Differential Biological Effects Research Articles

Design and implementation of a prospective cohort study of persons living with and without HIV infection who are initiating medication treatment for opioid use disorder

BackgroundOpioid use disorder (OUD) negatively impacts the HIV continuum of care for persons living with HIV. Medication treatment for OUD (MOUD) may have differential biological effects in individuals with HIV and OUD. To address the question of modulation of immune responses by MOUDs, we describe state of the art systems biology approaches to carry out the first prospective, longitudinal study of persons with and without HIV infection with OUD initiating MOUD. MethodsA prospective cohort study of persons with DSM-5 diagnosed OUD who are living with and without HIV infection and initiating treatment with methadone or buprenorphine is underway to assess biological effects of these medications on immunobiological outcomes. ResultsWe describe the recruitment, laboratory, and statistical methods of this study as well as the protocol details. Of those screened for enrollment into the study, 468 (36%) were eligible and 135 were enrolled thus far. Retention through month 6 has been high at 80%. ConclusionsThis study will use state of the art systems biology approaches to carry out the first prospective, longitudinal studies of persons living with and without HIV with DSM-5 OUD initiating treatment with MOUD.

African and European local ancestry surrounding Apolipoprotein E has a differential biological effect upon acute amyloid beta exposure in iPSC‐differentiated astrocytes

AbstractBackgroundStudies have shown that the lower risk associated with the ε4 allele for African ancestry is associated with the local ancestry (LA) surrounding the ApoE gene. Previous studies have shown differences between ApoE3 and ApoE4 alleles in isogenic induced pluripotent stem cell (iPSC) models when exposed to Aβ. We hypothesized that ApoE4 individuals with African LA would respond differently to Aβ compared to European ApoE3 and European ApoE4 LA lines. However, as we cannot produce isogenic lines to test LA, we used RNA expression changes to Aβ exposure to increase our sensitivity to potential differences.MethodWe differentiated European LA ε4/ε4 and African LA ε4/ε4 allele astrocytes from iPSC lines. Astrocytes were exposed to exogenous Aβ and RNA was obtained at 0 and 24 hours. We performed bioinformatic analyses with the STAR algorithm and differential expression calculation using linear models implemented in edgeR. Pathway enrichment analysis for Gene Ontology Biological Processes, KEGG and Reactome pathways was performed using Metascape.ResultTwenty‐four hours following Aβ exposure, 524 and 671 genes were deferentially expressed from baseline in African and European LA lines respectively. Analysis of the unregulated genes in the two different ancestries revealed markedly different pathways. The unregulated genes in African LA astrocytes were enriched for Ribosome Biogenesis and RNA modification processes while the upregulated genes in the European LA astrocytes were enriched for Cell Cycle and DNA modification processes. In the European LA astrocytes, downregulated genes were enriched for Synaptic Assembly and Kainate Receptor Activity while in the African LA astrocytes downregulated genes enriched for Extracellular Matrix‐related processes.ConclusionOur initial results suggest that the two ancestries respond differently to Aβ exposure. Whether this is due to global or local ancestry differences is unclear. Further studies including astrocytes bearing African LA ε3/ε3 are needed to clarify that question. Both ribosomal dysfunction and astrocyte‐neuronal and astrocyte‐microglia synaptic assembly have been implicated in Aβ clearance and/or AD. A potential link between LA and the regulation of these processes due to Aβ exposure could pave the path to a better understanding of LOAD pathology.

SP-0005: Differential biological effects of photon and particle irradiation; experimental highlights and clinical impact

SP-0005: Differential biological effects of photon and particle irradiation; experimental highlights and clinical impact

Synthesis of Phthalimide Imine Derivatives as a Potential Anticancer Agent

The outstanding evidence of phthalimide pharmacophore in securing enhanced biological activities had encouraged further research and development into phthalimide-based derivatives as potential new drugs. In this study, phthalimide core was hybridized with aldehydes giving integrated imines displaying different types of functionalities and at alternating positions. The resulting compounds, therefore, provide an innovative window to explore possible differential biological effects as antioxidants and anticancer agents. A total of sixteen compounds were synthesized, and each was verified by FT-IR, H NMR, C NMR, and MS characterization. Herein, a facile single-step synthesis method was employed substituting the conventional two-step chemical production routes. Among the sixteen tested compounds, the H7 compound with hydroxyl phenolic group has shown an eminent antioxidant activity with a 19.52% decrease to the IC50 value compared to that of the control standard BHT antioxidant. On the other hand, the halogenated H6 Schiff base structure was successful in securing effective cancer inhibition to both colon and breast cancer cell lines, while maintaining selective action toward normal tissues. Results have collectively indicated the importance and impactful effects of functional groups position and types within similar basic structures, in directing different biological outcomes.

Oxetanyl Sulfoxide MMS-350 Ameliorates Pulmonary Fibrosis In Vitro, In Vivo, and Ex Vivo.

Fibrosis is a common feature of several diseases, involves different organs, and results in significant morbidity and mortality. There are currently no effective therapies to halt the progression of fibrosis or reverse it. We have identified the highly water-soluble MMS-350, a novel bis-oxetanyl sulfoxide, as an antifibrotic agent. MMS-350 reduced the profibrotic phenotype induced in vitro in primary human fibroblasts and ameliorated bleomycin-induced pulmonary fibrosis in vivo. Furthermore, MMS-350 reversed fibrosis in human skin in organ culture. MMS-350 reduced levels of extracellular matrix proteins, the activation of fibroblasts, and the induction of pro-fibrotic factors. Similar effects at lower concentrations were observed with KRL507-031 and CL-613-091, two more lipophilic MMS-350 analogues. The fact that MMS-350 was effective at reducing pulmonary fibrosis induced by different triggers, the differential biological effects of its close structural analogues and its oral availability make it an attractive therapeutic candidate for organ fibrosis.

A novel screening approach comparing kinase activity of small molecule inhibitors with similar molecular structures and distinct biologic effects in triple-negative breast cancer to identify targetable signaling pathways.

Breast cancer affects women globally; the majority of breast cancer-related mortalities are due to metastasis. Acquisition of a mesenchymal phenotype has been implicated in the progression of breast cancer cells to an invasive, metastatic state. Triple-negative breast cancer (TNBC) subtypes have high rates of metastases, recurrence, and have poorer prognoses compared to other breast cancer types, partially due to lack of commonly targeted receptors. Kinases have diverse and pivotal functions in metastasis in TNBC, and discovery of new kinase targets for TNBC is warranted. We previously used a screening approach to identify intermediate-synthesis nonpotent, nonselective small-molecule inhibitors from the Published Kinase Inhibitor Set that reversed the mesenchymal phenotype in TNBC cells. Two of these inhibitors (GSK346294A and GSK448459A) are structurally similar, but have unique kinase activity profiles and exhibited differential biologic effects on TNBC cells, specifically on epithelial-to-mesenchymal transition (EMT). Here, we further interrogate these effects and compare activity of these inhibitors on transwell migration, gene (qRT-PCR) and protein (western blot) expressions, and cancer stem cell-like behavior. We incorporated translational patient-derived xenograft models in these studies, and we focused on the lead inhibitor hit, GSK346294A, to demonstrate the utility of our comparative analysis as a screening modality to identify novel kinase targets and signaling pathways to pursue in TNBC. This study introduces a new method for discovering novel kinase targets that reverse the EMT phenotype; this screening approach can be applied to all cancer types and is not limited to breast cancer.

Radiobiological effectiveness difference of proton arc beams versus conventional proton and photon beams

This paper aims to demonstrate the difference in biological effectiveness of proton monoenergetic arc therapy (PMAT) compared to intensity modulated proton therapy (IMPT) and conventional 6 MV photon therapy, and to quantify this difference when exposing cells of different radiosensitivity to the same experimental conditions for each modality.V79, H1299 and H460 cells were cultured in petri dishes placed in the central axis of a cylindrical and homogeneous solid water phantom of 20 cm in diameter. For the PMAT plan, cells were exposed to 13 mono-energetic proton beams separated every 15° over a 180° arc, designed to deliver a uniform dose of higher LET to the petri dishes. For the IMPT plans, 3 fields were used, where each field was modulated to cover the full target. Cells were also exposed to 6 MV photon beams in petri dishes to characterize their radiosensitivity. The relative biological effectiveness of the PMAT plans compared with those of IMPT was measured using clonogenic assays. Similarly, in order to study the quantity and quality of the DNA damage induced by the PMAT plans compared to that of IMPT and photons, γ-H2AX assays were conducted to study the relative amount of DNA damage induced by each modality, and their repair rate over time.The clonogenic assay revealed similar survival levels to the same dose delivered with IMPT or x-rays. However, a systematic average of up to a 43% increase in effectiveness in PMAT plans was observed when compared with IMPT. In addition, the repair kinetic assays proved that PMAT induces larger and more complex DNA damage (evidenced by a slower repair rate and a larger proportion of unrepaired DNA damage) than IMPT. The repair kinetics of IMPT and 6 MV photon therapy were similar.Mono-energetic arc beams offer the possibility of taking advantage of the enhanced LET of proton beams to increase TCP. This study presents initial results based on exposing cells with different radiosensitivity to other modalities under the same experimental conditions, but more extensive clonogenic and in-vivo studies will be required to confirm the validity of these results.

Sequence-Defined Heteromultivalent Precision Glycomacromolecules Bearing Sulfonated/Sulfated Nonglycosidic Moieties Preferentially Bind Galectin-3 and Delay Wound Healing of a Galectin-3 Positive Tumor Cell Line in an In Vitro Wound Scratch Assay.

Within this work, a new class of sequence-defined heteromultivalent glycomacromolecules bearing lactose residues and nonglycosidic motifs for probing glycoconjugate recognition in carbohydrate recognition domain (CRD) of galectin-3 is presented. Galectins, a family of β-galactoside-binding proteins, are known to play crucial roles in different signaling pathways involved in tumor biology. Thus, research has focused on the design and synthesis of galectin-targeting ligands for use as diagnostic markers or potential therapeutics. Heteromultivalent precision glycomacromolecules have the potential to serve as ligands for galectins. In this work, multivalency and the introduction of nonglycosidic motifs bearing either neutral, amine, or sulfonated/sulfated groups are used to better understand binding in the galectin-3 CRD. Enzyme-linked immunosorbent assays and surface plasmon resonance studies are performed, revealing a positive impact of the sulfonated/sulfated nonglycosidic motifs on galectin-3 binding but not on galectin-1 binding. Selected compounds are then tested with galectin-3 positive MCF 7 breast cancer cells using an in vitro would scratch assay. Preliminary results demonstrate a differential biological effect on MCF 7 cells with high galectin-3 expression in comparison to an HEK 293 control with low galectin-3 expression, indicating the potential for sulfonated/sulfated heteromultivalent glycomacromolecules to serve as preferential ligands for galectin-3 targeting.

The Enigma of Bioactivity and Toxicity of Botanical Oils for Skin Care.

Botanical oils have a long history of traditional use and are routinely applied to skin care. The focus of this review is to contrast the functionality of skin oils versus the differential biological and toxicological effects of major plant oils, and to correlate them to their compositional changes. In total, over 70 vegetable oils were clustered according to their lipid composition to promote awareness of health practitioners and botanical product manufacturers for the safety and efficacy of oil-based interventions based on their fatty acid profiles. Since multiple skin disorders result in depletion or disturbance of skin lipids, a tailored mixture of multiple botanical oils to simultaneously maintain natural skin-barrier function, promote repair and regeneration of wounded tissues, and achieve corrective modulation of immune disorders may be required. As bioactive constituents of botanical oils enter the human body by oral or topical application and often accumulate in measurable blood concentrations, there is also a critical need for monitoring their hazardous effects to reduce the possible over-added toxicity and promote maximal normal tissue sparing. The review also provides a useful tool to improve efficacy and functionality of fatty acid profiles in cosmetic applications.

MON-023 Dynamics of the Transcriptome in Rat Granulosa Cells Exposed to Different Follicle-Stimulating Hormone (FSH) Glycosylation Variants as Revealed by RNA-Seq/New Generation Sequencing (NGS)

Follicle-stimulating hormone exists as different major glycoforms defined by distinct glycosylation patterns of the hormone-specific β-subunit. It has been documented that variations in glycosylation confer differential biological effects to the glycoforms when multiple in vitro biochemical readings are analyzed. We here applied Next Generation Sequencing (NGS) to explore changes in the transcriptome of rat granulosa cells exposed for 0, 6, and 12 h to 100 ng/ml of four highly purified FSH glycoforms, each exhibiting distinctly different glycosylation patterns: human pituitary FSH21 and equine FSH (eFSH) (hypo-glycosylated), and human FSH24 and CHO cell-derived human recombinant FSH (recFSH) (fully-glycosylated). Total RNA from triplicate incubations was prepared from FSH glycoform-exposed cultured granulosa cells obtained from DES-pretreated immature female rats, and total RNA libraries were sequenced in a HighSeq 2500 sequencer (2 x 125 bp paired-end format, 10–15 x 106 reads/sample). The computational workflow was focused on investigating differences among the four FSH glycoforms at three levels: gene expression (Salmon and DESeq2 bioinformatic tools), enriched biological processes (DAVID tool), and perturbed pathways (GAGE tool). Among the top 200 differentially expressed genes, only 4 (0.6%) were shared by all 4 glycoforms at 6 h, whereas 118 genes (40%) were shared at 12 h. At 6 h, up-regulated genes in recFSH were associated with cell response, angiogenesis, extracellular matrix organization, and mitosis; eFSH with sex hormones (shared with FSH21); FSH21 with cellular response and response to drugs (shared with recFSH); and FSH24 with cAMP-related processes. There were more shared biological processes at 12 h, with fewer treatment-specific ones, except for recFSH, which exhibited stronger responses with more specifically associated processes. Similar results were found for down-regulated cell processes, with a greater number of processes at 6 h or 12 h, depending on the particular glycoform. In general, there were fewer down-regulated than up-regulated processes at both 6 h and 12 h, with FSH21 exhibiting the largest number of down-regulated associated processes at 6 h (10 vs 3 processes for eFSH, one process for FSH24, and one for recFSH), while eFSH exhibited the greatest number at 12 h (19 processes vs 4 for FSH21, 13 for FSH24, and 7 for recFSH). Two signaling cascades, largely linked to Rap-1 and cAMP pathways, were differentially activated by the glycoforms, with each glycoform exhibiting its own molecular signature. These transcriptomic data support previous biochemical observations demonstrating glycosylation-dependent differential regulation of intracellular signaling pathways triggered by FSH in granulosa cells.

Mechanisms of FH Protection Against Neovascular AMD.

A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NTal region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CTal region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential.

Proceedings to the 6th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA): 14-16 October 2019, Hosted by Miami Cancer Institute, part of Baptist Health South Florida, Miami, FL, USA.

Proceedings to the 6th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA): 14-16 October 2019, Hosted by Miami Cancer Institute, part of Baptist Health South Florida, Miami, FL, USA.

Hirshfeld Surface analysis, spectroscopic, biological studies and molecular docking of (4E)-4-((naphthalen-2-yl)methyleneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one

Abstract In the present work, the newly synthesized compound (4E)-4-((naphthalen-2-yl)methyleneamino)-1,2-dihydro-2,3-dimethyl-1-phenylpyrazol-5-one was studied by both structural and spectral (FT-IR, 1H and 13C NMR chemical shifts and electronic-UV-Vis.), using experimental and theoretical methods. All theoretical computations of the title compound were performed by using the density functional theory (DFT/B3LYP) quantum mechanical method with 6–311++G(d,p) basis set and Gaussian 09W program. The vibrational assignments were controlled and performed with VEDA 4 program based on potential energy distributions (PED). The experimental FT-IR spectrum was studied in solid phase in the range of 4000 and 400 cm−1. Also, the experimental and theoretical 1H and 13C NMR chemical shifts in chloroform and UV–Vis. spectral analysis in methanol were examined theoretically and experimentally. To support UV–Vis. data (both experimental and theoretical), the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) computations were carried out over with methanol optimized structure. Furthermore, Hirshfeld and MEP (Molecular Electrostatic Potential) surface analyses were performed to observe better intermolecular interactions in the crystal packing. Antimicrobial studies showed that the compound has inhibition zones with different sizes with various microorganisms, indicating the different interactions of the examined compound with the growth, cell wall structure and permeability of cell membrane of the tested organisms. Furthermore, molecular docking studies were conducted for the Schiff base compound and appropriate reference drugs against 5fsa and 1kzn proteins, highlighting the different mode of interactions assumed by the Schiff base compound compared to that of the reference drugs which rationalize the difference in biological effects.

Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2 result in receptor- and hormone-specific responses

Information on how insulin and insulin-like growth factors 1 and 2 (IGF-1 and -2) activate insulin receptors (IR-A and -B) and the IGF-1 receptor (IGF-1R) is crucial for understanding the difference in the biological activities of these peptide hormones. Cryo-EM studies have revealed that insulin uses its binding sites 1 and 2 to interact with IR-A and have identified several critical residues in binding site 2. However, mutagenesis studies suggest that Ile-A10, Ser-A12, Leu-A13, and Glu-A17 also belong to insulin's site 2. Here, to resolve this discrepancy, we mutated these insulin residues and the equivalent residues in IGFs. Our findings revealed that equivalent mutations in the hormones can result in differential biological effects and that these effects can be receptor-specific. We noted that the insulin positions A10 and A17 are important for its binding to IR-A and IR-B and IGF-1R and that A13 is important only for IR-A and IR-B binding. The IGF-1/IGF-2 positions 51/50 and 54/53 did not appear to play critical roles in receptor binding, but mutations at IGF-1 position 58 and IGF-2 position 57 affected the binding. We propose that IGF-1 Glu-58 interacts with IGF-1R Arg-704 and belongs to IGF-1 site 1, a finding supported by the NMR structure of the less active Asp-58–IGF-1 variant. Computational analyses indicated that the aforementioned mutations can affect internal insulin dynamics and inhibit adoption of a receptor-bound conformation, important for binding to receptor site 1. We provide a molecular model and alternative hypotheses for how the mutated insulin residues affect activity.

Radiobiological Difference Between Flattening Filter Free (FFF) Vs. Flattening Filter (FF) X-Ray Beams in Lung Cancer Cells

Stereotactic Body Radiotherapy (SBRT) is a well-established therapeutic option for early lung cancer, and many clinical trials indicate that SBRT can provide excellent local control and survival with limited toxicity. Compared with conventional flattening filter (FF) beams, flattening filter free (FFF) beams are characterized by higher average dose rate with higher dose per pulse and inhomogeneous dose distribution with reduced peripheral dose. These benefits make FFF beams an attractive alternative for SBRT. Therefore, it is crucially to determine whether there are any differences in biological effects of FFF beams compared with FF beams. However, there are still conflicts on them between two beams. Therefore, we investigated the radiobiological effect between FF and FFF beam in human lung cancer cell lines. Three human lung cancer cell lines with different genetic characteristics (A549, NCI-H1299, NCI-H1650) were used. Irradiation was performed with a 10 MV linear accelerator (Versa HD, Elekta AB). The dose rate and dose per pulse for FF and FFF beams were 5 and 22 Gy/min, and 0.042 cGy and 0.171 cGy, respectively. To investigate the effect by different dose rate, but with same dose per pulse, FFF beam of 22 Gy/ min was modified to 5 Gy/min by increasing pulse interval. The radiobiologic effect was studied with three different conditions: FF (5 Gy/min, 0.042 cGy/pulse), FFF (5 Gy/min, and 0.171 cGy/pulse) and FFF (22 Gy/min, 0.171 cGy/pulse). Cell survival was measured using clonogenic assay and protein expression was measured using Western blot analysis. No significant differences in cell survival were observed upon three kinds of irradiation for all the three cell lines. No significant differences were observed in the expression of γ-H2AX and repair proteins (DNA-PKcs, Rad 51) after irradiation in all the three cell lines. There is no radiobiological difference (cell survival, DNA damage and repair) between FF and FFF beams in lung cancer cells.

Targeted metabolomics reveals differential biological effects of nanoplastics and nanoZnO in human lung cells

Engineered nanomaterials are of public health concern. Recently, there has been an increasing attention on the toxicity of nanoplastics and nanoZnO because of their increasing utilization and presence in the environment. However, knowledge of their toxicological behavior and metabolic interactions with the cellular machinery that determine their potential health effects are extremely limited. In this study, the cellular uptake, cytotoxic effects, and metabolic responses of bronchus epithelial (BEAS-2B) cells exposed to nanopolystyrene (nanoPS) and a widely used metallic nanoparticle, nanoZnO, were investigated using a tandem mass spectrometry-based metabolomics approach. The results revealed that even with low cytotoxicity, these nanoparticles (NPs) affected cell metabolism. NanoPS exposure showed autophagic- and endoplasmic reticulum (ER) stress-related metabolic changes such as increased in amino acids and tricarboxylic acid cycle (TCA) intermediate metabolites, a process known to play a critical role in regulating cell resistance to cytotoxic effects. Both metabolomics profiling and ER-stress pathway, together with quantitative real-time RT-polymerase chain reaction (qRT-PCR) analyses, demonstrated that autophagy was reciprocally regulated to couple metabolic and transcriptional reprograming. In contrast, nanoZnO-induced ROS-mediated cell death was associated with mitochondrial dysfunction and interference in regulating energy metabolism. Collectively, these two types of NPs were observed to cause perturbations albeit differential in cellular metabolism associated with their cytotoxic effects. Our findings provided an in depth understanding of metabolic changes influenced by two different types of NPs, with contrasting molecular mechanisms for the adverse effects observed.

Differential biological effects in two pedigrees of clam Ruditapes philippinarum exposed to cadmium using iTRAQ-based proteomics

Due to the industrial discharges, cadmium (Cd) has been one of typical heavy metal pollutants in the Bohai Sea. Manila clam Ruditapes philippinarum is frequently used for pollution biomonitoring and consists of several pedigrees, of which White and Zebra clams are the dominant pedigrees along the Bohai Sea coast. However, limited attention has been paid on the differential biological effects in different pedigrees of clam to heavy metals. In this work, the proteome profiling analysis was performed to reveal the differential proteomic responses in White and Zebra clams to Cd exposure (200 μg/L) for 48 h, followed by bioinformatical analysis. The proteomic investigations showed that Cd treatment induced more differentially expressed proteins (DEPs) in White clam samples than in Zebra clam samples. Based on the DEPs, we found that some key biological processes consisting of immune response and metabolism were commonly induced in both two pedigrees of clam. Uniquely, some processes related to cellular signaling, proteolysis and energy production were enhanced in Cd-treated White clam samples. Comparatively, the depletion in some unique processes on proteolysis and energy production was elicited in Cd-treated Zebra clam samples, as well as disorder in gene expression. Moreover, Cd exposure caused increases in CAT and POD activities in White clam samples and decreases in SOD and CAT activities in Zebra clams samples, which were consistent with the proteomic responses. Overall, these findings confirmed the differential biological effects of White and Zebra clams to Cd treatment, suggesting that the pedigree of animal should be taken into consideration in ecotoxicology studies.

Clinical evidence for dose tolerance of the central nervous system in hypofractionated radiotherapy

Stereotactic radiosurgery (SRS), stereotactic body radiotherapy (SBRT), and stereotactic ablative body radiotherapy (SABR) are commonly used in the treatment of central nervous system (CNS) disease. This study has refined the radiation toxicity estimates for some normal tissues of the CNS based on review and analysis of the clinical evidence for single fraction radiosurgery, hypofractionated SBRT, and conventionally fractionated radiation therapy. Published guidelines and protocols are reviewed. In the past, many normal tissue tolerances were compiled based on the experience of the investigators and publications in the literature. Some tolerances were determined by modeling or calculation using the existing biological formulas, in particular the linear quadratic (LQ) model. In the present study, the estimate of risk for each dose tolerance limit in some CNS tissues is provided exclusively with normal tissue complication probability (NTCP). The clinical outcomes are compared to understand the difference in biological effect between radiosurgery and radiotherapy. Normal tissue dose tolerances and the corresponding complication rates are provided for brainstem, optic nerves, cochlea, and spinal cord, including single fraction SRS, five-fraction SBRT, and conventional radiation therapy. Calculation of biologically effective dose (BED) or single fraction equivalent dose (SFED) alone using the LQ model conveys no consensus on the biological effect across different fractionations. Comparison of conventional radiation therapy to brain and spinal cord with single fraction equivalent dose leads to even conflicting clinical outcomes. Effective differences between single fraction SRS and conventional radiotherapy need to be better understood. The existing biological model might not be valid to predict the radiosurgical outcomes based on conventionally fractionated radiotherapy. However, application of the statistical dose response models of clinical SRS and SBRT outcomes data to selected current dose tolerance guidelines into simple tables can be a clinically useful resource.

Analysis of DNA methylation alterations in rice seeds induced by different doses of carbon-ion radiation.

To investigate the mechanism underlying differences in biological effects induced by low- versus high-dose heavy-ion radiation (HIR) in rice plants, two-dimensional gel electrophoresis (2-DE) coupled with methylation-sensitive amplification polymorphism (MSAP) analysis were used to check the expression changes in rice leaf proteome profiles and the changes in DNA methylation after exposure of seeds to ground-based carbon-ion radiation at various cumulative doses (0, 0.01, 0.02, 0.1, 0.2, 1, 2, 5 or 20 Gy; 12C6+; energy, 165 MeV/u; mean linear energy transfer, 30 KeV/μm). In this study, principal component analysis (PCA) and gene ontology (GO) functional analysis of differentially expressed proteins of rice at tillering stage showed that proteins expressed in rice samples exposed to 0.01, 0.02, 0.1, 0.2 or 1 Gy differed from those exposed to 2, 5 or 20 Gy. Correspondingly, the proportion of hypermethylation was higher than that of hypomethylation at CG sites following low-dose HIR (LDR; 0.01, 0.2 or 1 Gy), whereas this was reversed at high-dose HIR (HDR; 2, 5 or 20 Gy). The hypomethylation changes tended to occur at CHG sites with both low- and high-dose HIR. Furthermore, sequencing of MSAP variant bands indicated that the plants might activate more metabolic processes and biosynthetic pathways on exposure to LDR, but activate stress resistance on exposure to HDR. This study showed that radiation induced different biological effects with low- and high-dose HIR, and that this may have been caused by different patterns of hyper- and hypomethylation at the CG sites.

Particle Radiation Induced Neurotoxicity in the Central Nervous System.

For patients with primary or metastatic brain tumors, radiation therapy plays a central role in treatment. However, despite its efficacy, cranial radiation is associated with a range of side effects ranging from mild cognitive impairment to overt brain necrosis. Given the negative effects on patient quality of life, radiation-induced neurotoxicities have been the subject of intense study for decades. Photon-based therapy has been and largely remains the standard of care for the treatment of brain tumors. This is particularly true for patients with metastatic tumors who may need treatment to the whole brain or those with very aggressive tumors and a limited life expectancy. Particle therapy is now becoming more widely available for clinical use with the two most common particles used being protons and carbon ions. For patients with favorable prognoses, particularly childhood brain tumors, proton therapy is increasingly used for treatment. This is, in part, driven by the desire to reduce the potential for radiation-induced side effects, including lasting cognitive impairment, which may potentially be achieved by reducing dose to normal tissues using the unique physical properties of particle therapy. There is also interest in using carbon ion therapy for the treatment of aggressive brain tumors, as this form of particle therapy not only spares normal tissues but may also improve tumor control. The biological effects of particle therapy, both proton and carbon, may differ substantially from those of photon radiation. In this review, we briefly describe the unique physical properties of particle therapy that produce differential biological effects. Focusing on the effects of various radiation types on brain parenchyma, we then describe biological effects and potential mechanisms underlying these, comparing to photon studies and highlighting potential clinical implications.