Allogeneic hematopoietic stem cell transplantation (alloHCT) represents the only potentially curative treatment in high-risk AML patients, but up to 40% of patients suffer from relapse after alloHCT. Treatment of overt relapse poses a major therapeutic challenge and long-term disease control is achieved only in a minority of patients. In order to avoid post-allograft relapse, maintenance as well as pre-emptive therapy strategies based on MRD-detection have been used. A prerequisite for the implementation of pre-emptive therapy is the accurate identification of patients at risk for imminent relapse. Detection of measurable residual disease (MRD) represents an effective tool for early relapse prediction in the post-transplant setting. However, using established MRD methods such as multicolor flow cytometry or quantitative PCR, sensitive MRD monitoring is only applicable in about half of the patients with AML and advanced MDS undergoing alloHCT. Donor chimerism analysis, in particular when performed on enriched leukemic stem and progenitor cells, e.g. CD34+ cells, is a sensitive method and has emerged as an alternative option in the post alloHCT setting. In this review, we will focus on the current strategies for lineage specific chimerism analysis, results of pre-emptive treatment using this technology as well as future developments in this field.

The ability to detect residual levels of leukemic blasts (measurable residual disease, MRD) has already been integrated in the daily routine for treatment of patients with chronic myeloid and acute lymphoblastic leukemia. In acute myeloid leukemia (AML), a variety of mostly retrospective studies have shown that individuals in AML remission who tested positive for MRD at specific time-points or had increasing MRD levels are at significantly higher risk of relapse and death compared to MRD-negative patients. However, these studies differ with respect to the “MRD-target”, time-point of MRD determination, material analyzed, and method applied. How this probably very valuable MRD information in individual patients may be adapted in the daily clinical routine, e.g., to separate patients who need more aggressive therapies from those who may be spared additional—potentially toxic—therapies is still a work-in-progress. With the exception of MRD assessment in acute promyelocytic leukemia (APL), the lack of randomized, prospective trials renders MRD-based decisions and clinical implications in AML a difficult task. As of today, we still do not have proof that early intervention in MRD-positive AML patients would improve outcomes, although this is very likely. In this article, we review the current knowledge on non-APL AML MRD assessment and possible clinical consequences.

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The article discusses the intersection of anti-money laundering (AML) compliance and the handling of Non-Fungible Tokens (NFTs) under German law or EU law applicable in Germany. It begins by acknowledging the negative perception of cryptocurrencies in the context of money laundering, emphasizing the need to explore AML regulations for NFTs, which have gained attention for tokenizing art. The text delves into the legal nature of NFTs, examining whether they can be classified as securities, asset investments, or crypto assets. It also explores the implications of these classifications on AML compliance, detailing the specific obligations for entities dealing with NFTs. The article concludes by highlighting the legal ambiguity surrounding NFTs and emphasizing the importance of conducting a case-by-case risk assessment for AML compliance.

Student Number : 9807768F - MSc (Med) research report - Faculty of Health Sciences / Fanconi anaemia (FA) is an autosomal recessive disorder characterised by aplastic anaemia (AA) and a high risk of developing acute myeloid leukaemia (AML). It is unknown whether heterozygote carriers are also predisposed to developing these disorders. The black South African population group is ideal for FA mutation screening because the presence of a founder mutation, FANCG 637-643, makes screening relatively straight forward. Three individuals with AML (115 screened) and one with AA (78 screened) were found to be heterozygous for the black South African founder mutation. From our data it seems unlikely that this mutation places heterozygous carriers of the mutation at high risk of developing AML or AA. Three children with AA out of 26 screened, were homozygous for the mutation. This finding reiterates the importance of screening all children with AA for FA. The frequency of certain congenital abnormalities in black South African FA patients was compared to patients described by other research groups. The frequencies of the abnormalities were similar to other FANCG cohorts described but significant differences to a group of FA patients from unspecified complementation groups were found. This difference could be because different complementation groups are associated more or less strongly with specific abnormalities. It was found previously that particular congenital abnormalities in FA patients are associated with a poor haematological outcome. We concluded that black South African FANCG patients have a high risk of early development of AA even though they do not have a high frequency of congenital abnormalities.

La survie des cellules cancéreuses dépend d’une activité énergétique et biosynthétique accrue et la glutamine participe à de nombreux processus nécessaires à cette adaptation métabolique. Dans les leucémies aiguës myéloïdes (LAM), la croissance et la prolifération sont favorisées par l’activation anormale de plusieurs voies de signalisation, et notamment par la voie mTORC1. Les acides aminés essentiels, et en particulier la leucine, sont indispensables à l’activation de mTORC1. La glutamine est captée par la cellule via le transporteur SLC1A5 et permet ensuite l’entrée de la leucine via le transporteur bidirectionnel SLC7A5. La concentration en glutamine est donc une étape limitante dans l’activation de mTORC1 par la leucine. Nous avons étudié les effets de la privation en glutamine dans les LAM à l’aide de différents outils (milieu sans glutamine, shARN inhibant l’expression du transporteur de la glutamine SLC1A5 et la drogue L-asparaginase, qui a une activité de glutaminase extracellulaire), et observé une inhibition de mTORC1 et de la synthèse protéique. L’inhibition du transporteur SLC1A5 inhibe la pousse tumorale dans un modèle de xénotransplantation. La L-asparaginase inhibe mTORC1 et induit une apoptose de façon proportionnelle à son activité glutaminase et complètement indépendante de la concentration en asparagine. La privation en glutamine induit l’expression de la glutamine synthase et l’autophagie, et ces deux processus peuvent être des mécanismes de résistance intrinsèques ou acquis dans certaines lignées leucémiques. L’apoptose induite par la privation en glutamine n’est cependant pas liée à l’inhibition de mTORC1, puisqu’elle n’est pas diminuée par l’utilisation d’un mutant de mTOR non inhibé par la privation en glutamine. Nous nous sommes donc intéressés à une autre voie dépendante de la glutamine dans de nombreux cancers, la phosphorylation oxydative. L’étape initiale du catabolisme intracellulaire de la glutamine est la conversion de la glutamine en glutamate par des enzymes appelées glutaminases. Différentes isoformes des glutaminases existent qui sont codées chez l’homme par les gènes GLS1 et GLS2. Le glutamate est ensuite transformé en α-cétoglutarate, intermédiaire du cycle TCA. Dans les lignées de LAM, la privation en glutamine inhibe la phosphorylation oxydative mitochondriale. Nous avons observé que la protéine glutaminase C (GAC), une des isoformes de GLS1, est constamment exprimée dans les LAM mais aussi dans les progéniteurs hématopoïétiques CD34+ normaux. L’inhibition d’expression de la GLS1 par des shARN inductibles ou bien par le composé CB-839 réduit la phosphorylation oxydative, conduisant à une inhibition de prolifération et à une induction d’apoptose des cellules leucémiques. L’invalidation génétique de la GLS1 inhibe la formation de tumeur et améliore la survie des souris dans un modèle de xénotransplantation. A l’inverse, le ciblage de la GLS1 n’a pas d’effets cytotoxiques ni cytostatiques sur les progéniteurs hématopoïétiques normaux. Ces effets anti-leucémiques sont inhibés par l’adjonction d’α-cétoglutarate, et ceux induit par le CB-839 sont abrogés lorsqu’est exprimé de façon ectopique un mutant GACK320A hyperactif, attestant du rôle essentiel du maintien d’un cycle TCA actif dans les cellules de LAM. Enfin, nous montrons que l’inhibition de la glutaminolyse active la voie d’apoptose mitochondriale intrinsèque et agit en synergie avec l’inhibition spécifique de BCL-2 par l’ABT-199. Ces résultats démontrent que le ciblage spécifique de la glutaminolyse est une autre façon d’exploiter l’addiction à la glutamine des cellules leucémiques de LAM et que le maintien d’un cycle TCA actif est essentiel à la survie de ces cellules. / Cancer cells survival is dependent on high energetic and biosynthetic activity, and glutamine is involved in many metabolic processes necessary for this adaptation. In acute myeloid leukemia (AML), growth and proliferation are promoted by activation of several signaling pathways, including mTORC1. Essential amino acids, in particular leucine, are required for mTORC1 activation. Glutamine enters into the cell via the SLC1A5 transporter and then allows the input of leucine via the bidirectional SLC7A5 transporter. Therefore, the intracellular glutamine concentration is a limiting step in the activation of mTORC1 by leucine. We studied the effects of glutamine deprivation in AML using different tools (medium without glutamine, shRNA against the SLC1A5 glutamine transporter and the drug L-asparaginase, which has an extracellular glutaminase activity) and observed mTORC1 and protein synthesis inhibition. SLC1A5 transporter knockdown inhibits tumor growth in a xenotransplantation model. L-asparaginase inhibits mTORC1 and induces apoptosis in proportion to its glutaminase activity and independently of asparagine concentration. Glutamine privation induces the expression of glutamine synthase and autophagy, and these two processes are involved in the resistance to glutamine privation in some leukemic cell lines. However, apoptosis induced by glutamine privation is not related to the inhibition of mTORC1, since it is not modified in the presence of a constitutively active mutant of mTOR. We next focused on the oxidative phosphorylation, another glutamine dependent pathway in many cancers. The initial step of the intracellular catabolism of glutamine is the conversion of glutamine to glutamate by enzymes called glutaminases. Different glutaminases isoforms exist that are encoded by the GLS1 and GLS2 genes. Glutamate is then converted to α-ketoglutarate, an essential TCA cycle intermediate. In AML cell lines, we observed that glutamine privation inhibits mitochondrial oxidative phosphorylation. The protein glutaminase C (GAC), an isoform of GLS1, is constantly expressed in AML but also in normal CD34 + hematopoietic progenitors. The knockdown of GLS1 by inducible shRNA or by the CB-839 compound reduced oxidative phosphorylation, leading to proliferation inhibition and apoptosis induction in leukemia cells. Genetic invalidation of GLS1 inhibits tumor formation and improves survival of mice in a xenograft model. Conversely, the targeting of GLS1 has no cytotoxic or cytostatic effects on normal hematopoietic progenitors. These anti-leukemic effects are inhibited by the addition of α-ketoglutarate, and those induced by the CB-839 are suppressed in the presence of an ectopically expressed GACK320A hyperactive mutant, confirming the essential role of maintaining an active TCA cycle in AML cells. Finally, we showed that glutaminolysis inhibition induces the intrinsic mitochondrial pathway of apoptosis and acts synergistically with the specific inhibition of BCL-2 by ABT-199. These results demonstrate that specific targeting of glutaminolysis is another way to exploit glutamine addiction in AML and that an active TCA cycle in essential for AML cell survival.

<p> </p><p> </p><p> </p><p><p>Personlig assistans är en relativt ny yrkesgrupp som skall utföra grundläggande behov åt brukaren så att denne har möjligheten att leva som alla andra. I arbetsmiljölagen (1977:1160; AML) finns regler om skyldigheter för arbetsgivare att verka för en god arbetsmiljö för sina arbetstagare samt att förebygga ohälsa och olycksfall. Denna lag utgör en rättighetslag för personliga assistenter. Lag (1993:387) om stöd och service till vissa funktionshindrade (LSS) är en rättighetslag för brukare med stora och varaktiga funktionshinder. I denna lag är brukares självbestämmande centralt.</p><p>Det förekommer dock att bestämmelser i dessa lagar hamnar i konflikt med varandra, vilket medför att personliga assistenters rättigheter ställs mot brukares rättigheter. Ingenstans finns det uttryckt att den ena lagen står över den andra men ofta utfaller praktiken i att personliga assistenter i dessa fall får ge vika för brukarens självbestämmande. Detta kan medföra praktiska problem för vårt uppsatsföretags personliga assistenter och dess brukare.</p><p>Företaget som vi skriver vårt examensarbete för är ett privat assistansföretag med omkring 150 anställda personlig assistenter. En av deras viktigaste uppgifter är att matcha den personliga assistentens och brukarens intressen.</p><p>Vi har i denna studie valt att inrikta oss mot psykosocial arbetsmiljö och ämnar genom intervjuer belysa ett antal personliga assistenters arbetssituation och deras tankar och upplevelser kring denna, med fokus på de motsättningar som kan uppstå i rättighetslagarna arbetsmiljölagen (1977:1160, AML) och lag om stöd och service för vissa funktionshindrade (1993:387, LSS). Vi har valt att undersöka och besvara följande frågeställningar:</p><p> </p><p>Vad uttrycker arbetsmiljölagstiftningen om den personliga assistentens rättigheter?</p><p>Vilken inverkan har lagen om stöd och service till vissa funktionshindrade på den personliga assistentens arbetsskyldighet?</p><p>Hur upplever de intervjuade personliga assistenterna sin psykosociala arbetssituation?</p><p>Hur förhåller sig den teoretiska konflikten i praktiken utifrån de anställdas perspektiv?</p></p><p><p>Vi analyserar de personliga assistenternas psykosociala arbetsmiljö utifrån Karaseks krav och kontroll, Johnsons vidareutvecklade dimension av modellen med socialt stöd samt även Antonovskys KASAM-modell. Vidare använder vi lagstiftning till grunden för vår uppsats. Utgångspunkten är att en personlig assistent skall utföra de funktionshindrades rätt enligt LSS så länge arbetsuppgifterna inte är farliga, förbjudna eller kränker den personliga assistenten. Vi har kommit fram till att upplevelsen av arbetssituationen för våra intervjupersoner skiljer sig beroende på vilken känsla av sammanhang de känner i arbetet.</p></p>

Personlig assistans är en relativt ny yrkesgrupp som skall utföra grundläggande behov åt brukaren så att denne har möjligheten att leva som alla andra. I arbetsmiljölagen (1977:1160; AML) finns regler om skyldigheter för arbetsgivare att verka för en god arbetsmiljö för sina arbetstagare samt att förebygga ohälsa och olycksfall. Denna lag utgör en rättighetslag för personliga assistenter. Lag (1993:387) om stöd och service till vissa funktionshindrade (LSS) är en rättighetslag för brukare med stora och varaktiga funktionshinder. I denna lag är brukares självbestämmande centralt. Det förekommer dock att bestämmelser i dessa lagar hamnar i konflikt med varandra, vilket medför att personliga assistenters rättigheter ställs mot brukares rättigheter. Ingenstans finns det uttryckt att den ena lagen står över den andra men ofta utfaller praktiken i att personliga assistenter i dessa fall får ge vika för brukarens självbestämmande. Detta kan medföra praktiska problem för vårt uppsatsföretags personliga assistenter och dess brukare. Företaget som vi skriver vårt examensarbete för är ett privat assistansföretag med omkring 150 anställda personlig assistenter. En av deras viktigaste uppgifter är att matcha den personliga assistentens och brukarens intressen. Vi har i denna studie valt att inrikta oss mot psykosocial arbetsmiljö och ämnar genom intervjuer belysa ett antal personliga assistenters arbetssituation och deras tankar och upplevelser kring denna, med fokus på de motsättningar som kan uppstå i rättighetslagarna arbetsmiljölagen (1977:1160, AML) och lag om stöd och service för vissa funktionshindrade (1993:387, LSS). Vi har valt att undersöka och besvara följande frågeställningar:   Vad uttrycker arbetsmiljölagstiftningen om den personliga assistentens rättigheter? Vilken inverkan har lagen om stöd och service till vissa funktionshindrade på den personliga assistentens arbetsskyldighet? Hur upplever de intervjuade personliga assistenterna sin psykosociala arbetssituation? Hur förhåller sig den teoretiska konflikten i praktiken utifrån de anställdas perspektiv? Vi analyserar de personliga assistenternas psykosociala arbetsmiljö utifrån Karaseks krav och kontroll, Johnsons vidareutvecklade dimension av modellen med socialt stöd samt även Antonovskys KASAM-modell. Vidare använder vi lagstiftning till grunden för vår uppsats. Utgångspunkten är att en personlig assistent skall utföra de funktionshindrades rätt enligt LSS så länge arbetsuppgifterna inte är farliga, förbjudna eller kränker den personliga assistenten. Vi har kommit fram till att upplevelsen av arbetssituationen för våra intervjupersoner skiljer sig beroende på vilken känsla av sammanhang de känner i arbetet.

Samli Fe-oxide (+Cu&plusmn / Au) deposit is hosted by Samli pluton and rocks of Karakaya Complex in western Anatolia. The pluton consists of both mafic and felsic phases showing magma mixing textures. 40Ar/39Ar geochronology yielded an age range of 23.2&plusmn / 0.5 to 22.42&plusmn / 0.11 Ma for the Samli pluton, overlapping with 40Ar/39Ar age of 22.33&plusmn / 0.59 Ma and U-Pb age of 23.34&plusmn / 0.19 Ma from alterations. Sr-Nd isotope data are suggestive of a metasomatized subcontinental lithospheric mantle (SCLM) source for the magma. Alteration-mineralization pattern is defined by a series of overlapping halos characterized by sodic-calcic (plagioclase-pyroxene&plusmn / scapolite), calcic (garnet-pyroxene&plusmn / epidote), potassic (biotite+magnetite+chalcopyrite), hematite-limonite, and late stage (chalcedony-calcite+native Cu) alterations. Stable (&delta / 18O, &delta / 34S) and radiogenic (87Sr/86Sr,143Nd/144Nd) isotope compositions suggest a magmatic source for the fluids responsible for alteration-mineralization. Given the spatial-temporal association of alteration- mineralization with magmatic rocks, the hydrothermal system that controls mineralization in Samli appears to be linked with emplacement and cooling of Samli pluton. Samli Fe-oxide (+Cu&plusmn / Au) deposit has features characteristic for both skarn- and Iron-Oxide-Copper-Gold (IOCG) type deposits. The spatial and temporal association with a porphyritic intrusion, widespread calc-silicate assemblage, metal content (abundant Fe-oxide with high copper content) are similar to calcic Fe-Cu skarns, whereas low-Ti (&le / 0.05% TiO2) magnetite/hematite, low-S sulfides (chalcopyrite&gt / pyrite), high Cu (up to 6.78%) and moderate Au (up to 8.82 ppm) grades, local structural control in alteration-mineralization, and the derivation of the causative magma from a SCLM resembles the features pertinent to IOCG type mineralization. Therefore, Samli deposit is defined as a skarn type Fe-Cu mineralization with a potential for IOCG type deposit.

Η θεραπεία της Οξείας Μυελογενούς Λευχαιμίας (ΟΜΛ) είναι συχνά ανεπιτυχής λόγω ανάπτυξης κυτταρικής αντίστασης στα αντιλευχαιμικά φάρμακα. Εκτός από την έκφραση Ρ-γλυκοπρωτείνης στα λευχαιμικά κύτταρα, άλλοι κυτταρικοί παράγοντες μπορούν επίσης να συμβάλλουν στην χημειοαντίσταση. Η c- Jun N-terminal Kinase (JNK) είναι μία πρωτεινική κινάση που ενεργοποιείται όταν τα κύτταρα εκτεθούν σε χημειοθεραπευτικά φάρμακα (ΧΜΘ). Πρόσφατες μελέτες σε συμπαγείς όγκους συσχετίζουν την χημειοαντίσταση με αδυναμία των καρκινικών κυττάρων να ενεργοποιήσουν τη JNK κατόπιν επίδρασης ΧΜΘ. Σκοπός της εργασίας είναι να διερευνήσει αν η χημειοαντίσταση στην ΟΜΛ οφείλεται σε ενδογενή αδυναμία των λευχαιμικών βλαστών να ενεργοποιήσουν τη JNK. Μεθοδολογία: Συγκρίναμε ευαίσθητες (U937) και ανθεκτικές (U937R) στις ανθρακυκλίνες κυτταρικές σειρές ΟΜΛ ως προς την δυνατότητα in vitro ενεργοποίησης της JNK κατόπιν επίδρασης ΧΜΘ (Western Blot). Επιπλέον, στις λευχαιμικές κυτταρικές σειρές ελέγξαμε απευθείας τη σημασία της JNK στην χημειοαντίσταση με πειράματα α) αποσιώπησης της JNK με JNK1–στοχεύον siRNA και β) ενεργοποίησης της JNK (διαμόλυνση με τον ΜΚΚ4/SEK1 άνωθεν ενεργοποιητή της JNK) Περαιτέρω, ελέγξαμε την in vitro δυνατότητα ενεργοποίησης της JNK σε 29 πρωτογενή μυελικά δείγματα ΟΜΛ κατόπιν βραχείας διάρκειας (30-60min) έκθεση στην daunorubicin (1μΜ) και συσχετίσαμε τα εργαστηριακά δεδομένα με κλινικά χαρακτηριστικά των ασθενών με ΟΜΛ. Αποτελέσματα: In vitro θεραπεία των U937 κυττάρων με ανθρακυκλίνες προκάλεσε ισχυρή και ταχεία ενεργοποίηση της JNK και απόπτωση. Αντίθετα, στα πολυανθεκτικά U937R κύτταρα δεν παρατηρήθηκε ενεργοποίηση της JNK, ακόμη και σε συνθήκες υψηλής ενδοκυττάριας συγκέντρωσης ανθρακυκλινών. Αποσιώπηση της JNK στα ευαίσθητα U937 κύτταρα τα έκανε ανθεκτικά στις ανθρακυκλίνες (JNK1-siRNA διαμολυσμένα U937 κύτταρα εμφάνισαν 50.4% και 61.3% ελαττωμένη daunorubicin- (DNR, 1μΜ 24hr) και doxorubicin- (DOX, 1.5μΜ 24hr) προκαλούμενη απόπτωση αντίστοιχα, συγκριτικά με U937 κύτταρα-μάρτυρες, P<0.001). Αντίστροφα, εκλεκτική ενεργοποίηση της ανενεργού JNK στα ανθεκτικά U937R κύτταρα τα έκανε 3.3 φορές πιο ευαίσθητα στη DNR και 3.1 φορά πιο ευαίσθητα στη DΟΧ, συγκριτικά με U937R κύτταρα-μάρτυρες. Επιπρόσθετα, παρατηρήσαμε ισχυρή συσχέτιση μεταξύ των in vitro φαρμακοδυναμικών αλλαγών των επιπέδων ενεργοποίησης της JNK στους λευχαιμικούς βλάστες και της ανταπόκρισης των ασθενών με ΟΜΛ στη χημειοθεραπευτική αγωγή (P=0.012). Η απουσία ενεργοποίησης της JNK στα βλαστικά κύτταρα συσχετίστηκε επίσης με αρνητικούς προγνωστικούς παράγοντες για την ΟΜΛ, όπως γηραιότερη ηλικία των ασθενών (P=0.046) και ΟΜΛ αναπτυσσόμενη επί εδάφους μυελοδυσπλασίας (P=0.017). Συνοψίζοντας, τα in vitro και in vivo αποτελέσματα μας προτείνουν την ενδογενή αποτυχία ενεργοποίησης της πρωτεινικής κινάσης JNK στους λευχαιμικούς βλάστες σαν έναν εναλλακτικό μηχανισμό χημειοαντίστασης στην ΟΜΛ. Η διελεύκανση των μηχανισμών εκείνων που επιφέρουν καταστολή της JNK στην χημειοανθεκτική ΟΜΛ μπορεί να ωφελήσει θεραπευτικά. / Chemotherapy resistance is a major challenge in acute myeloid leukemia (AML). Besides the P-glycoprotein efflux, additional cellular factors may contribute to drug-resistance in AML. c- Jun N-terminal Kinase (JNK) is activated after exposure of cells to chemotherapeutics. We asked whether chemoresistance in AML is attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative cell lines U937R and URD40 showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. RNA interference-based depletion of JNK1 in drug-sensitive U937 cells made them chemoresistant, whereas selective restoration of the inactive JNK pathway in the resistant U937R cells sensitized them to anthracyclines. Short-term in vitro exposure of primary AML cells (n=29) to daunorubicin showed a strong correlation between the in vitro pharmacodymanic changes of phospho-JNK levels and the response of patients to standard induction chemotherapy (P=0.012). We conclude that JNK activation failure confers another mechanism of anthracycline resistance in AML. Elucidating the ultimate mechanisms leading to JNK suppression in chemoresistant AML may be of major therapeutic value.