Osimertinib has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) in clinical trials. However, real-world data on its ...effectiveness remain scarce. Taiwanese patients with T790M-positive locally advanced or metastatic NSCLC and progressive disease following treatment with at least one EGFR tyrosine kinase inhibitor (TKI) were enrolled from the osimertinib early access program. Of the 419 patients (mean age, 63 years; female, 67%), 53% were heavily pretreated (≥ third-line 3L), making osimertinib a fourth-line (4L) intervention. The median progression-free survival (PFS) was 10.5 months (95% confidence interval CI: 8.95-11.41); the 18-month PFS rate was 26.5%. The median overall survival (OS) was 19.0 months (95% CI: 16.30-20.95); the 24-month OS rate was 40.9%. The objective response rate was 32.46%, and the disease control rate was 86.38%. The median time to treatment discontinuation of osimertinib monotherapy was 11.9 months (95% CI: 10.49-13.11). Subgroup analyses of median PFS and OS in the chemotherapy combination group vs. the osimertinib monotherapy group yielded no difference. Central nervous system (CNS) metastasis, number of prior lines of therapy, and types of initial EGFR-TKIs did not significantly impact outcomes. The median PFS values were 9.0 (95% CI: 5.18-11.34) and 10.9 (95% CI: 9.18-11.90) months with and without CNS metastasis, respectively, and 10.8 (95% CI: 8.59-12.69), 13.6 (95% CI: 10.89-16.3), and 9.2 (95% CI: 7.8-10.62) months for second-line (2L), 3L, and ≥4L therapy, respectively. In patients who received osimertinib as 2L therapy, the median PFS values in response to prior afatinib, erlotinib and gefitinib treatment were 11.2 (95% CI: 4.85-4.79), 10.5 (95% CI: 8.59-20.26) and 8.7 (95% CI: 7.21-16.79) months, respectively. Overall, real-world data from Taiwan support the clinical benefits of osimertinib in EGFR T790M -positive NSCLC.
Herein we report the employment of the quintuply bonded dichromium amidinates Cr{κ2‐HC(N‐2,6‐iPr2C6H3)(N‐2,6‐R2C6H3)}2 (R=iPr (1), Me (7)) as catalysts to mediate the 2+2+2 cyclotrimerization of ...terminal alkynes giving 1,3,5‐trisubstituted benzenes. During the catalysis, the ultrashort Cr−Cr quintuple bond underwent reversible cleavage/formation, corroborated by the characterization of two inverted arene sandwich dichromium complexes (μ‐η6:η6‐1,3,5‐(Me3Si)3C6H3)Cr{κ2‐HC(N‐2,6‐iPr2C6H3)(N‐2,6‐R2C6H3)}2 (R=iPr (5), Me (8)). In the presence of σ donors, such as THF and 2,4,6‐Me3C6H2CN, the bridging arene 1,3,5‐(Me3Si)3C6H3 in 5 and 8 was extruded and 1 and 7 were regenerated. Theoretical calculations were employed to disclose the reaction pathways of these highly regioselective 2+2+2 cylcotrimerization reactions of terminal alkynes.
On all fives: The quintuply bonded dichromium bisamidinate catalyzes the highly regioselective cyclotrimerization of terminal alkynes involving reversible cleavage of the Cr−Cr quintuple bond. From these catalytic reactions, two inverted arene sandwich dichromium amidinates were isolated, in which the bridging arene is 1,3,5‐(Me3Si)3C6H3.
Summary
The increased expression of programmed death‐ligands 1 and 2 (PD‐L1 and PD‐L2, respectively) on tumour cells contributes to immune evasion, suggesting that these proteins are attractive ...therapeutic targets. This study aimed to evaluate the validity of cerebrospinal fluid (CSF) soluble PD‐L1 (sPD‐L1) and soluble PD‐L2 (sPD‐L2) as biomarkers for primary central nervous system lymphoma (PCNSL). We determined the CSF concentrations of sPD‐L1 and sPD‐L2 in 46 patients with PCNSL using enzyme‐linked immunosorbent assays (ELISAs). A control group comprised 153 patients with other brain tumours, inflammatory/infectious status, or neurodegenerative diseases. Only CSF sPD‐L1 levels were significantly higher in patients with PCNSL relative to the controls. CSF sPD‐L1 also exhibited superior overall discrimination performance compared to CSF sPD‐L2 in diagnosing PCNSL. Compared with patients with PCNSL with low CSF sPD‐L1 levels, more patients with high levels had high serum lactate dehydrogenase levels, leptomeningeal involvement, and deep‐brain involvement. Furthermore, CSF sPD‐L1 could predict poor survival in PCNSL but CSF sPD‐L2 could not. Intriguingly, CSF sPD‐L1 levels were correlated with disease status and their dynamic changes post treatment could predict time to relapse. In conclusion, this study identified CSF sPD‐L1 as a promising prognostic biomarker, indicating a therapeutic potential of PD‐L1 blockade in PCNSL.
Adipose tissue is now considered as an endocrine organ involved in metabolic and inflammatory reactions. Adiponectin, a 244-amino acid peptide hormone, is associated with insulin resistance and ...carcinogenesis. Curcumin (diferuloylmethane) is the principal curcuminoid of the popular Indian spice, turmeric. Curcumin possesses antitumor effects, including the inhibition of neovascularization and regulation of cell cycle and apoptosis. However, the effects of adiponectin and curcumin on non-small cell lung cancer (NSCLC) remain unclear. In this study, we evaluated the expression of adiponectin in paired tumors and normal lung tissues from 77 patients with NSCLC using real-time polymerase chain reaction, western blotting, and immunohistochemistry. Kaplan-Meier survival analysis showed that patients with low adiponectin expression ratio (<1) had significantly longer survival time than those with high expression ratio (>1) (p = 0.015). Curcumin inhibited the migratory and invasive ability of A549 cells via the inhibition of adiponectin expression by blocking the adiponectin receptor 1. Curcumin treatment also inhibited the in vivo tumor growth of A549 cells and adiponectin expression. These results suggest that adiponectin can be a prognostic indicator of NSCLC. The effect of curcumin in decreasing the migratory and invasive ability of A549 cells by inhibiting adiponectin expression is probably mediated through NF-κB/MMP pathways. Curcumin could be an important potential adjuvant therapeutic agent for lung cancer in the future.
The shortest metal–metal bond so far is found in complex anion 2 (CrCr 1.7397(9) Å), which is the one‐electron reduction product of thermally stable mixed‐valent complex 1 (see scheme). Experimental ...data unambiguously show that the electronic configuration of 1 is σ2π4δ3, and theoretical studies confirm the presence of a CrCr quintuple bond in 2. Ar=2,6‐C6H3(CH3)2.
We devise a novel computational framework to achieve efficient multiscale modeling for suspension flows. The modeling framework comprises a particle-resolving direct numerical simulation for ...microscopic computation, a single-fluid continuum model to capture the bulk flow behavior at the macroscale, and a Gaussian process regression that connects the two modeling components. The microscopic calculation simulates detailed flow fields around individual suspended particles. Along with a coarse-grained method, we are able to obtain the mean volume fractions and stresses for discrete particles, which are then further used to calculate the rheological properties of the bulk flow fields at the macroscale under specific forcing conditions. Using Gaussian process regression, a few data points from the microscopic calculations can be further interpolated/extrapolated to form complete constitutive relationships that cover the whole forcing range in macroscopic calculations (i.e., continuum modeling). Moreover, via the uncertainties returned from the Gaussian process regression, the resulting active learning strategy using the Gaussian process regression automatically decides on the required the microscopic calculations given by a specified tolerance. As a result, complex suspension problems can be efficiently solved by the macroscopic continuum model to the desired accuracy with the minimum computational effort (i.e., minimum number of microscopic runs). Four examples are demonstrated, among which two examples involve particle migration as a function of the particle stress, and the resulting nonuniform distribution of particles. This demands a multivariate Gaussian process regression, which is found to be particularly effective in achieving high computational efficiency compared with the off-line cases, i.e., a large number of off-line microscopic calculations to obtain the prescribed constitutive relationships.
•A multiscale framework for modeling suspensions using active learning is presented.•The model utilizes GPR to connect microscopic and macroscopic models.•The multivariate GPR is utilized to solve complex suspension flows.
The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to ...enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.
The clinical characteristics of malignant melanoma are highly variable between patient populations of different ethnicities. To explore the underlining genetic variations, we reviewed the clinical ...data of 242 malignant melanoma cases from Taiwan and among them submitted formalin‐fixed paraffin‐embedded tissue samples from 37 patients for whole‐exome sequencing to identify the mutational signatures, tumor mutation burden and specific gene mutations. The genomic profiles and clinical outcomes were compared with the information derived from the publicly available TCGA and TGEN databases. Mutation signature 12 was the dominant signature in Taiwanese patients and represented approximately 45% of the mutation signatures observed. In contrast, mutation signature 7 was the most prominent among cases available in the TCGA database. Common gene mutations found in the TCGA melanoma dataset were not frequently found in melanomas from Taiwanese patients. There were a significant number of specific gene mutations that exclusively occurred in acral subtype but not in non‐acral subtype melanomas, and vice versa. While certain common mutations form a shared core of genetic features, there appear to be specific genetic pathways that are involved in the occurrence of melanomas that grow in non‐UV‐exposed areas. Our findings have shed light on the tumorigenesis pathways involved in malignant melanoma.
Bioactive glass is a potential biomaterial for bone reconstruction owing to its superior bioactivity and non-toxicity. Yet, the absence of a circulatory system to carry waste and nutrients is a key ...issue with biomaterials implanted in the body. Thus the development of functional and vascularized new tissue requires the development of angiogenesis, which involves the formation of new blood vessels. Based on this perspective, we aimed to fabricate boron-doped 58S bioactive glass microspheres using the spray drying method, which could offer great flowability, controllable morphology, and narrow size distribution. Characterization of particle morphology and elemental composition were examined using scanning electron microscopy along with energy dispersive spectroscopy, respectively. To evaluate the effect of the boron dopant on
bioactivity, X-ray diffraction and Fourier transform infrared spectroscopy were employed, while MC3T3-E1 osteoblast cells and BAOEC endothelial cells were used to assess the
osteoblast and angiogenic activities, respectively. Finally, the results showed that two distinct morphologies, smooth and concave spheres, were found, with discussion of the corresponding formation mechanism. In addition, positive effects of the boron dopant were demonstrated on the
bioactivity, and osteoblast and angiogenic activity when compared to the un-doped BG specimen.
Beta-tricalcium phosphate (β-TCP) has been applied in the fields of medical science owing to its osteoconductive properties which stimulate the growth of new bones. However, the material itself lacks ...of antibacterial properties which limits its applications. Thus, in this study antibacterial β-TCP specimens were proposed by Ag and Zn dopant. Preparation method of one-step spray pyrolysis was used with advantages of low contamination and continuous production over the sol-gel and wet chemical precipitation synthesis. The crystallographic structure, morphology and chemical composition of un-doped, Ag-doped and Ag/Zn co-doped β-TCP were characterized by X-ray diffraction, scanning electron microscopy, energy dispersive spectroscopy and transmission electron microscopy, respectively. Furthermore, the antibacterial activity against Escherichia coli was examined by colony count method. Finally, two dominant formation mechanisms were discussed and the antibacterial results indicate that the addition of Zinc nitrate precursor can enhance the activity of Ag/Zn co-doped β-TCP specimen.
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