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Abstract We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1). Overall survival (OS), progression-free survival (PFS), and toxicity were secondary endpoints. Sixteen patients with advanced/metastatic BCC were evaluable. The ORR was 31% (95% CI, 19–50%), and the 12-month OS, 75% (95% CI, 57–100%). Median PFS was 9.3 months (95% CI, 3.3–NA). Of 15 patients evaluable for clinical benefit, five partial responses (PRs) and five stable disease >6 months (total = 10/15 (66.7%)) were seen. The most common toxicities included fatigue (37.5%), pruritis (31.3%), and diarrhea (25%). In patients with advanced/metastatic BCC, ipilimumab and nivolumab produced an ORR of 31% and prolonged (>6 months) PFS in 73% of patients, with seven PFS/iPFS of >1 year, including one with prior anti-PD-1. ClinicalTrials.gov ID: NCT02834013 (Registered 7/15/2016; https://clinicaltrials.gov/ct2/show/NCT02834013 ).

Abstract Background Ulcerative colitis (UC) causes extensive ulceration attributable to intestinal inflammation. This study investigated the effect of past extensive ulcers (PEUs) on fecal calprotectin (FC). Methods This retrospective, single-center, observational study included patients with UC with a Mayo endoscopic subscore of 0. UC with scarring or pseudopolyposis was defined as PEU and FC and fecal immunochemical occult blood test (FIT) values were compared. The marker levels of patients in the PEU and non-PEU groups were examined to assess clinical relapse within 12 months. Results Of the 61 included patients, 27 had UC with PEUs and 34 had UC without PEUs. Albumin, hemoglobin, and FIT values between groups were not significantly different; however, the C-reactive protein and FC values of the PEU group were significantly higher than those of the non-PEU group. The FC values of the clinical relapse and remission groups within 12 months differed significantly. The cutoff values for the prediction of relapse within 12 months for all patients (area under the curve [AUC], 0.709; 95% confidence interval [CI], 0.512–0.907) and the non-PEU group (AUC, 0.893; 95% CI, 0.724–1.000) were both 118 mg/kg. Conclusions UC patients with PEUs have higher FC values than those without PEUs, even in remission. Additionally, FC values do not predict relapse in PEU patients. Therefore, FC may not be a sufficiently accurate biomarker for patients with PEUs.

ABSTRACT Aims/Introduction The study aim was to investigate sulfonylurea prescription patterns in elderly patients (age ≥65 years) with type 2 diabetes mellitus in Japan. Sulfonylurea use among older adults has been insufficiently examined, despite the associated risks of hypoglycemia. Materials and Methods This retrospective cross‐sectional survey entailed analysis of Japanese pharmacy data, extracted from the Musubi database, for patients (age 20–100 years) prescribed sulfonylureas between November 2022 and October 2023. Dose distribution, adherence to the Diabetes Treatment Guidelines for the Elderly 2023 and coprescription of other diabetes medications were investigated. Results Of the total 91,229 patients, 80.1% were prescribed glimepiride, 16.3% gliclazide and 3.6% glibenclamide. In patients aged ≥65 years, exceeding the recommended dose (>1 mg/day for glimepiride, >40 mg/day for gliclazide) was numerically higher for glimepiride (25.0%) than for gliclazide (7.8%). The most common prescribing patterns were quadruple therapy with a sulfonylurea, a dipeptidyl peptidase‐4 inhibitor, an sodium–glucose transporter 2 inhibitor and a biguanide in patients aged 65 to

Granulosa cell tumor (GCT) is the most common nonepithelial ovarian malignancy. Still, it is considered rare, with a paucity of high-level evidence guiding management, particularly in the metastatic setting. Advancements in molecular pathology allowed the identification of several targetable mutations that play an important role in GCT pathogenesis. Although current management approaches rely on guidelines extrapolated from the more common epithelial subtype, the unique histopathologic and molecular characteristics of GCTs entail a more focused approach. Systemic therapy remains the cornerstone treatment for advanced disease, and although chemotherapy has been the standard for decades, targeted treatments have gained considerable attention lately. Due to the rarity of this disease, validation of new therapies in large trials is the rate-limiting step for developing evidence-based recommendations. This review sheds light on pathogenesis, clinical and molecular characteristics, and prognostic factors, and discusses current treatment options including the role of novel therapies and immune checkpoint inhibitors in advanced GCT.

Abstract Objective Despite key differences in pathological processes, both Intramural Hematomas and Aortic Dissections are Acute Aortic Syndromes repaired with similar surgical technique. The objective of this study was to determine differences in surgical outcomes between patients with Intramural Hematoma versus Type A Aortic Dissection undergoing Ascending Aortic Arch repair. Methods This retrospective review of prospectively collected data included all patients with acute Intramural Hematoma or Type A Aortic Dissection who underwent emergent Ascending- or Arch Repair from January 2018 to May 2023 at a single academic institution. Primary outcomes included intraoperative mortality, 30-Day mortality, and postoperative stay. Secondary outcomes included postoperative complications. Outcomes were analyzed using Chi-squared, Fisher’s Exact, and t-tests, with significance set at p

Abstract Background Common cold coronaviruses (ccCoVs) and influenza virus are common infectious agents causing upper respiratory tract infections (RTIs). However, clinical symptoms, comorbidities, and health effects of ccCoV infection remain understudied. Methods A retrospective study evaluated 3,935 outpatients with acute upper RTI at a tertiary teaching hospital. The presence of ccCoV and influenza virus was determined by multiplex molecular assay. The demographic, clinical symptoms, and health outcomes were compared between patients with ccCoV (n = 205) and influenza (n = 417) infections. Multivariable logistic regression was employed to evaluate predictors and health outcomes over a one-year follow-up. Results Sore throat, nasal discharge, headache, and myalgia were more predominant in ccCoV infection; fever was common in influenza. Most patients reported moderate symptoms severity (49.8% ccCoV, 56.1% influenza). Subsequent primary care visits with symptoms of RTI within a year were comparable for both infections (27.3% ccCoV vs. 27.6% influenza). However, patients with influenza reported increased primary care visits for non-RTI episodes and all-cause hospital admission. Baseline comorbidities were associated with increased primary care visits with symptoms of RTI in either ccCoV (adjusted odds ratio [aOR] 2.5; 95% confidence interval [CI] 1.1–5.9; P = 0.034) or influenza (OR 1.9; 95% CI 1.1–3.1; P = 0.017) infections, due probably to the dysregulation of the host immune response following acute infections. In patients infected with influenza infection, dyslipidemia was a predictor for subsequent primary care visits with symptoms of RTI (unadjusted OR 1.8; 95% CI 1.0–3.0; P = 0.040). Conclusions Both influenza and ccCoV infection pose significant disease burden, especially in patients with comorbidities. The management of comorbidities should be prioritized to mitigate poor health outcomes in infected individuals.

ABSTRACT Background and Aim In terms of their longitudinal positioning, esophageal squamous cell carcinoma (ESCC) commonly arises in the middle segment of the esophagus. However, limited attention has been given to the circumferential aspect. This study aimed to investigate the prevalence and characteristics of ESCC lesions resected via endoscopic submucosal dissection (ESD), taking into consideration both longitudinal and circumferential positions. Methods We retrospectively evaluated 193 ESD‐resected ESCC lesions and compared the occurrence rate of ESCC development and the degree of histopathological invasion across various circumferential and longitudinal positions. We scrutinized lesion characteristics by location, with a particular focus on the proportion of early‐stage small lesions in each site. Results Regarding lesion location, 27 were situated on the anterior wall, 62 on the left, 66 on the posterior, and 38 on the right. Among the four circumferential positions, the anterior wall group had the smallest median tumor size. Additionally, the anterior wall group had the highest proportions of lesions with invasion depths limited to the epithelial layer and sizes

Abstract Microalgae are considered to be more useful and effective to use in biomass production than other photosynthesis organisms. However, microalgae need to be altered to acquire more desirable traits for the relevant purpose. Although neutron radiation is known to induce DNA mutations, there have been few studies on its application to microalgae, and the optimal relationship between irradiation intensity and mutation occurrence has not been established. In this study, using the unicellular red alga Cyanidioschyzon merolae as a model, we analyzed the relationship between the absorbed dose of two types of neutrons, high-energy (above 1 MeV) and thermal (around 25 meV) neutrons, and mutation occurrence while monitoring mutations in URA5.3 gene encoding UMP synthase. As a result, the highest mutational occurrence was observed when the cells were irradiated with 20 Gy of high-energy neutrons and 13 Gy of thermal neutrons. Using these optimal neutron irradiation conditions, we next attempted to improve the lipid accumulation of Euglena gracilis, which is a candidate strain for biofuel feedstock production. As a result, we obtained several strains with a maximum 1.3-fold increase in lipid accumulation compared with the wild-type. These results indicate that microalgae breeding by neutron irradiation is effective.

Abstract This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term “midline” areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4–78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9–11.9, 95% CI) and 16.6 ± 1.4 (13.9–19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma.

Abstract Background and Aim Chronic constipation negatively impacts work productivity and patients' quality of life. This retrospective study assessed the correlation between symptoms of chronic constipation and work/activity impairment with and without the use of laxative treatment. Methods This cross‐sectional, observational, web‐based survey was conducted using the Work Productivity and Activity Impairment‐Chronic Constipation Questionnaire and included Japanese patients with chronic constipation receiving prescribed medication. Outcomes of interest included total work productivity and activity impairment and their correlation with constipation symptoms. Results Among the 2351 analyzed patients (mean [SD] age, 51.7 [13.8] years), 80.7% were females, 63.3% had a disease duration of ≥10 years, and 1424 were working. The averages of total activity impairment, total work productivity impairment, presenteeism, and absenteeism were 39.2%, 33.9%, 31.2%, and 5.0%, respectively. The annual work productivity loss per patient was estimated to be 1.343 million Japanese Yen. Symptoms that had a statistically significant positive correlation with total work impairment (P

Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how cancer spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving progression. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models, which lack the major cell–cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. We show that the protein expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 as means to sense changes in static extracellular matrix stiffness, and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.

Introduction Previous research has highlighted the association between socioeconomic factors and diabetes management. This study aimed to elucidate the blood glucose control status among individuals with low income (ie, recipients of public assistance (PARs) and free/low-cost medical care (FLCMC) programme beneficiaries) and to investigate the effects of public subsidies for medical expenses on treatment adherence among low-income patients with diabetes.Methods We conducted a secondary analysis of medical records from 910 outpatients with diabetes who underwent pharmacological treatment for >90 days. Data on predictive variables, such as glycated haemoglobin (HbA1c) level and control variables, including sex, age and insurance type, were obtained retrospectively. The HbA1c levels among public health insurance (PHI)-only beneficiaries, FLCMC programme beneficiaries and PARs were compared using logistic regression analysis.Results The analysis included 874 individuals, among whom the majority were men (61.7%) and aged≥65 years (58.4%). Logistic regression analysis revealed that among individuals aged ˂65 years, the adjusted ORs for HbA1c levels above 9% were significantly higher in FLCMC programme beneficiaries (OR=5.37, 95% CI: 2.23 to 12.82) and PARs (OR=5.97, 95% CI: 2.91 to 12.74) than in PHI-only beneficiaries. Among patients aged ˂65 years with HbA1c levels above 7%, the adjusted OR was significantly higher in FLCMC programme beneficiaries (OR=3.82, 95% CI: 1.65 to 10.43) than in PHI-only beneficiaries. Additionally, the adjusted OR was significantly higher in FLCMC programme beneficiaries aged ˂65 years (OR=2.57, 95% CI: 1.02 to 7.44) than in PARs.Conclusions This study highlights the predictive value of public assistance or the FLCMC programme for poor blood glucose control and suggests the inadequacy of current medical expense subsidies to eliminate health disparities in diabetes control.

Objective: To investigate the effect of minimally invasive cardiac surgery (MICS) on resource utilization, cost, and postoperative outcomes in patients undergoing left-heart valve operations. Methods: Data were retrospectively reviewed for patients undergoing single-valve surgery (eg, aortic valve replacement, mitral valve replacement, or mitral valve repair) at a single center from 2018 to 2021, stratified by surgical approach: MICS vs full sternotomy (FS). Baseline characteristics and postoperative outcomes were compared. Primary outcome was high resource utilization, defined as direct procedure cost higher than the third quartile or either postoperative LOS ≥7 days or 30-day readmission. Secondary outcomes were direct cost, length of stay, 30-day readmission, in-hospital and 30-day mortality, and major morbidity. Multiple regression analysis was conducted, controlling for baseline characteristics, operative approach, valve operation, and lead surgeon to assess high resource utilization. Results: MICS was correlated with a significantly lower rate of high resource utilization (MICS, 31.25% [n = 115] vs FS 61.29% [n = 76]; P

A 35-year-old man was diagnosed with stage IIIC non-seminoma with paralysis of the lower half of his body due to 8th thoracic spine metastasis. The patient received bleomycin, etoposide, and cisplatin (BEP) therapy. On day 4 of the second course of BEP, the patient developed a fever and was diagnosed with coronavirus disease (COVID-19). COVID-19 was suspected to worsen because of cancer and chemotherapy-induced immunosuppression. However, the benefits of continuing BEP therapy outweighed these risks. After obtaining fully informed consent, BEP therapy was continued from day 5, while sotrovimab (anti-COVID-19 drug) was administered. The second course of BEP was completed without worsening severe COVID-19 or bleomycin-induced lung injury. The patient completed four courses of BEP, with normalization of tumor markers, partial response on imaging, and improvement in lower body paralysis. In this case, we successfully treated a patient with testicular germ cell tumor with chemotherapy while having COVID-19 without treatment delay. During the COVID-19 pandemic, concomitant chemotherapy and COVID-19 treatment are warranted because delaying treatment will decrease the efficacy of highly curative diseases such as germ cell tumors.

ABSTRACTThe production of dissolved organic matter during phytoplankton blooms and consumption by heterotrophic prokaryotes promote marine carbon biogeochemical cycling. Although prokaryotic viruses presumably affect this process, their dynamics during blooms are not fully understood. Here, we investigated the effects of taxonomic difference in bloom-forming phytoplankton on prokaryotes and their viruses. We analyzed the dynamics of coastal prokaryotic communities and viruses under the addition of dissolved intracellular fractions from taxonomically distinct phytoplankton, the diatom Chaetoceros sp. (CIF) and the raphidophycean alga Heterosigma akashiwo (HIF), using microcosm experiments. Ribosomal RNA gene amplicon and viral metagenomic analyses revealed that particular prokaryotes and prokaryotic viruses specifically increased in either CIF or HIF, indicating that taxonomic difference in bloom-forming phytoplankton promotes distinct dynamics of not only the prokaryotic community but also prokaryotic viruses. Furthermore, combining our microcosm experiments with publicly available environmental data mining, we identified both known and novel possible host-virus pairs. In particular, the growth of prokaryotes associating with phytoplanktonic organic matter, such as Bacteroidetes (Polaribacter and NS9 marine group), Vibrio spp., and Rhodobacteriales (Nereida and Planktomarina), was accompanied by an increase in viruses predicted to infect Bacteroidetes, Vibrio, and Rhodobacteriales, respectively. Collectively, our findings suggest that changes in bloom-forming species can be followed by an increase in a specific group of prokaryotes and their viruses and that elucidating these tripartite relationships among specific phytoplankton, prokaryotes, and prokaryotic viruses improves our understanding of coastal biogeochemical cycling in blooms.IMPORTANCEThe primary production during marine phytoplankton bloom and the consumption of the produced organic matter by heterotrophic prokaryotes significantly contribute to coastal biogeochemical cycles. While the activities of those heterotrophic prokaryotes are presumably affected by viral infection, the dynamics of their viruses during blooms are not fully understood. In this study, we experimentally demonstrated that intracellular fractions of taxonomically distinct bloom-forming phytoplankton species, the diatom Chaetoceros sp. and the raphidophycean alga Heterosigma akashiwo, promoted the growth of taxonomically different prokaryotes and prokaryotic viruses. Based on their dynamics and predicted hosts of those viruses, we succeeded in detecting already-known and novel possible host-virus pairs associating with either phytoplankton species. Altogether, we propose that the succession of bloom-forming phytoplankton would change the composition of the abundant prokaryotes, resulting in an increase in their viruses. These changes in viral composition, depending on bloom-forming species, would alter the dynamics and metabolism of prokaryotes, affecting biogeochemical cycling in blooms.

Background/purpose: In lower third molar (LM3) surgery, panoramic radiography (PAN) is important for the initial assessment of the anatomical association between LM3 and the inferior alveolar nerve (IAN). This study aimed to develop a deep learning model for the automated evaluation of the LM3–IAN association on PAN. Further, its performance was compared with that of oral surgeons using original and external datasets. Materials and methods: In total, 579 panoramic images of LM3 from 384 patients in the original dataset were utilized. The images were divided into 483 images for the training dataset and 96 for the testing dataset at a ratio of 83:17. The external dataset comprising 58 images from an independent institution was used for testing only. The LM3–IAN associations on PAN were categorized into direct or indirect contact based on cone-beam computed tomography (CBCT). The You Only Look Once (YOLO) version 3 algorithm, a fast object detection system, was applied. To increase the amount of training data for deep learning, PAN images were augmented using the rotation and flip techniques. Results: The final YOLO model had high accuracy (0.894 in the original dataset and 0.927 in the external dataset), recall (0.925, 0.919), precision (0.891, 0.971), and f1-score (0.908, 0.944). Meanwhile, oral surgeons had lower accuracy (0.628, 0.615), recall (0.821, 0.497), precision (0.607, 0.876), and f1-score (0.698, 0.634). Conclusion: The YOLO-driven deep learning model can help oral surgeons in the decision-making process of applying additional CBCT to confirm the LM3–IAN association based on PAN images.

Abstract ATP6AP2, also known as (pro)renin receptor, has been shown to be expressed in several tissues including pancreatic β cells. Whereas ATP6AP2 plays an important role in regulating insulin secretion in mouse pancreatic β cells, the expression profiles and roles of ATP6AP2 in human pancreatic endocrine cells and neuroendocrine tumor cells remain unclear. Here in this study, we investigated the expression profiles of ATP6AP2 in pancreatic endocrine cells, and found that ATP6AP2 is robustly expressed in pancreatic insulinoma cells as well as in normal β cells. Although ATP6AP2 was also expressed in low-grade neuroendocrine tumors, it was not or faintly detected in intermediate- and high-grade neuroendocrine tumors. Knockdown experiments of the Atp6ap2 gene in rat insulinoma-derived INS-1 cells demonstrated decreased cell viability accompanied by a significant increase in apoptotic cells. Taken together, these findings suggest that ATP6AP2 plays a role in maintaining cellular homeostasis in insulinoma cells, which could lead to possible therapeutic approaches for endocrine tumors.

We describe a rare complication of intraprocedural spontaneous thrombus formation on a transcatheter edge-to-edge repair (MitraClip; Abbott Laboratories) device in a hypercoagulable yet adequately anticoagulated patient. We also outline the novel use of a vacuum (Penumbra) aspiration system, which resulted in rapid and effective thrombus elimination.

Information regarding the endocrine regulation of oocyte maturation in cultured species is essential for the artificial seed production. To elucidate endocrine mechanisms that underlie oocyte maturation of the white-streaked grouper, Epinephelus ongus, a commercially important fish species, we collected and compared data linked to the ovaries of captive and wild white-streaked grouper specimens, and plasma steroids data were obtained using captive fish. This data allowed for a comparative analysis of the ovarian development of both groups; the comparison was necessary for the acquisition of physiological patterns universally representative of the species at hand. The dynamics of the gonadosomatic index (GSI) and oocyte development of both groups confirmed that vitellogenesis progressed toward the last quarter moon, final oocyte maturation began the day before the last quarter moon, and spawning occurred after the last quarter moon. These results indicate that the changes in ovarian development and GSI in wild and captive fish were synchronous, and that the endocrine changes observed in captive fish represent those that occur in wild fish. The changes in estradiol 17β (E2) levels in captive fish increased and decreased during the vitellogenic and final oocyte maturation phases, respectively. These dynamics were similar to those of GSI. We found that 17α, 20β-dihydroxy-4-pregnen-3-one (DHP) was consistently detected at concentrations higher than those of 17α, 20β-21-trihydroxy-4-pregnen-3-one (20β-S); this trend was constant across all stages of ovarian development. In contrast, 20β-S was detected at lower concentrations than DHP in all captive individuals, but at higher levels after the onset of final oocyte maturation. These results suggest that 20β-S and/or DHP may be maturation-inducing hormones (MIH) in this species. Our results also highlight the importance of integrative analyses of wild and captive individuals to comprehensively elucidate the endocrine regulation of cultured species of interest to improve aquaculture management practices.

Ken Satoh,1 Kan Nagasawa,1 Noriko Takebe,1 Hirofumi Kinno,1 Masaharu Shozushima,1 Ken Onodera,1 Tomoyasu Oda,1 Yutaka Hasegawa,1 Jo Satoh,2 Yasushi Ishigaki1 1Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan; 2Department of Diabetes, Tohoku Medical and Pharmaceutical University, Wakabayashi Hospital, Sendai, JapanCorrespondence: Yasushi Ishigaki, Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, 2-1-1 Idai-Dori, Yahaba, Iwate, 028-3695, Japan, Tel +81 19 613 7111, Fax +81 19 907 8270, Email ishigaki@iwate-med.ac.jpAims/Introduction: Adiponectin is generally regarded as a beneficial molecule, protecting against insulin resistance and atherosclerosis, and its serum levels are low in individuals with obesity as well as in those with type 2 diabetes (T2DM). However, several clinical studies have shown associations between high adiponectin values and major health concerns. These conflicting findings are termed the “adiponectin paradox”. Similarly, these paradoxical adiponectin elevations were observed in patients with diabetic microvascular complications. This cross-sectional study aimed to identify differences in factors, including adiponectin, related to diabetic vascular complications between non-obese and obese patients.Materials and Methods: Study patients with T2DM were non-obese (n=197) or obese (n=197), matched by a propensity score model adjusted with age and gender. Independent factors for each of the microvascular complications were determined using multivariate logistic regression analyses.Results: The prevalence of nephropathy was high in obese T2DM patients. In addition to long diabetes duration, elevated adiponectin was a common characteristic of patients with microvascular complications. Logistic regression analyses for microvascular complications revealed adiponectin to be highly related to retinopathy (odds ratio [OR], 1.138; 95%confidence intervals [CI], 1.004– 1.289, p< 0.001), nephropathy (OR, 1.192; CI, 1.077– 1.319, p< 0.001) and neuropathy (OR, 1.217; CI, 1.071– 1.384, p< 0.001), in non-obese patients. In contrast, the association between adiponectin values and complications was modest in obese patients.Conclusion: Adiponectin regulation in response to vascular damage differed between non-obese and obese patients, suggesting that adiponectin regulation is compromised by fat accumulation. Assuming that paradoxical elevation of adiponectin in vascular damage is a compensatory response, we speculate that responsive upregulation might be insufficient in obese patients. These newly-recognized differences in adiponectin values might lead to novel insights into adiponectin regulation and our understanding of the adiponectin paradox.Keywords: diabetic complications, obesity, adiponectin

A hand-made apparatus to react copper concentrate (Cc)/pyrite (Py)/silica sand (Ss) mixture was developed for an imitated concentrate burner at laboratory scale. An instantaneous (< 1 s) ignition reaction was macroscopically observed by preheated oxygen gas blowing to Cc/Py/Ss mixture with a Fe/SiO2 mass ratio of 1.1. SEM-EDS analysis was used to observe microstructure and phase distribution in reacted and water-quenched particles. As for the Cc/Ss samples collected at the point close to the gas blowing spot, 70–80 mass% Cu matte phase and heterogeneous slag phase including large amounts of magnetite (Mag) particles were formed. At the lower part from the gas blowing spot with a distance of 275 mm, 60–65 mass% Cu matte phase was confirmed. The area fraction of Mag particles in the slag phase decreased with increasing Py adding concentration in the mixture sample. Our results suggested the concentration and microscopic distribution of Py in the mixture including Cc contributed to control both Cu concentration in matter phase and Mag particle concentration in slag phase.

Summary: Synthetic protocols providing mechanical patterns to culture substrate are essential to control the self-condensation of cells for organoid engineering. Here, we present a protocol for preparing hydrogels with mechanical patterns. We describe steps for hydrogel synthesis, mechanical evaluation of the substrate, and time-lapse imaging of cell self-organization. This protocol will facilitate the rational design of culture substrates with mechanical patterns for the engineering of various functional organoids.For complete details on the use and execution of this protocol, please refer to Takebe et al. (2015) and Matsuzaki et al. (2014, 2022).1,2,3 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Objective Over the last two decades there has been an increase in the number of cardiac implantable electronic devices and consequently, there has also been an increased need for lead extractions. Fibrotic attachments develop between the lead and the venous and cardiac structures that may require the use of a laser to mobilize the lead. Cardiothoracic surgeons (CTS) have traditionally provided backup for surgical emergencies for these extractions. This study evaluates the surgical outcomes of patients undergoing transvenous laser lead extractions (TLE) and determines if CTS are still needed for backup. Methods A retrospective review of consecutive patients undergoing laser lead extractions at a single academic center. Lead extractions using only laser sheaths were analyzed. The clinical characteristics, complications, and mortality of the patients were evaluated. Results One hundred and twenty-one patients underwent TLEs from January 1st, 2014 to December 31st, 2018. The majority were male (N = 80, 66.1%), and the average age was 66.48 ± 14 years. The indication for removal was either laser lead malfunction or infection. A total of 30 patients (24.8%) had complications postoperatively including wound hematomas, superficial infections, and arrhythmias. The average length of stay was 9 ± 12 for all the patients in the study. 2 patients (1.6%) had injuries that required emergency surgical repair with injuries to the posterior superior vena cava and right ventricle. Both patients survived the initial injury with one patient was discharged home on day 4 and the other succumbing to his injuries on postoperative day 20. Conclusion Although the incidence of surgical emergencies is rare the morbidity and mortality for TLE require that surgical backup be available.

Abstract Background During restoration of poorly fitting complete dentures (CDs) in edentulous patients, liners are used to reconstruct the concave surfaces of CDs with a new base material. These relining materials are classified into resilient liners (RLs) and non-resilient liners (NRLs), but the clinical effects of these liners and their selection criteria remain unclear. The purpose of this study is to evaluate the clinical efficacy of relining mandibular CDs using RL and NRL and to conduct a follow-up study. Methods The study is currently being conducted at eight centers, and a parallel-group randomized controlled trial (RCT) is underway. One hundred thirty-two edentulous patients with poorly fitting mandibular CDs will be assigned to two groups based on whether they will receive RL or NRL. Participants will have an RL or NRL applied for relining their CDs using an indirect method of dynamic impressions. Data will be recorded at 1 week and 3, 6, and 12 months after denture delivery. The primary outcome will be assessment of the patients’ general satisfaction by using a 100-mm visual analog scale (VAS). Secondary outcomes will be measured as patient-reported outcomes, including food intake status and oral hygiene-related quality of life. Masticatory performance and the number of sore spots on the oral mucosa will also be recorded. Comparisons between the two groups and within-subject comparisons of pre- and post-intervention measurements will be conducted. Discussion For dentists and prosthetic researchers in Japan, this RCT will provide information on the clinical efficacy of RL materials in comparison to RNL in CD wearers. The new evidence regarding the use of RL materials in an aging population will also be useful to dentists in other countries in their routine clinical practice. Trial registration This clinical trial has been registered at the University Hospital Medical Information Network (UMIN) Center (UMIN000041950).

Copper slag (CS) granules received from a Japanese smelter were melted using an alumina crucible under Ar gas flow in an electric furnace. The melt was removed from the furnace and cooled slowly with various holding times in air and then water-quenched. The increase of cooling time in air promoted the partial crystallization of CS samples: the separation of Fe-rich and Si-rich phases, the precipitation of fayalite and magnetite phases and the formation of Al2O3- and SiO2-rich non-crystalline aluminosilicate phase. The CS melt was subdivided into smaller ones through a hand-made yttria-doped stabilized zirconia polycrystal sieve and repelled by a rotational graphite plate. After cooling crystallized CS granules were successfully fabricated. The crystallized CS granules including fayalite and magnetite phases satisfied a lower limit for the elution amounts of As and Pb fixed as ≤150 mg/kg in 1 mol/L HCl aqueous solution as specified in the guideline of JIS 0058-2:2005 as a test method for acid-extractable contents of chemicals.

The demand for stem cell-based cultured meat as an alternative protein source is increasing in response to global food scarcity. However, the definition of quality controls, including appropriate growth factors and cell characteristics, remains incomplete. Cluster of differentiation (CD) 29 is ubiquitously expressed in bovine muscle tissue and is a marker of progenitor cells in cultured meat. However, CD29+ cells are naturally heterogeneous, and this quality control issue must be resolved. In this study, the aim was to identify the subpopulation of the CD29+ cell population with potential utility in cultured meat production. The CD29+ cell population exhibited heterogeneity, discernible through the CD44 and CD344 markers. CD29+CD44−CD344− cells displayed the ability for long-term culture, demonstrating high adipogenic potential and substantial lipid droplet accumulation, even within 3D cultures. Conversely, CD29+CD44+ cells exhibited rapid proliferation but were not viable for prolonged culture. Using cells suitable for adipocyte and muscle differentiation, we successfully designed meat buds, especially those rich in fat. Collectively, the identification and comprehension of distinct cell populations within bovine tissues contribute to quality control predictions in meat production. They also aid in establishing a stable and reliable cultured meat production technique.

Abstract Objectives Synovial mesenchymal stem cells (MSCs) have high freeze–thaw tolerance, whereas human umbilical vein endothelial cells (HUVECs) have low freezing tolerance. The differences in cell type-specific freeze–thaw tolerance and the mechanisms involved are unclear. This study thus aimed to identify the biological and physical factors involved in the differences in freeze–thaw tolerance between MSCs and HUVECs. Materials and methods For biological analysis, MSC and HUVEC viability after freeze-thawing and alteration of gene expression in response to dimethyl sulfoxide (DMSO, a cryoprotectant) were quantitatively evaluated. For physical analysis, the cell membrane fluidity of MSCs and HUVECs before and after DMSO addition was assessed using a histogram for generalized polarization frequency. Results HUVECs showed lower live cell rates and higher gene expression alteration related to extracellular vesicles in response to DMSO than MSCs. Fluidity measurements revealed that the HUVEC membrane was highly fluidic and sensitive to DMSO compared to that of MSCs. Addition of CAY10566, an inhibitor of stearoyl-coA desaturase (SCD1) that produces highly fluidic desaturated fatty acids, decreased the fluidity of HUVECs and increased their tolerance to DMSO. The combination of CAY10566 and antioxidant glutathione (GSH) treatment improved HUVEC viability from 57 to 69%. Membrane fluidity alteration may thus contribute to pore-induced DMSO influx into the cytoplasm and reactive oxygen species production, leading to greater cytotoxicity in HUVECs, which have low antioxidant capacity. Conclusions Differences in freeze–thaw tolerance originate from differences in the cell membranes with respect to fluidity and antioxidant capacity. These findings provide a basis for analyzing cell biology and membrane-physics to establish appropriate long-term preservation methods aimed at promoting transplantation therapies.

Abstract Aim Pancreaticodigestive tract anastomotic stricture is a long‐term complication of pancreticoduodenectomy (PD). However, optimal treatment has not yet been defined. We conducted longitudinal pancreaticojejunostomy (LPJ) in symptomatic patients with anastomotic stricture after PD. This study aimed to evaluate the efficacy of this procedure. Methods Pancreticoduodenectomy was performed in 605 patients at our institution between January 2005 and April 2020. Of these, 15 patients (2.5%) developed symptomatic pancreaticodigestive tract anastomotic stricture after PD. Three patients were referred to our institution owing to recurrent pancreatitis with anastomotic stricture after PD. LPJ was indicated for these 18 patients, and they were enrolled in this study. Results The median time from the initial operation to LPJ was 2.0 y. Preoperative clinical presentations included obstructive pancreatitis in 10 patients, a rapid deterioration of glucose tolerance in nine, and severe steatorrhea in two. Surgical morbidity ≥grade III defined by the Clavien–Dindo classification was not observed. After LPJ, preoperative symptoms improved in 16 patients (89%) during a median follow‐up of 39 mo. Nine of the 10 patients with obstructive pancreatitis achieved complete pain relief. All nine patients with a rapid deterioration of glucose tolerance showed improved endocrine function. Daily insulin requirement was significantly decreased after LPJ (11.6 ± 3.3 vs 3.4 ± 4.3 units, P = .0239). Four of the seven patients who required insulin injections were free of insulin after LPJ. Conclusion LPJ is a safe and effective surgical procedure for symptomatic patients with stricture of the pancreaticodigestive tract anastomosis after PD.

Abstract Background Despite the clinical burden attributable to rhinovirus (RV) infections, the RV transmission dynamics and the impact of interventions on viral transmission remain elusive. Methods A total of 3,935 nasopharyngeal specimens were examined, from which the VP4/VP2 gene was sequenced and genotyped. RV transmission clusters were reconstructed using the genetic threshold of 0.005 substitutions/site, estimated from the global VP4/VP2 sequences. A transmission cluster is characterized by the presence of at least two individuals (represent by nodes), whose viral sequences are genetically linked (represent by undirected edges) at the estimated genetic distance threshold supported by bootstrap value of ≥ 90%. To assess the impact of facemask, pleconaril and social distancing on RV transmission clusters, trials were simulated for interventions with varying efficacy and were evaluated based on the reduction in the number of infected patients (nodes) and the reduction in the number of nodes-connecting edges. The putative impact of intervention strategies on RV transmission clusters was evaluated through 10,000 simulations. Results A substantial clustering of 168 RV transmission clusters of varying sizes were observed. This suggests that RV disease burden observed in the population was largely due to multiple sub-epidemics, predominantly driven by RV-A, followed by RV-C and -B. No misclassification of RV species and types were observed, suggesting the specificity and sensitivity of the analysis. Through 10,000 simulations, it was shown that social distancing may be effective in decelerating RV transmission, by removing more than 95% of nodes and edges within the RV transmission clusters. However, facemask removed less than 8% and 66% of nodes and edges, respectively, conferring moderate advantage in limiting RV transmission. Conclusion Here, we presented a network-based approach of which the degree of RV spread that fuel disease transmission in the region was mapped for the first time. The utilization of RV transmission clusters in assessing the putative impact of interventions on disease transmission at the population level was demonstrated.

Abstract The NCI-MATCH was designed to characterize the efficacy of targeted therapies in histology-agnostic driver mutation-positive malignancies. Sub-protocols F and G were developed to evaluate the role of crizotinib in rare tumors that harbored either ALK or ROS1 rearrangements. Patients with malignancies that progressed following at least one prior systemic therapy were accrued to the NCI-MATCH for molecular profiling, and those with actionable ALK or ROS1 rearrangements were offered participation in sub-protocols F or G, respectively. There were five patients who enrolled on Arm F (ALK) and four patients on Arm G (ROS1). Few grade 3 or 4 toxicities were noted, including liver test abnormalities, and acute kidney injury. For sub-protocol F (ALK), the response rate was 50% (90% CI 9.8–90.2%) with one complete response among the 4 eligible patients. The median PFS was 3.8 months, and median OS was 4.3 months. For sub-protocol G (ROS1) the response rate was 25% (90% CI 1.3–75.1%). The median PFS was 4.3 months, and median OS 6.2 months. Data from 3 commercial vendors showed that the prevalence of ALK and ROS1 rearrangements in histologies other than non-small cell lung cancer and lymphoma was rare (0.1% and 0.4% respectively). We observed responses to crizotinib which met the primary endpoint for ALK fusions, albeit in a small number of patients. Despite the limited accrual, some of the patients with these oncogenic fusions can respond to crizotinib which may have a therapeutic role in this setting.

Prophet of Pit1 (PROP1) is the pituitary specific transcription factor which was cloned as an upstream regulator of PIT1. Cushing’s disease is caused by corticotroph adenomas which does not belong to the PIT1 lineage. The aim of this study was to elucidate the involvement of PROP1 in the pathogenesis of Cushing’s disease. Since it is difficult to accurately evaluate PROP1 expression in pituitary adenomas by RT-PCR analysis due to the inevitable contamination of surgical tissue specimens with normal pituitary cells, we examined six corticotroph adenomas by immunohistochemistry. Adenomas were classified into 2 subtypes based on their staining patterns of CAM5.2: diffuse and non-diffuse types. It is likely that diffuse-type adenomas are composed of more differentiated tumor cells. PROP1 was positive in all three cases of non-diffuse-type adenomas, but negative in all three cases of diffuse-type adenomas, suggesting that PROP1 was prominently expressed in less differentiated non-PIT1 lineage corticotroph adenomas. This study is the first report to analyze PROP1 expression in pituitary adenomas by immunohistochemistry. PROP1 may have a role in tumorigenesis of pituitary adenomas in Cushing’s disease, and is expected to be a new therapeutic target for refractory pituitary adenomas.

Summary: The potential of extrapulmonary ventilation pathways remains largely unexplored. Here, we assessed the enteral ventilation approach in hypoxic porcine models under controlled mechanical ventilation. 20 mL/kg of oxygenated perfluorodecalin (O2-PFD) was intra-anally delivered by a rectal tube. We simultaneously monitored arterial and pulmonary arterial blood gases every 2 min up to 30 min to determine the gut-mediated systemic and venous oxygenation kinetics. Intrarectal O2-PFD administration significantly increased the partial pressure of oxygen in arterial blood from 54.5 ± 6.4 to 61.1 ± 6.2 mmHg (mean ± SD) and reduced the partial pressure of carbon dioxide from 38.0 ± 5.6 to 34.4 ± 5.9 mmHg. Early oxygen transfer dynamics inversely correlate with baseline oxygenation status. SvO2 dynamic monitoring data indicated that oxygenation likely originated from the venous outflow of the broad segment of large intestine including the inferior mesenteric vein route. Enteral ventilation pathway offers an effective means for systemic oxygenation, thus warranting further clinical development.

Correction of disease-causing large genomic inversions remains challenging. Here, the authors developed a dual designer-recombinase system (RecF8) that efficiently corrects a 140 kb inversion frequently found in patients with severe Hemophilia A.

Abstract Background The American Society of Surgery and American Society for Surgical Infections issued guidelines for surgical site infections (SSIs) in December 2016. These guidelines recommend a purse-string suture (PSS) for stoma closure as it facilitates granulation and enables open wound drainage. This study investigated the effect of using negative pressure wound therapy (NPWT) along with standard PSS and aimed to determine the optimal period of NPWT use. Methods The patients were divided into three groups as follows: Group A, postoperative wound management alone with gauze exchange as the representative of conventional PSS; Group B, the performed management was similar to that of Group A plus NPWT for 1 week; and Group C, the performed management was similar to that of Group A plus NPWT for 2 weeks. Regarding objective measures, the wound reduction rate was the primary outcome, and the incidence of SSIs, length of hospital stay, and wound healing duration were the secondary outcomes. Results In total, 30 patients (male: 18, female: 12) were enrolled. The average age was 63 (range: 43–84) years. The wound reduction rate was significantly higher in Group B than in Group A on postoperative days (PODs) 7 (66.1 vs. 48.4%, p = 0.049) and 10 (78.6 vs. 58.2%, p = 0.011), whereas no significant difference was observed on POD 14. Compared with Group A, Group C (POD 7: 65.9%, POD 10: 69.2%) showed an increase in the wound reduction rate on POD 7, although the difference was not significant (p = 0.075). SSIs were observed in Groups B (n = 2) and C (n = 2) (20%) but not in Group A (0%). Conclusions The most effective duration of NPWT use for ileostomy closure with PSS in terms of the maximum wound reduction rate was from PODs 3 to 10. However, NPWT did not shorten the wound healing duration. NPWT may reduce the wound size but should be used with precautions for SSIs. The small sample size (30 cases), the use of only one type of NPWT system, and the fact that wound assessment was subjective and not blinded were the limitations of this study. Further studies are needed to confirm our findings. Trial registration: UMIN Clinical Trials Registry; UMIN000032174 (10/04/2018).

Introduction: Atezolizumab plus bevacizumab therapy is extremely effective in the treatment of intermediate-stage hepatocellular carcinoma (HCC), with a response rate of 44%, as reported in the IMbrave150 trial. When tumor shrinkage is obtained, achieving complete response (CR) is possible in many cases using curative conversion with resection, ablation, or super selective transarterial chemoembolization (TACE) with curative intent. This concept, i.e., curative conversion by combining systemic therapy and locoregional therapy, has not been reported before. This multicenter proof-of-concept study was conducted to show the value of curative conversion in immunotherapy-treated intermediate-stage HCC meeting TACE-unsuitable criteria. Methods: This study included 110 consecutive Child-Pugh A patients who received atezolizumab plus bevacizumab as first-line treatment for unresectable and TACE-unsuitable intermediate-stage HCC at seven centers in Japan. CR rate, drug-free rate, time to CR, change in liver function, efficacy in positron emission tomography (PET)-positive HCC, progression-free survival (PFS), and overall survival (OS) were assessed in patients who achieved CR using resection, ablation, super selective TACE with curative intent following atezolizumab plus bevacizumab or atezolizumab plus bevacizumab alone. Results: Clinical or pathological CR was achieved in 38 patients (35%) (median observation period: 21.2 months). The modalities of curative conversion in 35 patients were as follows: resection, 7; ablation, 13; and superselective TACE, 15. Three patients achieved clinical CR with atezolizumab plus bevacizumab therapy alone. Among the 38 CR patients, 25 achieved drug-free status. PFS was not reached, and three patients experienced recurrence after reaching CR. Regarding OS, there were no deaths in any of the CR patients. The albumin-bilirubin score did not deteriorate after locoregional therapy or resection. Of seven PET-positive patients who achieved CR with atezolizumab plus bevacizumab followed by curative conversion, five achieved drug-free status. Discussion/Conclusion: The achievement of CR rate by curative conversion in patients treated with atezolizumab plus bevacizumab as the preceding therapy for unresectable and TACE-unsuitable intermediate-stage HCC was 35%. Overall, 23% of patients achieved drug-free status and no recurrence was observed from this patient subgroup with CR and drug free status. Thus, achieving CR and/or drug-free status should be a therapeutic goal for patients with intermediate-stage HCC without vascular invasion or extrahepatic spread.

Rodeheffer et al. (2012) showed that when people perceive resource scarcity, they are more likely to judge racially ambiguous people as out-group members. In their first experiment, 71 White participants viewed a slideshow depicting either resource scarcity or abundance; subsequently, they judged 20 biracial faces created by averaging a White and a Black face. We conducted this experiment's preregistered conceptual replication study in Japan. Specifically, after observing a slideshow depicting either resource scarcity or abundance, East Asian participants judged 20 biracial faces produced by averaging an East and a South Asian face. The statistical power to detect a small effect (d = 0.2) was 0.79 (N = 769). Although the pattern was the same as Rodeheffer et al.'s (2012) research, the priming effect was insignificant (d = 0.1). The reasons for this null result as well as future research directions are discussed.

The purpose of this review was to assess the literature regarding four types of fixed dental prostheses (FDPs)/resin-bonded FDPs (RBFDPs) to provide clinicians with a comparative overview of two myths: “RBFDPs are easy to debond in patients’ mouths” and “cantilever RBFDPs still have some clinical problems, especially in terms of overloading the abutment teeth and being easy to debond”. A total of 782 papers were identified, 753 of which were judged unsuitable and thus excluded, leaving a total of 29 articles for inclusion in this review. The results indicated that 1) Two-retainer RBFDPs achieve clinical results comparable to full-coverage three-unit FDPs; 2) Cantilever RBFDPs show excellent long-term clinical outcomes (especially in incisor teeth) compared with other FDPs; 3) RBFDPs typically show less catastrophic failure than conventional FDPs, rebonding should be considered when debonding occurs; and 4) Cantilever RBFDPs can be recommended as defect replacement prostheses for maxillary lateral incisors and mandibular incisor teeth.Scientific field: Prosthodontics, Adhesive dentistry, Esthetic dentistry

A stabilized zirconia oxygen probe was used to measure the oxygen partial pressure (OPP) at an electrode submerged in a copper slag melt at 1300 ℃. The OPP was controlled in the range of 10−10–10−5 atm owing to the presence or absence of a powdered carbon layer on the slag melt using a high-purity alumina crucible in argon (Ar) gas flow. Under suppression of magnetite formation at an OPP of approximately 10−10 atm, the viscosities of the copper slag and FeO-Fe2O3-SiO2-Al2O3 slag melts were measured between 1200 ℃ and 1300 ℃. The obtained values were in the range of 1.0×102–7.8×102 mPa・s. The dependences of total Fe/SiO2 mass ratio and Al2O3 concentration on viscosity were qualitatively interpreted from the aluminosilicate network structure viewpoint.

“Rare cancers” are a diverse collection of cancers that collectively account for approximately 20% of all adult cancers in the United States. Their rarity has caused an underrepresentation of these cancers in preclinical research and clinical trials, leading to fewer (and often no) treatment options for patients backed by robust clinical evidence. The recent advent of immune checkpoint inhibitors (ICIs) into the oncologist’s armamentarium, while revolutionizing the treatment of many common cancers, has also started to make gradual inroads into the treatment of certain rare cancers. One reason is that the efficacy of ICIs depends more on factors intrinsic to the tumor cells and the tumor microenvironment and less on tumor histology. Recent years have seen ICI approvals in many rare cancers, and many trials are being designed using ICIs as single agents or in combination. In this commentary, we present an overview of the emerging role of ICIs in some rare cancers.

Abstract Aims/Introduction Recent studies have suggested C‐X‐C motif chemokine ligand 14 (CXCL14), secreted from adipose tissue, to play an important role in the pathogenesis of metabolic syndrome. However, the clinical significance of CXCL14 in humans has not been elucidated. This study aimed to assess correlations between serum CXCL14 levels and clinical parameters in patients with type 2 diabetes mellitus. Materials and Methods In total, 176 individuals with type 2 diabetes mellitus were recruited. Serum CXCL14 concentrations were determined by enzyme‐linked immunosorbent assay. We examined the associations of serum CXCL14 levels with laboratory values, abdominal computed tomography image information, surrogate markers used for evaluating the pathological states of diabetes, obesity and atherosclerosis. Results Serum CXCL14 levels correlated positively with body mass index, waist circumference, subcutaneous and visceral fat areas, and serum alanine transaminase, uric acid, total cholesterol, low‐density lipoprotein cholesterol, triglycerides and C‐peptide (CPR) levels. In contrast, CXCL14 levels correlated inversely with age, pulse wave velocity and serum adiponectin levels. Multiple linear regression analysis showed serum levels of CPR (β = 0.227, P = 0.038) and the fatty liver index (β = 0.205, P = 0.049) to be the only parameters showing independent statistically significant associations with serum CXCL14 levels. Conclusions Serum CXCL14 levels were independently associated with serum CPR and fatty liver index in patients with type 2 diabetes mellitus. In these patients, a high serum CPR concentration might reflect insulin resistance rather than β‐cell function, because CXCL14 showed simple correlations with obesity‐related parameters. Collectively, these data suggested that serum CXCL14 levels in type 2 diabetes patients might be useful predictors of elevated serum CPR and hepatic steatosis.

Mixtures of copper concentrate and silica sand with various CuFeS2/FeS2 ratios and with 5 mg in weight were dropped from the top side of the silica tube filled with O2 gas and were reacted at 470℃. The Fe/SiO2 mass ratio of the mixtures was fixed at 1.1 as a typical composition of flash smelting. The samples exhibited the white light emission expecting the arrival temperature of > 1500℃ due to the ignition reaction of sulfide minerals. Reaction products were evaluated by using scanning electron micrograph-energy dispersive X-ray spectrometry (SEM-EDS) analysis. In addition to un-reacted oxide and sulfide particles, matte-slag-mineral-magnetite coexisted particles were recognized in microstructure observation. The products supported heterogeneous reactions occurring in the copper concentrate burner. The effect of FeS2 concentration on copper concentration in matte phase and magnetite phase fraction in slag phase was discussed.

Dental pulp stem cells (DPSCs) are considered a valuable cell source for regenerative medicine because of their high proliferative potential, multipotency, and availability. We established a new cryopreservation method (NCM) for collecting DPSCs, in which the tissue itself is cryopreserved and DPSCs are collected after thawing. We improved the NCM and developed a new method for collecting and preserving DPSCs more efficiently. Dental pulp tissue was collected from an extracted tooth, divided into two pieces, sandwiched from above and below using cell culture inserts, and cultured. As a result, the cells in the pulp tissue migrated vertically over time and localized near the upper and lower membranes over 2–3 days. With regard to the underlying molecular mechanism, SDF1 was predominantly involved in cell migration. This improved method is valuable and enables the more efficient collection and reliable preservation of DPSCs. It has the potential to procure a large number of DPSCs stably.

Abstract Background Coxsackievirus A21 (CVA21), a member of Enterovirus C from the Picornaviridae family, has been associated with respiratory illnesses in humans. Methods A molecular epidemiological investigation of CVA21 was conducted among patients presenting with acute upper respiratory illnesses in the ambulatory settings between 2012 and 2014 in Kuala Lumpur, Malaysia. Results Epidemiological surveillance of acute respiratory infections (n = 3935) showed low-level detection of CVA21 (0.08%, 1.4 cases/year) in Kuala Lumpur, with no clear seasonal distribution. Phylogenetic analysis of the new complete genomes showed close relationship with CVA21 strains from China and the United States. Spatio-temporal mapping of the VP1 gene determined 2 major clusters circulating worldwide, with inter-country lineage migration and strain replacement occurring over time. Conclusions The study highlights the emerging role of CVA21 in causing sporadic acute respiratory outbreaks.

Noriko Takebe,1,2 Kozo Tanno,2,3 Hideki Ohmomo,2 Mari Hangai,1,2 Tomoyasu Oda,1 Yutaka Hasegawa,1,2 Nobuyuki Takanashi,2,3 Ryohei Sasaki,2,4 Atsushi Shimizu,2 Akira Sasaki,5 Kiyomi Sakata,2,3 Makoto Sasaki,2 Yasushi Ishigaki1,2 1Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan; 2Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Yahaba, Japan; 3Department of Hygiene and Preventive Medicine, Iwate Medical University, Yahaba, Japan; 4Department of Human Sciences, Center for Liberal Arts and Sciences, Iwate Medical University, Yahaba, Japan; 5Department of Surgery, Iwate Medical University, Yahaba, JapanCorrespondence: Yasushi IshigakiDivision of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, 2-1-1 Idai-Dori, Yahaba, Iwate, 028-3695, JapanTel +81 19 613 7111Fax +81 19 907 8270Email ishigaki@iwate-med.ac.jpPurpose: It is unclear what kind of modifiable lifestyle factors are associated with long-time weight gain in adulthood. To clarify the lifestyle behavior related to body weight gain since the age of 20 years, we explored the lifestyle risk factor, independently associated with excessive weight gain after 20 years of age as compared to those in subjects with a stable weight, with matching of age, gender, and the current body mass index (BMI).Patients and Methods: From baseline data of a general population-based cohort study, we designed a cross-sectional analysis collecting individual data of medical health check-ups and a questionnaire related to lifestyle, including amount of sleep, frequency of eating breakfast, average times per day engaged in walking and sitting in the prior year, and smoking habits. These data were compared between the subjects with weight gain ≥ 10kg (n=3601) and < 10kg (n=3601) after age 20, matched by a propensity score model which included current BMI, age and gender. We used multivariable logistic regressions to assess the lifestyle factor’s association with high weight gain.Results: Participants who gained ≥ 10 kg were significantly more likely to sleep < 5 hours or ≥ 9 hours per night, skip breakfast, engage in walking < 1 hour per day, and sit ≥ 5 hours per day than those who gained < 10kg. Multivariable logistic regressions analyses showed that, with adjusting for potential confounder, the lifestyles with the positive association with high weight gain were skipping breakfast (OR 1.252; 95% CI 1.053– 1.489, vs regularly), long sleeping duration (9 hours/day≤ OR 1.613; 95% CI 1.018– 2.557 vs 5≤-< 7 hours/day), and former smoker (OR 1.163; 95% CI 1.008– 1.343 vs never smoker), while walking duration was negatively associated with high weight gain. Furthermore, despite similar current BMI, participants with weight gain ≥ 10kg had significantly higher values for waist circumference, blood pressure, HbA1c, LDL-C, triglycerides, and hepatic enzyme levels than those with weight gain < 10kg. Similarly, the prevalence rates of hypertension, dyslipidemia, metabolic syndrome (MetS), and former smoker were higher in the participants with weight gain ≥ 10kg.Conclusion: Major weight gain after 20 years of age was associated with unfavorable lifestyle factors and greater waist circumference, possibly leading to elevated risk for MetS and other non-communicable diseases. These findings highlight the importance of maintaining both weight at age 20 and a favorable lifestyle throughout adulthood.Keywords: metabolic syndrome, physical activity, skipping breakfast, sleep duration, waist circumference, weight gain

Abstract Background Extracellular vesicles (EVs) are known to be secreted by various cells. In particular, mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have tissue repair capacity and anti-inflammatory properties. Dental pulp stem cells (DPSCs), which are MSCs isolated from pulp tissue, are less invasive to the body than other MSCs and can be collected from young individuals. In this study, we investigated the efficacy of EVs secreted by DPSCs (DPSC-EVs) for bone formation. Methods DPSC-EVs were isolated from the cell culture medium of DPSCs. DPSC-EVs were unilaterally injected along with collagen (COL), beta-tricalcium phosphate (β-TCP) or hydroxyapatite (HA) into rat calvarial bone defects. The effects of DPSC-EVs were analyzed by micro-computed tomography (micro-CT) and histological observation. Results Micro-CT showed that administration of DPSC-EVs with the abovementioned scaffolds resulted in bone formation in the periphery of the defects. DPSC-EVs/COL specifically resulted in bone formation in the center of the defects. Histological observation revealed that DPSC-EVs/COL promoted new bone formation. Administration of DPSC-EVs/COL had almost the same effect on the bone defect site as transplantation of DPSCs/COL. Conclusions These results suggest that DPSC-EVs may be effective tools for bone tissue regeneration.

Abstract Clinical transplants of hematopoietic stem cells (HSC) can provide a lifesaving therapy for many hematological diseases; however, therapeutic applications are hampered by donor availability. In vivo, HSC exist in a specified microenvironment called the niche. While most studies of the niche focus on those residing in the bone marrow (BM), a better understanding of the fetal liver niche during development is vital to design human pluripotent stem cell (PSC) culture and may provide valuable insights with regard to expanding HSCs ex vivo for transplantation. This review will discuss the importance of the fetal liver niche in HSC expansion, a feat that occurs during development and has great clinical potential. We will also discuss emerging approaches to generate expandable HSC in cell culture that attain more complexity in the form of cells or organoid models in combination with engineering and systems biology approaches. Overall, delivering HSC by charting developmental principles will help in the understanding of the molecular and biological interactions between HSCs and fetal liver cells for their controlled maturation and expansion.

Subcellular Zn2+ compartmentalisation is essential for cell biology. Here the authors make a turn-on fluorescent Zn2+ probe that localises to multiple organelles, and correlate its location using organelle morphology derived from structured illumination microscopy.

Background/purpose: Inhibition of bone resorption is essential for periodontal treatment. Recently, it has been suggested that boric acid suppresses periodontitis, but the mechanism of this inhibition is still not well understood. Therefore, to analyze the cellular response to boric acid administration, we histologically evaluated alveolar bone in experimental periodontitis of rats administered boric acid. Materials and methods: 5-0 silk ligatures were placed around the cervix of the second maxillary molars of 4 week-old rats treated with or without boric acid. Five and 14 days after ligature placement, the periodontal tissues between first and second molars were investigated histologically and immunohistochemically using antibodies to CD68, cathepsin K, and α-smooth muscle actin (SMA). Results: Five days after the beginning of the experiment, many CD68-positive cells appeared in the periodontal tissues with ligature placement without boric acid administration. Also, the number of cathepsin K-positive osteoclasts had increased on the surface of alveolar bone. However, boric acid administration prevented severe bone resorption and reduced the number of cells positive for CD68 and cathepsin K. At day 14 post treatment, cells positive for α-SMA were seen in the periodontal tissues after boric acid administration, whereas no such cells were found around the alveolar bone without the administration of boric acid. Conclusion: Boric acid inhibited the inflammation of ligature-induced periodontitis. This agent might reduce bone resorption by inhibiting osteoclastogenesis and also could accelerate osteoblastogenesis.