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The intestinal epithelium harbours remarkable self-renewal capacity that is driven by Lgr5 intestinal stem cells (ISCs) at the crypt base. However, the molecular mechanism controlling Lgr5 ISC stemness is incompletely understood. We show that a Gata6 long noncoding RNA (lncGata6) is highly expressed in ISCs. LncGata6 knockout or conditional knockout in ISCs impairs the stemness of ISCs and epithelial regeneration. Mechanistically, lncGata6 recruits the NURF complex onto the Ehf promoter to induce its transcription, which promotes the expression of Lgr4/5 to enhance Wnt signalling activation. Moreover, the human orthologue lncGATA6 is highly expressed in the cancer stem cells of colorectal cancer and promotes tumour initiation and progression. Antisense oligonucleotides against lncGATA6 exhibit strong therapeutic efficacy on colorectal cancer. Thus, targeting lncGATA6 will have potential clinical applications in colorectal cancer treatment as an ideal therapeutic target.

Hepatocellular carcinoma (HCC) is the most prevalent liver cancer, characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanism underlying their self-renewal maintenance is poorly understood. Here, we identified a long noncoding RNA (lncRNA) termed HAND2-AS1 that is highly expressed in liver CSCs. Human HAND2-AS1 and its mouse ortholog lncHand2 display a high level of conservation. HAND2-AS1 is required for the selfrenewal maintenance of liver CSCs to initiate HCC development. Mechanistically, HAND2-AS1 recruits the INO80 chromatin-remodeling complex to the promoter of BMPR1A, thereby inducing its expression and leading to the activation of BMP signaling. Importantly, interfering with expression of HAND2-AS1 by antisense oligonucleotides (ASOs) and BMPR1A by siRNAs has synergistic antitumorigenic effects on humanized HCC models. Moreover, knockout of lncHand2 or Bmpr1a in mouse hepatocytes impairs BMP signaling and suppresses the initiation of liver cancer. Our findings reveal that HAND2-AS1 promotes the self-renewal of liver CSCs and drives liver oncogenesis, offering a potential new target for HCC therapy. The EMBO JournalYanying Wang et al to promote BMPR1A expression and activates BMP signaling for increasing self-renewal of liver CSCs. Moreover, the addition of ASOs of HAND2-AS1 along with siRNA against BMPR1A has potent therapeutic effect on HCC.

Surgery has passed through an intuitive and an empirical era and has now entered its modern phase characterized by everincreasing certainty in surgical practice.1 The enormous progress in biomedicine, the rise of evidence-based medicine, and the consensus on the need for humanistic patient care in the 21 st century have laid a foundation for a new surgical paradigm. This surgical paradigm featuring high-certainty clinical practice would enable simultaneous optimization of therapeutic effectiveness, surgical safety, and minimal invasiveness. We argued for the necessity of a paradigm shift in liver surgery, and advocated "precision liver resection" as a surgical concept for the first time in 2006, 2,3 and later extended the concept of "precision liver resection" to "precision liver surgery." 4,5 This concept is widely applicable within various surgical fields and is embraced by both the Chinese and international community. In this review, we advocate the new paradigm of "precision surgery" and attempt to establish its theoretical and technological framework by examining the evolution of surgery, the advances in surgical science and technology, and the health care needs within modern society. "Precision" does not just refer to the accuracy of operative manipulation, some idealized procedure, or a particular advanced technology, 6,7 "Precision" as we define it is a new approach to surgery and its derived system of theories and technologies covering all the elements of surgical practice, including preoperative evaluation, clinical decision making, surgical planning, operative manipulation, and perioperative management. 3 Emergence of Precision SurgerySurgery, as a direct and profound exploration of the human body, has always been a symphony of science and art. In this everlasting symphony, the surgical paradigm has evolved Keywords ► precision surgery ► liver surgery ► certainty ► multiobjective optimization AbstractContinuous theoretical and technological progress in the face of increasing expectations for quality health care has transformed the surgical paradigm. The authors systematically review these historical trends and propose the novel paradigm of "precision surgery," featuring certainty-based practice to ensure the best result for each patient with multiobjective optimization of therapeutic effectiveness, surgical safety, and minimal invasiveness. The main characteristics of precision surgery may be summarized as determinacy, predictability, controllability, integration, standardization, and individualization. The strategy of precision in liver surgery is to seek a balance of maximizing the removal of the target lesion, while maximizing the functional liver remnant and minimizing surgical invasiveness. In this article, the authors demonstrate the application of precision approaches in specific settings in complex liver surgery. They propose that the concept of precision surgery should be considered for wider application in liver surgery and other fields as a step toward the ultimate goal of perfect surgery.

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