Expression patterns of keratin family members during tooth development and the role of keratin 17 in cytodifferentiation of stratum intermedium and stellate reticulum.

Keratins are typical intermediate filament proteins of the epithelium that exhibit highly specific expression patterns related to the epithelial type and stage of cellular differentiation. They are important for cytoplasmic stability and epithelial integrity and are involved in various intracellular signaling pathways. Several keratins are associated with enamel formation. However, information on their expression patterns during tooth development remains lacking. In this study, we analyzed the spatiotemporal expression of keratin family members during tooth development using single-cell RNA-sequencing (scRNA-seq) and microarray analysis. scRNA-seq datasets from postnatal Day 1 mouse molars revealed that several keratins are highly expressed in the dental epithelium, indicating the involvement of keratin family members in cellular functions. Among various keratins, keratin 5 (Krt5), keratin 14 (Krt14), and keratin 17 (Krt17) are highly expressed in the tooth germ; KRT17 is specifically expressed in the stratum intermedium (SI) and stellate reticulum (SR). Depletion of Krt17 did not affect cell proliferation in the dental epithelial cell line SF2 but suppressed their differentiation ability. These results suggest that Krt17 is essential for SI cell differentiation. Furthermore, scRNA-seq results indicated that Krt5, Krt14, and Krt17 exhibited distinct expression patterns in ameloblast, SI, and SR cells. Our findings contribute to the elucidation of novel mechanisms underlying tooth development.

Destruxin E backbone modification effects on osteoclast Morphology: Synthesis and SAR study of N-Desmethyl and N-Methyl analogs.

The design and synthesis of N-desmethyl and N-methyl destruxin E analogs have been demonstrated. The X-ray single crystal structure of destruxin E (1a) revealed a stable three-dimensional (3D) structure, including a s-cis amide bond at the MeVal-MeAla moiety and two intramolecular hydrogen bonds between NH(ß-Ala) and OC(Ile) and between NH(Ile) and OC(ß-Ala). N-Desmethyl analogs 2a (MeAla â†’ Ala) and 2b (MeVal â†’ Val) were synthesized through macrolactonization similar to our previously reported synthesis of 1a. Conversely, for the synthesis of N-methyl analogs 2c (Ile â†’ MeIle) and 2d (ß-Ala â†’ Meß-Ala), macrolactonization did not proceed; therefore, cyclization precursors 10c and 10d were designed to maintain the intramolecular hydrogen bonds described above during their cyclization. The macrolactamization proceeded despite the presence of a less reactive N-methylamino group at the N-terminus in both cases. Analog 2a, which exhibits multiple conformers in solutions, was inactive at 50 µM, whereas analog 2b, which exhibits a conformation similar to that of 1a in solutions, exhibited morphological changes against osteoclast-like multinuclear cells at 1.6 µM. The activity of the MeIle analog 2c, which cannot take the intramolecular hydrogen bond (Ile)NH•••OC(ß-Ala) in 1a, was markedly diminished compared with that of 1a, and that of the Meß-Ala analog 2d, which cannot take the intramolecular hydrogen bond (ß-Ala)NH•••OC(Ile) in 1a, was further reduced to one-fourth of that of 2c. The overall results indicate that both the s-cis amide bond at the MeVal-MeAla moiety and two intramolecular hydrogen bonds (ß-Ala)NH•••OC(Ile) and (Ile)NH•••OC(ß-Ala) are important for constraining the conformation of the macrocyclic peptide backbone in destruxin E, thereby exhibiting its potent biological activity.

The real-world data of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study.

BACKGROUND: The real-world efficacy, feasibility, and prognostic factors of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer are not fully established. METHODS: This multi-institutional retrospective cohort study evaluated 71 consecutive patients treated with immune-checkpoint inhibitor combination therapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, safety, and long-term survival. RESULTS: In patients with measurable lesions, the response rate was 58%, and the disease control rate for all enrolled patients was 80%. Five patients (7.0%) underwent successful conversion surgery. Grade 3 or higher immune-related adverse events occurred in 13% of patients, and one patient (1.4%) died due to cholangitis. Median progression-free survival was 9.7 (95% confidence interval: 6.5-not reached). C-reactive protein levels and performance status were identified as significant predictors of progression-free survival through Cox proportional hazards analysis. CONCLUSIONS: Immune-checkpoint inhibitor combination therapy for esophageal cancer demonstrated comparable tumor response, safety, and long-term survival to previous randomized clinical trials. Patients with good performance status and low C-reactive protein levels may be suitable candidates for this treatment.

Kudoa tanakai n. sp. (Myxozoa: Myxosporea: Multivalvulida), a new kudoid species with spheroid myxospores from the scalpel sawtail (Actinopterygii: Prionurus scalparum) from western Japan.

We describe a new kudoid species, Kudoa tanakai n. sp., in the scalpel sawfish, Prionurus scalprum (Actinopterygii: Acanthuriformes: Acanthuridae), from the natural water around western Japan. The plasmodia were filamentous, localized in pseudocysts in the myofibers of the trunk muscles. The occurrence of plasmodia in the trunk muscle showed no site preference. Its myxospores were spheroid, measuring 6.6-7.6 (7.0) µm by 5.8-6.9 (6.3) µm in apical view (width) and 5.7-6.6 (6.2) in length (n = 30), with four shell valves and a corresponding number of spheroid polar capsules. Shell valves lacked apical protrusions, but scanning electron microscopy revealed that one of the four shell valves had two semi-lunar flaps at its apical terminus. Nucleotide sequencing of the small and large subunit ribosomal RNA genes of the present isolate showed phylogenetic affinities to kudoid species characterized by spheroid myxospores, such as K. musculoliquefaciens, K. hemiscylli, and K. carcharhini, but was molecularly and morphometrically distinct from these and other kudoid species. For direct comparison, Kudoa hemiscylli was collected from the Pacific spadenose shark, Scoliodon macrorhynchos (Elasmobranchii: Carcharhiniformes: Carcharhinidae), in the South China Sea off Guangdong Province, China, and the myxospore surface of the species was observed using scanning electron microscopy. Our study describes the new host and distribution record of this kudoid species originally described from a variety of elasmobranchs in the Australian Coral Sea.

New coccidian Eimeria iyoensis n. sp. (Apicomplexa: Eucoccidiorida: Eimeriidae) in farmed ring-necked pheasants (Phasianus colchicus L.) in Ehime, Japan.

Eight Eimeria spp. (Apicomplexa: Eimeriidae) have been isolated from the ring-necked pheasant (Phasianus colchicus Linnaeus), native to the temperate zone of Asia and eastern regions of Europe. Enteric coccidiosis has become a major issue associated with the breeding of farmed pheasants for game bird release or meat production. In this study, 35 fecal samples were collected from two-to-three-month-old ring-necked pheasants from four pheasant-rearing farms in Ehime Prefecture, Japan. Microscopic examination using a saturated sugar solution technique detected numerous subspherical oocysts from the samples of one farm and ellipsoidal Eimeria phasiani Tyzzer, 1929 oocysts from the three other farms. The subspherical oocysts were artificially sporulated and measured 18.6 µm by 15.7 µm with a 1.18 shape index (n = 150). Each oocyst contained four 10.7 µm × 5.8 µm sporocysts (n = 30) and one coarse refractile polar granule; no micropyle or residua were detected. Each sporocysts contained two sporozoites with one large and one small refractile body and sparsely distributed residua. The complete, 1,443-bp cytochrome c oxidase subunit I gene (cox1) of this isolate exhibited low sequence identity with published Eimeria spp. sequences including E. phasiani that was previously recorded in the same area. Meanwhile, the oocyst morphology most closely resembled that of Eimeria tetartooimia Wacha, 1973, but with distinct refractile polar granules and sporocyst residua. The available GenBank cox1 sequence of E. tetartooimia exhibited a sequence identity of < 94.5% with the study isolate. Here, the coccidian isolate identified in this study represents a new Eimeria iyoensis n. sp. capable of infecting ring-necked pheasant.

Factors contributing to the improvement in J-HAQ after 3 years of treatment with abatacept in biologic-naïve rheumatoid arthritis patients: Interim results of a long-term, observational, multicentre study in Japan (ORIGAMI).

OBJECTIVES: We investigated the long-term effectiveness, safety, and factors affecting Japanese Health Assessment Questionnaire (J-HAQ) improvement during abatacept treatment in Japanese rheumatoid arthritis (RA) patients. METHODS: The ORIGAMI study is an ongoing observational study of biologic-naïve RA patients with moderate disease activity treated with subcutaneous abatacept (125 mg, once-weekly). Patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) were extracted from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry as an historical, weighted control group. The primary endpoint for this interim analysis was the proportion of patients with J-HAQ remission (score ≤0.5) at 3 years. RESULTS: Among 279 abatacept-treated and 220 csDMARD-treated patients, J-HAQ remission was achieved at 3 years in 40.5% (95% confidence interval [CI] 34.7%-46.2%) and 28.9% (95% CI 9.9%-47.8%), respectively. Age, RA duration <1 year, baseline J-HAQ score, and Simplified Disease Activity Index remission at 6 months were associated with 3-year J-HAQ remission in the abatacept group. Overall, 24/298 patients (8.1%; safety analysis set) experienced serious adverse drug reactions with an incidence of 5.3 per 100 person-years. CONCLUSIONS: This study confirmed the 3-year effectiveness and safety, and revealed potential factors associated with J-HAQ remission in biologic-naïve RA patients treated with abatacept in real-world clinical practice.

Esophagectomy for esophageal cancer in patients with a history of total pharyngolaryngectomy: a Japanese nationwide retrospective cohort study.

BACKGROUND: Second primary esophageal cancer often develops in patients with head and neck cancer, and esophagectomy in patients with a history of total pharyngolaryngectomy (TPL) is challenging. However, the clinical outcomes of these patients have yet to be examined in a multicenter setting. METHODS: We evaluated the surgical outcomes of a nationwide cohort of 62 patients who underwent esophagectomy for esophageal cancer with a history of TPL. RESULTS: Ivor-Lewis and McKeown esophagectomies were performed in 32 (51.6%) and 30 (48.4%) patients, respectively. Postoperatively, 23 patients (37.1%) developed severe complications, and 7 patients (11.3%) required reoperation within 30 days. Pneumonia and anastomotic leakage occurred in 13 (21.0%) and 16 (25.8%) patients, respectively. Anastomotic leakage occurred more frequently in the McKeown group than in the Ivor-Lewis group (46.7% vs. 6.2%, P < 0.001). The adjusted odds ratio for anastomotic leakage in the McKeown group was 9.64 (95% confidence intervals (CI), 2.11-70.82, P = 0.008). Meanwhile, the 5-year overall survival rates were comparable between the groups (41.8% for Ivor-Lewis and 42.7% for McKeown), and the adjusted hazard ratio of overall survival was 1.44 (95% CI, 0.64-3.29; P = 0.381; Ivor-Lewis as the reference). CONCLUSIONS: In our cohort, anastomotic leakage occurred more frequently after McKeown than Ivor-Lewis esophagectomy, and almost half of patients in the McKeown group experienced leakage. Ivor-Lewis esophagectomy is preferred for decreasing anastomotic leakage when oncologically and technically feasible.

Evaluation of the blood flow in reconstructed gastric tube and its relation to anastomosis leakage.

OBJECTIVES: Anastomotic leakage in esophageal cancer surgery may be reduced by evaluating the blood flow to the reconstructed organ, but quantitative evaluation of arterial and venous blood flow is difficult. This study aimed to quantitatively assess blood flow using a new technique, as well as determine the relationship between the blood flow in the gastric tube and anastomotic leakage using near-infrared spectroscopy. METHODS: This single-center, observational study included 50 patients aged 51-82 years who underwent radical esophagectomy with gastric tube reconstruction for esophageal cancer between June 2022 and January 2023. Regional tissue oxygen saturation was measured at the antrum (point X), the anastomotic point (point Z), and the midpoint between points X and Z (point Y) before and after gastric tube formation. These three points of oxygen saturation were investigated in relation to anastomotic leakage. RESULTS: When comparing the presence of leakage to its absence, regional tissue oxygen saturation at points X and Z after gastric tube formation was significantly lower (X: p = 0.03, Z: p = 0.02), with the decreasing rate significantly higher at point Z (p = 0.01). There was no significant difference in the decreasing rate of regional tissue oxygen saturation between points X and Y (X: p = 0.052, Y: p = 0.83). CONCLUSION: Regional tissue oxygen saturation levels may be useful for measuring blood flow and could be a predictor of anastomotic leakage.

Effects of temperature on transient neurologic dysfunction after total arch replacement.

OBJECTIVES: The relationship between cooling status during aortic surgery with hypothermic circulatory arrest and postoperative neurologic dysfunction remains unknown. In the present study, we evaluated the effect of cooling status on transient neurologic dysfunction after total arch replacement. METHODS: We studied patients who underwent elective total arch replacement with hypothermic circulatory arrest and antegrade selective cerebral perfusion from December 2011 to January 2021. Changes in tympanic temperature trends recorded during surgery were plotted. Several parameters, including the nadir temperature, cooling speed, and degree of cooling (cooling area, or the area under the curve of inverted temperature trends from cooling to rewarming as calculated by the integral method), were analyzed. The relationships between these variables and transient neurologic dysfunction were evaluated. RESULTS: Transient neurologic dysfunction was observed in 33 (14.5%) of the 228 included patients. In the transient neurologic dysfunction group, the cooling area was larger (2417.3 vs. 1920.8 °C min; P < 0.001) and the cooling speed was higher (0.68 vs. 0.51 °C/min; P < 0.001) than in the non-transient neurologic dysfunction group. A multivariate logistic model revealed that both the cooling area (odds ratio = 1.13 per 100 °C min; P < 0.001) and cooling speed (odds ratio = 3.69 per °C/min; P = 0.041) were independent risk factors for transient neurologic dysfunction. CONCLUSIONS: Both the cooling area, which indicates the degree of cooling, and cooling speed had significant relationships with transient neurologic dysfunction after total arch replacement. Together, these findings indicate that overcooling and rapid cooling may contribute to brain injury.

Relationship Between the Lipidome Profile and Disease Activity in Patients with Rheumatoid Arthritis.

Lipid mediators have been suggested to play important roles in the pathogenesis of rheumatoid arthritis (RA). Lipidomics has recently allowed for the comprehensive analysis of lipids and has revealed the potential of lipids as biomarkers for the early diagnosis of RA and prediction of therapeutic responses. However, the relationship between disease activity and the lipid profile in RA remains unclear. In the present study, we performed a plasma lipidomic analysis of 278 patients with RA during treatment and examined relationships with disease activity using the Disease Activity Score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR). In all patients, five lipids positively correlated and seven lipids negatively correlated with DAS28-ESR. Stearic acid [FA(18:0)] (r = -0.45) and palmitic acid [FA(16:0)] (r = -0.38) showed strong negative correlations. After adjustments for age, body mass index (BMI), and medications, stearic acid, palmitic acid, bilirubin, and lysophosphatidylcholines negatively correlated with disease activity. Stearic acid inhibited osteoclast differentiation from peripheral blood monocytes in in vitro experiments, suggesting its contribution to RA disease activity by affecting bone metabolism. These results indicate that the lipid profile correlates with the disease activity of RA and also that some lipids may be involved in the pathogenesis of RA.

Prognostic factors of second-line nivolumab monotherapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study for 184 cases.

BACKGROUND: The real-world efficacy, prognostic factors, and adverse events of second-line nivolumab monotherapy and subsequent third-line therapy for unresectable or metastatic esophageal cancer have not been fully evaluated. METHODS: This multi-institutional retrospective cohort study evaluated 184 consecutive patients treated with second-line nivolumab monotherapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, adverse events, long-term survival, and prognostic factors. RESULTS: Among 128 patients with measurable lesions, the response rate was 23% and the disease control rate for all enrolled patients was 45%. The incidence of grade 3 or higher adverse events was 14%, but no treatment-related deaths presented. Median progression-free survival was 5.1 months and overall survival was 14 months, respectively. C-reactive protein level and performance status were identified as significant prognostic factors of overall survival through Cox proportional hazards analysis. The group with two favorable prognostic factors showed better overall survival than the groups with either one or zero prognostic factors (median overall survival: 22, 15, and 4.4 months, respectively). Among 69 patients who received third-line taxane anticancer agents, the progression-free survival was 6.7 months. CONCLUSIONS: Our study demonstrated that the real-world outcomes of second-line nivolumab monotherapy were comparable to those of previous randomized clinical trials in terms of tumor response, safety, and long-term survival. Furthermore, a good performance status and low C-reactive protein levels may identify patients who are likely to benefit from therapy. Third-line chemotherapy after nivolumab treatment may have an enhanced effect; however, further prospective studies are required to confirm this finding.

Individual acute-phase bleeding and thrombotic risk balance assessment in patients undergoing percutaneous coronary intervention for acute myocardial infarction.

Background: Individualized treatment approach based on pre-procedural precise risk balance assessment between bleeding and thrombosis would be desirable for patients with myocardial infarction (MI) undergoing emergent percutaneous coronary intervention (PCI) in this ultra-short dual antiplatelet therapy era. We aimed to develop and validate a quick thrombosis/bleeding risk-balance assessment tool. Methods: We developed and validated a novel thrombosis/bleeding risk-balance assessment tool using individual patient data from the prospective multicenter MI registry. Individual risks of thrombosis and bleeding within 7 days of the index PCI were estimated using a multinomial logistic regression model. The model was developed in the derivation cohort (4554 patients enrolled during 2003-2009) and validated in the validation cohort (2215 patients during 2010-2014). Results: A total of 6769 patients (66 ± 12 years, 5175 men) were eligible in this analysis. Predictive performance of the multinomial logistic regression models for bleeding and thrombosis assessed by calibration plots was good both in the derivation and validation cohorts. The net predicted probability (NPP) was defined as predicted probability of bleeding event (%) - predicted probability of thrombotic event (%). The NPP successfully stratified patients into those with a higher risk of bleeding than thrombosis and those with a higher risk of thrombosis than bleeding. This finding was consistent between the derivation and validation cohorts. Conclusions: We have established the risk balance assessment model for bleeding and thrombosis. Pre-procedural quick and precise assessment of the risk balance may help a decision making of procedural strategy and antithrombotic regimens in STEMI/non-STEMI patients undergoing PCI.

Diagnóstico presuntivo de Síndrome de Gilbert en una comunidad agraria del centro-este de Argentina / Presumptive diagnosis of Gilbert's syndrome in an agrarian community from the middle-east of Argentina

Introducción.El síndrome de Gilbert es una hiperbilirrubinemia no conjugada,leve,crónica,intermitente,denaturaleza benigna,que ocurre en ausencia de hemólisis o enfermedad hepatocelular y que afecta al 1-5 por ciento

Diagnóstico presuntivo de Síndrome de Gilbert en una comunidad agraria del centro-este de Argentina / Presumptive diagnosis of Gilberts syndrome in an agrarian community from the middle-east of Argentina

Introducción.El síndrome de Gilbert es una hiperbilirrubinemia no conjugada,leve,crónica,intermitente,denaturaleza benigna,que ocurre en ausencia de hemólisis o enfermedad hepatocelular y que afecta al 1-5 por ciento

A consideration of the mechanism for liquefaction-related large ground displacement

The authors discussed the mechanism of the liquefaction-related large ground displacement by referring the existing researches and an shaking table test result. Firstly, they reviewed the outcomes from case studies on large ground displacement during past earthquakes as well as empirical formulae proposed from regression analyses of the ground displacement with various factors such as gradient of ground surface, and studied fundamental characteristics of the large ground movement. Secondarily, the authors reviewed existing experimental works on ground displacement and on the mechanical properties of liquefaction soil during the ground movement. Furthermore, the authors conducted a shaking table test, where the ground surface was inclined after complete liquefaction of the soil. Based on the review of the existing researches and on the shaking table test they proposed an idea on the mechanism of the large ground displacement during liquefaction.(AU)

An experimental study of effects of laterally flowing ground on in-ground structures

This paper describes an experimental study of effects of laterally flowing ground induced by liquefaction on in-ground structures. In order to investigate the effects, the authors conducted shaking table tests concerning the mechanical properties of liquefied soil.(AU)

Experimental study of effects of liquefaction - induced ground displacement on in - ground structures

The authors have conducted the following experiments to investigate the fundamental characteristics of the effect that liquefaction-induced ground displacements have on in-ground structures: (i) experiments to measure the pressure of liquefied soil on a rigid in-ground wall (ii) experiments to measure the effects of liquefaction-induced ground displacements on a pile (iii) experiments on the load acting on spheres moving in liquefied soil. From these experiments it was concluded that the pressure exerted by liquefied soil on a rigid in-ground wall was approximately equal to the pressure of a liquid with an equivalent specific gravity. The force due to laterally flowing ground on in-ground structures did not depend on the magnitude of the ground displacement, but was greatly affected by the flow velocity.(AU)

Experimental study on mechanical properties of liquefied sand

The purpose of this study is to understand the mechanical properties of liquefied sand to estimate the behevior of ground after liquefaction and to investigate the mechanism of occurrence of liquefaction-induced large ground displacement. In this paper we consider that the mechanical properties of liquefied sand can be separated the following two phases, (1) the fluid characteristic of liquefied sand as viscous fluid, (2) the solid characteristic of liquefied sand under large deformation.(AU)