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BACKGROUND: Japanese spotted fever (JSF) is a tick-borne bacterial febrile disease caused by Rickettsia japonica characterized by fever, rash, and occasional death. The number of patients in Japan and the Tottori Prefecture has been increasing over the past 20 years. Most cases were found in Eastern Tottori; however, the distribution of patients has expanded to the Central and Western regions. Ticks carried by wild animals may be the cause, but the prevalence of R. japonica in ticks has not yet been analyzed. METHODS: Ticks were collected by flagging-dragging from 16 sites in Tottori, Japan. The ticks were morphologically classified and DNA was extracted. The 17-kDa antigen gene was amplified using nested PCR. PCR amplicons from ticks and JSF patients were sequenced and phylogenetically compared. RESULTS: In total, 177 ticks were collected and identified as Haemahysalis, Ixodes, Amblyomma, and Dermcentor. The Spotted Fever Group Rickettsia (SFGR) was detected in Haemahysalis and Amblyomma spp. using PCR, with positivity rates of 36.8% and 33.3%, respectively. DNA sequencing and phylogenetic analysis revealed that positive ticks harbored R. japonica, P. raoultii, and other Rickettsiae species; however, the patient’s samples were restricted to R. japonica. Similar to the incidence of JSF, the rate of R. japonica-positive ticks was higher in the Eastern region; however, R. japonica-positive ticks were also detected in the Western region. CONCLUSION: R. japonica sequences had been found in ticks collected in Tottori Prefecture. Ticks harboring R. japonica were found in the Eastern and Western parts of Tottori Prefecture and the sequences were identical to the human cases. Only the R. japonica sequence has been detected in patients with spotted fever symptoms, even though ticks were harboring various SFGRs.

The identification of biologically active target compounds and their binding proteins is important in mechanism-of-action studies for drug development. Additionally, the newly discovered binding proteins provide unforeseen ideas for novel drug discovery and for subsequent structural transformation to improve target specificity. Based on the lead and final candidate compounds related to the type 5 phosphodiesterase (PDE5) inhibitor E4021, we designed chemical probes and identified their target proteins by the affinity chromatography approach. Aldehyde dehydrogenase family 1 member A3 (ALDH1A3), currently reported as a cancer stem cell target, was clearly isolated as a binding protein of the lead 'immature' inhibitor probe against PDE5. In the early derivatization to the closely related structure, Compound 5 (ER-001135935) was found to significantly inhibit ALDH1A3 activity. The discovery process of a novel ALDH1A3-selective inhibitor with affinity-based binder identification is described, and the impact of this identification method on novel drug discovery is discussed.

Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with antimitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-851, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemoresistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, cotreatment of ER-851 and antimitotic drugs produced an antitumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-851 is a promising candidate therapeutic agent for use against AXL-expressing antimitotic-resistant tumors.

The liver function in outflow-obstructed regions is reportedly impaired; however, the functional decrease has not been quantitatively assessed. We therefore evaluated the uptake of indocyanine green (ICG) into hepatocytes and the mRNA expression associated with the liver function in outflow-obstructed regions using rat models.A total of 20 rats with the ligation of the right median hepatic vein to induce outflow obstruction were studied. Five rats each were grouped by the time of re-laparotomy, and the fluorescence intensity (FI) values of ICG. The mRNA expression, including that of Albumin, Cytochrome P450 (Cyp) 1a2, Cyp3a1, Cyp7a1, and Gamma-glutamylcysteine synthetase, in outflow-obstructed (mRNAMicroscopic fluorescence imaging showed that the FI values were significantly lower in outflow-obstructed regions than in non-outflow-obstructed regions at 12 h, 24 h, and 3 days after ligation of the hepatic vein. The mRNAThe liver function in outflow-obstructed regions was impaired in terms of the uptake of ICG and the mRNA expression. Our findings may help estimate the postoperative functional remnant liver volume by considering the decrease in the liver function in outflow-obstructed regions.

Background and ObjectivesTo assess the clinical and electrophysiologic features of female carriers and early-stage male patients with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiologic changes of the disease.MethodsFemale carriers, early-stage male patients with SBMA, and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between patients with SBMA and healthy male controls. EMG was also investigated in female carriers.ResultsWe enrolled 21 female carriers and 11 early-stage male patients. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and EMG abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in early-stage male patients with SBMA, but not in female carriers.DiscussionThe present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.

Background and ObjectivesPrevious studies have evaluated the diagnostic effect of amyloid PET in selected research cohorts. However, these studies did not assess the clinical impact of the combination of amyloid and tau PETs. Our objective was to evaluate the association of the combination of 2 PETs with changes in diagnosis, treatment, and management in a memory clinic cohort.MethodsAll participants underwent amyloid [18F]florbetaben PET and tau PET using [18F]PI-2620 or [18F]Florzolotau, which are potentially useful for the diagnosis of non-Alzheimer disease (AD) tauopathies. Dementia specialists determined a pre- and post-PET diagnosis that existed in both a clinical syndrome (cognitive normal [CN], mild cognitive impairment [MCI], and dementia) and suspected etiology, with a confidence level. In addition, the dementia specialists determined patient treatment in terms of ancillary investigations and management.ResultsAmong 126 registered participants, 84.9% completed the study procedures and were included in the analysis (CN [n = 40], MCI [n = 25], AD [n = 20], and non-AD dementia [n = 22]). The etiologic diagnosis changed in 25.0% in the CN, 68.0% in the MCI, and 23.8% with dementia. Overall changes in management between pre- and post-PET occurred in 5.0% of CN, 52.0% of MCI, and 38.1% of dementia. Logistic regression analysis revealed that tau PET has stronger associations with change management than amyloid PET in all participants and dementia groups.DiscussionThe combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia, and the second-generation tau PET has a strong impact on the changes in diagnosis and management in memory clinics.Classification of EvidenceThis study provides Class I evidence that the combination of amyloid and tau PETs was associated with changes in management and diagnosis of MCI and dementia.

Although drug-coated balloon (DCB) -based stent-less percutaneous coronary intervention (PCI) for de novo lesions has attracted more attention, outcomes of the DCB procedure for hemodialysis (HD) patients are reported to be inferior to those for non-HD patients, similarly to drug-eluting stent (DES). Recent several reports have shown that rotational atherectomy (RA) followed by DCB treatment (RA/DCB) could be an option of revascularization strategy particularly for calcified de novo lesions even in the new-generation DES era; however, efficacy of the RA/DCB procedure for HD patients remains unclear.A total of 47 consecutive cases (53 lesions) undergoing RA/DCB for de novo lesions were enrolled. According to the presence/absence of HD at baseline, the 47 cases were divided into the HD cases (n=16) and the non-HD cases (n=31), and the 53 lesions were divided into the HD lesions (n=20) and the non-HD lesions (n=33).The HD cases had a significantly lower prevalence of dyslipidemia and smoking than the non-HD cases. Final RA burr size, DCB diameter used, and angiographic success rate of PCI did not significantly differ between the 2 groups. Pre-procedural, post-procedural, and follow-up QCA parameters were also similar between the 2 groups. Twelve-month clinical outcomes were comparable between the 2 groups.Mid-term outcomes of stent-less PCI using RA/DCB for de novo lesions in HD patients might be comparable to those in non-HD patients, suggesting efficacy of pre-treatment of RA prior to DCB treatment in HD patients.

Recombinant production and evaluation of canine SIRPalpha protein.

Supplementary Data Figure S1-S7

Supplementary Table S1

Supplementary Table S1. Similarity between CD47 variants across species. Supplementary Table S2. Similarity between SIRPα variants across species. Supplementary Table S3. Summary of tumor necrosis scores following treatment with the indicated therapies. Supplementary Figure Legends. Supplementary Materials and Methods.

Cancer immunotherapies hold much promise, but their potential in veterinary settings has not yet been fully appreciated. Canine lymphomas are among the most common tumors of dogs and bear remarkable similarity to human disease. In this study, we examined the combination of CD47 blockade with anti-CD20 passive immunotherapy for canine lymphoma. The CD47/SIRPα axis is an immune checkpoint that regulates macrophage activation. In humans, CD47 is expressed on cancer cells and enables evasion from phagocytosis. CD47-blocking therapies are now under investigation in clinical trials for a variety of human cancers. We found the canine CD47/SIRPα axis to be conserved biochemically and functionally. We identified high-affinity SIRPα variants that antagonize canine CD47 and stimulate phagocytosis of canine cancer cells in vitro. When tested as Fc fusion proteins, these therapeutic agents exhibited single-agent efficacy in a mouse xenograft model of canine lymphoma. As robust synergy between CD47 blockade and tumor-specific antibodies has been demonstrated for human cancer, we evaluated the combination of CD47 blockade with 1E4-cIgGB, a canine-specific antibody to CD20. 1E4-cIgGB could elicit a therapeutic response against canine lymphoma in vivo as a single agent. However, augmented responses were observed when combined with CD47-blocking therapies, resulting in synergy in vitro and in vivo and eliciting cures in 100% of mice bearing canine lymphoma. Our findings support further testing of CD47-blocking therapies alone and in combination with CD20 antibodies in the veterinary setting. Cancer Immunol Res; 4(12); 1072–87. ©2016 AACR.

Nutritional and inflammatory status have been associated with postoperative recurrence and poor survival in patients with colorectal cancer. The aim of the present study is to investigate the relationship between serum cholinesterase levels and postoperative outcomes among patients who underwent curative resection for colorectal cancer.The study comprised 174 patients who had undergone curative resection for colorectal cancer. We explored the relationship between preoperative serum cholinesterase levels and disease-free survival and overall survival after curative resection. Then patients were divided into the high-cholinesterase group (n = 102) and the low-cholinesterase group (n = 72) to analyze their clinicopathological variables including other nutritional markers and systemic inflammatory responses.In multivariate analysis, lymph node metastasis (P = 0.011) and serum cholinesterase levels (P 0.01) were independent predictors of disease-free survival, while lymph node metastasis (P = 0.013), serum cholinesterase levels (P 0.01), and carbohydrate antigen19-9 (P = 0.022) were independent predictors of overall survival. In the low-cholinesterase group, neutrophil to lymphocyte ratio, (P = 0.021), C-reactive protein to albumin ratio (P 0.01), and distant metastasis (P 0.01) were higher, and prognostic nutritional index (P 0.01) was lower compared with the high-cholinesterase group.Preoperative low serum cholinesterase levels can be a prognostic factor for postoperative recurrence and poor prognosis in patients after curative resection for colorectal cancer, suggesting an important role of cholinesterase in the assessment of nutritional and inflammatory status in cancer patients.