Relapse fated latent diagnosis subclones in acute B lineage leukaemia are drug tolerant and possess distinct metabolic programs.
急性 B 谱系白血病的复发潜伏诊断亚克隆是药物耐受的，具有不同的代谢程序。
- 作者列表："Dobson SM","Garcia-Prat L","Vanner RJ","Wintersinger J","Waanders E","Gu Z","McLeod J","Gan OI","Grandal I","Payne-Turner D","Edmonson MN","Ma X","Fan Y","Voisin V","Chan-Seng-Yue M","Xie SZ","Hosseini M","Abelson S","Gupta P","Rusch M","Shao Y","Olsen SR","Neale G","Chan SM","Bader G","Easton J","Guidos CJ","Danska JS","Zhang J","Minden MD","Morris Q","Mullighan CG","Dick JE
:Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples show relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequencing, identified and isolated minor diagnosis subclones that initiate evolutionary trajectory toward relapse (termed diagnosis Relapse Initiating clones, dRI). Compared to other diagnosis subclones, dRI were drug tolerant with distinct engraftment and metabolic properties. Transciptionally, dRI displayed enrichment for chromatin remodelling, mitochondrial metabolism, proteostasis programs and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy resistant.
: 疾病复发导致 B-祖细胞急性淋巴细胞白血病 (B-ALL) 的显著死亡率。匹配诊断和复发样本的基因组分析显示复发常由次要诊断亚克隆引起。然而，为什么治疗根除一些亚克隆而另一些亚克隆存活并进展至复发仍不清楚。阐明这些不同命运的机制需要对分离的亚克隆进行功能分析。在这里，大规模限制稀释异种移植诊断和复发样本，结合靶向测序，鉴定和分离启动向复发进化轨迹的次要诊断亚克隆 (称为诊断复发启动克隆, dRI)。与其他诊断亚克隆相比，dRI 具有不同的植入和代谢特性的药物耐受性。从转运角度来看，dRI 显示了染色质重塑、线粒体代谢、蛋白停滞程序和干性通路增加的富集。DRI 亚克隆隔离和表征揭示了在进一步进化使 dRI 细胞完全耐药之前，通过靶向其不同的代谢和转录途径根除 dRI 细胞的新途径。
METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.
METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.