Head region of unconventional myosin I family members is responsible for the organ‐specificity of their roles in left–right polarity in Drosophila

In Drosophila, Myosin31DF (Myo31DF), encoding a Myosin ID protein, has crucial roles in left–right (LR) asymmetric development. Loss of Myo31DF function leads to laterality inversion for many organs, including the embryonic gut. Here, we found that Myo31DF was required before LR asymmetric morphogenesis in the hindgut, suggesting it functions in LR patterning instead of directly in hindgut morphological changes. Myosin61F (Myo61F) encodes another Myosin I, and Myo31DF or Myo61F overexpression reverses the laterality of different organs. Myo31DF and Myo61F have domains conserved in Myosin proteins, particularly in the proteins' head regions. We studied the roles of these domains in LR patterning using overexpression analysis. The Actin‐binding and ATP‐binding domains were essential for both proteins, but the IQ domains, binding sites for Myosin light chains, were required only by Myo31DF. Our results also suggest that the organ specificities of the Myo31DF and Myo61F activities depended on their head regions. Developmental Dynamics 237:3528–3537, 2008. © 2008 Wiley‐Liss, Inc.     

Desmoid‐type fibromatosis in a boy with Down syndrome

Patients with Down syndrome (DS) have a markedly higher incidence of childhood leukemia, but a lower incidence of most solid tumors, compared with age‐matched euploid individuals. Trisomy 21 might be protective against tumorigenesis because of several tumor suppressive mechanisms. Desmoid‐type fibromatosis (DF) is a rare monoclonal, fibroblastic proliferation characterized by a variable clinical course. In recent reports, almost all cases of DF involved genomic alterations associated with activation of the Wnt/β‐catenin pathway. Here, we report the case of a boy with DS who developed DF without activation of the Wnt/β‐catenin pathway. To the best of our knowledge, this is the first case of DS involving DF.     

Correcting Estimation Bias in Randomized Clinical Trials With a Test of Treatment-by-Biomarker Interaction

The key elements in recent drug development aiming toward personalized medicine involve the development of baseline predictive biomarkers to predict the responsiveness to new treatments. When biological evidence to support the biomarker hypothesis is not strong, it is particularly important to evaluate the clinical validity of a predictive biomarker based on data from clinical trials. All-comers randomized clinical trials stratified with biomarker measurements can provide the opportunity to evaluate the predictive value of the biomarker, and a test of treatment-by-biomarker interaction is applied for this purpose. If the interaction is significant, it is natural to proceed to a subgroup analysis that evaluates treatment efficacy within biomarker-based subgroups. However, estimation bias can arise when using the standard estimation method without regard to the significant interaction because of the correlation between the interaction test and subgroup analysis. In this paper, after evaluating the bias function for the standard estimators, we provide bias-corrected point and interval estimation methods, including polynomial approximations of the bias function previously developed for a fallback analysis plan. The magnitude of bias reduction and precision of the proposed estimators are assessed via simulations. Applications to biomarker-stratified, randomized phase III trials in oncology are provided. Supplementary materials for this article are available online.     

High total Joule heat increases the risk of post-endoscopic submucosal dissection electrocoagulation syndrome after colorectal endoscopic submucosal dissection

BACKGROUNDWe hypothesized that thermal damage accumulation during endoscopic submucosal dissection (ESD) causes the pathogenesis of post-ESD electrocoagulation syndrome (PECS).AIMTo determine the association between Joule heat and the onset of PECS.METHODSWe performed a retrospective cohort study in patients who underwent colorectal ESD from May 2013 to March 2021 in Japan. We developed a novel device that measures swift coagulation time with a sensor adjacent to the electrosurgical coagulation unit foot switch, which enabled us to calculate total Joule heat. PECS was defined as localized abdominal pain (visual analogue scale ≥ 30 mm during hospitalization or increased by ≥ 20 mm from the baseline) and fever (temperature ≥ 37.5 degrees or white blood cell count ≥ 10000 µ/L). Patients exposed to more or less than the median Joule heat value were assigned to the high and low Joule heat groups, respectively. Statistical analyses included Mann-Whitney U and chi-square tests and logistic regression and receiver operating characteristic curve (ROC) analyses.RESULTSWe evaluated 151 patients. The PECS incidence was 10.6% (16/151 cases), and all patients were followed conservatively and discharged without severe complications. In multivariate analysis, high Joule heat was an independent PECS risk factor. The area under the ROC curve showing the correlation between PECS and total Joule heat was high [0.788 (95% confidence interval: 0.666-0.909)].CONCLUSIONJoule heat accumulation in the gastrointestinal wall is involved in the onset of PECS. ESD-related thermal damage to the peeled mucosal surface is probably a major component of the mechanism underlying PECS.     

Advances in balloon endoscopes

In September 2003, a double-balloon endoscope (DBE) composed of balloons attached to a scope and an overtube was released in Japan prior to becoming available in other parts of the world. The DBE was developed by Dr. Yamamoto (1), and 5 different types of scopes with different uses have already been marketed. In April 2007, a single-balloon small intestinal endoscope was released with a balloon attached only to the overtube as a subsequent model. This article presents a detailed account of the development of these scopes up to the present time.     

Reduction in HPV16/18 prevalence among young women with high‐grade cervical lesions following the Japanese HPV vaccination program

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12‐16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population‐level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1‐3 (CIN1‐3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012‐2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6‐year period were observed in CIN1 (50.0% to 0.0%, P_trend < .0001) and CIN2‐3/AIS (83.3% to 45.0%, P_trend = .07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18‐attributable CIN2‐3/AIS from 47.7% to 33.0% (P = .003): from 43.5% to 12.5% as routine vaccination (P = .08) and from 47.8% to 36.7% as catch‐up vaccination (P = .04). The HPV16/18 prevalence in CIN2‐3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P = .02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18‐positive CIN/AIS in Japan; however, our data did not support catch‐up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government’s suspension of its vaccine recommendation could benefit from receiving catch‐up vaccination before age 20 years.     

Effects of antioxidant polyphenols on TNF-alpha-related diseases

Oxidative stress and inflammatory responses sustained for a long period of time cause many diseases. A proinflammatory cytokine, tumor necrosis factor α (TNF-α), plays a pivotal role in the pathogenesis of chronic and auto-immune diseases. The present review, supplemented by hitherto unpublished data of the authors and their coworkers, shows that the intake of polyphenols contained in natural sources, such as hydroxytyrosol, tyrosol, oleuropein (olives), naringin and hesperidin (Citrus fruits), resveratrol, procyanidins or oligomeric procyanidin (grapes or grape seed extracts), (-)-epigallocatechin gallate (green tea) and quercetin (grapes, green tea) etc., are able to modulate chronic inflammatory diseases, such as type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease, and affect the formation and interaction of advanced glycation end products with their respective receptors. Furthermore, potent activities of fermented grape marc, prepared as a fine lyophilized powder from fresh skin and seeds of a Japanese grape strain (Koshu) and then fermented with Lactobacillus plantarum, are described. Finally, the bioavailability of representative polyphenols will be discussed.     

A rare case of ACTH-independent macronodular adrenal hyperplasia associated with aldosterone-producing adenoma

A 52-year-old man was evaluated for incidentally discovered bilateral adrenal masses. He had drug-resistant hypertension but lacked Cushingoid features. Endocrinological tests revealed autonomous secretion of cortisol and aldosterone with suppressed plasma ACTH and renin activity. A selective adrenal venous sampling demonstrated aldosterone hypersecretion from the left adrenal vein. The clinical diagnosis of subclinical Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) associated with primary aldosteronism was made, and he underwent left adrenalectomy; the resected adrenal lesion was consistent with the pathological diagnosis of AIMAH coexistent with aldosterone-producing adenoma (APA). This is a very rare case of AIMAH with concomitant unilateral APA, whose hypertension improved after surgery.     

Clinicopathological features, biochemical and molecular markers in 5 patients with adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a very rare malignant tumor with poor prognosis. To gain insight into the pathogenic significance of ACC, we studied clinicopathological features and gene expression profile in ACC. We analyzed five ACC cases (two men and three women) with the median age of 45-year-old who underwent adrenalectomy at our institute. Endocrine studies revealed that two cases had subclinical Cushing's syndrome (SCS) and one with concomitant estrogen-secreting tumor, while the rest of three cases had non-functioning tumors. Analysis of urinary steroids profile by gas chromatography/mass spectrometry showed increased metabolites of corticosteroid precursors, such as 17-OH pregnenolone, 17-OH progesterone, dehydroepiandorosterone (DHEA), and 11-deoxycortisol in all five cases. The pathological diagnosis of ACC was based on Weiss's criteria with its score ≥ 3. The mean size of the resected tumors was 87 mm and Ki67/MIB1 labeling index, a proliferative marker, was 3-27%. Immunohistochemical analysis revealed a disorganized expression of several steroidogenic enzymes, such as 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and DHEA-sulfotransferase. Among several genes determined by RT-PCR, insulin-like growth factor (IGF)-II mRNA was consistently and abundantly expressed in all 5 tumor tissues. Postoperatively, two cases with SCS developed local recurrence and liver metastasis. The present study suggests that the disorganized expression of steroidogenic enzymes and the overexpression of IGF-II by the tumor are hallmarks of ACC, which could be used as biochemical and molecular markers for ACC.