Neoplastic Transformation Research Articles

Abstract C064: Mapping cellular plasticity through the lens of FRA1 during Kras G12D mediated pancreatic acinar to ductal metaplasia

Abstract Introduction: Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar to ductal metaplasia (ADM). ADM can be triggered by pancreatitis causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during Kras G12D acute pancreatitis-mediated injury. Herein, we explore the role of the FRA1 in the onset of ADM and neoplastic transformation. Methods: We generated tamoxifen (TAM)-inducible Ptf1aCre ERT ;Kras G12D ; Rosa26 YFP/YFP (TAM-KCY Fosl1 WT ) mice and bred in the Fosl1 fl/fl allele to create TAM- KCY Fosl1 KO mice and subjected them to caerulin (CCK analog) induced acute pancreatitis. First, we performed a time course of hematoxylin and eosin (H&E) images from mice either with Fosl1 WT or Fosl1 KO after induction of acute pancreatitis to understand the functional role of FRA1 during acinar de-differentiation. Next, after snap-freezing pancreata at the Day 5 post-caerulein timepoint and extracting nuclei, we sorted YFP+ nuclei for snATAC sequencing and bulk-RNA sequencing. We developed a pseudotime model and gene-regulatory network (GRN) to understand the dynamic landscape as cells transitioned from normal acinar to late ADM. Finally, to determine the functional role of in tumorigenesis, we bred an inducible mutant p53 R172H gain- of-function allele into TAM-KCY Fosl1 WT/KO mice to create TAM-KPCY Fosl1 WT/KO mice. These mice were subjected to the same tamoxifen and acute pancreatitis protocol as TAM-KCY Fosl1 WT/KO mice and monitored for tumor growth and overall survival. Results: A time course of H&E images demonstrated that FRA1 depletion slowed progression to maximum ADM in the first 5 days after caerulein treatment. We additionally observed a dramatic reduction in the amount of PanIN lesions formed between TAM-KCY Fosl1 WT and TAM-KCY Fosl KO mice, which occurred on day 7 in this caerulein model. Pseudotime analysis proposed a time point when FRA1 becomes active to prime ADM cells for recovery from inflammation and simultaneously undergo PanIN transformation. Furthermore, GRN analysis validated the differentially active transcription factors identified by pseudotime analysis of snATAC-seq. To elaborate on further timepoints, we observed a delay in the progression of TAM-KCY Fosl KO PanIN lesions at later Day 21, 8-week and 12-week timepoints. In the survival analysis, TAM-KPCY Fosl1 WT mice had a median survival time of 25.86 weeks, while TAM-KPCY Fosl1 KO mice survived for almost twice as long with a median survival time of 40.57 weeks. Histologically, the percentage of Ki-67- positive cells in TAM-KPCY Fosl1 WT tumors was significantly higher than in TAM-KPCY Fosl1 KO tumors, suggesting the loss of FRA1 reduce tumor aggressiveness. Conclusions: Our findings reveal that FRA1 is a critical mediator of ADM progression to PanIN and PDAC. Fosl1 genetic depletion can alter the kinetics of ADM formation and lead to a decrease in PanIN and eventual malignant transformation. Citation Format: Alina Li, Noriyuki Nishiwaki, Kensuke Sugiura, Kensuke Suzuki, Constanza Nicole Tapia Contreras, Dorsay Sadeghian, Anirban Maitra, Jason R Pitarresi, Rohit Chandwani, Peter A Sims, Anil K Rustgi. Mapping cellular plasticity through the lens of FRA1 during Kras G12D mediated pancreatic acinar to ductal metaplasia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C064.

Protein corona alleviates adverse biological effects of nanoplastics in breast cancer cells.

Pollution from micro- and nanoplastics (MNPs) has long been a topic of concern due to its potential impact on human health. MNPs can circulate through human blood and, thus far, have been found in the lungs, spleen, stomach, liver, kidneys and even in the brain, placenta, and breast milk. While data are already available on the adverse biological effects of pristine MNPs (e.g. oxidative stress, inflammation, cytotoxicity, and even cancer induction), no report thus far clarified whether the same effects are modulated by the formation of a protein corona around MNPs. To this end, here we use pristine and human-plasma pre-coated polystyrene (PS) nanoparticles (NPs) and investigate them in cultured breast cancer cells both in terms of internalization and cell biochemical response to the exposure. It is found that pristine NPs tend to stick to the cell membrane and inhibit HER-2-driven signaling pathways, including phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways, which are associated with cancer cell survival and growth. By contrast, the formation of a protein corona around the same NPs can promote their uptake by endocytic vesicles and final sequestration within lysosomes. Of note is that such intracellular fate of PS-NPs is associated with mitigation of the biochemical alterations of the phosphorylated AKT (pAKT)/AKT and phosphorylated ERK (pERK)/ERK levels. These findings provide the distribution of NPs in human breast cancer cells, may broaden our understanding of the interactions between NPs and breast cancer cells and underscore the crucial role of the protein corona in modulating the impact of MNPs on human health.

Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.

Neoplastic transformation reprograms tumor and surrounding host cell metabolism, increasing nutrient consumption and depletion in the tumor microenvironment. Tumors uptake nutrients from neighboring normal tissues or the bloodstream to meet energy and anabolic demands. Tumor-induced chronic inflammation, a high-energy process, also consumes nutrients to sustain its dysfunctional activities. These tumor-related metabolic and physiological changes, including chronic inflammation, negatively impact systemic metabolism and physiology. Furthermore, the adverse effects of antitumor therapy and tumor obstruction impair the endocrine, neural, and gastrointestinal systems, thereby confounding the systemic status of patients. These alterations result in decreased appetite, impaired nutrient absorption, inflammation, and shift from anabolic to catabolic metabolism. Consequently, cancer patients often suffer from malnutrition, which worsens prognosis and increases susceptibility to secondary adverse events. This review explores how neoplastic transformation affects tumor and microenvironment metabolism and inflammation, leading to poor prognosis, and discusses potential strategies and clinical interventions to improve patient outcomes.

BUB1 induces AKT/mTOR pathway activity to promote EMT induction in human small cell lung cancer

Small cell lung cancer (SCLC) is a very aggressive tumor. Abnormal expression of BUB1 has been reported in several cancer types, wherein it plays a range of functional roles. This work aimed to elucidate the functional significance and molecular impacts of BUB1 in SCLC. It was found that SCLC cell lines exhibited significant BUB1 upregulation relative to control bronchial cells using data from the Gene Expression Omnibus (GEO) database and verified by immunohistochemical staining. BUB1 was also found to promote the proliferative, migratory, invasive activity of SCLC cells, as shown by CCK-8, 3D migration wound-healing, and Transwell assays, as well as flow cytometry. Additionally, it was found that BUB1 silencing enhanced E-cadherin expression while suppressing N-cadherin, Vimentin, ZEB-1, and Snail levels, as shown by Western immunoblotting. The loss of BUB1 also reduced p-AKT and p-mTOR levels without altering total AKT or mTOR protein levels. In conclusion, BUB1 functions as an oncogenic promoter in SCLC, potentially regulating the epithelial-mesenchymal transition by activation of AKT/mTOR signaling.

Flubendiamide provokes oxidative stress, inflammation, miRNAs alteration, and cell cycle deregulation in human prostate epithelial cells: The attenuation impact of synthesized nano-selenium using Trichodermaaureoviride

Flubendiamide (FBD) is a novel diamide insecticide extensively used with potential human health hazards. This research aimed to examine the effects of FBD on PrEC prostate epithelial cells, including Oxidative stress, pro-inflammatory responses, modifications in the expression of oncogenic and suppressor miRNAs and their target proteins, disruption of the cell cycle, and apoptosis. Additionally, the research investigated the potential alleviative effect of T-SeNPs, which are selenium nanoparticles biosynthesized by Trichoderma aureoviride, against the toxicity induced by FBD. Selenium nanoparticles were herein synthesized by Trichoderma aureoviride. The major capping metabolites in synthesized T-SeNPs were Isochiapin B and Quercetin 7,3′,4′-trimethyl ether. T-SeNPs showed a spherical shape and an average size between 57 and 96.6 nm. FBD exposure (12 μM) for 14 days induced oxidative stress and inflammatory responses via overexpression of NF-κB family members. It also distinctly caused upregulation of miR-221, miR-222, and E2F2, escorted by downregulation of miR-17, miR-20a, and P27kip1. FBD encouraged PrEC cells to halt at the G1/S checkpoint. Apoptotic cells were drastically increased in FBD-treated sets. Treatment of T-SeNPs simultaneously with FBD revealed its antioxidant, anti-inflammatory, and antitumor activities in counteracting FBD-induced toxicity. Our findings shed light on the potential FBD toxicity that may account for the neoplastic transformation of epithelial cells in the prostate and the mitigating activity of eco-friendly synthesized T-SeNPs.

Analysis of changes in intestinal microbiota in female Wistar rats at the stage of breast cancer induction by N-methyl-N-nitrosourea

The intestinal microbiota, having enormous metabolic potential, makes a significant contribution to the physiological and pathological processes of humans and animals and is currently considered as an important factor in the pathogenesis of cancer. The aim of this study is to determine changes in the quantitative and qualitative composition of the intestinal microbiota in Wistar rats during chemical induction of breast cancer (BC). Material and methods. The work was performed on female Wistar rats (n = 40) aged 3 months, weighing 200–210 g, using cultural methods for studying fecal microbiota in intact rats (1 group) on the 1st, 14th, 35th days and in rats with induction of breast cancer and and in rats, whereby N-methyl-N-nitrosourea was administered to induce breast cancer (2 group) on the 1st (before injection of N-methyl-N-nitrosourea), 14th, 35th days after injection of N-methyl-N-nitrosourea. Results and discussion. In all experimental animals, representatives characteristic of the intestinal normobiota of warm-blooded animals predominated, namely: Bifidobacterium spp., Lactobacillus spp., Escherichia coli with pronounced enzymatic properties, Enterococcus spp., Clostridium spp. In addition, Staphylococcus spp., yeast-like fungi of the genus Candida and mold. Escherichia coli with reduced enzymatic activity was also detected. It was established that the isolated bacteria belonged to 3 types, 4 classes, 5 orders, 6 families, 6 genera of the bacterial domain. Also, 2 genera of fungi belonging to the order Saccharomycetales were isolated. The most significant changes in the composition of the intestinal microbiota were noted in rats with chemically induced breast cancer on the 35th day tumor induction: the appearance of pathogenic microflora in the intestine was revealed.

A case report of high-grade intraepithelial neoplasia of the bronchial mucosa

BackgroundLung cancer is the most common cause of cancer death worldwide and poses an immediate health threat. Despite decades of basic and clinical research, the 5-year survival rate for lung cancer patients is less than 10%.The most important drawbacks in efficient treatment of lung cancer are delayed diagnosis and absence of effective screening. Detection and study of precancerous lesions of the bronchial mucosa might be one of the turning points in understanding of neoplastic transformation. Therefore, it would be the most effective prevention and early treatment modality. We report a case of high-grade intraepithelial neoplasia of the bronchial mucosa in which a neoplastic growth in the lumen of intrinsic segment in the upper lobe of the left lung was detected on electronic bronchoscopy, and biopsy confirmed squamous papillary hyperplasia with high-grade intraepithelial neoplasia.Case presentationA 74-year-old male was admitted to the hospital due to a mass lesion in his left lung. After admission, computed tomography scan of the chest showed an intraluminal mass in the intrinsic segment of the upper lobe of the left lung and an enlarged left hilum.ConclusionsHigh-grade intraepithelial neoplasia of the bronchial mucosa is rare in the respiratory system. We report a case that can provide useful information for early diagnosis and treatment of the disease.

Single-cell and spatial transcriptome assays reveal heterogeneity in gliomas through stress responses and pathway alterations.

Glioma is a highly heterogeneous malignancy of the central nervous system. This heterogeneity is driven by various molecular processes, including neoplastic transformation, cell cycle dysregulation, and angiogenesis. Among these biomolecular events, inflammation and stress pathways in the development and driving factors of glioma heterogeneity have been reported. However, the mechanisms of glioma heterogeneity under stress response remain unclear, especially from a spatial aspect. This study employed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to explore the impact of oxidative stress response genes in oligodendrocyte precursor cells (OPCs). Our analysis identified distinct pathways activated by oxidative stress in two different types of gliomas: high- and low- grade (HG and LG) gliomas. In HG gliomas, oxidative stress induced a metabolic shift from oxidative phosphorylation to glycolysis, promoting cell survival by preventing apoptosis. This metabolic reprogramming was accompanied by epithelial-to-mesenchymal transition (EMT) and an upregulation of stress response genes. Furthermore, SCENIC (Single-Cell rEgulatory Network Inference and Clustering) analysis revealed that oxidative stress activated the AP1 transcription factor in HG gliomas, thereby enhancing tumor cell survival and proliferation. Our findings provide a novel perspective on the mechanisms of oxidative stress responses across various grades of gliomas. This insight enhances our comprehension of the evolutionary processes and heterogeneity within gliomas, potentially guiding future research and therapeutic strategies.

Impact of NSD1 Alternative Transcripts in Actin Filament Formation and Cellular Division Pathways in Fibroblasts.

Germline variants in the NSD1 gene are responsible for Sotos syndrome, while somatic variants promote neoplastic cell transformation. Our previous studies revealed three alternative RNA isoforms of NSD1 present in fibroblast cell lines (FBs): the canonical full transcript and 2 alternative transcripts, termed AT2 (NSD1 Δ5Δ7) and AT3 (NSD1 Δ19-23 at the 5' end). The precise molecular pathways affected by each specific isoform of NSD1 are uncharacterized to date. To elucidate the role of these isoforms, their expression was suppressed by siRNA knockdown in FBs and protein expression and transcriptome data was explored. We demonstrate that one gene target of NSD1 isoform AT2 is ARP3 actin-related protein 3 homolog B (ACTR3B). We show that loss of both canonical NSD1 and AT2 isoforms impaired the ability of fibroblasts to regulate the actin cytoskeleton, and we observed that this caused selective loss of stress fibers. Our findings provide novel insights into NSD1 function by distinguishing isoform function and demonstrating an essential role of NSD1 in regulating the actin cytoskeleton and stress fiber formation in fibroblasts.

Docosahexaenoic acid enhances the treatment efficacy for castration-resistant prostate cancer by inhibiting autophagy through Atg4B inhibition

Autophagy induction in cancer is involved in cancer progression and the acquisition of resistance to anticancer agents. Therefore, autophagy is considered a potential therapeutic target in cancer therapy. In this study, we found that long-chain fatty acids (LCFAs) have inhibitory effects on Atg4B, which is essential for autophagosome formation, through screening based on the pharmacophore of 21f, a recently developed Atg4B inhibitor. Among these fatty acids, docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibited the most potent Atg4B inhibitory activity. DHA inhibited autophagy induced by androgen receptor signaling inhibitors (ARSI) in LNCaP and 22Rv1 prostate cancer cells and significantly increased apoptotic cell death. Furthermore, we investigated the effect of DHA on resistance to ARSI by establishing darolutamide-resistant prostate cancer 22Rv1 (22Rv1/Dar) cells, which had developed resistance to darolutamide, a novel ARSI. At baseline, 22Rv1/Dar cells showed a higher autophagy level than parental 22Rv1 cells. DHA significantly suppressed Dar-induced autophagy and sensitized 22Rv1/Dar cells by inducing apoptotic cell death through mitochondrial dysfunction. These results suggest that DHA supplementation may improve prostate cancer therapy with ARSI.

Metabolic Function and Therapeutic Potential of CD147 for Hematological Malignancies: An Overview.

Hematological malignancies refer to a heterogeneous group of neoplastic conditions of lymphoid and hematopoietic tissues classified in leukemias, Hodgkin and non-Hodgkin lymphomas and multiple myeloma, according to their presumed cell of origin, genetic abnormalities, and clinical features. Metabolic adaptation and immune escape, which influence various cellular functions, including the proliferation and survival of hematological malignant tumor cells, are major aspects of these malignancies that lead to therapeutic drug resistance. Targeting specific metabolic pathways is emerging as a novel therapeutic strategy in hematopoietic neoplasms, particularly in acute myeloid leukemia and multiple myeloma. In this context, CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or Basigin, is one target candidate involved in reprograming metabolism in different cancer cells, including hematological malignant tumor cells. CD147 overexpression significantly contributes to the metabolic transformation of these cancer cells, by mediating signaling pathway, growth, metastasis and metabolic reprogramming, through its interaction, direct or not, with various membrane proteins related to metabolic regulation, including monocarboxylate transporters, integrins, P-glycoprotein, and glucose transporter 1. This review explores the metabolic functions of CD147 and its impact on the tumor microenvironment, influencing the progression and neoplastic transformation of leukemias, myeloma, and lymphomas. Furthermore, we highlight new opportunities for the development of targeted therapies against CD147, potentially improving the treatment of hematologic malignancies.

A Vector Nanoplatform for the Bioimaging of Deep-Seated Tumors.

Today, in preclinical studies, optical bioimaging based on luminescence and fluorescence is indispensable in studying the development of neoplastic transformations, the proliferative activity of the tumor, its metastatic potential, as well as the therapeutic effect of antitumor agents. In order to expand the capabilities of optical imaging, sensors based on the bioluminescence resonance energy transfer (BRET) mechanism and, therefore, independent of an external light source are being developed. A targeted nanoplatform based on HER2-specific liposomes whose internal environment contains a genetically encoded BRET sensor was developed in this study to visualize deep-seated tumors characterized by overexpression of human epidermal growth factor receptor type 2 (HER2). The BRET sensor is a hybrid protein consisting of the highly catalytic luciferase NanoLuc (an energy donor) and a LSSmKate1 red fluorescent protein with a large Stokes shift (an energy acceptor). During the bioimaging of disseminated intraperitoneal tumors formed by HER2-positive SKOV3.ip1cells of serous ovarian cystadenocarcinoma, it was shown that the developed system is applicable in detecting deep-seated tumors of a certain molecular profile. The developed system can become an efficient platform for optimizing preclinical studies of novel targeted drugs.

Rapamycin Reduces Carcinogenesis and Enhances Survival in Mice when Administered after Nonlethal Total-Body Irradiation.

The rationale of this study stems from the concern of a radiation-induced accident or terrorist-mediated nuclear attack resulting in large populations of people exposed to nonlethal radiation doses or after a course of definitive radiation therapy which could substantially increase the risk for cancer induction after exposure. Currently, there are no safe and effective interventions to reduce this increased cancer risk to humans. We have tested the hypothesis that the mTOR inhibitor, rapamycin, administered in the diet of mice would reduce or delay radiation-induced cancer when given after radiation exposure. A total-body irradiation (TBI) of 3 Gy was administered to female C3H/Hen mice. Immediately after TBI, along with untreated control groups, animals were placed on chow containing different concentrations of encapsulated rapamycin (14, 40, 140 mg/kg chow). Animals remained on the respective control or rapamycin diets and were followed for their entire lifespan (total of 795 mice). The endpoint for the study was tumor formation (not to exceed 1 cm) or until the animal reached a humane endpoint at which time the animal was euthanized and evaluated for the presence of tumors (pathology evaluated on all animals). Kaplan-Meier survival curves revealed that all three concentrations of rapamycin afforded a significant survival advantage by delaying the time at which tumors appeared and reduction of the incidence of certain tumor types such as hepatocellular carcinomas. The survival advantage was dependent on the rapamycin concentration used. Further, there was a survival advantage when delaying the rapamycin chow by 1 month after TBI. Rapamycin is FDA-approved for human use and could be considered for use in individuals exposed to nonlethal TBI from a nuclear accident or attack or after significant therapeutic doses for cancer treatment.

Expression profile and functional analysis of miR-301b in patients with breast cancer: A bioinformatics, biochemical, and histopathological study

BackgroundmicroRNAs (miRNAs) are crucial regulators of various biological processes and molecular functions. Aberrant miRNA expression has been linked in many studies to neoplastic transformation. Among these miRNAs, dysregulation of miR-301b-5p was associated with different types of cancer including breast cancer. Although many research works have investigated the function of miR-301b in carcinogenesis, few have examined its expression, biological, and clinical implications in breast cancer. Methodswe examined the expression levels of miR-301b-5p in human cancerous breast tissue compared to normal breast controls using different bioinformatic tools and RT-qPCR analyses. Resultswe detected that miR-301b-5p was differentially expressed in cancerous breast tissue when compared to normal controls. MiR-301b-5p was detected to be upregulated in high-grade (Grade 3) and triple-negative breast cancers. A significant strong positive correlation was detected between miR-301b and Ki-67, the commonly used proliferative marker in breast cancer. Bioinformatics analyses using the KM plotter revealed that miR-301b has significant prognostic power in assessing the OS of patients with breast cancer. The study also identified many fundamental biological processes and regulatory pathways associated with the investigated miR-301b-related hub genes. Interestingly, the expression pattern and prognostic significance of PTEN, the top hub gene regulated by miR-301b, highlighted the prognostic significance of PTEN in breast cancer. ConclusionThe current study findings suggest the potential use of miR-301b-5p as a possible diagnostic and prognostic biomarker in breast cancer. Moreover, this study emphasized the clinical and biological relevance of miR-301b-5p in breast cancer.

Prevalence of S-methyl-5'-thioadenosine Phosphorylase (MTAP) Deficiency in Human Cancer: A Tissue Microarray Study on 13,067 Tumors From 149 Different Tumor Types.

Loss of S-methyl-5'-thioadenosine phosphorylase (MTAP) expression is a common event in cancer leading to a critical vulnerability of cancer cells towards anti-cancer drugs. Homozygous MTAP deletions result in a complete expression loss that can be detected by immunohistochemistry (IHC). In this study, a tissue microarray containing 17,078 samples from 149 different tumor entities was analyzed by IHC, and complete MTAP loss was validated by fluorescence in situ hybridization. MTAP loss was observed in 83 of 149 tumor categories, including neuroendocrine neoplasms (up to 80%), Hodgkin lymphoma (50.0%), mesothelioma (32.0% to 36.8%), gastro-intestinal adenocarcinoma (4.0% to 40.5%), urothelial neoplasms (10.5% to 36.7%), squamous cell carcinomas (up to 38%), and various types of sarcomas (up to 20%) and non-Hodgkin lymphomas (up to 14%). Homozygous MTAP deletion was found in 90% to 100% of cases with MTAP expression loss in most tumor categories. However, neuroendocrine tumors, Hodgkin lymphomas, and other lymphomas lacked MTAP deletions. MTAP deficiency was significantly linked to unfavorable tumor phenotype in selected tumor entities and the presence of PD-L1 expression on tumor cells, absence of PD-L1 expression on immune cells, and a low density of CD8 + lymphocytes. In summary, MTAP deficiency can occur in various tumor entities and is linked to unfavorable tumor phenotype and noninflamed tumor microenvironment, but is not always related to deletions. MTAP IHC is of considerable diagnostic value for the detection of neoplastic transformation in multiple different applications.

Management of Soft Tissue Upper Jaw Tumor in a 51 Year Old Female Patient at Sultan Fatah Hospital, Demak Regency: Case Report

Background: Benign tumors are collections of cells, tissues or organs that grow slowly and usually enlarge with peripheral expansion, pushing on surrounding structures. Squamous odontogenic tumor (SOT) is a very rare benign epithelial intraosseous tumor, which can cause arising from the neoplastic transformation of Malassez epithelial cells on the lateral surface of the periodontal ligament. Objective : To discuss the management of odontogenic squamous tumors using conservative surgical excision. The goal of treatment for oral myxoma was surgical excision. Case management : A 51 year old female patient came to the SULTAN FATAH Hospital Polyclinic, Demak Regency on May 26 2023 with complaints of a lump on the upper left gum of the jaw. The patient felt the lump about 1 year ago. The patient does not feel pain in the lump. Clinical examination showed a lump in the upper jaw on the front of the patient's left side.Conclusion : Management of the patient undergoing surgical excision of the tumor with general anesthesia and infiltration in the case of odontogenic squamous tumor, based on subjective examination the patient complained of a lump with a tumor mass measuring 10 x 8 cm, redder than the surrounding tissue, round, not moving, attached to the gums of the upper jaw.

In vitro evaluation of mesenchymal stromal cell senescence

Mesenchymal stromal cells (MSCs) are adult multipotent stem cells that, for their immunomodulatory and reparative/anti-inflammatory properties, are a promising tool in cell therapy. For the treatment of patients, MSCs are in vitro stimulated to proliferate in a non-physiological condition and this situation could lead MSCs to malignant transformation. The clinical application of MSCs requires that the biosafety of these cells must be investigated. The cellular senescence is a crucial mechanism that prevents the growth of cells at risk for neoplastic transformation. The aim of this study was to investigate the capacity of healthy donor bone marrow derived MSCs to enter the senescence phase by evaluating the β-galactosidase activity. We tested 131 MSC batches after long-term in vitro culture, resulting positive for β-gal staining and showing a branched shape morphology typical of senescent cells. They displayed a progressive decline in proliferative capacity and none of them bypassed the senescence. In conclusions, our data indicate that MSCs are not inclined towards spontaneous neoplastic transformation. We believe that the control of MSC capacity to enter senescence is fundamental for quality and safety, considering the relevant interest in the MSC clinical applications.

A mini review of plan quality and secondary cancer risk in CyberKnife M6 radiosurgery for benign intracranial tumors.

With advancements in medical technology, stereotactic radiosurgery (SRS) has become an essential option for treating benign intracranial tumors. Due to its minimal side effects and high local control rate, SRS is widely applied. This paper evaluates the plan quality and secondary cancer risk (SCR) in patients with benign intracranial tumors treated with the CyberKnife M6 system. The CyberKnife M6 robotic radiosurgery system features both multileaf collimator (MLC) and IRIS variable aperture collimator systems, providing different treatment options. The study included 15 patients treated with the CyberKnife M6 system, examining the differences in plan quality and SCR between MLC and IRIS systems. Results showed that MLC and IRIS plans had equal PTV (planning target volume) coverage (98.57% vs. 98.75%). However, MLC plans demonstrated better dose falloff and conformity index (CI: 1.81 ± 0.26 vs. 1.92 ± 0.27, P = 0.025). SCR assessment indicated that MLC plans had lower cancer risk estimates, with IRIS plans having average LAR (lifetime attributable risk) and EAR (excess absolute risk) values approximately 25% higher for cancer induction and 15% higher for sarcoma induction compared to MLC plans. The study showed that increasing tumor volume increases SCR probability, but there was no significant difference between different plans in PTV and brainstem analyses.

FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia.

Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during KrasG12D acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D. Using a gene regulatory network and pseudotime trajectory inferred from single-nuclei ATAC-seq and bulk RNA sequencing (RNA-seq), we hypothesized a regulatory model of the acinar-ADM-pancreatic intraepithelial neoplasia (PanIN) continuum and experimentally validated that Fosl1 knockout mice are delayed in the onset of ADM and neoplastic transformation. Our study also identifies that pro-inflammatory cytokines, such as granulocyte colony stimulating factor (G-CSF), can regulate FRA1 activity to modulate ADM. Our findings identify that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation.

β-catenin, PAX2, and PTEN Aberrancy Across the Spectrum of Endometrioid Ovarian Lesions.

Endometriosis is a common condition, with the ovary being the most common anatomic site. Endometriosis-particularly in the ovary-is associated with a risk of malignant progression, with a histologic spectrum of lesions from benign to malignant. Recently, a panel of 3 markers consisting of β-catenin, PAX2, and PTEN has been described as a potentially useful diagnostic adjunct in the diagnosis of intrauterine endometrioid neoplasia, where aberrancy for one or more of the markers is strongly associated with neoplasia. Here, we applied the panel to ovarian endometrioid lesions, including endometriosis, endometriosis with flat cytologic atypia, endometrioid borderline tumors, and endometrioid adenocarcinoma (n=85 cases in total). The incidence of aberrancy for the 3 markers increased along this putative neoplastic spectrum, arguing for a role of each of the markers in the neoplastic transformation of ovarian endometriosis. Just 1/32 (3%) of cases of nonatypical endometriosis was marker-aberrant, and this case was aberrant only for PAX2. One of 5 cases (20%) of endometriosis with atypia was marker-aberrant (both PAX2 and PTEN), supporting prior findings that some cases of flat atypia may represent bona fide precursor lesions. Of 19 endometrioid borderline tumors, 10 (53%) were aberrant for one or more markers, with PAX2 being the most frequently aberrant. Of 29 endometrioid adenocarcinomas, 28 (96.6%) were aberrant for at least 1 marker, with PAX2 again the most frequently aberrant. Patterns of aberrancy were well-preserved in areas of nonatypical endometriosis adjacent to borderline tumor or adenocarcinoma, supporting a biological origin in a common marker-aberrant precursor. The findings show that the biomarker panel could be of some diagnostic utility in the characterization of ovarian endometrioid neoplasia, such as in the diagnosis of endometrioid borderline tumor, distinguishing endometrioid from nonendometrioid lesions, or in identifying other types of early precursors at a higher risk of malignant transformation.