Membrane Bound Peroxiredoxin-1 Serves as a Biomarker for Detection of Sessile Serrated Adenomas.

Sessile serrated adenomas (SSAs) are premalignant lesions driven by the BRAF mutation to give rise to colorectal cancers (CRCs). They are often missed during white light colonoscopy because of their subtle appearance. Previously, a fluorescently labeled 7mer peptide KCCFPAQ was shown to detect SSAs .

Combinatorial ETS1-dependent control of oncogenic NOTCH1 enhancers in T-cell leukemia.

Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to co-bind Notch response elements.

Kir2.1 Interactome Mapping Uncovers PKP4 as a Modulator of the Kir2.1-Regulated Inward Rectifier Potassium Currents.

Kir2.1, a strong inward rectifier potassium channel encoded by the gene, is a key regulator of the resting membrane potential of the cardiomyocyte and plays an important role in controlling ventricular excitation and action potential duration in the human heart. Mutations in result in inheritable cardiac diseases in humans, the type-1 Andersen-Tawil syndrome (ATS1).

Integrated Imaging Methodology Detects Claudin-1 Expression in Premalignant Nonpolypoid and Polypoid Colonic Epithelium in Mice.

Objectives: Conventional colonoscopy with white light illumination detects colonic adenomas based on structural changes alone and is limited by a high miss rate. We aim to demonstrate an integrated imaging strategy that combines wide-field endoscopy and confocal endomicroscopy in real time to visualize molecular expression patterns in vivo to detect premalignant colonic mucosa.

Methods: A peptide specific for claudin-1 is labeled with Cy5.

Murine Oviductal High-Grade Serous Carcinomas Mirror the Genomic Alterations, Gene Expression Profiles, and Immune Microenvironment of Their Human Counterparts.

Robust preclinical models of ovarian high-grade serous carcinoma (HGSC) are needed to advance our understanding of HGSC pathogenesis and to test novel strategies aimed at improving clinical outcomes for women with the disease. Genetically engineered mouse models of HGSC recapitulating the likely cell of origin (fallopian tube), underlying genetic defects, histology, and biologic behavior of human HGSCs have been developed. However, the degree to which the mouse tumors acquire the somatic genomic changes, gene expression profiles, and immune microenvironment that characterize human HGSCs remains unclear.

Trp53 null and R270H mutant alleles have comparable effects in regulating invasion, metastasis, and gene expression in mouse colon tumorigenesis.

Somatic APC (adenomatous polyposis coli), TP53, KRAS mutations are present in roughly 80%, 60%, and 40%, respectively, of human colorectal cancers (CRCs). Most TP53 mutant alleles in CRCs encode missense mutant proteins with loss-of-function (LOF) of p53's transcriptional activity and dominant negative (DN) effects on wild-type p53 function. Missense mutant p53 proteins have been reported to exert gain-of-function (GOF) effects in cancer.

Lineage tracing suggests that ovarian endosalpingiosis does not result from escape of oviductal epithelium.

Most high-grade serous carcinomas are thought to arise from Fallopian tube epithelium (FTE), but some likely arise outside of the tube, perhaps from ectopic tubal-type epithelium known as endosalpingiosis. Importantly, the origin of endosalpingiosis is poorly understood. The proximity of the tubal fimbriae to the ovaries has led to the proposal that disruptions in the ovarian surface that occur during ovulation may allow detached FTE to implant in the ovary and form tubal-type glands and cysts.

Identification of Tumor Specific Peptide as EpCAM Ligand and Its Potential Diagnostic and Therapeutic Clinical Application.

Tumor targeting agents are being developed for early tumor detection and therapeutics. We previously identified the peptide SNFYMPL (SNF*) and demonstrated its specific binding to human esophageal specimens of high-grade dysplasia (HGD) and adenocarcinoma with imaging ex vivo. Here, we aim to identify the target for this peptide and investigate its potential applications in imaging and drug delivery.

Constitutively Higher Level of GSTT2 in Esophageal Tissues From African Americans Protects Cells Against DNA Damage.

Background & Aims: African American and European American individuals have a similar prevalence of gastroesophageal reflux disease (GERD), yet esophageal adenocarcinoma (EAC) disproportionately affects European American individuals. We investigated whether the esophageal squamous mucosa of African American individuals has features that protect against GERD-induced damage, compared with European American individuals.

Methods: We performed transcriptional profile analysis of esophageal squamous mucosa tissues from 20 African American and 20 European American individuals (24 with no disease and 16 with Barrett's esophagus and/or EAC).

Loss of Impairs Hedgehog-Driven Medulloblastoma Tumorigenesis.

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that has a dual role in cancer, i.e., pro- or anti-tumorigenic, depending on the context.

Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development.

Notch1 signaling must elevate to high levels in order to drive the proliferation of CD4CD8 double-negative (DN) thymocytes and progression to the CD4CD8 double-positive (DP) stage through β-selection. During this critical phase of pre-T-cell development, which is also known as the DN-DP transition, it is unclear whether the Notch1 transcriptional complex strengthens its signal output as a discrete unit or through cofactors. We previously showed that the protein inhibitor of activated STAT-like coactivator Zmiz1 is a context-dependent cofactor of Notch1 in T-cell leukemia.

Multiplexed Targeting of Barrett's Neoplasia with a Heterobivalent Ligand: Imaging Study on Mouse Xenograft in Vivo and Human Specimens ex Vivo.

Esophageal adenocarcinoma (EAC) is a molecularly heterogeneous disease that is rising rapidly in incidence and has poor prognosis. We developed a heterobivalent peptide to target detection of early Barrett's neoplasia by combining monomer heptapeptides specific for either EGFR or ErbB2 in a heterodimer configuration. The structure of a triethylene glycol linker was optimized to maximize binding interactions to the surface receptors on cells.

Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow.

Endothelial cells are a critical component of the bone marrow (BM) stromal network, which maintains and regulates hematopoietic cells. Vascular regeneration precedes, and is necessary for, successful hematopoietic stem cell (HSC) transplantation, the only cure for most hematopoietic diseases. Recent data suggest that mature hematopoietic cells regulate BM stromal-cell function.

Identification and validation of FGFR2 peptide for detection of early Barrett's neoplasia.

The incidence of esophageal adenocarcinoma (EAC) is rising rapidly, and early detection within the precursor state of Barrett's esophagus (BE) is challenged by flat premalignant lesions that are difficult detect with conventional endoscopic surveillance. Overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in progression of BE to EAC, and is a promising imaging target. We used phage display to identify the peptide SRRPASFRTARE that binds specifically to the extracellular domain of FGFR2.

In vivo near-infrared imaging of ErbB2 expressing breast tumors with dual-axes confocal endomicroscopy using a targeted peptide.

ErbB2 expression in early breast cancer can predict tumor aggressiveness and clinical outcomes in large patient populations. Accurate assessment with physical biopsy and conventional pathology can be limited by tumor heterogeneity. We aim to demonstrate real-time optical sectioning using a near-infrared labeled ErbB2 peptide that generates tumor-specific contrast in human xenograft breast tumors in vivo.

RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1.

Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. Upon ligand binding, the Notch intracellular domain (NOTCH ICD) translocates into the nucleus and forms a complex with the transcription factor RBPJ (also known as CBF1 or CSL) to activate expression of Notch target genes. In the absence of a Notch signal, RBPJ acts as a transcriptional repressor.

Ultrasmall Paramagnetic Iron Oxide Nanoprobe Targeting Epidermal Growth Factor Receptor for In Vivo Magnetic Resonance Imaging of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common worldwide cancer that is rising rapidly in incidence. MRI is a powerful noninvasive imaging modality for HCC detection, but lack of specific contrast agents limits visualization of small tumors. EGFR is frequently overexpressed in HCC and is a promising target.

High-grade serous carcinomas arise in the mouse oviduct via defects linked to the human disease.

Recent studies have suggested that the most common and lethal type of 'ovarian' cancer, i.e. high-grade serous carcinoma (HGSC), usually arises from epithelium on the fallopian tube fimbriae, and not from the ovarian surface epithelium.

Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis.

Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy) have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed.

BRAF cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis.

While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or mutations in ~60% of cases and often together (p0.

Detection of Sessile Serrated Adenomas in the Proximal Colon Using Wide-Field Fluorescence Endoscopy.

Background & Aims: Many cancers in the proximal colon develop via from sessile serrated adenomas (SSAs), which have flat, subtle features that are difficult to detect with conventional white-light colonoscopy. Many SSA cells have the V600E mutation in BRAF. We investigated whether this feature could be used with imaging methods to detect SSAs in patients.

Overexpressed Claudin-1 Can Be Visualized Endoscopically in Colonic Adenomas In Vivo.

Background & Aims: Conventional white-light colonoscopy aims to reduce the incidence and mortality of colorectal cancer (CRC). CRC has been found to arise from missed polypoid and flat precancerous lesions. We aimed to establish proof-of-concept for real-time endoscopic imaging of colonic adenomas using a near-infrared peptide that is specific for claudin-1.

In vivo photoacoustic tomography of EGFR overexpressed in hepatocellular carcinoma mouse xenograft.

EGFR is a promising cell surface target for in vivo imaging that is highly overexpressed in hepatocellular carcinoma (HCC), a common cancer worldwide. Peptides penetrate easily into tumors for deep imaging, and clear rapidly from the circulation to minimize background. We aim to demonstrate use of an EGFR specific peptide to detect HCC xenograft tumors in mice with photoacoustic imaging.