The association between HLA class i and ii alleles and the occurrence of inhibitors in Turkish patients with hemophilia a: A pilot study

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A Novel Deletion in FERMT3 Causes LAD-III in a Turkish Family

Leukocyte adhesion deficiency-III (LAD-III) is an extremely rare autosomal recessive syndrome caused by mutations in FERMT3, the gene encoding kindlin-3. The genetic alterations in this gene lead to abnormal expression or activity of kindlin-3 in leukocytes and platelets. Kindlin-3 acts as an important regulator of integrin activation. LAD-III has features of the bleeding syndrome of Glanzmann and also of leukocyte adhesion deficiency. In this study, we report on two families, one of Turkish and one of Syrian origin, with clinical features of LAD-III, loss of kindlin-3 protein expression, and a functional leukocyte defect. A novel, homozygous deletion in FERMT3 (c.921delC, p.Ser307Argfs*21) was found in the Turkish patient. The parents were carriers of the mutation, consistent with an autosomal recessive inheritance. A common c.1525C > T (p.Arg509*) mutation was found in the Syrian patient. In conclusion, beside the variant c.1525C > T in the FERMT3 gene, which was previously found in more than 15 patients in Anatolia, our study is the first to identify the novel homozygous variant c.921delC in the FERMT3 gene

Collision Chronology Along the İzmir‐Ankara‐Erzincan Suture Zone: Insights From the Sarıcakaya Basin, Western Anatolia

International audienceDebate persists concerning the timing and geodynamics of intercontinental collision, style of syncollisional deformation, and development of topography and fold-and-thrust belts along the >1,700-km-long İzmir-Ankara-Erzincan suture zone (İAESZ) in Turkey. Resolving this debate is a necessary precursor to evaluating the integrity of convergent margin models and kinematic, topographic, and biogeographic reconstructions of the Mediterranean domain. Geodynamic models argue either for a synchronous or diachronous collision during either the Late Cretaceous and/or Eocene, followed by Eocene slab breakoff and postcollisional magmatism. We investigate the collision chronology in western Anatolia as recorded in the sedimentary archives of the 90-km-long Sarıcakaya Basin perched at shallow structural levels along the İAESZ. Based on new zircon U-Pb geochronology and depositional environment and sedimentary provenance results, we demonstrate that the Sarıcakaya Basin is an Eocene sedimentary basin with sediment sourced from both the İAESZ and Söğüt Thrust fault to the south and north, respectively, and formed primarily by flexural loading from north-south shortening along the syncollisional Söğüt Thrust. Our results refine the timing of collision between the Anatolides and Pontide terranes in western Anatolia to Maastrichtian-Middle Paleocene and Early Eocene crustal shortening and basin formation. Furthermore, we demonstrate contemporaneous collision, deformation, and magmatism across the İAESZ, supporting synchronous collision models. We show that regional postcollisional magmatism can be explained by renewed underthrusting instead of slab breakoff. This new İAESZ chronology provides additional constraints for kinematic, geodynamic, and biogeographic reconstructions of the Mediterranean domain

Kindlin3-Dependent CD11b/CD18-Integrin Activation Is Required for Potentiation of Neutrophil Cytotoxicity by CD47-SIRPα Checkpoint Disruption.

The CD47–signal regulatory protein-alpha (SIRPα) immune checkpoint constitutes a therapeutic target in cancer, and initial clinical studies using inhibitors of CD47–SIRPα interactions in combination with tumor-targeting antibodies show promising results. Blockade of CD47–SIRPα interaction can promote neutrophil antibody-dependent cellular cytotoxicity (ADCC) toward antibody-opsonized targets. Neutrophils induce killing of antibody-opsonized tumor cells by a process identified as trogoptosis, a necrotic/lytic type of cancer cell death that involves trogocytosis, the antibody-mediated endocytic acquisition of cancer membrane fragments by neutrophils. Both trogocytosis and killing strictly depend on CD11b/CD18-(Mac-1)–mediated neutrophil–cancer cell conjugate formation, but the mechanism by which CD47–SIRPα checkpoint disruption promotes cytotoxicity has remained elusive. Here, by using neutrophils from patients with leukocyte adhesion deficiency type III carrying&nbsp;FERMT3&nbsp;gene mutations, hence lacking the integrin-associated protein kindlin3, we demonstrated that CD47–SIRPα signaling controlled the inside-out activation of the neutrophil CD11b/CD18-integrin and cytotoxic synapse formation in a kindlin3-dependent fashion. Our findings also revealed a role for kindlin3 in trogocytosis and an absolute requirement in the killing process, which involved direct interactions between kindlin3 and CD18 integrin. Collectively, these results identified a dual role for kindlin3 in neutrophil ADCC and provide mechanistic insights into the way neutrophil cytotoxicity is governed by CD47–SIRPα interactions</p