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Brain metastasis (BrM) is one of the major causes of death in cancer patients and is associated with an estimated 10-40 % of total cancer cases. The survival rate of brain metastatic patients has not improved due to intratumor heterogeneity, the survival adaptations of brain homing metastatic cells, and the lack of understanding of underlying molecular mechanisms that limit the availability of effective therapies. The heterogeneous population of immune cells and tumor-initiating cells or cancer stem cells in the tumor microenvironment (TME) release various factors, such as chemokines that upon binding to their cognate receptors enhance tumor growth at primary sites and help tumor cells metastasize to the brain. Furthermore, brain metastatic sites have unique heterogeneous microenvironment that fuels cancer cells in establishing BrM. This review explores the crosstalk of chemokines with the heterogeneous TME during the progression of BrM and recognizes potential therapeutic approaches. We also discuss and summarize different targeted, immunotherapeutic, chemotherapeutic, and combinatorial strategies (with chemo-/immune- or targeted-therapies) to attenuate chemokines mediated BrM., Competing Interests: Declaration of Competing Interest SKB is co-founder of Sanguine Diagnostics and Therapeutics, Inc. Other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Severe Acute Respiratory Coronavirus (SARS-CoV-2) has been emerging in the form of different variants since its first emergence in early December 2019. A new Variant of Concern (VOC) named the Omicron variant (B.1.1.529) was reported recently. This variant has a large number of mutations in the S protein. To date, there exists a limited information on the Omicron variant. Here we present the analyses of mutation distribution, the evolutionary relationship of Omicron with previous variants, and probable structural impact of mutations on antibody binding. Our analyses show the presence of 46 high prevalence mutations specific to Omicron. Twenty-three of these are localized within the spike (S) protein and the rest localized to the other 3 structural proteins of the virus, the envelope (E), membrane (M), and nucleocapsid (N). Phylogenetic analysis showed that the Omicron is closely related to the Gamma (P.1) variant. The structural analyses showed that several mutations are localized to the region of the S protein that is the major target of antibodies, suggesting that the mutations in the Omicron variant may affect the binding affinities of antibodies to the S protein., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been rapidly evolving in the form of new variants. At least eleven known variants have been reported. The objective of this study was to delineate the differences in the mutational profile of Delta and Delta Plus variants. High-quality sequences (n = 1756) of Delta (B.1.617.2) and Delta Plus (AY.1 or B.1.617.2.1) variants were used to determine the prevalence of mutations (≥20 %) in the entire SARS-CoV-2 genome, their co-existence, and change in prevalence over a period of time. Structural analysis was conducted to get insights into the impact of mutations on antibody binding. A Sankey diagram was generated using phylogenetic analysis coupled with sequence-acquisition dates to infer the migration of the Delta Plus variant and its presence in the United States. The Delta Plus variant had a significant number of high-prevalence mutations (≥20 %) than in the Delta variant. Signature mutations in Spike (G142D, A222V, and T95I) existed at a more significant percentage in the Delta Plus variant than the Delta variant. Three mutations in Spike (K417N, V70F, and W258L) were exclusively present in the Delta Plus variant. A new mutation was identified in ORF1a (A1146T), which was only present in the Delta Plus variant with ~58 % prevalence. Furthermore, five key mutations (T95I, A222V, G142D, R158G, and K417N) were significantly more prevalent in the Delta Plus than in the Delta variant. Structural analyses revealed that mutations alter the sidechain conformation to weaken the interactions with antibodies. Delta Plus, which first emerged in India, reached the United States through England and Japan, followed by its spread to more than 20 the United States. Based on the results presented here, it is clear that the Delta and Delta Plus variants have unique mutation profiles, and the Delta Plus variant is not just a simple addition of K417N to the Delta variant. Highly correlated mutations may have emerged to keep the structural integrity of the virus., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Orthopoxviruses encode multiple proteins that modulate host immune responses. We determined whether cowpox virus (CPXV), a representative orthopoxvirus, modulated innate and acquired immune functions of human primary myeloid DCs and plasmacytoid DCs and monocyte-derived DCs (MDDCs). A CPXV infection of DCs at a multiplicity of infection of 10 was nonproductive, altered cellular morphology, and failed to reduce cell viability. A CPXV infection of DCs did not stimulate cytokine or chemokine secretion directly, but suppressed toll-like receptor (TLR) agonist-induced cytokine secretion and a DC-stimulated mixed leukocyte reaction (MLR). LPS-stimulated NF-κB nuclear translocation and host cytokine gene transcription were suppressed in CPXV-infected MDDCs. Early viral immunomodulatory genes were upregulated in MDDCs, consistent with early DC immunosuppression via synthesis of intracellular viral proteins. We conclude that a nonproductive CPXV infection suppressed DC immune function by synthesizing early intracellular viral proteins that suppressed DC signaling pathways., (Copyright © 2011 Elsevier Inc. All rights reserved.)