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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

Motivated by the structure evolution experiments of Janus NiAu nanoparticles (NPs), we present a detailed study on the thermodynamic evolution of Ni and Au NPs with different ratios of Au and Ni through the molecular dynamics (MD) simulations. It is found that, for fixed Ni particle size (5.8 nm in diameter), the energy variation with the increasing temperature is related to the Au sizes (1.5–9.6 nm in diameter), due to the diverse atomic segregation modes. For a small Au particle, due to lattice induction, the structure will change from order to disorder and then to order. The interface defects of the merging NPs could be automatically eliminated by coalescence processes. The change in energy as the temperature increases is similar to that of monometallic NPs. For larger Au particles, the irregular variation of energy occurs and the atomic energy experience one or two reductions at least with the increase of the temperature. The segregation of Au atoms to the surface of Ni particle is dominant during the continuous heating process. The coalescence processes of Au atoms strongly determine the final morphology of the particles. Dumbbell-like, Janus and eccentric core–shell spherical structures could be obtained during the heating process. Our results will provide an effective approach to the design of novel materials with specific properties through thermal control.

Background The impact of smokeless tobacco (SLT) use on the risk of oral cavity cancer (OCC) has been confirmed; however, the sex-based difference in this association remains inconclusive. Therefore, this study aimed to estimate the association between SLT use and OCC risk in women and compared it to that in men. Methods PubMed, Embase, and Cochrane Library databases were systematically searched for eligible studies from their inception up to August 2020. Studies reporting the effect estimates of SLT use on OCC risk in men and women, were eligible for inclusion. The relative risk ratio (RRR) was applied to calculate the sex-based difference in the relationship between SLT use and OCC risk, and pooled analysis was conducted using a random-effects model with inverse variance weighting. Results Nineteen studies reporting a total of 6593 OCC cases were included in the final meta-analysis. The pooled relative risk (RR) suggested that SLT use was associated with an increased risk of OCC in both men (RR, 2.94; 95% confidence interval [CI], 2.05–4.20; P  < 0.001) and women (RR, 6.39; 95%CI, 3.16–12.93; P  < 0.001). Moreover, the SLT-use-related risk of OCC was higher in women than that in men (RRR,1.79; 95%C, 1.21–2.64; P  = 0.003). The risk of OCC related to SLT use in women was still significantly higher than that in men (RRR, 1.75; 95%CI, 1.15–2.66; P  = 0.008) after excluding indirect comparison results. Finally, a subgroup analysis suggested significant sex-based differences only in individuals who received chewed smokeless products, regardless of the control definition. Pooled analysis of studies with high design quality confirmed the notably higher risk of OCC in women than in men. Conclusions This study found that SLT use was associated with a higher risk of OCC in women than in men. Further large-scale prospective cohort studies should be conducted to verify sex-based differences in the association between use of specific smokeless products and OCC risk.

Background The treatment of tuberous sclerosis complex (TSC) using mammalian target of rapamycin (mTOR) inhibitors is clinically promising. The aim of the present study was to evaluate the efficacy and safety of mTOR inhibitors for improving the clinical symptoms of TSC. Methods We performed a systematic search of major electronic databases (PubMed, EMBASE, Cochrane Library and WanFang, CNKI, and VIP databases) to identify randomized controlled trials (RCTs) and quasi-randomized studies from the date of database inception to November 2017; the Chinese Food and Drug Administration and clinicaltrials.gov were also searched for unpublished studies. The endpoints of the study were the tumor response rate and seizure frequency response rate (the proportion of patients achieving a ≥ 50% reduction relative to the baseline). Two researchers screened articles, assessed the risk of bias and extracted data independently. The included RCTs were analyzed using RevMan 5.3, which was provided by the Cochrane Collaboration. Results Compared with the placebo, mTOR inhibitors significantly reduced tumor volume in both angiomyolipoma (AML) (RR = 24.69, 95% CI = 3.51,173.41, P  = 0.001) and subependymal giant cell astrocytoma (SEGA) (RR = 27.85, 95% CI = 1.74,444.82, P  = 0.02). Compared with the placebo, mTOR inhibitors significantly reduced seizure frequency (RR = 2.12, 95% CI = 1.41,3.19, P  = 0.0003). Regarding safety, compared with patients who did not receive mTOR inhibitors, those who did had a higher risk of suffering stomatitis (RR = 3.20, 95% CI = 1.49,6.86, P  = 0.003). In contrast, patients who did and did not receive mTOR inhibitors experienced similar adverse events, such as upper respiratory tract infections (RR = 1.08, 95% CI = 0.81,1.45, P  = 0.59) and nasopharyngitis (RR = 0.86, 95% CI = 0.60,1.21, P  = 0.38). Conclusion In view of the efficacy and safety associated with tumor and seizure frequency in the TSC patients, mTOR inhibitors is a good therapeutic choice. Unlike the risks of upper respiratory tract infections and nasopharyngitis, mTOR inhibitors seem to increase the risk of stomatitis, mostly grade 1 and 2.

A number of tryptophan metabolites known to be neuroactive have been examined for their potential associations with cognitive deficits in schizophrenia. Among these metabolites, kynurenic acid (KYNA), 5-hydroxyindole (5-HI), and quinolinic acid (QUIN) are documented in their diverse effects on α-7 nicotinic acetylcholine receptor (α7nAChR) and/or N-methyl-D-aspartate receptor (NMDAR), two of the receptor types thought to contribute to cognitive impairment in schizophrenia. In this study, serum levels of KYNA, 5-HI, and QUIN were measured in 195 patients with schizophrenia and in 70 healthy controls using liquid chromatography-tandem mass spectrometry; cognitive performance in MATRICS Consensus Cognitive Battery and cortical thickness measured by magnetic resonance imaging were obtained. Patients with schizophrenia had significantly lower serum KYNA (p < 0.001) and QUIN (p = 0.02) levels, and increased 5-HI/KYNA (p < 0.001) and QUIN/KYNA ratios (p < 0.001) compared with healthy controls. Multiple linear regression showed that working memory was positively correlated with serum 5-HI levels (t = 2.10, p = 0.04), but inversely correlated with KYNA concentrations (t = −2.01, p = 0.05) in patients. Patients with high 5-HI and low KYNA had better working memory than other subgroups (p = 0.01). Higher 5-HI levels were associated with thicker left lateral orbitofrontal cortex (t = 3.71, p = 2.94 × 10−4) in patients. The different effects of 5-HI and KYNA on working memory may appear consistent with their opposite receptor level mechanisms. Our findings appear to provide a new insight into the dynamic roles of tryptophan pathway metabolites on cognition, which may benefit novel therapeutic development that targets cognitive impairment in schizophrenia.

Platelets are essential for blood clotting and maintaining normal hemostasis. In pathological conditions, platelets are increasingly recognized as crucial regulatory factors in various immune-mediated inflammatory diseases. Resting platelets are induced by various factors such as immune complexes through Fc receptors, platelet-targeting autoantibodies and other platelet-activating stimuli. Platelet activation in immunological processes involves the release of immune activation stimuli, antigen presentation and interaction with immune cells. Platelets participate in both the innate immune system (neutrophils, monocytes/macrophages, dendritic cells (DCs) and Natural Killer (NK) cells and the adaptive immune system (T and B cells). Clinical therapeutic strategies include targeting platelet activation, platelet-immune cell interaction and platelet-endothelial cell interaction, which display positive development prospects. Understanding the mechanisms of platelets in immunity is important, and developing targeted modulations of these mechanisms will pave the way for promising therapeutic strategies. Graphical abstract

The optical control of dielectric properties is a topic of concern, as it involves the development of new non-contact optoelectronic devices. The bandgap of dielectric materials is generally large, and only high-energy ultraviolet light can modulate the dielectric properties of these materials. Here, we present the Maxwell-Wagner relaxation in polycrystalline SmCrO 3 that can be modulated by visible light. The rate of change of dielectric constant shows negative and then positive change with frequency, with a minimum of −51% at 100 Hz (measure voltage 0.1 Ṽ) and a maximum of +654% peak around 8 kHz. Although Ti-doped SmCrO 3 samples become insulators, visible light can still modulate the appearance of Debye relaxation peaks, and a maximum of +790% ultrasensitive low-frequency photo-dielectric variation was observed in SmTi 0.05 Cr 0.95 O 3 sample. Analysis shows that localized features of the photogenerated carriers are the reason for the change in bidirectional photosensitive dielectric properties. The optical control of dielectric properties is important for developing non-contact optoelectronic devices. Here, the authors demonstrate a large modulation of the dielectric constant in polycrystalline SmCrO3 by visible light.