A realistic utilization of nanotechnology in molecular imaging and targeted radiotherapy of solid tumors

Precise dose delivery to malignant tissue in radiotherapy is of paramount importance for treatment efficacy while minimizing morbidity of surrounding normal tissues. Current conventional imaging techniques, such as magnetic resonance imaging (MRI) and computerized tomography (CT), are used to define the three-dimensional shape and volume of the tumor for radiation therapy. In many cases, these radiographic imaging (RI) techniques are ambiguous or provide limited information with regard to tumor margins and histopathology. Molecular imaging (MI) modalities, such as positron emission tomography (PET) and single photon-emission computed-tomography (SPECT) that can characterize tumor tissue, are rapidly becoming routine in radiation therapy. However, their inherent low spatial resolution impedes tumor delineation for the purposes of radiation treatment planning. This review will focus on applications of nanotechnology to synergize imaging modalities in order to accurately highlight, as well as subsequently target, tumor cells. Furthermore, using such nano-agents for imaging, simultaneous coupling of novel therapeutics including radiosensitizers can be delivered specifically to the tumor to maximize tumor cell killing while sparing normal tissue.     

Treatment of high-grade glioma with radiolabeled peptides

The management of high-grade glioma (HGG) patients in clinical routine represents a challenging task. HGG has a poor prognosis because of early recurrence or therapy-refractory disease following first-line standard therapy, which includes a multidisciplinary approach involving radical surgical resection followed by external beam radiation therapy in combination with chemotherapy.Glioma cells are known to express specific receptors or glycoproteins on their surface which can be used as biological targets for treatment. The application of radiopharmaceuticals consisting of a targeting and an effector domain has led to the introduction of new treatment approaches, aiming at a tumor-specific treatment sparing normal brain tissue.One of these new modalities is the peptide receptor radionuclide therapy (PRRT). Peptides labeled with radioactive nuclides can bind directly to the tumor cells and deliver high doses of radioactivity directly to the tumor tissue.This article reviews the literature for PRRT in HGG.     

Expert System for Modeling and Simulating the Action of Electric and Electromagnetic Fields on Biological Membranes

The biological effects and applications in the developing technology involving electric and electromagnetic fields are as promising as they are diverse. Their effects, leading to remission in certain patients, can be obtained through electroporation, electrochemotherapy, electrotherapy, electroimmunotherapy, and gene electrotherapy. The main therapeutic uses of electromagnetic fields (EMF) are the introduction of chemical or organic substances into opportunely opened cells (electro-chimiotherapy) and the stimulation of specific elements of the immune system (electro-immunotherapy). Their benefits can be modeled by the use of expert systems, constructed to mimic human reasoning. As well as testing new therapies, such systems can analyze and synthesize existing data, and provide a new pedagogical device, and can be implemented on the Internet network. These techniques can be performed conjointly with other therapies like X-ray therapy, neutrotherapy and, in certain conditions, will optimize their effects. Some mathematical models, representing the electromagnetic field's action on cellular membranes, have been elaborated by means of the SADT method (a structured hierarchy modular method) and implanted into the expert system SEI4. This expert system simulates the immune system's behavior when facing electromagnetic fields, in the face of immunodeficient illness such as some cancers or AIDS.     

Radiation increases the cellular uptake of exosomes through CD29/CD81 complex formation

Exosomes mediate intercellular communication, and mesenchymal stem cells (MSC) or their secreted exosomes affect a number of pathophysiologic states. Clinical applications of MSC and exosomes are increasingly anticipated. Radiation therapy is the main therapeutic tool for a number of various conditions. The cellular uptake mechanisms of exosomes and the effects of radiation on exosome–cell interactions are crucial, but they are not well understood. Here we examined the basic mechanisms and effects of radiation on exosome uptake processes in MSC. Radiation increased the cellular uptake of exosomes. Radiation markedly enhanced the initial cellular attachment to exosomes and induced the colocalization of integrin CD29 and tetraspanin CD81 on the cell surface without affecting their expression levels. Exosomes dominantly bound to the CD29/CD81 complex. Knockdown of CD29 completely inhibited the radiation-induced uptake, and additional or single knockdown of CD81 inhibited basal uptake as well as the increase in radiation-induced uptake. We also examined possible exosome uptake processes affected by radiation. Radiation-induced changes did not involve dynamin2, reactive oxygen species, or their evoked p38 mitogen-activated protein kinase-dependent endocytic or pinocytic pathways. Radiation increased the cellular uptake of exosomes through CD29/CD81 complex formation. These findings provide essential basic insights for potential therapeutic applications of exosomes or MSC in combination with radiation.     

The role of medical physics in prostate cancer radiation therapy

Medical physics, both as a scientific discipline and clinical service, hugely contributed and still contributes to the advances in the radiotherapy of prostate cancer. The traditional translational role in developing and safely implementing new technology and methods for better optimizing, delivering and monitoring the treatment is rapidly expanding to include new fields such as quantitative morphological and functional imaging and the possibility of individually predicting outcome and toxicity. The pivotal position of medical physicists in treatment personalization probably represents the main challenge of current and next years and needs a gradual change of vision and training, without losing the traditional and fundamental role of physicists to guarantee a high quality of the treatment. The current focus issue is intended to cover traditional and new fields of investigation in prostate cancer radiation therapy with the aim to provide up-to-date reference material to medical physicists daily working to cure prostate cancer patients. The papers presented in this focus issue touch upon present and upcoming challenges that need to be met in order to further advance prostate cancer radiation therapy. We suggest that there is a smart future for medical physicists willing to perform research and innovate, while they continue to provide high-quality clinical service. However, physicists are increasingly expected to actively integrate their implicitly translational, flexible and high-level skills within multi-disciplinary teams including many clinical figures (first of all radiation oncologists) as well as scientists from other disciplines.     

Therapeutic resistance resulting from mutations in Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR signaling pathways

Chemotherapy remains a commonly used therapeutic approach for many cancers. Indeed chemotherapy is relatively effective for treatment of certain cancers and it may be the only therapy (besides radiotherapy) that is appropriate for certain cancers. However, a common problem with chemotherapy is the development of drug resistance. Many studies on the mechanisms of drug resistance concentrated on the expression of membrane transporters and how they could be aberrantly regulated in drug resistant cells. Attempts were made to isolate specific inhibitors which could be used to treat drug resistant patients. Unfortunately most of these drug transporter inhibitors have not proven effective for therapy. Recently the possibilities of more specific, targeted therapies have sparked the interest of clinical and basic researchers as approaches to kill cancer cells. However, there are also problems associated with these targeted therapies. Two key signaling pathways involved in the regulation of cell growth are the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. Dysregulated signaling through these pathways is often the result of genetic alterations in critical components in these pathways as well as mutations in upstream growth factor receptors. Furthermore, these pathways may be activated by chemotherapeutic drugs and ionizing radiation. This review documents how their abnormal expression can contribute to drug resistance as well as resistance to targeted therapy. This review will discuss in detail PTEN regulation as this is a critical tumor suppressor gene frequently dysregulated in human cancer which contributes to therapy resistance. Controlling the expression of these pathways could improve cancer therapy and ameliorate human health.     

TEP/TDM au FDG et bilan initial des lymphomes : du diagnostic au pronostic

Lymphoma represents a very heterogeneous pathologic disease group and its initial assessment, treatment strategy and prognosis is closely related within each histological subtype. The diagnosis of lymphoma disease is often due to the development of a tumour mass at a lymph node area, or within an organ with or without systemic symptoms. However, all these signs remain non specific. Biopsy is the only reliable diagnostic tool, which can be carried out surgically or guided by the morphological and functional imaging. Once the histological diagnosis is determined by the WHO classification, the staging procedure aim is to provide the prognosis to assist the therapeutic decision. Morphologic imaging primarily based on CT remains the reference in exploring most cases. But in the last decade, the introduction of functional imaging using FDG-PET/CT has dramatically changed the therapeutic management of lymphoma. The additional clinical value provided by initial FDG-PET/CT could lead to an alteration of the therapeutic strategy, as well as to the optimization of radiation therapy or to the establishment of prognostic score and lead to improved lymphoma patient survival in the future.     

Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse

Attempts to cure breast cancer by adoptive cellular therapy (ACT) have not been successful. This is primarily due to the presence of tumor-induced immune-suppressive mechanisms as well as the failure of tumor-reactive T cells to provide long-term memory responses in vivo. To address these clinically important challenges, we developed an ex vivo protocol for the expansion of tumor-reactive immune cells obtained from tumor-bearing animals prior to or after local radiation therapy. We used an Ag-free protocol that included bryostatin 1/ionomycin and sequential common γ-chain cytokines (IL-7/IL-15 + IL-2). The proposed protocol expanded tumor-reactive T cells as well as activated non-T cells, including NKT cells, NK cells, and IFN-γ-producing killer dendritic cells. Antitumor efficacy of T cells depended on the presence of non-T cells. The effector non-T cells also rendered T cells resistant to myeloid-derived suppressor cells. Radiation therapy altered phenotypic distribution and differentiation of T cells as well as their ability to generate central memory T cells. ACT by means of the expanded cells protected animals from tumor challenge and generated long-term memory responses against the tumor, provided that leukocytes were derived from tumor-bearing animals prior to radiation therapy. The ex vivo protocol was also able to expand HER-2/neu-specific T cells derived from the PBMC of a single patient with breast carcinoma. These data suggest that the proposed ACT protocol should be studied further in breast cancer patients.     

Mycosporines and mycosporine-like amino acids: UV protectants or multipurpose secondary metabolites?

Mycosporines and mycosporine-like amino acids (MAAs) are low-molecular-weight water-soluble molecules absorbing UV radiation in the wavelength range 310-365 nm. They are accumulated by a wide range of microorganisms, prokaryotic (cyanobacteria) as well as eukaryotic (microalgae, yeasts, and fungi), and a variety of marine macroalgae, corals, and other marine life forms. The role that MAAs play as sunscreen compounds to protect against damage by harmful levels of UV radiation is well established. However, evidence is accumulating that MAAs may have additional functions: they may serve as antioxidant molecules scavenging toxic oxygen radicals, they can be accumulated as compatible solutes following salt stress, their formation is induced by desiccation or by thermal stress in certain organisms, they have been suggested to function as an accessory light-harvesting pigment in photosynthesis or as an intracellular nitrogen reservoir, and they are involved in fungal reproduction. Here, the evidence for these additional roles of MAAs as 'multipurpose' secondary metabolites is reviewed, with special emphasis on their functions in the microbial world.     

The future of Radiation Oncology: Considerations of Young Medical Doctor

Radiation therapy plays an increasingly important role in the management of cancer. Currently, more than 50% of all cancer patients can expect to receive radiotherapy during the course of their disease, either in a primary management (radical or adjuvant radiotherapy) or for symptom control (palliative radiotherapy).Radiation oncology is a very unique branch of medicine connected with clinical knowledge and also with medical physics. In recent years, this approach has become increasingly absorbed with technological advances. This increasing emphasis on technology, together with other important changes in the health-care economic environment, now place the specialty of radiation oncology in a precarious position. New treatment technologies are evolving at a rate unprecedented in radiation therapy, paralleled by improvements in computer hardware and software. These techniques allow assessment of changes in the tumour volume and its location during the course of therapy (interfraction motion) so that re-planning can adjust for such changes in an adaptive radiotherapy process.If radiation oncologists become simply the guardians of a single therapeutic modality they may find that time marches by and, while the techniques will live on, the specialty may not. This article discusses these threats to the field and examines strategies by which we may evolve, diversify, and thrive.     

Opportunities for rehabilitation of patients with radiation fibrosis syndrome

This review discusses the pathophysiology, evaluation, and treatment of neuromuscular, musculoskeletal, and functional disorders that can result as late effects of radiation treatment.Although radiation therapy is often an effective method of killing cancer cells, it can also damage nearby blood vessels that nourish the skin, ligaments, tendons, muscles, nerves, bones and lungs. This can result in a progressive condition called radiation fibrosis syndrome (RFS). It is generally a late complication of radiotherapy which may manifest clinically years after treatment. Radiation-induced damage can include “myelo-radiculo-plexo-neuro-myopathy,” causing muscle weakness and dysfunction and contributing to neuromuscular injury.RFS is a serious and lifelong disorder which, nevertheless, may often be decremented when identified and rehabilitated early enough. This medical treatment should be a complex procedure consisting of education, physical therapy, occupational therapy, orthotics as well as medications.     

Production of bioelectricity,bio-hydrogen,high value chemicals and bioinspired nanomaterials by electrochemically active biofilms

Microorganisms naturally form biofilms on solid surfaces for their mutual benefits including protection from environmental stresses caused by contaminants, nutritional depletion or imbalances. The biofilms are normally dangerous to human health due to their inherited robustness. On the other hand, a recent study suggested that electrochemically active biofilms (EABs) generated by electrically active microorganisms have properties that can be used to catalyze or control the electrochemical reactions in a range of fields, such as bioenergy production, bioremediation, chemical/biological synthesis, bio-corrosion mitigation and biosensor development. EABs have attracted considerable attraction in bioelectrochemical systems (BESs), such as microbial fuel cells and microbial electrolysis cells, where they act as living bioanode or biocathode catalysts. Recently, it was reported that EABs can be used to synthesize metal nanoparticles and metal nanocomposites. The EAB-mediated synthesis of metal and metal–semiconductor nanocomposites is expected to provide a new avenue for the greener synthesis of nanomaterials with high efficiency and speed than other synthetic methods. This review covers the general introduction of EABs, as well as the applications of EABs in BESs, and the production of bio-hydrogen, high value chemicals and bio-inspired nanomaterials.     

长链非编码RNA的功能与疾病

长链非编码RNAs（long noncoding RNAs,lncRNAs）是一类长度大于200 nt且不表现出任何蛋白质编码潜能的RNAs,在总非编码RNAs(ncRNA)中占有相当大的比例.对lncRNAs的研究将有助于理解生命体多层次的表达调控网络,并有望为复杂疾病的预测、诊断、和治疗提供新的分子依据.本文在简要介绍lncRNAs的基础上,综合分析了lncRNAs与表观遗传、基因表达调控和疾病发生的关系,以期为进一步的研究提供参考.     

National Surgical Breast Project

For public and professional acceptance, clinical studies in breast cancer must be scientifically necessary and ethically justifiable. To resolve controversy based upon retrospective data, they must be prospective and randomized. These guidelines have been used by the National Surgical Adjuvant Breast Project in its investigations carried out during the past 15 years in numerous cooperating institutions. Neither thio-tepa adjuvant to radical mastectomy, nor prophylactic oophorectomy, nor post-operative radiation therapy were found to prolong life. Therefore, prophylactic oophorectomy is contraindicated and adjuvant chemotherapy cannot be justified except perhaps under special circumstances and as part of carefully controlled clinical trials. Postoperative radiation therapy, even in the presence of positive axillary lymph nodes, cannot be recommended except to minimize the rate of local skin recurrences.The present study addresses itself to the timely controversy surrounding proper management of axillary lymph nodes in primary breast cancer. Does removing them alter the outcome of therapy? Total (simple) mastectomy is being compared with radical mastectomy. Women with clinically negative nodes on physical examination are treated either by total (simple) mastectomy alone or by total mastectomy plus radiation, or by radical mastectomy. When the nodes are clinically positive, either radical mastectomy or total mastectomy followed by radiation is being used.The protocol, now underway more than a year, has been well accepted by patients and by many well informed physicians and surgeons. In years ahead it will provide objective evidence as to whether or not removal of the axillary lymph nodes alters the therapeutic efficacy of mastectomy in the treatment of primary breast cancer.     

The potential of mesenchymal stem cells in the management of radiation enteropathy

Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies.     

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.     

Ionizing radiation can activate the insertion of mitochondrial DNA fragments in the nuclear genome

In analytical review is considered the possibility of the insertion of mitochondrial DNA (mtDNA) fragments into the nuclear genome of cells, exposed ionizing radiation (IR). Many studies show that integration fragment mtDNA in nuclear genome, as well as its fastening as NUMT-pseudogenes, proceed at ancient periods of the evolutions not only, but also at more late periods. The number of the investigations shows that under influence endogenous reactive oxygen species, chemical agent, UV-light and IR mtDNA is damaged with greater frequency, than nucleus DNA. Furthermore, the repair systems in mitochondria are low efficiency. In irradiated by IR cells mtDNA fragments can transition from the mitochondria to the cytoplasm. The binding of mtDNA fragment to a complex with proteins provides them the protection from nuclease destroying. Possibly, at such safe condition they and are carried to nucleus. At inductions of DNA double-strand breaks (under the action of IR and activated their reparation) mtDNA fragments may be inserted to nuclear genome. Such integration of mtDNA to nuclear genome, with shaping NUMT-pseudogenes de novo, may be proceed in irradiated cells in the course of the reparations DNA double-strand breaks by the nonhomologous end-joining pathway. These insertions of mtDNA can cardinally change the structure of nuclear genomes in area of their introduction and render the essential influence upon the realization of genetic information. Available information in literature also allows to suppose that integration mtDNA in nuclear genome can proceed and at raised genomic instability observed in cells at post radiation period. It in equal extent pertains and to malignant cells with raised by instability mitochondrial and nuclear genomes. As the most efficient agent, initiating insertion fragment mtDNA in nuclear genome, is considered ionizing radiation.     

SPM Receptor Expression and Localization in Irradiated Salivary Glands

Radiation therapy–mediated salivary gland destruction is characterized by increased inflammatory cell infiltration and fibrosis, both of which ultimately lead to salivary gland hypofunction. However, current treatments (e.g., artificial saliva and sialagogues) only promote temporary relief of symptoms. As such, developing alternative measures against radiation damage is critical for restoring salivary gland structure and function. One promising option for managing radiation therapy–mediated damage in salivary glands is by activation of specialized proresolving lipid mediator receptors due to their demonstrated role in resolution of inflammation and fibrosis in many tissues. Nonetheless, little is known about the presence and function of these receptors in healthy and/or irradiated salivary glands. Therefore, the goal of this study was to detect whether these specialized proresolving lipid mediator receptors are expressed in healthy salivary glands and, if so, if they are maintained after radiation therapy–mediated damage. Our results indicate that specialized proresolving lipid mediator receptors are heterogeneously expressed in inflammatory as well as in acinar and ductal cells within human submandibular glands and that their expression persists after radiation therapy. These findings suggest that epithelial cells as well as resident immune cells represent potential targets for modulation of resolution of inflammation and fibrosis in irradiated salivary glands.