Combinatorial Gene Expression Profiling of Serum HULC, HOTAIR, and UCA1 lncRNAs to Differentiate Hepatocellular Carcinoma from Liver Diseases: A Systematic Review and Meta-Analysis.

Hepatocellular carcinoma (HCC) presents a significant global health challenge due to limited early detection methods, primarily relying on conventional approaches like imaging and alpha-fetoprotein (AFP). Although non-coding RNAs (ncRNAs) show promise as potential biomarkers in HCC, their true utility remains uncertain. We conducted a comprehensive review of 76 articles, analyzing 88 circulating lncRNAs in 6426 HCC patients. However, the lack of a standardized workflow protocol has hampered holistic comparisons across the literature. Consequently, we herein confined our meta-analysis to only a subset of these lncRNAs. The combined analysis of serum highly upregulated in liver cancer (HULC) gene expression with homeobox transcript antisense intergenic RNA (HOTAIR) and urothelial carcinoma-associated 1 (UCA1) demonstrated markedly enhanced sensitivity and specificity in diagnostic capability compared to traditional biomarkers or other ncRNAs. These findings could have substantial implications for the early diagnosis and tailored treatment of HCC.

Deciphering the Biology of Circulating Tumor Cells through Single-Cell RNA Sequencing: Implications for Precision Medicine in Cancer.

Circulating tumor cells (CTCs) hold unique biological characteristics that directly involve them in hematogenous dissemination. Studying CTCs systematically is technically challenging due to their extreme rarity and heterogeneity and the lack of specific markers to specify metastasis-initiating CTCs. With cutting-edge technology, single-cell RNA sequencing (scRNA-seq) provides insights into the biology of metastatic processes driven by CTCs. Transcriptomics analysis of single CTCs can decipher tumor heterogeneity and phenotypic plasticity for exploring promising novel therapeutic targets. The integrated approach provides a perspective on the mechanisms underlying tumor development and interrogates CTCs interactions with other blood cell types, particularly those of the immune system. This review aims to comprehensively describe the current study on CTC transcriptomic analysis through scRNA-seq technology. We emphasize the workflow for scRNA-seq analysis of CTCs, including enrichment, single cell isolation, and bioinformatic tools applied for this purpose. Furthermore, we elucidated the translational knowledge from the transcriptomic profile of individual CTCs and the biology of cancer metastasis for developing effective therapeutics through targeting key pathways in CTCs.

The Role of Proteomics and Phosphoproteomics in the Discovery of Therapeutic Targets and Biomarkers in Acquired EGFR-TKI-Resistant Non-Small Cell Lung Cancer.

The discovery of potent EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has revolutionized the treatment of EGFR-mutated lung cancer. Despite the fact that EGFR-TKIs have yielded several significant benefits for lung cancer patients, the emergence of resistance to EGFR-TKIs has been a substantial impediment to improving treatment outcomes. Understanding the molecular mechanisms underlying resistance is crucial for the development of new treatments and biomarkers for disease progression. Together with the advancement in proteome and phosphoproteome analysis, a diverse set of key signaling pathways have been successfully identified that provide insight for the discovery of possible therapeutically targeted proteins. In this review, we highlight the proteome and phosphoproteomic analyses of non-small cell lung cancer (NSCLC) as well as the proteome analysis of biofluid specimens that associate with acquired resistance in response to different generations of EGFR-TKI. Furthermore, we present an overview of the targeted proteins and potential drugs that have been tested in clinical studies and discuss the challenges of implementing this discovery in future NSCLC treatment.

Characterization of Cell-Free DNA Size Distribution in Osteosarcoma Patients.

PURPOSE: Cell-free DNA (cfDNA) analysis is a powerful tool for noninvasively predicting patient outcomes. We analyzed the size distribution of cfDNA and assessed its prognostic and diagnostic values in an osteosarcoma cohort. EXPERIMENTAL DESIGN: The fragment size distribution and level of cfDNA were analyzed in 15 healthy donors and 50 patients with osteosarcoma using automated capillary electrophoresis. The prognostic performance of cfDNA size analysis was assessed using univariate and multivariable analyses. By performing whole-genome sequencing of matched cfDNA and osteosarcoma tissue samples, we investigated the correlation between the size and mutation profiles of cfDNA and the mutation concordance between cfDNA and paired tissue tumors. RESULTS: The size of cfDNA fragments in patients with osteosarcoma was significantly shorter than in healthy donors, with the integrative analysis of size distribution and level of cfDNA achieving a high specificity and sensitivity of 100%. The short cfDNA fragment (150-bp cut-off) was an independent prognostic predictor in this osteosarcoma cohort [HR, 9.03; 95% confidence interval (CI), 1.13-72.20; P = 0.038]. Shortened cfDNA fragments were found to be a major source of mutations. Enrichment of cfDNA fragments with less than or equal to 150 bp by in silico size selection remarkedly improved the detection of copy-number variation signals up to 2.3-fold when compared with total cfDNA, with a higher concordance rate with matched osteosarcoma tissue. CONCLUSIONS: This finding demonstrated the potential of cfDNA size profiling in the stratification of poor prognostic patients with osteosarcoma. The short fragments of cfDNA are a promising source for boosting the detection of significant mutations in osteosarcoma. See related commentary by Weiser et al., p. 2017.

Clinical Implication of Circulating Tumor Cells Expressing Epithelial Mesenchymal Transition (EMT) and Cancer Stem Cell (CSC) Markers and Their Perspective in HCC: A Systematic Review.

Circulating tumor cells (CTCs) play a key role in hematogenous metastasis and post-surgery recurrence. In hepatocellular carcinoma (HCC), CTCs have emerged as a valuable source of therapeutically relevant information. Certain subsets or phenotypes of CTCs can survive in the bloodstream and induce metastasis. Here, we performed a systematic review on the importance of epithelial-mesenchymal transition (EMT)-CTCs and circulating cancer stem cells (CCSCs) in metastatic processes and their prognostic power in HCC management. PubMed, Scopus, and Embase databases were searched for relevant publications. PRISMA criteria were used to review all studies. Twenty publications were eligible, of which 14, 5, and 1 study reported EMT-CTCs, CCSCs, and both phenotypes, respectively. Most studies evaluated that mesenchymal CTCs and CCSCs positivity were statistically associated with extensive clinicopathological features, including larger size and multiple numbers of tumors, advanced stages, micro/macrovascular invasion, and metastatic/recurrent disease. A preliminary meta-analysis showed that the presence of mesenchymal CTCs in pre- and postoperative blood significantly increased the risk of early recurrence. Mesenchymal-CTCs positivity was the most reported association with inferior outcomes based on the prognosis of HCC recurrence. Our finding could be a step forward, conveying additional prognostic values of CTC subtypes as promising biomarkers in HCC management.

An analysis of the incidence and survival rates of bone sarcoma patients in thailand: reports from population-based cancer registries 2001-2015.

BACKGROUND: Epidemiology data from population-based cancer registries (PBCR) can be very valuable in the development of health policy and for improving the quality of cancer control strategies. METHODS: This study analyzed the incidence of bone sarcomas in Thailand during 2001 - 2015 by analyzing data obtained from 5 PBCRs across country. Incidence rates per million person-years by sex, histological subtype, primary site and 5-year age group were calculated. Age-standardized incidence rates (ASR) were adjusted using the WHO's World Standard Population and comparisons between populations were done using standardized rate ratios (SRR). Incidence trends were evaluated using Joinpoint Trend Analysis. Survival rates were analyzed using STATA. RESULTS: The ASR of bone sarcomas in Thailand was 5.1/106 person-years, with an estimated 328 newly diagnosed bone sarcomas per year for the country overall. Osteosarcoma (52.5%), chondrosarcoma (18%), Ewing's sarcoma (11.6%), giant cell tumor (4.8%) and chordoma (4.7%) were the most common malignant bone tumors, representing 91.5% of all bone sarcomas. Bone sarcoma has a predilection for males (1.29:1) and an age-specific bimodal rate pattern closely related to the major histological subtypes, osteosarcoma. One- and five-year survival rates of Thai patients with bone sarcoma were 74% and 52%, respectively. Survival rates of bone sarcomas, particularly osteosarcoma, were lower than the rates reported from the United States, Europe and Japan. CONCLUSION: The lower overall survival rate of bone sarcoma represented the gap of bone sarcoma control program in Thailand. That indicates the need for improvement in health promotion, treatment process and chemotherapy for bone sarcoma patients in the future.

Size distribution of cell-free DNA in oncology.

Tumor-specific, circulating cell-free DNA (cfDNA) in liquid biopsy test is a novel promising biomarker in the advancement of cancer management, including early diagnosis, screening, prognosis, identification of actionable targets, and serial tumor monitoring. The specific size pattern of DNA fragments derived from cancer cells is observed to differ from that of cfDNA fragments shed by non-cancer cells. Research into the physiological and biological properties of cfDNA reveals the molecular signature carried by each cfDNA fragments, which can reflect their tissue origins, as well as the mutational profiles with significant genetic alterations. Understanding the fragmentation and size distribution of cfDNA might be a valuable hotspot in liquid biopsy research, with the potential to drive innovation in oncology.

Bacteriophage-mediated therapy of chondrosarcoma by selective delivery of the tumor necrosis factor alpha (TNFα) gene.

Chondrosarcoma is a cartilage-forming bone tumor, well known for intrinsic resistance to chemotherapy and radiotherapy. We have designed a targeted chondrosarcoma gene therapy using a bacteriophage (phage) particle to deliver therapeutic genes. Phage has no tropism for mammalian cells, allowing engineered phage to be targeted to specific cell surface receptors in cancer. We modified the phage capsid to display the RGD4C ligand on the pIII minor coat proteins to specifically bind to αvß3 or αvß5 integrin receptors. The endosomal escape peptide, H5WYG, was also displayed on recombinant pVIII major coat proteins to enhance gene delivery. Finally, a human tumor necrosis factor alpha (TNFα) therapeutic transgene expression cassette was incorporated into the phage genome. First, we found that human chondrosarcoma cells (SW1353) have high expression of αvß3, αvß5 integrin receptors, and both TNFα receptors. Targeted particle encoding a luciferase reporter gene efficiently and selectively mediated gene delivery to these cells. When SW1353 cells were treated with the targeted particle encoding a TNFα transgene, significant cell killing was evident and was associated with high expression of TNFα and apoptosis-related genes. In vivo, mice with established human chondrosarcoma showed suppression of tumors upon repetitive intravenous administrations of the targeted phage. These data show that our phage-based particle is a promising, selective, and efficient tool for targeted chondrosarcoma therapy.

Sesamin suppresses advanced glycation end products induced microglial reactivity using BV2 microglial cell line as a model.

Neuroinflammation-mediated microglial reactivity is a major process, which explains the increased risk of Alzheimer's disease (AD) development in patients with Type 2 diabetes mellitus (T2DM). Advanced glycation end products (AGEs), formed by hyperglycemic condition in diabetes, is characterized as an intermediary of brain injury with diabetes through induction of microglial reactivity. Here, we explored the effect of AGEs on microglial reactivity using BV2 as a model. The NF-κB, p38 and JNK pathways were found to be important mechanism in AGEs-induced BV2 microglial reactivity. NF-κB inhibitor (BAY-11-7082), p38 inhibitor (SB203580) and JNK inhibitor (SP600125) exhibited the potential inhibition of AGEs-induced NO production. We also found that the sesamin, a major lignan found in sesame seed oils, exerts an anti-inflammatory effect under AGEs-induced microglial reactivity via suppressing the phosphorylation of NF-κB, p38 and JNK pathways. Moreover, sesamin also ameliorated AGEs-induced-receptor for advanced glycation end products (RAGE) expression. Taken together, sesamin may be a promising phytochemical compound to delay inflammatory progress by AGEs microglia function. Similarly, inhibition of AGEs-induced microglial reactivity might be potential therapeutic targets of neuroinflammation-based mechanisms in T2DM link progressive AD.

Sesamin Promotes Neurite Outgrowth under Insufficient Nerve Growth Factor Condition in PC12 Cells through ERK1/2 Pathway and SIRT1 Modulation.

The promotion of neurogenesis can be a promising strategy to improve and restore neuronal function in neurodegenerative diseases. Nerve growth factor (NGF) plays a key role in neurite outgrowth and synaptic formation during brain repair stage. Nowadays, there are several studies on the developing methods to enhance the endogenous NGF activity for treatment and restore the neuronal function. In this study, the potentiating effect of sesamin, a major lignan in sesame seeds (Sesamum indicum) and oil, on NGF-induced neurogenesis and its involved mechanisms were firstly reported. Sesamin effectively enhanced the PC12 neuron-like cell differentiation and neurite length under insufficient conditions of NGF. The neuronal markers including synaptophysin and growth-associated protein-43 along with the synaptic connections were significantly increased in combination treatment between sesamin and NGF. Moreover, sesamin also increased the level of phospho-ERK1/2 and SIRT1 protein, an important regulatory protein of the neurogenesis process. The neurogenesis was blocked by the specific SIRT1 inhibitor, JGB1741, suggesting that the neuritogenic effect of sesamin was associated with SIRT1 protein modulation. Taken together, the potentiating effect of sesamin on NGF-induced neurogenesis in this finding could be used for alternative treatment in neurodegenerative diseases, including Alzheimer's disease.

Protocatechuic acid inhibits inflammatory responses in LPS-activated BV2 microglia via regulating SIRT1/NF-κB pathway contributed to the suppression of microglial activation-induced PC12 cell apoptosis.

SIRT1 exhibits inhibitory effects on microglial activation-induced neurodegeneration. Regulating SIRT1 may become a novel approach for curing neurodegenerative diseases. Protocatechuic acid (PA), a phenolic acid, has anti-neuroinflammatory effects. The effect of PA on SIRT1 in activated microglia remains unknown. Here, we examined whether PA has anti-inflammatory effects against microglial activation-induced neuronal cell death via regulating SIRT1 in microglia. We found that PA inhibited the release of inflammatory mediators in LPS-activated BV2 microglia via the SIRT1/NF-κB pathway and thereby attenuated microglial activation-induced PC12 cell apoptosis. This suggests that SIRT1 mediates the anti-neuroinflammatory effects of PA to ameliorate microglial activation-induced neuron death.

Cyanidin-3-O-Glucoside Protects PC12 Cells Against Neuronal Apoptosis Mediated by LPS-Stimulated BV2 Microglial Activation.

Neuroinflammation is a major factor in the pathogenesis of various neurodegenerative diseases. Microglia are resident macrophages that act as key mediators of inflammation in the brain. In response to inflammatory stimuli including lipopolysaccharide (LPS), microglial activation occurs immediately. Overproduction of inflammatory mediators released by activated microglia contributes to neuron damage in neurodegenerative disease. Therefore, identification of a compound that has anti-inflammatory activities and inhibits microglial activation may be an alternative therapeutic approach for the treatment of neurodegenerative diseases. Cyanidin-3-O-glucoside (C3G), a type of anthocyanin, possesses powerful anti-inflammatory activities. In this study, the anti-inflammatory effects of C3G were investigated in LPS-stimulated BV2 microglia. The results indicate that pretreatment with C3G significantly suppresses microglial activation and the production of neurotoxic mediators including nitric oxide (NO), prostaglandin E2 (PGE2), and pro-inflammatory cytokines such as interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in LPS-activated BV2 cells. Moreover, C3G downregulates the gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokines via the suppression of NF-κB and p38 MAPK signaling pathways. Furthermore, a co-culture system to determine the indirect neuroprotective effects of C3G was used. Results demonstrated that conditioned medium (CM) from LPS-stimulated BV2 cells can promote the apoptosis of differentiated pheochromocytoma (PC12) cells through the activation of caspase-3, while C3G pretreatment in BV2 microglia can protect differentiated PC12 cells from microglial activation-induced apoptosis. Therefore, C3G may be a potential therapeutic agent for the treatment and prevention of neurodegenerative diseases associated with microglial activation.