Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788

Anaplastic Thyroid Carcinoma (ATC) is one of the most aggressive human malignancies with a mean survival of only 6 months. The poor prognosis of patients with ATC reflects the current lack of curative therapeutic options and the need for development of novel therapeutic strategies. In this study, we report the results of a preclinical study of AEE788, a dual inhibitor of Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR) tyrosine kinases, against ATC. AEE788 was able to inhibit the proliferation and induce apoptosis of ATC cell lines in vitro. Administration of AEE788, alone and in combination with paclitaxel, to athymic nude mice bearing s.c. ATC xenografts inhibited the growth of ATC xenografts by 44% and 69%, respectively, compared with the control group. Furthermore, tumors from mice treated with AEE788, alone and in combination with paclitaxel, showed increase in apoptosis of tumor cells by ∼6- and 8-fold, respectively, compared with the control group. The microvessel density within the ATC xenografts was decreased by >80% in the mice treated with AEE788 alone and in combination with paclitaxel compared with the control group. Lastly, immunofluorescence microscopy showed the inhibition of EGFR autophosphorylation on the tumor cells as well as the inhibition of VEGFR-2 autophosphorylation on tumor endothelium. Considering the fact that curative options seldom exist for patients with ATC, concurrent inhibition of EGFR and VEGFR tyrosine kinases seems to be a valid and promising anticancer strategy for these patients

Epidermal Growth Factor Receptor (EGFR) is overexpressed in anaplastic thyroid cancer and the EGFR inhibitor gefitinib inhibits the growth of anaplastic thyroid cancer

Purpose: No effective treatment options currently are available to patients with Anaplastic Thyroid Cancer (ATC), resulting in high mortality rates. Epidermal Growth Factor (EGF) has been shown to play a role in the pathogenesis of many types of cancer and its receptor (EGFR) provides an attractive target for molecular therapy. Experimental Design: The expression of EGFR was determined in ATC in vitro and in vivo and in human tissue arrays of ATC. We assessed the potential of the EGFR inhibitor gefitinib (“Iressa,” ZD1839) to inhibit EGFR activation in vitro and in vivo, inhibit ATC cellular proliferation, induce apoptosis and reduce the growth of ATC cells in vivo when administered alone and in combination with paclitaxel. Results: EGFR was overexpressed in ATC cell lines in vitro and in vivo and in human ATC specimens. Activation of EGFR by EGF was blocked by the addition of gefitinib. In vitro studies showed that gefitinib greatly inhibited cellular proliferation and induced apoptosis in ATC cell lines and slowed tumor growth in a nude mouse model of thyroid carcinoma cells injected subcutaneously. Conclusions: ATC cells consistently overexpress EGFR, rendering this receptor a potential target for molecular therapy. Gefitinib effectively blocks activation of EGFR by EGF, inhibits ATC cellular proliferation and induces apoptosis in vitro. Our in vivo results show that gefitinib has significant antitumor activity against ATC in a subcutaneous nude mouse tumor model and therefore is a potential candidate for human clinical trials

A patient presenting with concha bullosa in another concha bullosa: a case report

Abstract Introduction Anatomic variations of the paranasal sinuses are very common. The paranasal sinus anatomy should be carefully examined prior to performing endoscopic sinus surgery in terms of both existent pathologies and anatomic variations. The anatomy of the paranasal sinuses and its variations have gained importance, along with advances in coronal paranasal sinus computed tomography and extensive use of endoscopic sinus surgery. Case presentation A 53-year-old Caucasian woman was admitted to our clinic with complaints of nasal breathing difficulties and headache persisting for a long time. Another concha bullosa was detected in the middle concha bullosa on preoperative paranasal computed tomography examination. It is known that the paranasal sinuses have a number of anatomical variations. Conclusion Herein we report a rare case, along with a review of the literature, to emphasize that a concha bullosa inside another concha bullosa should not be ignored.</p

A patient presenting with concha bullosa in another concha bullosa: a case report

INTRODUCTION: Anatomic variations of the paranasal sinuses are very common. The paranasal sinus anatomy should be carefully examined prior to performing endoscopic sinus surgery in terms of both existent pathologies and anatomic variations. The anatomy of the paranasal sinuses and its variations have gained importance, along with advances in coronal paranasal sinus computed tomography and extensive use of endoscopic sinus surgery. CASE PRESENTATION: A 53-year-old Caucasian woman was admitted to our clinic with complaints of nasal breathing difficulties and headache persisting for a long time. Another concha bullosa was detected in the middle concha bullosa on preoperative paranasal computed tomography examination. It is known that the paranasal sinuses have a number of anatomical variations. CONCLUSION: Herein we report a rare case, along with a review of the literature, to emphasize that a concha bullosa inside another concha bullosa should not be ignored

Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer

We investigated integrin-linked kinase (ILK), a focal adhesion serine-threonine protein kinase, as a new molecular target for treating anaplastic thyroid cancer. ILK mediates cell growth and survival signals and is overexpressed in a number of cancers. Therefore, we hypothesized that inhibition of ILK leads to growth arrest and apoptosis of thyroid cancer cells. According to Western blotting, the level of ILK protein was highly expressed in one papillary (NPA187) and four of five (Hth74, DRO, ARO, KAT4, and K4) anaplastic thyroid cancer cell lines. Immunohistochemical analysis of a human tissue microarray revealed that ILK was highly expressed in anaplastic thyroid cancer but not in normal human thyroid tissue. Treating thyroid cancer cell lines with a new ILK inhibitor, QLT0267, inhibited epidermal growth factor–induced phosphorylation of AKT, inhibited cell growth, and induced apoptosis in the NPA187, DRO, and K4 cell lines. QLT0267 also inhibited the kinase activity of immunoprecipitated ILK in four of five cell lines. Tumor volumes in mice treated with QLT0267 were significantly reduced compared with those in untreated mice. In immunohistochemical studies, QLT0267 suppressed phosphorylated p-AKT and angiogenesis (i.e., reduced mean vascular density) and induced apoptosis in both tumor cells and tumor-associated endothelial cells of the thyroid DRO xenografts. In summary, we found that ILK expression and activity were elevated in human anaplastic thyroid cancer and ILK inhibition led to growth arrest and apoptosis in vitro and in vivo. Our results provide preliminary evidence that ILK is a potential therapeutic target for treating anaplastic thyroid cancer

Two-particle Bose-Einstein correlations and their Lévy parameters in PbPb collisions at sNN\sqrt{s_\mathrm{NN}} = 5.02 TeV

Two-particle Bose-Einstein momentum correlation functions are studied for charged-hadron pairs in lead-lead collisions at a center-of-mass energy per nucleon pair of $\sqrt{s_\mathrm{NN}}$ = 5.02 TeV. The data sample, containing 4.27$\times10^{9}$ minimum bias events corresponding to an integrated luminosity of 0.607 nb$^{-1}$, was collected by the CMS experiment in 2018. The experimental results are discussed in terms of a L\'evy-type source distribution. The parameters of this distribution are extracted as functions of particle pair average transverse mass and collision centrality. These parameters include the L\'evy index or shape parameter ($\alpha$), the L\'evy scale parameter ($R$), and the correlation strength parameter ($\lambda$). The source shape, characterized by $\alpha$, is found to be neither Cauchy nor Gaussian, implying the need for a full L\'evy analysis. Similarly to what was previously found for systems characterized by Gaussian source radii, a hydrodynamical scaling is observed for the L\'evy $R$ parameter. The $\lambda$ parameter is studied in terms of the core-halo model.Comment: Submitted to Physical Review C. All figures and tables can be found at http://cms-results.web.cern.ch/cms-results/public-results/publications/HIN-21-011 (CMS Public Pages

Search for pair production of vector-like quarks in leptonic final states in proton-proton collisions at s \sqrt{s} = 13 TeV

A search is presented for vector-like T and B quark-antiquark pairs produced in proton-proton collisions at a center-of-mass energy of 13 TeV. Data were collected by the CMS experiment at the CERN LHC in 2016–2018, with an integrated luminosity of 138 fb$^{−1}$. Events are separated into single-lepton, same-sign charge dilepton, and multi-lepton channels. In the analysis of the single-lepton channel a multilayer neural network and jet identification techniques are employed to select signal events, while the same-sign dilepton and multilepton channels rely on the high-energy signature of the signal to distinguish it from standard model backgrounds. The data are consistent with standard model background predictions, and the production of vector-like quark pairs is excluded at 95% confidence level for T quark masses up to 1.54 TeV and B quark masses up to 1.56 TeV, depending on the branching fractions assumed, with maximal sensitivity to decay modes that include multiple top quarks. The limits obtained in this search are the strongest limits to date for $\textrm{T}\overline{\textrm{T}}$ production, excluding masses below 1.48 TeV for all decays to third generation quarks, and are the strongest limits to date for $\textrm{B}\overline{\textrm{B}}$ production with B quark decays to tW.[graphic not available: see fulltext