Central Giant Cell Granuloma of the Mandible and Maxilla: A Clinicopathological Study of 21 Cases.

Background Central giant cell granuloma (CGCG) presents as a locally invasive, intraosseous lesion characterized by the accumulation of multinucleated giant cells amidst a matrix of hemorrhage and reactive fibrous tissue that infiltrates bone trabeculae. This idiopathic non-neoplastic proliferative lesion primarily affects the mandible, typically presenting as either unilocular or multilocular radiolucencies on X-rays. Although trauma or intraosseous hemorrhages are potential triggers, the precise histogenesis and etiology remain unclear. CGCG predominantly occurs in children and young adults, with a slight female predilection. Methods and materials A retrospective analysis of 21 cases of CGCG diagnosed at the Oral Pathology/Pathology department of Temple University Hospital between 2015 and 2022 was conducted. Each case was evaluated based on various parameters, including age, gender, presenting symptoms, radiographic findings, clinical differential diagnosis, and histological confirmation. The primary radiographic technique employed for diagnosis was X-ray imaging of the mandible and maxilla. The histological examination involved cutting paraffin-embedded tissue into 5-micrometer-thick sections, which were then stained using routine hematoxylin and eosin (H&E) stain. Notably, no specialized histochemical or immunohistochemical stains were utilized in the evaluation process. Results In our study, we reviewed 21 cases; 9 were male, 11 were female, and one had no available gender data. The age range was 15-76 years, with a mean of 50 years. The mandible was the most commonly affected location (17 cases; 81%) while the maxilla was less commonly involved (4 cases; 19%). Many CGCG lesions were asymptomatic (13 cases; 62%); eight cases (38%) were symptomatic, with pain and fullness of the affected dental region being the main manifestations. In a few cases, conditions such as brown tumor (severe hyperparathyroidism) and odontogenic neoplasms, such as ameloblastoma, were suspected clinically and radiographically. The diagnosis of CGCG with associated acute and chronic inflammation was confirmed in all the cases. Histological evaluation of routinely stained slides was the main diagnostic tool utilized. No special stains or molecular studies were required to establish the final diagnosis. Conclusions Our investigation has determined that CGCG exhibits a non-neoplastic nature, displaying a spectrum of behaviors ranging from non-aggressive to aggressive tendencies. While CGCG is predominantly observed in the mandible, rare instances of involvement in the maxilla have also been documented. Importantly, no confirmed association with neoplastic lesions was identified during our analysis. The clinical course of CGCG tends to be indolent, with some cases presenting in association with impacted teeth. It's noteworthy that CGCG can present features mimicking neoplastic conditions, such as ameloblastoma, or localized lesions linked to systemic disorders such as hyperparathyroidism (brown tumor).

Activation of AMP-activated protein kinase attenuates ethanol-induced ER/oxidative stress and lipid phenotype in human pancreatic acinar cells.

Primary toxicity targets of alcohol and its metabolites in the pancreas are cellular energetics and endoplasmic reticulum (ER). Therefore, the role of AMP-Activated Protein Kinase (AMPKα) in amelioration of ethanol (EtOH)-induced pancreatic acinar cell injury including ER/oxidative stress, inflammatory responses, the formation of fatty acid ethyl esters (FAEEs) and mitochondrial bioenergetics were determined in human pancreatic acinar cells (hPACs) and AR42J cells incubated with/without AMPKα activator [5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)]. EtOH treated hPACs showed concentration and time-dependent increases for FAEEs and inactivation of AMPKα, along with the upregulation of ACC1 and FAS (key lipogenic proteins) and downregulation of CPT1A (involved ß-oxidation of fatty acids). These cells also showed significant ER stress as evidenced by the increased expression for GRP78, IRE1α, and PERK/CHOP arm of unfolded protein response promoting apoptosis and activating p-JNK1/2 and p-ERK1/2 with increased secretion of cytokines. AR42J cells treated with EtOH showed increased oxidative stress, impaired mitochondrial biogenesis, and decreased ATP production rate. However, AMPKα activation by AICAR attenuated EtOH-induced ER/oxidative stress, lipogenesis, and inflammatory responses as well as the formation of FAEEs and restored mitochondrial function in hPACs as well as AR42J cells. Therefore, it is likely that EtOH-induced inactivation of AMPKα plays a crucial role in acinar cell injury leading to pancreatitis. Findings from this study also suggest that EtOH-induced inactivation of AMPKα is closely related to ER/oxidative stress and synthesis of FAEEs, as activation of AMPKα by AICAR attenuates formation of FAEEs, ER/oxidative stress and lipogenesis, and improves inflammatory responses and mitochondrial bioenergetics.

Linking Dysregulated AMPK Signaling and ER Stress in Ethanol-Induced Liver Injury in Hepatic Alcohol Dehydrogenase Deficient Deer Mice.

Ethanol (EtOH) metabolism itself can be a predisposing factor for initiation of alcoholic liver disease (ALD). Therefore, a dose dependent study to evaluate liver injury was conducted in hepatic alcohol dehydrogenase (ADH) deficient (ADH-) and ADH normal (ADH+) deer mice fed 1%, 2% or 3.5% EtOH in the liquid diet daily for 2 months. Blood alcohol concentration (BAC), liver injury marker (alanine amino transferase (ALT)), hepatic lipids and cytochrome P450 2E1 (CYP2E1) activity were measured. Liver histology, endoplasmic reticulum (ER) stress, AMP-activated protein kinase (AMPK) signaling and cell death proteins were evaluated. Significantly increased BAC, plasma ALT, hepatic lipids and steatosis were found only in ADH- deer mice fed 3.5% EtOH. Further, a significant ER stress and increased un-spliced X-box binding protein 1 were evident only in ADH- deer mice fed 3.5% EtOH. Both strains fed 3.5% EtOH showed deactivation of AMPK, but increased acetyl Co-A carboxylase 1 and decreased carnitine palmitoyltransferase 1A favoring lipogenesis were found only in ADH- deer mice fed 3.5% EtOH. Therefore, irrespective of CYP2E1 overexpression; EtOH dose and hepatic ADH deficiency contribute to EtOH-induced steatosis and liver injury, suggesting a linkage between ER stress, dysregulated hepatic lipid metabolism and AMPK signaling.

Plexiform Schwannoma of the Tongue in a Pediatric Patient with Neurofibromatosis Type 2: A Case Report and Review of Literature.

INTRODUCTION: Plexiform schwannoma is a rare variant of schwannoma that accounts for only 5% of all schwannomas. Herein, we present a rare case of plexiform schwannoma of the tongue in a pediatric patient with neurofibromatosis type 2 (NF2). CASE PRESENTATION: A 13-year-old female presented with a growing left-sided tongue mass. The patient has a past medical history of NF2. The tongue mass was excised and histopathological examination revealed a spindle cell tumor with multinodular growth pattern, with Verocay bodies' formation. Tumor cells were strongly positive for S-100 protein and negative for smooth muscle actin (SMA), and EMA highlighted perineural fibroblasts surrounding tumor nodules. These findings were diagnostic of plexiform schwannoma. CONCLUSION: Plexiform schwannoma of the tongue is an extremely rare tumor seen in patients with NF2. Clinical examination and histopathological evaluation are important for diagnosis of plexiform schwannoma.

Hepatic alcohol dehydrogenase deficiency induces pancreatic injury in chronic ethanol feeding model of deer mice.

The single most common cause of chronic pancreatitis (CP, a serious inflammatory disease) is chronic alcohol abuse, which impairs hepatic alcohol dehydrogenase (ADH, a major ethanol oxidizing enzyme). Previously, we found ~5 fold greater fatty acid ethyl esters (FAEEs), and injury in the pancreas of hepatic ADH deficient (ADH-) vs. hepatic normal ADH (ADH+) deer mice fed 3.5g% ethanol via liquid diet daily for two months. Therefore, progression of ethanol-induced pancreatic injury was determined in ADH- deer mice fed ethanol for four months to delineate the mechanism and metabolic basis of alcoholic chronic pancreatitis (ACP). In addition to a substantially increased blood alcohol concentration and plasma FAEEs, significant degenerative changes, including atrophy and loss of acinar cells in some areas, ultrastructural changes evident by such features as swelling and disintegration of endoplasmic reticulum (ER) cisternae and ER stress were observed in the pancreas of ethanol-fed ADH- deer mice vs. ADH+ deer mice. These changes are consistent with noted increases in pancreatic injury markers (plasma lipase, pancreatic trypsinogen activation peptide, FAEE synthase and cathepsin B) in ethanol-fed ADH- deer mice. Most importantly, an increased levels of pancreatic glucose regulated protein (GRP) 78 (a prominent ER stress marker) were found to be closely associated with increased phosphorylated eukaryotic initiation factor (eIF) 2α signaling molecule in PKR-like ER kinase branch of unfolded protein response (UPR) as compared to X box binding protein 1S and activating transcription factor (ATF)6 - 50kDa protein of inositol requiring enzyme 1α and ATF6 branches of UPR, respectively, in ethanol-fed ADH- vs. ADH+ deer mice. These results along with findings on plasma FAEEs, and pancreatic histology and injury markers suggest a metabolic basis of ethanol-induced pancreatic injury, and provide new avenues to understand metabolic basis and molecular mechanism of ACP.

Proteomic Profiling of Liver and Plasma in Chronic Ethanol Feeding Model of Hepatic Alcohol Dehydrogenase-Deficient Deer Mice.

BACKGROUND: Chronic alcohol abuse, a major risk factor for such diseases as hepatitis and cirrhosis, impairs hepatic alcohol dehydrogenase (ADH; key ethanol [EtOH]-metabolizing enzyme). Therefore, differentially altered hepatic and plasma proteomes were identified in chronic EtOH feeding model of hepatic ADH-deficient (ADH- ) deer mice to understand the metabolic basis of alcoholic liver disease (ALD). METHODS: ADH- deer mice were fed 3.5 g% EtOH via Lieber-DeCarli liquid diet daily for 3 months and histology of the liver assessed. Liver and plasma proteins were separated by 2-dimensional gel electrophoresis. The proteins differentially expressed were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. RESULTS: Histology of the liver showed panlobular steatosis and infiltration of T lymphocytes. Using the criteria of ≥1.5 for fold change (p-value ≤0.05) with expectation value (E ≤10-3 ) and protein score (≥64), 18 proteins in the livers and 5 in the plasma of EtOH-fed mice were differentially expressed and identified. Prolyl 4-hydroxylase, cytochrome b-5, endo A cytokeratin, ATP synthase, heat-shock 70 kD proteins, enoyl CoA hydratase, stress-70 protein, peroxiredoxin 1, and ornithine carbamoyl transferase were up-regulated in the livers. However, carbonic anhydrase 3, mitochondrial ATP synthase, aldolase 2, actin γ, laminin receptor, and carbamoyl phosphate synthase were down-regulated. Contrary to the increased expression of creatine kinase M-type, a decreased expression of serine protease inhibitor A3A precursor, sulfated glycoprotein-2 (clusterin), and apolipoprotein E isoforms were found in the plasma of EtOH group. CONCLUSIONS: Chronic EtOH feeding in ADH- deer mice causes steatosis and infiltration of T lymphocytes in the livers along with increased expression of proteins involved in endoplasmic reticulum (ER) stress, fibrosis, fatty acid ß oxidation and biogenesis, and decreased expression of proteins involved in ATP synthesis, carbohydrate metabolism, in cell regulation and architecture. Reduced expression of various carrier proteins as found in the plasma of EtOH group has a biomarker potential.

Proteins Differentially Expressed in the Pancreas of Hepatic Alcohol Dehydrogenase-Deficient Deer Mice Fed Ethanol For 3 Months.

OBJECTIVES: The aim of this study was to identify differentially expressed proteins in the pancreatic tissue of hepatic alcohol dehydrogenase-deficient deer mice fed ethanol to understand metabolic basis and mechanism of alcoholic chronic pancreatitis. METHODS: Mice were fed liquid diet containing 3.5 g% ethanol daily for 3 months, and differentially expressed pancreatic proteins were identified by protein separation using 2-dimensional gel electrophoresis and identification by mass spectrometry. RESULTS: Nineteen differentially expressed proteins were identified by applying criteria established for protein identification in proteomics. An increased abundance was found for ribosome-binding protein 1, 60S ribosomal protein L31-like isoform 1, histone 4, calcium, and adenosine triphosphate (ATP) binding proteins and the proteins involved in antiapoptotic processes and endoplasmic reticulum function, stress, and/or homeostasis. Low abundance was found for endoA cytokeratin, 40S ribosomal protein SA, amylase 2b isoform precursor, serum albumin, and ATP synthase subunit ß and the proteins involved in cell motility, structure, and conformation. CONCLUSIONS: Chronic ethanol feeding in alcohol dehydrogenase-deficient deer mice differentially expresses pancreatic functional and structural proteins, which can be used to develop biomarker(s) of alcoholic chronic pancreatitis, particularly amylase 2b precursor, and 60 kDa heat shock protein and those involved in ATP synthesis and blood osmotic pressure.