•Sera of mice immunized with an HBV preS2-encoding plasmid neutralized HBV infectivity.•Competition assay using overlapping peptides revealed that the neutralizing epitope is located in the ...N-terminal amino acids 8-27 of preS2.•Monoclonal antibodies targeting the N-terminal region of preS2 also neutralized HBV infectivity.
Hepatitis B virus (HBV) infection is a major public health problem. The sodium taurocholate cotransporting polypeptide (NTCP) has been identified as an essential HBV receptor. Human hepatocytes are infected with HBV via binding between the preS1 region of the HBV large envelope protein and the NTCP. However, the role of preS2 in HBV entry is not well understood.
In this study, we induced anti-preS2 serum in mice by DNA immunization, and showed that the resulting antiserum neutralized HBV infectivity. Competition assays using overlapping peptides suggested that the neutralizing epitope is located in the N-terminal region of preS2. In addition, monoclonal antibodies targeting the N-terminal region of preS2 neutralized HBV infectivity, indicating that these domains are critical epitopes for viral neutralization. These findings provide new insights into the HBV entry machinery while suggesting a novel modality for the prevention and treatment of HBV infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent episodes of fever and serositis. Periodic febrile attack can be managed with biologic medication ...in colchicine-resistant FMF patients, however, no reports or guidelines exist regarding the postoperative management of elective joint surgery in these patients. Although it is not clear how FMF attacks are triggered, they may be precipitated by stress including anesthesia or surgery. This study reports the case of a 51-year-old FMF patient who received total hip replacement under canakinumab (a specific interleukin-1β monoclonal antibody) treatment. He had highly active FMF, which was resistant to colchicine; however, his recurrent febrile attack with serositis was successfully controlled with canakinumab. Four months later from the start of canakinumab treatment, his hip osteoarthritis was required for total hip replacement (THR) because of the traumatic fracture. THR was successfully done and FMF attack was not occurred after this elective surgery. Discontinuation of canakinumab 3 weeks before surgery and resumption 6 weeks after led to favorable outcome without complications. This case addresses the differential management concerning stopping and restating of canakinumab in the perioperative setting in contrast to the other biologics such as tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) blocking agents. This case report suggests that canakinumab may represent a safe and effective therapy for the colchicine-resistant FMF, even in the patients requiring THR therapy.
Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib ...and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model.
: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (
< 0.001 and
< 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs.
: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cancer treatment using immune checkpoint inhibitors is widely used, although biomarkers predictive of response are not well established. However, both the expressions of programmed cell death ligand ...1 (PD-L1) and the tumor mutation burden (TMB) hold promise as such biomarkers for immune checkpoint inhibitors; however, its characteristics and clinical and immunological impacts have not been fully analyzed. We, therefore, evaluated the clinical and immunological parameters related to TMB to identify potential new biomarkers. We enrolled 92 patients with non-small-cell lung cancer who underwent surgery at Fukushima Medical University Hospital from 2013 to 2016. TMB of individual tumors was calculated by whole-exome sequencing analysis. Major cancer-related gene mutations were evaluated using panel sequencing. Expression of PD-L1 and abundance of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry using surgical samples. The median TMB value was 60. TMB was significantly higher in men, current or former smokers, and in patients with squamous cell carcinoma, tumor size ≥ 2.8 cm, wild-type EGFR, TP53 gene mutation-positive status, and cyclin-dependent kinase-inhibitor gene 2A mutation-positive status. According to multivariate analysis, TMB was significantly associated with EGFR gene mutation-negative status (
p
= 0.0111) and TP53 gene mutation-positive status (
p
= 0.0425). If TMB is identified as a robust biomarker for immune checkpoint inhibitor administration, analysis of TP53 and EGFR mutations may provide a relatively rapid and easy proxy for predicting TMB.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Depression has major negative consequences for individuals and society, and psychological assessment tools for early disease detection are needed. The aim of this study was to investigate ...the reliability and validity of an updated Japanese version of the Children's Depression Inventory (CDI‐J) and set a cut‐off score for the detection of depression.
Methods
The participants consisted of 465 children and adolescents aged 7–17 years. The control (CON) groups consisted of students recruited from elementary and junior‐high school (CONEJ) and children recruited from among hospital staff members (CONRE), while the outpatient clinical (OPC) groups consisted of pediatric psychosomatic outpatients (OPCPD) and adolescent psychiatric outpatients (OPCPS). The CON and OPC CDI‐J scores underwent factor analysis using varimax rotation, followed by measurement invariance analysis. The Youth Self‐Report (YSR) was administered to assess concurrent validity. The Mini‐International Neuropsychiatric Interview was administered to the OPC group to diagnose current depressive symptoms. Receiver operating characteristics (ROC) analysis was conducted to evaluate case‐finding performance and to set cut‐off points for the detection of depression.
Results
The CDI‐J was reliable in terms of internal consistency (Cronbach α = 0.86; mean inter‐item correlation, 0.16). Re‐test reliability was substantial (mean interval 18 days: γ = 0.59, P < 0.05). The four‐factor solution exhibited adequate internal consistency (range, 0.52–0.73) and correspondence (Pearson correlation of 0.65 with the YSR) for both the CON and OPC groups. On ROC analysis the optimal cut‐off score was 23/24.
Conclusion
The CDI‐J can be used as a reliable and well‐validated instrument alongside standard diagnostic procedures.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•InAs on GaSb heteroepitaxial growth by molecular beam epitaxy was investigated.•Pits are easily formed on InAs surface at low growth temperatures.•Pits are suppressed by irradiation of trace Sb due ...to surfactant effect.•Without Sb irradiation, two step InAs growth sequence can suppress pits.•Extremely flat surface was obtained by initial at 400 °C and subsequent at 520 °C.
Heteroepitaxial growth of InAs on GaSb(0 0 1) by molecular beam epitaxy was investigated. Pits composed of high-index crystal planes easily formed on InAs surfaces at low growth temperatures. They were suppressed by adding traces of Sb, which has a surfactant effect. However, this caused the content of Sb in the InAs layer to be inhomogeneous. On the other hand, without irradiation by Sb, the size of the pits became smaller as the growth temperature increased. The pits were completely suppressed by applying a two-step growth sequence: initial growth at 400 °C followed by subsequent bulk growth at 520 °C. In this sequence, Sb carryover from the underlying GaSb was negligible and did not contribute to the elimination of the pits as a surfactant. Two factors seemed to be essential for suppressing the formation of pits: (1) initial planar growth of InAs on GaSb, which is favored at low temperature, and (2) preference for the (0 0 1) plane over high-index crystal planes at high temperature.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying ...the invasiveness of early CRCs. We performed RNA‐sequencing (RNA‐seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP‐1 cells suggested that interleukin 1β (IL‐1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL‐1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1‐like/M2‐like macrophages at SAA1‐positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase‐9 in macrophages. Our data suggest that tumor‐associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.
We identified that serum amyloid A1 (SAA1) is upregulated in the poorly differentiated regions at the invasive front of T1 stage colorectal cancer (CRC). We found that tumor‐associated macrophages accumulated at the invasive front, where they stimulated SAA1 upregulation in CRC cells via interleukin 1β and promoted CRC cell migration and invasion. We also show that SAA1 secreted by CRC cells stimulates matrix metalloproteinase‐9 upregulation in macrophages at the invasive front.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Mycoplasma pneumoniae is a leading causative pathogen of pneumonia among pediatric patients, and its accurate diagnosis may aid in the selection of appropriate antimicrobial agents. We established a ...rapid reporting system of a polymerase chain reaction (PCR) examination for M. pneumoniae that enables physicians to obtain test results approximately 90 minutes after ordering the test. In this study, we evaluated the impact of this system on antimicrobial prescriptions for pediatric pneumonia patients after its implementation from May 2016 to April 2017. In total, we identified 375 pediatric pneumonia patients, and the results of the rapid PCR examinations for Mycoplasma pneumoniae were reported immediately in 90.7% of patients (340/375), with physicians able to use these results to decide on patients’ management before the prescription of antimicrobial agents. Of the 375 pediatric pneumoniae patients, M. pneumoniae was detected in 223 (59.5%). Among the 223 M. pneumoniae-positive pneumonia cases, antimicrobial agents for atypical pathogens (macrolides, tetracyclines or quinolones) were prescribed in 97.3% (217/223) at the initial evaluation, and their prescription rates increased to 99.1% (221/223) during management. In contrast, antimicrobial agents for atypical pathogens were prescribed only in 10.5% of 152 M. pneumoniae-negative pneumonia cases at the initial evaluations, and only 1 additional case was prescribed clarithromycin for persistent symptoms during management. In conclusion, we show that molecular technology could be applicable in the field of point-of-care testing in infectious disease, and its implementation will ensure the correct antimicrobial prescription for pediatric pneumonia patients.
Transcranial Doppler ultrasonography (TCD) is used widely to evaluate dynamic cerebral autoregulation (dCA). However, the validity of TCD-determined dCA remains unknown because TCD is only capable of ...measuring blood velocity and thus only provides an index as opposed to true blood flow. To test the validity of TCD-determined dCA, in nine healthy subjects, dCA was evaluated by transfer function analysis (TFA) using cerebral blood flow (CBF) or TCD-measured cerebral blood velocity during a perturbation that induces reductions in TCD-determined dCA, lower body negative pressure (LBNP) at two different stages: LBNP − 15 mmHg and − 50 mmHg. Internal carotid artery blood flow (ICA Q) was assessed as an index of CBF using duplex Doppler ultrasound. The TFA low frequency (LF) normalized gain (ngain) calculated using ICA Q increased during LBNP at − 50 mmHg (LBNP50) from rest (
P
= 0.005) and LBNP at − 15 mmHg (LBNP15) (
P
= 0.015), indicating an impaired dCA. These responses were the same as those obtained using TCD-measured cerebral blood velocity (from rest and LBNP15;
P
= 0.001 and
P
= 0.015). In addition, the ICA Q-determined TFA LF ngain from rest to LBNP50 was significantly correlated with TCD-determined TFA LF ngain (r = 0.460,
P
= 0.016) despite a low intraclass correlation coefficient. Moreover, in the Bland–Altman analysis, the difference in the TFA LF ngains determined by blood flow and velocity was within the margin of error, indicating that the two measurement methods can be interpreted as equivalent. These findings suggest that TCD-determined dCA can be representative of actual dCA evaluated with CBF.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Radiation therapy (RT) can enhance the abscopal effect of immune checkpoint blockade. This phase I/II study investigated the efficacy and safety of nivolumab plus RT in HER2-negative metastatic ...breast cancer requiring palliative RT for bone metastases. Cohort A included luminal-like disease, and cohort B included both luminal-like and triple-negative disease refractory to standard systemic therapy. Patients received 8 Gy single fraction RT for bone metastasis on day 0. Nivolumab was administered on day 1 for each 14-day cycle. In cohort A, endocrine therapy was administered. The primary endpoint was the objective response rate (ORR) of the unirradiated lesions. Cohorts A and B consisted of 18 and 10 patients, respectively. The ORR was 11% (90% CI 4-29%) in cohort A and 0% in cohort B. Disease control rates were 39% (90% CI 23-58%) and 0%. Median progression-free survival was 4.1 months (95% CI 2.1-6.1 months) and 2.0 months (95% CI 1.2-3.7 months). One patient in cohort B experienced a grade 3 adverse event. Palliative RT combined with nivolumab was safe and showed modest anti-tumor activity in cohort A. Further investigations to enhance the anti-tumor effect of endocrine therapy combined with RT plus immune checkpoint blockade are warranted.Trial registration number and date of registration UMIN: UMIN000026046, February 8, 2017; ClinicalTrials.gov: NCT03430479, February 13, 2018; Date of the first registration: June 22, 2017.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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