Harm-to-self from gambling: A national study of Australian adults.

Aims: Understanding how gambling harm is distributed is essential to inform effective harm reduction measures. This first national Australian study of gambling harm-to-self examined the extent, distribution, risk factors, and health related quality of life (HRQoL) impacts of this harm. Methods: A Random Digit Dialling sample of 15,000 Australian adults was weighted to key population variables. Key measures included the Gambling Harms Scale-10 (GHS-10), PGSI, SF-6D, gambling behaviours, and demographics. Analyses included ordinal logistic regression. Results: Amongst gamblers, 14.7% reported harm on the GHS-10, including 1.9% reporting high-level harm. While high-level harm occurred mainly in the problem gambling group (77.3%), other PGSI groups accounted for most of the more prevalent low (98.5%) and moderate (87.2%) harms reported. Proximal predictors of greater harm were use of online gambling and more frequent gambling on electronic gaming machines (EGMs), race betting sports betting, poker, skin gambling, scratchies, and loot box purchasing. Distal predictors were being younger, male, single, Aboriginal or Torres Strait Islander, and speaking a non-English language at home. At the population level, the greatest aggregate HRQoL impacts were amongst lower-risk gamblers, confirming the results of other studies regarding the 'prevention paradox'. Conclusions: The distribution of harm across gambler risk groups indicates the need for preventive measures, not just interventions for problem gambling. Reducing harm requires modifying product features that amplify their risk, especially for EGMs, race betting and sports betting that are both inherently risky and widely used. Gambling harm exacerbates health disparities for disadvantaged and vulnerable groups, requiring targeted resources and support.

The COVID-19 lockdown experience suggests that restricting the supply of gambling can reduce gambling problems: An Australian prospective study.

Background and aims: COVID-19 lockdowns limited access to gambling but simultaneously elevated psychosocial stressors. This study assessed the relative effects of these changes on gambling risk status during and after the Australian COVID-19 lockdown from late-March to late-May 2020. Methods: The study administered three surveys to people who had gambled within the past year at T1. Wave 1 asked about before (T1, N = 2,125) and during lockdown (T2, N = 2,125). Subsequent surveys focused on one year (T3; N = 649) and two years after lockdown (T4, N = 458). The dependent variable was changes in reporting any problem gambling symptoms (PGSI 0 vs 1+). Bivariate analyses and multinomial logistic regression tested for significant associations with: demographics, psychosocial stressors (perceived stress, psychological distress, loneliness, health anxiety about COVID, financial hardship, stressful life events), gambling participation and gambling frequency. Results: Gambling participation and at-risk gambling decreased between T1 and T2, increased at T3, with little further change at T4. When gambling availability was curtailed, decreased gambling frequency on EGMs, casino games, sports betting or race betting, and lower psychosocial stress, were associated with transitions from at-risk to non-problem gambling. When gambling availability resumed, increased EGM gambling frequency, decreased online gambling frequency, and higher psychosocial stress were associated with transitions from non-problem to at-risk gambling. Discussion and conclusions: Gambling availability appears a stronger influence on gambling problems, at the population level, than psychosocial risk factors. Reducing the supply of high-risk gambling products, particularly EGMs, is likely to reduce gambling harm.

Electronic gaming machine accessibility and gambling problems: A natural policy experiment.

Background: Electronic gaming machines (EGMs) are one of the most harmful forms of gambling at an individual level. It is unclear whether restriction of EGM functions and accessibility results in meaningful reductions in population-level gambling harm. Methods: A natural policy experiment using a large (N = 15,000) national dataset weighted to standard population variables was employed to compare estimates of gambling problems between Australian residents in Western Australia (WA), where EGMs are restricted to one venue and have different structural features, to residents in other Australian jurisdictions where EGMs are widely accessible in casinos, hotels and clubs. Accessibility of other gambling forms is similar across jurisdictions. Results: Gambling participation was higher in WA, but EGM participation was approximately half that of the rest of Australia. Aggregate gambling problems and harm were about one-third lower in WA, and self-reported attribution of harm from EGMs by gamblers and affected others was 2.7× and 4× lower, respectively. Mediation analyses found that less frequent EGM use in WA accounted for the vast majority of the discrepancy in gambling problems (indirect path = -0.055, 95% CI -0.071; -0.038). Moderation analyses found that EGMs are the form most strongly associated with problems, and the strength of this relationship did not differ significantly across jurisdictions. Discussion: Lower harm from gambling in WA is attributable to restricted accessibility of EGMs, rather than different structural features. There appears to be little transfer of problems to other gambling forms. These results suggest that restricting the accessibility of EGMs substantially reduces gambling harm.

Simplified screening and referral protocol for sinonasal mucormycosis in post COVID-19 patients.

Background: To study incidence of sinonasal mucormycosis in active and post COVID-19 patients in a district-level hospital in India and develop a simplified screening and referral protocol for use at peripheral centres to aid rapid diagnosis/treatment. Methods: Study design: A prospective, interventional cohort study conducted from April 2021 to January 2022. Setting: Secondary level hospital in North India. Inclusion criteria: COVID-19 positive patients with diabetes mellitus as co-morbidity and with at least one of the following: received steroid therapy and/or on high flow oxygen therapy and/or had prolonged hospital stay (> 7 days). Exclusion criteria: Patients already immunocompromised/having malignancy/organ transplant recipients. Clinical workup: History, examination, imaging (CECT/MRI nose and paranasal sinuses if indicated), diagnostic nasal endoscopy + Nasal scrapings for KOH mount to detect fungal elements. STROBE guidelines were followed in the study. Results: Fourteen out of 250 patients tested positive for mucormycosis (incidence 5.6%). Thirteen were symptomatic, one patient was asymptomatic and detected on screening. No significant difference was found in mucormycosis versus non-mucormycosis group with respect to HbA1c status, vaccination status or steroid + oxygen treatment (p > 0.05 in all scenarios). Patients were treated with intravenous liposomal amphotericin B and surgical debridement when indicated. Two succumbed to disease (survival 85.7%). A clinical screening protocol was thus developed which can be used as an effective tool even at far-flung and remote healthcare facilities for diagnosis and timely referral of patients. Conclusions: Mucormycosis is a potentially lethal disease which needs rapid diagnosis and timely action to decrease morbidity and mortality.

A noncanonical enzymatic function of PIWIL4 maintains genomic integrity and leukemic growth in AML.

RNA-binding proteins (RBPs) form a large and diverse class of factors, many members of which are overexpressed in hematologic malignancies. RBPs participate in various processes of messenger RNA (mRNA) metabolism and prevent harmful DNA:RNA hybrids or R-loops. Here, we report that PIWIL4, a germ stem cell-associated RBP belonging to the RNase H-like superfamily, is overexpressed in patients with acute myeloid leukemia (AML) and is essential for leukemic stem cell function and AML growth, but dispensable for healthy human hematopoietic stem cells. In AML cells, PIWIL4 binds to a small number of known piwi-interacting RNA. Instead, it largely interacts with mRNA annotated to protein-coding genic regions and enhancers that are enriched for genes associated with cancer and human myeloid progenitor gene signatures. PIWIL4 depletion in AML cells downregulates the human myeloid progenitor signature and leukemia stem cell (LSC)-associated genes and upregulates DNA damage signaling. We demonstrate that PIWIL4 is an R-loop resolving enzyme that prevents R-loop accumulation on a subset of AML and LSC-associated genes and maintains their expression. It also prevents DNA damage, replication stress, and activation of the ATR pathway in AML cells. PIWIL4 depletion potentiates sensitivity to pharmacological inhibition of the ATR pathway and creates a pharmacologically actionable dependency in AML cells.

Npm1 haploinsufficiency in collaboration with MEIS1 is sufficient to induce AML in mice.

NPM1 is among the most frequently mutated genes in acute myeloid leukemia (AML). Mutations in the NPM1 gene result in the increased export of NPM1 to the cytoplasm (NPM1c) and are associated with multiple transforming events including the aberrant upregulation of MEIS1 that maintains stem cell and cell cycle-associated pathways in NPM1c AML. However, another consequence of the NPM1c mutation is the inadequate levels of NPM1 wild-type in the nucleus and nucleolus, caused by the loss of one wild-type allele in addition to enforced NPM1 nuclear export. The contribution of NPM1 haploinsufficiency independently of the NPM1 mutation to AML development and its relationship with MEIS1 function is poorly understood. Using mouse models, our study shows that NPM1 haploinsufficiency paired with MEIS1 overexpression is sufficient to induce a fully penetrant AML in mice that transcriptionally resembles human NPM1c AML. NPM1 haploinsufficiency alters MEIS1-binding occupancies such that it binds the promoter of the oncogene structural maintenance of chromosome protein 4 (SMC4) in NPM1 haploinsufficient AML cells but not in NPM1 wild-type-harboring Hoxa9/Meis1-transformed cells. SMC4 is higher expressed in haploinsufficient and NPM1c+ AML cells, which are more vulnerable to the disruption of the MEIS1-SMC4 axis compared with AML cells with nonmutated NPM1. Taken together, our study underlines that NPM1 haploinsufficiency on its own is a key factor of myeloid leukemogenesis and characterizes the MEIS1-SMC4 axis as a potential therapeutic target in this AML subtype.

Post-COVID Syndrome and Severity of COVID-19: A Cross-Sectional Epidemiological Evaluation From North India.

Background COVID-19 has now lasted for more than two years as a pandemic and has had enduring effects on the health of people as the post-COVID syndrome. Recent literature has shown the long-term effects of COVID-19 on various organ systems, including but not limited to respiratory, cardiovascular, neurological, musculoskeletal, and gastrointestinal systems. Methods and objectives We aimed to estimate the prevalence of post-acute COVID symptoms in a tertiary care center in northern India; observe the effects of the demographic profile of age, BMI, gender, and presence of comorbidities on the persistence of post-COVID syndrome, and explore any correlation between the severity of COVID-19 disease and the persistence of post-COVID symptoms. We designed a survey containing structured questions evaluating post-COVID symptoms beyond three weeks (post-acute COVID phase), six weeks (post-COVID phase), and 12 weeks of acute illness. It was administered online.  Results Prevalence of post-COVID symptoms both after three and six weeks was reported to be 16.67% and 7.37%, respectively. The most common symptoms to persist were musculoskeletal symptoms (fatigue), followed by upper respiratory symptoms. Disease severity (p<0.05), BMI (p<0.05), and comorbidities were seen to affect post-COVID symptoms significantly, whereas gender and age of the patient had no significant effect. Disease severity significantly affected the persistence of post-COVID symptoms up to 12 weeks; however, this effect does not hold true in long COVID haulers. Also, the risk of developing persistent post-acute COVID symptoms was more in moderate to severe disease than in mild disease. Conclusion The pandemic might be close to over, but it is not out of our lives yet, and the persistence of post-COVID symptoms is exigent.

Defining Terms Used for Animals Working in Support Roles for People with Support Needs.

The nomenclature used to describe animals working in roles supporting people can be confusing. The same term may be used to describe different roles, or two terms may mean the same thing. This confusion is evident among researchers, practitioners, and end users. Because certain animal roles are provided with legal protections and/or government-funding support in some jurisdictions, it is necessary to clearly define the existing terms to avoid confusion. The aim of this paper is to provide operationalized definitions for nine terms, which would be useful in many world regions: "assistance animal", "companion animal", "educational/school support animal", "emotional support animal", "facility animal", "service animal", "skilled companion animal", "therapy animal", and "visiting/visitation animal". At the International Society for Anthrozoology (ISAZ) conferences in 2018 and 2020, over 100 delegates participated in workshops to define these terms, many of whom co-authored this paper. Through an iterative process, we have defined the nine terms and explained how they differ from each other. We recommend phasing out two terms (i.e., "skilled companion animal" and "service animal") due to overlap with other terms that could potentially exacerbate confusion. The implications for several regions of the world are discussed.

Gambling-related harms to concerned significant others: A national Australian prevalence study.

Background and aims: Gambling-related harm to concerned significant others (CSOs) is an important public health issue since it reduces CSOs' health and wellbeing in numerous life domains. This study aimed to 1) estimate the first national prevalence of CSOs harmed by gambling in Australia; 2) identify the characteristics of CSOs most at risk of harm from another person's gambling; 3) compare the types and number of harms experienced by CSOs based on their relationship to the person who gambles; and 4) compare the number of harms experienced by CSOs by self-identified gender. Methods: Based on a national CATI survey weighted to population norms, 11,560 respondents reported whether they had been personally and negatively affected by another person's gambling in the past 12 months; and if so, answered detailed questions about the harms experienced from the person's gambling who had harmed them the most. Results: Past-year prevalence of gambling-related harm to adult Australian CSOs was (6.0%; 95% CI 5.6%-6.5%). CSOs most commonly reported emotional harms, followed by relationship, financial, health and vocational harms, respectively. Former partners reported the most harm, followed by current partners, other family members and non-family members, respectively. Female CSOs were more likely to report more harm and being harmed by a partner or other family member, and male CSOs from a non-family member. Discussion and conclusions: The findings provide new insights into the wider societal burden of gambling and inform measures aimed at reducing harm to CSOs from gambling and supporting them to seek help.

Benchmarking gambling screens to health-state utility: the PGSI and the SGHS estimate similar levels of population gambling-harm.

BACKGROUND: Both the Problem Gambling Severity Index (PGSI) and the Short Gambling Harms Screen (SGHS) purport to identify individuals harmed by gambling. However, there is dispute as to how much individuals are harmed, conditional on their scores from these instruments. We used an experienced utility framework to estimate the magnitude of implied impacts on health and wellbeing. METHODS: We measured health utility using the Short Form Six-Dimension (SF-6D), and used this as a benchmark. All 2603 cases were propensity score weighted, to balance the affected group (i.e., SGHS 1+ or PGSI 1+ vs 0) with a reference group of gamblers with respect to risk factors for gambling harm. Weighted regression models estimated decrements to health utility scores attributable to gambling, whilst controlling for key comorbidities. RESULTS: We found significant attributable decrements to health utility for all non-zero SGHS scores, as well as moderate-risk and problem gamblers, but not for PGSI low-risk gamblers. Applying these coefficients to population data, we find a similar total burden for both instruments, although the SGHS more specifically identified the subpopulation of harmed individuals. For both screens, outcomes on the SF-6D implies that about two-thirds of the 'burden of harm' is attributable to gamblers outside of the most severe categories. CONCLUSIONS: Gambling screens have hitherto provided nominal category membership, it has been unclear whether moderate or 'at-risk' scores imply meaningful impact, and accordingly, population surveys have typically focused on problem gambling prevalence. These results quantify the health utility decrement for each category, allowing for tracking of the aggregate population impact based on all affected gamblers.

TET3 promotes AML growth and epigenetically regulates glucose metabolism and leukemic stem cell associated pathways.

Acute myeloid leukemia (AML) is considered a poor prognosis malignancy where patients exhibit altered glucose metabolism and stem cell signatures that contribute to AML growth and maintenance. Here, we report that the epigenetic factor, Ten-Eleven Translocation 3 (TET3) dioxygenase is overexpressed in AML patients and functionally validated human leukemic stem cells (LSCs), is required for leukemic growth by virtue of its regulation of glucose metabolism in AML cells. In human AML cells, TET3 maintains 5-hydroxymethylcytosine (5hmC) epigenetic marks and expression of early myeloid progenitor program, critical glucose metabolism and STAT5A signaling pathway genes, which also positively correlate with TET3 expression in AML patients. Consequently, TET3 depletion impedes hexokinase activity and L-Lactate production in AML cells. Conversely, overexpression of TET3 in healthy human hematopoietic stem progenitors (HSPCs) upregulates the expression of glucose metabolism, STAT5A signaling and AML associated genes, and impairs normal HSPC lineage differentiation in vitro. Finally, TET3 depletion renders AML cells highly sensitive to blockage of the TET3 downstream pathways glycolysis and STAT5 signaling via the combination of 2-Deoxy-D-glucose and STAT5 inhibitor which preferentially targets AML cells but spares healthy CD34+ HSPCs.

Stressful Life Events Precede Gambling Problems, and Continued Gambling Problems Exacerbate Stressful Life Events; A Life Course Calendar Study.

Do stressful life events cause gambling problems, or do gambling problems cause stressful life events? This study used a retrospective design to examine the temporal order of these associations. Specifically, the study employed a life course calendar in a self-directed online survey to minimise memory biases common in retrospective designs. A total of 1564 US respondents who had gambled at any point in their life (51.0% female, median age 46) were asked whether, for each year of their adult life, they had experienced each of eight stressful life events, and whether they had engaged in casual or heavy gambling, drinking or drug use, with heavy gambling defined in line with a problem gambling definition. We found that five stressful life events were associated with the onset of heavy gambling: work issues, financial issues, legal issues, relationship issues and the death of a loved one. The same five stressful life events predict the cessation of an episode of heavy gambling, indicating a possible tendency for gambling problems to self-resolve in the presence of stress. Insights are also gained into comorbidities with alcohol and drug use, and the course of stressful life events and gambling and substance use throughout the life course, albeit with a non-representative sample. The methodology allows tentative conclusions in terms of possible causation pathways, indicating that stressful life events may play a role both in the onset and the maintenance (or cessation) of gambling problems.

Outcome of simultaneous angioembolization and nephron sparing surgery in large renal angiomyolipomas.

AIM: To study the outcome of simultaneous angioembolization and nephron sparing surgery in large renal angiomyolipomas. MATERIALS AND METHODS: A prospective study of carried out from 2016 to 2019. A total of 15 patients were included in the study with a lesion (angiomyolipoma) more than 10 cm in size, suitable for nephron sparing surgery. The workup of the patients included history, baseline blood investigations, ultrasonography, and CT urography including angiographic films. All the patients were taken up for selective of angioembolization of the feeding vessels of the AML carried out by the interventional radiologist followed by nephron sparing surgery in the same sitting. The short term outcomes studied were warm ischemia time, average blood loss, and length of post-operative hospital stay. The oncological outcome was evaluated by noting the surgical margins of histopathological specimen and functional outcome by assessing the function of the preserved renal parenchyma. RESULTS: Twelve out of fifteen cases were female. The mean age was 42.25 years. All the patients had lesion more than 10 cm with seven tumors located at the lower pole, four at mid-pole, and four at upper pole. Eight patients had low complexity score on RENAL score (i.e. 4-6), five patients medium complexity score (i.e. 7-9), and two had high complexity score (i.e. ⩾10). Average blood loss was 200 ml, warm ischemia time was 18.46 min and postoperative stay was 3.55 days. All the 15 specimens sent for histopathology were confirmed as AML (angiomyolipomas) with margins free of tumor. Follow up CECT done at 4 months postoperatively revealed functioning residual renal parenchyma with prompt excretion of contrast. CONCLUSION: Large AML's are also amenable to nephron sparing surgery. However patient should always be warned about the possibility of total nephrectomy. Selective angioembolization helps in reducing the blood supply and risk of torrential bleeding thus facilitates in the removal of the tumor and increasing the chances of nephron sparing surgery.

The Evolution of Gambling-Related Harm Measurement: Lessons from the Last Decade.

Jurisdictions around the world have a self-declared mandate to reduce gambling-related harm. However, historically, this concept has suffered from poor conceptualisation and operationalisation. However, recent years have seen swift advances in measuring gambling harm, based on the principle of it being a quantifiable decrement to the health and wellbeing of the gambler and those connected to them. This review takes stock of the background and recent developments in harm assessment and summarises recent research that has validated and applied the Short Gambling Harms Screen and related instruments. We recommend that future work builds upon the considerable psychometric evidence accumulated for the feasibility of direct elicitation of harmful consequences. We also advocate for grounding harms measures with respect to scalar changes to public health utility metrics. Such an approach will avoid misleading pseudo-clinical categorisations, provide accurate population-level summaries of where the burden of harm is carried, and serve to integrate gambling research with the broader field of public health.

Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström's Macroglobulinemia.

CXCR4 expression and downstream signaling have been identified as key factors in malignant hematopoiesis. Thus, up to 40% of all patients with Waldenström's macroglobulinemia (WM) carry an activating mutation of CXCR4 that leads to a more aggressive clinical course and inferior outcome upon treatment with the Bruton's tyrosine kinase inhibitor ibrutinib. Nevertheless, little is known about physiological mechanisms counteracting CXCR4 signaling in hematopoietic neoplasms. Recently, the endogenous human peptide EPI-X4 was identified as a natural CXCR4 antagonist that effectively blocks CXCL12-mediated receptor internalization and suppresses the migration and invasion of cancer cells towards a CXCL12 gradient. Here, we demonstrate that EPI-X4 efficiently binds to CXCR4 of WM cells and decreases their migration towards CXCL12. The CXCR4 inhibitory activity of EPI-X4 is accompanied by reduced expression of genes involved in MAPK signaling and energy metabolism. Notably, the anti-WM activity of EPI-X4 could be further augmented by the rational design of EPI-X4 derivatives showing higher binding affinity to CXCR4. In summary, these data demonstrate that a naturally occurring anti-CXCR4 peptide is able to interfere with WM cell behaviour, and that optimized derivatives of EPI-X4 may represent a promising approach in suppressing growth promoting CXCR4 signaling in WM.

TET1 promotes growth of T-cell acute lymphoblastic leukemia and can be antagonized via PARP inhibition.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer characterized by skewed epigenetic patterns, raising the possibility of therapeutically targeting epigenetic factors in this disease. Here we report that among different cancer types, epigenetic factor TET1 is highly expressed in T-ALL and is crucial for human T-ALL cell growth in vivo. Knockout of TET1 in mice and knockdown in human T cell did not perturb normal T-cell proliferation, indicating that TET1 expression is dispensable for normal T-cell growth. The promotion of leukemic growth by TET1 was dependent on its catalytic property to maintain global 5-hydroxymethylcytosine (5hmC) marks, thereby regulate cell cycle, DNA repair genes, and T-ALL associated oncogenes. Furthermore, overexpression of the Tet1-catalytic domain was sufficient to augment global 5hmC levels and leukemic growth of T-ALL cells in vivo. We demonstrate that PARP enzymes, which are highly expressed in T-ALL patients, participate in establishing H3K4me3 marks at the TET1 promoter and that PARP1 interacts with the TET1 protein. Importantly, the growth related role of TET1 in T-ALL could be antagonized by the clinically approved PARP inhibitor Olaparib, which abrogated TET1 expression, induced loss of 5hmC marks, and antagonized leukemic growth of T-ALL cells, opening a therapeutic avenue for this disease.

A framework for indirect elicitation of the public health impact of gambling problems.

Gambling problems are increasingly understood as a health-related condition, with harms from excessive time and money expenditure contributing to significant population morbidity. In many countries, the prevalence of gambling problems is known with some precision. However, the true severity of gambling problems in terms of their impact on health and wellbeing is the subject of ongoing debate. We firstly review recent research that has attempted to estimate harm from gambling, including studies that estimate disability weights using direct elicitation. Limitations of prior approaches are discussed, most notably potential inflation due to non-independent comorbidity with other substance use and mental health conditions, and potential biases in the subjective attribution of morbidity to gambling. An alternative indirect elicitation approach is outlined, and a conceptual framework for its application to gambling is provided. Significant risk factors for propensity to develop gambling problems are enumerated, and relative risks for comorbidities are calculated from recent meta-analyses and reviews. Indirect elicitation provides a promising alternative framework for assessing the causal link between gambling problems and morbidity. This approach requires implementation of propensity score matching to estimate the counterfactual, and demands high quality information of risk factors and comorbid conditions, in order to estimate the unique contribution of gambling problems. Gambling harm is best understood as a decrement to health utility. However, achieving consensus on the severity of gambling problems requires triangulation of results from multiple methodologies. Indirect elicitation with propensity score matching and accounting for comorbidities would provide an important step towards full integration of gambling within a public health paradigm.

Somatostatin receptor mediated targeting of acute myeloid leukemia by photodynamic metal complexes for light induced apoptosis.

Acute myeloid leukemia (AML) is characterized by relapse and treatment resistance in a major fraction of patients, underlining the need of innovative AML targeting therapies. Here we analysed the therapeutic potential of an innovative biohybrid consisting of the tumor-associated peptide somatostatin and the photosensitizer ruthenium in AML cell lines and primary AML patient samples. Selective toxicity was analyzed by using CD34 enriched cord blood cells as control. Treatment of OCI AML3, HL60 and THP1 resulted in a 92, and 99 and 97% decrease in clonogenic growth compared to the controls. Primary AML cells demonstrated a major response with a 74 to 99% reduction in clonogenicity in 5 of 6 patient samples. In contrast, treatment of CD34+ CB cells resulted in substantially less reduction in colony numbers. Subcellular localization assays of RU-SST in OCI-AML3 cells confirmed strong co-localization of RU-SST in the lysosomes compared to the other cellular organelles. Our data demonstrate that conjugation of a Ruthenium complex with somatostatin is efficiently eradicating LSC candidates of patients with AML. This indicates that receptor mediated lysosomal accumulation of photodynamic metal complexes is a highly attractive approach for targeting AML cells.

Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is propagated by leukemic stem cells (LSCs), often characterized by deregulated Wnt signaling. We previously showed that the central transcriptional mediator of Wnt signaling LEF1 is able to cause AML in mice and acts as an independent prognostic factor in normal karyotype AML. Here, we show that treatment naïve normal karyotype AML as well as samples AML LSCs predominantly express the long ß-catenin-binding isoform of LEF1 in sharp contrast to normal human hematopoietic stem cells, which lack expression of the long isoform, but express the short N-terminally truncated isoform with loss of the ß-catenin-binding site. Gene expression and ChiP-Seq analyses in mice linked the long isoform to Wnt-ß-catenin signaling and oncogenic pathways, the N-terminally truncated isoform to stemness associated genes. Approaches impairing binding of LEF1 to ß-catenin significantly impaired AML growth, but spared normal hematopoietic stem cells. This report now demonstrates a striking difference of LEF1 isoform expression between normal and AML cells, contributing to higher vulnerability of leukemic cells to approaches targeting ß-catenin/LEF1 interaction.