Search results for: sigmoid colon

Authors: Feng-Sheng Wang, Chao-Ting Cheng

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Developing a drug from conception to launch is costly and time-consuming. Computer-aided methods can reduce research costs and accelerate the development process during the early drug discovery and development stages. This study developed a fuzzy multi-objective hierarchical optimization framework for identifying potential anticancer targets in a metabolic model. First, RNA-seq expression data of colorectal cancer samples and their healthy counterparts were used to reconstruct tissue-specific genome-scale metabolic models. The aim of the optimization framework was to identify anticancer targets that lead to cancer cell death and evaluate metabolic flux perturbations in normal cells that have been caused by cancer treatment. Four objectives were established in the optimization framework to evaluate the mortality of cancer cells for treatment and to minimize side effects causing toxicity-induced tumorigenesis on normal cells and smaller metabolic perturbations. Through fuzzy set theory, a multiobjective optimization problem was converted into a trilevel maximizing decision-making (MDM) problem. The applied nested hybrid differential evolution was applied to solve the trilevel MDM problem using two nutrient media to identify anticancer targets in the genome-scale metabolic model of colorectal cancer, respectively. Using Dulbecco’s Modified Eagle Medium (DMEM), the computational results reveal that the identified anticancer targets were mostly involved in cholesterol biosynthesis, pyrimidine and purine metabolisms, glycerophospholipid biosynthetic pathway and sphingolipid pathway. However, using Ham’s medium, the genes involved in cholesterol biosynthesis were unidentifiable. A comparison of the uptake reactions for the DMEM and Ham’s medium revealed that no cholesterol uptake reaction was included in DMEM. Two additional media, i.e., a cholesterol uptake reaction was included in DMEM and excluded in HAM, were respectively used to investigate the relationship of tumor cell growth with nutrient components and anticancer target genes. The genes involved in the cholesterol biosynthesis were also revealed to be determinable if a cholesterol uptake reaction was not induced when the cells were in the culture medium. However, the genes involved in cholesterol biosynthesis became unidentifiable if such a reaction was induced.

Keywords: Cancer metabolism, genome-scale metabolic model, constraint-based model, multilevel optimization, fuzzy optimization, hybrid differential evolution

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Authors: Rajkumar Ghosh

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The paper presents a comprehensive study of the structural analysis of the Chaura Thrust in Himachal Pradesh, India. The research focuses on several key aspects, including the activation timing of the Main Central Thrust (MCT) and the South Tibetan Detachment System (STDS), the identification and characterization of mylonitised zones through microscopic examination, and the understanding of box fold characteristics and their implications in the regional geology of the Himachal Himalaya. The primary objective of the study is to provide field documentation of the Chaura Thrust, which was previously considered a blind thrust with limited field evidence. Additionally, the research aims to characterize box folds and their signatures within the broader geological context of the Himachal Himalaya, document the temperature range associated with grain boundary migration (GBM), and explore the overprinting structures related to multiple sets of Higher Himalayan Out-of-Sequence Thrusts (OOSTs). The research methodology employed geological field observations and microscopic studies. Samples were collected along the Jhakri-Chaura transect at regular intervals of approximately 1 km to conduct strain analysis. Microstructural studies at the grain scale along the Jhakri-Wangtu transect were used to document the GBM-associated temperature range. The study reveals that the MCT activated in two parts, as did the STDS, and provides insights into the activation ages of the Main Boundary Thrust (MBT) and the Main Frontal Thrust (MFT). Under microscopic examination, the study identifies two mylonitised zones characterized by S-C fabric, and it documents dynamic and bulging recrystallization, as well as sub-grain formation. Various types of crenulated schistosity are observed in photomicrographs, including a rare occurrence where crenulation cleavage and sigmoid Muscovite are found juxtaposed. The study also notes the presence of S/SE-verging meso- and micro-scale box folds around Chaura, which may indicate structural upliftment. Kink folds near Chaura are visible, while asymmetric shear sense indicators in augen mylonite are predominantly observed under microscopic examination. Moreover, the research highlights the documentation of the Higher Himalayan Out-of-Sequence Thrust (OOST) in Himachal Pradesh, which activated the MCT and occurred within a zone south of the Main Central Thrust Upper (MCTU). The presence of multiple sets of OOSTs suggests a zigzag pattern of strain accumulation in the area. The study emphasizes the significance of understanding the overprinting structures associated with OOSTs. Overall, this study contributes to the understanding of the structural analysis of the Chaura Thrust and its implications in the regional geology of the Himachal Himalaya. The research underscores the importance of microscopic studies in identifying mylonitised zones and various types of crenulated schistosity. Additionally, the study documents the GBM-associated temperature range and provides insights into the activation of the Higher Himalayan Out-of-Sequence Thrust (OOST) in Himachal Pradesh. The findings of the study were obtained through geological field observations, microscopic studies, and strain analysis, offering valuable insights into the activation timing, mylonitization characteristics, and overprinting structures related to the Chaura Thrust and the broader tectonic framework of the region.

Keywords: Main Central Thrust, Jhakri Thrust, Chaura Thrust, Higher Himalaya, Out-of-Sequence Thrust, Sarahan Thrust

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Authors: Shabnam Sarwar, Franck Lacoeuille, Nadia Withofs, Roland Hustinx

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After the development of a potential surrogate of MAA, and its successful application for the diagnosis of pulmonary embolism in artificially embolized rats’ lungs, this microparticulate system were radiolabelled with gallium-68 to synthesize 68Ga-SBMP with high radiochemical purity >99%. As a prerequisite step of clinical trials, 68Ga- labelled starch based microparticles (SBMP) were analysed for their in-vivo behavior in small animals. The purpose of the presented work includes the ex-vivo biodistribution studies of 68Ga-SBMP in order to assess the activity uptake in target organs with respect to time, excretion pathways of the radiopharmaceutical, %ID/g in major organs, T/NT ratios, in-vivo stability of the radiotracer and subsequently the microparticles in the target organs. Radiolabelling of starch based microparticles was performed by incubating it with 68Ga generator eluate (430±26 MBq) at room temperature and pressure without using any harsh reaction condition. For Ex-vivo biodistribution studies healthy White Wistar rats weighing between 345-460 g were injected intravenously 68Ga-SBMP 20±8 MBq, containing about 2,00,000-6,00,000 SBMP particles in a volume of 700µL. The rats were euthanized at predefined time intervals (5min, 30min, 60min and 120min) and their organ parts were cut, washed, and put in the pre-weighed tubes and measured for radioactivity counts through automatic Gamma counter. The 68Ga-SBMP produced >99% RCP just after 10-20 min incubation through a simple and robust procedure. Biodistribution of 68Ga-SBMP showed that initially just after 5 min post injection major uptake was observed in the lungs following by blood, heart, liver, kidneys, bladder, urine, spleen, stomach, small intestine, colon, skin and skeleton, thymus and at last the smallest activity was found in brain. Radioactivity counts stayed stable in lungs with gradual decrease with the passage of time, and after 2h post injection, almost half of the activity were seen in lungs. This is a sufficient time to perform PET/CT lungs scanning in humans while activity in the liver, spleen, gut and urinary system decreased with time. The results showed that urinary system is the excretion pathways instead of hepatobiliary excretion. There was a high value of T/NT ratios which suggest fine tune images for PET/CT lung perfusion studies henceforth further pre-clinical studies and then clinical trials should be planned in order to utilize this potential lung perfusion agent.

Keywords: starch based microparticles, gallium-68, biodistribution, target organs, excretion pathways

Procedia PDF Downloads 142

Authors: Catariny C. Aleman, Flavio B. Campos, Matheus A. Caliman, Everardo C. Mantovani

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The seedling production stage is a critical point in the vegetable production system. Obtaining high-quality seedlings is a prerequisite for subsequent cropping to occur well and productivity optimization is required. The water management is an important step in agriculture production. The adequate water requirement in horticulture seedlings can provide higher quality and increase field production. The practice of irrigation is indispensable and requires a duly adjusted quality irrigation system, together with a specific water management plan to meet the water demand of the crop. Irrigation management in seedling management requires a great deal of specific information, especially when it involves the use of inputs such as hydrorentering polymers and automation technologies of the data acquisition and irrigation system. The experiment was conducted in a greenhouse at the Federal University of Viçosa, Viçosa - MG. Tomato seedlings (Lycopersicon esculentum Mill) were produced in plastic trays of 128 cells, suspended at 1.25 m from the ground. The seedlings were irrigated by 4 micro sprinklers of fixed jet 360º per tray, duly isolated by sideboards, following the methodology developed for this work. During Phase 1, in January / February 2017 (duration of 24 days), the cultivation coefficient (Kc) of seedlings cultured in the presence and absence of hydrogel was evaluated by weighing lysimeter. In Phase 2, September 2017 (duration of 25 days), the seedlings were submitted to 4 irrigation managements (Kc, timer, 0.50 ETo, and 1.00 ETo), in the presence and absence of hydrogel and then evaluated in relation to quality parameters. The microclimate inside the greenhouse was monitored with the use of air temperature, relative humidity and global radiation sensors connected to a microcontroller that performed hourly calculations of reference evapotranspiration by Penman-Monteith standard method FAO56 modified for the balance of long waves according to Walker, Aldrich, Short (1983), and conducted water balance and irrigation decision making for each experimental treatment. Kc of seedlings cultured on a substrate with hydrogel (1.55) was higher than Kc on a pure substrate (1.39). The use of the hydrogel was a differential for the production of earlier tomato seedlings, with higher final height, the larger diameter of the colon, greater accumulation of a dry mass of shoot, a larger area of crown projection and greater the rate of relative growth. The handling 1.00 ETo promoted higher relative growth rate.

Keywords: automatic system; efficiency of water use; precision irrigation, micro sprinkler.

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Authors: Jannis Kountouras, Nikolaos Kapetanakis, Stergios A. Polyzos, Apostolis Papaeftymiou, Panagiotis Katsinelos, Ioannis Venizelos, Christina Nikolaidou, Christos Zavos, Iordanis Romiopoulos, Elena Tsiaousi, Evangelos Kazakos, Michael Doulberis

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Background & Aims: Helicobacter pylori infection (Hp-I) has been recognized as a substantial risk agent involved in gastrointestinal (GI) tract oncogenesis by stimulating cancer stem cells (CSCs), oncogenes, immune surveillance processes, and triggering GI microbiota dysbiosis. We aimed to investigate the possible involvement of active Hp-I in the sequence: chronic inflammation–adenoma–colorectal cancer (CRC) development. Methods: Four pillars were investigated: (i) endoscopic and conventional histological examinations of patients with CRC, colorectal adenomas (CRA) versus controls to detect the presence of active Hp-I; (ii) immunohistochemical determination of the presence of Hp; expression of CD44, an indicator of CSCs and/or bone marrow-derived stem cells (BMDSCs); expressions of oncogene Ki67 and anti-apoptotic Bcl-2 protein; (iii) expression of CD45, indicator of immune surveillance locally (assessing mainly T and B lymphocytes locally); and (iv) correlation of the studied parameters with the presence or absence of Hp-I. Results: Among 50 patients with CRC, 25 with CRA, and 10 controls, a significantly higher presence of Hp-I in the CRA (68%) and CRC group (84%) were found compared with controls (30%). The presence of Hp-I with accompanying immunohistochemical expression of CD44 in biopsy specimens was revealed in a high proportion of patients with CRA associated with moderate/severe dysplasia (88%) and CRC patients with moderate/severe degree of malignancy (91%). Comparable results were also obtained for Ki67, Bcl-2, and CD45 immunohistochemical expressions. Concluding Remarks: Hp-I seems to be involved in the sequence: CRA – dysplasia – CRC, similarly to the upper GI tract oncogenesis, by several pathways such as the following: Beyond Hp-I associated insulin resistance, the major underlying mechanism responsible for the metabolic syndrome (MetS) that increase the risk of colorectal neoplasms, as implied by other Hp-I related MetS pathologies, such as non-alcoholic fatty liver disease and upper GI cancer, the disturbance of the normal GI microbiota (i.e., dysbiosis) and the formation of an irritative biofilm could contribute to a perpetual inflammatory upper GIT and colon mucosal damage, stimulating CSCs or recruiting BMDSCs and affecting oncogenes and immune surveillance processes. Further large-scale relative studies with a pathophysiological perspective are necessary to demonstrate in-depth this relationship.

Keywords: Helicobacter pylori, colorectal cancer, colorectal adenomas, gastrointestinal oncogenesis

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Authors: Apurva Singh, S. P. Jaiswar, Apala Priyadarshini, Akancha Pandey

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Objective: The aim of this study is to find the association of PON1 gene polymorphism with pesticides In RPL subjects. Background: Recurrent pregnancy loss (RPL) is defined as three or more sequential abortions before the 20th week of gestation. Pesticides and its derivatives (organochlorine and organophosphate) are proposed to accommodate a ruler chemical for RPL in the sub-humid region of India. The paraoxonase-1 enzyme (PON1) plays an important role in the toxicity of some organophosphate pesticides, with low PON1 activity being associated with higher pesticide sensitivity Methodology: This is a case-control study done in Department of Obstetrics & Gynaecology & Department of Biochemistry, K.G.M.U, Lucknow, India. The subjects were enrolled after fulfilling the inclusion & exclusion criteria. Inclusion criteria: Cases- Subject having two or more spontaneous abortions & Control- Healthy female having one or more alive child was selected. Exclusion criteria: Cases & Control- Subject having the following disease will be excluded from the study Diabetes mellitus, Hypertension, Tuberculosis, Immunocompromised patients, any endocrine disorder and genital, colon or breast cancer any other malignancies. Blood samples were collected in EDTA tubes from cases & healthy control women & genomic DNA was extracted by phenol-chloroform method. The estimation of pesticides residue from blood was done by HPLC. Biochemical estimation was also performed. Genotyping of PON1 gene polymorphism was performed by RFLP. Statistical analysis of the data was performed using the SPSS16.3 software. Results: A sum of total 14 pesticides (12 organochlorine and 2 organophosphate) selected on the basis of their persistent nature and consumption rate. The significant level of pesticide (ppb) estimated by the Mann whiney test and it was found to be significant at higher level of β-HCH (p:0.04), γ-HCH (p:0.001), δ-HCH (p: 0.002), chloropyrifos (p:0.001), pp-DDD (p:0.001) and fenvalrate (p: 0.001) in case group compare to its control. The level of antioxidant enzymes were found to be significantly decreased among the cases. Wild homozygous TT was more frequent and prevalent among control groups. However, heterozygous group (Tt) was more in cases than control groups (CI-0.3-1.3) (p=0.06). Conclusion: Higher levels of pesticides with endocrine disrupting potential in cases indicate the possible role of these compounds as one of the causes of recurrent pregnancy loss. Possibly, increased pesticide level appears to indicate increased levels of oxidative damage that has been associated with the possible cause of Recurrent Miscarriage, it may reflect indirect evidence of toxicity rather than the direct cause. Since both factors are reported to increase risk, individuals with higher levels of these 'Toxic compounds' especially in 'high-risk genotypes' might be more susceptible to recurrent pregnancy loss.

Keywords: paraoxonase, pesticides, PON1, RPL

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Authors: S. Wiak, L. Szymanski, Z. Kolacinski, G. Raniszewski, L. Pietrzak, Z. Staniszewska

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The term ‘cancer’ is given to a collection of related diseases that may affect any part of the human body. It is a pathological behaviour of cells with the potential to undergo abnormal breakdown in the processes that control cell proliferation, differentiation, and death of particular cells. Although cancer is commonly considered as modern disease, there are beliefs that drastically growing number of new cases can be linked to the extensively prolonged life expectancy and enhanced techniques for cancer diagnosis. Magnetic hyperthermia therapy is a novel approach to cancer treatment, which may greatly contribute to higher efficiency of the therapy. Employing carbon nanotubes as nanocarriers for magnetic particles, it is possible to decrease toxicity and invasiveness of the treatment by surface functionalisation. Despite appearing in recent years, magnetic particle hyperthermia has already become of the highest interest in the scientific and medical environment. The reason why hyperthermia therapy brings so much hope for future treatment of cancer lays in the effect that it produces in malignant cells. Subjecting them to thermal shock results in activation of numerous degradation processes inside and outside the cell. The heating process initiates mechanisms of DNA destruction, protein denaturation and induction of cell apoptosis, which may lead to tumour shrinkage, and in some cases, it may even cause complete disappearance of cancer. The factors which have the major impact on the final efficiency of the treatment include temperatures generated inside the tissues, time of exposure to the heating process, and the character of an individual cancer cell type. The vast majority of cancer cells is characterised by lower pH, persistent hypoxia and lack of nutrients, which can be associated to abnormal microvasculature. Since in healthy tissues we cannot observe presence of these conditions, they should not be seriously affected by elevation of the temperature. The aim of this work is to investigate the influence of iron content in iron filled Carbon Nanotubes on the desired nanoparticles for cancer therapy. In the article, the development and demonstration of the method and the model device for hyperthermic selective destruction of cancer cells are presented. This method was based on the synthesis and functionalization of carbon nanotubes serving as ferromagnetic material nanocontainers. The methodology of the production carbon- ferromagnetic nanocontainers (FNCs) includes the synthesis of carbon nanotubes, chemical, and physical characterization, increasing the content of a ferromagnetic material and biochemical functionalization involving the attachment of the key addresses. The ferromagnetic nanocontainers were synthesised in CVD and microwave plasma system. The research work has been financed from the budget of science as a research project No. PBS2/A5/31/2013.

Keywords: hyperthermia, carbon nanotubes, cancer colon cells, radio frequency field

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Authors: Anthony S. Machi, Joseph Minardi

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We present a case report of left atrial myxoma diagnosed by bedside transesophageal (TEE) ultrasound. Left atrial myxoma is the most common benign cardiac tumor and can obstruct blood flow and cause valvular insufficiency. Common symptoms consist of dyspnea, pulmonary edema and other features of left heart failure in addition to thrombus release in the form of tumor fragments. The availability of bedside ultrasound equipment is essential for the quick diagnosis and treatment of various emergency conditions including cardiac neoplasms. A 48-year-old Caucasian female with a four-year history of an untreated renal mass and anemia presented to the ED with two months of sharp, intermittent, bilateral flank pain radiating into the abdomen. She also reported intermittent vomiting and constipation along with generalized body aches, night sweats, and 100-pound weight loss over last year. She had a CT in 2013 showing a 3 cm left renal mass and a second CT in April 2016 showing a 3.8 cm left renal mass along with a past medical history of diverticulosis, chronic bronchitis, dyspnea on exertion, uncontrolled hypertension, and hyperlipidemia. Her maternal family history is positive for breast cancer, hypertension, and Type II Diabetes. Her paternal family history is positive for stroke. She was a current everyday smoker with an 11 pack/year history. Alcohol and drug use were denied. Physical exam was notable for a Grade II/IV systolic murmur at the right upper sternal border, dyspnea on exertion without angina, and a tender left lower quadrant. Her vitals and labs were notable for a blood pressure of 144/96, heart rate of 96 beats per minute, pulse oximetry of 96%, hemoglobin of 7.6 g/dL, hypokalemia, hypochloremia, and multiple other abnormalities. Physicians ordered a CT to evaluate her flank pain which revealed a 7.2 x 8.9 x 10.5 cm mixed cystic/solid mass in the lower pole of the left kidney and a filling defect in the left atrium. Bedside TEE was ordered to follow up on the filling defect. TEE reported an ejection fraction of 60-65% and visualized a mobile 6 x 3 cm mass in the left atrium attached to the interatrial septum extending into the mitral valve. Cardiothoracic Surgery and Urology were consulted and confirmed a diagnosis of left atrial myxoma and clear cell renal cell carcinoma. The patient returned a week later due to worsening nausea and vomiting and underwent emergent nephrectomy, lymph node dissection, and colostomy due to a necrotic colon. Her condition declined over the next four months due to lung and brain metastases, infections, and other complications until she passed away.

Keywords: bedside ultrasound, echocardiography, emergency medicine, left atrial myxoma

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Authors: Binder Hans

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Cancer is no longer seen as solely a genetic disease where genetic defects such as mutations and copy number variations affect gene regulation and eventually lead to aberrant cell functioning which can be monitored by transcriptome analysis. It has become obvious that epigenetic alterations represent a further important layer of (de-)regulation of gene activity. For example, aberrant DNA methylation is a hallmark of many cancer types, and methylation patterns were successfully used to subtype cancer heterogeneity. Hence, unraveling the interplay between different omics levels such as genome, transcriptome and epigenome is inevitable for a mechanistic understanding of molecular deregulation causing complex diseases such as cancer. This objective requires powerful downstream integrative bioinformatics methods as an essential prerequisite to discover the whole genome mutational, transcriptome and epigenome landscapes of cancer specimen and to discover cancer genesis, progression and heterogeneity. Basic challenges and tasks arise ‘beyond sequencing’ because of the big size of the data, their complexity, the need to search for hidden structures in the data, for knowledge mining to discover biological function and also systems biology conceptual models to deduce developmental interrelations between different cancer states. These tasks are tightly related to cancer biology as an (epi-)genetic disease giving rise to aberrant genomic regulation under micro-environmental control and clonal evolution which leads to heterogeneous cellular states. Machine learning algorithms such as self organizing maps (SOM) represent one interesting option to tackle these bioinformatics tasks. The SOMmethod enables recognizing complex patterns in large-scale data generated by highthroughput omics technologies. It portrays molecular phenotypes by generating individualized, easy to interpret images of the data landscape in combination with comprehensive analysis options. Our image-based, reductionist machine learning methods provide one interesting perspective how to deal with massive data in the discovery of complex diseases, gliomas, melanomas and colon cancer on molecular level. As an important new challenge, we address the combined portrayal of different omics data such as genome-wide genomic, transcriptomic and methylomic ones. The integrative-omics portrayal approach is based on the joint training of the data and it provides separate personalized data portraits for each patient and data type which can be analyzed by visual inspection as one option. The new method enables an integrative genome-wide view on the omics data types and the underlying regulatory modes. It is applied to high and low-grade gliomas and to melanomas where it disentangles transversal and longitudinal molecular heterogeneity in terms of distinct molecular subtypes and progression paths with prognostic impact.

Keywords: integrative bioinformatics, machine learning, molecular mechanisms of cancer, gliomas and melanomas

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Authors: M. Koksal, T. Ozyazici, E. Gurdal, M. Yarım, E. Demirpolat, M. B. Y. Aycan

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The discovery of new drugs in cancer chemotherapy is still a major topic because of severe side effects, selectivity problems and resistance development potential of existing drugs. In recent years, combined anticancer therapies or multi-acting drugs are clinically preferred over traditional cytotoxic treatment, with the aim of avoiding resistance and toxic side effects. Arrangement of multi-acting targets can be carried out either by combination of several drugs with different mechanisms or by usage of a single chemical compound capable of regulating several targets of a disease with multiple factors. In literature, several pyrimidine and piperazine derivatives have been involved in the structure of many compounds which have been used as chemotherapeutic agents along with wide clinical applications. The aim of this study is to combine pyrimidine and piperazine core structures to research and develop novel piperazinylpyrimidine derivatives with selective cytotoxicity over cancer cells. In this study, a group of novel 6-fluorophenyl-3-[2-(substitutedpiperazinyl)ethyl] hexahydropyrimidine-2,4-dione derivatives designed to observe the desired anticancer activity due to pyrimidine and piperazine based scaffolds. Target compounds were obtained by the reaction of appropriate piperazine derivatives and 6-(2/4-fluorophenyl)-3-(2-chloroethyl)hexahydropyrimidine-2,4-dione. The synthetic pathway of 6-(2/4-fluorophenyl)-3-(2-chloroethyl)hexahydropyrimidine-2,4-dione was started with Rodionov reaction using aldehyde, malonic acid and ammonium acetate in ethanol. Isolated β-fluorophenyl-β-amino acids were treated with 2-chloroethylisocyanate in the presence of an aqueous sodium hydroxide solution at room temperature to yield the sodium salts of the corresponding ureido acids. By addition of a mineral acid, ureido acids were precipitated. Later, these ureido acids were refluxed in thionyl chloride to give the 6-(2/4-fluorophenyl)-3-(2-chloroethyl)hexahydropyrimidine-2,4-di-one which were furthermore treated with secondary amines. Structures of purified compounds were characterized with IR, 1H-NMR, 13C-NMR, mass spectroscopies and elemental analysis. All of the compounds gave satisfactory analytical and spectroscopic data, which were in full accordance with their depicted structures. In IR spectra of the compounds, N-H group was seen at 3230-3213 cm⁻¹. C-H was seen at 3100-2820 cm⁻¹ and C=O vibrational peaks were observed approximately at 1725 and 1665 cm⁻¹ in accordance with literature. In the NMR spectra of target compounds, the methylene protons of piperazine give two separate multiplet peaks around 3.5 and 4.5 ppm representing the successful N-alkylation of the structure. The cytotoxic activity of the synthesized compounds was investigated on human bronchial epithelial (BEAS 2B), lung (A549), colon adenocarcinoma (COLO205) and breast (MCF7) cell lines, by means of sulphorhodamine B (SRB) assays in triplicate. IC₅₀ values of the screened derivatives were found in range of 11.8-78 µM. This project was supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project no: 215S157).

Keywords: cytotoxicity, hexahydropyrimidine, piperazine, sulphorhodamine B assay

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Authors: Ruth Goldschmidt, Vyacheslav Kalchenko, Lilah Agemy, Rachel Elmoalem, Avigdor Scherz

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Vascular Targeted Photodynamic therapy (VTP) is a new modality for selective cancer treatment that leads to the complete tumor ablation. A photosensitizer, a bacteriochlorophyll derivative in our case, is first administered to the patient and followed by the illumination of the tumor area, by a near-IR laser for its photoactivation. The photoactivated drug releases reactive oxygen species (ROS) in the circulation, which reacts with blood cells and the endothelium leading to the occlusion of the blood vasculature. If the blood vessels are only partially closed, the tumor may recover, and cancer cells could survive. On the other hand, excessive treatment may lead to toxicity of healthy tissues nearby. Simultaneous VTP monitoring and image processing independent of the photoexcitation laser has not yet been reported, to our knowledge. Here we present a method for blood flow monitoring, using a real-time laser speckle imaging (RTLSI) in the tumor during VTP. We have synthesized over the years a library of bacteriochlorophyll derivatives, among them WST11 and STL-6014. Both are water soluble derivatives that are retained in the blood vasculature through their partial binding to HSA. WST11 has been approved in Mexico for VTP treatment of prostate cancer at a certain drug dose, and time/intensity of illumination. Application to other bacteriochlorophyll derivatives or other cancers may require different treatment parameters (such as light/drug administration). VTP parameters for STL-6014 are still under study. This new derivative mainly differs from WST11 by its lack of the central Palladium, and its conjugation to an Arg-Gly-Asp (RGD) sequence. RGD is a tumor-specific ligand that is used for targeting the necrotic tumor domains through its affinity to αVβ3 integrin receptors. This enables the study of cell-targeted VTP. We developed a special RTLSI module, based on Labview software environment for data processing. The new module enables to acquire raw laser speckle images and calculate the values of the laser temporal statistics of time-integrated speckles in real time, without additional off-line processing. Using RTLSI, we could monitor the tumor’s blood flow following VTP in a CT26 colon carcinoma ear model. VTP with WST11 induced an immediate slow down of the blood flow within the tumor and a complete final flow arrest, after some sporadic reperfusions. If the irradiation continued further, the blood flow stopped also in the blood vessels of the surrounding healthy tissue. This emphasizes the significance of light dose control. Using our RTLSI system, we could prevent any additional healthy tissue damage by controlling the illumination time and restrict blood flow arrest within the tumor only. In addition, we found that VTP with STL-6014 was the most effective when the photoactivation was conducted 4h post-injection, in terms of tumor ablation success in-vivo and blood vessel flow arrest. In conclusion, RTSLI application should allow to optimize VTP efficacy vs. toxicity in both the preclinical and clinical arenas.

Keywords: blood vessel occlusion, cancer treatment, photodynamic therapy, real time imaging

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Authors: Sachin Mulmi Shrestha, Xin Fang, Hui Ye, Lihua Ren, Qinghua Ji, Ruihua Shi

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Background: Esophageal squamous cell carcinoma (ESCC) is a tumor arising from esophageal epithelial cells and is one of the major disease subtype in Asian countries, including China. Esophageal cancer is the 7th highest incidence based on the 2020 data of GLOBOCAN. The pathogenesis of cancer is still not well understood as many molecular and genetic basis of esophageal carcinogenesis has yet to be clearly elucidated. Circular RNAs are RNA molecules that are formed by back-splicing covalently joined 3′- and 5′-endsrather than canonical splicing, and recent data suggest circular RNAs could sponge miRNAs and are enriched with functional miRNA binding sites. Hence, we studied the mechanism of circular RNA, its biological function, and the relationship between microRNA in the carcinogenesis of ESCC. Methods: 4 pairs of normal and esophageal cancer tissues were collected in Zhongda hospital, affiliated to Southeast University, and high-throughput RNA sequencing was done. The result revealed that circ_0032746 was upregulated, and thus we selected circ_0032746 for further study. The backsplice junction of circRNA was validated by sanger sequence, and stability was determined by RNASE R assay. The binding site of circRNA and microRNA was predicted by circinteractome,mirandaand RNAhybrid database. Furthermore, circRNA was silenced by siRNA and then by lentivirus. The regulatory axis of circ0032746/miR4270 was validated by shRNA, mimic, and inhibitor transfection. Then, in vitro experiments were performed to assess the role of circ0032746 on proliferation (CCK-8 assay and colon formation assay), migration and invasion (Transewell assay), and apoptosis of ESCC. Results: The upregulated circ0032746 was validated in 9 pairs of tissues and 5 types of cell lines by qPCR, which showed high expression and was statistically significant (P<0.005) ). Upregulated circ0032746 was silenced by shRNA, which showed significant knockdown in KYSE 30 and TE-1 cell lines expression compared to control. Nuclear and cytoplasmic mRNA fraction experiment displayed the cytoplasmic location of circ0032746. The sponging of miR4270 was validated by co-transfection of sh-circ0032746 and mimic or inhibitor. Transfection with mimic showed the decreased expression of circ_0032746, whereas inhibitor inhibited the result. In vitro experiments showed that silencing of circ_0032746 inhibited the proliferation, migration, and invasion compared to the negative control group. The apoptosis was seen higher in a knockdown group than in the control group. Furthermore, 11 common mircoRNA target mRNAs were predicted by Targetscan, MirTarbase, and miRanda database, which may further play role in the pathogenesis. Conclusion: Our results showed that novel circ_0032746 is upregulated in ESCC and plays role in itsoncogenicity. Silencing of circ_0032746 inhibits the proliferation and migration of ESCC whereas increases the apoptosis of cancer cells. Hence, circ0032746 acts as an oncogene in ESCC by sponging with miR4270 and could be a potential biomarker in the diagnosis of ESCC in the future.

Keywords: circRNA, esophageal squamous cell carcinoma, microRNA, upregulated

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Authors: Kristina Karapetyan, Flora Tkhruni, Tsovinar Balabekyan, Arevik Israyelyan, Tatyana Khachatryan

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The ability of the lactic acid bacteria (LAB) to prevent and cure a variety of diseases, their protective role against infections and colonization of pathogenic microorganisms in the digestive tract, has lead to the coining of the term probiotics or pro-life. LAB inhibiting the growth of pathogenic and food spoilage microorganisms, maintaining the nutritive quality and improving the shelf life of foods. They have also been used as flavor and texture producers. Enterococcus strains have been used for treatment of diseases such as diarrhea or antibiotic associated diarrhea, inflammatory pathologies that affect colon such as irritable bowel syndrome, or immune regulation, diarrhea caused by antibiotic treatments. The obtaining and investigation of biological properties of proteinoceous antibiotics, on the basis of probiotic LAB shown, that bacteriocins, metabiotics, and peptides of LAB represent bactericides have a broad range of activity and are excellent candidates for development of new prophylactic and therapeutic substances to complement or replace conventional antibiotics. The genotyping by 16S rRNA sequencing for LAB were used. Cell free culture broth (CFC) broth was purified by the Gel filtration method on the Sephadex Superfine G 25 resin. Antimicrobial activity was determined by spot-on-lawn method and expressed in arbitrary units (AU/ml). The diversity of multidrug-resistance (MDR) of pathogenic strains to antibiotics, most widely used for treatment of human diseases in the Republics of Armenia and Nagorno Karabakh were examined. It was shown, that difference of resistance of pathogens to antibiotics depends on their isolation sources. The influences of partially purified antimicrobial preparations (AMP), obtained from the different strains of Enterococcus genus on the growth of MDR pathogenic bacteria were investigated. It was shown, that bacteriocin containing partially purified preparations, obtained from different strains of Enterococcus faecium and durans species, possess bactericidal or bacteriostatic activity against antibiotic resistant intestinal, spoilage and food-borne pathogens such as Listeria monocytogenes, Staphylococcus aureus, E. coli, and Salmonella. Endemic strains of LAB, isolated from Matsoni made from donkey, buffalo and goat milk, shown broad spectrum of activity against food spoiling microorganisms, moulds and fungi, such as Salmonella sp., Esherichia coli, Aspergillus and Penicillium species. Highest activity against MDR pathogens shown bacteria, isolated from goat milk products. High stability of the investigated strains of the genus Enerococcus, isolated from samples of matsun from different regions of Nagorno-Karabakh (NKR) to the antibiotics was shown. The obtained data show high stability of the investigated different strains of the genus Enerococcus. The high genetic diversity in Enterococcus group suggests adaptations for specific mutations in different environments. Thus, endemic strains of LAB are able to produce bacteriocins with high and different inhibitory activity against broad spectrum of microorganisms isolated from different sources and belong to different taxonomic group. Prospect of the use of certain antimicrobial preparations against pathogenic strains is obvious. These AMP can be applied for long term use against different etiology antibiotic resistant pathogens for prevention or treatment of infectional diseases as an alternative to antibiotics.

Keywords: antimicrobial biopreparation, endemic lactic acid bacteria, intra-species diversity, multidrug resistance of pathogens

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Authors: Manuel I. Capel, Antonio Tomeu, Alberto Salguero

Abstract:

Tumor growth from a transformed cancer-cell up to a clinically apparent mass spans through a range of spatial and temporal magnitudes. Through computer simulations, Cellular Automata (CA) can accurately describe the complexity of the development of tumors. Tumor development prognosis can now be made -without making patients undergo through annoying medical examinations or painful invasive procedures- if we develop appropriate CA-based software tools. In silico testing mainly refers to Computational Biology research studies of application to clinical actions in Medicine. To establish sound computer-based models of cellular behavior, certainly reduces costs and saves precious time with respect to carrying out experiments in vitro at labs or in vivo with living cells and organisms. These aim to produce scientifically relevant results compared to traditional in vitro testing, which is slow, expensive, and does not generally have acceptable reproducibility under the same conditions. For speeding up computer simulations of cellular models, specific literature shows recent proposals based on the CA approach that include advanced techniques, such the clever use of supporting efficient data structures when modeling with deterministic stochastic cellular automata. Multiparadigm and multiscale simulation of tumor dynamics is just beginning to be developed by the concerned research community. The use of stochastic cellular automata (SCA), whose parallel programming implementations are open to yield a high computational performance, are of much interest to be explored up to their computational limits. There have been some approaches based on optimizations to advance in multiparadigm models of tumor growth, which mainly pursuit to improve performance of these models through efficient memory accesses guarantee, or considering the dynamic evolution of the memory space (grids, trees,…) that holds crucial data in simulations. In our opinion, the different optimizations mentioned above are not decisive enough to achieve the high performance computing power that cell-behavior simulation programs actually need. The possibility of using multicore and GPU parallelism as a promising multiplatform and framework to develop new programming techniques to speed-up the computation time of simulations is just starting to be explored in the few last years. This paper presents a model that incorporates parallel processing, identifying the synchronization necessary for speeding up tumor growth simulations implemented in Java and C++ programming environments. The speed up improvement that specific parallel syntactic constructs, such as executors (thread pools) in Java, are studied. The new tumor growth parallel model is proved using implementations with Java and C++ languages on two different platforms: chipset Intel core i-X and a HPC cluster of processors at our university. The parallelization of Polesczuk and Enderling model (normally used by researchers in mathematical oncology) proposed here is analyzed with respect to performance gain. We intend to apply the model and overall parallelization technique presented here to solid tumors of specific affiliation such as prostate, breast, or colon. Our final objective is to set up a multiparadigm model capable of modelling angiogenesis, or the growth inhibition induced by chemotaxis, as well as the effect of therapies based on the presence of cytotoxic/cytostatic drugs.

Keywords: cellular automaton, tumor growth model, simulation, multicore and manycore programming, parallel programming, high performance computing, speed up

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Authors: A. Aceranti, L. Moretti, S. Vernocchi, M. Colorato, P. Caristia

Abstract:

Irritable bowel syndrome (IBS) is the association between abdominal pain, abdominal distension and intestinal dysfunction for recurring periods. About 10% of the world's population has IBS at any given time in their life, and about 200 people per 100,000 receive an initial diagnosis of IBS each year. Persistent pain is recognized as one of the most pervasive and challenging problems facing the medical community today. Persistent pain is considered more as a complex pathophysiological, diagnostic and therapeutic situation rather than as a persistent symptom. The low efficiency of conventional drug treatments has led many doctors to become interested in the non-drug alternative treatment of IBS, especially for more severe cases. Patients and providers are often dissatisfied with the available drug remedies and often seek complementary and alternative medicine (CAM), a unique and holistic approach to treatment that is not a typical component of conventional medicine. Osteopathic treatment may be of specific interest in patients with IBS. Osteopathy is a complementary health approach that emphasizes the role of the musculoskeletal system in health and promotes optimal function of the body's tissues using a variety of manual techniques to improve body function. Osteopathy has been defined as a patient-centered health discipline based on the principles of interrelation between body structure and function, the body's innate capacity for self-healing and the adoption of a whole person health approach. mainly by practicing manual processing. Studies reported that osteopathic manual treatment (OMT) reduced IBS symptoms, such as abdominal pain, constipation, diarrhea, and improved general well-being. The focus in the treatment of IBS with osteopathy has gone beyond simple spinal alignment, to directly address the abnormal physiology of the body using a series of direct and indirect techniques. The topic of this study was chosen for different reasons: due to the large number of people involved who suffer from this disorder and for the dysfunction itself, since nowadays there is still little clarity about the best type of treatment and, above all, to its origin. The visceral component in the osteopathic field is still a world to be discovered, although it is related to a large part of patient series, it has contents that affect numerous disciplines and this makes it an enigma yet to be solved. The study originated in the didactic practice where the curiosity of a topic is marked that, even today, no one is able to explain and, above all, cure definitively. The main purpose of this study is to try to create a good basis on the osteopathic discipline for subsequent studies that can be exhaustive in the best possible way, resolving some doubts about which treatment modality can be used with more relevance. The path was decided to structure it in such a way that 3 types of osteopathic treatment are used on 3 groups of people who will be selected after completing a questionnaire, which will deem them suitable for the study. They will, in fact, be divided into three groups where: - the first group was given a visceral osteopathic treatment. - The second group was given a manual osteopathic treatment of neurological stimulation. - The third group received a placebo treatment. At the end of the treatment, questionnaires will be re-proposed respectively one week after the session and one month after the treatment from which any data will be collected that will demonstrate the effectiveness or otherwise of the treatment received. The sample of 50 patients examined underwent an oral interview to evaluate the inclusion and exclusion criteria to participate in the study. Of the 50 patients questioned, 17 people who underwent different osteopathic techniques were eligible for the study. Comparing the data related to the first assessment of tenderness and frequency of symptoms with the data related to the first follow-up shows a significant improvement in the score assigned to the different questions, especially in the neurogenic and visceral groups. We are aware of the fact that it is a study performed on a small sample of patients, and this is a penalizing factor. We remain, however, convinced that having obtained good results in terms of subjective improvement in the quality of life of the subjects, it would be very interesting to re-propose the study on a larger sample and fill the gaps.

Keywords: IBS, osteopathy, colon, intestinal inflammation

Procedia PDF Downloads 75