Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL.

Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance.

Oil uptake via marine snow: Effects on blue mussels (Mytilus sp.).

Accidental oil spills into the ocean can lead to downward transport and settling of oil onto the seafloor as part of marine snow, as seen during the Deepwater Horizon incident in 2010 in the Gulf of Mexico. The arctic and subarctic regions may favor conditions leading to this benthic oil deposition, prompting questions about the potential impacts on benthic communities. This study investigated the effects of oil-contaminated marine snow uptake on the blue mussel (Mytilus sp.

Quantitative review summarizing the effects of oil pollution on subarctic and arctic marine invertebrates.

While meta-analyses are common in the health and some biological sciences, there is a lack of such analyses for petroleum-related marine research. Oil is a highly complex substance consisting of thousands of different compounds. Measurement limitations, different protocols and a lack of standards in recording and reporting various elements of laboratory experiments impede attempts to homogenize and compare data and identify trends.

Longitudinal analyses of CLL in mice identify leukemia-related clonal changes including a Myc gain predicting poor outcome in patients.

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of TCL1 in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1 mice suggesting that TCL1 overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-TCL1 mice.

IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia.

Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio.

IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.

Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes.

Dissecting the Prognostic Significance and Functional Role of Progranulin in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is known for its strong dependency on the tumor microenvironment. We found progranulin (GRN), a protein that has been linked to inflammation and cancer, to be upregulated in the serum of CLL patients compared to healthy controls, and increased GRN levels to be associated with an increased hazard for disease progression and death. This raised the question of whether GRN is a functional driver of CLL.

IGF2 knockdown in two colorectal cancer cell lines decreases survival, adhesion and modulates survival-associated genes.

Increased expression of insulin-like growth factor 2 (IGF2) is found in tumors of colorectal cancer (CRC) patients exhibiting a gained region on chromosome 11q15 and is implicated in poor patient survival. This study analyzes in vitro phenotypic- and gene expression changes associated with IGF2 shRNA-mediated knockdown. Initially, doxycycline inducible IGF2 knockdown cell lines were generated in the CRC cell lines SW480 and LS174T.

Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo.

Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo.

CITED4 gene silencing in colorectal cancer cells modulates adherens/tight junction gene expression and reduces cell proliferation.

Purpose: CITED4 is one member of a family of transcriptional cofactors, several of which are deregulated in a variety of tumors, including colorectal cancer (CRC). We modulated CITED4 expression, in vitro, and analyzed the associated phenotypic and gene expression changes.

Methods: CITED4-overexpressing and shRNA-mediated knockdown cell lines and control cell lines were established in the CRC cell line SW480.

Thrombospondin 1 and its mimetic peptide ABT-510 decrease angiogenesis and inflammation in a murine model of inflammatory bowel disease.

Objective: Vascular abnormalities and expression of proangiogenic factors have been repeatedly reported in inflammatory bowel disease (IBD). Thrombospondin 1 (TSP-1) is a protein well known for its antiangiogenic and anti-inflammatory properties. Using the dextran sulfate sodium (DSS) model, the role of TSP-1 in IBD has been investigated in vivo.

Early-passage rat lung fibroblasts do not migrate in vitro to transforming growth factor-beta.

Lung fibrosis has been postulated to be mediated by the production of macrophage-derived growth factors that are both mitogenic and chemotactic for fibroblasts. In vitro studies from our laboratory demonstrated that alveolar and interstitial macrophages treated with iron and asbestos release platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) into the media. This conditioned media was capable of inducing proliferation and chemotaxis of primary rat lung fibroblasts (RLF).

Interstitial pulmonary macrophages produce platelet-derived growth factor that stimulates rat lung fibroblast proliferation in vitro.

Alveolar macrophages from humans and several animal species produce factors in vitro that modulate fibroblast growth and have been proposed as mediators of interstitial pulmonary fibrosis. Pulmonary interstitial macrophages (IMs) have not been studied previously in this regard. Pulmonary IMs were isolated from prelavaged rat lungs by enzymatic digestion of tissue and subsequent differential adherence of cells to culture dishes.

Receptors for transforming growth factor-beta (TGF-beta) on rat lung fibroblasts have higher affinity for TGF-beta 1 than for TGF-beta 2.

Most cell types have receptors for transforming growth factor-beta (TGF-beta) and respond similarly to TGF-beta 1 and TGF-beta 2. We have demonstrated the presence of a single class of high-affinity receptors (approximately 10,000 sites/cell) for TGF-beta 1 (Kd = 23 pM) and TGF-beta 2 (Kd = 41 pM) on early-passage rat lung fibroblasts (RLF). Incubation with unlabeled TGF-beta 1 and TGF-beta 2 resulted in concentration-dependent inhibition of binding of 15 pM [125I]TGF-beta 1 (ED50, 20 and 28 pM, respectively) and [125I]TGF-beta 2 (ED50, 36 and 56 pM, respectively).

A glial high-affinity binding site with specificity for angiotensin II not angiotensin III: a possible N-terminal-specific converting enzyme.

Anomalous binding properties of angiotensin II to fetal rat brain primary cultures suggested a possible contribution from contaminating glia. To investigate this possibility, cultures of C6 glioma, a clonal rat cell line, were examined for the presence of angiotensin II receptors. A specific high-affinity site for [125I]angiotensin II was measured both by traditional methodology using whole cells and by autoradiography.

Cycloheximide causes accumulation of insulin receptors at the cell surface of cultured fibroblasts.

Incubation of confluent cultures of mouse fibroblasts with cycloheximide caused a time-dependent increase in the binding of 125I-insulin. The increase was concentration-dependent between 0.05 and 3.