History of hadron therapy accelerators

In the last 60 years, hadron therapy has made great advances passing from a stage of pure research to a well-established treatment modality for solid tumours. In this paper the history of hadron therapy accelerators is reviewed, starting from the first cyclotrons used in the thirties for neutron therapy and passing to more modern and flexible machines used nowadays. The technical developments have been accompanied by clinical studies that allowed the selection of the tumours which are more sensitive to this type of radiotherapy. This paper aims at giving a review of the origin and the present status of hadron therapy accelerators, describing the technological basis and the continuous development of this application to medicine of instruments developed for fundamental science. At the end the present challenges are reviewed.     

External beam radiation therapy with kilovoltage x-rays

Kilovoltage (kV) x-rays are most commonly used for diagnostic imaging due to their sensitivity to tissue composition. In radiation therapy (RT), due to their fast attenuation, kV x-rays are typically only used for superficial irradiation of skin cancer and for intra-operative RT (IORT). Recently, however, a number of kV RT techniques have emerged. In this review article, we provide a brief overview of the use of kV x-rays for RT.Various kV x-ray source technologies suitable for RT, such as conventional x-ray tubes as well as novel x-ray sources, are first described. This x-ray source section is then followed by a section on their implementation in terms of clinical, veterinary and preclinical applications. Specifically, IORT, superficial RT and dose enhancement with iodine and gold nanoparticles, as well as microbeam RT and FLASH RT are discussed in this context. Then, a number of kV x-ray RT applications in modeling and proof-of-principle stages, such as breast external beam RT with rotational sources, kilovoltage arc therapy and the BriXS Compton pulsed x-ray sources, are reviewed. Finally, some clinical and economic considerations for the development of kV RT techniques are discussed.     

A Comparison of Bone Mineral Density and Its Predictors in HIV-Infected and HIV-Uninfected Older Men

ObjectiveBone health in older individuals with HIV infection has not been well studied. This study aimed to compare bone mineral density (BMD), trabecular bone score (TBS), and bone markers between HIV-infected men and age- and body mass index (BMI)-matched HIV-uninfected men aged ≥60 years. We investigated the associations of risk factors related to fracture with BMD, TBS, and bone markers in HIV-infected men.MethodsThis cross-sectional study included 45 HIV-infected men receiving antiretroviral therapy and 42 HIV-uninfected men. Medical history, BMD and TBS measurements, and laboratory tests related to bone health were assessed in all the participants. HIV-related factors known to be associated with bone loss were assessed in the HIV-infected men.ResultsThe mean BMD, TBS, and osteopenia or osteoporosis prevalence were similar among the cases and controls. The HIV-infected men had significantly higher mean N-terminal propeptide of type 1 procollagen and C-terminal cross-linking telopeptide of type I collagen levels. Stepwise multiple linear regression analysis demonstrated that low BMI (lumbar spine, P = .015; femoral neck, P = .018; and total hip, P = .005), high C-terminal cross-linking telopeptide of type I collagen concentration (total hip, P = .042; and TBS, P = .010), and low vitamin D supplementation (TBS, P = .035) were independently associated with low BMD and TBS.ConclusionIn older HIV-infected men with a low fracture risk, the mean BMD and TBS were similar to those of the age- and BMI-matched controls. The mean bone marker levels were higher in the HIV group. Traditional risk factors for fracture, including low BMI, high C-terminal cross-linking telopeptide of type I collagen level, and low vitamin D supplementation, were significant predictors of low BMD and TBS.     

Vascular Gene Transfer from Metallic Stent Surfaces Using Adenoviral Vectors Tethered through Hydrolysable Cross-linkers

In-stent restenosis presents a major complication of stent-based revascularization procedures widely used to re-establish blood flow through critically narrowed segments of coronary and peripheral arteries. Endovascular stents capable of tunable release of genes with anti-restenotic activity may present an alternative strategy to presently used drug-eluting stents. In order to attain clinical translation, gene-eluting stents must exhibit predictable kinetics of stent-immobilized gene vector release and site-specific transduction of vasculature, while avoiding an excessive inflammatory response typically associated with the polymer coatings used for physical entrapment of the vector. This paper describes a detailed methodology for coatless tethering of adenoviral gene vectors to stents based on a reversible binding of the adenoviral particles to polyallylamine bisphosphonate (PABT)-modified stainless steel surface via hydrolysable cross-linkers (HC). A family of bifunctional (amine- and thiol-reactive) HC with an average t_1/2 of the in-chain ester hydrolysis ranging between 5 and 50 days were used to link the vector with the stent. The vector immobilization procedure is typically carried out within 9 hr and consists of several steps: 1) incubation of the metal samples in an aqueous solution of PABT (4 hr); 2) deprotection of thiol groups installed in PABT with tris(2-carboxyethyl) phosphine (20 min); 3) expansion of thiol reactive capacity of the metal surface by reacting the samples with polyethyleneimine derivatized with pyridyldithio (PDT) groups (2 hr); 4) conversion of PDT groups to thiols with dithiothreitol (10 min); 5) modification of adenoviruses with HC (1 hr); 6) purification of modified adenoviral particles by size-exclusion column chromatography (15 min) and 7) immobilization of thiol-reactive adenoviral particles on the thiolated steel surface (1 hr). This technique has wide potential applicability beyond stents, by facilitating surface engineering of bioprosthetic devices to enhance their biocompatibility through the substrate-mediated gene delivery to the cells interfacing the implanted foreign material.     

Detailed dosimetry calculation for in-vitro experiments and its impact on clinical BNCT

PurposeBoron Neutron Capture Therapy (BNCT) is a form of hadrontherapy based on the selective damage caused by the products of neutron capture in ¹⁰B to tumour cells. BNCT dosimetry strongly depends on the parameters of the dose calculation models derived from radiobiological experiments. This works aims at determining an adequate dosimetry for in-vitro experiments involving irradiation of monolayer-cultured cells with photons and BNCT and assessing its impact on clinical settings.M&MDose calculations for rat osteosarcoma UMR-106 and human metastatic melanoma Mel-J cell survival experiments were performed using MCNP, transporting uncharged particles for KERMA determinations, and secondary particles (electrons, protons, ¹⁴C, ⁴He and ⁷Li) to compute absorbed dose in cultures. Dose-survival curves were modified according to the dose correction factors determined from computational studies. New radiobiological parameters of the photon isoeffective dose models for osteosarcoma and metastatic melanoma tumours were obtained. Dosimetry implications considering cutaneous melanoma patients treated in Argentina with BNCT were assessed and discussed.ResultsKERMA values for the monolayer-cultured cells overestimate absorbed doses of radiation components of interest in BNCT. Detailed dose calculations for the osteosarcoma irradiation increased the relative biological effectiveness factor RBE_1% of the neutron component in more than 30%. The analysis based on melanoma cases reveals that the use of survival curves based on KERMA leads to an underestimation of the tumour doses delivered to patients.ConclusionsConsidering detailed dose calculation for in-vitro experiments significantly impact on the prediction of the tumor control in patients. Therefore, proposed methods are clinically relevant.     

Simple oligonucleotide-based multiplexing of single-cell chromatin accessibility

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6-Shogaol induces apoptosis in acute lymphoblastic leukaemia cells by targeting p53 signalling pathway and generation of reactive oxygen species

Combination therapies, using medicinal herbs, are broadly recommended to attenuate the chemotherapy adverse effects. Based on our previous findings considering the anti-leukaemic effects of ginger extract on acute lymphoblastic leukaemia (ALL) cells, the present study was aimed to investigate the anti-cancer role of this pharmaceutical plant on ALL mice models. Moreover, we worked towards identifying the most anti-leukaemic derivative of ginger and the mechanism through which it may exert its cytotoxic impact. In vivo experiments were performed using five groups of six C57BL/6 nude mice, and the anti-leukaemic activity of ginger extract alone or in combination with methotrexate (MTX) was examined. Results showed increased survival rate and reduced damages in mice brain and liver tissues. Subsequently, MTT assay demonstrated synergistic growth inhibitory effect of 6-shogaol (6Sh) and MTX on ALL cell lines and patients primary cells. Eventually, the molecular anti-neoplastic mechanism of 6Sh was evaluated using Bioinformatics. Flow cytometry illustrated 6Sh-mediated apoptosis in Nalm-6 cells confirmed by Western blotting and RT-PCR assays. Further analyses exhibited the generation of reactive oxygen species (ROS) through 6Sh. The current study revealed the in vivo novel anti-leukaemic role of ginger extract, promoted by MTX. Moreover, 6-shogaol was introduced as the major player of ginger cytotoxicity through inducing p53 activity and ROS generation.