Oncogenic FGFR1 mutation and amplification in common cellular origin in a composite tumor with neuroblastoma and pheochromocytoma

Neuroblastoma (NB) and pheochromocytoma (PCC) are derived from neural crest cells (NCCs); however, composite tumors with NB and PCC are rare, and their underlying molecular mechanisms remain unknown. To address this issue, we performed exome and transcriptome sequencing with formalin-fixed paraffin-embedded (FFPE) samples from the NB, PCC, and mixed lesions in a patient with a composite tumor. Whole-exome sequencing revealed that most mutations (80%) were shared by all samples, indicating that NB and PCC evolved from the same clone. Notably, all samples harbored both mutation and focal amplification in the FGFR1 oncogene, resulting in an extraordinarily high expression, likely to be the main driver of this tumor. Transcriptome sequencing revealed undifferentiated expression profiles for the NB lesions. Considering that a metastatic lesion was also composite, most likely, the primitive founding lesions should differentiate into both NB and PCC. This is the first reported case with composite-NB and PCC genetically proven to harbor an oncogenic FGFR1 alteration of a common cellular origin

Investigation of cathodic reaction in SOFCs and PCFCs by using patterned thin film model electrodes

In recent years, fuel cells operating at relatively high temperatures, such as solid oxide fuel cells (SOFCs) using an oxide ion conducting electrolyte and proton ceramics fuel cells (PCFCs) using an proton conducting electrolyte, attract attentions as high-efficient energy-conversion devices. For further enhancements of the performance and the durability of SCFCs and PCFCs, it is essential to understand the electrode reactions. In particular, the knowledge on the dominant reaction path in the electrodes would help us to optimize the material and the microstructure of the electrode. Please click Additional Files below to see the full abstract

Diagnosis of chronic pancreatitis

近年，各種膵疾患に対する検査法の発達には目を見張るものがあるが，実際の運用にあたっては各検査法の適応，限界，組合わせおよび実施する順序等に迷うことが少なくない。本研究では，最近我々が経験した慢性膵炎Ⅰ群116例の診断過程を振り返ることにより，慢性膵炎の診断における理想的な検査法の組合わせとそれぞれの役割を検討し，同時に診断名のみならず病態と病期が容易に理解できる表現方法を提案した。画像診断法，膵外分泌機能検査法（EX），膵内分泌機能検査法（EN）を比較検討し，以下の結果を得た。①画像診断法は必須である。②内視鏡的逆行性膵胆管造影（ERCP）を軸とした腹部超音波検査（US）あるいは腹部CTスキャン（CT）の組合わせは欠くことができない。③EXもまた必須の検査法である。④ENは慢性膵炎の診断に必要不可欠ではないが，治療方針を決めるうえで重要である。⑤純粋膵液（PPJ）の生化学的検査と組織化学的検査は膵炎の診断と病態生理の解明に重要である。⑥PPJ中の細胞診は慢性膵炎に合併した膵癌の検索に有用である。⑦以下に示すような診断の記載方法を提案した。"Calcified chronic pancreatitis, alcoholic, diffuse,　ERCP-3, US-2, CT-3, EX-2, EN-1, Lf(＋)"。Endoscopic retrograde cholangiopancreatography (ERCP), ultrasonography (US), computed tomography (CT), exocrine pancreatic function test (EX), endocrine pancreatic function test (EN), and analysis of pure pancreatic juice (PPJ) are currently available for the investigation of pancreatic diseases. The purpose of the present study is to evaluate the roles and preferable combinations of these tests in the diagnosis of chronic pancreatitis and then to propose a way to describe the results of the tests along with diagnosis for a better understanding of the disease process. Comparative studies of imaging, EX and EN led to the following conclusions. 1) imaging procedures (ERCP, US and CT) are mandatory, partly because they were frequently the test that showed diagnostic changes and partly because they often gave key information for operative treatment. Among the imaging procedures, ERCP combined with US and/or CT is mandatory because these combinations alone can reveal detailes of structural changes attendant on chronic pancreatitis. 2) EX is also mandatory, because it was occasionally the only test that showed diagnostic changes and partly because it often gave important information for medical treatment. 3) EN is also important, not because it was indispensable for detecting chronic pancreatitis, but because it often gave important information for medical treatment. For btter understanding of the disease process as well as diagnosis, we propose, as suggested by Seligson, that the test used for the establishment of the diagnosis and the degree as well as extent of abnormalities. An example is "Calcified chronic pancreatitis, alcoholic, diffuse, ERCP-3, US-2, CT-3, EX-2, EN-1, Lf(+)". This attitude will lead to a more rational approach to both diagnosis and treatment

Endoscopic diagosis of gastric malignant lymphoma

To delineate the pitfalls and counter-measures in the endoscopic diagnosis of gastric malignant lymphoma (GML), reviewed were 32 cases of primary GML and 16 cases of systemic ML with gastric involvement (secondary GML). 1) Accurate diagnosis of GML had been made in only 13 cases of primary GML ; 18 cases had been diagnosed of gastric cancer (GC); the remaining one of benign ulcer (BU). Review of the endoscopic films, however, revealed more than two of the three findings characteristic, but not pathognomomic, of GML in 84 percent. This result indicates that possibility of GML must be kept in mind in the differential diagnosis of malignant lesions despite its rarity, because endoscopists tend to be predisposed with an impression of GC. 2) Follow-up examinations made in nine cases of primary GML revealed marked changes in endoscopic findings in three cases : healing of an ulcer lesion in one case, healing of an ulcer lesion on an unchanged tumor in another and enlargement of a tumor in the remaining one. The first case had been followed up for two years with an impression of BU. This result indicates that improvement of ulcer does not necessarily rule out GML because it can show "malignant cycle" just as GC. 3) Endoscopic biopsy performed in 30 cases of primary GML had led to accurate diagnosis in only 16 cases and erroneous diagnosis of GC in five and no malignancy in nine. Review of the cases revealed the importance of having suspicion of GML at first from endoscopic findings, because it can lead to an increase of the number of biopsy specimens, careful selection of biopsy sites, careful use of biopsy instruments to obtain good specimens and closer contact with pathologists. 4) Prospective studies on systemic ML revealed gastric involvement in 17 percent. Examinations of the GI tract, especially of the stomach is one of the important steps for staging of systemic ML and deciding therapeutic modalities. 5) It is extremely difficult to diffierentate primary GML and secondary GML from endoscopic findings alone, although there are a few findings characteristic of the latter

Identification of the ultrahigh-risk subgroup in neuroblastoma cases through DNA methylation analysis and its treatment exploiting cancer metabolism

神経芽腫の新たな診断法と治療戦略を創出 --がん細胞の生存戦略「がん代謝」を逆用する--. 京都大学プレスリリース. 2022-11-02.Neuroblastomas require novel therapies that are based on the exploitation of their biological mechanism. To address this need, we analyzed the DNA methylation and expression datasets of neuroblastomas, extracted a candidate gene characterizing the aggressive features, and conducted functional studies. Based on the DNA methylation data, we identified a subgroup of neuroblastoma cases with 11q loss of heterozygosity with extremely poor prognosis. PHGDH, a serine metabolism-related gene, was extracted as a candidate with strong expression and characteristic methylation in this subgroup as well as in cases with MYCN amplification. PHGDH inhibition suppressed neuroblastoma cell proliferation in vitro and in vivo, indicating that the inhibition of serine metabolism by PHGDH inhibitors is a therapeutic alternative for neuroblastoma. Inhibiting the arginine metabolism, which is closely related to serine metabolism using arginine deiminase, had a combination effect both in vitro and in vivo, especially on extracellular arginine-dependent neuroblastoma cells with ASS1 deficiency. Expression and metabolome analyses of post-dose cells confirmed the synergistic effects of treatments targeting serine and arginine indicated that xCT inhibitors that inhibit cystine uptake could be candidates for further combinatorial treatment. Our results highlight the rational therapeutic strategy of targeting serine/arginine metabolism for intractable neuroblastoma

Muscleblind-Like 1 Knockout Mice Reveal Novel Splicing Defects in the Myotonic Dystrophy Brain

Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by a CTG trinucleotide repeat expansion (CTGexp) in the DMPK gene. In skeletal muscle, nuclear sequestration of the alternative splicing factor muscleblind-like 1 (MBNL1) explains the majority of the alternative splicing defects observed in the HSALR transgenic mouse model which expresses a pathogenic range CTGexp. In the present study, we addressed the possibility that MBNL1 sequestration by CUGexp RNA also contributes to splicing defects in the mammalian brain. We examined RNA from the brains of homozygous Mbnl1ΔE3/ΔE3 knockout mice using splicing-sensitive microarrays. We used RT-PCR to validate a subset of alternative cassette exons identified by microarray analysis with brain tissues from Mbnl1ΔE3/ΔE3 knockout mice and post-mortem DM1 patients. Surprisingly, splicing-sensitive microarray analysis of Mbnl1ΔE3/ΔE3 brains yielded only 14 candidates for mis-spliced exons. While we confirmed that several of these splicing events are perturbed in both Mbnl1 knockout and DM1 brains, the extent of splicing mis-regulation in the mouse model was significantly less than observed in DM1. Additionally, several alternative exons, including Grin1 exon 4, App exon 7 and Mapt exons 3 and 9, which have previously been reported to be aberrantly spliced in human DM1 brain, were spliced normally in the Mbnl1 knockout brain. The sequestration of MBNL1 by CUGexp RNA results in some of the aberrant splicing events in the DM1 brain. However, we conclude that other factors, possibly other MBNL proteins, likely contribute to splicing mis-regulation in the DM1 brain

Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure

Accentuated sympathetic nerve activity (SNA) is a risk factor for cardiovascular events. In this review, we investigate our working hypothesis that potentiated activity of neurons in the rostral ventrolateral medulla (RVLM) is the primary cause of experimental and essential hypertension. Over the past decade, we have examined how RVLM neurons regulate peripheral SNA, how the sympathetic and renin-angiotensin systems are correlated and how the sympathetic system can be suppressed to prevent cardiovascular events in patients. Based on results of whole-cell patch-clamp studies, we report that angiotensin II (Ang II) potentiated the activity of RVLM neurons, a sympathetic nervous center, whereas Ang II receptor blocker (ARB) reduced RVLM activities. Our optical imaging demonstrated that a longitudinal rostrocaudal column, including the RVLM and the caudal end of ventrolateral medulla, acts as a sympathetic center. By organizing and analyzing these data, we hope to develop therapies for reducing SNA in our patients. Recently, 2-year depressor effects were obtained by a single procedure of renal nerve ablation in patients with essential hypertension. The ablation injured not only the efferent renal sympathetic nerves but also the afferent renal nerves and led to reduced activities of the hypothalamus, RVLM neurons and efferent systemic sympathetic nerves. These clinical results stress the importance of the RVLM neurons in blood pressure regulation. We expect renal nerve ablation to be an effective treatment for congestive heart failure and chronic kidney disease, such as diabetic nephropathy