Ecto-5'-nucleotidase (Nt5e/CD73)-mediated adenosine signaling attenuates TGFß-2 induced elastin and cellular contraction.

Arterial calcification due to deficiency of CD73 (ACDC) is a rare genetic disease caused by a loss-of-function mutation in the NT5E gene encoding the ecto-5'-nucleotidase (cluster of differentiation 73, CD73) enzyme. Patients with ACDC develop vessel arteriomegaly, tortuosity, and vascular calcification in their lower extremity arteries. Histological analysis shows that patients with ACDC vessels exhibit fragmented elastin fibers similar to that seen in aneurysmal-like pathologies. It is known that alterations in transforming growth factor ß (TGFß) pathway signaling contribute to this elastin phenotype in several connective tissue diseases, as TGFß regulates extracellular matrix (ECM) remodeling. Our study investigates whether CD73-derived adenosine modifies TGFß signaling in vascular smooth muscle cells (SMCs). We show that Nt5e-/- SMCs have elevated contractile markers and elastin gene expression compared with Nt5e+/+ SMCs. Ecto-5'-nucleotidase (Nt5e)-deficient SMCs exhibit increased TGFß-2 and activation of small mothers against decapentaplegic (SMAD) signaling, elevated elastin transcript and protein, and potentiate SMC contraction. These effects were diminished when the A2b adenosine receptor was activated. Our results identify a novel link between adenosine and TGFß signaling, where adenosine signaling via the A2b adenosine receptor attenuates TGFß signaling to regulate SMC homeostasis. We discuss how disruption in adenosine signaling is implicated in ACDC vessel tortuosity and could potentially contribute to other aneurysmal pathogenesis.

Recent Advances in Serum Biomarkers for Risk Stratification and Patient Management in Cardio-Oncology.

PURPOSE OF REVIEW: Following significant advancements in cancer therapeutics and survival, the risk of cancer therapy-related cardiotoxicity (CTRC) is increasingly recognized. With ongoing efforts to reduce cardiovascular morbidity and mortality in cancer patients and survivors, cardiac biomarkers have been studied for both risk stratification and monitoring during and after therapy to detect subclinical disease. This article will review the utility for biomarker use throughout the cancer care continuum. RECENT FINDINGS: A recent meta-analysis shows utility for troponin in monitoring patients at risk for CTRC during cancer therapy. The role for natriuretic peptides is less clear but may be useful in patients receiving proteasome inhibitors. Early studies explore use of myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and others as novel biomarkers in CTRC. Biomarkers have potential to identify subclinical CTRC and may reveal opportunities for early intervention. Further research is needed to elucidate optimal biomarkers and surveillance strategies.

CD73 (Cluster of Differentiation 73) and the Differences Between Mice and Humans.

As vascular disease is complex and the various manifestations are influenced by differences in vascular bed architecture, exposure to shear and mechanical forces, cell types involved, and inflammatory responses, in vivo models are necessary to recapitulate the complex physiology and dynamic cellular interactions during pathogenesis. Murine knockout models are commonly used tools for investigators to study the role of a specific gene or pathway in multifaceted disease traits. Although valuable, these models are not perfect, and this is particularly true in regard to CD73 (cluster of differentiation 73), the extracellular enzyme that generates adenosine from AMP. At baseline, CD73-deficient mice do not present with an overt phenotype, whereas CD73-deficient humans present with the complex phenotype of vascular calcification, arteriomegaly and tortuosity, and calcification in small joints. In this review, we highlight the differences between the mouse and human systems and discuss the potential to leverage findings in mice to inform us on the human conditions.

Effect of Distance From Fertility Center on Utilization of Fertility Preservation Referral in Men.

PURPOSE: Fertility preservation (FP) is underutilized in males with cancer or other diseases requiring gonadotoxic therapies. We sought to evaluate whether patient distance from FP center affected rates of providing a semen analysis after referral. MATERIALS AND METHODS: We performed a retrospective analysis of all males who were referred for FP at a single institution between 2013 and 2021. A multiple logistic regression model was conducted with semen sample submission as the variable of interest. Predictor variables were disease type, distance, and payment method. Secondary outcomes were number of semen samples submitted and number of vials collected. RESULTS: Records of 461 males referred to our center were analyzed. Of these patients, 326 (71%) provided a semen sample after referral and 135 (30%) did not. Further distance from our center was associated with lower odds of submitting a semen sample (OR, 0.85; 95% CI, 0.75 to 0.97; P < .05). For patients who submitted at least one sample, distance did not affect the total number of samples submitted but was associated with a small increase in total vials cryopreserved. CONCLUSION: Men referred for FP exhibit a high rate of sperm cryopreservation. Further distance from FP center was associated with decreased odds to provide semen sample after referral. Our model estimated a 15% decrease in odds of collection with every doubling of distance from our center. Efforts must be made to improve FP utilization for patients traveling far distances, but distance alone should not preclude referral.