H2A Histone Family Member X (H2AX) Is Upregulated in Ovarian Cancer and Demonstrates Utility as a Prognostic Biomarker in Terms of Overall Survival.

Background: H2AX can be of prognostic value in breast cancer, since in advanced stage patients with high levels, there was an association with worse overall survival (OS). However, the clinical relevance of H2AX in ovarian cancer (OC) remains to be elucidated. Methods: OC H2AX expression studied using the TCGA/GTEX datasets. Subsequently, patients were classified as either high or low in terms of H2AX expression to compare OS and perform gene set enrichment. qRT-PCR validated in-silico H2AX findings followed by immunohistochemistry on a tissue microarray. The association between single nucleotide polymorphisms in the area of H2AX; prevalence and five-year OC survival was tested in samples from the UK Biobank. Results: H2AX was significantly overexpressed in OCs compared to normal tissues, with higher expression associated with better OS (p = 0.010). Gene Set Enrichment Analysis demonstrated gene sets involved in G2/M checkpoint, DNA repair mTORC1 signalling were enriched in the H2AX highly expressing OCs. Polymorphisms in the area around the gene were associated with both OC prevalence (rs72997349-C, p = 0.005) and worse OS (rs10790282-G, p = 0.011). Finally, we demonstrated that H2AX gene expression correlated with γ-H2AX staining in vitro. Conclusions: Our findings suggest that H2AX can be a novel prognostic biomarker for OC.

Drug-coated balloons vs. drug-eluting stents for treatment of long femoropopliteal lesions.

PURPOSE: To compare the performance of drug-coated balloons (DCB) and drug-eluting stents (DES) in long femoropopliteal lesions. METHODS: A retrospective dual center study included 228 patients (139 men; median age 69 years) with femoropopliteal lesions ≥10 cm suffering from peripheral artery disease (Rutherford categories 1-5) treated either with DCB or DES. Propensity score stratification was used to minimize bias. The 131 DCB patients (77 men; mean age 68.9±10.5 years) had a mean lesion length of 194.4±86.3 mm (range 100-450), while the 97 DES patients (62 men; mean age 68.2±8.0 years) had lesions averaging 195.0±64.5 mm (range 100-350) in length. Restenotic lesions were treated in 68 (51.9%) DCB patients and 43 (44.3%) DES patients; over half the lesions in both groups were total occlusions [DCB: 69 (52.7%), DES: 61 (62.9%)]. Outcome measures were patency (peak systolic velocity ratio <2.4), clinically driven target lesion revascularization (TLR), event-free survival, and freedom from worsening of Rutherford classification by ≥2 categories. RESULTS: In the DCB cohort, provisional stent placement was performed in 24 (18.3%) lesions for refractory stenosis (5, 3.8%), flow-limiting dissection (13, 9.9%), and other reasons (6, 4.6%). There was no procedure-related mortality in either cohort. The binary restenosis rates were 23.9% (26/109) and 30.4% (24/79, p=0.319) in the DCB and DES cohorts, respectively, and clinically driven TLR rates were 15.6% (17/109) vs. 19.0% (15/79, p=0.543), respectively. Estimates for freedom from clinically driven TLR and event-free survival were not different between the study cohorts nor were outcomes regarding the ankle-brachial index and Rutherford category. CONCLUSION: DCB and DES perform equally well in the endovascular treatment of femoropopliteal lesions ≥10 cm and better than traditional endovascular treatment. In a real world setting of TASC C and D lesions, the provisional stent rate in the DCB cohort is low.

Eye muscle antibodies and subtype of thyroid-associated ophthalmopathy.

The eye changes associated with Graves' hyperthyroidism can be classified into two subtypes, congestive ophthalmopathy (CO), in which inflammatory changes in the periorbital tissues predominate, and ocular myopathy (OM), in which eye muscle damage is the main feature. Antibodies against the flavoprotein (Fp) subunit of succinate dehydrogenase (SDH), the 64-kd protein, and G2s, a thyroid and eye muscle shared protein of unknown function, are good markers of eye muscle cell damage in patients with OM. Another antigen associated with ophthalmopathy is the flavine adenine nucleotide (FAD) cofactor of several mitochondrial enzymes, including SDH. We tested for serum antibodies against purified human recombinant Fp, FAD, and a G2s fusion protein, in patients with thyroid-associated ophthalmopathy (TAO) and control patients and subjects, in enzyme-linked immunosorbent assay. Antibodies against Fp were detected in 32% of patients with TAO, 30% with Graves' hyperthyroidism (GH), 16% with Hashimoto's thyroiditis (HT), in 14% of patients with multi-nodular goiter (MNG), and in 6% of normal subjects. Antibodies against FAD were found in 24%, 30%, 24%, and 14%, respectively, of these patients and in 12% of the normals, while antibodies against G2s were detected in 50% of patients with TAO, 40% with GH, 40% with HT, in 29% of patients with MNG, and in 7% of normals. We also tested for antibodies against SDH, FAD, and G2s in 12 patients with GH who developed CO (6 patients) or OM (6 patients) after treatment with antithyroid drugs. Of the 6 patients who developed OM, antibodies against SDH preceded the onset of eye disease in 4 and coincided with it in 2, antibodies against G2s preceded eye muscle disease in 5 and coincided with it in 1 patient while antibodies against FAD preceded the development of OM in 5 patients. Of the 6 patients who developed CO, antibodies against SDH were detected in only one patient and borderline levels were demonstrated in 1, while anti-FAD and anti-G2s each preceded the onset of eye signs in 6 patients. Positive sera from another group of patients with TAO, and a second group of normal subjects, were tested at increasing serum dilutions. Sera from the two groups showed similar dilution patterns, except for a few patients with TAO in whom increasing dilutions was associated with increased, then decreased, antibody levels. In this experiment the prevalences of the two antibodies were much greater in patients with TAO namely, 67% for anti-Fp and 89% for anti-G2s, while the prevalences in the normals were 11% and 22%, respectively. The reason for this apparent discrepancy is not clear but may reflect subject and assay differences. Because Fp is found within the mitochondrial membrane it is likely that the corresponding antibodies are produced after eye muscle necrosis, and do not play a role in its pathogenesis. The primary reaction in the eye muscle may be T-cell autoimmunity against G2s, although this has not been proven. The mechanism for the production of antibodies against G2s, FAD, and Fp in subjects who do not have ophthalmopathy is unclear. The significance of such antibodies in control subjects is presently being addressed in our laboratory.