Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. ...Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (
Pt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive
Pt-BP complexes were synthesized using
Pt(NO
)
(en) as precursor and injected intravenously into mice. Specific accumulation of
Pt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that
Pt BP co-localized with calcium in the trabeculae of mice tibia.
Glucocorticoids (GCs) regulate various physiological processes, including bone remodeling. Whereas physiological amounts of GCs are required for proper human osteoblast differentiation, prolonged ...exposure to GCs leads to substantial bone loss in vivo predominantly by inhibiting osteoblast functions. Compound A (CpdA) is a novel GC receptor modulator with the potential of an improved benefit/risk profile. Here we tested the osteoimmunological effects of CpdA on primary human osteoblasts and their paracrine interactions with osteoclasts. To assess the antiinflammatory potential of CpdA in human bone marrow stromal cell (BMSC)-derived osteoblasts, cells were stimulated with lipopolysaccharide and cytokine expression was determined. Similar to dexamethasone (DEX), CpdA profoundly suppressed lipopolysaccharide-induced TNF-α (−63%), IL-1β (−38%), and IL-6 (−36%) (P < 0.05) mRNA levels. Of note, CpdA failed to induce osteogenic differentiation of BMSCs, whereas DEX and budesonide enhanced matrix mineralization an d increased runt-related transcription factor 2 and alkaline phosphatase mRNA levels up to 5-fold in a dose-dependent manner. Interestingly, each substance promoted cell proliferation by 7–10% and suppressed apoptosis by 25–30% at low concentrations and early differentiation stages, whereas high concentrations (1 μm) suppressed proliferation and stimulated apoptosis in mature osteoblasts. Finally, CpdA did not increase the receptor activator of nuclear factor-κB ligand to osteoprotegerin mRNA ratio as compared with DEX and did not stimulate the formation of osteoclasts in coculture with BMSCs. In summary, CpdA displays dissociated osteogenic and immunological effects in human BMSCs that are distinct from those of conventional GCs. Whether the specific osteoimmunological profile of CpdA translates into a relevant in vivo effect needs to be further explored.
Compound A displays dissociated osteogenic and immunological effects on bone marrow stromal cells that differ from those of conventional glucocorticoids and may improve bone health.
Abstract
Background
The incidence of melanoma increased rapidly throughout the last decades, with overexposure to ultraviolet (UV) radiation being an established risk factor. Due to their intensive ...sun exposure, many student athletes (SAs) have an increased risk for skin cancer. The Clever in Sun and Shade Program (CSSP) aims at enforcing positive attitudes toward UV protection (UVP) and at supporting sports schools in establishing UVP strategies.
Methods
CSSP was developed in 2019 using participatory program planning (PPP) as well as following WHO recommendations for UVP at schools. After drafting first material, within a PPP groups were conducted at a partner school (convenience sample 1) with students (
n
= 20), teachers (
n
= 5), school administration (
n
= 2), and coaches (
n
= 5). Materials were then adapted. Program acceptance and feasibility were tested at two further schools (convenience sample 2) with PPP groups of students (
n
= 95) and school administration (
n
= 2). Content analyses and descriptive statistics were conducted.
Results
Less than 50% of SAs and coaches of sample 1 expressed positive attitudes toward UVP, less than 10% reported appropriate UVP behavior. By using PPP, program material was adapted to the target groups’ needs, i.e., by including specific barriers and solutions. Only the most accepted video drafts were produced. The majority of SAs of sample 2 (80-86%) used predominantly positive adjectives such as “important” and “positive” to describe the completed videos and the behavior self-check poster.
Conclusions
PPP process has greatly influenced concept and materials of CSSP for sports schools. Integration of future program participants has proven to be an important component in creating a fitting and feasible program. CSSP for sports schools is a program free of charge that enables sports schools to integrate UVP into their daily routine. It will be disseminated in cooperation with
German Olympic Sports Confederation
and
German Cancer Aid
in 2021.
The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed ...factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors.
The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen-identical related (n = 103), or matched unrelated (n = 118) donor.
Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P =.014) or who relapsed (P <.001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P =.052), and Philadelphia chromosome-positive patients had no poorer outcome than Philadelphia chromosome-negative patients. Total-body irradiation-based conditioning improved DFS in comparison with busulfan (P =.041).
Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.
Summary Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that ...are detectable in the serum or urine. Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development of novel therapeutic drugs for use in combination with cytostatic therapy. Together with autologous stem cell transplantation and advances in supportive care, the use of novel drugs such as proteasome inhibitors and immunomodulatory drugs has increased response rates and survival substantially in the past several years. Present clinical research focuses on the balance between treatment efficacy and quality of life, the optimum sequencing of treatment options, the question of long-term remission and potential cure by multimodal treatment, the pre-emptive treatment of high-risk smouldering myeloma, and the role of maintenance. Upcoming results of ongoing clinical trials, together with a pipeline of promising new treatments, raise the hope for continuous improvements in the prognosis of patients with myeloma in the future.
Because no licensed chemotherapeutic compound has been shown to improve overall survival of patients with relapsed or refractory acute myeloid leukaemia, there is need to develop new drugs that can ...be tested in controlled clinical trials. ...the past decade has shown that acute myeloid leukaemia is a very heterogeneous disease that is unlikely to respond in a uniform pattern to a non-targeted therapeutic approach. ...novel trial designs are needed, in which patients with specific molecular and functionally defined disease entities are treated with compounds that should have activity against the individual leukaemic cells.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. According to Cell press guidelines, graphical abstracts should inspire ...audiences to browse, stimulate their interdisciplinary curiosity, and allow them to rapidly screen for papers in journals 4. The 10 rules are informed by our experience teaching biologists, clinicians, students, and established scientists, and from jointly preparing graphical abstracts for publications and grants (Fig 1). Biology and Medicine require specific icons which are available in the following repositories: * Phylopic (https://www.phylopic.org/) offers shapes of numerous animals, plants, and further model organisms, e.g., for phylogenetic trees. * The EBI (https://www.ebi.ac.uk/style-lab/general/fonts/v1.3/) provides some general scientific icons. * Reactome (https://reactome.org/icon-lib) provides scientific pictograms and chemical drawings for free re-use and encourages the upload of user-designed pictograms for sharing with the scientific community. * Smart (https://smart.servier.com/) is a free collection of medical drawings from Servier Medical Art and can be downloaded as a full slide-deck and used with attribution. * Bioicons (https://bioicons.com/) is an expanding set of biology and laboratory icons from Petri dishes to model organisms available under free licenses (CC0).
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