Irradiated Tissue Research Articles

MiRNA-Mediated Fibrosis in the Out-of-Target Heart following Partial-Body Irradiation

Simple SummaryRadiation exposure has been linked to non-cancer effects such as heart disease. This study aimed to investigate radiation-induced heart disease in mice where the radiation exposure was either administered to the whole body or only to the bottom third of the body (partial body). Radiation damage was found in the hearts of mice following both whole-body and partial-body exposure. MiRNAs released from directly irradiated skeletal muscle cells in vitro were shown to result in damaging effects in unirradiated ventricular cardiac cells. This study suggests that a partial-body exposure to radiation should be thought of as a systemic effect rather than only an effect on the exposed tissue.Recent reports have shown a link between radiation exposure and non-cancer diseases such as radiation-induced heart disease (RIHD). Radiation exposures are often inhomogeneous, and out-of-target effects have been studied in terms of cancer risk, but very few studies have been carried out for non-cancer diseases. Here, the role of miRNAs in the pathogenesis of RIHD was investigated. C57Bl/6J female mice were whole- (WBI) or partial-body-irradiated (PBI) with 2 Gy of X-rays or sham-irradiated (SI). In PBI exposure, the lower third of the mouse body was irradiated, while the upper two-thirds were shielded. From all groups, hearts were collected 15 days or 6 months post-irradiation. The MiRNome analysis at 15 days post-irradiation showed that miRNAs, belonging to the myomiR family, were highly differentially expressed in WBI and PBI mouse hearts compared with SI hearts. Raman spectral data collected 15 days and 6 months post-irradiation showed biochemical differences among SI, WBI and PBI mouse hearts. Fibrosis in WBI and PBI mouse hearts, indicated by the increased deposition of collagen and the overexpression of genes involved in myofibroblast activation, was found 6 months post-irradiation. Using an in vitro co-culture system, involving directly irradiated skeletal muscle and unirradiated ventricular cardiac human cells, we propose the role of miR-1/133a as mediators of the abscopal response, suggesting that miRNA-based strategies could be relevant for limiting tissue-dependent reactions in non-directly irradiated tissues.

Normal Tissue Sparing by FLASH as a Function of Single-Fraction Dose: A Quantitative Analysis

The FLASH effect designates normal tissue sparing by ultra-high dose rate (UHDR) compared with conventional dose rate irradiation without compromising tumor control. Understanding the magnitude of this effect and its dependency on dose are essential requirements for an optimized clinical translation of FLASH radiation therapy. In this context, we evaluated available experimental data on the magnitudes of normal tissue sparing provided by the FLASH effect as a function of dose, and followed a phenomenological data-driven approach for its parameterization. We gathered available in vivo data of normal tissue sparing of conventional (CONV) versus UHDR single-fraction doses and converted these to a common scale using isoeffect dose ratios, hereafter referred to as FLASH-modifying factors (FMF= (DCONV/DUHDR)|isoeffect). We then evaluated the suitability of a piecewise linear function with 2 pieces to parametrize FMF×DUHDR as a function of dose DUHDR. We found that the magnitude of FMF generally decreases (ie, sparing increases) as a function of single-fraction dose, and that individual data series can be described by the piecewise linear function. The sparing magnitude appears organ-specific, and pooled skin-reaction data followed a consistent trend as a function of dose. Average FMF values and their standard deviations were 0.95 ± 0.11 for all data <10 Gy, 0.92 ± 0.06 for mouse gut data between 10 and 25 Gy, and 0.96 ± 0.07 and 0.71 ± 0.06 for mammalian skin-reaction data between 10 and 25 Gy and >25 Gy, respectively. The magnitude of normal tissue sparing by FLASH increases with dose and is dependent on the irradiated tissue. A piecewise linear function can parameterize currently available individual data series.

Fenofibrate Attenuates Radiation-Induced Oxidative Damage to the Skin through Fatty Acid Binding Protein 4 (FABP4).

Radiation facilities and radioactive materials have been widely used in military, industry, medicine, science and nuclear facilities, which has significantly increased the potential of large-scale, uncontrolled exposure to radiation. The skin is one of the radiosensitive organ systems and radiation-induced skin injury remains a serious concern after ionizing radiation exposure. Our previous report indicates the involvement of the peroxisome proliferator-activated receptor pathway in the response of skin tissues to ionizing radiation. PPARα is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. However, the protection of fenofibrate against ionizing radiation in skin keratinocytes and fibroblasts has not been described. The PPARα mRNA levels in irradiated and nonirradiated skin tissues of rats were determined by real-time assay. The expression of PPARα, and FABP4 were evaluated by western blot and IHC assay. The cell proliferation was detected by colony formation. The γH2AX foci and ROS levels in irradiated WS1 cells with FABP4 overexpression than in control cells were performed by Immunofluorescence assay. We found that PPARα expression was lower in the irradiated skin tissues of mouse, rat, monkey, and human patients than in their nonirradiated counterparts. PPARα fenofibrate significantly decreased radiation-induced ROS and apoptosis in a dose-dependent manner in human keratinocyte HaCaT and skin fibroblast WS1 cells. Moreover, fenofibrate significantly decreased radiation-induced ROS and malondialdehyde (MDA) levels in electron beam irradiated skin tissues of rats. Mechanistically, the proximal promoter of fatty acid binding protein 4 (FABP4) harbored three binding sites of PPARα and fenofibrate stimulated the transcription of FABP4 in skin cells. FABP4 overexpression decreased radiation-induced ROS and γH2AX foci. FABP4 inhibitor BMS309403 abrogated the ROS-eliminating activity as well as the lipid-accumulating role of fenofibrate, indicating that FABP4 mediates the radioprotective role of fenofibrate. In addition, FABP4 overexpression significantly decreased radiation-induced oxidative damage in vivo. These results confirm that fenofibrate attenuated radiation-induced oxidative damage to the skin by stimulating FABP4.

Ocular proton therapy, pencil beam scanning high energy proton therapy or stereotactic radiotherapy for uveal melanoma; an in silico study

PurposeIn radiotherapy, the dose and volumes of the irradiated normal tissues is correlated to the complication rate. We assessed the performances of low-energy proton therapy (ocular PT) with eye-dedicated equipment, high energy PT with pencil-beam scanning (PBS) or CyberKnifeR -based stereotactic irradiation (SBRT). Material and methodsCT-based comparative dose distribution between external beam radiotherapy techniques was assessed using an anthropomorphic head phantom. The prescribed dose was 60Gy_RBE in 4 fractions to a typical posterior pole uveal melanoma. Clinically relevant structures were delineated, and doses were calculated using radiotherapy treatment planning softwares and measured using Gafchromic dosimetry films inserted at the ocular level. ResultsPrecision was significantly better with ocular PT than both PBS or SBRT in terms of beam penumbra (80%–20%: laterally 1.4 vs. ≥10mm, distally 0.8 vs. ≥2.5mm). Ocular PT duration was shorter, allowing eye gating and lid sparing more easily. Tumor was excellent with all modalities, but ocular PT resulted in more homogenous and conformal dose compared to PBS or SBRT. The maximal dose to ocular/orbital structures at risk was smaller and often null with ocular PT compared to other modalities. Mean dose to ocular/orbital structures was also lower with ocular PT. Structures like the lids and lacrimal punctum could be preserved with ocular PT using gaze orientation and lid retractors, which is easier to implement clinically than with the other modalities. The dose to distant organs was null with ocular PT and PBS, in contrast to SBRT. Conclusionsocular PT showed significantly improved beam penumbra, shorter treatment delivery time, better dose homogeneity, and reduced maximal/mean doses to critical ocular structures compared with other current external beam radiation modalities. Similar comparisons may be warranted for other tumor presentations.

SY29-4 Secondary effects of radiation exposure on host immune function in cancer immunotherapy

Upon irradiation of tumor tissue, the immunogenicity of tumor cells increases and host immune function is also activated. On the other hand, as was classically known, there are certainly cases in which irradiation significantly alters the profile of immune cells in the irradiated area and negatively affects immune function. At the basic research level, the conditions under which host immune function is activated or abrogated by irradiation have gradually been clarified. Of course, the results of basic research cannot be directly applied to clinical practice, but it is also not realistic to blindly incorporate many parameters, such as irradiation dose and the order of irradiation and drug administration, into the design of clinical trials.

Successful Treatment of Radiation-Induced Colitis and Enteritis with Hyperbaric Oxygen Therapy

Introduction Previously irradiated tissue is characterized by changes including decreased vascularity, impaired cellular proliferation, and local hypoxia consistent with fibroblastic atrophy which can persist long after radiation therapy. Hyperbaric oxygen therapy has been shown to be beneficial in the treatment of complications arising from these late effects of radiation on normal tissue through enhancing fibroblast proliferation, collagen maturation, stem cell recruitment, and angiogenesis. Methods We report on three patients with debilitating radiation enterocolitis causing issues including recurrent bowel obstruction, anorexia requiring total parenteral nutrition, pain, diarrhea, fecal incontinence, dehydration, and malnutrition. Results In all three cases marked improvement was the outcome with hyperbaric treatment. Conclusion Hyperbaric oxygen therapy should be routinely considered in the treatment of radiation-induced enteritis or colitis.

Enhancement of radiation-induced EPR signal in bioapatites

Amplification of a dosimetric EPR signal in mineralized biological materials available in limited quantities has been demonstrated in this paper. Powders of irradiated enamel, dentin, and bone tissue were placed into silica ampoules with the outer diameter close to 1.4 mm. To amplify the signal, the dielectric insert in the form of cylinder with the outer radius 2.85 mm, the inner radius 0.75 mm, and the height 1.85 mm made of a high-κ and low-loss ceramic material BaTi4O9 + 8.5% ZnO has been used. It has been shown that maximum signal amplification (about an order of magnitude) has been achieved when the sample is completely inserted into this dielectric. It has been found that the line shape of the dosimetric signal is not distorted, if using the dielectric insert. Decomposition of the amplified EPR spectra allowed us to determine the relative contribution of two types of CO2– radicals to the dosimetric signal, which coincides with the literature data.

Near-infrared Nrf2 activator IR-61 dye alleviates radiation-induced lung injury

Oxidative stress injury and subsequent inflammatory response are considered to play critical roles in radiation-induced lung injury (RILI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates oxidative stress response and represses inflammation, but its therapeutic value in RILI remains elusive. Our previous studies have shown that the near-infrared (NIR) IR-61 dye evokes intracellular antioxidant defense by enhancing Nrf2 signaling and promoting anti-inflammatory effects. We established a model of RILI in mice exposed to whole-thoracic irradiation. The results showed that IR-61 treatment notably improved pulmonary functions by decreasing lung density and diminishing airway resistance. In addition, IR-61 significantly ameliorated radiation-induced inflammatory cell infiltration and proinflammatory cytokine (IL-1β, IL-6, and TNF-α) release, thereby mitigating inflammatory response. Furthermore, IR-61 mitigated radiation-induced lung fibrosis by decreasing the collagen deposition and the levels of fibrogenesis-related factors (collagen I, collagen III, α-SMA, and fibronectin). More importantly, IR-61 was found to accumulate in the mitochondria of macrophages in irradiated lung tissues. Therefore, the functions of IR-61 in macrophages were further studied in irradiated macrophage cell lines, MH-s and RAW 264.7 in vitro. The results indicated that IR-61 upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1) and decreased the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (IL-1β and IL-6) in macrophages after radiation. In summary, our study suggests that IR-61 effectively mitigates RILI by activating Nrf2 signaling in irradiated lung tissues. In particular, Nrf2-mediated anti-inflammatory and antioxidant effects in irradiated lung tissue macrophages play critical roles in protecting against RILI.

Low-Energy Electron Induced Reactions in Metronidazole at Different Solvation Conditions.

Metronidazole belongs to the class of nitroimidazole molecules and has been considered as a potential radiosensitizer for radiation therapy. During the irradiation of biological tissue, secondary electrons are released that may interact with molecules of the surrounding environment. Here, we present a study of electron attachment to metronidazole that aims to investigate possible reactions in the molecule upon anion formation. Another purpose is to elucidate the effect of microhydration on electron-induced reactions in metronidazole. We use two crossed electron/molecular beam devices with the mass-spectrometric analysis of formed anions. The experiments are supported by quantum chemical calculations on thermodynamic properties such as electron affinities and thresholds of anion formation. For the single molecule, as well as the microhydrated condition, we observe the parent radical anion as the most abundant product anion upon electron attachment. A variety of fragment anions are observed for the isolated molecule, with NO2− as the most abundant fragment species. NO2− and all other fragment anions except weakly abundant OH− are quenched upon microhydration. The relative abundances suggest the parent radical anion of metronidazole as a biologically relevant species after the physicochemical stage of radiation damage. We also conclude from the present results that metronidazole is highly susceptible to low-energy electrons.

Diagnostic Value of 18F-NOTA-FAPI PET/CT in a Rat Model of Radiation-Induced Lung Damage.

In this study, we explore the diagnostic value of a novel PET/CT imaging tracer that specifically targets fibroblast activation protein (FAP), 18F-NOTA-FAPI, in a radiation induced lung damage (RILD) rat model. High focal radiation (40, 60, or 90 Gy) was administered to a 5-mm diameter area of the right lung in Wistar rats for evaluation of RILD induction. Lung tissues exposed to 90 Gy radiation were scanned with 18F-NOTA-FAPI PET/CT and with 18F-FDG. Dynamic 18F-NOTA-FAPI PET/CT scanning was performed on day 42 post-irradiation. After in vivo scanning, lung cryosections were prepared for autoradiography, hematoxylin and eosin (HE) and immunohistochemical (IHC) staining. An animal model of RILD was established and validated by histopathological analysis. On 18F-NOTA-FAPI PET/CT, RILD was first observed on days 42, 35 and 7 in the 40, 60 and 90 Gy groups, respectively. After treatment with 90 Gy, 18F-NOTA-FAPI uptake in an area of RILD emerged on day 7 (0.65 ± 0.05%ID/ml) and reappeared on day 28 (0.81 ± 0.09%ID/ml), remaining stable for 4–6 weeks. Autoradiography and HE staining IHC staining revealed that 18F-NOTA-FAPI accumulated mainly in the center of the irradiated area. IHC staining confirmed the presence of FAP+ macrophages in the RILD area, while FAP+ fibroblasts were observed in the peripheral area of irradiated lung tissue. 18F-NOTA-FAPI represents a promising radiotracer for in vivo imaging of RILD in a dose- and time-dependent manner. Noninvasive imaging of FAP may potentially aiding in the clinical management of radiotherapy patients.

Analytical 3D modeling of accumulative heating under multipulse laser irradiation of inorganic materials and biological tissues

• Analysis of accumulative 3D heating by laser pulses using Green's function method. • Accumulative heating under the pulse-periodic action of three types of heat sources. • Dynamics of residual temperature of titanium, monocrystalline silicon, dry bone. • Results useful for optimization of technological regimes of irradiation. In this paper, using analytical methods of the theory of thermal conductivity, the issue of accumulative 3D heating under multipulse laser irradiation of inorganic materials and biological tissues is studied. For a number of practically important cases, comparatively simple analytical dependences of the residual temperature on the number of laser pulses and their repetition rate have been obtained. The limits of their applicability are discussed. Examples of the application of the developed theory for specific cases of pulse-periodic laser irradiation of various materials, in particular, titanium, monocrystalline silicon, and bone tissue, are demonstrated.

The Effect of Fat Grafting on Expansion Pressures in Expander-Based Postmastectomy Breast Reconstruction: Outcomes in Normal and Irradiated Tissues.

The impact of fat grafting on the viscoelasticity of irradiated tissues is poorly defined. We investigate the effect of subcutaneous fat grafting on postmastectomy tissue expansion in patients undergoing delayed breast reconstruction. We quantify observed viscoelastic and trophic changes of the skin envelope. We hypothesize that fat grafting changes the trophic and viscoelastic properties of the breast soft tissue envelope. Postmastectomy defects delayed more than 2 years and reconstructed with subpectoral tissue expanders were prospectively studied. Control (no irradiation, no fat grafting, n = 7), fat grafted (no irradiation, fat grafting n = 8), and irradiated plus fat grafting (irradiation, fat grafting, n = 9) groups were included. Hydrostatic pressures of the tissue expanders were measured before and immediately after expansion, and again postexpansion day 1. Pressure changes calculated as "postexpansion-relaxation interval": difference between maximal pressure at each expansion and the minimal pressure before the next expansion session. Differences were analyzed between groups. Hydrostatic pressure plots reflect the soft tissue ability to accommodate sequential expansion. Fat grafted breasts demonstrated a statistically significant increased postexpansion-relaxation interval versus the nongrafted control group (P < 0.0001). Irradiated plus fat grafting breasts achieve similar postexpansion relaxation interval to the control group (P = 0.597). These changes are observed at postoperative week 6. Viscoelastic changes impact the overall expansion time: the fat grafted group achieved total expansion 2 weeks earlier than the nongrafted control group (P = 0.019). The fat grafted, radiated group completed expansion in similar time interval as nongrafted control group. Observed viscoelastic changes impact the overall expansion time. Fat grafting in nonradiated mastectomy defects allows for shorter expansion period. Fat grating in radiated postmastectomy defects allows expansion durations equivalent to nonradiated, nonfat grafted control defects. There is a delayed effect of fat grafting observed at postoperative week 6.

Beneficial role of customized intraoral stents in radiotherapy for nasopharyngeal carcinoma.

e18642 Background: The intraoral stent is a mouth-opening device which may be used in nasopharyngeal carcinoma (NPC) patients during radiotherapy with the intention of preventing unnecessary irradiation in normal adjacent tissue. The purpose of this study was to investigate the effects of individualized intraoral stent on the intensity modulated radiation therapy(IMRT) by evaluation dose distribution and consequent radiobiological derived outcomes for NPC patients. Methods: Sixteen patients with NPC who used intraoral stent and 17 patients without intraoral stent were enrolled in this study. All patients underwent Helical Tomotherapy (HT) in our center. For the planning target volume (PTV), the conformity index (CI) and homogeneity index (HI) were used to compare two groups of HT plans (with or without intraoral stent). The mean dose of normal tissues were recorded for the two groups. Oral mucositis, gustatory sense, mouth opening and salivary function of each patients were weekly assessed at the beginning, during and after radiotherapy by clinical examination. Results: The mean dose metrics of oral cavity, mandible, left and right parotid gland in patients with intraoral stent was significantly decreased by 11.6%, 12.2%, 15.4%, and 8.7% on average, respectively (P &lt; 0.05), while the conformity index (CI, P = 0.056) and homogeneity index (HI, P = 0.676) of the tumor target showed no statistically different. The rates of grade I，II, III of oral mucositis of patients with intraoral stent were 43.15%, 43.75%, 12.50% when radiotherapy was just over. While the rates of patients with intraoral stent were 23.53%, 17.65%, 58.82%. There were significantly different in two groups (p = 0.022). There was no significant difference in the decline of taste function among each groups. But the symptoms of xerostomia and mouth opening restriction in the group with intraoral stent had been relieved significantly compared the group without intraoral stent at 1 month and 6 months after radiation. Conclusions: The custom-made intraoral stents showed promising value at sparing normal tissue during radiotherapy for NPC without affecting target dose coverage or tumor control. Clinical trial information: No. NJSH-2021NL-041.

SPAR: A randomized placebo-controlled phase 2 trial of simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer: An AGITG clinical trial.

TPS3646 Background: In retrospective studies statin use during preoperative chemo-radiation (pCRT) for rectal cancer is associated with improved overall survival, pathological tumor response and treatment toxicity. In vivo preclinical studies show that statins radiosensitize cancer cells, with improved tumor control and reduced radiation-induced gastrointestinal (GI) and skin toxicities. A prospective randomized trial is justified to confirm these clinically important benefits. Tumor regression following pCRT has strong prognostic significance, as assessed radiologically (MRI-based tumor regression grading [mrTRG]) prior to, or pathologically (pathTRG) following, surgery. Using mrTRG after each treatment phase in total neoadjuvant therapy (TNT) programs could assess incremental tumor regression and optimize patient management including surgery. Methods: Design: This double-blind phase 2 trial is recruiting 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 17 sites in New Zealand and Australia. Patients are randomized to simvastatin 40mg or placebo daily for 90 days, starting 1 week prior to pCRT, with minimization for major prognostic variables. Pelvic MRI at baseline and 6-8 weeks after pCRT will assess mrTRG. A protocol amendment allows TNT using consolidation chemotherapy after pCRT; MRI timing is unchanged. Primary objective: comparison of rates of grades 1-2 mrTRG following pCRT with simvastatin or placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4-5). Secondary objectives: comparison of rates of grades 1-2 pathTRG in resected tumors; incidence of &gt; grade 2 acute GI and non-GI adverse events (AE); incidence of late GI AE; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection post-pCRT; 3-year local recurrence rate, disease-free and cancer-specific survival; and pathological scores for radiation colitis. Tertiary and correlative objectives: association between mrTRG and pathTRG grouping; inter-observer scoring agreement on mrTRG and pathTRG; comparison of the association between tumor CD3+ and/or CD8+ T-cell infiltrates in diagnostic biopsies and pathTRG; intensity and distribution of subsets of infiltrating T-cells in irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Eligibility criteria exclude statin use within 6 weeks prior to trial entry, patients intolerant of statins, and planned use of oxaliplatin or biological agents during pCRT. Trial recruitment commenced April 2018 and 95 of 222 patients have been recruited as at 21 January 2022. Clinical trial information: ACTRN12617001087347.

The risk of cancer following high, and very high, doses of ionising radiation

It is established that moderate-to-high doses of ionising radiation increase the risk of subsequent cancer in the exposed individual, but the question arises as to the risk of cancer from higher doses, such as those delivered during radiotherapy, accidents, or deliberate acts of malice. In general, the cumulative dose received during a course of radiation treatment is sufficiently high that it would kill a person if delivered as a single dose to the whole body, but therapeutic doses are carefully fractionated and high/very high doses are generally limited to a small tissue volume under controlled conditions. The very high cumulative doses delivered as fractions during radiation treatment are designed to inactivate diseased cells, but inevitably some healthy cells will also receive high/very high doses. How the doses (ranging from <1 Gy to tens of Gy) received by healthy tissues during radiotherapy affect the risk of second primary cancer is an increasingly important issue to address as more cancer patients survive the disease. Studies show that, except for a turndown for thyroid cancer, a linear dose–response for second primary solid cancers seems to exist over a cumulative gamma radiation dose range of tens of gray, but with a gradient of excess relative risk per Gy that varies with the type of second cancer, and which is notably shallower than that found in the Japanese atomic bomb survivors receiving a single moderate-to-high acute dose. The risk of second primary cancer consequent to high/very high doses of radiation is likely to be due to repopulation of heavily irradiated tissues by surviving stem cells, some of which will have been malignantly transformed by radiation exposure, although the exact mechanism is not known, and various models have been proposed. It is important to understand the mechanisms that lead to the raised risk of second primary cancers consequent to the receipt of high/very high doses, in particular so that the risks associated with novel radiation treatment regimens—for example, intensity modulated radiotherapy and volumetric modulated arc therapy that deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low/moderate doses, and treatments using protons or heavy ions rather than photons—may be properly assessed.

Numerical analysis of thermal damage and oxygen distribution in laser irradiated tissue

Journal of Applied Mathematics and Computational Mechanics, Prace Naukowe Instytutu Matematyki i Informatyki, Politechnika Częstochowska, Scientific Research of the Institute of Mathematics and Computer Science, Czestochowa University of Technology

Histopathological Analysis of the Effect of Photodynamic Action on Post-Chemotherapy Excised Breast Cancer Tissue.

Background and objectives: Breast cancer is the most commonly diagnosed cancer in women and its mortality is increasing. Therefore, research to improve treatment is of paramount importance. One method of treatment is photodynamic therapy. Photodynamic therapy selectively stimulates apoptosis in photosensitizer-treated neoplastic breast cells as a result of cytotoxic singlet oxygen generation via collisions between triplet excited state photosensitizer and triplet ground state oxygen upon tissue irradiation. The aim of this study was to evaluate the effects of photodynamic action on cancerous breast tissue samples as a model of photodynamic therapy. Materials and Methods: Breast cancer tissue samples were obtained from post-operative material and the patterns of histopathological changes in breast cancer tissue before and after photodynamic action on post-chemotherapy tissue were evaluated. Excised tissue samples were obtained from 48 female breast cancer patients who had previously undergone chemotherapy. Breast cancer tissues for this study were taken from macroscopically visible tumors larger than 10 mm. Histopathological analysis was performed to evaluate any morphological changes prior to and after photodynamic action on the post-chemotherapy tissue samples. Eighteen breast cancer tissue samples were analyzed before chemotherapy, fifteen after chemotherapy, and fifteen samples were analyzed after chemotherapy and application of photodynamic action. The photosensitizer Rose Bengal was applied to the samples subjected to photodynamic action. Results: Photodynamic action on post-chemotherapy neoplastic tissue showed histological changes under a light microscope. The results showed that morphological changes in breast cancer tissues after chemotherapy and photodynamic action were dependent on the concentration of Rose Bengal. In all cases, follow-up imaging showed tumor shrinkage of an average of 35% from baseline size. Conclusions: Histopathological examination revealed photosensitizer-concentration-dependent changes after photodynamic action in excised post-chemotherapy tissue. The effects of photodynamic action observed in this study suggest that the application of photodynamic therapy after chemotherapy can aid in breast cancer cell eradication.

Differential effects of cancer modifying agents during radiation therapy on Ehrlich solid tumor-bearing mice: A comparative investigation of metformin and ascorbic acid

BackgroundThis work was carried out to compare the modifying roles of ascorbic and metformin during Ehrlich (ESC) tumor-bearing mice irradiation. MethodsFifty Swiss albino male mice were segmented into seven groups, including one control group and six Ehrlich induced tumors treated with ascorbic, ascorbic plus radiation, metformin, metformin plus radiation, and radiation only. Many tests, including behavioral, biochemical, immunohistochemistry, gene expression, DNA fragmentation, oxidative stress markers, and EPR, were performed to interrogate the modifying effects on tumor and liver tissues. ResultsRemarkable apoptosis was found in metformin irradiated animals compared to irradiated ascorbic counterparts. The irradiated metformin mice showed the greatest reduction in PCNA. There was a significant reduction of DNA fragmentation in the liver tissues of the irradiated metformin group. Irradiated metformin and irradiated ascorbic acid animals showed a reduced signal of ERK as well as c-Fos genes. There was a tendency of metformin and metformin irradiated animals to reduce MDA levels in liver tissues. ESC-bearing mice treated with ascorbic or metformin showed an improvement in the spontaneous alternation percentage (SAP%) and improved short-term memory. There was also an improvement in long memory tests. ConclusionsThe study added more preclinical evidence on the utility of metformin in cancer treatment during radiotherapy. Metformin was shown to reduce lipid peroxidation in irradiated healthy tissues, increase tumor cytotoxicity, downregulate critical pathways involved in tumor progression and proliferation, and enhance tumor apoptosis. Controlled clinical trials using metformin are highly warranted.

In Vivo Characterization of a Red Light-Activated Vasodilation: A Photobiomodulation Study.

Nitric oxide dependent vasodilation is an effective mechanism for restoring blood flow to ischemic tissues. Previously, we established an ex vivo murine model whereby red light (670 nm) facilitates vasodilation via an endothelium derived vasoactive species which contains a functional group that can be reduced to nitric oxide. In the present study we investigated this vasodilator in vivo by measuring blood flow with Laser Doppler Perfusion imaging in mice. The vasodilatory nitric oxide precursor was analyzed in plasma and muscle with triiodide-dependent chemiluminescence. First, a 5–10 min irradiation of a 3 cm2 area in the hind limb at 670 nm (50 mW/cm2) produced optimal vasodilation. The nitric oxide precursor in the irradiated quadriceps tissue decreased significantly from 123 ± 18 pmol/g tissue by both intensity and duration of light treatment to an average of 90 ± 17 pmol/g tissue, while stayed steady (137 ± 21 pmol/g tissue) in unexposed control hindlimb. Second, the blood flow remained elevated 30 min after termination of the light exposure. The nitric oxide precursor content significantly increased by 50% by irradiation then depleted in plasma, while remained stable in the hindlimb muscle. Third, to mimic human peripheral artery disease, an ameroid constrictor was inserted on the proximal femoral artery of mice and caused a significant reduction of flow. Repeated light treatment for 14 days achieved steady and significant increase of perfusion in the constricted limb. Our results strongly support 670 nm light can regulate dilation of conduit vessel by releasing a vasoactive nitric oxide precursor species and may offer a simple home-based therapy in the future to individuals with impaired blood flow in the leg.

Technological advancements in brachytherapy of cancer

Emerging technological advancements in brachytherapy, when used alone or combined with conventional therapies have improved the therapeutic efficacy, leading to enhanced patient survival. Advancements in the use of various isotopes, delivery methods, incorporation of 3D imaging, and 3D printing, have significantly optimized the treatment planning and increased dose delivery accuracy, achieving high target volume irradiation and low normal tissue exposure. Real-time guidance during the implanting of radiation source into the tumor tissue has shown the promising outcome of brachytherapy. Integration of precise in vivo dosimetry methods have reduced the deviations in the measured dose, and associated operational errors, ensuring brachytherapy is accurate, and delivering more targeted doses over the course of the treatment. The use of new forms of radiation sources such as needles, pellets, tubes, overcomes the risk of source clumping and migration. Personalized applicators, biodegradable brachytherapy systems, injectable radiolabeled thermoresponsive polymers offer yet another promising brachytherapy approaches. Here we describe the recent technological innovations in brachytherapy and discuss various strategies adopted to overcome the associated challenges in preclinical and clinical settings.