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While awaiting the COVID-19 vaccines, researchers have been actively exploring the effectiveness of existing vaccines against the new virus, among which the BCG vaccine (Bacillus Calmette-Guérin) receives the most attention. While many reports suggest a potential role for BCG immunization in ameliorating SARS-CoV-2 infection, these findings remain controversial. With country-level COVID-19 outbreak data from Johns Hopkins University Coronavirus Resource Center, and BCG program data from World Atlas of BCG Policies and Practices and WHO/UNICE, we estimated a dynamic model to investigate the effect of BCG vaccination across time during the pandemic. Our results reconcile these varying reports regarding protection by BCG against COVID-19 in a variety of clinical scenarios and model specifications. We observe a notable protective effect of the BCG vaccine during the early stage of the pandemic. However, we do not see any strong evidence for protection during the later stages. We also see that a higher proportion of vaccinated young population may confer some level of communal protection against the virus in the early pandemic period, even when the proportion of vaccination in the older population is low. Our results highlight that while BCG may offer some protection against COVID-19, we should be cautious in interpreting the estimated effectiveness as it may vary over time and depend on the age structure of the vaccinated population.

Endothelial microparticles (EMPs) belong to a family of extracellular vesicles that are dynamic, mobile, biological effectors capable of mediating vascular physiology and function. The release of EMPs can impart autocrine and paracrine effects on target cells through surface interaction, cellular fusion, and, possibly, the delivery of intra-vesicular cargo. A greater understanding of the formation, composition, and function of EMPs will broaden our understanding of endothelial communication and may expose new pathways amenable for therapeutic manipulation.

Comprehensive molecular analysis of rare circulating tumor cells (CTCs) and cell clusters is often hampered by low throughput and purity, as well as cell loss. To address this, we developed a fully integrated platform for flow cytometry-based isolation of CTCs and clusters from blood that can be combined with whole transcriptome analysis or targeted RNA transcript quantification. Downstream molecular signature can be linked to cell phenotype through index sorting. This newly developed platform utilizes in-line magnetic particle-based leukocyte depletion, and acoustic cell focusing and washing to achieve >98% reduction of blood cells and non-cellular debris, along with >1.5 log-fold enrichment of spiked tumor cells. We could also detect 1 spiked-in tumor cell in 1 million WBCs in 4/7 replicates. Importantly, the use of a large 200μm nozzle and low sheath pressure (3.5 psi) minimized shear forces, thereby maintaining cell viability and integrity while allowing for simultaneous recovery of single cells and clusters from blood. As proof of principle, we isolated and transcriptionally characterized 63 single CTCs from a genetically engineered pancreatic cancer mouse model (n = 12 mice) and, using index sorting, were able to identify distinct epithelial and mesenchymal sub-populations based on linked single cell protein and gene expression.

The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A -rearranged ( KMT2A -R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A -R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A - AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A- R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A -R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.

Tumor biologist who set the stage for precision medicine Peter C. Nowell, a cancer researcher whose contributions to the field of tumor biology formed the basis of much of today's precision medicine, died in the early hours of 26 December 2016. He was 88 years old. With his passing, the scientific community lost a gifted scholar, a dedicated teacher and mentor, a true gentleman, and a good friend.

The presence of bone marrow (BM) disseminated tumor cells (DTC ) identifies early-stage breast cancer patients at increased risk of recurrence and poorer overall survival. However, limitations in detecting DTC by standard immunohistochemical approaches have hampered clinical application. To address this gap, we developed a flow cytometry-based method, DTC-Flow, that enables the sensitive and efficient detection and molecular characterization of breast cancer DTC . Our analysis identified HER2 as a sensitive marker for detecting breast cancer cells, including those lacking HER2 amplification are claudin-low. DTC-Flow using a HER2/EpCAM/CD45 marker panel enabled >90% cancer cell recovery and sensitivity of one cancer cell per million nucleated BM cells across a range of breast cancer subtypes. Molecular analyses of DTC-Flow-sorted DTC from metastatic patients suggested a quiescent state and demonstrated their close genomic relationship to primary/metastatic tumors, as well as continued genetic evolution. In early-stage breast cancer patients, DTC-Flow detected DTC with greater sensitivity than cytokeratin-based immunohistochemical approaches. Our data support the development of DTC-Flow as a sensitive and specific platform to identify breast cancer patients harboring DTC and better understand the biology of minimal residual disease. Ultimately, this platform could enable the selection of personalized therapeutic approaches based on molecular features of DTC , monitoring of DTC to assess the efficacy of such therapies, and the development of novel therapeutic approaches targeting unique biological vulnerabilities of DTCs in order to eradicate these cells before they can give rise to lethal recurrent cancers.

Circulating endothelial progenitor cells (EPCs) are reduced in patients with systemic lupus erythematosus (SLE). A reduced number of EPCs are associated with the presence of atherosclerosis in other populations. We sought to determine whether the reduction in EPC numbers in SLE is dependent on the presence of advanced coronary artery calcification (CAC). Patients with SLE had previous coronary calcium scores which placed them in either the >75th percentile or <25th percentile for their age. Seventeen patients with SLE and 13 healthy controls (HC) were included in the study. White blood cells were stained for EPC and progenitor cell markers including CD34, CD133, and VEGFR and analyzed by flow cytometry. SLE patients had repeated coronary imaging as well as carotid ultrasound. There was no difference in age between groups. SLE patients with advanced CAC were more likely to be hypertensive, to be smokers, and to have longer disease duration than SLE patients without CAC. SLE patients without evidence of CAC had a significantly lower number of EPCs (CD34+/CD133+/VEGFR+) compared to HC (median (IQR)) 0 (0, 6.7) vs. 10.2 (5.8, 12.3) ( P  = 0.02). Total numbers of PCs (CD133+/CD34+) were not significantly decreased in patients with SLE ((mean ± SEM) 1,007 ± 154 vs. 824 ± 170 ( P  = 0.20)). No significant difference was seen in EPC number between SLE patients without CAC and those with advanced CAC. Increased carotid intima-media thickness did not correlate with CAC or EPC number in SLE patients. Reduced numbers of EPCs in SLE patients may be observed compared to HC even in the absence of CAC. Differences in measured risk factor profiles and depletion of total circulating PCs do not fully explain this finding.

To determine whether exercise increases endothelial progenitor cells (EPCs) in patients with peripheral vascular disease, we developed a multi-parameter flow cytometry assay to rigorously assess EPCs and mature endothelial cells (ECs) in control subjects and patients with peripheral artery disease (PAD) subjected to graded exercise. Blood was collected from young healthy subjects (n = 9, mean age 33 years),older healthy subjects (n = 13,mean age 66 years),and older subjects with PAD (n = 15,mean age 69 years) before and 10 minutes after exercise. White blood cells were isolated and stained with a five-color antibody panel: FITC-anti-CD31, PE-anti-CD146, PE-anti-CD133, PerCP-Cy5.5-anti-CD3,-CD19,-CD33, PE-Cy7-anti-CD34, and APC-anti-VEGF-R2. Viability was assessed by propidium iodide exclusion. Viable, low, side scatter singlets that were CD3-, 19-, and 33-negative were counted. While baseline levels of EPCs and ECs were similar among all subjects, young healthy subjects demonstrated significantly greater (p < 0.05) levels of progenitor cells (PCs) than older healthy and PAD subjects. Levels of EPCs and ECs tended to increase in all subjects after exercise;however,increases in PCs were only observed in young healthy and PAD subjects. Further, trends in the magnitude of change of subsets with exercise were most similar between young and PAD subjects. Our findings suggest that aging may reduce baseline circulating levels of PCs, but not EPCs or ECs, and that exercise-induced mobilization of subsets may differ depending on age and presence of PAD.

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P  = 0.006 compared to historical 1-year OS of 35%, n  = 34) but was not met for sotiga/chemo (48.1%, P  = 0.062, n  = 36) or sotiga/nivo/chemo (41.3%, P  = 0.223, n  = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials. In a randomized phase 2 trial, sotigalimab, a CD40 agonist, did not significantly improve overall survival in patients with previously untreated metastatic pancreatic cancer when combined with chemotherapy or with nivolumab and chemotherapy. Multi-omic exploratory analyses provide insights into immunologic features associated with clinical benefit.