Diabetes and psoriasis are prevalent conditions with a spectrum of serious adverse outcomes. Both diseases are common comorbidities for each other, and diabetes is considered as a risk factor for psoriasis and vice versa. However, it is our contention that these diseases are not merely comorbidities of each other but rather share common underlying pathophysiologies (ie, genes and epigenetic changes, inflammation, abnormal environment, and insulin resistance) that drive disease. As such, they can be viewed as facets of the same prism. Genes can cause or permit susceptibility to damage from abnormal external and internal environmental factors, inflammation, and insulin resistance which can also drive epigenetic changes. These co-existing mechanisms act in a vicious cycle over time to potentiate cell and tissue damage to ultimately drive disease. Viewing diabetes and psoriasis through the same prism suggests potential for therapies that could be used to treat both conditions. Although additional controlled trials and research are warranted, we believe that our understanding of the overlapping pathophysiologies continues to grow, so too will our therapeutic options.

Quantifying multi-molecular complex assembly in specific cytoplasmic compartments is crucial to understand how cells use assembly/disassembly of these complexes to control function. Currently, biophysical methods like Fluorescence Resonance Energy Transfer and Fluorescence Correlation Spectroscopy provide quantitative measurements of direct protein-protein interactions, while traditional biochemical approaches such as sub-cellular fractionation and immunoprecipitation remain the main approaches used to study multi-protein complex assembly/disassembly dynamics. In this article, we validate and quantify multi-protein adherens junction complex assembly in situ using light microscopy and Fluorescence Covariance Analysis. Utilizing specific fluorescently-labeled protein pairs, we quantified various stages of adherens junction complex assembly, the multiprotein complex regulating epithelial tissue structure and function following de novo cell-cell contact. We demonstrate: minimal cadherin-catenin complex assembly in the perinuclear cytoplasm and subsequent localization to the cell-cell contact zone, assembly of adherens junction complexes, acto-myosin tension-mediated anchoring, and adherens junction maturation following de novo cell-cell contact. Finally applying Fluorescence Covariance Analysis in live cells expressing fluorescently tagged adherens junction complex proteins, we also quantified adherens junction complex assembly dynamics during epithelial monolayer formation.

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BACKGROUND: Paraganglioma (PGL) are tumors that arise from the ganglia of the sympathetic nervous system, and comprise 10% of all sympathetic nervous system tumors. There are at least 16 germline mutations that have been associated with increased risk of PGL. CASE PRESENTATION: A 32 year-old female with a history of PGL status-post resection presented with elevated plasma metanephrines during surveillance follow-up. She was diagnosed with PGL 7 years ago. Plasma free normetanephrine were elevated at 607 pg/ml (ref ≤ 148 pg/ml) and an MRI abdomen demonstrated a 6.6 x 4.5 x 7.8 cm para-aortic retroperitoneal mass. An MIBG scan showed no abnormal activity. She underwent resection of PGL. Postoperative labs showed normal plasma and urine metanephrines. Genetic testing was negative for known related mutations. She reported dizziness and palpitations six years later. Labs revealed elevated free normetanephrine 213 pg/ml and total metanephrine 238 pg/ml (ref ≤ 205 pg/ml). Repeat plasma and urine tests remained elevated, but an MRI abdomen/pelvis and two MIBG scans were unremarkable. The patient remained symptomatic. Six months later, CT abdomen/pelvis showed a retroperitoneal 2.5 x 1.8 x 1.7 cm necrotic mass and an 3.2 x 2.6 x 2.5 cm adnexal cystic lesion concerning for recurrent PGL. Repeat testing confirmed elevated plasma free normetanephrine 511 pg/ml and undetectable free metanephrine. PET/CT abdomen/pelvis demonstrated the retroperitoneal necrotic mass, two lesions anterior to the L3 and L4-L5 vertebral bodies, and a lytic lesion in the right iliac crest. The patient underwent surgical resection of three PGL, all with vascular and capsular invasion. Six months later, plasma and urinary levels were all normal. PET Ga-68 DOTATATE scan demonstrated uptake near the surgical bed and in the aorto-caval groove, suspicious for residual tumors, and several foci of somatostatin receptor positive osseous lesions, suspicious for skeletal metastases. An updated genetic test showed a variant of uncertain significance (VUS) of the SDHA gene. She is currently undergoing treatment with lanreotide. CONCLUSION: This case highlights the importance of continuous surveillance, as well as the swift advancements in genetics associated with paragangliomas and pheochromocytomas. REFERENCES: Fishbein, L.,et al. (2013). Inherited Mutations in Pheochromocytoma and Paraganglioma: Why All Patients Should Be Offered Genetic Testing. Annals of Surgical Oncology , 20 (5),1444-1450.