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At least 649 records · Page 36

Investigating the role of anhydrous oxidative weathering on sedimentary rocks in the Transantarctic Mountains and implications for the modern weathering of sedimentary lithologies on Mars

We present that alteration of the uppermost surfaces of geologic materials is a pervasive process on planetary surfaces that is dependent upon factors including parent composition and the environment under which alteration is occurring. While rapid and pervasive in hot and humid climates on Earth, chemical weathering of rock surfaces has also been found to dominate in some of Earth's coldest and driest landscapes as well. Specifically, surfaces dominated by resistant fine-grained igneous rocks in the Antarctic preserve evidence of oxidative weathering processes, which represent the initial immature surface alteration processes that stagnate due to the lack of available water and kinetics necessary for the production of more mature alteration phases. In this study, we test the hypothesis that oxidative weathering also dominates the surfaces of sedimentary rocks throughout the Antarctic. We investigated the chemistry and mineralogy of a suite of sedimentary rocks from the Transantarctic Mountains ranging from fine-grained tuffs to coarse-grained sandstones and conglomerates. Additionally, our results show that, like the previously studied fine-grained igneous rocks in the Antarctic, sedimentary rocks generally showed only minor chemical weathering signatures at their surfaces relative to their interiors. However, unlike the igneous rocks in this earlier study, the sedimentary rocks exhibited a wide variety of non-systematic differences between surface and interior compositions. This variability of surface weathering signatures is equally as complex as the physical properties and compositions inherently present within these different sedimentary lithologies. Based on these analyses, it is apparent that oxidative weathering products do not dominate the surfaces of sedimentary rocks throughout the Transantarctic Mountains, which instead exhibit a wide array of weathering signatures that are likely dependent on both lithological and environmental factors. Considering that sedimentary lithologies are widespread across a significant fraction of the martian surface, our results suggest that observed alteration signatures limited to the surfaces of martian sedimentary rocks are most likely to be minor and to vary as a result of the lithological properties of the specific rock unit and not as a result of the widespread influences of the modern cold and dry climatic conditions.

58 GEOSCIENCES↗

A Novel Peptide to Treat Oral Mucositis Blocks Endothelial and Epithelial Cell Apoptosis

Purpose: No effective agents currently exist to treat oral mucositis (OM) in patients receiving chemoradiation for the treatment of head-and-neck cancer. We identified a novel 21-amino acid peptide derived from antrum mucosal protein-18 that is cytoprotective, mitogenic, and motogenic in tissue culture and animal models of gastrointestinal epithelial cell injury. We examined whether administration of antrum mucosal protein peptide (AMP-p) could protect against and/or speed recovery from OM. Methods and Materials: OM was induced in established hamster models by a single dose of radiation, fractionated radiation, or fractionated radiation together with cisplatin to simulate conventional treatments of head-and-neck cancer. Results: Daily subcutaneous administration of AMP-p reduced the occurrence of ulceration and accelerated mucosal recovery in all three models. A delay in the onset of erythema after irradiation was observed, suggesting that a protective effect exists even before injury to mucosal epithelial cells occurs. To test this hypothesis, the effects of AMP-p on tumor necrosis factor-{alpha}-induced apoptosis were studied in an endothelial cell line (human dermal microvascular endothelial cells) as well as an epithelial cell line (human adult low-calcium, high-temperature keratinocytes; HaCaT) used to model the oral mucosa. AMP-p treatment, either before or after cell monolayers were exposed to tumor necrosis factor-{alpha}, protected against development of apoptosis in both cell types when assessed by annexin V and propidium iodide staining followed by flow cytometry or ligase-mediated polymerase chain reaction. Conclusions: These observations suggest that the ability of AMP-p to attenuate radiation-induced OM could be attributable, at least in part, to its antiapoptotic activity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Toxicities Affecting Quality of Life After Chemo-IMRT of Oropharyngeal Cancer: Prospective Study of Patient-Reported, Observer-Rated, and Objective Outcomes

Purpose: To test the hypothesis that intensity modulated radiation therapy (IMRT) aiming to spare the salivary glands and swallowing structures would reduce or eliminate the effects of xerostomia and dysphagia on quality of life (QOL). Methods and Materials: In this prospective, longitudinal study, 72 patients with stage III-IV oropharyngeal cancer were treated uniformly with definitive chemo-IMRT sparing the salivary glands and swallowing structures. Overall QOL was assessed by summary scores of the Head Neck QOL (HNQOL) and University of Washington QOL (UWQOL) questionnaires, as well as the HNQOL “Overall Bother” question. Quality of life, observer-rated toxicities (Common Toxicity Criteria Adverse Effects scale, version 2), and objective evaluations (videofluoroscopy assessing dysphagia and saliva flow rates assessing xerostomia) were recorded from before therapy through 2 years after therapy. Correlations between toxicities/objective evaluations and overall QOL were assessed using longitudinal repeated measures of analysis and Pearson correlations. Results: All observer-rated toxicities and QOL scores worsened 1-3 months after therapy and improved through 12 months, with minor further improvements through 24 months. At 12 months, dysphagia grades 0-1, 2, and 3, were observed in 95%, 4%, and 1% of patients, respectively. Using all posttherapy observations, observer-rated dysphagia was highly correlated with all overall QOL measures (P<.0001), whereas xerostomia and mucosal and voice toxicities were significantly correlated with some, but not all, overall QOL measures, with lower correlation coefficients than dysphagia. Late overall QOL (≥6 or ≥12 months after therapy) was primarily associated with observer-rated dysphagia, and to a lesser extent with xerostomia. Videofluoroscopy scores, but not salivary flows, were significantly correlated with some of the overall QOL measures. Conclusion: After chemo-IMRT, although late dysphagia was on average mild, it was still the major correlate of QOL. Further efforts to reduce swallowing dysfunction are likely to yield additional gains in QOL.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Targeting Nucleophosmin 1 Represents a Rational Strategy for Radiation Sensitization

Purpose: To test the hypothesis that small molecule targeting of nucleophosmin 1 (NPM1) represents a rational approach for radiosensitization. Methods and Materials: Wilde-type and NPM1-deficient mouse embryo fibroblasts (MEFs) were used to determine whether radiosensitization produced by the small molecule YTR107 was NPM1 dependent. The stress response to ionizing radiation was assessed by quantifying pNPM1, γH2AX, and Rad51 foci, neutral comet tail moment, and colony formation. NPM1 levels in a human-derived non-small-cell lung cancer (NSCLC) tissue microarray (TMA) were determined by immunohistochemistry. YTR107-mediated radiosensitization was assessed in NSCLC cell lines and xenografts. Results: Use of NPM1-null MEFs demonstrated that NPM1 is critical for DNA double- strand break (DSB) repair, that loss of NPM1 increases radiation sensitivity, and that YTR107-mediated radiosensitization is NPM1 dependent. YTR107 was shown to inhibit NPM1 oligomerization and impair formation of pNPM1 irradiation-induced foci that colocalized with γH2AX foci. Analysis of the TMA demonstrated that NPM1 is overexpressed in subsets of NSCLC. YTR107 inhibited DNA DSB repair and radiosensitized NSCLC lines and xenografts. Conclusions: These data demonstrate that YTR107-mediated targeting of NPM1 impairs DNA DSB repair, an event that increases radiation sensitivity.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Genomic Prostate Cancer Classifier Predicts Biochemical Failure and Metastases in Patients After Postoperative Radiation Therapy

Purpose: To test the hypothesis that a genomic classifier (GC) would predict biochemical failure (BF) and distant metastasis (DM) in men receiving radiation therapy (RT) after radical prostatectomy (RP). Methods and Materials: Among patients who underwent post-RP RT, 139 were identified for pT3 or positive margin, who did not receive neoadjuvant hormones and had paraffin-embedded specimens. Ribonucleic acid was extracted from the highest Gleason grade focus and applied to a high-density-oligonucleotide microarray. Receiver operating characteristic, calibration, cumulative incidence, and Cox regression analyses were performed to assess GC performance for predicting BF and DM after post-RP RT in comparison with clinical nomograms. Results: The area under the receiver operating characteristic curve of the Stephenson model was 0.70 for both BF and DM, with addition of GC significantly improving area under the receiver operating characteristic curve to 0.78 and 0.80, respectively. Stratified by GC risk groups, 8-year cumulative incidence was 21%, 48%, and 81% for BF (P<.0001) and for DM was 0, 12%, and 17% (P=.032) for low, intermediate, and high GC, respectively. In multivariable analysis, patients with high GC had a hazard ratio of 8.1 and 14.3 for BF and DM. In patients with intermediate or high GC, those irradiated with undetectable prostate-specific antigen (PSA ≤0.2 ng/mL) had median BF survival of >8 years, compared with <4 years for patients with detectable PSA (>0.2 ng/mL) before initiation of RT. At 8 years, the DM cumulative incidence for patients with high GC and RT with undetectable PSA was 3%, compared with 23% with detectable PSA (P=.03). No outcome differences were observed for low GC between the treatment groups. Conclusion: The GC predicted BF and metastasis after post-RP irradiation. Patients with lower GC risk may benefit from delayed RT, as opposed to those with higher GC; however, this needs prospective validation. Genomic-based models may be useful for improved decision-making for treatment of high-risk prostate cancer.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Grade Inflation in Medical Student Radiation Oncology Clerkships: Missed Opportunities for Feedback?

Purpose: To test the hypothesis that medical student radiation oncology elective rotation grades are inflated and cannot be used to distinguish residency applicants. Methods and Materials: The records of 196 applicants to a single radiation oncology residency program in 2011 and 2012 were retrospectively reviewed. The grades for each rotation in radiation oncology were collected and converted to a standardized 4-point grading scale (honors, high pass, pass, fail). Pass/fail grades were scored as not applicable. The primary study endpoint was to compare the distribution of applicants' grades in radiation oncology with their grades in medicine, surgery, pediatrics, and obstetrics/gynecology core clerkships. Results: The mean United States Medical Licensing Examination Step 1 score of the applicants was 237 (range, 188-269), 43% had additional Masters or PhD degrees, and 74% had at least 1 publication. Twenty-nine applicants were graded for radiation oncology rotations on a pass/fail basis and were excluded from the final analysis. Of the remaining applicants (n=167), 80% received the highest possible grade for their radiation oncology rotations. Grades in radiation oncology were significantly higher than each of the other 4 clerkships studied (P<.001). Of all applicants, 195 of 196 matched into a radiation oncology residency. Higher grades in radiation oncology were associated with significantly higher grades in the pediatrics core clerkship (P=.002). However, other medical school performance metrics were not significantly associated with higher grades in radiation oncology. Conclusions: Although our study group consists of a selected group of radiation oncology applicants, their grades in radiation oncology clerkships were highly skewed toward the highest grades when compared with grades in other core clerkships. Student grading in radiation oncology clerkships should be re-evaluated to incorporate more objective and detailed performance metrics to allow for meaningful feedback to trainees and to better evaluate residency applicants to radiation oncology.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902

Purpose: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). Methods and Materials: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥7 or clinical stage ≥T2 and GS ≥8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT. AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. Results: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). Conclusions: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Radiation-Induced Dedifferentiation of Head and Neck Cancer Cells Into Cancer Stem Cells Depends on Human Papillomavirus Status

Purpose: To test the hypothesis that the radiation response of cancer stem cells (CSCs) in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) differs and is not reflected in the radiation response of the bulk tumor populations, that radiation therapy (RT) can dedifferentiate non-stem HNSCC cells into CSCs, and that radiation-induced dedifferentiation depends on the HPV status. Methods and Materials: Records of a cohort of 162 HNSCC patients were reviewed, and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for CSCs, we characterized HPV-positive and HPV-negative lines via flow cytometry, sphere-forming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation, and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and quantitative reverse transcription–polymerase chain reaction for re-expression of reprogramming factors. Results: Patients with HPV-positive tumors have superior overall survival and local–regional control. Human papillomavirus–positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. Human papillomavirus–negative HNSCC cell lines lack hierarchy owing to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared with HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors. Conclusions: Supporting the favorable prognosis of HPV-positive HNSCCs, we show that (1) HPV-positive HNSCCs have a lower frequency of CSCs; (2) RT can dedifferentiate HNSCC cells into CSCs; and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Prospective Validation of a High Dimensional Shape Model for Organ Motion in Intact Cervical Cancer

Purpose: Validated models are needed to justify strategies to define planning target volumes (PTVs) for intact cervical cancer used in clinical practice. Our objective was to independently validate a previously published shape model, using data collected prospectively from clinical trials. Methods and Materials: We analyzed 42 patients with intact cervical cancer treated with daily fractionated pelvic intensity modulated radiation therapy and concurrent chemotherapy in one of 2 prospective clinical trials. We collected online cone beam computed tomography (CBCT) scans before each fraction. Clinical target volume (CTV) structures from the planning computed tomography scan were cast onto each CBCT scan after rigid registration and manually redrawn to account for organ motion and deformation. We applied the 95% isodose cloud from the planning computed tomography scan to each CBCT scan and computed any CTV outside the 95% isodose cloud. The primary aim was to determine the proportion of CTVs that were encompassed within the 95% isodose volume. A 1-sample t test was used to test the hypothesis that the probability of complete coverage was different from 95%. We used mixed-effects logistic regression to assess effects of time and patient variability. Results: The 95% isodose line completely encompassed 92.3% of all CTVs (95% confidence interval, 88.3%-96.4%), not significantly different from the 95% probability anticipated a priori (P=.19). The overall proportion of missed CTVs was small: the grand mean of covered CTVs was 99.9%, and 95.2% of misses were located in the anterior body of the uterus. Time did not affect coverage probability (P=.71). Conclusions: With the clinical implementation of a previously proposed PTV definition strategy based on a shape model for intact cervical cancer, the probability of CTV coverage was high and the volume of CTV missed was low. This PTV expansion strategy is acceptable for clinical trials and practice; however, we recommend daily image guidance to avoid systematic large misses in select patients.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Quantitative Evaluation of Head and Neck Cancer Treatment–Related Dysphagia in the Development of a Personalized Treatment Deintensification Paradigm

To test the hypothesis that quantifying swallow function with multiple patient-reported outcome (PRO) instruments is an important strategy to yield insights in the development of personalized deintensified therapies seeking to reduce the risk of head and neck cancer (HNC) treatment–related dysphagia (HNCTD).

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Using Auto-Segmentation to Reduce Contouring and Dose Inconsistency in Clinical Trials: The Simulated Impact on RTOG 0617

Contouring inconsistencies are known but understudied in clinical radiation therapy trials. We applied auto-contouring to the Radiation Therapy Oncology Group (RTOG) 0617 dose escalation trial data. We hypothesized that the trial heart doses were higher than reported due to inconsistent and insufficient heart segmentation. We tested our hypothesis by comparing doses between deep-learning (DL) segmented hearts and trial hearts.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Mithramycin A Radiosensitizes EWS:Fli1+ Ewing Sarcoma Cells by Inhibiting Double Strand Break Repair

The oncogenic EWS:Fli1 fusion protein is a key transcriptional mediator of Ewing sarcoma initiation, progression, and therapeutic resistance. Mithramycin A (MithA) is a potent and specific inhibitor of transcription mediated by the EWS:Fli1. We tested the hypothesis that pretreatment with MithA could selectively radiosensitize EWS:Fli1{sup +} tumor cells by altering the transcriptional response to radiation injury.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

The Importance of Radiation Dose to the Atherosclerotic Plaque in the Left Anterior Descending Coronary Artery for Radiation-Induced Cardiac Toxicity of Breast Cancer Patients?

Radiation-induced acute coronary events (ACEs) may occur as a treatment-related late adverse effect of breast cancer (BC) radiation. However, the underlying mechanisms behind this radiation-induced cardiac disease remain to be determined. The objective of this study was to test the hypothesis that radiation dose to calcified atherosclerotic plaques in the left anterior descending coronary artery (LAD) is a better predictor for ACEs than radiation dose to the whole heart or left ventricle in patients with BC treated with radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Effects of Single-Dose Versus Hypofractionated Focused Radiation on Vertebral Body Structure and Biomechanical Integrity: Development of a Rabbit Radiation-Induced Vertebral Compression Fracture Model

Vertebral compression fracture is a common complication of spinal stereotactic body radiation therapy. Development of an in vivo model is crucial to fully understand how focal radiation treatment affects vertebral integrity and biology at various dose fractionation regimens. We present a clinically relevant animal model to analyze the effects of localized, high-dose radiation on vertebral microstructure and mechanical integrity. Using this model, we test the hypothesis that fractionation of radiation dosing can reduce focused radiation therapy's harmful effects on the spine.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Parotid Gland Stem Cell Sparing Radiation Therapy for Patients With Head and Neck Cancer: A Double-Blind Randomized Controlled Trial

Radiation therapy for head and neck cancer frequently leads to salivary gland damage and subsequent xerostomia. The radiation response of the parotid glands of rats, mice, and patients critically depends on dose to parotid gland stem cells, mainly located in the gland's main ducts (stem cell rich [SCR] region). Therefore, this double-blind randomized controlled trial aimed to test the hypothesis that parotid gland stem cell sparing radiation therapy preserves parotid gland function better than currently used whole parotid gland sparing radiation therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

A fusion of the Bacteroides fragilis ferrous iron import proteins reveals a role for FeoA in stabilizing GTP-bound FeoB

Iron is an essential element for nearly all organisms, and under anoxic and/or reducing conditions, Fe 2+ is the dominant form of iron available to bacteria. The ferrous iron transport (Feo) system is the primary prokaryotic Fe 2+ import machinery, and two constituent proteins (FeoA and FeoB) are conserved across most bacterial species. However, how FeoA and FeoB function relative to one another remains enigmatic. In this work, we explored the distribution of feoAB operons encoding a fusion of FeoA tethered to the N-terminal, G-protein domain of FeoB via a connecting linker region. We hypothesized that this fusion poises FeoA to interact with FeoB to affect function. To test this hypothesis, we characterized the soluble NFeoAB fusion protein from Bacteroides fragilis, a commensal organism implicated in drug-resistant infections. Using X-ray crystallography, we determined the 1.50-Å resolution structure of BfFeoA, which adopts an SH3-like fold implicated in protein–protein interactions. Using a combination of structural modeling, small-angle X-ray scattering, and hydrogen–deuterium exchange mass spectrometry, we show that FeoA and NFeoB interact in a nucleotide-dependent manner, and we mapped the protein–protein interaction interface. Finally, using guanosine triphosphate (GTP) hydrolysis assays, we demonstrate that BfNFeoAB exhibits one of the slowest known rates of Feo-mediated GTP hydrolysis that is not potassium-stimulated. Importantly, truncation of FeoA from this fusion demonstrates that FeoA–NFeoB interactions function to stabilize the GTP-bound form of FeoB. Taken together, our work reveals a role for FeoA function in the fused FeoAB system and suggests a function for FeoA among prokaryotes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Environmental fate of radiocesium in biota inhabiting a contaminated ecosystem on the U.S. Department of Energy's Savannah River Site

Although biomagnification of radiocesium ( 137 Cs) has been reported in food webs, most previous research has been limited to select trophic linkages. Few studies have included a comprehensive survey of fauna associated with aquatic, semi-aquatic, and terrestrial habitats within a single study framework. The objectives of this study were to advance our understanding of the dynamics of 137 Cs accumulation within food webs by quantifying 137 Cs activity across a wide range of biota found within a contaminated canal, as well as test the hypothesis that life-stage and body size influence 137 Cs bioaccumulation in select herpetofauna. With extensive sampling across multiple taxa collected from a contaminated canal system and associated floodplain on the Savannah River Site, we assessed 137 Cs activity and stable nitrogen isotopes for both aquatic organisms that were restricted to the contaminated effluent canal, and semi-aquatic organisms able to move freely between the contaminated canal and the adjacent uncontaminated terrestrial habitat. We found 137 Cs activity to be highly variable among species, with evidence for and against biomagnification in semi-aquatic and aquatic organisms, respectively. Furthermore, 137 Cs activity decreased with life stage and body size in bullfrogs (Lithobates catesbeianus), despite post-metamorphic bullfrogs having a more carnivorous diet compared to tadpoles, while cottonmouths (Agkistrodon piscivorus) retained similar 137 Cs activity regardless of their age and size. While evidence of biomagnification has been observed in some contaminated systems, results of our study suggest the extent to which 137 Cs biomagnifies within food webs is context-dependent and likely influenced by a suite of biotic and abiotic factors. Further, our data indicate sampling of a broad suite of species and environmental attributes are needed to elucidate the fate and dynamics of anthropogenic pollutants within contaminated ecosystems.

54 ENVIRONMENTAL SCIENCES↗