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Local consolidative therapy (LCT) has emerged as a treatment option in patients with oligometastatic non-small cell lung cancer (NSCLC) undergoing chemotherapy or targeted therapy. However, the current literature lacks evidence as to whether LCT improves survival in NSCLC patients receiving immunotherapy. Our study aimed to assess whether LCT combined with pembrolizumab ± chemotherapy could improve the survival of patients with synchronous oligometastatic NSCLC.
Patients with NSCLC, without EGFR or ALK genetic aberrations, who were treated with first-line pembrolizumab ± chemotherapy, were included in the study. Survival analysis of the LCT and non-LCT groups was compared.
A total of 231 patients were included in the study. The median follow-up time was 15.24 months. Median progression-free survival (PFS) and overall survival (OS) of the entire cohort were 12.00 and 23.43 months, respectively. Of the 231 patients included, 76 patients received LCT combined with pembrolizumab ± chemotherapy (LCT group) while 155 patients received pembrolizumab ± chemotherapy alone (non-LCT group). Of note, the PFS of the LCT and non-LCT groups was 13.97 and 10.08 months (p=0.016), respectively. The OS were 30.67 and 21.97 months (p=0.011), respectively. The PFS and OS were significantly improved with LCT for patients with brain or lung metastases but not bone metastases. No significant increase in treatment-related toxicity was observed in the LCT group.
The present study shows that LCT to metastatic sites is an option for consideration in patients with synchronous oligometastatic NSCLC during first-line pembrolizumab treatment, with significantly improved PFS and OS compared with systemic treatment alone.
The present study shows that LCT to metastatic sites is an option for consideration in patients with synchronous oligometastatic NSCLC during first-line pembrolizumab treatment, with significantly improved PFS and OS compared with systemic treatment alone.
As an inflammatory factor and oncogenic driver protein, the pleiotropic cytokine macrophage migration inhibitory factor (MIF) plays a crucial role in the osteosarcoma microenvironment. Although 4-iodo-6-phenylpyrimidine (4-IPP) can inactivate MIF biological functions, its anti-osteosarcoma effect and molecular mechanisms have not been investigated. In this study, we identified the MIF inhibitor 4-IPP as a specific double-effector drug for osteosarcoma with both anti-tumour and anti-osteoclastogenic functions.
The anti-cancer effects of 4-IPP were evaluated by wound healing assay, cell cycle analysis, colony formation assay, CCK-8 assay, apoptosis analysis, and Transwell migration/invasion assays. Through the application of a luciferase reporter, chromatin immunoprecipitation assays, and immunofluorescence and coimmunoprecipitation analyses, the transcriptional regulation of the NF-κB/P-TEFb complex on c-Myb- and STUB1-mediated proteasome-dependent MIF protein degradation was confirmed. The effect of 4-IPPltaneously inactivating the biological functions of MIF and promoting its proteasomal degradation. Direct destabilization of the MIF protein with 4-IPP may be a promising therapeutic strategy for treating osteosarcoma.
Our findings demonstrate that the small molecule 4-IPP targeting the MIF protein exerts an anti-osteosarcoma effect by simultaneously inactivating the biological functions of MIF and promoting its proteasomal degradation. Direct destabilization of the MIF protein with 4-IPP may be a promising therapeutic strategy for treating osteosarcoma.
Compared to the exhaustive study of transgenerational programming of obesity and diabetes through exposures in the prenatal period, postnatal programming mechanisms are understudied, including the potential role of breast milk composition linking maternal metabolic status (body mass index and diabetes) and offspring growth, metabolic health and future disease risk.
This narrative review will principally focus on four emergent bioactive compounds [microRNA's (miRNA), lipokines/signalling lipids, small molecules/metabolites and fructose] that, until recently were not known to exist in breast milk. The objective of this narrative review is to integrate evidence across multiple fields of study that demonstrate the importance of these compositional elements of breast milk during lactation and the subsequent effect of breast milk components on the health of the infant.
Current knowledge on the presence of miRNA's, lipokines/signalling lipids, small molecules/metabolites and fructose in breast milk and their aonths of life whereas 12,13 diHOME (brown fat activator) and betaine are negatively associated with early adiposity and growth.This study aimed to investigate whether penicillin-resistant, ampicillin-susceptible E. faecalis (PRASEF) isolates are disseminated in non-clinical sources, and to compare the molecular characteristics and antimicrobial resistance (AMR) profile of clinical and non-clinical E. faecalis isolates. Non-clinical samples (n = 280) were collected and 101 E. faecalis isolates were recovered from food (n = 18), faeces of healthy animals (n = 24), water (n = 28) and sewage (n = 31). PRASEF (n = 68) and penicillin-susceptible, ampicillin-susceptible E. faecalis (n = 77) isolates of clinical origin were also evaluated. A significant variety of AMR profiles was observed among non-clinical isolates according to the source. No food isolate exhibited a multidrug resistance (MDR) phenotype different from those of isolates from animal faeces (50.0%) and sewage (38.7%). Overall, the MDR phenotype was more frequent among clinical (56.6%) than non-clinical isolates (22.8%) (p less then 0.01). Non-clinical PRASEF isolates (n = 3) were only recovered from hospital sewage. Note that representative clinical and non-clinical PRASEF isolates were grouped in pulsotype A, and belonged to CC9 (clonal complex). In conclusion, E. faecalis isolates exhibiting the unusual penicillin-resistant but ampicillin-susceptible phenotype appeared to be restricted to the hospital environment. Our findings highlight the ability of PRASEF isolates to survive in sewage, which could enable these hospital-adapted lineages to spread to new ecological niches.To accurately identify the blood authenticity, a set of photoacoustic detection system was established. In experiments, five kinds of blood in total of 125 groups were used, the time-resolved photoacoustic signals and peak-to-peak spectra were obtained in 700 to 1064 nm. Experimental results showed the accurate identification of blood authenticity was limited due to overlap of signals and spectra. To solve the problem, wavelet neural network (WNN) was employed to supervised train peak-to-peak spectra of 100 samples. The correct rate was 72% for 25 test samples. To improve correct rate, the parameters of WNN were optimized by quantum-behaved particle swarm optimization (QPSO) algorithm. Meanwhile, the effects of neurons number, learning rate factors, iteration times and training times on correct rate were studied and compared with WNN and WNN-PSO algorithms. Results showed the correct rate of WNN-QPSO was increased to 96%. Then, three kinds of dynamic contraction-expansion coefficients were used. Under the optimal dynamic coefficient, the correct rate reached 100%. Moreover, the truncated mean stabilization strategy (TMSS) was coupled to improve the convergent speed. Finally, 10 algorithms were compared. Results demonstrated that photoacoustic spectroscopy combined with WNN-QPSO coupled with TMSS and dynamic contraction-expansion coefficient had an excellent performance in the identification of blood authenticity.Despite the proposed safety, performance, and cost advantages, practical implementation of Mg-Li hybrid batteries is limited due to the unavailability of reliable cathodes compatible with the dual-ion system. Herein, a high-performance Mg-Li dual ion battery based upon cobalt-doped TiO2 cathode was developed. Extremely pseudocapacitance-type Ti1-x Cox O2-y nanosheets consist of an optimum 3.57 % Co-atoms. This defective cathode delivered exceptional pseudocapacitance (maximum of 93 %), specific capacities (386 mAh g-1 at 25 mA g-1 ), rate performance (191 mAh g-1 at 1 A g-1 ), cyclability (3000 cycles at 1 A g-1 ), and coulombic efficiency (≈100 %) and fast charging (≈11 min). This performance was superior to the TiO2 -based Mg-Li dual-ion battery cathodes reported earlier. Mechanistic studies revealed dual-ion intercalation pseudocapacitance with negligible structural changes. Excellent electrochemical performance of the cation-doped TiO2 cathode was credited to the rapid pseudocapacitance-type Mg/Li-ion diffusion through the disorder generated by lattice distortions and oxygen vacancies. Ultrathin nature, large surface area, 2D morphology, and mesoporosity also contributed as secondary factors facilitating superior electrode-electrolyte interfacial kinetics. The demonstrated method of pseudocapacitance-type Mg-Li dual-ion intercalation by introducing lattice distortions/oxygen vacancies through selective doping can be utilized for the development of several other potential electrodes for high-performance Mg-Li dual-ion batteries.DNA barcoding is based on the premise that the barcode sequences can distinguish individuals (strains) of different species because their sequence variation between species exceeds that within species. The primary barcodes used in fungal and yeast taxonomy are the ITS segments and the LSU (large subunit) D1/D2 domain of the homogenized multicopy rDNA repeats. The secondary barcodes are conserved segments of protein-encoding genes, which usually have single copies in haploid genomes. This study shows that the analysis of barcode sequences fails to reconstruct accurate species trees and differentiate species when the organisms have chimeric genomes composed of admixed mosaics of different origins. It is shown that the type strains of 10 species of the pulcherrima clade of the ascomycetous yeast genus Metschnikowia cannot be differentiated with standard barcodes because their intragenomic diversity is comparable to or even higher than the interstrain diversity. The analysis of a large group of genes of the sequenced genomes of the clade and the viability and segregation of the hybrids of ex-type strains indicate that the high intragenomic barcode differences can be attributed to admixed genome structures. Plinabulin solubility dmso Because of the mosaic structures of the genomes, the rDNA repeats do not form continuous arrays and thus cannot be homogenized. Since the highly diverse ITS and D1/D2 sequences of the type strains form a continuous pool including pseudogenes, the evolution of their rDNA appears to involve reticulation. The secondary barcode sequences and the nonbarcode genes included in the analysis show incongruent phylogenetic relationships among the type strains, which can also be attributed to differences in the phylogenetic histories of the genes.Phenyltetrahydroimidazothiazole (PTHIT, tetramisole) is the most frequently used adulterant of cocaine and exists in the two enantiomeric forms levamsiole (S) and dexamisole (R). Existing studies show diverse fractions of samples containing enantiopure levamsiole, levamisole-enriched mixtures, and racemic tetramisole as adulterant. However, blood samples have never been enantioselectively tested for PTHIT. Because enantiomers are usually metabolized stereoselectively, chiral analysis of blood samples can help estimate the time of drug use, provided that a racemic substance is ingested. Therefore, an enantioselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed using a chiral column. Validation of the method was carried out for methanolic substance samples as well as serum samples and showed satisfactory selectivity, sensitivity, linearity (0.05-100 ng/mL), precision, and accuracy; 151 cocaine samples seized in Germany between 2018 and 2021 were analyzed. Most (94%, n = 48) of the 51 PTHIT-positive samples contained racemic tetramsiole, whereas there were two samples containing levamisole-enriched mixtures and one sample containing nearly enantiopure levamisole.
