Microwave Scissors-Based Sutureless Laparoscopic Partial Nephrectomy Versus Conventional Open Partial Nephrectomy in a Porcine Model: Usefulness and Complications.

BACKGROUND: This study aimed to compare the benefits and safety of microwave scissors-based sutureless laparoscopic partial nephrectomy (MSLPN) with those of conventional open partial nephrectomy (cOPN). METHODS: Each kidney in nine pigs underwent MSLPN using microwave scissors (MWS) via transperitoneal laparoscopy or cOPN via retroperitoneal open laparotomy. The kidney's lower and upper poles were resected under temporary hilar-clamping. The renal calyces exposed during renal resections were sealed and transected using MWS in MSLPN and were sutured in cOPN. For MWS, the generator's power output was 60 W. Data on procedure time (PT), ischemic time (IT), blood loss (BL), normal nephron loss (NNL), and extravasation during retrograde pyelogram were compared between the two techniques. RESULTS: The authors successfully performed 22 MSLPNs and 10 cOPNs. Compared with cOPN, MSLPN was associated with significantly lower PT (median, 9.2 vs 13.0 min; p = 0.026), IT (median, 5.9 vs 9.0 min; p < 0.001), BL (median, 14.4 vs 38.3 mL; p = 0.043), and NNL (median, 7.6 vs 9.4 mm; p = 0.004). However, the extravasation rate was higher in the MSLPN group than in the cOPN group (54.5 % [n = 12] vs 30.0 % [n = 3]), albeit without a significant difference (p = 0.265). Pelvic stenosis occurred in one MSLPN procedure that involved deep lower pole resection near the kidney hilum. CONCLUSIONS: The study data show that MSLPN can improve intraoperative outcomes while reducing technical demands for selected patients with non-hilar-localized renal tumors. However, renal calyces, if violated, should be additionally sutured to prevent urine leakage.

Molecular Simulation Study of Surface-Enhanced Raman Scattering of Liquid Water.

We developed in our previous study [J. Chem. Phys., 2021, 155, 174118, J. Phys. Chem. A, 2022, 126, 4762] a classical electronic and molecular dynamics simulation method to describe the optical response of metal material in solution based on an atomistic model by incorporating the classical equation of motion for free electrons under an applied electric field. To show further usefulness of the method, in the present study, we apply it to surface-enhanced Raman scattering of liquid water to examine the signal enhancement of the solution system caused by plasmon resonance effects of a silver nanoparticle.

Deep learning-based vessel automatic recognition for laparoscopic right hemicolectomy.

BACKGROUND: In laparoscopic right hemicolectomy (RHC) for right-sided colon cancer, accurate recognition of the vascular anatomy is required for appropriate lymph node harvesting and safe operative procedures. We aimed to develop a deep learning model that enables the automatic recognition and visualization of major blood vessels in laparoscopic RHC. MATERIALS AND METHODS: This was a single-institution retrospective feasibility study. Semantic segmentation of three vessel areas, including the superior mesenteric vein (SMV), ileocolic artery (ICA), and ileocolic vein (ICV), was performed using the developed deep learning model. The Dice coefficient, recall, and precision were utilized as evaluation metrics to quantify the model performance after fivefold cross-validation. The model was further qualitatively appraised by 13 surgeons, based on a grading rubric to assess its potential for clinical application. RESULTS: In total, 2624 images were extracted from 104 laparoscopic colectomy for right-sided colon cancer videos, and the pixels corresponding to the SMV, ICA, and ICV were manually annotated and utilized as training data. SMV recognition was the most accurate, with all three evaluation metrics having values above 0.75, whereas the recognition accuracy of ICA and ICV ranged from 0.53 to 0.57 for the three evaluation metrics. Additionally, all 13 surgeons gave acceptable ratings for the possibility of clinical application in rubric-based quantitative evaluations. CONCLUSION: We developed a DL-based vessel segmentation model capable of achieving feasible identification and visualization of major blood vessels in association with RHC. This model may be used by surgeons to accomplish reliable navigation of vessel visualization.

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma.

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.

BMP-2-mediated signaling suppresses salivary gland development.

Research regarding the process of salivary gland development and elucidation of related mechanisms are considered essential for development of effective treatments for conditions associated with salivary disease. Various reports regarding the effects of bone morphogenetic protein (BMP)-2 on hard tissue cells have been presented, though few have examined those related to salivary gland formation. Using an organ culture system, the present study was conducted to investigate the function of BMP-2 in salivary gland formation. Salivary glands obtained from embryonic day 13.5 mice and treated with BMP-2 showed suppression of primordial cell differentiation and also gland formation in a concentration-dependent manner. Furthermore, gland formation inhibition was suppressed by concurrent treatment with dorsomorphin, an inhibitor of the Smad pathway. Expression levels of AQP5, a marker gene for acinar cells, and Prol1, an opiorphin expressed in the lacrimal gland, were decreased in salivary glands treated with BMP-2. The present findings indicate that suppression of salivary gland formation, especially acinar differentiation, is induced by BMP-2, a phenomenon considered to be related to the Smad pathway.

Effectiveness of Immediate Video-Assisted Thoracoscopic Surgery for Empyema: A Multicentre, Retrospective Cohort Study.

BACKGROUND: Because of limitations in previous randomised controlled trials and observational studies, the effectiveness of immediate video-assisted thoracoscopic surgery (VATS) for patients with empyema in real-world settings remains unclear. OBJECTIVE: This study aimed to evaluate whether immediate VATS improves clinical outcomes in patients with empyema. METHODS: This multicentre retrospective cohort study included 744 patients with physician-diagnosed empyema from six hospitals between 2006 and 2021. The exposure was VATS performed within 3 days of empyema diagnosis, the primary outcome was 30-day mortality, and secondary outcomes were 90-day mortality, length of hospital stay, and time from diagnosis to discharge. We used propensity score weighting to account for potential confounders. For outcome analyses, we used logistic regression for mortality outcomes and gamma regression for the number of days. RESULTS: Among the 744 patients, 53 (7.1%) underwent VATS within 3 days, and 691 (92.9%) initially received conservative treatment. After propensity score weighting, the differences in 30- and 90-day mortalities between the immediate VATS and initial conservative treatment groups were 1.18% (95% confidence interval [CI], -10.7 to 13.0%) and -0.08% (95% CI, -10.3 to 10.2%), respectively. The differences in length of hospital stay and time from diagnosis to discharge were -3.22 (95% CI, -6.19 to -0.25 days) and -5.04 days (95% CI, -8.19 to -1.90 days), respectively. CONCLUSIONS: Our real-world study showed that immediate VATS reduced the length of hospital stay and the time from diagnosis to discharge. Considering the small sample and differences in protocols between countries, further large-scale studies are warranted.

Feasibility of Microwave Scissors-Based Off-Clamp Laparoscopic Partial Nephrectomy in a Porcine Model.

OBJECTIVES: To assess the feasibility of off-clamp laparoscopic partial nephrectomy using microwave scissors. METHODS: We performed transperitoneal laparoscopic partial nephrectomy, without hilar clamping or renorrhaphy, using only microwave scissors for renal resection in a porcine model. For each kidney, 2 types of procedures were performed: a middle pole resection excising an area of 2-cm diameter and approximately 1-cm depth and a lower pole resection at the level of the lower polar line. The renal calyces exposed during renal resection were sealed and transected using microwave scissors. After 3 days of follow-up, the pigs were reoperated to inspect for postoperative complications. Euthanasia was performed to collect the remaining kidneys for histopathological examination. RESULTS: Ten procedures were successfully performed, without hilar clamping or suturing of the renal calyces and parenchyma, in 5 kidneys from 3 pigs. The median resecting time, blood loss, and lateral thermal injury were 23.2 min, 47.1 mL, and 6.8 mm in the middle pole resection, and were 15.1 min, 26.5 mL, and 6.9 mm in the lower pole resection, respectively. No complications were noted during reoperation, such as postoperative hemorrhage and major urine leakage. Extravasation occurred in 2 middle pole resections and 3 lower pole resections during retrograde pyelogram. Hematoxylin and eosin staining revealed thermal injury characterized by tissue microwave fixation in the near zone and acute coagulative necrosis in the intermediate zone. CONCLUSIONS: Microwave scissors-based off-clamp laparoscopic partial nephrectomy is feasible in pigs and can be used for clinical applications.

Cdc42 has important roles in postnatal angiogenesis and vasculature formation.

Cdc42, a Rho family low molecular weight G protein, has important roles in various cell functions, including cytoskeletal rearrangement, cell adhesion and cell proliferation and differentiation. To investigate the involvement of Cdc42 in the activities of vascular endothelial cells, we generated Cdc42 conditional knockout mice in which Cdc42 was time -specifically deficient in vascular endothelial cells (Cdc42 â€‹fl/fl; VE-Cad CreERT: Cdc42 cKO). When the Cdc42 gene was deleted after birth, Cdc42 cKO mice were smaller than the control mice, and died between postnatal day 8 (P8) and P10. Necropsy findings confirmed that these mice had various pathological aberrances in the vessels of most organs, such as blood flow congestion and blood cell invasion. Electron microscopic observations also revealed that capillary endothelial cells were detached from the basement membrane as well as phagocytosis of dead endothelial cells induced by macrophages. Moreover, vascular sprouting from aortic rings induced by VEGF-A was diminished in samples from the Cdc42 cKO mice because of an endothelial cell proliferation defect. These results suggest that Cdc42 in vascular endothelial cells has important roles in blood vessel formation after birth.

Extracellular acidification augments sclerostin and osteoprotegerin production by Ocy454 mouse osteocytes.

Osteocytes sense the microenvironmental stimuli, including mechanical stress, and regulate bone resorption by osteoclasts and bone formation by osteoblasts. Diabetes and cancer metastasis to bone raise l-lactic acid in the bone tissue, causing acidification. Here, we investigated the effects of l-lactic acid and extracellular acidification on the function of mouse Ocy454 osteocytes. L- and d-lactic acid with low chiral selectivity and acidification of the medium raised the production of sclerostin and osteoprotegerin by Ocy454 cells. The mRNA expression of their genes increased after either treatment of L- and d-lactic acid or acidification of the medium. Furthermore, the conditioned medium of Ocy454 cells cultured in an acidic environment suppressed the induction of alkaline phosphatase activity in MC3T3-E1 cells, which was recovered by the anti-sclerostin antibody. While it is reported that HDAC5 inhibits the transcription of the sclerostin gene, extracellular acidification reduced the nuclear localization of HDAC5 in Ocy454 cells. While calmodulin kinase II (CaMKII) is known to phosphorylate and induce extranuclear translocation of HDAC5, KN-62, an inhibitor of CaMKII lowered the expression of the sclerostin gene in Ocy454 cells. Collectively, extracellular acidification is a microenvironmental factor that modulates osteocyte functions.

Computational Analyses of Plasmonics of a Silver Nanoparticle in a Vacuum and in a Water Solution by Classical Electronic and Molecular Dynamics Simulations.

We present basic optical responses of a silver nanoparticle (Ag309) in a vacuum and a water solution obtained by classical electronic and molecular dynamics (CEMD) calculations, where the CEMD is our previously developed force-field based molecular dynamics simulation method that incorporates the classical equation of motion for free electrons in metal and an interaction with the applied oscillating electric field (Yamada, A. J. Chem. Phys. 2021, 155, 174118)). The present work is the follow-up of the previous study. Calculated absorption spectra in the visible region with various conditions are reported together with parameter determination for realistic analyses as well as the verification of the method. Time-domain optical responses of Ag309 in water solvent are as well analyzed in terms of the plasmon resonance excitation under a subpicosecond light pulse and its thermal relaxation.

Germline sequencing for presumed germline pathogenic variants via tumor-only comprehensive genomic profiling.

BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO-PMWG) published recommendations regarding confirmatory germline testing for presumed germline pathogenic variants (PGPVs) in tumor-only comprehensive genomic profiling (CGP). However, the clinical validity of these recommendations has not been investigated in a real-world practice. METHODS: Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOne® CDx, Foundation Medicine, Inc, Cambridge, MA, USA) between October 2018 and March 2020, were retrospectively reviewed. After excluding patients with no reported variants in 45 actionable genes (n = 6), or no archived germline DNA samples (n = 31), 143 patients were investigated. The PGPVs were selected from the CGP report and germline sequencing were performed using DNA samples archived in Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan). RESULTS: A total of 195 variants were classified as PGPV based on the conventional criteria. Germline sequencing disclosed that 12 variants (6.2%) were of germline origin. In contrast, after filtering these 195 variants through the ESMO-PMWG recommendation criteria for confirmatory germline testing, following seven PGPVs, BRCA2 (n = 2), BRIP1 (n = 1), BAP1 (n = 1), PMS2 (n = 1), MSH2 (n = 1), and SDHB (n = 1) remained and six variants (85.7%) were confirmed to be of germline origin. CONCLUSION: Our current data suggested that the application of ESMO-PMWG criteria is helpful in selecting PGPVs with a high likelihood of germline origin in a tumor-only CGP in daily clinical practice.

First-line pembrolizumab for patients with early relapsing urothelial carcinoma after perioperative chemotherapy: a retrospective analysis of bladder cancer and upper urinary tract cancer.

BACKGROUND: First-line pembrolizumab is available for recurrent disease within 12 months after the receipt of platinum-based perioperative chemotherapy. However, the benefit of first-line pembrolizumab is unclear. This study evaluated the oncological outcome of patients treated with pembrolizumab compared with chemotherapy as first-line therapy for early relapsing disease after the receipt of platinum-based perioperative chemotherapy. METHODS: Data from a multicenter study included 454 patients diagnosed with unresectable or metastatic UC from November 2006 to July 2021. We identified patients with early and non-early relapsing disease. Oncological outcomes were evaluated using progression-free survival, overall survival, and survival with disease control. RESULTS: Fifty-three patients with early relapsing disease and 15 patients with non-early relapsing disease were identified. Of 53 patients with early relapsing disease, 26 (49.1%) were treated with pembrolizumab and 27 (50.9%) were treated with chemotherapy as first-line therapy. Fifteen patients with non-early relapsing disease were treated with chemotherapy. Early relapsing disease was associated with shorter progression-free survival and overall survival than non-early relapsing disease. Pembrolizumab was associated with longer progression-free survival and survival with disease control than chemotherapy in patients with early relapsing disease. There was no significant difference in overall survival between pembrolizumab and chemotherapy, but overall survival plateau with a long tail was observed in pembrolizumab. CONCLUSIONS: First-line pembrolizumab in earlier clinical settings for highly malignant tumors might improve the prognosis of patients with early relapsing disease after the receipt of platinum-based perioperative chemotherapy.

Preliminary report of de novo adipogenesis using novel bioabsorbable implants and image evaluation using a porcine model.

Our bioabsorbable poly-L-lactic acid (PLLA) mesh implants containing collagen sponge are replaced with adipose tissue after implantation, and this is an innovative method for breast reconstruction. In this preliminary study, we investigated the formation of adipose tissue and evaluated the process via multimodal images in a porcine model using an implant aggregate to generate the larger adipose tissue. The implant aggregate consists of PLLA mesh implants containing collagen sponge and a poly-glycolic acid woven bag covering them. We inserted the implant aggregates under the porcine mammary glands. Magnetic resonance imaging (MRI), ultrasonography (USG), and 3-dimensional (3D) surface imaging and histological evaluations were performed to evaluate the formation of adipose tissue over time. The volume of the implant aggregate and the formed adipose tissue inside the implant aggregate could be evaluated over time via MRI. The space within the implant aggregate was not confirmed on USG due to the acoustic shadow of the PLLA threads. The change in volume was not confirmed precisely using 3D surface imaging. Histologically, the newly formed adipose tissue was confirmed on the skin side of the implant aggregate. This implant aggregate has the ability to regenerate adipose tissue, and MRI is an appropriate method for the evaluation of the volume of the implant aggregation and the formation of adipose tissue.

Low-Error Soil Moisture Sensor Employing Spatial Frequency Domain Transmissometry.

A new type of soil moisture sensor using spatial frequency domain transmissometry (SFDT) was evaluated. This sensor transmits and receives ultrawideband (1 to 6 GHz) radio waves between two separated antennas and measures the propagation delay time in the soil related to the dielectric constant. This method is expected to be less affected by air gaps between the probes and the soil, as well as being less affected by soil electrical conductivity (EC), than typical commercial sensors. The relationship between output and volumetric water content (θ), and the effects of air gaps and EC were evaluated through experiments using sand samples and the prototype SFDT sensor. The output of the SFDT sensor increased linearly with θ and was not affected by even a high salt concentration for irrigation water, such that the EC of the pore water was 9.2 dS·m-1. The SFDT sensor was almost unaffected by polyethylene tapes wrapped around the sensor to simulate air gaps, whereas a commercially available capacitance sensor significantly underestimated θ. Theoretical models of the SFDT sensor were also developed for the calibration equation and the air gaps. The calculation results agreed well with the experimental results, indicating that analytical approaches are possible for the evaluation of the SFDT sensor.

[A Practical Technique for Challenging Ureterocystoneostomy : Application of Casale Vesicostomy with Rink-Modification].

In order to treat the iatrogenic ureteral stricture of more than 8 cm length after transurethral ureterolithotripsy, we planned to perform ureterocystoneostomy with psoas hitch and Boari flap. Because of the longer defect of the affected ureter than presurgically expected and the rigid and thickened ureteral stump resulting from chronic inflammation, anti-reflux technique by forming submucosal tunnel could not be achieved as in the standard Boari flap and we reluctantly anastomosed the ureteral stump to the end of the tubularized bladder wall flap in end-to-end fashion. In order to secure the anti-reflux mechanism we created a submucosal tunnel in the posterior bladder wall according to the technique reported by Casale and Rink where it originally worked as anti-incontinence mechanism of catheterizable vesicostomy. The follow-up examinations showed no recurrence of ureteral stricture nor occurrence of vesicoureteral reflux.

Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in the presence of γδ T cells.

Bisphosphonates distributed to bone exert toxic effects specifically towards osteoclasts. On the other hand, intravenous administration of a nitrogen-containing bisphosphonate (N-BP) such as zoledronate induces acute-phase reactions (APRs), including influenza-like fever 1 day later, indicating an interaction with immunocompetent cells circulating blood. Although it has been reported that activation of γδ T cells is pivotal to induce an APR following treatment with zoledronate, downstream events, including the production of inflammatory cytokines after activation of γδ T cells, remain obscure. We investigated the effects of zoledronate on inflammatory cytokine expression in human peripheral blood mononuclear cells (PBMCs) in vitro. While zoledronate induced mRNA expressions of tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and interferon-γ (IFN-γ) in PBMC, depletion of γδ T cells abolished that zoledronate-induced expression of those cytokines, indicating the necessity of γδ T cells for expression induction by zoledronate. However, which types of cells were responsible for the production of those cytokines in blood remained unclear. As it is generally accepted that monocytes and macrophages are primary sources of inflammatory cytokines, CD14+ cells from PBMC were exposed to zoledronate in the presence of PBMC, which resulted in induced expression of mRNAs for IL-1ß, IL-6 and IFN-γ, but not for TNF-α. These results indicate that CD14+ cells are responsible, at least in part, for the production of IL-1ß, IL-6 and IFN-γ in blood exposed to zoledronate. This suggests that CD14+ cells play an essential role in the occurrence of APRs following N-BP administration.

Comprehensive genomic profiling for patients with chemotherapy-naïve advanced cancer.

Comprehensive genomic profiling (CGP) testing by next-generation sequencing has been introduced into clinical practice as part of precision cancer medicine to select effective targeted therapies. However, whether CGP testing at the time of first-line chemotherapy could be clinically useful is not clear. We conducted this single-center, prospective, observational study to investigate the feasibility of CGP testing for chemotherapy-naïve patients with stage III/IV gastrointestinal cancer, rare cancer, and cancer of unknown primary, using the FoundationOne® companion diagnostic (F1CDx) assay. The primary outcome was the detection rate of at least one actionable/druggable cancer genomic alteration. Actionable/druggable cancer genomic alterations were determined by the F1CDx report. An institutional molecular tumor board determined the molecular-based recommended therapies. A total of 197 patients were enrolled from October 2018 to June 2019. CGP success rate was 76.6% (151 of 197 patients), and median turnaround time was 19 days (range: 10-329 days). Actionable and druggable cancer genomic alterations were reported in 145 (73.6%) and 124 (62.9%) patients, respectively. The highest detection rate of druggable genomic alterations in gastrointestinal cancers was 80% in colorectal cancer (48 of 60 patients). Molecular-based recommended therapies were determined in 46 patients (23.4%). CGP testing would be a useful tool for the identification of a potentially effective first-line chemotherapy.

Vector incrimination and transmission of avian malaria at an aquarium in Japan: mismatch in parasite composition between mosquitoes and penguins.

BACKGROUND: Captive populations of penguins outside of their natural distributions are often maintained in outdoor facilities, such as zoos and aquariums. Consequently, such penguins in captivity are constantly exposed to mosquito vectors and risk of avian malarial infection during their active period from spring to autumn, which can be lethal to these naïve birds. Previous studies have investigated parasite prevalence in mosquitoes or penguins, but simultaneous investigations, which would be crucial to monitor the transmission dynamics and cycle within a facility, have not been done. To identify dominant lineages and trends, multiple-year surveys are recommended. METHODS: Avian malaria parasites (Plasmodium spp.) and related haemosporidia were tested in penguins and mosquitoes at an aquarium in Japan through multiple years from 2011 to 2018. Prevalence and dynamics were confirmed, and molecular analyses targeting the protozoal cytb gene were used to reveal the transmission cycle. Blood meals of mosquitoes were also identified using molecular methods. RESULTS: Parasite detection in penguins tended to fluctuate within an individual. Two Plasmodium lineages were consistently detected in mosquitoes that had fed on penguins and wild birds observed around the aquarium. Plasmodium lineage CXPIP09 was detected from both mosquitoes and penguins, suggesting active transmission at this facility. However, Plasmodium cathemerium PADOM02 was only detected in mosquitoes, which may be due to host, vector or parasite-related factors, or detection methods and their limits. Additionally, Haemoproteus larae SPMAG12 was detected from penguins, suggesting active transmission via biting midges. CONCLUSIONS: The mismatch in parasite composition between penguins and mosquitoes shows that multiple aspects such as captive birds, wild birds and vector insects should be monitored in order to better understand and control avian malarial infection within ex-situ conservation facilities. Furthermore, morphological analyses would be needed to confirm competency and infection dynamics of avian malaria parasites.

Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations.

BACKGROUND: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. METHODS: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. RESULTS: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression. CONCLUSIONS: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.

Classical electronic and molecular dynamics simulation for optical response of metal system.

An extended molecular dynamics simulation that incorporates classical free electron dynamics in the framework of the force-field model has been developed to enable us to describe the optical response of metal materials under the visible light electric field. In the simulation, dynamical atomic point charges follow equations of motion of classical free electrons that include Coulomb interactions with the oscillating field and surrounding atomic sites and collision effects from nearby electrons and ions. This scheme allows us to simulate an interacting system of metals with molecules using an ordinary polarizable force-field and preserves energy conservation in the case without applying an external electric field. As the first applications, we show that the presented simulation accurately reproduces (i) the classical image potential in a metal-charge interaction system and (ii) the dielectric function of bulk metal. We also demonstrate (iii) calculations of absorption spectra of metal nano-particles with and without a water solvent at room temperature, showing reasonable red-shift by the solvent effect, and (iv) plasmon resonant excitation of the metal nano-particle in solution under the visible light pulse and succeeding energy relaxation of the absorbed light energy from electrons to atoms on the metal and to the water solvent. Our attempt thus opens the possibility to expand the force-field based molecular dynamics simulation to an alternative tool for optical-related fields.