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Chromosomal translocations with gene fusions are uniquely rare events in paraganglioma, mostly involving UBTF::MAML3 gene fusion. Precedent literature suggests that tumors involving MAML3 gene fusion correlate with poor clinical outcomes. Herein, we report a case of metastatic sporadic paraganglioma harboring EWSR1::CREM gene fusion in a 36-year-old male, that has not been previously described. The patient presented with large paraspinal mass that was resected the same year. Tumor recurred 3-years later and on further work-up, patient was found to have metastases involving both lungs. Histopathologic evaluation of the original primary tumor showed tightly packed irregular nests and cords of cells containing palely eosinophilic cytoplasm. Features considered atypical included: areas of solid growth pattern, coagulative tumor necrosis, focal cellular atypia and angiolymphatic invasion were also identified. By immunohistochemistry, the tumor cells were positive for synaptophysin and chromogranin and negative for keratin. The S100 stain highlights the sustentacular cells and the Ki-67 proliferation index of 15%. The recurrence specimen was similar but showed increased cellularity, atypia, necrosis, and proliferative activity (Ki-67 proliferation index of 35%). CT guided biopsy of the right lung lesion was consistent with metastasis. Next generation sequencing identified EWSR1::CREM fusion. The breakpoints were found in chromosome 22: 29683123 for EWSR1 exon 7 (NM_005243.3) and at chromosome 10:35495823 for CREM exon 6 (NM_001267562.1). Fluorescence in situ hybridization for EWSR1 gene rearrangement was positive. In summary, we report a case of metastatic paraganglioma with EWSR1::CREM gene fusion, not previously described in this entity, and expands on the phenotypic diversity within the genetic landscape of EWSR1::CREM gene fusion positive tumors.

SS18::SSX gene fusions as a result of t(X,18)(p11;q11) have only been described in synovial sarcoma (SS). Recently, an SS18::NEDD4 gene fusion was identified in a single case of primary renal SS exhibiting a hypocellular and myxoid morphology. Herein, we report a case of an unclassified malignant cutaneous spindled and epithelioid neoplasm in a 60-year-old female that resembled an epithelioid sarcoma (ES) and harbored a rare SS18::NEDD4 gene fusion. Briefly, the patient presented with a progressively growing cutaneous mass involving the volar aspect of right hand, warranting an amputation. Histologic sections revealed a cutaneous ulcerative neoplasm composed of spindled and epithelioid cells, bearing a certain semblance to ES, with diffuse invasion into the subcutis and skeletal muscle. Coagulation tumor necrosis and mitotic figures were present. By immunohistochemistry, the tumor cells were positive for keratins (AE1/3 and cam5.2), vimentin, CMYC, BCL2, p53, smooth muscle actin (focal), and TLE1 (multifocal) and negative for p40, p63, CK5/6, CK7, CK20, CD56, CD31, CD34, ERG, desmin, SMMS, H-Caldesmon, myogenin, and S-100. Expression of INI1 stain was retained. The unusual histomorphology and inconclusive immunophenotypic profile lead to next-generation sequencing identifying an SS18::NEDD4 gene fusion with genomic coordinates 5'-SS18 (ex1-9 NM_005637)-NEDD4 (ex14-29 NM_006154). Fluorescence in situ hybridization confirmed SS18 gene rearrangement. Within 2 years, the patient developed widespread metastatic disease. Despite aggressive multimodality treatment, the patient succumbed to disease. In summary, we report a unique case of previously unclassified cytokeratin positive malignant cutaneous spindled and epithelioid sarcoma with aggressive behavior, harboring an SS18::NEDD4 fusion.

Nodular fasciitis (NF) is a benign proliferation of fibroblasts and myofibroblasts occurring most commonly in the upper extremities that can mimic a variety of mesenchymal tumors including sarcoma. Although reported in almost all anatomic locations, only 7 cases of intraneural nodular fasciitis have been reported in English literature. The CTNNB1::USP6 gene fusion has not been previously reported in intraneural nodular fasciitis, although it has been reported in three entities including aneurysmal bone cyst, nodular fasciitis, and intravascular fasciitis. We report a case of a 29-year-old female with a 6-month history of left leg weakness, myalgia, and paresthesia of the left foot prompting a clinical diagnosis of a peripheral nerve sheath tumor. Surgical resection was performed, and histologic sections revealed a circumscribed lesion composed of banal spindle cells with variable interstitial collagen and occasional mitotic figures. By immunohistochemistry, the lesional cells were positive for smooth muscle actin, smooth muscle heavy chain myosin, p16, and H-caldesmon and negative for desmin, S-100, SOX10, HMB45, CD34, and beta-catenin. Fluorescence in Situ Hybridization for USP6 gene rearrangement was positive and consistent with the diagnosis of nodular fasciitis. Next-generation sequencing uncovered the presence of a CTNNB1::USP6 gene fusion involving CTNNB1 gene in exon 1 at the genomic position chr3:41241161 and the USP6 gene in exon 1 at the genomic position chr17:5033231. This gene fusion was confirmed by Sanger sequencing. Herein, we report a case that underscores the rare incidence of intraneural nodular fasciitis and highlights the pitfalls associated with the clinical differential diagnoses of intraneural tumors.

Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular tumor with indolent biology, characterized by reciprocal t(1;3)(p36.6;q25) with resultant WWTR1::CAMTA1 gene fusion in the vast majority of cases, regardless of anatomic location. Only a small subset, exhibiting well formed vasoformative features will contain YAP1::TFE3 gene fusion. Primary intranodal EHE is exquisitely rare. We report a case in a 54-year-old male with persistent left groin mass with discomfort for nine months. A CT of the abdomen and pelvis showed a minimally enlarged left inguinal lymph node measuring 2.8 cm with no other masses or lymphadenopathy. PET/CT and MRI imaging of the abdomen showed no evidence of disease elsewhere. Sections showed an epithelioid vasoformative neoplasm, centrally necrotic and involving a lymph node. The cells were arranged in anastomosing cords with intracytoplasmic lumens, resembling “signet ring cells". By immunohistochemistry, the tumor cells were positive for vimentin, CD31, CD34, ERG and CAMTA1; and negative for AE1/3, CAM 5.2, KRT7, KRT20, desmin, actin, HMB-45 and S-100. Ki-67 proliferation index was estimated at

Soft tissue myoepitheliomas (STM) are benign myoepithelial neoplasms (of nonsalivary gland origin) arising, most commonly within subcutaneous and deep soft tissues of the extremities and rarely within bones. To the best of our knowledge, the intravascular location of STM as well as the identification of a novel IRF2BP2::CDX2 fusion have not been previously reported. Herein, we report a case of spindle cell myoepithelioma arising within the intravascular space of the right index finger in a 52-year-old male of more than 20 years duration. Histopathology demonstrated an intravascular tumefactive lesion composed of predominantly plump banal spindle cells in a fascicular arrangement within a mixed collagenous and chondromyxoid stroma colliding with papillary endothelial hyperplasia (Masson tumor). By immunohistochemistry, the lesional cells were positive for keratin-AE1/3, epithelial membrane antigen, S100, SOX10, glial fibrillary acid protein, calponin and negative for CD34, smooth muscle actin, desmin, p63, and ERG. Fluorescence in situ hybridization for EWSR1 gene rearrangement was negative. Next-generation sequencing detected a novel IRF2BP2::CDX2 fusion involving Exon 1 of the IRF2BP2 gene and Exon 2 of the CDX2 gene confirmed by reverse transcriptase polymerase chain reaction and Sanger sequencing. Further, clinical evaluation for a salivary gland mass in the head and neck region and magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis was performed with no evidence of tumor elsewhere. Taken together, the overall features were considered diagnostic of STM. Our current case underscores the novelty of the IRF2BP2::CDX2 gene fusion in STM and its exceptionally rare intravascular location.

Cutaneous fibromyxoid neoplasms (CFMN) comprise a vast category of benign and malignant tumors that include, but are not limited to, low-grade fibromyxoid sarcoma, myxofibrosarcoma, myxoid dermatofibrosarcoma protuberans, myxoid solitary fibrous tumor, and myxoid neurofibroma with differing implications for treatment and prognosis. Herein, a case of CFMN arising as a painless, slow-growing, flesh-colored forearm mass in a 53-year-old female is presented. The neoplasm comprised of copious myxoid material with banal spindle cells, exhibiting mild hyperchromasia, dissecting the dermal collagen table. Focal perivascular accentuation of spindle cells was identified in the absence of vasoformative features. Immunohistochemically, lesional cells were strongly and diffusely positive for CD34 and multifocally for Factor XIIIa and epithelial membrane antigen while negative for CD31, ERG, FLI-1, D2-40, smooth muscle actin, Desmin, S100, HMB-45, STAT6, MUC4, and keratins. RNA- and DNA-sequencing identified a YAP1::TFE3 fusion transcript that were subsequently corroborated by fluorescence in situ hybridization and immunohistochemistry for TFE3 (Xp11.23) locus rearrangement and strong, diffuse TFE3 immunoreactivity, respectively. To date, the YAP1::TFE3 fusion has only been identified in a subset of epithelioid hemangioendotheliomas and clear cell stromal tumors of the lung. This is the first report of a CFMN featuring a YAP1::TFE3 fusion (YAP1 Exon 1 and TFE3 Exon 4). The morphologic findings are unlike those previously described for epithelioid hemangioendothelioma and suggest that this neoplasm may represent a yet unclassified or novel CFMN entity. Although the patient is 1-year status postsurgical excision with no evidence of clinical recurrence, the clinical behavior of this novel entity remains to be fully characterized.

Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) represent a significant number of sarcomas arising within the paratesticular region. DDLPS is notorious for a broad histologic spectrum, but epithelioid morphology is rare. Herein, we describe a unique case of paratesticular DDLPS with prominent epithelioid features and molecular confirmation. The patient is 71-year-old-male who presented with multiple paratesticular masses. Morphologic review of the resection specimen revealed a biphasic adipocytic neoplasm consistent with DDLPS. Additionally, epithelioid foci with acinar and nested architecture and focal keratin expression were noted. These areas raised the possibility of a secondary neoplasm including sex cord stromal tumor, germ cell tumor, and paraganglioma. However, MDM2 immunohistochemistry and FISH showed these areas to express MDM2 and exhibit MDM2 amplification, respectively, confirming that they represented a component of DDLPS. This case further highlights the morphologic diversity of DDLPS as well as the utility of MDM2 studies.

Rationale: Influenza A virus (IAV) and SARS-CoV-2 are both acute respiratory viruses currently circulating in the human population. Prior IAV infection enhances SARS-CoV-2 infectivity and lung pathogenesis in mice; however, underlying mechanisms and the extent that co-infection leads to involvement of other organs in disease severity remains unknown. Objective: Herein, we investigated the impact of prior IAV infection on SARS-CoV-2 pathogenesis and cardiomyocyte function. Methods and Results: IAV infection in human primary lung epithelial cells, lung fibroblasts, macrophages, cardiac fibroblasts, and hiPSC-Cardiomyocytes enhances the expression of, the SARS-CoV-2 receptor ACE2. Also, we found that IAV infection enhances levels of ACE2 in the lungs of mice and humans. Interestingly, we detected poorly glycosylated ACE2 in A549 lung cells, primary lung epithelial cells, and cardiac fibroblasts. In contrast, expression of a heavily glycosylated form of ACE2 is induced by IAV infection in cardiomyocytes. In all cell types, IAV infection enhances SARS-CoV-2 spike protein binding and viral entry. However, efficient SARS-CoV-2 replication was uniquely inhibited in cardiomyocytes. Glycosylation of ACE2 correlated with enzymatic conversion of its substrate Ang II, induction of eNOS and nitric oxide production, providing a mechanistic underpinning for restricted viral replication in cardiomyocytes. Conclusions: Our results indicate that IAV-mediated induction of ACE2 is double-edged, providing increased risk for SARS-CoV-2 coinfection in human lung epithelial cells and cardiac fibroblasts , while limiting SARS-CoV-2 replication in cardiomyocytes. We conclude that differential glycosylation of ACE2 may be a molecular determinant- not of SARS-CoV-2 infection, but of replication. Funding: The work was supported by NIH grants AI 146252 and AI 146690. Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: All procedures were approved by the OSU IACUC.We have obtained ethics approval from the Ohio State University, The Institutional Animal Care and Use Committee (#2016A00000100-R1), Institutional Biosafety Committee (#2020R00000135) for animal work and Institutional Review Board (#2020H0222) for human subjects.

Obesity is a widespread condition that is more prevalent in Western countries compared to others. Aortic atherosclerosis (AA) is a condition that frequently has been associated with obesity. An obesity paradox, where morbidly obese decedents had either no or minimal AA compared to nonobese decedents, recently has been described by some of us. The explanation for this almost counterintuitive paradox has yet to be determined, but a number of hypotheses were advanced, including hemodynamic factors producing aortic wall shear stress (WSS). The purpose of the present study was to determine if there was a relationship between AA and WSS, as determined by postmortem measurement of aortic wall diameters.Circumferences of the aorta at the levels of the ascending, thoracic and abdominal aorta were measured in 274 consecutive autopsies over 2-year period of time. AA was assessed using a previously described grading scale as either mild or severe. Circumferences were mathematically converted to diameters and WSS was calculated using the Hagen-Poiseuille formula. Two different methods to estimate cardiac output were used, both based on literature methods, one of which was body mass index (BMI) dependent, and the other BMI independent. Univariate and multivariable analyses of the relationship between WSS, age, BMI, gender, race and severity of AA were performed.Of the 274 decedents, 140 had mild and 134 had moderate to severe AA. BMI35 was associated with moderate to severe AA. WSS was inversely correlated with AA in all these segments of the aorta in each BMI subgroup with the exception of the ascending aorta for decedents with BMI ≤35 kg/mOur data demonstrate that WSS was unexpectedly lower in decedents with moderate and severe AA as compared to those with mild AA. This observation, which requires further investigations, was seen in all BMI ranges and was confirmed by 2 methods to calculate WSS.

Influenza A virus (IAV) and SARS-CoV-2 are both acute respiratory viruses currently circulating in the human population. Prior IAV infection enhances SARS-CoV-2 infectivity and lung pathogenesis in mice; however, underlying mechanisms and the extent that co-infection leads to involvement of other organs in disease severity remains unknown. Herein, we investigated the impact of prior IAV infection on SARS-CoV-2 pathogenesis and cardiomyocyte function. IAV infection induces the expression of ACE2 in human lung epithelial cells, lung fibroblasts, macrophages, cardiac fibroblasts (HCFs), and hiPSC-Cardiomyocytes (CMs). Interestingly, we detected poorly glycosylated ACE2 in lung epithelial cells and cardiac fibroblasts. In contrast, expression of a heavily glycosylated form of ACE2 is induced by IAV in CMs. In all cell types, IAV infection enhances SARS-CoV-2 viral entry. However, efficient SARS-CoV-2 replication was uniquely inhibited in CMs. Glycosylation of ACE2 correlated with enzymatic conversion of its substrate Angiotension II, induction of eNOS and nitric oxide production, providing a mechanistic underpinning for restricted viral replication in CMs. Our results indicate that IAV-mediated induction of ACE2 is double-edged, providing increased risk for SARS-CoV-2 coinfection in epithelial cells and HCFs, while limiting SARS-CoV-2 replication in CMs. We conclude that differential glycosylation of ACE2 may be a molecular determinant, not of SARS-CoV-2 infection, but of replication. Funding: NIH grants R01-AI 146252, R21-AI 146690 Funding: NIH grants R01-AI 146252, R21-AI 146690

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases and has become the leading chronic liver disease worldwide. High-fat (HF) diets promote an increased uptake and storage of free fatty acids (FFAs) and triglycerides (TGs) in hepatocytes, which initiates steatosis and induces lipotoxicity, inflammation and insulin resistance. Activation and signaling of Toll-like receptor 4 (TLR4) by FFAs induces inflammation evident in NAFLD and insulin resistance. Currently, there are no effective treatments to specifically target inflammation associated with this disease. We have established the efficacy of phenylmethimazole (C10) to prevent lipopolysaccharide and palmitate-induced TLR4 signaling. Because TLR4 is a key mediator in pro-inflammatory responses, it is a potential therapeutic target for NAFLD. Here, we show that treatment with C10 inhibits HF diet-induced inflammation in both liver and mesenteric adipose tissue measured by a decrease in mRNA levels of pro-inflammatory cytokines. Additionally, C10 treatment improves glucose tolerance and hepatic steatosis despite the development of obesity due to HF diet feeding. Administration of C10 after 16 weeks of HF diet feeding reversed glucose intolerance, hepatic inflammation, and improved hepatic steatosis. Thus, our findings establish C10 as a potential therapeutic for the treatment of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of both metabolic and inflammatory diseases, and it has become pervasive worldwide. Inflammation, including inflammation resulting from free fatty acid (FFA) activation of toll-like receptor (TLR) signaling, has been suggested to be an essential component of the pathophysiology of both insulin resistance and NAFLD. High fat (HF) diets promote an increased uptake and storage of FFAs and triglycerides in hepatocytes, which initiates inflammation and steatosis that induces lipotoxicity and an exacerbation of inflammation. In previous studies, we have established the efficacy of phenylmethimazole, a TLR3/4 inhibitor, to prevent and reverse HF diet-induced NAFLD, inflammation, and insulin resistance. A new library of small molecule compounds, including COB-214, was generated to identify even more potent inhibitors of inflammation. The objectives of this study were to evaluate the efficacy of COB-214 to delay and/or prevent hepatic steatosis, inflammation, and insulin resistance in a HF diet-induced model of NAFLD. C57BL/6J male mice were fed a HF diet (60 % fat, 20% protein, 70% carbohydrate) and divided into 3 groups (N=8 for each group): sham injection (stress control), DMSO (vehicle control), COB-214. Each treatment was administered once daily at a dosage of 1mg/kg for 16 weeks. Histological examination of liver sections from these mice using hematoxylin and eosin (H&E) revealed less hepatic lipid accumulation in mice treated with COB-214 when compared to mice in the sham- and DMSO-treated groups. Transcription of pro-inflammatory cytokines was down-regulated in both liver and mesenteric adipose tissue isolated from COB-214-treated mice when compared to sham- and DMSO-treated mice. Treatment with COB-214 prevented HF diet-induced insulin resistance measured by a 3-hour intraperitoneal glucose tolerance test (IPGTT) and 1.5-hour intraperitoneal insulin tolerance test (IPITT). Future directions include determining the efficacy of COB-214 to reverse HF diet-induced NAFLD, inflammation, and insulin resistance. At the conclusion of this study, we hope to have established the role of a novel class of small molecule inhibitors of inflammation in the treatment and prevention of NAFLD.

Background: Bariatric surgery is a popular and effective therapeutic intervention for obesity, which is an abnormal health condition that is prevalent worldwide. Metabolic improvements that precede weight loss after bariatric surgery may be mediated, in part, through the fibroblast growth factor (FGF) 15/19 and FGF21 signaling pathways. Both FGF15/19 and FGF21 are hormone-like members of the FGF family and exert their metabolic effects in an endocrine manner. Enhanced bile acid recycling after bariatric surgery leads to increased circulating levels of FGF15/19 in the distal small intestine. Synthesis of FGF21 is upregulated predominately in the fasting state through peroxisome proliferator-activated receptor pathways and to a lesser extent by FGF15/19. Key Messages: The biological functions of FGF15/19 and FGF21 are diverse and complicated. The tissue targeted effects of FGF15/19 and FGF21 of importance after bariatric surgery include the regulation of hepatic bile acid biosynthesis and ketogenesis as well as thermogenesis in adipose tissue, respectively. Furthermore, FGF15/19 and FGF21 function to regulate carbohydrate and lipid metabolism. Conclusion: The long-term effects of bariatric surgery on weight loss are undisputable. However, the mechanism for improvements in glucose and lipid homeostasis observed shortly after bariatric surgery is less understood. This review article attempts to describe the known metabolic effects of FGF15/19 and FGF21 that may potentiate these improvements after bariatric surgery.