The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

The effectiveness of fascial closure with antimicrobial-coated sutures in preventing incisional surgical site infections in gastrointestinal surgery: a systematic review and meta-analysis.

The aim of this study was to conduct a systematic review and meta-analysis of the efficacy of fascial closure using antimicrobial-sutures specifically for the prevention of surgical site infections (SSIs) in gastrointestinal surgery, as part of the revision of the SSI prevention guidelines of the Japanese Society of Surgical Infectious Diseases (JSSI). We searched CENTRAL, PubMed and ICHUSHI-Web in May 2023, and included randomized controlled trials (RCTs) comparing antimicrobial-coated and non-coated sutures for fascial closure in gastrointestinal surgery (PROSPERO No. CRD42023430377). Three authors independently screened the RCTs. We assessed the risk of bias and the GRADE criteria for the extracted data. The primary outcome was incisional SSI and the secondary outcomes were abdominal wall dehiscence and the length of postoperative hospital stay. This study was supported partially by the JSSI. A total of 10 RCTs and 5396 patients were included. The use of antimicrobial-coated sutures significantly lowered the risk of incisional SSIs compared with non-coated suture (risk ratio: 0.79, 95% confidence intervals: 0.64-0.98). In subgroup analyses, antimicrobial-coated sutures reduced the risk of SSIs for open surgeries, and when monofilament sutures were used. Antimicrobial-coated sutures did not reduce the incidence of abdominal wall dehiscence and the length of hospital stay compared with non-coated sutures. The certainty of the evidence was rated as moderate according to the GRADE criteria, because of risk of bias. In conclusion, the use of antimicrobial-coated sutures for fascial closure in gastrointestinal surgery is associated with a significantly lower risk of SSI than non-coated sutures.

Impact of avalanche type of transport on internal transport barrier formation in tokamak plasmas.

In magnetic fusion plasmas, a transport barrier is essential to improve the plasma confinement. The key physics behind the formation of a transport barrier is the suppression of the micro-scale turbulent transport. On the other hand, long-range transport events, such as avalanches, has been recognized to play significant roles for global profile formations. In this study, we observed the impact of the avalanche-type of transport on the formation of a transport barrier for the first time. The avalanches are found to inhibit the formation of the internal transport barrier (ITB) observed in JT-60U tokamak. We found that (1) ITBs do not form in the presence of avalanches but form under the disappearance of avalanches, (2) the surface integral of avalanche-driven heat fluxe is comparable to the time rate change of stored energy retained at the ITB onset, (3) the mean E × B flow shear is accelerated via the ion temperature gradient that is not sustained under the existence of avalanches, and (4) after the ITB formation, avalanches are damped inside the ITB, while they remain outside the ITB.

3D metal powder additive manufacturing phased array antenna for multichannel Doppler reflectometer.

Measuring the time variation of the wavenumber spectrum of turbulence is important for understanding the characteristics of high-temperature plasmas, and the application of a Doppler reflectometer with simultaneous multi-frequency sources is expected. To implement this diagnostic in future fusion devices, the use of a phased array antenna (PAA) that can scan microwave beams without moving antennas is recommended. Since the frequency-scanning waveguide leaky-wave antenna-type PAA has a complex structure, we have investigated its characteristics by modeling it with 3D metal powder additive manufacturing (AM). First, a single waveguide is fabricated to understand the characteristics of 3D AM techniques, and it is clear that there are differences in performance depending on the direction of manufacture and surface treatment. Then, a PAA is made, and it is confirmed that the beam can be emitted in any direction by frequency scanning. The plasma flow velocity can be measured by applying the 3D manufacturing PAA to plasma measurement.

Recognition of pathogen-derived sphingolipids in Arabidopsis.

In plants, many invading microbial pathogens are recognized by cell-surface pattern recognition receptors, which induce defense responses. Here, we show that the ceramide Phytophthora infestans-ceramide D (Pi-Cer D) from the plant pathogenic oomycete P. infestans triggers defense responses in Arabidopsis. Pi-Cer D is cleaved by an Arabidopsis apoplastic ceramidase, NEUTRAL CERAMIDASE 2 (NCER2), and the resulting 9-methyl-branched sphingoid base is recognized by a plasma membrane lectin receptor-like kinase, RESISTANT TO DFPM-INHIBITION OF ABSCISIC ACID SIGNALING 2 (RDA2). 9-Methyl-branched sphingoid base is specific to microbes and induces plant immune responses by physically interacting with RDA2. Loss of RDA2 or NCER2 function compromised Arabidopsis resistance against an oomycete pathogen. Thus, we elucidated the recognition mechanisms of pathogen-derived lipid molecules in plants.

The cumulative incidence of and risk factors for morphometric severe vertebral fractures in Japanese men and women: the ROAD study third and fourth surveys.

This population-based cohort study with a 3-year follow-up revealed that the annual incidence rates of vertebral fracture (VF) and severe VF (sVF) were 5.9%/year and 1.7%/year, respectively. The presence of mild VF at the baseline was a significant risk factor for incident sVF in participants without prevalent sVF. INTRODUCTION: This study aimed to estimate the incidence of morphometric vertebral fracture (VF) and severe VF (sVF) in men and women and clarify whether the presence of a mild VF (mVF) increases the risk of incident sVF. METHODS: Data from the population-based cohort study, entitled the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study, were analyzed. In total, 1190 participants aged ≥ 40 years (mean age, 65.0 ± 11.2) years completed whole-spine lateral radiography both at the third (2012-2013, baseline) and fourth surveys performed 3 years later (2015-2016, follow-up). VF was defined using Genant's semi-quantitative (SQ) method: VF as SQ ≥ 1, mVF as SQ = 1, and sVF as SQ ≥ 2. Cumulative incidence of VF and sVF was estimated. Multivariate logistic regression analyses were performed to evaluate risk factors for incident sVF. RESULTS: The baseline prevalence of mVF and sVF were 16.8% and 6.0%, respectively. The annual incidence rates of VF and sVF were 5.9%/year and 1.7%/year, respectively. The annual incidence rates of sVF in participants without prevalent VF, with prevalent mVF, and with prevalent sVF were 0.6%/year, 3.8%/year, and 11.7%/year (p < 0.001), respectively. Multivariate logistic regression analyses in participants without prevalent sVF showed that the adjusted odds ratios for incident sVF were 4.12 [95% confident interval 1.85-9.16] and 4.53 [1.49-13.77] if the number of prevalent mVF at the baseline was 1 and ≥ 2, respectively. CONCLUSIONS: The annual incidence rates of VF and sVF were 5.9%/year and 1.7%/year, respectively. The presence of prevalent mVF was an independent risk factor for incident sVF.

Intervention of dementia support team pharmacists and its effects for the proper use of rivastigmine.

Pharmacist participation in the medical team is expected in dementia care. We investigated the use of rivastigmine, the intervention of pharmacists for its proper use, and its effects. The number of prescription proposals from the dementia care team pharmacist to the doctor was 87, and the number of acceptances was 57. The content of the proposal was 31/52 for additions/changes (number of acceptances/number of proposals), 21/28 for dose increase, 3/4 for discontinuation of administration, 2/2 for usage changes, and 1/1 for others. In increasing the dose, the number of patients who increased the maintenance dose to 18 mg was significantly higher in the group with the intervention of the pharmacist in the dementia care team than in the group without the intervention (3/12 cases vs. 0/24 cases, p = 0.031). The dose of the brought-in drug also significantly increased with pharmacist intervention compared with that in the non-intervention group (7/12 cases vs. 1/24 cases, p <0.001). The pharmacists of the dementia care team often intervened in the proper use of rivastigmine, which was found to be effective when increasing the dose. Thus, we believe that the active participation of pharmacists is necessary in dementia medication.

Analysis of the Motional Stark Effect (MSE) diagnostic to measure the rotational transform and current profile in the Large Helical Device.

The analysis method of the Motional Stark Effect (MSE) diagnostic to measure the rotational transform and current profiles in the Large Helical Device has been improved. This was done by using the Variational Moments Equilibrium Code to calculate an equilibrium database for various pressure profiles and current profiles. This method looks for the radial profile of the rotational transform in the equilibrium database that gives the best fit to the polarization angle profiles measured with the MSE diagnostic. This analysis improves the measurements of rotational transform, especially near the magnetic axis, where the sensitivity of the polarization angle measurements becomes low and the uncertainty due to error in the estimation of the Pfirsch-Schlüter current becomes large. The radial profiles of the rotational transform and current profiles for Electron Cyclotron Current Drive and Neutral Beam Current Drive are obtained in the new analysis method with a sufficiently high accuracy to discuss the discrepancy of the current density profiles between the measurements and the calculations.

Translating Dental, Oral, and Craniofacial Regenerative Medicine Innovations to the Clinic through Interdisciplinary Commercial Translation Architecture.

Few university-based regenerative medicine innovations in the dental, oral, and craniofacial (DOC) space have been commercialized and affected clinical practice in the United States. An analysis of the commercial translation literature and National Institute for Dental and Craniofacial Research's (NIDCR's) portfolio identified barriers to commercial translation of university-based DOC innovations. To overcome these barriers, the NIDCR established the Dental Oral Craniofacial Tissue Regeneration Consortium. We provide generalized strategies to inform readers how to bridge the "valley of death" and more effectively translate DOC technologies from the research laboratory or early stage company environment to clinical trials and bring needed innovations to the clinic. Three valleys of death are covered: 1) from basic science to translational development, 2) from translational technology validation to new company formation (or licensing to an existing company), and 3) from new company formation to scaling toward commercialization. An adapted phase-gate model is presented to inform DOC regenerative medicine teams how to involve regulatory, manufacturability, intellectual property, competitive assessments, business models, and commercially oriented funding mechanisms earlier in the translational development process. An Industrial Partners Program describes how to conduct market assessments, industry maps, business development processes, and industry relationship management methods to sustain commercial translation through the later-stage valley of death. Paramount to successfully implementing these methods is the coordination and collaboration of interdisciplinary teams around specific commercial translation goals and objectives. We also provide several case studies for translational projects with an emphasis on how they addressed DOC biomaterials for tissue regeneration within a rigorous commercial translation development environment. These generalized strategies and methods support innovations within a university-based and early stage company-based translational development process, traversing the many funding gaps in dental, oral, and craniofacial regenerative medicine innovations. Although the focus is on shepherding technologies through the US Food and Drug Administration, the approaches are applicable worldwide.

Effects of hydroxyapatite on PMMA-HAp cement for biomedical applications.

OBJECTIVE: The main goal of this study was to examine the influence of hydroxyapatite (HAp) macroaggreate concentrations on thermal and mechanical properties of radioactive bone cement and to study the relation of glass transition Tg with its mechanical properties. METHODS: The bone cement as (1-x)PMMA-xHAp binary system was prepared in six [x] distinct concentration parameters of 0.0 up to 0.5. The HAp was synthesized using a solgel procedure following calcination by thermal treatment. The composite was prepared in cold based (non-radioactive) mixing polymethyl methacrylate (PMMA) and HAp. Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and mechanical compressive strength (CS) were used to measure the thermal and mechanical properties. RESULTS: The DSC and TGA thermal profiles in function to concentration parameter [x] were presented. The CS lies in a range of 3.71-7.37 MPa and the glass transition temperature Tg = 126.27 °C. There was a direct relationship between the PMMA-HAp thermoplastic properties with mechanical and thermal properties in function of HAp concentrations. CONCLUSION: The specific PMMA-HAp composite, with a concentration ratio of 1:1 and HAp thermal treatment at the Tg, provides a material with a compression strength of 7.37 MPa and a suitable amount of porous similar to a trabecular bone, possible to apply in bone cement implants, regardless of whether they are radioactive or not.

Mottness versus unit-cell doubling as the driver of the insulating state in 1T-TaS2.

If a material with an odd number of electrons per unit-cell is insulating, Mott localisation may be invoked as an explanation. This is widely accepted for the layered compound 1T-TaS2, which has a low-temperature insulating phase comprising charge order clusters with 13 unpaired orbitals each. But if the stacking of layers doubles the unit-cell to include an even number of orbitals, the nature of the insulating state is ambiguous. Here, scanning tunnelling microscopy reveals two distinct terminations of the charge order in 1T-TaS2, the sign of such a double-layer stacking pattern. However, spectroscopy at both terminations allows us to disentangle unit-cell doubling effects and determine that Mott localisation alone can drive gap formation. We also observe the collapse of Mottness at an extrinsically re-stacked termination, demonstrating that the microscopic mechanism of insulator-metal transitions lies in degrees of freedom of inter-layer stacking.

Clinical and pathological features affecting cardiac sympathetic denervation in autopsy-confirmed dementia with Lewy bodies.

BACKGROUND AND PURPOSE: The aim was to clarify the features affecting cardiac sympathetic denervation in autopsy-confirmed dementia with Lewy bodies (DLB) patients. METHODS: Fifty-four autopsy-confirmed DLB patients were enrolled. Tissue samples of the left ventricular anterior wall were immunostained with anti-tyrosine hydroxylase antibody to identify catecholaminergic nerve axons. Immunostained areas were quantified as residual cardiac sympathetic nerve (CSN) axons and the relationship between the degree of residual CSN axons and clinical and neuropathological features was examined. RESULTS: Virtually all patients showed small amounts of residual CSN axons (0.87%, range 0.02%-9.98%), with 50 patients (92.6%) showing <2.0% of residual axons. The patients who showed psychological symptoms within the first year of the disease had significantly more residual CSN axons than the remaining patients did (1.50% vs. 0.40%, P < 0.01). Patients with a short disease duration and neocortical-type Lewy body pathology tended to have more preserved CSN axons, although this difference was not statistically significant. Fifty-three patients (98.1%) who had neurofibrillary tangles in the brain and strong concomitant Alzheimer's disease pathology also had statistically significantly more preserved CSN axons. The patient with the most preserved CSN axons showed different characteristics from the results, except for the first symptom. CONCLUSION: Psychological symptoms within the first year of the disease, a short disease duration, neocortical-type Lewy body pathology and strong concomitant Alzheimer's disease pathology may be related to mild CSN degeneration in DLB patients. Thus, DLB patients with broad Lewy body pathology in the brain in the early stages may show mild CSN degeneration.

Analysis of the cesium distribution in the JT-60SA negative ion sources for steady long-pulse operation.

To realize stable negative ion beams for 100 s required in the neutral beam injector of JT-60SA, a physical model to control cesium (Cs) distribution inside the negative ion source has been developed in order to maintain the stable negative ion production at the plasma grid (PG) surface with Cs. In this work, to quantitatively evaluate Cs coverage on the PG, a three-dimensional Cs transportation code was introduced to consider the spatial Cs distribution in the source. The spatial temperature distribution of the chamber wall was also introduced in this model. As a result, the reasonable variation of the Cs coverage for 100 s was obtained, compared to that in the initial model. Based on the modified model, the operational temperature of the chamber wall was proposed to be less than 60 °C to suppress the desorption of Cs in the chamber wall and to sustain the stable negative ion production. In addition, it was also suggested that a slightly higher wall temperature before the operation leads to a decrease in the amount of Cs stored at the chamber wall, resulting in suppression of Cs consumption in the ion source.

Achievement of high power and long pulse negative ion beam acceleration for JT-60SA NBI.

Long pulse acceleration of hydrogen negative ion beams with the power density over 70 MW/m2 and the pulse length over 100 s has been demonstrated for the first time by using a multi-aperture 3-stage accelerator. Such long pulse acceleration was achieved by integrating the design of beam optics and voltage holding capability to meet the requirements of JT-60SA. By using the newly designed accelerator for JT-60SA, voltage holding at 500 kV with beam acceleration was stably sustained even after 5 g of cesium was seeded, and heat load on each acceleration grid was reduced below the allowable level for long pulse, less than 5% of total acceleration power. As a result, 500 keV, 154 A/m2 for 118 s beam acceleration was achieved, which satisfies the requirement of the negative ion source for JT-60SA. This pulse length of such high-power density beams is longest in the world. In addition, the result contributes to the long pulse acceleration of multi-stage electrostatic accelerators, such as 1 MeV negative ion accelerator for ITER.

Design of photonic-crystal surface-emitting lasers with enhanced in-plane optical feedback for high-speed operation.

Photonic-crystal surface-emitting lasers (PCSELs) use the two-dimensional (2D) resonance at the band-edge of a photonic crystal for lasing, and they feature various outstanding functionalities such as high-brightness lasing, arbitrary shaping of beam patterns and on-chip 2D beam steering. In this paper, to investigate the applicability of PCSELs for high-speed operation, we design PCSELs with enhanced in-plane optical feedback, which enable single-mode lasing inside a circular region the diameter of which is less than 10 µm. To realize a strong in-plane confinement of the lasing mode, we increase the one-dimensional coupling coefficients between counter-propagating waves through the careful design of the lattice points. We also introduce an in-plane heterostructure composed of two photonic crystals with different photonic bandgaps and utilize reflection at the boundary of the two photonic crystals in addition to the optical feedback at the band-edge of each photonic crystal. By using three-dimensional finite-difference time-domain method (3D-FDTD), we confirm that the proposed hetero-PCSELs can achieve single-mode lasing operation inside a 9-µm-diameter and possibly realize a 3-dB modulation bandwidth larger than 40 GHz.

Oral function and vertical jump height among healthy older people in Japan.

OBJECTIVE: Vertical jump height and oral function affect the general muscle condition. This study aimed to evaluate the association between vertical jump height and oral function among healthy older individuals. BASIC RESEARCH DESIGN: Cross-sectional analytic study. PARTICIPANTS: 231 independent older people (mean age, 74.4 ± 5.6 years) who participated in the Kyoto Elders Physical Fitness Measurement Research Project. Individuals with partial or complete edentulousness who did not use a prosthetic device or complained of oral/maxillofacial pain were excluded from the study. INTERVENTIONS: Grip strength was measured using a Smedley Hand Dynamometer. To measure masticatory performance, the participants were instructed to chew a gummy jelly on their habitual chewing side (left or right) for 20 s. Occlusal force, contact area, and pressure were also assessed. MAIN OUTCOME MEASURES: The outcome variable was vertical jump height. The predictor variables were physical status (age, body mass index, and grip strength), oral status (number of present teeth and denture use), and oral function (masticatory performance, occlusal force, occlusal contact area, occlusal pressure, and tongue pressure). These relationships were evaluated with univariate analysis, and then multiple regression analysis was performed with age as the covariate for each male and female participant. RESULTS: Vertical jump height was significantly associated with grip strength in both men and women. Moreover, in women, it was associated with masticatory performance, occlusal force, and occlusal contact area. CONCLUSIONS: Vertical jump height was closely associated with oral function among healthy older women.

A population-based study identifies an association of THBS2 with intervertebral disc degeneration.

OBJECTIVE: To clarify the genetic mechanisms underlying intervertebral disc degeneration (IDD), we examined the associations between single-nucleotide polymorphisms (SNPs) and indicated as coefficient of interaction term (IDD) in a general population in Japan. METHODS: This was a cross-sectional study. In 1,605 participants, C2-3 to L5/S1 in the total spine magnetic resonance imaging (MRI) were evaluated using the Pfirrmann's scoring system. Disc scores of 4 and 5 were defined as IDD. Eight SNPs in eight genes associated with IDD were examined at each disc level, considering the non-genetic risk factors of age, sex, and body mass index (BMI). RESULTS: The highest odds ratio was found for rs9406328 in the THBS2 gene at disc level T12-L1 (OR 1.27, 95%CI 1.05 to 1.53), and this association was strengthened after adjustment for age using logistic regression (OR 1.37, 95%CI 1.12 to 1.67). Among participants aged <50 years and 50-59, the average IDD score in those with 2 risk alleles of rs9406328 was markedly higher than in those with 0 or 1 risk allele, and the difference is much wider than the elderly participants. It indicates the genetic effect of rs9406328 is stronger in the younger age groups. Finally, multiple linear regression analyses of the association between rs9406328 and IDD, adjusted for age, sex, and BMI at each disc level, showed a statistical interaction between age and the number of risk alleles at C7-T1, T3-4 and T4-T5 as well as T12-L1. CONCLUSION: CONCLUSION: The association between rs9406328 in THBS2 and IDD was replicated. The contributions of genetic and environmental factors to IDD differed by disc level.

Development and chemical characterization of biodegradable polymeric implants containing sirolimus for the treatment of malignant solid tumors.

The use of sirolimus and its analogs has been evaluated in studies aimed at combating several types of cancer; however, because of the limited bioavailability of the drug, the search for new forms of administration is required. Biodegradable polymeric implants containing sirolimus were developed and assessed as an alternative method of drug administration. Implants containing 25 % (w/w) sirolimus were prepared employing the polymer matrices chitosan, polycaprolactone and poly(lactic-co-glycolic acid) (PLGA) in two proportions: PLGA 50:50 and PLGA 75:25. Thermal analysis techniques such as thermogravimetry and differential scanning calorimetry, combined with x-ray diffraction were used to characterize and evaluate the compatibility of the constituents of the formulation. No incompatibilities were found between the components, but drug amorphization was observed in all samples. Implants made from the polymers chitosan and PCL may accelerate the degradation of SRL when these polymers are dissolved in methanol at 50 °C. HPLC analysis showed that the implant prepared with PLGA 75:25 did not present degradation products and maintained its appropriate drug content, even when dissolved in methanol and heated to 50 °C. Therefore, it represents the most suitable biodegradable polymer for use in implants developed for the treatment of malignant solid tumors. However, it is still necessary to further study the drug effects after amorphization of the crystal and also to perform stability and solubility analysis.