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The tumor immune microenvironment of oral tongue squamous cell carcinoma may be accountable for differences in clinical behavior, particularly between different age groups. We performed RNA expression profiling and evaluated tumor infiltrating lymphocytes (TILs) and their T-cell subsets in order to assess the functional status of oral tongue squamous cell carcinoma tumor microenvironment and detect potentially clinically useful associations. Archival surgical pathology material from sixteen oral tongue squamous cell carcinoma patients was microscopically evaluated for TIL densities. RNA was extracted from macrodissected whole tumor sections and normal controls and RNA expression profiling was performed by the NanoString PanCancer IO 360 Gene Expression Panel. Immunostains for CD4, CD8 and FOXP3 were evaluated manually and by digital image analysis. Oral tongue squamous cell carcinomas had increased TIL densities, numerically dominated by CD4 + T cells, followed by CD8 + and FOXP3 + T cells. RNA expression profiling of tumors versus normal controls showed tumor signature upregulation in inhibitory immune signaling (CTLA4, TIGIT and PD-L2), followed by inhibitory tumor mechanisms (IDO1, TGF-β, B7-H3 and PD-L1). Patients older than 44 years showed a tumor microenvironment with increased Tregs and CTLA4 expression. Immunohistochemically assessed CD8% correlated well with molecular signatures related to CD8 + cytotoxic T-cell functions. FOXP3% correlated significantly with CTLA4 upregulation. CTLA4 molecular signature could be predicted by FOXP3% assessed by immunohistochemistry (R(2) = 0.619, p = 0.026). Oral tongue squamous cell carcinoma hosts a complex inhibitory immune microenvironment, partially reflected in immunohistochemically quantified CD8 + and FOXP3 + T-cell subsets. Immunohistochemistry can be a useful screening tool for detecting tumors with upregulated expression of the targetable molecule CTLA4. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-020-01229-w) contains supplementary material, which is available to authorized users.

Salivary duct carcinoma (SDC) commonly expresses androgen receptor (AR) and HER2, giving rise to treatment implications. SDC may also express programmed-death-ligand-1 (PD-L1), a predictive marker of response to checkpoint inhibitors. PD-L1 can be associated with genomic instability and high density of tumor infiltrating lymphocytes (TILs). Evaluation of HER2 immunohistochemistry (IHC) in SDC is not standardized, and relationships between ERBB2 copy numbers, PD-L1 expression and TILs in SDC are unknown. We evaluated 32 SDCs for HER2, AR and PD-L1 expression (IHC), ERBB2 status (FISH) and TILs (slide review). HER2 was scored with three different systems (breast, gastric, proposed salivary gland). PD-L1 was evaluated with the combined positive score. Most patients were older men, presenting at advanced clinical stage with nodal or distant metastases. During follow-up (mean 5 years, range 6 months to 21 years), 25 of the 32 patients (78%) died of SDC. We propose a HER2 IHC scoring system which accurately predicts underlying ERBB2 amplification or increased copy numbers in SDC. Most tumors had increased ERBB2 copy numbers (19/32 amplification, 6/32 aneusomy), a finding associated with higher TIL densities (p = 0.045) and PD-L1 expression (p = 0.025). Patients with TILs ≥ 40% had better prognoses (Log-Rank p = 0.013), with TILs being favorable prognosticators in univariate analysis (Hazard ratio: 0.18, p = 0.024). A subset of SDCs with increased ERBB2 copy numbers have higher TILs and PD-L1 expression. TILs ≥ 40% are associated with better prognosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-020-01163-x) contains supplementary material, which is available to authorized users.

Ο εξευρωπαϊσμός, η διαδικασία δηλαδή διαμόρφωσης και μεταφοράς πολιτικών της Ευρωπαϊκής Ένωσης (ΕΕ) στα κράτη μέλη, είναι έννοια επίκαιρη, αφορώντας ολοένα και περισσότερα πεδία άσκησης πολιτικής. Σκοπός του άρθρου είναι η διερεύνηση της έκτασης και έντασης του εξευρωπαϊσμού στο πεδίο της πολιτικής υγείας και η δημιουργία ενός θεωρητικού, ταξινομητικού πλαισίου των μηχανισμών μέσω των οποίων αυτός συντελείται. Τα αποτελέσματα της μελέτης δείχνουν, πρώτον, ότι ο εξευρωπαϊσμός στο πεδίο της πολιτικής υγείας ως θεσμική πρακτική υφίσταται και συνεχώς διευρύνεται και, δεύτερον, ότι, ενώ πριν την εκδήλωση της οικονομικής κρίσης επιλέγονταν κύρια οριζόντιοι μη υποχρεωτικοί μηχανισμοί εξευρωπαϊσμού, κατά την περίοδο της κρίσης παρατηρείται μετακίνηση σε κάθετους υποχρεωτικούς μηχανισμούς, που αυξάνουν την ένταση των παρεμβάσεων της ΕΕ στο χώρο της υγείας., Europeanization, defined as the process of designing and transferring European Union (EU) policies to member states, is a topical issue affecting multiple areas of policy practice. The aim of this paper is to explore the width and depth of Europeanization in health systems and develop a classification framework of the mechanisms of Europeanization most commonly applied in health policy. Our results indicate that Europeanization is a gradually widening institutional practice in healthcare. The most recent economic crisis was marked by a clear shift from horizontal non-mandatory Europeanization practices to vertical and mandatory ones, increasing significantly EU’s intervention in domestic health policies.

Clinical immunotherapy approaches are lacking efficacy in the treatment of glioblastoma (GBM). In this study, we sought to reverse local and systemic GBM-induced immunosuppression using the Helicobacter pylori neutrophil-activating protein (NAP), a potent TLR2 agonist, as an immunostimulatory transgene expressed in an oncolytic measles virus (MV) platform, retargeted to allow viral entry through the urokinase-type plasminogen activator receptor (uPAR). While single-agent murine anti-PD1 treatment or repeat in situ immunization with MV-s-NAP-uPA provided modest survival benefit in MV-resistant syngeneic GBM models, the combination treatment led to synergy with a cure rate of 80% in mice bearing intracranial GL261 tumors and 72% in mice with CT-2A tumors. Combination NAP-immunovirotherapy induced massive influx of lymphoid cells in mouse brain, with CD8(+) T cell predominance; therapeutic efficacy was CD8(+) T cell dependent. Inhibition of the IFN response pathway using the JAK1/JAK2 inhibitor ruxolitinib decreased PD-L1 expression on myeloid-derived suppressor cells in the brain and further potentiated the therapeutic effect of MV-s-NAP-uPA and anti-PD1. Our findings support the notion that MV strains armed with bacterial immunostimulatory antigens represent an effective strategy to overcome the limited efficacy of immune checkpoint inhibitor–based therapies in GBM, creating a promising translational strategy for this lethal brain tumor.

Patient: Female, 66 Final Diagnosis: Metachronous ovarian metastasis Symptoms: No symptoms Medication: — Clinical Procedure: — Specialty: Surgery Objective: Unusual clinical course Background: Metachronous ovarian metastasis from primary colorectal cancer (CRC) is a rare condition that is diagnosed after the treatment of CRC. In most cases, ovarian metastases present without specific symptoms or signs and are usually diagnosed during follow-up imaging. A rare case is presented of metachronous ovarian metastasis from primary CRC, diagnosed on follow-up by computed tomography (CT) and magnetic resonance imaging (MRI), and includes a review of the literature. Case Report: A 66-year-old woman recently underwent a left hemicolectomy for a stage T3, N0, M0 primary adenocarcinoma of the sigmoid colon, which was completely excised. Three years later, follow-up CT and MRI imaging showed a right ovarian cyst. She underwent exploratory laparotomy and bilateral salpingo-oophorectomy, which identified tumor in the right ovary. Histopathology and immunohistochemistry confirmed metachronous ovarian metastasis from CRC. The patient was referred for further treatment. Conclusions: Newly-diagnosed ovarian metastasis from primary colorectal cancer (CRC) is challenging to diagnose and manage, and may initially be incorrectly diagnosed as malignancy of primary ovarian origin. This case demonstrated that it is important to confirm the diagnosis with imaging, histology, and the appropriate use of tumor markers. Because ovarian metastases do not respond favorably to chemotherapy, the treatment of choice is surgery. However, for women who are treated for CRC, the use of prophylactic oophorectomy remains controversial.

Fungal endophthalmitis is a serious and vision-threatening infection which requires an immediate and effective treatment approach. Our research aims to elucidate the histological effects of the intravitreal injection of the maximum safe dosage of voriconazole and micafungin on retina. Six albino New Zealand White Rabbits were used. In experimental animals, a solution of voriconazole (Group V) or micafungin (Group M) was intravitreally injected in the right eye, while in control animals, balanced salt solution was intravitreally injected in the left eye (Group C). Euthanasia was performed ten days post injection and the retina was removed and prepared for histological examination with a light and electron microscope. Eosin-hematoxylin staining did not reveal any pathological changes in any of the samples examined. The immunohistochemical staining for Tumor Necrosis Factor alpha (TNF-a) marker was detected as negative in all samples, while Interleukin 6 (IL-6) marker was detected as mild only in the group injected with voriconazole. Electron microscopy revealed several ultrastructural alterations in retinal layers in both groups of experimental animals. Histological retinal lesions, revealed with electron microscopy in the present investigation, raises the question of the safe usage of these antifungal agents in the treatment of fungal intraocular infections in the future.

Background: Inflammatory breast cancer is a highly aggressive form of breast cancer that robustly forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. Inflammatory breast cancers express high levels of E-cadherin, the major protein of adherens junctions, which may enhance the ability of tumor cells to form such clusters and contribute to metastasis. Seemingly contradictory, E-cadherin has both tumor-suppressing and tumor-promoting roles in cancer; previous studies suggest that this depends on the balance between apical and basolateral cadherin-catenin complexes. Methods: In the present study, we use immunohistochemistry of inflammatory breast cancer patient samples and biochemical analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We use viral transduction to ectopically express PLEKHA7 in the SUM149 inflammatory breast cancer cell line. The effect of PLEKHA7 on the aggressiveness of inflammatory breast cancer in 2D, 3D and in-vivo were examined. Results: We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in a strong majority of patient samples and very low expression in cell line models. We found that re-expressing PLEKHA7 is sufficient to suppress proliferation, anchorage independent growth, spheroid viability, and tumor growth in-vivo. We also observed a negative-selection pressure within the xenograft tumors to lose PLEKHA7 function or expression.Conclusions: The data indicate that PLEKHA7 is frequently deregulated and acts as a suppressor of inflammatory breast cancer. They also suggest that the resulting imbalance between apical and basolateral cadherin-catenin complexes contributes to growth, survival and emboli-forming capacities of inflammatory breast cancer.

BACKGROUND Buccal squamous cell carcinoma (SCC) is a locoregionally aggressive malignancy, representing a small subset of oral cancers in North America. We investigated the prognostic value of several clinicopathologic factors in a cohort of patients diagnosed with buccal SCC. METHODS Between years 1992 and 2017, 52 patients were diagnosed with conventional buccal SCC. Archival surgical pathology material was retrospectively reviewed for reportable findings according to the latest reporting guidelines published by the College of American Pathologists. Clinical data were obtained through chart review. RESULTS The majority of patients were of older age, current or past smokers, and without specific gender predilection. Most presented at a clinically advanced stage and were treated with surgery alone, or surgery followed by adjuvant radiotherapy. The tumor recurred in about 40% of patients, and almost half of the patients died from the disease by the end of the follow-up period. The worst pattern of invasion (WPOI) was associated with greater depth of invasion (DOI) (P = .031) and perineural invasion (P

Bisphosphonates are commonly used in clinical practice. Their effectiveness is indisputable, however their adverse effects, especially in the GI tract, are still controversial. In our report, we demonstrate pathological findings of the effect of systematic alendronate administration in esophagus, stomach and the liver of an in-vivo animal model of 15 Wistar rats. Light microscopy with immunohistochemistry and electron microscopy were used. Microscopic findings of inflammation of the stomach and mild hepatic dysfunction were observed. Conclusively, alendronate can potentially affect gastric mucosa and liver function on this animal experimental model.

Double functioning adrenocortical adenomas, occurring in the same gland is an extremely rare condition. This paper presents two cases of double functioning adrenocortical adenomas within the same adrenal gland, causing primary aldosteronism. Diagnosis was set histopathologically in one case since magnetic resonance imaging (MRI) failed to distinguish the two entities. In each case, a laparoscopic adrenalectomy was conducted. When preoperative imaging studies fail to report the presence of double adrenocortical adenomas, histopathology reports should be comprehensive enough so as to reveal such rare lesions.

Marginal zone lymphomas (MZLs) are rarely associated with amyloid deposits, calcification, and ossification. Herein, we describe a case of a MZL with a primary nodal mesenteric presentation, associated with amyloid deposits, calcification, and ossification, highlighting its clinicopathological features, based on our findings, but also on a brief review of the literature.

One of the biggest prerequisites for pregnancy is the fertilization step, where a human haploid spermatozoon interacts and penetrates one haploid oocyte in order to produce the diploid zygote. Although fertilization is defined by the presence of two pronuclei and the extraction of the second polar body the process itself requires preparation of both gametes for fertilization to take place at a specific time. These preparations include a number of consecutive biochemical and molecular events with the help of specific molecules and with the consequential interaction between the two gametes. These events take place at three different levels and in a precise order, where the moving spermatozoon penetrates (a) the outer vestments of the oocyte, known as the cumulus cell layer; (b) the zona pellucida (ZP); where exocytosis of the acrosome contents take place and (c) direct interaction of the spermatozoon with the plasma membrane of the oocyte, which involves a firm adhesion of the head of the spermatozoon with the oocyte plasma membrane that culminates with the fusion of both sperm and oocyte membranes (Part I). After the above interactions, a cascade of molecular signal transductions is initiated which results in oocyte activation. Soon after the entry of the first spermatozoon into the oocyte and oocyte activation, the oocyte’s coat (the ZP) and the oocyte’s plasma membrane seem to change quickly in order to initiate a fast block to a second spermatozoon (Part II). Sometimes, two spermatozoa fuse with one oocyte, an incidence of 1%–2%, resulting in polyploid fetuses that account for up to 10%–20% of spontaneously aborted human conceptuses. The present review aims to focus on the first part of the human sperm and oocyte interactions, emphasizing the latest molecular and cellular mechanisms controlling this process.

Exceptionally high catalytic activities (TOF = 110,000 h−1) have been achieved by water-dispersible palladium(0) nanoparticle catalysts stabilized by water-soluble nitrogen-containing ligands in the hydrogenation of renewable polyunsaturated methyl esters of soybean oil (MESBO) to their monounsaturated counterparts in aqueous/organic micellar systems. Palladium(II) chloride catalyst precursors exhibited a superior aqueous-phase catalytic activity with various nitrogen-containing ligands inter alia bathophenanthrolinedisulfonic acid disodium salt [(BPhDS) (TOF = 71,000 h−1)], diethylenetriaminepentakis (methylphosphonic acid) (TOF = 68,000 h−1), ethylenediaminetetraacetic acid tetrasodium salt (TOF = 50,000 h−1) compared with the TPPTS benchmark ligand modifier (TOF = 34,000 h−1) in this environmentally friendly biphasic catalytic hydrogenation reaction. Mercury poisoning experiments of preformed Pd/BPhDS catalysts proved the heterogeneous nature of this catalytic hydrogenation system. Dynamic light scattering experiments evidenced the presence of micellar nanoreactors with in situ prepared [Pd(OAc)2]3/BPhDS catalyst possessing an average hydrodynamic radius of 36 nm and with preformed and recycled PdCl2/BPhDS catalyst with an average hydrodynamic radius of 57 nm. The apparent activation energy of preformed palladium(0) nanoparticle hydrogenation catalysts stabilized by BPhDS in micellar systems was calculated to 23.7 kJ/mol which is of the same order of magnitude as reported earlier for palladium(0) nanoparticles stabilized by dendritic core-multishell architectures. A recycling experiment at 120 °C showed that the activity of palladium(0) nanoparticle catalyst stabilized by BPhDS in micellar systems in aqueous media remained high in a consecutive run indicating a stable palladium(0) catalytic nanoparticle system which is remarkable when one considers that transition metal(0) catalytic nanoparticles are usually applied at much lower temperatures due to their lower stabilities.

ΒACKGROUND Synchronous multiple malignancies of the larynx are rare. We present a case here of synchronous primary laryngeal squamous cell carcinoma (SCC) and malignant fibrous histiocytoma (MFH) in a patient with hoarseness though with no history of exposure to radiation. Clinical, intraoperative, and histopathological findings in this patient are discussed. METHODS Wide laser excision of the left supraglottic lesion and laser cordectomy of the right true vocal cord were performed. RESULTS The patient presented with a recurrence of the ΜFH alone (with no recurrence of the SCC) two months after the first operation and was managed with an extended second look laser cordectomy. The patient is under regular follow-up and remained disease-free nine months from diagnosis. CONCLUSIONS Our results show that early-stage simultaneous tumours of the larynx and particularly MFH and SCC can be treated efficiently with endoscopic laryngeal surgery alone. Close follow-up is of paramount importance because of the aggressive nature of MFH.

Exceptionally, high catalytic activities (TOF > 204,000 h−1) have been achieved in the hydrogenation of benzene to cyclohexane catalyzed by water-soluble Rh/TPPTS complexes [TPPTS = P(C6H4-m-SO3Na)3] in green aqueous/organic two-phase systems. The influence of several operating parameters on the biphasic benzene hydrogenation reaction was investigated. A great advantage of this reaction is that the highest catalytic activity was achieved at a low volume ratio of aqueous/benzene phase of 0.4. Rh/TPPTS catalytic complexes, which are stable toward sulfur-containing compounds, were easily recovered by a simple phase separation, and recycling experiments showed that the catalytic activity remained high in five consecutive runs.

This study deals with the influence of operating parameters on the selective hydrogenation of crude polyunsaturated methyl esters of linseed, sunflower and soybean oils in order to achieve high selectivities up to 79.8 mol% of monounsaturated (C18:1) fatty acid methyl esters (FAME) which is 1st generation biodiesel of increased oxidative stability, energy and environmental performance at a low pour point employing water-soluble Rh/TPPTS catalytic complexes [TPPTS = P(C6H4-m-SO3Na)3] in green aqueous/organic two-phase systems. This study also discloses the great potential of biphasic selective catalytic hydrogenation to produce 2nd generation biodiesel from polyunsaturated FAME of alternative, non-food oil feedstocks which are originally not suitable for biodiesel production or give poor quality biodiesel but combine the advantage that they would not affect food production. Because the mixture of methyl esters of linseed oil mainly consists of C18:3 FAME it constitutes a good model to investigate the effects of parameters on the whole spectrum of the stepwise hydrogenation: C18:3 (linolenates) → C18:2 (linoleates) → C18:1 (oleates) C18:0 (stearate) and to obtain first information on the selective hydrogenation of alternative, non-food oils with a high C18:3 FAME content to make them suitable for 2nd generation biodiesel formulations.

Solar chimney technology is a very promising solar thermal electricity generating technology. Solar chimney power plants have three major parts. A large greenhouse, a tall cylinder in the center of the greenhouse named solar chimney and an air turbine inside the solar chimney, geared to appropriate electric generators. Floating Solar Chimney (FSC) is a low cost alternative of the concrete solar chimney. The Floating solar chimney, as a lighter than air structure, can be raised anywhere and its cost is as low as 2% of the cost of the respective concrete chimney. Our approach includes a low cost greenhouse that can be used in FSC technology, which is also a low cost alternative to the usual glass roofed circular greenhouse related to the concrete chimney. This plastic covered low cost greenhouse could solve also the ingress of dust, which is a problem that could be a serious obstacle in desert installations of the FSC technology. Furthermore according to the construction cost and the electricity generation figures, we present a scale analysis of the FSC technology. Even with moderate height FSC structures of 650m, is possible the direct production cost to be approximately 45 USD/MWh. The unused mid-latitude desert or semi desert lands of high solar radiation in many countries in all the continents can be used for large-scale application of Floating Solar Chimney technology securing sustainability and mitigating global warming effects.

Floating Solar Chimney (FSC) technology is a low cost alternative technology to solar updraft tower technology which is using concrete solar chimneys. Floating Solar Chimneys are lighter as air fabric structures and can be as high as 700m, giving to their respective power plants efficiency up to 0.85 %. The axial shrouded air turbines of the FSC Power Plants can be connected through proper gear boxes to four-pole to eight-pole doubly fed induction generators, connected though appropriate transformers to the electric grid. Another option, is to connect the air turbines straightforward to multi-pole synchronous generators that will be connected to the electric grid through proper AC to AC converters and electric transformers. FSC technology characteristics in combination with doubly fed induction or multi-pole synchronous generators, leads to the optimum schema in order to convert the maximum of the mechanical energy of the air turbines of the FSC Power Plants to electricity, which is transferred to the electric grid. However in order this to be achieved, special control systems is necessary to be applied to the AC to AC converter.