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A 60-year-old male with cStage IVB lung cancer was treated with pembrolizumab. However, after five courses of pembrolizumab, he developed pembrolizumab-related cholangitis. Imaging studies showed enlargement and diffuse wall thickening of the gallbladder and mild dilation of the bile ducts without any obvious obstruction. As the patient experienced severe abdominal pain, we suspected bile stasis and performed biliary drainage. However, his condition did not improve, and he developed multiple liver abscesses and died during immunosuppressive therapy. Our case suggests that in ir-cholangitis, the indication and method of endoscopic retrograde cholangiopancreatography should be carefully judged.

Background and Aim Post‐endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most serious adverse event of ERCP. Therefore, it is important to identify high‐risk patients who require prophylactic measures. The aim of this study was to develop a practical prediction model for PEP that identifies high‐risk patients. Methods Patients who underwent ERCP at three tertiary hospitals between April 2010 and September 2012 were enrolled. The dataset was divided into a training set (two centers) and validation set (one center). Using the training set, univariable and multivariable analyses were performed to identify predictive factors for PEP. We constructed a scoring system and evaluated reproducibility using the validation set. Results A total of 2719 ERCPs were analyzed. PEP developed in 133 cases (4.9%). Risk factors (adjusted odds ratios [OR]) in the training set were a history of PEP (OR: 4.2), intact papilla (OR: 2.4), difficult cannulation (OR: 1.9), pancreatic guidewire‐assisted biliary cannulation (OR: 2.2), pancreatic injection (OR: 2.1), pancreatic intraductal ultrasonography (IDUS)/sampling from the pancreatic duct (OR: 2.2), and biliary IDUS/sampling from the biliary tract (OR: 2.8). A scoring system was constructed using these seven clinical variables. The areas under the receiver‐operating characteristic curve of this model were 0.799 in the training set and 0.791 in the validation set. In the high‐risk group at a score of 3 or higher, the incidence of PEP was 13.4%, and all severe/fatal cases were in the high‐risk group. Conclusions This scoring system helps to predict each patient's risk and select preventive measures., We develop and validate a practical prediction model for post‐endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis based on the ERCP database of three tertiary hospitals. This scoring system, which considers the respective weight of seven predictive factors, showed excellent discriminability and reproducibility, and identified high‐risk patients. The accurate quantification of each patient's risk of PEP will reduce unnecessary medication and facilitate the selection of appropriate prophylactic measures by clinicians.

A 43-year-old woman was suffering from epigastric pain. Her gastroscopy revealed polyposis of the stomach, and her biopsy revealed a hyperplastic polyp. During the 18-month follow-up, the polyps proliferated, and the patient was referred to our institute for further investigation and treatment. A juvenile gastric polyposis diagnosis was made. She refused to have the surgery despite the fact that it was necessary due to the anemia and hypoalbuminemia she was experiencing. Endoscopic biopsy results revealed gastric cancer at a follow-up visit 2 years and 3 months later; thus, a laparoscopic total gastrectomy was performed. Pathological examination revealed adenocarcinomas that were scattered and well-differentiated, with hyperplastic polyps in the background. No lymph node metastasis was found. Despite the fact that juvenile gastric polyposis is a pathologically benign disease, there have been numerous case reports of surgery being performed due to anemia, hypoalbuminemia, or gastric cancer associated with the disease. When gastric cancers are discovered in cases of juvenile gastric polyposis, they are usually in an early stage, making them a good candidate for laparoscopic total gastrectomy.

One of the unifying traits of life on this planet is reproduction, or life's ability to make copies of itself. The mode of reproduction has evolved over time, having almost certainly begun with simple asexual reproduction when the ancestral single celled organism divided into two. Since these beginnings' life has tried out numerous strategies, and perhaps one of the most important and successful has been sexual reproduction. This form of reproduction relies on the union of gametes, otherwise known as sperm and egg. Evolutionarily, sexual reproduction allows for greater adaptive potential because the genes of two unique individuals have a chance to recombine and mix in order to produce a new individual. Unlike asexual reproduction which produces genetically-identical clones of the parent individual, sex produces offspring with novel genes and combinations of genes. Therefore, in the face of new selective pressures there is a higher chance that one of these novel genetic profiles will produce an adaptation that is advantageous in the new circumstances. Dr Akihiko Watanabe is a reproductive biologist based in the Department of Biology, Faculty of Science Yamagata University in Japan, he is currently working on three research projects; a comparative study on the signalling pathways for inducing sperm motility and acrosome reaction in amphibians, the mechanism behind the adaptive modification of sperm morphology and motility, and the origin of sperm motility initiating substance (SMIS).

The N-methyl d-aspartate type glutamate receptor (NMDAR) is a ligand-gated cation channel that causes Ca2+ influx in nerve cells. An NMDAR agonist is effective to the sperm motility in fowls, although the actual role of NMDAR in sperm function is unknown. In the present study, RNA-seq of the spermatogenic testes suggested the presence of NMDAR in the sperm of the newt Cynops pyrrhogaster. Glutamate of at least 0.7 ± 0.5 mM was detected in the egg-jelly substances along with acrosome reaction-inducing substance (ARIS) and sperm motility-initiating substance (SMIS). In the egg-jelly extract (JE) that included the ARIS and SMIS, the acrosome reaction was inhibited by a NMDAR antagonists, memantine and MK801. MK801 also inhibited the spontaneous acrosome reaction in Steinberg's salt solution (ST). Furthermore, memantine and MK801 suppressed the progressive motility of the sperm in JE and spontaneous waving of the undulating membrane, which is the tail structure giving thrust for forward motility, in ST. The spontaneous waving of the undulating membrane was promoted when Mg2+ , which blocks Ca2+ influx through gated NMDARs, was removed from the ST. In addition, the ARIS-induced acrosome reaction was inhibited by a selective antagonist of the transient receptor potential vanilloid 4, whose activation might result in the membrane depolarization to release Mg2+ from the NMDAR. These results suggest that NMDAR acts together with other cation channels in the induction of the acrosome reaction and motility of the sperm during the fertilization process of C. pyrrhogaster.

Low osmolality of freshwater and/or sperm motility-initiating substance (SMIS) induce amphibian sperm motility through increases in intracellular Ca2+. In the internally fertilizing newt Cynops pyrrhogaster, the sperm motility-initiating substance engages T type voltage-dependent Ca2 + channels and N-methyl D-aspartate-type glutamate receptors to initiate sperm motility and L type voltage-dependent Ca2+ channels to enhance motility. In the present study, differences in the usages of SMIS and Ca2+ permeable channels for sperm motility regulation were examined in amphibians that undergo different reproductive modes. Proteins of 14-17 kDa were detected by antibody against the active site peptide of SMIS in the oviduct secretion of internal fertilizers (C. pyrrhogaster, Cynops ensicauda, and Ambystoma mexicanum) and arboreal fertilizers (Rhacophorus arboreus and Rhacophorus schlegelii), but not in Buergeria japonica, an external fertilizer in freshwater. In the pharmacological study, a blocker of some transient receptor potential channels (RN1734) additionally suppressed enhancement of sperm motility in C. pyrrhogaster. In R. schlegelii, blockers of four types of channels differently suppressed sperm motility induced by low osmolality with or without the active site peptide of SMIS. Notably, blockers of L type voltage-dependent Ca2+ channels (nifedipine) and N-methyl D-aspartate-type glutamate receptors (MK801) suppressed sperm motility in the presence and the absence of the peptide, respectively. Low osmolality-induced sperm motility was suppressed by RN1734 and MK801 in B. japonica, but not in Xenopus laevis. These results reveal complex differences in the signaling pathways for inducing sperm motility that may be partly related to reproductive modes in amphibians.

Abiraterone acetate plus prednisone/prednisolone (AAP) and androgen deprivation therapy (ADT) was approved for the treatment of high-risk metastatic hormone-sensitive prostate cancer (mHSPC) in Japan in 2018. We investigated 22 patients with mHSPC showing ≥2 of 3 high-risk factors (Gleason score ≥8, ≥3 bone lesions or measurable visceral metastases) who received AAP plus ADT at our hospital between March 2018 and October 2019. We compared outcomes between the propensity-score matched AAP plus ADT group and the combined androgen blockade (CAB) group (19 matched pairs, 38 patients) to evaluate the efficacy and safety of AAP plus ADT. Prostate-specific antigen progression-free survival (PSA-PFS) was significantly longer in the AAP group than in the CAB group (not reached vs 15.1 months, p=0.014). Time to achievement of serum PSA ≤0.2 ng/ml and ≤0.1 ng/ml was shorter in the AAP group than in the CAB group (6.4 months vs not reached, p=0.001 and 11.0 months vs not reached, p=0.004, respectively). Although no significant intergroup difference was observed in the overall survival rates and PSA-PFS2 (PSAPFS on subsequent anticancer therapy) owing to the shorter follow-up in the AAP group, our data suggest that the clinical efficacy of AAP is betterthan that of CAB in patients with mHSPC.

BACKGROUND: Cigarette smoking is known to be a significant risk factor associated with nonalcoholic fatty liver disease (NAFLD). We aimed to examine the association between smoking status and the severity of fatty liver with regard to sex and smoking cessation. METHODS: In total, 13,466 subjects (6,642 males and 6,824 females) who had undergone abdominal ultrasonography for health check-up, multivariable logistic regression analysis was retrospectively conducted to assess the association between smoking status and the prevalence of NAFLD stratified by sex after adjusting for other potential confounders. RESULTS: Male sex (odds ratio [OR] 3.27, 95% confidence interval [CI] 3.00–3.57) and smoking history (former smoker: OR 1.23, 95% CI 1.10–1.38, current smoker: OR 1.31, 95% CI 1.17–1.47) were significantly associated with NAFLD. In males with a smoking history, an increased pack-year was strongly associated with the prevalence and severity of NAFLD (prevalence of moderate to severe fatty liver: Pack-year from 0.01 to 9.99, 21.3%; Pack-year from 10.00 to 19.99, 27.2%; Pack-year ≥20.00, 33.7%; P

In amphibians, morphologically and physicochemically diversified egg jelly/nest is significant in the evolution of various reproductive modes, while sperm motility and signaling path to regulate it should be adaptively modified to penetrate the egg jelly/nest. Hyposmolality of freshwater and/or a cysteine knot protein called sperm motility-initiating substance (SMIS) initiates and enhances motility, allowing amphibian sperm to penetrate egg jelly/nest. By comparison of the sperm responses to SMIS and hyposmolality in some anuran and urodele species with different reproductive modes, sperm of internally fertilizing Cynops pyrrhogaster and those of arboreally fertilizing Rhacophorus arboreus initiate and enhance motility by SMIS and the combination of SMIS and hyposmolality. In externally fertilizing Buergeria japonica, sperm motility is initiated and enhanced by hyposmolality. A pharmacological study suggests that at least voltage-dependent Ca2+ channel and TRP channel mediate the initiation and enhancement of amphibian sperm motility with different combinations. It is suggested that in the diversification of reproductive modes from external fertilization in freshwater to arboreal fertilization and internal fertilization in amphibian evolution, TRP channel and voltage-dependent Ca2+ channel are critical in hyposmolality-triggered signaling. The SMIS-triggered one seems to add a specific feature to the regulation of sperm motility, which contributes to the achievement of advanced reproductive modes in amphibians.

Power devices are semiconductor devices that handle high voltages and large currents, which are used in electric vehicles, televisions, and trains. Therefore, high reliability and safety are required, and to ensure this, power cycle tests are performed to analyze the breakdown process. Conventional tests are often difficult to analyze due to the influence of sparks generated during the test. Therefore, new tests are being developed by adding ultrasound to conventional methods. The new technology is capable of continuously recording structural changes inside the device during testing, which is expected to make testing much easier than conventional testing. However, the new technology still has some challenges. The main problems are the lack of a method for analyzing large amounts of image data and the extraction of small changes in image features that are difficult to distinguish with the human eye, and the establishment of such a system is required. In this paper, we use deep learning for image classification of the obtained ultrasound images. We propose a new network model with the addition of Batch normalization and Global average pooling to VGG16, which is a pre-trained model. In the experiment, accuracy=98.29%, TPR=98.96% and FPR=7.43% classification accuracy was obtained.

The acrosome reaction is induced in the sperm of Cynops pyrrhogaster immediately in response to a ligand protein called acrosome reaction-inducing substance (ARIS) in the egg jelly at fertilization, whereas a spontaneous acrosome reaction occurs time-dependently in correlation with the decline of sperm quality for fertilization. The ARIS-induced acrosome reaction was recently found to be mediated by TRPV4 in association with the NMDA type glutamate receptor, although the intracellular mediators for the acrosome reaction are largely unclear. In the present study, spontaneous acrosome reaction was significantly inhibited by Ni2+, RN1734, and diltiazem, which blocks Cav3.2, TRPV4 or TRPM8, and the cyclic nucleotide-gated channel, respectively. In contrast, expression of Ca2+-activated transmembrane and soluble adenylyl cyclases was detected in the sperm of C. pyrrhogaster by reverse transcription-polymerase chain reaction. Activator of transmembrane or soluble adenylyl cyclases (forskolin or HCO3-) independently promoted spontaneous acrosome reaction, while an inhibitor of each enzyme (MD12330A or KH7) inhibited it only in the sperm with high potential for spontaneous acrosome reaction. An inhibitor of protein kinase A (H89) inhibited spontaneous acrosome reaction in a manner independent of sperm potential for spontaneous acrosome reaction. Surprisingly, KH7 significantly inhibited ARIS-induced acrosome reaction, but its effect was seen in a small percentage of sperm. H89 had no effect on ARIS-induced acrosome reaction. These results suggest that C. pyrrhogaster sperm possess multiple intracellular pathways for acrosome reaction, involving Ca2+ permeable channels, adenylyl cyclases and PKA, and that two pathways having distinct dependencies on adenylyl cyclases may contribute to ARIS-induced acrosome reaction at fertilization.

The newt, a group of urodele amphibians, has outstanding ability to repeatedly regenerate various body parts, even in the terrestrial life-stage. In this animal, when the limb is amputated, a cell mass named the blastema appears on the stump and eventually gives rise to a new functional limb. Erythrocytes (red blood cells) in most non-mammalian vertebrates, including the newt, preserve their nucleus throughout their life-span, although physiological roles of such nucleated erythrocytes, other than oxygen delivery, are not known. Here we report novel behavior of erythrocytes in the newt. We identified an orphan gene Newtic1, whose transcripts significantly increased in the blastema. Newtic1 was expressed in a subset of erythrocytes that formed a novel clump (EryC). EryC formed a complex with monocytes and was circulating throughout the body. When the limb was amputated, EryCs were newly generated in the stump and accumulated into a distal portion of the growing blastema. Our data suggested that the newt erythrocytes carried multiple secretory molecules including growth factors and matrix metalloproteases, and were capable of delivering these molecules into the blastema as a form of EryCs. This study provides insight into regulations and roles of nucleated erythrocytes, that are independent of oxygen delivery.

Sperm storage is supposed to influence sperm quality, although the details remain unclear. In the present study, we found that sperm stored in a sperm storage site, the vas deferens of Cynops pyrrhogaster, spontaneously undergo acrosome reaction following incubation in Steinberg's salt solution (ST). Percentages of acrosome-reacted sperm increased time-dependently to about 60% in 24 hr. The concentration of cyclic adenosine monophosphate (cAMP) was elevated after incubating sperm in ST, while dibutylyl cAMP induced an acrosome reaction. Chelating of extracellular Ca2+ suppressed the dibutylyl cAMP-induced acrosome reaction as well as spontaneous acrosome reaction in ST. These results suggest that cAMP elevation driven by Ca2+ influx can be a cue for spontaneous acrosome reaction. Relatively low Ca2+ concentration and pH in the vas deferens were sufficient to suppress spontaneous acrosome reaction within 1 hr. In addition, the cysteine rich secretory protein 2 gene was expressed in the vas deferens, indicating that it may be involved in the continuous suppression of spontaneous acrosome reaction. Sperm that underwent spontaneous acrosome reaction in ST was significantly increased when stored in the vas deferens for longer periods, or by males experiencing temperatures in excess of 12°C during hibernation conditions. Percentages of the spontaneously acrosome-reacted sperm were found to differ among males even though they were of identical genetic background. Taken together, C. pyrrhogaster sperm possess the potential for spontaneous acrosome reaction that does not become obvious in the vas deferens, unless promoted in correlation with sperm storage.

Sperm motility-initiating substance (SMIS) is a key protein for internal fertilization of the newt, Cynops pyrrhogaster, and commonly enhances forward sperm motility in some amphibian species, including external fertilizers. SMIS action varies among different species in correlation with a species-specific reproductive environment. In the present study, we identified the gene of C. ensicauda SMIS (CeSMIS) and examined the mechanism of SMIS action with reference to that of the closely related Cynops species. The CeSMIS was identified by a 176-amino acid sequence including seven amino acids critical for the initiation of sperm motility. The amino acid sequence showed 91% homology to the whole sequence of C. pyrrhogaster SMIS (CpSMIS). By immunostaining with an anti-CpSMIS antibody, CeSMIS was shown to be localized in the outer layer of the egg jelly. A peptide presenting the active site of SMIS was observed to bind to the axial rod of the midpiece in C. ensicauda sperm. The localization and binding patterns of CeSMIS were fundamentally similar to those of CpSMIS. However, the SMIS peptide did not induce forward motility of C. ensicauda sperm, although it induced a fast wave of the undulating membrane. Forward sperm motility was induced in the egg jelly extract containing CeSMIS. These results suggest that the mechanism of initiation of sperm motility is differentiated between C. ensicauda and C. pyrrhogaster.

Sperm intracellular Ca2+ is crucial for the induction of sperm-egg interaction, but little is known about the significance of Ca2+ maintenance prior to induction. In sperm of the newt Cynops pyrrhogaster, intracellular Ca2+ is localized to the midpiece during storage in the vas deferens, while extracellular Ca2+ is influxed in modified Steinberg’s salt solution to promote a spontaneous acrosome reaction related to the decline of sperm quality. In the present study, sperm from the vas deferens were loaded with the Ca2+ indicator Fluo8H, and changes in Ca2+ localization in modified Steinberg’s salt solution were examined. Calcium ions expanded from the cytoplasmic area of the midpiece to the entire tail in most sperm during a 1-h incubation and localized to the principal piece in some sperm within 24 h. Similar changes in Ca2+ localization were observed in reconstructed vas deferens solution that included ions and pH at equivalent levels to those in the vas deferens fluid. Sperm with Ca2+ localization in the entire tail or the principal piece weakened or lost responsiveness to sperm motility-initiating substances, which trigger sperm motility for fertilization, but responded to a trigger for acrosome reaction. The change in Ca2+ localization was delayed and transiently reversed by ethylene glycol tetraacetic acid or a mixture of Ca2+ channel blockers including Ni2+ and diltiazem. These results suggest that C. pyrrhogaster sperm localize intracellular Ca2+ to the midpiece through Ca2+ transport in the vas deferens to allow for responses to sperm motility-initiating substances.