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MicroRNA (miRNA/miR) 5′-isoforms (5′-isomiRs) differ from canonical sequences registered in the microRNA database in the length of their 5′ ends. The 'seed sequence' of miRNAs that bind to target mRNAs is 2-8 nucleotides from the 5′ end; thus, shifts at the 5′ end can cause a 'seed shift'. Accumulating data from miRNA deep sequencing have revealed that, in a substantial number of miRNAs, sequences corresponding to specific isomiRs, not the canonical form, are the most abundant. Studies have so far focused on circulating miRNAs as either markers or intercellular communication factors. miR-1246 is abundant in the serum and is a candidate diagnostic and prognostic marker for esophageal squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma, colorectal adenocarcinoma and non-small cell lung cancer (NSCLC). The present study analyzed the 5′-end of serum miR-1246 by fragment analysis and found that a 5′-isomiR, which is two bases shorter than the canonical sequence, was the most abundant sequence in patients with NSCLC as well as healthy donors. To quantify the 5′-isomiR, 5′-isomiR-specific primers based on primers for allele specific-PCR were used, primarily because commercially available methods for miRNA Reverse transcription-quantitative PCR cannot discriminate among sequences, especially those located at the 5′ end of miRNA. The total miR-1246 levels were significantly increased in patients with NSCLC; by contrast, the level of the canonical sequence was significantly decreased. Significant positive correlations were observed between the total miR-1246 levels and the 5′-isomiR levels, but not that of the canonical sequence. These results imply that the increase in levels of serum miR-1246 in patients with NSCLC depends on increase of the 5′-isomiR.

Hereditary cancer syndromes, which are characterized by onset at an early age and an increased risk of developing certain tumors, are caused by germline pathogenic variants in tumor suppressor genes and are mostly inherited in an autosomal dominant manner. Therefore, hereditary cancer syndromes have been used as powerful models to identify and characterize susceptibility genes associated with cancer. Furthermore, clarification of the association between genotypes and phenotypes in one disease has provided insights into the etiology of other seemingly different diseases. Molecular genetic discoveries from the study of hereditary cancer syndrome have not only changed the methods of diagnosis and management, but have also shed light on the molecular regulatory pathways that are important in the development and treatment of sporadic tumors. The main cancer susceptibility syndromes that involve gynecologic cancers include hereditary breast and ovarian cancer syndrome as well as Lynch syndrome. However, in addition to these two hereditary cancer syndromes, there are several other hereditary syndromes associated with gynecologic cancers. In the present review, we provide an overview of the clinical features, and discuss the molecular genetics, of four rare hereditary gynecological cancer syndromes; Cowden syndrome, Peutz-Jeghers syndrome, DICER1 syndrome and rhabdoid tumor predisposition syndrome 2.

Background Pregnancy in a rudimentary horn is an extremely rare type of ectopic pregnancy. A rudimentary uterine horn pregnancy is associated with a risk of spontaneous rupture and bleeding during surgery due to the increased uterine blood flow. Recent advances in imaging modalities have enabled laparoscopic surgery to be performed in cases without rupture in the early stages of pregnancy. However, there are few reports of successful pregnancies and deliveries after treatment of rudimentary horn pregnancies. We report the successful management of a case of non-communicating rudimentary horn pregnancy by local injection of methotrexate followed by complete laparoscopic excision along with a review of the literature. Case presentation The patient was a 29-year-old Japanese woman, gravida 2, nullipara. She was diagnosed with a left unicornuate uterus with a right non-communicating rudimentary horn on hysterosalpingography and magnetic resonance imaging. A gestational sac with a heartbeat was observed in the right rudimentary uterine horn at 6 weeks of gestation. A diagnosis of ectopic pregnancy in a non-communicating rudimentary horn was made. Color Doppler detected multiple blood flow signals around the gestational sac, which were clearly increased compared to the left unicornuate uterus. Her serum human chorionic gonadotropin level was 104,619 mIU/ml. A 100 mg methotrexate injection into the gestational sac was administered, and laparoscopic surgery was performed on day 48 after the methotrexate treatment. The right rudimentary horn and fallopian tube were successfully excised with minimal bleeding. A spontaneous normal pregnancy was established 6 months after the surgery. The pregnancy was uneventful, and a baby girl was born by elective cesarean section at 38w0d. Conclusion Combined local methotrexate injection and laparoscopic surgery are safe treatment options for patients with a unicornuate uterus with a non-communicating rudimentary horn pregnancy.

Once atherosclerosis develops, stenosis (or occlusion) may occur in the lumen of various arteries of the living body. This can lead to a range of conditions, including myocardial infarction, cerebral infarction, aortic aneurysm and peripheral artery disease. The acronym 'ATIS' (AtheroThrombosIS) is a collective term for diseases characterized by a common course of development based on atherosclerosis. This article reviews pathological findings in atherothrombotic lesions of human coronary, carotid, and vertebrobasilar arteries as well as leg arteries and veins. Histologically, atheromatous plaques of coronary arteries can broadly be typed as fibrous and lipid-rich (atheromatous). Macroscopically, fibrous plaque has a whitish appearance and is composed of smooth muscle cells and collagen fibres. Lipid-rich (atheromatous) plaque, on the other hand, appears yellow macroscopically, with the superficial layer (closer to the lumen) having a white fibrous cap which covers the atheroma. This fibrous cap is quite thin and is likely to rupture. Typical pathological features of such atherothrombosis are narrowing of the vascular lumen due to lipid-rich (atheromatous) plaque, and thrombus formation due to a broken fibrous cap. Such plaque rupture is the underlying cause of acute myocardial infarction in about 70% of patients, while acute myocardial infarction in the remaining patients (30%) results from plaque erosion. In cases of plaque erosion, atheroma is seldom seen, and atherosclerosis manifests in a full-circumferential manner, resulting in thrombus formation due to endothelial cell injury and eventually leading to obstructive thrombi. Thus, thrombus formation associated with myocardial infarction is attributable to plaque rupture if the lesion contains a lipid-rich (atheromatous) plaque. In cases where plaques cause particularly intense injury of endothelial cells, plaque erosion is likely to occur, resulting in formation of obstructive thrombi within the vascular lumen. Primary factors involved in the evolution of ATIS are injury of vascular endothelial cells, inflammation of a vulnerable plaque and intra-plaque haemorrhage. ATIS in other vascular systems has similar pathological features. The continued increase in the aged population and the morbidity of lifestyle-related diseases will make more cases of ATIS intractable. It will be of paramount importance to prevent intractable ATIS in the future.

Background: Treatment for platinum-resistant ovarian cancer is difficult and challenging because available chemotherapeutic agents only offer short survival improvements. The efficacy of re-treatment with platinum-based agents including nedaplatin for platinum-resistant patients has not been fully investigated. Case Report: We describe herein three cases of heavily treated platinum-resistant ovarian cancer that were successfully treated with weekly nedaplatin followed by olaparib. After becoming platinum-resistant, the cases were treated with non-platinum chemotherapies. Following these regimens, weekly nedaplatin was introduced, followed by olaparib. At the time of writing, survival since the start of weekly nedaplatin was 30 months for case 1, 20 months for case 2, and 17 months for case 3, with all patients showing no evidence of disease. Conclusion: Weekly nedaplatin followed by olaparib might represent a good treatment option for platinum-resistant ovarian cancer and is a solid candidate for further evaluation.

Circulating microRNAs (miRNAs) are promising markers for cancer diagnosis and prognosis. Numerous studies evaluating miRNAs as markers for non-small cell lung cancer (NSCLC) have been conducted in recent years; however, the majority of candidate markers proposed via individual studies were inconsistent and no marker miRNAs for the diagnosis of early stage NSCLC have been established. In the present study, miR-145, miR-20a, miR-21 and miR-223, which were previously reported as candidate diagnostic markers of NSCLC, were re-evaluated. The serum levels of these miRNAs were quantified in 56 patients with stage I-IV NSCLC using the TaqMan microRNA assays and separately compared the levels at each stage with those in 26 control patients. The level of miR-145 was significantly reduced in patients with NSCLC, regardless of clinical stage, and its level increased following tumor resection in patients with stage I-II disease. These results indicate that miR-145 is relevant as a diagnostic marker for stages I-IV NSCLC. Additionally, the levels of miR-20a and miR-21 demonstrated notable differences among patients at different clinical stages. These miRNAs distinguished patients in a number of, but not all, stages of NSCLC from cancer-free control patients. These results indicated that it is essential to analyze miRNA levels at each stage separately in order to evaluate marker miRNAs for NSCLC diagnosis.

Background LYVE-1, a specific marker of lymphatics, is expressed in hepatic sinusoidal endothelium. A previous study revealed that LYVE-1 expression in sinusoidal endothelium was reduced in cirrhosis. However, it is still obscure how LYVE-1 expression in sinusoidal endothelium was reduced during the disease progression. To elucidate whether there were relationships among LYVE-1 attenuation, sinusoidal capillarization, and disease progression, we performed immunohistochemical investigations based on frozen human livers. Methods Frozen liver sections of chronic hepatitis (n = 8), cirrhosis (n = 13), and normal/control liver (n = 10) were examined by immunostaining for lymphatic endothelial markers (LYVE-1 and D2-40) and vascular endothelial markers (CD31 and von Willebrand factor). Computer-aided morphometry was applied to obtain objective data. The diseased liver tissues were also examined ultrastructurally. Results In controls, sinusoidal endothelium was positive for LYVE-1 and CD31, but negative for D2-40 and von Willebrand factor. In chronic hepatitis and cirrhosis, LYVE-1 expression in sinusoidal endothelium was attenuated, especially in areas adjacent to active inflammatory or fibrotic lesions, while von Willebrand factor was reciprocally expressed in sinusoidal endothelium. The morphometric analyses revealed that LYVE-1 positivity in sinusoidal endothelium was significantly (P < 0.0001) decreased in chronic hepatitis and cirrhosis compared to controls and was negatively correlated (Rs = −0.72, P < 0.0001) to von Willebrand factor positivity. Furthermore, LYVE-1 positivity was negatively correlated to inflammatory grade (Rs = −0.51, P = 0.021) and fibrosis severity (Rs = −0.46, P = 0.038). Sinusoidal endothelium in the diseased livers showing LYVE-1 attenuation had lost fenestrations. Conclusions These findings indicated that LYVE-1 attenuation in sinusoidal endothelium was one of the manifestations of capillarization, and was associated with hepatic disease progression.

Silent brain infarction (SBI) is often found in patients with atrial fibrillation (AF) and may be related to cognitive decline. We investigated the predictors of SBI on brain magnetic resonance imaging (MRI) using transesophageal echocardiography (TEE) in patients with nonvalvular AF. The study population consisted of 103 neurologically asymptomatic patients with nonvalvular AF who underwent TEE before transcatheter AF ablation (76 men; mean age 63 ± 10 years). Left atrial (LA) abnormalities such as LA thrombus, spontaneous echo contrast, or abnormal LA appendage emptying velocity (<20 cm/s) and complex plaques in the aortic arch defined as large plaques ≥4 mm thickness, ulcerated plaques, or mobile plaques were evaluated by TEE. All patients were screened for SBI by brain MRI. Of 103 patients, 31 (30%) showed SBI on brain MRI. Most lesions were multiple (61%) and small (<15 mm) in diameter (84%). Patients with SBI had a higher prevalence of LA abnormalities (45% vs 14%; P < .001) and complex arch plaques (45% vs 7%; P < .001) compared with those without SBI. In a multivariate logistic regression analysis including age and CHADS2 score ≥2, LA abnormalities (odds ratio 4.13; 95% CI 1.34-12.72; P = .014) and complex arch plaques (odds ratio 4.82; 95% CI 1.23-18.92; P = .024) were independent predictors of SBI. Left atrial abnormalities and complex arch plaques detected by TEE were closely associated with the presence of SBI on brain MRI, suggesting that microembolization of small thrombi derived from the fibrillating LA or advanced aortic atherosclerotic lesions may be important causes of SBI in patients with nonvalvular AF.

Background Intestinal stricture lesions in Crohn's disease are characterized as submucosal fibromuscular accumulation. There has been a controversy about whether the fibrogenic cells in stricture lesions in Crohn's disease originate from a smooth muscle cell or a fibroblast lineage. In the present study, we aimed to elucidate: (1) the origin of the fibrogenic cells in stricture lesions; and (2) the roles of the local angiotensin II system, including mast cell chymase, in stricture formation. Methods Methanol-Carnoy's-fixed colonic tissues, obtained from the stricture sites of 18 patients with Crohn's disease, were analyzed by immunostaining for vimentin, smooth muscle actin (1A4 and CGA7), angiotensin II type-1 receptor, angiotensin II-converting enzyme, and mast cell tryptase and chymase. As controls, unaffected (normal) portions of 11 colonic tumor specimens were also investigated. Results Submucosal fibromuscular accumulation was seen in every stricture lesion. The majority of mesenchymal cells accumulated in the stricture lesions were moderately differentiated intestinal smooth muscle cells [vimentin(+), 1A4(+), and CGA7(+)]. Moreover, occasional intestinal smooth muscle cells in the muscular layers, adjacent to the site of the submucosal fibromuscular response, showed distinct positivity for vimentin, indicating phenotypic modulation toward an immature, or dedifferentiated state. These smooth muscle cells accumulated in the stricture lesions were positive for angiotensin II type-1 receptor. Abundant chymase-positive mast cells were distributed in these lesions. Conclusions These results suggest that the proliferation and migration of moderately differentiated intestinal smooth muscle cells from the muscular layers are the major pathologicalmechanisms in stricture formation in Crohn's disease, and the angiotensin II system is involved in this process.

Background Several noninvasive tests have been proposed to predict cirrhosis in patients with chronic hepatitis C, but not in patients with non-alcoholic steatohepatitis (NASH). We assessed whether noninvasive laboratory tests designed to predict the risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection could be used in patients with NASH. Methods The subjects were 50 patients with biopsy-proved NASH and 100 age- and sex-matched patients with HCV. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), age-platelet (AP) index, AST-to-platelet ratio index (APRI), cirrhosis discriminant score (CDS), and the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) model were calculated. Results The areas under the receiver-operating characteristic curves of the AAR, AP index, APRI, CDS, and HALT-C model for predicting cirrhosis were respectively 0.813, 0.877, 0.786, 0.949, and 0.908 in patients with NASH and 0.555, 0.652, 0.761, 0.782, and 0.782 in patients with HCV. A CDS cutoff value of less than 5 misclassified none of the 9 patients with NASH who had cirrhosis, while a value of more than 8 misclassified none of the 41 patients with NASH without cirrhosis. With the HALT-C model, a cutoff value of less than 0.6 classified non-cirrhotic NASH, while a cutoff value of 0.97 or higher classified cirrhotic NASH. The use of CDS and HALT-C model could avoid liver biopsy for predicting cirrhosis in 60 and 48% of the patients with NASH, respectively. Conclusions Noninvasive laboratory tests designed to predict cirrhosis in patients with HCV are also useful in patients with NASH.