The HGF/MET signaling pathway is critical in mediating a wide range of normal physiological functions including embryological development, wound healing, and tissue regeneration. Aberrant activation ...of the pathway has frequently been found in human cancers via protein overexpression, mutation, gene amplification, and also paracrine or autocrine up-regulation. In addition, the activation of HGF/MET signaling confers resistance to the effects of cancer treatments. Therefore, inhibition of the HGF/MET signaling pathway has great potential for therapeutic intervention in cancer. Currently, there are three approaches toward modulating HGF/MET signaling in human clinical studies of cancer: anti-HGF monoclonal antibodies, MET monoclonal antibodies, and small molecule MET inhibitors. Preliminary clinical benefit from inhibition of HGF or MET has been reported. This Perspective will provide an overview of the HGF/MET signaling pathway in cancer and then will review the development of small molecule MET inhibitors and their progress in clinical applications.
With the development of antitumor therapies, different treatment methods including monotherapy and combined therapy have achieved clinical efficacy in advanced epidermal growth factor receptor (EGFR) ...mutant non-small cell lung cancer (NSCLC) patients. Exon 19 deletion (ex19del) and exon 21 L858R mutation are common sensitive subtypes of EGFR mutation. However, potential distinct mechanisms are found from several dimensions including molecular structures, biological behaviors, concomitant mutations, resistance mechanisms and tumor mutation burdens. More evidence indicates the prognostic difference of EGFR subgroups. This review focused on the progress of potential distinct mechanisms and outcomes in clinical trials of advanced NSCLC patients with ex19del or exon 21 L858R mutation.
Circular RNAs (circRNAs) represent a class of non-coding RNAs that are widely expressed in mammals. However, it is largely unknown about the function of human circRNAs and the roles of circRNAs in ...human oral squamous cell carcinomas (OSCC). Here we performed a comprehensive study of circRNAs in human OSCC using circRNA and mRNA microarrays, and identified many circRNAs that are differentially expressed between OSCC tissue and paired non-cancerous matched tissue. We further found a circRNA termed circRNA_100290 that served as a critical regulator in OSCC development. We discovered that circRNA_100290 was upregulated and co-expressed with CDK6 in OSCC tissue. Knockdown of circRNA_100290 decreased expression of CDK6 and inhibited proliferation of OSCC cell lines in vitro and in vivo. Via luciferase reporter assays, circRNA_100290 was observed to directly bind to miR-29 family members. Further EGFP/RFP reporter assays showed that CDK6 was the direct target of miR-29b. Taken together, we conclude that circRNA_100290 may function as a competing endogenous RNA to regulate CDK6 expression through sponging up miR-29b family members. Taken together, it indicates that circRNAs may exert regulatory functions in OSCC and may be a potential target for OSCC therapy.
Broadband Ground-Plane Cloak Liu, R; Ji, C; Mock, J.J ...
Science (American Association for the Advancement of Science),
01/2009, Letnik:
323, Številka:
5912
Journal Article
Recenzirano
The possibility of cloaking an object from detection by electromagnetic waves has recently become a topic of considerable interest. The design of a cloak uses transformation optics, in which a ...conformal coordinate transformation is applied to Maxwell's equations to obtain a spatially distributed set of constitutive parameters that define the cloak. Here, we present an experimental realization of a cloak design that conceals a perturbation on a flat conducting plane, under which an object can be hidden. To match the complex spatial distribution of the required constitutive parameters, we constructed a metamaterial consisting of thousands of elements, the geometry of each element determined by an automated design process. The ground-plane cloak can be realized with the use of nonresonant metamaterial elements, resulting in a structure having a broad operational bandwidth (covering the range of 13 to 16 gigahertz in our experiment) and exhibiting extremely low loss. Our experimental results indicate that this type of cloak should scale well toward optical wavelengths.
To evaluate a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and compare it with RT-PCR.
...We designed primers specific to the orf1ab and S genes of SARS-CoV-2. Total viral RNA was extracted using the QIAamp Viral RNA Mini Kit. We optimized the RT-LAMP assay, and evaluated it for its sensitivity and specificity of detection using real-time turbidity monitoring and visual observation.
The primer sets orf1ab-4 and S-123 amplified the genes in the shortest times, the mean (±SD) times were 18 ± 1.32 min and 20 ± 1.80 min, respectively, and 63°C was the optimum reaction temperature. The sensitivities were 2 × 101 copies and 2 × 102 copies per reaction with primer sets orf1ab-4 and S-123, respectively. This assay showed no cross-reactivity with 60 other respiratory pathogens. To describe the availability of this method in clinical diagnosis, we collected 130 specimens from patients with clinically suspected SARS-CoV-2 infection. Among them, 58 were confirmed to be positive and 72 were negative by RT-LAMP. The sensitivity was 100% (95% CI 92.3%–100%), specificity 100% (95% CI 93.7%–100%). This assay detected SARS-CoV-2 in a mean (±SD) time of 26.28 ± 4.48 min and the results can be identified with visual observation.
These results demonstrate that we developed a rapid, simple, specific and sensitive RT-LAMP assay for SARS-CoV-2 detection among clinical samples. It will be a powerful tool for SARS-CoV-2 identification, and for monitoring suspected patients, close contacts and high-risk groups.
Although first-line crizotinib treatment leads to clinical benefit in
lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1
) mutation and progression in the central nervous system ...(CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in
patient-derived preclinical models.
Antitumor activity of repotrectinib was evaluated in
patient-derived preclinical models including treatment-naïve and ROS1
models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model.
Repotrectinib potently inhibited
and
tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood-brain barrier penetrating properties. Notably, repotrectinib showed selective and potent
and
activity against ROS1
. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial.
Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1
with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.
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