Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit bioinformation bidirectionally across the plasma membrane. Integrin αIIbβ3 is expressed at a high level in platelets and their progenitors, where it plays a central role in platelet functions, hemostasis, and arterial thrombosis. Integrin αIIbβ3 also participates in cancer progression, such as tumor cell proliferation and metastasis. In resting platelets, integrin αIIbβ3 adopts an inactive conformation. Upon agonist stimulation, the transduction of inside-out signals leads integrin αIIbβ3 to switch from a low- to high-affinity state for fibrinogen and other ligands. Ligand binding causes integrin clustering and subsequently promotes outside-in signaling, which initiates and amplifies a range of cellular events to drive essential platelet functions such as spreading, aggregation, clot retraction, and thrombus consolidation. Regulation of the bidirectional signaling of integrin αIIbβ3 requires the involvement of numerous interacting proteins, which associate with the cytoplasmic tails of αIIbβ3 in particular. Integrin αIIbβ3 and its signaling pathways are considered promising targets for antithrombotic therapy. This review describes the bidirectional signal transduction of integrin αIIbβ3 in platelets, as well as the proteins responsible for its regulation and therapeutic agents that target integrin αIIbβ3 and its signaling pathways.

The most common kind of acute leukemia in adults is acute myeloid leukemia (AML), which is often treated with induction chemotherapy regimens followed by consolidation or allogeneic hematopoietic stem cell transplantation (HSCT). However, some patients continue to develop relapsed or refractory AML (R/R-AML). Small molecular targeted drugs require long-time administration. Not all the patients hold molecular targets. Novel medicines are therefore needed to enhance treatment outcomes. T cells and natural killer (NK) cells engineered with chimeric antigen receptors (CARs) that target antigens associated with AML have recently been produced and are currently being tested in both pre-clinical and clinical settings. This review provides an overview of CAR-T/NK treatments for AML.

Early diagnosis of Parkinson's disease (PD) is still a clinical challenge. Most previous studies using manual or semi-automated methods for segmenting the substantia nigra (SN) are time-consuming and, despite raters being well-trained, individual variation can be significant. In this study, we used a template-based, automatic, SN subregion segmentation pipeline to detect the neuromelanin (NM) and iron features in the SN and SN pars compacta (SNpc) derived from a single 3D magnetization transfer contrast (MTC) gradient echo (GRE) sequence in an attempt to develop a comprehensive imaging biomarker that could be used to diagnose PD. A total of 100 PD patients and 100 age- and sex-matched healthy controls (HCs) were imaged on a 3T scanner. NM-based SN (SN_NM) boundaries and iron-based SN (SN_QSM) boundaries and their overlap region (representing the SNpc) were delineated automatically using a template-based SN subregion segmentation approach based on quantitative susceptibility mapping (QSM) and NM images derived from the same MTC-GRE sequence. All PD and HC subjects were evaluated for the nigrosome-1 (N1) sign by two raters independently. Receiver Operating Characteristic (ROC) analyses were performed to evaluate the utility of SN_NM volume, SN_QSM volume, SNpc volume and iron content with a variety of thresholds as well as the N1 sign in diagnosing PD. Correlation analyses were performed to study the relationship between these imaging measures and the clinical scales in PD. In this study, we verified the value of the fully automatic template based midbrain deep gray matter mapping approach in differentiating PD patients from HCs. The automatic segmentation of the SN in PD patients led to satisfactory DICE similarity coefficients and volume ratio (VR) values of 0.81 and 1.17 for the SN_NM, and 0.87 and 1.05 for the SN_QSM, respectively. For the HC group, the average DICE similarity coefficients and VR values were 0.85 and 0.94 for the SN_NM, and 0.87 and 0.96 for the SN_QSM, respectively. The SN_QSM volume tended to decrease with age for both the PD and HC groups but was more severe for the PD group. For diagnosing PD, the N1 sign performed reasonably well by itself (Area Under the Curve (AUC) = 0.783). However, combining the N1 sign with the other quantitative measures (SN_NM volume, SN_QSM volume, SNpc volume and iron content) resulted in an improved diagnosis of PD with an AUC as high as 0.947 (using an SN threshold of 50ppb and an NM threshold of 0.15). Finally, the SN_QSM volume showed a negative correlation with the MDS-UPDRS III (R² = 0.1, p = 0.036) and the Hoehn and Yahr scale (R² = 0.04, p = 0.013) in PD patients. In summary, this fully automatic template based deep gray matter mapping approach performs well in the segmentation of the SN and its subregions for not only HCs but also PD patients with SN degeneration. The combination of the N1 sign with other quantitative measures (SN_NM volume, SN_QSM volume, SNpc volume and iron content) resulted in an AUC of 0.947 and provided a comprehensive set of imaging biomarkers that, potentially, could be used to diagnose PD clinically.

Integrins are heterodimeric receptors comprising α and β subunits. They are expressed on the cell surface and play key roles in cell adhesion, migration, and growth. Several types of integrins are expressed on the platelets, including αvβ3, αIIbβ3, α2β1, α5β1, and α6β1. Among these, physically αIIbβ3 is exclusively expressed on the platelet surface and their precursor cells, megakaryocytes. αIIbβ3 adopts at least three conformations: i) bent-closed, ii) extended-closed, and iii) extended–open. The transition from conformation i) to iii) occurs when αIIbβ3 is activated by stimulants. Conformation iii) possesses a high ligand affinity, which triggers integrin clustering and platelet aggregation. Platelets are indispensable for maintaining vascular system integrity and preventing bleeding. However, excessive platelet activation can result in myocardial infarction (MI) and stroke. Therefore, finding a novel strategy to stop bleeding without accelerating the risk of thrombosis is important. Regulation of αIIbβ3 activation is vital for this strategy. There are a large number of molecules that facilitate or inhibit αIIbβ3 activation. The interference of these molecules can accurately control the balance between hemostasis and thrombosis. This review describes the structure and signal transduction of αIIbβ3, summarizes the molecules that directly or indirectly affect integrin αIIbβ3 activation, and discusses some novel antiαIIbβ3 drugs. This will advance our understanding of the activation of αIIbβ3 and its essential role in platelet function and tumor development.

Interaction of integrin β3 with c-Src plays critical roles in cellular signaling which is heavily implicated in platelet adhesion and aggregation, as well as in tumor cell proliferation and metastasis or in osteoclastic bone resorption. Selectively blocking integrin αIIbβ3 outside-in signaling in platelets has been a focus of attention because of its effective antithrombotic potential together with a sufficient hemostatic capacity. The myristoylated RGT peptide has been shown to achieve this blockade by targeting the association of c-Src with the integrin β3 tail, but the lack of key information regarding the mechanisms of action prevents this strategy from being further developed into practical antithrombotics. Therefore, in-depth knowledge of the precise mechanisms for RGT peptide in regulating platelet function is needed to establish the basis for a potential antithrombotic therapy by targeting c-Src. The reduction-sensitive peptides were applied to rule out the membrane anchorage after cytoplasmic delivery. The c-Src activity was assayed at living cell or at protein levels to assess the direct effect of RGT targeting on c-Src. Thrombus formation under flow in the presence of cytoplasmic RGT peptide was observed by perfusing whole blood through the collagen-coated micro-chamber. The RGT peptide did not depend on the membrane anchorage to inhibit outside-in signaling in platelets. The myr-AC ~ CRGT peptide readily blocked agonist-induced c-Src activation by disrupting the Src/β3 association and inhibited the RhoA activation and collagen-induced platelet aggregation in addition to the typical outside-in signaling events. The myr-AC ~ CRGT had no direct effect on the kinase activity of c-Src in living cells as evidenced by its inability to dissociate Csk from c-Src or to alter the phosphorylation level of c-Src Y416 and Y527, consistent results were also from in vitro kinase assays. Under flow conditions, the myr-AC ~ CRGT peptide caused an inhibition of platelet thrombus formation predominantly at high shear rates. These findings provide novel insights into the molecular mechanisms by which the RGT peptide regulates integrin signaling and platelet function and reinforce the potential of the RGT peptide-induced disruption of Src/β3 association as a druggable target that would finally enable in vivo and clinical studies using the structure-based small molecular mimetics.

Itgb3‑integrin‑deficient (Itgb3^‑/‑) mice have been reported as a Glanzmann thrombasthenia (GT) model and have been used for platelet research. However, it remains unclear whether this mouse model can fully simulate patients with GT or whether it has different characteristics from these patients. The present study aimed to answer this question. Itgb3^‑/‑ mice were tested for platelet function, tail bleeding, whole‑blood count, bone marrow hematopoiesis and organ enlargement. Itgb3^‑/‑ platelets showed impaired functions, including fibrinogen binding, aggregation, adhesion or spreading. Itgb3^‑/‑ mice demonstrated decreased platelet count and microcytic hypochromic anemia. Reduced iron staining of bone marrow and decreased plasma ferritin level confirmed the diagnosis of iron deficiency anemia. Evident splenomegaly was observed in Itgb3^‑/‑ mice. Immunohistochemical analysis of spleen biopsy revealed normal expression of CD3 and CD19, but elevated expression of CD71, which suggested that the splenomegaly in Itgb3^‑/‑ mice may be associated with extramedullary hematopoiesis. In conclusion, Itgb3^‑/‑ mice exhibited some unique characteristics that differed from those of human patients with GT and thus cannot completely simulate patients with GT.