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Abstract Some forms of Sjögren’s syndrome (SS) follow a clinical course accompanied by systemic symptoms caused by lymphocyte infiltration and proliferation in the liver, kidneys, and other organs. To better understand the clinical outcomes of SS, here we used minor salivary gland tissues from patients and examine their molecular, biological, and pathological characteristics. A retrospective study was performed, combining clinical data and formalin-fixed paraffin-embedded (FFPE) samples from female patients over 60 years of age who underwent biopsies at Okayama University Hospital. We employed direct digital RNA counting with nCounter® and multiplex immunofluorescence analysis with a PhenoCycler™ on the labial gland biopsies. We compared FFPE samples from SS patients who presented with other connective tissue diseases (secondary SS) with those from stable SS patients with symptoms restricted to the exocrine glands (primary SS). Secondary SS tissues showed enhanced epithelial damage and lymphocytic infiltration accompanied by elevated expression of autophagy marker genes in the immune cells of the labial glands. The close intercellular distance between helper T cells and B cells positive for autophagy-associated molecules suggests accelerated autophagy in these lymphocytes and potential B cell activation by helper T cells. These findings indicate that examination of FFPE samples from labial gland biopsies can be an effective tool for evaluating molecular histological differences between secondary and primary SS through multiplexed analysis of gene expression and tissue imaging.

Introduction: Basal cell carcinoma (BCC) is a common skin cancer that rarely metastasizes but can deeply infiltrate local tissues. The small number of unresectable BCC cases makes it difficult to conduct clinical trials, resulting in delays in the development of effective drugs for BCC. Cancer gene panel testing has led to an increasing number of new treatment proposals for patients with solid tumors for whom no standard treatment is available. Case Presentation: We described a case of unresectable BRCA1 L63*-mutated BCC invading the parietal bone, which was successfully treated with cisplatin and fluorouracil. Conclusion: Our present case suggests that comprehensive mutation analysis by gene panel testing is important in advanced BCC because genes other than those involved in the hedgehog signaling pathway can be driver genes.

Abstract Background We explore an optimized approach for increasing lesion size using a novel ablation catheter with a surface thermocouple and efficient irrigation in a temperature‐control setting. Methods We conducted radiofrequency applications at various power levels (35 W, 40 W, and 45 W), contact forces (CFs, 10 g/20 g), and durations (60 s/120 s/180 s) in perpendicular/parallel catheter orientations, with normal saline irrigation (NS‐irrigation) and Half NS‐irrigation (HNS‐irrigation) in an ex‐vivo model (Step 1). In addition, we performed applications (35 W/40 W/45 W for 60 s/120 s/180 s in NS‐irrigation and 35 W/40 W for 60 s/120 s/180 s in HNS‐irrigation) in four swine (Step 2), evaluating lesion characteristics and the occurrence of steam pops. Results In Step 1, out of 288 lesions, we observed 47 (16.3%) steam pops, with 13 in NS‐irrigation and 34 in HNS‐irrigation (p = .001). Although steam pops were mostly observed with the most aggressive setting (45 W/180 s, 54%) with NS‐irrigation, they happened in less aggressive settings with HNS irrigation. Lesion size significantly increased with longer‐duration ablation but not with HNS‐irrigation. The optimal %impedance‐drop cutoff to predict steam pops was 20% with a negative‐predictive‐value (NPV) = 95.1% including NS‐ and HNS‐irrigation groups, and 22% with an NPV = 96.1% in NS‐irrigation group. In Step 2, similar to the ex‐vivo model, lesion size significantly increased with longer‐duration ablation but not with HNS‐irrigation. Steam pops were absent with NS‐irrigation (0/35) even with the largest %impedance‐drop reaching 31% at 45 W/180 s. All steam pops were observed with HNS‐irrigation (6/21, 29%). The optimal %impedance‐drop cutoff predicting steam pops was 24% with an NPV = 96.3% including both NS‐ and HNS‐irrigation groups. Conclusions Rather than using HNS‐irrigation, very long‐duration of radiofrequency applications up to 45 W/180 s may be recommended to safely and effectively increase lesion dimensions using this catheter with NS‐irrigation.

Abstract Background This study investigated the correlation between the prevalence of dental caries and the presence and type of abuse. Methods Participants were 534 children admitted for care at two child guidance centers (CGCs) in Niigata, Japan. Data pertaining to abuse, including the reason for temporary protective care and the type of abuse, and the oral examination results of the children, were collected. These results were then compared with those of a national survey and analyzed in relation to the presence and type of abuse. Results The odds ratio for decayed teeth was 4.1, indicating a higher risk in children admitted to the CGCs. However, no significant association was found between the presence of decayed, filled, or caries-experienced teeth and the presence of abuse. A significant positive association was observed between dental caries and one type of abuse, indicating a greater prevalence of dental caries in cases of neglect. The findings of this study suggest that the type of abuse, rather than its presence, is associated with dental caries. Conclusions Our findings suggest that proactive support should be provided to children in problematic nurturing environments, regardless of whether they have been subjected to abuse.

Abstract This study investigates the efficacy of a collagen membrane as a substitute for autologous periosteum in atelocollagen-assisted autologous chondrocyte implantation (ACI) using J-TEC autologous cultured cartilage (JACC®). Sixty-nine patients with knee joint chondral defects underwent ACI using JACC®—34 with periosteum-covered ACI (P-ACIs) and 35 with collagen-covered ACI (C-ACIs). Clinical outcomes were compared through patient-reported measures, International Cartilage Repair Society (ICRS) Cartilage Repair Assessment (CRA) scores at second-look arthroscopy one year postoperatively, and adverse event incidence. Postoperative subjective scores significantly improved up to two years, with no significant differences between P-ACI and C-ACI groups. However, C-ACI exhibited a lower adverse event rate (p = 0.034) and significantly higher ICRS CRA scores (p = 0.0001). Notably, C-ACI outperformed P-ACI in both femoral condyle and trochlea assessments (p = 0.0157 and 0.0005, respectively). While clinical outcomes were comparable, the use of a collagen membrane demonstrated superiority in ICRS CRA during second-look arthroscopy and adverse event occurrence.

Background The process underlying Fontan pathophysiology is multifactorial and may include gut dysbiosis (GD). We investigated the presence of GD and elucidated its correlation with Fontan pathophysiology. Methods and Results Gut microbiomes of 155 consecutive patients with Fontan pathophysiology and 44 healthy individuals were analyzed using 16S rRNA sequencing of bacterial DNA extracted from fecal samples. GD was evaluated on the basis of α and ß diversities of the gut microbiome and was compared with natural log‐transformed C‐reactive protein, hemodynamics, von Willebrand factor antigen (a bacterial translocation marker), Mac‐2 binding protein glycosylation isomer (a liver fibrosis indicator), peak oxygen uptake, and heart failure hospitalization. Patients with Fontan exhibited GD in terms of α and ß diversities as compared with controls (P

Hamstring tendon autografts have emerged as the graft of choice by over 50% of sports surgeons worldwide performing anterior cruciate ligament reconstruction. A more recent technique in harvesting the semitendinosus tendon, the posteromedial approach, afforded multiple benefits compared with the anteromedial approach. However, for the inexperienced surgeon, the current techniques may not be as simple because of decreased tendon tension after general anesthesia induction and subcutaneous layer dissection, making it difficult to palpate the semitendinosus tendon. By utilizing ultrasound to assist us during our harvest, we can perform the procedure with increased accuracy and efficiency, which leads to a safer, more proficient, and less invasive procedure.

Introduction: This study validated real-world pharmacokinetic (PK) data using an established population PK (PopPK) model for atezolizumab in Japanese patients with NSCLC and explored the relationship between PK parameters, effectiveness, and adverse events (AEs) for the 1200 mg once every three weeks regimen. Methods: A subgroup of 262 of 1039 patients from J-TAIL consented to this exploratory research for PK evaluation of atezolizumab monotherapy for unresectable advanced/recurrent NSCLC (August 2018 to October 2019; 197 institutions). We evaluated plasma concentrations before the start of the third cycle of atezolizumab infusion classified into quartiles 1 to 4, their association with effectiveness, and the association between atezolizumab maximum plasma concentrations (Cmax) calculated using the existing PopPK model and AEs of special interest (AESIs). Results: Overall, 175 of 262 patients were included; baseline characteristics were similar to those of patients enrolled in J-TAIL (Eastern Cooperative Oncology Group performance status ≥ 2, 12.0%; age ≥ 75 y, 28.9%; atezolizumab as more than or equal to third-line treatment, 57.5%). Atezolizumab plasma concentrations were similar to previously reported data among Japanese/non-Japanese patients. The overall survival was significantly shorter in patients with lower atezolizumab plasma concentrations in Q1 versus Q2 to Q4, although progression-free survival remained the same. The PK data adequately fit the PopPK model, with the frequency of AESIs increasing as the calculated Cmax at cycle 1 increased. Conclusions: In real-world Japanese patients with unresectable advanced/recurrent NSCLC, PKs were similar to previous reports. Certain patient populations had shorter overall survival, and atezolizumab plasma concentrations in cycle 3 were lower in this population. Elevated Cmax at cycle 1 may be associated with an increased frequency of AESIs.

Abstract Obesity is among the risk factors for male infertility. Although several mechanisms underlying obesity-induced male subfertility have been reported, the entire mechanism of obesity-induced male infertility still remains unclear. Here, we show that sperm count, sperm motility and sperm fertilizing ability were decreased in male mice fed a high-fat diet and that the expression of the AdipoR1 gene and protein was decreased, and the expression of pro-apoptotic genes and protein increased, in the testis from mice fed a high-fat diet. Moreover, we demonstrate that testes weight, sperm count, sperm motility and sperm fertilizing ability were significantly decreased in AdipoR1 knockout mice compared to those in wild-type mice; furthermore, the phosphorylation of AMPK was decreased, and the expression of pro-apoptotic genes and proteins, caspase-6 activity and pathologically apoptotic seminiferous tubules were increased, in the testis from AdipoR1 knockout mice. Furthermore, study findings show that orally administrated AdipoRon decreased caspase-6 activity and apoptotic seminiferous tubules in the testis, thus ameliorating sperm motility in male mice fed a high-fat diet. This was the first study to demonstrate that decreased AdipoR1/AMPK signaling led to increased caspase-6 activity/increased apoptosis in the testis thus likely accounting for male infertility.

Abstract Background Total body water (TBW) fraction, which accounts for 60% of body weight, is an important indicator of body composition, and the extracellular water to TBW ratio (ECW/TBW) is reportedly useful in predicting clinical outcomes of patients with organ disorders. We aimed to clarify the clinical impact of preoperative ECW/TBW status on survival outcomes in cancer patients. Methods We used a database of 320 colorectal cancer (CRC) patients who underwent potentially curative resections. Preoperative ECW/TBW was measured using a bioelectrical impedance analysis (BIA), and its correlation with patient survival outcomes, clinicopathological factors, laboratory data, and comorbidities were analyzed. Results A high preoperative ECW/TBW was significantly associated with poorer relapse‐free survival (RFS; p = 0.001) and overall survival (OS; p = 0.003). A high ECW/TBW ratio was significantly associated with older age (p

Abstract Transient creep in olivine aggregates has been studied by stress‐relaxation experiments at pressures of 1.7–3.6 GPa and at temperatures of ≤1020 K in a DIA apparatus. Time‐dependent deformation of olivine at small strains (

Abstract Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.

Introduction: Chemoradiotherapy with taxanes is well-recognized as a first-line therapy for cutaneous angiosarcoma (CAS), but second-line therapy for CAS is still controversial. Case Presentation: In this report, we described a 75-year-old Japanese case of recurrent, tumor mutation burden-high CAS on the scalp treated with pembrolizumab. Our present case survived for 1 year despite of taxane refractory CAS with mediastinal lymph node metastasis, though the administration of anti-PD-1 Abs alone could not fully suppress the tumor progression of CAS. Conclusion: Since various factors such as pro-angiogenic molecules are correlated with the tumor progression in CAS, the administration of anti-PD-1 Abs alone could not fully suppress the tumor progression of CAS. Further novel anticancer drugs are needed in the future for the treatment of CAS.

Abstract Background Internal hernias are relatively rare and difficult to diagnose. Diagnostic delays lead to the progression of strangulation. In particular, pararectal fossa hernias are extremely rare. We encountered a case in which internal hernia occurred in the pararectal fossa. Case presentation An 87-year-old woman was referred to our hospital because of persistent lower abdominal pain and vomiting. Contrast-enhanced computed tomography revealed findings of intestinal ischemia, such as closed loop formation with reduced contrast effect on the left side of the rectum in the pelvis. Strangulation small bowel obstruction was diagnosed, and emergency laparotomy was performed. The small intestine was found to invade the peritoneal reflection on the left side of the rectum. The patient was finally diagnosed with pararectal fossa hernia. The incarcerated small intestine was released with no bowel resection. The 4-cm hernia phylum was observed and closed by simple suture. The patient had a good postoperative course without recurrence. Conclusions We encountered a very rare case of internal hernia in the left pararectal fossa. Preoperative diagnosis of this disease is difficult, but it should nevertheless be considered in cases in which the cause of the intestinal obstruction is unknown.

This research demonstrates that Ising machines can effectively solve optimal elemental configuration searches in crystals, with Au-Cu alloys serving as an example. The energy function is derived using the cluster expansion method in the form of a QUBO function, enabling efficient problem-solving via Ising machines. Using the third-generation Fujitsu's Digital Annealer, we have successfully obtained reasonable solutions for crystal structures consisting of over 10000 atoms. Notably, we have also obtained plausible solutions for optimization problems with constrained solutions, such as situations where the composition ratio of atomic species is predetermined. These findings suggest that Ising machines can be valuable tools for addressing materials science challenges.

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The pathological hallmark of PD is the appearance of intraneuronal cytoplasmic α-synuclein (α-Syn) aggregation, called Lewy bodies. α-Syn aggregation is deeply involved in the pathogenesis of PD. Oxidative stress is also associated with the progression of PD. In the present study, to investigate whether a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) inhibitor, FG-4592 (also called roxadustat), has neuroprotective effects against α-Syn-induced neurotoxicity, we employed a novel α-Syn stably expressing cell line (named α-Syn-N2a cells) utilizing a piggyBac transposon system. In α-Syn-N2a cells, oxidative stress and cell death were induced by α-Syn, and FG-4592 showed significant protection against this neurotoxicity. However, FG-4592 did not affect α-Syn protein levels. FG-4592 triggered heme oxygenase-1 (HO-1) expression downstream of HIF-1α in a concentration-dependent manner. In addition, FG-4592 decreased the production of reactive oxygen species possibly via the activation of HO-1 and subsequently suppressed α-Syn-induced neurotoxicity. Moreover, FG-4592 regulated mitochondrial biogenesis and respiration via the induction of the peroxisome proliferator-activated receptor-γ coactivator-1α. As FG-4592 has various neuroprotective effects against α-Syn and is involved in drug repositioning, it may have novel therapeutic potential for PD.

Vertebral hemangiomas are the most common benign lesion of the spine which are often an asymptomatic incidental finding. However, a few hemangiomas are aggressive and characterized by bone expansion and extraosseous extension into the paraspinal and epidural spaces. We report the case of a patient presenting an aggressive vertebral hemangioma causing back pain and bilateral numbness of the legs. Among various treatment modalities, a minimally invasive percutaneous sclerotherapy procedure using ethanolamine oleate under computed tomography and fluoroscopic guidance was safely and successfully performed with good clinical outcomes.

Abstract Objectives Graft‐versus‐host disease (GVHD) is an important complication of bone marrow transplantation. Recent reports suggest the significance of T‐cell subsets (Th1, Th17, and cytotoxic CD8+ T cells) as well as CD163+ macrophages in the development of cutaneous GVHD. CD163+ macrophages produce various chemokines to establish the immunological microenvironment following stimulation by stromal factors in lesional skin. Thus, the purpose of this study is to determine the main source of IFN‐inducible chemokines in the lesional skin of GVHD. Methods We employed immunohistochemical (IHC) staining for CD163 as well as interferon (IFN)‐inducible chemokines (CXCL9, CXCL10, CXCL11) to determine if the main source of IFN‐inducible chemokines in the lesional skin of GVHD was CD163+ macrophages. Moreover, we investigated the possible cytokine profiles of lesional skin in GVHD by evaluating phospho‐signal transducer and activator of transcription (pSTAT) expression in epidermal keratinocytes. Results Immunohistochemical staining of serial sections for CD163 revealed that CXCL9‐expressing cells, CXCL10‐expressing cells, and CXCL11‐expressing cells were detected in adjacent to CD163+ TAMs in the dermis. In contrast, there were no CCL17‐expressing cells or CCL22‐expressing cells in the dermis. The nuclei of epidermal keratinocytes in GVHD expressed pSTAT1, pSTAT3, and pSTAT5B. Conclusions The chemokine expression patterns on CD163+ macrophages matched the expected phosphorylation pattern of epidermal STATs. Our present study suggested that CD163 + macrophages may be a therapeutic target in GVHD.