The current study explores the impact of CLL on γδ T cells and, in an attempt to better understand the sources of immunosuppression, assesses the impact of M-MDSCs on γδ T cells in vitro.
The study included 163 CLL patients and 34 healthy volunteers. γδ T cells were screened with flow cytometry, including NKG2D, Fas, FasL, and TRAIL staining. Additionally, to deepen understanding of the immunosuppressive impact of CLL on γδ T, a set of in vitro co-cultures of γδ T and M-MDSCs was performed.
RNAseq revealed significant, though relatively minor, changes in the transcriptome. Functional analyses showed a minor drop in cytotoxic potential against CLL cells. Finally, depletion of M-MDSCs from CLL-derived peripheral blood mononuclear cells did not restore γδ T cells' proliferative response.
Altogether, this suggests a minor impact of M-MDSCs on activated γδ T. Thus, it seems probable that other mechanisms than M-MDSCs mediate the negative impact of CLL on circulating γδ T cells.

The sympathetic nervous system (SNS), particularly through the β2 adrenergic receptor (β2-AR), has been linked with breast cancer (BC) and the development of metastatic BC, specifically in the bone. Nevertheless, the potential clinical benefits of exploiting β2-AR antagonists as a treatment for BC and bone loss-associated symptoms remain controversial. In this work, we show that, when compared to control individuals, the epinephrine levels in a cohort of BC patients are augmented in both earlier and late stages of the disease. Furthermore, through a combination of proteomic profiling and functional in vitro studies with human osteoclasts and osteoblasts, we demonstrate that paracrine signaling from parental BC under β2-AR activation causes a robust decrease in human osteoclast differentiation and resorption activity, which is rescued in the presence of human osteoblasts. Conversely, metastatic bone tropic BC does not display this anti-osteoclastogenic effect. In conclusion, the observed changes in the proteomic profile of BC cells under β-AR activation that take place after metastatic dissemination, together with clinical data on epinephrine levels in BC patients, provided new insights on the sympathetic control of breast cancer and its implications on osteoclastic bone resorption.

h4>ABSTRACT/h4> Respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and human parainfluenza virus types one (HPIV1) and three (HPIV3) are a major cause of death, morbidity, and health care costs worldwide, and they can exact a significant toll on immunocompromised patients, the elderly, and those with underlying lung disease. There is an unmet medical need for safe and effective medications for many of the viruses responsible for common respiratory viral infections in vulnerable patient populations. While a protective monoclonal antibody exists for RSV, clinical use is limited to high-risk infant populations. Here, we present the discovery, in vitro characterization, and in vivo efficacy testing of two cross-neutralizing monoclonal antibodies, one targeting both HPIV3 and HPIV1 and the other targeting both RSV and HMPV. The 3×1 antibody is capable of targeting multiple parainfluenza viruses; the MxR antibody shares features with other previously reported monoclonal antibodies that are capable of neutralizing both RSV and HMPV. We obtained structures using cryo-electron microscopy of these antibodies in complex with their antigens to 3.62 Å resolution for 3×1:HPIV3 and to 2.24 Å for MxR:RSV, providing a structural basis to corroborate our in vitro characterization of binding and neutralization. Together, a cocktail of 3×1 and MxR could have clinical utility in providing broad protection against four of the respiratory viruses that cause significant morbidity and mortality in at-risk individuals.

This study aims at profiling the expression of dysregulated genes in circulating monocytes of patients with cancer-related lower limb lymphedema before and after treatment with supermicrosurgical lymphaticovenous anastomosis (LVA).
This prospective longitudinal cohort study enrolled 51 women with post-treatment gynecological cancer, including those with unilateral lymphedema (study group, n = 25) and those without (control group, n = 26). Venous blood samples obtained from the study group before and after LVA and those from the controls were sent for next-generation sequencing, which was validated by real-time PCR. Dysregulated gene expression in the study group, relative to expression in the controls, was recorded before LVA. After one month, postoperative changes in the expression of the identified genes were evaluated. Protein-protein interaction (PPI) was used to investigate dysregulated genes whose expression returned to baseline levels after LVA.
Of the 148 preoperative dysregulated genes, which comprised 108 up- and 40 down-regulated genes, 78 genes, consisting of 69 up- and 9 down-regulated genes, showed post-LVA recovery to baseline levels. Through PPI analysis, five functional modules involving immunity, lipid metabolism, oxidative stress, transcriptional regulators, and tumor suppression, as well as six hub genes (CCL2, LPL, PDK4, FOXO3, EGR1, and DUSP5), were identified. Cross-linking and co-regulated genes between modules were also identified.
Localized lymphedema leads to dysregulated gene expression in circulating monocytes. The current study is the first to identify the hub genes related to lymphedema and demonstrate the recovery of some dysregulated genes after LVA.
© 2022 Yang et al.

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, most of which are caused by atherosclerosis. Discerning processes that participate in macrophage-to-foam cell formation are critical for understanding the basic mechanisms underlying atherosclerosis. To explore the molecular mechanisms of foam cell formation, differentially expressed proteins were identified.
Human peripheral blood mononuclear cells were stimulated with macrophage colony-stimulating factor, and obtained macrophages were transformed into foam cells by oxidized low-density lipoprotein. Tandem mass tag (TMT) labeling combined with mass spectrometry was performed to find associations between foam cell transformation and proteome profiles.
Totally, 5146 quantifiable proteins were identified, among which 1515 and 182 differentially expressed proteins (DEPs) were found in macrophage/monocyte and foam cell/macrophage, respectively. Subcellular localization analysis revealed that downregulated DEPs of macrophages/monocytes were mostly located in the nucleus, whereas upregulated DEPs of foam cells/macrophages were mostly extracellular or located in the plasma membrane. Functional analysis of DEPs demonstrated that cholesterol metabolism-related proteins were upregulated in foam cells, whereas immune response-related proteins were downregulated in foam cells. The protein interaction network showed that the DEPs with the highest interaction scores between macrophages and foam cells were mainly concentrated in lysosomes and the endoplasmic reticulum.
Proteomics analysis suggested that cholesterol metabolism was upregulated, while the immune response was suppressed in foam cells. KEGG enrichment analysis and protein-protein interaction analysis indicated that DEPs located in the endoplasmic reticulum and lysosomes might be key drivers of foam cell formation. These data provide a basis for identifying the potential proteins associated with the molecular mechanism underlying macrophage transformation to foam cells.
© 2021. The Author(s).