Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 non-silent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 genes were among common targets for secondary mutations. Mutations in the latter were often subclonal and may be involved in the progression rather than the initiation of leukemia, and these mutations associated with poor clinical outcome. Our findings provide new insights into the pathogenesis and progression of JMML.

This paper presents a robust and efficient method for license plate detection with the purpose of accurately localizing vehicle license plates from complex scenes in real time. A simple yet effective image downscaling method is first proposed to substantially accelerate license plate localization without sacrificing detection performance compared with that achieved using the original image. Furthermore, a novel line density filter approach is proposed to extract candidate regions, thereby significantly reducing the area to be analyzed for license plate localization. Moreover, a cascaded license plate classifier based on linear support vector machines using color saliency features is introduced to identify the true license plate from among the candidate regions. For performance evaluation, a data set consisting of 3977 images captured from diverse scenes under different conditions is also presented. Extensive experiments on the widely used Caltech license plate data set and our newly introduced data set demonstrate that the proposed approach substantially outperforms state-of-the-art methods in terms of both detection accuracy and run-time efficiency, increasing the detection ratio from 91.09% to 96.62% while decreasing the run time from 672 to 42 ms for processing an image with a resolution of 1082×728 . The executable code and our collected data set are publicly available.

Juvenile myelomonocytic leukemia (JMML), a rare and aggressive myelodysplastic/myeloproliferative neoplasm that occurs in infants and during early childhood, is characterized by excessive myelomonocytic cell proliferation. More than 80% of patients harbor germ line and somatic mutations in RAS pathway genes (eg, ,, ,, and ), and previous studies have identified several biomarkers associated with poor prognosis. However, the molecular pathogenesis of 10% to 20% of patients and the relationships among these biomarkers have not been well defined. To address these issues, we performed an integrated molecular analysis of samples from 150 JMML patients. RNA-sequencing identified tyrosine kinase fusions (, and ) in 3 of 16 patients (18%) who lacked canonical RAS pathway mutations. Crizotinib, an ALK/ROS1 inhibitor, markedly suppressed fusion-positive JMML cell proliferation in vitro. Therefore, we administered crizotinib to a chemotherapy-resistant patient with the fusion who subsequently achieved complete molecular remission. In addition, crizotinib also suppressed proliferation of JMML cells with canonical RAS pathway mutations. Genome-wide methylation analysis identified a hypermethylation profile resembling that of acute myeloid leukemia (AML), which correlated significantly with genetic markers with poor outcomes such as gene mutations, 2 or more genetic mutations, an AML-type expression profile, and expression. In summary, we identified recurrent activated fusions in JMML patients without canonical RAS pathway gene mutations and revealed the relationships among biomarkers for JMML. Crizotinib is a promising candidate drug for the treatment of JMML, particularly in patients with fusions.

Obesity and related metabolic diseases associated with chronic low-grade inflammation greatly compromise human health. Previous observations on the roles of interferon regulatory factors (IRFs) in the regulation of metabolism prompted investigation of the involvement of a key family member, IRF3, in metabolic disorders. IRF3 expression in the liver is decreased in animals with diet-induced and genetic obesity. The global knockout (KO) of IRF3 significantly promotes chronic high-fat diet (HFD)-induced hepatic insulin resistance and steatosis; in contrast, adenoviral-mediated hepatic IRF3 overexpression preserves glucose and lipid homeostasis. Furthermore, systemic and hepatic inflammation, which is increased in IRF3 KO mice, is attenuated by the overexpression of hepatic IRF3. Importantly, inhibitor of nuclear factor kappa B kinase beta subunit / nuclear factor kappa B (IKKb/NF-jB) signaling is repressed by IRF3, and hepatic overexpression of the inhibitor of jB-a (IjBa) reverses HFD-induced insulin resistance and steatosis in IRF3 KO mice. Mechanistically, IRF3 interacts with the kinase domain of IKKb in the cytoplasm and inhibits its downstream signaling. Moreover, deletion of the region of IRF3 responsible for the IRF3/IKKb interaction inhibits the capacity of IRF3 to preserve glucose and lipid homeostasis. Conclusion: IRF3 interacts with IKKb in the cytoplasm to inhibit IKKb/NF-jB signaling, thus alleviating hepatic inflammation, insulin resistance, and hepatic steatosis. (HEPATOLOGY 2014;59:870-885) M etabolic diseases, including obesity, type 2 diabetes (T2D), and nonalcoholic fatty liver disease (NAFLD), currently threaten human lives due to continued urbanization and population aging.1 Evidence from both clinical and basic research substantiates the notion that inflammation underlies the etiology of obesity-related metabolic disorders.

A novel MEF2D-BCL9 fusion we identified characterizes a novel subset of pediatric ALL, predicts poor prognosis, and may be a candidate for novel molecular targeting.

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Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance. Am J Physiol Endocrinol Metab 305: E485-E495, 2013. First published May 20, 2013 doi:10.1152/ajpendo.00505.2012.-Obesity-related inflammation has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. In this study, we addressed the potential role of interferon regulatory factor 7 (IRF7), a master regulator of type I interferon-dependent immune responses, in the regulation of energy metabolism. The expression levels of IRF7 were increased in white adipose tissue, liver tissue, and gastrocnemius muscle of both dietinduced obese mice and ob/ob mice compared with their lean counterparts. After feeding a high-fat diet (HFD) for 24 wk, IRF7 knockout (KO) mice showed less weight gain and adiposity than wild-type controls. KO of IRF7 improved glucose and lipid homeostasis and insulin sensitivity. Additionally, KO of IRF7 ameliorated diet-induced hepatic steatosis. Next, we assessed the inflammatory state of the IRF7 KO mice on the HFD. These mice showed less macrophage infiltration into multiple organs and were protected from local and systemic inflammation. This study demonstrates a role for IRF7 in diet-induced alterations in energy metabolism and insulin sensitivity. Our results also suggest that IRF7 is involved in the etiology of metabolic abnormalities, which suggests a new strategy for treating obesity and type 2 diabetes. type 2 diabetes; adiposity; fatty liver; inflammation UNDER NORMAL PHYSIOLOGICAL conditions, organisms have a finetuned regulatory network to maintain metabolic homeostasis. However, energy imbalance develops with caloric excess and compromised regulatory functions that accompany aging. This imbalance leads to obesity, nonalcoholic fatty liver diseases (NAFLD), metabolic syndrome, and type 2 diabetes, which pose great challenges to public health (5, 45a). Obesity is now recognized as a chronic low-grade inflammatory state (19). Inflammatory mediators and cytokines are overexpressed in the adipose and other tissues in the obese state (45). Infiltration of immune cells and proinflammatory M1 polarization of macrophages are also associated with obesity (24). Activation of inflammatory signaling pathways, including c-Jun NH 2 -terminal kinase (JNK)/activator protein 1 (AP1) and IKK/NF-B pathways, blunts insulin activity (13). Loss of IB kinase ε (IKKε, also known as IKKi), a target gene of NF-B, has also been reported to improve the energy balance in diet-induced obese mice (7, 33). In addition to systemic inflammation, ectopic lipid accumulation and endoplasmic reticulum (ER) stress were also proposed to explain the pathogenesis of insulin resistance (12, 34). However, the underlying mechanism of obesity-related metabolic disorders is still not completely understood.Interferon (IFN) ␣ and IFN␤, collectively known as type I IFNs, are the major mediators of the host immune response against viral infections (14, 31). IFN regulatory factors (IRF) are a family of transcription facto...

Key Points Question Is tumor mutation burden (TMB) associated with improved outcomes of programmed cell death–1 (PD-1)/programmed death ligand–1 (PD-L1) inhibition across PD-L1 expression levels in non–small cell lung cancer (NSCLC)? Findings In this cohort study of 1552 patients with NSCLC, the group with high TMB had improved response rates and survival after receiving PD-1/PD-L1 inhibition therapy across PD-L1 expression subgroups compared with the group with low TMB. High TMB levels were associated with increased CD8-positive T-cell infiltration and distinct immune response gene expression signatures. Meaning These findings suggest that in NSCLC, a high number of nonsynonymous tumor mutations is associated with immune cell infiltration and inflammatory T-cell expression signatures, leading to increased sensitivity to PD-1/PD-L1 inhibition across PD-L1 expression subgroups.