Search results for: tumor necrosis factor-related apoptosis-inducing ligand

Authors: Jiri Kysucan, Dusan Klos, Katherine Vomackova, Pavel Koranda, Martin Lovecek, Cestmir Neoral, Roman Havlik

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Aim: The prognosis of patients with pancreatic cancer is poor. The median of survival after establishing diagnosis is 3-11 months without surgical treatment, 13-20 months with surgical treatment depending on the disease stage, 5-year survival is less than 5%. Radical surgical resection remains the only hope of curing the disease. Early diagnosis with valid establishment of tumor resectability is, therefore, the most important aim for patients with pancreatic cancer. The aim of the work is to evaluate the contribution and define the role of 18F-FDG PET/CT in preoperative staging. Material and Methods: In 195 patients (103 males, 92 females, median age 66,7 years, 32-88 years) with a suspect pancreatic lesion, as part of the standard preoperative staging, in addition to standard examination methods (ultrasonography, contrast spiral CT, endoscopic ultrasonography, endoscopic ultrasonographic biopsy), a hybrid 18F-FDG PET/CT was performed. All PET/CT findings were subsequently compared with standard staging (CT, EUS, EUS FNA), with peroperative findings and definitive histology in the operated patients as reference standards. Interpretation defined the extent of the tumor according to TNM classification. Limitations of resectability were local advancement (T4) and presence of distant metastases (M1). Results: PET/CT was performed in a total of 195 patients with a suspect pancreatic lesion. In 153 patients, pancreatic carcinoma was confirmed and of these patients, 72 were not indicated for radical surgical procedure due to local inoperability or generalization of the disease. The sensitivity of PET/CT in detecting the primary lesion was 92.2%, specificity was 90.5%. A false negative finding in 12 patients, a false positive finding was seen in 4 cases, positive predictive value (PPV) 97.2%, negative predictive value (NPV) 76,0%. In evaluating regional lymph nodes, sensitivity was 51.9%, specificity 58.3%, PPV 58,3%, NPV 51.9%. In detecting distant metastases, PET/CT reached a sensitivity of 82.8%, specificity was 97.8%, PPV 96.9%, NPV 87.0%. PET/CT found distant metastases in 12 patients, which were not detected by standard methods. In 15 patients (15.6%) with potentially radically resectable findings, the procedure was contraindicated based on PET/CT findings and the treatment strategy was changed. Conclusion: PET/CT is a highly sensitive and specific method useful in preoperative staging of pancreatic cancer. It improves the selection of patients for radical surgical procedures, who can benefit from it and decreases the number of incorrectly indicated operations.

Keywords: cancer, PET/CT, staging, surgery

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Authors: M. Bouhoun Ali, A. Y. Badjah Hadj Ahmed, M. Attou, A. Elias, M. A. Didi

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The extraction of uranium(VI) from aqueous solutions has been investigated using 1-hydroxyhexadecylidene-1,1-diphosphonic acid (HHDPA) and 1-hydroxydodecylidene-1,1-diphosphonic acid (HDDPA), which were synthesized and characterized by elemental analysis and by FT-IR, 1H NMR, 31P NMR spectroscopy. In this paper, we propose a tentative assignment for the shifts of those two ligands and their specific complexes with uranium(VI). We carried out the extraction of uranium(VI) by HHDPA and HDDPA from [carbon tetrachloride + 2-octanol (v/v: 90%/10%)] solutions. Various factors such as contact time, pH, organic/aqueous phase ratio and extractant concentration were considered. The optimum conditions obtained were: contact time= 20 min, organic/aqueous phase ratio = 1, pH value = 3.0 and extractant concentration = 0.3M. The extraction yields are more significant in the case of the HHDPA which is equipped with a hydrocarbon chain, longer than that of the HDDPA. Logarithmic plots of the uranium(VI) distribution ratio vs. pHeq and the extractant concentration showed that the ratio of extractant to extracted uranium(VI) (ligand/metal) is 2:1. The formula of the complex of uranium(VI) with the HHDPA and the DHDPA is UO2(H3L)2 (HHDPA and DHDPA are denoted as H4L). A spectroscopic analysis has showed that coordination of uranium(VI) takes place via oxygen atoms.

Keywords: liquid-liquid extraction, uranium(vi), 1-hydroxyalkylidene-1, 1-diphosphonic acids, hhdpa, hddpa, aqueous solution

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Authors: Elvin P. Chizenga, Heidi Abrahamse

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Cancer cell resistance to therapy is the main cause of treatment failures and the poor prognosis of cancer convalescence. The progression of cervical cancer to other parts of the genitourinary system and the reported recurrence rates are overwhelming. Current treatments, including surgery, chemo and radiation have been inefficient in eradicating the tumor cells. These treatments are also associated with poor prognosis and reduced quality of life, including fertility loss. This has inspired the need for the development of new treatment modalities to eradicate cervical cancer successfully. Photodynamic Therapy (PDT) is a modern treatment modality that induces cell death by photochemical interactions of light and a photosensitizer, which in the presence of molecular oxygen, yields a set of chemical reactions that generate Reactive Oxygen Species (ROS) and other free radical species causing cell damage. Enhancing PDT using modified drug delivery can increase the concentration of the photosensitizer in the tumor cells, and this has the potential to maximize its therapeutic efficacy. In cervical cancer, all infected cells constitutively express genes of the E6 and E7 HPV viral oncoproteins, resulting in high concentrations of E6 and E7 in the cytoplasm. This provides an opportunity for active targeting of cervical cancer cells using immune-mediated drug delivery to maximize therapeutic efficacy. The use of nanoparticles in PDT has also proven effective in enhancing therapeutic efficacy. Gold nanoparticles (AuNps) in particular, are explored for their use in biomedicine due to their biocompatibility, low toxicity, and enhancement of drug uptake by tumor cells. In this present study, a biomolecule comprising of AuNPs, anti-E6 monoclonal antibodies, and Aluminium Phthalocyanine photosensitizer was synthesized for use in targeted PDT of cervical cancer. The AuNp-Anti-E6-Sulfonated Aluminium Phthalocyanine mix (AlPcSmix) photosensitizing biomolecule was synthesized by coupling AuNps and anti-E6 monoclonal antibodies to the AlPcSmix via Polyethylene Glycol (PEG) chemical links. The final product was characterized using Transmission Electron Microscope (TEM), Zeta Potential, Uv-Vis Spectrophotometry, Fourier Transform Infrared Spectroscopy (FTIR), and X-ray diffraction (XRD), to confirm its chemical structure and functionality. To observe its therapeutic role in treating cervical cancer, cervical cancer cells, HeLa cells were seeded in 3.4 cm² diameter culture dishes at a concentration of 5x10⁵ cells/ml, in vitro. The cells were treated with varying concentrations of the photosensitizing biomolecule and irradiated using a 673.2 nm wavelength of laser light. Post irradiation cellular responses were performed to observe changes in morphology, viability, proliferation, cytotoxicity, and cell death pathways induced. Dose-Dependent response of the cells to treatment was demonstrated as significant morphologic changes, increased cytotoxicity, and decreased cell viability and proliferation This study presented a synthetic biomolecule for targeted PDT of cervical cancer. The study suggested that PDT using this AuNp- Anti-E6- AlPcSmix photosensitizing biomolecule is a very effective treatment method for the eradication of cervical cancer cells, in vitro. Further studies in vivo need to be conducted to support the use of this biomolecule in treating cervical cancer in clinical settings.

Keywords: anti-E6 monoclonal antibody, cervical cancer, gold nanoparticles, photodynamic therapy

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Authors: Nandhakumar Elumalai, Purushothaman Ayyakannu, Sachidanandam T. Panchanatham

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Background: Understanding the basic mechanisms and factors underlying the tumor growth and invasion has gained attention in recent times. The processes of angiogenesis and apoptosis are known to play a vital role in various stages of cancer. The vascular endothelial growth factor (VEGF) is well established as one of the key regulators of tumor angiogenesis while MMPs are known for their exclusive ability to degrade ECM. Objective: The present study was designed to evaluate the pro apoptotic and anti angiogenic activity of the herbal formulation Shemamruthaa. The anticancer activity of Shemamruthaa was tested in breast cancer cell line (MCF-7). Results of MTT, trypan blue and flow cytometric analysis of apoptotis suggested that Shemamruthaa can induce cytotoxicity in cancer cells, in a concentration- and time dependent manner and induce apoptosis. With these results, we further evaluated the antiangiogenic and pro-apoptotic activities of Shemamruthaa in DMBA induced mammary carcinoma in Sprague Dawley rats. Flavono tumour was induced in 8-week-old Sprague-Dawley rats by gastric intubation of 25 mg DMBA in 1ml olive oil. After 90 days of induction period, the rats were orally administered with Shemamruthaa (400 mg/kg body wt) for 45 days. Treatment with the drug SM significantly modulated the expression of p53, MMP-2, MMP-3, MMP-9 and VEGF by means of its anti angiogenic and protease inhibiting activity. Conclusion: Based on these results, it might be concluded that the formulation, Shemamruthaa, constituted of dried flowers of Hibiscus rosa-sinensis, fruits of Emblica officinalis, and honey has been found to exhibit pronounced antiproliferative and apoptotic effects. This enhanced anticancer effect of Shemamruthaa might be attributed to the synergistic action of polyphenols such as flavonoids, tannins, alkaloids, glycosides, saponins, steroids, terpenoids, vitamin C, niacin, pyrogallol, hydroxymethylfurfural, trilinolein, and other compounds present in the formulation. Collectively, these results demonstrate that Shemamruthaa holds potential to be developed as a potent chemotherapeutic agent against mammary carcinoma.

Keywords: Shemamruthaa, flavonoids, MCF-7 cell line, mammary cancer

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Authors: Ankur Chaudhuri, Sibani Sen Chakraborty

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In human, glutaminyl cyclase activity is highly abundant in neuronal and secretory tissues and is preferentially restricted to hypothalamus and pituitary. The N-terminal modification of β-amyloids (Aβs) peptides by the generation of a pyro-glutamyl (pGlu) modified Aβs (pE-Aβs) is an important process in the initiation of the formation of neurotoxic plaques in Alzheimer’s disease (AD). This process is catalyzed by glutaminyl cyclase (QC). The expression of QC is characteristically up-regulated in the early stage of AD, and the hallmark of the inhibition of QC is the prevention of the formation of pE-Aβs and plaques. A computer-aided drug design (CADD) process was employed to give an idea for the designing of potentially active compounds to understand the inhibitory potency against human glutaminyl cyclase (QC). This work elaborates the ligand-based and structure-based pharmacophore exploration of glutaminyl cyclase (QC) by using the known inhibitors. Three dimensional (3D) quantitative structure-activity relationship (QSAR) methods were applied to 154 compounds with known IC50 values. All the inhibitors were divided into two sets, training-set, and test-sets. Generally, training-set was used to build the quantitative pharmacophore model based on the principle of structural diversity, whereas the test-set was employed to evaluate the predictive ability of the pharmacophore hypotheses. A chemical feature-based pharmacophore model was generated from the known 92 training-set compounds by HypoGen module implemented in Discovery Studio 2017 R2 software package. The best hypothesis was selected (Hypo1) based upon the highest correlation coefficient (0.8906), lowest total cost (463.72), and the lowest root mean square deviation (2.24Å) values. The highest correlation coefficient value indicates greater predictive activity of the hypothesis, whereas the lower root mean square deviation signifies a small deviation of experimental activity from the predicted one. The best pharmacophore model (Hypo1) of the candidate inhibitors predicted comprised four features: two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature. The Hypo1 was validated by several parameters such as test set activity prediction, cost analysis, Fischer's randomization test, leave-one-out method, and heat map of ligand profiler. The predicted features were then used for virtual screening of potential compounds from NCI, ASINEX, Maybridge and Chembridge databases. More than seven million compounds were used for this purpose. The hit compounds were filtered by drug-likeness and pharmacokinetics properties. The selective hits were docked to the high-resolution three-dimensional structure of the target protein glutaminyl cyclase (PDB ID: 2AFU/2AFW) to filter these hits further. To validate the molecular docking results, the most active compound from the dataset was selected as a reference molecule. From the density functional theory (DFT) study, ten molecules were selected based on their highest HOMO (highest occupied molecular orbitals) energy and the lowest bandgap values. Molecular dynamics simulations with explicit solvation systems of the final ten hit compounds revealed that a large number of non-covalent interactions were formed with the binding site of the human glutaminyl cyclase. It was suggested that the hit compounds reported in this study could help in future designing of potent inhibitors as leads against human glutaminyl cyclase.

Keywords: glutaminyl cyclase, hit lead, pharmacophore model, simulation

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Authors: Salim Cerig, Fatime Geyikoglu, Pınar Akpulat, Suat Colak, Hasan Turkez, Murat Bakir, Mirkhalil Hosseinigouzdagani, Kubra Koc

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This study was designed to evaluate whether carvacrol (CAR) could provide protection against lung injury by acute pancreatitis development. The rats were randomized into groups to receive (I) no therapy; (II) 50 μg/kg cerulein at 1h intervals by four intraperitoneal injections (i.p.); (III) 50, 100 and 200 mg/kg CAR by one i.p.; and (IV) cerulein+CAR after 2h of cerulein injection. 12h later, serum samples were obtained to assess pancreatic function the lipase and amylase values. The animals were euthanized and lung samples were excised. The specimens were stained with hematoxylin-eosin (H&E), periodic acid–Schif (PAS), Mallory's trichrome and amyloid. Additionally, oxidative DNA damage was determined by measuring as increases in 8-hydroxy-deoxyguanosine (8-OH-dG) adducts. The results showed that the serum activity of lipase and amylase in AP rats were significantly reduced after the therapy (p<0.05). We also found that the 100 mg/kg dose of CAR significantly decreased 8-OH-dG levels. Moreover, the severe pathological findings in the lung such as necrosis, inflammation, congestion, fibrosis, and thickened alveolar septum were attenuated in the AP+CAR groups when compared with AP group. Finally, the magnitude of the protective effect on lung is certain, and CAR is an effective therapy for lung injury caused by AP.

Keywords: antioxidant activity, acute pancreatitis, carvacrol, experimental, lung injury, oxidative DNA damage

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Authors: Gagan Dhawan

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Mycobacterium tuberculosis was described as ‘captain of death’ with an inherent property of multiple drug resistance majorly caused by the competent mechanism of efflux pumps. In this study, various open source tools combining chemo-informatics with bioinformatics were used for efficient in-silico drug designing. The efflux pump, Rv1218c, belonging to the ABC transporter superfamily, which is predicted to be a tetronasin-transporter in M. tuberculosis was targeted. Recent studies have shown that Rv1218c forms a complex with two more efflux pumps (Rv1219c and Rv1217c) to provide multidrug resistance to the bacterium. The 3D structure of the protein was modeled (as the structure was unavailable in the previously collected databases on this gene). The TMHMM analysis of this protein in TubercuList has shown that this protein is present in the outer membrane of the bacterium. Virtual screening of compounds from various publically available chemical libraries was performed on the M. tuberculosis protein using various open source tools. These ligands were further assessed where various physicochemical properties were evaluated and analyzed. On comparison of different physicochemical properties, toxicity and docking, the ligand 2-(hydroxymethyl)-6-[4, 5, 6-trihydroxy-2-(hydroxymethyl) tetrahydropyran-3-yl] oxy-tetrahydropyran-3, 4, 5-triol was found to be best suited for further studies.

Keywords: drug resistance, efflux pump, molecular docking, virtual screening

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Authors: Muhammad Younus, Muhammad Sajid, Muti-ur-Rehman Khan, Aftab Ahmad Anjum, Muhammad Asif Idrees, Iahtasham Khan, Aman Ullah Khan, Sajid Umar, Raheela Akhtar

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The present study was conducted to investigate the hazardous effects of lead on health and edible organs of Lohi sheep. The adult Lohi sheep (n=48) were randomly divided into two equal groups. The first group was administered lead acetate at dose of 70 mg/kg live body weight daily as 10% solution by oral route for a period of 90 days and the second group served as a negative control. Blood and tissue samples were collected at day 0, 30, 60 and 90 and analyzed for lead concentration by atomic absorption spectrophotometry. The kidney showed the highest lead concentration (p < 0.05) followed by liver and then muscle. Lead acetate treated sheep showed structural and behavioral changes during the last month of trial. Liver showed necrosis, hemorrhages and hyperactivation of macrophages. Kidney showed degenerative and necrotic changes in glomeruli and tubules and the characteristic intranuclear inclusion bodies in tubular epithelial cells on H and E staining. It was concluded that Lohi sheep is affected by lead intoxication at low dose for longer period and hence exhibits lead accumulation in edible tissues.

Keywords: Lohi sheep, lead acetate, edible tissue, histopathology

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Authors: Amir Feily, Hazhir Shahmoradi Akram, Mojtaba Ghaedi, Farshid Javdani, Naser Hatami, Navid Kalani, Mohammad Zarenezhad

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Background: Filler-induced facial skin ischemia is a potential complication of dermal filler injections that can result in tissue damage and necrosis. Nitroglycerin has been suggested as a treatment option due to its vasodilatory effects, but its efficacy in this context is unclear. Methods: A narrative review was conducted to examine the available evidence on the efficacy of nitroglycerin in filler-induced facial skin ischemia. Relevant studies were identified through a search of electronic databases and manual searching of reference lists. Results: The review found limited evidence supporting the efficacy of nitroglycerin in this context. While there were case reports where the combination of nitroglycerin and hyaluronidase was successful in treating filler-induced facial skin ischemia, there was only one case report where nitroglycerin alone was successful. Furthermore, a rat model did not demonstrate any benefits of nitroglycerin and showed harmful results. Conclusion: The evidence regarding the efficacy of nitroglycerin in filler-induced facial skin ischemia is inconclusive and seems to be against its application. Further research is needed to determine the effectiveness of nitroglycerin alone and in combination with other treatments for this condition. Clinicians should consider limited evidence bases when deciding on treatment options for patients with filler-induced facial skin ischemia.

Keywords: nitroglycerin, facial, skin ischemia, fillers, efficacy, narrative review

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Authors: Naela Nabiela, Ahmad Hilmi Fahmi, M. Sukron, Ayu Elita Sari, Yusran, Suparmi

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Aspirin is one of NSAIDs (non-steroid inflammatory drugs), can cause gastric ulcer as an side effect of prolonged consumption. The effort to prevent the increase of gastric HCl level can by treating with amylopectin was reported that can cover the gastric mucose. However, the effect of amylopectin in starch from Manihot utilissima which is believed as traditional treatment gastric ulcer have not been clear yet. This study was conducted to determine the effect of starch formed as syrup to HCl level and gastric histopatology. This experiment post test only control group design used 42 male wistar rats divided into 7 groups. All groups, except first group, were induced by 60 mg/100gBW/day aspirin for 3 days. The following day for 2 days each group was treated by starch syrup at dosed 0.45% w/v, 0.9% w/v, 1.8% w/v, 0% w/v, and sucralfate. Respectively, HCl level were measured by acidi-alkalimetri titration method, while the gastric histopathology were prepared by hematoxylin-eosin staining. The result shows that aspirin induction can increase the HCl level as 0,00767 N. Starch syrup at dose 1.8% w/v was effective to reduce HCl level and the grade of second gastric necrosis. It can be conclude that starch syrup is potention as a treatment to cure gastric ulcer caused by NSAIDs side effect.

Keywords: concentration of HCl stomach, gastric histopathology, gastritis, starch

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Authors: Geliashvili T. M., Tyulyandina A. S., Valiev A. K., Kononets P. V., Kharatishvili T. K., Salkov A. G., Pronin A. I., Gadzhieva E. H., Parnas A. V., Ilyakov V. S.

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Aim/Introduction: Metastasis (Mts) to the sternum, while extremely rare in differentiated thyroid cancer (DTC) (1), requires a personalized, multidisciplinary treatment approach. In aggressively growing Mts to the sternum, which rapidly become unresectable, a comprehensive therapeutic and diagnostic approach is particularly important. Materials and methods: We present a clinical case of solitary Mts to the sternum as first manifestation of a papillary thyroid microcarcinoma in a 55-year-old man. Results: 18F-FDG PET/CT after thyroidectomy confirmed the solitary Mts to the sternum with extremely high FDG uptake (SUVmax=71,1), which predicted its radioiodine-refractory (RIR). Due to close attachment to the mediastinum and rapid growth, Mts was considered unresectable. During the next three months, the patient received targeted therapy with the tyrosine kinase inhibitor (TKI) Lenvatinib 24 mg per day. 1st course of radioiodine therapy (RIT) 6 GBq was also performed, the results of which confirmed the RIR of the tumor process. As a result of systemic therapy (targeted therapy combined with RIT and suppressive hormone therapy with L-thyroxine), there was a significant biochemical response (decrease of serum thyroglobulin level from 50,000 ng/ml to 550 ng/ml) and a partial response with decrease of tumor size (from 80x69x123 mm to 65x50x112 mm) and decrease of FDG accumulation (SUVmax from 71.1 to 63). All of this made possible to perform surgical treatment of Mts - sternal extirpation with its replacement by an individual titanium implant. At the control examination, the stimulated thyroglobulin level was only 134 ng/ml, and PET/CT revealed postoperative areas of 18F-FDG metabolism in the removed sternal Mts. Also, 18F-FDG PET/CT in the early (metabolic) stage revealed two new bone Mts (in the area of L3 SUVmax=17,32 and right iliac bone SUVmax=13,73), which, as well as the removed sternal Mts, appeared to be RIRs at the 2nd course of RIT 6 GBq. Subsequently, on 02.2022, external beam radiation therapy (EBRT) was performed on the newly identified oligometastatic bone foci. At present, the patient is under dynamic monitoring and in the process of suppressive hormone therapy with L-thyroxine. Conclusion: Thus, only due to the early prescription of targeted TKI therapy was it possible to perform surgical resection of Mts to the sternum, thereby improve the patient's quality of life and preserve the possibility of radical treatment in case of oligometastatic disease progression.

Keywords: differentiated thyroid cancer, metastasis to the sternum, radioiodine therapy, radioiodine-refractory cancer, targeted therapy, lenvatinib

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Authors: Nadeem Bashir, Ghulam Mustafa Peerzada

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The present study pertains to the nonlinear behavior of acetaminophen based uncatalyzed Belousov-Zhabotinsky (BZ) oscillator and its dynamics in the presence of Ferroin as the catalyst. The role of free metal ions as catalysts was examined and the results compared with corresponding complexed catalysts. Free metal ions were found to be sluggish with respect to the evolution of the oscillatory regime as compared to complexed ones. Effect of change of the ligand moiety of the catalyst complex on the oscillatory parameters was monitored. Since ethanol potentiates the hepatotoxicity caused by acetaminophen in-vivo, it is thought to understand this interaction by virtue of causing perturbation of the acetaminophen based oscillator with different concentrations of the ethanol with and without ferroin as the catalyst. Another dimension to the ethanol effect was added by perturbation of the system with ethanol at different stages of the reaction so as to get an idea whether it is acetaminophen or some reactive intermediate generated in the reaction system which reacts with ethanol. Further, the ferroin-catalyzed oscillator is taken as a prototype inorganic model of the acetaminophen-ethanol syndrome, as ferroin and HOBr were inorganic replacements to Cyt P450 and NADPH in the alcohol metabolism.

Keywords: Belousov-Zhabotinsky reaction, ferroin, Paracetamol-Ethanol syndrome, kinetics

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Authors: S. V. Akulinichev, S. A. Chaushansky, V. I. Derzhiev

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High dose rate (HDR) brachytherapy is a method of contact radiotherapy, when a single sealed source with an activity of about 10 Ci is temporarily inserted in the tumor area. The isotopes Ir-192 and (much less) Co-60 are used as active material for such sources. The other type of brachytherapy, the low dose rate (LDR) brachytherapy, implies the insertion of many permanent sources (up to 200) of lower activity. The pulse dose rate (PDR) brachytherapy can be considered as a modification of HDR brachytherapy, when the single source is repeatedly introduced in the tumor region in a pulse regime during several hours. The PDR source activity is of the order of one Ci and the isotope Ir-192 is currently used for these sources. The PDR brachytherapy is well recommended for the treatment of several tumors since, according to oncologists, it combines the medical benefits of both HDR and LDR types of brachytherapy. One of the main problems for the PDR brachytherapy progress is the shielding of the treatment area since the longer stay of patients in a shielded canyon is not enough comfortable for them. The use of Yb-169 as an active source material is the way to resolve the shielding problem for PDR, as well as for HRD brachytherapy. The isotope Yb-169 has the average photon emission energy of 93 KeV and the half-life of 32 days. Compared to iridium and cobalt, this isotope has a significantly lower emission energy and therefore requires a much lighter shielding. Moreover, the absorption cross section of different materials has a strong Z-dependence in that photon energy range. For example, the dose distributions of iridium and ytterbium have a quite similar behavior in the water or in the body. But the heavier material as lead absorbs the ytterbium radiation much stronger than the iridium or cobalt radiation. For example, only 2 mm of lead layer is enough to reduce the ytterbium radiation by a couple of orders of magnitude but is not enough to protect from iridium radiation. We have created an original facility to produce the start stable isotope Yb-168 using the laser technology AVLIS. This facility allows to raise the Yb-168 concentration up to 50 % and consumes much less of electrical power than the alternative electromagnetic enrichment facilities. We also developed, in cooperation with the Institute of high pressure physics of RAS, a new technology for manufacturing high-density ceramic cores of ytterbium oxide. Ceramics density reaches the limit of the theoretical values: 9.1 g/cm3 for the cubic phase of ytterbium oxide and 10 g/cm3 for the monoclinic phase. Source cores from this ceramics have high mechanical characteristics and a glassy surface. The use of ceramics allows to increase the source activity with fixed external dimensions of sources.

Keywords: brachytherapy, high, pulse dose rates, radionuclides for therapy, ytterbium sources

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Authors: Najla M. Salkho, Vinod Paul, Pierre Kawak, Rute F. Vitor, Ana M. Martin, Nahid Awad, Mohammad Al Sayah, Ghaleb A. Husseini

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Liposomes are popular lipid bilayer nanoparticles that are highly efficient in encapsulating both hydrophilic and hydrophobic therapeutic drugs. Liposomes promote a low risk controlled release of the drug avoiding the side effects of the conventional chemotherapy. One of the great potentials of liposomes is the ability to attach a wide range of ligands to their surface producing ligand-mediated active targeting of cancer tumour with limited adverse off-target effects. Ultrasound can also aid in the controlled and specified release of the drug from the liposomes by breaking it apart and releasing the drug in the specific location where the ultrasound is applied. Our research focuses on the synthesis of PEGylated liposomes (contain poly-ethylene glycol) encapsulated with the model drug calcein and studying the effect of low frequency ultrasound applied at different power densities on calcein release. In addition, moieties are attached to the surface of the liposomes for specific targeting of the cancerous cells which over-express the receptors of these moieties, ultrasound is then applied and the release results are compared with the moiety free liposomes. The results showed that attaching these moieties to the surface of the PEGylated liposomes not only enhance their active targeting but also stimulate calcein release from these liposomes.

Keywords: active targeting, liposomes, moieties, ultrasound

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Authors: Manasi Roy, Raju Mondal

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During last two decades the synthesis and design of MOFs or novel coordination polymers (CPs) has flourished as an emerging area of research due to their role as functional materials. Accordingly, ten new cobalt-based MOFs have been synthesized using a simple bispyrazole ligand, 4,4′-methylene-bispyrazole (H2MBP), and isophthalic acid (H2IPA) and its four 5-substituted derivatives R-H2IPA (R = COOH, OH, tBu, NH2). The major aim of this study was to validate the mutual influence of temperature and substitutions on the final structural self-assembly. Five different isophthalic acid derivatives were used to study the influence of substituents while each reaction was carried out at two different temperatures to assess the temperature effect. A clear correlation was observed between the reaction temperature and the coordination number of the cobalt atoms which consequently changes the self assembly pattern. Another fact that the periodical change in coordination number did bring about some systematic changes in the structural network via secondary building unit selectivity. With the presence of a tunable cavity inside the network, and unsaturated metal centers, MOFs show highly encouraging photocatalytic degradation of toxic dye with a potential application in waste water purification. Another fascinating aspect of this work is the construction of magnetic coordination polymers with the occurrence of a not-so-common MCE behavior of cobalt-based MOF.

Keywords: MOFs, temperature effect, MCE, dye degradation

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Authors: Romasa Qasim, G. M. Sayedur Rahman, Nahid Hasan, M. Shazzad Hosain

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Millions of people worldwide suffer from Hepatitis C, one of the fatal diseases. Interferon (IFN) and ribavirin are the available treatments for patients with Hepatitis C, but these treatments have their own side-effects. Our research focused on the development of an orally taken small molecule drug targeting the proteins in Hepatitis C Virus (HCV), which has lesser side effects. Our current study aims to the Pharmacophore based drug development of a specific small molecule anti-viral drug for Hepatitis C Virus (HCV). Drug designing using lab experimentation is not only costly but also it takes a lot of time to conduct such experimentation. Instead in this in silico study, we have used computer-aided techniques to propose a Pharmacophore-based anti-viral drug specific for the protein domains of the polyprotein present in the Hepatitis C Virus. This study has used homology modeling and ab initio modeling for protein 3D structure generation followed by pocket identification in the proteins. Drug-able ligands for the pockets were designed using de novo drug design method. For ligand design, pocket geometry is taken into account. Out of several generated ligands, a new Pharmacophore is proposed, specific for each of the protein domains of HCV.

Keywords: pharmacophore-based drug design, anti-viral drug, in-silico drug design, Hepatitis C virus (HCV)

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Authors: Noor Shafifiyaz Mohd Yazid, Najihah Mohd Hashim, Hapipah Mohd Ali, Syam Mohan, Rosea Go

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Artocarpus kemando is a plant species from Moraceae family. This plant is used as household utensil by the local and the fruits are edible. The plants’ bark was used for the extraction process and yielded the chloroform crude extract which was used to screen for anticancer potential. The cytotoxic effect of the extract on CAOV-3 and WRL 68 cell lines were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT assays. Qualitative AO/PI assay was performed to confirm the apoptosis and necrosis process. Meanwhile, the measurement of cell loss, nuclear morphology, DNA content, cell membrane permeability, mitochondrial membrane potential changes and cytochrome c release from mitochondria were detected through cytotoxicity 3 assay. In MTT assay, A. kemando inhibited 50% growth of CAOV-3 cells at 27.9 ± 0:03, 20.1± 0:03, 18.21± 0:04 µg/mL after 24, 48 and 72 hour, respectively. The morphology changes can be seen on CAOV-3 with a production of cell membrane blebbing, cromatin condensation and apoptotic bodies. Evaluation of cytotoxicity 3 on CAOV-3 cells after treated with extract resulting loss of mitochondrial membrane potential and release of cytochrome c from mitochondria. The results demonstrated A. kemando has potentially anticancer agent, particularly on human ovarian cancer.

Keywords: anticancer, Artocarpus kemando, ovarian cancer, cytotoxicity

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Authors: Harminder Kaur, Manpreet Kaur, Akanksha Kapila, Reenu

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Schiff base with general formula H₂L was derived from condensation of o-vanillin and 3-nitro-o-phenylenediamine. This Schiff base was used for the synthesis of organotin(IV) complexes with general formula R₂SnL [R=Phenyl or n-octyl] using equimolar quantities. Elemental analysis UV-Vis, FTIR, and multinuclear spectroscopic techniques (¹H, ¹³C, and ¹¹⁹Sn) NMR were carried out for the characterization of the synthesized complexes. These complexes were coloured and soluble in polar solvents. Computational studies have been performed to obtain the details of the geometry and electronic structures of ligand as well as complexes. Geometry of the ligands and complexes have been optimized at the level of Density Functional Theory with B3LYP/6-311G (d,p) and B3LYP/MPW1PW91 respectively followed by vibrational frequency analysis using Gaussian 09. Observed ¹¹⁹Sn NMR chemical shifts of one of the synthesized complexes showed tetrahedral geometry around Tin atom which is also confirmed by DFT. HOMO-LUMO energy distribution was calculated. FTIR, ¹HNMR and ¹³CNMR spectra were also obtained theoretically using DFT. Further IRC calculations were employed to determine the transition state for the reaction and to get the theoretical information about the reaction pathway. Moreover, molecular docking studies can be explored to ensure the anticancer activity of the newly synthesized organotin(IV) complexes.

Keywords: DFT, molecular docking, organotin(IV) complexes, o-vanillin, 3-nitro-o-phenylenediamine

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Authors: Marin Kanarev, Delyan Stoyanov, Ivanna Popova, Nadezhda Petrova

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Thanks to increased survival rates in patients bearing oncological malignancies due to recent developments in anti-cancer therapies and diagnostic techniques, observation of clinical cases of metachronous cancers is more common and can provide more in-depth knowledge of their development and, as a result, help clinicians apply suitable therapy. This unusual case of three metachronous tumors presented the opportunity to follow their occurrence, progression, and treatment thoroughly. A 77-year-old male presented with carcinoma ventriculi of the pylorus region, which was surgically removed via upper subtotal stomach resection, a lateral antecolical gastro-enteroanastomosis, and a subsequent Braun anastomosis. An EOX chemotherapy regimen followed. A CT scan four months later showed no indication of recurrence or dissemination. The same scan, performed as a part of the follow-up plan two years later, showed an indication of neoplastic growth in the urinary bladder. After the patient had been directed to a urologist, the suspicion was confirmed, and the growth was histologically diagnosed as a carcinoma of the urinary bladder. An immunohistochemistry test showed an expression of PDL1 of less than 5%, which resulted in treatment with GemCis chemotherapy regimen that led to full remission. Two years and seven months after the first surgery, a CT scan showed again that the two carcinomas were gone. However, four months later, elevated tumor markers prompted a PET/CT scan, which showed data indicative of recurring neoplastic growth in the region of the stomach cardia. It was diagnosed as an adenocarcinoma infiltrating the esophagus. Preoperative chemotherapy with the ECF regimen was completed in four courses, and a CT scan showed no progression of the disease. In less than a month after therapy, the patient underwent laparotomy, debridement, gastrectomy, and a subsequent mechanical terminal-lateral esophago-jejunoanasthomosis. It was verified that the tumor originated from metastasis from the carcinoma ventriculi, which was located in the pylorus. In conclusion, this case report highlights the importance of patient follow-up and studying recurring neoplastic growth. Despite the absence of symptoms, clinicians should maintain a high level of suspicion when evaluating the patient data and choosing the most suitable therapy.

Keywords: carcinoma, follow-up, metachronous, neoplastic growth, recurrence

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Authors: Mustapha Bouhoun Ali, Ahmed Yacine Badjah Hadj Ahmed, Mouloud Attou, Abdel Hamid Elias, Mohamed Amine Didi

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The extraction of uranium(VI) from aqueous solutions has been investigated using 1-hydroxyhexadecylidene-1,1-diphosphonic acid (HHDPA) and 1-hydroxydodecylidene-1,1-diphosphonic acid (HDDPA), which were synthesized and characterized by elemental analysis and by FT-IR, 1H NMR, 31P NMR spectroscopy. In this paper, we propose a tentative assignment for the shifts of those two ligands and their specific complexes with uranium(VI). We carried out the extraction of uranium(VI) by HHDPA and HDDPA from [carbon tetrachloride + 2-octanol (v/v: 90%/10%)] solutions. Various factors such as contact time, pH, organic/aqueous phase ratio and extractant concentration were considered. The optimum conditions obtained were: contact time = 20 min, organic/aqueous phase ratio = 1, pH value = 3.0 and extractant concentration = 0.3M. The extraction yields are more significant in the case of the HHDPA which is equipped with a hydrocarbon chain, longer than that of the HDDPA. Logarithmic plots of the uranium(VI) distribution ratio vs. pHeq and the extractant concentration showed that the ratio of extractant to extracted uranium(VI) (ligand/metal) is 2:1. The formula of the complex of uranium(VI) with the HHDPA and the DHDPA is UO2(H3L)2 (HHDPA and DHDPA are denoted as H4L). A spectroscopic analysis has showed that coordination of uranium(VI) takes place via oxygen atoms.

Keywords: liquid-liquid extraction, uranium(VI), 1-hydroxyalkylidene-1, 1-diphosphonic acids, HHDPA, HDDPA, aqueous solution

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Authors: Lamia Bensissaid

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Goals: Endometriosis affects 6 to 10% of women of childbearing age. 17 to 44% of them have ovarian endometriomas. Medical and surgical treatments represent the two therapeutic axes with which PMA can be associated. Laparoscopic intraperitoneal ovarian cystectomy is described as the reference technique in the management of endometriomas by learned societies (CNGOF, ESHRE, NICE). However, it leads to a significant short-term reduction in the AMH level and the number of antral follicles, especially in cases of bilateral cystectomy, large cyst size or cystectomy after recurrence. Often, the disease is at an advanced stage with several surgical patients. Most have adhesions, which increase the risk of surgical complications and suboptimal resection and, therefore recurrence of the cyst. These results led to a change of opinion towards a conservative approach. Sclerotherapy is an old technique which acts by fibrinoid necrosis. It consists of injecting a sclerosing agent into the cyst cavity. Results : Recurrence was less than 15% for a 12-month follow-up; these rates are comparable to those of surgery. It does not seem to have a negative impact on ovarian reserve, but this is not sufficiently evaluated. It has an advantage in IVF pregnancy rates compared to cystectomy, particularly in cases of recurrent endometriomas. It has the advantages: · To be done on an outpatient basis. · To be inexpensive. · To avoid sometimes difficult and iterative surgery: · To allow an increase in pregnancy rates and the preservation of the ovarian reserve compared to iterative surgery. · of great interest in cases of bilateral endometriomas (kissing ovaries) or recurrent endometriomas. Conclusions: Ethanol sclerotherapy could be a good alternative to surgery.

Keywords: Endometrioma, Sclerotherapy, infertility, Ethanol

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Authors: Abdul Musaweer Habib, Habibul Hasan Mazumder, Saiful Islam, Sohel Sikder, Omar Faruk Sikder

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The plethora of genome sequence information of bacteria in recent times has ushered in many novel strategies for antibacterial drug discovery and facilitated medical science to take up the challenge of the increasing resistance of pathogenic bacteria to current antibiotics. In this study, we adopted subtractive genomics approach to analyze the whole genome sequence of the Fusobacterium nucleatum, a human oral pathogen having association with colorectal cancer. Our study divulged 1499 proteins of Fusobacterium nucleatum, which has no homolog in human genome. These proteins were subjected to screening further by using the Database of Essential Genes (DEG) that resulted in the identification of 32 vitally important proteins for the bacterium. Subsequent analysis of the identified pivotal proteins, using the KEGG Automated Annotation Server (KAAS) resulted in sorting 3 key enzymes of F. nucleatum that may be good candidates as potential drug targets, since they are unique for the bacterium and absent in humans. In addition, we have demonstrated the 3-D structure of these three proteins. Finally, determination of ligand binding sites of the key proteins as well as screening for functional inhibitors that best fitted with the ligands sites were conducted to discover effective novel therapeutic compounds against Fusobacterium nucleatum.

Keywords: colorectal cancer, drug target, Fusobacterium nucleatum, homology modeling, ligands

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Authors: M. Ridwanul Hassan, Samuel George

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Aims: Steroid injections are commonly used as a diagnostic tool or an alternative to surgical management of carpal tunnel syndrome (CTS) and are generally safe. Ischaemia is a rare complication with very few cases reported in the literature. Methods: We report a case of a 50-year-old female that presented with a necrotic wound to her left palm one month after a steroid injection into the carpal tunnel. She had a 2-year history of CTS in her left hand that was treated with six previous steroid injections in primary care during this period. The wound evolved from a blister to a necrotic ulcer which led to a painful, hollow defect in the centre of her palm. She did not report any history of trauma, nor did she have any co-morbidities. Clinical photographs were taken. Results: On examination, she had a 0.5 cmx1 cm defect in the palm of her left hand down to aponeurosis. There was purulent discharge in the wound with surrounding erythema but no spreading cellulitis. She had full function of her fingers but was very tender on movements and at rest. She was admitted for intravenous antibiotics and underwent a debridement, washout, and carpal tunnel release the next day. The defect was packed to heal by secondary intention and has now fully healed one month following her operation. Conclusions: This is an extremely rare complication of steroid injections to the carpal tunnel and may have been avoided by earlier referral for surgery rather than treatment using multiple steroid injections.

Keywords: hand surgery, complication, rare, carpal tunnel syndrome

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Authors: D. F. Carvalho, A. O. Uscamayta, J. C. Guerrero, H. F. Oliveira, P. M. Azevedo-Marques

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The creation of vector contours slices (ROIs) on body silhouettes in oncologic patients is an important step during the radiotherapy planning in clinic and hospitals to ensure the accuracy of oncologic treatment. The radiotherapy planning of patients is performed by complex softwares focused on analysis of tumor regions, protection of organs at risk (OARs) and calculation of radiation doses for anomalies (tumors). These softwares are supplied for a few manufacturers and run over sophisticated workstations with vector processing presenting a cost of approximately twenty thousand dollars. The Brazilian project SIPRAD (Radiotherapy Planning System) presents a proposal adapted to the emerging countries reality that generally does not have the monetary conditions to acquire some radiotherapy planning workstations, resulting in waiting queues for new patients treatment. The SIPRAD project is composed by a set of integrated and interoperabilities softwares that are able to execute all stages of radiotherapy planning on simple personal computers (PCs) in replace to the workstations. The goal of this work is to present an image processing technique, computationally feasible, that is able to perform an automatic contour delineation in patient body silhouettes (SIPRAD-Body). The SIPRAD-Body technique is performed in tomography slices under grayscale images, extending their use with a greedy algorithm in three dimensions. SIPRAD-Body creates an irregular polyhedron with the Canny Edge adapted algorithm without the use of preprocessing filters, as contrast and brightness. In addition, comparing the technique SIPRAD-Body with existing current solutions is reached a contours similarity at least 78%. For this comparison is used four criteria: contour area, contour length, difference between the mass centers and Jaccard index technique. SIPRAD-Body was tested in a set of oncologic exams provided by the Clinical Hospital of the University of Sao Paulo (HCRP-USP). The exams were applied in patients with different conditions of ethnology, ages, tumor severities and body regions. Even in case of services that have already workstations, it is possible to have SIPRAD working together PCs because of the interoperability of communication between both systems through the DICOM protocol that provides an increase of workflow. Therefore, the conclusion is that SIPRAD-Body technique is feasible because of its degree of similarity in both new radiotherapy planning services and existing services.

Keywords: radiotherapy, image processing, DICOM RT, Treatment Planning System (TPS)

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Authors: Waseem Al Talalwah, Shorok Al Dorazi, Roger Soames

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The inferior gluteal artery is a prominent branch of the anterior trunk of internal iliac artery. It escapes from the pelvic cavity through the greater sciatic foramen below the lower edge of piriformis. In gluteal region, it provides several muscular branches to gluteal maximus and articular branch to hip joint. Further, it provides sciatic branch to sciatic nerve. Current study investigates the origin of the inferior gluteal artery of 41 cadavers in Centre for Anatomy and Human Identification, University of Dundee, UK. It arose from the anterior trunk in 37.5% independently and 45.7% dependently as with the internal pudendal artery. Therefore, it arose from the anterior trunk in 83.2%. However, it found to be as a branch of the posterior trunk of internal iliac artery in 7.7% which is either a direct branch in 6.2% as or indirect branch in 1.5%. Beside the inferior gluteal artery arose with internal pudendal artery as from GPT of anterior division in 45.7%, it arose from the GPT arising from the internal iliac artery bifurcation site in 1.5%. Further, the inferior gluteal artery arose from the trunk with internal pudendal and obturator arteries in 1.5% referred as obturatogluteopudendal trunk. Occasionally, it arose from the sciatic artery in 1.5%. In few cases, the inferior gluteal artery found to be congenital absence in 4.6% which is compensated by the persistent sciatic artery. Therefore, radiologists have to aware of the origin variability of the inferior gluteal artery to alert surgeons. Knowing the origin of the inferior gluteal artery may help the surgeons to avoid iatrogenic sciatic neuropathy in pelvic procedures such as removing prostate or of uterine fibroid. Further, it may also prevent avascular necrosis of femur neck as well as gluteal claudication.

Keywords: inferior gluteal artery, internal iliac artery, sciatic neuropathy, gluteal claudication

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Authors: Mohamed Eftal Bin Mohamed Ebrahim, Alexander Varey

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Aim: Topical negative pressure has been shown to enhance angiogenesis during wound healing, both for open and closed wounds. Since angiogenesis is a key requirement for successful fat grafting, there may be a role for topical negative pressure as a means of enhancing the take rate during autologous fat grafting to breasts. Here we present a systematic review of the literature on this topic. Methods: Ovid and Embase were utilized, with searches ranging between 1960 – 2019. Terms (“Liposculpting” OR “Fat grafting” OR “Lipofilling” OR “Lipograft” OR “Fat transfer”) AND (“Negative Pressure” OR “Brava” OR “Kiwi”) AND (“Breast”) were merged as keywords. Inclusion criteria were females, autologous fat graft to breast with topical negative pressure prior to the procedure. Studies were excluded if there was no primary endpoint or non-original article. Results: Upon reviewing 219 articles, 2 met inclusion criteria. A total of 565 and 46 breasts in each article were treated respectively using the negative pressure device BRAVA®, with each cohort having different pre-and post-operative pressure settings. Khouri et al. cohort had higher graft survival (79%) compared to Del Vecchio et al. cohort (64%); however, the latter had fewer complications compared to Khouri’s cohort, e.g., fat necrosis, pneumothorax and infection. Conclusion: There is limited evidence regarding the use of topical negative pressure for fat grafting to the breasts. However, in the two studies published, the reported rates of success are high, suggesting there may be a benefit. Consequently, a randomized controlled trial on this area is required.

Keywords: fat grafting, lipograft, negative pressure, breast, breast augmentation, brava

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Authors: Akulov M. A., Orlova O. R., Zaharov V. O., Tomskij A. A.

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Introduction: One of the common postoperative complications of posterior cranial fossa (PCF) and cerebello-pontine angle tumor treatment is a facial nerve palsy, which leads to multiple and resistant to treatment impairments of mimic muscles structure and functions. After 4-6 months after facial nerve palsy with insufficient therapeutic intervention patients develop a postparalythic syndrome, which includes such symptoms as mimic muscle insufficiency, mimic muscle contractures, synkinesis and spontaneous muscular twitching. A novel method of treatment is the use of a recent local neuromuscular blocking agent– botulinum toxin A (BTA). Experience of BTA treatment enables an assumption that it can be successfully used in late facial nerve palsy complications to significantly increase quality of life of patients. Study aim. To evaluate the efficacy of botulinum toxin A (BTA) (Xeomin) treatment in patients with late facial nerve palsy complications. Patients and Methods: 31 patients aged 27-59 years 6 months after facial nerve palsy development were evaluated. All patients received conventional treatment, including massage, movement therapy etc. Facial nerve palsy developed after acoustic nerve tumor resection in 23 (74,2%) patients, petroclival meningioma resection – in 8 (25,8%) patients. The first group included 17 (54,8%) patients, receiving BT-therapy; the second group – 14 (45,2%) patients continuing conventional treatment. BT-injections were performed in synkinesis or contracture points 1-2 U on injured site and 2-4 U on healthy side (for symmetry). Facial nerve function was evaluated on 2 and 4 months of therapy according to House-Brackman scale. Pain syndrome alleviation was assessed on VAS. Results: At baseline all patients in the first and second groups demonstrated аpostparalytic syndrome. We observed a significant improvement in patients receiving BTA after only one month of treatment. Mean VAS score at baseline was 80,4±18,7 and 77,9±18,2 in the first and second group, respectively. In the first group after one month of treatment we observed a significant decrease of pain syndrome – mean VAS score was 44,7±10,2 (р<0,01), whereas in the second group VAS score was as high as 61,8±9,4 points (p>0,05). By the 3d month of treatment pain syndrome intensity continued to decrease in both groups, but, the first group demonstrated significantly better results; mean score was 8,2±3,1 and 31,8±4,6 in the first and second group, respectively (р<0,01). Total House-Brackman score at baseline was 3,67±0,16 in the first group and 3,74±0,19 in the second group. Treatment resulted in a significant symptom improvement in the first group, with no improvement in the second group. After 4 months of treatment House-Brockman score in the first group was 3,1-fold lower, than in the second group (р<0,05). Conclusion: Botulinum toxin injections decrease postparalytic syndrome symptoms in patients with facial nerve palsy.

Keywords: botulinum toxin, facial nerve palsy, postparalytic syndrome, synkinesis

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Authors: Cecilia Moreira, Rita Paiva, Daniela Macedo, Leonor Ribeiro, Isabel Fernandes, Luis Costa

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Background: Head and neck paragangliomas are a rare group of tumors with a large spectrum of clinical manifestations. The approach to evaluate and treat these lesions has evolved over the last years. Surgery was the standard for the approach of these patients, but nowadays new techniques of imaging and radiation therapy changed that paradigm. Despite advances in treating, the growth potential and clinical outcome of individual cases remain largely unpredictable. Objectives: Characterization of our institutional experience with clinical management of these tumors. Methods: This was a cross-sectional study of patients followed in our institution between 01 January and 31 December 2017 with paragangliomas of the head and neck and cranial base. Data on tumor location, catecholamine levels, and specific imaging modalities employed in diagnostic workup, treatment modality, tumor control and recurrence, complications of treatment and hereditary status were collected and summarized. Results: A total of four female patients were followed between 01 January and 31 December 2017 in our institution. The mean age of our cohort was 53 (± 16.1) years. The primary locations were at the level of the tympanic jug (n=2, 50%) and carotid body (n=2, 50%), and only one of the tumors of the carotid body presented pulmonary metastasis at the time of diagnosis. None of the lesions were catecholamine-secreting. Two patients underwent genetic testing, with no mutations identified. The initial clinical presentation was variable highlighting the decrease of visual acuity and headache as symptoms present in all patients. In one of the cases, loss of all teeth of the lower jaw was the presenting symptomatology. Observation with serial imaging, surgical extirpation, radiation, and stereotactic radiosurgery were employed as treatment approaches according to anatomical location and resectability of lesions. As post-therapeutic sequels the persistence of tinnitus and disabling pain stands out, presenting one of the patients neuralgia of the glossopharyngeal. Currently, all patients are under regular surveillance with a median follow up of 10 months. Conclusion: Ultimately, clinical management of these tumors remains challenging owing to heterogeneity in clinical presentation, the existence of multiple treatment alternatives, and potential to cause serious detriment to critical functions and consequently interference with the quality of life of the patients.

Keywords: clinical outcomes, head and neck, management, paragangliomas

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Authors: Yuanyuan Zhang, Yujuan Zheng, Giuseppina Barutello, Sumako Kameishi, Kungchun Chiu, Katharina Hennig, Martial Balland, Federica Cavallo, Lars Holmgren

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Angiogenesis describes that new blood vessels migrate from pre-existing ones to form 3D lumenized structure and remodeling. During directional migration toward the gradient of pro-angiogenic factors, the endothelial cells, especially the tip cells need filopodia to sense the environment and exert the pulling force. Of particular interest are the integrin proteins, which play an essential role in focal adhesion in the connection between migrating cells and extracellular matrix (ECM). Understanding how these biomechanical complexes orchestrate intrinsic and extrinsic forces is important for our understanding of the underlying mechanisms driving angiogenesis. We have previously identified Angiomotin (Amot), a member of Amot scaffold protein family, as a promoter for endothelial cell migration in vitro and zebrafish models. Hence, we established inducible endothelial-specific Amot knock-out mice to study normal retinal angiogenesis as well as tumor angiogenesis. We found that the migration ratio of the blood vessel network to the edge was significantly decreased in Amotec- retinas at postnatal day 6 (P6). While almost all the Amot defect tip cells lost migration advantages at P7. In consistence with the dramatic morphology defect of tip cells, there was a non-autonomous defect in astrocytes, as well as the disorganized fibronectin expression pattern correspondingly in migration front. Furthermore, the growth of transplanted LLC tumor was inhibited in Amot knockout mice due to fewer vasculature involved. By using MMTV-PyMT transgenic mouse model, there was a significantly longer period before tumors arised when Amot was specifically knocked out in blood vessels. In vitro evidence showed that Amot binded to beta-actin, Integrin beta 1 (ITGB1), Fibronectin, FAK, Vinculin, major focal adhesion molecules, and ITGB1 and stress fibers were distinctly induced by Amot transfection. Via traction force microscopy, the total energy (force indicater) was found significantly decreased in Amot knockdown cells. Taken together, we propose that Amot is a novel partner of the ITGB1/Fibronectin protein complex at focal adhesion and required for exerting force transition between endothelial cell and extracellular matrix.

Keywords: angiogenesis, angiomotin, endothelial cell migration, focal adhesion, integrin beta 1

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Authors: N. D'Amico, E. Grossi, B. Colombo, F. Rigiroli, M. Buscema, D. Fazzini, G. Cornalba, S. Papa

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Purpose: To characterize, through a radiomic approach, the nature of nodules considered non-specific by expert radiologists, recognized in magnetic resonance mammography (MRm) with T1-weighted (T1w) sequences with paramagnetic contrast. Material and Methods: 47 cases out of 1200 undergoing MRm, in which the MRm assessment gave uncertain classification (non-specific nodules), were admitted to the study. The clinical outcome of the non-specific nodules was later found through follow-up or further exams (biopsy), finding 35 benign and 12 malignant. All MR Images were acquired at 1.5T, a first basal T1w sequence and then four T1w acquisitions after the paramagnetic contrast injection. After a manual segmentation of the lesions, done by a radiologist, and the extraction of 150 radiomic features (30 features per 5 subsequent times) a machine learning (ML) approach was used. An evolutionary algorithm (TWIST system based on KNN algorithm) was used to subdivide the dataset into training and validation test and to select features yielding the maximal amount of information. After this pre-processing, different machine learning systems were applied to develop a predictive model based on a training-testing crossover procedure. 10 cases with a benign nodule (follow-up older than 5 years) and 18 with an evident malignant tumor (clear malignant histological exam) were added to the dataset in order to allow the ML system to better learn from data. Results: NaiveBayes algorithm working on 79 features selected by a TWIST system, resulted to be the best performing ML system with a sensitivity of 96% and a specificity of 78% and a global accuracy of 87% (average values of two training-testing procedures ab-ba). The results showed that in the subset of 47 non-specific nodules, the algorithm predicted the outcome of 45 nodules which an expert radiologist could not identify. Conclusion: In this pilot study we identified a radiomic approach allowing ML systems to perform well in the diagnosis of a non-specific nodule at MR mammography. This algorithm could be a great support for the early diagnosis of malignant breast tumor, in the event the radiologist is not able to identify the kind of lesion and reduces the necessity for long follow-up. Clinical Relevance: This machine learning algorithm could be essential to support the radiologist in early diagnosis of non-specific nodules, in order to avoid strenuous follow-up and painful biopsy for the patient.

Keywords: breast, machine learning, MRI, radiomics

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