Photothermal therapy (PTT), in which nanoparticles embedded within tumors generate heat in response to exogenously applied laser light, has been well documented as an independent strategy for highly ...selective cancer treatment. Gold‐based nanoparticles are the main mediators of PTT because they offer: (1) biocompatibility, (2) small diameters that enable tumor penetration upon systemic delivery, (3) simple gold‐thiol bioconjugation chemistry for the attachment of desired molecules, (4) efficient light‐to‐heat conversion, and (5) the ability to be tuned to absorb near‐infrared light, which penetrates tissue more deeply than other wavelengths of light. In addition to acting as a standalone therapy, gold nanoparticle‐mediated PTT has recently been evaluated in combination with other therapies, such as chemotherapy, gene regulation, and immunotherapy, for enhanced anti‐tumor effects. When delivered independently, the therapeutic success of molecular agents is hindered by premature degradation, insufficient tumor delivery, and off‐target toxicity. PTT can overcome these limitations by enhancing tumor‐ or cell‐specific delivery of these agents or by sensitizing cancer cells to these additional therapies. All together, these benefits can enhance the therapeutic success of both PTT and the secondary treatment while lowering the required doses of the individual agents, leading to fewer off‐target effects. Given the benefits of combining gold nanoparticle‐mediated PTT with other treatment strategies, many exciting opportunities for multimodal cancer treatment are emerging that will ultimately lead to improved patient outcomes. WIREs Nanomed Nanobiotechnol 2017, 9:e1449. doi: 10.1002/wnan.1449
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Photothermal therapy that uses gold nanoparticles to convert light to heat is effective against cancer both alone and combined with other therapeutic strategies.
Microbially induced calcite precipitation (MICP) offers an attractive alternative to traditional grouting technologies for creating barriers to groundwater flow and containing subsurface ...contamination, but has only thus far been successfully demonstrated at the laboratory scale and predominantly in porous media. We present results of the first field experiments applying MICP to reduce fractured rock permeability in the subsurface. Initially, the ureolytic bacterium, Sporosarcina pasteurii, was fixed in the fractured rock. Subsequent injection of cementing fluid comprising calcium chloride and urea resulted in precipitation of large quantities (approximately 750 g) of calcite; significant reduction in the transmissivity of a single fracture over an area of several m2 was achieved in around 17 h of treatment. A novel numerical model is also presented which simulates the field data well by coupling flow and bacterial and solute reactive transport processes including feedback due to aperture reduction via calcite precipitation. The results show that MICP can be successfully manipulated under field conditions to reduce the permeability of fractured rock and suggest that an MICP-based technique, informed by numerical models, may form the basis of viable solutions to aid pollution mitigation.
SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the ...nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy and COVID-19 participants. During COVID-19, we observe expansion of secretory, loss of ciliated, and epithelial cell repopulation via deuterosomal cell expansion. In mild and moderate COVID-19, epithelial cells express anti-viral/interferon-responsive genes, while cells in severe COVID-19 have muted anti-viral responses despite equivalent viral loads. SARS-CoV-2 RNA+ host-target cells are highly heterogenous, including developing ciliated, interferon-responsive ciliated, AZGP1high goblet, and KRT13+ “hillock”-like cells, and we identify genes associated with susceptibility, resistance, or infection response. Our study defines protective and detrimental responses to SARS-CoV-2, the direct viral targets of infection, and suggests that failed nasal epithelial anti-viral immunity may underlie and precede severe COVID-19.
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•scRNA-seq on nasopharyngeal swabs of 58 COVID-19 and healthy participants•SARS-CoV-2 induces ciliated cell loss with secretory and deuterosomal expansion•Early, muted anti-viral responses in nasal epithelia in severe COVID-19•Host-virus co-detection maps cell tropism and intrinsic responses to SARS-CoV-2
A study of nasopharyngeal swabs from healthy and COVID-19-infected individuals shows how infection leads to compositional changes in the respiratory epithelium, with early dampened antiviral responses in the nasal epithelia likely underlying and preceding severe disease.
The brain’s default mode network (DMN) is highly active during wakeful rest when people are not overtly engaged with a sensory stimulus or externally oriented task. In multiple contexts, increased ...spontaneous DMN activity has been associated with self-reported episodes of mind-wandering, or thoughts that are unrelated to the present sensory environment. Mind-wandering characterizes much of waking life and is often associated with error-prone, variable behavior. However, increased spontaneous DMN activity has also been reliably associated with stable, rather than variable, behavior. We aimed to address this seeming contradiction and to test the hypothesis that single measures of attentional states, either based on self-report or on behavior, are alone insufficient to account for DMN activity fluctuations. Thus, we simultaneously measured varying levels of self-reported mind-wandering, behavioral variability, and brain activity with fMRI during a unique continuous performance task optimized for detecting attentional fluctuations. We found that even though mind-wandering co-occurred with increased behavioral variability, highest DMN signal levels were best explained by intense mind-wandering combined with stable behavior simultaneously, compared with considering either single factor alone. These brain–behavior–experience relationships were highly consistent within known DMN subsystems and across DMN subregions. In contrast, such relationships were absent or in the opposite direction for other attention-relevant networks (salience, dorsal attention, and frontoparietal control networks). Our results suggest that the cognitive processes that spontaneous DMN activity specifically reflects are only partially related to mind-wandering and include also attentional state fluctuations that are not captured by self-report.
During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) ...has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term “minority MOMP.” Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis.
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•MOMP can occur in a minority of mitochondria•Minority MOMP triggers caspase activity but fails to kill cells•Minority MOMP-induced caspase activity causes DNA damage and genomic instability•Minority MOMP promotes cellular transformation and tumorigenesis
During apoptosis, mitochondrial outer membrane permeabilization (MOMP) is widespread, leading to rapid cell death. Here, Ichim et al. demonstrate that MOMP can also be engaged in a minority of mitochondria without killing the cell. Instead, minority MOMP triggers caspase-dependent DNA damage and genomic instability, thereby promoting transformation and tumorigenesis.
Nonparametric multiple comparisons are a powerful statistical inference tool in psychological studies. In this paper, we review a rank-based nonparametric multiple contrast test procedure (MCTP) and ...propose an improvement by allowing the procedure to accommodate various effect sizes. In the review, we describe relative effects and show how utilizing the unweighted reference distribution in defining the relative effects in multiple samples may avoid the nontransitive paradoxes. Next, to improve the procedure, we allow the relative effects to be transformed by using the multivariate delta method and suggest a log odds-type transformation, which leads to effect sizes similar to Cohen’s
d
for easier interpretation. Then, we provide theoretical justifications for an asymptotic strong control of the family-wise error rate (FWER) of the proposed method. Finally, we illustrate its use with a simulation study and an example from a neuropsychological study. The proposed method is implemented in the ‘nparcomp’ R package via the ‘mctp’ function.
Analyses of endoscopic retrograde cholangiopancreatography (ERCP) complication are often constrained by the number of endpoints observed. This large-scale study aimed to identify the principal risk ...factors for ERCP complication.
This was a prospective multicenter study of ERCP complications, based in five English regions. An exploratory univariable analysis of patients' first recorded procedures identified potentially important patient- and procedure-related factors. For overall complications and pancreatitis, variables significant in univariable analysis were included in multiple regression.
A total of 66 centers collected data on 5264 ERCPs, performed on 4561 patients. A therapeutic intervention was attempted in 3447/4561 (76%) of patients as part of their first recorded ERCP. Following first recorded ERCP, 230 patients (5.0%) suffered > or = 1 complication: pancreatitis in 74 (1.6%), cholangitis in 48 (1.0 %), hemorrhage in 40 (0.9%), perforation in 20 (0.4%), and miscellaneous in 54 (1.2%). Significant factors from multiple regression were included in a multi-level analysis, which incorporated variables measured at the level of the endoscopist and hospital. For overall complication, risk factors ( P value, odds ratio OR, 95% confidence interval CI) were: cannulation attempts > 1 ( P = 0.094, OR 1.32, 95% CI 0.95-1.83), precut ( P = 0.033, OR 1.55, 95 % CI 1.04-2.32), and suspected sphincter of Oddi dysfunction ( P = 0.121, OR 1.97, 95 % CI 0.84-4.64). For pancreatitis, risk factors ( Pvalue, OR, and 95 % CI) were: cannulation attempts > 1 ( P = 0.0001, OR 3.14, 95% CI 1.74-5.67), female sex ( P < 0.001, OR 2.22, 95% CI 1.43-3.45), age ( P < 0.002, OR 1.09 per 5 year decrease, 95% CI 1.03-1.15), and performance in a district (as opposed to university) hospital ( P = 0.034, OR 2.41, 95% CI 1.08-5.41).
Careful patient selection combined with skilled cannulation minimizes complications. Higher-risk procedures should be performed in specialist centers.
Accurate antigen detection is imperative for clinicians to diagnose disease, assess treatment success, and predict patient prognosis. The most common technique used for the detection of ...disease-associated biomarkers is the enzyme linked immunosorbent assay (ELISA). In an ELISA, primary antibodies are incubated with biological samples containing the biomarker of interest. Then, detectible secondary antibodies conjugated with horseradish peroxidase (HRP) bind the primary antibodies. Upon addition of a color-changing substrate, the samples provide a colorimetric signal that directly correlates to the targeted biomarker concentration. While ELISAs are effective for analyzing samples with high biomarker content, they lack the sensitivity required to analyze samples with low antigen levels. We hypothesized that the sensitivity of ELISAs could be enhanced by replacing freely delivered primary antibodies with antibody-nanoparticle conjugates that provide excess binding sites for detectible secondary antibodies, ultimately leading to increased signal. Here, we investigated the use of nanoshells (NS) decorated with antibodies specific to epidermal growth factor receptor (EGFR) as a model system (EGFR-NS). We incubated one healthy and two breast cancer cell lines, each expressing different levels of EGFR, with EGFR-NS, untargeted NS, or unconjugated EGFR antibodies, as well as detectable secondary antibodies. We found that EGFR-NS consistently increased signal intensity relative to unconjugated EGFR antibodies, with a substantial 13-fold enhancement from cells expressing high levels of EGFR. Additionally, 40x more unconjugated antibodies were required to detect EGFR compared to those conjugated to NS. Our results demonstrate that antibody-nanoparticle conjugates lower the detection limit of traditional ELISAs and support further investigation of this strategy with other antibodies and nanoparticles. Owing to their enhanced sensitivity, we anticipate that nanoparticle-modified ELISAs can be used to detect low levels of biomarkers found in various diseases, such as cancers, tuberculosis, and rheumatoid arthritis, and may ultimately enable earlier diagnosis, better prognostication, and improved treatment monitoring.
Anticoagulant rodenticides (ARs) are increasingly recognized as a threat to nontarget wildlife. High exposure to ARs has been documented globally in nontarget predatory species and linked to the high ...prevalence of an ectoparasitic disease, notoedric mange. In southern California, mange associated with AR exposure has been the proximate cause of a bobcat (Lynx rufus) population decline. We measured AR exposure in bobcats from two areas in southern California, examining seasonal, demographic and spatial risk factors across landscapes including natural and urbanized areas. The long-term study included bobcats sampled over a 16-year period (1997–2012) and a wide geographic area. We sampled blood (N = 206) and liver (N = 172) to examine exposure ante- and post-mortem. We detected high exposure prevalence (89 %, liver; 39 %, blood) and for individuals with paired liver and blood data (N = 64), 92 % were exposed. Moreover, the animals with the most complete sampling were exposed most frequently to three or more compounds. Toxicant exposure was associated with commercial, residential, and agricultural development. Bobcats of both sexes and age classes were found to be at high risk of exposure, and we documented fetal transfer of multiple ARs. We found a strong association between certain levels of exposure (ppm), and between multiple AR exposure events, and notoedric mange. AR exposure was prevalent throughout both regions sampled and throughout the 16-year time period in the long-term study. ARs pose a substantial threat to bobcats, and likely other mammalian and avian predators, living at the urban-wildland interface.
Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. ...Because the main known regulators of mitophagy are frequently inactivated in cancer cells, the mechanisms that regulate mitophagy in cancer cells are not fully understood. Here, we identified an E3 ubiquitin ligase (ARIH1/HHARI) that triggers mitophagy in cancer cells in a PINK1-dependent manner. We found that ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal via autophagy. Importantly, ARIH1 is widely expressed in cancer cells, notably in breast and lung adenocarcinomas; ARIH1 expression protects against chemotherapy-induced death. These data challenge the view that the main regulators of mitophagy are tumor suppressors, arguing instead that ARIH1-mediated mitophagy promotes therapeutic resistance.
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•Parkin (RBR E3 ligase) is absent in most cancer cells when mitophagy is functional•ARIH1, an E3 ligase belonging to the RBR family, is expressed in cancer cells•ARIH1 controls mitophagy of damaged mitochondrial in a PINK1-dependent manner•ARIH1’s control of mitophagy protects cancer cells from chemotherapy-induced death
Clearance of damaged mitochondria (mitophagy) is involved in the resistance to chemotherapeutic-induced death, but the main known regulators of mitophagy are not expressed in cancer cells. Villa et al. show that the RBR E3 ligase ARIH1 is expressed in several cancer cell types. ARIH1 controls PINK1-dependent mitophagy and sensitivity to chemotherapies.
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