Greater Biological Effectiveness Research Articles

Systematic Review of Hypofractionated Radiation Therapy for the Treatment of Oesophageal Squamous Cell Carcinoma and Oesophageal Adenocarcinoma

Background and aimThere has been limited progress made in improving the suboptimal outcomes delivered by conventionally fractionated radiotherapy (RT) for oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC). A greater biological effect may be achieved using hypofractionated RT (HFRT), though the toxicity, tolerability and efficacy of this approach in OAC and OSCC is uncertain. MethodsA systematic literature review was carried out in accordance with Preferred Reporting Items for Systematic Reviews guidance. Medline, EMBASE, PubMed, Cochrane, CINAHL, Scopus and Web of Science databases were searched for terms relating to HFRT (>2.4Gy per fraction) for OAC or OSCC. All relevant clinical studies published between January 2000 and April 2023 were included. Study quality was assessed using predefined criteria. ResultsNinety-six studies were screened and 20 subsequently included, together incorporating 1208 patients. Fourteen studies focussed on neoadjuvant or definitive treatment. These were predominantly retrospective (n = 10, 71%) though two (n = 2, 14%) early phase trials were identified. Most focussed on OSCC (n = 7, 47%) or mixed OSCC/OAC (n = 6, 43%) populations. Four (28.6%) included a conventionally fractionated chemoradiotherapy (CRT) comparator, against which median overall (mOS) and progression free survival outcomes from HFRT did not differ. Reported mOS for HFRT ranged between 29-36 months at 2.5–3.125Gy per fraction (total dose 50–60Gy) for OAC and OSCC combined. Toxicity and tolerability with HFRT was comparable with conventionally fractionated CRT up to, but not exceeding, 5Gy. Three (50%) of the six palliative-intent studies were early phase trials and most (n = 4, 67%) focussed on OAC and OSCC. Response rates with HFRT in the palliative setting were 63.6–88.0%. ConclusionThese data provide evidence in OAC/OSCC for promising efficacy and an acceptable toxicity profile for moderately HFRT, alone or with concurrent chemotherapy. These data should prompt prospective, randomised comparisons of HFRT and conventionally fractionated CRT and single-modality RT schedules. Registration detailsPROSPERO; CRD42023457791.

DNA break clustering as a predictor of cell death across various radiation qualities: influence of cell size, cell asymmetry, and beam orientation

Abstract Cosmic radiation, composed of high charge and energy (HZE) particles, causes cellular DNA damage that can result in cell death or mutation that can evolve into cancer. In this work, a cell death model is applied to several cell lines exposed to HZE ions spanning a broad range of linear energy transfer (LET) values. We hypothesize that chromatin movement leads to the clustering of multiple double strand breaks (DSB) within one radiation-induced foci (RIF). The survival probability of a cell population is determined by averaging the survival probabilities of individual cells, which is function of the number of pairwise DSB interactions within RIF. The simulation code RITCARD was used to compute DSB. Two clustering approaches were applied to determine the number of RIF per cell. RITCARD outputs were combined with experimental data from four normal human cell lines to derive the model parameters and expand its predictions in response to ions with LET ranging from ~0.2 keV/μm to ~3000 keV/μm. Spherical and ellipsoidal nuclear shapes and two ion beam orientations were modeled to assess the impact of geometrical properties on cell death. The calculated average number of RIF per cell reproduces the saturation trend for high doses and high-LET values that is usually experimentally observed. The cell survival model generates the recognizable bell shape of LET dependence for the relative biological effectiveness (RBE). At low LET, smaller nuclei have lower survival due to increased DNA density and DSB clustering. At high LET, nuclei with a smaller irradiation area—either because of a smaller size or a change in beam orientation—have a higher survival rate due to a change in the distribution of DSB/RIF per cell. If confirmed experimentally, the geometric characteristics of cells would become a significant factor in predicting radiation-induced biological effects. Insight Box: High-charge and energy (HZE) ions are characterized by dense linear energy transfer (LET) that induce unique spatial distributions of DNA damage in cell nuclei that result in a greater biological effect than sparsely ionizing radiation like X-rays. HZE ions are a prominent component of galactic cosmic ray exposure during human spaceflight and specific ions are being used for radiotherapy. Here, we model DNA damage clustering at sub-micrometer scale to predict cell survival. The model is in good agreement with experimental data for a broad range of LET. Notably, the model indicates that nuclear geometry and ion beam orientation affect DNA damage clustering, which reveals their possible role in mediating cell radiosensitivity.

The fungicides effectiveness in soybean cultivation under irrigation in the conditions of the Central Caucasus

Studies conducted in 2018-2020 allowed us to determine the best protection system and biological effectiveness of fungicides when growing soybeans under irrigation in the conditions of the Central Caucasus. Soybeans were grown on ordinary chernozem after winter wheat on the basis of LLC "Agrosakhar" (Izobilnensky district, Stavropol Territory). Irrigation was carried out by sprinkling. Phytoexpertize of soybean seeds before sowing revealed the presence of infection represented by fungi from the genera: Alternaria, Ascochyta, Fusarium, Peronospora, Sclerotinia, Septoria, and bacteria from the genera: Xanthomonas, Pseudomonas. Fungicides were used for seed etching: Maxim, KS; Delit Pro, KS; TMTD, VSK; Protect,KS. During the budding phase, the crops were treated with fungicides Optimo, CS and Acanto Plus, CS. The maximum effectiveness in the fight against fusarium was established when seeds were treated with the fungicide Delit Pro, CS (0.5 l /t) – the prevalence of fusarium decreased by 82.0, and the development of the disease by 70.4%. The fungicide Acanto Plus, CS (0.6 l/ha) was more effective compared to the standard by an average of 5.7–12.4%. Combined application of seed pickling Divides Pro, CS (0.5 l /t), and the treatment of crops in the budding phase with the fungicide Acanto Plus, CS (0.6 l /ha) was characterized by the greatest effect: the number of plants affected by peronosporosis decreased by 84.3% and the development of the disease decreased by 81.2%. The greatest biological effect in the fight against soybean bacteriosis was after seed etching with TMTD, VSK (6 l/t) and treatment of vegetative plants with Acanto Plus fungicide, CS (0.6 l/ha), the prevalence of bacteriosis decreased by 69.4%, and development - by 39.8%. In this variant, the highest yield of soybean seeds was obtained at 3.36 t/ha, which is more than the control variant by 0.64 t/ha and more than the standard by 0.11 t/ha. The profitability of growing soybean seeds using the studied protection systems, depending on the fungicides used, varied from 89.7 (Protect, CS (2.0 l/t); Optimo, CS (0.5 l/ha)) up to 103.4% (TMTD, VSK (6.0 l/t); Acanto Plus, CS (0.6 l/ha)).

Effect of Nanopriming with Selenium Nanocomposites on Potato Productivity in a Field Experiment, Soybean Germination and Viability of Pectobacterium carotovorum

In recent decades, the use of nanocomposites (NCs) in crop production has been actively studied. We have previously shown that chemically synthesized selenium nanocomposites (Se NCs) based on natural polymeric matrices of arabinogalactan (Se/AG NCs), carrageenan (Se/CAR NCs), and starch (Se/ST NCs) stimulated the growth and development of potatoes in vitro and had an antibacterial effect against the phytopathogen Clavibacter sepedonicus. It is important to confirm that the results obtained in the laboratory are also reproducible in the field conditions of crop cultivation. In addition, the applications of NCs can be expanded if a wider range of their biological activity is revealed, and the effect on other types of cultivated plants and phytopathogens is shown. In this regard, the purpose of this research was to study the effect of nanopriming with Se NCs on the productivity of potatoes in a field experiment, the germination of soybeans, and the viability of the phytopathogen Pectobacterium carotovorum under in vitro conditions. The study included the use of traditional methods of conducting a field experiment in natural growing conditions, also using microbiological cultures and studying the bacterial profile from the endosphere of potato tubers by the imprint method, germinating Glycine max L. soybean seeds after nanopriming in Petri dishes, followed by the measurement of morphometric and biochemical parameters such as the activity of antioxidant enzymes and content of diene conjugates. Based on the results of field experiments, it was found that the preplant treatment of tubers with Se/AG and Se/CAR NCs stimulated a significant increase in the number of stems in potato plants and tubers per plant, but for Se/AG NC, the increase was observed only in 2020 and 2022, and the stimulating effect of Se/AG and Se/CAR NCs on the weight of tubers was observed only in 2020. In the yield structure, the proportion of marketable seed tubers was increased under the influence of all Se NCs. Endosphere cultures from tubers showed that bacteria were present in only 56% of the tubers in the control, while 78% of the tubers obtained from plants grown from seed tubers treated with Se/AG NC and 100% of the tubers from plants grown from seed tubers treated with Se/ST and Se/CAR NCs contained bacteria. The bacteria were represented by both spore-forming Gram-positive and Gram-negative bacteria of various sizes. The results presented in this article and previously published data showed that the maximum diversity of bacteria was observed after treatment with Se/ST NC. Experiments on potatoes showed that Se/AG NC had the greatest biological effect. In addition, the growth-stimulating effect of these NCs on the biomass of the roots of soybean seedlings was shown. It activated the antioxidant enzymes and reduced the level of diene conjugates (DCs), the amount of which increased significantly after seed biopriming with the phytopathogen Pectobacterium carotovorum. The antibacterial effect of Se/AG NC in relation to the P. carotovorum was observed as a reduction in the growth of the bacterial culture, biofilm formation, and dehydrogenase activity of cells. Thus, it has been shown that Se/AG NC has a stimulating effect on such agriculturally important crops as potatoes and soybeans, as well as an antibacterial effect against Gram-negative and Gram-positive phytopathogenic bacteria.

Chondrosarcoma Resistance to Radiation Therapy: Origins and Potential Therapeutic Solutions

Chondrosarcoma is a malignant cartilaginous tumor that is particularly chemoresistant and radioresistant to X-rays. The first line of treatment is surgery, though this is almost impossible in some specific locations. Such resistances can be explained by the particular composition of the tumor, which develops within a dense cartilaginous matrix, producing a resistant area where the oxygen tension is very low. This microenvironment forces the cells to adapt and dedifferentiate into cancer stem cells, which are described to be more resistant to conventional treatments. One of the main avenues considered to treat this type of tumor is hadrontherapy, in particular for its ballistic properties but also its greater biological effectiveness against tumor cells. In this review, we describe the different forms of chondrosarcoma resistance and how hadrontherapy, combined with other treatments involving targeted inhibitors, could help to better treat high-grade chondrosarcoma.

Antioxidant system of the body of young Ukrainian beef cattle under the action of microelements

Active forms of oxygen are formed in the course of the organism's vital activity in biochemical reactions. These forms, when the pro/antioxidant balance is disturbed, trigger a cascade of lipid peroxidation, which can be the cause of the development of various pathological conditions. To prevent the negative influence of lipid peroxidation products in the body, a powerful antioxidant system is activated. This system consists of an enzymatic and a non-enzymatic link. An important aspect of the normal functioning of this system is the provision of the body with important trace elements. A number of minerals are included in the active center of antioxidant enzymes or have an effect on the reactions of non-enzymatic antioxidants. Research was conducted on fattening bulls of the Ukrainian meat breed. During the monitoring of microelements in feed, it was found that the vast majority of farm feed was deficient in copper, selenium and manganese and for this reason the animals consumed an insufficient amount of these minerals. These data were confirmed by the low content of these trace elements in blood serum. The addition of inorganic salts of microelements to the basic diet led to an increase in the concentration of copper, manganese and selenium in the blood serum by 20.5%, 37.3% and 23.9%. The study of the content of lipid peroxidation products showed that during the 30 days of the experiment, the level of lipid hydroperoxide increased by 25.5%, diene conjugates by 22.8%, and malonic dialdehyde by 22.0%. This indicates that against the background of increased age-related metabolism in the body of young animals, the oxidation-reduction reactions that are a predictor of the start of peroxidation processes increase. It was also noted that with a deficiency of certain trace elements, the activity of both the enzymatic and non-enzymatic links of the antioxidant system was reduced. Thus, in 30 days, the level of catalase, superoxide dismutase, and glutathione peroxidase decreased by 9.4%, 15.3%, and 13.0%, respectively. During this time, the content of tocopherol and ceruloplasmin decreased by 16.8% and 9.8%. Additives also had a positive effect on the activity of the antioxidant system by increasing its components. Additives of trace elements had different effects on the activity of antioxidant enzymes. The greatest effect on the level of catalase and superoxide dismutase was observed when copper salts were added, when the increase of these enzymes was noted by 1.11 and 1.23 times, respectively. Accordingly, the level of glutathione peroxidase was the highest in animals that received additional selenium – 1.21 times. The addition of copper also had the greatest biological effect on the important non-enzymatic component of antioxidant protection – ceruloplasmin. Its level increased by 1.24 times under the action of copper sulfate. The level of tocopherol was higher under the action of manganese, when its concentration was 1.11 times higher than the control. Against this background, there was a decrease in the products of lipid peroxidation: lipid hydroperoxides – 1.19 times under the action of selenium; diene conjugates – by 1.22 times and malonіс dialdehyde – by 1.11 times under the influence of copper and manganese compounds, respectively.

Using 157Gd doped carbon and 157GdF4 nanoparticles in proton-targeted therapy for effectiveness enhancement and thermal neutron reduction: a simulation study

There are two major problems in proton therapy. (1) In comparison with the gamma-ray therapy, proton therapy has only ~ 10% greater biological effectiveness, and (2) the risk of the secondary neutrons in proton therapy is another unsolved problem. In this report, the increase of biological effectiveness in proton therapy has been evaluated with better performance than 11B in the presence of two proposed nanomaterials of 157GdF4 and 157Gd doped carbon with the thermal neutron reduction due to the presence of 157Gd isotope. The present study is based on the microanalysis calculations using GEANT4 Monte Carlo tool and GEANT4-DNA package for the strand breaks measurement. It was found that the proposed method will increase the effectiveness corresponding to the alpha particles by more than 100% and also, potentially will decrease the thermal neutrons fluence, significantly. Also, in this work, a discussion is presented on a significant contribution of the secondary alpha particles in total effectiveness in proton therapy.

Differential responses to 223Ra and Alpha-particles exposure in prostate cancer driven by mitotic catastrophe.

IntroductionRadium-223 (223Ra) has been shown to have an overall survival benefit in metastatic castration-resistant prostate cancer (mCRPC) involving bone. Despite its increased clinical usage, relatively little is known regarding the mechanism of action of 223Ra at the cellular level.MethodsWe evaluated the effects of 223Ra irradiation in a panel of cell lines and then compared them with standard X-ray and external alpha-particle irradiation, with a particular focus on cell survival and DNA damage repair kinetics.Results 223Ra exposures had very high, cell-type-dependent RBE50% ranging from 7 to 15. This was significantly greater than external alpha irradiations (RBE50% from 1.4 to 2.1). These differences were shown to be partially related to the volume of 223Ra solution added, independent of the alpha-particle dose rate, suggesting a radiation-independent mechanism of effect. Both external alpha particles and 223Ra exposure were associated with delayed DNA repair, with similar kinetics. Additionally, the greater treatment efficacy of 223Ra was associated with increased levels of residual DNA damage and cell death by mitotic catastrophe.ConclusionsThese results suggest that 223Ra exposure may be associated with greater biological effects than would be expected by direct comparison with a similar dose of external alpha particles, highlighting important challenges for future therapeutic optimization.

Carbon-ion radiotherapy for urological cancers.

Carbon-ions are charged particles with a high linear energy transfer, and therefore, they make a better dose distribution with greater biological effects on the tumors compared with photons and protons. Since prostate cancer, renal cell carcinoma, and retroperitoneal sarcomas such as liposarcoma and leiomyosarcoma are known to be radioresistant tumors, carbon-ion radiotherapy, which provides the advantageous radiobiological properties such as an increasing relative biological effectiveness toward the Bragg peak, a reduced oxygen enhancement ratio, and a reduced dependence on fractionation and cell-cycle stage, has been tested for these urological tumors at the National Institute for Radiological Sciences since 1994. To promote carbon-ion radiotherapy as a standard cancer therapy, the Japan Carbon-ion Radiation Oncology Study Group was established in 2015 to create a registry of all treated patients and conduct multi-institutional prospective studies in cooperation with all the Japanese institutes. Based on accumulating evidence of the efficacy and feasibility of carbon-ion therapy for prostate cancer and retroperitoneal sarcoma, it is now covered by the Japanese health insurance system. On the other hand, carbon-ion radiotherapy for renal cell cancer is not still covered by the insurance system, although the two previous studies showed the efficacy. In this review, we introduce the characteristics, clinical outcomes, and perspectives of carbon-ion radiotherapy and our efforts to disseminate the use of this new technology worldwide.

BIOLOGICAL EFFECTIVENESS OF BIOFUNGICIDE METABACTERIN, WP IN THE PROTECTION OF GLYCINE HISPIDA MAXIM., AND PISUM SATIVUM L. FROM ASCOCHITOSIS AND SOLANUM TUBEROSUM L. FROM LATE BLIGHT IN THE CONDITIONS OF THE ALTAI OB REGION

Continuous application of chemical crop protection products resulted in an agrocenosis imbalance. The number of pathogenic organisms does not decrease. Thus, one needs to search for newer and more effective active ingredients. New disease-resistant varieties quickly lose their resistance due to the high mutation activity of pathogenic organisms. In agriculture, the following fungal diseases are predominant: (1) Septoria blight, (2) Alternaria blight, (3) powdery mildew, (4) late blight, (5) rust, and others. Introducing biofungicides into plant protection systems can help reduce fungal infections in crops. For the first time in the conditions of the forest-steppe of the Ob region, the prospects of using the biofungicide Metabacterin, WP on soybean, pea, and potato crops are shown. The active ingredient in the product is a strain of the bacteria Methylobacterium extorquens Bousfieldand Green (1985), Streptomyces hygroscopicus Yüntsenetal. (19560, Bacillus subtilis Cohn (1872) and Validomycin. The paper aims to evaluate the effectiveness of the biofungicide Metabacterin, WP against Ascochyta blight on soybeans and peas, and late blight on potatoes in the forest-steppe of the Ob region of Altai. We evaluated the spreading, development, and biological effectiveness of the tested product and chemical fungicides according to the registration tests of fungicides in agriculture. We tested the product in an area of sufficient moisture. Weather conditions favored the growth and development of plants and the development of pathogens (particularly Ascochyta blight on legume crops and late blight on potatoes). Before the symptom expression of diseases, preventive spraying had greater biological effectiveness on peas and potatoes than treatment on soybeans (where the spraying of crops coincided with the appearance of the first symptoms of diseases). There is a high prevalence of Ascochyta blight (89.3%–90.7%). However, the intensity of development in the variants with biofungicide treatment was 10% lower than in the control variant. The potatoes showed high biological effectiveness of the product Metabacterin, WP, relative to the variant without protective treatment, and 5% higher than the variant with the use of chemical fungicides. The biofungicide Metabacterin, WP on potatoes, and peas had a long-lasting effect up to the ripening of the crop.

Controlled Release of Caffeic Acid and Pinocembrin by Use of nPSi-βCD Composites Improves Their Antiangiogenic Activity.

Although polyphenols have great pharmacological potential, the main disadvantage is that they have low bioavailability at the desired site. Thus, the use of biocompatible systems for drug delivery is a strategy that is currently gaining great interest. The objective of this study is to evaluate the effect of microencapsulation of caffeic acid and pinocembrin on the antioxidant and antiangiogenic activity of both polyphenols, by the use of nPSi-βCD composite microparticles. For this HUVEC, cells were exposed to H2O2 and to treatments with polyphenols in solution and loaded in the composite microparticle. The polyphenols were incorporated into a microparticle using nanoporous silicon, chitosan and a β-cyclodextrin polymer as the biomaterial. The evaluation of the antiangiogenic effect of the treatments with polyphenols in solution and microencapsulated was carried out through functional tests, and the changes in the expression of target genes associated with the antioxidant pathway and angiogenesis was performed through qPCR. The results obtained show that the caffeic acid and pinocembrin have an antioxidant and antiangiogenic activity, both in solution as microencapsulated. In the caffeic acid, a greater biological effect was observed when it was incorporated into the nPSi-βCD composite microparticle. Our results suggest that the nPSi-βCD composite microparticle could be used as an alternative oral drug administration system.

Synthesis of Highly Stabilized AuNPs Using 3,5-Dinitrobenzoic Acid and Sodium Acetate as Capping Agents in an Aqueous Solution and their Bioactivity

Gold nanoparticles (AuNPs) have received considerable attention recently because of their chemical properties and potential applications in the medical field.Monodispersed AuNPs in this paper are successfully synthesized by using some stabilized ligands including 3,5-dinitrobenzoic acid (DNBA) and sodium acetate (SA) dispersible in aqueous media, where NaBH4 was used as a reducing agent to reduce KAuCl4 from Au (III) to Au (0).The synthesized AuNPs are characterized by using UV–Vis spectroscopy to evaluate their surface plasmon resonance (SPR) absorption in a wavelength range of 500–650 nm. The size and morphology of AuNPs were determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS), where the results displayed that AuNPs with a strong SPR peak around 530 nm and 536 nm with an average size of 10 ± 1.2 nm and 14.0 ± 0.9 nm at the initial time for both DNBA-AuNP and SA-AuNP respectively. The synthesized AuNPs illustrate perfect chemical stability for more than 24 weeks in an aqueous solution. Therefore, the size of DNBA-AuNP was smaller and most stable than SA-AuNP, which may be due to 2 nitro groups that have resonance with the benzene ring leading to an increase in the stability of AuNPs.The stability of AuNPs in this work was monitored at a range of pH 2-12. Where high stability was showed at pH 6.6 ± 0.5, while the aggregation appears at more than pH 10 and less than pH.3.5.Herein, in this paper AuNPs have shown remarkable results against multi-drug resistance Pseudomonas aeruginosa. AuNP functionalized by SA ligand is shown to have a greater biological effect and be more effective than DNBA-AuNP. Due to the high stability of AuNP prepared in this work, it can be further tested to be an improved choice for more biomedical applications in the future.

Proton Therapy for Head and Neck Cancer: Current Clinical Applications and Future Direction

Intensity-modulated radiation therapy (IMRT) using X-rays is a standard technique implemented for treating head and neck cancer (HNC). Compared to 3D conformal RT, IMRT can significantly reduce the radiation dose to surrounding normal tissues by using a highly conformal dose to the tumor. Proton therapy is a type of RT that uses positively charged particles named protons. Proton therapy has a unique energy deposit (i.e., Bragg peak) and greater biological effectiveness than that of therapy using X-rays. These inherent properties of proton therapy make the technique advantageous for HNC treatment. Recently, advanced techniques such as intensity-modulated proton therapy have further decreased the dose to normal organs with a higher conformal dose to the tumor. The usage of proton therapy for HNC is becoming widespread as the number of operational proton therapy centers has increased worldwide. This paper aims to present the current clinical evidence of proton therapy utility to HNC clinicians through a literature review. It also discusses the challenges associated with proton therapy and prospective development of the technique. Key Words: Proton therapy, Intensity-modulated proton therapy, Radiation therapy, Head and neck cancer

Sex differences in cholinergic regulation of dopamine release mechanisms underlying reward learning

Substance use disorder (SUD) is a chronic, recurring brain disease characterized by significant dysfunction in reward-seeking behavior. SUD research focused on understanding the neural mechanisms in the brain's reward circuitry has overwhelmingly utilized male subjects, even though epidemiological evidence shows that women are the most susceptible population. The neural control of reward is dependent on tonic/phasic dopamine release in the NAc that are subject to heavy modulation by cholinergic interneurons (ChATs) signaling through nicotinic acetylcholine receptors (nAChRs) located directly on dopamine terminals; a process that is essential to encoding information about environmental reward predictive cues. Importantly, dopamine release in the NAc can be elicited completely independent of action potential firing from the soma – through activation of α4β2*-containing nAChRs located on dopamine terminals - highlighting the critical role that this local microcircuit plays in controlling dopamine neurotransmission. Previous work suggests that ChAT control of reward learning and regulation of dopamine release through nAChRs is fundamentally different between males and females, yet the reward information encoding processes and mechanisms that underlie sex differences in reward learning are largely unknown. To understand how the neural circuits that underlie reward learning are differentially modulated between males and females, we took a multifaceted approach to outlining sex differences in ChAT regulation of tonic/phasic dopamine release mechanisms through nAChR modulation in the NAc. Using fast-scan cyclic voltammetry paired with pharmacology we measured the potentiating effect of 17β-estradiol with and without application of the selective α4β2-nAChR antagonist, Dhβe, on sub-second tonic/phasic dopamine release in NAc slices from male and naturally cycling female mice. First, we found that 17β-estradiol enhanced tonic dopamine release in both sexes with greater biological effects in males. Additionally, 17β-estradiol potentiated dopamine release in response to phasic stimulation patterns in males with no significant effect in females. To investigate how ovarian activity affects the ability of 17β-estradiol to potentiate tonic/phasic dopamine release, ovariectomized females were utilized, showing a similar potentiating effect of 17β-estradiol on tonic/phasic dopamine release as seen in the males. Finally, blocking α4β2*-nAChRs with Dhβe reduced the potentiating effects of 17β-estradiol on dopamine release in males and ovariectomized females, but had no effect in female mice with intact ovaries. This data suggests that circulating ovarian hormones alter the effect of α4β2*-nAChRs on dopamine terminals to regulate dopamine release in the NAc. Moving forward, it will be critical to directly link these sex differences to reward learning for the development of sex-specific pharmacotherapies to treat SUD.

Potential Application of Upconverting Nanoparticles for Brain Photobiomodulation.

Brain photobiomodulation (PBM) describes the use of visible to near-infrared light for modulation or stimulation of the central nervous system in both healthy individuals and diseased conditions. Although the transcranial approach to delivering light to the head is the most common technique to stimulate the brain, delivery of light to deeper structures in the brain is still a challenge. The science of nanoparticle engineering in combination with biophotonic excitation could provide a way to overcome this problem. Upconversion is an anti-Stokes process that is capable of transforming low energy photons that penetrate tissue well to higher energy photons with a greater biological effect, but poor tissue penetration. Wavelengths in the third optical window are optimal for light penetration into brain tissue, followed by windows II, IV, and I. The combination of trivalent lanthanide ions within a crystalline host provides a nanostructure that exhibits the upconversion phenomenon. Upconverting nanoparticles (UCNPs) have been successfully used in various medical fields. Their ability to cross the brain-blood barrier and their low toxicity make them a good candidate for application in brain disorders. It is possible that delivery of UCNPs to the brainstem or deeper parts of the cerebral tissue, followed by irradiation using light wavelengths with good tissue penetration properties, could allow more efficient PBM of the brain.

Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation

Chondrosarcoma is a malignant tumor that arises from cartilaginous tissue and is radioresistant and chemoresistant to conventional treatments. The preferred treatment consists of surgical resection, which might cause severe disabilities for the patient; in addition, this procedure might be impossible for inoperable locations, such as the skull base. Carbon ion irradiation (hadron therapy) has been proposed as an alternative treatment, primarily due to its greater biological effectiveness and improved ballistic properties compared with conventional radiotherapy with X-rays. The goal of this study was to characterize the genetic mutations of a grade III chondrosarcoma cell line (CH2879) and examine the cellular responses to conventional radiotherapy (X-rays) and hadron therapy (proton and carbon ions) in the presence of the PARP inhibitor Olaparib. To better understand PARP inhibition, we first analyzed the formation of poly-ADP ribose chains by western blot; we observed an increase in its signal after irradiation, which disappeared on addition of the PARP inhibitor. PARPi enhanced ratio of approximately 1.3, 1.8, and 1.5 following irradiation of cells with X-rays, protons, and C-ions, respectively, as detected by clonogenic assay. The decrease in cell survival was confirmed by proliferation assay. The radiosensitivity of CH2879 cells was associated with mutations in homologous recombination repair genes, such as RAD50, SMARCA2 and NBN. This study demonstrates the capacity of the PARP inhibitor Olaparib to radiosensitize mutated chondrosarcoma cells to conventional photon irradiation, proton and carbon ion irradiation.

Evaluation of the cytotoxicity on breast cancer cell of extracts and compounds isolated from Hyptis pectinata (L.) poit

Hyptis pectinata is a herb popularly used in Brazil for the treatment of inflammations, pain, bacterial infections and cancer. In the present study, inflorescences (MPIn), leaves (MPL), branches (MPB), root (MPR) extracts and three compounds isolated from MPIn were assayed against breast tumor cell lines. The structures of the three compounds (pectinolide J, hyptolide and pectinolide E) were determined by means of spectroscopic analysis. Pectinolide J was isolated for the first time. The MPIn, MPL and MPR exhibited specific antiproliferative activity on tumor cell lines when compared to normal cell lines with IC50 of 52.01 ± 0.64, 45.91 ± 0.02 μg/mL and 82.84 ± 0.03 μg/mL, respectively. Although the isolated substances did not present good antiproliferative activity, when the three were associated, a greater biological effect was observed, suggesting a synergistic effect. Hyptolide (5.6 ± 0.4 μg/mL) showed IC50 sufficiently low to be considered as a drug prototype.

DNA damage response of clinical carbon ion versus photon radiation in human glioblastoma cells

Background and purposeCarbon ion radiotherapy is a promising therapeutic option for glioblastoma patients due to its high physical dose conformity and greater biological effectiveness than photons. However, the biological effects of carbon ion radiation are still incompletely understood. Here, we systematically compared the biological effects of clinically used carbon ion radiation to photon radiation with emphasis on DNA repair. Materials and methodsTwo human glioblastoma cell lines (U87 and LN229) were irradiated with carbon ions or photons and DNA damage response was systematically analyzed, including clonogenic survival, induction and repair of DNA double-strand breaks (DSBs), cell cycle arrest and apoptosis or autophagy. γH2AX foci were analyzed by flow cytometry, conventional light microscopy and 3D superresolution microscopy. ResultsDSBs were repaired delayed and with slower kinetics after carbon ions versus photons. Carbon ions caused stronger and longer-lasting cell cycle delays, predominantly in G2 phase, and a higher rate of apoptosis. Compared to photons, the effectiveness of carbon ions was less cell cycle-dependent. Homologous recombination (HR) appeared to be more important for DSB repair after carbon ions versus photons in phosphatase and tensin homolog (PTEN)-deficient U87 cells, as opposed to PTEN-proficient LN229 cells. ConclusionCarbon ions induced more severe DSB damage than photons, which was repaired less efficiently in both cell lines. Thus, carbon ion radiotherapy may help to overcome resistance mechanisms of glioblastoma associated with DNA repair for example in combination with repair pathway-specific drugs in the context of personalized radiotherapy.

Quality of Life Outcome in Patients with Localized Prostate Cancer after Hypofractionatied Carbon-Ion Radiation Therapy

Carbon ion radiotherapy (C-ion RT) has excellent dose conformity and greater biological effectiveness than X-ray and proton beam. Moreover hypofractionatied schedule is better than conventional fractionated schedule to treat prostate cancer (PC) from the view point of biological aspect. The excellent outcome of C-ion RT for the patients with localized PC was already published. In our country, national health insurance has started to cover C-ion RT for localized PC since April 2018. Our hypothesis is that quality of life (QOL) outcome is maintained after hypofractionatied C-ion RT. The purpose of this study is to assess QOL outcome of the patients with localized PC received hypofractionatied C-ion RT. QOL outcome of 213 patients with localized PC received C-ion RT from August 2013 to July 2014 were analyzed. The prescribed dose of the C-ion RT was 51.6 Gy (RBE) in 12 fractions in 3 weeks. The median age at the time of the C-ion RT was 68 (range 46-88). The number of the patients of low, intermediate and high risk according to D’Amico criteria were 28 (13.1%), 82 (38.5%) and 103 (48.4%), respectively. Out of the 213 patients, 186 patients (87.3%) received hormonal therapy (HT). Two QOL assessment questionnaires of International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC) were used at 6 points; before the C-ion RT, the last day of the C-ion RT, and 6, 12, 24 and 36 months after the C-ion RT. Among a subgroup of the 23 low risk patients not received any HT, the EPIC sexual domain was assessed in addition. The median follow-up time was 38.3 months (range 0.7-52.1). At the time of this analysis, 9 patients recurred and no patient experienced grade 3 and worse adverse event. The EPIC scores were available for 97.7%, 90.6%, 86.9%, 85.0%, 80.8% and 75.1% at the 6 points as above, respectively. The average IPSS and EPIC scores of the analyzed 213 patients are noted in the table. The IPSS score and the EPIC urinary score worsened temporarily during the C-ion RT and recovered to the baseline level. The EPIC bowel, sexual and hormonal scores did not change. The EPIC sexual scores of the subgroup of the 23 low risk patients not received any HT are also noted in the table, the score slightly worsened temporarily during the C-ion RT and recovered to the baseline level.Abstract SU_35_2341; Table 1The average scores of IPSS and EPICBefore the C-ion RTThe last day of the C-ion RT6 months12 months24 months36 monthsIPSS7.912.26.76.75.32.6EPICUrinary91.584.691.691.792.493.6Bowel93.892.394.194.592.794.2Sexual33.332.835.136.037.538.8(subgroup*Twenty-three low-risk patients not received any HT.)43.741.346.945.447.644.2Hormonal83.384.385.788.791.093.0∗ Twenty-three low-risk patients not received any HT. Open table in a new tab It is suggested that the QOL outcome of the patients with localized PC is well maintained after the hypofractionatied C-ion RT. Further studies are required to asses QOL outcome more precisely especially sexual function because most patients in this analysis received HT.

Fishing for radiation quality: chromosome aberrations and the role of radiation track structure.

The yield of chromosome aberrations is not only dependent on dose but also on radiation quality, with high linear energy transfer (LET) typically having a greater biological effectiveness per unit dose than those of low-LET radiation. Differences in radiation track structure and cell morphology can also lead to quantitative differences in the spectra of the resulting chromosomal rearrangements, especially at low doses associated with typical human exposures. The development of combinatorial fluorescent labelling techniques (such as mFISH and mBAND) has helped to reveal the complexity of rearrangements, showing increasing complexity of observed rearrangements with increasing LET but has a resolution limited to ∼10 MBp. High-LET particles have not only been shown to produce clustered sites of DNA damage but also produce multiple correlated breaks along its path resulting in DNA fragments smaller than the resolution of these techniques. Additionally, studies have shown that the vast majority of radiation-induced HPRT mutations were also not detectable using fluorescent in situ hybridisation (FISH) techniques, with correlation of breaks along the track being reflected in the complexity of mutations, with intra- and inter-chromosomal insertions, and inversions occurring at the sites of some of the deletions. Therefore, the analysis of visible chromosomal rearrangements observed using current FISH techniques is likely to represent just the tip of the iceberg, considerably underestimating the extent and complexity of radiation induced rearrangements.