SALL4, a human homolog to Drosophila spalt, is a novel zinc finger transcriptional factor essential for development. We cloned SALL4 and its isoforms (SALL4A and SALL4B).

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The pronounced biological influence of the tumor microenvironment on cancer progression and metastasis has gained increased recognition over the past decade, yet most preclinical antineoplastic drug testing is still reliant on conventional 2D cell culture systems. Although monolayer cultures recapitulate some of the phenotypic traits observed clinically, they are limited in their ability to model the full range of microenvironmental cues, such as ones elicited by 3D cell-cell and cell-extracellular matrix interactions. To address these shortcomings, we established an ex vivo 3D Ewing sarcoma model that closely mimics the morphology, growth kinetics, and protein expression profile of human tumors. We observed that Ewing sarcoma cells cultured in porous 3D electrospun poly(e-caprolactone) scaffolds not only were more resistant to traditional cytotoxic drugs than were cells in 2D monolayer culture but also exhibited remarkable differences in the expression pattern of the insulin-like growth factor-1 receptor/mammalian target of rapamycin pathway. This 3D model of the bone microenvironment may have broad applicability for mechanistic studies of bone sarcomas and exhibits the potential to augment preclinical evaluation of antineoplastic drug candidates for these malignancies.tissue engineering | tumor model | biological therapy | connective tissue D espite the primacy of the cancer cell's dysregulated genotype [e.g., a near universal translocation of the Ewing sarcoma (EWS) breakpoint region 1 gene in EWS cells] as the initial step in malignant transformation, it has become increasingly apparent that the overall tumor phenotype is also dictated by the 3D tumor microenvironment (1-4). Nonetheless, studies of cancer biology and evaluation of antineoplastic drug efficacy remain heavily dependent on conventional 2D cell culture systems despite their limited ability to reflect the 3D tumor architecture, extracellular matrix (ECM), and surrounding cell types that comprise the in vivo tumor milieu.To overcome some of these constraints, 3D in vitro models such as spheroid and gel systems have been extensively studied and, compared with 2D monolayer culture, appear to better mimic the profound effects that the in vivo 3D environment has upon the human tumor phenotype (5-9). For example, malignant cells cultured in 3D exhibit increased chemoresistance (10, 11) and decreased cell proliferation (12), and assume specific phenotypes inducible only under a 3D context, such as angiogenic capability (13-15). Furthermore, striking differences in signaling pathways targeted by proven and experimental therapies have been observed in 3D tumor models (16-18). Accordingly, heightened awareness of the importance of 3D culture for cancer cells has resulted in the increasing use of spheroid culture systems for cancer research. However, these non-adhesion-mediated systems provide poor control over the tumor architecture and cell-cell interactions; as a result of culture conditions that prohibit cellular attachment onto surrounding surfaces, ce...

Recently, the PD-1 antibody nivolumab, which was approved for advanced HCC refractory to sorafenib, demonstrated a 20% objective response rate in advanced HCC (13). While this is an encouraging step in HCC therapy, it also provides great opportunity to improve therapeutic efficacy. Because mechanism-driven Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6-activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined with anti-T cell immunoglobulin mucin-3 (anti-Tim-3) therapy in animal models. A positive correlation between IL-6 and PD-L1 expression was also observed in hepatocellular carcinoma patient tumor tissues. These results identify a mechanism regulating PD-L1 glycosylation initiation and suggest the combination of anti-IL-6 and anti-Tim-3 as an effective marker-guided therapeutic strategy.

Anaplastic large-cell lymphoma (ALCL) was initially recognized on the basis of morphologic features and the consistent expression of CD30. It then became evident that the majority of these tumors are derived from lymphoid cells of T or null immunophenotype. The subsequent finding that t(2;5)(p23;q35) occurs in 40% to 60% of ALCL patients established a distinct clinicopathologic entity. This chromosomal translocation induces the formation of the chimeric protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which possesses significant oncogenic potential resulting from the constitutive activation of the tyrosine kinase ALK. In addition to its specific pathophysiologic events, NPM-ALKexpressing lymphoma presents with consistent clinical manifestations. Only 13 years after the identification of NPM-ALK, tremendous progress has been made in our understanding of this molecule because of the relentless efforts of multiple investigators who have dissected its biologic roles using in vitro and in vivo experimental models. Several upstream modulators, cross-reacting oncogenes, and downstream effectors of NPM-ALK have been identified and characterized. Understanding these interacting oncogenic systems is expected to facilitate the design of new therapeutic strategies and agents. In this review, we briefly discuss ALCL and focus on NPM-ALK. IntroductionAnaplastic large-cell lymphoma (ALCL) is a relatively uncommon tumor. It was first recognized by Stein et al 1 in 1985, who reported the consistent expression of the Ki-1 antigen (later designated CD30) in tumors with frequent cohesive proliferation of large pleomorphic cells. Most of these tumors were labeled "histiocytic malignancies." 1 The Ki-1 monoclonal antibody was originally described by the same group and was used to identify a novel antigen in the Hodgkin lymphoma cell line L428. 2 Subsequent immunophenotyping and gene rearrangement studies showed that the vast majority of ALCL tumors are derived from lymphoid cells of T or null immunophenotype. 3 Histologically, several ALCL variants have been described. Of these variants, the common, lymphohistiocytic, and small-cell are the most frequently encountered. The "horseshoe" or "wreath" cell is considered the cytologic hallmark of this disease. 4 ALCL occurs as 2 distinct clinical entities, as a widespread systemic disease, or as a localized cutaneous disease. Systemic ALCL comprises 2% to 8% of non-Hodgkin lymphomas in adults and 10% to 15% of these lymphomas in children. 5 The frequency of ALCL increases to 30% to 40% of non-Hodgkin lymphomas in children when only cases with large-cell morphology are included. ALKThe recognition of t(2;5)(p23;q35) established the molecular definition of a subset of ALCL tumors that harbors this translocation. [6][7][8] In 1994, 2 independent groups cloned the genes involved in this translocation and illustrated the fusion of the nucleophosmin (NPM) gene on chromosome 5q35 to the previously unidentified gene anaplastic lymphoma kinase (ALK) gene on 2p23. 9,10 This chromosomal t...