Mass producible, robust SERS substrates based on metal film on nanosphere (MFON) on an adhesive substrate for detection of surface-adsorbed molecules and their evaluation by helium ion microscopy.

We have developed a SERS stamp that can be pressed directly onto a solid surface for characterization of surface-adsorbed target molecules. The stamp was fabricated by transfer of a dense monolayer of SiO2 nanospheres from a glass surface onto a piece of adhesive tape and subsequent evaporation of silver. The performance of the resulting SERS stamps was evaluated by their exposure to methyl mercaptan vapor, and immersion in rhodamine 6G and ferbam solutions. It was found that beside the nanosphere diameter and metal deposition thickness, the extent of burial of the nanospheres into the adhesive tape, dictated by the pressure during the nanosphere transfer process, had a significant effect. We carried out FDTD calculations of the near field. Models are based on morphological information obtained from helium ion microscopy, which can provide high-resolution images of poor electrical conductors such as our SERS stamp. While one of our main eventual goals is detection of pesticides on agricultural produce, we have begun to take a careful step by testing our SERS stamp on better characterized surfaces such as a porous gel surface, having been immersed in fungicides such as ferbam. We also present our preliminary results with ferbam on oranges. It is expected that our well-characterized SERS stamp will play a role in shedding light on the poorly studied transfer process of target molecules onto a SERS surface as well as serving as a new SERS platform.

Artificial intelligence for the automated single-shot assessment of psoriasis severity.

BACKGROUND: PASI score is globally used to assess disease activity of psoriasis. However, it is relatively complicated and time-consuming, and the score will vary due to the inconsistent subjectivity between dermatologists. Therefore, an AI system capable of assessing psoriasis severity will be useful. OBJECTIVES: To propose a simplified PASI system (Single-Shot PASI) and associated AI models capable of assessing psoriasis severity. METHODS: Overall, 705 psoriasis images of the trunk's front and back were used in our research. Considering the relatively small number of images, we used data augmentation techniques to expand the data. A psoriasis expert's scores were used as teacher data. Various convolutional neural network models and hyperparameters were adjusted using a fivefold cross-validation. From these adjustments, we discovered that fine-tuning Imagenet2012-pretrained InceptionV3 whose last linear layer was replaced by a two-layer perceptron (30 hidden units and five output units) exhibited the best performance. RESULTS: To validate our deep learning system, 10 images were selected as test sets and were excluded from the training sets. The AI assessment of Single-Shot PASI was almost consistent with the clinical severity. We examined whether AI assistance would affect human scoring. In this study, 13 dermatologists and 9 medical students were invited as evaluators. Mean absolute differences from AI scores and standard deviation among evaluators reduced with AI assistance. In addition, the evaluator's scores got close to the teacher's score with AI's assistance. CONCLUSIONS: We proposed a Single-Shot PASI system and developed an associated AI system capable of assessing psoriasis severity simply by uploading a single clinical image. An easy-to-use scoring system and our freely available AI software would help dermatologists and patients with psoriasis.

Assessment of the albumin-bilirubin grade as a prognostic factor in patients with non-small-cell lung cancer receiving anti-PD-1-based therapy.

INTRODUCTION: The albumin-bilirubin (ALBI) grade is a novel indicator of the liver function. Some studies showed that the ALBI grade was a prognostic and predictive biomarker for the efficacy of chemotherapy in cancer patients. The association between the ALBI grade and outcomes in patients with non-small-cell lung cancer (NSCLC) treated with cancer immunotherapy, however, is poorly understood. METHODS: We retrospectively enrolled 452 patients with advanced or recurrent NSCLC who received anti-programmed cell death protein 1 (PD-1)-based therapy between 2016 and 2019 at three medical centers in Japan. The ALBI score was calculated from albumin and bilirubin measured at the time of treatment initiation and was stratified into three categories, ALBI grade 1-3, with reference to previous reports. We examined the clinical impact of the ALBI grade on the outcomes of NSCLC patients receiving anti-PD-1-based therapy using Kaplan-Meier survival curve analysis with log-rank test and Cox proportional hazards regression analysis. RESULTS: The classifications of the 452 patients were as follows: grade 1, n = 158 (35.0%); grade 2, n = 271 (60.0%); and grade 3, n = 23 (5.0%). Kaplan-Meier survival curve analysis showed that the ALBI grade was significantly associated with progression-free survival and overall survival. Moreover, Cox regression analysis revealed that the ALBI grade was an independent prognostic factor for progression-free survival and overall survival. CONCLUSION: The ALBI grade was an independent prognostic factor for survival in patients with advanced or recurrent NSCLC who receive anti-PD-1-based therapy. These findings should be validated in a prospective study with a larger sample size.

Cell therapy for medication-related osteonecrosis of the jaw: update on treatment strategies.

Bioactive glasses (BAG) are used as bone-graft substitutes in orthopaedic surgery. A specific BAG scaffold was developed by sintering BAG-S53P4 granules. It is hypothesised that this scaffold can be used as a bone substitute to fill bone defects and induce a bioactive membrane (IM) around the defect site. Beyond providing the scaffold increased mechanical strength, that the initial inflammatory reaction and subsequent IM formation can be enhanced by coating the scaffolds with poly(DL-lactide-co-glycolide) (PLGA) is also hypothesised. To study the immunomodulatory effects, BAG-S53P4 (± PLGA) scaffolds were placed on monolayers of primary human macrophage cultures and the production of various pro- and anti-inflammatory cytokines was assessed using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and ELISA. To study the osteogenic effects, BAG-S53P4 (± PLGA) scaffolds were cultured with rabbit mesenchymal stem cells and osteogenic differentiation was evaluated by RT-qPCR and matrix mineralisation assays. The scaffold ion release was quantified and the BAG surface reactivity visualised. Furthermore, the pH of culture media was measured. BAG-S53P4 scaffolds had both anti-inflammatory and osteogenic properties that were likely attributable to alkalinisation of the media and ion release from the scaffold. pH change, ion release, and immunomodulatory properties of the scaffold could be modulated by the PLGA coating. Contrary to the hypothesis, the coating functioned by attenuating the BAG surface reactions and subsequent anti-inflammatory properties, rather than inducing an elevated inflammatory response compared to BAG-S53P4 alone. These results further validated the use of BAG-S53P4 (± PLGA) scaffolds as bone substitutes and indicate that scaffold properties can be tailored to a specific clinical need.

Single-blind randomized clinical trial of transinguinal preperitoneal repair using self-expanding mesh patch vs. Lichtenstein repair for adult male patients with primary unilateral inguinal hernia.

PURPOSE: The aim of the study was to compare proportions of chronic postoperative inguinal pain (CPIP) and other surgical outcomes between transinguinal preperitoneal repair with modified Kugel patch (MK) and Lichtenstein repair (LR). METHODS: Two-hundred adult male patients with primary unilateral inguinal hernia were randomized into MK or LR groups. The primary endpoint was CPIP, pain at 6 months after surgery. Secondary outcomes included recurrence rate, incidence of postoperative complications, time until return to activities, inguinal pain and sensory disturbances assessed at 1 week, 1 month, 3, 6, and 12 months after the operation using an 11-point numerical rating scale (NRS). The study was an intention-to-treat analysis. RESULTS: In comparison of MK (n = 100) and LR (n = 100) with similar backgrounds, proportions of CPIP were similar (7.2 vs. 11.1%, p = 0.3452). Favorable outcomes for MK were duration of operation (32 vs. 40 min, p < 0.0001), NRS of foreign body sensation at 1 year (0 [0-1] vs. 0 [0-2], p = 0.0067), and NRS of numbness at 1 month (0 [0-1] vs. 0 [0-3], p = 0.0078) after the operation. CONCLUSIONS: In regard to CPIP, the short-term results of MK and LR were similar.

Eldecalcitol (ED-71)-induced exosomal miR-6887-5p suppresses squamous cell carcinoma cell growth by targeting heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1).

Heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1) was purified from A431 cell-conditioned media based on its capacity to bind to fibroblast growth factor 1 and 2 (FGF-1 and FGF-2). HBp17/FGFBP-1 has been observed to induce the tumorigenic potential of epithelial cells and is highly expressed in oral cancer cell lines and tissues. HBp17/FGFBP-1 is also recognized as a pro-angiogenic molecule as a consequence of its interaction with FGF-2. We have previously reported that Eldecalcitol (ED-71), an analog of 1α,25(OH)2D3, downregulated the expression of HBp17/FGFBP-1 and inhibited the proliferation of squamous cell carcinoma (SCC) cells in vitro and in vivo through NF-κb inhibition. To explore the possibility of microRNA (miRNA) control of HBp17/FGFBP-1, we analyzed exosomal miRNAs from medium conditioned by A431 cells treated with ED-71. Microarray analysis revealed that 12 exosomal miRNAs were upregulated in ED-71-treated A431 cells. Among them, miR-6887-5p was identified to have a predicted mRNA target matching the 3' untranslated region (3'-UTR) of HBp17/FGFBP-1. The 3'-UTR of HBp17/FGFBP-1 was confirmed to be a direct target of miR-6887-5p in SCC/OSCC cells, as assessed with a luciferase reporter assay. Functional assessment revealed that overexpression of miR-6887-5p in SCC/OSCC cells inhibited cell proliferation and colony formation in vitro, and inhibited tumor growth in vivo compared with control. In conclusion, our present study supports a novel anti-cancer mechanism involving the regulation of HBp17/FGFBP-1 function by exosomal miR-6887-5p in SCC/OSCC cells, which has potential utility as a miRNA-based cancer therapy.

Metastasis of carcinoma ex pleomorphic adenoma to the brain without previous metastasis to the lungs or bones: a case report.

Carcinoma ex pleomorphic adenoma is a rare type of cancer of the salivary gland that involves the malignant transformation of a primary or recurrent pleomorphic adenoma, which often metastasises to the lungs or bones, or both. To the best of our knowledge, however, nobody has reported a distant metastasis of this lesion to the brain without such previous metastasis. We report a case in a 64-year-old man.

Pathological factors involved in local failure in squamous cell carcinoma of the oral cavity: retrospective study and proposal of a new clinical classification.

The control of local failure (LF) is essential to improve outcomes in patients with squamous cell carcinoma of the oral cavity (OSCC). In this study, LF of OSCC was classified into three clinical types: deep recurrence (type 1R), adjacent superficial recurrence (type 2R), and distant primary tumour (type 3R). LF was analyzed after surgical resection of OSCC to determine the validity and usefulness of this classification system. Of 257 patients with OSCC, 58 experienced LF; 21 had type 1R, 23 had type 2R, and 20 had type 3R. Clinical factors influencing LF were analyzed by log-rank test and Cox test. Type 1R was significantly related to the TN classification, resection margin status, and invasive pattern. Type 2R was strongly associated with the grade of epithelial dysplasia at the surgical margins. Type 1R rarely developed more than 1year after surgery, whereas type 2R did not develop within 2 years. Type 1R may be caused by residual cancer cells in the deep margins, and type 2R by precancerous cells remaining in the marginal epithelium and gradually becoming invasive cancer. Type 3R may be considered an independent tumour. The newly proposed clinical classification is convenient and roughly reflects the causes and mechanisms of relapse.

Correlation between dermoscopic and histopathological findings of leucoplakia of the tongue: a case report.

A 75-year-old Japanese man presented at our outpatient clinic with pain on the right side of his tongue. Comparison of histological and dermoscopic images showed that areas with hyperkeratosis were opaque white, areas above the papillary dermis were reddish, and that the lesion looked whiter on dermoscopy the longer the epithelial rete ridges were. A dermatocope shows structural information from the epidermis as well as the upper dermis, and could improve early diagnosis of oral mucosal squamous carcinoma in situ.

Usefulness of chemoradiotherapy for inoperable gastric cancer.

Introduction Radiotherapy is not commonly used for the treatment of gastric cancer in Japan, where surgery is the standard local treatment. We report the results of chemoradiotherapy in patients with advanced or recurrent gastric cancer which was deemed difficult to treat surgically. Methods Twenty-one patients with gastric cancer (including sixteen with advanced/recurrent gastric cancer and five with poor general condition) underwent chemo-radiotherapy, for whom the therapeutic efficacy, toxicity and survival period were analysed. Results The tumour response to chemoradiotherapy was categorised as complete, partial, stable or progressive in 5, 9, 3, and 4 patients, respectively, with an overall response rate of 67%. No serious complications such as gastrointestinal perforation or bleeding occurred, and no cardiac, hepatic or renal dysfunction developed during the follow-up period. The mean survival time was 19.8 months (range, 3-51 months). One patient died of another disease, 18 died of primary cancer and the cause of death was unknown in 2 patients. Conclusions Chemoradiotherapy appears to be an effective treatment for localised gastric cancer without distant metastases, but further studies are needed to determine the indications for chemoradiotherapy and late adverse effects, as well as the chemotherapy regimens to be used.

Effects of Acute Aerobic Exercise on Arterial Stiffness Before and After Glucose Ingestion.

The purpose of present study was to compare the acute effects of moderate-intensity aerobic exercise (65% peak oxygen uptake, 30 min) on arterial stiffness before and after glucose ingestion. 11 healthy young males completed 4 trials in random order. They started aerobic exercise at 90 min before (-90 min-EX), 60 min before (-60 min-EX), 30 min after (30 min-EX), and 60 min after (60 min-EX) the 75-g oral glucose tolerance test (OGTT). Aortic (carotid-femoral) and leg (femoral-ankle) pulse wave velocity (PWV), brachial and ankle blood pressure (BP), blood glucose (BG) and insulin levels were measured at 90 min (baseline) and 30 min before and at 30, 60 and 120 min after the 75-g OGTT. Aortic PWV and brachial systolic BP did not change from baseline after the 75-g OGTT in all trials. Leg PWV and ankle systolic BP increased from baseline after the 75-g OGTT in the -90, 30 and 60 min-EX, but not in the -60 min-EX. Levels of BG and insulin increased from baseline after the 75-g OGTT in all trials. These results suggest that the aerobic exercise most effectively suppresses the increase in peripheral arterial stiffness after glucose ingestion when implemented before glucose ingestion.

Multi-frequency force-detected electron spin resonance in the millimeter-wave region up to 150 GHz.

In this article, a novel technique is developed for multi-frequency force-detected electron spin resonance (ESR) in the millimeter-wave region. We constructed a compact ESR probehead, in which the cantilever bending is sensitively detected by a fiber-optic Fabry-Perot interferometer. With this setup, ESR absorption of diphenyl-picrylhydrazyl radical (<1 µg) was clearly observed at multiple frequencies of up to 150 GHz. We also observed the hyperfine splitting of low-concentration Mn(2+) impurities(∼0.2%) in MgO.

Argatroban more effectively inhibits the thrombin activity in synovial fluid than naturally occurring thrombin inhibitors.

The purpose of this study was to clarify the precise effect of argatroban on the inhibition of cytokine secretion induced by thrombin on synovial cells. The efficiency of thrombin inactivation by thrombin inhibitors was evaluated in human synovial fluids (SFs). In SFs from 13 osteoarthritis (OA) and 11 rheumatoid arthritis (RA) patients, thrombin, Factor Xa (FXa), plasmin activity, IL-6, MMP-3, VEGF, and D-dimer concentrations were measured. Tissue factor (TF) activity or IL-6, MMP-3, and VEGF secretion of human synovial cells with or without thrombin and argatroban were measured. The efficiency of thrombin inactivation in SFs was compared for thrombin inhibitors: argatroban, antithrombin III (ATIII), or heparin cofactor II (HCII). In SFs, thrombin, FXa, plasmin, D-dimer, IL-6, and MMP-3 were significantly higher in RA than in OA. In synovial cell experiments, TNF-alpha and thrombin enhanced TF activity on the cell surface, and IL-6, MMP-3, and VEGF secretion were enhanced by thrombin. Increased TF activity, and IL-6, MMP-3, and VEGF secretion induced by thrombin were inhibited by argatroban. In SFs, argatroban inactivated thrombin more effectively than ATIII or HCII. Since thrombin plays an important role in the disease activity of OA and RA, it is a potential therapeutic molecular target. Argatroban was the most effective anticoagulant to inhibit thrombin activity in SF. Intra-articular injection is ideal administration because it can deliver high dose of argatroban without high risk of systematic complication.

Eldecalcitol (ED-71), an analog of 1α,25-dihydroxyvitamin D3 as a potential anti-cancer agent for oral squamous cell carcinomas.

We have previously reported that 1,25(OH)2D3 inhibits NF-κB activity and thus inhibits growth of OSCC cells in serum-free culture and down-regulates HBp17/FGFBP-1 expression, which is important for cancer cell growth and angiogenesis. Here, we have investigated the effects of ED-71, an analog of vitamin D3 (VD) on OSCC cell lines in serum-free culture. It is known that ED-71 has a stronger inhibitory effect on bone resorption compared to VD and other VD analogs. To the best of our knowledge, there was no report examining the potential of ED-71 as an anti-cancer agent for OSCC. We found that ED-71 is able to inhibit the growth of cancer cell lines at a concentration of hundred times lower than calcitriol. As Cyp24A1 was reportedly induced in cancer cells, we measured the expression of CYP24A1 in OSCC cell lines (NA and UE), A431 epidermoid carcinoma and normal fibroblast cell (gfi) in serum-free culture. As a result, CYP24A1 mRNA and the protein expression in the OSCC cells treated with ED-71 increased in a dose-dependent manner. However, in vivo experiment, in which the A431 cells were implanted in mice, tumor formation was reduced by the ED-71 treatment with no significant difference between Cyp24A1 expression in the tumors of ED-71-treated and control group, as analyzed by western blotting and immunohistochemistry. These results suggest that ED-71 is a potential anti-cancer agent for OSCC.

Comparing Normothermic Machine Perfusion Preservation With Different Perfusates on Porcine Livers From Donors After Circulatory Death.

The utilization of normothermic machine perfusion (NMP) may be an effective strategy to resuscitate livers from donation after circulatory death (DCD). There is no consensus regarding the efficacy of different perfusates on graft and bile duct viability. The aim of this study was to compare, in an NMP porcine DCD model, the preservation potential of three different perfusates. Twenty porcine livers with 60 min of warm ischemia were separated into four preservation groups: cold storage (CS), NMP with Steen solution (Steen; XVIVO Perfusion Inc., Denver, CO), Steen plus red blood cells (RBCs), or whole blood (WB). All livers were preserved for 10 h and reperfused to simulate transplantation for 24 h. During preservation, the NMP with Steen group presented the highest hepatocellular injury. At reperfusion, the CS group had the lowest bile production and the worst hepatocellular injury compared with all other groups, followed by NMP with Steen; the Steen plus RBC and WB groups presented the best functional and hepatocellular injury outcomes, with WB livers showing lower aspartate aminotransferase release and a trend toward better results for most parameters. Based on our results, a perfusate that contains an oxygen carrier is most effective in a model of NMP porcine DCD livers compared with Steen solution. Specifically, WB-perfused livers showed a trend toward better outcomes compared with Steen plus RBCs.

Anterior mediastinal solid tumours in adults: characterisation using dynamic contrast-enhanced MRI, diffusion-weighted MRI, and FDG-PET/CT.

AIM: To find significant parameters to characterise anterior mediastinal solid tumours in adults using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), diffusion-weighted MRI (DWI), and combined 2-[(18)F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (FDG-PET/CT). MATERIALS AND METHODS: Forty-eight histologically confirmed anterior mediastinal solid tumours in 48 patients (24 men, 24 women; age range 21-83 years, mean 50.7 years) were examined. The parameters analysed were maximal diameter, presence of capsule/septa on T2-weighted images, time-signal intensity curves (TICs), apparent diffusion coefficient (ADC), and maximum standardised uptake value (SUVmax). Also examined was whether any differences between histological types could be seen in these parameters. In a validation study, 42 anterior mediastinal solid tumours in 42 patients were examined consecutively. RESULTS: The washout pattern on TIC was seen only in thymic epithelial tumours (20/32). SUVmax of lymphoma (mean, 17.9), malignant germ cell tumours (14.2), and thymic carcinomas (15.6) were significantly higher than that of thymomas (6.1). The mean maximal diameter of thymic epithelial tumours was significantly smaller than that of lymphomas (p<0.01) and malignant germ cell tumours (p<0.05). The validation study also yielded high accuracy (38/42, 91%) in differentiation among the anterior mediastinal solid tumours. CONCLUSION: The SUVmax, TIC pattern on DCE-MRI, and maximal diameter might be useful to differentiate anterior mediastinal solid tumours in adults.