Transcription factor expression repertoire basis for epigenetic and transcriptional subtypes of colorectal cancers.

Colorectal cancers (CRCs) form a heterogenous group classified into epigenetic and transcriptional subtypes. The basis for the epigenetic subtypes, exemplified by varying degrees of promoter DNA hypermethylation, and its relation to the transcriptional subtypes is not well understood. We link cancer-specific transcription factor (TF) expression alterations to methylation alterations near TF-binding sites at promoter and enhancer regions in CRCs and their premalignant precursor lesions to provide mechanistic insights into the origins and evolution of the CRC molecular subtypes.

A Rare Red Herring: Intrahepatic Splenosis Masquerading as Hepatocellular Carcinoma.

Splenosis is defined as viable splenic tissue that is autotransplanted into other compartments in the body. Intrahepatic splenosis is a rare diagnosis that can be difficult for clinicians to identify. The most common causes of splenosis include abdominal trauma and splenectomy.

Pancreatoblastoma in Elderly Adults: Report of Two Patients.

. Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas, which often shows multiple lines of differentiation, but is defined by neoplastic cells with acinar differentiation and characteristic squamoid nests. Pediatric patients are most commonly affected, and although a subset is known to occur in adults, the diagnosis is rarely considered in elderly adults.

Pediatric autoimmune gastritis: clinical correlates and histologic features.

Autoimmune gastritis is a well-known pathologic entity, but there are few studies that examine its clinical and histologic presentation in children. This is a single institution, retrospective study performed on patients diagnosed from 2011 through 2019. Patients were identified by their pathologic diagnosis within the laboratory information system.

Lenalidomide-Associated Secondary B-Lymphoblastic Leukemia/Lymphoma-A Unique Entity.

Objectives: Autologous stem cell transplant with lenalidomide maintenance therapy has greatly improved the relapse-free and overall survival rates of patients with multiple myeloma but also has been associated with an increased risk of secondary B-lymphoblastic leukemia/lymphoma (B-ALL).

Methods: We report a comprehensive review of the clinicopathologic features of 2 patients with multiple myeloma who developed secondary B-ALL during lenalidomide maintenance.

Results: Our observations showed that the disease may initially present with subtle clinical, morphologic, and flow-cytometric findings.

Smart Glasses as a Surgical Pathology Grossing Tool.

Context.—: Smart glasses are a wearable technology that enable hands-free data acquisition and entry.

Objective.

Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase.

Spatiotemporal control of Wnt/β-catenin signaling is critical for organism development and homeostasis. The poly-(ADP)-ribose polymerase Tankyrase (TNKS1) promotes Wnt/β-catenin signaling through PARylation-mediated degradation of AXIN1, a component of the β-catenin destruction complex. Although Wnt/β-catenin is a niche-restricted signaling program, tissue-specific factors that regulate TNKS1 are not known.

Regulation of tankyrase activity by a catalytic domain dimer interface.

Tankyrases (TNKS and TNKS2) are enzymes that catalyze poly-ADP-ribosylation (PARsylation) of their target proteins. Tankyrase-mediated PARsylation plays critical regulatory roles in cell signaling, particularly in the Wnt/β-catenin pathway. The sterile alpha motif (SAM) domain in tankyrases mediates their oligomerization, which is essential for tankyrase function.

Role of the Exocyst Complex Component Sec6/8 in Genomic Stability.

The exocyst is a heterooctomeric complex well appreciated for its role in the dynamic assembly of specialized membrane domains. Accumulating evidence indicates that this macromolecular machine also serves as a physical platform that coordinates regulatory cascades supporting biological systems such as host defense signaling, cell fate, and energy homeostasis. The isolation of multiple components of the DNA damage response (DDR) as exocyst-interacting proteins, together with the identification of Sec8 as a suppressor of the p53 response, suggested functional interactions between the exocyst and the DDR.

Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells.

Maintenance of chromosomal ends (telomeres) directly contributes to cancer cell immortalization. The telomere protection enzymes belonging to the tankyrase (Tnks) subfamily of poly(ADP-ribose) polymerases (PARPs) have recently been shown to also control transcriptional response to secreted Wnt signaling molecules. Whereas Tnks inhibitors are currently being developed as therapeutic agents for targeting Wnt-related cancers and as modulators of Wnt signaling in tissue-engineering agendas, their impact on telomere length maintenance remains unclear.

Identification of therapeutic small-molecule leads in cultured cells using multiplexed pathway reporter readouts.

The rapid expansion of molecular screening libraries in size and complexity in the last decade has outpaced the discovery rate of cost-effective strategies to single out reagents with sought-after cellular activities. In addition to representing high-priority therapeutic targets, intensely studied cell signaling systems encapsulate robust reference points for mapping novel chemical activities given our deep understanding of the molecular mechanisms that support their activity. In this chapter, we describe strategies for using transcriptional reporters of several well-interrogated signal transduction pathways coupled with high-throughput biochemical assays to fingerprint novel compounds for drug target identification agendas.

A multiplexed luciferase-based screening platform for interrogating cancer-associated signal transduction in cultured cells.

Genome-scale interrogation of gene function using RNA interference (RNAi) holds tremendous promise for the rapid identification of chemically tractable cancer cell vulnerabilities. Limiting the potential of this technology is the inability to rapidly delineate the mechanistic basis of phenotypic outcomes and thus inform the development of molecularly targeted therapeutic strategies. We outline here methods to deconstruct cellular phenotypes induced by RNAi-mediated gene targeting using multiplexed reporter systems that allow monitoring of key cancer cell-associated processes.