Background & Aims New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer Methods Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls) Results Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not. Conclusions Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.
The role of the epithelial-to-mesenchymal transition (EMT) during hepatocellular carcinoma (HCC) progression is well established, however the regulatory mechanisms modulating this phenomenon remain unclear. Here, we demonstrate that transcription factor glioma-associated oncogene 1 (GLI1) modulates EMT through direct up-regulation of SNAI1 and serves as a downstream effector of the transforming growth factor-β1 (TGFβ1) pathway, a well-known regulator of EMT in cancer cells. Overexpression of GLI1 increased proliferation, viability, migration, invasion, and colony formation by HCC cells. Conversely, GLI1 knockdown led to a decrease in all the above-mentioned cancer-associated phenotypes in HCC cells. Further analysis of GLI1 regulated cellular functions showed that this transcription factor is able to induce EMT and identified SNAI1 as a transcriptional target of GLI1 mediating this cellular effect in HCC cells. Moreover, we demonstrated that an intact GLI1-SNAI1 axis is required by TGFβ1 to induce EMT in these cells. Together, these findings define a novel cellular mechanism regulated by GLI1, which controls the growth and EMT phenotype in HCC.
The safety and feasibility of dendritic cell (DC)-based immunotherapies in cancer management have been well documented after more than twenty-five years of experimentation, and, by now, undeniably accepted. On the other hand, it is equally evident that DC-based vaccination as monotherapy did not achieve the clinical benefits that were predicted in a number of promising preclinical studies. The current availability of several immune modulatory and targeting approaches opens the way to many potential therapeutic combinations. In particular, the evidence that the immune-related effects that are elicited by immunogenic cell death (ICD)-inducing therapies are strictly associated with DC engagement and activation strongly support the combination of ICD-inducing and DC-based immunotherapies. In this review, we examine the data in recent studies employing tumor cells, killed through ICD induction, in the formulation of anticancer DC-based vaccines. In addition, we discuss the opportunity to combine pharmacologic or physical therapeutic approaches that can promote ICD in vivo with in situ DC vaccination.
Malignant syphilis in a patient infected by human immunodeficiency virus.Case report and literature reviewMalignant syphilis is a rare form of secondary syphilis strongly associated with human immunodeficiency virus infection (HIV). This clinical form of the disease is characterized by atypical cutaneous ulcerative and disseminated lesions and systemic compromise that can delay the final diagnosis. There are only few reports in the medical literature about malignant lues in HIV-infected patients. Malignant syphilis should be considered in the differential diagnosis in HIV-infected patients with fever and ulcerative skin lesions. Here we describe a man who developed clinical cutaneous and systemic manifestations pathologically confirmed as malignant syphilis and we performed a review of the literature. IntroducciónL a sífilis maligna es una forma clínica grave de esta enfermedad que en la actualidad se observa en asociación con la infección por el virus de la inmunodeficiencia humana (VIH). Se caracteriza por manifestaciones clínicas inespecíficas y lesiones cutáneas extensas, polimorfas, destructivas y ulcerativas, algunas con características rupioides, que pueden comprometer la vida del paciente. Las lesiones papulosas, nodulares y ulcerativas pueden estar cubiertas por costras y evolucionan en forma lenta hacia la cicatrización 1,2 . La incidencia global de sífilis secundaria maligna es baja; Shulkin y cols. 3 identificaron sólo 14 casos publicados en la literatura científica en idioma inglés entre los años 1900 y 1988. Sin embargo, a partir de la epidemia de VIH/ SIDA la incidencia se ha incrementado, sugiriendo que la infección por el retrovirus podría ser un factor de riesgo para desarrollar esta forma clínica 4,5 .Se presenta un paciente con infección por VIH con un cuadro clínico de sífilis maligna, diagnóstico confirmado por los hallazgos histopatológicos de una biopsia cutánea y que respondió favorablemente al tratamiento con penicilina. Caso clínicoPaciente varón, heterosexual, con diagnóstico de infección por VIH dos años antes, ocasión en que presentó una tuberculosis pulmonar. En ese momento, el VDRL era negativo y no refería antecedentes de otras infecciones de transmisión sexual. El paciente completó tratamiento antituberculoso con buena respuesta; al mes de iniciado el mismo, con una carga viral para VIH de 2.241 céls/ ml (log 10 3,35) y un recuento de linfocitos T CD4 de 354 céls/ml, comenzó con tratamiento anti-retroviral con zidovudina, lamivudina y efavirenz que abandonó un mes después. Fue internado por presentar compromiso del estado general con fiebre intermitente, artralgias, mialgias y lesiones cutáneas diseminadas, pápulo-nodulares y algunas ulceradas, en el tronco, cara y extremidades y lesiones maculares palmo-plantares de tres semanas de evolución. Algunas lesiones se encontraban cubiertas de costras (Figuras 1, 2 y 3). El examen de la mucosa oral, genital y anal no evidenció lesiones; el examen oftalmológico y la evaluación neurológica fueron normales. Los estudios de laboratorio i...
Photodynamic therapy (PDT), a promising treatment option for cancer, involves the activation of a photosensitizer (PS) by local irradiation with visible light. Excitation of the PS leads to a series of photochemical reactions and consequently the local generation of harmful reactive oxygen species (ROS) causing limited or none systemic defects. However, the development of resistance to this promising therapy has slowed down its translation into the clinical practice. Thus, there is an increase need in understanding of the molecular mechanism underlying resistance to PDT. Here, we aimed to examine whether a relationship exists between PDT outcome and ROS-involvement in the resistance mechanism in photosensitized cancer cells. In order to recapitulate tumor architecture of the respective original tumor, we developed a multicellular three-dimensional spheroid system comprising a normoxic periphery, surrounding a hypoxic core. Using Me-ALA, a prodrug of the PS PpIX, in human colorectal spheroids we demonstrate that HIF-1 transcriptional activity was strongly up-regulated and mediates PDT resistant phenotype. RNAi knockdown of HIF-1 impairs resistance to PDT. Oxidative stress-mediated activation of ERK1/2 followed PDT was involved on positive modulation of HIF-1 transcriptional activity after photodynamic treatment. ROS scavenging and MEK/ERK pathway inhibition abrogated the PDT-mediated HIF-1 upregulation. Together our data demonstrate that resistance to PDT is in part mediated by the activation of a ROS-ERK1/2-HIF-1 axis, thus, identifying novel therapeutic targets that could be used in combination with PDT.
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