Development of risk-score model in patients with negative surgical margin after robot-assisted radical prostatectomy.

A total of 739 patients underwent RARP as initial treatment for PCa from November 2011 to October 2018. Data on BCR status, clinical and pathological parameters were collected from the clinical records. After excluding cases with neoadjuvant and/or adjuvant therapies, presence of lymph node or distant metastasis, and positive SM, a total of 537 cases were eligible for the final analysis. The median follow-up of experimental cohort was 28.0 (interquartile: 18.0-43.0) months. We identified the presence of International Society of Urological Pathology grade group (ISUP-GG) ≥ 4 (Hazard ratio (HR) 3.20, 95% Confidence Interval (95% CI) 1.70-6.03, P < 0.001), lymphovascular invasion (HR 2.03, 95% CI 1.00-4.12, P = 0.049), perineural invasion (HR 10.7, 95% CI 1.45-79.9, P = 0.020), and maximum tumor diameter (MTD) > 20 mm (HR 1.9, 95% CI 1.01-3.70, P = 0.047) as significant factors of BCR in the multivariate analysis. We further developed a risk model according to these factors. Based on this model, 1-year, 3-year, and 5-year BCR-free survival were 100%, 98.9%, 98.9% in the low-risk group; 99.1%, 94.1%, 86.5% in the intermediate-risk group; 93.9%, 84.6%, 58.1% in the high-risk group. Internal validation using the bootstrap method showed a c-index of 0.742 and an optimism-corrected c-index level of 0.731. External validation was also carried out using an integrated database derived from 3 other independent institutions including a total of 387 patients for the final analysis. External validation showed a c-index of 0.655. In conclusion, we identified risk factors of biochemical failure in patients showing negative surgical margin after RARP and further developed a risk model using these risk factors.

Design of artificial molecular motor inheriting directionality and scalability.

Realizing artificial molecular motors with autonomous functionality and high performance is a major challenge in biophysics. Such motors not only provide new perspectives in biotechnology but also offer a novel approach for the bottom-up elucidation of biological molecular motors. Directionality and scalability are critical factors for practical applications. However, the simultaneous realization of both remains challenging. In this study, we propose a novel design for a rotary motor that can be fabricated using a currently available technology, DNA origami, and validate its functionality through simulations with practical parameters. We demonstrate that the motor rotates unidirectionally and processively in the direction defined by structural asymmetry, which induces kinetic asymmetry in motor motion. The motor also exhibits scalability, such that increasing the number of connections between the motor and stator allows for a larger speed, run length, and stall force.

Vaccination with a combination of STING agonist-loaded lipid nanoparticles and CpG-ODNs protects against lung metastasis via the induction of CD11bhighCD27low memory-like NK cells.

BACKGROUND: Natural killer (NK) cells are effective in attacking tumor cells that escape T cell attack. Memory NK cells are believed to function as potent effector cells in cancer immunotherapy. However, knowledge of their induction, identification, and potential in vivo is limited. Herein, we report on the induction and identification of memory-like NK cells via the action of a combination of a stimulator of interferon genes (STING) agonist loaded into lipid nanoparticles (STING-LNPs) and cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG-ODNs), and the potential of the inducted memory-like NK cells to prevent melanoma lung metastasis. METHODS: The antitumor effects of either the STING-LNPs, CpG-ODNs, or the combination therapy were evaluated using a B16-F10 lung metastasis model. The effect of the combined treatment was evaluated by measuring cytokine production. The induction of memory-like NK cells was demonstrated via flow cytometry and confirmed through their preventative effect. RESULTS: The combination of STING-LNPs and CpG-ODNs tended to enhance the production of interleukin 12 (IL-12) and IL-18, and exerted a therapeutic effect against B16-F10 lung metastasis. The combination therapy increased the population of CD11bhighCD27low NK cells. Although monotherapies failed to show preventative effects, the combination therapy induced a surprisingly strong preventative effect, which indicates that CD11bhighCD27low cells could be a phenotype of memory-like NK cells. CONCLUSION: As far as could be ascertained, this is the first report of the in vivo induction, identification, and confirmation of a phenotype of the memory-like NK cells through a prophylactic effect via the use of an immunotherapeutic drug. Our findings provide novel insights into the in vivo induction of CD11bhighCD27low memory-like NK cells thus paving the way for the development of efficient immunotherapies.

[Tips and Outcomes of Safe Laparoscopic Rectal Resection with Adequate Lymph Node Dissection in Patients with Obesity].

BACKGROUND: This study aimed to describe the surgical procedures involved in laparoscopic rectal resection in patients with obesity and report the short-term outcomes. MATERIALS AND METHODS: A total of 194 consecutive patients who underwent laparoscopic rectal resection in our department from 2013 to 2018 were divided into non-obese(body mass index[BMI] <25 kg/m2; n=161)and obese groups(BMI≥25 kg/m2; n=33)and subsequently analyzed. RESULTS: The operative time was significantly longer in the obese group(225 vs 266 min; p=0.003)than in the non-obese group. No conversions to laparotomy occurred in either group, and no discernible differences in blood loss(1 vs 5 mL; p=0.582), number of harvested lymph nodes(20 vs 17; p=0.356), and postoperative complication rates(9.3 vs 6.1%; p=0.547)were observed. CONCLUSION: Establishing an appropriate operative field, clarifying landmarks, and standardizing the procedure are important to assure safe laparoscopic rectal resection with adequate lymph node dissection in patients with obesity.

The hypothetical molecular mechanism of the ethnic variations in the manifestation of age-related macular degeneration; focuses on the functions of the most significant susceptibility genes.

Age-related macular degeneration (AMD) is the leading sight-threatening disease in developed countries. On the other hand, recent studies indicated an ethnic variation in the phenotype of AMD. For example, several reports demonstrated that the incidence of drusen in AMD patients is less in Asians compared to Caucasians though the reason has not been clarified yet. In the last decades, several genome association studies have disclosed many susceptible genes of AMD and revealed that the association strength of some genes was different among races and AMD phenotypes. In this review article, the essential findings of the clinical studies and genome association studies for the most significant genes CFH and ARMS2/HTRA1 in AMD of different races are summarized, and theoretical hypotheses about the molecular mechanisms underlying the ethnic variation in the AMD manifestation mainly focused on those genes between Caucasians and Asians are discussed.

Novel Repair Technique for Oral and Anal Side Stoma Prolapse of a Loop Colostomy With the Stapled Modified Altemeier Method Using Indocyanine Green Fluorescence Imaging.

BACKGROUND/AIM: Stoma prolapse is a common complication in the late phase after stoma creation. With advances in chemotherapy, a double-orifice colostomy or ileostomy and chemotherapy are used to treat primary unresectable colorectal cancer. Preoperative therapy with a double-orifice colostomy or ileostomy is performed to aid primary colorectal cancer miniaturization. Therefore, the number of stoma prolapses will likely increase in the future. Previous reports on the repair of stoma prolapse focused on unilateral stoma prolapse of loop colostomy, and there are no reports about the bilateral stoma prolapse of loop colostomy or ileostomy. CASE REPORT: We report a novel repair technique for oral and anal side (bilateral) stoma prolapse of a loop colostomy with the stapled modified Altemeier method using indocyanine green (ICG) fluorescence imaging considering the distribution of marginal artery in preventing marginal artery injury which has considerable clinical significance. CONCLUSION: Our novel technique for the oral and anal side prolapse of a loop colostomy is considered effective and safe.

Pretreatment periodontitis is predictive of a poorer prognosis after esophagectomy for esophageal cancer.

BACKGROUND: Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal cancer. Several studies have investigated short-term outcomes after esophagectomy and the impact of periodontal disease, but few have examined the impact of periodontal disease on long-term outcomes. The purpose of this study was to investigate the rate of periodontitis among esophagectomy patients and the prognostic value of periodontitis and its effect on prognosis after esophagectomy. METHODS: A total of 508 patients who underwent esophagectomy received oral health care from a dentist before cancer treatment at Akita University Hospital between January 2009 and December 2021. We assessed the presence and severity of the patients' periodontitis and divided them into no-periodontitis, mild periodontitis, severe periodontitis and edentulous jaw groups. We then assessed 10-year overall survival (OS) and disease-specific survival (DSS) and determined whether periodontitis was an independent prognostic factor affecting OS and DSS. RESULTS: We found that 101 (19.9%) patients had no periodontitis, 207 (40.8%) had mild periodontitis, 176 (34.6%) had severe periodontitis requiring tooth extraction, and 24 (4.7%) had edentulous jaw. Both OS and DSS were significantly poorer in the periodontitis than no-periodontitis group (p < 0.001). In detail, the edentulous jaw group had the poorest prognosis (p < 0.001). Multivariate analysis showed that periodontitis was an independent risk factor affecting OS and DSS. CONCLUSION: Esophageal cancer patients had a high prevalence of periodontitis. Moreover, the presence of periodontitis and severity of periodontitis are independent risk factors contributing to a poorer prognosis after esophagectomy.

Characterizing ATP processing by the AAA+ protein p97 at the atomic level.

The human enzyme p97 regulates various cellular pathways by unfolding hundreds of protein substrates in an ATP-dependent manner, making it an essential component of protein homeostasis and an impactful pharmacological target. The hexameric complex undergoes substantial conformational changes throughout its catalytic cycle. Here we elucidate the molecular motions that occur at the active site in the temporal window immediately before and after ATP hydrolysis by merging cryo-EM, NMR spectroscopy and molecular dynamics simulations. p97 populates a metastable reaction intermediate, the ADP·Pi state, which is poised between hydrolysis and product release. Detailed snapshots reveal that the active site is finely tuned to trap and eventually discharge the cleaved phosphate. Signalling pathways originating at the active site coordinate the action of the hexamer subunits and couple hydrolysis with allosteric conformational changes. Our multidisciplinary approach enables a glimpse into the sophisticated spatial and temporal orchestration of ATP handling by a prototype AAA+ protein.

Effect of soft denture liners on complete denture treatments: A systematic review.

PURPOSE: This systematic review examined the effectiveness of soft denture relining (SDR) materials. STUDY SELECTION: A comprehensive search of MEDLINE, Cochrane Library, and ICHUSHI was conducted up to July 26, 2020. Target outcomes were patient satisfaction, oral health-related quality of life (OHRQOL), masticatory ability (MA), denture functional duration, residual ridge resorption (RRR), and microbial contamination. An organization specializing in literature searches performed the reference searches, and two reviewers independently selected the literature sources, extracted the data, and assessed the risk of bias. The reviewers resolved any disagreements concerning the assortment of literature sources through discussion. SDR included acrylic- and silicone-based materials, which were evaluated separately. RESULTS: Reviewers selected 7, 5, 11, 1, 4, and 6 studies to assess patient satisfaction, OHRQOL, MA, functional duration, RRR, and microbial contamination, respectively. The results confirmed that SDR improved patient satisfaction, OHRQOL, MA, and RRR. However, the functional duration of SDR material is shorter than that of hard denture relining (HDR) or acrylic resin material. Furthermore, SDR material is more susceptible to microbial contamination in the long term. The risk of bias for the included studies tended to be high because of specific issues (difficulty in blinding SDR versus HDR). CONCLUSIONS: For patients who wear complete dentures, SDR often provides beneficial outcomes such as pain reduction and recovery from MA. However, caution should be exercised regarding their use owing to insufficient functional duration and the possibility of microbial contamination during long-term use.

Quasi-Periodic Growth of One-Dimensional Copper Boride on Cu(110).

An unexplored material of copper boride has been realized recently in two-dimensional form at a (111) surface of the fcc copper crystal. Here, one-dimensional (1-D) boron growth was observed on the Cu(110) surface, as probed by atomically resolved scanning probe microscopy. The 1-D copper boride was composed of quasi-periodic atomic chains periodically aligned parallel to each other, as confirmed by Fourier transform analysis. The 1-D growth unexpectedly proceeded across surface steps in a self-assembled manner and extended over several 100 nm. The long-range formation of a 1-D quasi-periodic structure on a surface has been theoretically modeled as a 1-D quasi-crystal and the predicted conditions matched the structural parameters obtained by the experimental work here. The quasi-periodic 1-D copper boride system enabled a way to examine 1-D quasi-crystallinity on an actual material.

Design of synthetic peptide-based fluorescence probes for turn-on detection of hyaluronan.

Herein, we designed and examined a series of fluorescent peptide-based probes for turn-on detection of hyaluronan (HA), a member of the glycosaminoglycan family. We utilized two kinds of synthetic HA-binding peptides as the binding unit for HA, and each peptide was coupled with three kinds of environment-sensitive fluorophores as the signaling unit. From the examination of the peptides, fluorophores, and the position and number of fluorophore modification, we found that X7 peptide (RYPISRPRKR) labelled with an aggregation-induced emission (AIE) fluorogen, tetraphenylethene (TPE), at the N-terminal (named TPE-X7) did function as a light-up probe for HA. The response of TPE-X7 was highly selective to higher molecular weight HA in comparison with lower ones, having the possible potential for the analysis of HA size. TPE-X7 was also applicable to the quantification of HA in synovial fluids.

Six-year outcomes of robot-assisted radical prostatectomy versus volumetric modulated arc therapy for localized prostate cancer: A propensity score-matched analysis.

BACKGROUND: Although robot-assisted radical prostatectomy (RARP) and intensity-modulated radiotherapy are the leading respective techniques of prostatectomy and radiotherapy for localized prostate cancer, almost no study has directly compared their outcomes; none have compared mortality outcomes. METHODS: We compared 6­year outcomes of RARP (n = 500) and volumetric modulated arc therapy (VMAT, a rotational intensity-modulated radiotherapy, n = 360) in patients with cT1-4N0M0 prostate cancer. We assessed oncological outcomes, namely overall survival (OS), cancer-specific survival (CSS), radiological recurrence-free survival (rRFS), and biochemical recurrence-free survival (bRFS), using propensity score matching (PSM). We also assessed treatment-related complication outcomes of prostatectomy and radiotherapy. RESULTS: The median follow-up duration was 79 months (> 6 years). PSM generated a matched cohort of 260 patients (130 per treatment group). In the matched cohort, RARP and VMAT showed equivalent results for OS, CSS, and rRFS: both achieved excellent 6­year outcomes for OS (> 96%), CSS (> 98%), and rRFS (> 91%). VMAT had significantly longer bRFS than RARP, albeit based on different definitions of biochemical recurrence. Regarding complication outcomes, patients who underwent RARP had minimal (2.6%) severe perioperative complications and achieved excellent continence recovery (91.6 and 68.8% of the patients achieved ≤ 1 pad/day and pad-free, respectively). Patients who underwent VMAT had an acceptable rate (20.0%) of grade ≥ 2 genitourinary complications and a very low rate (4.4%) of grade ≥ 2 gastrointestinal complications. CONCLUSION: On the basis of PSM after a 6-year follow-up, RARP and VMAT showed equivalent and excellent oncological outcomes, as well as acceptable complication profiles.

Albumin Hydrogel-Coated Mesoporous Silica Nanoparticle as a Carrier of Cationic Porphyrin and Ratiometric Fluorescence pH Sensor.

Here, we report that a mesoporous silica nanoparticle (MSN) coated with a fluoresceine-labeled bovine serum albumin (F-BSA) hydrogel layer works as a temperature-responsive nanocarrier for tetrakis-N-methylpyridyl porphyrin (TMPyP) and as a fluorescence ratiometric pH probe. F-BSA hydrogel-coated MSN containing TMPyP (F-BSA/MSN/TMPyP) was synthesized by thermal gelation of denatured F-BSA on the external surface of MSN. The F-BSA hydrogel layer was composed of an inner hard corona layer and an outer soft layer and was stable under physiological conditions. F-BSA/MSN/TMPyP exhibited temperature-dependent exponential release of TMPyP. In this release profile, the MSN was found to be a suitable host for stable encapsulation of tetracationic TMPyP by electrostatic interactions, and the F-BSA hydrogel layer mediated the diffusion of TMPyP from the MSN pore interior into the solution phase. Increasing temperature promoted partitioning of TMPyP from the pore interior to the F-BSA hydrogel layer, from where it was spontaneously released into the bulk solution phase by cation exchange. F-BSA/MSN/TMPyP also gave a linear ratiometric fluorescence response (1.3 per pH unit) in the pH range from 6.1 to 8.9.

Effect of denture adhesives on masticatory performance: Multicenter randomized controlled trial.

PURPOSE: The purpose of this study is to investigate the effects of denture adhesives on masticatory performance via a 10-center, parallel, randomized, controlled trial of complete denture wearers in Japan. METHODS: The trial was conducted between September 2013 and October 2016. The inclusion criteria were complete edentulism, willingness to undergo new complete denture treatment, and willingness to return for recall treatment. The exclusion criteria were age 90 years or older, presence of severe systemic illness, inability to understand the questionnaires, wearing metal base complete dentures, denture adhesive user, wearing prosthetics for maxillofacial defects, wearing complete dentures with tissue conditioners, and severe xerostomia. Randomization of the powder-type denture adhesive (powder), cream-type denture adhesive (cream), and control (saline) groups was performed using a sealed envelope system. Masticatory performance was measured using color-changeable chewing gum. Intervention blinding was not feasible. RESULTS: Sixty-seven control, 69 powder, and 64 cream participants are analyzed using the intention-to-treat principle. The participants in all groups show significantly improved masticatory performance at post-intervention (paired t-test with Bonferroni correction P < 0.0001). However, no significant difference in masticatory performance is detected among the three groups (one-way analysis of variance). A significant negative correlation between pre- and post-changes in masticatory performance and intraoral condition scores is observed (Pearson's correlation coefficient, P < 0.0001). CONCLUSIONS: Although denture adhesives improved the masticatory performance of complete denture wearers, their clinical effects are comparable to those of saline solution. The use of denture adhesives is more effective in complete denture wearers with unsatisfactory intraoral conditions.

Efficacy and safety of intravesical dimethyl sulfoxide treatment for patients with refractory Hunner-type interstitial cystitis: Real-world data postofficial approval in Japan.

OBJECTIVES: To examine real-world data regarding intravesical dimethyl sulfoxide (DMSO) therapy after official approval as a treatment for Hunner-type interstitial cystitis (HIC) in Japan. METHODS: This single institution, retrospective observational study was conducted between 2021 and 2022 to evaluate the outcomes of 30 patients with refractory HIC who received intravesical DMSO therapy according to the approved standardized regimen: administration of DMSO every 2 weeks for a total of 12 weeks. Treatment outcomes were evaluated using a 7-graded global response assessment scale, O'Leary and Sant's symptom and problem indices (OSSI/OSPI), the overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, quality of life (QOL) score, and frequency volume chart variables. Related complications were also documented. RESULTS: The response rates at 2, 4, 6, 8, 10, and 12 weeks were 36.7%, 43.3%, 53.3%, 60.0%, 70.0%, and 70.0%, respectively. Compared with baseline, OSSI/OSPI, pain intensity, urinary frequency, and the QOL score improved significantly from 4 weeks of treatment. The OABSS score and functional bladder capacity also showed a tendency toward moderate improvement, but the difference was not significant. The mean duration of symptom relapse after termination of treatment was 6.4 ± 3.9 months. No patients discontinued treatment due to adverse events, although acute bladder irritation during infusion was noted in 21 patients (70%), which disappeared within 3 days. CONCLUSIONS: This study verifies the safety, moderately durable efficacy, and tolerability of the standard intravesical treatment with DMSO for HIC in Japan.

Extragonadal recurrence of benign mature teratoma in the pouch of Douglas.

Laparoscopic cystectomy for mature teratomas is associated with a high incidence of intraperitoneal spillage and tumor spread; however, extragonadal recurrence of this benign tumor is rare. We hereby present an additional case of extragonadal mature teratoma that recurred in the pouch of Douglas after ovarian cystectomy. A 43-year-old Japanese woman presented with atypical genital bleeding. A 7 cm mature teratoma was detected using transvaginal ultrasonography and magnetic resonance imaging. At 26 years old, she underwent bilateral cystectomy for bilateral mature teratoma of the ovary. During laparoscopic surgery, a cystic tumor appeared in the pouch of Douglas and was firmly adhered to the surrounding tissues. Both ovaries were normal. The resected tumor was diagnosed as extragonadal, benign, mature teratoma. To avoid the extragonadal recurrence of mature teratoma, removal of tumor contents from intraperitoneal spillage by lavage should be performed at the end of surgery.

Achieving High Piezoelectric Performance across a Wide Composition Range in Tetragonal (Bi,Na)TiO3-BaTiO3 Films for Micro-electromechanical Systems.

Tetragonal (1-x)(Bi,Na)TiO3-xBaTiO3 films exhibit enhanced piezoelectric properties due to domain switching over a wide composition range. These properties were observed over a significantly wider composition range than the morphotropic phase boundary (MPB), which typically has a limited composition range of 1-2%. The polarization axis was found to be along the in-plane direction for the tetragonal composition range x = 0.06-1.0, attributed to the tensile thermal strain from the substrate during cooling after the film formation. A "two-step increase" in remanent polarization against an applied maximum electric field was observed at the high-field region due to the domain switching, and a very high piezoelectric response (effective d33 value, denoted as d33,f) over 220 pm/V was achieved for a wide composition range of x = 0.2-0.5 with high tetragonality, exceeding previously reported values for bulk ceramics. Moreover, a transverse piezoelectric coefficient, e31,f, of 19 C/m2 measured using a cantilever structure was obtained for a composition range of at least 10 atom % (for both x = 0.2 and 0.3). This value is the highest reported for Pb-free piezoelectric thin films and is comparable to the best data for Pb-based thin films. Reversible domain switching eliminates the need for conventional MPB compositions, allowing an improvement in the piezoelectric properties over a wider composition range. This strategy could provide a guideline for the development of environmentally acceptable lead-free piezoelectric films with composition-insensitive piezoelectric performance to replace Pb-based materials with MPB composition, such as PZT.

Development of Polymer-Lipid Hybrid Nanoparticles for Large-Sized Plasmid DNA Transfection.

RNA and DNA delivery technologies using lipid nanoparticles (LNPs) have advanced significantly, as demonstrated by their successful application in mRNA vaccines. To date, commercially available RNA therapeutics include Onpattro, a 21 bp siRNA, and mRNA vaccines comprising 4300 nucleotides for COVID-19. However, a significant challenge remains in achieving efficient transfection, as the size of the delivered RNA and DNA increases. In contrast to RNA transfection, plasmid DNA (pDNA) transfection requires multiple steps, including cellular uptake, endosomal escape, nuclear translocation, transcription, and translation. The low transfection efficiency of large pDNA is a critical limitation in the development of artificial cells and their cellular functionalization. Here, we introduce polymer-lipid hybrid nanoparticles designed for efficient, large-sized pDNA transfection. We demonstrated that LNPs loaded with positively charged pDNA-polycation core nanoparticles exhibited a 4-fold increase in transfection efficiency for 15 kbp pDNA compared with conventional LNPs, which encapsulate a negatively charged pDNA-polycation core. Based on assessments of the size and internal structure of the polymer-lipid nanoparticles as well as hemolysis and cellular uptake analysis, we propose a strategy to enhance large-sized pDNA transfection using LNPs. This approach holds promise for accelerating the in vivo delivery of large-sized pDNA and advancing the development of artificial cells.

Genetically engineered transfusable platelets using mRNA lipid nanoparticles.

Platelet transfusions are essential for managing bleeding and hemostatic dysfunction and could be expanded as a cell therapy due to the multifunctional role of platelets in various diseases. Creating these cell therapies will require modifying transfusable donor platelets to express therapeutic proteins. However, there are currently no appropriate methods for genetically modifying platelets collected from blood donors. Here, we describe an approach using platelet-optimized lipid nanoparticles containing mRNA (mRNA-LNP) to enable exogenous protein expression in human and rat platelets. Within the library of mRNA-LNP tested, exogenous protein expression did not require nor correlate with platelet activation. Transfected platelets retained hemostatic function and accumulated in regions of vascular damage after transfusion into rats with hemorrhagic shock. We expect this technology will expand the therapeutic potential of platelets.