Inflammatory Mechanisms of Chemokine Receptor 7 expression in Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

The microenvironment of aerodigestive cancers contains tumor promoting inflammatory signals often involved in innate immunity. SCCHN is an epithelial malignancy characterized by the secretion of inflammatory mediators that can promote tumorigenesis and lymph node metastasis. The chemokine receptor CCR7 is a key molecule whose aberrant expression in SCCHN has been linked to pro-survival, invasive and metastatic pathways. Indeed, the selective upregulation of CCR7 in metastatic SCCHN tumors has been previously described. However, the mechanisms of CCR7 expression have not yet been elucidated. Inflammatory cytokines are known to upregulate CCR7 in immune cells through downstream NF-κB dependent mechanisms. In addition, antimicrobial peptides such as human β-defensin 3 (HBD3) are capable of promoting an inflammatory microenvironment and may possess tumor-promoting properties. Given the frequent overexpression NF-κB in SCCHN and its association with a more aggressive SCCHN phenotype, I hypothesized that NF-κB may be a key mediator of invasive and metastatic disease by promoting CCR7 expression in SCCHN tumors. Indeed, I identified and studied four potential NF-κB binding sites in the promoter region upstream of the CCR7 gene and report on their relative contribution to CCR7 expression in metastatic SCCHN. Furthermore, I demonstrate that HBD3 induces CCR7 expression in dendritic cells as well as primary SCCHN tumors in an NF-κB-dependent fashion. Interestingly, HBD3 stimulation provides anti-apoptotic signals to SCCHN cells, as evidenced by tumor resistance to cisplatin-induced cell death. As presented in this dissertation, these findings suggest that HBD3 represents a novel, NF-κB-regulated mediator of CCR7 expression and anti-apoptotic pathways, which may be exploited by developing SCCHN tumors to enhance their growth, survival and evolution into a metastatic phenotype. NF-κB appears to be a key regulator of basal and inducible CCR7 expression. The observed NF-κB induction of CCR7 and its subsequent downstream pathways provide clinically important therapeutic targets to control the progression and metastasis of SCCHN tumors

Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes

Abstract Somatic mutations have a role in the pathogenesis of a number of diseases, particularly cancers. Here we present data supporting a role of mitochondrial somatic mutations in an autoimmune disease, rheumatoid arthritis (RA). RA is a complex, multifactorial disease with a number of predisposition traits, including major histocompatibility complex (MHC) type and early bacterial infection in the joint. Somatic mutations in mitochondrial peptides displayed by MHCs may be recognized as non-self, furthering the destructive immune infiltration of the RA joint. Because many bacterial proteins have mitochondrial homologues, the immune system may be primed against these altered peptides if they mimic bacterial homologues. In addition, somatic mutations may be influencing cellular function, aiding in the acquirement of transformed properties of RA synoviocytes. To test the hypothesis that mutations in mitochondrial DNA (mtDNA) are associated with RA, we focused on the MT-ND1 gene for mitochondrially encoded NADH dehydrogenase 1 (subunit one of complex I – NADH dehydrogenase) of synoviocyte mitochondria from RA patients, using tissue from osteoarthritis (OA) patients for controls. We identified the mutational burden and amino acid changes in potential epitope regions in the two patient groups. RA synoviocyte mtDNA had about twice the number of mutations as the OA group. Furthermore, some of these changes had resulted in potential non-self MHC peptide epitopes. These results provide evidence for a new role for somatic mutations in mtDNA in RA and predict a role in other diseases

Insufficient yet improving involvement of the global south in top sustainability science publications

International audienceThe creation of global research partnerships is critical to produce shared knowledge for the implementation of the UN 2030 Agenda for Sustainable Development. Sustainability science promotes the coproduction of inter- and transdisciplinary knowledge, with the expectation that studies will be carried out through groups and truly collaborative networks. As a consequence, sustainability research, in particular that published in high impact journals, should lead the way in terms of ethical partnership in scientific collaboration. Here, we examined this issue through a quantitative analysis of the articles published in Nature Sustainability (300 papers by 2135 authors) and Nature (2994 papers by 46,817 authors) from January 2018 to February 2021. Focusing on these journals allowed us to test whether research published under the banner of sustainability science favoured a more equitable involvement of authors from countries belonging to different income categories, by using the journal Nature as a control. While the findings provide evidence of still insufficient involvement of Low-and-Low-Middle-Income-Countries (LLMICs) in Nature Sustainability publications, they also point to promising improvements in the involvement of such authors. Proportionally, there were 4.6 times more authors from LLMICs in Nature Sustainability than in Nature articles, and 68.8–100% of local Global South studies were conducted with host country scientists (reflecting the discouragement of parachute research practices), with local scientists participating in key research steps. We therefore provide evidence of the promising, yet still insufficient, involvement of low-income countries in top sustainability science publications and discuss ongoing initiatives to improve this

Who is telling the story? A systematic review of authorship for infectious disease research conducted in Africa, 1980-2016.

Introduction Africa contributes little to the biomedical literature despite its high burden of infectious diseases. Global health research partnerships aimed at addressing Africa-endemic disease may be polarised. Therefore, we assessed the contribution of researchers in Africa to research on six infectious diseases. Methods We reviewed publications on HIV and malaria (2013-2016), tuberculosis (2014-2016), salmonellosis, Ebola haemorrhagic fever and Buruli ulcer disease (1980-2016) conducted in Africa and indexed in the PubMed database using Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. Papers reporting original research done in Africa with at least one laboratory test performed on biological samples were included. We studied African author proportion and placement per study type, disease, funding, study country and lingua franca. Results We included 1182 of 2871 retrieved articles that met the inclusion criteria. Of these, 1109 (93.2%) had at least one Africa-based author, 552 (49.8%) had an African first author and 41.3% (n=458) an African last author. Papers on salmonellosis and tuberculosis had a higher proportion of African last authors (p<0.001) compared with the other diseases. Most of African first and last authors had an affiliation from an Anglophone country. HIV, malaria, tuberculosis and Ebola had the most extramurally funded studies (≥70%), but less than 10% of the acknowledged funding was from an African funder. Conclusion African researchers are under-represented in first and last authorship positions in papers published from research done in Africa. This calls for greater investment in capacity building and equitable research partnerships at every level of the global health community

Ontogeny of human mucosal-associated invariant T cells and related T cell subsets.

Mucosal-associated invariant T (MAIT) cells are semi-invariant V alpha 7.2(+) CD161(high)CD4(-)T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied V alpha 7.2(+) CD161(high) T cell and related subset levels in infancy and after cord blood transplantation. We show that V alpha 7.2(+) and V alpha 7.2(-) CD161(high) T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood V alpha 7.2(+) CD161(high) T cells, the minority recognizing MR1 : 5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1 : 5-OP-RU reactive V alpha 7.2(+) CD161(high) T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other V alpha 7.2(+) CD161(high) and V alpha 7.2(-) CD161(high) populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCR alpha beta chains recognizing MR1-restricted microbial antigens