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[[beta].sub.IV]-Spectrin, along with ankyrin and [Ca.sup.2+]/calmodulin-dependent kinase II (CaMKII), has been shown to form local signaling domains at the intercalated disc, while playing a key role in the regulation of [Na.sup.+] and [K.sup.+] channels in cardiomyocytes. In this issue of theJCI, Unudurthi et al. show that under chronic pressure overload conditions, CaMKII activation leads to [[beta].sub.IV]-spectrin degradation, resulting in the release of sequestered STAT3 from the intercalated discs. This in turn leads to dysregulation of STAT3-mediated gene transcription, maladaptive remodeling, fibrosis, and decreased cardiac function. Overall, this study presents interesting findings regarding the role of CaMKII and [[beta].sub.IV]-spectrin under physiological as well as pathological conditions., Spectrins in the cardiomyocyte cytoskeletonCardiac function requires tightly regulated signaling from the extracellular space to the cytoplasm across the plasma membrane and from cell to cell across the intercalated disc. [...]

Introduction/Background With newly emerging targeted systemic therapies for atopic dermatitis (AD) there is a need to understand the evolving real-world treatment patterns and implications on AD management. Since the FDA approval of dupilumab for adults in 2017, three additional targeted therapies – the IL-13 inhibitor tralokinumab and 2 JAK inhibitors (abrocitinib and upadacitinib) – were approved for adults with moderate-to-severe AD as of January 2022. Additional treatment options are still awaiting FDA approval, including the IL-31 inhibitor nemolizumab, or undergoing clinical trials (e.g. OX40-OX40L inhibitors). Therefore, an update on real-world contemporary targeted treatment strategies for AD is warranted. Objectives To characterize current systemic treatment patterns in patients with AD. Methods A real-world retrospective observational analysis of US medical and prescription claims data (IQVIA, Durham, NC) was assessed. Individuals with an AD diagnosis were included in analysis if they initiated a modern targeted systemic AD prescription with a dermatology provider at index (patient selection event) for their first line of therapy (LOT) between January 2022 and June 2023, but had no AD systemic treatment 24 months prior to index and were continuously enrolled a minimum of six months for follow-up (n=7006). Treatment patterns, switch rates, comedications, comorbidities, and post-index events were evaluated. Results First line targeted systemic therapies for adults included dupilumab (91.2%), upadacitinib (4.3%), tralokinumab (3.9%), and abrocitinib (0.7%). Fifty-one percent of patients initiating on one of these therapies underwent a change in treatment during the follow-up period. Switch rates for monotherapy use of each of these targeted drugs to another targeted systemic therapy were 5%, 10%, 18%, and 17%, respectively. For the second LOT, dupilumab monotherapy decreased to 11% whereas upadacitinib use increased to 42%, tralokinumab to 25%, and abrocitinib to 8% of LOT-2. On average, switches to LOT-2 occurred within 5.5 months. Switches to later LOTs occurred at quicker rates, with patients switching to a third LOT at 4.6 months and to 4th and 5th LOTs at 3.1 and 3.3 months, respectively. Of patients only treated with a targeted systemic LOT-1, over one third discontinued the drug within ∼5 months and did not switch to another targeted AD therapy. These patients may have switched to other non-targeted systemic treatments, topicals, or ceased any treatment. In addition to those who switched therapies, some patients who remained on their first LOT had evidence of persisting disease burden. For instance, over half of individuals who maintained their first targeted systemic LOT also used topical therapies. Those who persisted on dupilumab treatment despite continuing pruritus (641/6001, 11%) had 2.6x higher rates of post-index biopsy (5% vs 14%, p<.001) accompanied by increased rates of other cutaneous diagnoses such as mycosis fungoides, contact dermatitis, tinea, and seborrheic dermatitis compared to those who did not. This suggests an unclear diagnosis or multiple pruritic conditions in some patients who did not achieve a robust response to targeted treatment. Post-index pruritus was suggestive of a higher level of overall disease burden and comorbidities as observed by increased proportions of patients using topical corticosteroids (61% vs 50%, p<.001) and antianxiety medications (33% vs 20%, p<.001), or seeing emergency medicine (35% vs 25%, p<.001) and cardiovascular specialists (25.9% vs 17.2%, p<.001) post index. As new therapies with different mechanisms of action are approved, there will be more options for patients with incomplete response to first-line AD therapy. Conclusions Irrespective of the index treatment for AD, >50% of patients discontinued or switched therapies. Some patients who remained on index treatment, had indicators of inadequate disease control, suggesting a need for improvement over empirical selection of therapies to support more proactive management strategies in the context of the emerging treatment landscape for AD. [ABSTRACT FROM AUTHOR]

Proper cardiac Ca2+ homeostasis is essential for normal excitation–contraction coupling. Perturbations in cardiac Ca2+ handling through altered kinase activity has been implicated in altered cardiac contractility and arrhythmogenesis. Thus, a better understanding of cardiac Ca2+ handling regulation is vital for a better understanding of various human disease processes. 'Striated muscle preferentially expressed protein kinase' (SPEG) is a member of the myosin light chain kinase family that is key for normal cardiac function. Work within the last 5 years has revealed that SPEG has a crucial role in maintaining normal cardiac Ca2+ handling through maintenance of transverse tubule formation and phosphorylation of junctional membrane complex proteins. Additionally, SPEG has been causally impacted in human genetic diseases such as centronuclear myopathy and dilated cardiomyopathy as well as in common acquired cardiovascular disease such as heart failure and atrial fibrillation. Given the rapidly emerging role of SPEG as a key cardiac Ca2+ regulator, we here present this review in order to summarize recent findings regarding the mechanisms of SPEG regulation of cardiac excitation–contraction coupling in both physiology and human disease. A better understanding of the roles of SPEG will be important for a more complete comprehension of cardiac Ca2+ regulation in physiology and disease. [ABSTRACT FROM AUTHOR]

Updates in the molecular understanding of common and often debilitating skin diseases such as atopic dermatitis (AD) and psoriasis led to the development of multiple targeted systemic drugs. Optimal response to these medications relies on correct diagnosis, as well as clinical, personal and molecular factors unique to each patient. Currently, unstandardized assessment of clinical characteristics and comorbidities drive the development of a therapeutic plan for patients with AD and psoriasis. The molecular mechanisms underlying each patient's disease are not routinely assessed when developing a treatment plan. This empirical approach to treatment selection delays optimal therapeutic response and leads to increased costs to healthcare systems. Therefore, incorporating molecular information from an individual patient's disease should inform better treatment decisions. Previously, we presented the proof of concept for a noninvasive skin scraping sample collection technique by assessing gene expression differences of select genes of interest from psoriasis and AD samples using quantitative polymerase chain reaction. Indeed, candidate genes were differentially expressed in AD and psoriasis lesions relative to nonlesional skin and in AD relative to psoriasis lesions, demonstrating the feasibility of this collection technique. An algorithm based on the gene expression profiles of AD and psoriasis samples could be used to help guide therapy selection. This study aims to assess the molecular profiles of AD and psoriasis samples collected using a noninvasive skin scraping method with the ultimate goal of developing and validating a molecular test for these common inflammatory skin diseases. The superficial epidermis of lesional and nonlesional skin from patients with AD or psoriasis from three dermatology centers in the USA was collected by gently scraping the skin 10 times with a curette and immediately preserving the sample in a proprietary buffer. RNA isolated from samples was stored at −80°C until further use. Library preparation and next generation RNA sequencing was performed using the Ion AmpliSeq Transcriptome Human Gene Expression panel on the S5XL sequencer (ThermoFisher). Differential expression of genes was assessed using DESeq2; Metascape was used to assess enriched gene ontology of differentially expressed genes. When comparing AD lesional and nonlesional skin, 1633 transcripts were differentially expressed (absolute value of log2fold change >1.0 and p adj < 0.05). Additionally, 4468 transcripts were differentially expressed between psoriasis lesional and nonlesional skin. Further, principal component analysis demonstrated that lesional and nonlesional samples for both AD and psoriasis could be distinguished by their respective gene expression profiles. Gene ontology enrichment analysis revealed that innate and adaptive immune system and cytokine signaling genes were among the most common types of differentially expressed genes between lesional and nonlesional samples. Moreover, gene expression differed between lesional AD and psoriasis samples. These results suggest that a molecular test could be developed from AD and psoriasis samples collected by a noninvasive scraping technique. Further, clinical correlation with therapeutic outcomes may be used in conjunction with molecular profiles to develop an algorithm to predict therapeutic response in these common inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy patients are prone to ventricular arrhythmias, which may be caused by abnormal calcium (Ca2+) homeostasis and elevated reactive oxygen species. CaMKII (Ca2+/calmodulin-dependent protein kinase II) is vital for normal Ca2+ homeostasis, but excessive CaMKII activity contributes to abnormal Ca2+ homeostasis and arrhythmias in cardiomyocytes. Reactive oxygen species induce CaMKII to become autonomously active. We hypothesized that genetic inhibition of CaMKII oxidation (ox-CaMKII) in a mouse model of Duchenne muscular dystrophy can alleviate abnormal Ca2+ homeostasis, thus, preventing ventricular arrhythmia. The objective of this study was to test if selective loss of ox-CaMKII affects ventricular arrhythmias in the mdx mouse model of Duchenne muscular dystrophy.Methods and Results: 5-(6)-Chloromethyl-2,7-dichlorodihydrofluorescein diacetate staining revealed increased reactive oxygen species production in ventricular myocytes isolated from mdx mice, which coincides with elevated ventricular ox-CaMKII demonstrated by Western blotting. Genetic inhibition of ox-CaMKII by knockin replacement of the regulatory domain methionines with valines (MM-VV [CaMKII M281/282V]) prevented ventricular tachycardia in mdx mice. Confocal calcium imaging of ventricular myocytes isolated from mdx:MM-VV mice revealed normalization of intracellular Ca2+ release events compared with cardiomyocytes from mdx mice. Abnormal action potentials assessed by optical mapping in mdx mice were also alleviated by genetic inhibition of ox-CaMKII. Knockout of the NADPH oxidase regulatory subunit p47 phox normalized elevated ox-CaMKII, repaired intracellular Ca2+ homeostasis, and rescued inducible ventricular arrhythmias in mdx mice.Conclusions: Inhibition of reactive oxygen species or ox-CaMKII protects against proarrhythmic intracellular Ca2+ handling and prevents ventricular arrhythmia in a mouse model of Duchenne muscular dystrophy. [ABSTRACT FROM AUTHOR]

Framingham Heart Study suggests that dysfunction of steroid receptor coactivator-1 may be involved in the development of hypertension. However, there is no functional evidence linking steroid receptor coactivator-1 to the regulation of blood pressure. We used immunohistochemistry to map the expression of steroid receptor coactivator-1 protein in mouse brain, especially in regions implicated in the regulation of blood pressure. Steroid receptor coactivator-1 protein was found in central amygdala, medial amygdala, supraoptic nucleus, arcuate nucleus, ventromedial, dorsomedial, paraventricular hypothalamus, and nucleus of the solitary tract. To determine the effects of steroid receptor coactivator-1 protein on cardiovascular system we measured blood pressures, blood flow velocities, echocardiographic parameters, and aortic input impedance in female steroid receptor coactivator-1 knockout mice and their wild type littermates. Steroid receptor coactivator-1 knockout mice had higher blood pressures and increased aortic stiffness when compared to female wild type littermates. Additionally, the hearts of steroid receptor coactivator-1 knockout mice seem to consume higher energy as evidenced by increased impedance and higher heart rate pressure product when compared to female wild type littermates. Our results demonstrate that steroid receptor coactivator-1 may be functionally involved in the regulation of blood pressure and aortic stiffness through the regulation of sympathetic activation in various neuronal populations. [ABSTRACT FROM AUTHOR]

Background: While patients with localized cutaneous melanoma (CM) generally have good five-year melanoma-specific survival rates, identifying patients with localized disease at a high risk of recurrence could allow them access to additional follow-up or surveillance.Objective: We sought to examine the prognostic value of the 31-gene expression profile (31-GEP) test for the risk of recurrence in stage I CM patients according to 31-GEP main class (low risk: Class 1 vs. high-risk: Class 2) and the lowest and highest risk 31-GEP subclasses (Class 1A vs. Class 2B).Methods: Data from a previously described meta-analysis detailing the 31-GEP results for patients with stage I CM (N = 623) were re-analyzed to determine 31-GEP accuracy.Results: Patients with stage I CM and a Class 1 31-GEP result were less likely to have a recurrence (15/556; 2.7% vs. 6/67; 9.0%; p=0.018) than patients with a Class 2 result and had a higher five-year recurrence-free survival (RFS) (96% vs. 85%). Patients with a Class 2 result were 2.8 times as likely to experience a recurrence (positive likelihood ratio: 2.82; 95% confidence interval: 1.38-5.77). In a subset of patients with stage I CM stratified further into 31-GEP subclasses (n = 206), patients with a Class 1A result had a higher five-year RFS than those with a Class 2B result (98% vs. 73%). Patients with a Class 2B result were also 6.5 times as likely to experience a recurrence (positive likelihood ratio: 6.45; 95% confidence interval: 2.44-17.00) than those with a Class 1A result, and the 31-GEP had a negative predictive value of 96.3% (95% confidence interval: 92.3%-98.4%).Conclusion: The 31-GEP test significantly differentiates between low and high recurrence risk in patients with stage I CM. [ABSTRACT FROM AUTHOR]

Objective: The 31-gene expression profile (31-GEP) can predict the risk of recurrence and metastasis in cutaneous melanoma (CM). We assessed the viewpoints and use of 31-GEP testing by physician assistants (PAs) and nurse practitioners (NPs) for patients with CM., Methods: NPs and PAs ( n = 369) completed an 18-question online survey about their viewpoints and use of the 31-GEP risk-stratification test., Results: Most practitioners ( n = 334, 90.5%) felt prognostic testing improved patient care and would recommend the 31-GEP to a colleague ( n = 333, 90.2%) or a friend or family member ( n = 289, 78.3%) who was diagnosed with CM. The 31-GEP test was used by 176 respondents in the preceding 12 months (53%). Among users of the 31-GEP test, 78% stated that the results would impact follow-up schedule and referral, 66% overall treatment decisions, 62% sentinel lymph node biopsy recommendations, and 50% surveillance imaging. In thin tumors (≤ 1 mm), 82% of 31-GEP users and 44% of nonusers stated that the 31-GEP results would impact their treatment plan decisions., Conclusion: The 31-GEP test significantly impacts treatment plans in CM, particularly for thin and stage I melanomas. Importantly, even nonusers stated that 31-GEP test results would impact treatment plans as well as recommendations to a friend or family member., Competing Interests: This study was funded by Castle Biosciences, Inc. Ms. Block has no conflicts of interest and nothing to declare. Ms. Patterson, Dr. Siegel, Dr. Martin, and Dr. Quick are employees, and stock and options holders at Castle Biosciences, Inc. Ms. Hunt is on the speakers bureau at Castle Biosciences, Inc., (© 2023 BroadcastMed LLC.)