Pathogenesis Of Tumors Research Articles

Dynamic Changes of the Gut Microbiota and Its Functional Metagenomic Potential during the Development of Non-Small Cell Lung Cancer.

The gut microbiota plays a significant role in tumor pathogenesis by regulating the host metabolism and immune response, and there are few studies focused on tracking changes in the gut microbiota from the onset of lung cancer. Therefore, the aim of our study is combining preclinical and clinical research to thoroughly analyze the signatures of fecal microbiota in lung cancer, which will be useful for early diagnosis and predicting the therapeutic efficacy of lung cancer. The first part of this study analyzed the fecal metagenomic differences between patients with non-small cell lung cancer and healthy subjects, and the second part of this work constructed a murine lung cancer model to monitor changes in mouse fecal metagenomics and T cell immunology during lung cancer progression. We found that the fecal microbiota was altered in both humans and mice with lung cancer, characterized by a significantly reduced microbial diversity and number of beneficial microbes, with increases in potential pathogens. The fecal level of Akkermansia muciniphila and the gut metabolic module of the secondary bile acid metabolism were diminished in both humans and mice with lung cancer compared with healthy subjects. Splenomegaly was observed in the lung cancer mice. Flow cytometer analysis of the splenocytes revealed substantial alterations in the proportions of T cell subsets in the lung cancer mice, characterized by significant increases in CD4+Foxp3+CD25+ T regulatory cells (p < 0.05) while significant decreases in CD3+ T cells (p < 0.001), CD4+ T cells (p < 0.001), and the CD4+/CD8+ ratio (p < 0.01). Vertical and longitudinal analyses of the fecal microbiota of the two mouse groups identified some lung cancer biomarkers (including Acutalibacter timonensis, Lachnospiraceae bacterium NSJ-38 sp014337195, etc.). The fecal microbiota of the lung cancer mice had a reduced metagenomic potential for neurotransmitters (melatonin, γ-aminobutyric acid, and histamine) compared with healthy mice. In summary, this study found that the diversity, structure, and composition of gut microbiota vary between cancer and healthy conditions, ultimately leading to changes in the potential for functional metagenomics.

FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.

EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).

Prior knowledge-guided multilevel graph neural network for tumor risk prediction and interpretation via multi-omics data integration.

The interrelation and complementary nature of multi-omics data can provide valuable insights into the intricate molecular mechanisms underlying diseases. However, challenges such as limited sample size, high data dimensionality and differences in omics modalities pose significant obstacles to fully harnessing the potential of these data. The prior knowledge such as gene regulatory network and pathway information harbors useful gene-gene interaction and gene functional module information. To effectively integrate multi-omics data and make full use of the prior knowledge, here, we propose a Multilevel-graph neural network (GNN): a hierarchically designed deep learning algorithm that sequentially leverages multi-omics data, gene regulatory networks and pathway information to extract features and enhance accuracy in predicting survival risk. Our method achieved better accuracy compared with existing methods. Furthermore, key factors nonlinearly associated with the tumor pathogenesis are prioritized by employing two interpretation algorithms (i.e. GNN-Explainer and IGscore) for neural networks, at gene and pathway level, respectively. The top genes and pathways exhibit strong associations with disease in survival analyses, many of which such as SEC61G and CYP27B1 are previously reported in the literature.

MiR-889-3p targeting BMPR2 promotes the development of retinoblastoma via JNK/MAPK/ERK signaling

MicroRNAs (miRNAs) are vital regulators of tumor pathogenesis, including that of retinoblastoma (Rb). This study investigated the functions and mechanisms of action of miR-889-3p in Rb. BMPR2 and miR-889-3p levels were assessed by quantitative reverse transcription PCR (qRT-PCR) or western blotting. Through several cell function tests, the effects of miR-889-3p and BMPR2 on cell proliferation, migration, and JNK/MAPK/ERK signaling were evaluated. The interaction between miR-889-3p and BMPR2 was investigated using a luciferase reporter assay. In vivo tumor development was investigated using a xenograft test. The association between miR-889-3p and BMPR2 expression was identified using Pearson’s correlation analysis. miR-889-3p was increased in Rb cells, and miR-889-3p knockdown inhibited Rb cell proliferation, migration, and phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and ERK1/2 in vitro, as well as tumor growth in vivo. Further, they were inversely associated in Rb tissues and miR-889-3p may directly attached to the 3′-UTR of BMPR2 mRNA. Finally, the inhibition of BMPR2 inverted the negative effects of the miR-889-3p inhibitor on migration, proliferation, and activation of JNK, p38 MAPK, and ERK1/2 in Rb cells. Our results indicate that miR-889-3p, which targets BMPR2 and promotes Rb growth by controlling the JNK/MAPK/ERK pathway, is an oncogene in Rb. These results suggested that the miR-889-3p/BMPR2 axis may be a new therapeutic target for Rb.

A Novel Cholesterol Metabolism-Related lncRNA Signature Predicts the Prognosis of Patients with Hepatocellular Carcinoma and Their Response to Immunotherapy.

The survival rate of hepatocellular carcinoma (HCC) is low and the prognosis is poor. Metabolic reprogramming is still an emerging hallmark of cancer, and reprogramming of cholesterol metabolism plays a crucial action in tumor pathogenesis. Increasing evidence suggests that cholesterol metabolism affects the cell proliferation, invasion, migration, and resistance to chemotherapy of HCC. To date, no long noncoding RNA (lncRNA) signature associated with cholesterol metabolism has been developed to predict the outcome of patients with HCC. The RNA-seq data as well as the prognostic and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We conducted univariate and multivariate analyses to assess cholesterol metabolism-related lncRNAs correlated with the prognosis of patients with HCC in order to construct a prognostic signature. Functional differences between low- and high-risk groups were investigated using genomic enrichment analysis (GSEA). Kaplan-Meier (KM) curves were applied to explore the overall survival (OS) of the low- and high-risk groups. Single-sample genomic enrichment analysis (ssGSEA) was applied to investigate the association between this predictive signature and immune function. We subsequently examined how this signature relates to treatment response in HCC patients. A prognostic signature comprising six lncRNAs related to cholesterol metabolism was constructed (AC124798.1, AL031985.3, AC103760.1, NRAV, WAC-AS1 and AC022613.1). We found that low-risk groups showed a better prognosis than high-risk groups. In HCC patients, the cholesterol metabolism-related lncRNA signature may be served as an independent prognostic factor. Cholesterol metabolism-related lncRNA signature had higher diagnostic efficiency compared to clinicopathologic variables. After stratifying patients according to different clinicopathological variables, patients with low-risk had a longer OS compared with high-risk patients. The ssGSEA demonstrated that this signature was closely related to the immune status of HCC patients. GSEA analysis demonstrated that immune- and tumor-related pathways were predominantly enriched in the high-risk group. High-risk patients were more responsive to immune checkpoint inhibitors (ICIs) and conventional chemotherapeutic agents. This cholesterol metabolism-related lncRNA signature can predict the prognosis of HCC patients and guide the clinical management of HCC patients, including immunotherapy.

Abstract 317: Using the Biomek NGeniuS Next Generation Library Prep System to automate the Illumina TruSight Oncology 500 assay

Abstract Cancer researchers using next generation sequencing (NGS) need reliable sample preparation methodologies that generate high-quality, sequence-ready libraries from often-challenging samples. This process can be aided using automated liquid handling systems. The Biomek NGeniuS Next Generation Library Prep System from Beckman Coulter Life Sciences is a reliable, easy-to-use, purpose-built liquid handler for NGS library preparation ideal for laboratories requiring more flexibility and less hands-on time. The user-friendly software requires no programming skills, making it easy to set up and run. Biomek NGeniuS Next Generation Library Prep System’s hardware features include an on-deck thermal cycler, gripper, temperature-controlled reagent storage, and high-density tip storage which reduces user interventions and enables more walkaway time. An extensive and growing library of complimentary demonstrated NGS sample prep protocols allows the user to select from a variety of applications for NGS workflows. One such workflow is Illumina TruSight Oncology 500 assay, which represents a comprehensive NGS assay targeting the full coding regions of 523 genes implicated in the pathogenesis of solid tumors. Using enrichment-based library preparation techniques for use with formalin-fixed, paraffin-embedded (FFPE) samples, the Illumina TruSight Oncology 500 assay, when running the DNA Only workflow, can detect single nucleotide variants (SNVs), indels, amplifications, and multinucleotide variants (MNVs) in a single sequencing run. The Illumina TruSight Oncology 500 assay also detects immunotherapy biomarkers for tumor mutational burden (TMB) and microsatellite instability (MSI) in DNA samples. The Illumina TruSight Oncology 500 assay also offers a combined RNA/DNA workflow that also allows for the assessment of fusion events. In this poster, we show the utility of the Biomek NGeniuS Next Generation Library Prep System to perform the Illumina TruSight Oncology 500 assay, which saves researchers valuable hands-on time and offers a highly streamlined setup process for users new to liquid handling automation. Confidential - Company Proprietary Citation Format: Zach Smith. Using the Biomek NGeniuS Next Generation Library Prep System to automate the Illumina TruSight Oncology 500 assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 317.

Abstract 7001: Profiling the CpG methylation patterns of Epstein-Barr virus DNA in lymphoma patients from Ethiopia

Abstract Introduction: Epstein-Barr virus (EBV) is a tumor virus associated with various malignancies, driven by genetic mutations and epigenetic alterations, including DNA methylation. Abnormal CpG methylation holds promise as a diagnostic and therapeutic biomarker for EBV-associated tumors. However, the understanding of EBV's epigenetic mechanisms remain limited. Determining the methylation profile of EBV is crucial for gaining insights into the pathogenesis of EBV-associated tumors, developing diagnostic biomarkers, and exploring potential therapeutic strategies. Therefore, our study aimed to assess the CpG methylation profile of EBV DNA in lymphoma patients from Ethiopia. Methods: This study enrolled 115 lymphoma patients from Tikur Anbessa Specialized Hospital in Addis Ababa, Ethiopia. Plasma and formalin-fixed paraffin-embedded blocks were collected from the participants, and isolation of DNA was performed from these samples. The methylation analysis was performed using the methylation-iPLEX assay. iPLEX capture and extension primers were designed to amplify and target EBV CpGs from bisulfite-converted DNA sequences. Ethical approval was also obtained from respected institutions. Results: Among the 115 participants, 65.2% (n = 75) were male patients. The largest proportion (n = 35, 30.4%) fell within the 41-60 age group. Non-Hodgkin lymphoma (NHL) was diagnosed in 96 patients, while 19 had Hodgkin lymphoma (HL). In the NHL group, the majority (n = 27, 28.1%) were classified as diffuse large cell lymphoma, followed by follicular lymphoma (n = 24, 25%). Out of the different EBV genome methylation sites, we have identified 24 EBV genes to assess the methylation status of the EBV genome. Average methylation levels of these genes were ranged from 45% to 50%. Notably, the HL group exhibited significant heterogeneity in methylation levels, while the CpG methylation status of EBV genes in NHL subtypes demonstrated a consistent pattern. A significant proportion of our samples exhibited methylation loss in the lytic gene BZLF1 and at the origin of replication associated with lytic replication. Conclusions: This study presents the first data from East Africa, shedding light on the EBV DNA methylation status in a diverse group of lymphoma patients. Further investigations in different locations are necessary to elucidate the impact of EBV DNA methylation on tumor progression. Citation Format: Seifegebriel T. Feleke, Kidist Z. Shita, Abdulaziz A. Sherif, Fisihatsion T. Woldegebriel, Christoph Weigel, Elshafa H. Ahmed, Tamrat A. Zeleke, Robert A. Baiocchi. Profiling the CpG methylation patterns of Epstein-Barr virus DNA in lymphoma patients from Ethiopia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7001.

Abstract 2990: Differential micro-RNA expression in circulating exosomes of pancreatic ductal adenocarcinoma patients

Abstract Pancreatic ductal Adenocarcinoma (PDAC) is a highly lethal solid tumor with 5-year survival rate of 5-8%. Extracellular vesicles like exosomes circulating in the blood are crucial mediators of intracellular communication, immunomodulation and tumor progression. The microRNAs being the major cargo of exosomes, are the primary carriers of intracellular information. The role of exosomal-miRNA (exoMIR’s) in regulating the pathogenesis of tumors is well-established in oncology but its potential is still unexplored. To the best of our knowledge no study has yet explored the contrasting exoMIR expression in cancer patients before and after their surgery. In this study, differential exoMIR’s profile of three pancreatic ductal adenocarcinoma patients at three stages: pre-surgery, post-surgery, and follow-up was established using small RNA sequencing on the Illumina platform. In blood samples taken before and after surgery total of 181, 201 and 201 microRNAs were dysregulated in circulating exosomes of three different patients viz. P_1, P_9 &amp; P_11 (Patient identifiers) respectively. Out of the total dysregulated microRNAs in post-op samples 76 were upregulated and 105 downregulated in P_1, 95 upregulated and 106 downregulated in P_9 &amp; 69 upregulated and 132 downregulated in P_11 as compared to their Pre surgery samples. Further, when exoMIR’s of post-op samples were compared to that of follow-up samples after 6 months of surgery their expression profile changed notably such that a total of 184, 157 &amp; 190 microRNAs dysregulated in follow-up of P_1, P_9 and P_11 respectively. Out of the total dysregulated microRNAs in follow up samples 93 were upregulated and 91 downregulated in P_1, 69 upregulated and 88 downregulated in P_9 &amp; 96 upregulated and 94 downregulated in P_11 as compared to their post-op samples. On Venn diagram analysis 27 microRNAs were found to be commonly dysregulated in all 3 patients before surgery and 22 common micro RNAs were again dysregulated even after 6 months of surgery. Bioinformatic analysis of these differentially expressed miRNAs and their respective protein targets revealed that their role in oncogenic molecular pathways is very prominent, thus highlighting their potential use in cancer therapeutics, diagnostics as well as prognosis. Citation Format: Rupinder Kaur, Sandeep Bhoriwal, Promod Kumar Gautam. Differential micro-RNA expression in circulating exosomes of pancreatic ductal adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2990.

Abstract 2448: Field cancerization proteomic analysis provides a novel class of functional risk biomarkers for non small cell lung cancer

Abstract Lung cancer carcinogenesis is the outcome of a field of premalignant changes that occur in the bronchial tree leading to the overt emergence of the malignant lung cancer (field cancerization). A tissue or blood proteomic signature of these premalignant changes represent a novel concept of risk biomarkers that can predict the probability of future emergence of Lung Cancer. In this study, we analyzed two independent cohorts of non-small cell lung cancer (NSCLC) patients. One cohort consisted of 18 patients who donated blood before and after tumor resection surgery and matched tissue samples (UAMS Medical Center). The second set derived from a longitudinal case-control study of plasma sample collected during the physician health study that were donated at different times prior to the diagnosis of Non-Small Cell Lung Cancer (N=272). We used affinity-enriched mass spectrometry analysis and statistical learning techniques to identify a set of common markers that discriminated plasma cases and controls and were conserved in different bronchial tissue compartments including tumor and adjacent tissue. The tumor microenvironment adjacent to and surrounding cancer cells undergoes to progressive stages of carcinogenesis during field cancerization. We identified 22 proteins involved in cell adhesion, protein folding, immune response, angiogenesis, and cancer proliferation. This is a novel class of functional risk biomarkers to determine the probability of NSCLC onset. In conclusion, our findings shed light on a new class of functional biomarkers that underly tumor pathogenesis mechanisms and can provide hints for new strategies of tumor prevention therapy or lifestyle modification. Citation Format: Rayan Ibrahim Alhammad, Ngoc Bao Vuong, Weidong Zhou, Donald J Johann Jr, Barbara Birkaya, Lance Liotta, Alessandra Luchini. Field cancerization proteomic analysis provides a novel class of functional risk biomarkers for non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2448.

Abstract 2303: Identifying and stratifying circulating tumor cell cluster subtypes in metastatic breast cancer patients and evaluating their clinical outcomes

Abstract Background: Circulating tumor cell clusters (CTCCs) are aggregated groups of tumor cells that detached from primary tumors and circulate the bloodstream. However, while Circulating Tumor Cells (CTCs) are a well studied phenomenon, CTCCs remain relatively unexplored and ill-defined, with only a few descriptive investigations evaluating their clinical utility. Adding to CTCC complexity is that various subtypes exist, including homotypic clusters consisting of a homogenous population of tumor cells and heterotypic CTCCs made of CTCs with immune/stromal white blood cells (WBCs). Furthermore, CTCs can undergo Epithelial-Mesenchymal Transition (EMT), a process characterized by loss of epithelial traits and upregulation of mesenchymal traits, and can form clustered EMTs (CEMTs). Moreover, CTCs can fuse with macrophages forming Tumor Macrophage Hybrid Cells, aka Cancer-Associated Macrophage Like cells (CAMLs) when in circulation. We enumerated all these types of cells and complex aggregates in the peripheral blood of patients with metastatic breast cancer (mBC). Methods: We enumerated the 6 populations from patient samples enrolled in IRB aproved prospective pilot studies. Whole peripheral blood (7.5mL) was filtered and stained with cytokeratin (CK) &amp; CD45/CD14 to identify CTCs. CTCs were defined as an intact DAPI nuclei and strong filamentous CK. Homotypic CTCCs were defined as ≥2 CTCs attached together. Heterotypic CTCCs were defined as ≥1 CTC attached to ≥1 WBC. EMTs were defined as having DAPI nuclei and weak non-filamentous CK. CEMTS were defined as ≥2 EMTs. CAMLs were defined as having an enlarged polynucleated DAPI, and positive for CD45/CD14 or non-filamentous CK. Median progression free survival (mPFS) and median overall survival (mOS) over 24 months (m) were evaluated. Results: We evaluated the blood of 79 mBC patients. Single CTCs were found in 57% of patients (n=34/79), homotypic CTCCs 15% (n=12/79), heterotypic CTCCs 66% (n=27/79), EMTs 56% (n=44/79), CEMTs 23% (n=18/79) and CAMLs 97% (n=77/79). Over 24 ms, patierns with detectable heterotypic CTCCs &amp; homotypic CTCCs had the shortest response times at mPFS=2.8 &amp; mOS=5.8 ms, or mPFS=2.1 &amp; mOS=4.3 ms, respectively. This was followed by CTCs mPFS=3.7 &amp; mOS=13.7 ms, EMTs mPFS=4.3 &amp; mOS=14.4 ms, CAMLs mPFS=4.3 &amp; mOS=14.4 ms, and CEMT mPFS=4.7 &amp; mOS=13.2 ms. Additionally, CTCCs were rare in HER2+ patients at 4.4% (n=1/23), but no associations to other hormone statuses were found. Conclusion: CTCCs appear to represent an array of subtypes with different biological and clinical meanings. Here we enumerated CTCC subtypes in the blood of mBC patients and stratified the various types to clinical outcomes. These data suggest CTCCs are clinically important and further understanding of their biology in the context of tumor pathogenesis is needed. Citation Format: Daniel L. Adams, Carolina Reduzzi, Aravind Aryasomayajula, R. Katherine Alpaugh, Saranya Chumsri, Cha-Mei Tang, Giuseppe Del Priore, William V. Williams, Massimo Cristofanilli. Identifying and stratifying circulating tumor cell cluster subtypes in metastatic breast cancer patients and evaluating their clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2303.

Intratesticular Mullerian Serous Borderline Tumor With Microinvasion: A Rare Tumor and Review of the Literature.

Ovarian-type (ie, Mullerian) epithelial tumors occurring in the testicular and paratesticular regions are exceptionally rare, with only a handful reported worldwide. Serous tumors are the most frequently encountered subtype among these rare tumors. The pathogenesis of these tumors within the testicular and paratesticular regions remains a subject of intrigue and debate, with various hypotheses attempting to explain their presence in the paratestis region, where most tumors occur. However, our understanding of the pathogenesis of intratesticular tumors is limited. To date, 11 known examples of intratesticular serous Mullerian tumors have been reported globally. In this report, we present an extraordinary tumor, an intratesticular Mullerian serous borderline tumor with foci of microinvasion, in a 38-year-old male patient. This tumor exhibits histological features similar to their ovarian counterparts and is confirmed through an immunohistochemical panel. Our report underscores the extreme rarity of these tumors, emphasizes the importance of heightened awareness among clinicians and pathologists, and provides valuable insights into their complex development and histogenesis. This contribution aims to enhance diagnostic precision and optimize therapeutic strategies for similar tumors.

Comprehensive analysis of the clinical and biological significances for chemokine CXCL3 in cholangiocarcinoma.

Cholangiocarcinoma (CHOL) is a race malignant cancer arising from bile duct epithelial cells in clinical practice. C-X-C motif chemokine ligand 3 (CXCL3) is a member of chemokines family, which participates in the pathogenesis of various tumors. However, the association between CXCL3 and CHOL is unclear. This present study was to assess the role of CXCL3 expression in the progress of CHOL. TIMER, GEPIA, UALCAN, GSCA, LinkedOmics, Metascape and STRING databases were performed to evaluate the clinical and biological significances for CXCL3 with CHOL patients including expression, clinicopathological factors, immune cell infiltration, GO enrichment and KEGG pathway analyses, as well as PPI network analysis. The immunohistochemistry analysis of tissue microarray was conducted to detect the protein expression level, subcellular localization, clinicopathological factors and prognosis of CXCL3 in CHOL. The mRNA and protein expression levels of CXCL3 were markedly increased in CHOL tissues. The overexpression of CXCL3 was strongly associated with maximum tumor diameter of patients with CHOL. Additionally, there were negative correlations between the expression of CXCL3 and monocyte as well as Th17. Low infiltration of neutrophil indicated significantly shorter cumulative survival in CHOL patients. And CXCL3 was significantly associated with arm-level deletion of CD8+ T cell. Furthermore, functional network analysis suggested that CXCL3 and its associated genes were mainly enriched for chemotaxis, secretory granule membrane, cytokine activity and IL-17 signaling pathway. CXCL3 might potentially participate in the carcinogenesis of CHOL, which provided a direction for future research on the mechanism of CXCL3 in CHOL.

Modifiable risk factors for thyroid cancer: lifestyle and residence environment.

In recent years, there has been a rapid increase in the prevalence of benign and malignant tumours of the thyroid gland worldwide, positioning it as one of the most prevalent neoplasms within the endocrine system. While the pathogenesis of thyroid tumours is still unclear, an increasing number of studies have found that certain lifestyle and residence environments are associated with their occurrence and development. This article endeavours to elucidate the correlation between lifestyle, residential environment, and the increased prevalence of thyroid cancer in recent years. It specifies the frequency of the lifestyle and outlines the scope of the residential environment. It also endeavours to summarise the main mechanistic pathways of various modifiable risk factors that cause thyroid cancer. Factors that prevent thyroid cancer include smoking and alcohol consumption, quality and regular sleep, consumption of cruciferous vegetables and dairy products, and consistent long-term exercise. Conversely, individuals with specific genetic mutations have an elevated risk of thyroid cancer from prolonged and frequent use of mobile phones. In addition, individuals who work in high-pressure jobs, work night shifts, and live near volcanoes or in environments associated with pesticides have an elevated risk of developing thyroid cancer. The impact of living near a nuclear power plant on thyroid cancer remains inconclusive. Raising awareness of modifiable risk factors for thyroid cancer will help to accurately prevent and control thyroid cancer. It will provide a scientific basis for future research on lifestyles and living environments suitable for people at high risk of thyroid cancer.

TMEM16A inhibits autophagy and promotes the invasion of hypopharyngeal squamous cell carcinoma through mTOR pathway.

Previous studies have indicated that transmembrane protein 16A (TMEM16A) plays a crucial role in the pathogenesis and progression of various tumors by influencing multiple signaling pathways. However, the role of TMEM16A in regulating autophagy via the mammalian target of rapamycin (mTOR) pathway and its impact on the development of hypopharyngeal squamous cell carcinoma (HSCC) remain unclear. Immunohistochemistry and western blotting were used to assess the expression of TMEM16A in HSCC tissues and metastatic lymph nodes. Manipulation of TMEM16A expression levels was achieved in the FaDu cell line through overexpression or knockdown, followed by assessment of its biological effects using cell colony formation, wound healing, transwell and invasion assays. Additionally, apoptosis and autophagy-related proteins, as well as autophagosome formation, were evaluated through western blotting, transmission electron microscopy and immunofluorescence following TMEM16A knockdown or overexpression in FaDu cells. Our study revealed significantly elevated levels of TMEM16A in both HSCC tissues and metastatic lymph nodes compared with normal tissues. In vitro experiments demonstrated that silencing TMEM16A led to a notable suppression of HSCC cell proliferation, invasion and migration. Furthermore, TMEM16A silencing effectively inhibited tumor growth in xenografted mice. Subsequent investigations indicated that knockdown of TMEM16A in HSCC cells could suppress mTOR activation, thereby triggering autophagic cell death by upregulating sequestosome-1 (SQSTM1/P62) and microtubule-associated protein light chain 3 II (LC3II). This study highlights the crucial role of TMEM16A in modulating autophagy in HSCC, suggesting its potential as a therapeutic target for the treatment of this malignancy.

Assessment of glypican-3 immune expression in ameloblastoma, ameloblastic fibroma, ameloblastic carcinoma (pilot study)

BackgroundOdontogenic tumors a variety of benign and malignant lesions developed exclusively in the jaws. They are known to have variable clinical behaviors and different histological features. The development of odontogenic tumors is attributed to alterations in some genetic and biological molecules. The aim of this study is to assess Glypican-3 immune expression in different groups of odontogenic neoplasms as in Ameloblastoma, Ameloblastic Fibroma, and Ameloblastic Carcinoma, and compare it to dental follicle tissue as control group. Also correlate the marker expression with the known biological behavior of these tumors. This study included 40 cases were selected from oral and maxillofacial pathology department (ten cases in each group). Some sections are prepared to be stained with H&E stain and other sections with Glypican-3 immune stain. Histological examination and Histomorphometric analysis were done finally under light microscope. The area percents of Glypican-3 immune expression in all tumor sections were measured.ResultsLevel of expression of Glypican-3 revealed significant difference between the study groups (P-value < or = 0.05). The level of immune expression was highest in ameloblastic carcinoma group (M = 58.7) followed by ameloblastoma group (M = 33.9), then ameloblastic fibroma (M = 5.6) and lowest in the control group of dental follicle (M = 1.3).ConclusionsGlypican-3 immune expression demonstrated statistically significant difference among the study groups, indicating that it may have contributing role in tumor pathogenesis and its biological behavior.

Repression of the SUMO-conjugating enzyme UBC9 is associated with lowered double minutes and reduced tumor progression

ABSTRACT Double minutes (DMs), extrachromosomal gene fragments found within certain tumors, have been noted to carry onco- and drug resistance genes contributing to tumor pathogenesis and progression. After screening for SUMO-related molecule expression within various tumor sample and cell line databases, we found that SUMO-conjugating enzyme UBC9 has been associated with genome instability and tumor cell DM counts, which was confirmed both in vitro and in vivo. Karyotyping determined DM counts post-UBC9 knockdown or SUMOylation inhibitor 2-D08, while RT-qPCR and Western blot were used to measure DM-carried gene expression in vitro. In vivo, fluorescence in situ hybridization (FISH) identified micronucleus (MN) expulsion. Western blot and immunofluorescence staining were then used to determine DNA damage extent, and a reporter plasmid system was constructed to detect changes in homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. Our research has shown that UBC9 inhibition is able to attenuate DM formation and lower DM-carried gene expression, in turn reducing tumor growth and malignant phenotype, via MN efflux of DMs and lowering NHEJ activity to increase DNA damage. These findings thus reveal a relationship between heightened UBC9 activity, increased DM counts, and tumor progression, providing a potential approach for targeted therapies, via UBC9 inhibition.

Do Alarmins Have a Role in Multiple Myeloma?

Calprotectin (CLP), S100A6, and high mobility group nucleosome-binding protein 1 (HMGN1), known as alarmins, are involved in the pathogenesis of many tumors. In this study, we aimed to investigate the relationships of serum CLP, S100A6, and HMGN1 levels with the clinical and laboratory findings of patients with multiple myeloma (MM) and their roles in the pathogenesis of MM. We measured the serum CLP, S100A6, and HMGN1 levels of 55 newly diagnosed patients and 32 healthy controls using the sandwich enzyme-linked immunosorbent assay method. The medical records of the patients were also reviewed. Serum CLP, S100A6, and HMGN1 levels were significantly decreased in MM patients compared to the control group (p=0.012, p=0.001, and p=0.030, respectively). Receiver operating characteristic analysis was used to determine diagnostic cut-off values for serum CLP, S100A6, and HMGN1 of <98 ng/mL (area under the curve [AUC]: 0.663, 95% confidence interval [CI]: 0.554-0.761, p=0.009), <1174.5 pg/mL (AUC: 0.706, 95% CI: 0.598-0.799, p=0.001), and <440.18 pg/mL (AUC: 0.640, 95% CI: 0.530-0.740, p=0.03), respectively. CLP levels were found to be statistically significantly higher in patients with light chain MM (91.58±22.57 ng/mL) compared to heavy chain MM (79.42±15.83 ng/mL) (p=0.03). A negative correlation was observed between CLP and M protein, immunoglobulin G, globulin, and beta-2 microglobulin (correlation coefficients: -0.361, -0.370, -0.279, -0.300, respectively; p=0.024, p=0.06, p=0.04, p=0.0033). In this study, we found that serum CLP, S100A6, and HMGN1 levels were statistically lower in patients with newly diagnosed MM compared to the control group. These results suggest that CLP may bind to the paraprotein produced by heavy chain MM in the blood, causing its blood levels to be low. Additionally, low levels of HMGN1, which is involved in DNA repair, suggest that HMGN1 may contribute to the complex genetic abnormalities found in cases of MM.

Reversing Sunitinib Resistance Facilitated by ITGA1 Through the PI3K/Akt/Bcl-2 Pathway Using Nano Co-Delivery System in Renal Cell Carcinoma

For genitourinary cancers, renal cell carcinoma (RCC) is the third leading cause of death, while target drug resistance has always been a difficult problem. Integrin alpha 1 (ITGA1) is a member of the integrin family, which is significant for the pathogenesis, development, and drug resistance of various malignant tumors. However, it remains unclear for the ITGA1 functions in renal cell carcinoma sunitinib resistance. In this study, we found that the ITGA1 gene facilitates renal cell carcinoma sunitinib resistance through the PI3K/Akt/Bcl-2 signaling pathway. Based on this, we developed a co-delivery system designated as Su/Si-PEAL NPs for the synergistic delivery of ITGA1 small interfering RNA (siRNA) and sunitinib using monomethoxy polyethylene glycol-polylactic acid/glycolic acid-poly-L-lysine triblock copolymer (mPEG-PLGA-PLL, PEAL) as the backbone material. Furthermore, the results of a series of functional experiments confirmed that this codelivery system was capable of downregulating the expression of ITGA1 and enhancing the sensitivity of 786-O-R cells to sunitinib. This co-delivery system could be an efficient approach for reversing sunitinib resistance in renal cell carcinoma.

The role of long noncoding RNA MEG3 in fibrosis diseases.

Fibrosis is a prevalent pathological condition observed in various organs and tissues. It primarily arises from the excessive and abnormal accumulation of the extracellular matrix, resulting in the structural and functional impairment of tissues and organs, which can culminate in death. Many forms of fibrosis, including liver, cardiac, pulmonary, and renal fibrosis, are considered irreversible. Maternally expressed gene 3 (MEG3) is an imprinted RNA gene. Historically, the downregulation of MEG3 has been linked to tumor pathogenesis. However, recent studies indicate an emerging association of MEG3 with fibrotic diseases. In this review, we delve into the current understanding of MEG3's role in fibrosis, aiming to shed light on the molecular mechanisms of fibrosis and the potential of MEG3 as a novel therapeutic target.

RAS/Mitogen-Activated Protein Kinase Signaling Pathway in Testicular Germ Cell Tumors.

Germ cell tumors (GCTs) are relatively rare tumors. However, they are the most diagnosed malignancies occurring in the testis among men aged between 15 and 40 years. Despite high aneuploidy and a paucity of somatic mutations, several genomic and transcriptomic assays have identified a few significantly mutated somatic genes, primarily KIT and K-RAS. The receptor Tyrosine Kinase (RTK) pathway and the downstream related Mitogen-Activated Protein Kinase (MAPK) cascades are crucial signal transduction pathways that preside over various cellular processes, including proliferation, differentiation, apoptosis, and responses to stressors. They are well described in solid malignancies, where many of the involved factors are used as prognostic molecular markers or targets for precision therapy. This narrative review focused, in the first part, on PGCs' survival/proliferation and differentiation and on the genetic and epigenetic factors involved in the pathogenesis of testicular germ cell tumors (TGCTs) and, in the second part, on the most recent investigations about the KIT-RAS pathway in TGCTs and in other cancers, highlighting the efforts that are being made to identify targetable markers for precision medicine approaches.