Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

Monoubiquitination of core histone 2A (H2A-K119u) has a critical role in gene regulation in hematopoietic differentiation and other developmental processes. To explore the interplay of histone H2A deubiquitinase Myb-like SWIRM and MPN domain containing1 (2A-DUB/Mysm1) with the p53 axis in the sequential differentiation of mature lymphocytes from progenitors, we systematically analyzed hematopoiesis and early T-cell development using Mysm1^−/− and p53^−/−Mysm1^−/− mice. Mysm1^−/− thymi were severely hypoplastic with <10% of wild-type cell numbers as a result of a reduction of early thymocyte progenitors in context with defective hematopoietic stem cells, a partial block at the double-negative (DN)1–DN2 transition and increased apoptosis of double-positive thymocytes. Increased rates of apoptosis were also detected in other tissues affected by Mysm1 deficiency, including the developing brain and the skin. By quantitative PCR and chromatin immunoprecipitation analyses, we identified p19^ARF, an important regulator of p53 tumor suppressor protein levels, as a potential Mysm1 target gene. In newly generated p53^−/−Mysm1^−/− double-deficient mice, anomalies of Mysm1^−/− mice including reduction of lymphoid-primed multipotent progenitors, reduced thymocyte numbers and viability, and interestingly defective B-cell development, growth retardation, neurological defects, skin atrophy, and tail malformation were almost completely restored as well, substantiating the involvement of the p53 pathway in the alterations caused by Mysm1 deficiency. In conclusion, this investigation uncovers a novel link between H2A deubiquitinase 2A-DUB/Mysm1 and suppression of p53-mediated apoptotic programs during early lymphoid development and other developmental processes.

Mobile and tablet apps, ubiquitous and pervasive computing, wearable computing and domotics for health.

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: There is strong evidence for the effectiveness of addressing tobacco use in healthcare settings. However, only a minority of smokers receive cessation advice when visiting a hospital. Implementing smoking cessation technology in outpatient waiting rooms could be an effective strategy for change, with the potential to expose almost all patients visiting a healthcare provider without preluding physician action needed. Patients positive for the human immunodeficiency virus (HIV) are twice as likely as the general population to be smokers and are significantly more vulnerable to smoking-associated diseases. Objective: To develop an intervention for smoking cessation that would make use of the time HIV-positive patients spend waiting in a waiting room by passively exposing them to a face-aging public morphing tablet-based application (app) and to measure the perceptions of smokers and non-smokers to such an intervention. Methods: We developed a kiosk version of our three-dimensional face-aging app “Smokerface,” which shows the user how their face would age with years of cigarette smoking. We placed a tablet with the app running on a table in the middle of the waiting room of our HIV outpatient clinic, connected to a large monitor attached to the opposite wall. A researcher recorded all the patients using the waiting room. If a patient did not initiate app-use within 30 s of waiting time, the researcher encouraged him/her to do so. Those using the app were asked to complete a questionnaire. Results: During a 19-day period, 464 patients visited the waiting room, of which 187 tried the app and 179 completed the questionnaire. Of these, 139 (77.7%) were men and 84 (47%) were smokers. Of the smokers, 55 (68%) said the intervention motivated them to quit [men, 45 (68%); women, 10 (67%)]; 41 (51%) said that it motivated them to discuss quitting with their doctor [men, 32 (49%); women, 9 (60%)]; and 72 (91%) perceived the intervention as fun [men, 57 (90%); women, 15 (94%)]. Of the non-smokers, 92 (98%) said that it motivated them never to take up smoking [men, 72 (99%); women, 20 (95%)]. Among the other patients, 102 (22.0%) watched another patient try the app without trying it themselves; thus, a total of 289 (62.3%) of the 464 patients were exposed to the intervention (average waiting time, 21 min). Conclusions: A face-aging app implemented in a waiting room provides a novel opportunity to motivate patients visiting a healthcare provider to quit smoking, to address quitting at their subsequent appointment and thereby encourage physician-delivered smoking cessation, or not to take up smoking.

Histone modifications critically contribute to the epigenetic orchestration of bone homeostasis—in part, by modifying the access of transcription factors to specific genes involved in the osteogenic differentiation process of bone marrow mesenchymal stem cells (MSCs) and osteoblasts. Based on our previous finding that histone H2A deubiquitinase 2A‐DUB/Mysm1 interacts with the p53 axis in hematopoiesis and tissue development, we analyzed the molecular basis of the skeletal phenotype of Mysm1‐deficient mice and dissected the underlying p53‐dependent and ‐independent mechanisms. Visible morphologic, skeletal deformations of young Mysm1‐deficient mice— including a kinked and truncated tail and shortened long bones—were associated with osteopenia of long bones. On the cellular level, Mysm1‐deficient primary osteoblasts displayed reduced potential to differentiate into mature osteoblasts, as indicated by decreased expression of osteogenic markers. Reduced osteogenic differentiation capacity of Mysm1‐deficient osteoblasts was accompanied by an impaired induction of osteogenic transcription factor Runx2 . Osteogenic differentiation of Mysm1 ^−/− MSCs, however, was not compromised in vitro . In line with defective hematopoietic development of Mysm1‐deficient mice, Mysm1 ^−/− osteoclasts had reduced resorption activity and were more prone to apoptosis in TUNEL assays. Skeletal alterations and osteopenia of Mysm1‐deficient mice were phenotypically completely rescued by simultaneous ablation of p53 in p53 ^−/− Mysm1 ^−/− double‐deficient mice— although p53 deficiency did not restore Runx2 expression in Mysm1 ^−/− osteoblasts on the molecular level but, instead, enhanced proliferation and osteogenic differentiation of MSCs. In summary, our results demonstrate novel roles for Mysm1 in osteoblast differentiation and osteoclast formation, resulting in osteopenia in Mysm1‐deficient mice that could be abrogated by the loss of p53 from increased osteogenic differentiation of Mysm1 ^−/− p53 ^−/− MSCs.— Haffner‐Luntzer, M., Kovtun, A., Fischer, V., Prystaz, K., Hainzl, A., Kroeger, C. M., Krikki, I., Brinker, T. J., Ignatius, A., Gatzka, M. Loss of p53 compensates osteopenia in murine Mysml deficiency. FASEB J. 32, 1957–1968 (2018). www.fasebj.org