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Background: Combination hormonal contraceptives are widely used and are available in various dosage forms. Thromboembolism is an established risk factor associated with the use of these agents, with increased rates of arterial thrombosis and venous thromboembolism reported. Arterial thromboembolism occurs much less frequently and is associated with more serious short‐term and long‐term consequences. Aim: We report a case of aortic thrombus occurring secondary to NuvaRing use with concomitant smoking. There are no other reports of aortic thrombus resulting from contraceptive vaginal ring (CVR) use reported in the literature. Clinical Details: This case describes a 35‐year‐old female patient with disabling claudication, severe aortoiliac stenosis, and end organ damage resulting from a nearly occlusive aortic thrombus with no identifiable source of emboli. The patient's past medical history was significant for tachycardia and tobacco use disorder. Her scheduled medicines most notably included NuvaRing for contraception. Oral anticoagulation was initiated, and the patient agreed to pursue tobacco cessation. Haematology consultation and workup was negative. Months later, an open infrarenal abdominal aorta thromboendarterectomy and bovine patch angioplasty were completed. The clinical pharmacist conducting intensive care unit admission medication reconciliation postoperatively identified continued NuvaRing use, in addition to smoking. NuvaRing was promptly discontinued. Repeat hypercoagulable workup has remained negative. Outcome: Following NuvaRing and smoking cessation, no thrombotic symptoms have recurred. Conclusion: NuvaRing should be considered as potential aetiology for venous and arterial thromboembolism. [ABSTRACT FROM AUTHOR]

Perioperative lumbar drains commonly are placed for spinal cord protection in patients undergoing endovascular aortic repair. However, the logistics of postoperative neuraxial drain removal is challenging in the presence of systemic antithrombotic therapy. This retrospective case series describes the novel use of cangrelor infusions in this high-risk setting. All lumbar drains were placed preoperatively, and descriptive data were collected including cangrelor infusion duration, time to lumbar drain removal after the infusion discontinuation, clinical course, and overall patient outcomes. There were no neurologic complications associated with lumbar drain insertion or removal, and median time to lumbar drain removal was 150 minutes after cangrelor infusion discontinuation. While further study is needed to validate its efficacy and safety, this case series highlights the promise of cangrelor infusions for systemic antithrombotic therapy in the cardiovascular/surgical intensive care unit. [ABSTRACT FROM AUTHOR]

Keratin 17 (KRT17; K17), a non-lamin intermediate filament protein, was recently found to occur in the nucleus. We report here on K17-dependent differences in nuclear morphology, chromatin organization, and cell proliferation. Human tumor keratinocyte cell lines lacking K17 exhibit flatter nuclei relative to normal. Re-expression of wild-type K17, but not a mutant form lacking an intact nuclear localization signal (NLS), rescues nuclear morphology in KRT17-null cells. Analyses of primary cultures of skin keratinocytes from a mouse strain expressing K17 with a mutated NLS corroborated these findings. Proteomics screens identified K17-interacting nuclear proteins with known roles in gene expression, chromatin organization and RNA processing. Key histone modifications and LAP2β (an isoform encoded by TMPO) localization within the nucleus are altered in the absence of K17, correlating with decreased cell proliferation and suppression of GLI1 target genes. Nuclear K17 thus impacts nuclear morphology with an associated impact on chromatin organization, gene expression, and proliferation in epithelial cells. [ABSTRACT FROM AUTHOR]

Plectin is a versatile cytolinker of the plakin family conferring cell resilience to mechanical stress in stratified epithelia and muscles. It acts as a critical organizer of the cytoskeletal system by tethering various intermediate filament (IF) networks through its C-terminal IFbinding domain (IFBD). Mutations affecting the IFBD cause devastating human diseases. Here, we show that serine 4642, which is located in the extreme C-terminus of plectin, is phosphorylated in different cell lines. Phosphorylation of S4642 decreased the ability of plectin IFBD to associate with various IFs, as assessed by immunofluorescence microscopy and cell fractionation studies, as well as in yeast two-hybrid assays. Plectin phosphorylated at S4642 was reduced at sites of IF network anchorage along cell-substrate contacts in both skin and cultured keratinocytes. Treatment of SK-MEL-2 and HeLa cells with okadaic acid increased plectin S4642 phosphorylation, suggesting that protein phosphatase 2A dephosphorylates this residue. Moreover, plectin S4642 phosphorylation was enhanced after cell treatment with EGF, phorbol ester, sorbitol and 8-bromo-cyclic AMP, as well as during wound healing and proteasemediated cell detachment. Using selective protein kinase inhibitors, we identified two different kinases that modulate the phosphorylation of plectin S4642 in HeLa cells: MNK2, which is downstream of the ERK1/2-dependent MAPK cascade, and PKA. Our study indicates that phosphorylation of S4642 has an important regulatory role in the interaction of plectin with IFs and identifies a novel link between MNK2 and the cytoskeleton. [ABSTRACT FROM AUTHOR]

Darier's disease (DD) is an inherited autosomal-dominant skin disorder characterized histologically by loss of adhesion between keratinocytes. DD is typically caused by mutations in sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 (SERCA2), a major regulator of intracellular C2+ homeostasis in the skin. However, a defined role for SERCA2 in regulating intercellular adhesion remains poorly understood. We found that diminution of SERCA2 function by pharmacological inhibition or siRNA silencing in multiple human epidermal-derived cell lines was sufficient to disrupt desmosome assembly and weaken intercellular adhesive strength. Specifically, SERCA2-deficient cells exhibited up to a 60% reduction in border translocation of desmoplakin (DP), the desmosomal cytolinker protein necessary for intermediate filament (IF) anchorage to sites of robust cell-cell adhesion. In addition, loss of SERCA2 impaired the membrane translocation of protein kinase C α (PKCα), a known regulator of DP-IF association and desmosome assembly, to the plasma membrane by up to 70%. Exogenous activation of PKCα in SERCA2-deficient cells was sufficient to rescue the defective DP localization, desmosome assembly, and intercellular adhesive strength to levels comparable to controls. Our findings indicate that SERCA2-deficiency is sufficient to impede desmosome assembly and weaken intercellular adhesive strength via a PKCα-dependent mechanism, implicating SERCA2 as a novel regulator of PKCα signaling. [ABSTRACT FROM AUTHOR]