Brg1/PRMT5 nuclear complex epigenetically regulates FOXO1 in IPF mesenchymal progenitor cells.

We have discovered intrinsically fibrogenic mesenchymal progenitor cells (MPCs) in the human idiopathic pulmonary fibrosis (IPF) lung. IPF MPCs display a durably distinct transcriptome, suggesting that they have undergone epigenetic modifications. Prior studies indicate that the chromatin remodeler Brg1 associates with the arginine methyltransferase PRMT5 to epigenetically regulate transcription factors. We hypothesize that a Brg1/PRMT5 nuclear complex epigenetically regulates critical nodes in IPF MPC self-renewal signaling networks. IPF and control MPCs were isolated from primary mesenchymal cell lines established from IPF and control patients. RNA-sequencing identified increased expression of the FOXO1 transcription factor in IPF MPCs compared with controls, a result we confirmed by Q-PCR and Western blot analysis. Immunoprecipitation identified a CD44/Brg1/PRMT5 nuclear complex in IPF MPCs. Chromatin immunoprecipitation assays showed that PRMT5 and its methylation mark H3R2me2 are enriched on the FOXO1 promoter. We show that loss of Brg1 and PRMT5 function decreases FOXO1 expression and impairs IPF MPC self-renewal, and that loss of FOXO1 function decreases IPF MPC self-renewal and expression of the SOX2 and OCT4 stemness markers. Our findings indicate that the FOXO1 gene is overexpressed in IPF MPCs in a CD44/Brg1/PRMT5 nuclear complex-dependent manner. Our data suggest that Brg1 alters chromatin accessibility, enriching PRMT5 occupancy on the FOXO1 promoter, and PRMT5 methylates histone H3 arginine 2 (H3R2) on the FOXO1 promoter, increasing its expression. Our data are in accord with the concept that this coordinated interplay is responsible for promoting IPF MPC self-renewal and maintaining a critical pool of fibrogenic MPCs that drive IPF progression.NEW & NOTEWORTHY Our research offers valuable understanding regarding the epigenetic control of IPF MPC. The data we obtained strongly support the idea that the coordination between chromatin remodeling and histone methylation plays a key role in regulating transcription factors. Specifically, our findings indicate that FOXO1, an essential transcription factor, likely governs the self-renewal of IPF MPC, which is crucial for maintaining a critical pool of fibrogenic MPCs. This interplay could be an important therapeutic target.

Meningeal rheumatoid nodules in a 55-year-old man presenting with chronic headaches and oculomotor nerve palsy: an uncommon extra-articular manifestation of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a multisystem inflammatory disease which can involve many organ systems including the central nervous system (CNS). Though not very common, the results can be severely debilitating. The spectrum of the CNS involvement includes meningitis, encephalitis and occasionally rheumatoid nodules. Its presentation is variable, though very rarely it can present as focal neurological deficits. Imaging can be suggestive, but diagnosis usually requires tissue biopsy. Treatment consists of high-dose steroids and immunosuppressants. We describe the case of a 55-year-old male patient with a history of RA presenting with a third nerve palsy and headache who was found to have rheumatoid nodules on biopsy. CNS involvement in RA should be considered in anyone with rheumatoid arthritis who presents with focal neurological deficits, though infections and space-occupying lesions should also be ruled out.

A Very Rare Case of Sarcoid-Lymphoma Syndrome Imposing an Intriguing Diagnostic Challenge.

An enigmatic association between sarcoidosis and lymphoma has been proposed in the past. This poses a significant diagnostic challenge, especially when the time interval is less than one year between the two diagnoses. A 54-year-old male patient presented to his primary care physician with worsening acute kidney injury and hypercalcemia. His chest x-ray showed bilateral interstitial nodular thickening and mild bilateral hilar fullness. After a diagnostic workup, the patient was diagnosed with sarcoidosis and started on prednisone. He initially improved, but returned with acute kidney injury, hypercalcemia, and generalized lymphadenopathy. An excisional lymph node biopsy was positive for diffuse large B-cell lymphoma. Our case illustrates the sarcoidosis-lymphoma syndrome. Although there is no recommendation to screen patients with sarcoidosis for malignancy, it is crucial to be aware of this association and to evaluate any new or enlarging lymphadenopathy with a biopsy. It is essential to assess response to prednisone in patients with sarcoidosis.

Coronary Artery Perforation Spilling into Right Ventricle: A Rare Complication of Percutaneous Coronary Intervention.

Injury to the coronary circulation during percutaneous interventions is an existent risk. One of these is coronary artery perforation that can have grave consequences. Fortunately, this is rare and overall there is a declining incidence of complications due to technological advances and extensive experience over time. Predictors of coronary artery perforation include the administration of glycoprotein IIb/IIIa inhibitors, the use of hydrophilic guide wires, and the use of noncompliant high-pressure intracoronary balloons. Complex coronary lesions and the presence of total chronic occlusion are additional risk factors. In this paper, we present a rare class III coronary artery perforation with spilling into the right ventricle. Our case exemplifies all the aforementioned risk factors for perforation. The perforation was successfully sealed with a polytetrafluoroethylene covered stent and the patient remained hemodynamically stable.

Mitral Stenosis Presenting as Asthma.

Although wheezing is one of the most common symptoms and physical findings in asthma, other causes of wheezing should be kept in mind: vocal cord dysfunction, postnasal drip syndrome, chronic obstructive pulmonary disease, bronchiectasis, and non-pulmonary diseases, like heart failure and pulmonary edema. Here, we present a case of severe mitral stenosis with pulmonary edema treated for resistant asthma. If asthma is difficult to control, other etiologies of wheezing, including cardiac disease, should be taken into consideration during diagnosis.

Blastomycosis and Histoplasmosis in a Patient with Glioblastoma Receiving Temozolomide.

Malignant glioblastoma multiform (GBM) is the most common primary malignancy of the brain in the U.S. Temozolomide (TMZ) is the cornerstone of management along with surgical resection and radiotherapy. Because of the reduction in the CD4+ lymphocyte count as a side effect of TMZ use, this patient population is under risk for opportunistic infections like Pneumocystis jiroveci. A male patient with newly diagnosed glioblastoma multiform presented with non-productive cough and chest pain. Before presentation, the patient received the standard therapy including surgical resection, radiation and TMZ. Computerized tomography of the chest showed a very large cavitary lesion in the upper segment of the right lower lobe and multiple nodular lesions with some starting to cavitate. Cytology of the bronchioalveolar lavage with special stain showed large, broad based budding yeast-like cells, morphologically consistent with blastomyces and macrophages filled with yeast-like forms, morphologically consistent with histoplasma. The patient was treated with intraconazole intended for 12 months. To the best of our knowledge, our case represents the first documented case of lung infection with both blastomyces and histoplasma in a patient after receiving TMZ for newly diagnosed GBM.