Radiation Medicine Commons^™

Verrucous Carcinoma Of The Vulva: Patterns Of Care And Treatment Outcomes., Sara M. Dryden, Leonid B. Reshko, Jeremy T. Gaskins, Scott R. Silva

Faculty and Staff Scholarship

Background: Verrucous vulvar carcinoma (VC) is an uncommon and distinct histologic subtype of squamous cell carcinoma (SCC). The available literature on VC is currently limited to case reports and small single institution studies. Aims: The goals of this study were to analyze data from the National Cancer Database (NCDB) to quantitate the incidence of VC and to investigate the effects of patient demographics, tumor characteristics, and treatment regimens on overall survival (OS) in women with verrucous vulvar carcinoma. Methods and results: Patients diagnosed with vulvar SCC or VC between the years of 2004 and 2016 were identified in the NCDB. …

Improved Radiation Expression Profiling In Blood By Sequential Application Of Sensitive And Specific Gene Signatures, Eliseos J. Mucaki, Ben C. Shirley, Peter K. Rogan

Biochemistry Publications

Purpose. Combinations of expressed genes can discriminate radiation-exposed from normal control blood samples by machine learning based signatures (with 8 to 20% misclassification rates). These signatures can quantify therapeutically-relevant as well as accidental radiation exposures. The prodromal symptoms of Acute Radiation Syndrome (ARS) overlap those present in Influenza and Dengue Fever infections. Surprisingly, these human radiation signatures misclassified gene expression profiles of virally infected samples as false positive exposures. The present study investigates these and other confounders, and then mitigates their impact on signature accuracy.

Methods. This study investigated recall by previous and novel radiation signatures independently derived …

Flash Radiotherapy: Skin Pigmentation As A Non-Invasive Indicator For Radiation-Induced Damage, Brady Mccallister

ENGS 88 Honors Thesis (AB Students)

FLASH ultra-high dose rate radiotherapy (RT) is one of the most rapidly growing subfields of radiation oncology today due to its potential to increase the limits of the therapeutic ratio. The FLASH effect, which includes heightened normal tissue sparing paired with iso-effective tumor cell killing, has been literature documented, in a limited manner, in rodent models, a few large animals, and one clinical patients.

A porcine-based experiment was conducted to test the effects of FLASH RT on normal tissue compared to conventional (CONV) RT. A clinical linear accelerator (LINAC) was reversibly converted to be capable of FLASH RT. A female …

Development And Clinical Validation Of Knowledge-Based Planning Models For Stereotactic Body Radiotherapy Of Early-Stage Non-Small-Cell Lung Cancer Patients, Justin David Visak

Theses and Dissertations--Radiation Medicine

Lung stereotactic body radiotherapy (SBRT) is a viable alternative to surgical intervention for the treatment of early-stage non-small-cell lung cancer (NSCLC) patients. This therapy achieves strong local control rates by delivering ultra-high, conformal radioablative doses in typically one to five fractions. Historically, lung SBRT plans are manually generated using 3D conformal radiation therapy, dynamic conformal arcs (DCA), intensity-modulated radiation therapy, and more recently via volumetric modulated arc therapy (VMAT) on a C-arm linear accelerator (linac). Manually planned VMAT is an advanced technique to deliver high-quality lung SBRT due to its dosimetric capabilities and utilization of flattening-filter free beams to improve …

Let-Dependent Low Dose And Synergistic Inhibition Of Human Angiogenesis By Charged Particles: Validation Of Mirnas That Drive Inhibition, Amber M. Paul, Yen-Ruh Wuu, Burong Hu, Hazeem Okunola, Elizabeth A. Blaber, Margareth Cheng-Campbell, Afshin Beheshti, Peter Grabham

Publications

Space radiation inhibits angiogenesis by two mechanisms depending on the linear energy transfer (LET). Using human 3D micro-vessel models, blockage of the early motile stage of angiogenesis was determined to occur after exposure to low LET ions (/AMU), whereas inhibition of the later stages occurs after exposure to high LET ions (>8 KeV/AMU). Strikingly, the combined effect is synergistic, detectible as low as 0.06 Gy making mixed ion space radiation more potent. Candidates for bystander transmission are microRNAs (miRNAs), and analysis on miRNA-seq data from irradiated mice shows that angiogenesis would in theory be downregulated. Further analysis of three …

Develop A High-Throughput Screening Method To Identify C-P4h1 (Collagen Prolyl 4-Hydroxylase 1) Inhibitors From Fda-Approved Chemicals, Shike Wang, Kuo-Hao Lee, Nathália Victoria Araujo, Chang-Guo Zhan, Vivek M. Rangnekar, Ren Xu

Pharmaceutical Sciences Faculty Publications

Collagen prolyl 4-hydroxylase 1 (C-P4H1) is an α-ketoglutarate (α-KG)-dependent dioxygenase that catalyzes 4-hydroxylation of proline on collagen. C-P4H1-induced prolyl hydroxylation is required for proper collagen deposition and cancer metastasis. Therefore, targeting C-P4H1 is considered a potential therapeutic strategy for collagen-related cancer progression and metastasis. However, no C-P4H1 inhibitors are available for clinical testing, and the high content assay is currently not available for C-P4H1 inhibitor screening. In the present study, we developed a high-throughput screening assay by quantifying succinate, a byproduct of C-P4H-catalyzed hydroxylation. C-P4H1 is the major isoform of collagen prolyl 4-hydroxylases (CP4Hs) that contributes the majority prolyl 4-hydroxylase …

Estimating Partial Body Ionizing Radiation Exposure By Automated Cytogenetic Biodosimetry, Peter Rogan

Biochemistry Publications

Purpose: Inhomogeneous exposures to ionizing radiation can be detected and quantified with the Dicentric Chromosome Assay (DCA) of metaphase cells. Complete automation of interpretation of the DCA for whole body irradiation has significantly improved throughput without compromising accuracy, however low levels of residual false positive dicentric chromosomes (DCs) have confounded its application for partial body exposure determination.

Materials and Methods: We describe a method of estimating and correcting for false positive DCs in digitally processed images of metaphase cells. Nearly all DCs detected in unirradiated calibration samples are introduced by digital image processing. DC frequencies of irradiated calibration …

The Effects Of Total Body Proton Irradiation On Mouse Myometrium, Lillith Bulawa

Undergraduate Honors Theses

The boundaries of human space exploration continue to expand with new technology and discoveries making it even more important to investigate the effects of space on biological systems. Although humans have explored space in small increments, reproductive studies must be conducted to determine if stable short- or long-term residences for humans can exist in space. This study explored the effects of whole-body proton radiation on uterine smooth muscle known as the myometrium. Two types of mice utilized in this study were C57BL/6 and B6.129S6Cybbtm1Din/J NOX2 knockout mice. C57BL/6 mice are standard laboratory mice that were used to represent the wildtype …

Meeting Radiation Dosimetry Capacity Requirements Of Population-Scale Exposures By Geostatistical Sampling., Peter K Rogan, Eliseos J Mucaki, Ruipeng Lu, Ben C Shirley, Edward Waller, Joan H M Knoll

Biochemistry Publications

BACKGROUND: Accurate radiation dose estimates are critical for determining eligibility for therapies by timely triaging of exposed individuals after large-scale radiation events. However, the universal assessment of a large population subjected to a nuclear spill incident or detonation is not feasible. Even with high-throughput dosimetry analysis, test volumes far exceed the capacities of first responders to measure radiation exposures directly, or to acquire and process samples for follow-on biodosimetry testing.

AIM: To significantly reduce data acquisition and processing requirements for triaging of treatment-eligible exposures in population-scale radiation incidents.

METHODS: Physical radiation plumes modelled nuclear detonation scenarios of simulated exposures at …

Evidence Of Y Chromosome Long Non-Coding Rnas Involved In The Radiation Response Of Male Non-Small Cell Lung Cancer Cells, Tayvia Brownmiller

Graduate Theses, Dissertations, and Problem Reports (ETD)

Non-small cell lung cancer (NSCLC) is the number one cause of cancer related mortality in the United States and worldwide. Advanced and therapeutically resistant lung tumors contribute to the high rate of mortality from NSCLC, therefore there is a need for new methods of diagnosing and treating this disease. Long non-coding RNAs (lncRNAs) have been shown to be a crucial component of human molecular biology, regulating nearly every cellular pathway from chromatin condensation to transcription and translation. Furthermore, many lncRNAs have been classified as oncogenes or tumor suppressors, highlighting the various molecular mechanisms they are involved in regarding the formation …

Mice Exposed To Combined Chronic Low-Dose Irradiation And Modeled Microgravity Develop Long-Term Neurological Sequelae, Amber M. Paul, Eliah G. Overbey, William A. Da Silveira, Candice G.T. Tahimic, Sigrid S. Reinsch, Nathaniel Szewczyk, Seta Stanbouly, Charles Wang, Jonathan M. Galazka, Xiao Wen Mao

Publications

Spaceflight poses many challenges for humans. Ground-based analogs typically focus on single parameters of spaceflight and their associated acute effects. This study assesses the long-term transcriptional effects following single and combination spaceflight analog conditions using the mouse model: simulated microgravity via hindlimb unloading (HLU) and/or low-dose γ-ray irradiation (LDR) for 21 days, followed by 4 months of readaptation. Changes in gene expression and epigenetic modifications in brain samples during readaptation were analyzed by whole transcriptome shotgun sequencing (RNA-seq) and reduced representation bisulfite sequencing (RRBS). The results showed minimal gene expression and cytosine methylation alterations at 4 months readaptation within single …

Meta-Analysis Of Cognitive Performance By Novel Object Recognition After Proton And Heavy Ion Exposures, Eliedonna Cacao, Francis A. Cucinotta

Health Physics and Diagnostic Sciences Faculty Research

Experimental studies of cognitive detriments in mice and rats after proton and heavy ion exposures have been performed by several laboratories to investigate possible risks to astronauts exposed to cosmic rays in space travel and patients treated for brain cancers with proton and carbon beams in Hadron therapy. However, distinct radiation types and doses, cognitive tests and rodent models have been used by different laboratories, while few studies have considered detailed dose-response characterizations, including estimates of relative biological effectiveness (RBE). Here we report on the first quantitative meta-analysis of the dose response for proton and heavy ion rodent studies of …

Fasting Reduces Intestinal Radiotoxicity Enabling Dose-Escalated Radiotherapy For Pancreatic Cancer, Marimar De La Cruz Bonilla

Dissertations and Theses (Open Access)

Surgical resection is the only potentially curative treatment for pancreatic cancer, but only 15-20% of patients have resectable tumors. In unresectable cases, stereotactic body radiotherapy (SBRT) may be used to give tumor-directed radiotherapy (RT). Unfortunately, this can cause severe gastrointestinal (GI) toxicity due to proximity of the pancreatic head to the duodenum. Protecting the intestine from the toxic side-effects of radiation may enable dose-escalation that could achieve more effective local control of disease. We and others have previously shown that a fast of 24 hours protects mice from lethal doses of the DNA-damaging agent etoposide. In this study, we demonstrate …

Radiation Dose Estimation By Completely Automated Interpretation Of The Dicentric Chromosome Assay, Peter Rogan, Yanxin Li, Ben Shirley, Ruth Wilkins, Farrah Norton, Joan Knoll

Biochemistry Publications

Accuracy of the automated dicentric chromosome (DC) assay relies on metaphase image selection. This study validates a software framework to find the best image selection models that mitigate inter-sample variability. Evaluation methods to determine model quality include the Poisson goodness-of-fit of DC distributions for each sample, residuals after calibration curve fitting and leave-one-out dose estimation errors. The process iteratively searches a pool of selection model candidates by modifying statistical and filter cut-offs to rank the best candidates according to their respective evaluation scores. Evaluation scores minimize the sum of squared errors relative to the actual radiation dose of the calibration …

Mnte-2-Pyp And Radiation In A Prostate Cancer Model: Implications For Radiotherapy, Adeola Y. Makinde

Loma Linda University Electronic Theses, Dissertations & Projects

A major limitation of successful radiation therapy in cancer treatment is the increase in normal tissue damage as higher doses are used to achieve greater tumor destruction. Radiation dose optimization in cancer therapy requires achieving maximum tumor destruction with minimal damage to normal tissue Antioxidants have been shown to protect normal tissues against radiation damage, as radiation-induced tissue damage results predominantly from reactive oxygen species that directly damage cellular components. However, for effective use as normal tissue radioprotectants in radiotherapy, these antioxidants must not protect the tumors. Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP) is a metalloporphyrin antioxidant that has been …

Mechanisms Of T Helper Cell Modulation In A Simulated Space Radiation Environment, Asma Rizvi

Loma Linda University Electronic Theses, Dissertations & Projects

Exposure to solar particle events (SPEs) poses the most serious threat to astronaut health. Due to this radiation environment, exploration of the solar system beyond Earth’s orbit entails many risks for the crew on these deep space missions. Depression or dysfunction of the immune system is a major concern due to its high radio-sensitivity; potential consequences include overwhelming infection, development of cancer, fibrosis, and poor wound healing. Astronauts are also exposed to low dose/low dose rate (LDR) radiation. A three month stay at the international space station exposes them to ~ 0.05 Gy of radiation.

C57BL/6 mice received LDR gamma-radiation …

Radiation-Induced Glutamate Transport Alterations In Neuron-Astrocyte Coupling, Martha Celia Sanchez

Loma Linda University Electronic Theses, Dissertations & Projects

Exposure of the central nervous system (CNS) to ionizing radiation is known to result in behavioral, cognitive, and motor deficits - effects similar to those seen in many neurodegenerative disorders. Neurons and astrocytes, two principal cell types in the brain, coexist as an interdependent metabolic unit via the neurotransmitter glutamate. Disruption of this metabolic coupling would have widespread effects within the CNS, therefore it is hypothesized that ionizing radiation impairs glutamate transport and metabolism, and increases oxidative stress, ultimately impairing neuron-astrocyte coupling. We propose to investigate the mechanism and determine the impetus for radiation-induced neurotoxicity by measuring the temporal sequence …

Radiation-Induced Increases In Pkc Modulate Integrin Expression And Contribute To Fibrotic Changes, Pinal Rushikesh Pandya

Loma Linda University Electronic Theses, Dissertations & Projects

The sequences of events in fibrosis are similar to those in wound healing; however, the normal termination and resolution stages do not take place. The initial cellular response following ionizing radiation involves accumulation of the ECM (extracellular matrix) including collagen, fibronectin and the interaction of many growth factors (cytokines) with their receptors. There are a number of unanswered questions regarding many aspects of radiation-induced fibrosis, including the initial triggers and physical changes that initiate the process. We have confirmed that elevated pKC and other cellular changes following radiation are similar to those found at sites of inflammation. This information leads …

Treponema Denticola In Disseminating Endodontic Infections, F. Foschi, Jacques Izard, H. Sasaki, V. Sambri, C. Prati, R. Müller, P. Stashenko

Department of Food Science and Technology: Faculty Publications

Treponema denticola is a consensus periodontal pathogen that has recently been associated with endodontic pathology. In this study, the effect of mono-infection of the dental pulp with T. denticola and with polymicrobial “red-complex” organisms (RC) (Porphyromonas gingivalis, Tannerella forsythia, and T. denticola) in inducing disseminating infections in wild-type (WT) and severe-combined-immunodeficiency (SCID) mice was analyzed. After 21 days, a high incidence (5/10) of orofacial abscesses was observed in SCID mice mono-infected with T. denticola, whereas abscesses were rare in SCID mice infected with the red-complex organisms or in wild-type mice. Splenomegaly was …

Simulations Of Nanopore Formation And Phosphatidylserine Externalization In Lipid Membranes Subjected To A High-Intensity, Ultrashort Electric Pulse, Q. Hu, R. P. Joshi, K. H. Schoenbach

Bioelectrics Publications

A combined MD simulator and time dependent Laplace solver are used to analyze the electrically driven phosphatidylserine externalization process in cells. Time dependent details of nanopore formation at cell membranes in response to a high-intensity (100kV∕cm), ultrashort (10ns) electric pulse are also probed. Our results show that nanosized pores could typically be formed within about 5ns. These predictions are in very good agreement with recent experimental data. It is also demonstrated that defect formation and PS externalization in membranes should begin on the anode side. Finally, the simulations confirm that PS externalization is a nanopore facilitated event, rather than the …

Radiation Effects On Dopamine-Mediated Prepulse Inhibition In The C57bl/6 Mouse, Cara Nicole Zuccarelli Miller

Loma Linda University Electronic Theses, Dissertations & Projects

This study examined the effects of proton and gamma radiation on a dopamine-dependent sensory gating mechanism: prepulse inhibition of the startle reflex. The purpose of this research was to describe potential hazards of proton radiation to the central nervous system in long-term space fight and for proton therapy patients. Results from previous research indicate that startle behavior is modified by proton and iron radiation. Forty-eight 10-½ week old, male C57BL/6 mice were used to characterize the optimal parameters for the model (prepulse duration, probe duration, and stimulus-onset-asynchrony). Three hundred and fifty two mice were used to characterize the time course …

Effects Of Liposome-Encapsulated Tnf-Alpha And Radiation Against Colon Cancer, Dong Won Kim

Loma Linda University Electronic Theses, Dissertations & Projects

Previous studies have shown that tumor necrosis factor-α (TNF-α) can augment the antitumor effects of radiation, inhibiting tumor progression to a greater extent than either modality alone. However, nonspecific toxicities associated with TNF-α have limited its use as an adjuvant. This limitation is potentially resolved with the encapsulation of TNF-α in sterically stabilized, PEGylated liposomes (STEALTH®). Thus, the overall hypothesis of the research was that the combination of radiation with STEALTH® liposome encapsulated TNF-α (SL-TNF-α) will have greater efficacy and fewer dose-limiting side effects in the LS174T human colorectal tumor xenograft model compared to the combination of free TNF-α and …

Connexin-32 Contributes To Radiation Resistance In Thyroid Follicles, Da-Thao Dinh Tran

Loma Linda University Electronic Theses, Dissertations & Projects

The objective of this study was to examine the role of gap junctions in the radiation resistance of thyroid follicles. The question of whether gap junctional intercellular communication plays an important role in the “contact effect”, wherein cells in direct apposition are more resistant to the damaging effects of radiation, has been debated for years. We used the Fischer rat thyroid cell line (FRTL-5) to carry out our experiments. This thesis is divided into two parts: 1) characterization of gap junctional properties in FRTL-5 cells and, 2) exposure of these cells to radiation.

We found that, unlike primary thyroid cells, …

Detection And Modeling Of Radiation Induced Effects In Tissues By Dielectric Spectroscopy, Dorin A. Todor

Physics Theses & Dissertations

The work presented here is applied physics research in the field of radiation treatment. We address the development of a new and innovative method, in vivo and possibly non-invasive, for tumor and healthy tissues control during and after the radiation treatment. The radiation treatment is delivered in an almost standardized manner for particular classes of tumors. The large variance in the individual radio sensitivity of healthy tissues and tumors often leads to local recurrence of neoplastic growth and/or distant metastatic disease which often remains untreated. The method is based on the measurement and analysis of electrical impedance data in …

A Preclinical Model Of Ionizing Radiation And Tnf-Alpha Gene Therapy For Cancer, Jun Li

Loma Linda University Electronic Theses, Dissertations & Projects

Long term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. This study sought to determine if pretreatment with plasmid DNA expressing Tumor Necrosis Factor-α (TNF-α) could enhance the effect of ionizing radiation in an aggressive, rapidly growing glioma tumor (C6) model. Plasmid DNA is an attractive vector system for delivery of foreign genes into eukaryotic cells due to its advantages including low immunogenicity in vivo, lesser toxicity and relatively low cost. We have constructed a plasmid-based mammalian expression vector (pGL1-TNF) to secrete human TNF-α from cancer cells. Plasmid DNA was successfully transfected into C6 cells …

A Model Using Radiation And Pws4-Htnf-Α Gene Therapy For Treatment Of Glioblastomas, Angelo G. Baher

Loma Linda University Electronic Theses, Dissertations & Projects

The efficacy of radiotherapy for cancer is limited by the dose that can be safely delivered to the tumor without causing debilitating side effects. In addition, successful treatment of highly malignant tumors such as glioblastomas is likely to require adjunctive therapies to enhance tumor response to radiation. Previous studies have shown immunomodulation and a synergestic reduction in tumor volume of malignant tumors when tumor necrosis factor-α (TNF-α) protein is administered prior to radiation. The major goal of the present investigation was to evaluate the efficacy of pWS4-human TNF-α (pWS4-hTNF-α), a new plasmid construct that expresses human TNF-α protein, together with …

Short And Long Term Effects Of Proton Microbeam Irradiation : In The Lateral Geniculate Nucleus Of Felis Domesticus, Chad Sherwood Reder

Loma Linda University Electronic Theses, Dissertations & Projects

Little is known of the effects of proton irradiation on neural tissue. A 1.0 mm microbeam was used on the cat lateral geniculate nucleus (LGN) to quantify the short term (< 3 months) and long term (< 9 months) effects of radiation damage. The LGN is a large structure with well defined afferent, efferent, and receptive field properties.

Electrophysiological and histological techniques were used to examine the effects of the microbeam at 60, 40, and 16 Gy, administered as a single bolus. Recordings of light evoked responses in the LGN were obtained using microelectrodes in nine animals within 12 weeks of irradiation, and 6 animals within 36 weeks of irradiation. Receptive fields were mapped onto a tangent screen using standard receptive field techniques. Histological measures included afferent …

Cell Mediated Immunity By Cytotoxicity Assay And The Effect Of Corynebacterium Parvum And Radiation On Mice Bearing Herpes-Induced Tumors, Robert B. Stagg

Loma Linda University Electronic Theses, Dissertations & Projects

Cell mediated immune (CMI) cytotoxic reactivity of Balb/c mice against H238 cells, a Herpes simplex virus (HSV) Type 2 - induced sarcoma, was measured by the ¹²⁵IUdR release assay. The Balb/c mouse response to the growing HSV-induced tumor, treated with radiation and , was measured by survival rate, tumor growth and immune cytotoxicity of spleen and peritoneal exudate cells (PEC) as determined by ¹²⁵IUdR release assay. Subcutaneous (s.c.) inoculation of 1 x 10⁶ H238 cells (high dose) produced progressive tumor growth while s.c. inoculation of 1 x 10⁴ H238 cells (low dose) produced no tumors. A …

The Effect Of Endodontic Therapy On The Incidence Of Radiation Caries In Dogs, James A. Abbott

Loma Linda University Electronic Theses, Dissertations & Projects

Endodontic therapy was evaluated as a possible control or prevention modality of radiation type dental caries in dogs. Two adult male dogs with permanent dentitions had endodontic therapy performed on alternating teeth in each jaw. The nontreated teeth served as controls.

The dogs were irradiated with 7000 rad Cobalt-60 radiation fractionated over an eight week period. The dogs were killed at 60 and 182 days post-irradiation. The teeth were removed from the jaws and immersed in methylene blue dye, sectioned, and the dye penetration pattern photographed. Diffusion of the dye into the tooth structure was quantified and statistically analyzed.

A …