Search results for: pediatric cancer

Authors: Nigar Kantarci Carsibasi

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Coarse-grained elastic network models, namely Gaussian network model (GNM) and Anisotropic network model (ANM), are utilized in order to investigate the fluctuation dynamics of Murine Double Minute 2 (MDM2), which is the native inhibitor of p53. Conformational dynamics of MDM2 are elucidated in unbound, p53 bound, and non-peptide small molecule inhibitor bound forms. With this, it is aimed to gain insights about the alterations brought to global dynamics of MDM2 by native peptide inhibitor p53, and two small molecule inhibitors (HDM201 and NVP-CGM097) that are undergoing clinical stages in cancer studies. MDM2 undergoes significant conformational changes upon inhibitor binding, carrying pieces of evidence of induced-fit mechanism. Small molecule inhibitors examined in this work exhibit similar fluctuation dynamics and characteristic mode shapes with p53 when complexed with MDM2, which would shed light on the design of novel small molecule inhibitors for cancer therapy. The results showed that residues Phe 19, Trp 23, Leu 26 reside in the minima of slowest modes of p53, pointing to the accepted three-finger binding model. Pro 27 displays the most significant hinge present in p53 and comes out to be another functionally important residue. Three distinct regions are identified in MDM2, for which significant conformational changes are observed upon binding. Regions I (residues 50-77) and III (residues 90-105) correspond to the binding interface of MDM2, including (α2, L2, and α4), which are stabilized during complex formation. Region II (residues 77-90) exhibits a large amplitude motion, being highly flexible, both in the absence and presence of p53 or other inhibitors. MDM2 exhibits a scattered profile in the fastest modes of motion, while binding of p53 and inhibitors puts restraints on MDM2 domains, clearly distinguishing the kinetically hot regions. Mode shape analysis revealed that the α4 domain controls the size of the cleft by keeping the cleft narrow in unbound MDM2; and open in the bound states for proper penetration and binding of p53 and inhibitors, which points to the induced-fit mechanism of p53 binding. P53 interacts with α2 and α4 in a synchronized manner. Collective modes are shifted upon inhibitor binding, i.e., second mode characteristic motion in MDM2-p53 complex is observed in the first mode of apo MDM2; however, apo and bound MDM2 exhibits similar features in the softest modes pointing to pre-existing modes facilitating the ligand binding. Although much higher amplitude motions are attained in the presence of non-peptide small molecule inhibitor molecules as compared to p53, they demonstrate close similarity. Hence, NVP-CGM097 and HDM201 succeed in mimicking the p53 behavior well. Elucidating how drug candidates alter the MDM2 global and conformational dynamics would shed light on the rational design of novel anticancer drugs.

Keywords: cancer, drug design, elastic network model, MDM2

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Authors: Felipa de Mello-Sampayo

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The aim of this study is to undertake, from patient’s perspective, the timing and probability of using teledermatology, comparing it with a conventional referral system. The dynamic stochastic model’s main value-added consists of the concrete application to patients waiting for dermatology surgical intervention. Patients with low health level uncertainty must use teledermatology treatment as soon as possible, which is precisely when the teledermatology is least valuable. The results of the model were then tested empirically with the teledermatology network covering the area served by the Hospital Garcia da Horta, Portugal, links the primary care centers of 24 health districts with the hospital’s dermatology department via the corporate intranet of the Portuguese healthcare system. Health level volatility can be understood as the hazard of developing skin cancer and the trend of health level as the bias of developing skin lesions. The results of the survival analysis suggest that the theoretical model can explain the use of teledermatology. It depends negatively on the volatility of patients' health, and positively on the trend of health, i.e., the lower the risk of developing skin cancer and the younger the patients, the more presurgical teledermatology one expects to occur. Presurgical teledermatology also depends positively on out-of-pocket expenses and negatively on the opportunity costs of teledermatology, i.e., the lower the benefit missed by using teledermatology, the more presurgical teledermatology one expects to occur.

Keywords: teledermatology, wait time, uncertainty, opportunity cost, survival analysis

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Authors: Kamila Dus-Szachniewicz, Artur Bednarkiewicz, Katarzyna Gdesz-Birula, Slawomir Drobczynski

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In modern oncology hyperthermia (HT) is defined as a controlled tumor heating. HT treatment temperatures range between 40–48 °C and can selectively damage heat-sensitive cancer cells or limit their further growth, usually with minimal injury to healthy tissues. Despite many advantages, conventional whole-body and regional hyperthermia have clinically relevant side effects, including cardiac and vascular disorders. Additionally, the lack of accessibility of deep-seated tumor sites and impaired targeting micrometastases renders HT less effective. It is believed that above disadvantages can significantly overcome by the application of biofunctionalized microparticles, which can specifically target tumor sites and become activated by an external stimulus to provide a sufficient cellular response. In our research, the unique optical tweezers system have enabled capturing the silica microparticles, primary cells and tumor spheroids in highly controllable and reproducible environment to study the impact of localized heat stimulation on normal and pathological cell and within multicellular tumor spheroid. High throughput spheroid model was introduced to better mimic the response to HT treatment on tumors in vivo. Additionally, application of local heating of tumor spheroids was performed in strictly controlled conditions resembling tumor microenvironment (temperature, pH, hypoxia, etc.), in response to localized and nonhomogeneous hyperthermia in the extracellular matrix, which promotes tumor progression and metastatic spread. The lack of precise control over these well- defined parameters in basic research leads to discrepancies in the response of tumor cells to the new treatment strategy in preclinical animal testing. The developed approach enables also sorting out subclasses of cells, which exhibit partial or total resistance to therapy, in order to understand fundamental aspects of the resistance shown by given tumor cells in response to given therapy mode and conditions. This work was funded by the National Science Centre (NCN, Poland) under grant no. UMO-2017/27/B/ST7/01255.

Keywords: cancer spheroids, hyperthermia, microparticles, optical tweezers

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Authors: H. S. Niroshani, W. M. Ediri Arachchi, R. Tudugala, U. J. M. A. L. Jayasinghe, U. M. U. J. Jayasekara, P. B. Hewavithana

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Mammography is used as a screening tool for early diagnosis of breast cancer. It is also useful in refining the diagnosis of breast cancer either by assessment or work up after a suspicious area in the breast has been detected. In order to detect breast cancer accurately and at the earliest possible stage, the image must have an optimum contrast to reveal mass densities and spiculated fibrous structures radiating from them. In addition, the spatial resolution must be adequate to reveal the suffusion of micro calcifications and their shape. The above factors can be optimized by implementing an effective QA programme to enhance the accurate diagnosis of mammographic imaging. Therefore, the radiographer’s knowledge on QA is greatly instrumental in routine mammographic practice. The aim of this study was to assess the radiographer’s knowledge on Quality Assurance and Quality Control programmes in relation to mammographic procedures. A cross-sectional study was carried out among all radiographers working in each mammography setting in Sri Lanka. Pre-tested, anonymous self-administered questionnaires were circulated among the study population and duly filled questionnaires returned within a period of three months were taken into the account. The data on demographical information, knowledge on QA programme and associated QC tests, overall knowledge on QA and QC programmes were obtained. Data analysis was performed using IBM SPSS statistical software (version 20.0). The total response rate was 59.6% and the average knowledge score was 54.15±11.29 SD out of 100. Knowledge was compared on the basis of education level, special training of mammography, and the years of working experience in a mammographic setting of the individuals. Out of 31 subjects, 64.5% (n=20) were graduate radiographers and 35.5% (n=11) were diploma holders while 83.9% (n=26) of radiographers have been specially trained for mammography and 16.1% (n=5) have not been attended for any special training for mammography. It is also noted that 58.1% (n=18) of individuals possessed their experience of less than one year and rest 41.9% (n=13) of them were greater than that. Further, the results found that there is a significant difference (P < 0.05) in the knowledge of QA and overall knowledge on QA and QC programme in the categories of education level and working experience. Also, results imply that there was a significant difference (P < 0.05) in the knowledge of QC test among the groups of trained and non-trained radiographers. This study reveals that education level, working experience and the training obtained particularly in the field of mammography have a significant impact on their knowledge on QA and QC in mammography.

Keywords: knowledge, mammography, quality assurance, quality control

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Authors: Miloud Abid Brahim

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Herpetic gingivostomatitis is a prevalent viral infection in children, predominantly caused by herpes simplex virus type 1 (HSV-1). This case report details the clinical presentation and management of a 9-year-old patient diagnosed with this condition. The child exhibited fever, oral pain, and vesicular lesions that progressed to painful erosions affecting the inner cheeks, tongue, lips, and gums. The diagnosis was established based on clinical findings. Treatment included symptomatic care with analgesics and antipyretics, antimicrobial therapy with antibiotics and antiseptics, and early administration of antiviral medication (aciclovir). The comprehensive approach led to complete resolution of symptoms within 10 days. This case underscores the significance of early recognition and prompt treatment to mitigate the impact of this condition on the patient’s quality of life and to prevent complications.

Keywords: gingivostomatitis, case report, pediatric oral health, herpes simplex virus (HSV-1)

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Authors: Inna Kornienko, Svetlana Guryeva, Natalia Danilova, Elena Petersen

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Drug toxicity often goes undetected until clinical trials, the most expensive and dangerous phase of drug development. Both human cell culture and animal studies have limitations that cannot be overcome by improvements in drug testing protocols. Tissue engineering is an emerging alternative approach to creating models of human malignant tumors for experimental oncology, personalized medicine, and drug discovery studies. This new generation of bioengineered tumors provides an opportunity to control and explore the role of every component of the model system including cell populations, supportive scaffolds, and signaling molecules. An area that could greatly benefit from these models is cancer research. Recent advances in tissue engineering demonstrated that decellularized tissue is an excellent scaffold for tissue engineering. Decellularization of donor organs such as heart, liver, and lung can provide an acellular, naturally occurring three-dimensional biologic scaffold material that can then be seeded with selected cell populations. Preliminary studies in animal models have provided encouraging results for the proof of concept. Decellularized Organs preserve organ microenvironment, which is critical for cancer metastasis. Utilizing 3D tumor models results greater proximity of cell culture morphological characteristics in a model to its in vivo counterpart, allows more accurate simulation of the processes within a functioning tumor and its pathogenesis. 3D models allow study of migration processes and cell proliferation with higher reliability as well. Moreover, cancer cells in a 3D model bear closer resemblance to living conditions in terms of gene expression, cell surface receptor expression, and signaling. 2D cell monolayers do not provide the geometrical and mechanical cues of tissues in vivo and are, therefore, not suitable to accurately predict the responses of living organisms. 3D models can provide several levels of complexity from simple monocultures of cancer cell lines in liquid environment comprised of oxygen and nutrient gradients and cell-cell interaction to more advanced models, which include co-culturing with other cell types, such as endothelial and immune cells. Following this reasoning, spheroids cultivated from one or multiple patient-derived cell lines can be utilized to seed the matrix rather than monolayer cells. This approach furthers the progress towards personalized medicine. As an initial step to create a new ex vivo tissue engineered model of a cancer tumor, optimized protocols have been designed to obtain organ-specific acellular matrices and evaluate their potential as tissue engineered scaffolds for cultures of normal and tumor cells. Decellularized biomatrix was prepared from animals’ kidneys, urethra, lungs, heart, and liver by two decellularization methods: perfusion in a bioreactor system and immersion-agitation on an orbital shaker with the use of various detergents (SDS, Triton X-100) in different concentrations and freezing. Acellular scaffolds and tissue engineered constructs have been characterized and compared using morphological methods. Models using decellularized matrix have certain advantages, such as maintaining native extracellular matrix properties and biomimetic microenvironment for cancer cells; compatibility with multiple cell types for cell culture and drug screening; utilization to culture patient-derived cells in vitro to evaluate different anticancer therapeutics for developing personalized medicines.

Keywords: 3D models, decellularization, drug discovery, drug toxicity, scaffolds, spheroids, tissue engineering

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Authors: Douglas Dunn, Ricahrd Walton, Matthew Warner-Smith, Chirag Mistry, Kan Ren, David Roder

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Introduction: Breast density is a risk factor for breast cancer, both due to increased fibro glandular tissue that can harbor malignancy and the masking of lesions on mammography. Therefore, evaluation of breast density measurement is useful for risk stratification on an individual and population level. This study investigates the performance of Lunit INSIGHT MMG for automated breast density measurement. We analyze the reliability of Lunit compared to breast radiologists, explore density variations across the BreastScreen NSW population, and examine the impact of breast implants on density measurements. Methods: 15,518 mammograms were utilized for a comparative analysis of intra- and inter-reader reliability between Lunit INSIGHT MMG and breast radiologists. Subsequently, Lunit was used to evaluate 624,113 mammograms for investigation of density variations according to age and birth country, providing insights into diverse population subgroups. Finally, we compared breast density in 4,047 clients with implants to clients without implants, controlling for age and birth country. Results: Inter-reader variability between Lunit and Breast Radiologists weighted kappa coefficient was 0.72 (95%CI 0.71-0.73). Highest breast densities were seen in women with a North-East Asia background, whilst those of Aboriginal background had the lowest density. Across all backgrounds, density was demonstrated to reduce with age, though at different rates according to country of birth. Clients with implants had higher density relative to the age-matched no-implant strata. Conclusion: Lunit INSIGHT MMG demonstrates reasonable inter- and intra-observer reliability for automated breast density measurement. The scale of this study is significantly larger than any previous study assessing breast density due to the ability to process large volumes of data using AI. As a result, it provides valuable insights into population-level density variations. Our findings highlight the influence of age, birth country, and breast implants on density, emphasizing the need for personalized risk assessment and screening approaches. The large-scale and diverse nature of this study enhances the generalisability of our results, offering valuable information for breast cancer screening programs internationally.

Keywords: breast cancer, screening, breast density, artificial intelligence, mammography

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Authors: Mohd Jaish Siddiqui

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Laryngeal TB is extremely rare in the pediatric population, accounting for 1% of all cases. Here, we present a case of laryngeal TB with miliary tuberculosis and tuberculous encephalitis, presented with sore throat, hoarseness, severe cough and, acute obstruction the larynx, sputum for AFB was negative, T-SPOT was positive and X-pert was positive, bronchoscopy revealed multiple nodules and edema around the larynx, epiglottis, bilateral arytenopharyngeal folds and vocal cord. Enhanced MRI revealed multiple small nodules in bilateral cerebral hemispheres and right thalamus, however CSF was negative. We reviewed the LTB cases that were published up to 2021. A total of twenty fine cases were identified in English literature. The most common manifestation was hoarseness of voice with 80% followed by stridor 40% of cases. Pulmonary involvement was found in 36% of cases, whereas, 45% of cases had no underlying TB. We did not find any case who developed tuberculous encephalitis in the literature.

Keywords: laryngeal tb, treatment, tuberculous encephalitis, children

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Authors: Roberto Coppo, Francesca Orso, Daniela Dettori, Elena Quaglino, Lei Nie, Mehran M. Sadeghi, Daniela Taverna

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Malignant melanoma is currently the fifth most common cancer in the white population and it is fatal in its metastatic stage. Several research studies in recent years have provided evidence that cancer initiation and progression are driven by genetic alterations of the tumor and paracrine interactions between tumor and microenvironment. Scattered data show that the Endothelial and Smooth muscle cell-Derived Neuropilin-like molecule (ESDN) controls cell proliferation and movement of stroma and tumor cells. To investigate the role of ESDN in the tumor microenvironment during melanoma progression, murine melanoma cells (B16 or B16-F10) were injected in ESDN knockout mice in order to evaluate how the absence of ESDN in stromal cells could influence melanoma progression. While no effect was found on primary tumor growth, increased cell extravasation and lung metastasis formation was observed in ESDN knockout mice compared to wild type controls. In order to understand how cancer cells cross the endothelial barrier during metastatic dissemination in an ESDN-null microenvironment, structure, and permeability of lung blood vessels were analyzed. Interestingly, ESDN knockout mice showed structurally altered and more permeable vessels compared to wild type animals. Since cell surface molecules mediate the process of tumor cell extravasation, the expression of a panel of extravasation-related ligands and receptors was analyzed. Importantly, modulations of N-cadherin, E-selectin, ICAM-1 and VAP-1 were observed in ESDN knockout endothelial cells, suggesting the presence of a favorable tumor microenvironment which facilitates melanoma cell extravasation and metastasis formation in the absence of ESDN. Furthermore, a potential contribution of immune cells in tumor dissemination was investigated. An increased recruitment of macrophages in the lungs of ESDN knockout mice carrying subcutaneous B16-F10 tumors was found. In conclusion, our data suggest a functional role of ESDN in the tumor microenvironment during melanoma progression and the identification of the mechanisms that regulate tumor cell extravasation could lead to the development of new therapies to reduce metastasis formation.

Keywords: melanoma, tumor microenvironment, extravasation, cell surface molecules

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Authors: Felipe H. Sanders, Bryan A. Edwards, Matthew Fusco, Rod J. Oskouian, R. Shane Tubbs

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Introduction: Sinus pericranii is a rare vascular malformation that connects the intracranial dural sinuses to the extracranial venous drainage system and is caused by either trauma or congenital defects. Although the majority of these vascular structures are due to trauma, some are congenital. Case report: Herein, we report a 5-month-old patient with a very large and fluctuating subcutaneous mass over the occiput and the diagnosis of Crouzon’s syndrome. The child presented with a large midline mass that on imaging, connected to the underlying torcular and was diagnosed as a sinus pericranii. At long-term follow up and without operative intervention, the sinus pericranii resolved. This uncommon relationship is reviewed. Conclusion: Premature closure of posterior fossa sutures as part of Crouzon syndrome can present with large sinus pericranii. Such subcutaneous swellings might resolve spontaneously.

Keywords: congenital, craniosynostosis, pediatric, vascular malformation

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Authors: Almudena Espin Perez, Tyler Risom, Carl Pelz, Isabel English, Robert M. Angelo, Rosalie Sears, Andrew J. Gentles

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly malignancies. The role of the tumor microenvironment (TME) is gaining significant attention in cancer research. Despite ongoing efforts, the nature of the interactions between tumors, immune cells, and stromal cells remains poorly understood. The cell-intrinsic properties that govern cell lineage plasticity in PDAC and extrinsic influences of immune populations require technically challenging approaches due to the inherently heterogeneous nature of PDAC. Understanding the cell lineage plasticity of PDAC will improve the development of novel strategies that could be translated to the clinic. Members of the team have demonstrated that the acquisition of ductal to neuroendocrine lineage plasticity in PDAC confers therapeutic resistance and is a biomarker of poor outcomes in patients. Our approach combines computational methods for deconvolving bulk transcriptomic cancer data using CIBERSORTx and high-throughput single-cell imaging using Multiplexed Ion Beam Imaging (MIBI) to study lineage plasticity in PDAC and its relationship to the infiltrating immune system. The CIBERSORTx algorithm uses signature matrices from immune cells and stroma from sorted and single-cell data in order to 1) infer the fractions of different immune cell types and stromal cells in bulked gene expression data and 2) impute a representative transcriptome profile for each cell type. We studied a unique set of 300 genomically well-characterized primary PDAC samples with rich clinical annotation. We deconvolved the PDAC transcriptome profiles using CIBERSORTx, leveraging publicly available single-cell RNA-seq data from normal pancreatic tissue and PDAC to estimate cell type proportions in PDAC, and digitally reconstruct cell-specific transcriptional profiles from our study dataset. We built signature matrices and optimized by simulations and comparison to ground truth data. We identified cell-type-specific transcriptional programs that contribute to cancer cell lineage plasticity, especially in the ductal compartment. We also studied cell differentiation hierarchies using CytoTRACE and predict cell lineage trajectories for acinar and ductal cells that we believe are pinpointing relevant information on PDAC progression. Collaborators (Angelo lab, Stanford University) has led the development of the Multiplexed Ion Beam Imaging (MIBI) platform for spatial proteomics. We will use in the very near future MIBI from tissue microarray of 40 PDAC samples to understand the spatial relationship between cancer cell lineage plasticity and stromal cells focused on infiltrating immune cells, using the relevant markers of PDAC plasticity identified from the RNA-seq analysis.

Keywords: deconvolution, imaging, microenvironment, PDAC

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Authors: Eashwar V. Somasundaram, Raoul R. Wadhwa, Jacob G. Scott

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The use of radiomics in measuring geometric properties of tumor images such as size, surface area, and volume has been invaluable in assessing cancer diagnosis, treatment, and prognosis. In addition to analyzing geometric properties, radiomics would benefit from measuring topological properties using persistent homology. Intuitively, features uncovered by persistent homology may correlate to tumor structural features. One example is necrotic cavities (corresponding to 2D topological features), which are markers of very aggressive tumors. We develop a data pipeline in R that clusters tumors images based on persistent homology is used to identify meaningful clinical distinctions between tumors and possibly new relationships not captured by established clinical categorizations. A preliminary analysis was performed on 16 Magnetic Resonance Imaging (MRI) breast tissue segments downloaded from the 'Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis' (I-SPY TRIAL or ISPY1) collection in The Cancer Imaging Archive. Each segment represents a patient’s breast tumor prior to treatment. The ISPY1 dataset also provided the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status data. A persistent homology matrix up to 2-dimensional features was calculated for each of the MRI segmentation. Wasserstein distances were then calculated between all pairwise tumor image persistent homology matrices to create a distance matrix for each feature dimension. Since Wasserstein distances were calculated for 0, 1, and 2-dimensional features, three hierarchal clusters were constructed. The adjusted Rand Index was used to see how well the clusters corresponded to the ER/PR/HER2 status of the tumors. Triple-negative cancers (negative status for all three receptors) significantly clustered together in the 2-dimensional features dendrogram (Adjusted Rand Index of .35, p = .031). It is known that having a triple-negative breast tumor is associated with aggressive tumor growth and poor prognosis when compared to non-triple negative breast tumors. The aggressive tumor growth associated with triple-negative tumors may have a unique structure in an MRI segmentation, which persistent homology is able to identify. This preliminary analysis shows promising results in the use of persistent homology on tumor imaging to assess the severity of breast tumors. The next step is to apply this pipeline to other tumor segment images from The Cancer Imaging Archive at different sites such as the lung, kidney, and brain. In addition, whether other clinical parameters, such as overall survival, tumor stage, and tumor genotype data are captured well in persistent homology clusters will be assessed. If analyzing tumor MRI segments using persistent homology consistently identifies clinical relationships, this could enable clinicians to use persistent homology data as a noninvasive way to inform clinical decision making in oncology.

Keywords: cancer biology, oncology, persistent homology, radiomics, topological data analysis, tumor imaging

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Authors: Ľudmila Ballová, Slavomír Kurhajec, Eva Petrovová, Jarmila Eftimová

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Angiogenesis, a formation of new blood vessels from a pre-existing vasculature, plays an important role in pathologic processes such as the growth and metastasis of tumours. Tumours cannot grow beyond a few millimetres without blood supply from the newly formed blood vessels from the host tissue, a process called tumour-induced angiogenesis. The successful research of antiangiogenic treatment of cancer has focused on nutraceuticals with angiogenesis-modulating properties. Berberine, as a major active component of the bark of Phellodendron amurense Rupr., has shown antitumour activity by intervening into different steps of carcinogenesis. The influence of ethanolic extract of Phellodendron amurese bark on the angiogenesis was tested in vivo on chick chorioallantoic membrane (CAM). The irritancy of the CAM after the application of the crude bark extract dissolved in normal saline (10 mg/mL) was investigated on embryonic day 7. No significant signs of the irritancy, such as vasoconstriction, hyperaemia, haemorrhage or coagulation were observed which indicates the harmless character of the extract. A significant reduction in vessel sprouting and higher percentage of avascular zone was observed in the case of CAM treated with the extract in comparison with non-treated CAM (control), which is a proof of the antiangiogenic potential of the extract. These results could contribute to the development of novel drugs for the treatment of cancer or other diseases, in which angiogenesis plays a significant role.

Keywords: angiogenesis, berberine, chorioallantoic membrane, irritancy, phellodendron amurense

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Authors: Philip Friedlander, John Rutledge, Jason Suh

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Inhibition of programmed death-1 (PD-1) or its ligand PD-L1 confers therapeutic efficacy in a wide range of solid tumor malignancies. Primary or acquired resistance can develop through activation of immunosuppressive immune cells such as tumor-associated macrophages. The renin angiotensin system (RAS) systemically regulates fluid and sodium hemodynamics, but components are expressed on and regulate the activity of immune cells, particularly of myeloid lineage. We hypothesized that inhibition of RAS would improve the efficacy of PD-1/PD-L-1 treatment. A retrospective analysis was performed through a chart review of patients with solid metastatic malignancies treated with a PD-1/PD-L1 inhibitor between 1/2013 and 6/2019 at Valley Hospital, a community hospital in New Jersey, USA. Efficacy was determined by medical oncologist documentation of clinical benefit in visit notes and by the duration of time on immunotherapy treatment. The primary endpoint was the determination of efficacy differences in patients treated with an inhibitor of RAS ( ace inhibitor, ACEi, or angiotensin blocker, ARB) compared to patients not treated with these inhibitors. To control for broader antihypertensive effects, efficacy as a function of treatment with beta blockers was assessed. 173 patients treated with PD-1/PD-L-1 inhibitors were identified of whom 52 were also treated with an ACEi or ARB. Chi-square testing revealed a statistically significant relationship between being on an ACEi or ARB and efficacy to PD-1/PD-L-1 therapy (p=0.001). No statistically significant relationship was seen between patients taking or not taking beta blocker antihypertensives (p= 0.33). Kaplan-Meier analysis showed statistically significant improvement in the duration of therapy favoring patients concomitantly treated with ACEi or ARB compared to patients not exposed to antihypertensives and to those treated with beta blockers. Logistic regression analysis revealed that age, gender, and cancer type did not have significant effects on the odds of experiencing clinical benefit (p=0.74, p=0.75, and p=0.81, respectively). We conclude that retrospective analysis of the treatment of patients with solid metastatic tumors with anti-PD-1/PD-L1 in a community setting demonstrates greater clinical benefit in the context of concomitant ACEi or ARB inhibition, irrespective of gender or age. This data supports the development of prospective assessment through randomized clinical trials.

Keywords: angiotensin, cancer, immunotherapy, PD-1, efficacy

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Authors: Mustafa Metin Donma

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Metabolic syndrome (MetS) is characterized by a series of biochemical, physiological and anthropometric indicators and is a life-threatening health problem due to its close association with chronic diseases such as diabetes mellitus, hypertension, cancer and cardiovascular diseases. The syndrome deserves great interest both in adults and children. Central obesity is the indispensable component of MetS. Particularly, children, who are morbidly obese have a great tendency to develop the disease, because they are under the threat in their future lives. Preventive measures at this stage should be considered. For this, investigators seek for an informative scale or an index for the purpose. So far, several, but not many suggestions come into the stage. However, the diagnostic decision is not so easy and may not be complete particularly in the pediatric population. The aim of the study was to develop a MetS index capable of predicting MetS, while children are at the morbid obesity stage. This study was performed on morbid obese (MO) children, which were divided into two groups. Morbid obese children, who do not possess MetS criteria comprised the first group (n=44). The second group was composed of children (n=42) with MetS diagnosis. Parents were informed about the signed consent forms, which are required for the participation of their children in the study. The approval of the study protocol was taken from the institutional ethics committee of Tekirdag Namik Kemal University. Helsinki Declaration was accepted prior to and during the study. Anthropometric measurements including weight, height, waist circumference (WC), hip C, head C, neck C, biochemical tests including fasting blood glucose (FBG), insulin (INS), triglycerides (TRG), high density lipoprotein cholesterol (HDL-C) and blood pressure measurements (systolic (SBP) and diastolic (DBP)) were performed. Body fat percentage (BFP) values were determined by TANITA’s Bioelectrical Impedance Analysis technology. Body mass index and MetS indices were calculated. The equations for MetS index (MetSI) and advanced Donma MetS index (ADMI) were [(INS/FBG)/(HDL-C/TRG)]*100 and MetSI*[(SBP+DBP/Height)], respectively. Descriptive statistics including median values, compare means tests, correlation-regression analysis were performed within the scope of data evaluation using the statistical package program, SPSS. Statistically significant mean differences were determined by a p value smaller than 0.05. Median values for MetSI and ADMI in MO (MetS-) and MO (MetS+) groups were calculated as (25.9 and 36.5) and (74.0 and 106.1), respectively. Corresponding mean±SD values for BFPs were 35.9±7.1 and 38.2±7.7 in groups. Correlation analysis of these two indices with corresponding general BFP values exhibited significant association with ADMI, close to significance with MetSI in MO group. Any significant correlation was found with neither of the indices in MetS group. In conclusion, important associations observed with MetS indices in MO group were quite meaningful. The presence of these associations in MO group was important for showing the tendency towards the development of MetS in MO (MetS-) participants. The other index, ADMI, was more helpful for predictive purpose.

Keywords: body fat percentage, child, index, metabolic syndrome, obesity

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Authors: Neeraj Vij, Amber Brennan, Jenni Winters, Hadi Salehi, Hamy Temkit, Emily Andrisevic, Mohan V. Belthur

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Idiopathic clubfoot is a common lower extremity deformity with an incidence of 1:500. The Ponseti Method is well known as the gold standard of treatment. However, there is limited functional data demonstrating correction of the clubfoot after treatment with the Ponseti method. The purpose of this study was to study the clinical and functional outcomes after the Ponseti method with the Clubfoot Disease-Specific Instrument (CDS) and pedobarography. This IRB-approved prospective study included patients aged 3-18 who were treated for idiopathic clubfoot with the Ponseti method between January 2008 and December 2018. Age-matched controls were identified through siblings of clubfoot patients and other community members. Treatment details were collected through a chart review of the included patients. Laboratory assessment included a physical exam, gait analysis, and pedobarography. The Pediatric Outcomes Data Collection Instrument and the Clubfoot Disease-Specific Instrument were also obtained on clubfoot patients (CF). The Wilcoxson rank-sum test was used to study differences between the CF patients and the typically developing (TD) patients. Statistical significance was set at p < 0.05. There were a total of 37 enrolled patients in our study. 21 were priorly treated for CF and 16 were TD. 94% of the CF patients had bilateral involvement. The age at the start of treatment was 29 days, the average total number of casts was seven to eight, and the average total number of casts after Achilles tenotomy was one. The reoccurrence rate was 25%, tenotomy was required in 94% of patients, and ≥1 tenotomy was required in 25% of patients. There were no significant differences between step length, step width, stride length, force-time integral, maximum peak pressure, foot progression angles, stance phase time, single-limb support time, double limb support time, and gait cycle time between children treated with the Ponseti method and typically developing children. The average post-treatment Pirani and Dimeglio scores were 5.50±0.58 and 15.29±1.58, respectively. The average post-treatment PODCI subscores were: Upper Extremity: 90.28, Transfers: 94.6, Sports: 86.81, Pain: 86.20, Happiness: 89.52, Global: 88.6. The average post-treatment Clubfoot Disease-Specific Instrument scores subscores were: Satisfaction: 73.93, Function: 80.32, Overall: 78.41. The Ponseti Method has a very high success rate and remains to be the gold standard in the treatment of idiopathic clubfoot. Timely management leads to good outcomes and a low need for repeated Achilles tenotomy. Children treated with the Ponseti method demonstrate good functional outcomes as measured through pedobarography. Pedobarography may have clinical utility in studying congenital foot deformities. Objective measures for hours of brace wear could represent an improvement in clubfoot care.

Keywords: functional outcomes, pediatric deformity, patient-reported outcomes, talipes equinovarus

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Authors: Malgorzata J. Rybak-Smith, Benedicte Thiebaut, Simon Johnson, Peter Bishop, Helen E. Townley

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Gadolinium doped titania (TiO2:Gd) nanoparticles (NPs) can be activated by X-ray radiation to generate Reactive Oxygen Species (ROS), which can be effective in killing cancer cells. As such, treatment with these NPs can be used to enhance the efficacy of conventional radiotherapy. Incorporation of the NPs in to tumour tissue will permit the extension of radiotherapy to currently untreatable tumours deep within the body, and also reduce damage to neighbouring healthy cells. In an attempt to find a fast and scalable method for the synthesis of the TiO2:Gd NPs, the use of Flame Spray Pyrolysis (FSP) was investigated. A series of TiO2 NPs were generated with 1, 2, 5 and 7 mol% gadolinium dopant. Post-synthesis, the TiO2:Gd NPs were silica-coated to improve their biocompatibility. Physico-chemical characterisation was used to determine the size and stability in aqueous suspensions of the NPs. All analysed TiO2:Gd NPs were shown to have relatively high photocatalytic activity. Furthermore, the FSP synthesized silica-coated TiO2:Gd NPs generated enhanced ROS in chemico. Studies on rhabdomyosarcoma (RMS) cell lines (RD & RH30) demonstrated that in the absence of irradiation all TiO2:Gd NPs were inert. However, application of TiO2:Gd NPs to RMS cells, followed by irradiation, showed a significant decrease in cell proliferation. Consequently, our studies showed that the X-ray-activatable TiO2:Gd NPs can be prepared by a high-throughput scalable technique to provide a novel and affordable anticancer therapy.

Keywords: cancer, gadolinium, ROS, titania nanoparticles, X-ray

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Authors: Xuechun Kan, Dongdong Li, Fan Li, Peidang Liu

Abstract:

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with a poor prognosis, and radiotherapy is one of the main treatment methods. However, due to the obvious resistance of tumor cells to radiotherapy, high dose of ionizing radiation is required during radiotherapy, which causes serious damage to normal tissues near the tumor. Therefore, how to improve radiotherapy resistance and enhance the specific killing of tumor cells by radiation is a hot issue that needs to be solved in clinic. Recent studies have shown that silver-based nanoparticles have strong radiosensitization, and silver nanoclusters (AgNCs) also provide a broad prospect for tumor targeted radiosensitization therapy due to their ultra-small size, low toxicity or non-toxicity, self-fluorescence and strong photostability. Aptamer 5TR1 is a 25-base oligonucleotide aptamer that can specifically bind to mucin-1 highly expressed on the membrane surface of TNBC 4T1 cells, and can be used as a highly efficient tumor targeting molecule. In this study, AgNCs were synthesized by DNA template based on 5TR1 aptamer (NC-T5-5TR1), and its role as a targeted radiosensitizer in TNBC radiotherapy was investigated. The optimal DNA template was first screened by fluorescence emission spectroscopy, and NC-T5-5TR1 was prepared. NC-T5-5TR1 was characterized by transmission electron microscopy, ultraviolet-visible spectroscopy and dynamic light scattering. The inhibitory effect of NC-T5-5TR1 on cell activity was evaluated using the MTT method. Laser confocal microscopy was employed to observe NC-T5-5TR1 targeting 4T1 cells and verify its self-fluorescence characteristics. The uptake of NC-T5-5TR1 by 4T1 cells was observed by dark-field imaging, and the uptake peak was evaluated by inductively coupled plasma mass spectrometry. The radiation sensitization effect of NC-T5-5TR1 was evaluated through cell cloning and in vivo anti-tumor experiments. Annexin V-FITC/PI double staining flow cytometry was utilized to detect the impact of nanomaterials combined with radiotherapy on apoptosis. The results demonstrated that the particle size of NC-T5-5TR1 is about 2 nm, and the UV-visible absorption spectrum detection verifies the successful construction of NC-T5-5TR1, and it shows good dispersion. NC-T5-5TR1 significantly inhibited the activity of 4T1 cells and effectively targeted and fluoresced within 4T1 cells. The uptake of NC-T5-5TR1 reached its peak at 3 h in the tumor area. Compared with AgNCs without aptamer modification, NC-T5-5TR1 exhibited superior radiation sensitization, and combined radiotherapy significantly inhibited the activity of 4T1 cells and tumor growth in 4T1-bearing mice. The apoptosis level of NC-T5-5TR1 combined with radiation was significantly increased. These findings provide important theoretical and experimental support for NC-T5-5TR1 as a radiation sensitizer for TNBC.

Keywords: 5TR1 aptamer, silver nanoclusters, radio sensitization, triple-negative breast cancer

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Authors: T. Al-Alawi, N. Shorbaji, E. Rashaidi, M.Alidrisi

Abstract:

Purpose/Objective(s): The main purpose of this study is to analyze the planning of SBRT treatments for localized prostate cancer with 6FFF and 10FFF energies to see if there is a dosimetric difference between the two energies and how we can increase the plan efficiency and reduce its complexity. Also, to introduce a planning method in our department to treat prostate cancer by utilizing high energy photons without increasing patient toxicity and fulfilled all dosimetric constraints for OAR (an organ at risk). Then toevaluate the target 95% coverage PTV95, V5%, V2%, V1%, low dose volume for OAR (V1Gy, V2Gy, V5Gy), monitor unit (beam-on time), and estimate the values of homogeneity index HI, conformity index CI a Gradient index GI for each treatment plan.Materials/Methods: Two treatment plans were generated for15 patients with localized prostate cancer retrospectively using the CT planning image acquired for radiotherapy purposes. Each plan contains two/three complete arcs with two/three different collimator angle sets. The maximum dose rate available is 1400MU/min for the energy 6FFF and 2400MU/min for 10FFF. So in case, we need to avoid changing the gantry speed during the rotation, we tend to use the third arc in the plan with 6FFF to accommodate the high dose per fraction. The clinical target volume (CTV) consists of the entire prostate for organ-confined disease. The planning target volume (PTV) involves a margin of 5 mm. A 3-mm margin is favored posteriorly. Organs at risk identified and contoured include the rectum, bladder, penile bulb, femoral heads, and small bowel. The prescription dose is to deliver 35Gyin five fractions to the PTV and apply constraints for organ at risk (OAR) derived from those reported in references. Results: In terms of CI=0.99, HI=0.7, and GI= 4.1, it was observed that they are all thesame for both energies 6FFF and 10FFF with no differences, but the total delivered MUs are much less for the 10FFF plans (2907 for 6FFF vs.2468 for 10FFF) and the total delivery time is 124Sc for 6FFF vs. 61Sc for 10FFF beams. There were no dosimetric differences between 6FFF and 10FFF in terms of PTV coverage and mean doses; the mean doses for the bladder, rectum, femoral heads, penile bulb, and small bowel were collected, and they were in favor of the 10FFF. Also, we got lower V1Gy, V2Gy, and V5Gy doses for all OAR with 10FFF plans. Integral dosesID in (Gy. L) were recorded for all OAR, and they were lower with the 10FFF plans. Conclusion: High energy 10FFF has lower treatment time and lower delivered MUs; also, 10FFF showed lower integral and meant doses to organs at risk. In this study, we suggest usinga 10FFF beam for SBRTprostate treatment, which has the advantage of lowering the treatment time and that lead to lessplan complexity with respect to 6FFF beams.

Keywords: FFF beam, SBRT prostate, VMAT, prostate cancer

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Authors: Adekunle O. Afolabi, Pekka Toivanen

Abstract:

The world is expected to experience growth in the number of ageing population, and this will bring about high cost of providing care for these valuable citizens. In addition, many of these live with chronic diseases that come with old age. Providing adequate care in the face of rising costs and dwindling personnel can be challenging. However, advances in technologies and emergence of the Internet of Things are providing a way to address these challenges while improving care giving. This study proposes the integration of recommendation systems into homecare to provide real-time recommendations for effective management of people receiving care at home and those living with chronic diseases. Using the simplified Training Logic Concept, stakeholders and requirements were identified. Specific requirements were gathered from people living with cancer. The solution designed has two components namely home and community, to enhance recommendations sharing for effective care giving. The community component of the design was implemented with the development of a mobile app called Recommendations Sharing Community for Aged and Chronically Ill People (ReSCAP). This component has illustrated the possibility of real-time recommendations, improved recommendations sharing among care receivers and between a physician and care receivers. Full implementation will increase access to health data for better care decision making.

Keywords: recommendation systems, Internet of Things, healthcare, homecare, real-time

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Authors: Priyanka Manghani, Manthan Patel, Rahul Peddawad

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Cervical Cancer is a major public health hurdle in the area of women’s health. The most common cause of Cervical Cancer is the Human Papilloma Virus (HPV). Human papilloma virus has various genotypes, with HPV 16 and HPV 18 being the major etiological factor causing carcinoma of the Cervix. Early screening and detection by Papanicolaou Smears (PAP) is an effective method for identifying premalignant and malignant lesions. In case of existing pre- malignant lesions /cervical dysplasia’s found with HPV 16 or 18, appropriate follow up can be done to prevent it from developing into a neoplasm. Aims and Objectives: Primary Aim; To study various abnormal cervical cytology reports as detected by Pap Smear Tests, using the Bethesda System in women at a Tertiary Care Hospital. Secondary Aim; To discuss the importance of Pap smear in Cervical Cancer Screening Program. Materials and Methods: Our study is a prospective study, based on 101 women who attended the Out-patient department of Obstetrics and Gynecology at a tertiary care hospital in age group 20-40 years with chief complaints of white/foul vaginal discharge, post-coital Bleeding, low back pain, irregular menstruation, etc. 60 women, who were tested, of the total no of women, were commercial sex workers, thus being a high-risk group for HPV infection. All women underwent conventional cytology. For all the abnormal smears, further cervical biopsies were done, and the final diagnosis was done on the basis of histopathology (gold standard). Results: In all these patients, 16 patients presented with normal smears out of which 2 belonged to the category of commercial sex workers (3.33%) and 14 being from the normal/control group (34.15%). 44 women presented with inflammatory smears out of which 30 were commercial sex workers (50%) and 14 from the control Group (34.15%). A total of 11 women presented with infectious etiology with 6 being commercial sex workers (10%) and 5 (12.2%) being in the control group. A total of 8 patients presented with low-grade squamous intra epithelial lesion (LSIL) with 7 (11.7%) being commercial sex workers and 1(2.44%) patient belonging to the control group. A Total of 7 patients presented with high-grade squamous intraepithelial lesion (HSIL) with 6 (10%) being commercial sex workers and 1 (2.44%) belonging to the control group. 9 patients in total presented with atypical squamous cells of undetermined significance (ASCUS) with 6(10%) being commercial sex workers and 3 (7.32%) belonging to the control group. Squamous cell carcinoma(SCC) presence was found only in 1(1.7%) commercial sex worker. Conclusion – We conclude that HSIL, LSIL, SCC and sexually related infections are comparatively more common in vulnerable groups such as sex workers due to a variety of factors such as multiple sexual partners and poor genital hygiene. Early screening and follow up interventions are highly needed for them along with Health education for risk factors and to emphasize on the importance of Pap smear screening.

Keywords: cervical cancer, papanicolaou (pap) smear, bethesda system, neoplasm

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Authors: Mudafara Bengleil

Abstract:

Estimation of the magnitude and causes of poisoning was the objective of the current study. A retrospective study of medical records of all poisoning children admitted to Benghazi Children Hospital in Libya from January 2008 up to December 2010. Number of children admitted was 244; the age ranged from less than one to 13 years old. Most of cases were admitted with mild symptom and the majority of them were boys. Only few cases admitted to intensive care unit and there was no mortality recorded through the period of study. Age group 1 to 3 years (50.8%) had the highest frequency of admission and the peak of admission was during summer. The most common cause of admission was due to ingestion of medication (53.69%), House hold product exposure (26.64%) was the second causes of admission while, 19.67% of admissions were due to Food poisoning. Almost all admitted cases were accidental and medicines were the most consumed substances in addition, improper storage of toxic agents were the first risk factor of poisoning. Present results indicated that, children poisoning seems to be a common pediatric care problem which need to control and prevent.

Keywords: poisoning, children, hospital, medical

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Authors: Ki-Yeo Kim

Abstract:

Trends in genetics are transforming in order to identify differential coexpressions of correlated gene expression rather than the significant individual gene. Moreover, it is known that a combined biomarker pattern improves the discrimination of a specific cancer. The identification of the combined biomarker is also necessary for the early detection of invasive oral squamous cell carcinoma (OSCC). To identify the combined biomarker that could improve the discrimination of OSCC, we explored an appropriate number of genes in a combined gene set in order to attain the highest level of accuracy. After detecting a significant gene set, including the pre-defined number of genes, a combined expression was identified using the weights of genes in a gene set. We used the Principal Component Analysis (PCA) for the weight calculation. In this process, we used three public microarray datasets. One dataset was used for identifying the combined biomarker, and the other two datasets were used for validation. The discrimination accuracy was measured by the out-of-bag (OOB) error. There was no relation between the significance and the discrimination accuracy in each individual gene. The identified gene set included both significant and insignificant genes. One of the most significant gene sets in the classification of normal and OSCC included MMP1, SOCS3 and ACOX1. Furthermore, in the case of oral dysplasia and OSCC discrimination, two combined biomarkers were identified. The combined genomic expression achieved better performance in the discrimination of different conditions than in a single significant gene. Therefore, it could be expected that accurate diagnosis for cancer could be possible with a combined biomarker.

Keywords: oral squamous cell carcinoma, combined biomarker, microarray dataset, correlated genes

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Authors: Akterono Budiyati, Gita Kusumo, Teguh Putra, Fritzie Rexana, Antonius Kurniawan, Aru Sudoyo, Ahmad Utomo, Andi Utama

Abstract:

The presence of the programmed death ligand-1 (PD-L1) has been used in multiple clinical trials and approved as biomarker for selecting patients more likely to respond to immune checkpoint inhibitors. However, the expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence. Positive PD-L1 within tumors may result from two mechanisms, induced PD-L1 expression by T-cell presence or genetic mechanism that lead to constitutive PD-L1 expression. Amplification of PD-L1 genes was found as one of genetic mechanism which causes an increase in PD-L1 expression. In case of colorectal cancer (CRC), targeting immune checkpoint inhibitor has been recommended for patients with microsatellite instable (MSI). Although the correlation between PD-L1 expression and MSI status has been widely studied, so far the precise mechanism of PD-L1 gene activation in CRC patients, particularly in MSI population have yet to be clarified. In this present study we have profiled 61 archived formalin fixed paraffin embedded CRC specimens of patients from Medistra Hospital, Jakarta admitted in 2010 - 2016. Immunohistochemistry was performed to measure expression of PD-L1 in tumor cells as well as MSI status using antibodies against PD-L1 and MMR (MLH1, MSH2, PMS2 and MSH6), respectively. PD-L1 expression was measured on tumor cells with cut off of 1% whereas loss of nuclear MMR protein expressions in tumor cells but not in normal or stromal cells indicated presence of MSI. Subset of PD-L1 positive patients was then assessed for copy number variations (CNVs) using single Tube TaqMan Copy Number Assays Gene CD247PD-L1. We also observed KRAS mutation to profile possible genetic mechanism leading to the presence or absence of PD-L1 expression. Analysis of 61 CRC patients revealed 15 patients (24%) expressed PD-L1 on their tumor cell membranes. The prevalence of surface membrane PD-L1 was significantly higher in patients with MSI (87%; 7/8) compared to patients with microsatellite stable (MSS) (15%; 8/53) (P=0.001). Although amplification of PD-L1 gene was not found among PD-L1 positive patients, low-level amplification of PD-L1 gene was commonly observed in MSS patients (75%; 6/8) than in MSI patients (43%; 3/7). Additionally, we found 26% of CRC patients harbored KRAS mutations (16/61), so far the distribution of KRAS status did not correlate with PD-L1 expression. Our data suggest genetic mechanism through amplification of PD-L1 seems not to be the mechanism underlying upregulation of PD-L1 expression in CRC patients. However, further studies are warranted to confirm the results.

Keywords: colorectal cancer, gene amplification, microsatellite instable, programmed death ligand-1

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Authors: Han Xiao

Abstract:

The development of nanomedicines has recently achieved several breakthroughs in the field of cancer treatment; however, the biocompatibility and targeted burst release of these medications remain a limitation, which leads to serious side effects and significantly narrows the scope of their applications. The self-assembly of intermediate filament protein (IFP) peptides was triggered by a hydrophobic cation drug 7-amino actinomycin D (7-AAD) to synthesize pH-activatable nanoparticles (NPs) that could simultaneously locate tumors and produce antitumor effects. The designed IFP peptide included a target peptide (arginine–glycine–aspartate), a negatively charged region, and an α-helix sequence. It also possessed the ability to encapsulate 7-AAD molecules through the formation of hydrogen bonds and hydrophobic interactions by a one-step method. 7-AAD molecules with excellent near-infrared fluorescence properties could be target delivered into tumor cells by NPs and released immediately in the acidic environments of tumors and endosome/lysosomes, ultimately inducing cytotoxicity by arresting the tumor cell cycle with inserted DNA. It is noteworthy that the IFP/7-AAD NPs tail vein injection approach demonstrated not only high tumor-targeted imaging potential, but also strong antitumor therapeutic effects in vivo. The proposed strategy may be used in the delivery of cationic antitumor drugs for precise imaging and cancer therapy.

Keywords: 7-amino actinomycin D, intermediate filament protein, nanoparticle, tumor image

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Authors: Viviane A. O. Silva, Angela M. Costa, Glaucia N. M. Hajj, Ana Preto, Aline Tansini, Martin Roffé, Peter Jordan, Rui M. Reis

Abstract:

Autophagy is a recycling and degradative system suggested to be a major cell death pathway in cancer cells. Autophagy pathway is interconnected with the endocytosis pathways sharing the same ultimate lysosomal destination. Lysosomes are crucial regulators of cell homeostasis, responsible to downregulate receptor signalling and turnover. It seems highly likely that derailed endocytosis can make major contributions to several hallmarks of cancer. WNK2, a member of the WNK (with-no-lysine [K]) subfamily of protein kinases, had been found downregulated by its promoter hypermethylation, and has been proposed to act as a specific tumour-suppressor gene in brain tumors. Although some contradictory studies indicated WNK2 as an autophagy modulator, its role in cancer cell death is largely unknown. There is also growing evidence for additional roles of WNK kinases in vesicular traffic. Aim: To evaluate the role of WNK2 in autophagy and endocytosis on glioma context. Methods: Wild-type (wt) A172 cells (WNK2 promoter-methylated), and A172 transfected either with an empty vector (Ev) or with a WNK2 expression vector, were used to assess the cellular basal capacities to promote autophagy, through western blot and flow-cytometry analysis. Additionally, we evaluated the effect of WNK2 on general endocytosis trafficking routes by immunofluorescence. Results: The re-expression of ectopic WNK2 did not interfere with autophagy-related protein light chain 3 (LC3-II) expression levels as well as did not promote mTOR signaling pathway alteration when compared with Ev or wt A172 cells. However, the restoration of WNK2 resulted in a marked increase (8 to 92,4%) of Acidic Vesicular Organelles formation (AVOs). Moreover, our results also suggest that WNK2 cells promotes delay in uptake and internalization rate of cholera toxin B and transferrin ligands. Conclusions: The restoration of WNK2 interferes in vesicular traffic during endocytosis pathway and increase AVOs formation. This results also suggest the role of WNK2 in growth factor receptor turnover related to cell growth and homeostasis and associates one more time, WNK2 silencing contribution in genesis of gliomas.

Keywords: autophagy, endocytosis, glioma, WNK2

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Authors: Suhas Pednekar, Prashant Chavan, Ramesh Chaughule, Deepak Patkar

Abstract:

Iron oxide (Fe3O4) magnetic nanoparticles (MNPs) are one of the most attractive nanomaterials for various biomedical applications. An important potential medical application of polymer-coated iron oxide nanoparticles (NPs) is as imaging agents. Composition, size, morphology and surface chemistry of these nanoparticles can now be tailored by various processes to not only improve magnetic properties but also affect the behavior of nanoparticles in vivo. MNPs are being actively investigated as the next generation of magnetic resonance imaging (MRI) contrast agents. Also, there is considerable interest in developing magnetic nanoparticles and their surface modifications with therapeutic agents. Our study involves the synthesis of biocompatible cancer drug coated with iron oxide nanoparticles and to evaluate their efficacy as MRI contrast agents. A simple and rapid microwave method to prepare Fe3O4 nanoparticles has been developed. The drug was successfully conjugated to the Fe3O4 nanoparticles which can be used for various applications. The relaxivity R2 (reciprocal of the spin-spin relaxation time T2) is an important factor to determine the efficacy of Fe nanoparticles as contrast agents for MRI experiments. R2 values of the coated magnetic nanoparticles were also measured using MRI technique and the results showed that R2 of the Fe complex consisting of Fe3O4, polymer and drug was higher than that of bare Fe nanoparticles and polymer coated nanoparticles. This is due to the increase in hydrodynamic sizes of Fe NPs. The results with various amounts of iron molar concentrations are also discussed. Using MRI, it is seen that the R2 relaxivity increases linearly with increase in concentration of Fe NPs in water.

Keywords: cancer drug, hydrodynamic size, magnetic nanoparticles, MRI

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Authors: Alex Hughes

Abstract:

Patients with advanced heart failure develop specific palliative care needs due to the progressive symptom burden and unpredictable disease trajectory. NICE guidance advises that palliative care should be provided to patients with both cancer and non-cancer conditions as and when required. However, there is some way to go before this guidance is consistently and effectively implemented nationwide in conditions such as heart failure. The Ambitions for Palliative and End of Life Care: A national framework for local action in England provides a set of foundations and ambitions which outline a vision for what high-quality palliative and end-of-life care look like in England. This poster aims to critically consider how to improve access to palliative care for heart failure patients in England by analysing the foundations taken from this framework to generate specific recommendations using Soft Systems Methodology (SSM). The eight foundations analysed are: ‘Personalised care planning’, ‘Shared records’, ‘Evidence and information’, ‘Involving, supporting and caring for those important to the dying Person’, ‘Education and training’, ‘24/7 access’, ‘Co-design’ and ‘Leadership.’ A number of specific recommendations have been generated which highlight a need to close the evidence-policy gap and implement policy with sufficient evidence. These recommendations, alongside the creation of an evidence-based national strategy for palliative care and heart failure, should improve access to palliative care for heart failure patients in England. Once implemented, it will be necessary to evaluate the effect of these proposals to understand if access to palliative care for heart failure patients actually improves.

Keywords: access, health systems, heart failure, palliative care

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Authors: Yao Song, Danni Cheng, Jianjun Ren

Abstract:

Objectives: We aimed to explore the prognostic effects of absolute values and dynamic changes of common hematological indices on oropharynx squamous cell carcinoma (OPSCC) patients treated with radiation. Methods and materials: The absolute values of white blood cell (WBC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), hemoglobin (Hb), platelet (Plt), albumin (Alb), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at baseline (within 45 days before radiation), 1-, 3-, 6- and 12-months after the start of radiotherapy were retrospectively collected. Locally-estimated smoothing scatterplots were used to describe the smooth trajectory of each index. A mixed-effect model with a random slope was fitted to describe the changing rate and trend of indices over time. Cox proportional hazard analysis was conducted to assess the correlation between hematological indices and treatment outcomes. Results: Of the enrolled 85 OPSCC patients, inflammatory indices, such as WBC and ALC, dropped rapidly during acute treatment and gradually recovered, while NLR and PLR increased at first three months and subsequently declined within 3-12 months. Higher absolute value or increasing trend of nutritional indices (Alb and Hb) was associated with better prognosis (all p<0.05). In contrast, patients with higher absolute value or upward trend of inflammatory indices (WBC, ANC, Plt, PLR and NLR) had worse survival (all p<0.05). Conclusions: The absolute values and dynamic changes of hematological indices were valuable prognostic factors for OPSCC patients who underwent radiotherapy.

Keywords: hematological indices, oropharyngeal cancer, radiotherapy, NLR, PLR

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Authors: Harish Rajak, Preeti Patel

Abstract:

The application of histone deacetylase inhibitors is a well-known strategy in prevention of cancer which shows acceptable preclinical antitumor activity due to its ability of growth inhibition and apoptosis induction of cancer cell. Molecular docking were performed using Histone Deacetylase protein (PDB ID:1t69) and prepared series of hydroxamic acid based HDACIs. On the basis of docking study, it was predicted that compound 1 has significant binding interaction with HDAC protein and three hydrogen bond interactions takes place, which are essential for antitumor activity. On docking, most of the compounds exhibited better glide score values between -8 to -10 which is close to the glide score value of suberoylanilide hydroxamic acid. The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. The 3D-QSAR models provided a good correlation between predicted and actual anticancer activity. Best QSAR model showed Q2 (0.7974), R2 (0.9200) and standard deviation (0.2308). QSAR visualization maps suggest that hydrogen bond acceptor groups at carbonyl group of cap region and hydrophobic groups at ortho, meta, para position of R9 were favorable for HDAC inhibitory activity. We established structure activity correlation using docking, pharmacophore modeling and atom based 3D QSAR model for hydroxamic acid based HDACIs.

Keywords: HDACIs, QSAR, e-pharmacophore, docking, suberoylanilide hydroxamic acid

Procedia PDF Downloads 304