Au nanostar nanoparticle as a bio-imaging agent and its detection and visualization in biosystems.

In the present work, we report the imaging of Au nanostars nanoparticles (AuNSt) and their multifunctional applications in biomedical research and theranostics applications. Their optical and spectroscopic properties are considered for the multimodal imaging purpose. The AuNSt are prepared by the seed-meditated method and characterized for use as an agent for bio-imaging. To demonstrate imaging with AuNSt, penetration and localization in different biological models such as cancer cell culture (A549 lung carcinoma cell), 3D tissue model (multicellular tumor spheroid on the base of human oral squamous carcinoma cell, SAS) and murine skin tissue are studied. AuNSt were visualized using fluorescence lifetime imaging (FLIM) at two-photon excitation with a pulse duration 140 fs, repetition rate 80 MHz and 780 nm wavelength femtosecond laser. Strong emission of AuNSt at two-photon excitation in the near infrared range and fluorescence lifetime less than 0.5 ns were observed. It allows using AuNSt as a fluorescent marker at two-photon fluorescence microscopy and lifetime imaging (FLIM). It was shown that AuNSt can be observed inside a thick sample (tissue and its model). This is the first demonstration using AuNSt as an imaging agent for FLIM at two-photon excitation in biosystems. Increased scattering of near-infrared light upon excitation of AuNSt surface plasmon oscillation was also observed and rendered using a possible contrast agent for optical coherence tomography (OCT). AuNSt detection in a biological system using FLIM is compared with OCT on the model of AuNSt penetrating into animal skin. The AuNSt application for multimodal imaging is discussed.

Dairy cattle with bovine leukaemia virus RNA show significantly increased leukocyte counts.

Infection with bovine leukaemia virus (BLV), a retrovirus, causes dysfunction of the immune system and can have a marked economic impact on dairy industries due to decreased milk production and reduced lifespan in affected dairy cattle. The presence of proviral DNA has been the major diagnostic indicator of BLV infection. However in the course of BLV infection, the viral genome can be dormant, without detectable gene expression, resulting in limited impact on infected animals. At present, there is limited knowledge regarding haematological indices in dairy cattle that could indicate activation of the BLV genome and suggest reactivated BLV infection. In this study, BLV infection and BLV genome reactivation were evaluated based on the presence of BLV DNA and BLV env gene transcripts, respectively. BLV RNA transcription was confirmed. Among 93 whole blood samples obtained from asymptomatic dairy cattle, the prevalence of BLV proviral DNA and transcripts was 93.5% (n = 87/93) and 83.9% (n = 78/93), respectively. Between groups with and without BLV, the mean counts of white blood cells and lymphocytes in whole blood were significantly associated with the presence of BLV RNA (P < 0.05), but not with BLV proviral DNA. These results shed light on the activation status of the BLV genome and should be taken into account when evaluating the possible impact of BLV on cattle.

Correction to: CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation.

Following publication of their article "CCN2 inhibits lung cancer metastasis through promoting DAPK-dependent anoikis and inducing EGFR degradation", the authors reported an error in Fig.6b. α-Tubulin image of rCCN2 treatment  (upper panel in CL1-5) only showed eight lanes, when there should be nine.

Intraoperative placement of total hip arthroplasty components with robotic-arm assisted technology correlates with postoperative implant position: a CT-based study.

AIMS: The aim of this study was to evaluate the accuracy of implant placement when using robotic assistance during total hip arthroplasty (THA). PATIENTS AND METHODS: A total of 20 patients underwent a planned THA using preoperative CT scans and robotic-assisted software. There were nine men and 11 women (n = 20 hips) with a mean age of 60.8 years (sd 6.0). Pelvic and femoral bone models were constructed by segmenting both preoperative and postoperative CT scan images. The preoperative anatomical landmarks using the robotic-assisted system were matched to the postoperative 3D reconstructions of the pelvis. Acetabular and femoral component positions as measured intraoperatively and postoperatively were evaluated and compared. RESULTS: The system reported accurate values for reconstruction of the hip when compared to those measured postoperatively using CT. The mean deviation from the executed overall hip length and offset were 1.6 mm (sd 2.9) and 0.5 mm (sd 3.0), respectively. Mean combined anteversion was similar and correlated between intraoperative measurements and postoperative CT measurements (32.5°, sd 5.9° versus 32.2°, sd 6.4°; respectively; R2 = 0.65; p < 0.001). There was a significant correlation between mean intraoperative (40.4°, sd 2.1°) acetabular component inclination and mean measured postoperative inclination (40.12°, sd 3.0°, R2 = 0.62; p < 0.001). There was a significant correlation between mean intraoperative version (23.2°, sd 2.3°), and postoperatively measured version (23.0°, sd 2.4°; R2 = 0.76; p < 0.001). Preoperative and postoperative femoral component anteversion were significantly correlated with one another (R2 = 0.64; p < 0.001). Three patients had CT scan measurements that differed substantially from the intraoperative robotic measurements when evaluating stem anteversion. CONCLUSION: This is the first study to evaluate the success of hip reconstruction overall using robotic-assisted THA. The overall hip reconstruction obtained in the operating theatre using robotic assistance accurately correlated with the postoperative component position assessed independently using CT based 3D modelling. Clinical correlation during surgery should continue to be practiced and compared with observed intraoperative robotic values. Cite this article: Bone Joint J 2018;100-B:1303-9.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) promotes EGF receptor signaling of oral squamous cell carcinoma metastasis via the complex N-glycosylation.

Aberrant protein glycosylation could be a distinct surface-marker of cancer cells that influences cancer progression and metastasis because glycosylation can regulate membrane protein folding which alters receptor activation and changes epitope exposure for antibody (Ab) recognition. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a glycophosphoinositol-anchored protein, is a heavily glycosylated tumor antigen. However, the clinical significance and biological effect of CEACAM6 glycosylation has not been addressed in cancers. We recently developed an anti-CEACAM6 Ab (TMU) from an immune llama library which can be engineered to a single-domain (sd)Ab or a heavy-chain (HC)Ab. The TMU HCAb specifically recognized glycosylated CEACAM6 compared to the conventional antibodies. Using the TMU HCAb, we found that glycosylated CEACAM6 was a tumor marker associated with recurrence in early-stage OSCC (oral squamous cell carcinoma) patients. CEACAM6 promoted OSCC cell invasion, migration, cytoskeletal rearrangement, and metastasis via interaction with epidermal growth factor (EGF) receptor (EGFR) and enhancing EGFR activation, clustering and intracellular signaling cascades. These functions were modulated by N-acetylglucosaminyltransferase 5 (MGAT5) which mediated N-glycosylation at Asn256 (N256) of CEACAM6. Finally, the TMU sdAb and HCAb treatment inhibited the migration, invasion and EGF-induced signaling in CEACAM6-overexpressing cells. In conclusion, the complex N-glycosylation of CEACAM6 is critical for EGFR signaling of OSCC invasion and metastasis. Targeting glycosylated CEACAM6 with the TMU sdAb or TMU HCAb could be a feasible therapy for OSCC.

Risk of epilepsy in surgical patients undergoing general or neuraxial anaesthesia.

Limited information is available on the risks of epilepsy after surgery in patients receiving general or neuraxial anaesthesia. Using Taiwan's National Health Insurance Research Database, we identified 1,478,977 patients aged ≥ 20 years who underwent surgery (required general or neuraxial anaesthesia with hospitalisation for more than one day) between 2004 and 2011. We selected 235,066 patients with general anaesthesia and 235,066 patients with neuraxial anaesthesia using a frequency-matching procedure for age and sex. We did not study those with co-existing epilepsy-related risk factors. The adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of newly diagnosed epilepsy 1 year after surgery associated with general anaesthesia were analysed in the multivariate Poisson regression model. The one-year incidence of postoperative epilepsy for patients with general anaesthesia and neuraxial anaesthesia were 0.41 and 0.32 per 1000 persons, respectively, and the corresponding RR was 1.27 (95%CI 1.15-1.41). The association between general anaesthesia and postoperative epilepsy was significant in men (RR = 1.22; 95%CI 1.06-1.40), women (RR = 1.33; 95%CI 1.15-1.55) and 20-39-year-old patients. The risk of postoperative epilepsy increased in patients with general anaesthesia who had co-existing medical conditions and postoperative complications.

Anesthesia for patients with tracheal bronchus.

Tracheal bronchus is a congenital anatomical variant of patients with accessory bronchus in the right upper lobe deriving directly from the supracarinal trachea. Pre-operative consultation with the anesthesiologist is important for patient safety and can avoid adverse effects induced by endotracheal intubation. In this report, we described a case of tracheal bronchus in which general anesthesia was performed for video-assisted thoracoscopic surgery. We discussed some of the issues surrounding to complications in tracheal bronchus.

B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway.

This corrects the article DOI: 10.1038/onc.2014.43.

Perioperative medicine and Taiwan National Health Insurance Research Database.

"Big data", characterized by 'volume', 'velocity', 'variety', and 'veracity', being routinely collected in huge amounts of clinical and administrative healthcare-related data are becoming common and generating promising viewpoints for a better understanding of the complexity for medical situations. Taiwan National Health Insurance Research Database (NHIRD), one of large and comprehensive nationwide population reimbursement databases in the world, provides the strength of sample size avoiding selection and participation bias. Abundant with the demographics, clinical diagnoses, and capable of linking diverse laboratory and imaging information allowing for integrated analysis, NHIRD studies could inform us of the incidence, prevalence, managements, correlations and associations of clinical outcomes and diseases, under the universal coverage of healthcare used. Perioperative medicine has emerged as an important clinical research field over the past decade, moving the categorization of the specialty of "Anesthesiology and Perioperative Medicine". Many studies concerning perioperative medicine based on retrospective cohort analyses have been published in the top-ranked journal, but studies utilizing Taiwan NHIRD were still not fully visualized. As the prominent growth curve of NHIRD studies, we have contributed the studies covering surgical adverse outcomes, trauma, stroke, diabetes, and healthcare inequality, etc., to this ever growing field for the past five years. It will definitely become a trend of research using Taiwan NHIRD and contributing to the progress of perioperative medicine with the recruitment of devotion from more research groups and become a famous doctrine.

Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3ß pathway.

Pregnenolone sulfate, an endogenous neurosteroid in the central nervous system, is a positive allosteric modulator of the NMDA receptor, and plays a role in the modulation of learning and memory. Here, we study the actions of pregnenolone sulfate using the dopamine transporter knockout (DAT-KO) mice, which exhibit endophenotypes that recapitulate certain symptoms of schizophrenia, including the psychomotor agitation, stereotypy, prepulse inhibition (PPI) deficits and cognitive impairments. We found that acute treatment with pregnenolone sulfate normalized the hyperlocomotion and stereotypic bouts, and rescued the PPI deficits of DAT-KO mice. In addition, long-term treatment with pregnenolone sulfate rescued the cognitive deficits of DAT-KO mice in the novel object recognition and social transmission of food preference tests. We also showed that pregnenolone sulfate normalized behavioral abnormalities in MK801-treated wild-type mice, whereas pregnenolone, its precursor, only partially rescued MK801-induced behavioral abnormalities. This indicates that there are distinct mechanisms of action between pregnenolone sulfate and pregnenolone, and the involvement of NMDA receptor signaling in the action of pregnenolone sulfate. Moreover, we found that acute treatment with pregnenolone sulfate increased the phosphorylation levels of striatal AKT and GSK3ß in DAT-KO mice, and that long-term treatment with pregnenolone sulfate increased expression levels of NR1 subunit of the NMDA receptor in hippocampus. Thus, pregnenolone sulfate was able to rescue the behavioral anomalies of DAT-KO mice through the NMDA receptor-mediated, AKT/GSK3ß signaling pathway.

Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes.

BACKGROUND: Liver transplant recipients frequently develop acute kidney injury (AKI), but the predisposing factors and long-term consequences of AKI are not well understood. The aims of this study were to identify predisposing factors for early post-transplant AKI and the impact of AKI on patient and graft survival and to construct a model to predict AKI using clinical variables. METHODS: In this 5-year retrospective study, we analysed clinical and laboratory data from 424 liver transplant recipients from our centre. RESULTS: By 72 h post-transplant, 221 patients (52%) had developed AKI [according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria]. Predisposing factors for development of AKI were female sex, weight (>100 kg), severity of liver disease (Child-Pugh score), pre-existing diabetes mellitus, number of units of blood or fresh frozen plasma transfused during surgery, and non-alcoholic steatohepatitis as the aetiology of end-stage liver disease (P≤0.05). Notably, preoperative serum creatinine (SCr) was not a significant predisposing factor. After fitting a forward stepwise regression model, female sex, weight >100 kg, high Child-Pugh score, and diabetes remained significantly associated with the development of AKI within 72 h (P≤0.05). The area under the receiver operator characteristic curve for the final model was 0.71. The incidence of new chronic kidney disease and requirement for dialysis at 3 months and 1 yr post-transplant were significantly higher among patients who developed AKI. CONCLUSIONS: Development of AKI within the first 72 h after transplant impacted short-term and long-term graft survival.

B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway.

B-cell lymphoma/leukemia 10 (BCL10) is an apoptotic regulatory protein related to advanced TNM stage and disease recurrence in oral squamous cell carcinoma (OSCC). However, the regulatory mechanism of BCL10 in OSCC progression is still unknown. Here, we showed that knockdown of endogenous BCL10 could significantly reduce cell migration and invasion abilities, retard cell proliferation by G0/G1 phase accumulation and inhibit tumorigenicity in vivo. In molecular level, we identified S100P as a crucial downstream effector of BCL10-inhibited OSCC progression by high-throughput microarray analysis. S100P messenger RNA and protein expression levels were significantly diminished in silenced-BCL10 clones, and transfected S100P expression plasmids restored migration, invasion, proliferation abilities and tumorigenicity in shBCL10 transfectants. Furthermore, we provided evidence that BCL10 regulated S100P expression through signal transducers and activators of transcription 1 (STAT1) and activating transcription factor 4 (ATF4). Knockdown of BCL10 decreased S100P promoter activity, but showed no effect in truncated STAT1/ATF4 S100P promoter.  In addition, we also found that the P50/P65 signaling pathway was involved in BCL10-enhanced OSCC progression. Restored S100P in silenced-BCL10 clones could markedly reverse P65 activation via outside-in signaling. Taken together, we discovered a novel axis of BCL10-regulated OSCC progression via STAT1/ATF4/S100P/P65 signaling, which could predict the prognosis of OSCC and will be beneficial for developing therapeutic strategy against advanced OSCC.

Introduction to the updated Australian and New Zealand consensus guidelines for the use of antifungal agents in the haematology/oncology setting, 2014.

This article introduces the second revision of the Australian and New Zealand consensus guidelines for the use of antifungal agents in the haematology/oncology setting. The current update occurs within the context of a growing population at risk of invasive fungal disease, improved understanding of risk factors, availability of new diagnostic tests, a much-expanded evidence base and changing clinical paradigms. Here, we provide an overview of the history and purpose of the guidelines, including changes in scope since the last clinical update was published in 2008. The process for development, and for enabling review of draft recommendations by end-users and other relevant stakeholders, is described. The approach to assigning levels of evidence and grades of recommendation is also provided, along with a comparison to international grading systems.

Consensus guidelines for the treatment of yeast infections in the haematology, oncology and intensive care setting, 2014.

Pathogenic yeast forms are commonly associated with invasive fungal disease in the immunocompromised host, including patients with haematological malignancies and patients of haemopoietic stem cell transplants. Yeasts include the Candida spp., Cryptococcus spp., Pneumocystis jirovecii and some lesser-known pathogens. Candida species remain the most common cause of invasive yeast infections (and the most common human pathogenic fungi). These guidelines present evidence-based recommendations for the antifungal management of established, invasive yeast infections in adult and paediatric patients in the haematology/oncology setting. Consideration is also given to the critically ill patient in intensive care units, including the neonatal intensive care unit. Evidence for 'pre-emptive' or 'diagnostic-driven antifungal therapy' is also discussed. For the purposes of this paper, invasive yeast diseases are categorised under the headings of invasive candidiasis, cryptococcosis and uncommon yeast infections. Specific recommendations for the management of Pneumocystis jirovecii are presented in an accompanying article (see consensus guidelines by Cooley et al. appearing elsewhere in this supplement).

Consensus guidelines for implementation of quality processes to prevent invasive fungal disease and enhanced surveillance measures during hospital building works, 2014.

Healthcare-associated fungal outbreaks impose a substantial economic burden on the health system and typically result in high patient morbidity and mortality, particularly in the immunocompromised host. As the population at risk of invasive fungal infection continues to grow due to the increased burden of cancer and related factors, the need for hospitals to employ preventative measures has become increasingly important. These guidelines outline the standard quality processes hospitals need to accommodate into everyday practice and at times of healthcare-associated outbreak, including the role of antifungal stewardship programmes and best practice environmental sampling. Specific recommendations are also provided to help guide the planning and implementation of quality processes and enhanced surveillance before, during and after high-risk activities, such as hospital building works. Areas in which information is still lacking and further research is required are also highlighted.

Anticancer effects of suberoylanilide hydroxamic acid in esophageal squamous cancer cells in vitro and in vivo.

The effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, have not been studied in esophageal squamous cell cancer (ESCC). Cell viability assay; flow cytometry for cell cycle and annexin V apoptosis assays; assays for cell migration, invasion, and adhesion to extracellular matrix (ECM); and immunoblotting and immunofluorescence staining were performed in three ESCC cell lines. Tumor xenograft with semiquantitative immunohistochemistry was used to study the effects of SAHA in vivo. SAHA effectively inhibited growth of ESCC cells with half-inhibitory concentrations (IC50 ) ranging from 2.6 to 6.5 µmol/L. SAHA restored acetylation of histone 3 lysine 9 (H3K9Ac) and histone 4 lysine 12 (H4K12Ac) with an induction of G1 or G2 cell cycle arrest and apoptosis. Expression of cell cycle checkpoint regulatory proteins including cyclin-dependent kinases (CDKs) and cyclins was decreased, whereas expression of cell cycle suppressors, p21, p27, and Rb was increased in ESCC cells after SAHA treatment. SAHA inhibited migration, invasion, and ECM adhesion in ESCC cells with an induction of E-cadherin expression. SAHA significantly inhibited growth of ESCC tumors with increased expression of p21, p27, Rb, and E-cadherin while decreasing expression of CDK4 and cyclin D1 within the murine tumors. In conclusion, SAHA had antigrowth activity against ESCC cells in vitro and in vivo while inhibiting cell migration, cell invasion, and ECM adhesion, suggesting its potential as an epigenetic therapeutic agent for ESCC.

Postoperative adverse outcomes after non-hepatic surgery in patients with liver cirrhosis.

BACKGROUND: Postoperative adverse outcomes in patients with liver cirrhosis are not completely understood. This study evaluated the association between liver cirrhosis and adverse outcomes after non-hepatic surgery. METHODS: Reimbursement claims were used to identify patients with preoperative liver cirrhosis who underwent non-hepatic surgery from 2004 to 2007. Control patients without cirrhosis were matched by age, sex, type of surgery and anaesthesia. The adjusted odds ratios (ORs) and 95 per cent confidence intervals (c.i.) of postoperative adverse events associated with liver cirrhosis were analysed by multivariable logistic regression. RESULTS: Thirty-day mortality rates among 24 282 patients with cirrhosis and 97 128 control patients were 1·2 per cent (299 deaths) and 0·7 per cent (635 deaths) respectively. Liver cirrhosis was associated with postoperative 30-day mortality (OR 1·88, 95 per cent c.i. 1·63 to 2·16), acute renal failure (OR 1·52, 1·34 to 1·74), septicaemia (OR 1·42, 1·33 to 1·51) and intensive care unit admission (OR 1·39, 1·33 to 1·45). Postoperative mortality increased in patients who had liver cirrhosis with viral hepatitis (OR 2·87, 1·55 to 5·30), alcohol dependence syndrome (OR 3·74, 2·64 to 5·31), jaundice (OR 5·47, 3·77 to 7·93), ascites (OR 5·85, 4·62 to 7·41), gastrointestinal haemorrhage (OR 3·01, 2·33 to 3·90) and hepatic coma (OR 5·11, 3·79 to 6·87). CONCLUSION: Patients with liver cirrhosis had increased mortality and complications after non-hepatic surgery, particularly those with cirrhosis-related clinical indicators.

A novel baculovirus vector shows efficient gene delivery of modified porcine reproductive and respiratory syndrome virus antigens and elicits specific immune response.

Porcine reproductive and respiratory syndrome (PRRS) is an economically devastating epizootic of porcine species. Current vaccines are inadequate to control the disease burden and outbreaks in the field. We report a novel baculovirus vaccine vector with White spot syndrome virus immediate early 1 shuttle promoter, with strong activity in both insect cells and mammalian cells, for immunization against PRRSV. The insect cell cultured baculovirus vector produces PRRSV envelope glycoproteins ORF2a, ORF3, ORF4 and ORF5, which are similar to the antigens in the infectious PRRS virion, and these antigens are stably incorporated on the surface of the baculovirus. Further, the baculovirus vector efficiently transduces these antigens in cells of porcine origin, thereby simulating a live infection. The baculovirus vectored PRRSV antigens, upon inoculation in mice, elicits robust neutralizing antibodies against the infective PRRS virus. Further, the experiments indicate that hitherto under emphasized ORF2a and ORF4 are important target antigens for neutralizing PRRSV infectivity.

PPARα-mediated responses in human adult liver stem cells: In vivo/in vitro and cross-species comparisons.

The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that regulates a variety of biological processes including lipid metabolism and energy homeostasis. Peroxisome proliferators (PPs) are carcinogens in rodents, while humans are resistant to peroxisome proliferation and carcinogenesis. In this study, we examined the differential gene expression elicited by clofibrate (CLO) and WY-14,643 (WY) in C57BL/6 mouse liver compared to responses in human HepG2 hepatoma and HL1-1 adult stem cells. Mice were gavaged with sesame oil, 300mg/kg CLO or WY for 2, 4, 8, 12, 18 or 24h, or daily for 4 or 14 days. Although no significant changes in body weight gain were observed, WY induced relative liver weight at 4 and 14 days. Genome-wide hepatic gene expression analysis identified 719 and 1443 differentially expressed unique genes elicited by CLO and WY, respectively (|fold change|>1.5, P1(t)>0.99). Functional analysis associated the gene expression changes with lipid metabolism, transport, cell cycle and immune response. Most differentially expressed genes were in common to both treatments and clustered together only at early time points (2-8h). Complementary QRT-PCR studies in human HL1-1 and HepG2 cells treated with 50µM WY or DMSO for 1, 2, 4, 8, 12, 24 or 48h identified a minimal number of conserved orthologous responses (e.g., Pdk4, Adfp and Angptl4) while some genes (i.e., Bmf, a tumor suppressor) exhibited induction in human cells but repression in mice. These data suggest that PPs elicit species-specific PPARα-mediated gene expression.