Search results for: in vitro and in vivo cancer therapy

Authors: Sanjay Singh, Karunanithi Priyanka, Ramoji Kosuru, Raju Prasad Sharma

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Herbal drugs are well known for their mixed pharmacological activities with the benefit of no harmful side effects. The use of herbal drugs is limited because of their higher dose requirement, frequent drug administration, poor bioavailability of phytochemicals and delayed onset of action. Ficus religiosa, a potent anti-oxidant plant useful in the treatment of diabetes and cancer was selected for the study. Solid lipid nanoparticles (SLN) of Ficus religiosa extract was developed for the enhancement in oral bioavailability of stigmasterol and β-sitosterol-d-glucoside, principal components present in the extract. Hot homogenization followed by ultrasonication method was used to develop extract loaded SLN. Developed extract loaded SLN were characterized for particle size, PDI, zeta potential, entrapment efficiency, in vitro drug release and kinetics, fourier transform infra-red spectroscopy, differential scanning calorimetry, powder X-ray diffractrometry and stability studies. Entrapment efficiency of optimized extract loaded SLN was found to be 68.46 % (56.13 % of stigmasterol and 12.33 % of β-sitosteryl-d-glucoside, respectively). RP HPLC method development was done for simultaneous estimation of stigmasterol and β-sitosterol-d-glucoside in Ficus religiosa extract in rat plasma. Bioavailability studies were carried out for extract in suspension form and optimized extract loaded SLN. AUC of stigmasterol and β-sitosterol-d-glucoside were increased by 6.7-folds by 9.2-folds, respectively in rats treated with extract loaded SLN compared to extract suspension. Also, Cmax of stigmasterol and β-sitosterol-d-glucoside were increased by 4.3-folds by 3.9-folds, respectively in rats treated with extract loaded SLN compared to extract suspension. Mean residence times (MRT) for stigmasterol were found to be 12.3 ± 0.67 hours from extract and 7.4 ± 2.1 hours from SLN and for β-sitosterol-d-glucoside, 10.49 ± 2.9 hours from extract and 6.4 ± 0.3 hours from SLN. Hence, it was concluded that SLN enhanced the bioavailability and reduced the MRT of stigmasterol and β-sitosterol-d-glucoside in Ficus religiosa extract which in turn may lead to reduction in dose of Ficus religiosa extract, prolonged duration of action and also enhanced therapeutic efficacy.

Keywords: Ficus religiosa, phytosterolins, bioavailability, solid lipid nanoparticles, stigmasterol and β-sitosteryl-d-glucoside

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Authors: M. Rahimnejad, B. Vahidi, B. Ebrahimi Hoseinzadeh, F. Yazdian, P. Motamed Fath, R. Jamjah

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In this study, we developed and simulated nano-drug delivery systems efficacy in compare to free drug prescription. Computational models can be utilized to accelerate experimental steps and control the experiments high cost. Molecular dynamics simulation (MDS), in particular NAMD was utilized to better understand the anti-cancer drug interaction with cell membrane model. Paclitaxel (PTX) and dipalmitoylphosphatidylcholine (DPPC) were selected for the drug molecule and as a natural phospholipid nanocarrier, respectively. This work focused on two important interaction parameters between molecules in terms of center of mass (COM) and van der Waals interaction energy. Furthermore, we compared the simulation results of the PTX interaction with the cell membrane and the interaction of DPPC as a nanocarrier loaded by the drug with the cell membrane. The molecular dynamic analysis resulted in low energy between the nanocarrier and the cell membrane as well as significant decrease of COM amount in the nanocarrier and the cell membrane system during the interaction. Thus, the drug vehicle showed notably better interaction with the cell membrane in compared to free drug interaction with the cell membrane.

Keywords: anti-cancer drug, center of mass, interaction energy, molecular dynamics simulation, nanocarrier

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Authors: M. Borgie, Z. Dagher, F. Ledoux, A. Verdin, F. Cazier, H. Greige, P. Shirali, D. Courcot

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In October 2013, the International Agency for Research on Cancer (IARC) classified outdoor air pollution and fine particulate matter (PM2.5) as carcinogenic to humans. Despite the clearly relationship established by epidemiological studies between PM exposure and the onset of respiratory and cardiovascular diseases, uncertainties remain about the physiopathological mechanisms responsible for these diseases. The aim of this work was to evaluate the toxicological effects of two samples of atmospheric PM2.5 collected at urban and rural sites on human bronchial epithelial cells, BEAS-2B, especially to investigate the metabolic activation of organic compounds, the alteration of epigenetic mechanisms (i.e. microRNAs genes expression), the phosphorylation of H2AX and the telomerase activity. Our results showed a significant increase in CYP1A1, CYP1B1, and AhRR genes expression, miR-21 gene expression, H2AX phosphorylation and telomerase activity in BEAS-2B cells after their exposure to PM2.5, both in a dose and site-dependent manner. These results showed that PM2.5, especially urban PM, are able to induce the expression of metabolizing enzymes which can provide metabolic biotransformation of organic compounds into more toxic and carcinogenic metabolites, and to induce the expression of the oncomiR miR-21 which promotes cell growth and enhances tumor invasion and metastasis in lung cancer. In addition, our results have highlighted the role of PM2.5 in the activation of telomerase, which can maintain the telomeres length and subsequently preventing cell death, and have also demonstrated the ability of PM2.5 to induce DNA breaks and thus to increase the risk of mutations or chromosomal translocations that lead to genomic instability. All these factors may contribute to cell abnormalities, and thus the development of cancer.

Keywords: BEAS-2B cells, carcinogenesis, epigenetic alterations and genotoxicity, PM2.5

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Authors: Richard I. Licayan, Aisle Janne B. Dagpin, Romeo M. Del Rosario, Nenita D. Palmes

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Hiptage benghalensis, Antigonon leptopus, Macroptillium atropurpureum, and Dioscorea bulbifera L. are herbal weeds that have been used by traditional healers in rural communities in the Philippines as medicine. In this study, the basic pharmacological components of the crude secondary metabolites extracted from the four herbal weeds and their in vitro antioxidant properties was investigated to provide baseline data for the possible development of these metabolites in pharmaceutical products. Qualitative screening of the secondary metabolites showed that alkaloids, tannins, saponins, steroids, and flavonoids were present in their leaf extracts. All of the plant extracts showed varied antioxidant activity. The greatest DPPH radical scavenging activity was observed in H. begnhalensis (84.64%), followed by A. leptopus (68.21%), M. atropurpureum (26.62%), and D. bulbifera L. (19.04%). The FRAP assay revealed that H. benghalensis had the highest antioxidant activity (8.32 mg/g) while ABTS assay showed that M. atropurpureum had the strongest scavenging ability of free radicals (0.0842 mg Trolox/g). The total flavonoid content (TFC) analysis showed that D. bulbifera L. had the highest TFC (420.35 mg quercetin per gram-dried material). The total phenolic content (TPC) of the four herbal weeds showed large variations, between 26.56±0.160 and 55.91±0.087 mg GAE/g dried material. The plant leaf extracts arranged in increasing values of TPC are H. benghalensis (26.565) < A. leptopus (37.29) < D. bulbifera L. (46.81) < M. atropurpureum (55.91). The obtained results may support their use in herbal medicine and as baseline data for the development of new drugs and standardized phytomedicines.

Keywords: antioxidant properties, total flavonoids, total phenolics, creeping herbal weeds

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Authors: Hendra Wibowo, Suprayitno Wardoyo, Dhama Shinta

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Introduction: Pediatric pulmonary tuberculosis (TB) incidence was increasing, with many undetected cases. In complicated TB, treatment should consist of returning pulmonary function, preventing further complications, and eliminating bacteria. Complicated TB management was still controversial, and surgery was one of the treatments that should be evaluated in accordance with its role in the treatment of complicated TB. Method: This study was an evidence-based case report. The database used for the literature search were Cochrane, Medline, Proquest, and ScienceDirect. Keywords for the search were ‘primary pulmonary tuberculosis’, ‘surgery’, ‘lung resection’, and ‘children’. Inclusion criteria were studies in English or Indonesian, with children under 18 years old as subject, and full-text articles available. The assessment was done according to Oxford Centre for evidence-based medicine 2011. Results: Six cohort studies were analyzed. Surgery was indicated for patients with complicated TB that were unresponsive towards treatment. It should be noted that the experiments were done before the standard WHO antituberculosis therapy was applied; thus, the result may be different from the current application. Conclusion: Currently, there was no guideline on pulmonary resection. However, surgery yielded better mortality and morbidity in children with complicated pulmonary TB.

Keywords: pediatric, pulmonary, surgery, therapy, tuberculosis

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Authors: M. Owlia, M. H. Azarsa, M. Khabbazan, A. Mirbagheri

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Proprioceptive neuromuscular facilitation exercises are a series of stretching techniques that are commonly used in rehabilitation and exercise therapy. Assessment of these exercises for true maneuvering requires extensive experience in this field and could not be down with patients themselves. In this paper, we developed software that uses Microsoft Kinect sensor, a spherical color marker, and real-time image processing methods to evaluate patient’s performance in generating true patterns of movements. The software also provides the patient with a visual feedback by showing his/her avatar in a Virtual Reality environment along with the correct path of moving hand, wrist and marker. Primary results during PNF exercise therapy of a patient in a room environment shows the ability of the system to identify any deviation of maneuvering path and direction of the hand from the one that has been performed by an expert physician.

Keywords: image processing, Microsoft Kinect, proprioceptive neuromuscular facilitation, upper extremities assessment, virtual reality

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Authors: Saba Ebrahimi, Saeed Ahmadian, Hedie Ashrafi

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Selecting appropriate patients for surgery is one of the main issues in thoracic surgery (TS). Both short-term and long-term risks and benefits of surgery must be considered in the patient selection criteria. There are some limitations in the existing datasets of TS patients because of missing values of attributes and imbalanced distribution of survival classes. In this study, a novel ensemble architecture of deep learning networks is proposed based on stacking different linear and non-linear layers to deal with imbalance datasets. The categorical and numerical features are split using different layers with ability to shrink the unnecessary features. Then, after extracting the insight from the raw features, a novel biased-kernel layer is applied to reinforce the gradient of the minority class and cause the network to be trained better comparing the current methods. Finally, the performance and advantages of our proposed model over the existing models are examined for predicting patient survival after thoracic surgery using a real-life clinical data for lung cancer patients.

Keywords: deep learning, ensemble models, imbalanced classification, lung cancer, TS patient selection

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Authors: R. Stalin, D. Karthick, H. Haseena Banu, T. P. Sachidanandam, P. Shanthi

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Background: Breast cancer is emerging as one of the leading cause of cancer related deaths and hence there arises the need to look out for drugs which are more targets specific with minimal side effects. In recent times, there is a shift towards alternative medicine due to low cost and less side effects. Siddha system of medicine is one the oldest system of medicine practiced against various ailments. Tridham (TD) is a herbal formulation prepared in our laboratory consisting of Terminalia chebula, Elaeocarpus ganitrus and Prosopis cineraria in a definite ratio (TD) and its anticancer potential is evaluated in terms of induction of apoptosis. Objective: The present study was designed to investigate the anti proliferative effect of TD and 1,2,3,4,6-penta-O-galloyl-b-D-glucose (PGG), a pure compound isolated from TD on human mammary carcinoma cell line (MCF-7). Materials and Methods: Cell viability was studied using MTT analysis and trypan blue staining. Mitochondrial membrane potential was studied using DAPI staining. The protein and mRNA expressions of pro-apoptotic and anti- apoptotic markers namely Bax, Bad, Bcl-2 and caspases were also assessed by Western Blotting and RT PCR. Results: Viability studies of TD and PGG treated MCF-7 cells showed an inhibition in cell growth in time and dose dependent manner. The alteration in mitochondrial membrane potential was restored through treatment with TD and PGG which was confirmed by DAPI staining. The protein and mRNA expression of pro-apoptotic markers was found to be significantly increased in TD and PGG treated cells with a concomitant decrease in anti-apoptotic markers. Conclusion: The results of the study suggest that TD and PGG exhibit their anticancer effect through its membrane stabilizing property and activation of apoptotic cascade in MCF-7 cells.

Keywords: apoptosis, mammary carcinoma, MCF-7, penta galloyl glucose, Tridham

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Authors: Silvia Ximena Barrios, Diego Armando Villamizar Mantilla, Raquel Elvira Ocazionez, , Elena E. Stashenko, María Pilar Vinardell, Jorge Luis Fuentes

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Introduction: Skin overexposure to solar radiation has been a serious public health concern, because of its potential carcinogenicity. Therefore, preventive protection strategies using photoprotective agents are critical to counteract the harmful effect of solar radiation. Plants may be a source of photoprotective compounds that inhibit cellular mutations involved in skin cancer initiation. This work evaluated the photoprotective and antigenotoxic effects against ultraviolet B (UVB) radiation of a mixture of Posoqueria latifolia flower extract and Kaempferol (MixPoKa). Methods: The photoprotective efficacy of MixPoka (Posoqueria latifolia flower extract 250 μg/ml and Kaempferol 349.5 μM) was evaluated using in vitro indices such as sun protection factor SPFᵢₙ ᵥᵢₜᵣₒ and critical wavelength (λc). The MixPoKa photostability (Eff) at human minimal erythema doses (MED), according to the Fitzpatrick skin scale, was also estimated. Cytotoxicity and genotoxicity/antigenotoxicity were studied in MRC5 human fibroblasts using the trypan blue exclusion and Comet assays, respectively. Kinetics of the genetic damage repair post irradiation in the presence and absence of the MixPoka, was also evaluated. Results: The MixPoka -UV absorbance spectrum was high across the spectral bands between 200 and 400 nm. The UVB photoprotection efficacy of MixPoka was high (SPFᵢₙ ᵥᵢₜᵣₒ = 25.70 ± 0.06), showed wide photoprotection spectrum (λc = 380 ± 0), and resulted photostable (Eff = 92.3–100.0%). The MixPoka was neither cytotoxic nor genotoxic in MRC5 human fibroblasts; but presented significant antigenotoxic effect against UVB radiation. Additionally, MixPoka stimulate DNA repair post-irradiation. The potential of this phytochemical mixture as sunscreen ingredients was discussed. Conclusion: MixPoka showed a significant antigenotoxic effect against UVB radiation and stimulated DNA repair after irradiation. MixPoka could be used as an ingredient in a sunscreen cream.

Keywords: flower extract, photoprotection, antigenotoxicity, cytotoxicity, genotoxicit

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Authors: Rona Lee Suelo-Calanao, Mahmoud Loubani

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Objective: Sternal wound infection (SWI) following cardiac operation has a significant impact on patient morbidity and mortality. It also contributes to longer hospital stays and increased treatment costs. SWI management is mainly focused on treatment rather than prevention. This study looks at the effect of closed incision negative pressure therapy (ciNPT) dressing to help reduce the incidence of superficial SWI in high-risk patients after cardiac surgery. The ciNPT dressing was evaluated at 3 cardiac hospitals in the United Kingdom". Methods: All patients who had cardiac surgery from 2013 to 2021 were included in the study. The patients were classed as high risk if they have two or more of the recognised risk factors: obesity, age above 80 years old, diabetes, and chronic obstructive pulmonary disease. Patients receiving standard dressing (SD) and patients using ciNPT were propensity matched, and the Fisher’s exact test (two-tailed) and unpaired T-test were used to analyse categorical and continuous data, respectively. Results: There were 766 matched cases in each group. Total SWI incidences are lower in the ciNPT group compared to the SD group (43 (5.6%) vs 119 (15.5%), P=0.0001). There are fewer deep sternal wound infections (14(1.8%) vs. 31(4.04%), p=0.0149) and fewer superficial infections (29(3.7%) vs. 88 (11.4%), p=0.0001) in the ciNPT group compared to the SD group. However, the ciNPT group showed a longer average length of stay (11.23 ± 13 days versus 9.66 ± 10 days; p=0.0083) and higher mean logistic EuroSCORE (11.143 ± 13 versus 8.094 ± 11; p=0.0001). Conclusion: Utilization of ciNPT as an approach to help reduce the incidence of superficial and deep SWI may be effective in high-risk patients requiring cardiac surgery.

Keywords: closed incision negative pressure therapy, surgical wound infection, cardiac surgery complication, high risk cardiac patients

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Authors: Ntokozo Dambuza, Maryna Van De Venter, Trevor Koekemoer

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Oxidative stress contributes to the pathogenesis of many diseases and consequently antioxidant therapy has attracted much attention as a potential therapeutic strategy. Regardless of the quantities ingested, antioxidants need to reach the diseased tissues at concentrations sufficient to combat oxidative stress. Bioavailability is thus a defining criterion for the therapeutic efficacy of antioxidants. In addition, therapeutic antioxidants must possess biologically relevant characteristics which can target the specific molecular mechanisms responsible for disease related oxidative stress. While many chemical antioxidant assays are available to quantify antioxidant capacity, they relate poorly to the biological environment and provide no information as to the bioavailability. The present comparative study thus aims to characterise green and fermented rooibos extracts, well recognized for their exceptional antioxidant capacity, in terms of antioxidant bioavailability and efficacy in a disease relevant cellular setting. Chinese green tea antioxidant activity was also evaluated. Chemical antioxidant assays (FRAP, DPPH and ORAC) confirmed the potent antioxidant capacity of both green and fermented rooibos, with green rooibos possessing antioxidant activity superior to that of fermented rooibos and Chinese green tea. Bioavailability was assessed using the PAMPA assay and the results indicate that green and fermented rooibos have a permeation coefficient of 5.7 x 10-6 and 6.9 x 10-6 cm/s, respectively. Chinese green tea permeability coefficient was 8.5 x 10-6 cm/s. These values were comparable to those of rifampicin, which is known to have a high permeability across intestinal epithelium with a permeability coefficient of 5 x 10 -6 cm/s. To assess the antioxidant efficacy in a cellular context, U937 and red blood cells were pre-treated with rooibos and Chinese green tea extracts in the presence of a dye DCFH-DA and then exposed to oxidative stress. Green rooibos exhibited highest activity with an IC50 value of 29 μg/ml and 70 μg/ml, when U937 and red blood cells were exposed oxidative stress, respectively. Fermented rooibos and Chinese green tea had IC50 values of 61 μg/ml and 57 μg/ml for U937, respectively, and 221 μg/ml and 405 μg/ml for red blood cells, respectively. These results indicate that fermented and green rooibos extracts were able to permeate the U937 cells and red blood cell membrane and inhibited oxidation of DCFH-DA to a fluorescent DCF within the cells.

Keywords: rooibos, antioxidants, permeability, bioavailability

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Authors: Sevdenur Onger, Ali Asram Sagiroglu

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Hyperpigmentation is a cosmetically unappealing skin problem caused by an overabundance of melanin in the skin. Its pathophysiology is caused by melanocytes being exposed to paracrine melanogenic stimuli, which can upregulate melanogenesis-related enzymes (such as tyrosinase) and cause melanosome formation. Tyrosinase is linked to the development of melanosomes biochemically, and it is the main target of hyperpigmentation treatment. therefore, decreasing tyrosinase activity to reduce melanosomes has become the main target of hyperpigmentation treatment. Niacinamide (NA) is a natural chemical found in a variety of plants that is used as a skin-whitening ingredient in cosmetic formulations. NA decreases melanogenesis in the skin by inhibiting melanosome transfer from melanocytes to covering keratinocytes. Furthermore, NA protects the skin from reactive oxygen species and acts as a main barrier with the skin, reducing moisture loss by increasing ceramide and fatty acid synthesis. However, it is very difficult for hydrophilic compounds such as NA to penetrate deep into the skin. Furthermore, because of the nicotinic acid in NA, it is an irritant. As a result, we've concentrated on strategies to increase NA skin permeability while avoiding its irritating impacts. Since nanotechnology can affect drug penetration behavior by controlling the release and increasing the period of permanence on the skin, it can be a useful technique in the development of whitening formulations. Liposomes have become increasingly popular in the cosmetics industry in recent years due to benefits such as their lack of toxicity, high penetration ability in living skin layers, ability to increase skin moisture by forming a thin layer on the skin surface, and suitability for large-scale production. Therefore, liposomes containing NA were developed for this study. Different formulations were prepared by varying the amount of phospholipid and cholesterol and examined in terms of particle sizes, polydispersity index (PDI) and pH values. The pH values of the produced formulations were determined to be suitable with the pH value of the skin. Particle sizes were determined to be smaller than 250 nm and the particles were found to be of homogeneous size in the formulation (pdi<0.30). Despite the important advantages of liposomal systems, they have low viscosity and stability for topical use. For these reasons, in this study, liposomal cream formulations have been prepared for easy topical application of liposomal systems. As a result, liposomal cream formulations containing NA have been successfully prepared and characterized. Following the in-vitro release and ex-vivo diffusion studies to be conducted in the continuation of the study, it is planned to test the formulation that gives the most appropriate result on the volunteers after obtaining the approval of the ethics committee.

Keywords: delivery systems, hyperpigmentation, liposome, niacinamide

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Authors: Shweta Jha, Nandita Chaube

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The concept of self has a major role to play in the study of personality which drives the current study in its present form. This is a case of Miss S, a 17-year-old Hindu, currently in eleventh standard, with no family history of mental illness but with a past history of inability to manage relationships, multiple emotional and sexual relationships, repeated self harming behaviour, and sexual abuse over a period of 2 months at the age of 10 years. She comes with a psychiatric history of one episode of dissociative fall followed by a stressful event which left the patient with many psychological disturbances matching the criterion of Cluster B and C traits. Current episode precipitated due to the relationship failure, predisposing factor is her personality traits, and poor social and family support. Considering the patient’s aspiration for positivity and demand of the therapy, ventilation sessions were carried out which made her capable of understanding and dealing with her negative emotions, also strengthened mother child bond, helped her maintain meaningful and healthy relationships, also helped her increase her problem solving ability and adaptive coping skills making her feel more positive and acceptable towards herself, family members and others.

Keywords: cluster B and C traits, personality, therapy, self

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Authors: Chen Wang, Chun Liang

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Microsatellite instability (MSI) is characterized by high degree of polymorphism in microsatellite (MS) length due to a deficiency in mismatch repair (MMR) system. MSI is associated with several tumor types and its status can be considered as an important indicator for tumor prognostic. Conventional clinical diagnosis of MSI examines PCR products of a panel of MS markers using electrophoresis (MSI-PCR) which is laborious, time consuming, and less reliable. MSIpred, a python 2 package for automatic classification of MSI was released by this study. It computes important somatic mutation features from files in mutation annotation format (MAF) generated from paired tumor-normal exome sequencing data, subsequently using these to predict tumor MSI status with a support vector machine (SVM) classifier trained by MAF files of 1074 tumors belonging to four types. Evaluation of MSIpred on an independent 358-tumor test set achieved overall accuracy of over 98% and area under receiver operating characteristic (ROC) curve of 0.967. These results indicated that MSIpred is a robust pan-cancer MSI classification tool and can serve as a complementary diagnostic to MSI-PCR in MSI diagnosis.

Keywords: microsatellite instability, pan-cancer classification, somatic mutation, support vector machine

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Authors: Aakriti Lohiya

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This study examines the commonly recognised childhood trauma that can have a significant and enduring effect on a person's cognitive and psychological health. The purpose of this study was to look at the intricate interactions that exist between negative self-identity, cognitive distortions, and early trauma. For the study, a sample of (200 women were taken, who were socially active) was gathered. Standardised measures were utilised to evaluate the participants' experiences of childhood trauma, and validated psychological tools were employed to assess negative self-identity and cognitive distortions. The links and predicting correlations between childhood trauma, negative self-identity, and cognitive distortions were investigated using statistical techniques, such as correlation analysis and multiple regression modelling. The results demonstrated that there is no correlation between the degree of early trauma and the emergence of a negative self-identity and cognitive distortions. It examines whether cognitive distortion and events in childhood have any relationship with negative self-identity using various scales. Participants completed the Childhood Trauma Questionnaire, which assessed retrospective accounts of childhood trauma; the Cognitive Distortions Scale, which measured internal attributions and perceptions of controllability; and the attachment style questionnaire, which assessed the attachment attribute of their daily life, which will lead negative. The implications for therapy were also considered.

Keywords: cognitive distortion, therapy, childhood trauma, attachment

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Authors: John Carlo Combista, Jimbert Tan

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The orchid, Vanda tessellata was chosen by the researchers because of the presence of the constituents in the family Orchidaceae such as alkaloids, flavonoids and glycosides that might give an inhibition activity of the carbonic anhydrase enzyme. This study aimed to determine the in vitro inhibition of carbonic anhydrase of Vanda tessellata flower extract. With the use of modified colorimetric Maren T.H. (1960) method, the time in seconds each test solution changed its color after the rate of CO2 hydration were recorded. Two solvents were used: the semi-polar, 95% ethanol and the non-polar, dichloromethane solvents. The percent inhibition activity of carbonic anhydrase of the different concentrations of solvents ethanol (1%, 25% and 50%) and dichloromethane (1% and 10%) test solutions were determined. Results showed that the ethanol-based extract of Vanda tessellata in different concentrations showed an inhibitory effect while the dichloromethane-based extract of Vanda tessellata showed no inhibitory effect of carbonic anhydrase activity. For ethanol extract, the concentration with the highest activity was 50% followed by 25% which changed its color from red to yellow with an average time of 13.11 seconds and 11.57 seconds but 1% with an average time of 7.56 seconds did not exhibit an effect. The researchers recommend the isolation of the specific active constituents of Vanda tessellata that is responsible for the inhibitory effect of carbonic anhydrase enzyme. It is also recommended to utilize different blood types to observe different reactions to the inhibition of the carbonic anhydrase.

Keywords: carbonic anhydrase, inhibition, modified colorimetric Maren TH method, Vanda orchid

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Authors: Adela Diepoltova, Klara Konecna, Ondrej Jandourek, Petr Nachtigal

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A loss of control over antibiotic-resistant pathogens has become a global issue due to severe and often untreatable infections. This state is reflected in complicated treatment, health costs, and higher mortality. All these factors emphasize the urgent need for the discovery and development of new anti-infectives. One of the most common pathogens mentioned in the phenomenon of antibiotic resistance are bacteria of the genus Staphylococcus. These bacterial agents have developed several mechanisms against the effect of antibiotics. One of them is biofilm formation. In staphylococci, biofilms are associated with infections such as endocarditis, osteomyelitis, catheter-related bloodstream infections, etc. To author's best knowledge, no validated and standardized methodology evaluating candidate compound activity against staphylococcal biofilms exists. However, a variety of protocols for in vitro drug activity testing has been suggested, yet there are often fundamental differences. Based on our experience, a key methodological step that leads to credible results is to form a robust biofilm with appropriate attributes such as firm adherence to the substrate, a complex arrangement in layers, and the presence of extracellular polysaccharide matrix. At first, for the purpose of drug antibiofilm activity evaluation, the focus was put on various conditions (supplementation of cultivation media by human plasma/fetal bovine serum, shaking mode, the density of initial inoculum) that should lead to reproducible and robust in vitro staphylococcal biofilm formation in microtiter plate model. Three model staphylococcal reference strains were included in the study: Staphylococcus aureus (ATCC 29213), methicillin-resistant Staphylococcus aureus (ATCC 43300), and Staphylococcus epidermidis (ATCC 35983). The total biofilm biomass was quantified using the Christensen method with crystal violet, and results obtained from at least three independent experiments were statistically processed. Attention was also paid to the viability of the biofilm-forming staphylococcal cells and the presence of extracellular polysaccharide matrix. The conditions that led to robust biofilm biomass formation with attributes for biofilms mentioned above were then applied by introducing an alternative method analogous to the commercially available test system, the Calgary Biofilm Device. In this test system, biofilms are formed on pegs that are incorporated into the lid of the microtiter plate. This system provides several advantages (in situ detection and quantification of biofilm microbial cells that have retained their viability after drug exposure). Based on our preliminary studies, it was found that the attention to the peg surface and substrate on which the bacterial biofilms are formed should also be paid to. Therefore, further steps leading to the optimization were introduced. The surface of pegs was coated by human plasma, fetal bovine serum, and L-polylysine. Subsequently, the willingness of bacteria to adhere and form biofilm was monitored. In conclusion, suitable conditions were revealed, leading to the formation of reproducible, robust staphylococcal biofilms in vitro for the microtiter model and the system analogous to the Calgary biofilm device, as well. The robustness and typical slime texture could be detected visually. Likewise, an analysis by confocal laser scanning microscopy revealed a complex three-dimensional arrangement of biofilm forming organisms surrounded by an extracellular polysaccharide matrix.

Keywords: anti-biofilm drug activity screening, in vitro biofilm formation, microtiter plate model, the Calgary biofilm device, staphylococcal infections, substrate modification, surface coating

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Authors: Muhammad Mustafa Jafar, Syed Ashar Mahfooz, Muhammad Ejaz Saleem, Muhammad Asif Raza, Asghar Abbas, Rao Zahid Abbas, Muhammad Kasib Khan, Hafiz Muhammad Ishaq

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The Babesia gradually attained resistance against the synthetic medicines. To overcome the drug resistance, herbal therapy has gained more attention as compared to allopathic therapy. Peganumharmala (harmal) is a plant which has shown effective results against various protozoal diseases. Therefore, the present study was planned to monitor the efficacy of Peganumharmala (aqueous extract) against Babesiosis in cattle. For this purpose, a total of forty (n=40) infected animals were randomly divided into four equal groups (A, B, C, and D). Group A was treated with aqueous extract of Peganum harmala at 7.5 mg/kg, group B at 10 mg/kg and group C at 12.5 mg/kg of body weight. Group D served as a control group (normal). It was observed that there was a stabilization in hematological parameters (white and red blood cells, hemoglobin and Packed cell volume) in infected animals treated with Peganum harmala at different doses. Results of this study hence indicated that Peganum harmala extract at 12.5mg/kg BW is more effective against Babesiosis than lower doses.

Keywords: Babesiosis, cattle, control, Peganum harmala

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Authors: Eman Abdullah Morsi, Hend Okasha, Heba Abdel Hady, Mortada El-Sayed, Mohamed Abbas Shemis

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Context: Linum usitatissimum (Linn), known as Flaxseed, is one of the most important medicinal plants traditionally used for various health as nutritional purposes. Objective: Estimation of total phenolic and flavonoid contents as well as evaluate the antioxidant using α, α-diphenyl-β-picrylhydrazyl (DPPH), 2-2'azinobis (3-ethylbenzthiazoline-6-sulphonic acid (ABTS) and total antioxidant capacity (TAC) assay and investigation of anti-inflammatory by Bovine serum albumin (BSA) and anticancer activities of hepatocellular carcinoma cell line (HepG2) and breast cancer cell line (MCF7) have been applied on hexane, ethyl acetate, n-butanol and methanol extracts and also, fractions of methonal extract (hexane, ethyl acetate and n-butanol). Materials and Methods: Phenolic and flavonoid contents were detected using spectrophotometric and colorimetric assays. Antioxidant and anti-inflammatory activities were estimated in-vitro. Anticancer activity of extracts and fractions of methanolic extract were tested on (HepG2) and (MCF7). Results: Methanolic extract and its ethyl acetate fraction contain higher contents of total phenols and flavonoids. In addition, methanolic extract had higher antioxidant activity. Butanolic and ethyl acetate fractions yielded higher percent of inhibition of protein denaturation. Meanwhile, ethyl acetate fraction and methanolic extract had anticancer activity against HepG2 and MCF7 (IC50=60 ± 0.24 and 29.4 ± 0.12µg.mL⁻¹) and (IC50=94.7 ± 0.21 and 227 ± 0.48µg.mL⁻¹), respectively. In Gas chromatography-mass spectrometry (GC-MS) analysis, methanolic extract has 32 compounds, whereas; ethyl acetate and butanol fractions contain 40 and 36 compounds, respectively. Conclusion: Flaxseed contains totally different biologically active compounds that have been found to possess good variable activities, which can protect human body against several diseases.

Keywords: phenolic content, flavonoid content, HepG2, MCF7, hemolysis-assay, flaxseed

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Authors: Mahmoud M. Zakaria, Omnia F. Elmoursi, Mahmoud M. Gabr, Camelia A. AbdelMalak, Mohamed A. Ghoneim

Abstract:

Many protocols were publicized for differentiation of human mesenchymal stem cells (MSCS) into insulin-producing cells (IPCs) in order to excrete insulin hormone ingoing to treat diabetes disease. Our aim is to evaluate relative gene expression for each independent protocol. Human bone marrow cells were derived from three volunteers that suffer diabetes disease. After expansion of mesenchymal stem cells, differentiation of these cells was done by three different protocols (the one-step protocol was used conophylline protein, the two steps protocol was depending on trichostatin-A, and the three-step protocol was started by beta-mercaptoethanol). Evaluation of gene expression was carried out by real-time PCR: Pancreatic endocrine genes, transcription factors, glucose transporter, precursor markers, pancreatic enzymes, proteolytic cleavage, extracellular matrix and cell surface protein. Quantitation of insulin secretion was detected by immunofluorescence technique in 24-well plate. Most of the genes studied were up-regulated in the in vitro differentiated cells, and also insulin production was observed in the three independent protocols. There were some slight increases in expression of endocrine mRNA of two-step protocol and its insulin production. So, the two-step protocol was showed a more efficient in expressing of pancreatic endocrine genes and its insulin production than the other two protocols.

Keywords: mesenchymal stem cells, insulin producing cells, conophylline protein, trichostatin-A, beta-mercaptoethanol, gene expression, immunofluorescence technique

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Authors: Tomi Lois Olatunji, Frances Siebert, Ademola Emmanuel Adetunji, Brian Harvey, Johane Gericke, Josias Hamman, Frank Van Der Kooy

Abstract:

Ethnopharmacological relevance: Sceletium tortuosum (L.) N.E.Br, the most sought after and widely researched species in the genus Sceletium is a succulent forb endemic to South Africa. Traditionally, this medicinal plant is mainly masticated or smoked and used for the relief of toothache, abdominal pain, and as a mood-elevator, analgesic, hypnotic, anxiolytic, thirst and hunger suppressant, and for its intoxicating/euphoric effects. Sceletium tortuosum is currently of widespread scientific interest due to its clinical potential in treating anxiety and depression, relieving stress in healthy individuals, and enhancing cognitive functions. These pharmacological actions are attributed to its phytochemical constituents referred to as mesembrine-type alkaloids. Aim of the review: The aim of this review was to comprehensively summarize and critically evaluate recent research advances on the phytochemistry, pharmacokinetics, biological and clinical activities of the medicinal plant S. tortuosum. Additionally, current ongoing research and future perspectives are also discussed. Methods: All relevant scientific articles, books, MSc and Ph.D. dissertations on botany, behavioral pharmacology, traditional uses, and phytochemistry of S. tortuosum were retrieved from different databases (including Science Direct, PubMed, Google Scholar, Scopus and Web of Science). For pharmacokinetics and pharmacological effects of S. tortuosum, the focus fell on relevant publications published between 2009 and 2021. Results: Twenty-five alkaloids belonging to four structural classes viz: mesembrine, Sceletium A4, joubertiamine, and tortuosamine, have been identified from S. tortuosum, of which the mesembrine class is predominant. The crude extracts and commercially available standardized extracts of S. tortuosum have displayed a wide spectrum of biological activities (e.g. antimalarial, anti-oxidant, immunomodulatory, anti-HIV, neuroprotection, enhancement of cognitive function) in in vitro or in vivo studies. This plant has not yet been studied in a clinical population, but has potential for enhancing cognitive function, and managing anxiety and depression. Conclusion: As an important South African medicinal plant, S. tortuosum has garnered many research advances on its phytochemistry and biological activities over the last decade. These scientific studies have shown that S. tortuosum has various bioactivities. The findings have further established the link between the phytochemistry and pharmacological application, and support the traditional use of S. tortuosum in the indigenous medicine of South Africa.

Keywords: Aizoaceae, Mesembrine, Serotonin, Sceletium tortuosum, Zembrin®, psychoactive, antidepressant

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Authors: Adelson G. Guillarte, M. D., Noel J. Belonguel, Jarungchai Anton S. Vatanagul

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Patients with malignant middle cerebral infarction (MCA) (with massive brain swelling and herniation) were reported to have a mortality rate of 80% even with the appropriate conservative medical therapy. European Trials (DECIMAL, DESTINY I, and II, HAMLET) showed significant improvement in mortality and functional outcome with hemicraniectomy. No known published local studies in the region, thus a local study is vital. This is a single center, retrospective, descriptive, cross-sectional, chart review study which includes ≥18 year-old patients with malignant MCA infarction, who underwent hemicraniectomy, and those who were given conservative medical therapy alone, from January 2008 to December 2012 at Perpetual Succour Hospital. Excluded were patients whose charts are with insufficient data, prior MCA stroke, with concomitant intracerebral hemorrhage and with other serious medical conditions or terminal illnesses. Minimum of 32 populations were needed. Data were presented in mean, standard deviation, frequency and percentage distribution. Man n Whitney U test and Chi Square test were used. P-values lesser than 0.05 alpha were considered statistically significant. A total of 672 stroke patients were admitted. 34 patients pass the inclusion criteria. 9 underwent hemicraniectomy and 25 were treated by conservative medical therapy alone. Although not statistically significant (64% vs 33%, p=0.112) there were more patients noted improved in the conservative treatment group. Meanwhile, the Hemicraniectomy group have increased percentage of mortality (67%) (p=0.112). There was a decreasing trend in the average NIHSS score in both groups from admission to post-op 7 days (p=0.198, p=0.78). A bigger multicenter prospective study is recommended to control inherent biases and limitations of a retrospective and smaller study.

Keywords: cerebral infarct, hemicraniectomy, ischemic stroke, malignant middle cerebral artery (MCA) infarct

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Authors: S. AlBustan, B. AlGhannam

Abstract:

This oral presentation discusses a proposal for a study that evaluates the usability of an evidence based application named ProxTalker App. The significance of this study will inform administration and faculty staff at the Department of Communication Sciences Disorders (CDS), College of Life Sciences, Kuwait University whether the app is a suitable tool to use for CDS students. A case study will be used involving a sample of CDS students taking practicum and internship courses during the academic year 2018/2019. The study will follow a process used by previous study. The process of calculating SUS is well documented and will be followed. ProxTalker App is an alternative and augmentative tool that speech language pathologist (SLP) can use to customize boards for their clients. SLPs can customize different boards using this app for various activities. A board can be created by the SLP to improve and support receptive and expressive language. Using technology to support therapy can aid SLPs to integrate this ProxTalker App as part of their clients therapy. Supported tools, games and motivation are some advantages of incorporating apps during therapy sessions. A quantitative methodology will be used. It involves the utilization of a standard tool that was the was adapted to the Arabic language to accommodate native Arabic language users. The tool that will be utilized in this research is the Arabic Standard Usability Scale (A-SUS) questionnaire which is an adoption of System Usability Scale (SUS). Standard usability questionnaires are reliable, valid and their process is properly documented. This study builds upon the development of A-SUS, which is a psychometrically evaluated questionnaire that targets Arabic native speakers. Results of the usability will give preliminary indication of whether the ProxTalker App under investigation is appropriate to be integrated within the practicum and internship curriculum of CDS. The results of this study will inform the CDS department of this specific app is an appropriate tool to be used for our specific students within our environment because usability depends on the product, environment, and users.

Keywords: A-SUS, communication disorders practicum, evidence based app, Standard Usability Scale

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Authors: Fakhr Eddin Alnaal, Angela Dahdal, Duaa Aladib, Sabeen Ibrahim, Ibrahim Ghoraibi, Bissan Ahmed

Abstract:

Dementia is one of the diseases which had several stages and Alzheimer’s term was selected in respect for the first doctor Alzheimer who defined the first symptoms of this diseases in a woman whom was well treated by him. The fact that this is a type of a silent disease on which you have a long-term process of neurological degradation and suddenly gives symptoms which are most often irreversible, on clinical level likely we can consider it as a malignancy, one in terms of that it is sudden shocking irreversible and on the level of behavior and some mortality beside the lack of early detection tools for diagnosis. Therefore, the goal of our project is to test the concept of the ability of Statin in prevention of such disease and we investigated that both on experimental level and most importantly on clinical one, the clinical part was performed in a recognized house of aged people who had accidently a high cholesterol and were for years given Statin to treat that elevation, however after the symptoms of Alzheimer’s appeared and when diagnosed, they were well treated and rapidly recovered compared to Alzheimer’s patients in the same house who did not receive Statin had a mild improvement in their symptoms after the therapy, on the other hand we confirmed such observation by a well-organized experimental work.

Keywords: Alzheimer's, dementia, silent disease, statin

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Authors: Eric Beyegue, Boris Azantza, Judith Laure Ngondi, Julius E. Oben

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Background: It is clearly that phytochemical constituents of plants in relation exhibit free radical scavenging, antioxidant and glycosylation properties. This study investigated the in vitro antioxidant and free radical scavenging, inhibited activities against α-amylase and invertase enzymes of stem bark extracts C. edulis (Olacaceae). Methods: Four extracts (hexane, dichloromethane, ethanol and aqueous) from the barks of C. edulis were used in this study. Colorimetric in vitro methods were using for evaluate free radical scavenging activity DPPH, ABTS, NO, OH, antioxidant capacity, glycosylation activity, inhibition of α-amylase and invertase activities, phenolic, flavonoid and alkaloid contents. Results: C. edulis extracts (CEE) had a higher scavenging potential on the 2, 2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl (OH), nitrite oxide (NO), 2, 2-azinobis (3-ethylbenzthiazoline)-6-sulfonic acid (ABTS) radicals and glucose scavenging with the IC50 varied between 41.95 and 36694.43 µg/ml depending on the solvent of extraction. The ethanol extract of C. edulis stem bark (CE EtOH) showed the highest polyphenolic (289.10 + 30.32), flavonoid (1.12 + 0.09) and alkaloids (18.47 + 0.16) content. All the tested extracts demonstrated a relative high inhibition potential against α-amylase and invertase digestive enzymes activities. Conclusion: This study suggests that CEE exhibited higher antioxidant potential and significant inhibition potential against digestive enzymes.

Keywords: Coula edulis, antioxidant, scavenging activity, amylase, invertase

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Authors: Van Tang Nguyen, Jennette A. Sakoff, Christopher J. Scarlett

Abstract:

Phyllanthus amarus (P. amarus) has been used as a traditional herbal plant for the treatment of chronic ailments such as hepatitis, diabetes and cancer. The objectives of this study were to determine the physicochemical properties, antioxidant and cytotoxic activities of crude P. amarus extracts and fractions using MTT and CCK-8 assays for cytotoxic evaluation. The outcomes indicated that P. amarus methanol (PAM) extract had lower residual moisture (7.40%) and water activity (0.24) and higher contents of saponins, phenolics, flavonoids and proanthocyanidins (1657.86 mg escin equivalents, 250.45 mg gallic acid equivalents, 274.73 mg rutin equivalents and 61.22 mg catechin equivalents/g dried extract, respectively) than those of P. amarus water (PAW) extract, resulting antioxidant activity of PAM extract was significantly higher (P < 0.05) than that of PAW extract, PAM fractions and phyllanthin (a major compound in P. amarus). Cytotoxic activity of PAM extract for cancer cell lines of MiaPaCa-2 (pancreas), HT29 (colon), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), MCF-7 (breast), MCF-10A (normal breast), and U87, SJ-G2, SMA (glioblastoma) was higher than those of PAW extract and PAM fractions. Therefore, we can conclude that the PA extracts are a potential source for the development of natural antioxidant products and/or novel anticancer drugs.

Keywords: antioxidant, cytotoxicity, Phyllanthus amarus, physicochemical

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Authors: Zenah Gheblawi, Susan Armijo-Olivo, Elisa B. Pelai, Vaishali Sharma, Musa Tashfeen, Angela Fung, Francisca Claveria

Abstract:

Due to physiological differences between men and women, pain is experienced differently between the two sexes. Chronic pain disorders, notably temporomandibular disorders (TMDs), disproportionately affect women in diagnosis, and pain severity in opposition of their male counterparts. TMDs are a type of musculoskeletal disorder that target the masticatory muscles, temporalis muscle, and temporomandibular joints, causing considerable orofacial pain which can usually be referred to the neck and back. Therapeutic methods are scarce, and are not TMD-centered, with the latest research suggesting that subjects with chronic musculoskeletal pain disorders have abnormal alterations in the grey matter of their brains which can be remedied with exercise, and thus, decreasing the pain experienced. The aim of the study is to investigate the effects of exercise therapy in TMD female patients experiencing chronic jaw pain and to assess the consequential effects on brain activity. In a randomized controlled trial, the effectiveness of an exercise program to improve brain alterations and clinical outcomes in women with TMD pain will be tested. Women with chronic TMD pain will be randomized to either an intervention arm or a placebo control group. Women in the intervention arm will receive 8 weeks of progressive exercise of motor control training using visual feedback (MCTF) of the cervical muscles, twice per week. Women in the placebo arm will receive innocuous transcutaneous electrical nerve stimulation during 8 weeks as well. The primary outcomes will be changes in 1) pain, measured with the Visual Analogue Scale, 2) brain structure and networks, measured by fractional anisotropy (brain structure) and the blood-oxygen level dependent signal (brain networks). Outcomes will be measured at baseline, after 8 weeks of treatment, and 4 months after treatment ends and will determine effectiveness of MCTF in managing TMD, through improved clinical outcomes. Results will directly inform and guide clinicians in prescribing more effective interventions for women with TMD. This study is underway, and no results are available at this point. The results of this study will have substantial implications on the advancement in understanding the scope of plasticity the brain has in regards with pain, and how it can be used to improve the treatment and pain of women with TMD, and more generally, other musculoskeletal disorders.

Keywords: exercise therapy, musculoskeletal disorders, physical therapy, rehabilitation, tempomandibular disorders

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Authors: Ali A. Bazzi, Ameer Hamza, Riley O’Hara, Kimberly Kado, Karen H. Hagglund, Lamia Fathallah, Robert T. Morris

Abstract:

Introduction: Endometrial Cancer is a common gynecologic malignancy primarily treated with complete surgical staging, which may include complete pelvic and para-aortic lymphadenectomy. The role of lymphadenectomy is controversial, especially the intraoperative indications for the procedure. Three factors are important in decision to proceed with lymphadenectomy: Myometrial invasion, maximum tumor dimension, and histology. Many institutions incorporate these criteria in varying degrees in the decision to proceed with lymphadenectomy. This investigation assesses the use of intraoperatively measured MTD with and without pre-operative histologic grade. Methods: This study compared retrospectively EEC patients with intraoperatively measured MTD ≤2 cm to those with MTD >2 cm from January 1, 2002 to August 31, 2017. This assessment compared those with MTD ≤ 2cm with endometrial biopsy (EB) grade 1-2 to patients with MTD > 2cm with EB grade 3. Lymph node metastasis (LNM), recurrence, and survival were compared in these groups. Results: This study reviewed 222 patient cases. In tumors > 2 cm, LNM occurred in 20% cases while in tumors ≤ 2 cm, LNM was found in 6% cases (p=0.04). Recurrence and mean survival based on last follow up visit in these two groups were not statistically different (p=0.78 and 0.36 respectively). Data demonstrated a trend that when combined with preoperative EB International Federation of Gynecology and Obstetrics (FIGO) grade, a higher proportion of patients with EB FIGO Grade 3 and MTD > 2 cm had LNM compared to those with EB FIGO Grade 1-2 and MTD ≤ 2 cm (43% vs, 11%, p=0.06). LNM was found in 15% of cases in which lymphadenectomy was performed based on current practices, whereas if the criteria of EB FIGO 3 and MTD > 2 cm were used the incidence of LNM would have been 44% cases. However, using this criterion, two patients would not have had their nodal metastases detected. Compared to the current practice, the sensitivity and specificity of the proposed criteria would be 60% and 81%, respectively. The PPV and NPV would be 43% and 90%, respectively. Conclusion: The results indicate that MTD combined with EB FIGO grade can detect LNM in a higher proportion of cases when compared to current practice. MTD combined with EB FIGO grade may eliminate the need of frozen section sampling in a substantial number of cases.

Keywords: endometrial cancer, FIGO grade, lymphadenectomy, tumor size

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Authors: Ainoa Guinart, Maria Korpidou, Daniel Doellerer, Cornelia Palivan, Ben L. Feringa

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Stimuli responsive systems arise from the need to meet unsolved needs of current molecular drugs. Our study presents the design of a delivery system with high spatiotemporal control and tuneable release profiles. We study the incorporation of a hydrophobic synthetic molecular motor into PDMS-b-PMOXA block copolymer vesicles to create a self-assembled system. We prove their successful incorporation and selective activation by low powered visible light (λ 430 nm, 6.9 mW). We trigger the release of a fluorescent dye with high release efficiencies over sequential cycles (up to 75%) with the ability to turn on and off the release behaviour on demand by light irradiation. Low concentrations of photo-responsive units are proven to trigger release down to 1 mol% of molecular motor. Finally, we test our system in relevant physiological conditions using a lung cancer cell line and the encapsulation of an approved drug. Similar levels of cell viability are observed compared to the free-given drugshowing the potential of our platform to deliver functional drugs on demand with the same efficiency and lower toxicity.

Keywords: molecular motor, polymer, drug delivery, light-responsive, cancer, selfassembly

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Authors: Vidia A. Nuraini, Eugene M. H. Yee, Mohan Bhadbhade, David StC. Black, Naresh Kumar

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Flavonoids are naturally occurring compounds that have been shown to exhibit a wide range of biological properties including anticancer and anti-inflammatory activities. However, flavonoids suffer from low bioavailability, which limits their overall utility for therapeutic applications. One of the methods to overcome this limitation is through structural modification of natural flavonoids. In this study, flavanone, isoflavanone, and isoflavene, were structurally modified through the introduction of additional fused-ring systems via ortho-quinone methide intermediates (o-QMs). These intermediates can readily undergo a [4+2] cycloaddition through an inverse-electron-demand Diels–Alder reaction with electron-rich dienophiles. A regioselective Mannich reaction using bis-(N,N-dimethylamino)methane was employed to generate the o-QM precursors of flavanone, isoflavanone, and isoflavene. The o-QM intermediates were subsequently generated in situ through thermal elimination of the dimethylamine functionality and reacted with a variety of dienophiles to produce novel flavonoids with fused-ring systems. A total of 21 novel flavonoid analogs were successfully synthesized. The X-ray crystal structure of cycloaddition adducts, particularly those derived from 3,4-dihydro-2H-pyran and p-methoxystyrene revealed a special case of enantiomeric disorder, where two enantiomers in equal amounts superpose with one another, with the exception for atoms that have opposite configuration. The anticancer properties of fused-ring systems derived from isoflavene were evaluated against the neuroblastoma SKN-BE(2)C, the triple negative breast cancer MDA-MB-231, and the glioblastoma U87 cancer cell lines. One of these cycloaddition adducts had displayed improved anti-proliferative activity against MDA-MB-231 and U87 cancer cell lines as compared to the parent compound. Further anticancer and anti-inflammatory activities of the flavanone and isoflavanone analogs are currently being investigated.

Keywords: Diels-Alder reaction, flavonoids, Mannich reaction, ortho-quinone methide.

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