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BACKGROUND: Diabetes mellitus affects more than a quarter of patients with thalassemia major (TM) worldwide, and increases the risk for cardiac complications, contributing to significant morbidity. Pancreatic iron overload (IO) and fat infiltration have been correlated with this endocrinal complication in adult TM patients. It has been shown that in adult TM patients, iron accumulation and fat infiltration are found to be heterogeneous in the pancreatic head, body, and tail region. R2* and a fat fraction (FF) generated by gradient-echo imaging can be used as quantitative parameters to assess the iron and fat contents of the pancreas. This study aimed to determine the pattern of pancreatic iron accumulation and fat infiltration in pediatric TM patients with gradient-echo imaging and evaluate the association between pancreatic IO and fat infiltration and glucose disturbances. METHODS: A total of 90 children with TM (10.7±3.1 years) were included. All patients underwent pancreatic magnetic resonance imaging (MRI) using multi-echo gradient-echo sequences. IO was measured by R2* relaxometry in 90 patients, and FF values were measured using iterative decomposition of water and fat with echo asymmetry and the least-squares estimation (IDEAL) method in 40 patients. R2* and FF were assessed in the pancreatic head, body, and tail. The global R2* and global FF values were obtained by averaging the respective values from the pancreatic head, body, and tail. The correlations between global R2*, global FF, and fasting glucose were determined using Spearman’s correlation analysis. The Friedman test was used to compare R2* and FF among different pancreatic regions. Receiver operating characteristic (ROC) analysis was used to determine the performance of global R2* and global FF in discriminating impaired fasting glucose from normal fasting glucose patients. RESULTS: The global R2* was positively correlated with the global FF in the pancreas (r=0.895, P

Background: There is no information on the association between exposure to fine particulate matter with an aerodynamic diameter of 2·5 μm or less (PM2·5) and the date-based secondary attack rate (DBSAR) of COVID-19. Methods: In this retrospective cohort study performed in Guangzhou, China, based on hourly concentration data of PM>sub>2·5, PM10, SO2, NO2, and CO from January 1, 2020 to February 15, 2020 from approximately 1,500 monitoring stations in China and the addresses of the participants, we used the Kriging interpolation method to calculate the moving average (MA) concentrations of the pollutants over the previous 1 to 14 days before symptom onset of secondary cases. After simultaneously adjusting for a series of key covariates, we evaluated the dose-response relationship between PM2·5 and DBSAR using a generalized linear mixed model. Findings: DBSAR fluctuated from 2·12% on January 17 to 6·61% on February 13. The significantly positive relationship between PM2·5 exposure and DBSAR at prior 1 to 14 MA days. For example, the dose-response relationship was as follows, for every 10 μg/m 3 increase in PM2·5, DBSAR increased by 2·77% (95% CI: 1·32% to 4·22%; P < 0·001) at prior 1 MA day and 5·82% (95% CI: 4·00% to 7·65%; P < 0·0001) at prior 14 MA days. The effect of PM2·5 exposure in DBSAR significantly differed by age and exposure time. Interpretation: There was a strong nonlinear dose-response relationship between exposure to PM2·5 and DBSAR at prior 1 to 14 MA days, which provide significant evidence and suggests that transmission by aerosol is possible. Funding Statement: This study was supported by grants from the Health Science and Technology Plan Project of Guangzhou (20191A01158). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: This study was approved by the ethics committee of the Guangzhou CDC (Guangzhou, China). Analyses involving personally identifiable data were conducted at the Guangzhou CDC. The analyses were performed with anonymized data.

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Babesia gibsoni is increasingly recognized globally as a cause of canine tick-borne anemic disease; however, only a few clinical reports of naturally acquired infection are available. In this systematic study of dogs presenting with B. gibsoni infection, clinical and laboratory data were collected for dogs with PCR-confirmed B. gibsoni infection admitted to the National Taiwan University Veterinary Teaching Hospital (NTUVH) from January 2014 through December 2015. Of the 60 dogs recruited, 20 (33.3%) had concurrent disease and 40 (66.7%) had only B. gibsoni infection. The severity of anemia in B. gibsoni infected dogs with concurrent or without concurrent infection was not significantly different. The most commonly observed hematological abnormalities were anemia (49/60, 81.7%) and thrombocytopenia (37/60, 61.7%). Of 49 dogs, 24 (49%) had severe to very severe anemia (PCV 20%). The main biochemical abnormalities included hyperglobulinemia (28/53, 52.8%), hyperbilirubinemia (10/28, 35.7%) and elevated hepatic enzyme activity (7/48, 14.6%). In addition, 2 of the 60 the client-owned dogs and 5 of the 33 B. gibsoni-positive stray dogs were detected as having a naturally atovaquone-resistant strain, using the SimpleProbe® assay. The study results provide a useful clinical presentation of B. gibsoni infection and raise the issue of the naturally atovaquone-resistant strain currently existing in Taiwan.

Background Cancer stem cells are capable of undergoing cell division after surviving cancer therapies, leading to tumor progression and recurrence. Inhibitory agents against cancer stem cells may be therapeutically used for efficiently eradicating tumors. Therefore, the aim of this study was to identify the relevant driver genes that maintain cancer stemness in epidermal growth factor receptor (EGFR)-positive colorectal cancer (CRC) cells and to discover effective therapeutic agents against these genes. Methods In this study, EGFR-positive cancer stem-like cells (CSLCs) derived from HCT116 and HT29 cells were used as study models for in vitro inductions. To identify the differential genes that maintain CSLCs, RNAseq analysis was conducted followed by bioinformatics analysis. Moreover, a panel containing 172 therapeutic agents targeting the various pathways of stem cells was used to identify effective therapeutics against CSLCs. Results RNAseq analysis revealed that 654 and 840 genes were significantly upregulated and downregulated, respectively, in the HCT116 CSLCs. Among these genes, notably, platelet-derived growth factor A (PDGFA) and signal transducer and activator of transcription 3 (STAT3) were relevant according to the cancer pathway analyzed using NetworkAnalyst. Furthermore, therapeutic screening revealed that the agents targeting STAT3 and Wnt signaling pathways were efficient in reducing the cell viabilities of both HCT116 and HT29 cells. Consequently, we discovered that STAT3 inhibition using homoharringtonine and STAT3 knockdown significantly reduced the formation and survival of HT29-derived tumorspheres. We also observed that STAT3 phosphorylation was regulated by epidermal growth factor (EGF) to induce PDGFA and Wnt signaling cascades. Conclusions We identified the potential genes involved in tumorsphere formation and survival in selective EGFR-positive CRCs. The results reveal that the EGF-STAT3 signaling pathway promotes and maintains CRC stemness. In addition, a crosstalk between STAT3 and Wnt activates the Wnt/β-catenin signaling pathway, which is also responsible for cancer stemness. Thus, STAT3 is a putative therapeutic target for CRC treatment. Electronic supplementary material The online version of this article (10.1186/s12929-018-0456-y) contains supplementary material, which is available to authorized users.

Background Babesia gibsoni is the predominant tick-borne protozoan blood parasite affecting dogs throughout the Oriental region. Babesia gibsoni is transmitted by Haemaphysalis longicornis, whereas a similar role has been suggested for Rhipicephalus sanguineus. Haemaphysalis longicornis does not occur in Taiwan, but R. sanguineus is widely distributed on dogs. However, clinical cases of babesiosis are mainly restricted to the northern part of the island. The discrepancy between tick distribution and clinical cases stimulated us to investigate the tick species distribution on dogs in northern Taiwan, with the aim to identify the local vector for canine babesiosis. Methods Ticks were collected from stray dogs or free ranging pet dogs in northern Taiwan between 2015 and 2017 and, after identification, were tested for the presence of tick-borne Babesia parasites using PCR and reverse line blot (RLB) hybridisation. Moreover, engorged ticks collected from the dogs were incubated at 28 °C to allow them to oviposit. Their subsequent larval progeny was also examined by PCR/RLB. Results A total of 1085 ticks collected from 144 stray dogs at different residential areas consisted of 5 different species: H. hystricis (n = 435), R. sanguineus (n = 582), R. haemaphysaloides (n = 43), Amblyomma testudinarium (n = 14) and Ixodes ovatus (n = 11) were identified. Babesia gibsoni DNA was detected in H. hystricis females (10.3%), males (7.0%) and in 2.6% of the nymphs. One R. sanguineus female and one A. testudinarium female tick also carried B. gibsoni DNA. DNA of B. gibsoni was demonstrated in 11 out of 68 (16.2%) batches of larval ticks derived from engorged H. hystricus ticks only. Babesia vogeli DNA was detected only in R. sanguineus females (2.6%) and males (2.4%). DNA of B. vogeli was detected in 13 out of 95 (13.7%) batches of larval ticks derived from engorged R.sanguineus females. Conclusions Babesia gibsoni DNA was detected in the larval progeny of H. hystricis ticks only, whereas B. vogeli was restricted to the larvae of R. sanguineus. This provides evidence for transovarial passage of B. gibsoni in H. hystricis and evidence that this tick does act as the local vector for this parasite on dogs in northern Taiwan where most cases of babesiosis are reported. The vectorial capacity of R. sanguineus for babesiosis is probably restricted to the transmission of B. vogeli only.

Objectives YM155, an inhibitor of interleukin enhancer-binding factor 3 (ILF3), significantly suppresses cancer stemness property, implying that ILF3 contributes to cell survival of cancer stem cells. However, the molecular function of ILF3 inhibiting cancer stemness remains unclear. This study aimed to uncover the potential function of ILF3 involving in cell survival of epidermal growth factor receptor (EGFR)-positive lung stem-like cancer, and to investigate the potential role to improve the efficacy of anti-EGFR therapeutics. Materials and methods The association of EGFR and ILF3 in expression and regulations was first investigated in this study. Lung cancer A549 cells with deprivation of ILF3 were created by the gene-knockdown method and then RNAseq was applied to identify the putative genes regulated by ILF3. Meanwhile, HCC827- and A549-derived cancer stem-like cells were used to investigate the role of ILF3 in the formation of cancer stem-like tumorspheres. Results We found that EGFR induced ILF3 expression, and YM155 reduced EGFR expression. The knockdown of ILF3 reduced not only EGFR expression in mRNA and protein levels, but also cell proliferation in vitro and in vivo, demonstrating that ILF3 may play an important role in contributing to cancer cell survival. Moreover, the knockdown and inhibition of ILF3 by shRNA and YM155, respectively, reduced the formation and survival of HCC827- and A549-derived tumorspheres through inhibiting ErbB3 (HER3) expression, and synergized the therapeutic efficacy of afatinib, a tyrosine kinase inhibitor, against EGFR-positive A549 lung cells. Conclusion This study demonstrated that ILF3 plays an oncogenic like role in maintaining the EGFR-mediated cellular pathway, and can be a therapeutic target to improve the therapeutic efficacy of afatinib. Our results suggested that YM155, an ILF3 inhibitor, has the potential for utilization in cancer therapy against EGFR-positive lung cancers.

In order to develop a clinically applicable severity scoring system in cats with pancreatitis, 41 cats diagnosed with pancreatitis and hospitalized between 2011 and 2013 with their complete medical history were selected for analysis. Clinical signs, physical examination findings, laboratory findings, diagnostic imaging results, complications and concurrent diseases were analyzed to evaluate potential prognostic factors and further establish the severity scoring system. The mortality of cats selected in this study due to pancreatitis was 48.8%. Abnormalities in hemoglobin, albumin, blood urea nitrogen, total bilirubin, phosphorous and blood pressure were significantly associated with disease severity and prognosis and were selected for constructing the system. The abnormal range for each variable was further partitioned into quartiles, which were recorded into categorical variables. The weighting factors were calculated from the odds ratios (OR) between each of the quartiles and the normal range category. The area under curve (AUC) of the six continuous variables system at presentation and after rehydration of the cats was 0.873 and 0.976, respectively. The scores of 41 cats after rehydration ranged from 7 to 36 points. The mean score was [Formula: see text], the median 17 points and the mode 32 points. The optimal cut-off point for outcome prediction was 17.5 with a sensitivity of 95.2% and specificity of 95.5%. The mortality was 95% with a [Formula: see text], whereas 4.8 % had a [Formula: see text]. The severity scoring system provides a reliable and clinically applicable method to predict disease severity in cats with pancreatitis.

Purpose To evaluate the value of T2, T1rho, and diffusion metrics in assessment of liver fibrosis in rats. Materials and Methods Liver fibrosis in a rat model (n = 72) was induced by injection of carbon tetrachloride (CCl4) at 3T. T2, T1rho, and diffusion parameters (apparent diffusion coefficient (ADC), Dtrue) via spin echo (SE) diffusion-weighted imaging (DWI) and stimulated echo acquisition mode (STEAM) DWI with three diffusion times (DT: 80, 106, 186 msec) were obtained in surviving rats with hepatic fibrosis (n = 52) and controls (n = 8). Liver fibrosis stage (F0–F6) was identified based on pathological results using the traditional liver fibrosis staging method for rodents. Nonparametric statistical methods and receiver operating characteristic (ROC) curve analysis were employed to determine the diagnostic accuracy. Results Mean T2, T1rho, ADC, and Dtrue with DT = 186 msec correlated with the severity of fibrosis with r = 0.73, 0.83, −0.83, and −0.85 (all P < 0.001), respectively. The average areas under the ROC curve at different stages for T1rho and diffusion parameters (DT = 186 msec) were larger than those of T2 and SE DWI (0.92, 0.92, and 0.92 vs. 0.86, 0.82, and 0.83). The corresponding average sensitivity and specificity for T1rho and diffusion parameters with a long DT were larger (89.35 and 88.90, 88.36 and 89.97, 90.16 and 87.13) than T2 and SE DWI (90.28 and 79.93, 85.30 and 77.64, 78.21 and 82.41). The performances of T1rho and Dtrue (DT = 186 msec) were comparable (average AUC: 0.92 and 0.92). Conclusion Among the evaluated sequences, T1rho and STEAM DWI with a long DT may serve as superior imaging biomarkers for assessing liver fibrosis and monitoring disease severity. Level of Evidence: 1 J. Magn. Reson. Imaging 2017;45:741–750.

A diblock copolymer of poly(ethylene glycol) (PEG) and poly(γ-benzyl L-glutamate) (PBLG), PEG-PBLG, was synthesized via the ring-opening polymerization of γ-benzyl L-glutamate N-carboxyanhydride (BLG-NCA) using allyl-PEG-NH2 as a macroinitiator. After deprotection of the benzyl groups, N,N-diisopropyl ethylenediamine (DIP) was conjugated to poly(L-glutamic acid) (PGA) blocks as side groups. The pendant DIP groups on the PGA blocks greatly enhance the pH-sensitivity of poly(ethylene glycol)-block-poly[N-(N',N'-diisopropylaminoethyl) glutamide] [PEG-PGA(DIP)] micelles, and a higher grafting percentage of DIP favors a faster acid-response. In neutral aqueous solution, the PEG-PGA(DIP) can self-assemble into stable micelles featuring an acid-responsive PGA(DIP) core with the encapsulated anticancer drug doxorubicin (DOX). In an acidic environment, the hydrophobic-hydrophilic transition of the PGA block leads to the gradual expansion and disassembly of these micelles and, consequently, an accelerated release of DOX. Thus, DOX transported by PEG-PGA(DIP) micelles can be entrapped more efficiently into the nuclei of hepatoma Bel 7402 cells.