Smoothened (SMO) receptor mutations dictate resistance to\ua0vismodegib in basal cell carcinoma

Basal cell carcinomas (BCCs) and a subset of medulloblastomas are characterized by loss- of-function mutations in the tumor suppressor gene, PTCH1. PTCH1 normally functions by repressing the activity of the Smoothened (SMO) receptor. Inactivating PTCH1 mutations result in constitutive Hedgehog pathway activity through uncontrolled SMO signaling. Tar- geting this pathway with vismodegib, a novel SMO inhibitor, results in impressive tumor regression in patients harboring genetic defects in this pathway. However, a secondary mutation in SMO has been reported in medulloblastoma patients following relapse on vis- modegib to date. This mutation preserves pathway activity, but appears to confer resis- tance by interfering with drug binding. Here we report for the first time on the molecular mechanisms of resistance to vismodegib in two BCC cases. The first case, showing progression after 2 months of continuous vismo- degib (primary resistance), exhibited the new SMO G497W mutation. The second case, showing a complete clinical response after 5 months of treatment and a subsequent pro- gression after 11 months on vismodegib (secondary resistance), exhibited a PTCH1 nonsense mutation in both the pre- and the post-treatment specimens, and the SMO D473Y mutation in the post-treatment specimens only. In silico analysis demonstrated that SMOG497W undergoes a conformational rearrangement resulting in a partial obstruc- tion of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mech- anisms leading to primary and secondary resistance to vismodegib, respectively

Cytogenetic analysis of human cells reveals specific patterns of DNA damage in replicative and oncogene‐induced senescence

Summary Senescence is thought to be triggered by DNA damage, usually indirectly assessed as activation of the DNA damage response (DDR), but direct surveys of genetic damage are lacking. Here, we mitotically reactivate senescent human fibroblasts to evaluate their cytogenetic damage. We show that replicative senescence is generally characterized by telomeric fusions. However, both telomeric and extratelomeric aberrations are prevented by hTERT, indicating that even non-telomeric damage descends from the lack of telomerase. Compared with replicative senescent cells, oncogene-induced senescent fibroblasts display significantly higher levels of DNA damage, depicting how oncogene activation can catalyze the generation of further, potentially tumorigenic, genetic damage

The future search for low-frequency axions and new physics with the FLASH resonant cavity experiment at Frascati National Laboratories

We present a proposal for a new experiment, the FINUDA magnet for Light Axion SearcH (FLASH), a large resonant-cavity haloscope in a high static magnetic field which is planned to probe new physics in the form of dark matter (DM) axions, scalar fields, chameleons, hidden photons, as well as high frequency gravitational waves (GWs). Concerning the QCD axion, FLASH will search for these particles as the DM in the mass range (0.49-1.49) ueV, thus filling the mass gap between the ranges covered by other planned searches. A dedicated Microstrip SQUID operating at ultra-cryogenic temperatures will amplify the signal. The frequency range accessible overlaps with the Very High Frequency (VHF) range of the radio wave spectrum and allows for a search in GWs in the frequency range (100-300) MHz. The experiment will make use of the cryogenic plant and magnet of the FINUDA experiment at INFN Frascati National Laboratories near Rome (Italy); the operations needed to restore the functionalities of the apparatus are currently underway. We present the setup of the experiment and the sensitivity forecasts for the detection of axions, scalar fields, chameleons, hidden photons, and GWs

OUTCOMES OF ELDERLY PATIENTS WITH ST-ELEVATION OR NON-ST-ELEVATION ACUTE CORONARY SYNDROME UNDERGOING PERCUTANEOUS CORONARY INTERVENTION

Acute coronary syndromes have been classified according to the finding of ST-segment elevation on the presenting ECG, with different treatment strategies and practice guidelines. However, a comparative description of the clinical characteristics and outcomes of acute coronary syndrome elderly patients undergoing percutaneous coronary intervention during index admission has not been published so far

Patterns of recurrences in sinonasal cancers undergoing an endoscopic surgery-based treatment: Results of the MUSES* on 940 patients: *MUlti-institutional collaborative Study on Endoscopically treated Sinonasal cancers

The improvements in survival with expansion of the survivors' population, along with evolution of endoscopically-based treatment modalities, have contributed to emphasize the clinical relevance of recurrences in sinonasal cancers. However, at present, literature is scant regarding the pattern of recurrences and the therapeutic strategies available to manage long survivors who experienced single or multiple failures. The aim of the present study was to analyze sinonasal cancers recurrences to provide data regarding rates and patterns of relapse, predictors of failure and prognostic impact of the recurrence

Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications

Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined

Dark sectors 2016 Workshop: community report

This report, based on the Dark Sectors workshop at SLAC in April 2016, summarizes the scientific importance of searches for dark sector dark matter and forces at masses beneath the weak-scale, the status of this broad international field, the important milestones motivating future exploration, and promising experimental opportunities to reach these milestones over the next 5-10 years