Purpose: Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, ChemR23. RARRES2 is widely expressed in nonhematopoietic tissues and often downregulated across multiple tumor types compared with normal tissue. Recent studies show that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, in part, by immune effector cells recruitment. However, as tumor cells express functional chemokine/chemoattractant receptors that impact their phenotype, we hypothesized that chemerin may have additional, tumor-intrinsic effects. Experimental Design: We investigated the effect of exogenous chemerin on human prostate and sarcoma tumor lines. Key signaling pathway components were elucidated using qPCR, Western blotting, siRNA knockdown, and specific inhibitors. Functional consequences of chemerin treatment were evaluated using in vitro and in vivo studies. Results: We show for the first time that human tumors exposed to exogenous chemerin significantly upregulate PTEN expression/ activity, and concomitantly suppress programmed death ligand-1 (PD-L1) expression. CMKLR1 knockdown abrogated chemerininduced PTEN and PD-L1 modulation, exposing a novel CMKLR1/ PTEN/PD-L1 signaling cascade. Targeted inhibitors suggested signaling was occurring through the PI3K/AKT/mTOR pathway. Chemerin treatment significantly reduced tumor migration, while significantly increasing T-cell-mediated cytotoxicity. Chemerin treatment was as effective as both PD-L1 knockdown and the anti-PD-L1 antibody, atezolizumab, in augmenting T-cellmediated tumor lysis. Forced expression of chemerin in human DU145 tumors significantly suppressed in vivo tumor growth, and significantly increased PTEN and decreased PD-L1 expression. Conclusions: Collectively, our data show a novel link between chemerin, PTEN, and PD-L1 in human tumor lines, which may have a role in improving T-cell-mediated immunotherapies.

Both apheresis protocols collect sufficient numbers of PBSCs for allogeneic transplantation. The AutoPBSC operates in a fully automatic fashion, avoiding manual adjustment and interindividual variations. The loss of platelets is lower with AutoPBSC than with Version 4.7, but the apheresis time is slightly longer.

Myeloproliferative neoplasms (MPN) are chronic blood diseases with significant morbidity and mortality. Although sequencing studies have elucidated the genetic mutations that drive these diseases, MPNs remain largely incurable with a significant proportion of patients progressing to rapidly fatal secondary acute myeloid leukemia (sAML). Therapeutic discovery has been hampered by the inability of genetically engineered mouse models to generate key human pathologies such as bone marrow fibrosis. To circumvent these limitations, here we present a humanized animal model of myelofibrosis (MF) patient-derived xenografts (PDX). These PDXs robustly engrafted patient cells that recapitulated the patient's genetic hierarchy and pathologies such as reticulin fibrosis and propagation of MPN-initiating stem cells. The model can select for engraftment of rare leukemic subclones to identify patients with MF at risk for sAML transformation and can be used as a platform for genetic target validation and therapeutic discovery. We present a novel but generalizable model to study human MPN biology. SIGNIFICANCE:Although the genetic events driving MPNs are well defined, therapeutic discovery has been hampered by the inability of murine models to replicate key patient pathologies. Here, we present a PDX system to model human myelofibrosis that reproduces human pathologies and is amenable to genetic and pharmacologic manipulation.

Myeloproliferative neoplasms (MPNs) are chronic blood diseases with significant morbidity and mortality. While sequencing studies have elucidated the genetic mutations that drive these diseases, MPNs remain largely incurable with a significant proportion of patients progressing to rapidly fatal secondary acute myeloid leukemia (sAML). Therapeutic discovery has been hampered by the inability of genetically-engineered mouse models to generate key human pathologies such as bone marrow fibrosis. To circumvent these limitations, here we present a humanized animal model of myelofibrosis (MF) patient-derived xenografts (PDXs). These PDXs robustly engrafted patient cells which recapitulated the patient’s genetic hierarchy and pathologies such as reticulin fibrosis and propagation of MPN-initiating stem cells. The model can select for engraftment of rare leukemic subclones to identify MF patients at-risk for sAML transformation, and can be used as a platform for genetic target validation and therapeutic discovery. We present a novel but generalizable model to study human MPN biology.STATEMENT OF SIGNIFICANCEAlthough the genetic events driving myeloproliferative neoplasms (MPNs) are well-defined, therapeutic discovery has been hampered by the inability of murine models to replicate key patient pathologies. Here, we present a patient-derived xenograft (PDX) system to model human myelofibrosis that reproduces human pathologies and is amenable to genetic and pharmacological manipulation.

The acute phase of severe acute respiratory syndrome coronavirus 2 [coronavirus disease (COVID)] infection has many well-documented cardiovascular manifestations, however, the long-term sequelae are less understood. In this focused review, we explore the risk factors, character, and rates of cardiovascular events in patients with Long COVID, which is defined as symptoms occurring more than 4 weeks following initial infection.Research has identified increased rates of cerebrovascular disease, dysrhythmias, ischemic and inflammatory heart disease, cardiopulmonary symptoms, and thrombotic events among those with Long COVID, though the risk rates and potential mechanisms behind each cardiovascular event vary. Finally, we discuss the current gaps in the literature as well as how COVID compares to other viral infections when it comes to causing long-term cardiovascular sequelae.