Entwicklung eines Importmoduls für medizinische und psychotherapeutische Anwendungen

Die Zahl der Gesundheits-Apps wächst stetig. Ihr Potential für Vorsorge oder Therapie wird von Ärzten anerkannt, allerdings mangelt es an wissenschaftlicher Evaluation. Für Nutzer stehen nur subjektive Bewertungen durch andere Nutzer, die Laien sind, zur Verfügung. Ziel der mobile Health App Database (mHAD) ist es in Zusammenarbeit mit Experten der jeweiligen medizinischen und psychotherapeutischen Fachrichtungen diesem Umstand Abhilfe zu schaffen. Die Experten bewerten Gesundheits-Apps nach festgelegten Kriterien. Diese Ratings werden an die mHAD geschickt, die sie speichert und Nutzern der mHAD anzeigt. In der vorliegenden Arbeit wurde der Import der Ratings in die mHAD neu implementiert. Der Import umfasst Daten aus zwei verschiedenen Datenformaten und lässt sich jetzt leicht um zusätzliche Formate erweitern. Die Daten werden validiert, damit nur formal korrekte und anzeigbare Daten in die Datenbank übernommen werden. Außerdem wurden graphische Benutzeroberflächen für den Upload von Dateien und anschließendes Anzeigen der Daten in tabellarischer Form entwickelt. Mit diesem System können Experten ihre Ratings vor dem Import in die Datenbank validieren lassen und korrigieren

Treatment of Cutaneous Melanoma Harboring SMO p.Gln216Arg Mutation with Imiquimod: An Old Drug with New Results

: Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options. Here we report, for the first time to our knowledge, a clinical case where a melanoma patient harboring the SMO p.Gln216Arg mutation has been treated with imiquimod, showing a complete and durable response. To better explain this outstanding response to the treatment, we transfected a melanoma cell line (MeWo) with the SMO p.Gln216Arg mutation in order to evaluate its role in response to the imiquimod treatment. Moreover, to better demonstrate that the antitumor activity of imiquimod was due to its role in suppressing the oncogenic SMO signaling pathway, independently of its immune modulating function, an in vivo experiment has been performed. This clinical case opens up a new scenario for the treatment of melanoma patients identifying a new potentially druggable target

Supplementation of Acqua Lete® (Bicarbonate Calcic Mineral Water) improves hydration status in athletes after short term anaerobic exercise

Background: Experimental studies suggest that mineral waters with high concentrations of calcium and bicarbonate can impact acid–base balance. The purpose of this study was to test the effect on acid–base balance and specific urine gravity, of a bicarbonate calcic mineral water (Acqua Lete®) compared to a minimally mineralized water. Methods: 88 amateur male athletes underwent two experimental trials with a modified Wingate test: the first was carried out without hydration (Control Test, Test C, n = 88); the second was carried out after one week of controlled hydration (Test with hydration, Test H, n = 88), with 1.5 L/day of a very low mineral content water (Group A, n = 44) or 1.5 L/day of Acqua Lete® (Group B, n = 44). Measure of body temperature, bioimpedance analysis, muscular ultrasound, and urinalysis were taken before (t0), immediately after (t1), 5’ (t2), and 30’ (t3) after exercise. Results: Hydration results in a decreased core temperature; muscular ultrasound showed increased muscle thickness after exercise related to content of body water. Regarding urinalysis, in test H, we found in both groups after exercise a significant decrease of specific urine gravity with significantly lower levels in Group B. We also found a significant increase of pH in the same Group B. Conclusions: In conclusion all the athletes hydrated with Acqua Lete® showed a positive impact on hydration status after anaerobic exercise with significant decrease of specific urine gravity and a positive effect on pH

Breast tumor cell invasion and pro-invasive activity of cancer-associated fibroblasts co-targeted by novel urokinase-derived decapeptides

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Among peritumoral cells, cancer-associated fibroblasts (CAFs) are major facilitators of tumor progression. This study describes the effects of two urokinase-derived, novel decapeptides, denoted as Pep 1 and its cyclic derivative Pep 2. In a mouse model of tumor dissemination, using HT1080 fibrosarcoma cells, Pep 2 reduced the number and size of lung metastases. Specific binding of fluoresceinated Pep 2 to HT1080 and telomerase immortalised fibroblasts (TIF) cell surfaces was enhanced by αv overexpression or abolished by excess vitronectin, anti-αv antibodies or silencing of ITGAV αv gene, identifying αv-integrin as the Pep 2 molecular target. In 3D-organotypic assays, peptide-exposed TIFs and primary CAFs from breast carcinoma patients both exhibited a markedly reduced pro-invasive ability of either HT1080 fibrosarcoma or MDA-MB-231 mammary carcinoma cells, respectively. Furthermore, TIFs, either exposed to Pep 2, or silenced for αv integrin, were impaired in their ability to chemoattract cancer cells and to contract collagen matrices, exhibiting reduced α-smooth muscle actin (α-SMA) levels. Finally, peptide exposure of αv-expressing primary CAFs led to the downregulation of α-SMA protein and to a dramatic reduction of their pro-invasive capability. In conclusion, the ability of the novel decapeptides to interfere with tumor cell invasion directly and through the down-modulation of CAF phenotype suggests their use as lead compounds for co-targeting anti-cancer strategies

Urokinase receptor derived peptides as potent inhibitors of the formyl peptide receptor type 1-triggered cell migration

The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration. We and others have previously documented that the uPAR(84–95) sequence, interacts with the formyl peptide receptors (FPR)s, henceforth inducing cell migration of several cell lines, including leukocytes, and the synthetic shorter peptide (Ser88-Arg-Ser-Arg-Tyr92, SRSRY) retains chemotactic activity in vitro and in vivo. Recently, we have developed the head-to-tail cyclic analog [SRSRY], a new potent and stable inhibitor of monocyte trafficking. This prompted us to develop novel cyclic and linear analogs of [SRSRY] with the aim to broaden the knowledge about structure-activity relationships of peptide [SRSRY]. Herein we report their synthesis, effects on cell migration, conformational and docking analyses which served to envisage a new pharmacophore model for inhibitors of FPR1-triggered cell migration

Disulfide bond replacement with 1,4‐ and 1,5‐disubstituted [1,2,3]‐triazole on C‐X‐C chemokine receptor type 4 (CXCR4) peptide ligands: small changes that make big differences

Here we investigate the structural and biological effects ensuing form the disulfide bond replacement of a potent and selective C-X-C chemokine receptor type 4 (CXCR4) peptide antagonist, with 1,4- and 1,5- disubstituted 1,2,3-triazole moieties. Both strategies produced candidates that showed high affinity and selectivity against CXCR4. Notably, when assessed for their ability to modulate the CXCL12-mediated cell migration, the 1,4-triazole variant conserved the antagonistic effect in the low-mid nanomolar range, while the 1,5-triazole one displayed the ability to activate the migration, becoming the first in class low-molecular-weight CXCR4 peptide agonist. By combining NMR and computational studies, we provided a valuable model that highlighted differences in the interactions of the two peptidomimetics with the receptor that could account for their different functional profile. Finally, we envisage that our findings could be translated to different GPCR-interacting peptides for the pursuit of novel chemical probes that could assist in dissecting the complex puzzle of this fundamental class of transmembrane receptors

Treatment of Cutaneous Melanoma Harboring SMO p.Gln216Arg Mutation with Imiquimod: An Old Drug with New Results

Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options. Here we report, for the first time to our knowledge, a clinical case where a melanoma patient harboring the SMO p.Gln216Arg mutation has been treated with imiquimod, showing a complete and durable response. To better explain this outstanding response to the treatment, we transfected a melanoma cell line (MeWo) with the SMO p.Gln216Arg mutation in order to evaluate its role in response to the imiquimod treatment. Moreover, to better demonstrate that the antitumor activity of imiquimod was due to its role in suppressing the oncogenic SMO signaling pathway, independently of its immune modulating function, an in vivo experiment has been performed. This clinical case opens up a new scenario for the treatment of melanoma patients identifying a new potentially druggable target

Discovery of PTPRJ Agonist Peptides That Effectively Inhibit in Vitro Cancer Cell Proliferation and Tube Formation

PTPRJ is a receptor protein tyrosine phosphatase involved in both physiological and oncogenic pathways. We previously reported that its expression is strongly reduced in the majority of explored cancer cell lines and tumor samples; moreover, its restoration blocks in vitro cancer cell proliferation and in vivo tumor formation. By means of a phage display library screening, we recently identified two peptides able to bind and activate PTPRJ, resulting in cell growth inhibition and apoptosis of both cancer and endothelial cells. Here, on a previously discovered PTPRJ agonist peptide, PTPRJ-pep19, we synthesized and assayed a panel of nonapeptide analogues with the aim to identify specific amino acid residues responsible for peptide activity. These second-generation nonapeptides were tested on both cancer and primary endothelial cells (HeLa and HUVEC, respectively); interestingly, one of them (PTPRJ-19.4) was able to both dramatically reduce cell proliferation and effectively trigger apoptosis of both HeLa and HUVECs compared to its first-generation counterpart. Moreover, PTPRJ-pep19.4 significantly inhibited in vitro tube formation on Matrigel. Intriguingly, while ERK1/2 phosphorylation and cell proliferation were both inhibited by PTPRJ-pep19.4 in breast cancer cells (MCF-7 and SKBr3), no effects were observed on primary normal human mammary endothelial cells (HMEC). We further characterized these peptides by molecular modeling and NMR experiments reporting, for the most active peptide, the possibility of self-aggregation states and highlighting new hints of structure-activity relationship. Thus, our results indicate that this nonapeptide might represent a great potential lead for the development of novel targeted anticancer drug

Discovery of 2,3-Diaminoindole Derivatives as a Novel Class of NOD Antagonists

NOD1 and NOD2 are members of the pattern recognition receptors involved in the innate immune response. Overactivation of NOD1 is implicated in inflammatory disorders, multiple sclerosis, and cancer cell metastases. NOD1 antagonists would represent valuable pharmacological tools to gain further insight into protein roles, potentially leading to new therapeutic strategies. We herein report the expansion of the chemical space of NOD1 antagonists via a multicomponent synthetic approach affording a novel chemotype, namely, 2,3-diaminoindoles. These efforts resulted in compound 37, endowed with low micromolar affinity toward NOD1. Importantly, a proof-of-evidence of direct binding to NOD1 of Noditinib-1 and derivative 37 is provided here for the first time. Additionally, the combination of computational studies and NMR-based displacement assays enabled the characterization of the binding modality of 37 to NOD1, thus providing key unprecedented knowledge for the design of potent and selective NOD1 antagonists