Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbed non-tyrosine kinase oncogenes and pathways and detected a significant up-regulation of tyrosine phosphorylation at the carcinoma stage. Phosphotyrosine peptide enrichment and quantitative mass spectrometry identified oncogene-specific tyrosine kinase signatures, including activation of EGFR, ephrin type-A receptor 2 (EPHA2), and JAK2. Kinase:substrate relationship analysis of the phosphopeptides also revealed ABL1 and SRC tyrosine kinase activation. The observation of elevated tyrosine kinase signaling in advanced prostate cancer and identification of specific tyrosine kinase pathways from genetically defined tumor models point to unique therapeutic approaches using tyrosine kinase inhibitors for advanced prostate cancer.AKT | androgen receptor | ERG | K-RAS | bioinformatics

Burkitt lymphoma (BL) is a highly aggressive, rapidly growing B cell non-Hodgkin lymphoma, which manifests in several subtypes including sporadic, endemic, and immunodeficiency-associated forms. Pathologically, BL is classically characterized by translocations of chromosomes 8 and 14 resulting in upregulation of the c-myc protein transcription factor with upregulation of cell proliferation. BL affects nearly every organ system, most commonly the abdomen and pelvis in the sporadic form. Imaging using a multimodality approach plays a crucial role in the management of BL from diagnosis, staging, and evaluation of treatment response to therapy-related complications with ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography playing roles. In this article, we review the pathobiology and classification of BL, illustrate a multimodality imaging approach in evaluating common and uncommon sites of involvement within the trunk and head and neck, and review common therapies and treatment-related complications.

Owing to the urgent need for more effective treatment against nicotine addiction, a hybrid nanoparticle-based nicotine vaccine (NanoNiccine) was developed in this study. NanoNiccine was composed of a poly(lactide-co-glycolide) acid (PLGA) core, keyhole limpet hemocyanin (KLH) as an adjuvant protein enclosed within the PLGA core, a lipid layer, and nicotine haptens conjugated to the outer surface of the lipid layer. In contrast to the traditional nicotine vaccine, NanoNiccine is not a nicotine-protein conjugate vaccine. Instead, the nicotine hapten and protein are separately located in the nanostructure to minimize antibody production towards KLH. The cellular uptake study demonstrated that NanoNiccine was ideal for internalization and processing by dendritic cells (DCs). Mice immunized with NanoNiccine produced much lower IgG level against KLH as compared to that immunized with the traditional nicotine-KLH (Nic-KLH) vaccine. In addition, NanoNiccine achieved up to a 400% higher titer of anti-nicotine IgG than the positive control, Nic-KLH. Additionally, the Th1/Th2 index of NanoNiccine suggested that the immune response induced by NanoNiccine was antibody response dominant. Furthermore, NanoNiccine was found to be safe in mice.

Src family kinases (SFKs) are pleiotropic activators that are responsible for integrating signal transduction for multiple receptors that regulate cellular proliferation, invasion, and metastasis in a variety of human cancers. Independent groups have identified increased expression of individual SFK members during prostate cancer progression, raising the question of whether SFKs display functional equivalence. Here, we show that Src kinase, followed by Fyn kinase and then Lyn kinase, exhibit ranked tumorigenic potential during both paracrine-induced and cell-autonomousinitiated prostate cancer. This quantitative variation in transformation potential appears to be regulated in part by posttranslational palmitoylation. Our data indicate that development of inhibitors against specific SFK members could provide unique targeted therapeutic strategies.paracrine FGF10 signaling | tyrosine kinase | tissue regeneration S rc family kinases (SFKs) are a group of nonreceptor tyrosine kinases composed of nine highly homologous members with four conserved protein domains (1). All SFK members have an SH4 domain that mediates membrane association via myristoylation and, depending on the SFK, palmitoylation, as well as SH3 and SH2 domains that mediate inter-and intramolecular interactions, and finally the SH1 kinase domain (1). SFKs represent central convergence points for multiple receptors and cellautonomous signaling pathways that mediate enhanced cellular proliferation, cell migration, and metastatic potential in cancer progression (1, 2). Drug resistance and failure to efficiently inhibit SFKs have spurred the development of a new generation of SRC inhibitors that are currently in clinical trials. These drugs represent a prospectively efficacious therapeutic strategy against numerous solid malignancies and second-line treatment of leukemia (3). However, due to the high homology of SFK members and kinase domains conserved in numerous receptor tyrosine kinases, these inhibitors targeting Src kinase and BCR/ABL also inhibit other SFK members and/or several receptor tyrosine kinases (3). Off-target effects by these drugs can impair normal tissue function, leading to clinically adverse symptoms including diarrhea, rash, and cardiac toxicity (4, 5).Despite structural similarities, individual SFK members have specific cellular functions in normal development. Genetic knockout of Src, Lyn, or Fyn kinases in mice and derivative cells, respectively, exhibit defects in the development of bone, peripheral B cells, or T-cell receptor signaling (6-8). The specificity of individual SFK members may rely on their preferential association with cell surface receptors. For example, c-Src, but not Fyn or Lyn, is associated with α IIb β 3 integrin in blood platelet signal cascades (9). In contrast, Lyn and Fyn, but not Src, are preferentially recruited to the Fc receptor γ-chain and mediate platelet glycoprotein VI receptor signal transduction (10). In human glioblastoma cells, cooperation of integrin α v β 3 with platelet-derived growth factor ...

The Smads are the signaling mediators of the TGFb superfamily. In the present study, we examined Smad expression in mouse epidermis and chemically-induced skin tumors. Mutations in Smad2 and -4 genes were also screened. Transcripts of Smad1 through -5 were constantly expressed in the epidermis regardless of changes in TGFb signaling, state of dierentiation and stages of carcinogenesis. Smad7 transcripts were barely detectable in keratinocytes, but were induced by TGFb1 treatment and in chemically-induced skin tumors. At the protein level, Smad1 was detected throughout the epidermis, whereas Smad2 through -5 exhibited greater levels in suprabasal layers than basal keratinocytes. In cultured keratinocytes, Smad2, -3 and -4 underwent nuclear translocation upon TGFb1 treatment. Furthermore, nuclear translocation of Smads correlated with decreased BrdU labeling in proliferative keratinocytes. Although no mutations were detected in the Smad2 and -4 genes in tumors, proteins of Smad1 through -5 were partially or completely lost in carcinomas. These data document that Smads are expressed at high levels in the epidermis and mediate signaling of the TGFb superfamily. During skin carcinogenesis, loss of Smad1 through -5 and overexpression of Smad7 may contribute to the loss of growth inhibition mediated by TGFb superfamily members, thus resulting in tumor progression. Oncogene (2001) 20, 471 ± 483.

A high-throughput screen of the NIH-MLSMR compound collection, along with a series of secondary assays to identify potential targets of hit compounds, previously identified a 1,3-diaminobenzene scaffold that targets protease-activated receptor 1 (PAR1). We now report additional structure–activity relationship (SAR) studies that delineate the requirements for activity at PAR1 and identify plasma-stable analogues with nanomolar inhibition of PAR1-mediated platelet activation. Compound 4 was declared as a probe (ML161) with the NIH Molecular Libraries Program. This compound inhibited platelet aggregation induced by a PAR1 peptide agonist or by thrombin but not by several other platelet agonists. Initial studies suggest that ML161 is an allosteric inhibitor of PAR1. These findings may be important for the discovery of antithrombotics with an improved safety profile.

Progesterone, an agonist for the progesterone receptor (PR), can be an efficacious and well-tolerated treatment in endometrial cancer. The clinical use of progesterone is limited due to the lack of biomarkers that predict hormone sensitivity. Despite its efficacy in cancer therapy, mechanisms and site of action for progesterone remain unknown. Using an in vivo endometrial cancer mouse model driven by clinically relevant genetic changes but dichotomous responses to hormonal therapy, we demonstrate that signaling through stromal PR is necessary and sufficient for progesterone anti-tumor effects. Endometrial cancers resulting from epithelial loss of PTEN (PTENKO) were hormone sensitive and had abundant expression of stromal PR. Stromal deletion of PR as a single genetic change in these tumors induced progesterone resistance indicating that paracrine signaling through the stroma is essential for the progesterone therapeutic effects. A hormone refractory endometrial tumor with low levels of stromal PR developed when activation of KRAS was coupled with PTEN-loss (PTENKO/Kras). The innate progesterone resistance in PTENKO/Kras tumors stemmed from methylation of PR in the tumor microenvironment. Add-back of stromal PR expressed from a constitutively active promoter sensitized these tumors to progesterone therapy. Results demonstrate that signaling through stromal PR is sufficient for inducing hormone responsiveness. Our findings suggest that epigenetic de-repression of stromal PR could be a potential therapeutic target for sensitizing hormone refractory endometrial tumors to progesterone therapy. Based on these results, stromal expression of PR may emerge as a reliable biomarker in predicting response to hormonal therapy.

Non-dysplastic mucosa (ND-) in Barrett's esophagus (BE) shows clonal molecular aberrations, loss of cell cycle control, and other features of "neoplasia." These changes occur prior to morphologic expression of neoplasia (dysplasia). Morphologic evaluation of dysplasia is fraught with error, and, as a result, often leads to false-negative and false-positive diagnoses. Early "crypt dysplasia" is difficult to detect, and is often missed in routine biopsy specimens. Some studies show substantial progression rates of low-grade dysplasia (LGD), and crypt dysplasia, to esophageal adenocarcinoma (EAC). Dysplasia, even when fully developed, may, in certain circumstances, be difficult to differentiate from non-dysplastic (regenerating) BE. Radiofrequency ablation (RFA) is a safe and effective method for removing mucosa at risk of cancer. Given the difficulties of dysplasia assessment in mucosal biopsies, and the molecular characteristics of ND-BE, this technique should be considered for treatment of all BE patients, including those with ND or LGD. Post-ablation neo-squamous epithelium reveals no molecular abnormalities, and is biologically stable. Given that prospective randomized controlled trials of ablative therapy for ND-BE aiming at reducing EAC incidence and mortality are unlikely to be completed in the near future, endoscopic ablation is a valid management option. The success of RFA in achieving safe, uniform, reliable, and predictable elimination of BE allows surgeons to combine fundoplication with RFA. Currently, there is no type of treatment for dysplastic or non-dysplastic BE that achieves a complete response in 100% of patients, eliminates all risk of developing cancer, results in zero adverse events, is less expensive in terms of absolute costs than surveillance, is durable for 20+ years, or eliminates the need for surveillance. Regardless, RFA shows established safety, efficacy, durability, and cost-effective profiles that should be considered in the management of patients with non-dysplastic or low-grade dysplastic BE.