Human y chromosome variation and the peopling of the African continent

The analysis, by Next Generation Sequencing, of 1.5 Mb of the Male-Specific region of the Y chromosome (MSY), in a sample carefully selected to represent a wide range of diversity and antiquity among MSY lineages, led to the identification of 2,386 variable positions, 80% of which were novel. Many aspects of this pool of variants resembled the pattern observed among genome- wide de novo events, suggesting that in the MSY a large proportion of newly arisen alleles have survived in the phylogeny. Some degree of purifying selection emerged in the form of an excess of private missense variants. We used these markers to reconstruct a phylogenetic tree, which showed remarkable differences with the one known in literature, although recapitulating the previously known topology. The relative lengths of the tree branches have been notably altered, and the time estimates associated with the tree nodes have moved towards more ancient times. Keeping into account the present day distribution of patrilineages, and the fossil remains of Homo sapiens found to date, our data enabled us to draw hypotheses on the evolutionary events that involved the human species, since its origin, up to its migration out of the African continent

Human y chromosome variation and the peopling of the African continent

The analysis, by Next Generation Sequencing, of 1.5 Mb of the Male-Specific region of the Y chromosome (MSY), in a sample carefully selected to represent a wide range of diversity and antiquity among MSY lineages, led to the identification of 2,386 variable positions, 80% of which were novel. Many aspects of this pool of variants resembled the pattern observed among genome- wide de novo events, suggesting that in the MSY a large proportion of newly arisen alleles have survived in the phylogeny. Some degree of purifying selection emerged in the form of an excess of private missense variants. We used these markers to reconstruct a phylogenetic tree, which showed remarkable differences with the one known in literature, although recapitulating the previously known topology. The relative lengths of the tree branches have been notably altered, and the time estimates associated with the tree nodes have moved towards more ancient times. Keeping into account the present day distribution of patrilineages, and the fossil remains of Homo sapiens found to date, our data enabled us to draw hypotheses on the evolutionary events that involved the human species, since its origin, up to its migration out of the African continent

Metabolic approaches to rescue antitumor Vγ9Vδ2 T-cell functions in myeloma.

Vγ9Vδ2 T cells are immune effector cells very well-suited for immunotherapy, but clinical results have been disappointing in multiple myeloma (MM) and other cancers. We have shown that Vg9Vd2 T cells are victimized prematurely by the immune suppressive tumor microenvironment (TME) established by myeloma and neighbouring cells in the bone marrow (BM) of MM patients. One major mechanism is the highly redundant expression of multiple immunecheckpoints/immune checkpoint-ligands (ICP/ICP-L) in the TME impairing antimyeloma Vg9Vd2 T-cell immune responses. Another major immune suppressive mechanism is the metabolic reset driven by myeloma cells in the TME to satisfy their energetic needs to the detriment of effector cells. Recently, it has become clear that the ICP/ICP-L circuitry and metabolic checkpoints (MCP) jointly operate in the TME of cancer patients to promote tumor cell growth and suppress antitumor immune responses. In this review, we discuss the possible interactions between ICP/ICP-L and MCP in the TME of MM patients that may compromise the immune competence of BM Vγ9Vδ2 T cells, envisaging novel combination therapies to improve the outcome of immune-based interventions

The immune suppressive tumor microenvironment in multiple myeloma: The contribution of myeloid-derived suppressor cells

Myeloid derived suppressors cells (MDSC) play major roles in regulating immune homeostasis and immune responses in many conditions, including cancer. MDSC interact with cancer cells within the tumor microenvironment (TME) with direct and indirect mechanisms: production of soluble factors and cytokines, expression of surface inhibitory molecules, metabolic rewiring and exosome release. The two-way relationship between MDSC and tumor cells results in immune evasion and cancer outgrowth. In multiple myeloma (MM), MDSC play a major role in creating protumoral TME conditions. In this minireview, we will discuss the interplay between MDSC and MM TME and the possible strategies to target MDSC