Atezolizumab (Tecentriq, MPDL3280A; Genentech/Roche) is an FcγR binding-deficient, fully humanized IgG1 mAb designed to interfere with the binding of PD-L1 ligand to its two receptors, PD-1 and B7.1. ...By blocking the PD-L1/PD-1 immune checkpoint, atezolizumab reduces immunosuppressive signals found within the tumor microenvironment and, consequently, increases T-cell-mediated immunity against the tumor. Atezolizumab has been FDA approved as second-line therapy for advanced bladder cancer. This accelerated approval was based on phase II trial data in patients with metastatic bladder cancer that showed unexpected and durable tumor responses. In subjects whose tumors progressed on first-line platinum-based chemotherapy, the objective response rate was 15%, the complete response rate was 5%, and 1-year overall survival was 36%. In subjects that were chemotherapy naïve and cisplatin ineligible, the objective response rate was 24%, the complete response rate was 7%, and 1-year overall survival was 57%. Better responses were associated with higher PD-L1 expression on the tumor-infiltrating leukocytes. These data suggest that patients with advanced bladder cancer treated with atezolizumab have significantly better response rates and survival than historical controls treated with other second-line regimens. The toxicity profile of atezolizumab is also favorable. Trials are currently assessing whether atezolizumab is effective in earlier bladder cancer stages and in the first-line metastatic setting.
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Carbon dots are a family of optically-active nanoparticles displaying a combination of useful properties that make them attractive for many applications in photonics and photochemistry. Despite the ...initial claims of high photostability of carbon dots even under prolonged illuminations, several recent studies have evidenced their photobleaching (PB) under UV light, detrimental for some applications. A study of the mechanism and dynamics of carbon dot PB can be considered a useful route to gather relevant information on the underlying photophysics of these nanoparticles, which is still widely debated. Here we report a study of the PB of carbon dots under UV light, conducted through optical experiments under well-controlled illumination conditions. In particular, the use of a laser as an irradiation source allows a precise control of the irradiated volume, and provides accurate estimates and control of the administered energy. Besides, our setup allows spectroscopic measurements to be carried out in situ at the irradiated site, thus allowing us to investigate in real time the progress of photobleaching effects through a time-resolved approach. Therefore, our experiments allow the precise kinetics of the undergoing PB process to be captured which is found to be significantly affected by disorder and photoselection effects. Furthermore, our study discloses several pieces of information on the nature of the main blue chromophore absorbing at 340 nm and emitting at 430 nm, and on its PB mechanism. We propose that the emissive units consist in small molecular-like chromophores adsorbed on carbon dot surfaces and are in a dynamical equilibrium with free diffusing molecules in solution. Their photobleaching proceeds in two distinct steps: in the first phase, linear absorption of UV photons rapidly converts the molecular surface chromophores into a non-emissive form, likely through an isomerization, causing the disappearance of the fluorescence properties but almost no changes in the optical absorption spectra. At higher fluences, a complete destruction of the optically-active centers is observed, which completely wipes out all the absorption features of surface chromophores and only leaves a fully carbonized, yet non-fluorescent, dot core.
Continuous-wave laser emission is challenging to obtain in organic lasers, whether in the solid or liquid form, a limitation caused by long-lived triplet states and by thermal effects. In liquid dye ...lasers, both issues can be fixed by rapidly flowing the dye, which is technically complex and prevents those lasers to be further miniaturized or easily integrated. Here we address the issue of the maximal pulsewidth that can be obtained in liquid dye lasers in the absence of any dye flow, in a compact and cost-effective diode-pumped laser system. Pulses as long as 80 μs have been obtained, thanks to the combination of a hemispherical resonator design, almost insensitive to thermal-lens effects, and an intentional mismatch between pump and cavity spatial modes. The limitation in pulse duration is shown to be entirely due to thermal blooming, and more specifically to diffraction losses brought by the spherical aberration of the thermal lens.
Inhibition of Adipogenesis by Wnt Signaling Ross, Sarah E.; Hemati, Nahid; Longo, Kenneth A. ...
Science (American Association for the Advancement of Science),
08/2000, Letnik:
289, Številka:
5481
Journal Article
Recenzirano
Wnts are secreted signaling proteins that regulate developmental processes. Here we show that Wnt signaling, likely mediated by Wnt-10b, is a molecular switch that governs adipogenesis. Wnt signaling ...maintains preadipocytes in an undifferentiated state through inhibition of the adipogenic transcription factors CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ). When Wnt signaling in preadipocytes is prevented by overexpression of Axin or dominant-negative TCF4, these cells differentiate into adipocytes. Disruption of Wnt signaling also causes transdifferentiation of myoblasts into adipocytes in vitro, highlighting the importance of this pathway not only in adipocyte differentiation but also in mesodermal cell fate determination.
MicroRNAs are predicted to regulate almost equal to30% of all human genes by targeting sequences in their 3' UTR. Polymorphisms in 3' UTR of several genes have been reported to affect gene ...expression, but the mechanism is not fully understood. Here, we demonstrate that 829Crightward arrowT, a naturally occurring SNP, near the miR-24 binding site in the 3' UTR of human dihydrofolate reductase (DHFR) affects DHFR expression by interfering with miR-24 function, resulting in DHFR overexpression and methotrexate resistance. miR-24 has a conserved binding site in DHFR 3' UTR. DHFR with WT and 3' UTR containing the 829Crightward arrowT mutation were expressed in DG44 cells that lack DHFR. Overexpression of miR-24 in cells with WT DHFR resulted in down-regulation of DHFR protein, whereas no effect on DHFR protein expression was observed in the mutant 3' UTR-expressing cells. Inhibition of endogenous miR-24 with a specific inhibitor led to up-regulation of DHFR in WT and not in mutant cells. Cells with the mutant 3' UTR had a 2-fold increase in DHFR mRNA half-life, expressed higher DHFR mRNA and DHFR protein, and were 4-fold more resistant to methotrexate as compared with WT cells. SNP-829Crightward arrowT, therefore, leads to a decrease in microRNA binding leading to overexpression of its target and results in resistance to methotrexate. We demonstrate that a naturally occurring miRSNP (a SNP located at or near a microRNA binding site in 3' UTR of the target gene or in a microRNA) is associated with enzyme overproduction and drug resistance.
Shiga toxin 2 (Stx2) from enterohemorrhagic
Escherichia coli
(EHEC) produces hemorrhagic colitis, hemolytic uremic syndrome (HUS), and acute encephalopathy. The mortality rate in HUS increases ...significantly when the central nervous system (CNS) is involved. Besides, EHEC also releases lipopolysaccharide (LPS). Many reports have described cognitive dysfunctions in HUS patients, the hippocampus being one of the brain areas targeted by EHEC infection. In this context, a translational murine model of encephalopathy was employed to establish the deleterious effects of Stx2 and the contribution of LPS in the hippocampus. The purpose of this work is to elucidate the signaling pathways that may activate the inflammatory processes triggered by Stx2, which produces cognitive alterations at the level of the hippocampus. Results demonstrate that Stx2 produced depression-like behavior, pro-inflammatory cytokine release, and NF-kB activation independent of the ERK1/2 signaling pathway, while co-administration of Stx2 and LPS reduced memory index. On the other hand, LPS activated NF-kB dependent on ERK1/2 signaling pathway. Cotreatment of Stx2 with LPS aggravated the pathologic state, while dexamethasone treatment succeeded in preventing behavioral alterations. Our present work suggests that the use of drugs such as corticosteroids or NF-kB signaling inhibitors may serve as neuroprotectors from EHEC infection.
Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the degeneration and death of upper (UMN) and lower (LMN) motor neurons. In the last decade, it ...has been shown that Chitinases are an important prognostic indicator of neuro-inflammatory damage induced by microglia and astrocytes.
We analyzed microarray datasets obtained from the Array Express in order to verify the expression levels of CHI3L1 and CHI3L2 in motor cortex biopsies of sALS patients with different survival times. We also divided the sALS patients into smokers and non-smokers. In order to extend our analysis, we explored two additional microarray datasets, GSE833 and GSE26927, of post-mortem spinal cord biopsies from sALS patients.
The analysis showed that CHI3L1 and CHI3L2 expression levels were significantly upregulated in the motor cortex of sALS patients, compared to the healthy controls. Moreover, their expression levels were negatively correlated with survival time. Interesting results were obtained when we compared the expression levels of Chitinases among smokers. We showed that CHI3L1 and CHI3L2 were significantly upregulated in sALS smokers compared to non-smokers. Furthermore, we found that four genes belonging to the Chitinases network (SERPINA3, C1s, RRAD, HLA-DQA1) were significantly upregulated in the motor cortex of sALS patients and positively correlated with Chitinases expression levels. Similar results were obtained during the exploration of the two-microarray dataset.
This study suggests that CHI3L1 and CHI3L2 are associated with the progression of neurodegeneration in motor cortex and spinal cord of sALS patients.
•CHI3L1 and CHI3L2 were significantly upregulated in motor cortex and spinal cord of sALS patients.•Cigarette smoke, modulates the CHI3L1 and CHI3L2 expression levels in the CNS of ALS patients.•CHI3L1 and CHI3L2 expression levels were negatively correlated to the survival time sALS patients.•The Chitinases network is modulated in motor cortex and spinal cord of sALS patients.
Regulation of Osteoblastogenesis and Bone Mass by Wnt10b Bennett, Christina N.; Longo, Kenneth A.; Wright, Wendy S. ...
Proceedings of the National Academy of Sciences - PNAS,
03/2005, Letnik:
102, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Wnts comprise a family of secreted signaling proteins that regulate diverse developmental processes. Activation of Wnt signaling by Wnt10b inhibits differentiation of preadipocytes and blocks adipose ...tissue development; however, the effect of Wnt10b on other mesenchymal lineages has not been defined. To explore the physiological role of Wnt signaling in bone development, we analyzed FABP4-Wnt10b mice, which express the Wnt10b transgene in marrow. Femurs from FABP4-Wnt10b mice have almost four times as much bone in the distal metaphyses and are mechanically stronger. These mice maintain elevated bone mass at least through 23 months of age. In addition, FABP4-Wnt10b mice are protected from the bone loss characteristic of estrogen deficiency. We used pharmacological and genetic approaches to demonstrate that canonical Wnt signaling stimulates osteoblastogenesis and inhibits adipogenesis of bipotential mesenchymal precursors. Wnt10b shifts cell fate toward the osteoblast lineage by induction of the osteoblastogenic transcription factors Runx2, Dlx5, and osterix and suppression of the adipogenic transcription factors C/EBPα and PPARγ. One mechanism whereby Wnt10b promotes osteoblastogenesis is suppression of PPARγ expression. Finally, Wnt10b-/- mice have decreased trabecular bone and serum osteocalcin, confirming that Wnt10b is an endogenous regulator of bone formation.
This study focuses on the application of Electro-Fenton technique for the remediation of wastewater contaminated with synthetic dyes. A bubble reactor was designed to develop this treatment operating ...in continuous mode. In order to increase the efficiency of Electro-Fenton treatment, the effect of key parameters (iron dosage and pH) that play an important role in this process was investigated for Lissamine Green B decoloration in batch mode. Operating at the optimal conditions, determined for Lissamine Green B, several dyes (Methyl Orange, Reactive Black 5 and Fuchsin Acid) were decolorized by using Electro-Fenton process. A first-order kinetic model was used to simulate the experimental results operating at different pH, and iron concentration of 150
mg
L
−1. This kinetic model for Lissamine Green, Methyl Orange and Reactive Black 5 was successfully used in the progression of the process from batch to continuous mode. About 80% color removal was achieved for Lissamine Green and Methyl Orange with a residence time of 21
h. The decoloration for Reactive Black 5 was lower, reached a value around 60% at the same residence time. Nevertheless in all assays a good agreement between experimental results and proposed model in a continuous bubble reactor was detected. In addition a continuous treatment with a mixture of dyes was carried out. Operating with a residence time of 21
h the obtained decoloration was close to 43% which is squared with a TOC reduction around 46%. Therefore, the results provide fundamental knowledge for the treatment of a real wastewater stream.
Small-molecule inhibitors have revolutionized treatment of certain genomically defined solid cancers. Despite breakthroughs in treating systemic disease, central nervous system (CNS) metastatic ...progression is common, and advancements in treating CNS malignancies remain sparse. By improving drug penetration across a variably permeable blood-brain barrier and diffusion across intratumoral compartments, more uniform delivery and distribution can be achieved to enhance efficacy.
Ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), were functionalized with α
integrin-binding (cRGD), or nontargeting (cRAD) peptides, and PET labels (
I,
Zr) to investigate the utility of dual-modality cRGD-C' dots for enhancing accumulation, distribution, and retention (ADR) in a genetically engineered mouse model of glioblastoma (mGBM). mGBMs were systemically treated with
I-cRGD- or
I-cRAD-C' dots and sacrificed at 3 and 96 hours, with concurrent intravital injections of FITC-dextran for mapping blood-brain barrier breakdown and the nuclear stain Hoechst. We further assessed target inhibition and ADR following attachment of dasatinib, creating nanoparticle-drug conjugates (Das-NDCs). Imaging findings were confirmed with
autoradiography, fluorescence microscopy, and p-S6RP IHC.
Improvements in brain tumor delivery and penetration, as well as enhancement in the ADR, were observed following administration of integrin-targeted C' dots, as compared with a nontargeted control. Furthermore, attachment of the small-molecule inhibitor, dasatinib, led to its successful drug delivery throughout mGBM, demonstrated by downstream pathway inhibition.
These results demonstrate that highly engineered C' dots are promising drug delivery vehicles capable of navigating the complex physiologic barriers observed in a clinically relevant brain tumor model.
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