Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis.

Biosimilars are increasingly available for the treatment of many serious disorders, however some concerns persist about switching a patient to a biosimilar whose condition is stable while on the reference biologic. Randomized controlled studies and extension studies with a switch treatment period (STP) to or from a biosimilar and its reference biologic were identified from publicly available information maintained by the U.S.

Drug-biomarker co-development in oncology - 20 years and counting.

Predictive biomarkers for oncology are necessary to accurately identify patients who will benefit from anticancer treatment. Recently approved oncology drugs target discrete molecular aberrations or pathways in tumor cells and consequently are active on a subset of patient population, yet clinical studies have shown that not all biomarker-positive patients respond. The advancement of predictive biomarkers needs to detect novel and evolving drug resistance mechanisms, not only to guide the selection of patient subsets for specific treatments, but to identify new therapeutic targets.

Differences in binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation.

Kindlins are essential FERM-domain-containing focal adhesion (FA) proteins required for proper integrin activation and signaling. Despite the widely accepted importance of each of the three mammalian kindlins in cell adhesion, the molecular basis for their function has yet to be fully elucidated, and the functional differences between isoforms have generally not been examined. Here, we report functional differences between kindlin-2 and -3 (also known as FERMT2 and FERMT3, respectively); GFP-tagged kindlin-2 localizes to FAs whereas kindlin-3 does not, and kindlin-2, but not kindlin-3, can rescue α5β1 integrin activation defects in kindlin-2-knockdown fibroblasts.

Integrin cytoplasmic tail interactions.

Integrins are heterodimeric cell surface adhesion receptors essential for multicellular life. They connect cells to the extracellular environment and transduce chemical and mechanical signals to and from the cell. Intracellular proteins that bind the integrin cytoplasmic tail regulate integrin engagement of extracellular ligands as well as integrin localization and trafficking.

Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics.

Focal adhesions (FAs), sites of tight adhesion to the extracellular matrix, are composed of clusters of transmembrane integrin adhesion receptors and intracellular proteins that link integrins to the actin cytoskeleton and signaling pathways. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. Migfilin, originally identified in a yeast two-hybrid screen for kindlin-2-interacting proteins, is a LIM domain-containing adaptor protein found in FAs and implicated in control of cell adhesion, spreading, and migration.

Structural and functional characterization of the kindlin-1 pleckstrin homology domain.

Inside-out activation of integrins is mediated via the binding of talin and kindlin to integrin β-subunit cytoplasmic tails. The kindlin FERM domain is interrupted by a pleckstrin homology (PH) domain within its F2 subdomain. Here, we present data confirming the importance of the kindlin-1 PH domain for integrin activation and its x-ray crystal structure at a resolution of 2.

Cell adhesion: a FERM grasp of the tail sorts out integrins.

As well as modulating integrin activation, a conserved NPxY motif in integrin cytoplasmic tails that binds the FERM-domain-containing proteins kindlin and sorting nexin 17 plays pivotal roles in integrin recycling and degradation.

Filamin A controls matrix metalloproteinase activity and regulates cell invasion in human fibrosarcoma cells.

Filamins are an important family of actin-binding proteins that, in addition to bundling actin filaments, link cell surface adhesion proteins, signaling receptors and channels to the actin cytoskeleton, and serve as scaffolds for an array of intracellular signaling proteins. Filamins are known to regulate the actin cytoskeleton, act as mechanosensors that modulate tissue responses to matrix density, control cell motility and inhibit activation of integrin adhesion receptors. In this study, we extend the repertoire of filamin activities to include control of extracellular matrix (ECM) degradation.

A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated αIIbβ3 integrin coactivation.

The activation of heterodimeric integrin adhesion receptors from low to high affinity states occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin β subunits. Binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to the integrin β tail provides one key activation signal, but recent data indicate that the kindlin family of FERM domain proteins also play a central role. Kindlins directly bind integrin β subunit cytoplasmic domains at a site distinct from the talin-binding site, and target to focal adhesions in adherent cells.