108 research outputs found
PEG Branched Polymer for Functionalization of Nanomaterials with Ultralong Blood Circulation
Nanomaterials have been actively pursued for biological and medical
applications in recent years. Here, we report the synthesis of several new
poly(ethylene glycol) grafted branched-polymers for functionalization of
various nanomaterials including carbon nanotubes, gold nanoparticles (NP) and
gold nanorods (NRs), affording high aqueous solubility and stability for these
materials. We synthesize different surfactant polymers based upon
poly-(g-glutamic acid) (gPGA) and poly(maleic anhydride-alt-1-octadecene)
(PMHC18). We use the abundant free carboxylic acid groups of gPGA for attaching
lipophilic species such as pyrene or phospholipid, which bind to nanomaterials
via robust physisorption. Additionally, the remaining carboxylic acids on gPGA
or the amine-reactive anhydrides of PMHC18 are then PEGylated, providing
extended hydrophilic groups, affording polymeric amphiphiles. We show that
single-walled carbon nanotubes (SWNTs), Au NPs and NRs functionalized by the
polymers exhibit high stability in aqueous solutions at different pHs, at
elevated temperatures and in serum. Morever, the polymer-coated SWNTs exhibit
remarkably long blood circulation (t1/2 22.1 h) upon intravenous injection into
mice, far exceeding the previous record of 5.4 h. The ultra-long blood
circulation time suggests greatly delayed clearance of nanomaterials by the
reticuloendothelial system (RES) of mice, a highly desired property for in vivo
applications of nanomaterials, including imaging and drug delivery
(Z)3,4,5,4'-trans-tetramethoxystilbene, a new analogue of resveratrol, inhibits gefitinb-resistant non-small cell lung cancer via selectively elevating intracellular calcium level.
Calcium is a second messenger which is required for regulation of many cellular processes. However, excessive elevation or prolonged activation of calcium signaling would lead to cell death. As such, selectively regulating calcium signaling could be an alternative approach for anti-cancer therapy. Recently, we have identified an effective analogue of resveratrol, (Z)3,4,5,4âČ-trans-tetramethoxystilbene (TMS) which selectively elevated the intracellular calcium level in gefitinib-resistant (G-R) non-small-cell lung cancer (NSCLC) cells. TMS exhibited significant inhibitory effect on G-R NSCLC cells, but not other NSCLC cells and normal lung epithelial cells. The phosphorylation and activation of EGFR were inhibited by TMS in G-R cells. TMS induced caspase-independent apoptosis and autophagy by directly binding to SERCA and causing endoplasmic reticulum (ER) stress and AMPK activation. Proteomics analysis also further confirmed that mTOR pathway, which is the downstream of AMPK, was significantly suppressed by TMS. JNK, the cross-linker of ER stress and mTOR pathway was significantly activated by TMS. In addition, the inhibition of JNK activation can partially block the effect of TMS. Taken together, TMS showed promising anti-cancer activity by mediating calcium signaling pathway and inducing apoptosis as well as autophagy in G-R NSCLC cells, providing strategy in designing multi-targeting drug for treating G-R patients
Ezrin interacts with the SARS coronavirus spike protein and restrains infection at the entry stage
© 2012 Millet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process. Methodology/Principal Findings: We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S pseudotyped particles and potentiated S-dependent membrane fusion. Conclusions/Significance: Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.This work was supported by the Research Grant Council of Hong Kong (RGC#760208)and the RESPARI project of the International Network of Pasteur Institutes
Treatment Duration of Febrile Urinary Tract Infections
Although febrile urinary tract infections (UTIs) are relatively common in adults, data on optimal treatment duration are limited. Randomized controlled trials specifically addressing the elderly and patients with comorbidities have not been performed. This review highlights current available evidence. Premenopausal, non-pregnant women without comorbidities can be treated with a 5â7Â day regimen of fluoroquinolones in countries with low levels of fluoroquinolone resistance, or, if proven susceptible, with 14Â days of trimethoprim-sulfamethoxazole. Oral ÎČ-lactams are less effective compared with fluoroquinolones and trimethoprim-sulfamethoxazole. In men with mild to moderate febrile UTI, a 2-week regimen of an oral fluoroquinolone is likely sufficient. Although data are limited, this possibly holds even in the elderly patients with comorbidities or bacteremia
High Performance In Vivo Near-IR (>1 {\mu}m) Imaging and Photothermal Cancer Therapy with Carbon Nanotubes
Short single-walled carbon nanotubes (SWNTs) functionalized by PEGylated
phospholipids are biologically non-toxic and long-circulating nanomaterials
with intrinsic near infrared photoluminescence (NIR PL), characteristic Raman
spectra, and strong optical absorbance in the near infrared (NIR). This work
demonstrates the first dual application of intravenously injected SWNTs as
photoluminescent agents for in vivo tumor imaging in the 1.0-1.4 {\mu}m
emission region and as NIR absorbers and heaters at 808 nm for photothermal
tumor elimination at the lowest injected dose (70 {\mu}g of SWNT/mouse,
equivalent to 3.6 mg/kg) and laser irradiation power (0.6 W/cm2) reported to
date. Ex vivo resonance Raman imaging revealed the SWNT distribution within
tumors at a high spatial resolution. Complete tumor elimination was achieved
for large numbers of photothermally treated mice without any toxic side effects
after more than six months post-treatment. Further, side-by-side experiments
were carried out to compare the performance of SWNTs and gold nanorods (AuNRs)
at an injected dose of 700 {\mu}g of AuNR/mouse (equivalent to 35 mg/kg) in NIR
photothermal ablation of tumors in vivo. Highly effective tumor elimination
with SWNTs was achieved at 10 times lower injected doses and lower irradiation
powers than for AuNRs. These results suggest there are significant benefits of
utilizing the intrinsic properties of biocompatible SWNTs for combined cancer
imaging and therapy.Comment: Nanoresearch, in pres
Functionalization of single- and multi-walled carbon nanotubes with cationic amphiphiles for plasmid DNA complexation and transfection
The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study
AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4âweeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4âweeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, PÂ =Â 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, Pâ<â0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, PÂ =Â 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, PÂ =Â 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease
The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy
Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations.
Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (>â90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves.
Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45â85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations >â90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SEâ=â0.013, pââ90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score.
Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care
Mapping genomic loci implicates genes and synaptic biology in schizophrenia
Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies
CMB-S4: Forecasting Constraints on Primordial Gravitational Waves
CMB-S4---the next-generation ground-based cosmic microwave background (CMB)
experiment---is set to significantly advance the sensitivity of CMB
measurements and enhance our understanding of the origin and evolution of the
Universe, from the highest energies at the dawn of time through the growth of
structure to the present day. Among the science cases pursued with CMB-S4, the
quest for detecting primordial gravitational waves is a central driver of the
experimental design. This work details the development of a forecasting
framework that includes a power-spectrum-based semi-analytic projection tool,
targeted explicitly towards optimizing constraints on the tensor-to-scalar
ratio, , in the presence of Galactic foregrounds and gravitational lensing
of the CMB. This framework is unique in its direct use of information from the
achieved performance of current Stage 2--3 CMB experiments to robustly forecast
the science reach of upcoming CMB-polarization endeavors. The methodology
allows for rapid iteration over experimental configurations and offers a
flexible way to optimize the design of future experiments given a desired
scientific goal. To form a closed-loop process, we couple this semi-analytic
tool with map-based validation studies, which allow for the injection of
additional complexity and verification of our forecasts with several
independent analysis methods. We document multiple rounds of forecasts for
CMB-S4 using this process and the resulting establishment of the current
reference design of the primordial gravitational-wave component of the Stage-4
experiment, optimized to achieve our science goals of detecting primordial
gravitational waves for at greater than , or, in the
absence of a detection, of reaching an upper limit of at CL.Comment: 24 pages, 8 figures, 9 tables, submitted to ApJ. arXiv admin note:
text overlap with arXiv:1907.0447
- âŠ