Abstract An “abscopal” effect occurs when localized irradiation perturbs the organism as a whole, with consequences that can be either beneficial or detrimental. Mechanistic explanations of this ...effect are challenging. From the oncologist’s perspective, the term refers to distant tumor regression after localized irradiation. On the other hand, from a biologist’s point of view, abscopal effects include induction of genomic instability, cell death, and oncogenic transformation in normal tissues. This conceptual dichotomy is explored in this review, with a focus on clinically documented cases of anti-tumor abscopal effects and abscopal effects in normal tissues. This review also outlines several suggested mechanisms for abscopal effects.
p21: A Two-Faced Genome Guardian Georgakilas, Alexandros G; Martin, Olga A; Bonner, William M
Trends in molecular medicine,
04/2017, Letnik:
23, Številka:
4
Journal Article
Recenzirano
Upon DNA damage or other stressors, the tumor suppressor p53 is activated, leading to transient expression of the cyclin-dependent kinase inhibitor (CKI) p21. This either triggers momentary G1 cell ...cycle arrest or leads to a chronic state of senescence or apoptosis, a form of genome guardianship. In the clinic, the presence of p21 has been considered an indicator of wildtype p53 activity. However, recent evidence suggests that p21 also acts as an oncogenic factor in a p53-deficient environment. Here, we discuss the controversial aspects of the two-faced involvement of p21 in cancer and speculate on how this new information may increase our understanding of its role in cancer pathogenesis. Prevailing notions indicate that p21 might also act as antiapoptotic agent, which may have relevant implications for future therapeutic strategies.
•Immune alterations are present in many ionizing radiation-induced adverse health outcomes.•Low doses of ionizing radiation induce subtle but persistent immune function alterations.•High doses are ...mainly immune suppressive, low dose effects are immune modulatory.•High doses are pro-inflammatory, low doses can have anti-inflammatory effects, as well.•Immune aging is accelerated by ionizing radiation.
Ionizing radiation interacts with the immune system in many ways with a multiplicity that mirrors the complexity of the immune system itself: namely the need to maintain a delicate balance between different compartments, cells and soluble factors that work collectively to protect, maintain, and restore tissue function in the face of severe challenges including radiation damage. The cytotoxic effects of high dose radiation are less relevant after low dose exposure, where subtle quantitative and functional effects predominate that may go unnoticed until late after exposure or after a second challenge reveals or exacerbates the effects. For example, low doses may permanently alter immune fitness and therefore accelerate immune senescence and pave the way for a wide spectrum of possible pathophysiological events, including early-onset of age-related degenerative disorders and cancer. By contrast, the so called low dose radiation therapy displays beneficial, anti-inflammatory and pain relieving properties in chronic inflammatory and degenerative diseases. In this review, epidemiological, clinical and experimental data regarding the effects of low-dose radiation on the homeostasis and functional integrity of immune cells will be discussed, as will be the role of immune-mediated mechanisms in the systemic manifestation of localized exposures such as inflammatory reactions. The central conclusion is that ionizing radiation fundamentally and durably reshapes the immune system. Further, the importance of discovery of immunological pathways for modifying radiation resilience amongst other research directions in this field is implied.
Formation of γ-H2AX in response to DNA double stranded breaks (DSBs) provides the basis for a sensitive assay of DNA damage in human biopsies. The review focuses on the application of γ-H2AX-based ...methods to translational studies to monitor the clinical response to DNA targeted therapies such as some forms of chemotherapy, external beam radiotherapy, radionuclide therapy or combinations thereof. The escalating attention on radiation biodosimetry has also highlighted the potential of the assay including renewed efforts to assess the radiosensitivity of prospective radiotherapy patients. Finally the γ-H2AX response has been suggested as a basis for an in vivo imaging modality.
Despite progressive improvements in the management of patients with locoregionally confined, advanced-stage solid tumours, distant metastasis remains a very common - and usually fatal - mode of ...failure after attempted curative treatment. Surgery and radiotherapy are the primary curative modalities for these patients, often combined with each other and/or with chemotherapy. Distant metastasis occurring after treatment can arise from previously undetected micrometastases or, alternatively, from persistent locoregional disease. Another possibility is that treatment itself might sometimes cause or promote metastasis. Surgical interventions in patients with cancer, including biopsies, are commonly associated with increased concentrations of circulating tumour cells (CTCs). High CTC numbers are associated with an unfavourable prognosis in many cancers. Radiotherapy and systemic antitumour therapies might also mobilize CTCs. We review the preclinical and clinical data concerning cancer treatments, CTC mobilization and other factors that might promote metastasis. Contemporary treatment regimens represent the best available curative options for patients who might otherwise die from locally confined, advanced-stage cancers; however, if such treatments can promote metastasis, this process must be understood and addressed therapeutically to improve patient survival.
Clostridium difficile is an emergent pathogen, and the most common cause of nosocomial diarrhea. In an effort to understand the role of small noncoding RNAs (sRNAs) in C. difficile physiology and ...pathogenesis, we used an in silico approach to identify 511 sRNA candidates in both intergenic and coding regions. In parallel, RNA-seq and differential 5'-end RNA-seq were used for global identification of C. difficile sRNAs and their transcriptional start sites at three different growth conditions (exponential growth phase, stationary phase, and starvation). This global experimental approach identified 251 putative regulatory sRNAs including 94 potential trans riboregulators located in intergenic regions, 91 cis-antisense RNAs, and 66 riboswitches. Expression of 35 sRNAs was confirmed by gene-specific experimental approaches. Some sRNAs, including an antisense RNA that may be involved in control of C. difficile autolytic activity, showed growth phase-dependent expression profiles. Expression of each of 16 predicted c-di-GMP-responsive riboswitches was observed, and experimental evidence for their regulatory role in coordinated control of motility and biofilm formation was obtained. Finally, we detected abundant sRNAs encoded by multiple C. difficile CRISPR loci. These RNAs may be important for C. difficile survival in bacteriophage-rich gut communities. Altogether, this first experimental genome-wide identification of C. difficile sRNAs provides a firm basis for future RNome characterization and identification of molecular mechanisms of sRNA-based regulation of gene expression in this emergent enteropathogen.
•Advantages and current limitations of FLASH and spatially fractionated radiotherapy (SFRT).•Similarities and differences between FLASH and SFRT.•Devices for simultaneous application of FLASH and ...SFRT: current status and perspectives.
FLASH radiotherapy (FLASH-RT) and spatially fractionated radiation therapy (SFRT) are two new therapeutical strategies that use non-standard dose delivery methods to reduce normal tissue toxicity and increase the therapeutic index. Although likely based on different mechanisms, both FLASH-RT and SFRT have shown to elicit radiobiological effects that significantly differ from those induced by conventional radiotherapy. With the therapeutic potential having been established separately for each technique, the combination of FLASH-RT and SFRT could therefore represent a winning alliance. In this review, we discuss the state of the art, advantages and current limitations, potential synergies, and where a combination of these two techniques could be implemented today or in the near future.
Current advances in cancer biology have identified major pathways involved in tumorigenesis. The association of DNA damage with premalignant stages of tumor progression, genome instability and ...further oncogenic transformation opens the possibility of using common DNA damage markers for early cancer detection, prediction, prognosis, therapeutics and possibly for cancer prevention. Perhaps the most sensitive DNA damage marker is γ-H2AX formation in the chromatin flanking the free DNA double-stranded ends in double-strand breaks (DSBs) and eroded telomeres, both present during oncogenic transformation. Our group and others found elevated endogenous levels of γ-H2AX in various human cancer cell lines, premalignant lesions and solid tumors. These data suggest that increased DNA damage is a general characteristic of cancer development. γ-H2AX-based assay can be applied to human biopsies, aspirates and, possibly, to mononuclear cells of the peripheral blood. We propose that detection of γ-H2AX could benefit for the early cancer screening and to ascertain the efficiency of clinical treatment involving chemo- and radiotherapeutic protocols.
Radiation therapy is an effective means of achieving local control in a wide range of primary tumours, with the reduction in the size of the tumour(s) thought to mediate the observed reductions in ...metastatic spread in clinical trials. However, there is evidence to suggest that the complex changes induced by radiation in the tumour environment can also present metastatic risks that may counteract the long-term efficacy of the treatment. More than 25 years ago, several largely theoretical mechanisms by which radiation exposure might increase metastatic risk were postulated. These include the direct release of tumour cells into the circulation, systemic effects of tumour and normal tissue irradiation and radiation-induced changes in tumour cell phenotype. Here, we review the data that has since emerged to either support or refute these putative mechanisms focusing on how the unique radiobiology underlying modern radiotherapy modalities might alter these risks.
PDF
