Hypertension is a major preventable risk factor for atherosclerosis and ischemic heart disease. Although modern and effective antihypertensive drugs are available, most patients remain with a ...suboptimal blood pressure control. Most hypertensive patients will need a combination of antihypertensive agents to achieve the therapeutic goals - recent guidelines recommend initiating treatment with two drugs in those patients with a systolic blood pressure >20 mmHg and/or a diastolic blood pressure >10 mmHg above the goals, and in those patients with high cardiovascular risk. In addition, approximately 25% of patients will require three antihypertensive agents to achieve the therapeutic targets. In this review, we analyse the latest information available regarding the treatment of hypertension with combination therapy.
There is agreement that high-LET radiation has a high Relative Biological Effectiveness (RBE) when delivered as a single treatment, but how it interacts with radiations of different qualities, such ...as X-rays, is less clear. We sought to clarify these effects by quantifying and modelling responses to X-ray and alpha particle combinations. Cells were exposed to X-rays, alpha particles, or combinations, with different doses and temporal separations. DNA damage was assessed by 53BP1 immunofluorescence, and radiosensitivity assessed using the clonogenic assay. Mechanistic models were then applied to understand trends in repair and survival. 53BP1 foci yields were significantly reduced in alpha particle exposures compared to X-rays, but these foci were slow to repair. Although alpha particles alone showed no inter-track interactions, substantial interactions were seen between X-rays and alpha particles. Mechanistic modelling suggested that sublethal damage (SLD) repair was independent of radiation quality, but that alpha particles generated substantially more sublethal damage than a similar dose of X-rays, Formula: see text. This high RBE may lead to unexpected synergies for combinations of different radiation qualities which must be taken into account in treatment design, and the rapid repair of this damage may impact on mechanistic modelling of radiation responses to high LETs.
Background
Cancer is a highly heterogeneous disease, driven by frequent genetic alterations which have significant effects on radiosensitivity. However, radiotherapy for a given cancer type is ...typically given with a standard dose determined from population‐level trials. As a result, a proportion of patients are under‐ or over‐dosed, reducing the clinical benefit of radiotherapy. Biological optimization would not only allow individual dose prescription but also a more efficient allocation of limited resources, such as proton and carbon ion therapy.
Proton and ion radiotherapy offer an advantage over photons due to their elevated Relative Biological Effectiveness (RBE) resulting from their elevated Linear Energy Transfer (LET). Despite significant interest in optimizing LET by tailoring radiotherapy plans, RBE's genetic dependence remains unclear.
Purpose
The aim of this study is to better define the RBE/LET relationship in a panel of cell lines with different defects in DSB repair pathways, but otherwise identical biological features and genetic background to isolate these effects.
Methods
Normal human cells (RPE1), genetically modified to introduce defects in DNA double‐strand break (DSB) repair genes, ATM, BRCA1, DCLRE1C, LIG4, PRKDC and TP53, were used to map the RBE‐LET relationship. Cell survival was measured with clonogenic assays after exposure to photons, protons (LET 1 and 12 keV/µm) and alpha particles (129 keV/µm). Gene knockout sensitizer enhancement ratio (SER) values were calculated as the ratio of the mean inactivation dose (MID) of wild‐type cells to repair‐deficient cells, and RBE values were calculated as the ratio of the MID of X‐ray and particle irradiated cells. 53BP1 foci were used to quantify radiation‐induced DSBs and their repair following irradiation.
Results
Deletion of NHEJ genes had the greatest impact on photon sensitivity (ATM−/− SER = 2.0 and Lig4−/− SER = 1.8), with genes associated with HR having smaller effects (BRCA1−/− SER = 1.2). Wild‐type cells showed RBEs of 1.1, 1.3, 5.0 for low‐ and high‐LET protons and alpha particles respectively. SERs for different genes were independent of LET, apart from NHEJ knockouts which proved to be markedly hypersensitive across all tested LETs. Due to this hypersensitivity, the impact of high LET was reduced in cell models lacking the NHEJ repair pathway. HR‐defective cells had moderately increased sensitivity across all tested LETs, but, notably, the contribution of HR pathway to survival appeared independent of LET. Analysis of 53BP1 foci shows that NHEJ‐defective cells had the least DSB repair capacity after low LET exposure, and no visible repair after high LET exposure. HR‐defective cells also had slower repair kinetics, but the impact of HR defects is not as severe as NHEJ defects.
Conclusions
DSB repair defects, particularly in NHEJ, conferred significant radiosensitivity across all LETs. This sensitization appeared independent of LET, suggesting that the contribution of different DNA repair pathways to survival does not depend on radiation quality.
Targeted Alpha Therapy: Current Clinical Applications Guerra Liberal, Francisco D C; O'Sullivan, Joe M; McMahon, Stephen J ...
Cancer biotherapy & radiopharmaceuticals,
08/2020, Letnik:
35, Številka:
6
Journal Article
Recenzirano
Odprti dostop
α-Emitting radionuclides have been approved for cancer treatment since 2013, with increasing degrees of success. Despite this clinical utility, little is known regarding the mechanisms of action of α ...particles in this setting, and accurate assessments of the dosimetry underpinning their effectiveness are lacking. However, targeted alpha therapy (TAT) is gaining more attention as new targets, synthetic chemistry approaches, and α particle emitters are identified, constructed, developed, and realized. From a radiobiological perspective, α particles are more effective at killing cells compared to low linear energy transfer radiation. Also, from these direct effects, it is now evident from preclinical and clinical data that α emitters are capable of both producing effects in nonirradiated bystander cells and stimulating the immune system, extending the biological effects of TAT beyond the range of α particles. The short range of α particles makes them a potent tool to irradiate single-cell lesions or treat solid tumors by minimizing unwanted irradiation of normal tissue surrounding the cancer cells, assuming a high specificity of the radiopharmaceutical and good stability of its chemical bonds. Clinical approval of
RaCl
in 2013 was a major milestone in the widespread application of TAT as a safe and effective strategy for cancer treatment. In addition,
Ac-prostate specific membrane antigen treatment benefit in metastatic castrate-resistant prostate cancer patients, refractory to standard therapies, is another game-changing piece in the short history of TAT clinical application. Clinical applications of TAT are growing with different radionuclides and combination therapies, and in different clinical settings. Despite the remarkable advances in TAT dosimetry and imaging, it has not yet been used to its full potential. Labeled
Th and
Ac appear to be promising candidates and could represent the next generation of agents able to extend patient survival in several clinical scenarios.
New models for teaching sports have arisen in the last years, characterised by the use of more contextualised situations, modified games, tactical awareness, transference of technical-tactical ...learning and different teaching progression, among other aspects. In this regard, small-sided games must be highlighted, due to their ability to integrate physical fitness, technique and tactical behaviour stimuli in similar conditions to the real game. Therefore, the aim of this systematic review was to analyse and describe the methodological possibilities that SSGs can provide regarding the teaching of technical-tactical aspects in team sports at young ages. The guidelines of the PRISMA declaration were followed with the purpose of conducting a systematic search. The search was performed in the databases
,
,
and
. From the 451 identified in an early phase, plus the 20 found in the references of other studies, only 47 met the inclusion criteria and were selected. The results yielded scientific evidence that justifies the use of small-sided games as a methodological resource for sports teaching at young ages. Among the main reasons, it can be highlighted that a reduction in the number of players and in the size of the pitch area increases the total ball contact per player and, therefore, the number of technical actions. Moreover, the intentional modification of certain rules helps to develop some sport training fundamentals.
Pharmacological inhibitors of DNA damage response (DDR) proteins, such as the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases and poly (ADP-ribose) ...polymerase (PARP), have been developed to overcome tumor radioresistance. Despite demonstrating radiosensitization preclinically, they have performed suboptimally in clinical trials, possibly due to an incomplete understanding of the influence of DDR inhibition on ionizing radiation (IR) dose fractionation and sublethal damage repair. Hence, this study aimed to evaluate the radiosensitizing ability under fractionation of ATM inhibitor AZD0156, ATR inhibitor AZD6738 and PARP inhibitor AZD2281 (olaparib), utilizing MDA-MB-231 and MCF-7 human breast cancer cells. Clonogenic assays were performed to assess cell survival and sublethal damage repair after treatment with DDR inhibitors and either single-dose or fractionated IR. Immunofluorescence microscopy was utilized to evaluate DNA double-strand break repair kinetics. Cell cycle distributions were investigated using flow cytometry. All inhibitors showed significant radiosensitization, which was significantly greater following fractionated IR than single-dose IR. They also led to more unrepaired DNA double-strand breaks at 24 h post-IR. This study provides preclinical evidence for the role of AZD0156, AZD6738 and olaparib as radiosensitizing agents. Still, it highlights the need to evaluate these drugs in fractionated settings mirroring clinical practice to optimize the trial design.
Intrinsic radiosensitivity is a major determinant of radiation response. Despite the extensive amount of radiobiological data available, variability among different studies makes it very difficult to ...produce high-quality radiosensitivity biomarkers or predictive models. Here, we characterize a panel of 27 human cell lines, including those derived from lung cancer, prostate cancer, and normal tissues. In addition, we used CRISPR-Cas9 to generate a panel of lines with known DNA repair defects. These cells were characterised by measuring a range of biological features, including the induction and repair of DNA double-strand breaks (DSBs), cell cycle distribution, ploidy, and clonogenic survival following X-ray irradiation. These results offer a robust dataset without inter-experimental variabilities for model development. In addition, we used these results to explore correlations between potential determinants of radiosensitivity. There was a wide variation in the intrinsic radiosensitivity of cell lines, with cell line Mean Inactivation Doses (MID) ranging from 1.3 to 3.4 Gy for cell lines, and as low as 0.65 Gy in Lig4
cells. Similar substantial variability was seen in the other parameters, including baseline DNA damage, plating efficiency, and ploidy. In the CRISPR-modified cell lines, residual DSBs were good predictors of cell survival (R
= 0.78,
= 0.009), as were induced levels of DSBs (R
= 0.61,
= 0.01). However, amongst the normal and cancerous cells, none of the measured parameters correlated strongly with MID (R
< 0.45), and the only metrics with statistically significant associations are plating efficiency (R
= 0.31,
= 0.01) and percentage of cell in S phase (R
= 0.37,
= 0.005). While these data provide a valuable dataset for the modelling of radiobiological responses, the differences in the predictive power of residual DSBs between CRISPR-modified and other subgroups suggest that genetic alterations in other pathways, such as proliferation and metabolism, may have a greater impact on cellular radiation response. These pathways are often neglected in response modelling and should be considered in the future.
Primary and secondary alcohols have been converted into 2-amino-1,3-thiazoles under microwave irradiation, employing trichloroisocyanuric acid (TCCA) as a dual oxidant and chlorine source, TEMPO as a ...co-oxidant, and thiourea. Secondary alcohols underwent a single-stage, one-pot conversion process, while primary alcohols required a two-stage, one-pot procedure. Both transformations were completed within minutes (25–45 min). The versatility of this protocol extends to the synthesis of other heterocycles, including 1,3-selenazoles, 2-aminoimidazoles, imidazo1,2-apyridines, quinoxalines, and hydrazino thiazoles by replacing thiourea with the appropriate surrogates.
The question of how games should be taught is still a controversial subject. There has been a growing number of studies on teaching games and coaching sports since the first publication of Bunker and ...Thorpe on Teaching Games for Understanding (TGfU). In this sense, the present systematic review and meta-analysis aimed to systematically review the scientific literature about the effects of technical and tactical approach interventions on skill execution and decision making, and to examine the influence of the teacher/coach management style. A systematic literature search was carried out in accordance with PRISMA guidelines in Web of Science (WOS), PubMed (Medline), Scopus, and SportDiscus electronic databases. A total of seven and six studies were deemed to meet the inclusion criteria for decision making and skill execution, respectively. Meta-analysis results showed that tactical interventions achieved significant improvements in decision making (effect size = 0.89 with 95% confidence interval (CI) from 0.12 to 1.65), but they did not show significant improvements in skill execution (effect size = 0.89 with 95% CI from -0.45 to 2.23) compared to technical approaches. However, the heterogeneity of interventions was large and the quality of evidence was low according to GRADE. In conclusion, tactical approaches are recommended to teach games and sports in order to develop technique, understanding, tactical knowledge, and decision making, which are demanded in game play. These findings could be useful for teachers and coaches to improve these aspects of their players and students.
In this research, a set of CuNiCrSiCoTi (H-0Nb), CuNiCrSiCoTiNb0.5 (H-0.5Nb) and CuNiCrSiCoTiNb1 (H-1Nb) high-entropy alloys (HEAs) were melted in a vacuum induction furnace. The effects of Nb ...additions on the microstructure, hardness, and wear behavior of these HEAs (compared with a CuBe commercial alloy) in the as-cast (AC) condition, and after solution (SHT) and aging (AT) heat treatments, were investigated using X-ray diffraction, optical microscopy, and electron microscopy. A ball-on-disc configuration tribometer was used to study wear behavior. XRD and SEM results showed that an increase in Nb additions and modification by heat treatment (HT) favored the formation of BCC and FCC crystal structures (CS), dendritic regions, and the precipitation of phases that promoted microstructure refinement during solidification. Increases in hardness of HEA systems were recorded after heat treatment and Nb additions. Maximum hardness values were recorded for the H-1Nb alloy with measured increases from 107.53 HRB (AC) to 112.98 HRB, and from 1104 HV to 1230 HV (aged for 60 min). However, the increase in hardness caused by Nb additions did not contribute to wear resistance response. This can be attributed to a high distribution of precipitated phases rich in high-hardness NiSiTi and CrSi. Finally, the H-0Nb alloy exhibited the best wear resistance behavior in the aged condition of 30 min, with a material loss of 0.92 mm3.
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