Dermatology medications with the highest cost burden on Medicare Part D: Potential implications of the Inflation Reduction Act.

Signed into law in August 2022, the Inflation Reduction Act includes provisions requiring the federal government to negotiate prices for medications covered under Medicare Part D. Initial negotiations will target drugs with the highest total spending and price increases relative to inflation. In this study, we identify dermatology prescriptions with the highest cost burden on Medicare Part D and analyze recent trends in total spending and unit costs.

FGF-dependent metabolic control of vascular development.

Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/Fgfr3 double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development.

Indurated purple plaques on the scalp.

Cutaneous epithelioid angiosarcoma is a rare neoplasm of vascular endothelial cell origin that can mimic a cutaneous lymphoma, metastatic carcinoma, or Kaposi sarcoma. It is one of the most malignant cutaneous tumors and early diagnosis is essential, as the tumor metastasizes quickly. We describe a 75-year-old man who presented with three tender, indurated violaceous plaques on his scalp. Biopsy revealed a poorly circumscribed infiltrate extending into the subcutaneous fat, composed of atypical epithelioid cells lining vascular spaces. We provide a brief review of the clinical presentation, histopathologic features, differential diagnosis, and management of this rare tumor.

Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death.

Elevating Akt activation is an obvious clinical strategy to prevent progressive neuronal death in neurological diseases. However, this endeavor has been hindered because of the lack of specific Akt activators. Here, from a cell-based high-throughput chemical genetic screening, we identified a small molecule SC79 that inhibits Akt membrane translocation, but paradoxically activates Akt in the cytosol. SC79 specifically binds to the PH domain of Akt. SC79-bound Akt adopts a conformation favorable for phosphorylation by upstream protein kinases. In a hippocampal neuronal culture system and a mouse model for ischemic stroke, the cytosolic activation of Akt by SC79 is sufficient to recapitulate the primary cellular function of Akt signaling, resulting in augmented neuronal survival. Thus, SC79 is a unique specific Akt activator that may be used to enhance Akt activity in various physiological and pathological conditions.

Lymphatic fate specification: an ERK-controlled transcriptional program.

Lymphatic vessels are intimately involved in the regulation of water and solute homeostasis by returning interstitial fluid back to the venous circulation and play an equally important role in immune responses by providing avenues for immune cell transport. Defects in the lymphatic vasculature result in a number of pathological conditions, including lymphedema and lymphangiectasia. Knowledge of molecular mechanisms underlying lymphatic development and maintenance is therefore critical for understanding, prevention and treatment of lymphatic circulation-related diseases. Research in the past two decades has uncovered several key transcriptional factors (Prox1, Sox18 and Coup-TFII) controlling lymphatic fate specification. Most recently, ERK signaling has emerged as a critical regulator of this transcriptional program. This review summarizes our current understanding of lymphatic fate determination and its transcriptional controls.

Benign purely intraosseous meningioma of the skull: Diagnosis and surgical outcomes.

Primary intraosseous meningioma (PIM) is a rare subtype of extradural meningiomas that originates within bone. We aimed to characterize the clinical, radiographic, and pathologic features of PIM and the resulting outcomes following resection. Herein we examined a retrospective case series of all patients with a pathologically confirmed WHO grade I PIM that were managed at one of three tertiary care centers. Patients with tumors that demonstrated extraosseous extension or involvement of the dura mater were excluded. The main outcomes included surgical safety and duration of local tumor control. Nine patients were identified with benign PIMs, presenting with headaches or painless enlarging subcutaneous masses if involving the calvarium or with neurologic deficits if involving the skull base, or otherwise incidentally identified. Surgery was pursued for symptomatic relief and/or tissue diagnosis. Lesions were evaluated by radiographic imaging - including sensitive detection by plain X-ray films - and definitive diagnosis ascertained by histopathological examination. Maximal resection of both calvarial and skull base lesions was safely tolerated. PIM represents a rare benign skull lesion, whose identification depends on the integration of radiographic findings with intraoperative findings and histopathological confirmation; it should be considered in the differential for slow-growing expansile intraosseous lesions of the skull.