Reduced FBXW7 expression in pancreatic cancer correlates with poor prognosis, and chemotherapeutic resistance via accumulation of MCL1

学位記番号：医博甲168

Whole genome sequencing-based mapping and candidate identification of mutations from fixed zebrafish tissue

As forward genetic screens in zebrafish become more common, the number of mutants that cannot be identified by gross morphology or through transgenic approaches, such as many nervous system defects, has also increased. Screening for these difficult-to-visualize phenotypes demands techniques such as whole-mount in situ hybridization (WISH) or antibody staining, which require tissue fixation. To date, fixed tissue has not been amenable for generating libraries for whole genome sequencing (WGS). Here, we describe a method for using genomic DNA from fixed tissue and a bioinformatics suite for WGS-based mapping of zebrafish mutants. We tested our protocol using two known zebrafish mutant alleles, gpr126st49 and egr2bfh227, both of which cause myelin defects. As further proof of concept we mapped a novel mutation, stl64, identified in a zebrafish WISH screen for myelination defects. We linked stl64 to chromosome 1 and identified a candidate nonsense mutation in the F-box and WD repeat domain containing 7 (fbxw7) gene. Importantly, stl64 mutants phenocopy previously described fbxw7vu56 mutants, and knockdown of fbxw7 in wild-type animals produced similar defects, demonstrating that stl64 disrupts fbxw7. Together, these data show that our mapping protocol can map and identify causative lesions in mutant screens that require tissue fixation for phenotypic analysis

Clinicopathological and targeted exome gene features of a patient with metastatic acinic cell carcinoma of the parotid gland harboring an ARID2 nonsense mutation and CDKN2A/B deletion

We describe the presentation, treatment, clinical outcome, and targeted genome analysis of a metastatic salivary acinic cell carcinoma (AciCC). A 71-year-old male presented with a 3 cm right tail of a parotid lesion, first detected as a nodule by the patient seven months earlier. He had a right total parotidectomy with cranial nerve VII resection, right facial nerve resection and grafting, resection of the right conchal cartilage, and right modified radical neck dissection. The primary tumor revealed AciCC with two distinct areas: a well-differentiated component with glandular architecture and a dedifferentiated component with infiltrative growth pattern associated with prominent stromal response, necrosis, perineural invasion, and cellular pleomorphism. Tumor staging was pT4 N0 MX. Immunohistochemistry staining showed pankeratin (+), CD56 (−), and a Ki67 proliferation index of 15%. Upon microscopic inspection, 49 local lymph nodes resected during parotidectomy were negative for cancer cells. Targeted sequencing of the primary tumor revealed deletions of CDKN2A and CDKN2B, a nonsense mutation in ARID2, and single missense mutations of unknown significance in nine other genes. Despite postoperative localized radiation treatment, follow-up whole body PET/CT scan showed lung, soft tissue, bone, and liver metastases. The patient expired 9 months after resection of the primary tumor

MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency

open9siopenFong, Louise Y.; Taccioli, Cristian; Jing, Ruiyan; Smalley, Karl J.; Alder, Hansjuerg; Jiang, Yubao; Fadda, Paolo; Farber, John L.; Croce, Carlo M.Fong, Louise Y.; Taccioli, Cristian; Jing, Ruiyan; Smalley, Karl J.; Alder, Hansjuerg; Jiang, Yubao; Fadda, Paolo; Farber, John L.; Croce, Carlo M

The molecular basis of T cell acute lymphoblastic leukemia

T cell acute lymphoblastic leukemias (T-ALLs) arise from the malignant transformation of hematopoietic progenitors primed toward T cell development, as result of a multistep oncogenic process involving constitutive activation of NOTCH signaling and genetic alterations in transcription factors, signaling oncogenes, and tumor suppressors. Notably, these genetic alterations define distinct molecular groups of T-ALL with specific gene expression signatures and clinicobiological features. This review summarizes recent advances in our understanding of the molecular genetics of T-ALL

MicroRNA co-expression networks exhibit increased complexity in pancreatic ductal compared to Vater’s papilla adenocarcinoma

iRNA expression abnormalities in adenocarcinoma arising from pancreatic ductal system (PDAC) and Vater’s papilla (PVAC) could be associated with distinctive pathologic features and clinical cancer behaviours. Our previous miRNA expression profiling data on PDAC (n=9) and PVAC (n=4) were revaluated to define differences/ similarities in miRNA expression patterns. Afterwards, in order to uncover target genes and core signalling pathways regulated by specific miRNAs in these two tumour entities, miRNA interaction networks were wired for each tumour entity, and experimentally validated target genes underwent pathways enrichment analysis. One hundred and one miRNAs were altered, mainly over-expressed, in PDAC samples. Twenty-six miRNAs were deregulated in PVAC samples, where more miRNAs were down-expressed in tumours compared to normal tissues. Four miRNAs were significantly altered in both subgroups of patients, while 27 miRNAs were differentially expressed between PDAC and PVAC. Although miRNA interaction networks were more complex and dense in PDAC than in PVAC, pathways enrichment analysis uncovered a functional overlapping between PDAC and PVAC. However, shared signalling events were influenced by different miRNA and/or genes in the two tumour entities. Overall, specific miRNA expression patterns were involved in the regulation of a limited core signalling pathways in the biology landscape of PDAC and PVAC

Gallbladder cancer: South American experience

Large differences in terms of incidence and mortality due to gallbladder cancer (GBC) have been reported worldwide. Moreover, it seems that GBC has unique characteristics in South America. We surveyed the literature looking for information about the epidemiology, basic and translational research, and clinical trials performed in South America in order to critically analyze the magnitude of this health problem in the region. Compared to other geographic areas, age-standardized mortality rates (ASMR) for GBC in women are very high, particularly in many western areas of South America. Genetic, as well as dietary and environmental factors likely contribute to the pathogenesis of this disease in the area. Compared to other regions the profile of abnormalities of key genes such as KRAS and TP53 in GBC seems to slightly differ in South America, while the clinical behavior appears to be similar with a median overall survival (OS) of 6.5 to 8 months in advanced GBC. In contrast to Europe and USA, prophylactic cholecystectomy is a common practice in western areas of South America. GBC particularly affects women in South America, and represents a significant public health problem. It appears to have peculiarities that pose an urgent need for additional research aimed to discover risk factors, molecular events associated with its development and new treatment options for this lethal disease.Fil: Arroyo, Gerardo F.. Intergrupo Latinoamericano de Oncología Gastrointestinal; ArgentinaFil: Gentile, Alberto. Provincia de Salta. Ministerio de Salud Pública; ArgentinaFil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentin

Modest Declines in Proteome Quality Impair Hematopoietic Stem Cell Self-Renewal.

Low protein synthesis is a feature of somatic stem cells that promotes regeneration in multiple tissues. Modest increases in protein synthesis impair stem cell function, but the mechanisms by which this occurs are largely unknown. We determine that low protein synthesis within hematopoietic stem cells (HSCs) is associated with elevated proteome quality in vivo. HSCs contain less misfolded and unfolded proteins than myeloid progenitors. Increases in protein synthesis cause HSCs to accumulate misfolded and unfolded proteins. To test how proteome quality affects HSCs, we examine Aarssti/sti mice that harbor a tRNA editing defect that increases amino acid misincorporation. Aarssti/sti mice exhibit reduced HSC numbers, increased proliferation, and diminished serial reconstituting activity. Misfolded proteins overwhelm the proteasome within Aarssti/sti HSCs, which is associated with increased c-Myc abundance. Deletion of one Myc allele partially rescues serial reconstitution defects in Aarssti/sti HSCs. Thus, HSCs are dependent on low protein synthesis to maintain proteostasis, which promotes their self-renewal