Materials informatics for the screening of multi-principal elements and high-entropy alloys.

The field of multi-principal element or (single-phase) high-entropy (HE) alloys has recently seen exponential growth as these systems represent a paradigm shift in alloy development, in some cases exhibiting unexpected structures and superior mechanical properties. However, the identification of promising HE alloys presents a daunting challenge given the associated vastness of the chemistry/composition space. We describe here a supervised learning strategy for the efficient screening of HE alloys that combines two complementary tools, namely: (1) a multiple regression analysis and its generalization, a canonical-correlation analysis (CCA) and (2) a genetic algorithm (GA) with a CCA-inspired fitness function. These tools permit the identification of promising multi-principal element alloys. We implement this procedure using a database for which mechanical property information exists and highlight new alloys having high hardnesses. Our methodology is validated by comparing predicted hardnesses with alloys fabricated by arc-melting, identifying alloys having very high measured hardnesses.

Eigentumors for prediction of treatment failure in patients with early-stage breast cancer using dynamic contrast-enhanced MRI: a feasibility study.

We present a radiomics model to discriminate between patients at low risk and those at high risk of treatment failure at long-term follow-up based on eigentumors: principal components computed from volumes encompassing tumors in washin and washout images of pre-treatment dynamic contrast-enhanced (DCE-) MR images. Eigentumors were computed from the images of 563 patients from the MARGINS study. Subsequently, a least absolute shrinkage selection operator (LASSO) selected candidates from the components that contained 90% of the variance of the data. The model for prediction of survival after treatment (median follow-up time 86 months) was based on logistic regression. Receiver operating characteristic (ROC) analysis was applied and area-under-the-curve (AUC) values were computed as measures of training and cross-validated performances. The discriminating potential of the model was confirmed using Kaplan-Meier survival curves and log-rank tests. From the 322 principal components that explained 90% of the variance of the data, the LASSO selected 28 components. The ROC curves of the model yielded AUC values of 0.88, 0.77 and 0.73, for the training, leave-one-out cross-validated and bootstrapped performances, respectively. The bootstrapped Kaplan-Meier survival curves confirmed significant separation for all tumors (P < 0.0001). Survival analysis on immunohistochemical subgroups shows significant separation for the estrogen-receptor subtype tumors (P < 0.0001) and the triple-negative subtype tumors (P = 0.0039), but not for tumors of the HER2 subtype (P = 0.41). The results of this retrospective study show the potential of early-stage pre-treatment eigentumors for use in prediction of treatment failure of breast cancer.

Uptake of selenium and mercury by captive mink: Results of a controlled feeding experiment.

Captive, juvenile, ranch-bred, male mink (Neovison vison) were fed diets containing various concentrations of methyl-mercury (MeHg) and selenium (Se) for a period of 13 weeks and then sacrificed to determine total Hg levels in fur, blood, brain, liver and kidneys and total Se concentrations in brain tissue. As MeHg concentrations in the diet increased, concentrations of total Hg in the tissues also increased with the highest level occurring in the fur > liver = kidney > brain > blood. Concentrations of Hg in the fur were correlated (r(2) > 0.97) with liver, kidney, blood and brain concentrations. The addition of Se to the mink diet did not appear to affect most tissue concentrations of total Hg nor did it affect the partitioning of Hg between the liver:blood, kidney:blood and brain:blood; however, partitioning of Hg between fur and blood was apparently affected.

Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors.

The histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2) is frequently dysregulated in cancers, and gain-of-function (GOF) EZH2 mutations have been identified in non-Hodgkin lymphomas. Small-molecule inhibitors against EZH2 demonstrated anti-tumor activity in EZH2-mutated lymphomas and entered clinical trials. Here, we developed models of acquired resistance to EZH2 inhibitor EI1 with EZH2-mutated lymphoma cells. Resistance was generated by secondary mutations in both wild-type (WT) and GOF Y641N EZH2 alleles. These EZH2 mutants retained the substrate specificity of their predecessor complexes but became refractory to biochemical inhibition by EZH2 inhibitors. Resistant cells were able to maintain a high level of H3K27Me3 in the presence of inhibitors. Interestingly, mutation of EZH2 WT alone generated an intermediate resistance phenotype, which is consistent with a previously proposed model of cooperation between EZH2 WT and Y641N mutants to promote tumorigenesis. In addition, the findings presented here have implications for the clinical translation of EZH2 inhibitors and underscore the need to develop novel EZH2 inhibitors to target potential resistance emerging in clinical settings.

Long-term clinical outcomes after Streptococcus bovis isolation in asymptomatic blood donors in Hong Kong.

BACKGROUND: Risk of transfusion-transmitted bacterial sepsis has been substantially reduced by a bacterial surveillance program (BST). However, new problems emerge as asymptomatic bacteremia is detected in blood donors. Streptococcus bovis bacteremia, which is known to associate with infective endocarditis and colonic carcinoma, is an example. STUDY DESIGN AND METHODS: A retrospective study was conducted to examine the demographic and clinical outcome of this group of donors. All confirmed culture-positive cases under the BST were retrieved and those donors with S. bovis bacteremia were contacted for follow-up. Viable culture samples were sent for detailed microbiologic analysis. RESULTS: From 1998 to 2012, a total of 16 donors were found to have S. bovis bacteremia, giving an estimated prevalence of 1 in 110,800 donations. They consisted of nine men and seven women with median age of 43.5 years. Eight donors had undergone colonoscopy with colonic carcinoma detected in two and benign adenoma in four. Five of the 16 isolates could be retrieved for 16S DNA sequencing. Four were identified as S. gallolyticus ssp. pasteurianus and one as S. gallolyticus ssp. gallolyticus. The two patients with colonic carcinoma had one each of subspecies pasteurianus and gallolyticus. CONCLUSION: The findings highlight a close association of S. bovis and colonic carcinoma. We recommend prompt donor follow-up if S. bovis bacteremia is detected. Besides, all confirmed S. bovis should be fully characterized by molecular technique.

Interdiction of a blood donation containing varicella-zoster virus by donor self-report of chickenpox.

Nowadays, risk of transfusion-transmitted infection has been substantially minimized by stringent donor eligibility screening and infectious disease testing. However, we report an interdiction of a blood donation containing varicella-zoster virus (VZV) by donor self-reporting of chickenpox. The donor developed varicella infection shortly after blood donation despite vaccination. Varicella-zoster virus DNA was detected in her fresh-frozen plasma before the blood components were issued for clinical transfusion. The report indicates the importance of donors' education and awareness of their obligation to report any symptoms developed shortly after blood donation in order to further secure blood safety.

Spray freeze drying with polyvinylpyrrolidone and sodium caprate for improved dissolution and oral bioavailability of oleanolic acid, a BCS Class IV compound.

Spray-freeze-drying (SFD) of oleanolic acid (OA), a BCS Class IV compound, with polyvinylpyrrolidone-40 (PVP-40) as stabilizer and sodium caprate (SC) as wetting agent and penetration enhancer produced kinetically stable, amorphous solid dispersion systems with superior in vitro dissolution performance, and better and more uniform absorption in comparison with commercial OA tablet. Relative to the SC-free formulation, the presence of SC in the formulation resulted in a significant increase in the in vivo absorption rate of OA while exerting no apparent impact on the extent of OA absorption. The SFD-processed OA formulations and commercial OA tablet generally exhibited large inter-animal variability in oral bioavailability, consistent with the absorption characteristics of BCS Class IV compounds. Inclusion of SC coupled with the replacement of OA with its sodium salt (OA-Na) in the formulation was shown to substantially decrease the observed absorption variability. Above results suggested that increases in both dissolution rate and intestinal permeability of BCS Class IV compounds, as exemplified by the SFD-processed dispersion system containing both OA-Na and SC, are critical to reducing the large inter-individual absorption variability commonly observed with this class of drugs.

Predictors of important neurological causes of dizziness among patients presenting to the emergency department.

OBJECTIVES: Dizziness is a common presenting complaint in the emergency department (ED). This prospective study describes the incidence, causes and outcome of ED patients presenting with dizziness and tries to identify predictors of central neurological causes of dizziness. METHODS: Single-centre prospective observational study in a university teaching hospital ED in Hong Kong. All ED patients (> or = 18 years old) presenting with dizziness were recruited for 1 month. Symptoms, previous health, physical findings, diagnosis and disposition were recorded. The outcome at 3 months was evaluated using hospital records and telephone interviews. Follow-up was also performed at 55 months using computerised hospital records to identify patients with subsequent stroke and those who had died. RESULTS: 413 adults (65% female, mean 57 years) were recruited. The incidence of dizziness was 3.6% (413/11 319). Nausea and/or vomiting (46%) and headache (20%) were the commonest associated findings. Hypertension (33%) was the commonest previous illness. Central neurological causes of dizziness were found in 6% (23/413) of patients. Age > or = 65 years (OR=6.13, 95% CI 1.97 to 19.09), ataxia symptoms (OR=11.39, 95% CI 2.404 to 53.95), focal neurological symptoms (OR=11.78, 95% CI 1.61 to 86.29), and history of previous stroke (OR=3.89, 95% CI 1.12 to 13.46) and diabetes mellitus (OR=3.57, 95% CI 1.04 to 12.28) predicted central causes of dizziness. CONCLUSIONS: Most dizzy patients had benign causes. Several clinical factors favoured a diagnosis of central neurological causes of dizziness.

Distribution of voriconazole in seven body fluids of adult horses after repeated oral dosing.

The purpose of this study was to assess safety and alterations in body fluid concentrations of voriconazole in normal horses on days 7 and 14 following once daily dose of 4 mg/kg of voriconazole orally for 14 days. Body fluid drug concentrations were determined by the use of high performance liquid chromatography (HPLC). On day 7, mean voriconazole concentrations of plasma, peritoneal, synovial and cerebrospinal fluids, aqueous humor, epithelial lining fluid (ELF), and urine were 1.47 +/- 0.63, 0.61 +/- 0.22, 0.70 +/- 0.20, 0.62 +/- 0.26, 0.55 +/- 0.32, 79.45 +/- 69.4, and 1.83 +/- 0.44 microg/mL respectively. Mean voriconazole concentrations in the plasma, peritoneal, synovial and cerebrospinal fluids, aqueous humor, ELF and urine on day 14 were 1.60 +/- 0.37, 1.02 +/- 0.27, 0.86 +/- 0.25, 0.64 +/- 0.21, 0.68 +/- 0.13, 47.76 +/- 45.4 and 3.34 +/- 2.17 respectively. Voriconazole concentrations in the bronchoalveolar cell pellet were below the limit of detection. There was no statistically significant difference between voriconazole concentrations of body fluids when comparing days 7 and 14. Results indicated that voriconazole distributes widely into body fluids.

Process-induced phase transformation of berberine chloride hydrates.

Berberine is a natural quaternary ammonium alkaloid used clinically in the chloride salt form for the treatment of diarrhea in many Asian countries. Although the hydrate formation of berberine chloride (BCl) is well documented, the associated mechanism and implications in pharmaceutical formulation have not been studied in detail. In this study, pure BCl dihydrate and BCl tetrahydrate were recrystallized from water and their phase transformation behaviors under defined conditions were investigated. Additionally, pharmacopoeial grade BCl material consisting predominantly of the dihydrate form was examined for potential phase changes when being subjected to a conventional wet granulation procedure for tablet production. Results from solubility measurements, thermal analysis, variable temperature-powder X-ray diffraction (VT-PXRD), and variable temperature-Fourier transform infrared spectroscopy (VT-FTIR) confirmed the solid-state interconversions between the tetrahydrate and dihydrate at 30-49 degrees C and between the dihydrate and anhydrate at 70-87 degrees C. Consistent with the observed phase changes of the two pure hydrates, wet massing of the pharmacopoeial grade BCl sample led to a thermodynamics-driven transition to the tetrahydrate form at room temperature while subsequent tray drying at 50 degrees C caused a reversion back to the dihydrate form. The rate and extent of such hydrate conversion depended largely on the water activity of the granulated powder matrix, which in turn was governed by the particular excipients employed. The present findings have important implications in the regulation of the hydrate forms of BCl in the finished products using specific excipients.

Pharmacokinetics of voriconazole after single dose intravenous and oral administration to alpacas.

Voriconazole is a new antifungal drug that has shown effectiveness in treating serious fungal infections and has the potential for being used in large animal veterinary medicine. The objective of this study was to determine the plasma concentrations and pharmacokinetic parameters of voriconazole after single-dose intravenous (i.v.) and oral administration to alpacas. Four alpacas were treated with single 4 mg/kg i.v. and oral administrations of voriconazole. Plasma voriconazole concentrations were measured by a high-performance liquid chromatography method. The terminal half-lives following i.v. and oral administration were 8.01 +/- 2.88 and 8.75 +/- 4.31 h, respectively; observed maximum plasma concentrations were 5.93 +/- 1.13 and 1.70 +/- 2.71 microg/mL, respectively; and areas under the plasma concentration vs. time curve were 38.5 +/- 11.1 and 9.48 +/- 6.98 mg.h/L, respectively. The apparent systemic oral availability was low with a value of 22.7 +/- 9.5%. The drug plasma concentrations remained above 0.1 microg/mL for at least 24 h after single i.v. dosing. The i.v. administration of 4 mg/kg/day voriconazole may be a safe and appropriate option for antifungal treatment of alpacas. Due to the low extent of absorption in alpacas, oral voriconazole doses of 20.4 to 33.9 mg/kg/day may be needed.

Carcinoembryonic antigen in monitoring of response to cetuximab plus FOLFIRI or FOLFOX-4 in patients with metastatic colorectal cancer.

First-line treatment of metastatic colorectal cancer with combinations of cetuximab and irinotecan-based or oxaliplatin-based chemotherapy has shown promising efficacy. The clinical response to such treatment is generally assessed by tumor measurement through imaging. This study was performed to evaluate the correlation between serial changes in imaging results and carcinoembryonic antigen (CEA) levels. In 64 patients with metastatic colorectal cancer receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy we retrospectively analyzed the relationship between changes in serum CEA and changes in imaging results throughout the treatment course. Response in terms of serum CEA change was defined as a >/=50% drop in CEA level for more than 4 weeks. The sensitivity and specificity of serum CEA changes after targeted chemotherapy in relation to imaging results were 80.5% (33/41) and 73.9% (17/23), respectively, with a diagnostic accuracy of 78.1% (50/64). The progression-free survival time of responders assessed by serum CEA change was significantly longer than that of nonresponders (p=0.0091). Our results highlight the importance of serum CEA monitoring in assessing the response to targeted chemotherapy and in predicting the prognosis of patients with metastatic colorectal cancer.

Cholinesterase and monoamine oxidase activity in relation to mercury levels in the cerebral cortex of wild river otters.

Mercury (Hg) is a global pollutant that is neurotoxic to many mammalian species. The present study was conducted to determine if the bioaccumulation of Hg by wild river otters (Lontra canadensis) could be related to variations in the activities of key neurochemical enzymes. River otters were collected from Ontario and Nova Scotia (Canada) during the trapping seasons, spanning 2002-2004, and their brains were dissected into the cerebral cortex and cerebellum. The activities of cholinesterase (ChE) and monoamine oxidase (MAO) were measured from each sample and correlated with concentrations of brain Hg from the same animal. Significant negative correlations were found between concentrations of brain Hg and ChE (total Hg: r= -0.42; MeHg: r= -0.33) and MAO (total Hg: r= -0.31; MeHg: r= -0.42) activity in the cerebral cortex. The scatterplots relating concentrations of brain Hg and enzyme activity in the cerebral cortex were wedge-shaped, and could be fitted with quantile regression modeling, suggesting that Hg may act as a limiting factor for ChE and MAO activity. No relationships were found in the cerebellum. These data suggest that environmentally relevant concentrations of Hg may influence the activities of ChE and MAO in the cerebral cortex of river otters, and by extension, other fish-eating mammals.

Selection criteria for recipients of scarce donor livers: a public opinion survey in Hong Kong.

OBJECTIVE: To explore the public preference in determining the selection criteria for recipients of scarce donor livers. DESIGN: Structured interview survey. SETTING: Hong Kong community. PARTICIPANTS: Participants from Hong Kong households, randomly drawn from 18 districts in Hong Kong by the Census and Statistics Department. MAIN OUTCOME MEASURES: Age of patients, causes of liver failure, capacity for survival and benefit, time spent on the waiting list, and transplantation status. RESULTS: A total of 281 participants were recruited with the response rate of 26.2%. In all sections of the questionnaire, there was a strong preference for the young over the old, non-drinkers over drinkers, those more likely to survive, those who had waited longest on the list, and primary candidates over re-transplant candidates. Approximately 91% of participants agreed or strongly agreed that priority should be given to patients most likely to survive and benefit from a liver transplant, and 39% of participants also ranked 'survival and benefit' as the most important criterion in determining allocation of donor livers. Nonetheless when participants were asked to allocate a finite number (100) of donor livers to two groups of individuals with different characteristics in a set of eight hypothetical scenarios, they preferred giving priority to patients who had waited longer on the waiting list. CONCLUSION: Although comparatively the general public surveyed had dominant preferences to maximise benefit and survival, they were unlikely to rely on one criterion for allocation. Overall cost-effectiveness of the intervention was not the sole deciding factor.

Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma.

Macrophage migration inhibitory factor (MIF) has been defined as a novel oncogene. Our previous results have shown that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors. The aim of this study was to test whether tumor growth could be inhibited by reduction of endogenous MIF expression in neuroblastoma and clarify the molecular mechanisms underlying MIF reduction on the control of neuroblastoma growth. We established human neuroblastoma cell lines stably expressing antisense MIF (AS-MIF) cDNA. These stable transfectants were characterized by cell proliferation, gene expression profile, tumorigenicity and metastasis in vitro and in vivo. Decreased MIF expression was observed after transfection with AS-MIF in neuroblastoma cells and downregulation of MIF expression significantly correlated with decreased expression of N-Myc, Ras, c-Met and TrkB at protein level. Affymetrix microarray analysis revealed that expression of IL-8 and c-met was inhibited and neuroblastoma-favorable genes such as EPHB6 and BLU were upregulated in MIF reduced cells. Neuroblastoma cell growth exhibited a nearly 80% reduction in AS-MIF transfectants in vitro. Furthermore, mice in which tumors formed after subcutaneous injection of AS-MIF transfectants showed a 90% reduction in tumor growth compared to control. Metastasis in mice was also suppressed dramatically. Our data demonstrate that targeting MIF expression is a promising therapeutic strategy in human neuroblastoma therapy, and also identifies the MIF target genes for further study.

Effects of nontoxic shot regulations on lead accumulation in ducks and American woodcock in Canada.

Prior to the first nontoxic shot zones being established in Canada, a nationwide survey of lead (Pb) concentrations in wing bones of hatch year (HY) dabbling and diving ducks determined the incidence of elevated Pb exposure in waterfowl in different parts of the country (Scheuhammer and Dickson 1996). The main objectives of the present study were (1) to compare these previously collected data with the incidence of elevated Pb accumulation in the same species several years after the establishment of a national regulation in 1997 prohibiting the use of Pb shot for waterfowl hunting; and (2) to survey waterfowl hunters to determine reported levels of compliance with the nontoxic shot regulation. Average bone-Pb concentrations in dabbling ducks (mallards [Anas platyrhyncos] and American black ducks [Anas rubripes] combined) decreased significantly between 1989+1990 and 2000 (11 microg/g vs. 4.8 microg/g, respectively [p < 0.01]). Ring-necked ducks (Aythya collaris) showed a similar decrease in mean bone-Pb concentrations, from 28 microg/g to 10 microg/g (p < 0.01). These declines in bone-Pb concentration were consistent with the results of a large anonymous hunter survey, which indicated a high level of reported compliance (>80%) with the nontoxic shot regulation among waterfowl hunters residing in Ontario and British Columbia. Conversely, American woodcock (Scolopax minor), an important upland game species not affected by the nontoxic shot regulation, showed no decrease in mean bone-Pb concentration since the national regulation came into effect (19 microg/g in 1995 vs. 21 microg/g in 2000). A majority (70%) of waterfowl hunters in British Columbia and Ontario who also hunt upland game birds report continued (legal) use of Pb shot for upland game bird hunting.

Growth, nutritional composition, and hematology of Arctic charr (Salvelinus alpinus) exposed to toxaphene and tapeworm (Diphyllobothrium dendriticum) larvae.

Toxaphene, an organochlorine pesticide, is the major contaminant of Arctic charr (Salvelinus alpinus) in the Canadian Arctic. The objective of this study was to investigate the combined effects of toxaphene exposure and infection by the larval stage of the cestode Diphyllobothrium dendriticum on fish growth, nutritional composition, and hematology. Hatchery-reared Arctic charr were subjected to one of four treatments: (1) oral administration of corn oil (control); (2) single oral dose of 10 microg/g wet wt toxaphene dissolved in corn oil; (3) exposure to 15 larval D. dendriticum; and (4) exposure to toxaphene and D. dendriticum in combination. The experiment was run for 104 days. Mean final toxaphene concentrations in charr muscle were 0.121, 0.336, 0.131 and 0.458 microg/g wet wt in each treatment group, respectively. Exposure to toxaphene and D. dendriticum decreased fish growth and condition as well muscle lipid and protein content. However, toxaphene did not increase the susceptibility of Arctic charr to parasite infection. Overall, 25 of 40 fish (62.5%) exposed to larval D. dendriticum became infected. Parasitized charr had decreased hematocrits and increased lymphocyte:erythrocyte ratios. Although total blood cell counts were decreased in all treatments compared with controls, differential leucocyte counts were unaffected. Our results suggest that toxaphene does not moderate Arctic charr resistance to D. dendriticum and there is no contaminant-parasite interaction at environmental levels.

Role of blood transfusion in trichosanthin-induced anaphylaxis.

Trichosanthin (TCS) is a type 1 ribosome inactivating protein extracted from Chinese medicinal herb. It possesses various biological functions such as abortifacient, anti-tumor and anti-viral activities. Clinical trial of this compound against human immunodeficiency virus (HIV) had been conducted. However, its use is limited by its high immunogenicity that elicits hypersensitivity reaction. This may lead to fatal anaphylactic response. The study described an approach of using blood transfusion to reduce TCS induced anaphylaxis in rats using a cross-circulation model. A TCS-sensitized Sprague Dawley rat was connected to a normal rat via the femoral vessels in a cross-circulation circuit before antigenic challenge. The donor rat served as a blood exchange basin to lower the level of the blood-borne components responsible for the anaphylactic reaction in the sensitized rat. Our results showed that cross-circulation shortened the duration of circulatory hypotension and reduced mortality of TCS induced anaphylaxis. The control group not undergoing cross-circulation had a mortality of 50% at 2h post-TCS challenge and there was no mortality in the cross-circulation group. This demonstrated that prior blood transfusion can be one of the alternatives to reduce anaphylactic response of TCS.