Trabectedin enhances the antitumor effects of IL-12 in triple-negative breast cancer.

Interleukin-12 (IL-12) is a potent NK cell-stimulating cytokine, but the presence of immunosuppressive myeloid cells such as myeloid-derived suppressor cells (MDSC) can inhibit IL 12-induced NK-cell cytotoxicity. Thus, we hypothesized that trabectedin, a myeloid cell-depleting agent, would improve the efficacy of IL-12 in triple-negative breast cancer (TNBC). In vitro treatment of healthy donor NK cells with trabectedin increased expression of the activation marker CD69 and mRNA expression of T BET (Tbx21), the cytotoxic ligands TRAIL (TNFSF10) and Fas ligand (FASLG) and the dendritic cell (DC)-recruiting chemokine lymphotactin (XCL1).

Single Nuclei Sequencing Reveals Intratumoral Cellular Heterogeneity and Replication Stress in Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and limited treatment options. Bulk genomic characterization of ACC has not yielded obvious therapeutic or immunotherapeutic targets, yet novel therapies are needed. We hypothesized that elucidating the intratumoral cellular heterogeneity by single nuclei RNA sequencing analyses would yield insights into potential therapeutic vulnerabilities of this disease.

Optical Genome Mapping (OGM) Identifies Multiple Structural Variants in a Case With Atypical Phelan-McDermid Syndrome.

Here we describe a neonate exhibiting hypotonia, macrocephaly, renal cysts, and respiratory failure requiring tracheostomy and ventilator support. Genetic analysis via rapid genome sequencing (rGS) identified a loss on chromosome 4 encompassing polycystin-2 (PKD2) and a loss on chromosome 22 encompassing SH3 and Multiple Ankyrin Repeat Domains 3 (SHANK3), indicative of Phelan-McDermid syndrome. Further analysis via traditional karyotyping, Optical Genome Mapping (OGM), and PacBio long-read sequencing revealed a more complex landscape of chromosomal rearrangements in this individual, including a balanced 3;12 translocation, and an unbalanced 17;22 translocation.

Defining the transcriptome of PIK3CA-altered cells in a human capillary malformation using single cell long-read sequencing.

PIK3CA-related overgrowth spectrum (PROS) disorders are caused by somatic mosaic variants that result in constitutive activation of the phosphatidylinositol-3-kinase/AKT/mTOR pathway. Promising responses to molecularly targeted therapy have been reported, although identification of an appropriate agent can be hampered by the mosaic nature and corresponding low variant allele frequency of the causal variant. Moreover, our understanding of the molecular consequences of these variants-for example how they affect gene expression profiles-remains limited.

Associations between neighborhood factors and insomnia and their spatial clustering in Philadelphia, Pennsylvania.

Background: Neighborhood-level adverse social determinants may be a risk factor for sleep health disparities. We examined the associations between neighborhood factors and insomnia and explored their spatial clustering in the city of Philadelphia, Pennsylvania.

Methods: We conducted a cross-sectional analysis of data from Philadelphia residents who participated in online screening for insomnia-related research.

Multiomic profiling identifies predictors of survival in African American patients with acute myeloid leukemia.

Genomic profiles and prognostic biomarkers in patients with acute myeloid leukemia (AML) from ancestry-diverse populations are underexplored. We analyzed the exomes and transcriptomes of 100 patients with AML with genomically confirmed African ancestry (Black; Alliance) and compared their somatic mutation frequencies with those of 323 self-reported white patients with AML, 55% of whom had genomically confirmed European ancestry (white; BeatAML). Here we find that 73% of 162 gene mutations recurrent in Black patients, including a hitherto unreported PHIP alteration detected in 7% of patients, were found in one white patient or not detected.

Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia.

Leukemias arise from recurrent clonal mutations in hematopoietic stem/progenitor cells (HSPCs) that cause profound changes in the bone marrow microenvironment (BMM) favoring leukemic stem cell (LSC) growth over normal HSPCs. Understanding the cross talk between preleukemic mutated HSPCs and the BMM is critical to develop novel therapeutic strategies to prevent leukemogenesis. We hypothesize that preleukemic-LSCs (pLSCs) induce BMM changes critical for leukemogenesis.

Corrigendum: Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors.

[This corrects the article DOI: 10.3389/fimmu.2024.

Germline susceptibility from broad genomic profiling of pediatric brain cancers.

Background: Identifying germline predisposition in CNS malignancies is of increasing clinical importance, as it contributes to diagnosis and prognosis, and determines aspects of treatment. The inclusion of germline testing has historically been limited due to challenges surrounding access to genetic counseling, complexity in acquiring a germline comparator specimen, concerns about the impact of findings, or cost considerations. These limitations were further defined by the breadth and scope of clinical testing to precisely identify complex variants as well as concerns regarding the clinical interpretation of variants including those of uncertain significance.

Combinatorial macrophage induced innate immunotherapy against Ewing sarcoma: Turning "Two Keys" simultaneously.

Background: Macrophages play important roles in phagocytosing tumor cells. However, tumors escape macrophage phagocytosis in part through the expression of anti-phagocytic signals, most commonly CD47. In Ewing sarcoma (ES), we found that tumor cells utilize dual mechanisms to evade macrophage clearance by simultaneously over-expressing CD47 and down-regulating cell surface calreticulin (csCRT), the pro-phagocytic signal.

Temporal regulation of the Mediator complex during muscle proliferation, differentiation, regeneration, aging, and disease.

Genesis of skeletal muscle relies on the differentiation and fusion of mono-nucleated muscle progenitor cells into the multi-nucleated muscle fiber syncytium. The temporally-controlled cellular and morphogenetic changes underlying this process are initiated by a series of highly coordinated transcription programs. At the core, the myogenic differentiation cascade is driven by muscle-specific transcription factors, i.

Integrating Multisector Molecular Characterization into Personalized Peptide Vaccine Design for Patients with Newly Diagnosed Glioblastoma.

Purpose: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines.

Sleep Disturbances Associated With Posttraumatic Stress Disorder.

Sleep disturbances, namely insomnia and recurrent nightmares, are ubiquitous following trauma exposure and are considered hallmarks of posttraumatic stress disorder (PTSD). Other sleep disorders frequently co-occur with PTSD. This article describes research examining sleep problems most common in PTSD, including prevalence and clinical characteristics.

Full-length isoform concatenation sequencing to resolve cancer transcriptome complexity.

Background: Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts.

The importance of REM sleep fragmentation in the effects of stress on sleep: Perspectives from preclinical studies.

Psychological stress poses a risk for sleep disturbances. Importantly, trauma-exposed individuals who develop posttraumatic stress disorder (PTSD) frequently report insomnia and recurrent nightmares. Clinical studies have provided insight into the mechanisms of these sleep disturbances.

Identifying predictors of the amount of veteran participation in cognitive behavioral therapy for insomnia in the Veterans Affairs health care system.

Insomnia is a prevalent and negatively impactful disorder among veterans. The Department of Veterans Affairs (VA) has committed significant resources to the development and dissemination of training related to cognitive behavioral therapy for insomnia (CBT-I), the recommended first-line intervention for chronic insomnia disorder. It has been established that VA clinicians can be effectively trained to deliver high fidelity CBT-I and that treatment results in significant improvements in insomnia.

Oncolytic virus-driven immune remodeling revealed in mouse medulloblastomas at single cell resolution.

Oncolytic viruses, modified for tumor-restricted infection, are a promising cancer immunotherapeutic, yet much remains to be understood about factors driving their activity and outcome in the tumor microenvironment. Here, we report that oncolytic herpes simplex virus C134, previously found to exert T cell-dependent efficacy in mouse models of glioblastoma, exerts T cell-independent efficacy in mouse models of medulloblastoma, indicating this oncolytic virus uses different mechanisms in different tumors. We investigated C134's behavior in mouse medulloblastomas, using single cell RNA sequencing to map C134-induced gene expression changes across cell types, timepoints, and medulloblastoma subgroup models at whole-transcriptome resolution.

Neighborhood disadvantage is associated with sleep disturbance in a sample of trauma-exposed Veterans.

Objectives: This study examined associations among neighborhood disadvantage, all-night respiratory sinus arrhythmia, fear of sleep, nightmare frequency, and sleep duration in a sample of trauma-exposed Veterans.

Methods: Participants completed baseline assessments and slept on a mattress actigraphy system for seven nights. Neighborhood disadvantage was assessed with the Area Deprivation Index, a census-based socioeconomic index.

Longitudinal profiles of sleep during residential PTSD treatment.

We investigated longitudinal profiles of objectively measured sleep periods (SP) over the course of residential treatment for posttraumatic stress disorder (PTSD) in a cohort of U.S. male veterans.

A novel transcriptional signature identifies T-cell infiltration in high-risk paediatric cancer.

Background: Molecular profiling of the tumour immune microenvironment (TIME) has enabled the rational choice of immunotherapies in some adult cancers. In contrast, the TIME of paediatric cancers is relatively unexplored. We speculated that a more refined appreciation of the TIME in childhood cancers, rather than a reliance on commonly used biomarkers such as tumour mutation burden (TMB), neoantigen load and PD-L1 expression, is an essential prerequisite for improved immunotherapies in childhood solid cancers.