Association Between Thrombus Composition and Etiology in Patients With Acute Ischemic Stroke Treated by Thrombectomy.

Background: In ischemic stroke due to large vessel occlusion, cerebral blood flow is impaired by thromboemboli, which can originate from various sources in the body. A better understanding of thromboembolus composition can improve our understanding of the underlying pathophysiology and potentially guide improvement of prevention strategies. The aim of this study therefore was to perform a large-sample multi-parameter quantitative histological analysis of retrieved thromboemboli from stroke patients.

Synergistic Strategies for KMT2A-Rearranged Leukemias: Beyond Menin Inhibitor.

KMT2A-rearranged leukemias are a highly aggressive subset of acute leukemia, characterized by poor prognosis and frequent relapses despite intensive treatment. Menin inhibitors, which target the critical KMT2A-menin interaction driving leukemogenesis, have shown promise in early clinical trials. However, resistance to these inhibitors, often driven by menin mutations or alternative oncogenic pathways, remains a significant challenge.

Early assessment of antibodies decline in Chagas patients following treatment using a serological multiplex immunoassay.

Chagas disease following infection with Trypanosoma cruzi is a major public health issue, with the disease spreading beyond endemic regions and becoming more global due to the migration of infected individuals. The currently available anti-parasitic drugs, nifurtimox and benznidazole, remain insufficiently evaluated for their efficacy in adult patients. A key challenge is the lack of markers for parasitological cure, which also precludes the development of new treatments.

Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes.

Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells.

Optimising Patient Outcomes in Tongue Cancer: A Multidisciplinary Approach.

A multidisciplinary approach to the management of tongue cancer is vital for achieving optimal patient outcomes. Nursing and allied health professionals play essential roles within the team. We developed symposia comprising a series of online lectures offering a detailed perspective on the role each discipline and consumer perspective has in the management of patients with tongue cancer.

Clinical activity in general practice before sarcoma diagnosis: an Australian cohort study.

Background: Increased time to diagnosis in sarcoma is associated with poor prognosis and patient outcomes. Research is needed to identify whether opportunities to expedite the diagnosis of sarcoma in general practice exist.

Aim: To examine pre-diagnostic GP clinical activity before sarcoma diagnosis.

FDA-approved disulfiram as a novel treatment for aggressive leukemia.

Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound.

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction.

Advances in the clinical management of pediatric B-cell acute lymphoblastic leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases.

A novel assessment method for COVID-19 humoral immunity duration using serial measurements in naturally infected and vaccinated subjects.

Background: Collecting information on sustainability of immune responses after infection or vaccination is crucial to inform medical decision-making and vaccination strategies. Data on how long-lasting antibodies against SARS-COV-2 could provide a humoral and protective immunity and prevent reinfection with SARS-CoV-2 or its variants is particularly valuable. This study presents a novel method to quantitatively measure and monitor the diversity of SARS-CoV-2 specific antibody profiles over time.

Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.

Background: Improving the poor prognosis of infant leukaemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven paediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity.

Identification of a c-MYB-directed therapeutic for acute myeloid leukemia.

A significant proportion of patients suffering from acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, relapsed disease being a common problem. Molecular targeting of essential oncogenic mediators is an attractive approach to improving outcomes for this disease. The hematopoietic transcription factor c-MYB has been revealed as a central component of complexes maintaining aberrant gene expression programs in AML.

Optimising the quality of multidisciplinary team meetings: A narrative review.

Background: Understanding of factors that contribute to implementation of effective cancer multidisciplinary team meetings (MDMs) is still limited. Published literature on the effect of teamwork function, leadership roles, decision-making processes and structural components on the quality of MDMs was reviewed and synthesised.

Methods: In this paper, a MEDLINE review (September 2020) was performed to assess clinical decision-making in the context of MDM discussions.

A novel high performing multiplex immunoassay Multi-HTLV for serological confirmation and typing of HTLV infections.

Background: Human T-Cell Lymphotropic Viruses (HTLV) type 1 and type 2 account for an estimated 5 to 10 million infections worldwide and are transmitted through breast feeding, sexual contacts and contaminated cellular blood components. HTLV-associated syndromes are considered as neglected diseases for which there are no vaccines or therapies available, making it particularly important to ensure the best possible diagnosis to enable proper counselling of infected persons and avoid secondary transmission. Although high quality antibody screening assays are available, currently available confirmatory tests are costly and have variable performance, with high rates of indeterminate and non-typable results reported in many regions of the world.

Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation.

Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects.

Prediction of parasitological cure in children infected with Trypanosoma cruzi using a novel multiplex serological approach: an observational, retrospective cohort study.

Background: Assessment of therapeutic response with standard serological diagnostic assays in patients with chronic Chagas disease is a major challenge due to the long persistence of parasite-specific antibodies. The current consensus for parasitological cure is to monitor conversion from positive to negative Trypanosoma cruzi serology (seroreversion). However, because of robust humoral immune response, seroreversion by standard serological tests can take years to decades.

Towards Routine Implementation of Liquid Biopsies in Cancer Management: It Is Always Too Early, until Suddenly It Is Too Late.

Blood-based liquid biopsies are considered a new and promising diagnostic and monitoring tool for cancer. As liquid biopsies only require a blood draw, they are non-invasive, potentially more rapid and assumed to be a less costly alternative to genomic analysis of tissue biopsies. A multi-disciplinary workshop ( = 98 registrations) was organized to discuss routine implementation of liquid biopsies in cancer management.

Accurate non-invasive diagnosis and staging of non-alcoholic fatty liver disease using the urinary steroid metabolome.

Background: The development of accurate, non-invasive markers to diagnose and stage non-alcoholic fatty liver disease (NAFLD) is critical to reduce the need for an invasive liver biopsy and to identify patients who are at the highest risk of hepatic and cardio-metabolic complications. Disruption of steroid hormone metabolic pathways has been described in patients with NAFLD.

Aim(s): To assess the hypothesis that assessment of the urinary steroid metabolome may provide a novel, non-invasive biomarker strategy to stage NAFLD.

Mutant IDH Sensitizes Gliomas to Endoplasmic Reticulum Stress and Triggers Apoptosis via miR-183-Mediated Inhibition of Semaphorin 3E.

Human astrocytomas and oligodendrogliomas are defined by mutations of the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2, resulting in the production of the abnormal metabolite D-2 hydroxyglutarate. Here, we studied the effect of mutant IDH on cell proliferation and apoptosis in a glioma mouse model. Tumors were generated by inactivating and in forebrain progenitors and compared with tumors additionally expressing the Idh1 R132H mutation.

The AAA+ATPase RUVBL2 is essential for the oncogenic function of c-MYB in acute myeloid leukemia.

Subtype-specific leukemia oncogenes drive aberrant gene expression profiles that converge on common essential mediators to ensure leukemia self-renewal and inhibition of differentiation. The transcription factor c-MYB functions as one such mediator in a diverse range of leukemias. Here we show for the first time that transcriptional repression of myeloid differentiation associated c-MYB target genes in AML is enforced by the AAA+ ATPase RUVBL2.

Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between and fusions.

The t(4;11)(q21;q23) translocation is associated with high-risk infant pro-B-cell acute lymphoblastic leukemia and arises prenatally during embryonic/fetal hematopoiesis. The developmental/pathogenic contribution of the t(4;11)-resulting (MA4) and (A4M) fusions remains unclear; MA4 is always expressed in patients with t(4;11) B-cell acute lymphoblastic leukemia, but the reciprocal fusion A4M is expressed in only half of the patients. Because prenatal leukemogenesis manifests as impaired early hematopoietic differentiation, we took advantage of well-established human embryonic stem cell-based hematopoietic differentiation models to study whether the A4M fusion cooperates with MA4 during early human hematopoietic development.

Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia.

Decreased autophagy contributes to malignancies, however it is unclear how autophagy impacts on tumour growth. Acute myeloid leukemia (AML) is an ideal model to address this as (i) patient samples are easily accessible, (ii) the hematopoietic stem and progenitor population (HSPC) where transformation occurs is well characterized, and (iii) loss of the key autophagy gene in hematopoietic stem and progenitor cells (HSPCs) leads to a lethal pre-leukemic phenotype in mice. Here we demonstrate that loss of results in an identical HSPC phenotype as loss of , confirming a general role for autophagy in HSPC regulation.