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Despite the prevalence of earth ovens, a subclass of pit features used for cooking, there is little consensus regarding how these cooking features were used or about the foodstuffs that were prepared in them. To provide a more detailed understanding of earth oven cooking in the archaeological record, we analyze the archaeobotanical contents, stratigraphy, and morphology of a cooking pit recently excavated at C. W. Cooper, an early Mississippian (A.D. 1150-1200) site in west-central Illinois in order to contribute to research on late Prehistoric foodways. Filled with nearly 100 ears of maize, this earth oven presents the opportunity to document the process of undertaking a maize roast. The volume of maize and its presence within a dense concentration of cooking, processing, and storage facilities allows us to consider the communal nature of outdoor earth oven cooking in the 12th century Central Illinois Valley and the socioeconomic dimensions of commensal politics more broadly during the Precolumbian era.

We consider the causes and timing of maize (Zea mays) intensification in the central Illinois River valley and argue that an understanding of changes in maize production requires a consideration of changes occurring in the entire plant subsistence system. To this end, we explore trends in the collection and production of plant foods from the Late Woodland (A.D. 600-1100) to Early Mississippian periods (A.D. 1100-1200). The plant data reveal a stepwise decrease in nut collection during the Late Woodland period, and again during the transition to the Early Mississippian period. This pattern is accompanied by statistical increases in maize abundance, indicating an intensification of maize production around A.D. 1100. We consider these patterns in light of similar maize increases occurring throughout the Eastern Woodlands and evaluate several possible interpretations related to population pressure, climate change, competitive generosity, and cultural emulation, the latter which appears to have been inspired by prolonged contact between local populations and Mississippian groups in the greater Cahokia area.

Objective. The purpose of this investigation was to develop a sub-maximal exercise test for estimating VO2max utilizing aerobic dance. Experimental Design. One hundred females between the ages 18 to 40 yr served as the subjects for test validation. The subjects completed a treadmill test to determine VO2max and were assessed for heart rate (HR) response to a bout of aerobic dance. The data associated with responses to treadmill exercise and the aerobic dance test, in conjunction with descriptive variables (e.g., age, BMI) were utilized in the validation of the multiple regression model. Measures. Reliability was determined by correlation and paired 't'-tests of the aerobic dance routine test and retest trials. The construction of the multiple regression equation, via forward entry analysis, and the cross-validation of the regression equation were completed to ensure the validity and reliability of the protocol in accurately estimating VO2max. Results. Test, retest reliability for the dance-exercise routine was demonstrated (r=0.98). Moreover, no significant differences were shown between the HR responses for the test and retest trials. The multiple regression analysis yielded a three variable multiple prediction equation for estimating VO2max (R=0.84; SEE, 5.5 ml x kg-1 x min-1). The three variables were the HR response to four min of aerobic dance (HR4), body mass index (BMI), and age (years). Cross-validation of the aerobic dance test was determined with a second group of 50 female subjects (R=0.83; SEE, 5.5 ml x kg-1 x min-1). [ABSTRACT FROM AUTHOR]

Purpose: To investigate the metabolic information provided by (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) during the early response of head-and-neck squamous cell carcinoma (HNSCC) xenografts to radiotherapy (RT). Methods and Materials: Low-passage HNSCC cells (UT14) were injected into the rear flanks of female nu/nu mice to generate xenografts. After tumors grew to 400-500 mm(3), they were treated with either 15 Gy in one fraction (n = 18) or sham RT (n = 12). At various time points after treatment, tumors were assessed with 2-h dynamic FDG-PET and immediately harvested for direct histological correlation. Different analytical parameters were used to process the dynamic PET data: kinetic index (Ki), standard uptake value (SUV), sensitivity factor (SF), and retention index (RI). Tumor growth was assessed using the specific growth rate (SGR) and correlated with PET parameters using the Pearson correlation coefficient (r). Receiver operating characteristic (ROC) and the area under the ROC curve (AUC) were used to test PET parameters for their ability to predict for radiation necrosis and radiation change. Results: Tumor growth was arrested for the first 20 days after RT and recovered thereafter. Histologically, radiation change was observed in the peripheral regions of tumors between days 7 and 23 after RT, and radiation necrosis were observed in the central regions of tumors between days 7 and 40. Ki provided the best correlation with SGR (r = 0.51) and was the optimal parameter to predict for early radiation necrosis (AUC = 0.804, p = 0.07). SUV(30 min) was the strongest predictor for late radiation necrosis (AUC = 0.959, p = 0.004). Both RI(30-60 min) and SF(12-70 min) were very accurate in predicting for radiation change (AUC = 0.891 and 0.875, p = 0.009 and 0.01, respectively). Conclusions: Dynamic FDG-PET analysis (such as Ki or SF) may provide informative assessment of early radiation necrosis or radiation change of HNSCC xenografts after RT. [ABSTRACT FROM AUTHOR]

Purpose: We report neurocognitive, imaging, ophthalmologic, and safety outcomes following low-dose whole brain radiation therapy (LD-WBRT) for patients with early Alzheimer dementia (eAD) treated in a pilot trial., Methods and Materials: Trial-enrolled patients were at least 55 years of age, had eAD meeting NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) Alzheimer's Criteria with confirmatory fluorodeoxyglucose and florbetapir positron emission tomography findings; had the capacity to complete neurocognitive function, psychological function, and quality-of-life assessments; had a Rosen modified Hachinski score ≤4; and had estimated survival >12 months., Results: Five patients were treated with LD-WBRT (2 Gy × 5 over 1 week; 3 female; mean age, 73.2 years [range, 69-77]). Four of 5 patients had improved (n = 3) or stable (n = 1) Mini-Mental State Examination (second edition) T-scores at 1 year. The posttreatment scores of all 3 patients who improved increased to the average range. There were additional findings of stability of naming and other cognitive skills as well as stability to possible improvement in imaging findings. No safety issues were encountered. The only side effect was temporary epilation with satisfactory hair regrowth., Conclusions: Our results from 5 patients with eAD treated with LD-WBRT (10 Gy in 5 fractions) demonstrate a positive safety profile and provide preliminary, hypothesis-generating data to suggest that this treatment stabilizes or improves cognition. These findings will require further evaluation in larger, definitive, randomized trials., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Alzheimer's Disease (AD) represents a major health problem without effective treatments. As the incidence of the disease will continue to rise, it is imperative to find new treatment options to halt or slow disease progression. In recent years, several groups have begun to study the utility of low total dose radiation therapy (LTDRT) to inhibit some of the pathological features of AD and improve cognition in a variety of animal models. These preclinical studies have led to Phase 1 and 2 trials in different centers around the world. In this review, we present and interpret the pre-clinical evidence report some preliminary clinical data from a Phase 2 trial in early-stage AD patients., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed., (Creative Commons Attribution license.)

Introduction: In this pilot study we have taken a novel functional approach to assess whether differences exist in the activity of key genes involved in the response to radiation and oxidative stress between patients with radiation cystitis., Materials and Methods: Arm 1 consisted of patients who had previously been treated for prostate cancer and who had received definitive radiation treatment and had subsequently developed cystitis and/or proctitis and were being treated by hyperbaric oxygen (HBO). Arm 2 consisted of patients who had never been treated by radiation but who were scheduled for HBO treatment for another pathology. The genes chosen for the study were HMOX1, NOS2, SOD2, TNFα, IL-6 and TGFβ. Blood and urine was collected pre and post HBO treatment., Results: Gene expression showed a significant difference in NOS2 (p = 0.0178) and TNFα (p = 0.037) between the control and cystitis patients. The plasma levels of VEGF-A were significantly elevated in cystitis patients and there was a strong trend for significant overexpression in urine. Comparing pre and post-dive samples showed little difference in both groups of patients except for VEGF-A which was reduced after the dive in plasma from cystitis patients., Conclusions: This study uncovered some physiological differences in patients with radiation-induced cystitis using HBO treatment as a stimulus to induce mild oxidative stress. Further research is ongoing to assess whether the acute exposure to HBO might be a physiological screening tool to identify patients susceptible to chronic radiation toxicity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Bone-marrow-derived haematopoietic stem and progenitor cells (HSPCs) are a prominent part of the highly complex tumour microenvironment (TME) where they localise within tumours and maintain haematopoietic potency. Understanding the role HSPCs play in tumour growth and response to radiation therapy (RT) may lead to improved patient treatments and outcomes., Methods: We used a mouse model of non-small cell lung carcinoma where tumours were exposed to RT regimens alone or in combination with GW2580, a pharmacological inhibitor of colony stimulating factor (CSF)-1 receptor. RT-PCR, western blotting and immunohistochemistry were used to quantify expression levels of factors that affect HSPC differentiation. DsRed + HSPC intratumoural activity was tracked using flow cytometry and confocal microscopy., Results: We demonstrated that CSF-1 is enhanced in the TME following exposure to RT. CSF-1 signaling induced intratumoural HSPC differentiation into M2 polarised tumour-associated macrophages (TAMs), aiding in post-RT tumour survival and regrowth. In contrast, hyperfractionated/pulsed radiation therapy (PRT) and GW2580 ablated this process resulting in improved tumour killing and mouse survival., Conclusions: Tumours coopt intratumoural HSPC fate determination via CSF-1 signaling to overcome the effects of RT. Thus, limiting intratumoural HSPC activity represents an attractive strategy for improving the clinical treatment of solid tumours., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: We have developed a novel imaging analysis procedure that is highly predictive of local failure after chemoradiation in head and neck cancer. In this study we investigated whether any pretreatment biomarkers correlated with key imaging parameters., Methods: Pretreatment biopsy material was available for 28 patients entered into an institutional trial of adaptive radiotherapy in which FDG-PET images were collected weekly during treatment. The biopsies were immunohistochemically stained for CD44, EGFR, GLUT1, ALDH1, Ki-67 and p53 and quantified using image analysis. Expression levels were correlated with previously derived imaging parameters, the pretreatment SUV max and the dose response matrix (DRM)., Results: The different parameters of the SUV max and DRM did not correlate with each other. We observed a positive and highly significant (p = 0.0088) correlation between CD44 expression and volume of tumor with a DRM greater than 0.8. We found no correlation between any DRM parameter and GLUT1, p53, Ki-67 and EGFR or ALDH1. GLUT1 expression did correlate with the maximum SUV 0 and the volume of tumor with an SUV 0 greater than 20., Conclusions: The pretreatment SUV max and DRM are independent imaging parameters that combine to predict local recurrence. The significant correlation between CD44 expression, a known cancer stem cell (CSC) marker, and volume of tumor with a DRM greater than 0.8 is consistent with concept that specific foci of cells are responsible for tumor recurrence and that CSCs may be randomly distributed in tumors in specific niches. Dose painting these small areas may lead to improved tumor control., Competing Interests: Conflict of Interest Statement The authors have no conflicts of interest associated with this manuscript, (Copyright © 2021 Elsevier B.V. All rights reserved.)

We evaluated the utility of leucocyte epigenomic-biomarkers for Alzheimer's Disease (AD) detection and elucidates its molecular pathogeneses. Genome-wide DNA methylation analysis was performed using the Infinium MethylationEPIC BeadChip array in 24 late-onset AD (LOAD) and 24 cognitively healthy subjects. Data were analyzed using six Artificial Intelligence (AI) methodologies including Deep Learning (DL) followed by Ingenuity Pathway Analysis (IPA) was used for AD prediction. We identified 152 significantly (FDR p<0.05) differentially methylated intragenic CpGs in 171 distinct genes in AD patients compared to controls. All AI platforms accurately predicted AD with AUCs ≥0.93 using 283,143 intragenic and 244,246 intergenic/extragenic CpGs. DL had an AUC = 0.99 using intragenic CpGs, with both sensitivity and specificity being 97%. High AD prediction was also achieved using intergenic/extragenic CpG sites (DL significance value being AUC = 0.99 with 97% sensitivity and specificity). Epigenetically altered genes included CR1L & CTSV (abnormal morphology of cerebral cortex), S1PR1 (CNS inflammation), and LTB4R (inflammatory response). These genes have been previously linked with AD and dementia. The differentially methylated genes CTSV & PRMT5 (ventricular hypertrophy and dilation) are linked to cardiovascular disease and of interest given the known association between impaired cerebral blood flow, cardiovascular disease, and AD. We report a novel, minimally invasive approach using peripheral blood leucocyte epigenomics, and AI analysis to detect AD and elucidate its pathogenesis., Competing Interests: The authors have read the journal’s policy and have the following competing interest: BA is a paid employee of Meridian HealthComms Ltd. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Pulsed radiation therapy (PRT) has shown effective tumor control and superior normal-tissue sparing ability compared with standard radiotherapy (SRT) in preclinical models and retrospective clinical series. This is the first prospective trial to investigate PRT in the treatment of patients with newly diagnosed glioblastoma (GBM)., Methods: This is a single-arm, prospective study. Patients with newly diagnosed GBM underwent surgery, followed by 60 Gy of PRT with concurrent temozolomide (TMZ). Each day, a 2-Gy fraction was divided into ten 0.2-Gy pulses, separated by 3-minute intervals. Patients received maintenance TMZ. Neurocognitive function (NCF) and quality of life (QoL) were monitored for 2 years using the Hopkins Verbal Learning Test‒Revised and the European Organisation for Research and Treatment of Cancer QLQ-C30 QoL questionnaire. Change in NCF was evaluated based on a minimal clinically important difference (MCID) threshold of 0.5 standard deviation., Results: Twenty patients were enrolled with a median follow-up of 21 months. Median age was 60 years. Forty percent underwent subtotal resection, and 60% underwent gross total resection. One patient had an isocitrate dehydrogenase (IDH)-mutated tumor. Median progression-free survival (PFS) and overall survival (OS) were 10.7 and 20.9 months, respectively. In a post-hoc comparison, median OS for the prospective cohort was longer, compared with a matched cohort receiving SRT (20.9 vs 14 mo, P = 0.042). There was no decline in QoL, and changes in NCF scores did not meet the threshold of an MCID., Conclusions: Treatment of newly diagnosed GBM with PRT is feasible and produces promising effectiveness while maintaining neurocognitive function and QoL. Validation of our results in a larger prospective trial warrants consideration., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The molecular drivers of human papillomavirus-related head and neck squamous cell carcinoma (HPV + HNSCC) are not entirely understood. This study evaluated the relationship between HPV integration, expression of E6/E7, and patient outcomes in p16+ HNSCCs., Methods: HPV type was determined by HPV PCR-MassArray, and integration was called using detection of integrated papillomavirus sequences polymerase chain reaction (PCR). We investigated whether fusion transcripts were produced by reverse transcriptase polymerase chain reaction (RT-PCR). E6/E7 expression was assessed by quantitative RT-PCR. We assessed if there was a relationship between integration and E6/E7 expression, clinical variables, or patient outcomes., Results: Most samples demonstrated HPV integration, which sometimes resulted in a fusion transcript. HPV integration was positively correlated with age at diagnosis and E6/E7 expression. There was a significant difference in survival between patients with vs without integration., Conclusions: Contrary to previous reports, HPV integration was associated with improved patient survival. Therefore, HPV integration may act as a molecular marker of good prognosis., (© 2020 Wiley Periodicals LLC.)

Background and Purpose: There has been little success targeting individual genes in combination with radiation in head and neck cancer. In this study we investigated whether targeting two key pathways simultaneously might be more effective., Materials and Methods: We studied the effect of combining dacomitinib (pan-HER, irreversible inhibitor) and gedatolisib (dual PI3K/MTOR inhibitor) with radiation in well characterized, low passage xenograft models of HNSCC in vitro and in vivo ., Results: Dacomitinib showed differential growth inhibition in vitro that correlated to EGFR expression whilst gedatolisib was effective in both cell lines. Neither agent radiosensitized the cell lines in vitro. In vivo studies demonstrated that dacomitinib was an effective agent alone and in combination with radiation whilst the addition of gedatolisib did not enhance the effect of these two modalities despite inhibiting phosphorylation of key genes in the PI3K/MTOR pathway., Conclusions: Our results showed that combining two drugs with radiation provided no added benefit compared to the single most active drug. Dacomitinib deserves more investigation as a radiation sensitizing agent in HNSCC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Purpose: Intratumoral dose response can be detected using serial fluoro-2-deoxyglucose-(FDG) positron emission tomography (PET)/computed tomography (CT) imaging feedback during treatment and used to guide adaptive dose painting by number (DPbN). However, to reliably implement this technique, the effect of uncertainties in quantitative PET/CT imaging feedback on tumor voxel dose-response assessment and DPbN needs to be determined and reduced., Methods: Three major uncertainties, induced by (a) PET imaging partial volume effect (PVE) and (b) tumor deformable image registration (DIR), and (c) variation of the time interval between FDG injection and PET image acquisition (TI), were determined using serial FDG-PET/CT images acquired during chemoradiotherapy of 18 head and neck cancer patients. PET imaging PVE was simulated using the discrepancy between with and without iterative deconvolution-based PVE corrections. Effect of tumor DIR uncertainty was simulated using the discrepancy between two DIR algorithms, including one with and one without soft-tissue mechanical correction for the voxel displacement. The effect of TI variation was simulated using linear interpolation on the dual-point PET/CT images. Tumor voxel pretreatment metabolic activity (SUV 0 ) and dose-response matrix (DRM) discrepancies induced by each of the three uncertainties were quantified, respectively. Adverse effects of tumor voxel SUV 0 and DRM discrepancies on tumor control probability (TCP) in DPbN were assessed., Results: Partial volume effect and TI variations of 10 mins induced a mean ± standard deviation (SD) of tumor voxel SUV 0 discrepancies to be -0.7% ± 9.2% and 0% ± 4.8%, respectively. Tumor voxel DRM discrepancies induced by PVE, tumor DIR discrepancy, and TI variations were 0.6% ± 8.9%, 1.7% ± 9.1%, and 0% ± 7%, respectively. Partial volume effect induced SUV 0 and DRM discrepancies correlated significantly with the tumor shape and FDG uptake heterogeneity. Tumor DIR uncertainty-induced DRM discrepancy correlated significantly with the tumor volume and shrinkage during treatment. Among the three uncertainties, PVE dominated the adverse effects on the TCP, with a mean ± SD of TCP reduction to be 12.7% ± 9.8% for all tumors if no compensation was applied for., Conclusions: Effect of uncertainties in quantitative FDG-PET/CT imaging feedback on intratumoral dose-response quantification was not negligible. These uncertainties primarily caused by PVE and tumor DIR were highly dependent on individual tumor shape, volume, shrinkage during treatment, and pretreatment SUV heterogeneity, which can be managed individually. The adverse effects of these uncertainties could be minimized by using proper PVE corrections and DIR methods and compensated for in the clinical implementation of DPbN., (© 2020 American Association of Physicists in Medicine.)

Historic data show that home flea infestations can be managed by treating all animals on the premises with a highly effective flea control product. The use of effective products has also been shown to reduce pruritus and minimize dermatologic lesions in both cats and dogs. Therefore, an in-home study was conducted in West Central Florida USA to evaluate the efficacy of a topically applied selamectin-sarolaner formulation to control fleas in naturally infested cats over a 12-week period. Thirty-seven cats in 21 households were treated once monthly with the selamectin-sarolaner topical solution. In the topical fluralaner treatment (positive control) group, forty-three cats in 20 households were treated once on day 0. A combined total of thirty dogs in both groups were treated once monthly with oral sarolaner. Fleas on cats were counted by flea combing, fleas on dogs were counted using visual area counts and fleas in the indoor premises were assessed using intermittent-light flea traps. Blinded-assessments of feline dermatologic lesions (modified-SCORFAD) were conducted monthly by a boarded-dermatologist and pruritus severity was evaluated by pet owners. Three consecutive monthly treatments of selamectin-sarolaner reduced flea populations on cats by 96.3 % within 7 days and by 100% from week 6 to the end of the 12-week study. The topical application of fluralaner reduced flea populations by 98.1 % within 7 days and efficacy reached 100% by week 12. At the end of the study, fleas were completely eradicated (from cats, dogs and homes) in every home regardless of treatment group. Owner reported cat pruritus was reduced by > 87 % in both treatment groups by week 12. Significant improvements in dermatologic lesion scores (> 81 %) were achieved by both products by the end of the study. Monthly applications of topical selamectin-sarolaner or topical fluralaner to cats living in the heavy flea challenge environment of West Central Florida USA were effective in eradicating flea infestations, reducing pruritus and improving dermatologic lesions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The mechanistic target of rapamycin (MTOR) plays a key role in regulating cell growth and metabolism and is commonly overexpressed in head and neck cancer (HNSCC). This study investigated the association of MTOR with clinical outcome in human papilloma virus (HPV) positive and negative HNSCC patients treated by chemoradiation., Methods: A tissue microarray (TMA) consisting of cores from 109 HNSCC patients treated by definitive chemoradiation was constructed and stained with antibodies against p16 and MTOR and expression correlated with clinicopathological features and clinical outcome., Results: MTOR varied widely between tumor cores and was not associated with HPV status or clinicopathological features. There was a positive correlation with pre-treatment FDG uptake. (P = .01). In HPV negative patients, MTOR predicted for shorter locoregional control (P = .02), diseases free survival (P = .02), and overall survival (P = .04). MTOR expression was not associated with outcome in HPV positive patients., Conclusions: Prognostic significance of MTOR expression depends on HPV status., (© Wiley Periodicals, Inc.)

We have previously reported that low doses of external beam ionizing irradiation reduced amyloid-β (Aβ) plaques and improved cognition in APP/PS1 mice. In this study we investigated the effects of radiation in an age-matched series of 3xTg-AD mice. Mice were hemibrain-irradiated with 5 fractions of 2 Gy and sacrificed 8 weeks after the end of treatment. Aβ and tau were assessed using immunohistochemistry and quantified using image analysis with Definiens Tissue Studio. We observed a significant reduction in Aβ plaque burden and tau staining; these two parameters were significantly correlated. This preliminary data is further support that low doses of radiation may be beneficial in Alzheimer's disease.

Despite rapid advances in diagnostic and therapeutic medicine, renal cell carcinoma (RCC) continues to cause significant morbidity and mortality in patients. While there has been a shift towards earlier detection, approximately 16% of patients present with metastatic disease at the time of diagnosis. Kidney injury molecule-1 (KIM-1) is a glycoprotein that has been shown to be a robust and reliable biomarker of acute proximal tubular injury. As KIM-1 is mainly expressed in RCC derived from the proximal tubules, it is a reliable marker to differentiate between proximal tubular primary RCC and distal nephron primary RCC. Several studies have investigated urinary KIM-1 (uKIM-1) in RCC and demonstrated that it is a sensitive and specific marker for detecting localized RCC, as patients had markedly reduced uKIM-1 levels following nephrectomy, with uKIM-1 levels correlating with tumor size and grade. In addition, levels of KIM-1 present in plasma have also shown utility as a biomarker of RCC with levels being elevated in RCC cases at least 5 years before diagnosis. This review focuses on a progressive understanding of KIM-1 in the diagnosis of RCC using biopsies, urine, and plasma samples, and it will also provide some insight into potential roles of KIM-1 in the growth and spread of RCC.

Background/aim: We tested JP4-039, a GS-nitroxide radiation damage mitigator in proton therapy of Fanconi anemia (FA) mice., Materials and Methods: Fanca -/- and Fanca +/+ bone marrow stromal cells were pre-treated with JP4-039 and irradiated with either protons or photons (0-10 GyRBE) followed by clonogenic survival and β-Galactosidase senescence analysis. Fanca -/- and Fanca +/+ mice were pretreated with JP4-039 for 10 min prior to oropharyngeal irradiation with either protons or photons (0 or 30 GyRBE) followed by sacrifice and measurement of oral cavity ulceration, distant hematopoietic suppression, and real-time polymerase chain reaction analysis., Results: JP4-039 reduced oral cavity ulceration in Fanca -/- mice, transcripts Nfkb, Ap1, Sp1, and Nrf2, and proton therapy induced distant marrow suppression., Conclusion: JP4-039 protected Fanca -/- and Fanca +/+ cells and mouse oral cavity from both proton and photon radiation., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Molecular Interaction Network Approach (MINA) was used to elucidate candidate disease genes. The approach was implemented to identify novel gene association with commonly known autoimmune diseases [1]. In MINA, we evaluated the hypothesis that "network proximity" within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. There are now numerous examples of gene discoveries based upon network proximity between novel and previously identified disease genes (Yin et al., 2017 [2], Wang et al., 2011 [3], and Barrenas et al., 2009 [4]). This study extends the application of interaction networks to the interrogation of Genome Wide Association studies: first, by showing that a group of nine autoimmune diseases (AuD) genes "seed genes", are connected in a highly non-random manner within a whole genome network; and second, by showing that the minimal number of connecting genes required to connect a maximal number of AuD candidate genes are highly enriched as candidate genes for AuD predisposing mutations. The findings imply that a threshold number of candidate genes for any heritable disorder can be used to "seed" a molecular interaction network that •Serves to validate the disease status of closely associated seed genes•Identifies genes that are highly enriched as novel candidate disease genes•Provides a strategy for elucidation of epistatic gene x gene interactions The method could provide a critical toll for understanding the genetic architecture of common traits and disorders.

Purpose: To construct a tumor voxel dose response matrix (DRM) and dose prescription function (DPF) for adaptive dose painting by number (DPbN) based on treatment feedback of fluoro-2-deoxyglucose (FGD) positron emission tomography (PET)/computed tomography (CT) imaging., Methods and Materials: FDG-PET/CT images obtained before and after chemoradiation therapy and at weekly chemoradiation therapy sessions for each of 18 patients with head and neck cancer, as well as the treatment outcomes, were used in the modeling. All weekly and posttreatment PET/CT images were registered voxel-to-voxel to the corresponding pretreatment baseline PET/CT image. Tumor voxel DRM was created using serial FDG-PET imaging of each patient with respect to the baseline standardized uptake value (SUV 0 ). A tumor voxel control probability (TVCP) lookup table was created using the maximum likelihood estimation on the tumor voxel (SUV 0 , DRM) domain of all tumors. Tumor voxel DPF was created from the TVCP lookup table and used as the objective function for DPbN-based inverse planning optimization., Results: Large intertumoral and intratumoral variations on both tumor voxels (SUV 0 , DRM) were identified. Tumor voxel dose resistance did not show correlation with its baseline SUV 0 value and was the major cause of the tumor local failures. Tumor voxel DPF as the function of tumor voxel (SUV 0 , DRM) values also showed a very large intertumoral and intratumoral heterogeneity. Most human papillomavirus-negative tumors require a treatment dose >100 Gy to certain local tumor regions. These treatment doses, which are most unlikely to be implementable in conventional radiation therapy, can be achieved using adaptive DPbN treatment. Clinical feasibility was evaluated by comparing the adaptive DPbN treatment plan with the conventional intensity modulated radiation therapy plan., Conclusions: Tumor voxel (SUV 0 , DRM) provides an intratumoral prognostic map to target tumor locoregional-resistant regions. The corresponding TVCP or DPF provides a quantitative objective to optimize the intratumoral dose distribution for the individuals. The adaptive DPbN with FDG-PET/CT imaging feedback is feasible to implement in clinics., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Convergent evidence from multiple and independent genetics studies implicate a small number of genes that predispose individuals to multiple autoimmune disorders (AuD). These intersecting loci reinforced the hypothesis that disorders with overlapping etiology group into a cluster of closely related genes within a whole genome molecular interaction network. We tested the hypothesis that "biological network proximity" within a whole genome molecular interaction network can be used to inform the search for multigene inheritance. Using a set of nine previously published genome wide association studies (GWAS) of AuD genes, we generated AuD-specific molecular interaction networks to identify networks of associated genes. We show that all nine "seed genes" can be connected within a 35-member network via interactions with 26 connecting genes. We show that this network is more connected than expected by chance, and 13 of the connecting genes showed association with multiple AuD upon GWAS reanalysis. Furthermore, we report association of SNPs in five new genes (IL10RA, DGKA, GRB2, STAT5A, and NFATC2) which were not previously considered as AuD candidates, and show significant association in novel disease samples of Crohn's disease and systemic lupus erythematosus. Furthermore, we show that the connecting genes show no association in four non-AuD GWAS. Finally, we test the connecting genes in psoriasis GWAS, and show association to previously identified loci and report new loci. These findings support the hypothesis that molecular interaction networks can be used to inform the search for multigene disease etiology, especially for disorders with overlapping etiology., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Immune checkpoint inhibitors designed to revert tumor-induced immunosuppression have emerged as potent anticancer therapies. Tryptophan metabolism represents an immune checkpoint, and targeting this pathway's rate-limiting enzyme IDO1 is actively being investigated clinically. Here, we studied the intermediary metabolism of tryptophan metabolism in glioblastoma and evaluated the activity of the IDO1 inhibitor GDC-0919, both alone and in combination with radiation (RT). Experimental Design: LC/GC-MS and expression profiling was performed for metabolomic and genomic analyses of patient-derived glioma. Immunocompetent mice were injected orthotopically with genetically engineered murine glioma cells and treated with GDC-0919 alone or combined with RT. Flow cytometry was performed on isolated tumors to determine immune consequences of individual treatments. Results: Integrated cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant tryptophan metabolism as a metabolic node specific to the mesenchymal and classical subtypes of glioblastoma. GDC-0919 demonstrated potent inhibition of this node and effectively crossed the blood-brain barrier. Although GDC-0919 as a single agent did not demonstrate antitumor activity, it had a strong potential for enhancing RT response in glioblastoma, which was further augmented with a hypofractionated regimen. RT response in glioblastoma involves immune stimulation, reflected by increases in activated and cytotoxic T cells, which was balanced by immune checkpoint reactivation, reflected by an increase in IDO1 expression and regulatory T cells (Treg). GDC-0919 mitigated RT-induced Tregs and enhanced T-cell activation. Conclusions: Tryptophan metabolism represents a metabolic node in glioblastoma, and combining RT with IDO1 inhibition enhances therapeutic response by mitigating RT-induced immunosuppression. Clin Cancer Res; 24(15); 3632-43. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: To summarize important talking points from a 2016 symposium focusing on real-world challenges to advancing precision medicine in radiation oncology, and to help radiation oncologists navigate the practical challenges of precision, radiation oncology., Methods and Materials: The American Society for Radiation Oncology, American Association of Physicists in Medicine, and National Cancer Institute cosponsored a meeting on precision medicine in radiation oncology. In June 2016 numerous scientists, clinicians, and physicists convened at the National Institutes of Health to discuss challenges and future directions toward personalized radiation therapy. Various breakout sessions were held to discuss particular components and approaches to the implementation of personalized radiation oncology. This article summarizes the genomically guided radiation therapy breakout session., Results: A summary of existing genomic data enabling personalized radiation therapy, ongoing clinical trials, current challenges, and future directions was collected. The group attempted to provide both a current overview of data that radiation oncologists could use to personalize therapy, along with data that are anticipated in the coming years. It seems apparent from the provided review that a considerable opportunity exists to truly bring genomically guided radiation therapy into clinical reality., Conclusions: Genomically guided radiation therapy is a necessity that must be embraced in the coming years. Incorporating these data into treatment recommendations will provide radiation oncologists with a substantial opportunity to improve outcomes for numerous cancer patients. More research focused on this topic is needed to bring genomic signatures into routine standard of care., (Published by Elsevier Inc.)

Introduction: This study explores the hypothesis that dominant molecular oncogenes in non-small cell lung cancer (NSCLC) are associated with metastatic spread to the brain., Methods: NSCLC patient groups with no evidence of metastasis, with metastatic disease to a non-CNS site, who developed brain metastasis after diagnosis, and patients with simultaneous diagnosis of NSCLC and metastatic brain lesions were studied using targeted sequencing., Results: In patients with brain metastasis versus those without, only 2 variants (one each in BCL6 and NOTHC2) were identified that occurred in ≥ 4 NSCLC of patients with brain metastases but ≤ 1 of the NSCLC samples without brain metastases. At the gene level, 20 genes were found to have unique variants in more than 33% of the patients with brain metastases. When analyzed at the patient level, these 20 genes formed the basis of a predictive test to discriminate those with brain metastasis. Further analysis showed that PI3K/AKT signaling is altered in both the primary and metastases of NSCLC patients with brain lesions., Conclusion: While no single variant was associated with brain metastasis, this study describes a potential gene panel for the identification of patients at risk and implicates PI3K/AKT signaling as a therapeutic target., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Alzheimer's disease is rapidly becoming an endemic for people over the age of 65. A vital path towards reversing this ominous trend is the building of reliable diagnostic devices for definite and early diagnoses in lieu of the longitudinal, usually inconclusive and non-generalize-able methods currently in use. In this article, we present a survey of methods for mining pools of mass spectrometer saliva data in relation to diagnosing Alzheimer's disease. The computational methods provides new approaches for appropriately gleaning latent information from mass spectra data. They improve traditional machine learning algorithms and are most fit for handling matrix data points including solving problems beyond protein identifications and biomarker discovery.

The practice of radiation oncology is primarily based on precise technical delivery of highly conformal, image-guided external beam radiotherapy or brachytherapy. However, systematic research efforts are being made to facilitate individualised radiation dose prescriptions on the basis of gene-expressssion profiles that reflect the radiosensitivity of tumour and normal tissue. This advance in precision radiotherapy should complement those benefits made in precision cancer medicine that use molecularly targeted agents and immunotherapies. The personalisation of cancer therapy, predicated largely on genomic interrogation, is facilitating the selection of therapies that are directed against driver mutations, aberrant cell signalling, tumour microenvironments, and genetic susceptibilities. With the increasing technical power of radiotherapy to safely increase local tumour control for many solid tumours, it is an opportune time to rigorously explore the potential benefits of combining radiotherapy with molecular targeted agents and immunotherapies to increase cancer survival outcomes. This theme provides the basis and foundation for this American Society for Radiation Oncology guideline on combining radiotherapy with molecular targeting and immunotherapy agents., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background and Purpose: In this study we have combined fractionated radiation treatment (RT) with two molecular targeted agents active against key deregulated signaling pathways in head and neck cancer., Materials and Methods: We used two molecularly characterized, low passage HNSCC cell lines of differing biological characteristics to study the effects of binimetinib and buparlisib in combination with radiation in vitro and in vivo ., Results: Buparlisib was active against both cell lines in vitro whereas binimetinib was more toxic to UT-SCC-14. Neither agent modified radiation sensitivity in vitro . Buparlisib significantly inhibited growth of UT-SSC-15 alone or in combination with RT but was ineffective in UT-SCC-14. Binimetinib did cause a significant delay with RT in UT-SCC-14 and it significantly reduced growth of the UT-SCC-15 tumors both alone and with RT. The tri-modality treatment was not as effective as RT with a single effective agent., Conclusions: No significant benefit was gained by the combined use of the two agents with RT even though each was efficacious when used alone.