Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

Simple Summary AML is a genetically heterogeneous disease with a median age of diagnosis between 60 and 70 years. Thus, many AML patients are not eligible for intensive chemotherapy. Often, the disease is accompanied by a poor prognosis due to high-risk genetic features or due to antecedent hematologic disorders (e.g., myelodysplastic syndrome). Therefore, AML treatment remains a challenge; even after intensive chemotherapy and allogeneic stem cell transplantation (alloHSCT), AML relapses are regularly observed. Thus, new concepts of AML therapy, considering tailored treatment approaches after comprehensive molecular diagnostic or implementing new immunotherapeutic strategies, are urgently needed. This review provides a detailed overview of recent developments and current promising concepts to improve the treatment and the outcome of AML patients. Abstract Treatment of acute myeloid leukemia (AML) has improved in recent years and several new therapeutic options have been approved. Most of them include mutation-specific approaches (e.g., gilteritinib for AML patients with activating FLT3 mutations), or are restricted to such defined AML subgroups, such as AML-MRC (AML with myeloid-related changes) or therapy-related AML (CPX-351). With this review, we aim to present a comprehensive overview of current AML therapy according to the evolved spectrum of recently approved treatment strategies. We address several aspects of combined epigenetic therapy with the BCL-2 inhibitor venetoclax and provide insight into mechanisms of resistance towards venetoclax-based regimens, and how primary or secondary resistance might be circumvented. Furthermore, a detailed overview on the current status of AML immunotherapy, describing promising concepts, is provided. This review focuses on clinically important aspects of current and future concepts of AML treatment, but will also present the molecular background of distinct targeted therapies, to understand the development and challenges of clinical trials ongoing in AML patients

Wire arc additive manufacturing (WAAM) of aluminium alloy AlMg5Mn with energy-reduced gas metal arc welding (GMAW)

Large-scale aluminum parts are used in aerospace and automotive industries, due to excellent strength, light weight, and the good corrosion resistance of the material. Additive manufacturing processes enable both cost and time savings in the context of component manufacturing. Thereby, wire arc additive manufacturing (WAAM) is particularly suitable for the production of large volume parts due to deposition rates in the range of kilograms per hour. Challenges during the manufacturing process of aluminum alloys, such as porosity or poor mechanical properties, can be overcome by using arc technologies with adaptable energy input. In this study, WAAM of AlMg5Mn alloy was systematically investigated by using the gas metal arc welding (GMAW) process. Herein, correlations between the energy input and the resulting temperature–time-regimes show the effect on resulting microstructure, weld seam irregularities and the mechanical properties of additively manufactured aluminum parts. Therefore, multilayer walls were built layer wise using the cold metal transfer (CMT) process including conventional CMT, CMT advanced and CMT pulse advanced arc modes. These processing strategies were analyzed by means of energy input, whereby the geometrical features of the layers could be controlled as well as the porosity to area portion to below 1% in the WAAM parts. Furthermore, the investigations show the that mechanical properties like tensile strength and material hardness can be adapted throughout the energy input per unit length significantl

Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance

OBJECTIVES: Internal tandem duplications (ITDs) of the Fms-like tyrosine kinase 3 (FLT3) represent the most frequent molecular aberrations in acute myeloid leukemia (AML) and are associated with an inferior prognosis. The pattern of downstream activation by this constitutively activated receptor tyrosine kinase is influenced by the localization of FLT3-ITD depending on its glycosylation status. Different pharmacological approaches can affect FLT3-ITD-driven oncogenic pathways by the modulation of FLT3-ITD localization. AIMS: The objective of this study was to investigate the effects of N-glycosylation inhibitors (tunicamycin or 2-deoxy-D-glucose) or the histone deacetylase inhibitor valproic acid (VPA) on FLT3-ITD localization and downstream activity. We sought to determine the potential differences between the distinct FLT3-ITD variants, particularly concerning their susceptibility towards combined treatment by addressing either N-glycosylation and the heat shock protein 90 (HSP90) by 17-AAG, or by targeting the PI3K/AKT/mTOR pathway by rapamycin after treatment with VPA. METHODS: Murine Ba/F3 leukemia cell lines were stably transfected with distinct FLT3-ITD variants resulting in IL3-independent growth. These Ba/F3 FLT3-ITD cell lines or FLT3-ITD-expressing human MOLM13 cells were exposed to tunicamycin, 2-deoxy-D-glucose or VPA, and 17-AAG or rapamycin, and characterized in terms of downstream signaling by immunoblotting. FLT3 surface expression, apoptosis, and metabolic activity were analyzed by flow cytometry or an MTS assay. Proteome analysis by liquid chromatography–tandem mass spectrometry was performed to assess differential protein expression. RESULTS: The susceptibility of FLT3-ITD-expressing cells to 17-AAG after pre-treatment with tunicamycin or 2-deoxy-D-glucose was demonstrated. Importantly, in Ba/F3 cells that were stably expressing distinct FLT3-ITD variants that were located either in the juxtamembrane domain (JMD) or in the tyrosine kinase 1 domain (TKD1), response to the sequential treatments with tunicamycin and 17-AAG varied between individual FLT3-ITD motifs without dependence on the localization of the ITD. In all of the FLT3-ITD cell lines that were investigated, incubation with tunicamycin was accompanied by intracellular retention of FLT3-ITD due to the inhibition of glycosylation. In contrast, treatment of Ba/F3-FLT3-ITD cells with VPA was associated with a significant increase of FLT3-ITD surface expression depending on FLT3 protein synthesis. The allocation of FLT3 to different cellular compartments that was induced by tunicamycin, 2-deoxy-D-glucose, or VPA resulted in the activation of distinct downstream signaling pathways. Whole proteome analyses of Ba/F3 FLT3-ITD cells revealed up-regulation of the relevant chaperone proteins (e.g., calreticulin, calnexin, HSP90beta1) that are directly involved in the stabilization of FLT3-ITD or in its retention in the ER compartment. CONCLUSION: The allocation of FLT3-ITD to different cellular compartments and targeting distinct downstream signaling pathways by combined treatment with N-glycosylation and HSP90 inhibitors or VPA and rapamycin might represent new therapeutic strategies to overcome resistance towards tyrosine kinase inhibitors in FLT3-ITD-positive AML. The treatment approaches addressing N-glycosylation of FLT3-ITD appear to depend on patient-specific FLT3-ITD sequences, potentially affecting the efficacy of such pharmacological strategies

Pseudoxanthoma elasticum – Genetics, pathophysiology, and clinical presentation

Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystem disease. Mutations in the ABCC6-gene are causative, coding for a transmembrane transporter mainly expressed in hepatocytes, which promotes the efflux of adenosine triphosphate (ATP). This results in low levels of plasma inorganic pyrophosphate (PPi), a critical anti-mineralization factor. The clinical phenotype of PXE is characterized by the effects of elastic fiber calcification in the skin, the cardiovascular system, and the eyes. In the eyes, calcification of Bruch's membrane results in clinically visible lesions, including peau d'orange, angioid streaks, and comet tail lesions. Frequently, patients must be treated for secondary macular neovascularization. No effective therapy is available for treating the cause of PXE, but several promising approaches are emerging. Finding appropriate outcome measures remains a significant challenge for clinical trials in this slowly progressive disease. This review article provides an in-depth summary of the current understanding of PXE and its multi-systemic manifestations. The article offers a detailed overview of the ocular manifestations, including their morphological and functional consequences, as well as potential complications. Lastly, previous and future clinical trials of causative treatments for PXE are discussed

Sazaroto ķēžu aminoskābju lietošanas riski sportistiem

MedicīnaVeselības aprūpeMedicineHealth CareKopsavilkums Pamatojums: Diētai un uzturam tiek arvien vairāk pievērsta uzmanība ikdienā. Līdz ar to arī uzturvielu papildus uzņemšana un stingra diēta ir biežs ikdienas ieradums daudziem cilvēkiem. Sazaroto ķēžu aminoskābes (BCAA) ir viens no biežākajiem uztura bagātinātājiem. Tomēr interesants fakts, ka ir ļoti maz pētījumu par to lietošanu. Pētnieciskā darba mērķis bija apkopot zinātnisko pētījumu rezultātus, lai izvērtētu BCAA papildus lietošanu un tās riskus. Pirmais uzdevums bija noskaidrot normālo BCAA fizioloģisko nepieciešamību un darbības mehānismu. Metodes: Šajā neempīriskajā literatūras apskatā teorētiskās bāzes avoti ir ņemti no zinātnisko pētījumu materiāliem, kā arī pētījumiem, kas publicēti starptautiskajā un vietējā periodikā. Datu ieguvei izmantots interneta resurss “Pubmed”. Šeit meklēšana tika veikta, izmantojot atslēgas vārdus un MeSH terminus. Meklēšana tika iedalīta pēc atslēgas vārdiem, sākot ar galveno tēmu “aminoskābes” līdz sīkākām – “BCAA”, atsevišķas BCAA (“valīns”, “leicīns”, “izoleicīns”), līdz to funkcijām. Tos kombinējot tika atrastas publikācijas un to references izmantotas. Publikāciju atlasei tika ievērotas šādas darbības un kritēriji izstrādāti. Pētījumam jābūt saprotamam un ticamam. Publikāciju avotiem jābūt zinātniski nozīmīgiem. Rakstam jāatbilst šī darba mērķim. Pētījumu dalībniekiem jāatbilst pēc vecuma, fiziskā stāvokļa, uztura paradumiem u.c. Kopumā vairāk nekā 40 publikācijas, žurnālu raksti un grāmatas ir iekļauti šajā literatūras apskatā. Secinājumi: Šis apskats par sazaroto ķēžu aminoskābju lietošanu, riska izvērtējumu un darbības mehānismu sniedz priekšstatu par BCAA papildus lietošanas pierādītajiem efektiem, bet arī riski tiek iezīmēti. Tā kā nav zināms precīzs darbības mehānisms visa organismā un to funkcijas, nav iespējams spriest par to lietošanu bez risku iespējamības. Ir redzams, ka daudzi cilvēku – gan profesionāli sportisti, gan amatieri – lieto BCAA vienu un to pašu iemeslu dēļ. Palielināt muskuļu masu ir visizplatītākais. BCAA lietošanas pozitīvais efekts ir izmērāms. Teorētiski, pēc pašreiz pieejamās zinātniskās bāzes, ir pierādīts, ka BCAA veicina anaboliskus procesus cilvēka oeganismā. Galvenais mehānisms ir MTOR ceļš, kas palielina olbaltumvielu sintēzi. Turklāt BCAA papildus lietošanai piemīt pozitīva ietekme uz imūno un gastrointestinālo sistēmu. Riski, kas saistīti ar pārāk liela daudzuma BCAA lietošanu, ir maz zināmi. Ir dažas statistiskas analīzes par riska faktoriem, teorētiski pētījumi par mehānismiem, kas varētu izraisīt metaboliskas vai kardiovaskulāras slimības, bet tiem vēl nav praktisku pierādījumu.Background: Diet and nutrition are more and more in focus on daily basis. Therefore, supplementation of nutrients and a strict diet is common and a daily habit of many people. Branched chain amino acids (BCAA) are hereby one of the most common supplements. Hereby it is interesting that there are only very few studies were made and published for its use. The aim of this study is to collect data from scientific studies to access the use and risks of BCAA supplementation. Hereby the first task is to figure out the normal physiological need for BCAAs and to check the mechanism of action. Methods: In this non-empiric literature review the sources for theoretical basis is coming from scientific study materials for medical studies and professionals, as well as from studies published in international and national journals. To collect data the publication website “PubMed” is used. Here the search went through keyword search and mesh search. Hereby the search splited by the key words starting with the main topic of “Amino acids”, to smaller topics like “BCAA”, the BCAA themselves (“Valine”, ”Leucine”, ”Isoleucine”), to their function. In the combination further articles were found and references of the articles were used. For the collection of articles following steps were followed and criteria were made. The procedures of the study should be understandable and reliable. The sources of the article should be from scientific relevance. The article itself must have a relevance to the aim of the thesis. Tested subjects should be in same condition as age, physical condition, nutrition etc. In total over 40 publications, journal articles and books are covering and included in this literature review. Conclusion: In this overview about branched chain amino acids its use, risk assessment and the mechanism of action it is clear that the supplementation of BCAA gives already proven benefits but also risks are predicted. Due to the lack of knowledge in the exact mechanism of action in all body regions and body function it is not possible to say that its use is without risk. It is seen that many people who either do professional sport or just as hobby sportists are using BCAA for the same reasons. Hereby building up muscle mass is the most popular one. This beneficial effect of an BCAA intake could be already measured. In theory as far as the scientific community has done research, it is true and proven that BCAA help the anabolic process in the human body. Hereby is the major mechanism the MTOR pathway which increases protein synthesis. . Furthermore a BCAA supplementation leads to positive effects on the Immune and gastrointestinal system. The risks of a too high concentration of BCAA in the human body are only poorly known. There are some statistical analysis of risk factors, theoretical studies about the mechanisms which could lead to diseases of the metabolic or cardiovascular but there is no practical evidence yet

Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments

Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML

An Integrated Framework for Data Quality Fusion in Embedded Sensor Systems

The advancement of embedded sensor systems allowed the monitoring of complex processes based on connected devices. As more and more data are produced by these sensor systems, and as the data are used in increasingly vital areas of applications, it is of growing importance to also track the data quality of these systems. We propose a framework to fuse sensor data streams and associated data quality attributes into a single meaningful and interpretable value that represents the current underlying data quality. Based on the definition of data quality attributes and metrics to determine real-valued figures representing the quality of the attributes, the fusion algorithms are engineered. Methods based on maximum likelihood estimation (MLE) and fuzzy logic are used to perform data quality fusion by utilizing domain knowledge and sensor measurements. Two data sets are used to verify the proposed fusion framework. First, the methods are applied to a proprietary data set targeting sample rate inaccuracies of a micro-electro-mechanical system (MEMS) accelerometer and second, to the publicly available Intel Lab Data set. The algorithms are verified against their expected behavior based on data exploration and correlation analysis. We prove that both fusion approaches are capable of detecting data quality issues and providing an interpretable data quality indicator

Synergistic Effects of the RAR<i>alpha</i> Agonist Tamibarotene and the Menin Inhibitor Revumenib in Acute Myeloid Leukemia Cells with KMT2A Rearrangement or NPM1 Mutation

Inhibition of menin in acute myeloid leukemia (AML) harboring histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or the mutated Nucleophosmin gene (NPM1c) is considered a novel and effective treatment approach in these patients. However, rapid acquisition of resistance mutations can impair treatment success. In patients with elevated retinoic acid receptor alpha (RARA) expression levels, promising effects are demonstrated by the next-generation RARalpha agonist tamibarotene, which restores differentiation or induces apoptosis. In this study, the combination of revumenib and tamibarotene was investigated in various KMT2Ar or NPM1c AML cell lines and patient-derived blasts, focusing on the potential synergistic induction of differentiation or apoptosis. Both effects were analyzed by flow cytometry and validated by Western blot analysis. Synergy calculations were performed using viability assays. Regulation of the relevant key mediators for the MLL complex were quantified by RT-qPCR. In MV4:11 cells characterized by the highest relative mRNA levels of RARA, highly synergistic induction of apoptosis is demonstrated upon combination treatment. Induction of apoptosis by combined treatment of MV4:11 cells is accompanied by pronounced induction of the pro-apoptotic protein BAX and a synergistic reduction in CDK6 mRNA levels. In MOLM13 and OCI-AML3 cells, an increase in differentiation markers like PU.1 or a decreased ratio of phosphorylated to total CEBPA is demonstrated. In parts, corresponding effects were observed in patient-derived AML cells carrying either KMT2Ar or NPM1c. The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics

Hidradenitis suppurativa /acne inversa—surgical options, reconstruction and combinations with drug therapies—an update

Hidradenitis suppurativa/Acne inversa (HS/AI) ist eine chronisch-entzündliche Hauterkrankung, deren Behandlung sowohl konservative als auch chirurgische Behandlungsmöglichkeiten umfasst. In den Hurley-Stadien II und III ist die chirurgische Resektion irreversibel zerstörten Gewebes anzustreben. Hierzu existieren verschiedene Resektionstechniken, die sich vor allem in ihrer Invasivität und Rezidivneigung unterscheiden. Bis heute gibt es keinen allgemein akzeptierten Konsens hinsichtlich verschiedener Resektions- und Rekonstruktionstechniken sowie der Einbeziehung medikamentöser Therapien in das therapeutische Gesamtkonzept.Hidradenitis suppurativa/acne inversa (HS/AI) is a chronic inflammatory skin disease whose treatment includes both conservative and surgical treatment options. In Hurley stages II and III, surgical resection of irreversibly destroyed tissue should be the objective. For this purpose several resection techniques exist, which differ primarily with regard to their invasiveness and tendency to recur. To date, there is no generally accepted consensus on the use of different resection and reconstruction techniques or the inclusion of drug therapies in the overall therapeutic concept