BackgroundAcute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment.MethodsWe tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells.ResultsThe CLL-1 CAR-T cells specifically lysed CLL-1+ cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1+ myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression.ConclusionsCLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.Electronic supplementary materialThe online version of this article (10.1186/s13045-017-0553-5) contains supplementary material, which is available to authorized users.

Background Interleukin-6 (IL-6) was proposed to be associated with the severity of coronavirus disease 2019 (COVID-19). The present study aimed to explore the kinetics of IL-6 levels, validate this association in COVID-19 patients, and report preliminary data on the efficacy of IL-6 receptor blockade. Methods We conducted a retrospective single-institutional study of 901 consecutive confirmed cases. Serum IL-6 concentrations were tested on admission and/or during hospital stay. Tocilizumab was given to 16 patients with elevated IL-6 concentration. Results 366 patients were defined as common cases, 411 patients as severe, and 124 patients as critical according to the Chinese guideline on diagnosis and treatment of COVID-19. The median concentration of IL-6 was < 1.5 pg/ml (IQR < 1.50–2.15), 1.85 pg/ml (IQR < 1.50–5.21), and 21.55 pg/ml (IQR 6.47–94.66) for the common, severe, and critical groups respectively (P < 0.001). The follow-up kinetics revealed serum IL-6 remained high in critical patients even when cured. An IL-6 concentration higher than 37.65 pg/ml was predictive of in-hospital death (AUC 0.97 [95% CI 0.95–0.99], P < 0.001) with a sensitivity of 91.7% and a specificity of 95.7%. In the 16 patients who received tocilizumab, IL-6 concentrations were significantly increased after administration, and survival outcome was not significantly different from that of propensity-score matched counterparts (n = 53, P = 0.12). Conclusion Serum IL-6 should be included in diagnostic work-up to stratify disease severity, but the benefit of tocilizumab needs further confirmation. Trial registration retrospectively registered.

We report the design, synthesis, and implemention in semiconducting polymers of a novel head-to-head linkage containing the TRTOR (3-alkyl-3′-alkoxy-2,2′-bithiophene) donor subunit having a single strategically optimized, planarizing noncovalent S•••O interaction. Diverse complementary thermal, optical, electrochemical, X-ray scattering, electrical, photovoltaic, and electron microscopic characterization techniques are applied to establish structure−property correlations in a TRTOR-based polymer series. In comparison to monomers having double S•••O interactions, replacing one alkoxy substituent with a less electron-donating alkyl one yields TRTOR-based polymers with significantly depressed (0.2−0.3 eV) HOMOs. Furthermore, the weaker single S•••O interaction and greater TRTOR steric encumberance enhances materials processability without sacrificing backbone planarity. From another perspective, TRTOR has comparable electronic properties to ring-fused 5Hdithieno[3,2-b:2′,3′-d]pyran (DTP) subunits, but a centrosymmetric geometry which promotes a more compact and ordered structure than bulkier, axisymmetric DTP. Compared to monosubstituted TTOR (3-alkoxy-2,2′-bithiophene), alkylation at the TRTOR bithiophene 3-position enhances conjugation and polymer crystallinity with contracted π−π stacking. Grazing incidence wide-angle X-ray scattering (GIWAXS) data reveal that the greater steric hindrance and the weaker single S•••O interaction are not detrimental to close packing and high crystallinity. As a proof of materials design, copolymerizing TRTOR with phthalimides yields copolymers with promising thin-film transistor mobility as high as 0.42 cm 2 /(V•s) and 6.3% power conversion efficiency in polymer solar cells, the highest of any phthalimide copolymers reported to date. The depressed TRTOR HOMOs imbue these polymers with substantially increased I on /I off ratios and V oc 's versus analogous subunits with multiple electron donating, planarizing alkoxy substituents. Implementing a head-to-head linkage with an alkyl/alkoxy substitution pattern and a single S•••O interaction is a promising strategy for organic electronics materials design.

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Long non-coding RNAs (lncRNAs) are a major class of non-coding RNAs, and the functional deregulations of lncRNAs have been shown to be associated with the development and progression of BC. In this work, we conduct an integrative analysis on five re-annotated lncRNA expression datasets from the Gene Expression Omnibus (GEO) which included a total of 891 BC samples. We identified a five-lncRNA signature that was significantly associated with DFS in the training cohort of 327 patients. We found the five-lncRNA signature could effectively stratify patients in the training dataset into high- and low-risk groups with significantly different DFS (p = 3.29 × 10 , log-rank test). The five-lncRNA signature was effectively validated in four independent cohorts, and prognostic analysis results showed that the five-lncRNA signature was independent of clinical prognostic factors, such as BC subtypes and adjuvant treatments. Furthermore, GSEA suggested that the five-lncRNA signature was involved in BC metastasis-related pathways. Our findings indicate that these five lncRNAs may be implicated in BC pathogenesis, and further, these lncRNAs may potentially serve as novel candidate biomarkers for the identification of BC patients at high risk for tumor recurrence.

Cancer stem cells (CSCs) are characterized by self‐renewal and ‐differential potential as compared to common cancer cells and play an important role in the development and therapeutic resistance of liver hepatocellular carcinoma (LIHC). However, the specific pathogenesis of LIHC stem cells is still unclear, and the genes involved in the stemness of LIHC stem cells are currently unknown. In this study, we investigated novel biomarkers associated with LIHC and explored the expression characteristics of stem cell‐related genes in LIHC. We found that mRNA expression‐based stemness index (mRNAsi) was significantly overexpressed in liver cancer tissues. Further, mRNAsi expression in LIHC increased with the tumor pathological grade, with grade 4 tumors harboring the greatest stem cell features. Upon establishing mRNAsi scores based on mRNA expression of every gene, we found an association with poor overall survival in LIHC. Moreover, modules of interest were determined based on weighted gene co‐expression network analysis (WGCNA) inclusion criteria, and three significant modules (red, green, and brown) and 21 key genes (DCN, ECM1, HAND2, PTGIS, SFRP1, SRPX, COLEC10, GRP182, ADAMTS7, CD200, CDH11, COL8A1, FAP, LZTS1, MAP1B, NAV1, NOTCH3, OLFML2A, PRR16, TMEM119, and VCAN) were identified. Functional analysis of these 21 genes demonstrated their enrichment in pathways involved in angiogenesis, negative regulation of DNA‐binding transcription factor activity, apoptosis, and autophagy. Causal relationship with proteins indicated that the Wnt, Notch, and Hypoxia pathways are closely related to LIHC tumorigenesis. To our knowledge, this is the first report of a novel CSC biomarker, mRNAsi, to predict the prognosis of LIHC. Further, we identified 21 key genes through mRNA expression network analysis, which could be potential therapeutic targets to inhibit the stemness of cancer cells in LIHC.

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Background/Aims: The metabolic features of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. The expression of glycolytic enzyme enolase 2 (ENO2) was found to be closely associated with the clinical features of acute lymphoblastic leukemia (ALL) patients, but its functions remain unclear in ALL. Methods: We evaluated the association between ENO2 mRNA expression in bone marrow mononuclear cells (BM-MNCs) and the efficacy of chemotherapy, and further explored the function of ENO2 in ALL. The molecular mechanisms of ENO2 expression and its effects on cell growth, glycolysis and glucocorticoid resistance were explored by Cell Counting Kit-8, glucose-consumption assay, Quantitative RT-PCR, Western blotting and in vivo tumorigenesis in NOD/SCID mice. Results: The results showed that ENO2 mRNA expression in BM-MNCs was significantly decreased when patients completed induction chemotherapy and reached complete remission (CR). ENO2 mRNA expression was increased when patients suffered relapse. Functional studies demonstrated that ENO2 promoted cell growth, glycolysis, and glucocorticoid resistance, all of which were effectively inhibited when ENO2 was silenced with shRNAs. Further studies revealed that ENO2 up-regulated various glycolysis-related genes and enhanced Akt activity with subsequent glycogen synthase kinase3β (GSK-3β) phosphorylation, inducing cell proliferation and glycolysis. The combination of silencing ENO2 and 2-deoxyglucose (2-DG) synergistically inhibited leukemia cell survival. Conclusions: These results indicate that ENO2 may be a biological marker for monitoring chemotherapeutic efficacy and relapse in ALL. ENO2 may provide a potential therapeutic strategy for ALL.