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The increase in high-precision radiation therapy, particularly volumetric-modulated arc therapy (VMAT), has increased patient numbers and expanded treatment sites. However, a significant challenge in VMAT treatment planning is the inconsistent plan quality among different planners and facilities. This study explored the use of dose-volume histogram (DVH) prediction tools to address these disparities, specifically focusing on RapidPlan (Varian Medical Systems) and PlanIQ (Sun Nuclear). RapidPlan predicts achievable DVHs and automatically generates optimization objectives. While it has demonstrated organ-at-risk (OAR) dose reduction benefits, the quality of the plan used to build its model significantly affects its predictions. On the other hand, PlanIQ offers ease of use and does not require prior model-building. Five planners participated in this study, each creating two treatment plans: one referencing RapidPlan and the other using PlanIQ. The planners had the freedom to adjust parameters while referencing the DVH predictions. The plans were evaluated using "Plan Quality Metric" (PQM) scores to assess the planning target volume excluding the rectum and OARs. The results revealed that RapidPlan-referenced plans often outperformed PlanIQ-based plans, with less interplanner variability. PlanIQ played a pivotal role in the construction of the RapidPlan model. This study is the first to compare plans generated by multiple planners using both tools. This study provides insights into optimizing treatment planning by considering the characteristics of both RapidPlan and PlanIQ., Competing Interests: Declaration of competing interest Yuji Nakaguchi is an employee of TOYO MEDIC Co., Ltd., (Copyright © 2024 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

The enhancement of insulin secretion and of the proliferation of pancreatic β cells are promising therapeutic options for diabetes. Signals from the vagal nerve regulate both processes, yet the effectiveness of stimulating the nerve is unclear, owing to a lack of techniques for doing it so selectively and prolongedly. Here we report two optogenetic methods for vagal-nerve stimulation that led to enhanced glucose-stimulated insulin secretion and to β cell proliferation in mice expressing choline acetyltransferase-channelrhodopsin 2. One method involves subdiaphragmatic implantation of an optical fibre for the photostimulation of cholinergic neurons expressing a blue-light-sensitive opsin. The other method, which suppressed streptozotocin-induced hyperglycaemia in the mice, involves the selective activation of vagal fibres by placing blue-light-emitting lanthanide microparticles in the pancreatic ducts of opsin-expressing mice, followed by near-infrared illumination. The two methods show that signals from the vagal nerve, especially from nerve fibres innervating the pancreas, are sufficient to regulate insulin secretion and β cell proliferation., (© 2023. The Author(s).)

Introduction Surgery is the recommended treatment for medication-related osteonecrosis of the jaw (MRONJ). However, the disease may recur postoperatively. We reviewed imaging findings in patients undergoing three or more surgeries. Patients and methods One hundred fifty patients with MRONJ underwent surgery at our hospital. Here, we present the characteristics of 34 surgeries in nine patients (two men and seven women; mean age, 73.9 years) who underwent surgery at least three times. Results Three and six patients had maxillary and mandibular lesions, respectively. The primary disease was malignancy in eight patients, and denosumab was used in seven patients. All patients initially underwent either partial maxillectomy or marginal mandibulectomy, and segmental mandibulectomy was not performed. The number of surgeries ranged from three to six (average, 3.8). Healing was eventually achieved in seven cases, but not in two cases. Of the 27 unsuccessful surgeries, postoperative cone-beam computed tomography revealed no residual osteolysis, periosteal reaction, or osteosclerosis after seven surgeries and some residual lesions after 19 surgeries; imaging was not performed after one surgery. In contrast, among the seven successful surgeries, no residual osteolysis, periosteal reaction, or osteosclerosis was observed in all six cases in which postoperative computed tomography was performed. Conclusion Recurrence is more common in patients with residual areas of osteolysis, periosteal reactions, or mixed-type osteosclerosis, and including these areas in the resection is desirable., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board (IRB) of Kansai Medical University issued approval 2022166. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sawada et al.)

Background: Rapid identification of causative bacteria in treatment of acute otitis media (AOM) is of paramount importance for appropriate antibiotic use., Materials and Methods: This prospective observational study was conducted in 15 hospitals and clinics in Japan between 2018 and 2020. A new rapid antigen test kit (AOS-116), which simultaneously detects antigens for Streptococcus pneumoniae (Sp) and Haemophilus influenzae (Hi), was applied for middle ear fluids (MEFs) and nasopharyngeal secretions (NPSs) in patients with moderate to severe AOM. We investigated relationship between the results of rapid test, severity at initial visit, and clinical course., Results: Regarding performance accuracy based on culture results, AOS-116 showed 1) high (>80%) sensitivity, specificity, and negative predictive value (NPV) in MEFs for both antigens, 2) high sensitivity, specificity, and positive predictive value (PPV) in NPSs for Hi antigen, and 3) high specificity, and PPV in NPSs for Sp antigen. Regarding predictive value of nasopharyngeal culture and antigen detection for causative middle ear pathogens, similar results were observed between AOS-116 and culture, which was characterized with high sensitivity and NPV for both pathogens. MEFs/NPSs positive for Hi antigen were significantly associated with eardrum findings, and severity. MEFs/NPSs positive for pneumococcal antigen were significantly associated with severity of otalgia, fever, and otorrhea. Among patients with prior antimicrobial treatment, improvement tended to be slower in cases positive for Hi than in cases negative., Conclusion: The rapid antigen detection test is useful as a decision-making tool for prescribing antimicrobial agents and may play an important role in promoting appropriate antimicrobial use., Competing Interests: Declaration of competing interest The authors declare financial support from ASAHI KASEI Corporation. Takuji Miyata and Norikazu Okamura are employees of Asahi Kasei Corporation. The funder had no role in the experimental design, implementation of the study, interpretation of the data, or decision to submit the manuscript for publication. This does not alter the authors’ adherence to any publication policies on sharing data and materials., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction Medication-related osteonecrosis of the jaw (MRONJ) develops from odontogenic infection. However, there are also some cases of MRONJ developing from sites with no teeth, no root canal lesions, or no periodontal disease. This study aimed to retrospectively review radiographic images of MRONJ cases and examine the differences in characteristics between MRONJ suspected to be related to dental infection (odontogenic MRONJ) and MRONJ that occurred without dental involvement or of unknown cause (non-odontogenic MRONJ). Materials and methods One hundred and forty-five patients were diagnosed with MRONJ at Kansai Medical University Hospital and Kansai Medical University Medical Center. The following variables were investigated: sex, age, primary disease, MRONJ site, body mass index, smoking habit, diabetes, corticosteroids, type of antiresorptive agent, administration period, CT findings (separation of sequestrum, osteolysis, periosteal reaction, and osteosclerosis), trigger, leukocytes, neutrocytes, neutrophil-lymphocyte ratio, serum albumin, and serum creatinine levels. Results In the univariate analysis, significant differences between odontogenic and non-odontogenic MRONJs were found in patients whose primary disease was malignancy, receiving denosumab (DMB), and with short administration period of antiresorptive agent, no osteolysis, periosteal reaction, and serum creatinine level. In multivariate analysis, non-odontogenic MRONJ was significantly more common in patients with no osteolysis and with periosteal reaction. Conclusion Non-odontogenic MRONJ tends to occur more frequently in patients treated with high-dose DMB, and there were significantly more cases of non-osteolytic MRONJ without radiographic evidence of osteolysis or with periosteal reactions., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Sakamoto et al.)

Introduction: Eosinophils contribute to the pathogenesis of allergic diseases, including asthma, allergic rhinitis, and atopic dermatitis. We previously reported that human tissue eosinophils have high CD69 expression compared to blood eosinophils, and its expression is correlated with disease severity and the number of infiltrated eosinophils. However, biological CD69 signaling activity in eosinophils remains unclear., Methods: CD69 expression on lung tissue eosinophils obtained from mice with ovalbumin-induced asthma was measured using flow cytometry. CD69 crosslinking was performed on eosinophils purified from the spleen of IL-5 transgenic mice to investigate CD69 signaling and its function in eosinophils. Then, qPCR, Western blot, enzyme-linked immunosorbent assay, and survival assay results were analyzed., Results: Surface CD69 expression on lung tissue eosinophils in the asthma mice model was 2.91% ± 0.76%, whereas no expression was detected in the healthy group. CD69-expressed eosinophils intrinsically have an upregulation of IL-10 mRNA expression. Moreover, CD69 crosslinking induced further pronounced IL-10 production and apoptosis; these responses were mediated via the Erk1/2 and JNK pathways, respectively., Conclusions: Our results suggested that CD69 + eosinophils play an immunoregulator role in type 2 inflammation, whereas activated tissue eosinophils contribute to the pathogenesis of asthma.

Background/aim: A genomic analysis based on next-generation sequencing is important for deciding cancer treatment strategies. Cancer tissue sometimes displays intratumor heterogeneity and a pathologic specimen may contain more than two tumor grades. Although tumor grades are very important for the cancer prognosis, the impact of higher tumor grade distribution in a specimen used for a genomic analysis is unknown., Patients and Methods: We retrospectively analyzed the data of 61 clear cell carcinoma and 46 prostate cancer patients that were diagnosed between December 2018 and August 2022 using the GeneRead Human Comprehensive Cancer Panel or SureSelect PrePool custom Tier2. Genome annotation and curation were performed using the GenomeJack software., Results: Tumor mutation burden (TMB) was increased in proportion to the higher tumor grade distribution in grade 2 clear cell renal cell carcinoma (ccRCC). In PC, Grade Group 3/4 specimens that included an increased distribution of Gleason pattern 4 had more frequent gene mutations., Conclusion: Our results suggest the importance of selecting the maximum distribution of higher tumor grade areas to obtain results on the precise gene alterations for genomics-focused treatments., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Surgery is the standard treatment for medication-related osteonecrosis of the jaw (MRONJ). This study reviewed patients with mandibular MRONJ who underwent surgical treatment, and in particular the characteristics of non-osteolytic MRONJ with no evidence of osteolysis on CT were described., Materials and Methods: We conducted a retrospective study of patients with mandibular MRONJ who underwent surgery between January 2016 and September 2022. Various clinical and imaging factors regarding treatment outcomes were investigated and analyzed. Additionally, the disease course of non-osteolytic MRONJ was examined in detail., Results: This study included 55 patients (66 surgeries) with a mean age of 74.7. The primary disease was osteoporosis (24 patients) and malignancy (31 patients); the type of antiresorptive agent was bisphosphonate (BP) in 21 patients and denosumab (DMB) in 26. BP was initially administered; however, it was changed to DMB in eight patients. Preoperatively, the cumulative cure rates for all 66 surgeries were 72.8% at 1 year and 77.3% at 2 years. Cure rates were significantly lower in patients with malignancy, those without osteolysis, and those who underwent sequestrum removal or marginal mandibulectomy than those with osteoporosis, osteolysis, and segmental mandibulectomy. Non-osteolytic MRONJ was observed in eight patients, all with malignancy and receiving high-dose DMB. Only two patients were cured after the initial surgery, and most patients ultimately underwent segmental mandibulectomy., Conclusions: Surgical treatment yielded good treatment outcomes in most patients with mandibular MRONJ; however, the cure rate was lower in patients with malignancy who showed no osteolysis on CT images., (© 2024. The Japanese Society Bone and Mineral Research.)

Intestinal perforation and obstruction are known to be one of the adverse events caused by antipsychotics; however, warning information on package inserts varies among antipsychotics. To investigate the risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics compared with those in patients prescribed typical antipsychotics, a nested case-control study was conducted utilizing real-world data from the MID-NET ® medical information database in Japan. The study period spanned from January 1, 2009, to December 31, 2018. We found that the risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics were significantly lower than those in patients prescribed typical antipsychotics (adjusted odds ratio, 0.48; 95% confidence interval, 0.29-0.80). This finding was supported with prolonged periods for the exposure definition in the sensitivity analyses. In addition, no major differences in the risks of atypical antipsychotics, such as risperidone, quetiapine, olanzapine, and aripiprazole, were identified in this study. The safety profile regarding the lower risks of gastrointestinal perforation and intestinal obstruction in patients prescribed atypical antipsychotics should be considered when choosing antipsychotics in clinical practice in terms of the proper use of such drugs., (© 2023. The Author(s).)

Myocardial calcification in myocarditis is rare and may be linked to poor outcomes. We herein report a case of fulminant myocarditis with massive myocardial calcification and its pathological outcomes at autopsy. A 49-year-old man experienced chest pain and was diagnosed with acute myocarditis. His cardiac function did not recover despite mechanical circulatory support in combination with V-A extracorporeal membrane oxygenation and IMPELLA CP ® . He eventually developed sepsis and gastrointestinal bleeding and died on day 27. Diffuse myocardial calcification was observed on computed tomography at autopsy. The pathological autopsy depicted that calcification filled every myocardial cell in the left ventricle.

Sacubitril/valsartan, a novel therapy in chronic heart failure (CHF), inhibits the breakdown of various peptides. However, whether or not sacubitril/valsartan administration affects urinary C-peptide levels is unclear. We herein report a 70-year-old man with type 2 diabetes mellitus (T2DM) and hypertension coexisting with CHF and nephrotic syndrome. The patient's urinary C-peptide levels dramatically increased after sacubitril/valsartan administration and decreased after discontinuation of the drug. Furthermore, sacubitril/valsartan administration to five other patients with hypertension and T2DM markedly increased urinary C-peptide levels. Thus, the insulin secretory capacity of patients with T2DM receiving sacubitril/valsartan may be overestimated when their urinary C-peptide level is measured.

Objective: Acute myeloid leukemia (AML) is the most common form of leukemia among adults in Japan. This study aimed to understand the treatment patterns, health care resource utilization, and costs of FMS-like tyrosine kinase 3 mutation-positive (FLT3m+) AML patients in Japan., Methods: A retrospective cohort study of Japanese FLT3m + AML patients was conducted using data extracted from a national hospital-based claims database provided by Medical Data Vision Co. Ltd. (MDV; Tokyo, Japan). Patients were identified from the MDV database between April 2008 and April 2021 inclusive., Results: A total of 360 patients were included in this study. The study results suggest that cytarabine + anthracyclines was the most common first-line (1 L) treatment, accounting for 41.3% of the patients. FLT3 inhibitors (FLT3i) was the most common treatment across the study period (95.7%). The mean age of patients was 62.4 years, and most were 65 years or older. The median overall survival (OS) after initiating FLT3i treatment was 394 days. The median treatment duration of FLT3i was 88.5 days, while it was 66.0 days for patients treated with FLT3i within 60 days after hematopoietic stem cell transplantation (HSCT). The overall mean monthly total treatment cost was JPY 2,009,531.7/per patient per month (PPPM) (USD 17,967.9/PPPM)., Conclusions: The study found specific treatment patterns, trends and features in patients with FLT3m + AML. FLT3i was the most prescribed treatment across the study period and the overall median OS after initiating FLT3i treatment was over 1 year. The findings of this study could be helpful for clinicians to optimize treatment strategies for FLT3m + AML in Japan.

Background/purpose: Denosumab is used to treat bone metastases from malignant tumors. Unlike bisphosphonates, denosumab is not deposited in the bone; thus, withdrawal for a relatively short period would help recovery from osteoclast suppression. This study investigated the relationship between drug holidays and recovery from osteoclast suppression., Materials and Methods: Seven patients who received high-dose denosumab and underwent segmental mandibulectomy for medication-related osteonecrosis of the jaw were enrolled in this study. Osteoclast suppression (+) was defined as the absence of cathepsin K-positive cells or cathepsin K-positive mononuclear or small multinucleated cells observed on the bone surface of both mesial and distal specimens. When normal osteoclasts were found, osteoclast suppression was defined as (-); when both suppressed cathepsin K-positive cells and normal morphological osteoclasts were found, it was defined as (±)., Results: Osteoclast suppression was: (+) in four patients, three without a drug holiday and one with a 9-month drug holiday; (±) in one patient with an 8-month drug holiday, and (-) in two patients with drug holidays for 13 and 20 months., Conclusion: These findings suggest that a long-term drug holiday, such as 12 months, is required for recovery from osteoclast suppression in patients with cancer receiving high-dose denosumab., Competing Interests: The authors declare no conflict of interest., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background: Adenoid ameloblastoma (AdAM) is a frequently recurrent tumor that shows hybrid histological features of both ameloblastoma and adenomatoid odontogenic tumor (AOT). AdAM is expected to be classified as a new subtype of ameloblastoma in the next revision of the World Health Organization (WHO) odontogenic tumor classification. However, whether AdAM is a histologic variant of ameloblastoma or AOT remains unclear. To establish a new category, genetic evidence indicating the tumor category is necessary., Methods: We present a case of a 23-year-old Japanese woman with AdAM who underwent genetic/DNA analysis for ameloblastoma-related mutation using immunohistochemical staining, Sanger sequencing, and next-generation sequencing (NGS) analyses with reliable clinicopathological evidence., Results: Immunohistochemical expression of BRAF p.V600E was diffusely positive for both ameloblastoma- and AOT-like components. Sanger sequencing and NGS analyses showed missense mutations in BRAF p.V600E (c.1799T > A), a gene that is commonly altered in ameloblastomas but not in KRAS, another gene associated with AOT., Conclusion: This case report is the first to provide genetic evidence on the ameloblastomatous origin of AdAM with a BRAF p.V600E mutation. A larger series of AdAM groups' molecular testing is needed to aptly classify them and prognosticate the best treatment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Medication-related osteonecrosis of the jaw (MRONJ) is a refractory osteonecrosis caused by antiresorptive agents such as bisphosphonate and denosumab (DMB). In MRONJ surgery, computed tomography (CT) is generally used to determine the extent of bone resection. However, in some recent MRONJ cases, no abnormal findings were detected on CT. Therefore, we aimed to clarify the characteristics of MRONJ without osteolysis. This retrospective and observational study included 18 patients diagnosed with MRONJ between October 2020 and October 2022 at Department of Dentistry and Oral Surgery, Kansai Medical University Medical Center. In four of 18 patients with MRONJ, no abnormal findings such as osteolysis, separation of sequestrum, and periosteal reaction were observed on CT images at the first visit. All four patients with non-osteolytic MRONJ had malignant tumors and received high-dose DMB, and in the four patients there were no preceding dental infections such as apical lesions or periodontal disease and the trigger of MRONJ was unknown. Surgery was performed in three of the four patients. The extent of bone resection was determined using magnetic resonance imaging and intraoperative gross findings. In the future, it is necessary to establish a method for diagnosing non osteolytic MRONJ and determining the extent of bone resection., (© 2023. Springer Nature Limited.)

We present measurements of the cross section and double-helicity asymmetry A&#95;{LL} of direct-photon production in p[over →]+p[over →] collisions at sqrt[s]=510  GeV. The measurements have been performed at midrapidity (|η|<0.25) with the PHENIX detector at the Relativistic Heavy Ion Collider. At relativistic energies, direct photons are dominantly produced from the initial quark-gluon hard scattering and do not interact via the strong force at leading order. Therefore, at sqrt[s]=510  GeV, where leading-order-effects dominate, these measurements provide clean and direct access to the gluon helicity in the polarized proton in the gluon-momentum-fraction range 0.02

Cell proliferation processes play pivotal roles in timely adaptation to many biological situations. Herein, we establish a highly sensitive and simple strategy by which time-series showing the proliferation of a targeted cell type can be quantitatively monitored in vivo in the same individuals. We generate mice expressing a secreted type of luciferase only in cells producing Cre under the control of the Ki67 promoter. Crossing these with tissue-specific Cre-expressing mice allows us to monitor the proliferation time course of pancreatic β-cells, which are few in number and weakly proliferative, by measuring plasma luciferase activity. Physiological time courses, during obesity development, pregnancy and juvenile growth, as well as diurnal variation, of β-cell proliferation, are clearly detected. Moreover, this strategy can be utilized for highly sensitive ex vivo screening for proliferative factors for targeted cells. Thus, these technologies may contribute to advancements in broad areas of biological and medical research., (© 2023. The Author(s).)

Lithium sulfur batteries are suitable for drones due to their high gravimetric energy density (2600 Wh/kg of sulfur). However, on the cathode side, high specific capacity with high sulfur loading (high areal capacity) is challenging due to the poor conductivity of sulfur. Shuttling of Li-sulfide species between the sulfur cathode and lithium anode also limits specific capacity. Sulfur-carbon composite active materials with encapsulated sulfur address both issues but require expensive processing and have low sulfur content with limited areal capacity. Proper encapsulation of sulfur in carbonaceous structures along with active additives in solution may largely mitigate shuttling, resulting in cells with improved energy density at relatively low cost. Here, composite current collectors, selected binders, and carbonaceous matrices impregnated with an active mass were used to award stable sulfur cathodes with high areal specific capacity. All three components are necessary to reach a high sulfur loading of 3.8 mg/cm 2 with a specific/areal capacity of 805 mAh/g/2.2 mAh/cm 2 . Good adhesion between the carbon-coated Al foil current collectors and the composite sulfur impregnated carbon matrices is mandatory for stable electrodes. Swelling of the binders influenced cycling retention as electroconductivity dominated the cycling performance of the Li-S cells comprising cathodes with high sulfur loading. Composite electrodes based on carbonaceous matrices in which sulfur is impregnated at high specific loading and non-swelling binders that maintain the integrated structure of the composite electrodes are important for strong performance. This basic design can be mass produced and optimized to yield practical devices.

The receptor activator of NF-κB ligand (RANKL)-binding peptide is known to accelerate bone morphogenetic protein (BMP)-2-induced bone formation. Cholesterol-bearing pullulan (CHP)-OA nanogel-crosslinked PEG gel (CHP-OA nanogel-hydrogel) was shown to release the RANKL-binding peptide sustainably; however, an appropriate scaffold for peptide-accelerated bone formation is not determined yet. This study compares the osteoconductivity of CHP-OA hydrogel and another CHP nanogel, CHP-A nanogel-crosslinked PEG gel (CHP-A nanogel-hydrogel), in the bone formation induced by BMP-2 and the peptide. A calvarial defect model was performed in 5-week-old male mice, and scaffolds were placed in the defect. In vivo μCT was performed every week. Radiological and histological analyses after 4 weeks of scaffold placement revealed that the calcified bone area and the bone formation activity at the defect site in the CHP-OA hydrogel were significantly lower than those in the CHP-A hydrogel when the scaffolds were impregnated with both BMP-2 and the RANKL-binding peptide. The amount of induced bone was similar in both CHP-A and CHP-OA hydrogels when impregnated with BMP-2 alone. In conclusion, CHP-A hydrogel could be an appropriate scaffold compared to the CHP-OA hydrogel when the local bone formation was induced by the combination of RANKL-binding peptide and BMP-2, but not by BMP-2 alone.

Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. The liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival during food shortages., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The conventional hydration number, λ, of a polymer electrolyte membrane (PEM) is estimated by the gravimetric measurement of the total water uptake in the membrane. This is the overall water molecules divided by the number of ionic groups covering the water distribution from the macroscale to the molecular level. For a more precise evaluation of the local ion-water interactions and ion transport efficiency in hydrophilic channels, in contrast to λ, we here propose an index, local hydration number (λ local ), defined as the number of water molecules located adjacent to and interacting with ionic groups in a PEM, per ionic group in the hydrophilic channels. We introduce an experimental method using partial scattering function analysis through a contrast-variation small-angle neutron scattering technique to precisely determine λ local at the micro- (nano-) scale to the molecular level for PEMs. When applied to the benchmark material Nafion and the well-studied radiation-grafted PEM, consisting of poly(styrene sulfonic acid) grafted onto poly(ethylene- co -tetrafluoroethylene) (ETFE- g -PSSA), the obtained λ local was close to the conventional λ. This means all water molecules interacted with sulfonic acid groups, which is much different from the case of anion-type grafted PEMs. Comparing the λ local value obtained in this study with the conventional λ value confirmed that water existed only in nanostructured hydrophilic channels in these PEMs. The result of this work provides a route to understand local molecular structures of high-performing PEMs for energy conversion applications.

Patients with primary intestinal follicular lymphoma are often followed-up without a specific treatment, and this approach is called the "watch-and-wait approach." However, the long-term outcomes of this patient group have not been sufficiently investigated. We enrolled patients with primary intestinal follicular lymphoma who were diagnosed before 2016 and managed with the watch-and-wait approach in 20 institutions. We retrospectively investigated the overall, disease-specific, and event-free survival rates as well as the rate of spontaneous regression. Among the 248 patients with follicular lymphoma with gastrointestinal involvement, 124 had localized disease (stage I or II 1 ). We analyzed the data of 73 patients who were managed using the watch-and-wait approach. During the mean follow-up period of 8.3 years, the follicular lymphoma had spontaneously resolved in 16.4% of the patients. The 5-year and 10-year overall survival rates were 92.9% and 87.1%, respectively. With disease progression (n = 7), initiation of therapy (n = 7), and histologic transformation to aggressive lymphoma (n = 0) defined as events, the 5-year and 10-year event-free survival rates were 91.1% and 86.9%, respectively. No patient died of progressive lymphoma. Thus, both 5-year and 10-year disease-specific survival rates were 100%. In conclusion, an indolent long-term clinical course was confirmed in the patients with primary intestinal follicular lymphoma. The watch-and-wait strategy is a reasonable approach for the initial management of these patients., (© 2023. The Author(s).)

The Pharmaceuticals and Medical Devices Agency (PMDA) has conducted many pharmacoepidemiological studies for postmarketing drug safety assessments based on real-world data from medical information databases. One of these databases is the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), containing health insurance claims of almost all Japanese individuals (over 100 million) since April 2009. This article describes the PMDA's regulatory experiences in utilizing the NDB for postmarketing drug safety assessment, especially focusing on the recent cases of use of the NDB to examine the practical utilization and safety signal of a drug. The studies helped support regulatory decision-making for postmarketing drug safety, such as considering a revision of prescribing information of a drug, confirming the appropriateness of safety measures, and checking safety signals in real-world situations. Different characteristics between the NDB and the MID-NET ® (another database in Japan) were also discussed for appropriate selection of data source for drug safety assessment. Accumulated experiences of pharmacoepidemiological studies based on real-world data for postmarketing drug safety assessment will contribute to evolving regulatory decision-making based on real-world data in Japan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shida, Kajiyama, Sawada, Ishiguro, Kubo, Kimura, Hirano, Komiyama, Iguchi, Oniyama and Uyama.)

In the present study, we aimed to investigate the association between urate-lowering drugs and cardiovascular events, primarily focusing on the risk of febuxostat and topiroxostat when compared with allopurinol in Japan. We conducted an observational study with a cohort design using the National Database of Health Insurance Claims and Specific Health Checkups of Japan, including new urate-lowering drugs users between August 1, 2010, and March 31, 2018. Exposure and control groups were defined based on the first prescription of urate-lowering drugs as follows: febuxostat or topiroxostat for exposure groups, allopurinol for the control group, and benzbromarone for the secondary control group. The primary outcome was cardiovascular events, defined as a composite of acute coronary syndrome, cerebral infarction, and cerebral hemorrhage. Hazard ratios were estimated using a Cox proportional hazards model. The number of patients in each exposure and control group was 1,357,671 in the febuxostat group, 83,683 in the topiroxostat group, 1,273,211 in the allopurinol group, and 258,786 in the benzbromarone group. The adjusted hazard ratios for the cardiovascular risk were 0.97 (95% confidence interval [CI]: 0.95-0.98) for febuxostat and 0.84 (95% CI: 0.78-0.90) for topiroxostat groups. The benzbromarone group exhibited similar results. No increased cardiovascular risk was observed with febuxostat or topiroxostat when compared with allopurinol in patients with hyperuricemia in Japan. These results provide real-world evidence regarding the cardiovascular risk associated with urate-lowering drugs, indicating that no additional safety-related regulatory actions are warranted in Japan., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Conjugating small-molecule ligands to synthetic motifs that can localize to specific organelles or membranes in living cells is a practical approach to develop compounds as chimeric tools or drugs that can manipulate biological processes in a subcellular site-specific manner. However, the number of available organelle-targeted synthetic motifs for small-molecule localization is limited. We have recently developed a synthetic myristoyl- D Cys motif for small-molecule localization that undergoes S -palmitoylation via the cellular palmitoylation machinery and localizes to the Golgi surface. Herein, we show that the lipid acyl chain of the myristoyl (C14)- D Cys motif can be as short as 10-carbons and still retain the palmitoylation-dependent Golgi localization property in cells. This discovery led to the identification of four new derivatives for small-molecule localization: tridecanoyl (C13)-, dodecanoyl (C12)-, undecanoyl (C11)-, and decanoyl (C10)- D Cys motifs. We demonstrated that even the short decanoyl- D Cys palmitoylation motif could be used to generate small-molecule ligand conjugates that functioned as chemical tools for controlling protein localization and cell signaling. The miniaturized synthetic palmitoylation motifs identified in this work may find applications in creating various Golgi-localizable chimeric molecules for use in chemical biology and drug development.

To examine the effects of blindness on sleep/wakefulness states, we compared locomotor activity and delayed recovery from isoflurane anesthesia induced by hypnotics during light and dark periods in sighted CBA/N and blind CBA/J mice. Locomotor activity around the switch from the dark to light period significantly differed in both mice. Delayed recovery induced by brotizolam was attenuated in both periods in CBA/J mice. In addition, the period specificity of delayed recovery caused by suvorexant or diphenhydramine in CBA/N mice was abolished in CBA/J mice. These results suggest that blindness impairs sleep quality.

We examined urine excretion during primary acute sympathetic activation (PASA) in anesthetized Wistar-Kyoto rats. Since arterial pressure (AP) changes with sympathetic nerve activity (SNA) during PASA, urine excretion reflects a neurally mediated antidiuretic effect combined with an effect of pressure diuresis. We hypothesized that preventing AP changes under PASA would enable the direct estimation of the neurally mediated antidiuretic effect alone. We changed the isolated carotid sinus pressure stepwise from 60 to 180 mmHg and compared the relationship of normalized urine flow (nUF, urine flow normalized by body weight) versus SNA between conditions allowing and preventing baroreflex-mediated changes in the mean AP. The slope of the SNA-nUF relationship was [Formula: see text]nUF var = 0.444 ± 0.074 μL·min -1 ·kg -1 ·% -1 when the mean AP was variable, whereas it was [Formula: see text]nUF fix = -0.143 ± 0.032 μL·min -1 ·kg -1 ·% -1 when the mean AP was fixed at 100 mmHg ( n = 7 rats). The slope associated with the effect of pressure diuresis alone, calculated as [Formula: see text]nUF var - [Formula: see text]nUF fix , was 0.586 ± 0.105 μL·min -1 ·kg -1 ·% -1 . Hence, the potency of the neurally mediated antidiuretic effect |[Formula: see text]nUF fix |/([Formula: see text]nUF var - [Formula: see text]nUF fix ) was 0.235 ± 0.014 relative to the effect of pressure diuresis under PASA. Our findings would aid an integrative understanding of the effects of renal hemodynamic and sympathetic modulations on urine output function.

Biohybrid materials, which are defined as engineered functional materials combining living components with nonliving synthetic materials, are considered promising bioactive materials for applications in in vivo tissue engineering. However, the rational design of biohybrid materials applicable to in vivo tissue engineering faces major challenges associated with techniques for combining living cells with nonliving synthetic materials and cell sources. Here, we report injectable covalent stem cell-combing biohybrid materials prepared via a bio-orthogonal click cross-linking reaction of azide-modified adipose-derived stem cells (N 3 [+]ADSCs), one of the most promising cell sources utilized clinically, with alkyne-modified biocompatible alginate polymers. The mechanical properties of the covalent stem cell-combining biohybrid materials can be adapted to the mechanical properties of the surrounding environment in which they are transplanted by alternating the number of N 3 [+]ADSCs, the concentration of alkyne-modified alginate, and the number of alkyne groups. Importantly, ADSCs in the covalent biohybrid materials expressed a high level of CD-105, a marker for undifferentiated mesenchymal stem cells, in the body in the absence of differentiation signals, whereas very little CD-105 was expressed in the control physical cell-loading materials, demonstrating that this covalent stem cell-combining approach results in enhanced retention of the material's "stemness" and controlled differentiation in the body. We assessed the potential utility of the covalent stem cell-combining biohybrid materials for in vivo tissue engineering using a murine severe skeletal muscle defect-healing model. Importantly, all of the tissues regenerated by the covalent biohybrid material treatment expressed MYH3, a myogenic marker protein, whereas no expression of MYH3 was detected in the tissues reconstructed by treatment with control physical stem cell-loading materials and Matrigel, indicating that this covalent stem cell-combining approach results in controlled differentiation in the body. Our data demonstrate the potential utility of covalent stem cell-combining biohybrid materials with host tissue-integrative and controlled differentiation capabilities available for in vivo tissue engineering.

Insulin like growth factor-1 (IGF-1) plays important roles in metabolic functions, especially in adulthood. Additionally, obese subjects are reportedly predisposed to having low absolute IGF-1 levels. However, the prevalence and clinical characteristics of obese subjects with low IGF-1 levels are unknown. We examined 64 obese subjects with a body mass index (BMI) ≥ 35 kg/m 2 , with no history of endocrinological disorders, receiving inpatient care. IGF-1 levels were interpreted based on the IGF-1 standard deviation score (SDS) clinically used and standardized by age and sex (low IGF-1 group; ≤ - 2.0 SDS and standard IGF-1 group; - 2.0 < and <  + 2.0 SDS). Notably, 26.6% of the subjects had low IGF-1. Body fat mass and percentage, but not BMI, were significantly higher in the low than in the standard IGF-1 group. Furthermore, natural log-transformed high-sensitivity C-reactive protein, and the frequencies of dyslipidemia and hyperuricemia were higher in the low IGF-1 group. Moreover, among the subjects without diabetes, fasting glucose levels were significantly higher in the low IGF-1 group. Stepwise variable selection procedure revealed body fat percentage to be a parameter most strongly associated with low IGF-1. Thus, low IGF-1 levels may be an important marker of adiposity-associated metabolic disorders in obese patients., (© 2022. The Author(s).)

Background/aim: The Von Hippel-Lindau (VHL) gene encodes a protein (pVHL) that plays an important role in proteasome degradation of hypoxia inducible factor α (HIFα) through E3 activation. Accumulation of HIFα by loss of functional pVHL promotes tumorigenesis, thus, VHL has tumor suppressor gene capability in clear cell renal cell carcinoma (ccRCC). VHL is the most frequently mutated gene in ccRCC. The complete loss of VHL is mainly achieved by loss of chromosome 3p, which has a VHL coding region in combination with mutation or hypermethylation of the remaining copy of VHL. Given the risk of constitutional chromosome 3 translocation for RCC, it is important to detect the translocation and understand the mechanism underlying the development of multifocal ccRCC., Case Report: A 67-year-old female patient diagnosed with multifocal RCC underwent robot-assisted partial nephrectomy (RAPN) for three kidney tumors. A cancer gene panel test using next generation sequencing (NGS) detected differential VHL mutations (c.533T>G; p.L178R, c.465&#95;466insTA; p.T157Ifs*3, c.343C>A; p.H115N), while VHL mutation was not detected in peripheral blood DNA. A tendency toward copy number loss of genes on der(3) was also detected in all tumors, but not in the germline one. A karyotype analysis revealed a germline translocation between 3 and 6, t(3;6)(q12;q14)., Conclusion: Chromosome 3 translocation and loss of derivative chromosome containing 3p and subsequent somatic differential VHL mutations in this case strongly support the previously proposed three-step model to explain the development of familial conventional ccRCC., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aims: The study aimed to identify the aspects and items of nurse turnover impact on organizations as perceived by nursing management., Background: Turnover rate does not capture the extent to which an organization is affected by turnover. Another indicator is required to assess the control status of turnover impact., Methods: A Delphi study was conducted in 2021, where 2670 managers of nursing at 712 hospitals were asked to complete the survey three times. Factor analysis was conducted on these items for which a consensus was reached., Results: Overall, 232 managers who responded multiple times, including the third survey, were included in the analysis. Consensus was reached for 36 items affected by turnover and considered important for nursing management. Using exploratory factor analysis, the following six factors were extracted: quality of nursing care, physical and mental health of nursing staff, workload and working conditions of nursing staff, relationships among nursing staff members, sense of responsibility among nursing staff, and cost and benefit of hiring replacement personnel., Conclusions: Six factors consisting of 36 items were extracted that can be used to assess the impact of nurse turnover., Implications for Nursing Management: Nurse managers can assess the status of the organization more appropriately by understanding the factors that impact nurse turnover in vaious facilitites and look at strategies to overcome the impact on nurse staffing., (© 2022 John Wiley & Sons Ltd.)

Chemogenetic methods enabling the rapid translocation of specific proteins to the plasma membrane (PM) in a single protein-single ligand manner are useful tools in cell biology. We recently developed a technique, in which proteins fused to an Escherichia coli dihydrofolate reductase (eDHFR) variant carrying N-terminal hexalysine residues are recruited from the cytoplasm to the PM using the synthetic myristoyl-d-Cys-tethered trimethoprim (m D cTMP) ligand. However, this system achieved PM-specific translocation only when the eDHFR tag was fused to the N terminus of proteins, thereby limiting its application. In this report, we engineered a universal PM-targeting tag for m D cTMP-induced protein translocation by grafting the hexalysine motif into an intra-loop region of eDHFR. We demonstrate the broad applicability of the new loop-engineered eDHFR tag and m D cTMP pair for conditional PM recruitment and activation of various tag-fused signaling proteins with different fusion configurations and for reversibly and repeatedly controlling protein localization to generate synthetic signal oscillations., Competing Interests: Declarations of interest S. Suzuki, A.N., T.Y., and S.T. are co-inventors of a patent application related to this work. The other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We examined urine excretion during primary acute sympathetic activation (PASA) in Wistar-Kyoto rats with myocardial infarction (MI). The rats underwent unilateral renal denervation (RDN) 7 weeks after coronary artery ligation. 4-10 days later, an acute experiment was performed under anesthetized conditions (n = 8 rats). Isolated carotid sinus pressure was changed stepwise from 60 to 180 mmHg, and the relationship between the arterial pressure (AP) and the normalized urine flow (nUF, urine flow normalized by the body weight) was examined. After obtaining the control data, an angiotensin II type 1 receptor blocker telmisartan (2.5 mg/kg) was intravenously administered. The effects of RDN, telmisartan, and heart weight (biventricular weight) on the relationship between AP and nUF were examined using multiple regression analyses. Regarding the slope of nUF versus AP (nUF slope ), the constant term of the regression was positive (0.315 ± 0.069 μL·min -1 ·kg -1 ·mmHg -1 ), indicating that nUF increased with AP. The heart weight had a negative effect on nUF slope (P < 0.05), suggesting that the severity of MI was associated with the impairment of urine excretion. Telmisartan increased nUF slope by 0.358 ± 0.080 μL·min -1 ·kg -1 ·mmHg -1 (P < 0.001), whereas RDN had no significant effect on this parameter. The results indicate that unilateral RDN was unable to abolish the effect of the renin-angiotensin system on urine excretion during PASA. Circulating or locally produced angiotensin II, rather than ongoing renal sympathetic nerve activity, played a dominant role in the impairment of urine excretion during PASA in rats with chronic MI., (© 2022. Springer Japan KK, part of Springer Nature.)

Patients with differentiated thyroid cancer (DTC) usually have good prognosis, while those with advanced disease have poor clinical outcomes. This study aimed to investigate the antitumor effects of combination therapy with lenvatinib and 131 I (CTLI) using three different types of DTC cell lines with different profiling of sodium iodide symporter (NIS) status. The radioiodine accumulation study revealed a significantly increased radioiodine uptake in K1-NIS cells after lenvatinib treatment, while there was almost no uptake in K1 and FTC-133 cells. However, lenvatinib administration before radioiodine treatment decreased radioiodine uptake of K1-NIS xenograft tumor in the in vivo imaging study. CTLI synergistically inhibited colony formation and DTC cell migration, especially in K1-NIS cells. Finally, 131 I treatment followed by lenvatinib administration significantly inhibited tumor growth of the NIS-expressing thyroid cancer xenograft model. These results provide important clinical implications for the combined therapy that lenvatinib should be administered after 131 I treatment to maximize the treatment efficacy. Our synergistic treatment effects by CTLI suggested its effectiveness for RAI-avid thyroid cancer, which retains NIS function. This potential combination therapy suggests a powerful and tolerable new therapeutic strategy for advanced thyroid cancer.

The receptor activator of NF-κB ligand (RANKL)-binding peptide, OP3-4, is known to stimulate bone morphogenetic protein (BMP)-2-induced bone formation, but peptides tend to aggregate and lose their bioactivity. Cholesterol-bearing pullulan (CHP) nanogel scaffold has been shown to prevent aggregation of peptides and to allow their sustained release and activity; however, the appropriate design of CHP nanogels to conduct local bone formation needs to be developed. In the present study, we investigated the osteoconductive capacity of a newly synthesized CHP nanogel, CHPA using OP3-4 and BMP-2. We also clarified the difference between perforated and nonperforated CHPA impregnated with the two signaling molecules. Thirty-six, five-week-old male BALB/c mice were used for the calvarial defect model. The mice were euthanized at 6 weeks postoperatively. A higher cortical bone mineral content and bone formation rate were observed in the perforated scaffold in comparison to the nonperforated scaffold, especially in the OP3-4/BMP-2 combination group. The degradation rate of scaffold material in the perforated OP3-4/BMP-2 combination group was lower than that in the nonperforated group. These data suggest that perforated CHPA nanogel could lead to local bone formation induced by OP3-4 and BMP-2 and clarified the appropriate degradation rate for inducing local bone formation when CHPA nanogels are designed to be perforated.

Background: Low cardiorespiratory fitness (CRF) is an independent predictor of morbidity and mortality. Most health care settings use some type of electronic health record (EHR) system. However, many EHRs do not have CRF or physical activity data collected, thereby limiting the types of investigations and analyses that can be done., Objective: This study aims to develop a nonexercise equation to estimate and classify CRF (in metabolic equivalent tasks) using variables commonly available in EHRs., Methods: Participants were 42,676 healthy adults (female participants: n=9146, 21.4%) from the Aerobics Center Longitudinal Study examined from 1974 to 2005. The nonexercise estimated CRF was based on sex, age, measured BMI, measured resting heart rate, measured resting blood pressure, and smoking status. A maximal treadmill test measured CRF., Results: After conducting nonlinear feature augmentation, separate linear regression models were used for male and female participants to calculate correlation and regression coefficients. Cross-classification of actual and estimated CRF was performed using low CRF categories (lowest quintile, lowest quartile, and lowest tertile). The multiple correlation coefficient (R) was 0.70 (mean deviation 1.33) for male participants and 0.65 (mean deviation 1.23) for female participants. The models explained 48.4% (SE estimate 1.70) and 41.9% (SE estimate 1.56) of the variance in CRF for male and female participants, respectively. Correct category classification for low CRF (lowest tertile) was found in 77.2% (n=25,885) of male participants and 74.9% (n=6,850) of female participants., Conclusions: The regression models developed in this study provided useful estimation and classification of CRF in a large population of male and female participants. The models may provide a practical method for estimating CRF derived from EHRs for population health research., (©Robert Sloan, Marco Visentini-Scarzanella, Susumu Sawada, Xuemei Sui, Jonathan Myers. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 06.07.2022.)

An association between kidney disease and direct-acting antivirals against hepatitis C (DAAs) has been suggested, however the warning on the package insert (PI) of the drug varies among DAAs. In this study, the risk of decreased kidney function associated with DAAs marketed in Japan was investigated to determine whether the risk of kidney disease is a common adverse event and class effect of DAAs. Data for patients who were new users of DAAs marketed in Japan, with eGFR ≥ 45 mL/min/1.73 m 2 and without specific risk factors, were extracted from the MID-NET ® medical information database network in Japan. Changes from the baseline on estimated glomerular filtration rate (eGFR) categories (eGFR ≥ 90, 90 > eGFR ≥ 60, 60 > eGFR ≥ 45, 45 > eGFR ≥ 30, 30 > eGFR ≥ 15, 15 > eGFR; unit: mL/min/1.73 m 2 ) were used for evaluating the risk of decreased kidney function. Exposure groups for DAAs and relevant concomitant drugs were categorized into 10 patterns based on the PI. Among the 10 patterns, a significant increase in the incidence rate ratio (P < 0.01) was observed in the prescription patterns of concomitant use of telaprevir with peginterferon alpha and ribavirin, concomitant use of daclatasvir hydrochloride with asunaprevir, and ombitasvir hydrate combined with paritaprevir hydrate and ritonavir, which were concomitantly used with ribavirin; such an increase was not observed in the other prescription patterns. The effects of DAAs on kidney function may differ among drugs, suggesting the possibility that the risk of kidney disease is not a class effect of DAAs and should be evaluated individually for each DAA., (© 2022. The Author(s).)

Recent reports have shown that better treatment outcomes are obtained with surgical therapy in patients with medication-related osteonecrosis of the jaw (MRONJ) than with conservative therapy. However, conservative treatment is selected due to factors such as old age and poor general condition. Conservative therapy aims to relieve symptoms and prevent lesion exacerbation; however, the lesion may expand rapidly in some cases. This study investigated the clinical and imaging findings of 53 MRONJ patients undergoing conservative therapy, and the changes in the clinical findings and the lesion enlargement on CT imaging were examined. Improved clinical findings and no worsening of the imaging findings were considered overall comprehensive treatment successes. Among the 53 patients, the clinical symptoms disappeared or improved in 15 patients, whereas they worsened in 6. In contrast, osteolytic lesion enlargement occurred in 17 patients. The comprehensive treatment outcome of conservative therapy was successful in 12 patients and unsuccessful in 41 patients. The periosteal reaction was significantly correlated with poor comprehensive treatment outcomes ( p = 0.038). MRONJ lesions may advance, even if they appear to improve clinically while undergoing conservative treatments. Patients, especially those with periosteal reactions, must be closely followed up with CT examinations, regardless of the clinical findings.

Here, we describe the design and synthesis of a new reduction-cleavable spacer (RCS) based on a nitrobenzene scaffold for constructing reduction-responsive oligonucleotides according to standard phosphoramidite chemistry. In addition, we demonstrate that the introduction of the RCS in the middle of an oligonucleotide (30 nt) enables the construction of a self-assembled microsphere capable of exhibiting a reduction-responsive disassembly., (© 2022 Wiley-VCH GmbH.)

It is controversial as to whether the withdrawal of antiresorptive (AR) agents is necessary while treating medication-related osteonecrosis of the jaw (MRONJ). In this study, we investigated whether a drug holiday promoted sequestrum separation and improved the surgical outcomes of MRONJ patients with malignant tumors, who were undergoing high-dose AR therapy. In total, we included 103 MRONJ patients with malignant tumors as their primary disease who underwent surgery at Nagasaki University Hospital or Kansai Medical University Hospital from January 2009 to December 2020. We recorded the patients' age, sex, primary disease, MRONJ stage, type and administration period of the AR agent, presence of diabetes, corticosteroid use, drug holiday period, white blood cell count, serum albumin, serum creatinine, outcomes, and computed tomography findings. The relationships between a drug holiday and sequestrum separation, and between a drug holiday and outcome, were analyzed. Drug holidays of 60, 90, and 120 days were not significant factors of sequestrum separation and did not influence patients' surgical outcomes as per the univariate and multivariate analyses. MRONJ patients with cancer as their primary disease should be operated upon immediately and without drug holidays if their general condition permits surgery.

Background: Secretory carcinoma (SC) of the salivary gland is a recently described malignant tumor harboring characteristic ETV6-NTRK3 gene fusion. SC generally has a favorable clinical course, and is currently regarded as a low-grade carcinoma. However, a small subset of SCs demonstrates aggressive clinical features with histologically high-grade transformed morphology, the molecular pathogenesis of which has not yet been elucidated. In this study, we performed a clinicopathological and molecular genetic study of patients with SC of the head and neck displaying various clinical characteristics to investigate the differences of pathological and molecular genetics between low-grade and high-grade components of SC., Case Presentation: Three cases with SC of the head and neck, including a conventional low-grade SC and two high-grade transformed SCs are described. High-grade transformed SCs with histological features such as nuclear polymorphism, distinctive nucleoli and increased mitotic activity developed locoregional recurrence and distant metastasis. Immunohistochemical analysis revealed that low- and high-grade components showed different expression patterns for S-100 protein and mammaglobin, whereas all examined components were positive for p-STAT5. p53-positive cell population was markedly higher in one case with high-grade transformed SC. The proliferative activity of high-grade components was markedly increased, with the Ki-67 labeling index ranging up to 30-32%. A fluorescence in situ hybridization study with an ETV6 (12p13) break apart probe revealed split signals in the nuclei in all 3 cases. A targeted next-generation sequencing-based fusion assay demonstrated that all 6 clinical samples from the 3 patients showed the presence of the ETV6-NTRK3 fusion transcripts. One patient with high-grade transformed SC showed a dramatic clinical response to the pan-TRK inhibitor, entrectinib, for the treatment of locoregional recurrence and pulmonary metastasis., Conclusions: High-grade transformed SC showed aggressive clinical and pathological features with increased Ki-67 labeling index. Molecular genetic study of gene rearrangement appears to be beneficial treatment as the presence of ETV6-NTRK3 translocation may represent a therapeutic target in SC, particularly the high-grade transformed type., (© 2022. The Author(s).)

Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Telomere (TL) is a biomarker of biological aging, and its shortening is associated with major risk factors for cardiovascular diseases (CVD). This study aimed to identify whether TL is associated with arterial stiffness as reflected by brachial-ankle pulse wave velocity (baPWV). This population-based cross-sectional study involved 1065 individuals in the Iwaki area, Japan. Total TL length and TL G-tail length were measured by hybridization protection assay. The baPWV was measured on the right and left sides using a non-invasive vascular screening device. The associations between TL and baPWV were assessed by multivariate linear regression. Compared with the shortest total TL tertile, the longest total TL group showed a significant decrease in baPWV (lowest vs. highest tertile: adjusted beta: -41.24, 95% confidence interval (CI): -76.81, -5.68). The mean baPWV decreased with a longer TL (TL G-tail length: p trend < 0.001, total TL: p trend < 0.001). TL G-tail and total TL lengths were inversely associated with baPWV, implicating TL shortening in the development of CVD. This study provides evidence of the factors influencing CVD risks at a very early stage when individuals can still take necessary precautions before CVD gives rise to a symptomatic health outcome.