Unveiling Gene Interactions in Alzheimer's Disease by Integrating Genetic and Epigenetic Data with a Network-Based Approach.

Alzheimer's Disease (AD) is a complex disease and the leading cause of dementia in older people. We aimed to uncover aspects of AD's pathogenesis that may contribute to drug repurposing efforts by integrating DNA methylation and genetic data. Implementing the network-based tool, a dense module search of genome-wide association studies (dmGWAS), we integrated a large-scale GWAS dataset with DNA methylation data to identify gene network modules associated with AD. Our analysis yielded 286 significant gene network modules. Notably, the foremost module included the BIN1 gene, showing the largest GWAS signal, and the GNAS gene, the most significantly hypermethylated. We conducted Web-based Cell-type-Specific Enrichment Analysis (WebCSEA) on genes within the top 10% of dmGWAS modules, highlighting monocyte as the most significant cell type (p < 5 × 10-12). Functional enrichment analysis revealed Gene Ontology Biological Process terms relevant to AD pathology (adjusted p < 0.05). Additionally, drug target enrichment identified five FDA-approved targets (p-value = 0.03) for further research. In summary, dmGWAS integration of genetic and epigenetic signals unveiled new gene interactions related to AD, offering promising avenues for future studies.

Pancreatic tumor microenvironmental acidosis and hypoxia transform gold nanorods into cell-penetrant particles for potent radiosensitization.

Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l-glutamic acid and l-lysine within an amphiphilic polymer of poly(l-glutamic acid-co-l-lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate in the periphery and core of tumors without any signs of serum biochemical or hematological alterations, normal organ histopathological abnormalities, or overt deterioration in animal health. Furthermore, P(Glu-co-Lys)-GNRs penetrated the tumor microenvironment to accumulate in the hypoxic cores of tumors to potently radiosensitize heterotopic and orthotopic pancreatic cancers in vivo.

MR-Guided Adaptive Radiotherapy for OAR Sparing in Head and Neck Cancers.

MR-linac devices offer the potential for advancements in radiotherapy (RT) treatment of head and neck cancer (HNC) by using daily MR imaging performed at the time and setup of treatment delivery. This article aims to present a review of current adaptive RT (ART) methods on MR-Linac devices directed towards the sparing of organs at risk (OAR) and a view of future adaptive techniques seeking to improve the therapeutic ratio. This ratio expresses the relationship between the probability of tumor control and the probability of normal tissue damage and is thus an important conceptual metric of success in the sparing of OARs. Increasing spatial conformity of dose distributions to target volume and OARs is an initial step in achieving therapeutic improvements, followed by the use of imaging and clinical biomarkers to inform the clinical decision-making process in an ART paradigm. Pre-clinical and clinical findings support the incorporation of biomarkers into ART protocols and investment into further research to explore imaging biomarkers by taking advantage of the daily MR imaging workflow. A coherent understanding of this road map for RT in HNC is critical for directing future research efforts related to sparing OARs using image-guided radiotherapy (IGRT).

Intensity standardization methods in magnetic resonance imaging of head and neck cancer.

BACKGROUND AND PURPOSE: Conventional magnetic resonance imaging (MRI) poses challenges in quantitative analysis because voxel intensity values lack physical meaning. While intensity standardization methods exist, their effects on head and neck MRI have not been investigated. We developed a workflow based on healthy tissue region of interest (ROI) analysis to determine intensity consistency within a patient cohort. Through this workflow, we systematically evaluated intensity standardization methods for MRI of head and neck cancer (HNC) patients. MATERIALS AND METHODS: Two HNC cohorts (30 patients total) were retrospectively analyzed. One cohort was imaged with heterogenous acquisition parameters (HET cohort), whereas the other was imaged with homogenous acquisition parameters (HOM cohort). The standard deviation of cohort-level normalized mean intensity (SD NMIc), a metric of intensity consistency, was calculated across ROIs to determine the effect of five intensity standardization methods on T2-weighted images. For each cohort, a Friedman test followed by a post-hoc Bonferroni-corrected Wilcoxon signed-rank test was conducted to compare SD NMIc among methods. RESULTS: Consistency (SD NMIc across ROIs) between unstandardized images was substantially more impaired in the HET cohort (0.29 ± 0.08) than in the HOM cohort (0.15 ± 0.03). Consequently, corrected p-values for intensity standardization methods with lower SD NMIc compared to unstandardized images were significant in the HET cohort (p < 0.05) but not significant in the HOM cohort (p > 0.05). In both cohorts, differences between methods were often minimal and nonsignificant. CONCLUSIONS: Our findings stress the importance of intensity standardization, either through the utilization of uniform acquisition parameters or specific intensity standardization methods, and the need for testing intensity consistency before performing quantitative analysis of HNC MRI.

External Dose to Recovery Teams Following a Wide-area Nuclear or Radiological Release Event.

ABSTRACT: The common radionuclide 137Cs is a gamma-ray source term for nuclear reactor accidents, nuclear detonations, and potential radionuclide dispersal devices. For wide-area contamination events, one remediation option integrates water washing activities with on-site treatment of water for its immediate reuse. This remediation option includes washing building and roadways via firehose, collecting the wash water, and passing the contaminated water through chemical filtration beds. The primary objective of this study was to quantify the dose incurred to workers performing a remediation recovery effort for roadways and buildings following a wide-area release event. MicroShield® was employed to calculate the dose to workers at the roadway level and to calculate total dose rates while performing washing activities. This study finds that for a realistic contamination scenario for a wide area of a large urban environment, decontamination crews would be subjected to <220 µSv per person, much less than the 50,000 µSv limit for occupational dose. By extrapolation, one decontamination team of 48 people could continue washing operations on a total of 2.8 km2 before reaching their incurred annual dose limits. Though it is unrealistic to assign one team that entire area, we can conclude external dose will not limit worker deployment given the range of contamination levels adopted in this study.

Genomic and Transcriptomic Characterisation of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT), followed by surgical resection. However, >70% of patients do not achieve a complete pathological response and have higher rates of relapse and death. There are no validated pre- or on-treatment factors that predict response to NACRT besides tumour stage and size. We characterised the response of 33 LARC patients to NACRT, collected tumour samples from patients prior to, during and after NACRT, and performed whole exome, transcriptome and high-depth targeted sequencing. The pre-treatment LARC genome was not predictive of response to NACRT. However, in line with the increasing recognition of microbial influence in cancer, RNA analysis of pre-treatment tumours suggested a greater abundance of Fusobacteria in intermediate and poor responders. In addition, we investigated tumour heterogeneity and evolution in response to NACRT. While matched pre-treatment, on-treatment and post-treatment tumours revealed minimal genome evolution overall, we identified cases in which microsatellite instability developed or was selected for during NACRT. Recent research has suggested a role for adaptive mutability to targeted therapy in colorectal cancer cells. We provide preliminary evidence of selection for mismatch repair deficiency in response to NACRT. Furthermore, pre-NACRT genomic landscapes do not predict treatment response but pre-NACRT microbiome characteristics may be informative.

Enhancing Colorectal Cancer Radiation Therapy Efficacy using Silver Nanoprisms Decorated with Graphene as Radiosensitizers.

Metal nanoparticles have significant interaction cross-sections with electromagnetic waves due to their large surface area-to-volume ratio, which can be exploited in cancer radiotherapy to locally enhance the radiation dose deposition in tumors. We developed a new type of silver nanoparticle composite, PEGylated graphene quantum dot (GQD)-decorated Silver Nanoprisms (pGAgNPs), that show excellent in vitro intracellular uptake and radiosensitization in radiation-sensitive HCT116 and relatively radiation-resistant HT29 colorectal cancer cells. Furthermore, following biodistribution analysis of intravenously injected nanoparticles in nude mice bearing HCT116 tumors radiosensitization was evaluated. Treatment with nanoparticles and a single radiation dose of 10 Gy significantly reduces the growth of colorectal tumors and increases the survival time as compared to treatment with radiation only. Our findings suggest that these novel nanoparticles offer a promising paradigm for enhancing colorectal cancer radiation therapy efficacy.

Biomarkers of radiation-induced vascular injury.

OBJECTIVE: Cancer survivorship has thrown the spotlight on the incidence of nonmalignant chronic diseases in cancer patients. Endothelial injury is increasingly recognized as a consequence of cancer treatment, particularly after radiation therapy (RT). This review is to provide a current understanding on the pathophysiological mechanisms and predictive biomarkers of radiation-induced vascular injury. RECENT FINDINGS: Radiation directly impacts vasculature by causing endothelial apoptosis and senescence, and alterations in normal homeostasis. This altered milieu at the endothelial surface may contribute to a systemic chronic inflammatory state that is superimposed upon the cascade of normal senescence processes leading to acceleration of age-related disorders, atherosclerosis, and chronic fibrosis. Vasculature imaging, blood-based or cell-component biomarkers, and signatures of genomics, proteomics, metabolomics, and radiomics are potential tools for detection of vascular damage after irradiation. CONCLUSIONS: Development of a valid prediction model by combining an array of imaging tools, blood-based biomarkers, coupled with novel predictors like exosomes and metabolic degradation products can serve to identify RT-induced vascular injury early for subsequent introduction of newer therapeutic approaches to counter radiation morbidity.

Recent advances in radiation therapy of pancreatic cancer.

Pancreatic cancer has a dismal prognosis with an overall survival outcome of just 5% at five years. However, paralleling our improved understanding of the biology of pancreatic cancer, treatment paradigms have also continued to evolve with newer advances in surgical techniques, chemotherapeutic agents, radiation therapy (RT) techniques, and immunotherapy paradigms. RT dose, modality, fraction size, and sequencing are being evaluated actively, and the interplay between RT and immune effects has opened up newer avenues of research. In this review, we will emphasize recent advances in RT for pancreatic cancer, focusing on preoperative chemoradiation, RT dose escalation, sparing of the spleen to reduce lymphopenia, and combination of RT with immunotherapy.

Improving Telestroke Treatment Times in an Expanding Network of Hospitals.

BACKGROUND: Like all medical innovations, telestroke must demonstrate successful outcomes to achieve sustained growth and acceptance. Asserting that telemedicine is faster, employs the latest technology, or promotes a better use of limited resources is laudable but insufficient. An analysis of stroke treatment within a telemedicine network in 2013 showed that tissue-type plasminogen activator (tPA) could be safely and reliably administered within a practice-based model of telestroke care. Since then, hospital volume and tPA administration within this network have tripled. We hypothesize that a practice-based model of telestroke can maintain positive outcomes in the face of rapid growth. METHODS: Data on tPA treatment times and outcomes after thrombolysis were gathered for 165 patients treated with alteplase between November 2012 and November 2014. Comparisons were made to a previous published study of 54 patients seen between October 2010 and October 2012 in the same network. Primary outcome measures were average door-to-needle (DTN) time for TPA administration and average call-to-needle (CTN) time. RESULTS: Significant reductions were observed in median DTN (93 versus 75 minutes, P < .01) and median CTN (56 versus 41 minutes, P < .01). Quality outcome measures such as post-tPA symptomatic hemorrhage (2 [4%] versus 9 [5%], P = .23), length of stay (4 versus 4 days, P = .45), mortality (8 [15%] versus 16 [10%]; P = .32), and percentage of stroke patients treated remained stable. CONCLUSIONS: This study shows that a practice-based telemedicine system can produce meaningful improvement in markers of telestroke efficiency in the face of rapid growth of a telestroke network.

Expanding access to intravenous tissue-type plasminogen activator treatment with a practice-based telestroke system.

Emergency stroke treatment would benefit from the increased use of thrombolysis via academic or practice-based telemedicine systems. However, a comparative analysis of these systems has not been undertaken. Data on stroke severity and outcomes after thrombolysis were gathered on patients treated by a practice-based system and compared to published data from academic systems. Patient demographics and outcome measures were not significantly different for patients treated by practice-based or academic providers with the exceptions of lower age and shorter duration of stay in the practice-based treatment group. This study shows that emergency stroke care provided by academic and practice-based telemedicine systems can achieve similar outcomes.