JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.

A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets

Therapy-induced tumour secretomes promote resistance and tumour progression.

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy

A Framework on Analyzing Long-Term Drought Changes and Its Influential Factors Based on the PDSI

Drought is one of the most frequent and most widespread natural disasters worldwide, significantly impacting agricultural production and the ecological environment. An investigation of long-term drought changes and its influencing factors provides not only an understanding of historical droughts but also a scientific basis for the protection of future water resources. This study investigated the temporal characteristics of drought in a study site located in the center of Southwest China (SWC) over a 700-year period (AD 1300–2005) using the Palmer Drought Severity Index (PDSI). The linkage between drought and its influencing factors is discussed. An algorithm based on the random forest (RF) method was proposed to analyze the dynamic influence of the factors on drought. We also examined the linkages between the demise of two dynasties and historical drought events. The results showed that the study site was a drought-prone area in the study period and experienced a non-significant drying trend in all centuries, except for the 17th century; a total of 232 droughts were detected in the study site from AD 1300–2005. The wavelet spectrum of the PDSI series showed the existence of 4-, 8-, 16-, 32-, and 128-year-periods. A strong correlation existed between the sunspot numbers and the PDSI. The correlation of the period between the PDSI and El Niño-Southern Oscillation (ENSO) series in the same frequency domain was weak, while the ENSO exhibited a strong interaction with the PDSI in some time periods. The Pacific Decadal Oscillation (PDO) and PDSI had no resonance period in the low-frequency region, but there was a period of 80–130 years in the high-frequency region. The relative rates of influence of the ENSO, sunspot numbers, and PDO during AD 1700–1996 were 38.40%, 31.81%, and 29.8%, respectively. However, the mechanism of the interaction between droughts and the influential factors is complex, and the dominant factor changed over time. The analysis of long-term drought changes based on the PDSI series may provide clues to understand the development of historical events

Mangiferin Improved Palmitate-Induced-Insulin Resistance by Promoting Free Fatty Acid Metabolism in HepG2 and C2C12 Cells via PPARα: Mangiferin Improved Insulin Resistance

Elevated free fatty acid (FFA) is a key risk factor for insulin resistance (IR). Our previous studies found that mangiferin could decrease serum FFA levels in obese rats induced by a high-fat diet. Our research was to determine the effects and mechanism of mangiferin on improving IR by regulating FFA metabolism in HepG2 and C2C12 cells. The model was used to quantify PA-induced lipid accumulation in the two cell lines treated with various concentrations of mangiferin simultaneously for 24 h. We found that mangiferin significantly increased insulin-stimulated glucose uptake, via phosphorylation of protein kinase B (P-AKT), glucose transporter 2 (GLUT2), and glucose transporter 4 (GLUT4) protein expressions, and markedly decreased glucose content, respectively, in HepG2 and C2C12 cells induced by PA. Mangiferin significantly increased FFA uptake and decreased intracellular FFA and triglyceride (TG) accumulations. The activity of the peroxisome proliferator-activated receptor α (PPARα) protein and its downstream proteins involved in fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT1) and the fatty acid β-oxidation rate corresponding to FFA metabolism were also markedly increased by mangiferin in HepG2 and C2C12 cells. Furthermore, the effects were reversed by siRNA-mediated knockdown of PPARα. Mangiferin ameliorated IR by increasing the consumption of glucose and promoting the FFA oxidation via the PPARα pathway in HepG2 and C2C12 cells

Therapy-induced tumour secretomes promote resistance and tumour progression.

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy

Aluminum Fluoride Modified HZSM-5 Zeolite with Superior Performance in Synthesis of Dimethyl Ether from Methanol

A series of HZSM-5 catalysts modified with various loadings of aluminum fluoride (AlF₃) were prepared from a mechanical mixture route. Combined characterizations of X-ray diffraction, Fourier transform infrared (FT-IR), ²⁷Al, ²⁹Si, ¹⁹F MAS NMR, N₂ sorption, and NH₃-tempeature-programmed desorption (NH₃-TPD) techniques show that the structure, texture, and acidity of HZSM-5 catalysts can be adjusted with the loading of AlF₃. A suitable amount of AlF₃ modification (2 wt %) could increase the framework aluminum content and the surface area of HZSM-5. However, when the loading of AlF₃ came to 3 wt % or more, the contrary results were obtained, which could be ascribed to the dealumination of the zeolitic framework. The catalytic activities for dehydration of methanol to dimethyl ether (DME) show that suitable amount of AlF₃-modified HZSM-5 exhibited much higher activity and better stability than parent HZSM-5. The combination of “tunable” synthesis and “superior” properties is very much valuable in the academic and industry

Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance

Clinically acquired resistance to MAPK inhibitor (MAPKi) therapies for melanoma cannot be fully explained by genomic mechanisms and may be accompanied by co-evolution of intra-tumoral immunity. We sought to discover non-genomic mechanisms of acquired resistance and dynamic immune compositions by a comparative, transcriptomic-methylomic analysis of patient-matched melanoma tumors biopsied before therapy and during disease progression. Transcriptomic alterations across resistant tumors were highly recurrent, in contrast to mutations, and were frequently correlated with differential methylation of tumor cell-intrinsic CpG sites. We identified in the tumor cell compartment supra-physiologic c-MET up-expression, infra-physiologic LEF1 down-expression and YAP1 signature enrichment as drivers of acquired resistance. Importantly, high intra-tumoral cytolytic T cell inflammation prior to MAPKi therapy preceded CD8 T cell deficiency/exhaustion and loss of antigen presentation in half of disease-progressive melanomas, suggesting cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy. Thus, melanoma acquires MAPKi resistance with highly dynamic and recurrent non-genomic alterations and co-evolving intra-tumoral immunity