Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis.

ADAM12 belongs to the transmembrane metalloprotease ADAM ("a disintegrin and metalloprotease") family. ADAM12 has been implicated in muscle cell differentiation and fusion, but its precise function remains unknown. Here, we show that ADAM12 is dramatically up-regulated in regenerated, newly formed fibers in vivo. In C2C12 cells, ADAM12 is expressed at low levels in undifferentiated myoblasts and is transiently up-regulated at the onset of differentiation when myoblasts fuse into multinucleated myotubes, whereas other ADAMs, such as ADAMs 9, 10, 15, 17, and 19, are expressed at all stages of differentiation. Using the yeast two-hybrid screen, we found that the muscle-specific ␣-actinin-2 strongly binds to the cytoplasmic tail of ADAM12. In vitro binding assays with GST fusion proteins confirmed the specific interaction. The major binding site for ␣-actinin-2 was mapped to a short sequence in the membrane-proximal region of ADAM12 cytoplasmic tail; a second binding site was identified in the membranedistal region. Co-immunoprecipitation experiments confirm the in vivo association of ADAM12 cytoplasmic domain with ␣-actinin-2. Overexpression of the entire cytosolic ADAM12 tail acted in a dominant negative fashion by inhibiting fusion of C2C12 cells, whereas expression of a cytosolic ADAM12 lacking the major ␣-actinin-2 binding site had no effect on cell fusion. Our results suggest that interaction of ADAM12 with ␣-actinin-2 is important for ADAM12 function.ADAMs (for "a disintegrin and metalloprotease") 1 are a family of transmembrane glycoproteins encoded by at least 30 genes identified in Caenorhabditis elegans, Drosophila, Xenopus, and various mammalian species. The extracellular portion of ADAMs share a high sequence homology and domain organization with the class III snake venom metalloprotease-disintegrins. Both ADAMs and snake venom metalloprotease-disintegrins contain a metalloprotease-like domain with an associated regulatory prodomain, a disintegrin-like domain, a cysteine-rich domain, and an epidermal growth factor-like domain. In addition, ADAMs contain a transmembrane domain and a cytoplasmic tail (1-4). ADAMS with active metalloprotease are involved in diverse and important cellular processes (5-7). ADAM17 (tumor necrosis factor converting enzyme; TACE), ADAM10 (Kuzbanian), and ADAM9 function in the shedding of the ectodomain of membrane-anchored proteins, such as the cytokine tumor necrosis factor-␣ (8, 9), the tumor necrosis factor receptor, transforming growth factor-␣ (10, 11), the heparin-binding epidermal growth factor-like growth factor (12), and the cleavage of the amyloid precusor protein (13-15). ADAM12 is also an active metalloprotease, which binds to ␣2-macroglobulin in vitro (16), but its physiological substrates have not been identified.The other extracellular domains of ADAMs, the disintegrin and the cysteine-rich domains, also play important roles in cell-cell and cell-matrix adhesion, cell differentiation, and fusion. The disintegrin-like domains of ADAMs are the most highly conserved...

The extracellular matrix (ECM), constituting the follicular basal lamina and present also between follicular cells and in the follicular fluid, is believed to regulate granulosa cell (GC) function during follicular development. Ovine GCs isolated from small (1-3 mm in diameter) or large (4-7 mm in diameter) antral follicles were cultured on various pure ECM components (type I collagen, fibronectin, laminin), synthetic substrata enhancing (RGD peptides) or impairing (poly 2-hydroxyethylmethacrylate (poly-hema)) cell adhesion, or in the presence of heparin. The effects of these factors, used alone or in combination with IGF-I and/or FSH, were evaluated in terms of GC spread, survival, proliferation and steroidogenesis.When grown on type I collagen (CI) gel, poly-hema or heparin, GCs from both large and small follicles exhibited a round shape and a low proliferation rate. Compared with non-coated plastic substratum as a control, these ECM or synthetic compounds enhanced estradiol secretion and reduced progesterone secretion by large-follicle GCs. In contrast, GCs from both large and small follicles spread extensively on CI coating, fibronectin, laminin and RGD peptides. Fibronectin and laminin dramatically increased the proliferation rate and enhanced survival of GCs from both origins. Moreover, fibronectin, laminin and RGD peptides reduced estradiol secretion by large-follicle GCs. Unexpectedly, CI coating increased estradiol secretion and reduced progesterone secretion by large-follicle GCs, suggesting that type I collagen was able to maintain estradiol secretion independently of GC shape. Finally, GC responsiveness to IGF-I and FSH, in terms of proliferation and steroidogenesis, was generally maintained when cells were grown on ECM components, RGD peptides and in the presence of heparin. However, when large-follicle GCs were grown as non-adherent clusters (as observed on poly-hema) basal and IGF-I-and/or FSH-stimulated progesterone secretions were totally abolished.Overall, this study shows that GC shape, survival, proliferation and steroidogenesis can be modulated in vitro by pure ECM components in a specific and coordinated manner. It is suggested that, in vivo, fibronectin and laminin would sustain follicular development by enhancing the survival and proliferation of GCs, whereas type I collagen might participate in the maintenance of estradiol secretion in large antral follicles.

ADAMs (a disintegrin and metalloproteases) are members of the metzincin superfamily of metalloproteases. Among integrins binding to disintegrin domains of ADAMs are ␣ 9 ␤ 1 and ␣ v ␤ 3 , and they bind in an RGDindependent and an RGD-dependent manner, respectively. Human ADAM15 is the only ADAM with the RGD motif in the disintegrin domain. Thus, both integrin ␣ 9 ␤ 1 and ␣ v ␤ 3 recognize the ADAM15 disintegrin domain. We determined how these integrins recognize the ADAM15 disintegrin domain by mutational analysis. We found that the Arg 481 and the Asp-Leu-Pro-Glu-Phe residues (residues 488 -492) were critical for ␣ 9 ␤ 1 binding, but the RGD motif (residues 484 -486) was not. In contrast, the RGD motif was critical for ␣ v ␤ 3 binding, but the other residues flanking the RGD motif were not. As the RX 6 DLPEF ␣ 9 ␤ 1 recognition motif (residues 481-492) is conserved among ADAMs, except for ADAM10 and 17, we hypothesized that ␣ 9 ␤ 1 may recognize disintegrin domains in all ADAMs except ADAM10 and 17. Indeed we found that ␣ 9 ␤ 1 bound avidly to the disintegrin domains of ADAM1, 2, 3, and 9 but not to the disintegrin domains of ADAM10 and 17. As several ADAMs have been implicated in sperm-oocyte interaction, we tested whether the functional classification of ADAMs, based on specificity for integrin ␣ 9 ␤ 1 , applies to sperm-egg binding. We found that the ADAM2 and 15 disintegrin domains bound to oocytes, but the ADAM17 disintegrin domain did not. Furthermore, the ADAM2 and 15 disintegrin domains effectively blocked binding of sperm to oocytes, but the ADAM17 disintegrin domain did not. These results suggest that oocytes and ␣ 9 ␤ 1 have similar binding specificities for ADAMs and that ␣ 9 ␤ 1 , or a receptor with similar specificity, may be involved in sperm-egg interaction during fertilization. As ␣ 9 ␤ 1 is a receptor for many ADAM disintegrins and ␣ 9 ␤ 1 and ADAMs are widely expressed, ␣ 9 ␤ 1 -ADAM interaction may be of a broad biological importance. ADAMs1 (a disintegrin and metalloproteases) or MDC (metalloprotease/disintegrin/cysteine-rich) proteins are a family of transmembrane glycoproteins of more than 30 members (see www.people.virginia.edu/ϳjag6n/Table_of_the_ADAMs.html and www.gene.ucl.ac.uk/nomenclature/genefamily/metallo. html). ADAMs have a prodomain, a metalloprotease domain, a disintegrin domain, a cysteine-rich region, an EGF-like domain, a transmembrane domain, and a cytoplasmic tail (1-3). Several ADAMs are involved in crucial biological processes such as fertilization (ADAM1, 2, and 3) (4 -6) and muscle cell differentiation (meltrin-␣, ADAM12) (7, 8). Most, but not all, ADAMs have a catalytically active metalloprotease domain, which processes several biologically important cell surface proteins including tumor necrosis factor-␣ (tumor necrosis factor converting enzyme (TACE), ADAM17) (for reviews, see Refs. 9 and 10), Alzheimer protein precursor (ADAM10 and 17) (11, 12), Delta (ADAM10) (9, 13, 14), and heparin-binding EGF (ADAM9) (15).The ADAM disintegrin domains are homologous to snake ven...

To investigate the involvement of extracellular matrix (ECM) in folliculogenesis in the sheep, parallel changes in ECM components and key steroidogenic enzymes were studied by quantitative immunohistochemistry and immunoblotting during follicular growth and atresia.Growth of ovarian follicles from 1 to 5 mm in diameter was characterized by a progressive increase in P450 cholesterol sidechain cleavage levels in both thecal (p < 0.001) and granulosa cells (p < 0.001), an increase in P450 aromatase levels in granulosa cells of follicles larger than 3.5 mm (p < 0.001), and an increase in levels of P450 17ot-hydroxylase C 17 , 20 lyase (P450 1 7 .) in the theca interna. In addition, during follicular growth, a change in localization of cells expressing P450 17 . within the theca interna was observed, positive cells being sparse within the theca interna of small follicles and specifically located close to the basal laminae in large follicles. In parallel, follicular growth was associated with an increase in levels of type I collagen in granulosa cell layers (p < 0. 01) and an increase in levels of fibronectin (p < 0.05), particularly the specific ED-A alternatively spliced variant of fibronectin, in the theca externa. Follicular atresia was characterized by a loss of P450 aromatase in granulosa cells (p < 0.001) and a decrease in levelsof P450, 17 in the theca interna (p < 0.05). Simultaneously, levels of fibronectin (p < 0.05), particularly the ED-A variant of fibronectin, decreased in the theca externa of atretic follicles. Within the wall of granulosa cells, levels of fibronectin (p < 0.05), laminin, type IV collagen, and heparan sulfate proteoglycans strongly increased during follicular atresia.Overall, these results show that follicular growth and atresia were associated with distinct changes in levels of ECM components, suggesting that ECM components may play a role in the regulation of proliferation, differentiation, and apoptosis of follicular cells.