Effect Of Radiation Treatment Research Articles

PATIENT EDUCATION: Counseling of oral cancer patients

The purpose of this manuscript is to summarize key aspects of care for patients with advanced oral cancer, metastatic to the head and neck region. Patients with advanced oral cancer are treated with multimodal treatment. Surgical intervention leads to limitation in speech and swallowing abilities while adverse effects of chemotherapy and radiation treatment can include nausea, vomiting, diarrhea, mucositis, cystitis, dehydration, nephrotoxicity, skin dermatitis, myelosuppression, and nutritional deficiencies leading to weight loss. These toxicities could be overcome through self-care measures practiced by the patient. Oncology nurses could impart knowledge about self-care measures via patient and family counseling. Keywords: advanced oral cancer, head and neck cancer, counseling, self-care measures

Abstract 3757: The development of MAGMAS as a potential therapeutic target in temozolomide-resistant glioma

Abstract Glioblastoma (GBM) is one of the most aggressive types of brain cancer and remains a significant challenge for drug development in oncology today. Temozolomide (TMZ) is the standard of care for GBM, and resistance to this drug is modulated partly by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Clinical studies demonstrated that low MGMT expression in GBM enhances sensitivity to TMZ and prolongs survival for patients. However, recent clinical studies indicate MGMT is a discordant biomarker since the predictive value of MGMT methylation is relatively low and there is a lack of modalities to inhibit MGMT expression. Furthermore, glioma stem cells (GSC) are another contributing factor for resistance due to tumor heterogeneity, self-renewal capacity and activation of DNA repair responses to overcome the effect of radiation and TMZ treatment. These resistance mechanisms contribute to tumor recurrence and present major impediments for the development of effective treatments. MAGMAS, 13.8 kDa mitochondria protein, is a translocase of the inner mitochondrial membrane and regulates oxidative phosphorylation. Specifically, MAGMAS regulates the ATP stimulatory activity of DNAJC19 on mtHSP70 that drives the movement of peptides through the TIM23 complex into the mitochondrial matrix. Recent evidence suggests that MAGMAS can regulate oxidative phosphorylation via interactions with the respiratory complexes present in the inner mitochondrial membrane. Previously, our lab has shown MAGMAS overexpression in malignant glioma tissues of patients and murine intracranial xenografts. Additionally, pharmacological inhibition of MAGMAS with the small molecule BT9 promoted cytotoxicity and impaired respiratory functions in malignant glioma cells demonstrating that MAGMAS is a promising potential target for GBM patients. However, further studies are needed to investigate the role of MAGMAS across the spectrum from initial tumorigenesis to disease progression and to further determine how MAGMAS is implicated during the development of treatment resistance. This study is designed to investigate the role of MAGMAS in GSCs and their contribution to TMZ resistance. We observed temozolomide-resistant (TR) U251-TR and D54 MG-TR GBM cell lines expressed significantly higher levels of MAGMAS and several stem cell markers than their drug-sensitive (S) parental cell lines. Therefore, we hypothesized that silencing MAGMAS re-sensitizes TR GBM cell lines to TMZ. We found that MAGMAS knockdown in D54-MG and U251 S/TR cells in the presence of escalating TMZ concentrations, caused enhanced sensitivity to TMZ. Consistent with these results, inhibition of MAGMAS with the novel BT9 inhibitor enhances the TMZ sensitivity in the TMZ-resistant cell lines. Additional studies of patient-derived cell lines are being utilized further to validate MAGMAS as it is an attractive target in TMZ-resistant GBM patients. Citation Format: Jennifer D. Tran, Javier J. Lepe, Maria C. Kenney, Bhaskar C. Das, Daniela A. Bota. The development of MAGMAS as a potential therapeutic target in temozolomide-resistant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3757.

Synthetic Curcumin Analogs in the Treatment of Cancer: A Literature Review.

Treatment of cancer, one of the most fatal diseases in the present century, has become a topic of global concern. Unfavorable unintentional effects of chemotherapy and radiation treatments have been the main reasons for the research on the discovery of drugs with a broader spectrum of effectiveness and efficiency, with minimal side effects. Curcumin (diferuloylmethane) is a naturally occurring phenolic structure with anticancer properties through its inhibition of cell multiplication, metastasis, and prolongation of cell cycle suppression of apoptosis in various tumor cells. The primary restriction regarding the use of curcumin in cancer treatment is related to poor bioavailability and unfavorable pharmacokinetic profiles of curcumin due to its poor absorption rate, fast metabolism, and systemic elimination. A variety of ways have been proposed to overcome these limitations. With this background, the present study focuses on providing a comprehensive overview of the anticancer properties of curcumin derivatives and the synthesis of curcumin analogs with application to different types of cancers. The regulation of various target and signaling pathways is considered in various cancers, including breast, gastrointestinal, pancreatic, prostate, skin, and lung cancers. A review of the literature indicates that modifying the structure of curcumin through the substitution of the phenyl group and unsaturated carbon branch around the two main sites of oxygen can result in the improvement of physical and chemical properties, as well as the enhancement of physiological activities of the curcumin molecule and the anti-cancer activities of this polyphenol. Curcumin analogs demonstrate anticancer properties at multiple targets at different cell stages and by various signaling biochemical pathways. These include cytokines, transcription factors, growth factors, and modulation of genes involved in cellular proliferation and apoptosis in breast, gastrointestinal, skin, prostate, and lung cancers, thereby mitigating tumor progression.

Effect of UV-C Radiation and Thermal Treatment on Volatile Compounds, Physicochemical, Microbiological and Phytochemical Parameters on Apple Juice (Malus domestica) with Raspberry (Rubus idaleus L.)

Volatile compounds contribute to aroma and flavor, these being the main sensory attributes in food acceptance. This work addresses the physicochemical, volatile compounds, polyphenols, and flavonoids content and, antioxidant activity of apple-raspberry (90/10%) juice treated by thermal and ultraviolet radiation (UV-C) alone or in combination with moderate heat-treatment. Nineteen volatile compounds were identified which experienced changes depending on the treatment. Compounds such as α-ionone and β-ionone, that contribute to raspberries characteristic aroma, were present in a greater concentration in the UV-C treatment and lower in the thermal treatment. Likewise, 2-methyl butyl acetate, which give a fruity-sweet aroma typical of apples was present in a greater concentration in the UV-C treatment. Regarding polyphenol content, control and combined treatment presented the greater concentrations. However, after twenty days of storage, control and combined treatment presented the lower flavonoid concentration. Nevertheless, at this time, treatments showed no variations in antioxidant activity. Yeast and mold and total aerobic mesophilic and psychrophilic counts were reduced in the heat and combined treatments. In conclusion, UV-C and moderate heat might successfully be used to process a stable apple-raspberry juice while maintaining its quality and safety.

Effect of phytosanitary radiation treatments on storage quality and microbiological safety of fresh table apricots (Prunus armeniaca L) Cv. CITH-2

Matured table apricots harvested at commercial maturity were irradiated in the dose range of 0.25-1.0 kGy and stored under refrigerated (3±1 0C, RH 85 %) conditions. The fruits were evaluated at intervals of 5 days for various physico-chemical parameters. Studies revealed that phytosanitary irradiation treatment maintained the storage quality of table apricots under refrigerated conditions. Positive correlations (r = 0.89) existed between irradiation treatment and firmness retention, whereas an inverse correlation (r = –0.86) existed between radiation and water-soluble pectin. Color scores revealed that L, a and b values increased by 13.1%, 68.9% and 21.5% in un-irradiated apricots compared to 6.1%, 44.9% and 14.1% in samples irradiated at 1.0 kGy, after 30 days of storage. During storage, ascorbic acid decreased by 86.8% in control compared to 56.2% in 1.0 kGy treated apricots. Phytosanitary radiation treatment at 1.0 kGy caused a significant (p ? 0.05) increase (7.5%) in total phenolics, besides minimizing subsequent degradation of phenols during storage. Microbial analysis indicated that in samples irradiated at 0.75 kGy and 1.0 kGy, no microbial load was detected up to 10 and 20 days of storage and resulted in about 1.0 log reduction in microbial load after 30 days of storage.

Radiation processing of dried Ker (Capparis deciduas): Effect on microbial safety and nutritional quality

Radiation processing of fresh and market (0-6 months old) dried ker at different doses of 2.5, 5.0 and 7.0 kGy was investigated. The effect of radiation treatment on total bacterial counts and nutritional quality parameters like moisture, protein, fat, ash, fibre, total sugar and starch contents were determined over a storage period of 3 months at ambient temperature. The findings of the study indicated that the radiation treatment reduces total bacterial counts in both fresh and market-dried ker at all doses. However, a dose of 5 kGy eliminated total bacterial counts in samples after storage. No significant changes were found in the proximate composition of both fresh and market-dried ker. On the contrary, total sugar content was observed to be increased in both control as well as irradiated samples during storage. Thus, radiation processing with 5.0 kGy did not affect significantly the nutritional quality of fresh and market-dried ker samples.

Metabolomics analysis of pathways underlying radiation-induced salivary gland dysfunction stages.

Salivary gland hypofunction is an adverse side effect associated with radiotherapy for head and neck cancer patients. This study delineated metabolic changes at acute, intermediate, and chronic radiation damage response stages in mouse salivary glands following a single 5 Gy dose. Ultra-high performance liquid chromatography-mass spectrometry was performed on parotid salivary gland tissue collected at 3, 14, and 30 days following radiation (IR). Pathway enrichment analysis, network analysis based on metabolite structural similarity, and network analysis based on metabolite abundance correlations were used to incorporate both metabolite levels and structural annotation. The greatest number of enriched pathways are observed at 3 days and the lowest at 30 days following radiation. Amino acid metabolism pathways, glutathione metabolism, and central carbon metabolism in cancer are enriched at all radiation time points across different analytical methods. This study suggests that glutathione and central carbon metabolism in cancer may be important pathways in the unresolved effect of radiation treatment.

NIMG-24. RECURRENT OLIGODENDROGLIOMA DEMONSTRATES EARLY INCREASE IN CEREBRAL BLOOD FLOW AND NORMALIZATION IN RESPONSE TO TREATMENT

Abstract Oligodendrogliomas, molecularly defined by the presence of both IDH mutation and 1p/19q codeletion, are more treatment responsive than other gliomas, and due to short capillary segments, demonstrate elevated CBF regardless of grade or contrast enhancement. Arterial Spin Labeling (ASL) allows noninvasive perfusion imaging assessment of cerebral blood flow (CBF) without contrast administration. Changes in CBF are recognized in association with malignant transformation of gliomas however in the setting of treatment, CBF has only been studied to assist in differentiating radiation treatment effect from progressive glioma. This single center retrospective study was undertaken to evaluate if CBF, measured by ASL, might normalize following treatment of recurrent oligodendrogliomas. Clinical database query identified 151 patients with molecularly confirmed oligodendroglioma, 34 of which had available ASL imaging. Expert reader review of all available MRI sequences, blinded to treatment timeline, were performed by two independent radiologists at a PACS station. There were 6 radiographic recurrences identified and in 5/6 CBF was the first radiographic change. Contrast enhancement did not develop for 1.5-12 months after change in CBF for 4/5 recurrences. ASL imaging before and after non-surgical therapy for recurrent disease was available for 4 patients. Two patients were treated with lomustine, one with bevacizumab and one with proton re-radiation. By the second MRI following treatment initiation, all patients had normalization of CBF. At the first post treatment MRI, 3/4 of patients demonstrated normalization of CBF while only 2/4 demonstrated normalization of dynamic susceptibility contrast-derived cerebral blood volume. During the subsequent 6 months, FLAIR hyperintensities remained stable in all patients. This work supports further study if normalization of ASL-derived CBF may be an early radiographic biomarker for response to treatment, especially in non or minimally enhancing recurrent gliomas.

Experimental study of dosimetric properties of thermoluminescent powder TLD-100

The creation of a scientifically substantiated quality assurance system for dosimetry and the optimization of medical exposure of the population of Ukraine during diagnostic and therapeutic procedures (and the possibility of dosimetric control and monitoring of emergency situations) falls within the field of the application of ionizing radiation sources (IRs). Trends in modern medicine in most countries, including Ukraine, prove a continued increase in the share of medical exposure. The main requirements and recommendations for the use of IRs for medical purposes while ensuring the radiation safety requirements for patients are provided in the documents of such International Organizations as the International Commission on Radiological Protection (ICRP), the International Atomic Energy Agency (IAEA), the World Health Organization (WHO) and the European Commission (EC).
 One of the key factors to ensure the quality of radiation therapy is metrological and dosimetric support. To enhance the effectiveness of radiation treatment and reduce the number of complications in the future, it is necessary to irradiate the local target within the patient’s body with a dose error of no more than 5%. Control of the radiation output of the therapeutic device, i.e., the calibration of the therapeutic beam used in the treatment process, is an essential element of radiation therapy.
 Radiation protection programmes are based on checking the accuracy of the calibration of remote radiotherapy devices using thermoluminescent dosimeters (TLDs) – small plastic capsules filled with thermoluminescent powder that are sent by post to radiology centres for exposure to a specific dose in a water phantom.
 Radiation therapy in Ukraine is primarily conducted using cobalt machines, X-ray therapy devices and linear accelerators.
 The results of the study include the examination of the dependency of measurement results on various exposure parameters using the automatic reader PCL-3, the determination of dosimetric characteristics of the thermoluminescent powder TLD-100, and the development of a calibration method for thermoluminescent dosimeters under standard irradiation conditions on a remote gamma therapy device.
 Therefore, the accuracy of beam calibration using TLD dosimeters has been studied, which will enable to timely detect errors in clinical dosimetry and reduce the number of cases of radiation-related complications for patients during their treatment.

Tumor Regression with 5-Aminolevulinic Acid (5-ALA)-Mediated Radiodynamic Therapy (RDT) Using Different Megavoltage Energies

5-aminolevulinic acid (5-ALA) accumulates in target tumor cells, where it is metabolized to a photosensitizer - protoporphyrin IX (PpIX). Cherenkov light induced by high-energy photon beams effectively activates the PpIX due to the Soret band. The activated photosensitizers lead to cellular toxicities to kill malignant tumor cells by converting surrounding tissue oxygens into singlet oxygens. Radiodynamic therapy (RDT) utilizes cellular damage caused by both radiation dose and activated photosensitizer. The emission of Cherenkov light was observed higher with higher energy irradiation in phantom and ex-vivo tissues. Therefore, using an in-vivo mouse model, this study aimed to investigate the efficacy and energy dependency of RDT combined with 5-ALA and different ranges of megavoltage photon irradiation. In order to investigate individual and synergistic effects of 5-ALA administration and radiation treatment, the tumors (n = 344) were randomized into eight groups: control (untreated), 5-ALA only, 6-, 15-, and 45-MV conventional radiation treatment (RT) only, 6-, 15-, and 45-MV RDT. 4 Gy in a single fraction was delivered to the tumors using three different energy photons for RT only and RDT groups. 5-ALA was systemically injected into 5-ALA only and RDT groups at 100 mg/kg by tail-vein 4 hours before irradiation for endogenous PpIX accumulation in the tumor. Tumor growth was measured using a 1.5 T MR scanner on the day of treatment (prior to the treatment), 3, 7, and 14 days post-treatment. Two-way repeated ANOVA with Bonferroni correction was used to compare each treatment group to determine the statistically significant difference in tumor growth. A total of 45 MV RDT resulted in the most significant decrease in tumor growth by 58.8 ± 3.4 %, 58.0 ± 3.0 %, and 55.0 ± 3.0 % compared to 5-ALA, 45 MV RT, and control group on 7 days post-treatment (P<0.001), respectively. Moreover, a synergistic effect of 45 MV RDT causes a 47.1-54.1 % additional decrease in tumor growth toward the effective treatment outcome. Compared to the different energies, 45 MV RDT resulted in a 52.2 ± 3.1 % and 19.7 ± 7.2 % decrease in tumor growth compared to 6 MV RDT and 15 MV RDT on 7 days post-treatment, respectively (P<0.001), whereas the conventional RT was not. Radiodynamic therapy using 5-ALA administration and 45MV photon beam irradiation resulted in the most significant tumor growth control. A photon energy dependency was observed in radiodynamic therapy. 45MV photon beams showed greater in activating PpIX, improving the synergistic effects of radiation dose and activated photosensitizer than the other energies. The preliminary results provide a foundation for new innovative treatment strategies that have the potential to improve cancer treatment.

Analysis of the Cancer Imaging Archive for Patterns of Locoregional Failure in Relation to the Mucous Membranes among Patients with Head and Neck Squamous Cell Carcinoma: Potential Organ at Risk that can be Spared?

Radiation-induced oral mucositis (RIOM), a painful inflammation and ulceration of the mucous membranes (MM), occurs as a common and severe side effect of radiation treatment (RT) for head and neck cancers. It worsens significant quality of life leading to treatment interruption or cancellation. In RIOM, radiation injury of the MM basal epithelial cells may be one of the critical pathophysiological mechanisms. However, it is unclear if advanced radiation treatments could spare MM, without compromise on tumor control. The purpose of this study is to determine whether the MM that do not overlap with the prescription target volumes are a common site of locoregional recurrence in head and neck cancers. A de-identified data collection of 215 head and neck cancer patients stored within The Cancer Imaging Archive was downloaded for analysis. Imaging series both before and after RT were downloaded, as well as RT structures and RT dosimetric data. Diagnostic CECT and/or PET/CT and/or MRI scans documenting the initial evidence of recurrence were co-registered with corresponding original planning CTs. Radiologically evident recurrent gross disease (rGTV) was manually contoured, as well as the MM (defined as an approximately 3mm thick wall of mucosa tissue lining the oral cavity and pharynx and excluding any overlap with the radiation prescription targets). Contoured MM structures were cross-referenced with the sites of recurrence by examining the overlap of the MM volumes with the rGTV volumes. A total of 40 patients had documented evidence of recurrence; 38 of which had images available for analysis. Overall, 23 (60.5%) were oropharynx cancer. Of the 38 recurrences, 35 (92%) were locoregional: 23 with only local (60.5%) recurrences, 9 with only regional (23.7%) recurrences and 3 (7.9%) with both local and regional recurrences. One patient (2.6%) had distant recurrence, one patient had both regional and distant recurrences concomitantly, and one patient had local, regional and distant recurrences simultaneously. Overall, 30 patients (78.9%) had recurrences located exclusively within prescription PTV volumes/isodose lines. Four patients (10.5%) had recurrences located outside prescription PTV volumes/isodose lines, four patients (10.5%) had recurrences located both within and outside prescription PTV volumes/isodose lines (i.e., 2 sites of concomitant recurrence). Importantly, 0 patients (0%) had recurrences located in the contoured MM (excluding any overlap with the radiation prescription targets). Based on this retrospective series, the MM (excluding the areas of overlap with radiation prescription targets) are a rare location of locoregional recurrence. Hence, sparing the MM using radiation advanced dosimetry techniques could be a reasonable approach to reducing the incidence/severity of radiation-induced oral mucositis, without compromising tumor control. However, this requires further prospective investigation.

Impact of radiation dose on patient-reported acute taste alteration in a prospective observational study cohort in head and neck squamous cell cancer (HNSCC)

PurposeTaste alteration (TA) is a frequent acute side effect of radiation treatment in HNSCC patients. Principal aim of our study was to investigate dosimetric parameters in relation to patient-assessed taste impairment in a prospective cohort treated with intensity-modulated radiotherapy.MethodsAll patients with locally advanced HNSCC and amenable to radical treatment were included. Chemotherapy-induced taste alteration scale (CITAS), EORTC QLQ-C30 and QLQ-HN43 questionnaires at baseline (T0), 3 weeks (T1) and 3 months (T2) after radiotherapy conclusion were used to assess taste impairment. Base of tongue, submandibular glands (SG), parotid glands (PG) and taste buds, along with anterior and medium third of the tongue, were considered as organs at risk and thus delineated according to consensus guidelines. The mean dose to the above-mentioned structures was correlated with patient-reported outcomes.ResultsBetween September 2019 and November 2020, 33 patients were recruited, 31 of which analyzed. 71% had oropharyngeal carcinoma, mostly HPV-related (60%). All were treated with tomotherapy. 77.4% had concurrent cisplatin. Mean scores of general taste alterations, global health status and dry mouth and sticky saliva were assessed. The mean doses to the anterior third, medium third and base of the tongue were 23.85, 35.50 and 47.67 Gy, respectively. Taste buds received 32.72 Gy; right and left parotid 25 and 23 Gy; right and left submandibular glands 47.8 and 39.4 Gy. At univariate analysis, dysgeusia correlated with SG mean dose (95% CI 0–0.02 p = 0.05) and PG mean dose (95% CI 0–0.02 p = 0.05); dry mouth with mean dose to anterior (95% CI 0.03–1.47 p = 0.04) and medium third (95% CI 0.02–0.93 p = 0.04) of the tongue, to taste buds (95% CI 0.06–0.96 p = 0.03) and to SGs (95% CI 0.06–0.63 p = 0.02); pain mouth with mean dose to taste buds (95% CI 0–0.02 p = 0.04), to SGs (95% CI 0–0.03 p = 0.03) and to base tongue (95% CI 0–0.02 p = 0.02).ConclusionsOur analysis supports the influence of dose distribution on the development of TA in HNSCC patients. The contribution of dose to taste buds and tongue subvolumes remains unclear and worthy of further investigation.

Cardiac toxic effect of radiation therapy in patients receiving adjuvant trastuzumab treatment, as examined by LVEF of echocardiography: an experimental research.

This study aimed to evaluate the cardiotoxic consequences of radiotherapy in breast cancer patients who underwent adjuvant trastuzumab treatment by echocardiographic left ventricular ejection fraction (LVEF) measurement. In this retrospective study patients treated with postoperative breast irradiation with adjuvant trastuzumab were examined in terms of LVEF. Eithy five patients with age of 31-76 referred to the radiotherapy department of 5 Azar Hospital of Gorgan, Iran between years 2013 and 2020 were analyzed. Patients were divided into two left sided and right sided breast groups. Patients are routinely assessed every 3 months by echocardiocraphgy. LVEF values was measured at intervals of 3, 6, and 12 months after treatment onset. On the left side, the average of LVEF immediately decreased after treatment, compared to before treatment (∆ LVEF= 0.021), which shows the impact of trastuzumab. The LVEF average 3 months after treatment onset showed a significant decrease (∆ LVEF= 0.043) indicating a synergistic effect of trastuzumab and radiotherapy. LVEF average 6 months and 1 year after treatment onset showed a decrease but not significant (∆ LVEF= 0.009 and 0.013, respectively).In the right breast LVEF average immediately 3 months after treatment showed a significant decrease (∆ LVEF= 0.011 and 0.057, respectively). Nevertheless, LVEF average does not show a significant decrease after 6 months and 1 year after treatment in the right side group (∆ LVEF= 0.0002 and 0.018, respectively). Our results showed LVEF changes within one year following treatment in left sided breast cancer was more than right side , but the difference was not significant ,which may be due to the short period of our study based on the protocol of our department. More changes in the left side must be due to placing of the heart in the path of radiation. The study showed that LVEF may be an indicative measure for assessing radiation and adjuvant treatment effects on cardiac function.

Genetic and environmental influences on one-trial conditioned context aversion in mice.

Anticipatory nausea (AN) is caused by an association between contextual cues and the experience of nausea (the side effects of chemotherapy or radiation treatment) and it develops predominantly in female patients undergoing chemotherapy. Preclinical studies in rodents show that the administration of an illness-inducing agent in the presence of novel contextual cues can cause conditioned context aversion (CCA) and this has been proposed to model AN. The literature also suggests that brief pre-exposure to a novel context prior to shock delivery is critical in the development of contextual fear conditioning in rodents (a phenomenon known as Immediate Shock Deficit), but this has not been assessed in CCA. The aim of present study was to develop a CCA paradigm to assess this in outbred (CD1) and inbred (C57BL/6J) mice and evaluate potential sex differences. The results revealed that a single conditioning trial in which a distinctive context was paired with LiCl-induced illness was sufficient to elicit a conditioned response in both female and male CD1 outbred mice, but not in C57BL/6J inbred mice. In addition, CCA was facilitated when animals had prior experience with the context. Finally, outbred female mice showed longer and more robust retention of CCA than male mice, which parallels clinical findings. The results indicate the importance of using CD1 outbred mice as an animal model of AN as well as examining sex differences in the CCA paradigm. Similar findings in humans encourage the future use of this novel CCA preclinical mouse model.

Abstract A006: Loss of PMEPA1 gene isoform facilitates the development of hormone and radiation therapies resistance in prostate cancer cells

Abstract Introduction: Nearly all the patients receiving hormone treatment eventually progress into castration resistance stage. In addition, approximately 30% to 40% of patients receiving radiation treatment will develop resistance. The aberrant alterations of androgen receptor (AR) and transforming growth factor-β (TGF-β) signaling play critical roles in such processes. Our studies identified five PMEPA1 (Prostate Transmembrane Protein Androgen Induced 1) gene isoforms in prostate cancer cells. PMEPA1-b isoform was androgen responsive and inhibited androgen signaling. In contrast, PMEPA1 isoforms a and d were TGF-β inducible and suppressed TGF-β signaling. Loss or reduced expressions of PMEPA1 was detected in over 60% of prostate cancer samples. In this study, we investigated the impacts of PMEPA1 isoforms (a, b and d) on the development of hormone and radiation therapies resistance in prostate cancer. Methods: RNA-seq data of unmatched 50 benign and 499 malignant prostate samples from The Cancer Genome Atlas (TCGA) dataset, as well as 101 metastatic castration resistant prostate cancer (mCRPC) biopsy samples from Quigley lab at UCSF (WCDT dataset) were used to study the transcript levels of PMEPA1 isoforms (a, b and d) and their correlations to disease progression. Hormone dependent LNCaP cells and androgen independent PC-3, DU-145 cells were utilized to investigate the impacts of PMEPA1 isoforms (a, b and d) on the responses to of androgen inhibitors (enzalutamide and bicalutamide, 0, 5.0 and 25.0 nM) and radiation (0, 1.0 and 5.0 Gy). The vectors of pcDNA3.1-PMEPA1-a, -b and -d were transfected into prostate cancer cells via Lipofectamine, and endogenous PMEPA1 isoforms were knocked down by isoforms specific siRNAs. The cell growth was assessed by cell counting, BrdU incorporation and cell plating efficiency assays. The protein levels of AR and PSA were evaluated by immunoblotting. The transcript levels of PSA, NKX3.1, NEDD9 and THBS1 were assessed by RT-PCR technology. Results: The reduced transcript levels of PMEPA1 isoforms (a, b and d) were detected in mCRPC group. Lower expression of PMEPA1-b was significantly associated with earlier biochemical recurrence. The growth inhibition and androgen signaling blockage mediated by androgen inhibitors were explicitly reversed by depletion of PMEPA1-b in LNCaP cells. Ectopic PMEPA1-b in isoform b depleted LNCaP cells reinstituted the growth inhibition induced by androgen inhibitors. Knockdown of isoforms a and d conspicuously rescued the decreased cell proliferation and suppressed TGF-β signaling resulted from radiation treatment in PC-3 and DU-145 cells. Similarly, over-expression of PMEPA1-a and -d in siRNA treated cells recapitulated the growth inhibitory effects of radiation treatments. Conclusion: Loss of PMEPA1 gene isoforms (a, b and d) induced the development of resistance to hormone ablation and radiation treatments in prostate cancer cells in vitro through activating androgen and TGF-β signaling. Our research provided a new insight into treatment resistance mechanism of prostate cancer cells. Citation Format: Shashwat Sharad, Hua Li. Loss of PMEPA1 gene isoform facilitates the development of hormone and radiation therapies resistance in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A006.

Contrasting effects of different light regimes on the photoreactivities of allochthonous and autochthonous chromophoric dissolved organic matter

Chromophoric dissolved organic matter (CDOM) plays an important role in ultraviolet (UV) light absorption in the ocean. CDOM is known to originate from either an allochthonous or autochthonous source and has varying compositions and levels of reactivity; however, the effects of individual radiation treatments and the combined effects of UVA and UVB on allochthonous and autochthonous CDOM remain poorly understood. Thus, here, we measured changes in the common optical properties of CDOM collected from China's marginal seas and the Northwest Pacific, using full-spectrum, UVA (315–400 nm), and UVB (280–315 nm) irradiation to induce photodegradation over the same time period (60 h). Excitation–emission matrices (EEMs) combined with parallel factor analysis (PARAFAC) identified four components: marine humic-like C1, terrestrial humic-like C2, soil fulvic-like C3, and tryptophan-like C4. Although the behaviours of these components during full-spectrum irradiation exhibited similar decreasing tendencies, three components (C1, C3, and C4) underwent direct photodegradation under UVB exposure, whereas C2 was more susceptible to UVA degradation. The diverse photoreactivities of the source-dependent components to different light treatments led to differing photochemical behaviours of other optical indices [aCDOM(355), aCDOM(254), SR, HIX, and BIX]. The results indicate that irradiation preferentially reduced the high humification degree or humic substance content of allochthonous DOM, and promoted the transformation from the allochthonous humic DOM components to recently produced components. Although values for the samples from different sources overlapped frequently, principal component analysis (PCA) indicated that the overall optical signatures could be linked to the original CDOM source features. The degradation of CDOM humification, aromaticity, molecular weight, and autochthonous fractions under exposure can drive the CDOM biogeochemical cycle in marine environments. These findings can aid in a better understanding of the effects of different combinations of light treatments and CDOM characteristics on CDOM photochemical processes.

Effects of irradiation treatments on genetic variation and damage repair in the rice blast fungus Magnaporthe oryzae

Effects of irradiation treatments on genetic variation and damage repair in the rice blast fungus Magnaporthe oryzae

Abstract SY31-02: Determinants of hypoxia in pancreatic cancer and identification of ULK1 as a potential therapeutic target

Abstract The effectiveness of radiation treatment is impacted by spatially defined features of the tumor microenvironment including areas of tumor hypoxia. This is due in part to direct protection against radiation damage by hypoxia, as well as through the influence of hypoxia on tumor, stroma and immune cell phenotypes. Despite this understanding, our progress in advancing therapies to address tumor hypoxia in patients have been largely unsuccessful. This is driven in part to the incredible variability in tumor hypoxia across patients as well as to a limited understanding of the underlying causes and consequences of hypoxia on an individual patient basis. As a step towards more precision approaches for hypoxia directed therapies we are characterizing hypoxia and its causes in individual patients and in matched patient derived xenografts. Our data reveal a striking variation in hypoxia across patients, and a corresponding variation in both oxygen consumption and hypoxia tolerance in patient derived organoids. We hypothesize that levels of hypoxia within individual tumors are determined through separate processes that drive changes in oxygen demand coupled with those that influence adaptation and survival to hypoxic stress. We have also identified ULK1 as a key contributor to both of these processes. Loss or inhibition of ULK1, a gene activated downstream of the unfolded protein response during hypoxia, results in defects in both mitochondrial and ER turnover leading to increases in both oxygen consumption and ER stress. Consequently, knockdown of ULK1 in established pancreatic cancer xenografts results in development of more hypoxia, while at the same time promotes the death of cells that become hypoxic. This has a dramatic impact on tumor growth, leading to complete remission in some models and suggesting that ULK1 should be pursued as a tumor microenvironment therapeutic target. Citation Format: Ji Zhang, Dan Cojocari, Rob Cairns, Marianne Koritzinsky, Bradly G. Wouters. Determinants of hypoxia in pancreatic cancer and identification of ULK1 as a potential therapeutic target. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY31-02.

Study of Properties of Polyethylene Glycol and Its Glass Fibers Composites under UV-Rad for Oils Filtration Applications

This study determines the effects of UV radiation and heat treatment on many flow and mechanical parameters of PEG 4000, including flow time and viscosity (specific, reduced, relative, and intrinsic). Solubility time and shore D hardness are among the mechanical characteristics. By adjusting the concentrations of solutions in the range (0.01–0.03) g/ml of heating and non-heating PEG powders, and examining the polymer's solubility at the same time, the flow characteristics of the polymer are explored. Random glass fiber reinforcement in the range of 0.1–0.4 wt has also been studied to indicate the effect on shore hardness. After exposing the produced plates to ultraviolet light, the efficacy of the plates in purifying the oil from contaminants was investigated. The results show that increasing the concentration increases all types of viscosity and flow time, with the exception of intrinsic viscosity, which decreases as concentrations increase. Other parameters decrease after the first UV ray and heat treatment, but increase as the time of UV ray treatment increases. Furthermore, increasing the weight ratio of glass fibers from 0.1 to 0.4 wt lowered shore hardness, whereas increasing the weight ratio at the same previous range increased it after UV rad. While solubility data refers to increasing polymer weight and radiation help increase solubility time. The filtration efficacy of the small particles of the produced filters increased after the overlapping plates were exposed to UV radiation, owing to the smaller pore diameters.

Application of nano-radiosensitizers in combination cancer therapy.

Radiosensitizers are compounds or nanostructures, which can improve the efficiency of ionizing radiation to kill cells. Radiosensitization increases the susceptibility of cancer cells to radiation-induced killing, while simultaneously reducing the potentially damaging effect on the cellular structure and function of the surrounding healthy tissues. Therefore, radiosensitizers are therapeutic agents used to boost the effectiveness of radiation treatment. The complexity and heterogeneity of cancer, and the multifactorial nature of its pathophysiology has led to many approaches to treatment. The effectiveness of each approach has been proven to some extent, but no definitive treatment to eradicate cancer has been discovered. The current review discusses a broad range of nano-radiosensitizers, summarizing possible combinations of radiosensitizing NPs with several other types of cancer therapy options, focusing on the benefits and drawbacks, challenges, and future prospects.