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

Authors: Włodzimierz Lewandowski, Renata Świsłocka, Aleksandra Golonko, Grzegorz Świderski, Monika Kalinowska

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Caffeic acid (3,4-dihydroxycinnamic) is distributed in a free form or as ester conjugates in many fruits, vegetables and seasonings including plants used for medical purpose. Caffeic acid is present in propolis – a substance with exceptional healing properties used in natural medicine since ancient times. The antioxidant, antibacterial, antiinflammatory and anticarcinogenic properties of caffeic acid are widely described in the literature. The biological activity of chemical compounds can be modified by the synthesis of their derivatives or metal complexes. The structure of the compounds determines their biological properties. This work is a continuation of the broader topic concerning the investigation of the correlation between the electronic charge distribution and biological (anticancer and antioxidant) activity of the chosen phenolic acids and their metal complexes. In the framework of this study the synthesis of new metal complexes of sodium, magnesium, aluminium, iron (III) ruthenium (III) and osmium (III) with caffeic acid was performed. The spectroscopic properties of these compounds were studied by means of FT-IR, FT-Raman, UV-Vis, ¹H and ¹³C NMR. The quantum-chemical calculations (at B3LYP/LAN L2DZ level) of caffeic acid and selected complexes were done. Moreover the antioxidant properties of synthesized complexes were studied in relation to selected stable radicals (method of reduction of DPPH and method of reduction of ABTS). On the basis of the differences in the number, intensity and locations of the bands from the IR, Raman, UV/Vis and NMR spectra of caffeic acid and its metal complexes the effect of metal cations on the electronic system of ligand was discussed. The geometry, theoretical spectra and electronic charge distribution were calculated by the use of Gaussian 09 programme. The geometric aromaticity indices (Aj – normalized function of the variance in bond lengths; BAC - bond alternation coefficient; HOMA – harmonic oscillator model of aromaticity and I₆ – Bird’s index) were calculated and the changes in the aromaticity of caffeic acid and its complexes was discussed. This work was financially supported by National Science Centre, Poland, under the research project number 2014/13/B/NZ7/02-352.

Keywords: antioxidant properties, caffeic acid, metal complexes, spectroscopic methods

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Authors: Arpit Kumar Shrivastava, Subrat Kumar, Rajani Kanta Mohapatra, Priyadarshi Soumyaranjan Sahu

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Computational approaches to predict structure, function and other biological characteristics of proteins are becoming more common in comparison to the traditional methods in drug discovery. Cryptosporidiosis is a major zoonotic diarrheal disease particularly in children, which is caused primarily by Cryptosporidium hominis and Cryptosporidium parvum. Currently, there are no vaccines for cryptosporidiosis and recommended drugs are not effective. With the availability of complete genome sequence of C. hominis, new targets have been recognized for the development of effective and better drugs and/or vaccines. We identified a unique hypothetical epitopic protein in C. hominis genome through BLASTP analysis. A 3D model of the hypothetical protein was generated using I-Tasser server through threading methodology. The quality of the model was validated through Ramachandran plot by PROCHECK server. The functional annotation of the hypothetical protein through DALI server revealed structural similarity with human Transportin 3. Phylogenetic analysis for this hypothetical protein also showed C. hominis hypothetical protein (CUV04613) was the closely related to human transportin 3 protein. The 3D protein model is further subjected to virtual screening study with inhibitors from the Zinc Database by using Dock Blaster software. Docking study reported N-(3-chlorobenzyl) ethane-1,2-diamine as the best inhibitor in terms of docking score. Docking analysis elucidated that Leu 525, Ile 526, Glu 528, Glu 529 are critical residues for ligand–receptor interactions. The molecular dynamic simulation was done to access the reliability of the binding pose of inhibitor and protein complex using GROMACS software at 10ns time point. Trajectories were analyzed at each 2.5 ns time interval, among which, H-bond with LEU-525 and GLY- 530 are significantly present in MD trajectories. Furthermore, antigenic determinants of the protein were determined with the help of DNA Star software. Our study findings showed a great potential in order to provide insights in the development of new drug(s) or vaccine(s) for control as well as prevention of cryptosporidiosis among humans and animals.

Keywords: cryptosporidium hominis, hypothetical protein, molecular docking, molecular dynamics simulation

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Authors: Allam Srinivasa Rao, Ch. Annapurna Devi, G. Vijaya Prakash

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A new-fangled series of white light emitting 1 mol% of Dy3+ ions doped Single-Alklai and Mixed-Alkai fluoro tungstunate tellurite glasses have been prepared using melt quenching technique and their spectroscopic behaviour was investigated by studying XRD, optical absorption, photoluminescence and lifetime measurements. The bonding parameter studies reveal the ionic nature of the Dy-O bond in the present glasses. From the absorption spectra, the Judd–Ofelt (J-O) intensity parameters have been determined which are used to explore the nature of bonding and symmetry orientation of the Dy–ligand field environment. The evaluated J-O parameters (Ω_4>Ω_2>Ω_6) for all the glasses are following the same trend. The photoluminescence spectra of all the glasses exhibit two intensified peaks in blue and Yellow regions corresponding to the transitions 4F9/2→6H15/2 (483 nm) and 4F9/2→6H13/2 (575 nm) respectively. From the photoluminescence spectra, it is observed that the luminescence intensity is maximum for Dy3+ ion doped potassium combination of fluoro tungstunate tellurite glass (TeWK: 1Dy). The J-O intensity parameters have been used to determine the various radiative properties for the different emission transitions from the 4F9/2 fluorescent level. The highest emission cross-section and branching ratio values observed for the 4F9/2→6H15/2 and 4F9/2→6H13/2 transitions suggest the possible laser action in the visible region from these glasses. By using the experimental lifetimes (τ_exp) measured from the decay spectral features and radiative lifetimes (τ_R), the quantum efficiencies (η) for all the glasses have been evaluated. Among all the glasses, the potassium combined fluoro tungstunate tellurite (TeWK:1Dy) glass has the highest quantum efficiency (94.6%). The CIE colour chromaticity coordinates (x, y), (u, v), colour correlated temperature (CCT) and Y/B ratio were also estimated from the photoluminescence spectra for different compositions of glasses. The (x, y) and (u, v) chromaticity colour coordinates fall within the white light region and the white light can be tuned by varying the composition of the glass. From all these studies, we are suggesting that the 1 mol% of Dy3+ ions doped TeWK glass is more suitable for lasing and White-LED applications.

Keywords: dysprosium, Judd-Ofelt parameters, photo luminescence, tellurite glasses

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Authors: Eddy K. Mukadi

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This work is a documentary and descriptive study devoted to the epidemiological, clinical, histopathological and therapeutic profile of breast cancer deals with the department of gynecology and obstetrics of the university clinics of Kinshasa during the period from 1 January 2014 to 31 December 2014. We have identified 56 cases of breast cancer. These cancers accounted for 45.2% of gynecological mammary cancers. The youngest in our series was 18 years old while the oldest was 74 years old; And the mean age of these patients was 43.4 years and mostly multiparous (35.7%). Brides (60.7%) and bachelors (26.8%) were the most affected by breast cancer. The reasons for consultation were dominated by nodules in the breast (48.2%) followed by pain (35.7%) and nipple discharge (14.3%). In 89.2% of the cases, it was the advanced clinical stage (stage 3 and 4) and the infiltrating ductal carcinoma was the most frequent histological type (75%) The malignant tumor was mainly in the left breast (55.3%), and chemotherapy with hormone therapy and patey was the most convenient treatment (42.8%), while patey mastectomy was performed in 12.5% of patients. Because of the high incidence of breast cancer identified in our study, some preventive measures must be taken into account to address this public health problem, including breast autopalpation once a month, Early detection system development of a national breast cancer policy and the implementation of a national breast cancer control program.

Keywords: breast cancer, histopathological profile, epidemiological profile, Kinshasa

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Authors: Xian-Peng Jiang, Catherine C. Baucom, Toby Jiang, Robert L. Elliott

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HLA-G binds to the inhibitory receptors of uterine NK cells and plays an important role in protection of fetal cells from maternal NK lysis. HLA-G also mediates tumor escape, but the immunosuppressive role is often neglected. These studies have focused on the examination of HLA-G expression in human breast carcinoma and HLA-G immunosuppressive role in NK cytolysis. We examined HLA-G expression in breast cell lines by real time PCR, ELISA and immunofluorescent staining. We treated the breast cancer cell lines with anti-human HLA-G antibody or progesterone. Then, NK cytolysis was measured by using MTT assay. We find that breast carcinoma cell lines increase the expression of HLA-G mRNA and protein, compared to normal cells. Blocking HLA-G of the breast cancer cells by the antibody increases NK cytolysis. Progesterone upregulates HLA-G mRNA and protein of human breast cancer cell lines. The increased HLA-G expression suppresses NK cytolysis. In summary, human breast carcinoma overexpress HLA-G immunosuppressive molecules. Blocking HLA-G protein by antibody improves NK cytolysis. In contrast, upregulation of HLA-G expression by progesterone impairs NK cytolytic function. Thus, HLA-G is a new immunosuppressive checkpoint and potential cancer immunotherapeutic target.

Keywords: HLA-G, Breast carcinoma, NK cells, Immunosuppressive checkpoint

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Authors: Vandana Singh, Subash Singh

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Introduction: Oral squamous cell carcinoma is the most common malignant tumor of the oral cavity. Normally the death of cell and the growth are active processes and depend not only on external factors but also on the expression of genes like Bcl-2, which activate and inhibit apoptosis. The term Bcl-2 is an acronym for B-cell lymphoma/ leukemia -2 genes. Objectives: An attempt was made to evaluate Bcl-2 oncoprotein expression in patients with oral precancer and cancer and to assess possible correlation between Bcl-2 oncoprotein expression and clinicopathological features of oral precancer and cancer. Material and Methods: This is a selective prospective clinical and immunohistochemical study. Clinicopathological examination is correlated with immunohistochemical findings. The immunolocalization of Bcl-2 protein is performed using the labeled streptavidin biotin (LSAB) method. To visualize the reaction, 3, 3-diaminobenzidine (DAB) is used. Results: Bcl-2 expression was positive in 11 [36.66 %, low Bcl-2 expression 3 (10.00 %), moderate Bcl-2 expression 7 (23.33 %), and high Bcl-2 expression 1 (3.33 %)] oral cancer cases and in 14 [87.50 %, low expression 8 (50 %), moderate expression 6 (37.50 %)] precancer cases. Conclusion: On the basis of the results of our study we conclude that positive Bcl-2 expression may be an indicator of poor prognosis in oral cancer and precancer. Relevance: It has been reported that there is deregulation of Bcl-2 expression during progression from oral epithelial dysplasia to squamous cell carcinoma. It can be used for revealing progression of epithelial dysplasia to malignancy and as a prognostic marker in oral precancer and cancer.

Keywords: BcL-2, immunohistochemistry, oral cancer, oral precancer

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Authors: Wellemans Isabelle, Remmelink Myriam, Foucart Annick, Rusu Stefan, Compère Christophe

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Primary pulmonary meningioma (PPM) is a very rare tumor, and its occurrence has been reported only sporadically. Multiple PPMs are even more exceptional, and herein, we report, to the best of our knowledge, the fourth case, focusing on the clinicopathological features of the tumor. Moreover, the possible relationship between the use of progesterone–only contraceptives and the development of these neoplasms will be discussed. Case Report: We report a case of a 51-year-old female presenting three solid pulmonary nodules, with the following localizations: right upper lobe, middle lobe, and left lower lobe, described as incidental findings on computed tomography (CT) during a pre-bariatric surgery check-up. The patient revealed no drinking or smoking history. The physical exam was unremarkable except for the obesity. The lesions ranged in size between 6 and 24 mm and presented as solid nodules with lobulated contours. The largest lesion situated in the middle lobe had mild fluorodeoxyglucose (FDG) uptake on F-18 FDG positron emission tomography (PET)/CT, highly suggestive of primary lung neoplasm. For pathological assessment, video-assisted thoracoscopic middle lobectomy and wedge resection of the right upper nodule was performed. Histological examination revealed relatively well-circumscribed solid proliferation of bland meningothelial cells growing in whorls and lobular nests, presenting intranuclear pseudo-inclusions and psammoma bodies. No signs of anaplasia were observed. The meningothelial cells expressed diffusely Vimentin, focally Progesterone receptors and were negative for epithelial (cytokeratin (CK) AE1/AE3, CK7, CK20, Epithelial Membrane Antigen (EMA)), neuroendocrine markers (Synaptophysin, Chromogranin, CD56) and Estrogenic receptors. The proliferation labelling index Ki-67 was low (<5%). Metastatic meningioma was ruled out by brain and spine magnetic resonance imaging (MRI) scans. The third lesion localized in the left lower lobe was followed-up and resected three years later because of its slow but significant growth (14 mm to 16 mm), alongside two new infra centimetric lesions. Those three lesions showed a morphological and immunohistochemical profile similar to previously resected lesions. The patient was disease-free one year post-last surgery. Discussion: Although PPMs are mostly benign and slow-growing tumors with an excellent prognosis, they do not present specific radiological characteristics, and it is difficult to differentiate it from other lung tumors, histopathologic examination being essential. Aggressive behavior is associated with atypical or anaplastic features (WHO grades II–III) The etiology is still uncertain and different mechanisms have been proposed. A causal connection between sexual hormones and meningothelial proliferation has long been suspected and few studies examining progesterone only contraception and meningioma risk have all suggested an association. In line with this, our patient was treated with Levonorgestrel, a progesterone agonist, intra-uterine device (IUD). Conclusions: PPM, defined by the typical histological and immunohistochemical features of meningioma in the lungs and the absence of central nervous system lesions, is an extremely rare neoplasm, mainly solitary and associating, and indolent growth. Because of the unspecific radiologic findings, it should always be considered in the differential diagnosis of lung neoplasms. Regarding multiple PPM, only three cases are reported in the literature, and this is the first described in a woman treated by a progesterone-only IUD to the best of our knowledge.

Keywords: pulmonary meningioma, multiple meningioma, meningioma, pulmonary nodules

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Authors: Richa Dhingra, Monika, Manav Malhotra, Tilak Raj Bhardwaj, Neelima Dhingra

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5-Alpha-reductases (5AR), a membrane bound, NADPH dependent enzyme and convert male hormone testosterone (T) into more potent androgen dihydrotestosterone (DHT). DHT is the required for the development and function of male sex organs, but its overproduction has been found to be associated with physiological conditions like Benign Prostatic Hyperplasia (BPH). Thus the inhibition of 5ARs could be a key target for the treatment of BPH. In present study, 2D and 3D Quantitative Structure Activity Relationship (QSAR) pharmacophore models have been generated for 5AR based on known inhibitory concentration (IC₅₀) values with extensive validations. The four featured 2D pharmacophore based PLS model correlated the topological interactions (–OH group connected with one single bond) (SsOHE-index); semi-empirical (Quadrupole2) and physicochemical descriptors (Mol. wt, Bromines Count, Chlorines Count) with 5AR inhibitory activity, and has the highest correlation coefficient (r² = 0.98, q² =0.84; F = 57.87, pred r² = 0.88). Internal and external validation was carried out using test and proposed set of compounds. The contribution plot of electrostatic field effects and steric interactions generated by 3D-QSAR showed interesting results in terms of internal and external predictability. The well validated 2D Partial Least Squares (PLS) and 3D k-nearest neighbour (kNN) models were used to search novel 5AR inhibitors with different chemical scaffold. To gain more insights into the molecular mechanism of action of these steroidal derivatives, molecular docking and in silico absorption, distribution, metabolism, and excretion (ADME) studies were also performed. Studies have revealed the hydrophobic and hydrogen bonding of the ligand with residues Alanine (ALA) 63A, Threonine (THR) 60A, and Arginine (ARG) 456A of 4AT0 protein at the hinge region. The results of QSAR, molecular docking, in silico ADME studies provide guideline and mechanistic scope for the identification of more potent 5-Alpha-reductase inhibitors (5ARI).

Keywords: 5α-reductase inhibitor, benign prostatic hyperplasia, ligands, molecular docking, QSAR

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Authors: Minzi Mao, Jianjun Ren, Yu Zhao

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Objectives: The absence of a uniform staging scheme for temporal bone carcinoma (TBC) seriously impedes the improvement of its management strategies. Therefore, this research was aimed to investigate the prognostic values of two currently applying staging schemes, namely, the modified Pittsburgh staging system (MPB) and Stell’s T classification (Stell-T) in patients with TBC. Methods: Areal-world single-institution retrospectivereview of patientsdiagnosed with TBC between2008 and 2019 was performed. Baseline characteristics were extracted, and patients were retrospectively staged by both the MPB and Stell-T classifications. Cox regression analyseswereconductedtocomparetheoverall survival (OS). Results: A total of 69 consecutive TBC patients were included in thisstudy. Univariate analysis showed that both Stell-T and T- classifications of the modified Pittsburgh staging system (MPB-T) were significant prognostic factors for all TBC patients as well as temporal bone squamous cell carcinoma (TBSCC, n=50) patients (P < 0.05). However, only Stell-T was confirmed to be an independent prognostic factor in TBSCC patients (P = 0.004). Conclusions: Tumor extensions, quantified by both Stell-T and MPB-T classifications, are significant prognostic factors for TBC patients, especially for TBSCC patients. However, only the Stell-T classification is an independent prognostic factor for TBSCC patients.

Keywords: modified pittsburgh staging system, overall survival, prognostic factor, stell’s T- classification, temporal bone carcinoma

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Authors: Jinfeng Zhang, Chun-Sing Lee

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The use of different nanocarriers for delivering hydrophobic pharmaceutical agents to tumor sites has garnered major attention. Despite the merits of these nanocarriers, further studies are needed for improving their drug loading capacities (typically less than 10%) and reducing their potential systemic toxicity. So development of alternative self-carried nanodrug delivery strategies without using any inert carriers is highly desirable. In this study, we developed a self-carried theranostic curcumin (Cur) nanodrug for highly effective cancer therapy in vitro and in vivo with real-time monitoring of drug release. With a biocompatible C18PMH-PEG functionalization, the Cur nanoparticles (NPs) showed excellent dispersibility and outstanding stability in physiological environment, with drug loading capacity higher than 78 wt.%. Both confocal microscopy and flow cytometry confirmed the cellular fluorescent “OFF-ON” activation and real-time monitoring of Cur molecule release, showing its potential for cancer diagnosis. In vitro and in vivo experiments clearly show that therapeutic efficacy of the PEGylated Cur NPs is much better than that of free Cur. This self-carried theranostic strategy with real-time monitoring of drug release may open a new way for simultaneous cancer therapy and diagnosis.

Keywords: drug delivery, in vitro and in vivo cancer therapy, real-time monitoring, self-carried

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Authors: Yanuarti Retnaningrum, Cendrawasih A. Farmasyanti, Kuswahyuning

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Orthodontists find challenges in treating patients who have cases of macroglossia and multiple tooth agenesis because difficulties in determining the causes, formulating a diagnosis and the potential for relapse after treatment. Definition of macroglossia is a tongue enlargement due to muscle hypertrophy, tumor or an endocrine disturbance. Macroglossia may cause many problems such as anterior proclination of upper and lower incisors, development of general diastema and anterior and/ or posterior open bite. Treatment for such patients with multiple tooth agenesis and macroglossia can be complex and must consider orthodontic and/or surgical interventions. This article discusses an orthodontic non surgical approach to a patient with a general diastema in both maxilla and mandible associated with multiple tooth agenesis and macroglossia. Fixed orthodontic therapy with straightwire appliance was used for space closure in anterior region of maxilla and mandible, also to create a space suitable for future prosthetic restoration. After 12 months treatment, stable and functional occlusal relationships was achieved, although still have edentulous area in both maxilla and mandible. At the end of the orthodontic treatment was obtained with correct overbite and overjet values. After removal of the brackets, a maxillary and mandibular removable retainer combine with artificial tooth were placed for retention.

Keywords: general diastema, macroglossia, space closure, tooth agenesis

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Authors: Santosh Tummidi, Pragati Sathe, Kanchan Kothari, Prachi Gholap, Mona Agnihotri, Gwendolyn Fernandes, Leena Naik, Rachana Chaturvedi

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Introduction: EUS-Guided Fine Needle Aspiration/Brush (EUS-FNA/Brush) has become increasingly popular for the diagnosis and staging of gastrointestinal and peri-gastrointestinal lesions. Objective: To evaluate the diagnostic accuracy and spectrum of lesions in gastrointestinal EUS-FNA. Material and Methods: A total of 124 EUS-FNA during the period from Aug 2015-Nov 2016 were studied. Results: Age ranged from 13-80 years with a slight female predominance. CBD was the most common site with 47 cases amongst which were 9 adenocarcinoma, and 7 cases were suspicious for malignancy. Pancreatic EUS-FNA showed 5 adenocarcinoma, 2 SPEN, 1 case each of neuroendocrine tumor, anaplastic carcinoma and NHL. Amongst oesophageal lesions, 3 cases were suspicious for malignancy, and 4 were inflammatory, 4 showed SCC, 1case each adenocarcinoma and leiomyoma. Stomach- 1 case each of adenocarcinoma, granulomatous inflammation, and GIST. Periportal lymph nodes were the commonest nodes, and there were 11 necrotising granulomatous inflammations, 3 metastatic adenocarcinoma, 2 cases of atypical cells and 1 case of NHL. 17 cases were unsatisfactory, 41 cases had histopathology follow up with 85% cases being concordant. Conclusion: EUS-FNA is reliable, sensitive and specific. It can be utilized for better management of intra-abdominal lesions.

Keywords: EUS-FNA, brush, cytology, histopathology

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Authors: Aya Al Masri, Stefaan Carpentier, Fabrice Leroy, Thibault Julien, Safoin Aktaou, Malorie Martin, Fouad Maaloul

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Introduction: During an 'Interventional Radiology (IR)' procedure, the patient's skin-dose may become very high for a burn, necrosis and ulceration to appear. In order to prevent these deterministic effects, an accurate calculation of the patient skin-dose mapping is essential. For most machines, the 'Dose Area Product (DAP)' and fluoroscopy time are the only information available for the operator. These two parameters are a very poor indicator of the peak skin dose. We developed a mathematical model that reconstructs the magnitude (delivered dose), shape, and localization of each irradiation field on the patient skin. In case of critical dose exceeding, the system generates warning alerts. We present the results of its comparison with clinical studies. Materials and methods: Two series of comparison of the skin-dose mapping of our mathematical model with clinical studies were performed: 1. At a first time, clinical tests were performed on patient phantoms. Gafchromic films were placed on the table of the IR machine under of PMMA plates (thickness = 20 cm) that simulate the patient. After irradiation, the film darkening is proportional to the radiation dose received by the patient's back and reflects the shape of the X-ray field. After film scanning and analysis, the exact dose value can be obtained at each point of the mapping. Four experimentation were performed, constituting a total of 34 acquisition incidences including all possible exposure configurations. 2. At a second time, clinical trials were launched on real patients during real 'Chronic Total Occlusion (CTO)' procedures for a total of 80 cases. Gafchromic films were placed at the back of patients. We performed comparisons on the dose values, as well as the distribution, and the shape of irradiation fields between the skin dose mapping of our mathematical model and Gafchromic films. Results: The comparison between the dose values shows a difference less than 15%. Moreover, our model shows a very good geometric accuracy: all fields have the same shape, size and location (uncertainty < 5%). Conclusion: This study shows that our model is a reliable tool to warn physicians when a high radiation dose is reached. Thus, deterministic effects can be avoided.

Keywords: clinical experimentation, interventional radiology, mathematical model, patient's skin-dose mapping.

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Authors: Jamboor K. Vishwanatha

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Among the potent anti-cancer agents, curcumin has been found to be very efficacious against various cancer cells. Despite multiple medicinal benefits of curcumin, poor water solubility, poor physiochemical properties and low bioavailability continue to pose major challenges in developing a formulation for clinical efficacy. To improve its potential application in the clinical area, we formulated poly lactic-co-glycolic acid (PLGA) nanoparticles. The PLGA nanoparticles were formulated using solid-oil/water emulsion solvent evaporation method and then characterized for percent yield, encapsulation efficiency, surface morphology, particle size, drug distribution within nanoparticles and drug polymer interaction. Our studies showed the successful formation of smooth and spherical curcumin loaded PLGA nanoparticles with a high percent yield of about 92.01±0.13% and an encapsulation efficiency of 90.88±0.14%. The mean particle size of the nanoparticles was found to be 145nm. The in vitro drug release profile showed 55-60% drug release from the nanoparticles over a period of 24 hours with continued sustained release over a period of 8 days. Exposure to curcumin loaded nanoparticles resulted in reduced cell viability of cancer cells compared to normal cells. We used a novel non-covalent insertion of a homo-bifunctional spacer for targeted delivery of curcumin to various cancer cells. Functionalized nanoparticles for antibody/targeting agent conjugation was prepared using a cross-linking ligand, bis(sulfosuccinimidyl) suberate (BS3), which has reactive carboxyl group to conjugate efficiently to the primary amino groups of the targeting agents. In our studies, we demonstrated successful conjugation of antibodies, Annexin A2 or prostate specific membrane antigen (PSMA), to curcumin loaded PLGA nanoparticles for targeting to prostate and breast cancer cells. The percent antibody attachment to PLGA nanoparticles was found to be 92.8%. Efficient intra-cellular uptake of the targeted nanoparticles was observed in the cancer cells. These results have emphasized the potential of our multifunctional curcumin nanoparticles to improve the clinical efficacy of curcumin therapy in patients with cancer.

Keywords: polymeric nanoparticles, cancer therapy, sustained release, curcumin

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Authors: Basma Hassabo, Sarah Ahmed, Aisha Hameed

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Aims and Objectives: To determine the incidence of maternal mortality amongst pregnant women with sickle cell disease (SCD) in the United Kingdom and to determine exact cause of death in these women. Background: SCD is caused by the ‘sickle’ gene and is characterized by episodes of severe bone pain and other complications like acute chest syndrome, chronic pulmonary hypertension, stroke, retinopathy, chronic renal failure, hepato-splenic crises, avascular bone necrosis, sepsis and leg ulcers. SCD is a continual cause of maternal mortality and fetal complications, and it comprises 1.5% of all Direct and Indirect deaths in the UK. Sepsis following premature rupture of membranes with ascending infection, post-partum infection and pre-labour overwhelming septic shock is one of its leading causes of death. Over the last fifty years of maternal mortality reports in UK, between 1 to 4 pregnant women died in each triennium. Material and Method: This is a retrospective study that involves pregnant women who died from SCD complications in the UK between 1952-2012. Data were collected from the UK Confidential Enquiries into Maternal Death and its causes between 1952–2012. Prior to 1985, exact cause of death in this cohort was not recorded. Results: 33 deaths reported between 1964 and 1984. 17 deaths were reported due to sickle cell disease between 1985 and 2012. Five women in this group died of sickle cell crisis, one woman had liver sequestration crisis, two women died of venous thromboembolism, two had myocardial fibrosis and three died of sepsis. Remaining women died of amniotic fluid embolism, SUDEP, myocardial ischemia and intracranial haemorrhage. Conclusion: The leading causes of death in sickle cell sick pregnant women are sickle cell crises, sepsis, venous thrombosis and thromboembolism. Prenatal care for women with SCD should be managed by a multidisciplinary team that includes an obstetrician, nutritionist, primary care physician, and haematologist. In every sick Sickle Cell woman Sickle Cell crises should be on the top of the list of differential diagnosis. Aggressive treatment of complications with low threshold to commence broad-spectrum antibiotics and LMWH contribute to better outcomes.

Keywords: incidence, maternal mortality, sickle cell disease (SCD), uk

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Authors: Mariam Mojally, Randa Abdou, Wisal Bokhari, Sultan Sab, Mohammed Dawoud, Amjad Albohy

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Secondary metabolites produced by endophytes are an excellent source of biologically active compounds. In our current study, we evaluated terezine E and 14-hydroxyterezine D for binding to the active site of histone deacetylase (PDB ID: 4CBT) and matrix metalloproteinase 9 (PDB ID: 4H3X) by molecular docking using AutoDock Vina software after having tested their cytotoxic activities on three cell lines (human ductal breast epithelial tumor cells (T47D)-HCC1937), human hepatocarcinoma cell line (HepG2)-HB8065), and human colorectal carcinoma cells (HCT-116)-TCP1006, purchased from ATCC, USA)). Additionally, their antimicrobial activities were investigated, and their minimum inhibitory concentration (MIC) values were determined against P. notatum and S. aureus by the broth microdilution method. Higher cytotoxicity was observed for terezine E against all tested cell lines compared to 14-hydroxyterezine D. Molecular docking results supported the high cytotoxicity of terezine E and showed higher binding affinity with 4CBT with an energy score of 9 kcal/mol. Terezine E showed higher antibacterial and antifungal activities than 14-hydroxyrerezine D: MIC values were 15.45 and 21.73 mg/mL against S. aureus and 8.61 and 11.54 mg/mL against P. notatum, respectively

Keywords: Terezine E, 14-Hydroxyterezine D, cytotoxicity, antimicrobial activity, molecular docking

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Authors: Musatafa Abbas Abbood Albadr, Masri Ayob, Sabrina Tiun, Fahad Taha Al-Dhief, Mohammad Kamrul Hasan

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Breast Cancer (BC) is considered one of the most frequent reasons of cancer death in women between 40 to 55 ages. The BC is diagnosed by using digital images of the FNA (Fine Needle Aspirate) for both benign and malignant tumors of the breast mass. Therefore, this work proposes the Online Sequential Extreme Learning Machine (OSELM) algorithm for diagnosing BC by using the tumor features of the breast mass. The current work has used the Wisconsin Diagnosis Breast Cancer (WDBC) dataset, which contains 569 samples (i.e., 357 samples for benign class and 212 samples for malignant class). Further, numerous measurements of assessment were used in order to evaluate the proposed OSELM algorithm, such as specificity, precision, F-measure, accuracy, G-mean, MCC, and recall. According to the outcomes of the experiment, the highest performance of the proposed OSELM was accomplished with 97.66% accuracy, 98.39% recall, 95.31% precision, 97.25% specificity, 96.83% F-measure, 95.00% MCC, and 96.84% G-Mean. The proposed OSELM algorithm demonstrates promising results in diagnosing BC. Besides, the performance of the proposed OSELM algorithm was superior to all its comparatives with respect to the rate of classification.

Keywords: breast cancer, machine learning, online sequential extreme learning machine, artificial intelligence

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Authors: Neeraj Kumar Mishra, In Su Kim

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The isoindoline, indazole and indole heterocycles are ubiquitous structural motif found in heterocyclic compounds as they exhibit biological and medicinal applications. For example, isoindoline motif is present in molecules that act as endothelin-A receptor antagonists and dipeptidyl peptidase inhibitors. Moreover, isoindoline derivatives are very crucial constituents in the field of materials science as attractive candidates for organic light-emitting devices. However, compounds containing the indazole motif are known to exhibit to a variety of biological activities, such as estrogen receptor, HIV protease inhibition and anti-tumor activity. The prevalence of indazoles and indoles has led to the development of many useful methods for their preparation. Thus, isoindoline, indazole and indole heterocycles can be new candidates for the next generation of pharmaceuticals. Therefore, the development of highly efficient strategies for the formation of these heterocyclic architectures is an area of great interest in organic synthesis. The past years, transition-metal-catalyzed C−H activation followed by annulation reaction has been frequently used as a powerful tool to construct various heterocycles. Herein, we describe our recent achievements about the transition-metal-catalyzed tandem cyclization reactions of N-benzyltriflamides, 1,2-disubstituted arylhydrazines, acetanilides, etc. via C−H bond activation to access the corresponding bioactive heterocylic scaffolds.

Keywords: biologically active, C-H activation, heterocyclic compounds, transition-metal catalysts

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Authors: Madhusudan Purohit, Stephen Philip, Bharathkumar Inturi

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In this paper we report the quantitative structure activity relationship of novel bis-triazole derivatives for predicting the activity profile. The full model encompassed a dataset of 46 Bis- triazoles. Tripos Sybyl X 2.0 program was used to conduct CoMSIA QSAR modeling. The Partial Least-Squares (PLS) analysis method was used to conduct statistical analysis and to derive a QSAR model based on the field values of CoMSIA descriptor. The compounds were divided into test and training set. The compounds were evaluated by various CoMSIA parameters to predict the best QSAR model. An optimum numbers of components were first determined separately by cross-validation regression for CoMSIA model, which were then applied in the final analysis. A series of parameters were used for the study and the best fit model was obtained using donor, partition coefficient and steric parameters. The CoMSIA models demonstrated good statistical results with regression coefficient (r2) and the cross-validated coefficient (q2) of 0.575 and 0.830 respectively. The standard error for the predicted model was 0.16322. In the CoMSIA model, the steric descriptors make a marginally larger contribution than the electrostatic descriptors. The finding that the steric descriptor is the largest contributor for the CoMSIA QSAR models is consistent with the observation that more than half of the binding site area is occupied by steric regions.

Keywords: 3D QSAR, CoMSIA, triazoles, novel heterocycles

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Authors: Shakir H. Mohammed Al-Alwany, Saad Hasan M. Ali, Ibrahim Mohammed S. Shnawa

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The study was aimed to define the percentage of detection of high-oncogenic risk types of HPV and their genotyping in archival tissue specimens that ranged from apparently healthy tissue to invasive breast cancer by using one of the recent versions of In Situ Hybridization(ISH) 0.2. To find out rational significance of such genotypes as well as over expressed products of mutants P53 and RB genes on the severity of underlying breast cancers. The DNA of HPV was detected in 46.5 % of tissues from breast cancers while HPV DNA in the tissues from benign breast tumours was detected in 12.5%. No HPV positive–ISH reaction was detected in healthy breast tissues of the control group. HPV DNA of genotypes (16, 18, 31 and 33) was detected in malignant group in frequency of 25.6%, 27.1%, 30.2% and 12.4%, respectively. Over expression of p53 was detected by IHC in 51.2% breast cancer cases and in 50% benign breast tumour group, while none of control group showed P53- over expression. Retinoblastoma protein was detected by IHC test in 49.7% of malignant breast tumours, 54.2% of benign breast tumours but no signal was reported in the tissues of control group. The significance prevalence of expression of mutated p53 & Rb genes as well as detection of high-oncogenic HPV genotypes in patients with breast cancer supports the hypothesis of an etiologic role for the virus in breast cancer development.

Keywords: human papilloma virus, P53, RB, breast cancer

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Authors: Aditya Karade, Sharada Falane, Dhananjay Deshmukh, Vijaykumar Mantri

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Brain tumors pose a significant challenge in healthcare due to their complex nature and impact on patient outcomes. The application of deep learning (DL) algorithms in medical imaging have shown promise in accurate and efficient brain tumour detection. This paper explores the performance of various pre-trained DL models ResNet50, Xception, InceptionV3, EfficientNetB0, DenseNet121, NASNetMobile, VGG19, VGG16, and MobileNet on a brain tumour dataset sourced from Figshare. The dataset consists of MRI scans categorizing different types of brain tumours, including meningioma, pituitary, glioma, and no tumour. The study involves a comprehensive evaluation of these models’ accuracy and effectiveness in classifying brain tumour images. Data preprocessing, augmentation, and finetuning techniques are employed to optimize model performance. Among the evaluated deep learning models for brain tumour detection, ResNet50 emerges as the top performer with an accuracy of 98.86%. Following closely is Xception, exhibiting a strong accuracy of 97.33%. These models showcase robust capabilities in accurately classifying brain tumour images. On the other end of the spectrum, VGG16 trails with the lowest accuracy at 89.02%.

Keywords: brain tumour, MRI image, detecting and classifying tumour, pre-trained models, transfer learning, image segmentation, data augmentation

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Authors: Azhar Jabareen, Mahmoud Huleihel

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BRCA-1 is a multifunctional tumor suppressor, whose expression is activated by the estrogen (E2)-liganded ERα receptor. The activated ERα is a transcriptional factor which activates various genes either by direct binding to the DNA at E2-responsive elements (EREs) and indirectly associated with a range of alternative non-ERE elements. Interference with BRCA-1 expression and/or functions leads to high risk of breast or/and ovarian cancer. Our lab investigated the involvement of Human T-cell leukemia Virus Type 1 (HTLV-1) in breast cancer, since HTLV-1 Tax was found to strongly inhibit BRCA-1 expression. In addition, long exposure of 12-O-tetradecanoylphorbol-13-acetate (TPA), which is one of the stress-inducing agents activated the HTLV-1 promoter. So here the involvement of TPA in breast cancer had been examined by testing the effect of TPA on BRCA-1 and ERE expression. The results showed that TPA activated both BRCA-1 and ERE expression. In the 12 hours TPA activated the tow promoters more than others time, and after 24 hours the level of the tow promoters was decreased. Tax inhibited BRCA-1 expression but did not succeed to inhibit the effect of TPA. Then the activation of the two promoters was not through ERα pathway because TPA had no effect on ERα binding to the two promoters of the BRCA-1 and ERE. Also, the activation was not via nuclear factor kappa B (NF-κB) pathway because when the inhibitory of NF-κB had been added to the TPA, it still activated the tow promoters. However, it seems that 53BP1 may be involved in TPA activation of these promoters because ectopic high expression of 53BP1 significantly reduced the TPA activity. In addition, in the presence of Bisindolylmaleimide-I (BI)- the inhibitor of Protein Kinase C (PKC)- there was no activation for the two promoters, so the PKC is agonized BRCA-1 and ERE activation.

Keywords: BRCA-1, ERE, HTLV-1, TPA

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Authors: Chengcao Sun, Shujun Li, Cuili Yang, Yongyong Xi, Liang Wang, Feng Zhang, Dejia Li

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Recently, the long non-coding RNA (lncRNA) NEAT1 has been identified as an oncogenic gene in multiple cancer types and elevated expression of NEAT1 was tightly linked to tumorigenesis and cancer progression. However, the molecular basis for this observation has not been characterized in progression of non-small cell lung cancer (NSCLC). In our studies, we identified NEAT1 was highly expressed in NSCLC patients and was a novel regulator of NSCLC progression. Patients whose tumors had high NEAT1 expression had a shorter overall survival than patients whose tumors had low NEAT1 expression. Further, NEAT1 significantly accelerates NSCLC cell growth and metastasis in vitro and tumor growth in vivo. Additionally, by using bioinformatics study and RNA pull down combined with luciferase reporter assays, we demonstrated that NEAT1 functioned as a competing endogenous RNA (ceRNA) for has-miR-377-3p, antagonized its functions and led to the de-repression of its endogenous targets E2F3, which was a core oncogene in promoting NSCLC progression. Taken together, these observations imply that the NEAT1 modulated the expression of E2F3 gene by acting as a competing endogenous RNA, which may build up the missing link between the regulatory miRNA network and NSCLC progression.

Keywords: long non-coding RNA NEAT1, hsa-miRNA-377-3p, E2F3, non-small cell lung cancer, tumorigenesis

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Authors: Veronica Sorgato, Jeremy Belhassen, Philippe Chartier, Roddy Sihanath, Nicolas Docquiere, Jean-Yves Giraud

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We analyzed the image-guided radiotherapy method used by the TomoTherapy® System (Accuray Corp.) for patient repositioning in clinical routine. The TomoTherapy® System computes X, Y, Z and roll displacements to match the reference CT, on which the dosimetry has been performed, with the pre-treatment MV CT. The accuracy of the repositioning method has been studied according to the treatment localization. For this, a database of 18774 treatment sessions, performed during 2 consecutive years (2016-2017 period) has been used. The database includes the X, Y, Z and roll displacements proposed by TomoTherapy® System as well as the manual correction of these proposals applied by the radiation therapist. This manual correction aims to further improve the repositioning based on the clinical situation and depends on the structures surrounding the target tumor tissue. The statistical analysis performed on the database aims to define repositioning limits to be used as security and guiding tool for the manual adjustment implemented by the radiation therapist. This tool will participate not only to notify potential repositioning errors but also to further improve patient positioning for optimal treatment.

Keywords: accuracy, IGRT MVCT, image-guided radiotherapy megavoltage computed tomography, statistical analysis, tomotherapy, localization

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Authors: Hatem A. El-Mezayen, Hossam Darwesh

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Background/Aim: Hepatocellular carcinoma (HCC) is often diagnosed at advanced stage where effective therapies are lacking. Identification of new scoring system is needed to discriminate HCC patients from those with chronic liver disease. Based on the link between vascular endothelial growth factor (VEGF) and HCC progression, we aimed to develop a novel score based on combination of VEGF and routine laboratory tests for early prediction of HCC. Methods: VEGF was assayed for HCC group (123), liver cirrhosis group (210) and control group (50) by Enzyme Linked Immunosorbent Assay (ELISA). Data from all groups were retrospectively analyzed including α feto protein (AFP), international normalized ratio (INR), albumin and platelet count, transaminases, and age. Areas under ROC curve were used to develop the score. Results: A novel index named hepatocellular carcinoma-vascular endothelial growth factor score (HCC-VEGF score)=1.26 (numerical constant) + 0.05 ×AFP (U L-1)+0.038 × VEGF(ng ml-1)+0.004× INR –1.02 × Albumin (g l-1)–0.002 × Platelet count × 109 l-1 was developed. HCC-VEGF score produce area under ROC curve of 0.98 for discriminating HCC patients from liver cirrhosis with sensitivity of 91% and specificity of 82% at cut-off 4.4 (ie less than 4.4 considered cirrhosis and greater than 4.4 considered HCC). Conclusion: Hepatocellular carcinoma-VEGF score could replace AFP in HCC screening and follow up of cirrhotic patients.

Keywords: Hepatocellular carcinoma, cirrhosis, HCV, diagnosis, tumor markers

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Authors: I. Iroka, L. Mgidlana, J. Willoughby, S. Dhlamini, P. Nxumalo, S. Sefadi, A. Mthembu, E. Gerber, E. Brits

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Introduction: Nephroblastoma is a common paediatric tumor with good survival rates when diagnosed and treated early. Method: This retrospective study aimed to describe the patients with nephroblastoma seen at Universitas Academic Hospital Complex between the years 2000 and 2020. Results: In the study period, there were 207 patients identified. The patient profile had slightly more male than female patients; the median age was under four years of age. The study found a median delay of one month between symptom onset and diagnosis; a common cause was a delay in seeking care. Patients diagnosed and treated more than a month after symptoms started had poorer survival rates. There was a higher rate of Stage IV disease compared to similar studies in South Africa. Good preoperative histology and no relapse had good survival rates.. Patients from Lesotho had longer delays and presented with more severe diseases than the South African cohort. Conclusion: Early identification and treatment lead to better outcomes. Health-seeking behaviour, misdiagnosis, and referral delays might contribute to the long delays. A targeted study for patients from Lesotho is recommended.

Keywords: nephroblastoma, South Africa, Lesotho, developing country

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Authors: Lamis Naddaf, Yuval Tabach

Abstract:

In this research, we identified the missense genetic variants that have the potential to enhance resistance against cancer. Such field has not been widely explored, as researchers tend to investigate mutations that cause diseases, in response to the suffering of patients, rather than those mutations that protect from them. In conjunction with the genomic revolution, and the advances in genetic engineering and synthetic biology, identifying the protective variants will increase the power of genotype-phenotype predictions and can have significant implications on improved risk estimation, diagnostics, prognosis and even for personalized therapy and drug discovery. To approach our goal, we systematically investigated the sites of the coding genomes and picked up the alleles that showed a correlation with the species’ cancer resistance. We predicted 250 protecting variants (PVs) with a 0.01 false discovery rate and more than 20 thousand PVs with a 0.25 false discovery rate. Cancer resistance in Mammals and reptiles was significantly predicted by the number of PVs a species has. Moreover, Genes enriched with the protecting variants are enriched in pathways relevant to tumor suppression like pathways of Hedgehog signaling and silencing, which its improper activation is associated with the most common form of cancer malignancy. We also showed that the PVs are more abundant in healthy people compared to cancer patients within different human races.

Keywords: comparative genomics, machine learning, cancer resistance, cancer-protecting alleles

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Authors: H. Yousefnia, S. Zolghadri, A. Golabi Dezfuli

Abstract:

Tris (1,10-phenanthroline) lanthanum(III)] trithiocyanate is a new compound that has shown to stop DNA synthesis in CCRF-CEM and Ehrlich ascites cells leading to a cell cycle arrest in G0/G1. One other important property of the phenanthroline nucleus is its ability to act as a triplet-state photosensitizer especially in complexes with lanthanides. In Nowadays, the radiation dose assessment resource (RADAR) method is known as the most common method for absorbed dose calculation. 177Lu was produced by irradiation of a natural Lu2O3 target at a thermal neutron flux of approximately 4 × 1013 n/cm2•s. 177Lu-PL3 was prepared in the optimized condition. The radiochemical yield was checked by ITLC method. The biodistribution of the complex was investigated by intravenously injection to wild-type rats via their tail veins. In this study, the absorbed dose of 177Lu-PL3 to human organs was estimated by RADAR method. 177Lu was prepared with a specific activity of 2.6-3 GBq.mg-1 and radionuclide purity of 99.98 %. The 177Lu-PL3 complex can prepare with high radiochemical yield (> 99 %) at optimized conditions. The results show that liver and spleen have received the highest absorbed dose of 1.051 and 0.441 mSv/MBq, respectivley. The absorbed dose values for these two dose-limiting tissues suggest more biological studies special in tumor-bearing animals.

Keywords: internal dosimetry, Lutetium-177, radar, animals

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Authors: Lamis Naddaf, Yuval Tabach

Abstract:

We identified missense genetic variants with the potential to enhance resistance against cancer. Such a field has not been widely explored as researchers tend to investigate the mutations that cause diseases, in response to the suffering of patients, rather than those mutations that protect from them. In conjunction with the genomic revolution and the advances in genetic engineering and synthetic biology, identifying the protective variants will increase the power of genotype-phenotype predictions and have significant implications for improved risk estimation, diagnostics, prognosis, and even personalized therapy and drug discovery. To approach our goal, we systematically investigated the sites of the coding genomes and selected the alleles that showed a correlation with the species’ cancer resistance. Interestingly, we found several amino acids that are more generally preferred (like the Proline) or avoided (like the Cysteine) by the resistant species. Furthermore, Cancer resistance in mammals and reptiles is significantly predicted by the number of the predicted protecting variants (PVs) a species has. Moreover, PVs-enriched-genes are enriched in pathways relevant to tumor suppression. For example, they are enriched in the Hedgehog signaling and silencing pathways, which its improper activation is associated with the most common form of cancer malignancy. We also showed that the PVs are mostly more abundant in healthy people compared to cancer patients within different human races.

Keywords: cancer resistance, protecting variant, naked mole rat, comparative genomics

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Authors: Yousif Mohamed Y. Abdallah

Abstract:

This is an experimental study deals with detection, measurement and analysis of the periodic physiological organ motion during external beam radiotherapy; to improve the accuracy of the radiation field placement, and to reduce the exposure of healthy tissue during radiation treatments. The importance of this study is to detect the maximum path of the mobile structures during radiotherapy delivery, to define the planning target volume (PTV) and irradiated volume during both inspiration and expiration period and to verify the target volume. In addition to its role to highlight the importance of the application of Intense Guided Radiotherapy (IGRT) methods in the field of radiotherapy. The results showed (body contour was equally (3.17 + 0.23 mm), for left lung displacement reading (2.56 + 0.99 mm) and right lung is (2.42 + 0.77 mm) which the radiation oncologist to take suitable countermeasures in case of significant errors. In addition, the use of the image registration technique for automatic position control is predicted potential motion. The motion ranged between 2.13 mm and 12.2 mm (low and high). In conclusion, individualized assessment of tumor mobility can improve the accuracy of target areas definition in patients undergo Sterostatic RT for stage I, II and III lung cancer (NSCLC). Definition of the target volume based on a single CT scan with a margin of 10 mm is clearly inappropriate.

Keywords: respiratory motion, external beam radiotherapy, image processing, lung

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