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Background Difficulty in activities of daily living (ADL) is common in patients with cardiovascular disease (CVD) and is associated with mortality. Objectives The relationship between gait speed/6-minute walking distance (6MWD) and difficulties in ADL in patients with CVD was explored. Methods The study population consisted of 447 patients with CVD for whom data on gait speed, 6MWD, and difficulty in ADL during outpatient rehabilitation were available. Relationships of gait speed/6MWD and difficulty in ADL were examined using propensity-adjusted logistic regression analysis. Results Both gait speed and 6MWD were significantly related to difficulty in ADL, and the areas under the curves were large. The cutoff values ranged from 0.93 to 1.30 m/s for gait speed and 370 to 500 m for 6MWD, from basic ADL to vigorous activities. Conclusions Both gait speed and 6MWD were used for the estimation of difficulty in ADL in patients with CVD. Gait speed can be measured easily and therefore could be incorporated in busy clinical practice to identify patients at risk for functional decline.

Background: The significance of circulating tumor DNA (ctDNA) in primary papillary thyroid cancer (PTC) has yet to be well established. This study aimed to clarify whether ctDNA carrying the BRA...

We herein report two cases of locally advanced unresectable hepatocellular carcinoma (u-HCC) that were resected after achieving a radiological complete response to initially administered lenvatinib followed by transcatheter arterial chemoembolization (LEN-TACE sequential therapy). A 78-year-old woman and an 80-year-old man with HCC of Barcelona Clinic Liver Cancer classification stage C were treated for 15 and 14 months with lenvatinib, respectively. Both patients were subsequently treated with TACE, resulting in complete remission on imaging. The α-fetoprotein level in the woman and man decreased markedly from 9370 ng/ml to 46 ng/ml and from 6380 ng/ml to 3 ng/ml, respectively, leading to hepatectomy. A histopathological examination showed coagulative necrosis of the entire HCC in one case, while the other showed a small population of viable HCC cells. The results showed that LEN-TACE sequential therapy has a synergic effect and could be a promising option for locally advanced u-HCC.

Necrosis, a form of cell death, occurs not only with the development of various diseases but also with a tumor tissue response to cancer treatment. Therefore, pursuing progress for cancer therapy through induction of necrosis may be one of the most effective approaches for cancer eradication. We herein describe the development of a real-time imaging system to visualize intratumoral necrosis. The system is composed of two types of cells expressing either one of two necrosis imaging reporters that consist of a DnaE intein sequence linking to one of two split-luciferase fragments. When necrosis occurs in a tumor composed of both of the cells, the two types of leaked reporters can reconstitute the enzymatic activity as a result of protein trans-splicing and thereby emit bioluminescence in the presence of the substrate. This system, which was constructed with shrimp-derived luciferase, allowed in vitro imaging of necrosis. We further confirmed real-time imaging of intratumoral necrosis caused by physical or chemical tissue disruption, validating its application in in vivo necrosis imaging. Thus, the constructed imaging system could be a powerful tool for the optimization of the therapeutic condition for cancer therapy and for the evaluation of novel anticancer drugs targeting necrosis., Graphical Abstract, Necrosis occurs with the development of various diseases and in tumor tissue responding to cancer treatment. To evaluate the preclinical effectiveness of different anticancer drugs and radiation therapy, Kagiya and colleagues have constructed a real-time visualization system for intratumoral necrosis using split-luciferase reconstitution by protein trans-splicing.

Although microRNAs (miRNAs) play an important role in invasive tumor lesions, which involve cancer tissues mixed with stromal tissues, the differences in miRNA expression between cancer and stromal cells remain unclear. We selected 13 miRNAs and examined their differential expression patterns in cancer gland cells and surrounding stromal cells isolated from 24 colorectal cancer (CRC) specimens using a crypt isolation method. Although six miRNAs were upregulated in gland cells, only three were upregulated in the corresponding stromal cells, in the cancer compared with non-cancer specimens. Next, we examined the differences in miRNA expression between isolated cancer gland and stromal cells. Five miRNAs showed statistical differences in their cancer-related differential expression patterns between isolated cancer gland and stromal cells. We then compared these miRNA expression patterns in isolated cancer gland and stromal cells with those in fresh intact tumor tissues, consisting of cancer nests and stromal tissue, obtained from the 24 CRCs. The expression patterns of three miRNAs in the intact cancer tissue samples did not correspond with those in the isolated components. Identification of the expression patterns of miRNAs in both the cancer gland and stromal cell components of the tumor microenvironment greatly contributes to evaluating epigenetic regulation in CRC.

OBJECTIVE This study was aimed to evaluate the outcomes of performing open repair or thoracic endovascular aortic repair for chronic type B dissecting aortic aneurysm. METHODS From July 2004 to February 2019, 52 patients underwent surgery as open repair (n=32) or endovascular repair (n=20) for chronic type B dissecting aortic aneurysm. Replacement of the aorta was limited to the aneurysmal portion with or without reconstructing the visceral arteries or the segmental arteries. Stent grafts were deployed in the true lumen above the celiac artery to cover the primary entry for even DeBakey IIIb dissection. RESULTS Operative mortality and morbidity rates, including spinal cord ischemia incidence, did not differ between the groups. Operative mortality and morbidity rates, including spinal cord ischemia incidence, did not differ between the groups. In the endovascular repair group, three patients died due to rupture of residual false lumen in the early and late postoperative follow-up. The 5-year rate of freedom from all-cause death, aorta-related death, and aorta-related event were 84% ± 6%, 94% ± 3% and 84% ± 6%. The endovascular repair was independently associated with all-cause death (hazard ratio [HR], 5.7; confidence interval [CI], 1.02-31.6; P=0.04) and aorta-related event (HR, 30.9; CI 4.9-195.0; P

A 78-year-old woman diagnosed with an infected descending aortic aneurysm underwent graft replacement through a left rib-cross thoracotomy. She developed shock suddenly on the postoperative day 3 owing to cardiac tamponade. We performed emergent surgery and identified a small myocardial laceration in the left ventricular obtuse marginal area and a small perforation on the pericardium. One of the claws used to fix the titanium plate in the cross-rib repair caused this complication. This is a cautionary note regarding this type of titanium plate, which is used in many procedures.

Background Angiosarcoma of the breast is rare. It carries a poor prognosis because of its high risk of local recurrence and distant metastases. Presently, there are still no established systemic therapies. Thus, the main treatment strategy for breast angiosarcoma is complete resection. This underscores the importance of closely monitoring the spread of the tumor lesion, particularly for multifocal angiosarcoma, and to plan an optimal operative procedure. We herein present the successful surgical treatment of a rare case of multifocal primary breast angiosarcoma. Case presentation A 43-year-old woman visited our hospital with a growing lump on her right breast accompanied by pain. Clinical and radiological examinations revealed a well-circumscribed 40-mm-diameter tumor at the inner lower quadrant of her right breast. Histological examination of a needle biopsy specimen revealed angiosarcoma. Based on a precise evaluation of the tumor by contrast-enhanced MRI and contrast-enhanced CT scan, a wide local excision with sufficient margins was performed. In the resected specimen, three discontinuous small lesions of angiosarcoma were observed around the main tumor. Therefore, total mastectomy was additionally performed. Pathological examination revealed two other small nodules of angiosarcoma in the remnant right breast, which appeared to be close but not continuous to the defective part of the initial resection. Postoperative follow-up at 1 year showed no signs of recurrence or distant metastasis. Multifocal primary breast angiosarcoma is extremely rare with only two previous reports describing its multifocality. Conclusions Owing to its rarity, a standardized surgical treatment for breast angiosarcoma remains controversial. Our case suggests that primary breast angiosarcoma may occasionally present with multifocal tumor. Thus, it is important to keep in mind the multifocality of breast angiosarcoma when assessing its spread by diagnostic imaging and when planning the surgical strategy.

Oligodontia, a severe type of hypodontia generally characterized as tooth agenesis of six or more permanent teeth excluding third molars, is known to have a multifactorial etiology and the characteristics of orthodontic patients are not fully understood. The aim of the present study was to investigate the risks of tooth agenesis between tooth types of permanent dentition in orthodontic patients with non-syndromic oligodontia. Panoramic radiographs of 292 orthodontic patients (184 females and 108 males) were obtained from one university-based orthodontic clinic and 79 private orthodontic clinics in Japan. Agenesis of permanent teeth excluding third molars was evaluated. Multiple logistic regression analysis was conducted to evaluate the risk of simultaneous tooth agenesis between all tooth type combinations. Significant symmetry of tooth agenesis was observed for all tooth types. Twenty-six tooth type combinations showed a significantly increased risk of simultaneous tooth agenesis [odds ratios (ORs): 1.99⬜14.51], and 15 tooth type combinations showed a significantly decreased risk of simultaneous tooth agenesis (ORs: 0.11⬜0.56). These findings suggest early detection to establish appropriate multidisciplinary treatment planning and prediction of the risk for tooth agenesis of non-syndromic oligodontia.

Background/Aims: To evaluate gastric early differentiate-type carcinogenesis, we attempted to identify clinicopathological and biological differences in differentiated-type minute intramucosal neoplasia (MIMN), which was defined as a tumor with a diameter of < 5 mm. Methods: We examined clinicopathological findings and biological factors, including TP53 overexpression, mucin phenotype, Ki-67-positive rate, MLH1, intranuclear accumulation of β-catenin, and DNA methylation status (low methylation epigenotype [LME], intermediate methylation epigenotype, and high methylation epigenotype [HME]) in MIMNs. In addition, non-MIMNs were also analyzed. In the present study, MIMN and non-MIMN were also examined based on low-grade dysplasia, high-grade dysplasia, and intramucosal cancer (IMC). Results: In clinicopathological findings, there were significant differences in sex ratios and tumor locations between MIMNs and non-MIMNs. Among the examined biological factors, no significant differences in the frequencies of biological factors were observed between the 2 intramucosal neoplasia types. However, the frequency of intranuclear accumulation of β-catenin was higher in non-MIMNs than in MIMNs. Finally, although the frequency of HME was significantly lower in MIMNs than in non-MIMNs, the opposite was observed for LME. Conclusions: The current finding suggested that DNA methylation and accumulation of β-catenin were closely associated with tumor development from MIMN to non-MIMN.

Anaplasma phagocytophilum is an obligate intracellular bacterium that causes human granulocytic anaplasmosis (HGA), an emerging tick-borne infectious disease. This bacterium expresses various 44-kDa major outer membrane proteins encoded by the p44/msp2 multigene family to avoid the host immune system. We previously detected A. phagocytophilum p44/msp2 from the tick Haemaphysalis longicornis in Mie Prefecture, Japan in 2008. In this study, we further investigated a total of 483 H. longicornis ticks (220 adults and 263 nymphs) collected from the Mie Prefecture by PCR targeting p44/msp2 to characterize the p44/msp2 multigene family of A. phagocytophilum. Six of the 483 ticks tested were PCR-positive for A. phagocytophilum p44/msp2, and these positive individuals were at the nymph stage of the tick life cycle. Cloning, sequencing, and phylogenetic analyses of the amplicons revealed that the 11 p44/msp2 clones obtained from the positive ticks shared a 54.9%-99.3% amino acid sequence similarity with the 27 previously identified clones from HGA patients in Japan. In particular, 6 p44/msp2 clones displayed the highest similarities (97.2%-99.3%) with 3 previously identified clones (FJ417343, FJ417345, FJ417357). Thus, the data from this study provide important public health information regarding A. phagocytophilum infection transmitted by H. longicornis ticks, especially at the nymph stage.

Objective: The usefulness of abdominal duplex ultrasound (DUS) for the detection of endoleaks after endovascular aneurysm repair (EVAR) was evaluated. Materials and Methods: Among 286 patients who underwent EVAR between September 2007 and July 2017, 241 patients were followed up using abdominal DUS. Endoleaks were detected in 74 patients (31%), who were divided into enlarged and nonenlarged sac groups. Endoleak velocities and widths were measured using abdominal DUS every 6 months after EVAR and were compared between the 2 groups. Results: The aneurysm diameter in the nonenlarged sac group was 54.4±8.7 mm in the final follow-up. None of the patients in the nonenlarged sac group were subjected to reintervention, whereas all patients in the enlarged sac group were subjected to reintervention. The aneurysm diameter in the enlarged sac group was 62.8±8.8 mm at the time of reintervention, and the maximum endoleak flow velocities and endoleak widths were significantly higher in the enlarged sac group than in the nonenlarged sac group (p

Brain development is a highly orchestrated process requiring spatiotemporally regulated mitochondrial dynamics. Drp1, a key molecule in the mitochondrial fission machinery, undergoes various post-translational modifications including conjugation to the small ubiquitin-like modifier (SUMO). However, the functional significance of SUMOylation/deSUMOylation on Drp1 remains controversial. SUMO-specific protease 5 (Senp5L) catalyzes the deSUMOylation of Drp1. We revealed that a splicing variant of Senp5L, Senp5S, which lacks peptidase activity, prevents deSUMOylation of Drp1 by competing against other Senps. The altered SUMOylation level of Drp1 induced by Senp5L/5S affects Drp1 ubiquitination and tubulation of the endoplasmic reticulum (ER), thereby influencing mitochondrial morphology. A dynamic SUMOylation/deSUMOylation balance controls neuronal polarization and migration during the development of the cerebral cortex. These findings suggest a novel role of post translational modification, in which a deSUMOylation enzyme isoform competitively regulates mitochondrial dynamics and ER tubulation via Drp1 SUMOylation levels in a tightly controlled process of neuronal differentiation and corticogenesis.

Agenesis of two or more consecutive adjacent permanent teeth (consecutive tooth agenesis, CTA) is a serious manifestation of oligodontia requiring long-term, multi-disciplinary treatment. Therefore, the present study investigated the characteristics of the CTA pattern in orthodontic patients with non-syndromic oligodontia. Using panoramic radiographs, the number of agenetic permanent teeth excluding third molars in non-syndromic orthodontic patients was evaluated, and patients with six or more agenetic teeth (oligodontia group, n = 97) and with one to five agenetic teeth (hypodontia group, n = 107) were selected. The numbers of CTA including third molars in each quadrant and in each patient were compared between the groups. Each quadrant with CTA of patients was categorized into one of the following four types: (I) involves anterior teeth only; (II) involves posterior teeth only; (IIIA) includes anterior and posterior teeth; and (IIIB) separate in the anterior and posterior teeth. CTA in at least one quadrant was found in 91.8 and 4.7% of patients in the oligodontia and hypodontia groups, respectively. The highest frequency CTA patterns included agenesis of the first and second premolars and of the second and third molars in the oligodontia and hypodontia groups, respectively. In the oligodontia group, type IIIA was significantly more frequent in the maxillary than in the mandibular quadrant. Most oligodontia patients who visit orthodontic clinics have CTA. A rare but severe CTA pattern that continues from the anterior to posterior segments is more frequent in the maxillary than in the mandibular quadrant.

This study evaluated the effect of temporary sealing materials and cleaning protocols on the bond strength of resin cement applied to dentin using resin-coating technique. Scotchbond Universal Adhesive and Filtek Supreme Ultra Flowable were applied to bovine dentin. Forty-five specimens were divided into the following three groups according to the temporary sealing materials: Cav-: CAVITON EX, Vas-: COCOA BUTTER and FIT SEAL, and Sep-: Washable SEP and FIT SEAL. Each material was placed on resin-coated dentin. After 1-week water storage, one of the following three cleaning protocols was performed: -WA: washed with water, -BR: brushed with PRESSAGE, and -AF: cleaned with AIR-FLOW. Microtensile bond strength test and EDS analysis were conducted. Irrespective of the cleaning protocol used, Washable SEP demonstrated less residual debris on resin-coated dentin, resulting in high bond strength. Regardless of the temporary sealing material applied, AIR-FLOW demonstrated less residual debris, resulting in high bond strength.

Patient: Female, 70-year-old Final Diagnosis: Hepatocellular carcinoma with extrahepatic portal vein obstruction Symptoms: — Medication:— Clinical Procedure: Preoperative simulation and intraoperative navigation technique Specialty: Surgery Objective: Unusual setting of medical care Background: Extrahepatic portal vein obstruction (EHPVO) is one of the most important diseases that causes pre-hepatic portal hypertension, and EHPVO sometimes develops cavernous transformation to maintain hepatopetal flow. In this report, we describe the first case of hepatocellular carcinoma (HCC) with EHPVO having underwent pure laparoscopic left hepatectomy with middle hepatic vein (MHV) resection. Case Report: A 70-year-old woman with a diagnosis of mixed-type HCC or cholangiocarcinoma located in segment 4b was referred to our hospital, and computed tomography revealed EHPVO with cavernous transformation. We successfully performed pure laparoscopic left hepatectomy with MHV resection by using the individual hilar approach, frequent intraoperative sonography, and indocyanine green imaging. In this case, the routine Glissonian approach was impossible due to cavernous transformation growth and the absence of a portal vein. Therefore, frequent confirmation of intrahepatic flow was crucial to avoid intraoperative complications. The patient was discharged with no complications on postoperative day 7. A histopathological examination revealed that the moderately differentiated HCC formed a pseudoglandular pattern and cord-like structures, thereby defined as type II according to Edmondson’s classification. Conclusions: Currently, difficulty scoring systems for laparoscopic liver resection (LLR) usually contain the procedure and location of the hepatic tumor, but they do not contain the variety of anatomical abnormality due to its rarity. However, the false recognition of hilar vessels and biliary ducts in patients with an anatomical abnormality, including EHPVO, leads to severe injury; therefore, anatomical variety and abnormality are also important factors increasing the difficulty of LLR.

Background: Pulmonary epithelial–myoepithelial carcinoma is a rare subtype of lung cancer. Because of its rarity, the molecular information on this carcinoma is insufficient.Case presentation: We report a case of pulmonary epithelial–myoepithelial carcinoma without AKT1, HRAS or PIK3CA mutations in a 76-year-old woman. Computed tomography revealed a tumor located in the left lower lung. Thoracoscopic left lower lobectomy was performed. Histopathologically, the tumor consisted of duct-like structures and polygonal-to-spindle-cell features. The duct-like structures were composed of two distinct cell layers. Immunohistochemically, the inner layer consisted of cuboidal cells that were positive for pan-cytokeratin and negative for p63, whereas the outer layer consisted of polygonal and spindle cells that were positive for p63 and weakly positive for pan-cytokeratin. We evaluated mutations in AKT1, BRAF, CTNNB1, HRAS, KRAS and PIK3CA but did not detect any mutations.Conclusion: Pulmonary epithelial–myoepithelial carcinoma is a rare subtype of lung cancer, with only 56 previous cases reported in the English literature. The genetic alterations in pulmonary epithelial–myoepithelial carcinoma are still unclear. To our knowledge, only one study described HRAS mutations in pulmonary epithelial–myoepithelial carcinoma, detected in all three tumors evaluated. However, our case did not show any mutations in any of the above-examined genes.

The aim of this study was to compare outcomes of the full maze procedure with left atrial appendage closure (LAAc) as concomitant procedures for atrial fibrillation (AF) in patients undergoing cardiovascular surgery. A total of 151 patients (88 men, 62 women) underwent elective AF surgery concomitantly with cardiovascular surgery from April 2005 to December 2019. The mean age at time of operation was 70 years and the mean follow-up period was 5.2 ± 3.8 years. Patients were divided into two groups according to the procedure performed: the maze group (n = 87) and the LAAc group (n = 63). Patients in the LAAc group were significantly older and had more comorbidities than those in the maze group. The operative mortality rate was significantly higher in the LAAc group. There was no difference in the rate of freedom from cardiac-related death between the groups (p = 0.86). Furthermore, there was no difference in the 5-year rate of freedom from thromboembolic stroke between the maze group and the LAAc group (p = 0.17). However, the 5-year rate of freedom from heart failure was significantly higher in the maze group compared with the LAAc group (100% vs. 86% ± 6%, respectively; p = 0.006). Patients undergoing the maze procedure had good operative and long-term results, suggesting that this procedure should be performed if indicated. Concomitant LAAc may be effective for preventing thromboembolic stroke in patients with AF if they have no indication for the maze procedure.

MicroRNAs (miRNAs) are potential biomarkers of neoplastic lesions, but additional information on dysregulated miRNA expression during progression of the adenoma-adenocarcinoma sequence may be helpful to identify the role of miRNAs in this sequence. We examined the expression levels of 13 miRNAs (hsa-miRNA-19a-3p, hsa-miRNA-21-5p, hsa-miRNA-27a-3p, hsa-miRNA-27b-3p, hsa-miRNA-31-5p, hsa-miRNA-34b-3p, hsa-miRNA-125b-5p, hsa-miRNA-143-3p, miRNA-191-5p, hsa-miRNA-193b-3p, hsa-miRNA-195-5p, hsa-miRNA-206 and hsa-let-7a-5p) that are closely associated with colorectal carcinogenesis in 40 conventional adenomas (tubular and tubulovillous adenomas), 20 intramucosal carcinomas (IMCs) and 60 invasive colorectal cancers (iCRCs) using reverse-transcription polymerase chain reaction. These 120 tumors were divided into two cohorts, that is, cohort 1 (60 cases) and cohort 2 (for validation; 60 cases). We analyzed the expression levels of these miRNAs in the first step (adenoma→IMC) and second step IMC→iCRC) of the adenoma-carcinoma sequence in both cohorts. Although no significant differences in the expression of any of the 13 miRNAs were found between adenomas and IMCs consistently in both cohorts, the expression levels of hsa-miRNA-125b-5p, hsa-miRNA-143-3p, and hsa-miRNA-206 were significantly upregulated in iCRC in both cohorts compared with those in IMC. The current results suggest that certain miRNAs, including hsa-miRNA-125b-5p, hsa-miRNA-143-3p and hsa-miRNA-206, are candidate markers that play critical roles in the progression of IMC to iCRC.

Background: Locomotive syndrome (LoS) is defined as the loss of mobility due to age-related impairment of motor organs. The purpose of this study was to evaluate the prevalence and severity of LoS, muscular strength and balancing ability, and prevalence of sarcopenia in relation to the presence of LoS according to sex and age groups ranging between 50-89 years.Methods: Male and female participants between the ages of 50-89 were randomly selected in the resident registry of a cooperating town. Calls for participation continued until approximately 50 consenting participants were successfully recruited for each age group and sex. A total of 413 participants (203 male and 210 female) were enrolled for undergoing a LoS risk test and measuring their physical function. Physical function was compared to participants with or without LoS.Results: A total of 312 patients (75.5%) were diagnosed as LoS, of which 144 (46.2%) were male and 168 (53.8%) were female. The severity of LoS for the 312 patients were 210 (67.3%) for stage 1 and 102 (32.7%) for stage 2. The prevalence of LoS in males were 37%, 59%, 91%, and 100% in the 50s, 60s, 70s, and 80s age strata, respectively. The prevalence of LoS in females were 71%, 62%, 89%, and 98% in the 50s, 60s, 70s, and 80s age strata, respectively. The prevalence of sarcopenia was significantly higher as the age strata in males grew higher. Knee extension strength was significantly lower for participants in their 50s and females in addition to females in their 60s with LoS. The 31 patients diagnosed as sarcopenia included 29 (93.5%) with LoS, 11 (35.4%) classified as LoS stage 1, and 18 (58.1%) classified as stage 2.Conclusions: The prevalence of LoS was high in participants over 70 years of age. In males, the prevalence of sarcopenia was higher as the age strata grew higher. Patients with LoS exhibited lower knee extension strength. We believe that some measures to prevent or improve LoS may require exercise to increase the muscle strength of the lower limbs.

It is unclear whether somatic copy number alterations (SCNAs) contribute to the development of colorectal cancer (CRC). Here, we aimed to identify the molecular profiles of early colorectal carcinogenesis based on SCNAs and determine the associations of other molecular abnormalities for the detection of neoplasia in both intramucosal neoplasia (IMN) and invasive CRC with invasion into the muscular layer without metastasis (early invasive CRC). A single nucleotide polymorphism array was used to examine 100 colorectal IMNs (low-grade adenoma [LGA], 40; high-grade adenoma [HGA], 25; intramucosal adenocarcinoma [IMA], 35) and early invasive CRC (20 tumors). In addition, genetic mutations (KRAS, BRAF), TP53 overexpression, microsatellite instability (MSI), and DNA methylation (low, intermediate, high) were examined. Hierarchical clustering analysis based on the SCNA pattern was carried out to identify molecular profiles in IMNs and early invasive CRC. Colorectal tumors were classified into three subgroups based on SCNA patterns. Subgroup 1 was characterized by multiple SCNAs, subgroup 3 was closely associated with infrequent SCNAs, and subgroup 2 was an intermediate subgroup in SCNA pattern between subgroups 1 and 3. Although mutations in KRAS were commonly found in all three subgroups, overexpression of TP53 was observed primarily in subgroup 1 and 2. DNA methylation showed a low/intermediate type. Finally, no MSI was detected. Each subgroup was correlated with histology (subgroup 1, early invasive CRC; subgroup 2, LGA; subgroups 2 and 3, HGA and IMA). Considerable SCNAs may be required for acquisition of invasive ability in CRC. Our results provide novel insights into early CRC.

The Ultimatum Game (UG) allows for the assessment of altruistic behavior as well as the perception of fairness. We examined the effects of visual social cues (gaze of others), factors associated with autism, and trust on UG performance in typical adults (TAs) and individuals with autism spectrum disorder (ASD). We hypothesized that individuals with ASD would be less affected by visual social cues than TAs. We recruited 30 TAs and 30 individuals with ASD. Participants completed 30 trials of the UG, during which the visual background was altered to include either stylized eyespots, flowers, or a neutral background. Reaction times and money distributed in each condition were recorded. Reaction times did not vary among background conditions in either group, although individuals with ASD responded more slowly overall. TAs distributed less money in the neutral background and flowers conditions than in the eyespots condition, while no significant differences in the amount of money distributed were observed among background conditions for individuals with ASD, who also distributed more money overall than TAs. Such findings may be due to decreased susceptibility to social cues among individuals with ASD.

Objectives: Circulating tumor DNA (ctDNA) is shown to provide the real-time genomic information of metastatic breast cancer. This study elucidates the clinico-pathological significance of ctDNA in early-stage breast cancer using the PIK3CA mutation as an indicator. Materials and Methods: Twenty-seven primary breast cancers without metastasis were surgically resected and pathologically diagnosed at the University of Tokyo Hospital, Japan. Genomic DNA of primary tumor was extracted from formalin-fixed and paraffin-embedded specimens. ctDNA was extracted from fresh-frozen plasma from patients. The PIK3CA mutations at E542K, E545K and H1047R were examined by Sanger sequencing or droplet digital PCR in 27 tumors and pre- and post-surgery plasma. Results: The PIK3CA mutations were detected in 13 (48%) of 27 primary tumors. These mutations did not significantly correlate with specific clinico-pathological characteristics of tumors. When ctDNA was examined, 4 (33%) of 12 cases carrying the mutated PIK3CA showed the identical mutation in pre-surgery plasma and 2 (50%) of them showed the identical mutations in post-surgery plasma. Interestingly, in these 2 cases in pathological stages IIIA and IA, fractional abundance of the mutated PIK3CA alleles to the total alleles in pre-surgery ctDNA was around 1% or more and was higher than that of the other two cases without PIK3CA mutations in post-surgery ctDNA. Conclusions: The PIK3CA mutation in ctDNA is detectable even in a subset of early-stage breast cancer. Furthermore, fractional abundance of the mutated PIK3CA in pre-surgery ctDNA could provide a possible predictive indicator for tumor burden and for choosing the appropriate adjuvant treatment of breast cancer.

Summary The molecular alterations and pathological features of gastric papillary adenocarcinoma (GPA) remain unknown. We examined GPA samples and compared their molecular and pathological characteristics with those of gastric tubular adenocarcinoma (GTA). Additionally, we identified pathological and molecular features of GPA that vary with microsatellite stability. In the present study, samples from 63 GPA patients and 47 GTA patients were examined using a combination of polymerase chain reaction (PCR)-microsatellite assays and PCR-pyrosequencing in order to detect microsatellite instability (microsatellite instability, MSI; microsatellite stable, MSS), methylation status (low methylation, intermediate methylation and high methylation level), and chromosomal AI in multiple cancer-related loci. Additionally, the expression levels of TP53 and Her2 were evaluated using immunohistochemistry. GTA and GPA are statistically different in their frequency of pathological features, including mucinous, poorly differentiated and invasive micropapillary components. Clear genetic patterns differentiating GPA and GTA could not be identified with a hierarchical cluster analysis, but microsatellite stability was linked with TP53 and Her2 overexpression. Methylation status in GPA was also associated with the development of high microsatellite instability. However, no pathological differences were associated with microsatellite stability. We suggest that although molecular alterations in a subset of GPAs are closely associated with microsatellite stability, they play a minor role in GPA carcinogenesis.

Force sensing is one of the key challenges in realizing mechanical characterizations of living samples. Since living samples are normally cultured within a medium and tend to have nonlinearity in terms of their strain–stress curve, the two important features; a wide measurement range and being waterproof are required for the force sensor. Given these key requirements, in this paper, we present a force sensor probe that uses a quartz crystal resonator (QCR) to achieve the mechanical characterization of a HepG2 spheroid. The force sensor probe was fabricated using five-layered structure of quartz wafers; here, the layers are packaged using atomic diffusion bonding. We evaluated the performance of the fabricated force sensor probe, with results showing that the sensor had a wide measurement range of 1.8 × 10 6 from 0.19 μN to 340 mN. By using a constructed mechanical characterization system integrated with the QCR force sensor probe, we evaluated the stiffness of HepG2 spheroids over different culture periods. To evaluate the stiffness as a mechanical characteristics of HepG2 spheroid, we introduced an index SI Slope . The results of mechanical characterization indicated that the measured SI Slope changed along with each culture day. From these results, we succeeded in measuring mechanical characteristics of spheroids using our fabricated force sensor probe.

Mitral annular structure and dynamics after mitral ring annuloplasty using transesophageal echocardiography during the operation have been reported. We evaluated mitral annular structure and dynamics of three different rings in the mid-term period postoperatively. Thirty-one patients underwent mitral valve repair for degenerative mitral insufficiency. The MEMO 3D ring (semi-flexible), Carpentier–Edwards Physio II ring (semi-rigid), and St. Jude Medical Rigid Saddle Ring (rigid) were implanted in 15, 12, and eight patients, respectively, from September 2009 to February 2015. Electrocardiogram-gated three-dimensional computed tomography was performed in the mid-term period postoperatively. The postoperative antero-posterior rate of reduction in diameter from end-diastole to end-systole was slightly larger in the MEMO3D (0.57 ± 0.69%) than in the Physio II (0.08 ± 0.60%) and Rigid Saddle Ring (0.11 ± 0.59%). There was no significant difference in the commissure-to-commissure rate of reduction in diameter among the groups. The postoperative end-systolic annular height to commissure width ratio was significantly larger in the Physio II (20.4 ± 1.7%) and Rigid Saddle Ring (21.3 ± 1.7%) than in the MEMO3D (10.8 ± 3.1%, both p

P2Y2 receptor (P2Y2R) is a G-protein-coupled receptor (GPCR) that couples with Gαq/11 and is stimulated by ATP and UTP. P2Y2R is involved in pain, proinflammatory changes, and blood pressure control. Some GPCRs are localized in lipid rafts for interaction with other signaling molecules. In this study, we prepared N-glycan-deficient mutants by mutating the two consensus Asn residues for N-glycosylation to Gln to examine intracellular localization and association with lipid rafts. Western blotting of the wild type (WT) protein and mutants (N9Q, N13Q, N9Q/N13Q) in COS-7 cells showed that both Asn residues were glycosylated in the WT. Fluorescent microscopy analysis showed that WT, N9Q and N13Q were expressed in the endoplasmic reticulum (ER), Golgi body, and cell membrane, but N9Q/N13Q was only found in the ER. WT, N9Q and N13Q moved from the cell surface to endosomes within 15 min after UTP stimulation. WT and the N9Q/N13Q glycosylation-deficient mutant appeared in the detergent insoluble membrane fraction, lipid raft. These findings suggest that P2Y2R is localized in lipid rafts in the ER during biosynthesis, and that N-glycosylation is required for subsequent expression in the cell membrane. In the presence of epoxomicin, a proteasome inhibitor, there was a significant increase in the level of N9Q/N13Q, which suggests that N-glycan-deficient P2Y2R undergoes proteasomal degradation.

Background This study aimed to evaluate the impact of previous local treatment on lymphatic drainage patterns in ipsilateral breast tumor recurrence (IBTR) based on our data on re-operative sentinel lymph node biopsy (re-SLNB) for IBTR. Methods Between April 2005 and December 2016, re-SLNB using lymphoscintigraphy with Tc-99 m phytate was performed in 136 patients with cN0 IBTR. Patients were categorized into two groups: the AX group included 55 patients with previous axillary lymph node dissection; the non-AX group included 69 patients with previous SLNB and 12 patients with no axillary surgery. The whole breast irradiation (RT) after initial surgery had performed in 17 patients in the AX group and 27 patients in the non-AX group. Results Lymphatic drainage was visualized in 80% of the AX group and 95% of the non-AX group (P

Background: The concept of sentinel lymph node biopsy (SLNB) has been introduced recently in cases with cN0 ipsilateral breast tumor recurrence (IBTR) after initial SLNB. However, data on survival following repeat SLNB (re-SLNB) are not sufficient. Methods: Patients who developed IBTR and underwent re-SLNB at our institution were included. The prognosis of patients who had axillary lymph node dissection (ALND) omitted by negative SLNs were investigated. Results: Sixty-nine patients were included. The median observation period after re-SLNB was 61 months. Among the 47 patients who had ALND omitted by negative SLNs at the ipsilateral axilla, only 1 patient had axillary lymph node recurrence, and the disease-free survival, distant disease-free survival, and overall survival at 5 years were89.3%, 91.6% and 97.9%, respectively. Conclusions: The survival outcome of ALND omission following re-SLNB was acceptable, indicating that re-SLNB is a clinically useful procedure once validated in a larger study.

Significance Tumors are composed of both cancer stem-like cells (CSCs) and differentiated cancer cells. Each CSC can undergo either a symmetric cell division to produce two CSCs or an asymmetric cell division to produce one CSC and one differentiated cancer cell. It is believed that the rate of symmetric division increases as more CSCs become malignant; however, underlying molecular mechanisms remain elusive. Here we show that stimulation with a cytokine, semaphorin (Sema), activates monooxygenase of MICAL3, a cytoplasmic signal transducer, through the neuropilin (NP) receptor that is specifically expressed on the breast CSC plasma membrane. The activation of MICAL3 induces symmetric division of CSCs. Each molecule in this signaling pathway represents a promising therapeutic target for eliminating CSCs., Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

Blood glucose management is important for cardiovascular surgery using cardiopulmonary bypass. The usefulness of an artificial pancreas apparatus (STG-55) to control blood glucose in patients undergoing cardiopulmonary bypass was investigated. Subjects comprised 44 patients using the artificial pancreas during cardiopulmonary bypass between June 2016 and March 2017; 55 were initially enrolled, but 11 were excluded because of blood removal failure. Patients were divided into a monitoring group in which blood glucose levels were only monitored using the artificial pancreas (11 patients: six people with diabetes and 5 people without diabetes) and a management group with glycemic control by automatic insulin administration using the artificial pancreas (33 patients: people with diabetes and 21 people without diabetes). Mean maximum blood glucose levels and variation ranges significantly differed between the monitoring and management groups (p = 0.02). The variation range significantly differed between people with and without diabetes in the monitoring group (p = 0.008), but not in the management group. The artificial pancreas apparatus continuously and accurately reflected glycemic variations, facilitating strict and favorable control.

Wide individual variation observed in tooth agenesis patterns in patients with non-syndromic oligodontia could be affected by sexual dimorphism. Therefore, the present study investigated sex-associated differences in tooth agenesis patterns in patients with non-syndromic oligodontia.Subjects were 108 male (ages 7-46 years) and 184 female (ages 7-43 years) orthodontic patients missing ≥6 permanent teeth, excluding third molars. The number of agenetic teeth per patient, excluding third molars, and the prevalence of agenesis of each tooth type were evaluated using panoramic radiographic images. Rankings of the most common tooth agenesis patterns in the maxillary and mandibular arches were calculated. The number of agenetic teeth per patient was compared between sexes using the Mann-Whitney test. The prevalence of tooth agenesis for each tooth type was compared between sexes using the χNo significant sex difference in the distribution of the number of agenetic teeth was observed. The prevalence of agenesis of the maxillary second premolars was significantly higher in females (P0.007) and the prevalence of agenesis of the mandibular central incisors was significantly higher in males (P0.007). Sexual dimorphism was observed in the highly ranked tooth agenesis patterns.No significant difference in the severity of tooth agenesis was observed between sexes; however, sexual dimorphism was observed in the tooth agenesis patterns of patients with non-syndromic oligodontia. Although various tooth agenesis patterns were identified, sex-specific tendencies suggest that categories can be utilized in future epidemiologic research and planning.

Background Perioperative stroke is a major complication after debranching thoracic endovascular aortic repair (TEVAR), with a reported incidence of 7.0–26.9%. Subsequent functional recovery is difficult in most cases. This study was performed to evaluate the efficacy of mini-cardiopulmonary bypass (mini-CPB) support in debranching TEVAR to prevent perioperative stroke. Methods From December 2010 to July 2017, 32 patients with a shaggy aorta or intimal irregularity in the aortic arch identified on preoperative computed tomography underwent debranching TEVAR. Nineteen patients underwent debranching TEVAR without mini-CPB, and 13 patients underwent debranching TEVAR with a mini-CPB support. Mini-CPB support had been used in November 2014 to treat perioperative stroke, which had occurred in 8 (42%) patients at that time. The form of the debranching arch vessels was not changed; bypass from the right axillary artery to the left axillary artery was performed for one debranching, and bypass from the right axillary artery to the left common carotid artery and left axillary artery was performed for two debranchings. After establishment of mini-CPB support through this debranching graft and right femoral vein cannulation, all endovascular manipulations were initiated. The left subclavian artery was occluded with a plug at the end of the procedure. Results The proximal landing zones of the endoprosthesis were as follows: zone 0 in 9 patients, zone 1 in 5 patients, and zone 2 in 5 patients in the no-CPB era and zone 1 in 3 patients and zone 2 in 10 patients in the CPB era. The mean mini-CPB support period was 51 minutes. Postoperative respiratory support and hospitalization were not prolonged with mini-CPB support. The incidence of perioperative stroke was 42% in the no-CPB era and 8% in the CPB era. No operative mortality was observed in the CPB era, although 5 (26%) patients died in the no-CPB era. The cause of operative mortality in the no-CPB era was perioperative stroke in 4 patients and acute myocardial infarction in 1 patient. No significant difference in the cumulative survival rate was found between patients with and without mini-CPB support. Conclusions Our mini-CPB system may have the potential to prevent perioperative stroke during debranching TEVAR for treatment of aortic arch pathologies.

CD56, the neural cell adhesion molecule (NCAM), is a member of the immunoglobulin superfamily and is associated with cell-to-cell adhesion and migration.1 Among haematological malignancies, CD56 expression has been described mainly in NK/T cell lymphoma, plasma cell myeloma and acute myeloid leukaemia, and rarely in B cell lymphomas, accounting for no more than 0.5% of all B lymphomas.2–8 Malignant lymphoma constitutes

Dear Editor, Recently, percutaneous imaging-guided core needle biopsy (CNB) ensuring a high degree of diagnostic accuracy and minimal invasiveness has been widely practiced as an alternative to surgical biopsy [1]. However, the procedure itself can, very rarely, contribute to disease recurrence [1, 2]. The WHO classifies mammary carcinomas with neuroendocrine (NE) features as a special tumor entity, representing

Here we report an additional Drosophila transheterozygote InR(GS15311)/InR(GS50346) carrying two different P-element-inducible alleles of insulin-like receptor gene (InR). InR(GS15311)/InR(GS50346) flies exhibit the following phenotypes previously reported in InR and insulin/IGF-1 signaling (IIS) pathway-related gene mutants: small bodies, developmental delay, shortened lifespan, and increased fasting resistance. All of these characteristics are shared among flies carrying mutated genes implicated in the pathway. This heteroallelic combination exhibited fertility but resulted in male semilethality, while females were viable and grew into adults. Furthermore, an experimental model employing the InR(GS15311)/InR(GS50346) strain confirmed negligible involvement of royal jelly in IIS. Thus, the heteroallelic InR mutant, discovered in this study, will serve as a good model for multiple purposes: investigating the IIS mechanisms; identifying and validating the ingredients that prevent type II diabetes; and screening of food constituents associated with IIS.

Antioxidants and antioxidant activity confer important protective eects in plants ag ainst the eects of free radicals, which are generated by biotic and abiotic stresses, such as cold. In another study, we identied SlICE1 as a basic helix-loop-helix transcription factor to improve cold tolerance. Here, we demonstrate that SlICE1 plays an important role in the accumulation of antioxidants and in the regulation of antioxidant activity in tomato Sol anum lycopersicum. Overexpression of SlICE1 in tomatoes enhanced the accumulation of antioxidants, such as �-carotene, lycopene, and ascorbic acid, as well as antioxidant activity, measured as the scavenging of 2,2-diphenyl-1-picrylhydazyl (DPPH) free radicals and O2 radicals. Furthermore, the sugar content in SlICE1-overexpressing tomatoes red fruits was higher than that in wild-type red fruits. Metabolite proling analysis performed by capillary electrophoresis time-of-�ight mass spectrometry (CE-TOFMS) revealed that several amino acids and amines were more highly accumulated in SlICE1-overexpressing tomato red fruits compared to those in wild-type tomatoes. �ese results suggest that SlICE1 plays a role in the regulation of antioxidant activity through the accumulation of several antioxidants.

In this study, we examined 7B2 (secretogranin V)-like immunoreactivity (IR) in the Japanese red-bellied newt (Cynops pyrrhogaster) pituitary. Results showed that the pars nervosa was filled with immunoreactive granules. In the pars intermedia, all melanotrophs showed 7B2-IR. In the pars distalis, immunoreactive cells were dispersed, and the 7B2-immunoreactive cells were also immunopositive for the β-subunit of bullfrog luteinizing hormone (fLHβ). 7B2-IR co-localized with fLHβ-IR in the same secretory granules. Our results suggest that 7B2 may participate in the secretion processes of gonadotropins in the pars distalis.

Objective Although protein malnutrition impairs immune functions, several studies have recently shown that protein restriction without malnutrition is beneficial to host defenses against invading pathogens and cancer. In an effort to establish the optimum diet for host resistance, we investigated the effect of different dietary protein levels on host resistance to Paracoccidioides brasiliensis . Methods Mice were fasted for 2 days and then infected with P. brasiliensis . Immediately after challenge with this fungus, mice were refed on diets with three different levels (0%, 1.5%, or 20%) of casein. On days 0–7 after infection, antifungal activity and levels of proinflammatory mediators in the spleen and liver were measured. Results Mice refed on the 1.5% casein diet showed higher antifungal activity in the spleen and liver compared with mice on the 20% casein diet. The antifungal activity in the spleens of mice refed on the 0% casein diet was intermediate between the antifungal activities of those refed the 1.5% and 20% casein diets. After infection, increases in spleen and liver levels of interleukin-6 and interferon-γ, liver mRNA levels of antimicrobial proteins (myeloperoxidase, cathepsin-G, and elastase-2), and liver mRNA levels of proinflammatory mediators (interleukin-18, chemokine C-X-C motif ligand 10, nuclear factor-κB, inducible nitric oxide synthase, and granulocyte–macrophage colony-stimulating factor) were less profound in mice on the 1.5% or 0% casein diet compared with mice refed the 20% casein diet. Conclusion The present results suggest that protein restriction without malnutrition could be beneficial to host resistance to P. brasiliensis .

Inhalation of Stachybotrys chartarum, a ubiquitous fungus in our living environment, has been suspected as a cause of acute idiopathic pulmonary haemorrhage in infants, but its relation to human diseases is not yet known. The aim of present study was to investigate the effect of repeated intratracheal injection of the fungus into mice, paying special attention to the pulmonary vascular system. Spores of S. chartarum were injected into the trachea of mice from 6 to 18 times over 4-12 weeks, and the lungs were examined by histopathology, morphometrics and haemodynamics. When 1 x 10(4) spores/mouse were injected, histopathological examination showed the development of pulmonary arterial hypertension (PAH). Symmetrical thickening of the intima and media of the pulmonary arterial walls was seen after six injections over 4 weeks. Right ventricular hypertrophy was also evident after 12 injections. PAH was confirmed by the elevation of right ventricular systolic pressure (20.1 +/- 5.7 mmHg in the injected group vs. 12.0 +/- 2.4 mmHg in the control group, P < 0.01). This study showed that the inhalation of S. chartarum caused PAH in mice, suggesting a potential of S. chartarum as a cause of human health problem such as PAH.

An 81-year-old woman developed severe hemolytic anemia after aortic valve replacement. The anemia was not caused by paravalvular leakage, as in most cases. Instead, it occurred secondary to left ventricular outflow tract obstruction that had not been seen preoperatively and was induced by afterload reduction following aortic valve replacement. The hemolytic anemia was drug-refractory and finally treated with dual-chamber pacing, as for hypertrophic cardiomyopathy.