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Objective: Drug sustainability (DS), a surrogate marker for drug efficacy, is important, especially when aiming for precision medicine. However, it lacks reliable prediction methods., Aims: To develop and externally validate a web-based artificial intelligence(AI)-derived tool for predicting DS of infliximab and vedolizumab in patients with moderate-to-severe Ulcerative Colitis (UC)., Methods: Data from three Israeli centers included infliximab or vedolizumab patients treated for >54 weeks. Sustainability meant no corticosteroids, hospitalizations or surgeries. Machine learning techniques predicted >54-week and overall DS using baseline clinical data., Results: The model was developed using data from 246 patients from Rabin Medical Center and externally validated on 67 patients from Rambam Health Care Campus and Sheba Medical Center. No significant difference in DS was observed across the datasets. Most patients were biologic-naïve and primarily treated with vedolizumab. The model performed well, with an area under the ROC curve of 0.86, and showed good accuracy (65.5 %-76.9 %) across the test sets., Conclusions: The study introduces a novel, AI-based tool for predicting >54-week DS of infliximab and vedolizumab in moderate-to-severe UC, using baseline parameters. This can aid clinical decision-making in the framework of precision medicine, promising to optimize disease management while maintaining physician autonomy., Competing Interests: Conflicts of interest HY- Has received research grants from Pfizer; consulting fees from Abbvie, Janssen, Pfizer, Takeda, and BMS; Speaker fees from Abbvie, Janssen, Pfizer, Takeda, and Bristol Myers Squibb; Data Safety Monitoring Board or Advisory Board fees from Abbvie, Pfizer Takeda and Bristol Myers Squibb. JEO- Has received grant support from Pfizer, consulting fees from Takeda, and speaker fees from Abbvie, Janssen, Pfizer, Takeda, Novartis, and Bristol Myers Squibb. IAB- Has received speaker fees from Abbvie, Janssen, Pfizer, Takeda, and Neopharm. ID- consultation fee or honorarium from: Abbott, Abbvie, Athos, Arena, Altman Research, Cambridge Healthcare, Celltrion, Celgene/BMS, Eli-Lilly, Ferring, Falk Pharma, Food Industries Organization, Gilead, Galapagos, Iterative Scopes, Integra Holdings, Janssen, Neopharm, Pfizer, Rafa laboratories, Roche/Genentech, Sangamo, Sublimity, Sandoz, Takeda, Wildbio. Grants: Altman Research, BMS, Pfizer UK- Research support- Jannsen, Takeda, Medtronic, speaker/advisory fees- Abbvie BMS Celtrion Jannsen Pfizer Takeda Medtronic Roche No specific funding has been received for this study., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: We examined corticosteroid use among Israeli patients with Inflammatory Bowel Disease (IBD), focusing on demographic, disease-related, and psychosocial factors. The objective was to contribute to the development of strategies minimizing corticosteroid dependence and improving patient outcomes, given the adverse effects associated with prolonged corticosteroid use., Methods: A comprehensive analysis was conducted on data collected from adult IBD patients attending six gastroenterological outpatient clinics in Israel. The data collected encompassed disease characteristics, demographic information, service level characteristics, social data, and steroid use. Statistical analyses were performed to associate these variables with steroid use., Results: Out of 402 patients, 26 % had been treated with corticosteroids in the previous year, with a majority of these having only one treatment course. Of patients treated with steroids, 57% (n-44) met steroid dependent/excess criteria. Steroid use was more common in patients diagnosed with ulcerative colitis (UC) compared to those with Crohn's disease. Factors such as a diagnosis of UC, male gender, elevated C-reactive protein and fecal calprotectin, and decreased albumin and hemoglobin were associated with steroid use., Conclusion: Corticosteroid use among Israeli IBD patients was associated with disease-related factors and some demographic characteristics. The results highlight the need for continued research to inform strategies aimed at reducing corticosteroid dependence in managing IBD, thereby improving patient outcomes., Competing Interests: Conflict of interest None., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Surveillance colonoscopies are crucial for high-risk patients with inflammatory bowel diseases (IBD) to detect colorectal carcinoma (CRC). However, there is no established quality metric for dysplasia detection rate (DDR) in IBD surveillance. This study assessed the DDR in a dedicated surveillance program at a tertiary referral center for IBD., Methods: Consecutive patients with quiescent colitis were enrolled in a cross-sectional study evaluating DDR. High-definition colonoscopy with dye chromoendoscopy (DCE) was performed by a specialized operator. Advanced dysplasia (AD) was defined as low-grade dysplasia ≥ 10 mm, high-grade dysplasia, or colorectal cancer. Risk factors for dysplasia detection were analyzed., Results: In total, 119 patients underwent 151 procedures, identifying 206 lesions, of which 40 dysplastic with seven AD . Per-lesion and per-procedure DDR were 19.4 % and 20.5 %, respectively. The per-procedure AD detection rate (ADDR) was 4.6 %. A Kudo pit pattern of II-V had a sensitivity of 92.5 % for dysplasia detection but a false positive rate of 64.8 % (p < 0.001). Age at diagnosis and at index colonoscopy and past or indefinite dysplasia were associated with per-procedure dysplasia detection., Conclusions: In a real-world setting, a dedicated surveillance program achieved a high DDR. We suggest that optimal DDR in high-risk IBD patients be defined and implemented as a standardized quality measure for surveillance programs., Competing Interests: Conflict of interest H.Y.- reports institutional research grants from Pfizer and the ISF; consulting fees from Abbvie, Janssen, Pfizer, and Takeda; honoraria for lectures from Abbvie, Janssen, Pfizer, Takeda, and BMS; participation in a Data Safety Monitoring Board or Advisory Board from Abbvie, Pfizer, Takeda, and BMS. I.D.: Advisory boards, consultation, speaking and teaching: Abbvie, Abbott, Arena, Athos, BMS/Celgene, Cambridge Healthcare, Celltrion, Genentech/Roche, Gilead, Galapagos, Eli-Lilly, Ferring, Falk Pharma, Food industries organization, Integra Holdings, Iterative Scopes, Janssen, Neopharm, Wild bio, Pfizer, Rafa Laboratories, Sangamo, Sublimity, Takeda J.E.O.: consultation fees from Pfizer, Abbvie, and Takeda; honoraria for lectures from Pfizer, Abbvie, and Takeda I.A.B.: consultation fees from Pfizer, Abbvie, and Takeda; honoraria for lectures from Pfizer, Abbvie, and Takeda, (Copyright © 2023. Published by Elsevier Ltd.)

Background: We sought to define the effectiveness and safety of tofacitinib in a real-world (RW) cohort of Israeli patients with moderate to severe ulcerative colitis (UC)., Methods: This was a multi-center retrospective observational cohort study (2019-2020) to assess the effectiveness and safety of tofacitinib induction and maintenance therapy up to 26 weeks. Clinical response and remission were defined as a reduction in Simple Clinical Colitis Activity Index (SCCAI) or partial Mayo score (PMS) of ≥3 points, and SCCAI ≤2 or a PMS ≤1, respectively., Results: We included 73 patients, 47% male; median age 26 years [IQR: 19.5-39.5], disease duration 7 years [IQR: 2.5-14.5], follow-up 7.1 months [IQR: 3-12], 91% biologics-experienced, and 74% ≥ 2-biologics. Half of patients used concomitant corticosteroids (CS). Overall, 56.1% discontinued therapy due to either lack of response and/or adverse events (AEs), median time to discontinuation - 9.7 months [IQR 3.4-16]. Overall, response, remission, and CS-free-remission were achieved in 47.6%, 20.6%, and 17.5% of patients, respectively. At early maintenance (week 26), response, remission, and CS-free-remission were achieved in 65%, 22.5%, and 20% of patients, respectively. At week 26, tofacitinib 10 mg BID was still used in 43%. Seventeen patients (23.2%) had an adverse event including herpes zoster- 2.7%, hospitalization- 12.3%, and colectomy- 2.7%., Conclusions: Tofacitinib was effective in achieving CS-free-remission in about 1/5 of highly biologics -experienced patients with UC. Despite a considerable proportion of patients maintained on tofacitinib 10 mg bid, it was well tolerated and safe. Earlier positioning of tofacitinib in the therapeutic algorithm may result in improved outcomes., Competing Interests: Conflict of interest H. Yanai: reports institutional research grants from Pfizer; consulting fees from Abbvie, Ferring, Janssen, Neopharm Ltd., Pfizer, Takeda; honoraria for lectures from Abbvie, Janssen, Pfizer, Takeda; participation on a Data Safety Monitoring Board or Advisory Board from Abbvie, Neopharm Ltd., Pfizer, Takeda. I. Avni Biron: Consulting fees from Takeda; honoraria for lectures from Abbvie, Janssen, Pfizer, Takeda, Neopharm Ltd; Clinical R&D team employee, Medtronic. I.Dotan: Consultation: Arena, Athos therapeutics, Gilead, Cambridge Healthcare, Wild bio, Food industries organization, Integra Holdings, Iterative Scopes. Speakers Bureau/lectures: Janssen, Abbvie, Takeda, Pfizer, Genentech/Roche, Arena, Neopharm, Celltrion, Rafa Laboratories, Ferring, Falk Pharma, Nestle, Celgene/BMS, Abbott. DSMB/advisory boards: SPARE consortium Janssen, Abbvie, Takeda, Pfizer, Genentech/Roche, Arena, Neopharm, Gilead, Galapagos, Celltrion, Sublimity, Wild bio, Athos therapeutics, Food industries organization, Celgene/BMS, Abbott, Sublimity, Sandoz. A. Bar-Gil Shitrit: Research grants from Takeda and Janssen, Consulting and honoraria for lectures from Takeda, Janssen' Abbvie, Pfizer and Neopharm. U. Kopylov: Research grants from Janssen, Takeda Medtronic, Consulting and honoraria- Abbvie, BMS, Janssen, MSD Medtronic, Takeda, Pfizer R. Weisshof: Consulting and honoraria for lectures from Takeda, Janssen, Abbvie. Advisory board fees from Janssen and AMAG Pharmaceuticals N. Maharshak: speaking and/ or consulting fees from Pfizer, Takeda, Janssen, Ferring, BiomX, BMS, Nestle and grant support from Takeda, Janssen, Abbott, Pfizer, BMS, Corundum Innovation Ltd E. Israeli: Research grants from Abbvie; Consulting and honoraria for lectures from Takeda, Janssen, Abbvie, Pfizer, Ferring Teva and BMS. I. Goren: Institutional research grant from Pfizer JE Ollech: Institutional research grant from Pfizer B. Koslowsky, A. Levartovsky, N. Aviv Cohen, D. Hovel, T. Naftali, Y. Snir, H. Banai-Eran, Y. Broitman, T. Sharar-Fischler -None., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Patients with Crohn's disease (CD) frequently undergo abdominopelvic computed tomography (APCT) in the emergency department (ED). It's essential to diagnose clinically actionable findings (CAF) as they may need immediate intervention, frequently surgical. However, repeated APCT's includes increased ionizing radiation exposure. Guidance regarding APCT performance is mostly clinical and empiric., Aims: We used a machine learning (ML) approach for predicting CAF on APCT in the ED., Methods: We performed a retrospective cohort study of patients with CD who presented to the ED and underwent APCT. CAF were defined as bowel obstruction, perforation, intra-abdominal abscess or complicated fistula. ML was used to predict the probability of having CAF on APCT, using routine clinical variables., Results: Of 101 admissions included, 44 (43.5%) had CAF on APCT. ML successfully identified patients at low (NPV 91.6%, CI-95% 90.6-92.5) and high (PPV 92.8%, CI-95%, 92.3-93.2) risk for CAF (AUROC = 0.774), using beats-per-minute, mean arterial pressure, neutrophil-to-lymphocyte ratio and sex. This allowed the construction of a risk stratification scheme according to patients' probability for CAF on APCT., Conclusion: We present a novel artificial intelligence-based approach, utilizing readily available clinical variables to better select patients with CD in the ED for APCT. This might reduce the number of APCTs performed, avoiding related hazards while ensuring high-risk patients undergo APCT., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: To elucidate the antigenic potential of dormancy-associated antigens Rv2659c and Rv3128c of Mycobacterium tuberculosis by examining the persistence of specific IgG and IgA memory B cells (MBCs) among patients with active tuberculosis (TB), household contacts with latent tuberculosis (LTBI), and an endemic healthy control group., Methods: Fresh peripheral blood mononuclear cells from the three study groups were used to enumerate the numbers of IgG and IgA MBCs specific to recombinant protein Rv2659c and Rv3128c by ELISpot assay. The composition of MBC subsets IgA + and IgG + was analyzed by flow cytometry., Results: The number of IgA MBCs specific to antigen Rv2659c was significantly higher in the LTBI group than the TB group. In contrast, no significant difference was found in IgA or IgG MBCs against antigen Rv3128c. The number of IgA + MBCs was significantly higher than that of IgG + MBCs in the classical MBC subset of the LTBI group., Conclusion: The results indicated that the dormancy-associated antigen Rv2659c induced an IgA MBCs response in individuals with latent TB, and IgA + classical MBCs formed a major portion of the MBCs subset. This new knowledge will be beneficial for the development of novel TB vaccines and their control of latent TB., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Numerous basic studies have shown a relationship between interleukin-6 (IL-6) and the development or severity of myocarditis. However, there has been no study in which the effect of IL-6 levels in patients with myocarditis was evaluated., Methods: We enrolled control patients (n = 12) and consecutive patients with acute myocarditis (n = 13), including lymphocytic, eosinophilic, and giant cell myocarditis, and investigated the pathological and clinical effects of IL-6 on human myocarditis., Results: The serum IL-6 level in patients with myocarditis (16.7 [9.9, 103.8] pg/mL) was significantly higher than that in the control patients (1.4 [1.0, 1.9] pg/mL) (P<0.001). Immunohistochemical analysis showed that IL-6 was expressed in infiltrating inflammatory cells of endomyocardial biopsy samples from all patients with myocarditis. Moreover, the log-transformed value of serum IL-6 level showed significant positive correlations with serum creatine kinase (CK) level, CK-MB level, peak CK level, peak CK-MB level and C-reactive protein level (all P ≤ 0.005) and a negative correlation with the left ventricular (LV) ejection fraction (p = 0.014). We divided the patients with myocarditis into a low IL-6 group (9.9 [4.5, 14.2] pg/dL, n = 7) and a high IL-6 group (108.9 [51.1, 130.9] pg/dL, n = 6). The degree of infiltration of IL-6-expressing inflammatory cells in myocardial samples obtained from patients in the high IL-6 group was significantly more severe than that in samples obtained from patients in the low IL-6 group. Furthermore, patients in the high IL-6 group significantly more frequently received catecholamine therapy (P = 0.005), venoarterial extracorporeal membrane oxygenation (P = 0.029), and artificial respirator support (P = 0.021) in the acute phase of myocarditis., Conclusion: The results suggest that there is a strong impact of IL-6 on cardiac injury and dysfunction in patients with myocarditis., (Copyright © 2021. Published by Elsevier Ltd.)

The current Thai guideline recommends that among people living with HIV, isoniazid preventive therapy (IPT) should be given to those with a positive tuberculin skin test (TST). We conducted a case-control study, nested within a cohort study, in Chiang Rai Province in Thailand to determine the role of TST in predicting the development of active tuberculosis (TB) within the following 2 years. Comparison between participants with CD4+ counts <50cells/mm 3 to those with CD4+ ≥200cells/mm 3 revealed that TST results were less sensitive (7.7% vs 50.0%) and had a lower negative predictive value (73.1% vs 97.3%) in those with a CD4+ count <50cells/mm 3 . In people with HIV, using a positive TST result as a criterion for initiating IPT inadvertently decreases the benefits of IPT, especially among those with low CD4+ counts., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined., Methods: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations., Results: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively., Conclusions: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations., Trial Registry: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000019691., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Several real-world experience (RWE) studies with vedolizumab (VDZ) for induction of remission in inflammatory bowel diseases (IBD) have been published; however, long-term RWE data is scarce., Aims: To describe the effectiveness and safety of VDZ in maintenance treatment of IBD., Methods: A multicenter retrospective national study. The primary outcome of was clinical response at week 52; main secondary aims included clinical remission at week 52, rates of secondary loss of response and treatment discontinuation., Results: We included 193 (133-CD; 60-UC) patients from 9 Israeli IBD centers. At week 52, response was observed in 62/133 (46.7%) CD patients, including 28 (21%) in clinical remission; 71 (53.3%) discontinued treatment or did not respond. For UC, response at week 52 was observed in 27/60 (45%), including 20 (33%) in clinical remission; 33 (55%) discontinued treatment or did not respond. Secondary non-response by week 52 occurred in 19.4% and 23.5% of week 14 responders in CD and UC, respectively. Week 14 response was associated with treatment continuation at week 52: no predictors of secondary loss of response were identified., Summary: VDZ is safe and effective for maintenance of response and remission in IBD; week 14 response is positively associated with long-term response in both UC and CD., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: Skeletal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor for poor outcomes in various malignancies. However, the prognostic significance of sarcopenia in patients with NSCLC after surgery has not been adequately determined. This study investigated the impact of sarcopenia in patients undergoing pulmonary resection for lung cancer., Methods: This retrospective study consisted of 328 patients with pathologically confirmed NSCLC who underwent curative resection between January 2005 and April 2017. Preoperative computed tomography imaging at the third lumbar vertebrae level was assessed to measure the psoas muscle mass index (PMI, cm 2 /m 2 ). Sarcopenia was defined as a cutoff value of PMI less than 6.36 cm 2 /m 2 for males and 3.92 cm 2 /m 2 for females, based on PMI values from "healthy" subjects., Results: The median patient age was 71 years and 59% were male. Sarcopenia was present in 183 (55.8%) and was significantly related with increasing age (p < 0.001), being male (p < 0.001), smoking habit (p < 0.001), lower body mass index (p < 0.001), and postoperative major complication (Clavien-Dindo grade ≥3, p = 0.036). The prevalence of sarcopenia was higher in men than in women, and the prevalence increased with age in men, whereas the prevalence did not increase in females older than 70 years. The 5-year survival rate was 61% in patients with sarcopenia and 91% in those without. Multivariate analysis revealed that sarcopenia was an independent unfavorable prognostic factor (p = 0.019)., Conclusions: Sarcopenia as determined using preoperative computed tomography could be used to predict postoperative major complication and prognosis in patients with resected NSCLC. Our results may provide some important information for preoperative management., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy., Objectives: We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations., Methods: Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared., Results: Of 77 tissue samples, BRAF V600E was detected in 21 samples (27%), CDK4 R24C in 7, EPHB6 G404S in 6, BRAF V600K in 2, NEK10 E379K in 2, and CDK4 R24H, NRAS Q61K, NRAS Q61R, KRAS G12A, KIT L576P, KIT V559A, ERBB4 E452K, and PDGFRA E996K in one sample each. No driver mutations related to the MAPK cascade including RAS and BRAF were detected in the chronically sun-damaged (CSD) group of melanoma. Dual or triple driver mutations were found in four of 40 (10%) samples from the primary melanomas, and three of 37 (8%) of the metastatic melanomas. Fourteen of 26 (54%) samples of non-CSD melanoma, and 3 of 6 (50%) melanomas of unknown primary origin had the BRAF V600E mutation. Mutations in membrane-bound receptors including KIT, ERBB4 and EPHB6 were detected in 8 of 77 (10%) samples. Of 17 pairs of primary and metastatic melanomas from the same patient, the primary mutation pattern was changed to a novel one in three cases, and only one of the plural mutations in the primary melanoma was found in the metastatic lesions in two cases., Conclusions: BRAF V600E is a predominant mutation in non-CSD melanoma and melanomas of unknown primary origin. Mutational heterogeneity may exist in the primary melanoma (intra-tumor heterogeneity), and between the primary and metastatic lesions (inter-tumor heterogeneity)., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Organizing pneumonia (OP) is a nonspecific response to various forms of lung injury and has been reported in association with several infectious agents. However, little is known about the relationship between OP and chronic pulmonary aspergillosis, and the mechanism of this linkage has not been elucidated. Here, we present a case of chronic pulmonary aspergillosis that led to the development of OP, which was successfully treated with corticosteroid and surgical intervention. In a review of the literature, we aim to highlight the possible relationship between OP and chronic pulmonary aspergillosis., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The treatment outcome has been unsatisfactory for patients with non-small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age ≥ 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The skin is responsible for a variety of physiological functions and is critical for wound healing and repair. Therefore, the regenerative capacity of the skin is important. However, stem cells responsible for maintaining the acral epithelium had not previously been identified. In this study, we identified the specific stem cells in the acral epithelium that participate in the long-term maintenance of sweat glands, ducts, and interadnexal epidermis and that facilitate the regeneration of these structures following injury. Lgr6-positive cells and Bmi1-positive cells were found to function as long-term multipotent stem cells that maintained the entire eccrine unit and the interadnexal epidermis. However, while Lgr6-positive cells were rapidly cycled and constantly supplied differentiated cells, Bmi1-positive cells were slow to cycle and occasionally entered the cell cycle under physiological conditions. Upon irradiation-induced injury, Bmi1-positive cells rapidly proliferated and regenerated injured epithelial tissue. Therefore, Bmi1-positive stem cells served as reservoir stem cells. Lgr5-positive cells were rapidly cycled and maintained only sweat glands; therefore, we concluded that these cells functioned as lineage-restricted progenitors. Taken together, our data demonstrated the identification of stem cells that maintained the entire acral epithelium and supported the different roles of three cellular classes., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to retrospectively compare the volume doubling time (VDT) on serial computed tomography (CT) of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation with that of NSCLC without the mutation., Methods: One hundred and two pathologically proven NSCLCs, including 69 patients with lung adenocarcinoma, were reviewed with helical CT. Each tumor underwent at least two CT scans. The VDT was calculated using a modified Schwartz formula. EGFR mutations at exons 18-21 were determined by common fragment analysis and Cycleave method., Result: The median VDT of all the patients was 188 days. EGFR mutations were noted in 35 of the 102 patients. The VDT in the 35 patients with EGFR mutations (median 676 days) was longer than that in the 67 patients without EGFR mutations (median 139 days) (p <0.001). By histology subtype, the VDT of adenocarcinoma (305 days) was longer than that of squamous cell carcinoma (81 days) and other types (90 days; p <0.001)., Conclusion: In NSCLC patients, positive EGFR mutation status may be associated with longer VDT, which seemed to have a slowly progressive and less-aggressive character. More accurate evaluation of VDT may be helpful for understanding the natural history of EGFR mutation-positive NSCLC and treatment with EGFR tyrosine kinase inhibitors.

Chronic kidney disease (CKD) is a major epidemiologic problem and a risk factor for cardiovascular events and cerebrovascular accidents. Because CKD shows irreversible progression, early diagnosis is desirable. Renal function can be evaluated by measuring creatinine-based estimated glomerular filtration rate (eGFR). This method, however, has low sensitivity during early phases of CKD. Cystatin C (CysC) may be a more sensitive predictor. Using a metabolomic method, we previously identified metabolites in CKD and hemodialysis patients. To develop a new index of renal hypofunction, plasma samples were collected from volunteers with and without CKD and metabolite concentrations were assayed by quantitative liquid chromatography/mass spectrometry. These results were used to construct a multivariate regression equation for an inverse of CysC-based eGFR, with eGFR and CKD stage calculated from concentrations of blood metabolites. This equation was able to predict CKD stages with 81.3% accuracy (range, 73.9-87.0% during 20 repeats). This procedure may become a novel method of identifying patients with early-stage CKD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In the stomach of a gastric ulcer patient who had been administered an anti-acid, a gram-negative and urease-negative bacillus similar in size to Helicobacter pylori was infected together with H. pylori. According to biochemical test and 16S rRNA gene analysis, the urease-negative bacterium was identified as Kingella denitrificans, a human nasopharyngeal commensal. In contrast to the standard strain of K. denitrificans, the isolate showed catalase activity, did not produce acid from glucose, and exhibited acid tolerance. Acid tolerance of H. pylori was increased by cocultivation with the K. denitrificans isolate, but not with other isolates of K. denitrificans. Disruption of physiological and immunological niche by dysbiotic colonization of bacterium may provide pathological attributes to human stomach. Collectively, a careful administration of anti-acids to the elderly, especially those with atrophic gastritis, is necessary to avoid repression of the gastric barrier to bacteria., (Copyright © 2013 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Cholesterol levels of non-high-density lipoprotein (non-HDL), which contains low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL) and chylomicron (CM) remnant, have been proven to perform a significant predictor of coronary heart disease (CHD) better than LDL-cholesterol regardless of triglyceride (TG) levels. The present study investigated the relevance of TG-rich lipoproteins (IDL, VLDL, CM) to Framingham risk score (FRS) predictive of 10-year CHD risk., Methods: Lipoprotein profiles (cholesterol levels of HDL, LDL, IDL, VLDL, CM) in Japanese men (n = 487) who underwent medical check-up were determined by using our developed anion-exchange high performance liquid chromatography (AEX-HPLC). Total-cholesterol (TC), TG, fasting blood sugar (FBS) and hemoglobin (Hb) A1c were measured by routine methods. The lipoprotein profiles, non-HDL-cholesterol, TC, and TG were examined on these associations with FRS., Results: The lipid levels except for CM-cholesterol were significantly different between two groups (low FRS, < 10%; high FRS, ≥10%) (P < 0.0001), and body mass index (BMI), TC, TG, IDL-, and VLDL-cholesterol were significantly and positively correlated with FRS. Among them, the significant association of non-HDL-cholesterol to FRS was noted (r = 0.411, P < 0.0001). Multiple stepwise regression analysis shows that, in addition to non-HDL-cholesterol, IDL-cholesterol in TG-rich lipoproteins was significantly correlated with FRS in independently of BMI. These correlation results were similarly found even when the part of the study subjects (n = 348) without the drug therapy for hyperlipidemia, diabetes, and hypertension was investigated., Conclusions: These results suggest that IDL-cholesterol may serve as a useful marker for CHD risk in Japanese men with increased non-HDL-cholesterol., (© 2013.)

The regulation of the Il12b gene, encoding the shared p40 subcomponent for IL-12 and IL-23, is critical for innate immune responses and subsequent T cell polarization. This gene is robustly induced upon Toll-like receptor (TLR) stimulation, wherein an enhancer located 10kb upstream of the transcription start site is required for promoter activity; however, the underlying mechanisms that regulate this enhancer in cooperation with the promoter has remained elusive. We show here that the Il12b enhancer contains functional ISREs for recognition by interferon regulatory factors (IRFs), and provide evidence that TLR-activated IRF5 mediates cooperativity of the enhancer with the promoter which also contains ISREs. By contrast, IRF3 activated by cytosolic RIG-I-like receptor (RLR) signaling binds to these ISREs and causes gene suppression. Consistently, IRF5 binding is accompanied with chromatin remodeling of both regulatory regions and the formation of a productive transcriptional complex containing other transcription factors, whereas these events are inhibited by IRF3 binding. We show that the ISREs embedded in the enhancer are indeed critical for its activation by IRF5. We also adduce evidence that the 5' sequences of the enhancer and promoter ISREs, all of which deviate from consensus ISREs, critically affect the function of IRF3. The dual commitment of these IRFs in the regulation of the Il12b enhancer and promoter is unique and may have implications for understanding the evolution of this gene., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: The effects of potent statins on oxidized lipoprotein biomarkers are not well defined., Methods and Results: The VISION (Value of oxIdant lipid lowering effect by Statin InterventiON in hypercholesterolemia) Trial randomized patients with hypercholesterolemia to 12-week administration of pitavastatin 2 mg/day (n = 21) or atorvastatin 10 mg/day (n = 21) and a variety of lipoprotein oxidative biomarkers were measured. Between-group analysis did not reveal any differences except in the ratio of malondialdehyde (MDA)-LDL over apolipoprotein B-100 (MDA-LDL/apoB) in pitavastatin vs. atorvastatin group (-13% vs. -0.7%, p = 0.04). Within-group changes from baseline to 12-week revealed significant increases in OxPL/apoB and reductions in small-dense LDL, MDA-LDL, and lipoprotein-associated phospholipase A(2) measured on circulating apoB particles (Lp-PLA(2)/apoB) in both groups and significant reductions in OxPL/apoAI in the atorvastatin group., Conclusions: The VISION study describes the first comparison on lipoprotein oxidation biomarkers between pitavastatin and atorvastatin and suggests diverse effects on lipoprotein oxidation markers in patients with hypercholesterolemia., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Remnant lipoprotein (RLP), associated with atherosclerosis progression, is often elevated in diabetes mellitus. The RLP level is estimated by immune-separation method and agarose-gel electrophoresis (AGE)., Methods: The patients were grouped into three groups according to tertile of RLP-cholesterol (RLP-C) levels. The lipoprotein profiles of type II diabetic patients (T2DM) (n=194) were measured by an anion-exchange liquid chromatography (AEX-HPLC) and an AGE with lipid-staining or cholesterol-staining., Results: IDL- and VLDL-cholesterol by the AEX-HPLC, and VLDL-levels by the AGE with lipid-staining and with cholesterol-staining were significantly different in the three groups. In all the subjects, IDL-cholesterol (r=0.531) and VLDL-cholesterol (r=0.880) by the AEX-HPLC method were strongly correlated with RLP-C, but only VLDL levels were correlated with RLP-C in AGE, respectively., Conclusion: These results suggest that the AEX-HPLC, which can provide cholesterol levels of not only VLDL but also IDL, is helpful for estimation of lipid profiles in T2DM with high RLP-C., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Chelating fibers containing polymer ligands such as carboxymethylated polyallylamine, carboxymethylated polyethyleneimine, and a copolymer of diallylamine hydrochloride/maleic acid were prepared with a wet spinning technique using mixtures of a viscose solution and the polymer ligands. The chelating fibers obtained effectively adsorbed various metal ions, including Cd(II), Co(II), Cr(III), Cu(II), Fe(III), Mn(II), Ni(II), Pb(II), Ti(IV), and Zn(II). The metal ions adsorbed could be readily desorbed using 0.1 or 0.5 mol L(-1) HNO(3). The chelating fiber containing carboxymethylated polyallylamine was available for the separation of some metal ions in synthetic wastewater containing a large amount of Na(2)SO(4). The wet spinning technique using a solution containing a base polymer and a polymer ligand was quite simple and effective and would be applicable for preparing various chelating fibers., (Copyright © 2011 Elsevier B.V. All rights reserved.)

NF-κB-inducing kinase (NIK) plays critical roles in the development of lymph nodes and Peyer's patches, and microarchitecture of the thymus and spleen via NF-κB activation. Alymphoplasia (aly/aly) mice have a point mutation in the NIK gene that causes a defect in the activation of an NF-κB member RelB. Here, we developed a novel method to determine the aly mutation by genetic typing using PCR. This method facilitated the easy establishment of a congeneic aly/aly mouse line. Indeed, we generated a mouse line with aly mutation on a BALB/cA background (BALB/cA-aly/aly). BALB/cA-aly/aly mice showed significant splenomegaly with extramedullary hemopoiesis, which was not significant in aly/aly mice on a C57BL/6 background. Interestingly, the splenomegaly and extramedullary hemopoiesis caused by the aly mutation was gender-dependent. These data together with previous reports on extramedullary hemopoiesis in RelB-deficient mice suggest that NIK-RelB signaling may be involved in the suppression of extramedullary hemopoiesis in adult mice., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The activation of innate immune responses is critical to host defense against microbial infections, wherein nucleic acid-sensing pattern recognition receptors recognize DNA or RNA from viruses or bacteria and activate downstream signaling pathways. In a search for new DNA-sensing molecules that regulate innate immune responses, we identified RNA-binding motif protein 3 (RBM3), whose role has been implicated in the regulation of cell growth. In this study, we generated Rbm3-deficient (Rbm3(-/-)) mice to study the role of RBM3 in immune responses and cell growth. Despite evidence for its interaction with immunogenic DNA in a cell, no overt phenotypic abnormalities were found in cells from Rbm3(-/-) mice for the DNA-mediated induction of cytokine genes. Interestingly, however, Rbm3(-/-) mouse embryonic fibroblasts (MEFs) showed poorer proliferation rates as compared to control MEFs. Further cell cycle analysis revealed that Rbm3(-/-) MEFs have markedly increased number of G2-phase cells, suggesting a hitherto unknown role of RBM3 in the G2-phase control. Thus, these mutant mice and cells may provide new tools with which to study the mechanisms underlying the regulation of cell cycle and oncogenesis., (Copyright © 2011. Published by Elsevier Inc.)

Medullary thymic epithelial cells (mTECs) are essential for thymic negative selection to prevent autoimmunity. Previous studies show that mTEC development is dependent on the signal transducers TRAF6 and NIK. However, the downstream target genes of signals controlled by these molecules remain unknown. We performed a microarray analysis on mRNAs down-regulated by deficiencies in TRAF6 or functional NIK in an in vitro organ culture of fetal thymic stromata (2DG-FTOC). An in silico analysis of transcription factor binding sites in plausible promoter regions of differentially expressed genes suggests that STAT1 is involved in TRAF6- and NIK-dependent gene expression. Indeed, the signal of RANK, a TNF receptor family member that activates TRAF6 and NIK, induces the activation of STAT1 in 2DG-FTOC. Moreover, RANK signaling induces the up-regulation of interferon (IFN)-stimulated gene (ISG) expression, suggesting that the RANKL-dependent activation of STAT1 up-regulates ISG expression. The RANKL-dependent expression levels of ISGs were reduced but not completely abolished in interferon α receptor 1-deficient (Ifnar1(-/-)) 2DG-FTOC. Our data suggest that RANK signaling induces ISG expression in both type I interferon-independent and interferon-dependent mechanisms., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We previously established an analysis method for determining the cholesterol levels of five major lipoprotein classes [HDL, LDL, intermediate density lipoprotein (IDL), VLDL, and chylomicrons] in serum by an anion-exchange (AEX)-HPLC method, but lipoprotein(a) [Lp(a)], a well-known risk factor for atherosclerotic diseases, was not determinable. Therefore, we established new AEX-HPLC separation conditions for analyzing the cholesterol levels of six lipoprotein classes, including Lp(a). Serum lipoproteins were separated by HPLC with a diethylaminoethyl-ligand nonporous polymer-based column by elution with a stepwise gradient of the sodium perchlorate concentration. In this improved method, HDL, LDL, IDL, VLDL, chylomicrons, and Lp(a) were each eluted from the column. The cholesterol levels of the eluted lipoproteins were measured enzymatically by a postcolumn reaction. The within-day assay and between-day assay coefficients of variation for the lipoprotein cholesterol levels were in the ranges of 0.29-11.86% and 0.57-11.99%, respectively. The Lp(a) cholesterol levels determined by AEX-HPLC were significantly correlated with the amounts of Lp(a) protein measured by an immunoturbidimetry method available commercially (r = 0.9503, P < 0.0001). Taken together, this AEX-HPLC method may be effectively applied to the analysis of serum lipoproteins with high levels of Lp(a).

Background: Astaxanthin has been reported to improve dyslipidemia and metabolic syndrome in animals, but such effects in humans are not well known., Methods: Placebo-controlled astaxanthin administration at doses of 0, 6, 12, 18 mg/day for 12 weeks was randomly allocated to 61 non-obese subjects with fasting serum triglyceride of 120-200mg/dl and without diabetes and hypertension, aged 25-60 years., Results: In before and after tests, body mass index (BMI) and LDL-cholesterol were unaffected at all doses, however, triglyceride decreased, while HDL-cholesterol increased significantly. Multiple comparison tests showed that 12 and 18 mg/day doses significantly reduced triglyceride, and 6 and 12 mg doses significantly increased HDL-cholesterol. Serum adiponectin was increased by astaxanthin (12 and 18 mg/day), and changes of adiponectin correlated positively with HDL-cholesterol changes independent of age and BMI., Conclusions: This first-ever randomized, placebo-controlled human study suggests that astaxanthin consumption ameliorates triglyceride and HDL-cholesterol in correlation with increased adiponectin in humans., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

A chelate resin immobilizing carboxymethylated pentaethylenehexamine (CM-PEHA resin) was prepared, and the potential for the separation and preconcentration of trace elements in water samples was evaluated through the adsorption/elution test for 62 elements. The CM-PEHA resin could quantitatively recover various elements, including Ag, Cd, Co, Cu, Fe, Ni, Pb, Ti, U, and Zn, and rare earth elements over a wide pH range, and also Mn at pH above 5 and V and Mo at pH below 7. This resin could also effectively remove major elements, such as alkali and alkaline earth elements, under acidic and neutral conditions. Solid phase extraction using the CM-PEHA resin was applicable to the determination of 10 trace elements, Cd, Co, Cu, Fe, Mn, Mo, Ni, Pb, V, and Zn, in certified reference materials (EnviroMAT EU-L-1 wastewater and ES-L-1 ground water) and treated wastewater and all elements except for Mn in surface seawater using inductively coupled plasma atomic emission spectrometry. The detection limits, defined as 3 times the standard deviation for the procedural blank using 500 mL of purified water (50-fold preconcentration, n=8), ranged from 0.003 microg L(-1) (Mn) to 0.28 microg L(-1) (Zn) as the concentration in 500 mL of solution.

Objectives: The Short Form-8 (SF-8) questionnaire is a commonly used 8-item instrument of health-related quality of life (QOL) and provides a health profile of eight subdimensions. Our aim was to examine the psychometric properties of the Japanese version of the SF-8 instrument using methodology based on nominal categories model., Methods: Using data from an adjusted random sample from a nationally representative panel, the nominal categories modeling was applied to SF-8 items to characterize coverage of the latent trait (theta). Probabilities for response choices were described as functions on the latent trait. Information functions were generated based on the estimated item parameters., Results: A total of 3344 participants (53%, women; median age, 35 years) provided responses. One factor was retained (eigenvalue, 4.65; variance proportion of 0.58) and used as theta. All item response category characteristic curves satisfied the monotonicity assumption in accurate order with corresponding ordinal responses. Four items (general health, bodily pain, vitality, and mental health) cover most of the spectrum of theta, while the other four items (physical function, role physical [role limitations because of physical health], social functioning, and role emotional [role limitations because of emotional problems] ) cover most of the negative range of theta. Information function for all items combined peaked at -0.7 of theta (information = 18.5) and decreased with increasing theta., Conclusion: The SF-8 instrument performs well among those with poor QOL across the continuum of the latent trait and thus can recognize more effectively persons with relatively poorer QOL than those with relatively better QOL.