UNC119 regulates T-cell receptor signalling in primary T cells and T acute lymphocytic leukaemia.

T-cell receptor recognition of cognate peptide-MHC leads to the formation of signalling domains and the immunological synapse. Because of the close membrane apposition, there is rapid exclusion of CD45, and therefore LCK activation. Much less is known about whether spatial regulation of the intracellular face dictates LCK activity and TCR signal transduction.

Randomized waitlist-controlled trial of buried in treasures facilitated support groups and in-home uncluttering (BIT+) for hoarding disorder.

Objective: The Buried in Treasures (BIT) workshop is a promising treatment for hoarding disorder (HD), though many participants struggle with home uncluttering. This randomized waitlist-controlled trial investigated the efficacy of a version of BIT, augmented with in-home uncluttering practice (BIT+).

Method: Adults (N = 41) with hoarding disorder were recruited from the community and randomly assigned to BIT+ or waitlist.

IL-27 maintains cytotoxic Ly6C γδ T cells that arise from immature precursors.

In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αβ-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus.

Experiences of participant and public involvement in an international randomized controlled trial for people living with dementia and their informal caregivers.

Background: This study was initiated and co-designed by a Participant and Public Involvement (PPI) group attached to HOMESIDE, a randomized controlled trial that investigated music and reading interventions for people living with dementia and their family caregivers across five countries: Australia, Germany, Norway, Poland, and the UK. The aim was to capture experiences of PPI across the five countries, explore the benefits and challenges of PPI in dementia research, and identify contributions made to the study.

Methods: We surveyed PPI members and academic researchers who collaborated on the HOMESIDE study.

HER2 heterogeneity and treatment response-associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial.

BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR).METHODSTo investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial.

Thymic lymphoma detection in RORγ knockout mice using 5-hydroxymethylcytosine profiling of circulating cell-free DNA.

A high incidence of thymic lymphoma has been noted in mice deficient of retinoid-related orphan receptor γ2 (RORγ2), which is required for differentiation of naïve CD4 T cells into T17 cells. Using a RORγ homozygous knockout (KO) mouse model of thymic lymphoma, we characterized this tumor progression and investigated the utility of 5-hydroxymethylcytosine (5hmC) signatures as a non-invasive circulating biomarker for early prediction of malignancy. No evidence for malignancy was noted in the wild-type mice, while primary thymic lymphoma with multi-organ metastasis was observed microscopically in 97% of the homozygous RORγ KO mice.

hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia.

Leukemia cells re-program their microenvironment to augment blast proliferation and enhance treatment resistance. Means of clinically targeting such niche-driven treatment resistance remain ambiguous. We develop human induced pluripotent stem cell (hiPSC)-engineered niches to reveal druggable cancer-niche dependencies.

Catabolic Ornithine Carbamoyltransferase Activity Facilitates Growth of Staphylococcus aureus in Defined Medium Lacking Glucose and Arginine.

Previous studies have found that arginine biosynthesis in Staphylococcus aureus is repressed via carbon catabolite repression (CcpA), and proline is used as a precursor. Unexpectedly, however, robust growth of S. aureus is not observed in complete defined medium lacking both glucose and arginine (CDM-R).

A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program.

Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis for infant-ALL remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: an MLL/KMT2A gene rearrangement (MLL-r). This is sufficient to induce a uniquely aggressive and treatment-refractory leukemia compared to older children.

The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13.

B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults.

The redox-responsive transcriptional regulator Rex represses fermentative metabolism and is required for Listeria monocytogenes pathogenesis.

The Gram-positive bacterium Listeria monocytogenes is the causative agent of the foodborne disease listeriosis, one of the deadliest bacterial infections known. In order to cause disease, L. monocytogenes must properly coordinate its metabolic and virulence programs in response to rapidly changing environments within the host.

Investigating the Roles of Listeria monocytogenes Peroxidases in Growth and Virulence.

Bacteria have necessarily evolved a protective arsenal of proteins to contend with peroxides and other reactive oxygen species generated in aerobic environments. Listeria monocytogenes encounters an onslaught of peroxide both in the environment and during infection of the mammalian host, where it is the causative agent of the foodborne illness listeriosis. Despite the importance of peroxide for the immune response to bacterial infection, the strategy by which L.

Severe toxicity free survival: physician-derived definitions of unacceptable long-term toxicities following acute lymphocytic leukaemia.

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting.

miR-130b and miR-128a are essential lineage-specific codrivers of t(4;11) MLL-AF4 acute leukemia.

t(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in the infant and pediatric population, yet we have little information on the molecular mechanisms responsible for disease progression. This impairs the development of therapeutic regimens that can address the aggressive phenotype and lineage plasticity of MLL-AF4-driven leukemogenesis. This study highlights novel mechanisms of disease development by focusing on 2 microRNAs (miRNAs) upregulated in leukemic blasts from primary patient samples: miR-130b and miR-128a.

Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment is dependent on Stearoyl CoA desaturase.

Metabolic reprogramming is a key hallmark of cancer, but less is known about metabolic plasticity of the same tumor at different sites. Here, we investigated the metabolic adaptation of leukemia in two different microenvironments, the bone marrow and the central nervous system (CNS). We identified a metabolic signature of fatty-acid synthesis in CNS leukemia, highlighting Stearoyl-CoA desaturase () as a key player.

The Feasibility of Patient-Specific Circulating Tumor DNA Monitoring throughout Multi-Modality Therapy for Locally Advanced Esophageal and Rectal Cancer: A Potential Biomarker for Early Detection of Subclinical Disease.

As non-operative management (NOM) of esophageal and rectal cancer is becoming more prevalent, blood-biomarkers such as circulating tumor DNA (ctDNA) may provide clinical information in addition to endoscopy and imaging to aid in treatment decisions following chemotherapy and radiation therapy. In this feasibility study, we prospectively collected plasma samples from locally advanced esophageal ( = 3) and rectal cancer ( = 2) patients undergoing multimodal neoadjuvant therapy to assess the feasibility of serial ctDNA monitoring throughout neoadjuvant therapy. Using the Dual-Index Degenerate Adaptor-Sequencing (DIDA-Seq) error-correction method, we serially interrogated plasma cell-free DNA at 28-41 tumor-specific genomic loci throughout therapy and in surveillance with an average limit of detection of 0.

CD79a promotes CNS-infiltration and leukemia engraftment in pediatric B-cell precursor acute lymphoblastic leukemia.

Central nervous system (CNS) involvement remains a challenge in the diagnosis and treatment of acute lymphoblastic leukemia (ALL). In this study, we identify CD79a (also known as Igα), a signaling component of the preB cell receptor (preBCR), to be associated with CNS-infiltration and -relapse in B-cell precursor (BCP)-ALL patients. Furthermore, we show that downregulation of CD79a hampers the engraftment of leukemia cells in different murine xenograft models, particularly in the CNS.

Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Ph acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors results in elevated expression of IL7R which enables the survival of transformed cells when IL7 was added together with the kinase inhibitors.

Listeria monocytogenes SpxA1 is a global regulator required to activate genes encoding catalase and heme biosynthesis enzymes for aerobic growth.

An imbalance of cellular oxidants and reductants causes redox stress, which must be rapidly detected to restore homeostasis. In bacteria, the Firmicutes encode conserved Spx-family transcriptional regulators that modulate transcription in response to redox stress. SpxA1 is an Spx-family orthologue in the intracellular pathogen Listeria monocytogenes that is essential for aerobic growth and pathogenesis.

Leptomeningeal malignancy of childhood: sharing learning between childhood leukaemia and brain tumour trials.

Leptomeningeal malignancy complicates childhood cancers, including leukaemias, brain tumours, and solid tumours. In leukaemia, such malignancy is thought to invade leptomeninges via the vascular route. In brain tumours, dissemination from the primary tumour, before or after surgery, via CSF pathways is assumed; however, evidence exists to support the vascular route of dissemination.