Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer.

Background: Over a century ago, Virchow proposed that cancer represents a chronically inflamed, poorly healing wound. Normal wound healing is represented by a transitory phase of inflammation, followed by a pro-resolution phase, with prostaglandin (PGE2/PGD2)-induced 'lipid class switching' producing inflammation-quenching lipoxins (LXA4, LXB4).

Objective: We explored if lipid dysregulation in colorectal cancers (CRCs) is driven by a failure to resolve inflammation.

Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi and SRCi Combination to Induce Apoptosis in Colorectal Cancer.

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. The RAS pathway is activated in more than 55% of CRC and has been targeted for therapeutic intervention with MEK inhibitors. Unfortunately, many patients have de novo resistance, or can develop resistance to this new class of drugs.

An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy.

Background: Over half of colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors, has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms that are not well understood. This study aims to investigate MEK inhibitor-associated resistance signaling and identify subpopulation(s) of CRC patients who may be sensitive to biomarker-driven drug combination(s).

and Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes.

Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that and as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use and mutations (AP) to refine the CMS classification to better predict responses to cetuximab.

PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC.

PTPRS is the most commonly mutated receptor tyrosine phosphatase in colorectal cancer (CRC). PTPRS has been shown to directly affect ERK and regulate its activation and nuclear localization. Here we identify that PTPRS may play a significant role in developing adaptive resistance to MEK/ERK inhibitors (MEKi/ERKi) through SRC activation.

PTPRS Regulates Colorectal Cancer RAS Pathway Activity by Inactivating Erk and Preventing Its Nuclear Translocation.

Colorectal cancer (CRC) growth and progression is frequently driven by RAS pathway activation through upstream growth factor receptor activation or through mutational activation of KRAS or BRAF. Here we describe an additional mechanism by which the RAS pathway may be modulated in CRC. PTPRS, a receptor-type protein tyrosine phosphatase, appears to regulate RAS pathway activation through ERK.

Angiopoietin-like-4 and minimal change disease.

Background: Minimal Change Disease (MCD) is the most common type of nephrotic syndrome in children. Angiopoietin-like-4 (Angplt4) has been proposed as mediator of proteinuria in MCD. The aim of this study was to evaluate the role of Angptl4 as a biomarker in MCD.

Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis.

Background: Minimal Change Disease (MCD) in relapse is associated with increased podocyte CD80 expression and elevated urinary CD80 excretion, whereas focal segmental glomerulosclerosis (FSGS) has mild or absent CD80 podocyte expression and normal urinary CD80 excretion.

Methods: One patient with MCD, one patient with primary FSGS and three patients with recurrent FSGS after transplantation received CD80 blocking antibodies (abatacept or belatacept). Urinary CD80 and CTLA-4 levels were measured by ELISA.

Minimal change disease: a dysregulation of the podocyte CD80-CTLA-4 axis?

Background: Minimal Change Disease (MCD) is associated with CD80 expression in podocytes and elevated urinary CD80 excretion during active renal disease. We have evaluated the urinary excretion of CTLA-4 and CD80 during different stages of the nephrotic syndrome in patients with MCD to test the hypothesis that persistent increased urinary CD80 excretion in patients with MCD in relapse is due to an ineffectual CTLA-4 response of the host to curtail the activation of CD80.

Methods: Thirty-two children with biopsy-proven MCD were studied during relapse and/or remission.

Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes.

Background: Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children and is associated with the expression of CD80 in podocytes and the increased excretion of CD80 in urine. We hypothesized that serum from patients with MCD might stimulate CD80 expression in cultured podocytes.

Methods: Sera and peripheral blood mononuclear cells (PBMCs) were collected from subjects with MCD in relapse and remission and from normal controls.

Restraint of angiogenesis by zinc finger transcription factor CTCF-dependent chromatin insulation.

Angiogenesis is meticulously controlled by a fine balance between positive and negative regulatory activities. Vascular endothelial growth factor (VEGF) is a predominant angiogenic factor and its dosage is precisely regulated during normal vascular formation. In cancer, VEGF is commonly overproduced, resulting in abnormal neovascularization.

Response of estrogen receptor-positive breast cancer tumorspheres to antiestrogen treatments.

Estrogen signaling plays a critical role in the pathogenesis of breast cancer. Because the majority of breast carcinomas express the estrogen receptor ERα, endocrine therapy that impedes estrogen-ER signaling reduces breast cancer mortality and has become a mainstay of breast cancer treatment. However, patients remain at continued risk of relapse for many years after endocrine treatment.

Involvement of estrogen-related receptors in transcriptional response to hypoxia and growth of solid tumors.

The development of intratumoral hypoxia is a universal hallmark of rapidly growing solid tumors. Adaptation to the hypoxic environment, which is critical for tumor cell survival and growth, is mediated primarily through a hypoxia-inducible factor (HIF)-dependent transcriptional program. HIF activates genes that facilitate crucial adaptive mechanisms including increased glucose uptake and glycolysis and tumor angiogenesis, making it an important therapeutic target.

Protein kinase C epsilon is overexpressed in primary human non-small cell lung cancers and functionally required for proliferation of non-small cell lung cancer cells in a p21/Cip1-dependent manner.

The protein kinase C (PKC) family of proteins plays important roles in growth regulation and is implicated in tumorigenesis. It has become clear that the role of PKC in tumorigenesis is cell context dependent and/or isoform specific. In this study, we showed for the first time by immunohistochemistry that overexpression of PKC epsilon was detected in the vast majority (>90%) of primary human non-small cell lung cancers (NSCLC) compared with normal lung epithelium.

Genetic relationships and evolution of genotypes of yellow fever virus and other members of the yellow fever virus group within the Flavivirus genus based on the 3' noncoding region.

Genetic relationships among flaviviruses within the yellow fever (YF) virus genetic group were investigated by comparing nucleotide sequences of the 3' noncoding region (3'NCR). Size heterogeneity was observed between members and even among strains of the same viral species. Size variation between YF strains was due to duplications and/or deletions of repeated nucleotide sequence elements (RYF).

Cooperation between PKC-alpha and PKC-epsilon in the regulation of JNK activation in human lung cancer cells.

Phorbol esters can induce activation of two mitogen-activated protein kinase (MAPK) pathways, the extracellular signal-regulated kinase (ERK) pathway and the c-Jun N-terminal kinase (JNK) pathway. Unlike ERK activation, JNK activation by phorbol esters is somehow cell-specific. However, the mechanism(s) that contribute to the cell-specific JNK activation remain elusive.

Enzootic transmission of yellow fever virus in Peru.

The prevailing paradigm of yellow fever virus (YFV) ecology in South America is that of wandering epizootics. The virus is believed to move from place to place in epizootic waves involving monkeys and mosquitoes, rather than persistently circulating within particular locales. After a large outbreak of YFV illness in Peru in 1995, we used phylogenetic analyses of virus isolates to reexamine the hypothesis of virus movement.

Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway.

The serine/threonine protein kinase C (PKC) has been implicated in the regulation of drug resistance and cell survival in many types of cancer cells. However, the one or more precise mechanisms remain elusive. In this study, we have identified and determined the mechanism by which PKC-epsilon, a novel PKC isoform, modulates drug resistance in lung cancer cells.

Phylogeny of the Simbu serogroup of the genus Bunyavirus.

The Simbu serogroup of the genus Bunyavirus, family Bunyaviridae contains 25 viruses. Previous serological studies provided important information regarding some but not all of the relationships among Simbu serogroup viruses. This report describes the nucleotide sequence determination of the nucleocapsid (N) gene of the small genomic segment of 14 Simbu serogroup viruses and partial nucleotide sequence determination of the G2 glycoprotein-coding region (encoded by the medium RNA segment) of 19 viruses.