EGFR Inhibition Overcomes Resistance to FGFR4 Inhibition and Potentiates FGFR4 Inhibitor Therapy in Hepatocellular Carcinoma.

Aberrant activation of the FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of hepatocellular carcinoma (HCC). As such, FGFR4 inhibition has emerged as a novel therapeutic option for the treatment of HCC and has shown preliminary efficacy in recent clinical trials for patients exhibiting aberrant FGF19 expression. Resistance to kinase inhibitors is common in oncology, presenting a major challenge in the clinical treatment process. Hence, we investigated the potential mechanisms mediating and causing resistance to FGFR4 inhibition in HCC. Upon the successful establishment of a battery of cellular models developing resistance to FGFR4 inhibitors, we have identified the activation of EGFR, MAPK, and AKT signaling as the primary mechanisms mediating the acquired resistance. Combination of inhibitors against EGFR or its downstream components restored sensitivity to FGFR4 inhibitors. In parental HCC cell lines, EGF treatment also resulted in resistance to FGFR4 inhibitors. This resistance was effectively reverted by inhibitors of the EGFR signaling pathway, suggesting that EGFR activation is a potential cause of intrinsic resistance. We further confirmed the above findings in vivo in mouse xenograft tumor models. Genomic analysis of patient samples from The Cancer Genome Atlas confirmed that a segment of patients with HCC harboring FGF19 overexpression indeed exhibited increased activation of EGFR signaling. These findings conclusively indicate that both induced and innate activation of EGFR could mediate resistance to FGFR4 inhibition, suggesting that dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for the treatment of FGF19-FGFR4 altered HCC.

Elevated lncRNA MIAT in peripheral blood mononuclear cells contributes to post-menopausal osteoporosis.

Inflammatory cytokines contribute to the development of osteoporosis with sophisticated mechanisms. Globally alteration of long-chain non-coding RNA was screened in osteoporosis, while we still know little about their functional role in the inflammatory cytokine secretion. In this study, we collected the peripheral blood mononuclear cells (PBMCs) from post-menopausal osteoporosis patients to measure lncRNA MIAT (lncMIAT) expression levels, and explored the molecular mechanism of lncMIAT induced inflammatory cytokine secretion. We identified increased lncMIAT expression in the PBMCs of post-menopausal osteoporosis patients, which was an important predictive biomarker for the diagnosis. LncMIAT expression in PBMCs was positively correlated with the inflammatory cytokine secretion. Mechanism study indicated that lncMIAT increased the expression levels of p38MAPK by crosstalk with miR-216a in PBMCs. The lncMIAT/miR-216a/p38MAPK signaling contributed predominantly to the increased inflammatory cytokine secretion in the PBMCs from postmenopausal osteoporosis. In conclusion, we identified that increased lncMIAT in PBMCs induced inflammatory cytokine secretion, which contributed to the development of post-menopausal osteoporosis. lncMIAT/miR-216a axis was critical for the regulation of AMPK/p38MAPK signaling, which may be a promising therapeutic target for osteoporosis treatment by inflammatory cytokine inhibition.

PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity.

The Beclin1-VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation. However, the underlying molecular mechanism that coordinates the timely activation of VPS34 complex is poorly understood. Here, we identify that PAQR3 governs the preferential formation and activation of ATG14L-linked VPS34 complex for autophagy initiation via two levels of regulation. Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. Deletion of PAQR3 leads to reduction of exercise-induced autophagy in mice, accompanied by a certain degree of disaggregation of ATG14L-associated VPS34 complex. Together, this study uncovers that PAQR3 can not only enhance the capacity of pro-autophagy class III PI3K due to its scaffold function, but also integrate AMPK signal to activation of ATG14L-linked VPS34 complex upon glucose starvation.

[Efficient genome editing in human pluripotent stem cells through CRISPR/Cas9].

The RNA-guided CRISPR (clustered regularly interspaced short palindromic repeat)-associated Cas9 nuclease has offered a new platform for genome editing with high efficiency. Here, we report the use of CRISPR/Cas9 technology to target a specific genomic region in human pluripotent stem cells. We show that CRISPR/Cas9 can be used to disrupt a gene by introducing frameshift mutations to gene coding region; to knock in specific sequences (e.g. FLAG tag DNA sequence) to targeted genomic locus via homology directed repair; to induce large genomic deletion through dual-guide multiplex. Our results demonstrate the versatile application of CRISPR/Cas9 in stem cell genome editing, which can be widely utilized for functional studies of genes or genome loci in human pluripotent stem cells.

Use of genome editing tools in human stem cell-based disease modeling and precision medicine.

Precision medicine emerges as a new approach that takes into account individual variability. The successful conduct of precision medicine requires the use of precise disease models. Human pluripotent stem cells (hPSCs), as well as adult stem cells, can be differentiated into a variety of human somatic cell types that can be used for research and drug screening. The development of genome editing technology over the past few years, especially the CRISPR/Cas system, has made it feasible to precisely and efficiently edit the genetic background. Therefore, disease modeling by using a combination of human stem cells and genome editing technology has offered a new platform to generate " personalized " disease models, which allow the study of the contribution of individual genetic variabilities to disease progression and the development of precise treatments. In this review, recent advances in the use of genome editing in human stem cells and the generation of stem cell models for rare diseases and cancers are discussed.

[HUANG Yu-jie, the famous traditional Chinese medical physician of Taiwan in the late Qing dynasty and early republican period of China].

HUANG Yu-jie, the famous TCM physician of Taiwan in the late Qing dynasty and early Republican period of China, was a physician with noble medical morality and perfect medical skill. He made distinguished contributions especially to the prevention and treatment of epidemic disease. During the time he undertook the medical work, he also actively took part in the social activities and made changes in customs and traditions to promote the development of society. His medical morality and skill not only were the model for the medical field at that time but also had an extensive and profound impact on the common people.