug resistance in melanoma management.

As a main subtype of lung cancer, the current situation of non-small cell lung cancer (NSCLC) remains severe worldwide with a 19% survival rate at 5 years. As the conventional therapy approaches, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy, gradually develop into therapy resistance, searching for a novel therapeutic strategy for NSCLC is urgent. Ferroptosis, an iron-dependent programmed necrosis, has now been widely considered as a key factor affecting the tumorigenesis and progression in various cancers. Focusing on its effect in NSCLC, in different situations, ferroptosis can be triggered or restrained. When ferroptosis was induced in NSCLC, it was available to inhibit the tumor progression both in vitro and in vivo. The dominating mechanism was due to a regulation of the classic ferroptosis-repressed GSH-dependent GPX4 signaling pathway instead of other fractional regulating signal axes that regulated ferroptosis via impacting on the ROS, cellular iron levels, etc. In terms of the prevention of ferroptosis in NSCLC, an GSH-independent mechanism was also discovered, interestingly exhibiting the same upstream as the GPX4 signaling. In addition, this review summarizes the progression of ferroptosis in NSCLC and elaborates their association and specific mechanisms through bioinformatics analysis with multiple experimental evidence from different cascades. Finally, this review also points out the possibility of ferroptosis working as a novel strategy for therapy resistance in NSCLC, emphasizing its therapeutic potential.

Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGF-β) superfamily, has been reported to be overexpressed in different kinds of cancer types. However, the function and mechanism of GDF15 in head and neck cancer (HNC) remains unclear. The Cancer Genome Atlas (TCGA) data show that the expression of GDF15 is significantly associated with tumor AJCC stage, lymph vascular invasion and tumor grade in HNC. In this study, we confirmed that knockdown of GDF15 attenuated: cell proliferation, migration and invasion via regulation of EMT through a canonical pathway; SMAD2/3 and noncanonical pathways; PI3K/AKT and MEK/ERK in HNC cell lines. Furthermore, we found that early growth response 1 (EGR1) was a transcription factor of GDF15. Interestingly, we also demonstrated that GDF15 could regulate the expression of EGR1, which meant a positive feedback loop occurred between these two factors. Moreover, combined inhibition of both GDF15 and EGR1 in a HNC mouse xenograft model showed significantly decreased tumor volume compared to inhibition of EGR1 or GDF15 alone. Our study showed that the GDF15–EGR1 signaling axis may be a good target in HNC patients.

Resembling the development of cancer by multistep carcinogenesis, the evolution towards metastasis involves several passages, from local invasion and intravasation, encompassing surviving anoikis into the circulation, landing at distant sites and therein establishing colonization, possibly followed by the outgrowth of macroscopic lesions. Within this cascade, epithelial to mesenchymal transition (EMT) works as a pleiotropic program enabling cancer cells to overcome local, systemic, and distant barriers against diffusion by replacing traits and functions of the epithelial signature with mesenchymal-like ones. Along the transition, a full-blown mesenchymal phenotype may not be accomplished. Rather, the plasticity of the program and its dependency on heterotopic signals implies a pendulum with oscillations towards its reversal, that is mesenchymal to epithelial transition. Cells in intermixed E⇔M states can also display stemness, enabling their replication together with the epithelial reversion next to successful distant colonization. If we aim to include the EMT among the hallmarks of cancer that could modify clinical practice, the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers needs to be filled. We review the knowledge on EMT, derived from models and mechanistic studies as well as from translational studies, with an emphasis on gastrointestinal cancers (GI).

The review begins with molecular genetics, which hit the field unveiling the involvement of oncogenes and tumor suppressor genes in the pathogenesis of colorectal cancer (CRC) and uncovering genetic predispositions. Then the notion of molecular phenotypes with different clinical behaviors was introduced and translated in the clinical arena, paving the way to next-generation sequencing that captured previously unrecognized heterogeneity. Among other molecular regulators of CRC progression, the extent of host immune response within the tumor micro-environment has a critical position. Translational sciences deeply investigated the field, accelerating the pace toward clinical transition, due to its strong association with outcomes. While the perturbation of gut homeostasis occurring in inflammatory bowel diseases can fuel carcinogenesis, micronutrients like vitamin D and calcium can act as brakes, and we discuss underlying molecular mechanisms. Among the components of gut microbiota, Fusobacterium nucleatum is over-represented in CRC, and may worsen patient outcome. However, any translational knowledge tracing the multifaceted evolution of CRC should be interpreted according to the prognostic and predictive frame of the TNM-staging system in a perspective of clinical actionability. Eventually, we examine challenges and promises of pharmacological interventions aimed to restrain disease progression at different disease stages.

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has long been implicated in modeling antitumor immunity; PD-1/PD-L1 axis inhibitors exert their antitumor effects by relieving PD-L1-mediated suppression on tumor-infiltrating T lymphocytes. However, recent studies have unveiled a distinct, tumor-intrinsic, potential role for PD-L1. In this review, we focus on tumor-intrinsic PD-L1 signaling and delve into preclinical evidence linking PD-L1 protein expression with features of epithelial-to-mesenchymal transition program, cancer stemness and known oncogenic pathways. We further summarize data from studies supporting the prognostic significance of PD-L1 in different tumor types. We show that PD-L1 may indeed have oncogenic potential and act as a regulator of tumor progression and metastasis.

DNA methylation is an epigenetic change to the genome that impacts gene activities without modification to the DNA sequence. Alteration in the methylation pattern is a naturally occurring event throughout the human life cycle which may result in the development of diseases such as cancer. In this study, we analyzed methylation data from The Cancer Genome Atlas, under the Lower-Grade Glioma (LGG) and Glioblastoma Multiforme (GBM) projects, to identify methylation markers that exhibit unique changes in DNA methylation pattern along with tumor grade progression, to predict patient survival. We found ten glioma grade-associated Cytosine-phosphate-Guanine (CpG) sites that targeted four genes (SMOC1, KCNA4, SLC25A21, and UPP1) and the methylation pattern is strongly associated with glioma specific molecular alterations, primarily isocitrate dehydrogenase (IDH) mutation and chromosome 1p/19q codeletion. The ten CpG sites collectively distinguished a cohort of diffuse glioma patients with remarkably poor survival probability. Our study highlights genes (KCNA4 and SLC25A21) that were not previously associated with gliomas to have contributed to the poorer patient outcome. These CpG sites can aid glioma tumor progression monitoring and serve as prognostic markers to identify patients diagnosed with less aggressive and malignant gliomas that exhibit similar survival probability to GBM patients.