Crumbs3 is a critical factor that regulates invasion and metastasis of colon adenocarcinoma via the specific interaction with FGFR1

Epithelial cell polarity regulator Crumbs3 (Crb3), a mammalian homolog within the Drosophila Crb gene family, was initially identified as an essential embryonic development factor. It is recently implicated in tumor suppression, though its specific functions are controversial. We here demonstrate that Crb3 strongly promotes tumor invasion and metastasis of human colon adenocarcinoma cells. Crb3 centrality to tumor migration was supported by strong expression at invasive front and metastatic foci of colonic adenocarcinoma of the patient tissues. Accordingly, two different Crb3-knockout (KO) lines, Crb3-KO (Crb3 −/−) DLD-1 and Crb3-KO WiDr from human colonic adenocarcinomas, were generated by the CRISPR-Cas9 system. Crb3-KO DLD-1 cells exhibited loss of cellular mobility in vitro and dramatic suppression of liver metastases in vivo in contrast to the wild type of DLD-1. Unlike DLD-1, Crb3-KO WiDr mobility and metastasis were unaffected, which were similar to wild-type WiDr. Proteome analysis of Crb3-coimmunopreciptated proteins identified different respective fibroblast growth factor receptor (FGFR) isotypes specifically bound to Crb3 isoform a through their intracellular domain. In DLD-1, Crb3 showed membranous localization of FGFR1 leading to its functional activation, whereas Crb3 bound to cytoplasmic FGFR4 in WiDr without FGFR1 expression, leading to cellular growth. Correlative expression between Crb3 and FGFR1 was consistently detected in primary and metastatic colorectal cancer patient tissues. Taking these together, Crb3 critically accelerates cell migration, namely invasion and metastasis of human colon cancers, through specific interaction to FGFR1 on colon cancer cells.     

Prevalence of bone pain decreases as lymph node stage increases in nonsmall cell lung cancer patients

According to lung cancer guidelines, positron emission tomography scan is recommended for initial evaluation of bone metastasis. However, guidelines differ in their recommendations for when it should be used. We investigated the appropriate use of bone imaging in nonsmall cell lung cancer (NSCLC) patients.One hundred seventy-seven consecutive NSCLC patients who had distant metastases at presentation and were admitted between January 2012 and April 2016 were retrospectively reviewed. Among patients with bone metastases, we explored bone pain, number of bone metastases, location of bone metastases, and clinical tumor (T) and lymph node (N) classification.Sixty-three patients had bone metastases. There was a trend toward an increase in prevalence of bone metastases as lymph node stage increased. The prevalence of bone pain significantly decreased as N stage increased (p?=?0.017). N0 and N2-3 patients were more likely to have multiple bone metastases (p?=?0.038). Compared with patients who had a single bone metastasis, patients with multiple metastases had a significantly higher probability of having at least 1 bone metastasis located in the thorax or upper abdomen. All N0 patients have at least 1 bone metastasis in the thorax or upper abdomen.Clinical N0 NSCLC patients with bone metastasis are likely to have bone pain and have multiple bone metastases. N2-3 patients are more likely to have bone metastases but less likely to have bone pain. If NSCLC patients do not have bone pain, and CT of the chest and upper abdomen does not reveal any lymph node or bone metastasis, further survey for bone metastases may be omitted; bone imaging should be performed in N2 and N3 patients regardless of symptoms.     

Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11–RAGE–TPL2–COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.     

Advanced dynamic statistical parametric mapping with MEG in localizing epileptogenicity of the bottom of sulcus dysplasia

Objective

To investigate whether advanced dynamic statistical parametric mapping (AdSPM) using magnetoencephalography (MEG) can better localize focal cortical dysplasia at bottom of sulcus (FCDB).

Severe interstitial pneumonia associated with anti-PD-1 immune checkpoint antibody after talc slurry pleurodesis

A 70-year-old Japanese man with recurrent squamous cell carcinoma of the head and neck presented with severe interstitial pneumonia associated with nivolumab, after talc slurry pleurodesis. Following the development of malignant pleural effusion, he underwent chest drainage and was administered intrathoracic talc as a pleurodesis. Two weeks later, we administered nivolumab (3 mg/kg) to be repeated every 2 weeks. However, on day 12, chest computed tomography scan demonstrated diffuse non-segmental ground-glass opacity and mild bronchiectasis. We diagnosed interstitial pneumonia associated with nivolumab. Although corticosteroid pulse therapy was initiated, the patient died of respiratory failure on day 14.     

An infant case of diffuse cerebrospinal lesions and cardiomyopathy caused by a BOLA3 mutation

Introduction: Mitochondrial dysfunction results in a wide range of organ disorders through diverse genetic abnormalities. We herein present the detailed clinical course of an infant admitted for extensive, rapidly progressing white matter lesions and hypertrophic cardiomyopathy due to a BOLA3 gene mutation.Case: A 6-month-old girl with no remarkable family or past medical history until 1?month prior presented with developmental regression and feeding impairment. Ultrasound cardiography and brain magnetic resonance imaging (MRI) respectively disclosed the presence of hypertrophic cardiomyopathy and symmetrical deep white matter lesions. She was transferred to our hospital at age 6?months. High lactate levels in her cerebrospinal fluid suggested mitochondrial dysfunction. Despite vitamin supplementation therapy followed by a ketogenic diet, the patient began exhibiting clusters of myoclonic seizures and respiratory failure. Brain and spinal cord MRI revealed rapid progression of the white matter lesions. She died at 10?months of age. Fibroblasts obtained pre-mortem displayed low mitochondrial respiratory chain complex I and II activity. A homozygous H96R (c. 287 A?>?G) mutation was identified in the BOLA3 gene.Discussion: No reported case of a homozygous BOLA3 gene mutation has survived past 1?year of life. BOLA3 appears to play a critical role in the electron transport system and production of iron-sulfur clusters that are related to lipid metabolism and enzyme biosynthesis.