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Adenosine deaminase (ADA) in pleural fluid is a useful marker for diagnosing tuberculous pleurisy. However, recent studies have reported a lower specificity of pleural fluid ADA levels. We previously developed a diagnostic flowchart for patients with pleural fluid ADA ≥40 U/L, incorporating variables such as pleural fluid lactate dehydrogenase <825 U/L, predominant pleural fluid neutrophils or cell degeneration, and a pleural fluid ADA/total protein ratio <14. This flowchart was effective in distinguishing between tuberculous pleurisy and other diseases. Here, we conducted a validation analysis of this flowchart.

Ionizing radiation (IR) causes DNA damage, particularly DNA double-strand breaks (DSBs), which have significant implications for genome stability. The major pathways of repairing DSBs are homologous recombination (HR) and nonhomologous end joining (NHEJ). However, the repair mechanism of IR-induced DSBs in embryos is not well understood, despite extensive research in somatic cells. The externally developing aquatic organism, Xenopus tropicalis, serves as a valuable model for studying embryo development. A significant increase in zygotic transcription occurs at the midblastula transition (MBT), resulting in a longer cell cycle and asynchronous cell divisions. This study examines the impact of X-ray irradiation on Xenopusembryos before and after the MBT. The findings reveal a heightened X-ray sensitivity in embryos prior to the MBT, indicating a distinct shift in the DNA repair pathway during embryo development. Importantly, we show a transition in the dominant DSB repair pathway from NHEJ to HR before and after the MBT. These results suggest that the MBT plays a crucial role in altering DSB repair mechanisms, thereby influencing the IR sensitivity of developing embryos.

AbstractRemdesivir is an antiviral drug for the treatment of coronavirus disease 2019 (COVID-19), and the sustained antiviral activity against Omicron variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been reported. In this single-center retrospective study, we first compared the clinical effectiveness of remdesivir-based therapy between Omicron and other variant phases of moderate COVID-19 in a real-world setting. Between Dec 2020 and July 2022, a total of 406 patients with COVID-19 pneumonia were treated with remdesivir-based therapy on admission. The oxygen deterioration rate after initiation of treatment significantly decreased in the Omicron variant phase compared to the alpha and delta variant phases. In an adjusted multivariate Cox proportional hazards model, Omicron variant phase was significantly associated with delayed oxygen deterioration and early recovery from hypoxia. These favorable outcomes during the Omicron variant phase, compared to previous variant phases, might be due to the attenuation and the popularization of vaccination.

Intramuscular adipose tissue (IMAT) formation derived from muscle fibro‐adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice. Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross‐sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)‐knockout (Gipr−/−) and wild‐type (Gipr+/+) mice. FAPs isolated from lower limb muscles of 12‐week‐old Gipr+/+mice were cultured with GIP, and their differentiation into mature adipocytes was examined. Furthermore, TA muscle IMAT area and fibre CSA were measured in untreated Gipr−/−mice and GIP receptor antagonist‐treated Gipr+/+mice after glycerol injection into the TA muscles. Body composition analysis revealed that 104‐week‐old Gipr−/−mice had a greater proportion of lean tissue mass (73.7 ± 1.2% vs. 66.5 ± 2.7%, P< 0.05 vs. 104‐week‐old Gipr+/+mice) and less adipose tissue mass (13.1 ± 1.3% vs. 19.4 ± 2.6%, P< 0.05 vs. 104‐week‐old Gipr+/+mice). Eighty‐four‐week‐old Gipr−/−mice exhibited increases in grip strength (P< 0.05), weights of TA (P< 0.05), soleus (P< 0.01), gastrocnemius (P< 0.05) and quadriceps femoris (P< 0.01) muscles, and average TA muscle fibre CSA (P< 0.05) along with a reduction in TA muscle IMAT area assessed by the number of perilipin‐positive cells (P< 0.0001) compared with 84‐week‐old Gipr+/+mice. Oil Red O staining analysis revealed 1.6‐ and 1.7‐fold increased adipogenesis in muscle FAPs cultured with 10 and 100 nM of GIP (P< 0.01 and P< 0.001 vs. 0 nM of GIP, respectively). Furthermore, both untreated Gipr−/−mice and GIP receptor antagonist‐treated Gipr+/+mice for 14 days after glycerol injection into the TA muscles at 12 weeks of age showed reduced TA muscle IMAT area (1.39 ± 0.38% and 2.65 ± 0.36% vs. 6.54 ± 1.30%, P< 0.001 and P< 0.01 vs. untreated Gipr+/+mice, respectively) and increased average TA muscle fibre CSA (P< 0.01 and P< 0.05 vs. untreated Gipr+/+mice, respectively). GIP promotes the differentiation of muscle FAPs into adipocytes and its receptor antagonism suppresses IMAT accumulation and promotes muscle regeneration. Pharmacological GIP receptor antagonism may serve as a novel therapeutic approach for sarcopenia.

The long‐term relationship between fracture‐prone implantable cardioverter‐defibrillator (ICD) leads and poor prognosis remains unclear in Japanese patients. We conducted a retrospective review of the records of 445 patients who underwent implantation of advisory/Linox leads (Sprint Fidelis, 118; Riata, nine; Isoline, 10; Linox S/SD, 45) and non‐advisory leads (Endotak Reliance, 33; Durata, 199; Sprint non‐Fidelis, 31) between January 2005 and June 2012 at our hospital. The primary outcomes were all‐cause mortality and ICD lead failure. The secondary outcomes were cardiovascular mortality, heart failure (HF) hospitalization, and the composite outcome of cardiovascular mortality and HF hospitalization. During the follow‐up period (median, 8.6 [4.1–12.0] years), there were 152 deaths: 61 (34%) in patients with advisory/Linox leads and 91 (35%) in those with non‐advisory leads. There were 32 ICD lead failures: 27 (15%) in patients with advisory/Linox leads and five (2%) in those with non‐advisory leads. Multivariate analysis for ICD lead failure demonstrated that the advisory/Linox leads had a 6.65‐fold significantly greater risk of ICD lead failure than non‐advisory leads. Congenital heart disease (hazard ratio 2.51; 95% confidence interval 1.08–5.83; p= .03) could also independently predict ICD lead failure. Multivariate analysis for all‐cause mortality demonstrated no significant association between advisory/Linox leads and all‐cause mortality. Patients who have implanted fracture‐prone ICD leads should be carefully followed up for ICD lead failure. However, these patients have a long‐term survival rate comparable with that of patients with non‐advisory ICD leads in Japanese patients. Patients who were implanted with fracture‐prone ICD leads should be carefully followed up for ICD lead failure. However, such patients have comparable long‐term survival rates with those with non‐advisory ICD leads.

Background: Central diabetes insipidus (CDI) is a rare condition caused by various underlying diseases, including neoplasms, autoimmune diseases, and infiltrative diseases. Differentiating between CDI etiologies is difficult. What has initially been classified as “idiopathic” central diabetes insipidus might in fact underlie various pathogenic mechanisms that are less understood to date and/or are not obvious at initial presentation. Therefore, even if idiopathic CDI is diagnosed at the time of onset, it is common for tumors such as germinoma to develop during surveillance. Crucially, a delayed diagnosis of germinoma may be associated with a worse prognosis. Recently, the presence of anti–rabphilin-3A antibodies has been found to be a highly sensitive and specific marker of lymphocytic infundibuloneurohypophysitis, an autoimmune-mediated CDI. Case presentation: We herein present two cases, namely, a 13-year-old boy (patient 1) and a 19-year-old young man (patient 2) who were diagnosed with idiopathic CDI. In both patients, panhypopituitarism developed. Magnetic resonance imaging revealed pituitary stalk thickening and pituitary swelling approximately 1 1/2 years after the onset of CDI. Western blotting did not reveal the presence of anti-rabphilin-3A antibodies in serum in either patient, suggesting that autoimmune mechanisms might not be involved. Both patients were subsequently diagnosed with germinoma on pathological examination. They received chemotherapy, followed by radiation therapy. Notably, testosterone and insulin-like growth factor-1 levels normalized, and libido and beard growth recovered after chemoradiotherapy in patient 2. Conclusion: Our data suggest that the absence of anti-rabphilin-3A antibodies in young patients clinically diagnosed with idiopathic CDI may increase the probability of the development of non-lymphocytic lesions, including germinoma. We thus recommend a more attentive approach at the onset of these diseases.

Over 200 interstitial lung diseases, from ultra rare to relatively common, are recognised. Most interstitial lung diseases are characterised by inflammation or fibrosis within the interstitial space, the primary consequence of which is impaired gas exchange, resulting in breathlessness, diminished exercise tolerance, and decreased quality of life. Outcomes vary considerably for each of the different interstitial lung diseases. In some conditions, spontaneous reversibility or stabilisation can occur, but unfortunately in many people with interstitial lung disease, especially in those manifesting progressive pulmonary fibrosis, respiratory failure and death are a sad reality. Over the past 3 years, the field of interstitial lung disease has had important advances, with the approval of drugs to treat systemic sclerosis-associated interstitial lung disease, interstitial lung disease-associated pulmonary hypertension, and different forms of progressive pulmonary fibrosis. This Seminar provides an update on epidemiology, pathogenesis, presentation, diagnosis, disease course, and management of the interstitial lung diseases that are most frequently encountered in clinical practice. Furthermore, we describe how developments have led to a shift in the classification and treatment of interstitial lung diseases that exhibit progressive pulmonary fibrosis and summarise the latest practice-changing guidelines. We conclude with an outline of controversies, uncertainties, and future directions.

A study was performed on the electronic structures and properties of perovskite compounds with the chemical formula ABX3and the monovalent copper ion (Cu+) as the A-site cation. Most Cu+-based perovskite chlorides (CuMCl3, where M denotes an element) had lower total energies than cesium (Cs)-based perovskite crystals. The energy gaps of CuMCl3perovskites with B-site cations spanning chromium (Cr) to zinc (Zn) were close to the ideal value for photovoltaic materials. The calculated carrier effective mass ratios indicated that CuMCl3should have a similar or higher carrier mobility than CsPbCl3(Pb=lead). Unlike Cs-based perovskites, the electron orbitals of Cu and the MCl6octahedron overlap, suggesting that the Cu+at the A-site should affect the stability of the crystal structure and the carrier mobility. The Cu+ion can be used as the A-site cation in ABX3perovskites to tune the composition of all-inorganic perovskite crystals and thereby increase the diversity of physical properties.

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Background: Opioids have been reported to be effective for refractory dyspnea in patients with advanced heart failure (HF) in the palliative care setting. Objective: The aim of this study was to evaluate the incidence of adverse drug reactions (ADRs) and their relationship with morphine dose/duration or renal insufficiency in patients with end-stage HF receiving continuous morphine infusion. Methods: We retrospectively studied 38 patients with end-stage HF receiving continuous intravenous or subcutaneous morphine infusion for the relief of breathlessness between 2014 and 2019 (mean age 78 years). The endpoints were nausea/vomiting, respiratory depression, and drowsiness, which are common morphine-related ADRs. Results: Of 38 patients with end-stage HF receiving continuous intravenous/subcutaneous morphine infusion, 14 (37%) experienced ADRs. The median estimated glomerular filtration rate (eGFR) was lower in patients with than in those without ADRs (16 [range 9–48] vs. 41 [range 8–133], respectively; p= 0.011). The ADRs with the highest incidence were drowsiness (n= 13), nausea/vomiting (n=5), and respiratory depression (n=3). There were no differences in the maintenance dose or duration of morphine administration between patients with and without ADRs. A baseline eGFR of 32 mL/min/1.73 m2was a good cutoff value for ADR prediction (sensitivity 86%, specificity 96%). A baseline eGFR &lt; 32 mL/min/1.73 m2was significantly associated with the occurrence of morphine-related ADRs (odds ratio 6.63, 95% confidence interval 1.19–37.01). Conclusions: Our results showed that 37% of patients with end-stage HF receiving continuous intravenous/subcutaneous morphine infusion experienced ADRs, especially drowsiness. Patients with eGFR &lt; 32 mL/min/1.73 m2were likely to experience morphine-related ADRs.

Radiocarbon (14C) in corals can be used as a relatively high‐sensitivity indicator of vertical and horizontal advection of water masses, which contributes to the understanding of ocean circulation. In this study, we reconstruct Kuroshio and Ryukyu current transport with a seasonal resolution Δ14C record spanning 1947–2009. This record covers the beginning of the atomic era and was obtained from a coral on Kikai Island in the south of Japan. The Kikai Δ14C curve features a newly discovered Δ14C spike in July 1955, a rapid increase after 1962, and a steady decrease after 1980. The spike in 1955 may directly reflect ocean current transport. The lack of periodicity in the Δ14C record suggests the existence of mesoscale eddies and the complexity of Kuroshio and Ryukyu current transport. In addition, comparing the high‐resolution Δ14C of Kikai and Ishigaki islands, both situated along the path of the Kuroshio, reveals the influence of Pacific Decadal Oscillation and El Niño‐Southern Oscillation on the Kuroshio and Ryukyu currents. This suggests that seasonally resolved Δ14C in corals along an ocean current can produce a long‐term record of ocean mixing that responds to climate variability. The Kuroshio Current and Ryukyu Current in the western North Pacific play important roles in the climate of East Asia since they bring rain and transport heat from low latitudes to higher latitudes. However, due to a lack of long‐term continuous high‐resolution records, the detailed understanding of those currents is limited. Radiocarbon (14C) generated by natural and anthropogenic activities is incorporated into the ocean and taken up by corals, which vary with different locations and water depths. Coral 14C can be a very sensitive indicator of vertical and horizontal advection of water masses. Here, we present a coral 14C record in 1947–2009 from Kikai Island in the south of Japan. The coral 14C record captures clear signatures of vertical mixing and effects of gyres near Kikai Island. The seasonal‐resolution record shows no continuous periodicity, reflecting variable Kuroshio and Ryukyu current transport and mesoscale eddies. These data also support the idea that Kuroshio and Ryukyu current transport is affected by the Pacific Decadal Oscillation and El Niño‐Southern Oscillation. A Δ14C spike is observed in 1955 in Kikai and it may reflect the condition of ocean current transportLack of periodicity in Δ14C record possibly reflects mesoscale eddies and complex Kuroshio and Ryukyu Current variabilityKuroshio and Ryukyu Current are influenced by global climate change such as Pacific Decadal Oscillation and El Niño‐Southern Oscillation A Δ14C spike is observed in 1955 in Kikai and it may reflect the condition of ocean current transport Lack of periodicity in Δ14C record possibly reflects mesoscale eddies and complex Kuroshio and Ryukyu Current variability Kuroshio and Ryukyu Current are influenced by global climate change such as Pacific Decadal Oscillation and El Niño‐Southern Oscillation

This study aimed to compare the efficacy and safety of ablation with high and low power settings using either a flexible tip or straight SF tip irrigated catheter in the left ventricle (LV) using a peripheral microemboli monitoring system.

Objectives: Stroke is a substantial complication of left ventricular assist device (LVAD) implantation. The relationship between stroke and the anatomical position of the inflow cannula of patients who underwent LVAD implantation was investigated.Methods: We enrolled 15 patients with advanced-stage heart failure who underwent implantation of continuous-flow-LVAD. Data of patients who suffered a stroke within 6 months after LVAD implantation were retrospectively compared to those who remained free of stroke. The distance between the inflow duct and left ventricular (LV) septum (duct-sep distance) and its ratio to LV diastolic diameter (LVDd) were measured from echocardiography at 1 month after LVAD implantation. Receiver operating characteristic curves for the endpoint of stroke using the duct-sep distance to LVDd ratio was created and the cut-off value was calculated. The incidence of stroke during the 6 months after LVAD implantation according to this ratio was estimated using the Kaplan-Meier method.Results: At 1 month after LVAD implantation, there were no significant differences in baseline characteristics and echocardiography parameters between the stroke and stroke-free groups. Receiver operating characteristic curve analysis for the endpoint of stroke using the duct-sep distance to LVDd ratio revealed 0.217 as a cut-off value (sensitivity: 80%, specificity: 80%, area under the curve: 0.72). Stroke was more frequent in patients with a duct-sep distance to LVDd ratio ⩾0.217 at 1 month than in those with a lower ratio.Conclusion: The duct-sep distance to LVDd ratio was associated with the occurrence of stroke, suggesting that inflow cannula position influences the incidence of stroke.

In general, a steel beam is assembled with a concrete slab by shear connectors. The connection requires high stiffness and strength to secure the composite effect even in the ultimate state. Facing this need, perfobond shear connectors are attracting a great attention by virtue of its outstanding mechanical performance. However, the connector is subjected to the fully reversed cyclic stress between the compression and tension during an earthquake. Therefore, as presented in the earlier research addressing stud shear connectors, the concrete may originate cracks under the tensile stress; and eventually, the expected composite effect is not possibly performed. To address this concern, this research carried out a total of three fully reversed cyclic loading tests using the component model of perfobond shear connection. The parameters are the presence of reinforcing bars and concrete strength. In conclusion, it was found that perfobond shear connectors exhibit more stable mechanical behavior and capacity than stud shear connectors regardless of stress orientation due to a localized stress transfer mechanism that results in smaller cracks in the slab under a fully reversed cyclic loading.

Patients with heart failure (HF) and low left ventricular ejection fraction (LVEF) are at high risk of sudden cardiac death (SCD). Optimal HF treatment can improve LVEF and reduce the risk of SCD. The aim of this study was to evaluate the incidence and predictors of SCD in Japanese patients with new‐onset systolic HF and to investigate factors that affect LVEF improvement. We retrospectively studied 174 consecutive hospitalized patients with new‐onset HF and LVEF ≤35% (median age, 66 years; men, 71%). The primary outcome was a composite of SCD, sustained ventricular arrhythmias, and appropriate implantable cardioverter‐defibrillator therapy. The cumulative rates of meeting of the primary outcome at 3, 12, and 36 months after discharge were 3.9%, 8.1%, and 10.5%, respectively. Atrial fibrillation was a significant predictor of the primary outcome within 12 months after discharge (odds ratio, 5.87; 95% confidence interval [CI], 1.60–21.57). Among 104 patients who completed follow‐up echocardiography within 12 months after discharge, changes in LVEF were inversely associated with SCD (odds ratio/1% increase, 0.78; 95% CI, 0.65–0.93). A QRS duration <130 ms and a B‐type natriuretic peptide level <170 pg/mL were predictors of LVEF improvement to >35% (odds ratio, 3.69; 95% CI, 1.15–11.77; odds ratio, 3.19; 95% CI, 1.33–7.69, respectively). Our results showed a high incidence of meeting of the primary outcome within 12 months after discharge in hospitalized patients with new‐onset systolic HF. An improved LVEF may reduce the risk of late SCD. There were high incidences of the primary outcome (sudden cardiac death, sustained ventricular tachycardia/fibrillation, and appropriate implantable cardioverter‐defibrillator therapy) and all‐cause death within 12 months, especially within 3 months, after discharge in hospitalized Japanese patients with new‐onset heart failure and LVEF ≤35%.

A monovalent copper ion (Cu+) with the same valence as formamidinium is focused on the present work, and the effects of A-site inorganic cations on the electronic structures and device performance are discussed from the experiments and the first-principles calculations. The addition of inorganic cations increased the conversion efficiencies, and the copper-doped device showed the highest conversion efficiency. In particular, the hysteresis of current density–voltage characteristics was significantly suppressed by the addition of Cu+, which would be due to suppression of iodine ion (I−) diffusion by electrostatic interaction between Cu+and I−. The addition of rubidium or cesium contributed to the increase in short-circuit current density by suppressing decomposition of perovskite crystals and formation of PbI2.

Epidemiological studies have identified associations between gastroesophageal reflux (GER) and cow's milk allergy (CMA) in infants. However, the role of GER in the development of CMA remains poorly understood. Our primary objectives were to develop a mouse model that suggests GER as a potential pathogenic mechanism for CMA and to elucidate the immunological mechanisms that connect lung innate immunity with CMA.

Background. Gestational diabetes insipidus (DI) is a very rare complication of pregnancy. We present a case of gestational DI combining two different types of DI. Case Presentation. A 39-year-old pregnant woman suddenly presented with thirst, polydipsia, and polyuria after 31 gestation weeks (GWs). Based on laboratory findings of hypotonic urine (78 mOsm/kgH2O) with higher plasma osmolality (298 mOsm/kgH2O) and higher serum sodium levels (149 mEq/L), gestational DI was suspected, and the clinical course was monitored without therapy until the results of a measurement of plasma arginine vasopressin (AVP) levels were available. However, she subsequently developed acute prerenal failure and underwent an emergency cesarean section at 34 GWs. Her resected placenta weighed 920 g, nearly twice the normal weight. Immediately following delivery, intranasal 1-desamino-8-D-arginine vasopressin was administered, and her symptoms promptly disappeared. Afterward, her predelivery plasma AVP level was found to have been inappropriately low (0.7 pg/mL) given her serum sodium level. The patient’s serum vasopressinase level just before delivery was 2,855 ng/mL, more than 1,000 times the upper limit of the normal range, suggesting excess vasopressinase-induced DI. The presence of anti-rabphilin-3A antibodies in the patient’s blood, a hypertonic saline infusion test result, and loss of the high-intensity signal of the posterior pituitary on fat-suppressed T1-weighted magnetic resonance images without thickening of the stalk and enlargement of the neurohypophysis suggested concurrent central DI-like lymphocytic infundibulo-neurohypophysitis (LINH). Conclusion. In addition to the degradation of AVP by excess placental vasopressinase due to the enlarged placenta, an insufficient compensatory increase in AVP secretion from the posterior pituitary gland due to LINH-like pathogenesis might have led to DI symptoms.

Hair follicle morphogenesis during embryonic development is driven by the formation of hair follicle germs (HFGs) via interactions between epithelial and mesenchymal cells. Bioengineered HFGs are potential tissue grafts for hair regenerative medicine because they can replicate interactions and hair follicle morphogenesis after transplantation. However, a mass preparation approach for HFGs is necessary for clinical applications, given that thousands of de novo hair follicles are required to improve the appearance of a single patient with alopecia. In this study, we developed a microfluidics-based approach for the large-scale preparation of HFGs. A simple flow-focusing microfluidic device allowed collagen solutions containing epithelial and mesenchymal cells to flow and generate collagen microbeads with distinct Janus structures. During the 3 days of culture, the collagen beads contracted owing to cellular traction forces, resulting in collagen- and cell-dense HFGs. The transplantation of HFGs into nude mice resulted in highly efficient de novo hair follicle regeneration. This method provides a scalable and robust tissue graft preparation approach for hair regeneration.

Despite the effectiveness of implantable cardioverter defibrillators (ICDs) in the prevention of sudden cardiac death, shock therapy causes patients to experience pain and psychological distress, which contradicts the purpose of palliative care. It is difficult to predict the time course for heart failure (HF) patients, unlike that for cancer patients. The aim of this study was to evaluate the deactivation status of ICD therapy in Japanese patients with end‐stage HF. We retrospectively studied 51 ICD patients who died due to worsening HF at Tokyo Women's Medical University Hospital from 2010 to 2019. The frequency of ICD therapy delivered before death and information about the discussion of deactivation and do not attempt resuscitation (DNAR) decisions were reviewed using medical charts. Of 51 patients, 12 (24%) patients deactivated ICD therapy and seven patients underwent deactivation within 24 hours of a DNAR order. The median time from deactivation to death was 3 days (range, 0‐56). Of 39 patients with DNAR orders, 27 (69%) did not undergo deactivation. A relatively high proportion of patients (n = 14, 27%) experienced ICD shocks within 1 month of death. The frequency of electrical storms within 1 month of death was also high (n = 12, 24%). Our study showed that only one‐fourth of Japanese patients with end‐stage HF underwent deactivation of ICD therapy. A relatively high frequency of shock therapy was observed in the last month before death. Only one fourth of Japanese patients with end‐stage heart failure underwent deactivation of implantable cardioverter defibrillator (ICD) therapy. The frequency of ICD therapy within one month of death was higher than that prior to one month before death in patients with end‐stage heart failure, and some patients received shocks within 24 hours of death.

Snail is a transcription factor that regulates many cellular events involved in development, homeostasis, and disease. In hepatocellular carcinoma (HCC), Snail induces epithelial-to-mesenchymal transition that confers invasive properties on tumor cells during HCC progression and malignancy. Snail activation observed in HCC mouse models suggests its involvement not only in progression, but also onset of HCC. However, it remains unclear whether Snail directly contributes to HCC initiation or whether it supports HCC initiation promoted by other oncogenes. In this study, we generated mouse models for liver-specific and hepatocyte-specific overexpression of Snailto show the independent roles of Snail in liver homeostasis and disease. Enforced Snailexpression resulted in liver and hepatocyte enlargement, inflammatory cell infiltration in the liver, lipid accumulation in hepatocytes, substantial increases in serum alanine aminotransferase and bile acids, yellow discoloration of tissues caused by bilirubin accumulation, and liver tumorigenesis. Snailoverexpression suppressed mRNA expression of the tight junction components claudins and occludin and that of proteins associated with bile acid metabolism, leading to disruption of the biliary canaliculus formed among hepatocytes and excretion of abnormal amounts of unusual bile acids from hepatocytes. In conclusion, enforced Snailexpression in hepatocytes is sufficient for induction of steatohepatitis and liver tumorigenesis through disruption of the biliary canaliculus and bile acid homeostasis in the liver.

SLAMF7 is expressed mainly on multiple myeloma (MM) cells and considered an ideal target for immunotherapeutic approaches. Indeed, elotuzumab, an anti-SLAMF7 antibody, is used for the treatment of MM in combination with immunomodulatory drugs. SLAMF7 is cleaved via unknown mechanisms and detected as a soluble form (sSLAMF7) exclusively in the serum of MM patients; however, little is known about the role of sSLAMF7 in MM biology. In this study, we found that sSLAMF7 enhanced the growth of MM cells via homophilic interaction with surface SLAMF7 and subsequent activation of the SHP-2 and ERK signaling pathways. Elotuzumab suppressed sSLAMF7-induced MM cell growth both in vitro and in vivo. Promoter analyses identified IKZF1 (Ikaros) as a pivotal transcriptional activator of the SLAMF7gene. Pharmacological targeting of Ikaros by lenalidomide and its analog pomalidomide downregulated SLAMF7 expression and ameliorated the response of MM cells to sSLAMF7. Elotuzumab blocked the growth-promoting function of sSLAMF7 when combined with lenalidomide in a murine xenograft model. Neutralization of sSLAMF7 is a novel antimyeloma mechanism of elotuzumab, which is enhanced by immunomodulatory drugs via downregulation of surface SLAMF7 expression on MM cells. These findings may provide important information for the optimal use of elotuzumab in MM treatment.

ABSTRACTThe trajectory of the Kuroshio, the western boundary current in the north Pacific, influences regional climate. It intrudes into the South China Sea (SCS) through the Luzon Strait, resulting in the exchange of water, nutrients, heat, and salt between the Pacific and SCS. It has been reported that the trajectory of the Kuroshio has varied with decadal climate changes. However, there has been no report of an observation-based estimate of the variation in the Luzon Strait transport. Here, a 50-year, high-resolution coral skeletal radiocarbon (Δ14C) dataset from 1946 to 1994 is reported from Currimao, northwest of Luzon Island. Δ14C has been used as a sensitive tracer of seawater, and our data indicates a significant increase in Δ14C from 1946 to 1994 related to atmospheric nuclear bomb testing, with more rapid increase in the SCS than in the Pacific. The unusual, rapid Δ14C increase in the 1950s found in our SCS corals together with seasonal variation in Δ14C will helps constrain physical oceanographic models for the western Pacific, including the SCS.

Background:Advance care planning (ACP) is recommended as part of the management of patients with heart failure (HF).Aims:To develop and validate ACP support tools for patients with HF.Methods:An ACP support tool was developed based on a systematic literature review. A multi-center, prospective before and after study was conducted to evaluate the usefulness of the support tool. This study included 21 patients with HF, 11 patients formed the control group and 10 patients were part of the intervention group who received ACP from medical staff using the ACP support tools developed for this study. Participants of the study were surveyed about their experience of ACP using a 6-point Likert scale.Findings:All of the healthcare professionals (n=9) involved in the study found the ACP tool useful and about 90% of patients considered the support tool useful. The score for ‘the patient did not feel anxious about the future after receiving ACP discussion’ was significantly higher (3.5 [3.0, 4.0] vs 2.0 [1.0, 3.0]; P=0.04) in the intervention group that used the ACP tool.Conclusion:ACP support tools are useful to manage patients with HF and could enable effective ACP without increasing patient anxiety.