Since the emergence of cancer nanomedicine, researchers have had intense interest in developing nanoparticles (NPs) that can specifically target diseased sites while avoiding healthy tissue to ...mitigate the off-target effects seen with conventional treatments like chemotherapy. Initial endeavors focused on the bioconjugation of targeting agents to NPs, and more recently, researchers have begun to develop biomimetic NP platforms that can avoid immune recognition to maximally accumulate in tumors. In this review, we describe the advantages and limitations of each of these targeting strategies. First, we review developments in bioconjugation strategies, where NPs are coated with biomolecules such as antibodies, aptamers, peptides, and small molecules to enable cell-specific binding. While bioconjugated NPs offer many exciting features and have improved pharmacokinetics and biodistribution relative to unmodified NPs, they are still recognized by the body as “foreign”, resulting in their clearance by the mononuclear phagocytic system (MPS). To overcome this limitation, researchers have recently begun to investigate biomimetic approaches that can hide NPs from immune recognition and reduce clearance by the MPS. These biomimetic NPs fall into two distinct categories: synthetic NPs that present naturally occurring structures, and NPs that are completely disguised by natural structures. Overall, bioconjugated and biomimetic NPs have substantial potential to improve upon conventional treatments by reducing off-target effects through site-specific delivery, and they show great promise for future standards of care. Here, we provide a summary of each strategy, discuss considerations for their design moving forward, and highlight their potential clinical impact on cancer therapy.
Postoperative spinopelvic changes are associated with increased dislocation risk following total hip arthroplasty (THA). The aim of this study was to identify preoperative patient and radiographic ...factors associated with high‐risk postoperative spinopelvic parameters. A retrospective review of consecutive THA patients who received preoperative and postoperative sitting and standing lateral lumbar spine‐hip radiographs with minimum radiographic and clinical follow‐up of 10 months was performed. Patient demographics were recorded and preoperative standing and sitting sacral slope (SS), anteinclination, pelvic femoral angle (PFA), and combined sagittal index (CSI) were measured. High‐risk patients were defined by decreased spinopelvic motion (∆SS from sitting to standing of >10°), increased hip motion (∆PFA from sitting to standing of >10°), or decreased CSI of >10° at final follow‐up compared with preoperative measurements. Univariate and multivariate regression analyses were used to identify preoperative demographic and radiographic factors associated with these high‐risk categories. One hundred and fifty‐three patients were included with an average age of 62 years, average body mass index of 27.8 kg/m2, and average follow‐up of 16.2 months. At 1‐year follow‐up, 43 (28.1%) patients demonstrated a decreased ∆SS > 10° and 67 (43.7%) patients demonstrated an increased ∆PFA > 10° compared with preoperative values. Sitting CSI decreased by >10° in 17 (11.1%) patients. Preoperative increased sitting PFA (adjusted odds ratio aOR 1.057, p < 0.001) and decreased preoperative hip motion (∆PFA) were associated with decreased sitting CSI of >10° at 10‐month follow‐up. Increased spinopelvic motion (∆SS) and decreased hip motion (∆PFA) preoperatively are associated with postoperative radiographic changes that be associated with increased dislocation risk.
Background
Childhood cancer survivors are at risk for adverse psychological outcomes. Whether exercise can attenuate this risk is unknown.
Methods
In total, 6199 participants in the Childhood Cancer ...Survivor Study (median age, 34.3 years range, 22.0‐54.0 years; median age at diagnosis, 10.0 years range, 0‐21.0 years) completed a questionnaire assessing vigorous exercise and medical/psychological conditions. Outcomes were evaluated a median of 7.8 years (range, 0.1‐10.0 years) later and were defined as: symptom level above the 90th percentile of population norms for depression, anxiety, or somatization on the Brief Symptom Inventory‐18; cancer‐related pain; cognitive impairment using a validated self‐report neurocognitive questionnaire; or poor health‐related quality of life. Log‐binomial regression estimated associations between exercise (metabolic equivalent MET‐hours per week−1) and outcomes adjusting for cancer diagnosis, treatment, demographics, and baseline conditions.
Results
The prevalence of depression at follow‐up was 11.4% (95% CI, 10.6%‐12.3%), anxiety 7.4% (95% CI, 6.7%‐8.2%) and somatization 13.9% (95% CI, 13.0%‐14.9%). Vigorous exercise was associated with lower prevalence of depression and somatization. The adjusted prevalence ratio for depression was 0.87 (95% CI, 0.72‐1.05) for 3 to 6 MET hours per week−1, 0.76 (95% CI, 0.62‐0.94) for 9 to 12 MET‐hours per week−1, and 0.74 (95% CI, 0.58‐0.95) for 15 to 21 MET‐hours per week−1. Compared with 0 MET hours per week−1, 15 to 21 MET‐hours per week−1 were associated with an adjusted prevalence ratio of 0.79 (95% CI, 0.62‐1.00) for somatization. Vigorous exercise also was associated with less impairment in the physical functioning, general health and vitality (Ptrend < .001), emotional role limitations (Ptrend = .02), and mental health (Ptrend = .02) domains as well as higher cognitive function in the domains of task completion, organization, and working memory (P < .05 for all), but not in the domain of cancer pain.
Conclusions
Vigorous exercise is associated with less psychological burden and cognitive impairment in childhood cancer survivors.
In this report from the Childhood Cancer Survivor Study, vigorous exercise is associated with a lower risk of subsequent depression and somatization; even small amounts of vigorous exercise appear to be beneficial.
Researchers document bidirectional pathways linking peripheral inflammation and neural circuitries subserving emotion processing and regulation. To extend this work, we present results from two ...independent studies examining the relationship between inflammation and resting-state functional connectivity (rsFC), as measured by functional magnetic resonance imaging.
Study 1 involved 90 rural African American young adults, 25 years of age (52% female), and study 2 involved 82 urban African American youths, 13 to 14 years of age (66% female). Both studies measured circulating inflammatory biomarkers (C-reactive protein, interleukin 6, interleukin 10, tumor necrosis factor alpha), and the measures were averaged to form a composite. Study 2 also enumerated classical monocytes, a key leukocyte subpopulation involved in immune-to-brain signaling. All participants completed a resting-state functional magnetic resonance imaging scan.
Consistent with our prediction, higher scores on the inflammatory composite were associated with lower rsFC within an emotion regulation network in study 1, controlling for sex. Study 2 replicated study 1, showing that higher scores on the inflammatory composite were associated with lower rsFC within the emotion regulation network, controlling for sex, age, and pubertal status, and found a similar pattern for rsFC within a central executive network. Study 2 also found that higher numbers of classical monocytes were associated with lower rsFC within both the emotion regulation and central executive networks. There was no relationship between rsFC in the anterior salience or default mode networks with inflammation in either study.
With these findings, we document relationships between peripheral inflammation and rsFC within an emotion regulation and central executive network and replicate these associations with the emotion regulation network across two independent samples.
Acute erythroid leukemia (AEL) is characterized by a distinct morphology, mutational spectrum, lack of preclinical models, and poor prognosis. Here, using multiplexed genome editing of mouse ...hematopoietic stem and progenitor cells and transplant assays, we developed preclinical models of AEL and non-erythroid acute leukemia and describe the central role of mutational cooperativity in determining leukemia lineage. Different combination of mutations in Trp53, Bcor, Dnmt3a, Rb1, and Nfix resulted in the development of leukemia with an erythroid phenotype, accompanied by the acquisition of alterations in signaling and transcription factor genes that recapitulate human AEL by cross-species genomic analysis. Clonal expansion during tumor evolution was driven by mutational cooccurrence, with clones harboring a higher number of founder and secondary lesions (eg, mutations in signaling genes) showing greater evolutionary fitness. Mouse and human AEL exhibited deregulation of genes regulating erythroid development, notably Gata1, Klf1, and Nfe2, driven by the interaction of mutations of the epigenetic modifiers Dnmt3a and Tet2 that perturbed methylation and thus expression of lineage-specific transcription factors. The established mouse leukemias were used as a platform for drug screening. Drug sensitivity was associated with the leukemia genotype, with the poly (ADP-ribose) polymerase inhibitor talazoparib and the demethylating agent decitabine efficacious in Trp53/Bcor-mutant AEL, CDK7/9 inhibitors in Trp53/Bcor/Dnmt3a-mutant AEL, and gemcitabine and bromodomain inhibitors in NUP98-KDM5A leukemia. In conclusion, combinatorial genome editing has shown the interplay of founding and secondary genetic alterations in phenotype and clonal evolution, epigenetic regulation of lineage-specific transcription factors, and therapeutic tractability in erythroid leukemogenesis.
Background and Aims
Insulin resistance and poor glycemic control are key drivers of the development of NAFLD and have recently been shown to be associated with fibrosis progression in NASH. However, ...the underlying mechanisms involving dysfunctional glucose metabolism and relationship with NAFLD/NASH progression remain poorly understood. We set out to determine whether protease‐activated receptor 2 (PAR2), a sensor of extracellular inflammatory and coagulation proteases, links NAFLD and NASH with liver glucose metabolism.
Approach and Results
Here, we demonstrate that hepatic expression of PAR2 increases in patients and mice with diabetes and NAFLD/NASH. Mechanistic studies using whole‐body and liver‐specific PAR2‐knockout mice reveal that hepatic PAR2 plays an unexpected role in suppressing glucose internalization, glycogen storage, and insulin signaling through a bifurcating Gq‐dependent mechanism. PAR2 activation downregulates the major glucose transporter of liver, GLUT2, through Gq‐MAPK‐FoxA3 and inhibits insulin‐Akt signaling through Gq‐calcium‐CaMKK2 pathways. Therapeutic dosing with a liver‐homing pepducin, PZ‐235, blocked PAR2‐Gq signaling and afforded significant improvements in glycemic indices and HbA1c levels in severely diabetic mice.
Conclusions
This work provides evidence that PAR2 is a major regulator of liver glucose homeostasis and a potential target for the treatment of diabetes and NASH.
PAR2, a cell‐surface receptor for inflammatory and coagulation proteases, plays an unexpected role in glucose uptake and insulin resistance in hepatocytes of patients and mice with diabetes and NAFLD.
To overcome the increasing resistance of pathogens to existing antibiotics the 10×'20 Initiative declared the urgent need for a global commitment to develop 10 new antimicrobial drugs by the year ...2020. Naturally occurring animal antibiotics are an obvious place to start. The recently sequenced genomes of mammals that are divergent from human and mouse, including the tammar wallaby and the platypus, provide an opportunity to discover novel antimicrobials. Marsupials and monotremes are ideal potential sources of new antimicrobials because they give birth to underdeveloped immunologically naïve young that develop outside the sterile confines of a uterus in harsh pathogen-laden environments. While their adaptive immune system develops innate immune factors produced either by the mother or by the young must play a key role in protecting the immune-compromised young. In this study we focus on the cathelicidins, a key family of antimicrobial peptide genes.
We identified 14 cathelicidin genes in the tammar wallaby genome and 8 in the platypus genome. The tammar genes were expressed in the mammary gland during early lactation before the adaptive immune system of the young develops, as well as in the skin of the pouch young. Both platypus and tammar peptides were effective in killing a broad range of bacterial pathogens. One potent peptide, expressed in the early stages of tammar lactation, effectively killed multidrug-resistant clinical isolates of Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii.
Marsupial and monotreme young are protected by antimicrobial peptides that are potent, broad spectrum and salt resistant. The genomes of our distant relatives may hold the key for the development of novel drugs to combat multidrug-resistant pathogens.
Despite molecular and serologic evidence of Nipah virus in bats from various locations, attempts to isolate live virus have been largely unsuccessful. We report isolation and full-genome ...characterization of 10 Nipah virus isolates from Pteropus medius bats sampled in Bangladesh during 2013 and 2014.
Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ...ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention.
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