It is poorly understood how solid peripheral tumors affect brain neuroimmune responses despite the various brain-mediated side effects and higher rates of infection reported in cancer patients. We ...hypothesized that chronic low-grade peripheral tumor-induced inflammation conditions microglia to drive suppression of neuroinflammatory responses to a subsequent peripheral immune challenge. Here, Balb/c murine mammary tumors attenuated the microglial inflammatory gene expression responses to lipopolysaccharide (LPS) and live Escherichia coli (E. coli) challenges and the fatigue response to an E. coli infection. In contrast, the inflammatory gene expression in response to LPS or a toll-like receptor 2 agonist of Percoll-enriched primary microglia cultures was comparable between tumor-bearing and -free mice, as were the neuroinflammatory and sickness behavioral responses to an intracerebroventricular interleukin (IL)-1β injection. These data led to the hypothesis that Balb/c mammary tumors blunt the neuroinflammatory responses to an immune challenge via a mechanism involving tumor suppression of the peripheral humoral response. Balb/c mammary tumors modestly attenuated select circulating cytokine responses to LPS and E. coli challenges. Further, a second mammary tumor/mouse strain model (E0771 tumors in C57Bl/6 mice) displayed mildly elevated inflammatory responses to an immune challenge. Taken together, these data indicate that tumor-induced suppression of neuroinflammation and sickness behaviors may be driven by a blunted microglial phenotype, partly because of an attenuated peripheral signal to the brain, which may contribute to infection responses and behavioral side effects reported in cancer patients. Finally, these neuroimmune effects likely vary based on tumor type and/or host immune phenotype.
•Chemotherapy induces microbiome disruption, inflammation, and cognitive decline.•The resulting microbiome disruption relates to cognitive decline and inflammation.•Those cognitively impaired have ...unique chemotherapy-induced microbiome alterations.
Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.
A randomized trial involving patients with acute coronary syndromes showed that prasugrel was superior to ticagrelor with regard to the incidence of death, myocardial infarction, or stroke within 1 ...year, with no increased risk of bleeding.
Patients with breast cancer have increased circulating inflammatory markers and mammary tumors increase neuroinflammation in rodent models. Menopausal status is not only important in the context of ...breast cancer as circulating estrogen influences tumor progression, but also because estrogen is anti-inflammatory and an essential modulator of endocrine function in the brain and body. Here, we manipulated "menopause" status (ovary-intact and ovariectomized) in an estrogen receptor (ER)+ mouse mammary tumor model to determine the extent to which ovarian status modulates:
) tumor effects on estrogen concentrations and signaling in the brain,
) tumor effects on estrogen-associated neurobiology and inflammation, and
) the ability for tumor resection to resolve the effects of a tumor. We hypothesized that reduced circulating estradiol (E
) after an ovariectomy exacerbates tumor-induced peripheral and central inflammation. Notably, we observed ovarian-dependent modulation on tumor-induced peripheral outcomes, including E
-dependent processes and, to a lesser degree, circulating inflammatory markers. In the brain, ovariectomy exacerbated neuroinflammatory markers in select brain regions and modulated E
-related neurobiology due to a tumor and/or resection. Overall, our data suggest that ovarian status has moderate implications for tumor-induced alterations in neuroendocrinology and neuroinflammation and mild effects on peripheral inflammatory outcomes in this murine mammary tumor model.
To assess the current use of glucocorticoids (GCs) in Duchenne muscular dystrophy in the UK, and compare the benefits and the adverse events of daily versus intermittent prednisolone regimens.
A ...prospective longitudinal observational study across 17 neuromuscular centres in the UK of 360 boys aged 3-15 years with confirmed Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off) prednisolone for a mean duration of treatment of 4 years.
The median loss of ambulation was 12 years in intermittent and 14.5 years in daily treatment; the HR for intermittent treatment was 1.57 (95% CI 0.87 to 2.82). A fitted multilevel model comparing the intermittent and daily regiments for the NorthStar Ambulatory Assessment demonstrated a divergence after 7 years of age, with boys on an intermittent regimen declining faster (p<0.001). Moderate to severe side effects were more commonly reported and observed in the daily regimen, including Cushingoid features, adverse behavioural events and hypertension. Body mass index mean z score was higher in the daily regimen (1.99, 95% CI 1.79 to 2.19) than in the intermittent regimen (1.51, 95% CI 1.27 to 1.75). Height restriction was more severe in the daily regimen (mean z score -1.77, 95% CI -1.79 to -2.19) than in the intermittent regimen (mean z score -0.70, 95% CI -0.90 to -0.49).
Our study provides a framework for providing information to patients with Duchenne muscular dystrophy and their families when introducing GC therapy. The study also highlights the importance of collecting longitudinal natural history data on patients treated according to standardised protocols, and clearly identifies the benefits and the side-effect profile of two treatment regimens, which will help with informed choices and implementation of targeted surveillance.
In this paper, investigations on gallium indium nitride (GaInN) quantum well structures as optochemical transducers in (bio)chemical sensing are presented. In contrast to the conventional electrical ...read-out of III-nitride-based sensors, a purely optical photoluminescence read-out is performed. A significant spectral shift of the quantum well photoluminescence is observed with varying surface modification. The spectral photoluminescence shift can be attributed to an externally induced quantum confined Stark effect caused by the adsorbed species deposited on the quantum well surface. In order to improve the sensitivity of the transducer elements, different chemical surface treatments are studied. In particular, optical sensing experiments with reducing and oxidizing gases are performed in order to investigate the quantum well photoluminescence response. Additionally, optical investigations of the iron-storage molecule ferritin with varying iron load are presented. The iron load of this molecule is generally considered as a superior biomarker for severe illnesses, such as Alzheimer's disease. In contrast to conventional fluorescent labels, GaInN quantum wells provide a much more stable luminescence signal, and hence, are promising candidates for next generation bioanalytical sensor structures.
With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate ...whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer.
We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60–74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333.
From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9–54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% 95% CI 5–21 vs 29% 17–38 at 1 year; HR 0·57 95% CI 0·30–1·06). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% 95% CI 9–24 vs 30% 20–39 at 1 year; HR 0·64 95% CI 0·37–1·10). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 16% of 99 patients in the conventional target group vs 17 16% of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 12% vs 11 10%). 20 deaths potentially related to study treatment were reported (seven vs 13).
18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours.
German Cancer Aid (Deutsche Krebshilfe).
Surface enhanced Raman spectroscopy (SERS) measurements are conventionally performed using assemblies of metal nanostructures on a macro- to micro-sized substrate or by dispersing colloidal metal ...nanoparticles directly onto the sample of interest. Despite intense use, these methods allow neither the removal of the nanoparticles after a measurement nor a defined confinement of the SERS measurement position. So far, tip enhanced Raman spectroscopy is still the key technique in this regard but not adequate for various samples mainly due to diminished signal enhancement compared to other techniques, poor device fabrication reproducibility, and cumbersome experimental setup requirements. Here, we demonstrate that a rational combination of only four gold nanoparticles (AuNPs) on a DNA origami template, and single silicon nanowires (SiNWs) yield functional optical amplifier nanoprobes for SERS. These nanoscale SERS devices offer a spatial resolution below the diffraction limit of light and still a high electric field intensity enhancement factor (EF) of about 105 despite of miniaturization.
4q deletions are rare chromosome disorders (RCD), with an estimated incidence of 1:50,000-100,000 that is rising as a result of routine introduction of chromosomal microarray testing. The diagnosis ...of a 4q deletion, as of any RCD, confers a sense of exclusion, isolation and guilt on families with an affected child. Reliable information available to a lay audience is scant. To address these issues, Unique, the Rare Chromosome Disorder Support Group, hosted the first international meeting on 4q deletions. Families valued the opportunity to meet genetics and medical professionals with an interest in 4q deletions and to exchange information with each other. In this paper, we intend to summarize all the information presented in this study meeting.
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