The reaction pathway of Ti–SiC system in Cu melts

International audienc

The in-situ synthesis of TiC in Cu melts based on Ti–C–Si system and its mechanism

International audienc

Dual inhibitors of DNMT and HDAC remodels the immune microenvironment of colorectal cancer and enhances the efficacy of anti-PD-L1 therapy

Colorectal cancer is the second most prevalent and deadly cancer worldwide. The emergence of immune checkpoint therapy has provided a revolutionary strategy for the treatment of solid tumors. However, less than 5 % of colorectal cancer patients respond to immune checkpoint therapy. Thus, it is of great scientific significance to develop “potentiators” for immune checkpoint therapy. In this study, we found that knocking down different DNMT and HDAC isoforms could increase the expression of IFNs in colorectal cancer cells, which can enhance the effectiveness of immune checkpoint therapy. Therefore, the combined inhibition of DNMT and HDAC cloud synergistically enhance the effect of immunotherapy. We found that dual DNMT and HDAC inhibitors C02S could inhibit tumor growth in immunocompetent mice but not in immunocompromised nude mice, which indicates that C02S exerts its antitumor effects through the immune system. Mechanistically, C02S could increase the expression of ERVs, which generated the intracellular levels of dsRNA in tumor cells, and then promotes the expression of IFNs through the RIG-I/MDA5-MAVS signaling pathway. Moreover, C02S increased the immune infiltration of DCs and T cells in microenvironment, and enhanced the efficacy of anti-PD-L1 therapy in MC38 and CT26 mice model. These results confirmed that C02S can activate IFNs through the RIG-I/MDA5-MAVS signaling pathway, remodel the tumor immune microenvironment and enhance the efficacy of immune checkpoint therapy, which provides new evidence and solutions for the development of “potentiator” for colorectal cancer immunotherapy

DataSheet_1_A novel genomic instability-derived lncRNA signature to predict prognosis and immune characteristics of pancreatic ductal adenocarcinoma.docx

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor of the digestive system. Its grim prognosis is mainly attributed to the lack of means for early diagnosis and poor response to treatments. Genomic instability is shown to be an important cancer feature and prognostic factor, and its pattern and extent may be associated with poor treatment outcomes in PDAC. Recently, it has been reported that long non-coding RNAs (lncRNAs) play a key role in maintaining genomic instability. However, the identification and clinical significance of genomic instability-related lncRNAs in PDAC have not been fully elucidated.MethodsGenomic instability-derived lncRNA signature (GILncSig) was constructed based on the results of multiple regression analysis combined with genomic instability-associated lncRNAs and its predictive power was verified by the Kaplan-Meier method. And real-time quantitative polymerase chain reaction (qRT-PCR) was used for simple validation in human cancers and their adjacent non-cancerous tissues. In addition, the correlation between GILncSig and tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) was investigated by Pearson correlation analysis.ResultsThe computational framework identified 206 lncRNAs associated with genomic instability in PDAC and was subsequently used to construct a genome instability-derived five lncRNA-based gene signature. Afterwards, we successfully validated its prognostic capacity in The Cancer Genome Atlas (TCGA) cohort. In addition, via careful examination of the transcriptome expression profile of PDAC patients, we discovered that GILncSig is associated with EMT and an adaptive immunity deficient immune profile within TME.ConclusionsOur study established a genomic instability-associated lncRNAs-derived model (GILncSig) for prognosis prediction in patients with PDAC, and revealed the potential functional regulatory role of GILncSig.</p

The HSP90 Inhibitor Ganetespib Alleviates Disease Progression and Augments Intermittent Cyclophosphamide Therapy in the MRL/lpr Mouse Model of Systemic Lupus Erythematosus

<div><p>Systemic lupus erythematosus (SLE) is a complex, systemic autoimmune disease with a diverse range of immunological and clinical manifestations. The introduction of broad spectrum immunosuppressive therapies and better management of acute disease exacerbations have improved outcomes for lupus patients over recent years. However, these regimens are burdened by substantial toxicities and confer significantly higher risks of infection, thus there remains a significant and unmet medical need for alternative treatment options, particularly those with improved safety profiles. Heat shock protein 90 (HSP90) is a ubiquitously expressed molecular chaperone that acts as an important modulator of multiple innate and adaptive inflammatory processes. Of note, accumulating clinical and experimental evidence has implicated a role for HSP90 in the pathogenesis of SLE. Here we evaluated the potential of HSP90 as a therapeutic target for this disease using the selective small molecule inhibitor ganetespib in the well-characterized MRL/lpr autoimmune mouse model. In both the prophylactic and therapeutic dosing settings, ganetespib treatment promoted dramatic symptomatic improvements in multiple disease parameters, including suppression of autoantibody production and the preservation of renal tissue integrity and function. In addition, ganetespib exerted profound inhibitory effects on disease-related lymphadenopathy and splenomegaly, and reduced pathogenic T and B cell lineage populations in the spleen. Ganetespib monotherapy was found to be equally efficacious and tolerable when compared to an effective weekly dosing regimen of the standard-of-care immunosuppressive agent cyclophosphamide. Importantly, co-treatment of ganetespib with a sub-optimal, intermittent dosing schedule of cyclophosphamide resulted in superior therapeutic indices and maximal disease control. These findings highlight the potential of HSP90 inhibition as an alternative, and potentially complementary, strategy for therapeutic intervention in SLE. Such approaches may have important implications for disease management, particularly for limiting or preventing treatment-related toxicities, a major confounding factor in current SLE therapy.</p></div

Ganetespib prevents the development of renal damage in a pilot prophylactic dosing study.

<p>(A) Mean pharmacokinetic plasma concentration-time profile after i.v. administration of ganetespib to MRL/lpr mice. Ganetespib was dosed at 50 mg/kg twice weekly and samples were taken after the second dose. Data represent mean ± SD (n = 3). (B) Average proteinuria scores (±SE) are plotted for vehicle and ganetespib-treated mice over the time course of the study. Average proteinuria scores for non-lupus parental strain (MRL/mp) mice from 8–15 weeks of age are included for comparison. (C) HSP70 induction as a pharmacodynamic marker of ganetespib activity in kidneys from drug-treated animals. Kidneys were harvested at 6 and 24 hours following the second intra-weekly dose of ganetespib (or vehicle) and lysates immunoblotted for HSP70 expression. GAPDH included as a loading control. Each lane represents renal tissue from an individual animal. (D) Representative H&E stained renal histopathology showing extensive chronic inflammation and thickening of the basement membrane with crescent formation in the glomerulus of a vehicle-treated mouse (<i>left panel</i>). In contrast, the kidneys of a ganetespib-treated animal showed no evident pathologic changes (<i>right panel</i>). Original magnification, 40X; scale bar represents 50 μm. (E) To evaluate total lupus-related renal damage 7 primary characteristics of GN (glomerular capillary deposits, hypercellularity, necrosis, tubular atrophy, intratubular casts, interstitial chronic inflammation, and fibrosis) were scored for each animal and summed for a composite disease score. The average summed pathology scores for each treatment group are plotted. (E) Representative IgG immunohistochemical staining of renal tissues harvested from vehicle- and ganetespib-treated animals at 22 weeks of age. Red arrows highlight the marked reduction in glomerular IgG deposition seen following HSP90 inhibitor treatment. Original magnification 20X: scale bar represents 100 μm. (F) Quantification of IgG glomerular immunoreactivity observed in vehicle and drug treated animals.</p

Absence of lymphoproliferation in combination-treated MRL/lpr mice.

<p>(A) Lymph nodes were harvested from mice upon completion of the individual therapeutic dosing regimens. Data are expressed as median pooled lymph node weights for each treatment (± SD). *p<0.05. <i>Gpib</i>, <i>ganetespib; Comb</i>, <i>combination</i>. (B) Representative images of regional lymph nodes harvested from vehicle- and combination (ganetespib + CTX/2)-treated animals at the end of the study. (C) Spleens were harvested at necropsy and weighed. Data are expressed as median spleen weights per treatment group (± SD).*p<0.05. (D) Representative images of spleens taken from mice from all treatment groups.</p

Ganetespib prevents the development of renal damage in a pilot prophylactic dosing study.

<p>(A) Mean pharmacokinetic plasma concentration-time profile after i.v. administration of ganetespib to MRL/lpr mice. Ganetespib was dosed at 50 mg/kg twice weekly and samples were taken after the second dose. Data represent mean ± SD (n = 3). (B) Average proteinuria scores (±SE) are plotted for vehicle and ganetespib-treated mice over the time course of the study. Average proteinuria scores for non-lupus parental strain (MRL/mp) mice from 8–15 weeks of age are included for comparison. (C) HSP70 induction as a pharmacodynamic marker of ganetespib activity in kidneys from drug-treated animals. Kidneys were harvested at 6 and 24 hours following the second intra-weekly dose of ganetespib (or vehicle) and lysates immunoblotted for HSP70 expression. GAPDH included as a loading control. Each lane represents renal tissue from an individual animal. (D) Representative H&E stained renal histopathology showing extensive chronic inflammation and thickening of the basement membrane with crescent formation in the glomerulus of a vehicle-treated mouse (<i>left panel</i>). In contrast, the kidneys of a ganetespib-treated animal showed no evident pathologic changes (<i>right panel</i>). Original magnification, 40X; scale bar represents 50 μm. (E) To evaluate total lupus-related renal damage 7 primary characteristics of GN (glomerular capillary deposits, hypercellularity, necrosis, tubular atrophy, intratubular casts, interstitial chronic inflammation, and fibrosis) were scored for each animal and summed for a composite disease score. The average summed pathology scores for each treatment group are plotted. (E) Representative IgG immunohistochemical staining of renal tissues harvested from vehicle- and ganetespib-treated animals at 22 weeks of age. Red arrows highlight the marked reduction in glomerular IgG deposition seen following HSP90 inhibitor treatment. Original magnification 20X: scale bar represents 100 μm. (F) Quantification of IgG glomerular immunoreactivity observed in vehicle and drug treated animals.</p