Stabilization of TGF-ß Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-ß Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance.

Dysregulation of the transforming growth factor-ß (TGF-ß) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-ß receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-ß-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-ß receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-ß signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-ß signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-ß signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-ß signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-ß signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy.

Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor microenvironment, dysregulation of amino acid consumption in immune cells is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered amino acid metabolism is tightly linked to tumor outgrowth, metastasis, and therapeutic resistance through governing the fate of various immune cells. During these processes, the concentration of free amino acids, their membrane bound transporters, key metabolic enzymes, and sensors such as mTOR and GCN2 play critical roles in controlling immune cell differentiation and function. As such, anti-cancer immune responses could be enhanced by supplement of specific essential amino acids, or targeting the metabolic enzymes or their sensors, thereby developing novel adjuvant immune therapeutic modalities. To further dissect metabolic regulation of anti-tumor immunity, this review summarizes the regulatory mechanisms governing reprogramming of amino acid metabolism and their effects on the phenotypes and functions of tumor-infiltrating immune cells to propose novel approaches that could be exploited to rewire amino acid metabolism and enhance cancer immunotherapy.

The composition and roles of gastric stem cells in epithelial homeostasis, regeneration, and tumorigenesis.

The epithelial lining of the stomach undergoes rapid turnover to preserve its structural and functional integrity, a process driven by long-lived stem cells residing in the antral and corpus glands. Several subpopulations of gastric stem cells have been identified and their phenotypic and functional diversities linked to spatiotemporal specification of stem cells niches. Here, we review the biological features of gastric stem cells at various locations of the stomach under homeostatic conditions, as demonstrated by reporter mice, lineage tracing, and single cell sequencing. We also review the role of gastric stem cells in epithelial regeneration in response to injury. Moreover, we discuss emerging evidence demonstrating that accumulation of oncogenic drivers or alteration of stemness signaling pathways in gastric stem cells promotes gastric cancer. Given a fundamental role of the microenvironment, this review highlights the role reprogramming of niche components and signaling pathways under pathological conditions in dictating stem cell fate. Several outstanding issues are raised, such as the relevance of stem cell heterogeneity and plasticity, and epigenetic regulatory mechanisms, to Helicobacter pylori infection-initiated metaplasia-carcinogenesis cascades. With the development of spatiotemporal genomics, transcriptomics, and proteomics, as well as multiplexed screening and tracing approaches, we anticipate that more precise definition and characterization of gastric stem cells, and the crosstalk with their niche will be delineated in the near future. Rational exploitation and proper translation of these findings may bring forward novel modalities for epithelial rejuvenation and cancer therapeutics.

Effect of gonadotropin-releasing hormone analogue treatment in improving final adult height of children with central precocious puberty or early and fast puberty: a Meta analysis. / ä¿ƒæ€§è ºæ¿€ç´ é‡Šæ”¾æ¿€ç´ ç±»ä¼¼ç‰©æ²»ç–—å¯¹ä¸­æž¢æ€§æ€§æ—©ç†Ÿå’Œå¿«é€Ÿè¿›å±•åž‹é’æ˜¥æœŸæ‚£å„¿æˆå¹´ç»ˆèº«é«˜æ”¹å–„çš„Meta分析.

OBJECTIVES: To systematically evaluate the effect of gonadotropin-releasing hormone analogue (GnRHa) treatment on the final adult height of children over 6 years of age with central precocious puberty (CPP) or early and fast puberty (EFP). METHODS: PubMed, MEDLINE, Embase, Cochrane Library, CNKI, and Wanfang Data were searched for related articles on GnRHa treatment for children with CPP or EFP. Stata 12.0 software was used to perform a Meta analysis of related data. RESULTS: A total of 10 studies were included, and the total sample size was 720 children, with 475 children in the GnRHa treatment group and 245 children in the control group. The Meta analysis showed that compared with the control group, the GnRHa treatment group had significantly better final adult height (WMD=3.30, 95%CI: 2.49-4.12, P<0.001), standard deviation score of final adult height (WMD=0.51, 95%CI: 0.29-0.73, P<0.001), and height gain (WMD=2.89, 95%CI: 2.17-3.60, P<0.001). No severe adverse events were reported in these studies. CONCLUSIONS: GnRHa treatment is safe and effective in improving the final adult height of children over 6 years of age with CPP or EFP.