36 research outputs found

    Activation of Host Translational Control Pathways by a Viral Developmental Switch

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    In response to numerous signals, latent herpesvirus genomes abruptly switch their developmental program, aborting stable host–cell colonization in favor of productive viral replication that ultimately destroys the cell. To achieve a rapid gene expression transition, newly minted capped, polyadenylated viral mRNAs must engage and reprogram the cellular translational apparatus. While transcriptional responses of viral genomes undergoing lytic reactivation have been amply documented, roles for cellular translational control pathways in enabling the latent-lytic switch have not been described. Using PEL-derived B-cells naturally infected with KSHV as a model, we define efficient reactivation conditions and demonstrate that reactivation substantially changes the protein synthesis profile. New polypeptide synthesis correlates with 4E-BP1 translational repressor inactivation, nuclear PABP accumulation, eIF4F assembly, and phosphorylation of the cap-binding protein eIF4E by Mnk1. Significantly, inhibiting Mnk1 reduces accumulation of the critical viral transactivator RTA through a post-transcriptional mechanism, limiting downstream lytic protein production, and impairs reactivation efficiency. Thus, herpesvirus reactivation from latency activates the host cap-dependent translation machinery, illustrating the importance of translational regulation in implementing new developmental instructions that drastically alter cell fate

    Indications for locoregional tumor therapies: CRC liver metastases

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    The liver represents the most affected site in patients affected by colorectal carcinoma (mCRC) [1]. More than half cases develop colorectal liver metastases (CLMs) during the evolution of the disease, and about one-quarter occur at the disease onset [1, 2]. To date, the standard treatment of CLM is represented by liver surgery, which has allowed to achieve interesting long-term survival rates (40-60%) [3] in reported series, while it is less than 25% for patients who do not undergo surgery [4]. Unfortunately, most patients (80%), however, are not immediately eligible for surgery [5, 6]. For these patients, surgical treatment may be administered in combination with chemotherapy regimens (+/− target agents) aiming to downsize neoplasm and to allow a surgically and oncologically radical intervention. In addition, the greater effectiveness of the abovementioned new chemotherapeutic options has allowed to revolutionize the liver resection criteria considered until recently, thus widening the proportion of patients able to obtain long-term benefit from surgery. Locoregional liver treatments (including ablative technologies and transarterial treatments) can be considered additional options able to downsize CLMs and have been shown to improve quality of life, prolonging time to local progression and overall survival [7, 8]. Of course, to achieve optimal results, it is necessary to set up a multidisciplinary team, including interventionist radiologists, able to evaluate individual cases in order to select the best therapeutic strategy for each patient

    Dramatic Response of Leptomeningeal Carcinomatosis to Nivolumab in PD-L1 Highly Expressive Non-small Cell Lung Cancer: A Case Report

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    In a patient who had been diagnosed of located squamous cell lung carcinoma, pneumonectomy, and adjuvant chemotherapy were performed. Brain recurrence and subsequent lung metastatic disease were uncontrolled by neurosurgery, holocranial radiotherapy, and first-line chemotherapy. In August 2015, appearance of leptomeningeal carcinomatosis triggered severe clinical deterioration and threatened the patient's life. Anti-PD1 immune checkpoint inhibitor Nivolumab was initiated in an attempt to stop tumor growth, achieving a spectacular brain and pulmonary complete response and clinical improvement, without serious adverse effects. High expression PD-L1 level (100%) was found in the pathological tissue sample. Nivolumab was maintained for more than 2 years and stopped in December 2017 after 28 months of treatment, with no disease evidence. More than 3 years after its onset, the patient maintains an outstanding PS with complete tumor response and no evidence of disease in last surveillance CT scan and brain MRI
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