Spatiotemporal Profiling Defines Persistence and Resistance Dynamics During Targeted Treatment of Melanoma.

Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. A better understanding of the temporal dynamics and specific pathways leading into and out of the persister state is needed to identify strategies to prevent treatment failure. Using spatial transcriptomics in patient-derived xenograft models, we captured clonal lineage evolution during treatment.

HIV Clinical Providers' Awareness, Attitudes, and Willingness to Support Patient Outreach Efforts for HIV Cure-Directed Research in Philadelphia, United States.

Background: Ethical patient outreach is critical for engaging patients with HIV in HIV cure-directed research. We sought to examine HIV clinical providers' awareness of current HIV cure-directed research strategies investigated through the Martin Delaney Collaboratories (MDC) and providers' attitudes toward patient outreach for HIV cure-directed research and to identify opportunities for clinical provider education on MDC research strategies.

Methods: We conducted a 1-time, cross-sectional, web-based survey with 64 HIV clinical providers (physicians, physician assistants, and nurses) in Philadelphia.

Cognate antigen engagement induces HIV-1 expression in latently infected CD4 T cells from people on long-term antiretroviral therapy.

Despite antiretroviral therapy (ART), HIV-1 persists in latently infected CD4 T cells, preventing a cure. Antigens drive the proliferation of infected cells, precluding latent reservoir decay. However, the relationship between antigen recognition and HIV-1 gene expression is poorly understood because most studies of latency reversal use agents that induce non-specific global T cell activation.

Medicinal Plant and Traditional Knowledge-guided Strategies to Combat HIV Persistence.

Purpose Of Review:  Combination antiretroviral therapy (cART) does not act on latent HIV reservoirs, and no latency-reversing agent (LRA) to date consistently reduces viral reservoirs in humans. In Sub-Saharan Africa and elsewhere, complementary and alternative medicines (CAM) are traditionally used to manage HIV/AIDS, including a subset with LRA properties.

Recent Findings: Several plants from the Euphorbiaceae and Thymelaeaceae families have been recently documented for traditional HIV/AIDS management and contain LRAs that function through protein kinase C activation.

The enhancer module of Integrator controls cell identity and early neural fate commitment.

Lineage-specific transcription factors operate as master orchestrators of developmental processes by activating select cis-regulatory enhancers and proximal promoters. Direct DNA binding of transcription factors ultimately drives context-specific recruitment of the basal transcriptional machinery that comprises RNA polymerase II (RNAPII) and a host of polymerase-associated multiprotein complexes, including the metazoan-specific Integrator complex. Integrator is primarily known to modulate RNAPII processivity and to surveil RNA integrity across coding genes.

Pierre & Hutch (Euphorbiaceae) Extracts and Isolated Compounds Reverse HIV-1 Latency.

Background: Pierre & Hutch is a tropical tree that grows in West and Central Africa, used in ethnomedicine to treat cancer, diabetes, headaches, convulsions, urinary diseases, and inflammatory diseases. As other species have been observed to possess chemical compounds that target HIV latency-reversal, we hypothesized that this species may have similar properties.

Aim Of The Study: The identification of extracts and compounds of this species, which have HIV-1 latency-reversing activity in J-Lat T cell lines.

ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.

Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively.

Myeloid activation clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer.

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of <30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity.

Structure and sequence engineering approaches to improve in vivo expression of nucleic acid-delivered antibodies.

Monoclonal antibodies are an important class of biologics with over 160 Food and Drug Administration/European Union-approved drugs. A significant bottleneck to global accessibility of recombinant monoclonal antibodies stems from complexities related to their production, storage, and distribution. Recently, gene-encoded approaches such as mRNA, DNA, or viral delivery have gained popularity, but ensuring biologically relevant levels of antibody expression in the host remains a critical issue.

A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition.

Background And Objectives: TBCK syndrome is a rare fatal pediatric neurodegenerative disease caused by biallelic loss-of-function mutations in the gene. Previous studies by our lab and others have implicated mTOR, autophagy, lysosomes, and intracellular mRNA transport, however the exact primary pathologic mechanism is unknown. This gap has prevented the development of targeted therapies.

Tumor Heterogeneity Shapes Survival Dynamics in Drug-Treated Cells, Revealing Size-Drifting Subpopulations.

The goal of this project was to demonstrate that subpopulations of cells in tumors can uniquely fluctuate in size in response to environmental conditions created during drug treatment, thereby acting as a dynamic "rheostat" to create a favorable tumor environment for growth. The cancer modeling used for these studies was subpopulations of melanoma cells existing in cultured and tumor systems that differed in aldehyde dehydrogenase (ALDH) activity. However, similar observations were found in other cancer types in addition to melanoma, making them applicable broadly across cancer.

The Ashkenazi-Centric G334R Variant of is Severely Impaired for Transactivation but Retains Tumor Suppressor Function in a Mouse Model.

Mutations in the tumor suppressor gene are the most abundant genetic occurrences in cancer. Some of these mutations lead to loss of function of p53 protein, some are gain of function, and some variants are hypomorphic (partially functional). Currently, there is no clinical distinction between different p53 mutations and cancer therapy or prognosis.

The imprint of viral oncoproteins on the variable clinical behavior among human papilloma virus-related oropharyngeal squamous cell carcinomas.

Human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are variable in their progression, immune landscape, treatment responses, and clinical outcomes. Their behavior is impacted not only by differences in host genomic alterations but also by diversity in levels and activity of HPV-encoded oncoproteins. Striking differences in HPV mRNA levels are found among HPV+ OPSCCs and likely derive in part from variations in the structurally diverse mix of integrated and episomal HPV genomes they often contain.

PD-L1 in Melanoma and Extracellular Vesicles Promotes Local and Regional Immune Suppression through M2-like Macrophage Polarization.

Tumor-associated macrophages (TAMs) play dual roles in tumor progression. TAMs are known to induce programmed death ligand-1 (PD-L1) expression in cancer cells. However, the regulatory effects of PD-L1 in melanoma cells on TAM phenotypical switching remain underexplored.

Inflammatory bowel disease, colitis, and cancer: unmasking the chronic inflammation link.

Background: Chronic inflammation is a significant driver in the development of various diseases, including cancer. Colitis-associated colorectal cancer (CA-CRC) refers to the increased risk of colorectal cancer in individuals with chronic inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease.

Methods: This narrative review examines the link between chronic inflammation and CA-CRC.

Positive allosteric modulation of glutamate transporter reduces cocaine-induced locomotion and expression of cocaine conditioned place preference in rats.

The glutamatergic system, located throughout the brain including the prefrontal cortex and nucleus accumbens, plays a critical role in reward and reinforcement processing, and mediates the psychotropic effects of addictive drugs such as cocaine. Glutamate transporters, including EAAT2/GLT-1, are responsible for removing glutamate from the synaptic cleft. Reduced expression of GLT-1 following chronic cocaine use and abstinence has been reported.

Molecular glues that inhibit deubiquitylase activity and inflammatory signalling.

Deubiquitylases (DUBs) are crucial in cell signalling and are often regulated by interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). As a Zn-dependent JAMM/MPN DUB, BRCC36 is challenging to target with selective inhibitors.

Divergent effects of acute and chronic PPT1 inhibition in melanoma.

Macroautophagy/autophagy-lysosome function promotes growth and survival of cancer cells, making them attractive targets for cancer therapy. One intriguing lysosomal target is PPT1 (palmitoyl-protein thioesterase 1). PPT1 inhibitors derived from chloroquine block autophagy, have significant antitumor activity in preclinical models and are being developed for clinical trials.

HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages.

Unlabelled: HIV establishes long-term latent infection in memory CD4 T cells and also establishes sustained long-term productive infection in macrophages, especially in the central nervous system (CNS). To better understand how HIV sustains infection in macrophages, we performed RNAseq analysis after infection of human monocyte-derived macrophages (MDMs) with the brain-derived HIV-1 strain YU2 and compared this with acute infection of CD4 T cells. HIV infection in MDM and CD4 T cells altered many gene transcripts, but with few overlaps between these different cell types.

The DNA loop release factor WAPL suppresses Epstein-Barr virus latent membrane protein expression to maintain the highly restricted latency I program.

Epstein-Barr virus (EBV) uses latency programs to colonize the memory B-cell reservoir, and each program is associated with human malignancies. However, knowledge remains incomplete of epigenetic mechanisms that maintain the highly restricted latency I program, present in memory and Burkitt lymphoma cells, in which EBNA1 is the only EBV-encoded protein expressed. Given increasing appreciation that higher order chromatin architecture is an important determinant of viral and host gene expression, we investigated roles of Wings Apart-Like Protein Homolog (WAPL), a host factor that unloads cohesin to control DNA loop size and that was discovered as an EBNA2-associated protein.