Search

Purpose: Left ventricular assisting device (LVAD) is a vital mechanical circulatory assist device for patients with end-stage heart disease, serving as either a bridge to transplantation or palliative destination therapy. Yet device infection represents a major lethal complication, warranting a multi-step, complex therapy approach including an urgent device exchange or heart transplantation. Still, timely diagnosis of site and extent of VAD-specific infection for a proper therapy planning poses challenges in regular clinical care. This single-center, retrospective study aimed to evaluate the impact of volumetric PET parameters with different thresholding compared to semiquantitative PET parameters for accurate diagnosis of VAD-specific infection., Procedures: Seventeen patients (1 female, 16 males; mean age 57 ± 11 years) underwent [ 18 F]FDG imaging for suspected VAD-specific infection between April 2013 and October 2023. Various metabolic and volumetric PET parameters with different thresholding were collected for specific LVAD components including driveline entry point, subcutaneous driveline, pump pocket, inner cannula and outflow tract. Microbiology and clinical follow-up were used as the final diagnosis standard., Results: Nine of eleven patients with VAD-specific infection underwent urgent heart transplantation, and one had a surgical revision of LVAD. Two patients had non-VAD specific infections, and two had non-VAD related infections. Metabolic burden determination using a fixed absolute threshold provided the best outcome compared to relative thresholding or other metabolic SUV parameters. The total metabolic tumor volume (MTV) cutoff value was 9.3 cm 3 , and the corresponding sensitivity, specificity, accuracy, and AUC were 90.0%, 71.43%, 82.5%, and 0.814 (95% CI 0.555-0.958), respectively. The total lesion glycolysis (TLG) was 30.6, and the corresponding sensitivity, specificity, accuracy, and AUC were 90.0%, 71.4%, 82.5%, and 0.829 (95% CI 0.571-0.964), respectively., Conclusions: Volumetric PET parameters with fixed absolute thresholding appear to be a valuable auxiliary tool in the evaluation of [ 18 F]FDG imaging to enhance the diagnostic accuracy of VAD-specific infection., (© 2024. The Author(s).)

In recent years, eye lens exposure among radiation workers has become a serious concern in medical X-ray fluoroscopy and interventional radiology (IVR), highlighting the need for radiation protection education and training. This study presents a method that can maintain high accuracy when calculating spatial dose distributions obtained via Monte Carlo simulation and establishes another method to three-dimensionally visualize radiation using the obtained calculation results for contributing to effective radiation-protection education in X-ray fluoroscopy and IVR. The Monte Carlo particle and heavy ion transport code system (PHITS, Ver. 3.24) was used for calculating the spatial dose distribution generated by an angiography device. We determined the peak X-ray tube voltage and half value layer using Raysafe X2 to define the X-ray spectrum from the source and calculated the X-ray spectrum from the measured results using an approximation formula developed by Tucker et al. Further, we performed measurements using the "jungle-gym" method under the same conditions as the Monte Carlo calculations for verifying the accuracy of the latter. An optically stimulated luminescence dosimeter (nanoDot dosimeter) was used as the measuring instrument. In addition, we attempted to visualize radiation using ParaView (version 5.12.0-RC2) using the spatial dose distribution confirmed by the above calculations. A comparison of the measured and Monte Carlo calculated spatial dose distributions revealed that some areas showed large errors (12.3 and 24.2%) between the two values. These errors could be attributed to the scattering and absorption of X-rays caused by the jungle gym method, which led to uncertain measurements, and (2) the angular and energy dependencies of the nanoDot dosimetry. These two causes explain the errors in the actual values, and thus, the Monte Carlo calculations proposed in this study can be considered to have high-quality X-ray spectra and high accuracy. We successfully visualized the three-dimensional spatial dose distribution for direct and scattered X-rays separately using the obtained spatial dose distribution. We established a method to verify the accuracy of Monte Carlo calculations performed through the procedures considered in this study. Various three-dimensional spatial dose distributions were obtained with assured accuracy by applying the Monte Carlo calculation (e.g., changing the irradiation angle and adding a protective plate). Effective radiation-protection education can be realized by combining the present method with highly reliable software to visualize dose distributions., (© 2024. The Author(s).)

Lung neuroendocrine neoplasms (NENs) are a diverse group of tumors characterized by neuroendocrine (NE) differentiation. Among lung NENs, lung carcinoid (LC) is a rare tumor with unique characteristics. Recent research has highlighted the importance of transcription factors (TFs) in establishing gene expression programs in lung NENs such as small cell lung carcinoma. However, the TFs that control the gene expression of LC are largely unknown. In this study, we report the expression and potential function of a TF called Prospero homeobox protein1 (PROX1) in LC. Publicly available transcriptome data suggested that PROX1 was highly expressed in LC tissues, which was confirmed by immunohistochemical analysis on a tissue microarray. Knockdown of PROX1 did not impact the cellular viability of an LC-derived cell line, NCI-H727. Meanwhile, transcriptome analysis revealed that PROX1 knockdown altered the expression of genes involved in NE differentiation. ASCL1, CHGA, CALCA, and LINC00261 were suggested as downstream genes of PROX1. These findings indicate that PROX1 may play an important role in the NE identity of LC by regulating the expression of key target genes., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Fibroblast activation protein (FAP) is mainly found on the surface of activated fibroblasts but is not expressed on the surface of inactive fibroblasts. Selective FAP inhibitors (FAPI), which are coupled to a radioactive tracer, can be used to quantify profibrotic and proinflammatory fibroblasts in patients using FAPI positron emission tomography (PET) computed tomography (CT). Following initial applications in neoplastic diseases, FAPI-PET/CT is also increasingly being applied in rheumatological diseases. The first studies have shown that in patients with systemic sclerosis (SSc) FAPI accumulates in actively fibrotically remodeled pulmonary and myocardial areas, that a high FAPI accumulation is associated with the risk of short-term progression and that this accumulation in the lungs regresses after successful treatment. In cases of immunoglobulin 4 (IgG4)-associated diseases (IgG4 rheumatic disease, RD), the FAPI signal correlates with the histological accumulation of activated fibroblasts and a poorer response to treatment to inhibit inflammation. Fibroblasts in chronically inflamed tissue, such as patients with inflammatory joint diseases, vasculitis or myositis, also express FAP and can be quantified by FAPI-PET/CT. The treatment-induced change of the phenotype from a destructive IL-6+/MMP3+THY1+ fibroblast subtype to an inflammation inhibiting CD200+DKK3+ subtype can be mechanistically demonstrated using FAPI-PET/CT. These studies provide indications that FAPI-PET/CT enables quantification of the tissue response in patients with fibrosing and chronic inflammatory diseases and can be used for patient stratification; however, further studies are essential for validation of the use of FAPI-PET/CT as a molecular imaging marker., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Sarcopenia has been reported to be associated with short-term outcomes after gastric endoscopic submucosal dissection (ESD). The "strength, assistance with walking, rising from a chair, climbing stairs, and falls" (SARC-F) questionnaire has been widely used as a screening tool for sarcopenia; however, SARC-F combined with body mass index and age (SARC-F+EBM) has recently been reported to be more useful than SARC-F alone. This study aimed to investigate the association between sarcopenia, measured using SARC-F+EBM, and short-term outcomes after gastric ESD., Methods: Patients who underwent gastric ESD at our institution between May 2020 and June 2023 were included, and their medical records were reviewed retrospectively. A SARC-F+EBM score ≥ 12 indicated sarcopenia. We evaluated the incidence of adverse events and the length of hospital stay in the sarcopenia and non-sarcopenia groups., Results: Overall, 263 patients (64 and 199 in the sarcopenia and non-sarcopenia groups, respectively) were investigated. The incidence of adverse events with a Common Terminology Criteria for Adverse Events grade ≥ 3 was not significantly different between the sarcopenia and non-sarcopenia groups (6.2% vs. 8.5%, p = 0.791). The proportion of patients with an extended hospital stay (≥ 10 days) was significantly higher in the sarcopenia group than that in the non-sarcopenia group (12.5% [8/64] vs. 3.5% [7/199], p = 0.012). Multivariate analysis showed that sarcopenia and lesions that present technical difficulty in ESD were independent risk factors for extended hospital stays (≥ 10 days). Of the eight cases having extended hospital stays in the sarcopenia group, four were due to the management after gastric ESD, three were due to family circumstances, and one was due to decreased activities of daily living., Conclusions: Sarcopenia is not a predictor of adverse events associated with gastric ESD. However, patients with sarcopenia may be hospitalized for longer owing to non-ESD-related factors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Calcium oxalate kidney stones, the most prevalent type of kidney stones, undergo a multi-step process of crystal nucleation, growth, aggregation, and secondary transition. The secondary transition has been rather overlooked, and thus, the effects on the disease and the underlying mechanism remain unclear. Here, we show, by periodic micro-CT images of human kidney stones in an ex vivo incubation experiment, that the growth of porous aggregates of calcium oxalate dihydrate (COD) crystals triggers the hardening of the kidney stones that causes difficulty in lithotripsy of kidney stone disease in the secondary transition. This hardening was caused by the internal nucleation and growth of precise calcium oxalate monohydrate (COM) crystals from isolated urine in which the calcium oxalate concentrations decreased by the growth of COD in closed grain boundaries of COD aggregate kidney stones. Reducing the calcium oxalate concentrations in urine is regarded as a typical approach for avoiding the recurrence. However, our results revealed that the decrease of the concentrations in closed microenvironments conversely promotes the transition of the COD aggregates into hard COM aggregates. We anticipate that the suppression of the secondary transition has the potential to manage the deterioration of kidney stone disease., (© 2024. The Author(s).)

Estrogen receptor (ER) expression in breast cancer can change during progression and the treatment, but the mechanism has not been well studied. In this study, we successfully prepared organoids from samples obtained from 33 luminal-type breast cancer patients and studied their ER expression. The expression status was well maintained in primary organoids, whereas it decreased after passaging in most of the cases. In fact, the studied organoid lines were classified into those that retained a high level of ER expression (9%), those that completely lost it (9%), and those that repressed it to varying degrees (82%). In some cases, the ER expression was suddenly and drastically decreased after passaging. Marker protein immunohistochemistry revealed that after passaging, the differentiation status shifted from a luminal- to a basal-like status. Differentially expressed genes suggested the activation of NOTCH signaling in the passaged organoids, wherein a NOTCH inhibitor was able to substantially rescue the decreased ER expression and alter the differentiation status. Our findings suggest that the differentiation status of luminal-type cancer cells is quite flexible, and that by inhibiting the NOTCH signaling we can preserve the differentiation status of luminal-type breast cancer organoids., (© 2023. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: According to the National Clinical Database of Japan, the incidence of bile duct injury (BDI) during laparoscopic cholecystectomy has hovered around 0.4% for the last 10 years and has not declined. On the other hand, it has been found that about 60% of BDI occurrences are due to misidentifying anatomical landmarks. However, the authors developed an artificial intelligence (AI) system that gave intraoperative data to recognize the extrahepatic bile duct (EHBD), cystic duct (CD), inferior border of liver S4 (S4), and Rouviere sulcus (RS). The purpose of this research was to evaluate how the AI system affects landmark identification., Methods: We prepared a 20-s intraoperative video before the serosal incision of Calot's triangle dissection and created a short video with landmarks overwritten by AI. The landmarks were defined as landmark (LM)-EHBD, LM-CD, LM-RS, and LM-S4. Four beginners and four experts were recruited as subjects. After viewing a 20-s intraoperative video, subjects annotated the LM-EHBD and LM-CD. Then, a short video is shown with the AI overwriting landmark instructions; if there is a change in each perspective, the annotation is changed. The subjects answered a three-point scale questionnaire to clarify whether the AI teaching data advanced their confidence in verifying the LM-RS and LM-S4. Four external evaluation committee members investigated the clinical importance., Results: In 43 of 160 (26.9%) images, the subjects transformed their annotations. Annotation changes were primarily observed in the gallbladder line of the LM-EHBD and LM-CD, and 70% of these shifts were considered safer changes. The AI-based teaching data encouraged both beginners and experts to affirm the LM-RS and LM-S4., Conclusion: The AI system provided significant awareness to beginners and experts and prompted them to identify anatomical landmarks linked to reducing BDI., (© 2023. The Author(s).)

Background: Heart failure is common and is associated with high rates of hospitalization. Home care support clinics/hospitals (HCSCs) and enhanced HCSCs were introduced in Japan in 2006 and 2012, respectively., Objective: This study aimed to examine the effect of post-discharge care by conventional or enhanced HCSCs on readmission, compared with general clinics., Design: Retrospective cohort study using the Japanese nationwide health insurance claims database., Participants: Participants were ≥65 years of age, admitted for heart failure and discharged between July 2014 and August 2015 and received a home visit within a month following the discharge (n=12,393)., Main Measures: The exposure was the type of medical facility that provides post-discharge home healthcare: general clinics, conventional HCSCs, and enhanced HCSCs. The primary outcome was all-cause readmission for 6 months after the first visit; the incidence of emergency house calls was a secondary outcome. We used a competing risk regression using the Fine and Gray method, in which death was regarded as a competing event., Key Results: At 6 months, readmissions were lower in conventional (38%) or enhanced HCSCs (38%) than general clinics (43%). The adjusted subdistribution hazard ratio (sHR) of readmission was 0.87 (95% CI: 0.78-0.96) for conventional and 0.86 (0.78-0.96) for enhanced HCSCs. Emergency house calls increased with conventional (sHR: 1.77, 95% CI:1.57-2.00) and enhanced HCSCs (sHR: 1.93, 95% CI: 1.71-2.17)., Conclusions: Older Japanese patients with heart failure receiving post-discharge home healthcare by conventional or enhanced HCSCs had lower readmission rates, possibly due to compensation with more emergency house calls. Conventional and enhanced HCSCs may be effective in reducing the risk of rehospitalization. Further studies are necessary to confirm the medical functions performed by HCSCs., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Since particle beam distribution is vulnerable to change in bowel gas because of its low density, we developed a deep neural network (DNN) for bowel gas segmentation on X-ray images. We used 6688 image datasets from 209 cases as training data, 736 image datasets from 23 cases as validation data and 102 image datasets from 51 cases as test data (total 283 cases). For the training data, we prepared three types of digitally reconstructed radiographic (DRR) images (all-density, bone and gas) by projecting the treatment planning CT image data. However, the real X-ray images acquired in the treatment room showed low contrast that interfered with manual delineation of bowel gas. Therefore, we used synthetic X-ray images converted from DRR images in addition to real X-ray images.We evaluated DNN segmentation accuracy for the synthetic X-ray images using Intersection over Union, recall, precision, and the Dice coefficient, which measured 0.708 ± 0.208, 0.832 ± 0.170, 0.799 ± 0.191, and 0.807 ± 0.178, respectively. The evaluation metrics for the real X-images were less accurate than those for the synthetic X-ray images (0.408 ± 0237, 0.685 ± 0.326, 0.490 ± 0272, and 0.534 ± 0.271, respectively). Computation time was 29.7 ± 1.3 ms/image. Our DNN appears useful in increasing treatment accuracy in particle beam therapy., (© 2023. Australasian College of Physical Scientists and Engineers in Medicine.)

Purpose: Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early gastric cancer. However, perforations may happen and cause peritonitis during ESD. Thus, there is a potential demand for a computer-aided diagnosis system to support physicians in ESD. This paper presents a method to detect and localize perforations from colonoscopy videos to avoid perforation ignoring or enlarging by ESD physicians., Method: We proposed a training method for YOLOv3 by using GIoU and Gaussian affinity losses for perforation detection and localization in colonoscopic images. In this method, the object functional contains the generalized intersection over Union loss and Gaussian affinity loss. We propose a training method for the architecture of YOLOv3 with the presented loss functional to detect and localize perforations precisely., Results: To qualitatively and quantitatively evaluate the presented method, we created a dataset from 49 ESD videos. The results of the presented method on our dataset revealed a state-of-the-art performance of perforation detection and localization, which achieved 0.881 accuracy, 0.869 AUC, and 0.879 mean average precision. Furthermore, the presented method is able to detect a newly appeared perforation in 0.1 s., Conclusions: The experimental results demonstrated that YOLOv3 trained by the presented loss functional were very effective in perforation detection and localization. The presented method can quickly and precisely remind physicians of perforation happening in ESD. We believe a future CAD system can be constructed for clinical applications with the proposed method., (© 2023. CARS.)

Purpose: Precise polyp detection and localisation are essential for colonoscopy diagnosis. Statistical machine learning with a large-scale data set can contribute to the construction of a computer-aided diagnosis system for the prevention of overlooking and miss-localisation of a polyp in colonoscopy. We propose new visual explaining methods for a well-trained object detector, which achieves fast and accurate polyp detection with a bounding box towards a precise automated polyp localisation., Method: We refine gradient-weighted class activation mapping for more accurate highlighting of important patterns in processing a convolutional neural network. Extending the refined mapping into multiscaled processing, we define object activation mapping that highlights important object patterns in an image for a detection task. Finally, we define polyp activation mapping to achieve precise polyp localisation by integrating adaptive local thresholding into object activation mapping. We experimentally evaluate the proposed visual explaining methods with four publicly available databases., Results: The refined mapping visualises important patterns in each convolutional layer more accurately than the original gradient-weighted class activation mapping. The object activation mapping clearly visualises important patterns in colonoscopic images for polyp detection. The polyp activation mapping localises the detected polyps in ETIS-Larib, CVC-Clinic and Kvasir-SEG database with mean Dice scores of 0.76, 0.72 and 0.72, respectively., Conclusions: We developed new visual explaining methods for a convolutional neural network by refining and extending gradient-weighted class activation mapping. Experimental results demonstrated the validity of the proposed methods by showing that accurate visualisation of important patterns and localisation of polyps in a colonoscopic image. The proposed visual explaining methods are useful for the interpreting and applying a trained polyp detector., (© 2022. CARS.)

ABCC10/MRP7, an ATP-binding cassette (ABC) transporter, has been implicated in the extracellular transport of taxanes. Our group reported that the ABCC10 single nucleotide polymorphism (SNPs), rs2125739, influences docetaxel cytotoxicity in lung cancer cell lines as well as its side effects in clinical practice. In this study, we investigated whether the rs2125739 variant could affect paclitaxel (PTX) cytotoxicity in lung cancer cell lines. We also investigated the effect of rs2125739 on the efficacy and safety of nanoparticle albumin-bound PTX (nab-PTX) in clinical practice. The association between rs2125739 genotypes and the 50% inhibitory concentration (IC 50 ) of PTX was investigated in 18 non-small cell lung cancer (NSCLC) cell lines, HeLa cells, and genome-edited HeLa cells. Next, blood samples from 77 patients with NSCLC treated with carboplatin plus nab-PTX were collected and analyzed for six SNPs, including rs2125739. The clinical outcomes among the different genotype groups were evaluated. In NSCLC cell lines, HeLa cells, and genome-edited HeLa cells, the IC 50 was significantly higher in the ABCC10 rs2125739 T/T group than in the T/C and C/C groups. In 77 patients with NSCLC, there were no significant differences in clinical outcomes between the T/T and T/C groups. However, the rs2125739 T/T genotype was associated with a higher frequency of Grades 3/4 neutropenia. In contrast, there was no association between other SNPs and clinical efficacy or neutropenia. Our results indicate that the ABCC10 rs2125739 variant is associated with neutropenia in response to nab-PTX treatment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The standard treatment for unresectable advanced/recurrent esophageal cancer in Japan is 5-fluorouracil plus platinum-containing drugs as first-line chemotherapy and taxanes as second-line chemotherapy. However, the standard regimen after patients become refractory to these treatments remains to be established. Therefore, we investigated the efficacy of trifluridine/tipiracil (FTD/TPI) in patients with esophageal cancer who are refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes., Methods: This single-arm phase II trial was conducted in seven hospitals in Japan. Eligible patients were those with unresectable advanced/recurrent esophageal cancer that was refractory or intolerant to 5-fluorouracil, platinum-containing drugs, and taxanes. The primary endpoint was the 3-month progression-free survival rate, and the secondary endpoints were the 6-month progression-free survival rate, progression-free survival, overall survival, response rate, disease control rate, and toxicity., Results: Forty-two patients were enrolled between October 2015 and June 2016. All tumors were squamous cell carcinomas. The progression-free survival rates at 3 and 6 months were 15.4% (90% confidence interval 7.4-26.0%) and 7.7% (90% confidence interval 2.6-16.6%), respectively. The median progression-free survival and median overall survival were 1.3 (95% confidence interval 1.0-1.8) months and 4.5 (95% confidence interval 3.6-5.7) months, respectively. The response rate was 0%, and the disease control rate was 23.8% (95% confidence interval 13.5-38.5%). The major grade 3/4 toxicities were neutropenia (47.6%), leukocytopenia (35.7%), and anemia (21.4%). No treatment-related deaths occurred. Exploratory subgroup analyses showed better progression-free survival in the subgroup without distant metastasis at diagnosis., Conclusions: Trifluridine/tipiracil monotherapy is feasible and shows modest activity in patients with refractory esophageal squamous cell carcinoma., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Using the nationwide health insurance claims database in Japan, we estimated total annual medical expenditures for fragility hip fracture across the population at 329.2 billion yen (2.99 billion US dollars). Long-term care expenditures were not included. Fragility hip fracture imposes a considerable health economic burden on society in Japan., Purpose: Fragility hip fracture imposes a substantial health economic burden on society globally. We aimed to estimate medical expenditures for fragility hip fracture using the nationwide health insurance claims database in Japan., Methods: We included adults aged 60 and over without prior hip fracture who were admitted for fragility hip fracture (i.e., femoral neck or extracapsular) between October 2014 and October 2015 (13 months). Fragility hip fracture was identified through newly assigned disease codes for fracture and procedure codes associated with the fracture. As a proxy for medical expenditures per patient, incremental payments were calculated (i.e., the difference between the total payments 6 months before and after fragility hip fracture). The total payments included health insurance reimbursements and copayments for inpatient and outpatient services. Long-term care expenditures were not included in this study., Results: We identified 142,361 individuals (28,868 male and 113,493 female) with fragility hip fracture. Mean medical expenditures for fragility hip fracture per patient were 2,550,000 yen (¥) (23,180 US dollars [$]; ¥110 = $1) in male and ¥2,494,000 ($22,670) in female patients, respectively. Total annual medical expenditures for fragility hip fracture across the population were 329.2 billion yen (2.99 billion US dollars): 67.96 billion yen (620 million US dollars) in male and 261.24 billion yen (2.37 billion US dollars) in female patients, respectively., Conclusion: This is the first study to estimate medical expenditures for hip fracture using the nationwide health insurance claims database, which represents almost all health insurance claims in Japan. Fragility hip fracture inflicts a considerable health economic burden on society in Japan., (© 2022. The Author(s).)

Background: Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies., Methods: Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib., Results: Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (C max and AUC) after single and multiple dosing was slightly higher proportionally with talazoparib 1 mg than talazoparib 0.75 mg. The overall disease control rate was 44.4%, including 2 patients with stable disease. The recommended phase 2 dose of talazoparib was established as 1 mg once daily., Conclusions: Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017)., (© 2021. The Author(s).)

Purpose: The size information of detected polyps is an essential factor for diagnosis in colon cancer screening. For example, adenomas and sessile serrated polyps that are [Formula: see text] mm are considered advanced, and shorter surveillance intervals are recommended for smaller polyps. However, sometimes the subjective estimations of endoscopists are incorrect and overestimate the sizes. To circumvent these difficulties, we developed a method for automatic binary polyp-size classification between two polyp sizes: from 1 to 9 mm and [Formula: see text] mm., Method: We introduce a binary polyp-size classification method that estimates a polyp's three-dimensional spatial information. This estimation is comprised of polyp localisation and depth estimation. The combination of location and depth information expresses a polyp's three-dimensional shape. In experiments, we quantitatively and qualitatively evaluate the proposed method using 787 polyps of both protruded and flat types., Results: The proposed method's best classification accuracy outperformed the fine-tuned state-of-the-art image classification methods. Post-processing of sequential voting increased the classification accuracy and achieved classification accuracy of 0.81 and 0.88 for polyps ranging from 1 to 9 mm and others that are [Formula: see text] mm. Qualitative analysis revealed the importance of polyp localisation even in polyp-size classification., Conclusions: We developed a binary polyp-size classification method by utilising the estimated three-dimensional shape of a polyp. Experiments demonstrated accurate classification for both protruded- and flat-type polyps, even though the flat type have ambiguous boundary between a polyp and colon wall., (© 2021. CARS.)

Purpose: Early detection of pancreatic ductal adenocarcinoma (PDAC) may improve the prognosis. We evaluated novel imaging findings that may contribute to early detection., Methods: This single-center, retrospective study enrolled 37 patients with a localized main pancreatic duct (MPD) stricture and no obvious pancreatic mass. All patients underwent endoscopic retrograde cholangiopancreatography and brush sampling with cytology and serial pancreatic juice aspiration cytologic examination via endoscopic naso-pancreatic drainage. Patients with cytology-confirmed malignancy underwent surgical resection. The remaining patients were followed by contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI), and endoscopic retrograde cholangiopancreatography., Results: Twenty patients had confirmed malignancy (cancer group) and 17 did not (non-cancer group). Age, MPD stricture location, and PDAC risk factors were similar, but the sex predominance and symptom rate differed between the two groups. In the cancer group, 17 patients were diagnosed by cytology and three by clinical symptoms. CECT, MRI, and endoscopic ultrasonography (EUS) revealed no solid tumors in either group. CECT revealed no significant differences between groups. Diffusion-weighted MRI revealed significant differences in the signal intensity between groups. EUS detected indistinct and small hypoechoic areas in 70% and 41.2% of patients in the cancer and non-cancer groups, respectively. In the cancer group, 11 were diagnosed with cancer at the first indication, and nine were diagnosed at follow-up; the prognosis did not differ between these two subgroups.ss CONCLUSIONS: High signal intensity in diffusion-weighted MRI may be useful for detecting early-stage PDAC and may be an indication for surgical resection even without pathologic confirmation., Clinical Trial Registration: The study was a registered at the University Hospital Medical Information Network (UMIN000039623)., (© 2021. The Author(s).)

Purpose: A three-dimensional (3D) structure extraction technique viewed from a two-dimensional image is essential for the development of a computer-aided diagnosis (CAD) system for colonoscopy. However, a straightforward application of existing depth-estimation methods to colonoscopic images is impossible or inappropriate due to several limitations of colonoscopes. In particular, the absence of ground-truth depth for colonoscopic images hinders the application of supervised machine learning methods. To circumvent these difficulties, we developed an unsupervised and accurate depth-estimation method., Method: We propose a novel unsupervised depth-estimation method by introducing a Lambertian-reflection model as an auxiliary task to domain translation between real and virtual colonoscopic images. This auxiliary task contributes to accurate depth estimation by maintaining the Lambertian-reflection assumption. In our experiments, we qualitatively evaluate the proposed method by comparing it with state-of-the-art unsupervised methods. Furthermore, we present two quantitative evaluations of the proposed method using a measuring device, as well as a new 3D reconstruction technique and measured polyp sizes., Results: Our proposed method achieved accurate depth estimation with an average estimation error of less than 1 mm for regions close to the colonoscope in both of two types of quantitative evaluations. Qualitative evaluation showed that the introduced auxiliary task reduces the effects of specular reflections and colon wall textures on depth estimation and our proposed method achieved smooth depth estimation without noise, thus validating the proposed method., Conclusions: We developed an accurate depth-estimation method with a new type of unsupervised domain translation with the auxiliary task. This method is useful for analysis of colonoscopic images and for the development of a CAD system since it can extract accurate 3D information.

Purpose: Sleep-disordered breathing (SDB) is associated with hypertension, poor glycemic control and dyslipidemia. Usually, apnoea events tend to be more prominent during rapid eye movement (REM) sleep than non-REM (NREM) sleep. We examined which SDB parameters are associated with blood pressure (BP), HbA1c and lipid profile in patients with type 2 diabetes (T2D)., Methods: A total of 185 patients with T2D who underwent polysomnography were analysed. Exclusion criteria were: the presence of pulmonary diseases, central sleep apnoea, treated SDB, or REM sleep < 30 min. To predict BP, HbA1c, and lipid profiles, we performed multiple linear regression analyses adjusted for known risk factors. Subsequently, we performed multivariable logistic regression analyses., Results: Patient characteristics (mean ± standard deviation/median) were as follows: age 58.0 ± 11.8 years, body mass index 26.0 kg/m2 (24.1-28.9 kg/m2 ), systolic BP 134 ± 19 mmHg, mean BP 98 ± 14 mmHg, HbA1c 7.4% (6.8-8.4%), triglyceride 143 mg/dL (97-195 mg/dL), non-high density lipoprotein (non-HDL) cholesterol 143 mg/dL (120-163 mg/dL), REM-apnoea-hypopnea index (AHI) 35.1/h (21.1-53.1/h). The analyses revealed that REM-AHI was independently associated with systolic and mean BP, whereas NREM-AHI was not. A statistically significant association was not observed between REM-AHI and HbA1c or lipid profile., Conclusion: In patients with T2D, REM-AHI was associated with systolic and mean BP. The alteration of BP, associated with SDB during REM sleep, may be an important pathophysiological link between SDB and cardiovascular diseases.

Purpose: An endocytoscope is a new type of endoscope that enables users to perform conventional endoscopic observation and ultramagnified observation at the cell level. Although endocytoscopy is expected to improve the cost-effectiveness of colonoscopy, endocytoscopic image diagnosis requires much knowledge and high-level experience for physicians. To circumvent this difficulty, we developed a robust endocytoscopic (EC) image classification method for the construction of a computer-aided diagnosis (CAD) system, since real-time CAD can resolve accuracy issues and reduce interobserver variability., Method: We propose a novel feature extraction method by introducing higher-order symmetric tensor analysis to the computation of multi-scale topological statistics on an image, and we integrate this feature extraction with EC image classification. We experimentally evaluate the classification accuracy of our proposed method by comparing it with three deep learning methods. We conducted this comparison by using our large-scale multi-hospital dataset of about 55,000 images of over 3800 patients., Results: Our proposed method achieved an average 90% classification accuracy for all the images in four hospitals even though the best deep learning method achieved 95% classification accuracy for images in only one hospital. In the case with a rejection option, the proposed method achieved expert-level accurate classification. These results demonstrate the robustness of our proposed method against pit pattern variations, including differences of colours, contrasts, shapes, and hospitals., Conclusions: We developed a robust EC image classification method with novel feature extraction. This method is useful for the construction of a practical CAD system, since it has sufficient generalisation ability.

Purpose: CD81 is a member of the tetraspanin family of membrane proteins. Recently, it has been shown that CD81 may be involved in cancer cell proliferation and metastasis. As yet, however, there have been few reports on the expression and role of CD81 in osteosarcoma., Methods: The expression of CD81 was investigated in human osteoblast cell line hFOB1.19 and in human osteosarcoma cell lines Saos2, MG63 and 143B. The expression of CD81 was inhibited in osteosarcoma cells using siRNA after which cell proliferation, migration and invasion were assessed. We also used Western blotting to investigate the phosphorylation status of Akt, Erk, JNK and p38, and measured the expression of MMP-2, MMP-9 and MT1-MMP. In addition, we used a CRISPR/Cas9 system to stably knock out CD81 expression in 143B cells, transplanted the cells into mice, and assessed tumor formation and lung metastasis in these mice compared to those in the control group., Results: We found that CD81 was expressed in the human osteoblast cell line and in all osteosarcoma cell lines tested. The osteosarcoma cell line 143B exhibited a particularly high level of expression. In addition, we found that osteosarcoma cell proliferation, migration and invasion were decreased after CD81 inhibition, and that the phosphorylation of Akt and Erk was suppressed. Also, the expression levels of MMP-2, MMP-9 and MT1-MMP were found to be suppressed, with MMP-9 showing the greatest suppression. In vivo, we found that mice transplanted with CD81 knockout 143B cells exhibited significantly less tumor formation and lung metastasis than mice in the control group., Conclusion: Based on our findings we conclude that inhibition of CD81 suppresses intracellular signaling and reduces tumorigenesis and lung metastasis in osteosarcoma cells.

In the published article, the Fig. 4a was published incorrectly.

Fibrillin microfibrils are ubiquitous elements of extracellular matrix assemblies that play crucial roles in regulating the bioavailability of growth factors of the transforming growth factor beta superfamily. Recently, several "a disintegrin and metalloproteinase with thrombospondin motifs" (ADAMTS) proteins were shown to regulate fibrillin microfibril function. Among them, ADAMTS17 is the causative gene of Weill-Marchesani syndrome (WMS) and Weill-Marchesani-like syndrome, of which common symptoms are ectopia lentis and short stature. ADAMTS17 has also been linked to height variation in humans; however, the molecular mechanisms whereby ADAMTS17 regulates skeletal growth remain unknown. Here, we generated Adamts17-/- mice to examine the role of Adamts17 in skeletogenesis. Adamts17-/- mice recapitulated WMS, showing shorter long bones, brachydactyly, and thick skin. The hypertrophic zone of the growth plate in Adamts17-/- mice was shortened, with enhanced fibrillin-2 deposition, suggesting increased incorporation of fibrillin-2 into microfibrils. Comprehensive gene expression analysis of growth plates using laser microdissection and RNA sequencing indicated alteration of the bone morphogenetic protein (BMP) signaling pathway after Adamts17 knockout. Consistent with this, phospho-Smad1 levels were downregulated in the hypertrophic zone of the growth plate and in Adamts17-/- primary chondrocytes. Delayed terminal differentiation of Adamts17-/- chondrocytes, observed both in primary chondrocyte and primordial metatarsal cultures, and was prevented by BMP treatment. Our data indicated that Adamts17 is involved in skeletal formation by modulating BMP-Smad1/5/8 pathway, possibly through inhibiting the incorporation of fibrillin-2 into microfibrils. Our findings will contribute to further understanding of disease mechanisms and will facilitate the development of therapeutic interventions for WMS.

Purpose: To evaluate the diagnostic performance of superparamagnetic iron-oxide (SPIO)-enhanced diffusion-weighted image (DWI) for distinguishing an intrapancreatic accessory spleen from pancreatic tumors., Materials and Methods: Twenty-six cases of intrapancreatic accessory spleen and nine cases of pancreatic tail tumors [neuroendocrine tumor (n = 8) and pancreatic adenocarcinoma (n = 1)] were analyzed. Two blind reviewers retrospectively reviewed the SPIO-enhanced magnetic resonance imaging (MRI) scans. The lesion visibility grades were compared and the diagnostic performance of SPIO-enhanced DWI was compared to those of SPIO-enhanced T2WI and T2*WI with the use of a receiver operating characteristic (ROC) analysis., Results: The grade of lesion visibility was the highest on DWI [mean ± standard deviation (SD): 2.8 ± 0.3] followed by T2WI (2.3 ± 0.7, p < 0.001) and T2*WI (2.1 ± 0.7, p < 0.0001). Reviewers 1 and 2 correctly characterized the presence or absence of SPIO uptake in 34 of 35 cases (97.1%) on DWI, 24 (68.6%) and 25 (71.4%) cases on T2WI, respectively, and 16 (45.7%) and 17 (48.6%) cases on T2*WI. The area under the ROC curve (AUC) of DWI was 0.974 and 0.989 for reviewers 1 and 2, respectively. For Reviewer 1, the AUC of DWI was significantly higher than that of T2*WI (0.756, p < 0.01), although it was not significantly different from that of T2WI (0.868, p = 0.0857). For Reviewer 2, the AUC of DWI was significantly higher than those of T2WI (0.846, p < 0.05) and T2*WI (0.803, p < 0.01)., Conclusion: The diagnostic performance of SPIO-enhanced DWI was better than those of SPIO-enhanced T2*WI and T2WI for the diagnosis of intrapancreatic accessory spleen.

Background: Hepatocyte nuclear factor 1β (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan., Methods: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted., Results: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m 2 ; p = 0.0091)., Conclusion: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm because of difficulties in early detection. Several studies have recently suggested that exosomes may have potential as novel biomarkers. This study aimed to isolate exosomes from pancreatic juice and to investigate whether exosomal microRNAs (ex-miRs) could be used as biomarkers for PDAC., Methods: Pancreatic juice was collected from patients with PDAC and chronic pancreatitis (CP) by endoscopic retrograde pancreatography. Exosomes were extracted by ultracentrifugation. The presence of exosomes was confirmed by electron microscopy and Western blotting using anti-CD63, -CD81, and -TSG101 antibodies. Relative levels of ex-miR-21 and ex-miR-155 were quantified and compared between PDAC and CP patients., Results: A total of 35 pancreatic juice samples (27 PDAC and 8 CP) were collected. Relative levels of both ex-miR-21 and ex-miR-155 were significantly higher in PDAC patients compared with CP patients (p < 0.001 and p = 0.008, respectively). By contrast, no significant difference was apparent in relative levels of miR-21 and miR-155 in whole pancreatic juice from PDAC patients compared with CP patients (p = 0.08 and p = 0.61, respectively). Ex-miR-21 and ex-miR-155 levels discriminated PDAC patients from CP patients with area under the curve values of 0.90 and 0.89, respectively. The accuracies of ex-miR-21 levels, ex-miR-155 levels, and pancreatic juice cytology were 83%, 89%, and 74%, respectively. When combining the results of ex-miR profiling with pancreatic juice cytology, the accuracy was improved to 91%., Conclusions: We successfully extracted exosomes from pancreatic juice. Ex-miRs, including ex-miR-21 and ex-miR-155, in pancreatic juice may be developed as biomarkers for PDAC.

Purpose: To determine whether functional near-infrared spectroscopy (fNIRS) allows monitoring fatigue in radiologists during prolonged image interpretation., Materials and Methods: Nine radiologists participated as subjects in the present study and continuously interpreted medical images and generated reports for cases for more than 4 h under real clinical work conditions. We measured changes in oxygenated hemoglobin concentrations [oxy-Hb] in the prefrontal cortex using 16-channel fNIRS (OEG16ME, Spectratech) every hour during the Stroop task to evaluate fatigue of radiologists and recorded fatigue scale (FS) as a behavior data., Results: Two subjects showed a subjective feeling of fatigue and an apparent decrease in brain activity after 4 h, so the experiment was completed in 4 h. The remaining seven subjects continued the experiment up to 5 h. FS decreased with time, and a significant reduction was observed between before and the end of image interpretation. Seven out of nine subjects showed a minimum [oxy-Hb] change at the end of prolonged image interpretation. The mean change of [oxy-Hb] at the end of all nine subjects was significantly less than the maximum during image interpretation., Conclusion: fNIRS using the change of [oxy-Hb] may be useful for monitoring fatigue in radiologists during image interpretation.

Generalized-ensemble algorithms are powerful techniques for investigating biomolecules such as protein, DNA, lipid membrane, and glycan. The generalized-ensemble algorithms were originally developed in the canonical ensemble. On the other hand, not only temperature but also pressure is controlled in experiments. Additionally, pressure is used as perturbation to study relationship between function and structure of biomolecules. For this reason, it is important to perform efficient conformation sampling based on the isothermal-isobaric ensemble. In this article, we review a series of the generalized-ensemble algorithms in the isothermal-isobaric ensemble: multibaric-multithermal, pressure- and temperature-simulated tempering, replica-exchange, and replica-permutation methods. These methods achieve more efficient simulation than the conventional isothermal-isobaric simulation. Furthermore, the isothermal-isobaric generalized-ensemble simulation samples conformations of biomolecules from wider range of temperature and pressure. Thus, we can estimate physical quantities more accurately at any temperature and pressure values. The applications to the biomolecular system are also presented.

Background: Accumulation of evidence suggests that neoadjuvant chemotherapy improves the outcomes of borderline resectable pancreatic cancer (BRPC). Gemcitabine plus nab-paclitaxel (GnP) has been widely accepted as systemic chemotherapy for unresectable pancreatic cancer and reportedly results in remarkable tumor shrinkage. This study was performed to evaluate the safety and efficacy of neoadjuvant chemotherapy using neoadjuvant GnP for BRPC., Methods: The medical records of 57 patients who underwent treatment of BRPC from 2010 to 2017 were retrospectively reviewed. The patient characteristics and short- and intermediate-term outcomes were compared between the GnP and upfront surgery (UFS) groups., Results: The GnP group comprised 31 patients and the UFS group comprised 26 patients. The patient characteristics were comparable with the exception of a higher prevalence of arterial involvement in the GnP group. Twenty-seven of the 31 patients (87%) in the GnP group and all 26 patients in the UFS group underwent resection. The GnP group showed a significantly shorter operation time (429 vs. 509.5 min, p = 0.0068), less blood loss (760 vs. 1324 ml, p = 0.0115), and a higher R0 resection rate (100% vs. 77%, p = 0.0100) than the UFS group. Postoperative complications and hospital stay were comparable between the two groups, and no treatment-related mortality occurred in either group. Both the disease-free survival and overall survival times were significantly longer in the GnP group (p = 0.0018 and p = 0.0024, respectively)., Conclusions: Neoadjuvant GnP is a safe and effective treatment strategy for BRPC. It potentially improves patients' prognosis and facilitates surgical procedures.

Purpose: To evaluate whether quantitative analysis of perfusion contrast-enhanced ultrasound (CE-US) could predict early lymph-node (LN) metastasis in clinically node-negative breast cancer., Materials and Methods: In this prospective study, 64 breast cancer patients were selected for perfusion CE-US imaging. Regions of interest were placed where the strongest and weakest signal increases were found to obtain peak intensities (PIs; PI max and PI min , respectively) for time-intensity curve analyzes. The PI difference and PI ratio were calculated as follows: PI difference = PI max -PI min ; PI ratio = PI max /PI min ., Results: Forty-seven cases were histologically diagnosed as negative for LN metastasis and 17 were positive. There was a significant difference in PI min and the PI ratio between the LN-negative and -positive metastasis groups (p = 0.0053 and 0.0082, respectively). Receiver-operating curve analysis revealed that the area under the curve of PI min and the PI ratio were 0.73 and 0.72, respectively. The most effective threshold for the PI ratio was 1.52, and the sensitivity, specificity, positive predictive value, and negative predictive value were 59% (10/17), 87% (41/47), 63% (10/16), and 85% (41/48), respectively., Conclusions: Parameters from the quantitative analysis of perfusion CE-US imaging showed significant differences between the LN-negative and -positive metastasis groups in clinically node-negative breast cancer.

Background: Preoperative nutritional and immunological patient factors have been found to be associated with prognostic outcomes of malignant tumors; however, the clinical significance of these factors in pancreatic ductal adenocarcinoma (PDAC) remains controversial., Objective: The aim of this study was to evaluate the prognostic value of nutritional and immunological factors in predicting survival of patients with PDAC., Methods: Retrospective studies of 329 patients who underwent surgical resection for PDAC and 95 patients who underwent palliative surgery were separately conducted to investigate the prognostic impact of tumor-related factors and patient-related factors, including Glasgow Prognostic Score (GPS), modified GPS, Prognostic Nutritional Index (PNI), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, and lymphocyte/monocyte ratio., Results: In multivariate analysis for patients with surgical resection for PDAC, PNI was an independent factor for overall survival (OS) and disease-free survival. The median OS of patients with PNI ≤ 45 was significantly shorter than that of patients with PNI > 45 (17.5 and 36.2 months, respectively; p < 0.001). In multivariate analysis for patients undergoing palliative surgery for PDAC, only NLR was an independent prognosis factor. The median OS of patients with NLR > 5 was significantly shorter than that of patients with NLR ≤ 5 (2.7 and 8.9 months, respectively; p < 0.001)., Conclusions: PNI in patients with surgical resection and NLR in patients with palliative surgery for PDAC may be useful prognostic factors.

Background: Precise understanding of kidney disease activity is needed to design therapeutic strategies. CD147/basigin is involved in the pathogenesis of acute kidney injury and renal fibrosis through inflammatory cell infiltration. The present study examined the clinical relevance of CD147 in biopsy-proven kidney diseases that lead to the progression of chronic kidney disease., Methods: Kidney biopsy specimens and plasma and urine samples were obtained from patients with kidney diseases, including IgA nephropathy (IgAN), Henoch-Schönlein purpura nephritis (HSPN), diabetic kidney disease (DKD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), who underwent renal biopsy between 2011 and 2014. Plasma and urinary CD147 levels were measured and evaluated for their ability to reflect histological features. Disease activity of IgAN tissues was evaluated according to the Oxford classification and the Japanese histological grading system., Results: In biopsy tissues, CD147 induction was detected in injured lesions representing renal inflammation. Plasma CD147 values correlated with eGFR in patients with inflammation-related kidney diseases such as IgAN, HSPN, and DKD. Particularly in IgAN patients, plasma CD147 levels were correlated with injured regions comprising more than 50% of glomeruli or with tubular atrophy/interstitial injury in biopsy tissues. Proteinuria showed a closer correlation with urinary values of CD147 and L-FABP. Of note, plasma and urinary CD147 levels showed a strong correlation with eGFR or proteinuria, respectively, only in DKD patients., Conclusion: Evaluation of plasma and urinary CD147 levels might provide key insights for the understanding of the activity of various kidney diseases.

Ganoderma lingzhi is a traditional medicinal mushroom, and its extract contains many bioactive compounds. Triterpenoids and polysaccharides are the primary bioactive components that contribute to its medicinal properties. In this study, we quantified 18 triterpenoids, total triterpenoid content and total polysaccharide content in the ethanol and water extracts of G. lingzhi at different growth stages. Triterpenoids were quantified by liquid chromatograph-tandem mass spectrometry in the multiple-reaction-monitoring mode. Total triterpenoid and total polysaccharide content were determined by colorimetric analysis. The results indicated that the fruit bodies at an early growth stage had a higher content of ganoderic acid A, C2, I and LM2, as well as of ganoderenic acid C and D, than those at a later growth stage. In contrast, ganoderic acid K, TN and T-Q contents were higher in mature fruit bodies (maturation stage). The highest total triterpenoid and total polysaccharide contents were found in fruit bodies before maturity (stipe elongation stage or early stage of pileus formation). Our results provide information which will contribute to the establishment of an efficient cultivation system for G. lingzhi with a higher content of triterpenoids.

Using the Short Form 12 Health Survey this cross-sectional study examined parental well-being in caregivers of children with one of three genetic disorders associated with intellectual disability; Down syndrome, Rett syndrome and the CDKL5 disorder. Data were sourced from the Western Australian Down Syndrome (n = 291), Australian Rett Syndrome (n = 187) and International CDKL5 Disorder (n = 168) Databases. Among 596 mothers (median age, years 43.7; 24.6-72.2), emotional well-being was poorer than general female populations across age groups. Multivariate linear regression identified the poorest well-being in parents of children with the CDKL5 disorder, a rare but severe and complex encephalopathy, and negative associations with increased clinical severity irrespective of diagnosis. These findings are important for those providing healthcare and social services for these populations.

We investigated the depth profiles of radioactive Cs, ignition loss, and cation exchange capacity (CEC) in five types of forest soils sampled using scraper plates. We then simulated the monitored depth profiles in a compartment model, taking ignition loss as a parameter based on experimental results showing a positive correlation between ignition loss and the CEC. The calculated values were comparable with the monitored values, though some discrepancy was observed in the middle of the soil layer. Based on decontamination data on the surface dose rate and surface contamination concentration, we newly defined a surface residual index (SRI) to evaluate the residual radioactive Cs on surfaces. The SRI value tended to gradually decrease in forests and unpaved roads and was much smaller in forests and on unpaved roads than on paved roads. The radioactive Cs was assumed to have already infiltrated underground 18 months after the nuclear power plant accident, and the sinking was assumed to be ongoing. The SRI values measured on paved roads suggested that radioactive Cs remained on the surfaces, though a gradual infiltration was observed towards the end of the monitoring term. The SRI value is thought to be effective in grasping the rough condition of residual radioactive Cs quickly at sites of decontamination activity in the field. The SRI value may be serviceable for actual contamination works after further research is done to elucidate points such as the relation between the SRI and the infiltration of radioactive Cs in various types of objects.

Introduction: Atherosclerotic diseases are the leading cause of death worldwide. Biomarkers of atherosclerosis are required to monitor and prevent disease progression. While mass spectrometry is a promising technique to search for such biomarkers, its clinical application is hampered by the laborious processes for sample preparation and analysis., Methods: We developed a rapid method to detect plasma metabolites by probe electrospray ionization mass spectrometry (PESI-MS), which employs an ambient ionization technique enabling atmospheric pressure rapid mass spectrometry. To create an automatic diagnosis system of atherosclerotic disorders, we applied machine learning techniques to the obtained spectra., Results: Using our system, we successfully discriminated between rabbits with and without dyslipidemia. The causes of dyslipidemia (genetic lipoprotein receptor deficiency or dietary cholesterol overload) were also distinguishable by this method. Furthermore, after induction of atherosclerosis in rabbits with a cholesterol-rich diet, we were able to detect dynamic changes in plasma metabolites. The major metabolites detected by PESI-MS included cholesterol sulfate and a phospholipid (PE18:0/20:4), which are promising new biomarkers of atherosclerosis., Conclusion: We developed a remarkably fast and easy method to detect potential new biomarkers of atherosclerosis in plasma using PESI-MS.

Background: This prospective multicenter phase 2 study aimed to evaluate the feasibility and efficacy of neoadjuvant chemotherapy (NAC) without radiotherapy for locally advanced rectal cancer (LARC)., Methods: Patients with LARC (cStage II and III) were included in the study. Those with cT4b tumor were excluded. Six cycles of modified FOLFOX6 (mFOLFOX6) plus either bevacizumab or cetuximab, depending on KRAS status, were administered before surgery. The primary end point of the study was the R0 resection rate. The secondary end points were adverse effect, rate of NAC completion, postoperative complications, and pathologic complete response (pCR) rate., Results: The study enrolled 60 patients from eight institutions. For the study, mFOLFOX6 was administered with cetuximab to 40 patients who had wild-type KRAS and with bevacizumab to 20 patients who had KRAS mutations. The completion rate for NAC was 88.4%. Sphincter-preserving surgery was performed for 43 patients and abdominoperineal resection for 17 patients. The median operation time was 335 min, and the median blood loss was 40 g. The R0 resection rate was 98.3%, and the pCR rate was 16.7%. The overall postoperative complication rate (≥grade 2) was 21.7%. The complications included anastomotic leakage (11.6%), surgical-site infection (6.7%), and urinary dysfunction (3.3%). The patients with wild-type KRAS did not differ significantly from those with KRAS mutations in terms of response rate, postoperative complication rate, and pCR rate., Conclusion: The findings show that NAC is a feasible and promising treatment option for LARC (This study is registered with UMIN-CTR, UMIN000005654).

Although advances in chemotherapy have improved the prognosis for osteosarcoma, some patients do not respond sufficiently to treatment. Heat shock protein 70 (Hsp70) is expressed at high levels in cancer cells and attenuates the therapeutic efficacy of anticancer agents, resulting in a poorer prognosis. This study investigated whether small interfering RNA (siRNA)-mediated inhibition of Hsp70 expression in an osteosarcoma cell line would enhance sensitivity to cisplatin. The expression of Hsp70 with cisplatin treatment was observed by using Western blotting and real-time reverse transcription polymerase chain reaction (RT-PCR). Changes in the IC 50 of cisplatin when Hsp70 was inhibited by siRNA were evaluated. Cisplatin's effectiveness in inducing apoptosis was assessed by assay of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), caspase-3 activity, and mitochondrial membrane potential. Up-regulation of Hsp70 expression was dependent on the concentration of cisplatin. Inhibition of Hsp70 expression significantly reduced the IC 50 of cisplatin. When cisplatin was added to osteosarcoma cells with Hsp70 expression inhibited, a significant increase in apoptosis was demonstrated in TUNEL, caspase-3, and mitochondrial membrane potential assays. Inhibition of Hsp70 expression induced apoptosis in cultured osteosarcoma cells, indicating that Hsp70 inhibition enhanced sensitivity to cisplatin. Inhibition of Hsp70 expression may provide a new adjuvant therapy for osteosarcoma.

Purpose: Real-time characterization of colorectal lesions during colonoscopy is important for reducing medical costs, given that the need for a pathological diagnosis can be omitted if the accuracy of the diagnostic modality is sufficiently high. However, it is sometimes difficult for community-based gastroenterologists to achieve the required level of diagnostic accuracy. In this regard, we developed a computer-aided diagnosis (CAD) system based on endocytoscopy (EC) to evaluate cellular, glandular, and vessel structure atypia in vivo. The purpose of this study was to compare the diagnostic ability and efficacy of this CAD system with the performances of human expert and trainee endoscopists., Methods: We developed a CAD system based on EC with narrow-band imaging that allowed microvascular evaluation without dye (ECV-CAD). The CAD algorithm was programmed based on texture analysis and provided a two-class diagnosis of neoplastic or non-neoplastic, with probabilities. We validated the diagnostic ability of the ECV-CAD system using 173 randomly selected EC images (49 non-neoplasms, 124 neoplasms). The images were evaluated by the CAD and by four expert endoscopists and three trainees. The diagnostic accuracies for distinguishing between neoplasms and non-neoplasms were calculated., Results: ECV-CAD had higher overall diagnostic accuracy than trainees (87.8 vs 63.4%; [Formula: see text]), but similar to experts (87.8 vs 84.2%; [Formula: see text]). With regard to high-confidence cases, the overall accuracy of ECV-CAD was also higher than trainees (93.5 vs 71.7%; [Formula: see text]) and comparable to experts (93.5 vs 90.8%; [Formula: see text])., Conclusions: ECV-CAD showed better diagnostic accuracy than trainee endoscopists and was comparable to that of experts. ECV-CAD could thus be a powerful decision-making tool for less-experienced endoscopists.

Each taste bud cell (TBC) type responds to a different taste. Previously, we showed that an unidentified cell type(s) functionally expresses a muscarinic acetylcholine (ACh) receptor subtype, M3, and we suggested the ACh-dependent modification of its taste responsiveness. In this study, we found that M3 is expressed by type III TBCs, which is the only cell type that possesses synaptic contacts with taste nerve fibers in taste buds. The application of ACh to the basolateral membrane of mouse fungiform TBCs in situ increased the intracellular Ca 2+ concentration in 2.4 ± 1.4 cells per taste bud (mean ± SD, n = 14). After Ca 2+ imaging, we supravitally labeled type II cells (phospholipase C β2 [PLCβ2]-immunoreactive cells) with Lucifer yellow CH (LY), a fluorescent dye and investigated the positional relationship between ACh-responding cells and LY-labeled cells. After fixation, the TBCs were immunohistostained to investigate the positional relationships between immunohistochemically classified cells and LY-labeled cells. The overlay of the two positional relationships obtained by superimposing the LY-labeled cells showed that all of the ACh-responding cells were type III cells (synaptosomal-associated protein 25 [SNAP-25]-immunoreactive cells). The ACh responses required no added Ca 2+ in the bathing solution. The addition of 1 μM U73122, a phospholipase C inhibitor, decreased the magnitude of the ACh response, whereas that of 1 μM U73343, a negative control, had no effect. These results suggest that type III cells respond to ACh and release Ca 2+ from intracellular stores. We also discuss the underlying mechanism of the Ca 2+ response and the role of M3 in type III cells., Competing Interests: Compliance with ethical standards All of the experiments were performed in accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Sciences approved by the Council of the Physiological Society of Japan, and they were permitted by the Animal Institutional Review Board of Kyushu Institute of Technology in accordance with the guidelines of the US National Institutes of Health.

Cortical spreading depression (SD) is a spreading disruption in brain ionic homeostasis during which neurons experience complete and prolonged depolarizations. SD is generally believed to be the physiological substrate of migraine aura and is associated with many other brain pathologies. Here, we perform simulations with a model of SD treating brain tissue as a triphasic continuum of neurons, glia and the extracellular space. A thermodynamically consistent incorporation of the major biophysical effects, including ionic electrodiffusion and osmotic water flow, allows for the computation of important physiological variables including the extracellular voltage (DC) shift. A systematic parameter study reveals that glia can act as both a disperser and buffer of potassium in SD propagation. Furthermore, we show that the timing of the DC shift with respect to extracellular [Formula: see text] rise is highly dependent on glial parameters, a result with implications for the identification of the propagating mechanism of SD.