Leveraging altered lipid metabolism in treating B cell malignancies.

B cell malignancies, comprising over 80 heterogeneous blood cancers, pose significant prognostic challenges due to intricate oncogenic signaling. Emerging evidence emphasizes the pivotal role of disrupted lipid metabolism in the development of these malignancies. Variations in lipid species, such as phospholipids, cholesterol, sphingolipids, and fatty acids, are widespread across B cell malignancies, contributing to uncontrolled cell proliferation and survival. Phospholipids play a crucial role in initial signaling cascades leading to B cell activation and malignant transformation through constitutive B cell receptor (BCR) signaling. Dysregulated cholesterol and sphingolipid homeostasis support lipid raft integrity, crucial for propagating oncogenic signals. Sphingolipids impact malignant B cell stemness, proliferation, and survival, while glycosphingolipids in lipid rafts modulate BCR activation. Additionally, cancer cells enhance fatty acid-related processes to meet heightened metabolic demands. In obese individuals, the obesity-derived lipids and adipokines surrounding adipocytes rewire lipid metabolism in malignant B cells, evading cytotoxic therapies. Genetic drivers such as MYC translocations also intrinsically alter lipid metabolism in malignant B cells. In summary, intrinsic and extrinsic factors converge to reprogram lipid metabolism, fostering aggressive phenotypes in B cell malignancies. Therefore, targeting altered lipid metabolism has translational potential for improving risk stratification and clinical management of diverse B cell malignancy subtypes.

ZFYVE21 promotes endothelial nitric oxide signaling and vascular barrier function in the kidney during aging.

ZFYVE21 is an ancient, endosome-associated protein that is highly expressed in endothelial cells (ECs) but whose function(s) in vivo are undefined. Here, we identified ZFYVE21 as an essential regulator of vascular barrier function in the aging kidney. ZFYVE21 levels significantly decline in ECs in aged human and mouse kidneys. To investigate attendant effects, we generated EC-specific Zfyve21-/- reporter mice. These knockout mice developed accelerated aging phenotypes including reduced endothelial nitric oxide (ENOS) activity, failure to thrive, and kidney insufficiency. Kidneys from Zfyve21 EC-/- mice showed interstitial edema and glomerular EC injury. ZFYVE21-mediated phenotypes were not programmed developmentally as loss of ZFYVE21 in ECs during adulthood phenocopied its loss prenatally, and a nitric oxide donor normalized kidney function in adult hosts. Using live cell imaging and human kidney organ cultures, we found that in a GTPase Rab5- and protein kinase Akt-dependent manner, ZFYVE21 reduced vesicular levels of inhibitory caveolin-1 and promoted transfer of Golgi-derived ENOS to a perinuclear Rab5+ vesicular population to functionally sustain ENOS activity. Thus, our work defines a ZFYVE21- mediated trafficking mechanism sustaining ENOS activity and demonstrates the relevance of this pathway for maintaining kidney function with aging.

Anticoagulation in Patients with Premature Peripheral Artery Disease Undergoing Lower Extremity Revascularization.

BACKGROUND: Premature peripheral artery disease (PAD), defined by lower extremity revascularization (LER) at age ≤ 50 years, is associated with poor major adverse limb events. The early onset of disease is thought to be influenced by genetic factors that regulate homeostasis of the vascular wall and coagulation. The aim of this study is to investigate the effect of anticoagulation as an adjunct to antiplatelet therapy on the outcomes of LER in patients with premature PAD. METHODS: There were 8,804 patients with premature PAD on preoperative and postoperative antiplatelet therapy only and 1,236 patients on preoperative and postoperative anticoagulation plus antiplatelet therapy in the Vascular Quality Initiative peripheral vascular intervention, infrainguinal, and suprainguinal files. Propensity score matching (2:1) was performed between patients with premature PAD who were on antiplatelet therapy and those on anticoagulation plus antiplatelet therapy. Perioperative and 1-year outcomes were analyzed including reintervention, major amputation, and mortality. RESULTS: Patients on anticoagulation were more likely to have coronary artery disease (48.7% vs. 41.2%, P < 0.001), congestive heart failure (20.2% vs. 13.1%, P < 0.001), and have undergone prior LER (73.9% vs. 49.2%, P < 0.001) compared to patients on antiplatelet therapy only. They were also less likely to be independently ambulatory (74.2% vs. 81.8%, P < 0.001) and be on a statin medication (66.8% vs. 74.3%, P < 0.001) compared to patients on antiplatelet therapy only. Patients on anticoagulation were also less likely to be treated for claudication (38.1% vs. 48.6%, P < 0.001), and less likely to be treated with an endovascular procedure (64.8% vs. 73.8%, P < 0.001). After matching for baseline characteristics, there were 1,256 patients on antiplatelet therapy only and 628 patients on anticoagulation. Patients on anticoagulation were more likely to require a return to the operating room (3.7% vs. 1.6%, P < 0.001) and had higher perioperative mortality (1.1% vs. 0.3%, P = 0.032), but major amputation was not significantly different (1.8% vs. 1.6%, P = 0.798) compared to patients on antiplatelet therapy alone. At 1 year, amputation-free survival was higher in patients on antiplatelets only compared to patients on anticoagulation and antiplatelet medications (87.5% vs. 80.9%, log-rank P = 0.001). CONCLUSIONS: Anticoagulation in addition to antiplatelet therapy in patients with premature PAD undergoing LER is associated with increased reintervention and mortality at 1 year.