ReseaRch aRticleEpithelial ovarian cancer is the leading cause of death from gynecologic malignancy, and its molecular basis is poorly understood. We previously demonstrated that opioid binding protein cell adhesion molecule (OPCML) was frequently epigenetically inactivated in epithelial ovarian cancers, with tumor suppressor function in vitro and in vivo. Here, we further show the clinical relevance of OPCML and demonstrate that OPCML functions by a novel mechanism in epithelial ovarian cancer cell lines and normal ovarian surface epithelial cells by regulating a specific repertoire of receptor tyrosine kinases: EPHA2, FGFR1, FGFR3, HER2, and HER4. OPCML negatively regulates receptor tyrosine kinases by binding their extracellular domains, altering trafficking via nonclathrin-dependent endocytosis, and promoting their degradation via a polyubiquitination-associated proteasomal mechanism leading to signaling and growth inhibition. Exogenous recombinant OPCML domain 1-3 protein inhibited the cell growth of epithelial ovarian cancers cell in vitro and in vivo in 2 murine ovarian cancer intraperitoneal models that used an identical mechanism. These findings demonstrate a novel mechanism of OPCML-mediated tumor suppression and provide a proofof-concept for recombinant OPCML protein therapy in epithelial ovarian cancers. siGNiFicaNce:The OPCML tumor suppressor negatively regulates a specific spectrum of receptor tyrosine kinases in ovarian cancer cells by binding to their extracellular domain and altering trafficking to a nonclathrin, caveolin-1-associated endosomal pathway that results in receptor tyrosine kinase polyubiquitination and proteasomal degradation. Recombinant OPCML domain 1-3 recapitulates this mechanism and may allow for the implementation of an extracellular tumor-suppressor replacement strategy.

Our data support the advantage of a centralised laboratory for screening an elevated number of samples and making decisions if relying on a clinical network able to provide fast treatment and a good outcome in the screened cases.

An annotated checklist of the 271 strict-endemic taxa (235 species) and 387 near-endemic taxa (337 species) of vascular plants in Mozambique is provided. Together, these taxa constitute c. 9.3% of the total currently known flora of Mozambique and include five strict-endemic genera (Baptorhachis, Emicocarpus, Gyrodoma, Icuria and Micklethwaitia) and two near-endemic genera (Triceratella and Oligophyton). The mean year of first publication of these taxa is 1959, with a marked increase in description noted following the onset of the two major regional floristic programmes, the “Flora of Tropical East Africa” and “Flora Zambesiaca”, and an associated increase in botanical collecting effort. New taxa from Mozambique continue to be described at a significant rate, with 20 novelties described in 2018. Important plant families for endemic and near-endemic taxa include Fabaceae, Rubiaceae and Euphorbiaceae s.s. There is a high congruence between species-rich plant families and endemism with the notable exceptions of the Poaceae, which is the second-most species rich plant family, but outside of the top ten families in terms of endemism, and the Euphorbiaceae, which is the seventh-most species rich plant family, but third in terms of endemism. A wide range of life-forms are represented in the endemic and near-endemic flora, with 49% being herbaceous or having herbaceous forms and 55% being woody or having woody forms. Manica Province is by far the richest locality for near-endemic taxa, highlighting the importance of the cross-border Chimanimani-Nyanga (Manica) Highlands shared with Zimbabwe. A total of 69% of taxa can be assigned to one of four cross-border Centres of Endemism: the Rovuma Centre, the Maputaland Centre sensu lato, and the two mountain blocks, Chimanimani-Nyanga and Mulanje-Namuli-Ribaue. Approximately 50% of taxa have been assessed for their extinction risk and, of these, just over half are globally threatened (57% for strict-endemics), with a further 10% (17% for strict-endemics) currently considered to be Data Deficient, highlighting the urgent need for targeted conservation of Mozambique’s unique flora. This dataset will be a key resource for ongoing efforts to identify “Important Plant Areas – IPAs” in Mozambique, and to promote the conservation and sustainable management of these critical sites and species, thus enabling Mozambique to meet its commitments under the Convention on Biological Diversity (CBD).