Does the use of recombinant AAV2 in pulmonary gene therapy damage lung function?

Forty-eight BALB/c mice were divided into two groups of 24 animals each. In the control group (CTRL) saline was intratracheally instilled, while the virus group (VR) received rAAV2-GFP (4 x 10(9) particles). These groups were subdivided into four sub-groups (n=6). Pulmonary mechanical parameters were analyzed after 3 weeks (VR1d3w) and at 1 (VR2d1w), 2 (VR2d2w) and 3 weeks (VR2d3w) after a second AAV2 dose. Fractions of the area of alveolar collapse and the amount of polymorpho- and mononuclear cells were determined by point-counting technique. Viral transduction was evaluated by immunohistochemistry. Lung mechanical data were similar in all groups. However, there was an increase in airway and lung parenchyma cellularity and in the fraction of area of alveolar collapse in the VR2d2w group, which nonetheless decreased with time. There was no evidence of apoptosis in any group. In conclusion, the gene transfer vector AAV2 induces, in the lung, a discrete inflammatory reaction that does not affect either baseline lung mechanics or airway hyperresponsiveness.     

Infrasound a new weapon in cancer therapy?

BackgroundResearchers take different positions when describing the effects of infrasound on the human body. Although several studies investigated the likely harmful effects of infrasound exposure from wind turbines a significant connection has not been found yet. There is evidence that infrasound interacts with cell metabolism and may disrupt cell membrane integrity.ObjectivesThe suggested impairment of the cells’ ultrastructure by infrasound leads to the question of whether infrasound can be therapeutically used, for instance in cancer therapy. This review provides the current state of the literature.MethodCurrent literature on infrasound in cancer therapy including all studies with the search terms ‘cancer’ and ‘infrasound’ were identified and reviewed until the year 2020.ResultsThe present state of research reveals promising effects of targeted infrasound in cancer therapy. Infrasound directly affects the tumor cells’ ultrastructure and seems to sensitize several types of cancer to chemotherapy, presumably due to membrane permeabilization. The application of infrasound on tumor cells without other therapeutic agents demonstrates different effects that probably depend on the type of cells, the applied frequency and sound pressure level as well as the time of exposure.ConclusionsThe mechanism of infrasound on cancer cells is not completely understood yet, hence, further studies have to be conducted to clarify the ultrastructural and metabolic changes inside the tumor cells. The development of suitable infrasound generators for the application in a clinical setting would be an important course of action.     

Haematopoietic stem cell transplantation and gene therapy in the fetus: ready for clinical use?

Allogeneic haematopoietic stem cell transplantation in utero has been successfully used for the prenatal treatment of severe combined immunodefiency syndrome. However, this treatment has not been successful in the therapy of other conditions in which the fetus is immunologically competent. The main obstacles to success are lack of competitive advantage of donor versus host stem cells, preventing stable engraftment and graft rejection. Several strategies are being explored to overcome these problems, and some of them have been successful in animal studies. Prenatal gene therapy, using ex-vivo transduced autologous haematopoietic cells or direct gene targeting in utero, is another potential approach in the treatment of immunocompetent fetal recipients. Although this has been shown to be feasible in animal models, safety concerns regarding transduction of fetal germ cells or maternal cells should be addressed in preclinical experiments prior to initiation of clinical trials.     

Does gene therapy become pharmacotherapy?

Recent progress in molecular and cellular biology has led to the development of numerous effective cardiovascular drugs. However, there are still a number of diseases for which no known effective therapy exists, such as peripheral arterial disease, ischaemic heart disease, restenosis after angioplasty, and vascular bypass graft occlusion. Currently, gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease despite its limitations. The first human trial in gene therapy for cardiovascular disease was started at 1994 to treat peripheral vascular disease using vascular endothelial growth factor (VEGF). Then, many different potent angiogenic growth factors were tested in clinical trials to treat peripheral arterial disease and ischaemic heart disease. Improvement of clinical symptoms in peripheral arterial disease and ischaemic heart disease has been reported. This review focuses on the future potential of gene therapy for the treatment of cardiovascular disease. In the future, gene therapy might become a real pharmacotherapy to treat cardiovascular disease.     

Formation and repair of DNA lesions in the p53 gene: Relation to cancer mutations?

The number and diversity of mutations in the p53 mutation data base provides indirect evidence that implicates environmental mutagens in human carcinogenesis. The p53 gene has a large mutational target size; more than 280 out of 393 amino acids are found mutated in tumors. We argue that there is possibly a limited involvement of selection for specific mutations in the central domain of the protein, and that the distribution of DNA damage along the p53 gene caused by environmental carcinogens can be correlated with the mutational spectra, i.e., hotspots and types of mutations, of certain cancers. This concept has been validated by experiments with sunlight and the cigarette smoke component benzo[a]pyrene representing the polycyclic aromatic hydrocarbon class of carcinogens. The damage/repair data obtained for these mutagens can predict certain parameters of the mutational spectra including the distribution of hotspots in human nonmelanoma skin cancers and lung cancers from smokers. Future studies with suspected mutagens may help to implicate causative agents involved in other cancers, such as colon and breast cancer, where the exact carcinogen has not yet been identified but an environmental factor is suspected. Environ. Mol. Mutagen. 31:197–205, 1998 © 1998 Wiley-Liss, Inc.     

Can estrogen receptor overexpression in normal tissues due to previous estrogen deprivation explain the fulvestrant efficacy in breast cancer therapy?

Fulvestrant is a down-regulator of estrogen receptors (ERs) with still evolving optimal dosage for ER-positive breast cancer patients. The CONFIRM phase III trial in women with advanced breast cancer proved fulvestrant 500-mg to be associated with a longer time till progression (TTP) than the 250-mg schedule. Detailed results suggest that the fulvestrant in both schedules depended on the previous endocrine therapy. All complete responses and the only significant TTP difference between the two schedules was found among women previously treated with tamoxifen (TAM) and not in women after aromatase inhibitors (AIs).Noting that TAM competes with estrogen binding to ERs is important, so the optimal TAM dosage produces drug concentrations comparable to concentrations of available ER ligands. All AIs diminish production of the main ER ligand, so the optimal AI dosage depends on the overall pool of aromatase molecules in the body. Both treatments are not directly related to the pool of available ERs in the body.Here proposed interpretation is that estrogen deprivation due to years of endocrine breast cancer therapy increases ER expression in breast cancer cells and in other healthy estrogen target tissues. The breast cancer exposure to fulvestrant depends on the presence of all ERs in the body. Only when this overall pool is sufficiently saturated with fulvestrant, we can expect to achieve some breast cancer response due to down-regulation of ER in cancer tissue.The CONFIRM data suggest that among patients switching from TAM to fulvestrant, only the 500-mg schedule could down-regulate the moderately enlarged total body ER pool and thus induce breast cancer regression. In patients switching from previous AI treatments, both 250 and 500-mg schedules were unable to prolong the TTP, suggesting that in both doses, fulvestrant showed no efficacy since the overall ER pool was more enlarged after AIs.Fulvestrant might be more effective before TAM and AIs, in the first line endocrine therapy of metastatic breast cancer, since an unaltered ER pool in normal tissues is expected in this setting.     

Can estrogen receptor overexpression in normal tissues due to previous estrogen deprivation explain the fulvestrant efficacy in breast cancer therapy?

Fulvestrant is a down-regulator of estrogen receptors (ERs) with still evolving optimal dosage for ER-positive breast cancer patients. The CONFIRM phase III trial in women with advanced breast cancer proved fulvestrant 500-mg to be associated with a longer time till progression (TTP) than the 250-mg schedule. Detailed results suggest that the fulvestrant in both schedules depended on the previous endocrine therapy. All complete responses and the only significant TTP difference between the two schedules was found among women previously treated with tamoxifen (TAM) and not in women after aromatase inhibitors (AIs).     

Can 3D bioprinting solve the mystery of senescence in cancer therapy?

Tumor dormancy leading to cancer relapse is still a poorly understood mechanism. Several cell states such as quiescence and diapause can explain the persistence of tumor cells in a dormant state, but the potential role of tumor cell senescence has been met with hesitance given the historical understanding of the senescent growth arrest as irreversible. However, recent evidence has suggested that senescence might contribute to dormancy and relapse, although its exact role is not fully developed. This limited understanding is largely due to the paucity of reliable study models. The current 2D cell modeling is overly simplistic and lacks the appropriate representation of the interactions between tumor cells (senescent or non-senescent) and the other cell types within the tumor microenvironment (TME), as well as with the extracellular matrix (ECM). 3D cell culture models, including 3D bioprinting techniques, offer a promising approach to better recapitulate the native cancer microenvironment and would significantly improve our understanding of cancer biology and cellular response to treatment, particularly Therapy-Induced Senescence (TIS), and its contribution to tumor dormancy and cancer recurrence. Fabricating a novel 3D bioprinted model offers excellent opportunities to investigate both the role of TIS in tumor dormancy and the utility of senolytics (drugs that selectively eliminate senescent cells) in targeting dormant cancer cells and mitigating the risk for resurgence. In this review, we discuss literature on the possible contribution of TIS in tumor dormancy, provide examples on the current 3D models of senescence, and propose a novel 3D model to investigate the ultimate role of TIS in mediating overall response to therapy.     

Do we need to challenge thoughts in cognitive behavior therapy?

Cognitive behavior therapy (CBT) emphasizes the primacy of cognition in mediating psychological disorder. It aims to alleviate distress by modifying cognitive content and process, realigning thinking with reality. Recently, various authors have questioned the need for CBT therapists to use logico-rational strategies to directly challenge maladaptive thoughts. Hayes [Hayes, S.C. (2004). Acceptance and commitment therapy and the new behavior therapies. In S.C. Hayes, V.M. Follette, & M.M. Linehan (Eds.), Mindfulness and acceptance: Expanding the cognitive behavioral tradition. (pp. 1-29). New York: Guilford] has identified three empirical anomalies in the research literature. Firstly, treatment component analyzes have failed to show that cognitive interventions provide significant added value to the therapy. Secondly, CBT treatments have been associated with a rapid symptomatic improvement prior to the introduction of specific cognitive interventions. Thirdly, there is a paucity of data that changes in cognitive mediators instigate symptomatic change. This paper critically reviews the empirical literature that addresses these significant challenges to CBT. A comprehensive review of component studies finds little evidence that specific cognitive interventions significantly increase the effectiveness of the therapy. Although evidence for the early rapid response phenomenon is lacking, there is little empirical support for the role of cognitive change as causal in the symptomatic improvements achieved in CBT. These findings are discussed with reference to the key question: Do we need to challenge thoughts in CBT?     

CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity?

For most autoimmune disorders, the pattern of inheritance is very complex. The major histocompatibility complex (MHC) gene complex has been implicated as the major genetic component in the predisposition to these diseases but other genes are likely to be involved. Based on function and experimental data, the gene encoding cytotoxic T lymphocyte-associated antigen 4 (CTLA4) has been suggested as a candidate gene for conferring susceptibility to autoimmunity. In this review, we critically evaluate the evidence for pathogenetical involvement of CTLA-4 in the different autoimmune diseases with focus on the possible role of genetic variation of the CTLA4 locus.     

Anti-ageing gene therapy: Not so far away?

Improving healthspan is the main objective of anti-ageing research. Currently, innovative gene therapy-based approaches seem to be among the most promising for preventing and treating chronic polygenic pathologies, including age-related ones. The gene-based therapy allows to modulate the genome architecture using both direct (e.g., by gene editing) and indirect (e.g., by viral or non-viral vectors) approaches. Nevertheless, considering the extraordinary complexity of processes involved in ageing and ageing-related diseases, the effectiveness of these therapeutic options is often unsatisfactory and limited by their side-effects. Thus, clinical implementation of such applications is certainly a long-time process that will require many translation phases for addressing challenges. However, after overcoming these issues, their implementation in clinical practice may obviously provide new possibilities in anti-ageing medicine. Here, we review and discuss recent advances in this rapidly developing research field.