Search results for: liver cancer

Authors: Beata J. Lehka, Samuel A. Bradley, Frederik G. Hansson, Khem B. Adhikari, Daniela Rago, Paulina Rubaszka, Ahmad K. Haidar, Ling Chen, Lea G. Hansen, Olga Gudich, Konstantina Giannakou, Yoko Nakamura, Thomas Dugé de Bernonville, Konstantinos Koudounas, Sarah E. O’Connor, Vincent Courdavault, Jay D. Keasling, Jie Zhang, Michael K. Jensen

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Monoterpenoid indole alkaloids (MIAs) represent a large class of natural plant products with marketed pharmaceutical activities against a wide range of applications, including cancer and mental disorders. Halogenated MIAs have shown improved pharmaceutical properties; however, characterisation and synthesis of new-to-nature halogenated MIAs remain a challenge in slow-growing plants with limited genetic tractability. Here, we demonstrate a platform for de novo biosynthesis of two bioactive MIAs, serpentine and alstonine, in baker’s yeast Saccharomyces cerevisiae, reaching titers of 8.85 mg/L and 4.48 mg/L, respectively, when cultivated in fed-batch micro bioreactors. Using this MIA biosynthesis platform, we undertake a systematic exploration of the derivative space surrounding these compounds and produce halogenated MIAs. The aim of the current study is to develop a fermentation process for halogenated MIAs.

Keywords: monoterpenoid indole alkaloids, Saccharomyces cerevisiae, halogenated derivatives, fermentation

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Authors: Jianli Dong, Fangling Xu, Gengming Huang

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Human endogenous retroviral elements (HERVs) comprise approximately 8% of the human genome. They are thought to be germline-integrated genetic remnants of retroviral infections. Although HERV sequences are highly defective, some, especially the K type (HERV-K), have been shown to be expressed and may have biological activities in the pathogenesis of cancer, chronic inflammation and autoimmune diseases. We found that HERV-K GAG and ENV proteins were strongly expressed in pleomorphic melanoma cells. We also detected a critical role of HERV-K ENV in mediating intercellular fusion and colony formation of melanoma cells. Interestingly, we found that levels of HERV-K GAG and ENV expression correlated with the activation of ERK and loss of p16INK4A in melanoma cells, and inhibition of MEK or CDK4, especially in combination, reduced HERV-K expression in melanoma cells. We also performed a reverse transcription-polymerase chain reaction (RT-PCR) assay using DNase I digestion to remove “contaminating” HERV-K genomic DNA and examined HERV-K RNA expression in plasma samples from HIV-1 infected individuals. We found a covariation between HERV-K RNA expression and CD4 cell counts in HIV-1 positive samples. Although a causal link between HERV-K activation and melanoma development, and between HERV-K activation, HIV-1 infection and CD4 cell count have yet to be determined, existing data support the further research efforts in HERV-K.

Keywords: CD4 cell, HERV-K, HIV-1, melanoma

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Authors: Danyi Wang, Andrew Schriefer, Dennis O'Rourke, Brajendra Kumar, Yang Liu, Fei Zhong, Juergen Scheuenpflug, Zheng Feng

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Purpose: It has been recognized that the microbiome plays critical roles in disease pathogenesis, including cancer, autoimmune disease, and multiple sclerosis. To develop a clinical-grade assay for exploring microbiome-derived clinical biomarkers across disease areas, a two-phase approach is implemented. 1) Identification of the optimal sample preparation reagents using pre-mixed bacteria and healthy donor stool samples coupled with proprietary Sigma-Aldrich® bioinformatics solution. 2) Exploratory analysis of patient samples for enabling precision medicine. Study Procedure: In phase 1 study, we first compared the 16S sequencing results of two ATCC® microbiome standards (MSA 2002 and MSA 2003) across five different extraction kits (Kit A, B, C, D & E). Both microbiome standards samples were extracted in triplicate across all extraction kits. Following isolation, DNA quantity was determined by Qubit assay. DNA quality was assessed to determine purity and to confirm extracted DNA is of high molecular weight. Bacterial 16S ribosomal ribonucleic acid (rRNA) amplicons were generated via amplification of the V3/V4 hypervariable region of the 16S rRNA. Sequencing was performed using a 2x300 bp paired-end configuration on the Illumina MiSeq. Fastq files were analyzed using the Sigma-Aldrich® Microbiome Platform. The Microbiome Platform is a cloud-based service that offers best-in-class 16S-seq and WGS analysis pipelines and databases. The Platform and its methods have been extensively benchmarked using microbiome standards generated internally by MilliporeSigma and other external providers. Data Summary: The DNA yield using the extraction kit D and E is below the limit of detection (100 pg/µl) of Qubit assay as both extraction kits are intended for samples with low bacterial counts. The pre-mixed bacterial pellets at high concentrations with an input of 2 x106 cells for MSA-2002 and 1 x106 cells from MSA-2003 were not compatible with the kits. Among the remaining 3 extraction kits, kit A produced the greatest yield whereas kit B provided the least yield (Kit-A/MSA-2002: 174.25 ± 34.98; Kit-A/MSA-2003: 179.89 ± 30.18; Kit-B/MSA-2002: 27.86 ± 9.35; Kit-B/MSA-2003: 23.14 ± 6.39; Kit-C/MSA-2002: 55.19 ± 10.18; Kit-C/MSA-2003: 35.80 ± 11.41 (Mean ± SD)). Also, kit A produced the greatest yield, whereas kit B provided the least yield. The PCoA 3D visualization of the Weighted Unifrac beta diversity shows that kits A and C cluster closely together while kit B appears as an outlier. The kit A sequencing samples cluster more closely together than both the other kits. The taxonomic profiles of kit B have lower recall when compared to the known mixture profiles indicating that kit B was inefficient at detecting some of the bacteria. Conclusion: Our data demonstrated that the DNA extraction method impacts DNA concentration, purity, and microbial communities detected by next-generation sequencing analysis. Further microbiome analysis performance comparison of using healthy stool samples is underway; also, colorectal cancer patients' samples will be acquired for further explore the clinical utilities. Collectively, our comprehensive qualification approach, including the evaluation of optimal DNA extraction conditions, the inclusion of positive controls, and the implementation of a robust qualified bioinformatics pipeline, assures accurate characterization of the microbiota in a complex matrix for deciphering the deep biology and enabling precision medicine.

Keywords: 16S rRNA sequencing, analytical validation, bioinformatics pipeline, metagenomics

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Authors: N. A. Ahmad Zubairi, H. Takaijudin, K. W. Yusof

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Pesticides have been used widely over the world in agriculture to protect from pests and reduce crop losses. However, it affects the environment with toxic chemicals. Exceed of toxic constituents in the ecosystem will result in bad side effects. The hydrological cycle is related to the existence of pesticides and heavy metal which it can penetrate through varieties of sources into the soil or water bodies, especially runoff. Therefore, proper mechanisms of pesticide and heavy metal removal should be studied to improve the quality of ecosystem free or reduce from unwanted substances. This paper reviews the use of treatment train and its mechanisms to minimize pesticides and heavy metal from agricultural runoff. Organochlorine (OCL) is a common pesticide that was found in the agricultural runoff. OCL is one of the toxic chemicals that can disturb the ecosystem such as inhibiting plants' growth and harm human health by having symptoms as asthma, active cancer cell, vomit, diarrhea, etc. Thus, this unwanted contaminant gives disadvantages to the environment and needs treatment system. Hence, treatment train by bioretention system is suitable because removal efficiency achieves until 90% of pesticide removal with selected vegetated plant and additive.

Keywords: pesticides, heavy metal, agricultural runoff, bioretention, mechanism removal, treatment train

Procedia PDF Downloads 142

Authors: Sunghee Nam

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Entomopathogenic fungi is a Cordyceps species that is isolated from dead silkworm and cicada. Fungi on cicadas were described in old Chinese medicinal books and from ancient times, vegetable wasps and plant worms were widely known to have active substance and have been studied for pharmacological use. Among many fungi belonging to the genus Cordyceps, Cordyceps sinensis have been demonstrated to yield natural products possessing various biological activities and many bioactive components. Generally, It is commonly used to replenish the kidney and soothe the lung, and for the treatment of fatigue. Due to their commercial and economic importance, the demand for Cordyceps has been rapidly increased. However, a supply of Cordyceps specimen could not meet the increasing demand because of their sole dependence on field collection and habitat destruction. Because it is difficult to obtain many insect hosts in nature and the edibility of host insect needs to be verified in a pharmacological aspect. Recently, this setback was overcome that P. tenuipes was able to be cultivated in a large scale using silkworm as host. Pharmacological effects of P. tenuipes cultured on silkworm such as strengthening immune function, anti-fatigue, anti-tumor activity and controlling liver etc. have been proved. They are widely commercialized. In this study, we attempted to establish a method for stable growth inhibition of P. tenuipes on silkworm hosts and an optimal condition for synnemata formation. To determine optimum culturing conditions, temperature and light conditions were varied. The length and number of synnemata was highest at 25℃ temperature and 100~300 lux illumination. On an average, the synnemata of wild P. tenuipes measures 70 ㎜ in length and 20 in number; those of the cultured strain were relatively shorter and more in number. The number of synnemata may have increased as a result of inoculating the host with highly concentrated conidia, while the length may have decreased due to limited nutrition per individual. It is not able that changes in light illumination cause morphological variations in the synnemata. However, regulation of only light and temperature could not produce stromata like perithecia, asci, and ascospores.

Keywords: optimization of culture conditions of paecilomyces tenuipes, entomopathogenic fungi optimization of culture conditions of paecilomyces tenuipes, entomopathogenic fungi silkworm larva, bombyx mori

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Authors: Akash Bera, Suraj Singh, Jacinta Dsouza, Ramakrishna V. Hosur, Pushpa Mishra

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Ultraviolet C (UVC) radiation induces apoptosis in mammalian cells and it is suggested that the mechanism by which this occurs is the mitochondrial pathway of apoptosis through the release of cytochrome c from the mitochondria into the cytosol. The Bcl-2 family of proteins pro-and anti-apoptotic is the regulators of the mitochondrial pathway of apoptosis. Upon UVC irradiation, the proliferation of apoptosis is enhanced through the downregulation of the anti-apoptotic protein Bcl-xl and up-regulation of Bax. Although the participation of the Bcl-2 family of proteins in apoptosis appears responsive to UVC radiation, to the author's best knowledge, it is unknown how the structure and, effectively, the function of these proteins are directly impacted by UVC exposure. In this background, we present here a structural rationale for the effect of UVC irradiation in restoring apoptosis using two of the relevant proteins, namely, Bid-FL and Bcl-xl ΔC, whose solution structures have been reported previously. Using a variety of biophysical tools such as circular dichroism, fluorescence and NMR spectroscopy, we show that following UVC irradiation, the structures of Bcl-xlΔC and Bid-FL are irreversibly altered. Bcl-xLΔC is found to be more sensitive to UV exposure than Bid-FL. From the NMR data, dramatic structural perturbations (α-helix to β-sheet) are seen to occur in the BH3 binding region, a crucial segment of Bcl-xlΔC which impacts the efficacy of its interactions with pro-apoptotic tBid. These results explain the regulation of apoptosis by UVC irradiation. Our results on irradiation dosage dependence of the structural changes have therapeutic potential for the treatment of cancer.

Keywords: Bid, Bcl-xl, UVC, apoptosis

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Authors: Kevser Cakmak, Adrián Montesano, Lourdes Artigas, Marta Salla, Clara Mateu

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The main objective of this research is to explore the relational letter writing technique as an intervention in couple therapy for reconnecting couples with their values and ethical preferences. This is a recently developed therapeutic tool within the framework of Narrative Therapy that consists of two interviews and a letter writing task, in which a meta-conversation between the relationship itself, the couple members, and the therapists is fostered. Although this specific therapeutic technique can be used within the therapy process, in this case study, it is used as a brief stand-alone narrative intervention for a middle age heterosexual couple breast cancer survivor. Couple’s relational and personal wellbeing was monitored before, during, and after the intervention by means of the dyadic adjustment and the clinical outcomes in routine evaluation-outcome measure, respectively. The couple showed a significant improvement after the intervention in both levels. The content of the letter writing exercises was qualitatively analysed to explore the reconstruction of their ethical values. Results from both methods are integrated in order to get an in-depth perspective of the newly developed tool. The potential of the letter writing technique as stand-alone and as adjunct brief intervention is discussed.

Keywords: couple therapy, narrative therapy, psychotherapy tool, relational letter writing

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Authors: Sweta Pandey, Samridhi Dhyani, Susmita Chaudhuri

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Klebsiella pneumoniae causes a wide range of infections, including urinary tract infections, sepsis, bacteremia, pneumonia, and liver abscesses. The emergence of multi-drug resistance in this bacterium led to a major setback for clinical management. WHO also endorsed a need for finding alternative therapy to antibiotics for the treatment of these infections. Development of vaccines and passive antibody therapy has been proven as a potent alternative to antibiotics in the case of MDR, XDR, and PDR Klebsiella infections. Siderophore receptors have been demonstrated to be overexpressed for the internalization of iron siderophore complexes during infections in most Gram-negative bacteria. For the present study, immune response to siderophore receptors to establish this protein as a potential immunogen for the development of therapeutic leads was explored. Clinical strains of Klebsiella pneumoniae were grown in iron-deficient conditions, and the iron-regulated outer membrane proteins were extracted and characterized through mass spectrometry for specific identification. The gene for identified protein was cloned in pET- 28a vector and expressed in E. coli. The native protein and the recombinant protein were isolated and purified and used as antigens for the generation of immune response in BALB/c mice. The native protein of Klebsiella pneumoniae grown in iron-deficient conditions was identified as FepA (Ferrienterobactin receptor) and other siderophore receptors. This 80 kDa protein generated an immune response in BALB/c mice. The antiserum from mice after subsequent booster doses was collected and showed binding with FepA protein in western blot and phagocytic uptake of the K. pneumoniae in the presence antiserum from immunized mice also observed from the animal studies after bacterial challenge post immunisation in mice have shown bacterial clearance. The antiserum from mice showed binding and clearance of the Klebsiella pneumoniae bacteria in vitro and in vivo. These antigens used for generating an active immune response in mice can further be used for therapeutic monoclonal antibody development against Klebsiella pneumoniae infections.

Keywords: antiserum, FepA, Klebsiella pneumoniae, multi drug resistance, siderophore receptor

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Authors: Onur Karaman, A. Gunes Tanir

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Photon radiation therapy used to treat cancer is one of the most important methods. However, photon beam collimator materials in Linear Accelerator (LINAC) head generally contains heavy elements is used and the interaction of bremsstrahlung photon with such heavy nuclei, the neutron can be produced inside the treatment rooms. In radiation therapy, neutron contamination contributes to the risk of secondary malignancies in patients, also physicians working in this field. Since the neutron is more dangerous than photon, it is important to determine neutron dose during radiotherapy treatment. In this study, it is aimed to analyze the effect of field size, distance from axis and depth on the amount of in-field and out-field neutron contamination for ElektaVmat accelerator with 18 MV nominal energy. The photon spectra at the distance of 75, 150, 225, 300 cm from target and on the isocenter of beam were scored for 5x5, 10x10, 20x20, 30x30 and 40x40 cm2 fields. Results demonstrated that the neutron spectra and dose are dependent on field size and distances. Beyond 225 cm of isocenter, the dependence of the neutron dose on field size is minimal. As a result, it is concluded that as the open field increases, neutron dose determined decreases. It is important to remember that when treating with high energy photons, the dose from contamination neutrons must be considered as it is much greater than the photon dose.

Keywords: radiotherapy, neutron contamination, linear accelerators, photon

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Authors: Huayang Yu, Nicola Ingram, David C. Green, Paul D. Thornton

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The dual stimuli-controlled release of doxorubicin from gel-embedded nanoparticles is reported. Non-cytotoxic polymer nanoparticles are formed from poly(ethylene glycol)-b-poly(benzyl glutamate) that, uniquely, contain a central ester link. This connection renders the nanoparticles pH-responsive, enabling extensive doxorubicin release in acidic solutions (pH 6.5), but not in solutions of physiological pH (pH 7.4). Doxorubicin loaded nanoparticles were found to be stable for at least 31 days and lethal against the three breast cancer cell lines tested. Furthermore, doxorubicin-loaded nanoparticles could be incorporated within a thermoresponsive poly(2-hydroxypropyl methacrylate) gel depot, which forms immediately upon injection of poly(2-hydroxypropyl methacrylate) into aqueous solution. The combination of the poly(2-hydroxypropyl methacrylate) gel and poly(ethylene glycol)-b-poly(benzyl glutamate) nanoparticles yields an injectable doxorubicin delivery system that facilities near-complete drug release when maintained at elevated temperatures (37 °C) in acidic solution (pH 6.5). In contrast, negligible payload release occurs when the material is stored at room temperature in a non-acidic solution (pH 7.4). The system has great potential as a vehicle for the prolonged, site-specific release of chemotherapeutics.

Keywords: biodegradable, nanoparticle, polymer, thermoresponsive

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Authors: Jan F. Talts, Amit Saxena, Kåre Engkilde

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Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by anti-neoplastic agents, with a prevalence from 19 % to 85 %. Clinically, CIPN is a mostly sensory neuropathy leading to pain and to motor and autonomic changes. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors, especially because currently, there is no single effective method of preventing CIPN. Hearing loss is the most common form of sensory impairment in humans and can be caused by ototoxic chemical compounds such as chemotherapy (platinum-based antineoplastic agents).In rodents, single or repeated cisplatin injections induce peripheral neuropathy and hearing impairment mimicking human disorder, allowing studying the efficacy of new pharmacological candidates in chemotherapy-induced hearing loss and peripheral neuropathy. RNA sequencing data from full term amniotic fluid (TAF) mesenchymal stemcell (MSC) clones was used to identify neural-specific markers present on TAF-MSC. Several prospective neural markers were tested by flow cytometry on cultured TAF-MSC. One of these markers was used for cell-sorting using Tyto MACSQuant cell sorter, and the neural marker positive cell population was expanded for several passages to the final therapeutic product stage. Peripheral neuropathy and hearing loss was induced in mice by administration of cisplatin in three week-long cycles. The efficacy of neural-specific TAF-MSC in treating hearing loss and pain perception was evaluated by administration of three injections of 3 million cells/kg by intravenous route or three injections of 3 million cells/kg by intra-arterial route after each cisplatin cycle treatment. Auditory brainstem responses (ABR) are electric potentials recorded from scalp electrodes, and the first ABR wave represents the summed activity of the auditory nerve fibers contacting the inner hair cells. For ABR studies, mice were anesthetized, then earphones were placed in the left ear of each mouse, an active electrode was placed in the vertex of the skull, a reference electrode under the skin of the mastoid bone, and a ground electrode in the neck skin. The stimuli consisted of tone pips of five frequencies (2, 4, 6, 12, 16, and 24 kHz) at various sound levels (from 0 to 90 dB) ranging to cover the mouse auditory frequency range. The von Frey test was used to assess the onset and maintenance of mechanical allodynia over time. Mice were placed in clear plexiglass cages on an elevated mesh floor and tested after 30 min of habituation. Mechanical paw withdrawal threshold was examined using an electronic von Frey anesthesiometer. Cisplatin groups treated with three injections of 3 million cells/kg by intravenous route and three injections of 3 million cells/kg by intra-arterial route after each cisplatin cycle treatment presented, a significant increase of hearing acuity characterized by a decrease of ABR threshold and a decrease of neuropathic pain characterized by an increase of von Frey paw withdrawal threshold compared to controls only receiving cisplatin. This study shows that treatment with MSCselected for neural specificity presents significant positive efficacy on the chemotherapy-induced neuropathic pain and the chemotherapy-induced hearing loss.

Keywords: mesenchymal stem cell, peripheral neuropathy, amniotic fluid, regenerative medicine

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Authors: Tamer El-Messery, Beraat Ozcelik

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This study aimed to produce functional yogurt supplemented with microencapsulated krill oil as a source of omega 3, which is known, to maintain the normal brain function, reduce the risk of cancer, and preventing cardiovascular disease. Krill oil was mixed with black cumin oil (1:1) in order to increase its oxidative stability. β-caroteine (10 mg/100 ml) was used as a standard antioxidant. Maltodextrin (MD) was mixed with whey protein concentrate (WPC) and gum Arabic (GA) at the ratio of 8:2:0.5 ratios and used for microencapsulation of single or mixed oils. The microcapsules were dried by freeze and spray drying in order to maximize encapsulation efficiency and minimize lipid oxidation. The feed emulsions used for particle production were characterized for stability, viscosity and particle size, zeta potential, and oxidative stability. The oxidative stability for mixed krill oil and black cumin oil was the highest. The highest encapsulation efficiency was obtained using spray drying, which also showed the highest oxidative stability. The addition of encapsulated krill and black cumin oils (1:1) powder in yogurt manufacture reduced slightly effects on the development of acidity, textural parameters, and water holding capacity of yogurt as compared to control.

Keywords: Krill oil, black cumin oil, micro-encapsulation, oxidative stability, functional yogurt

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Authors: Fawad Ali, Muhammad Ateeq, Ikhtiar Khan

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Ground water, a major source of drinking water supply in Peshawar has been severely contaminated by leather tanning industry. Effluents from the tanneries contain high concentration of chromium besides several other chemical species. Release of untreated effluents from the tanning industry has severely damaged surface and ground water, agriculture soil as well as vegetables and crops. Chromium is a well-known carcinogenic and mutagenic agent. Once in the human food chain, it causes multiple problems to the exposed population including various types of cancer, skin dermatitis, and DNA damage. In order to assess the extent of chromium and other heavy metals contamination, water samples were analyzed for heavy metals using Graphite Furnace Atomic Absorption Spectrometer (GFAAS, Analyst 700, Perkin Elmer). Total concentration of chromium was above the permissible limit (0.048 mg/l) in 85% of the groundwater (drinking water) samples. The concentration of cobalt, manganese, cadmium, nickel, lead, zinc and iron was also determined in the ground water, surface water, agriculture soil, and vegetables samples from the affected area.

Keywords: heavy metals, soil, groundwater, tannery effluents, food chain

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Authors: Juan Francisco Morales Arteaga, Simon Gluhar, Anela Kaurin, Domen Lestan

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Contaminated soils are recognized as one of the most pressing global environmental problems. As is one of the most hazardous elements: chronic exposure to arsenic has devastating effects on health, cardiovascular diseases, cancer, and eventually death. Pb, Zn and Cd are very highly toxic metals that affect almost every organ in the body. With this in mind, new technologies for soil remediation processes are urgently needed. Calcareous artificially contaminated soil containing 231 mg kg-1 As and historically contaminated with Pb, Zn and Cd was washed with a 1:1.5 solid-liquid ratio of 90 mM EDTA, 100 mM oxalic acid, and 50 mM sodium dithionite to remove 59, 75, 29, and 53% of As, Pb, Zn, and Cd, respectively. To reduce emissions of residual EDTA and chelated metals from the remediated soil, zero valent iron (ZVI) was added (1% w/w) to the slurry of the washed soil immediately prior to rinsing. Experimental controls were conducted without the addition of ZVI after remediation. The use of ZVI reduced metal leachability and minimized toxic emissions 21 days after remediation. After this time, NH4NO3 extraction was performed to determine the mobility of toxic elements in the soil. In addition, Unified Human BioaccessibilityMethod (UBM) was performed to quantify the bioaccessibility levels of metals in stimulated human gastric and gastrointestinal phases.

Keywords: soil remediation, soil science, soil washing, toxic metals removal

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Authors: Atitallah Sofien, Bouyahia Olfa, Attar Souleima, Missaoui Nada, Ben Rabeh Rania, Yahyaoui Salem, Mazigh Sonia, Boukthir Samir

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Introduction: Ciliopathies are a spectrum of diseases that have in common a defect in the synthesis of ciliary proteins. It is a rare cause of neonatal cholestasis. Clinical presentation varies extremely, and the main affected organs are the kidneys, liver, and pancreas. Methodology: This is a descriptive case report of a newborn who was admitted for exploration of neonatal cholestasis in the Paediatric Department C at the Children’s Hospital of Tunis, where the investigations concluded with a rare genetic mutation. Results: This is the case of a newborn male with no family history of hepatic and renal diseases, born to consanguineous parents, and from a well-monitored uneventful pregnancy. He developed jaundice on the second day of life, for which he received conventional phototherapy in the neonatal intensive care unit. He was admitted at 15 days for mild bronchiolitis. On clinical examination, intense jaundice was noted with normal stool and urine colour. Initial blood work showed an elevation in conjugated bilirubin and a high gamma-glutamyl transferase level. Transaminases and prothrombin time were normal. Abdominal sonography revealed hepatomegaly, splenomegaly, and undifferentiated renal cortex with bilateral medullar micro-cysts. Kidney function tests were normal. The infant received ursodeoxycholic acid and vitamin therapy. Genetic testing showed a homozygous mutation in the DCDC2 gene that hadn’t been documented before confirming the diagnosis of renal-hepatic ciliopathy. The patient has regular follow-ups, and his conjugated bilirubin and gamma-glutamyl transferase levels have been decreasing. Conclusion: Genetic testing has revolutionized the approach to etiological diagnosis in pediatric cholestasis. It enables personalised treatment strategies to better enhance the quality of life of patients and prevent potential complications following adequate long-term monitoring.

Keywords: cholestasis, newborn, ciliopathy, DCDC2, genetic

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Authors: Subrata Kar, Banani Kundu, Papiya Nandy, Ruma Basu, Sukhen Das

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Natural montmorilollite clay is a common ingredient in pharmaceutical products, both as excipients and active support; hence considered as suitable candidate for Drug Delivery System. In this work, cationic detergent CTAB is used to increase the interlayer spacing of Na+-Montmoriollite clay to intercalate curcumin and methotrexate. Methotrexate is a folic acid antagonist, anti-proliferative and immunosuppressive agent; while curcumin is a bioactive constituent of rhizomes of Curcuma longa, possessing remarkable chemo-preventive and anti-inflammatory properties. The resultant inorganic-organic hybrids are characterized by X-ray diffraction (XRD), Infrared spectroscopy (FTIR) and Thermo Gravimetric Analysis (TGA) to confirm successful intercalation of curcumin and Methotrexate within clay layers. Pharmaceutical investigation of the hybrids is explored by studying the drug loading (%), encapsulation efficiency and release kinetics. Finally in-vitro studies are performed using cancer cells to find the effect of released curcumin to improve the sensitivity of clay bound methotrexate to ameliorate cell death compared to their effectiveness when used without the inorganic aluminosilicate vehicle.

Keywords: montmorillonite, methotrexate, curcumin, loading efficiency, release kinetics, anticancer activity

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Authors: Hamidreza Jabal Ameli, Anahita Movahedi

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Purpose: In radionuclide therapy, radioactive atoms are coupled to monoclonal antibodies (mAbs) for treating cancer tumor while limiting radiation to healthy tissues. We know that tumoral and normal tissues are not equally sensitive to radiation. In fact, biological effects such as cellular repair processes or the presence of less radiosensitive cells such as hypoxic cells should be taken account. For this reason, in this paper, we want to calculate biological effect dose (BED) inside tumoral area and healthy cells around tumors. Methods: In this study, deposited doses of a radionuclide, gold-198, inside cells lattice and surrounding healthy tissues were calculated with Monte Carlo method. The elemental compositions and density of malignant and healthy tissues were obtained from ICRU Report 44. For reaching to real condition of oxygen effects, the necrosis and hypoxia area inside tumors has been assessed. Results: With regard to linear-quadratic expression which was defined in Monte Carlo, results showed that a large amount of BED is deposited in the well-oxygenated part of the hypoxia area compared to necrosis area. Moreover, there is a significant difference between the curves of absorbed dose with BED and without BED.

Keywords: biological dose, monte carlo, hypoxia, radionuclide therapy

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Authors: M. Dabirinezhad, M. Bayat Pour, A. Dabirinejad

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In 2020, the technology was introduced to solve some of the deficiencies of direct digital radiology. SDDR is an invention that is capable of capturing dental images without human intervention, and it was invented by the authors of this paper. Adjusting the radiology wave dose is a part of the dentists, radiologists, and dental nurses’ tasks during the radiology photography process. In this paper, an improvement will be added to enable SDDR to set the suitable radiology wave dose according to the density and age of the patients automatically. The separate sensors will be included in the sensors’ package to use the ultrasonic wave to detect the density of the teeth and change the wave dose. It facilitates the process of dental photography in terms of time and enhances the accuracy of choosing the correct wave dose for each patient separately. Since the radiology waves are well known to trigger off other diseases such as cancer, choosing the most suitable wave dose can be helpful to decrease the side effect of that for human health. In other words, it decreases the exposure time for the patients. On the other hand, due to saving time, less energy will be consumed, and saving energy can be beneficial to decrease the environmental impact as well.

Keywords: dental direct digital imaging, environmental impacts, SDDR technology, wave dose

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Authors: Sadia Arshad, Yifa Tang, Dumitru Baleanu

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A fractional order mathematical model is proposed that incorporate CD8+ cells, natural killer cells, cytokines and tumor cells. The tumor cells growth in the absence of an immune response is modeled by logistic law as it was the simplest form for which predictions also agreed with the experimental data. Natural Killer Cells are our first line of defense. NK cells directly kill tumor cells through several mechanisms, including the release of cytoplasmic granules containing perforin and granzyme, expression of tumor necrosis factor (TNF) family members. The effect of the NK cells on the tumor cell population is expressed with the product term. Rational form is used to describe interaction between CD8+ cells and tumor cells. A number of cytokines are produced by NKs, including tumor necrosis factor TNF, IFN, and interleukin (IL-10). Source term for cytokines is modeled by Michaelis-Menten form to indicate the saturated effects of the immune response. Stability of the equilibrium points is discussed for biologically significant values of bifurcation parameters. We studied the treatment of fractional order system by investigating analytical conditions of tumor eradication. Numerical simulations are presented to illustrate the analytical results.

Keywords: cancer model, fractional calculus, numerical simulations, stability analysis

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Authors: Darya O. Prima, Elena V. Vorontsova, Yuri G. Slizhov, Andrey V. Zibarev

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A broad family of carbocycle-fluorinated aza-heterocycles including 1,3-benzodiazoles (benzimidazoles), 1,2,3-benzotriazoles, 2,1,3-benzothia/selenadiazoles and 1,4-benzodiazines (quinoxalines) was synthesized in the unified way and assessed for cytotoxicity towards the Hep2 (laryngeal epidermoid carcinoma, a kind of oral cancer) cells. The diazoles, triazoles and selenadiazoles revealed low medium inhibitory concentrations IC50 = 2.2-26.4 µМ and induced the cells’ apoptosis at low concentrations C = 1-25 µМ. For selenadiazoles, cell death dynamics was observed already in the first hours after the treatment. Replacement of one atom F by group Me2N in some cases enlarged apoptotic activity of the compounds towards the Hep2 cells. In contrast, the archetypal (i.e. non-fluorinated) 1,3-benzodiazole, 1,2,3-benzotriazole and 2,1,3-benzoselenadiazole were low toxic (IC50 > 100 µM) and induced apoptosis only at high concentrations. The chlorinated congeners of the heterocycles under discussion were highly toxic towards the Hep2 cells but revealed insignificant ability to induce their apoptosis. Overall, the findings above suggest that fluorinated 1,3-benzodiazole, 1,2,3-benzotriazole and 2,1,3-benzoselenadiazole derivatives can be considered as potential anticancer drugs. For the laryngeal epidermoid carcinoma (for which, according to available statistics, the five-year survival rate remained ~50% during the past 30 years), it is especially important since surgical treatment is seriously complicated here thus encouraging medicament one.

Keywords: Apoptosis, aza-heterocycles, cytotoxicity, fluorinated, Hep2 cells, synthesis

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Authors: Rafat M. Mohareb

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Several D-ring alkylated estrone analogues display exceptionally high affinity for estrogen receptors. In particular, compounds in which an E-ring is formed are known to be involved in the inhibition of steroidogenic enzymes. Such compounds also have an effect on steroid dehydrogenase activity and the ability to inhibit the detrimental action of the steroid sulfatase enzyme. Generally, E-ring extended steroids have been accessed by modification of the C17-ketone in the D-ring by either arylimine or oximino formation, addition of a carbon nucleophile or hydrazone formation. Other approaches have included ketone reduction, silyl enol ether formation or ring-closing metathesis (giving five- or six-membered E-rings). Chemical modification of the steroid D-ring provides a way to alter the functional groups, sizes and stereochemistry of the D-ring, and numerous structure-activity relationships have been established by such synthetic alterations. Steroids bearing heterocycles fused to the D-ring of the steroid nucleus have been of pharmaceutical interest. In the present paper, we report on the efficient synthesis of estrone possessing pyran, pyrimidine and thiazole ring systems. This study focused on the synthesis and biochemical evaluation of newly synthesized heterocyclic compounds which were then subjected through inhibitory evaluations towards human cancer and normal cell lines.

Keywords: estrone, heterocyclization, cytotoxicity, biomedicine

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Authors: Brahim Sow

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Background: Throughout West Africa, Balanites aegyptiaca (BA), or Zygophyllaceae, is widely used in traditional medicine to treat diabetes, hypertension, inflammation, malaria and liver disorders. In our recent research, we found that BA has nephroprotective potential against diabetes mellitus, hypertension and kidney disorders. However, to our knowledge, no systematic studies have been carried out on its derivative (toxicity) profile. Aim of the study: The study was conducted to assess the potential potency of the hydroalcoholic extract of BA bark in rats by the acute and sub-acute oral route. Materials and methods: Male and female rats in the acute depression study received BA extract orally at single doses of 500 mg/kg, 2000 mg/kg, 3000 mg/kg and 5000 mg/kg (n = 6 per group/sex). To assess acute depression, abnormal behaviour, toxic symptoms, weight and death were observed for 14 consecutive days. For the subacute impairment study, Wistar rats received the extract orally at doses of 125, 250 and 500 mg/kg (n=6 per group/sex) per day for 28 days. Behaviour and body weight were monitored daily. At the end of the treatment period, biochemical, haematological and histopathological examinations were performed, and gross and histopathological examinations of several organs were carried out. To determine the presence or absence of phytochemicals, the BA extract was subjected to gage phage chromatographic examination. Results: The absence of absorption chromatography of BA indicates the absence of cyanide groups. This suggests that the BA extract does not contain toxic substances. No mortality or adverse effects were observed at 5000 mg/kg in the acute depression test. With regard to body weight, general behaviour, relative organ weights, haematological and biochemical parameters, BA extract did not induce any mortality or potentially treatment-related effects in the sub-acute study. The normal architecture of the vital organs was revealed by histopathological examination, indicating the absence of morphological alterations. Conclusion: BA extract administered orally for 28 days at doses up to 500 mg/kg did not cause toxicological damage in rats in the present study. The median lethal dose (LD50) of the extract was estimated to be over 5000 mg/kg in an acute hyperglycaemia study.

Keywords: Balanites aegyptiaca L Delile, haematology, biochemistry, rat

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Authors: Arulselvi Subramanian, Albert Venencia, Sanjeev Bhoi

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Coagulopathy of trauma is an early endogenous coagulation abnormality that occurs shortly resulting in high mortality. In emergency trauma situations, viscoelastic tests may be better in identifying the various phenotypes of coagulopathy and demonstrate the contribution of platelet function to coagulation. We aimed to determine thrombin generation and clot strength, by estimating a ratio of Maximum amplitude and R-time (MA-R ratio) for identifying trauma coagulopathy and predicting subsequent mortality. Methods: We conducted a prospective cohort analysis of acutely injured trauma patients of the adult age groups (18- 50 years), admitted within 24hrs of injury, for one year at a Level I trauma center and followed up on 3rd day and 5th day of injury. Patients with h/o coagulation abnormalities, liver disease, renal impairment, with h/o intake of drugs were excluded. Thromboelastography was done and a ratio was calculated by dividing the MA by the R-time (MA-R). Patients were further stratified into sub groups based on the calculated MA-R quartiles. First sampling was done within 24 hours of injury; follow up on 3rd and 5thday of injury. Mortality was the primary outcome. Results: 100 acutely injured patients [average, 36.6±14.3 years; 94% male; injury severity score 12.2(9-32)] were included in the study. Median (min-max) on admission MA-R ratio was 15.01(0.4-88.4) which declined 11.7(2.2-61.8) on day three and slightly rose on day 5 13.1(0.06-68). There were no significant differences between sub groups in regard to age, or gender. In the lowest MA-R ratios subgroup; MA-R1 (<8.90; n = 27), injury severity score was significantly elevated. MA-R2 (8.91-15.0; n = 23), MA-R3 (15.01-19.30; n = 24) and MA-R4 (>19.3; n = 26) had no difference between their admission laboratory investigations, however slight decline was observed in hemoglobin, red blood cell count and platelet counts compared to the other subgroups. Also significantly prolonged R time, shortened alpha angle and MA were seen in MA-R1. Elevated incidence of mortality also significantly correlated with on admission low MA-R ratios (p 0.003). Temporal changes in the MA-R ratio did not correlated with mortality. Conclusion: The MA-R ratio provides a snapshot of early clot function, focusing specifically on thrombin burst and clot strength. In our observation, patients with the lowest MA-R time ratio (MA-R1) had significantly increased mortality compared with all other groups (45.5% MA-R1 compared with <25% in MA-R2 to MA-R3, and 9.1% in MA-R4; p < 0.003). Maximum amplitude and R-time may prove highly useful to predict at-risk patients early, when other physiologic indicators are absent.

Keywords: coagulopathy, trauma, thromboelastography, mortality

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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: Pei-Wen Lin, Ta-I Yang

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Cancer has been one of the leading causes of human death for centuries. Considerable effort has been devoted to developing new treatments to reduce and control cancers. Magnetic particle hyperthermia and near-infrared photothermal therapy are the promising strategies to treat cancers due to its effectiveness with only mild side effects. This study focused on synthesizing magnetic Ag@Fe3O4 nanoparticles applicable for both of magnetic hyperthermia and near-infrared photothermal therapy. The hydrophilic poly(diallyldimethylammonium chloride) polymer was utilized to prepare superparamagnetic Fe3O4 clusters and to promote silver nanoparticles grown on Fe3O4 surfaces, obtaining Ag@Fe3O4 nanoparticles. The morphology (shape and dimension) of Ag nanoparticles was subsequently tailored using commercial LED lights. Therefore, the resulting Ag@Fe3O4 nanoparticles can absorb specific wavelength of light ranging from 400 nm to 800 nm by adjusting the wavelength of LED lights and the free silver ions in reaction solution. Heating performance tests confirmed that the synthesized Ag@Fe3O4 nanoparticles show appreciable heating capability for both of magnetic particle hyperthermia and near-infrared photothermal therapy. The findings in this study could provide new ideas to design functional materials to treat cancers.

Keywords: light-emitting diode assisted synthesis, magnetic particles, photothermal materials, hyperthermia

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Authors: Jack S. Pullman, Daniel Wen, Avinash Sharma, Bert Van Der Werf, Richard Martin

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Background: New Zealand (NZ) melanoma incidence rates are amongst the highest in the world. Previous studies investigating the incidence of melanoma in NZ were performed for the periods 1995 – 1999 and 2000 – 2004 and suggested increasing melanoma incidence rates. Aim: The aim of the study is to provide an up-to-date review of trends in cutaneous melanoma in NZ from the New Zealand Cancer Registry (NZCR) 2010 – 2020. Methods: De-identified data were obtained from the NZCR, and relevant demographic and histopathologic information was extracted. Statistical analyses were conducted to calculate age-standardized incidence rates for invasive melanoma (IM) and melanoma in situ (MIS). Secondary results included Breslow thickness and melanoma subtype analysis. Results: There was a decline in the IM age-standardized incidence rate from 30.4 to 23.9 per 100,000 person-years between 2010 to 2020, alongside an increase in MIS incidence rate from 37.1 to 50.3 per 100,000 person-years. Men had a statistically significant higher IM incidence rate (p <0.001) and Breslow thickness (p <0.001) compared with women. Increased age was associated with a higher incidence of IM, presentation with melanoma of greater Breslow thickness and more advanced T stage. Conclusion: The incidence of IM in NZ has decreased in the last decade and was associated with an increase in MIS incidence over the same period. This can be explained due to earlier detection, dermoscopy, the maturity of prevention campaigns and/or a change in skin protection behavior.

Keywords: melanoma, incidence, epidemiology, New Zealand

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Authors: Reham Hajomer, Ikram Elsiddig, Amna Hamad

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Lepidium sativum (Garden Cress) belonging to Brassicaceae family is an annual herb locally known as El-rshad. In Ayurveda it is an important medicinal plant, traditionally used for the treatment of jaundice, liver problems, spleen diseases, gastrointestinal disorders, menstrual problems, fracture, arthritis, inflammatory conditions and for treatment of hypothyroidism. Hypothyroidism is a condition in which the thyroid gland does not produce enough thyroid hormones (Triiodithyronine T3 and Thyroxine T4) which are commonly caused by iodine deficiency. It’s divided into primary and secondary hypothyroidism, the primary caused by failure of thyroid function and secondary due to the failure of adequate thyroid-stimulating hormone (TSH) secretion from the pituitary gland or thyroid -releasing hormone (TRH) from the hypothalamus. The disease is most common in women over age 60. The objective regarding this study is to know whether Lepidium sativum would affect the level of thyroid hormones. The extract was prepared with 96% ethanol using Soxhlet apparatus. The anti-hypothyroidism activity was tested by using thirty male Wistar rats weighing (100-140 g) were used in the experiment. They were grouping into five groups, Group 1: Normal group= Administered only distilled water. Then 10 mg/kg Propylthiouracil was added to the drinking water of all other groups to induce hypothyroidism. Group 2: Negative control without any treatment; Group 3: Test group= treated with oral administration of 500mg/kg extract; Group 4: treated with oral administration of 250mg/kg of the extract; Group 5: Standard group (positive control) = treated with intraperitoneal Levothyroxine. All rats were incubated for 20 days at animal house with room temperature of proper ventilation provided with standard diet. The result show that the Lepidium sativum extract was found to increases the T3 and T4 in the propylthiouracil induced rats with values (0.29 ng/dl T3 and 0.57 U T4) for the 500mg/kg and (0.27 ng/dl T3 and 0.517 U T4) for the 250mg/kg in comparison with standard with values (0.241 ng/dl T3 and 0.516 U T4) so that Lepidium sativum can be stimulatory to thyroid function and possess significant anti-hypothyroidism effect with p-values ranges from (0.000006*-0.893472). In conclusion, from results obtained, Lepidium sativum plant extract was found to posses anti-hypothyroidism effects so its act as an agent that stimulates thyroid hormone secretion.

Keywords: anti-hypothyroidism, extract, lepidium, sativum

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Authors: Daruliza Kernain, Shaharum Shamsuddin, See Too Wei Cun

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CTCF is a unique, highly conserved and ubiquitously expressed 11 zinc finger (ZF) transcriptional factor with multiple target sites. It is able to bind to various target sequences to perform different regulatory roles including promoter activation or repression, creating hormone-responsive gene silencing element, and functional block of enhancer-promoter interactions. The binding of CTCF to the essential binding site is through the combination of different ZF domain. On the other hand, BORIS for brother of the regulator of imprinted sites, which expressed only in the testis and certain cancer cell line is homology to CTCF 11 ZF domains. Since both transcriptional factors share the same ZF domains hence there is a possibility for both to bind to the same target sequences. In this study, the interaction of these two proteins to multi-functional Y-box DNA/RNA-binding factor, YB-1 was determined. The protein-protein interaction between CTCF/YB-1 and BORIS/YB-1 were discovered by Co-immuno-precipitation (CO-IP) technique through reciprocal experiment from RGBM total cell lysate. The results showed that both CTCF and BORIS were able to interact with YB-1 in Glioma RGBM cell line. To the best of our knowledge, this is the first findings demonstrating the ability of BORIS and YB-1 to form a complex in vivo.

Keywords: immunoprecipitation, CTCF/BORIS/YB-1, transcription factor, molecular medicine

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Authors: Fern Baedyananda, Arkom Chaiwongkot, Somchai Niruthisard, Nakarin Kitkumthorn, Parvapan Bhattarakosol

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High-risk human papillomavirus (HPV) infections cause transformation of the host cells by down-regulating and inhibiting host regulatory proteins such as p53 and pRb by overexpressing the viral oncoproteins E6 and E7. However, the E1 protein which is the only enzyme encoded by HPV has also been shown to cause DNA instability leading to the integration of the virus into the host genome and triggering carcinogenic events. A 63bp duplication in the E1 helicase region has been detected in European patients. However, the clinical prognosis of these patients is still controversial. This study was performed to determine the presence of the HPV-16 E1 63bp duplication in patient cervical samples in Thai women and determine the sequence of the variant in the Thai population. Detection of the HPV-16 E1 duplication in the helicase region was performed in 90 patient cell samples across normal, cervical intraepithelial neoplasia I-III, and squamous cervical carcinoma stages by PCR. The PCR products were purified and sequenced to determine the presence of duplication variants.The variant form was found in 10% of all CIN 1 patients. In this study, the presence of the 63 bp duplication variant in the Thai population was found to be present and was further characterized. Interestingly, all samples that exhibited the variant form of HPV-16 E1 were classified as CIN I. Presence of the variant, constricted to mild dysplasia signifies the importance of HPV-16 E1 in carcinogenesis.

Keywords: carcinogenesis, cervical cancer, human papillomavirus, HPV-16 E1

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Authors: Elham Ahmadi, Mehrdad Ravanshad, Joyce Fingeroth, Mazyar Ziyaeyan, Rajesh Panigrahi, Jun Xie, Gao Guangping

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B-cell proliferative disorders often occur among persons that are T-cell compromised. These disorders are primarily EBV+ and can first present with a focal lesion. Direct introduction of oncolytic viruses into localized tumors provides theoretical advantages over chemotherapy and immunotherapy by reducing systemic toxicity, to which the immunocompromised host is most vulnerable. Widely studied as a vehicle for gene therapy, AAV has only rarely been applied to treat cancer. As a prelude to development of a therapeutic vehicle, we assessed the ability of 15 distinct recombinant AAV serotypes (rAAV1, rAAV2, rAAV3b, rAAV4, rAAV5, rAAV6, rAAV6.2, rAAV6TM, rAAV7, rAAV8, rAAVrh8, rAAV9, rAAVrh10, rAAV39, rAAV43) bearing eGFP to infect human B-cell tumor lines compared with primary B-cells in vitro. Enhanced infection of tumor lines by AAV 6.2 was demonstrated by flow cytometry. EBV superinfection of EBV negative B-cell tumor lines increased susceptibility to AAV6.2 infection. As proof of concept, AAV6.2 bearing HSV-1 thymidine kinase in place of eGFP eliminated tumor cells upon exposure to ganciclovir.

Keywords: AAV, gene therapy, lymphoma, malignancy, tropism

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