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Metastasis to bone frequently occurs in majority of patients with advanced breast cancer and prostate cancer, leading to devastating skeletal-related events and substantially reducing ...the survival of patients. Currently, the crosstalk between tumor cells and the bone stromal compartment was widely investigated for bone metastasis and the resistance to many conventional therapeutic methods. Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein 1), a secreted and chemokine-like glyco-phosphoprotein is involved in tumor progression such as cell proliferation, angiogenesis, and metastasis. The expression of OPN in tumor tissue and plasma has been clinically proved to be correlated to poor prognosis and shortened survival in patients with breast cancer and prostate cancer. This review summarizes the multifaceted roles that OPN plays in bone microenvironment and drug resistance, with emphasis on breast and prostate cancers, via binding to αvβ3 integrin and CD44 receptor and inducing signaling cascades. We further discuss the promising therapeutic strategy for OPN targeting, mainly inhibiting OPN at transcriptional or protein level or blocking it binding to receptor or its downstream signaling pathways. The comprehending of the function of OPN in bone microenvironment is crucial for the development of novel biomarker and potential therapeutic target for the diagnosis and treatment of bone metastasis and against the emergence of drug resistance in advanced cancers.
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.
Abstract
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.
IMPORTANCE: Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE: To test the primary hypothesis that ...therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS: The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20 702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS: Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10 348) or a tablet containing enalapril, 10 mg, alone (n = 10 354). MAIN OUTCOMES AND MEASURES: The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS: During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril–folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril–folic acid group vs 3.4% in the enalapril alone group; hazard ratio HR, 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril–folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril–folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE: Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00794885
Increasing evidence points to the urinary microbiota as a possible key susceptibility factor for early-stage bladder cancer (BCa) progression. However, the interpretation of its underlying mechanism ...is often insufficient, given that various environmental conditions have affected the composition of urinary microbiota. Herein, we sought to rule out confounding factors and clarify how urinary
sp.
promoted non-muscle invasive bladder cancer (NMIBC) development.
Differentially abundant urinary microbiota of 51 NMIBC patients and 47 healthy controls (as Cohort 1) were first determined by metagenomics analysis. Then, we modeled the coculture of NMIBC organoids with candidate urinary
sp.
in anaerobic conditions and explored differentially expressed genes of these NMIBC tissues by RNA-Seq. Furthermore, we dissected the mechanisms involved into
sp.
by inducing extracellular matrix protein 1 (ECM1) and matrix metalloproteinase 9 (MMP9) upregulation. Finally, we used multivariate Cox modeling to investigate the clinical relevance of urinary
sp.
16S ribosomal RNA (16SrRNA) levels to the prognosis of 406 NMIBC patients (as Cohort 2).
sp.
infection accelerated the proliferation of NMIBC organoids (
< 0.01); ECM1 and MMP9 were the most upregulated genes induced by the increased colony forming units (CFU) gradient of
sp.
infection via phosphorylating ERK1/2 in NMIBC organoids of Cohort 1. Excluding the favorable impact of potential contributing factors, the ROC curve of Cohort 2 manifested its 3-year AUC value as 0.79 and the cut-off point of
sp.
16SrRNA as 10.3 (delta CT value).
Our evidence suggests that urinary
sp.
promoted NMIBC progression through the ECM1/MMP9 pathway, which may serve as the promising noninvasive diagnostic biomarker for NMIBC.
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. Keywords: Smokeless tobacco, Oral cavity cancer, Sex-based difference, Meta-analysis
Integrins are main cell adhesion receptors serving as linker attaching cells to extracellular matrix (ECM) and bidirectional hubs transmitting biochemical and mechanical signals between cells and ...their environment. Integrin αvβ3 is a critical family member of integrins and interacts with ECM proteins containing RGD tripeptide sequence. Accumulating evidence indicated that the abnormal expression of integrin αvβ3 was associated with various tumor progressions, including tumor initiation, sustained tumor growth, distant metastasis, drug resistance development, maintenance of stemness in cancer cells. Therefore, αvβ3 has been explored as a therapeutic target in various types of cancers, but there is no αvβ3 antagonist approved for human therapy. Targeting-integrin αvβ3 therapeutics has been a challenge, but lessons from the past are valuable to the development of innovative targeting approaches. This review systematically summarized the structure, signal transduction, regulatory role in cancer, and drug development history of integrin αvβ3, and also provided new insights into αvβ3-based therapeutics in cancer from bench to clinical trials, which would contribute to developing effective targeting αvβ3 agents for cancer treatment.
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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.
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.
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).
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.
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