Search results for: breast cancer

Authors: Jolene M. Helena, Annie M. Joubert, Peace Mabeta, Magdalena Coetzee, Roy Lakier, Anne E. Mercier

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Targeting the distant tumour and its microenvironment whilst preserving bone density is important in improving the outcomes of patients with bone metastases. 2-Ethyl-3-O-sulphamoyl-estra1,3,5(10)16-tetraene (ESE-16) is an in-silico-designed 2- methoxyestradiol analogue which aimed at enhancing the parent compound’s cytotoxicity and providing a more favourable pharmacokinetic profile. In this study, the potential radiosensitization effects of ESE-16 were investigated in an in vitro bone metastasis model consisting of murine pre-osteoblastic (MC3T3-E1) and pre-osteoclastic (RAW 264.7) bone cells, metastatic prostate (DU 145) and breast (MDA-MB-231) cancer cells, as well as human umbilical vein endothelial cells (HUVECs). Cytotoxicity studies were conducted on all cell lines via spectrophotometric quantification of 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide. The experimental set-up consisted of flow cytometric analysis of cell cycle progression and apoptosis detection (Annexin V-fluorescein isothiocyanate) to determine the lowest ESE-16 and radiation doses to induce apoptosis and significantly reduce cell viability. Subsequent experiments entailed a 24-hour low-dose ESE-16-exposure followed by a single dose of radiation. Termination proceeded 2, 24 or 48 hours thereafter. The effect of the combination treatment was investigated on osteoclasts via tartrate-resistant acid phosphatase (TRAP) activity- and actin ring formation assays. Tumour cell experiments included investigation of mitotic indices via haematoxylin and eosin staining; pro-apoptotic signalling via spectrophotometric quantification of caspase 3; deoxyribonucleic acid (DNA) damage via micronuclei analysis and histone H2A.X phosphorylation (γ-H2A.X); and Western blot analyses of bone morphogenetic protein-7 and matrix metalloproteinase-9. HUVEC experiments included flow cytometric quantification of cell cycle progression and free radical production; fluorescent examination of cytoskeletal morphology; invasion and migration studies on an xCELLigence platform; and Western blot analyses of hypoxia-inducible factor 1-alpha and vascular endothelial growth factor receptor 1 and 2. Tumour cells yielded half-maximal growth inhibitory concentration (GI50) values in the nanomolar range. ESE-16 concentrations of 235 nM (DU 145) and 176 nM (MDA-MB-231) and a radiation dose of 4 Gy were found to be significant in cell cycle and apoptosis experiments. Bone and endothelial cells were exposed to the same doses as DU 145 cells. Cytotoxicity studies on bone cells reported that RAW 264.7 cells were more sensitive to the combination treatment than MC3T3-E1 cells. Mature osteoclasts were more sensitive than pre-osteoclasts with respect to TRAP activity. However, actin ring morphology was retained. The mitotic arrest was evident in tumour and endothelial cells in the mitotic index and cell cycle experiments. Increased caspase 3 activity and superoxide production indicated pro-apoptotic signalling in tumour and endothelial cells. Increased micronuclei numbers and γ-H2A.X foci indicated increased DNA damage in tumour cells. Compromised actin and tubulin morphologies and decreased invasion and migration were observed in endothelial cells. Western blot analyses revealed reduced metastatic and angiogenic signalling. ESE-16-induced radiosensitization inhibits metastatic signalling and tumour cell survival whilst preferentially preserving bone cells. This low-dose combination treatment strategy may promote the quality of life of patients with metastatic bone disease. Future studies will include 3-dimensional in-vitro and murine in-vivo models.

Keywords: angiogenesis, apoptosis, bone metastasis, cancer, cell migration, cytoskeleton, DNA damage, ESE-16, radiosensitization.

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Authors: Nasrin Hosseinzad

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Troxerutin, a trihydroxyethylated derived of rutin, is a flavonoid existing in tea, coffee, cereal grains, various fruits and vegetables have been conveyed to display radioprotective, antithrombotic, nephron-protective and hepato-protective possessions. Troxerutin, has been well-proved to utilize hepatoprotective assets. Troxerutin could upturn the resistance of hippocampal neurons alongside apoptosis by lessening the action of AChE and oxidative stress. Consequently, troxerutin may have advantageous properties in the administration of Alzheimer's disease and cancer. Troxerutin has been testified to have several welfares and medicinal stuffs. It could shelter the mouse kidney against d-gal-induced damage by refining renal utility, decreasing histopathologic changes, dropping ROS construction, reintroducing the activities of antioxidant enzymes and reducing DNA oxidative destruction. The DNA cleavage study clarifies that troxerutin showed DNA protection against hydroxyl radical persuaded DNA mutilation. Troxerutin uses anti-cancer effect in HuH-7 hepatocarcinoma cells conceivably through synchronized regulation of the molecular signalling pathways, Nrf2 and NF-κB. DNA binding at slight channel by troxerutin may have donated to feature breaks leading to improved radiation brought cell death. Furthermore, the mechanism principal the observed variance in the antioxidant activities of troxerutin and its esters was qualified to equally their free radical scavenging capabilities and dissemination on the cell membrane outward.

Keywords: troxerutin, DNA, oxidative stress, antioxidant, free radical

Procedia PDF Downloads 145

Authors: Maryam Hajrezaie, Mahmood Ameen Abdulla, Nazia Abdul Majid, Hapipa Mohd Ali, Pouya Hassandarvish, Maryam Zahedi Fard

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Background: Colon cancer is one of the most prevalent cancers in the world and is the third leading cause of death among cancers in both males and females. The incidence of colon cancer is ranked fourth among all cancers but varies in different parts of the world. Cancer chemoprevention is defined as the use of natural or synthetic compounds capable of inducing biological mechanisms necessary to preserve genomic fidelity. Andrographolide is the major labdane diterpenoidal constituent of the plant Andrographis paniculata (family Acanthaceae), used extensively in the traditional medicine. Extracts of the plant and their constituents are reported to exhibit a wide spectrum of biological activities of therapeutic importance. Laboratory animal model studies have provided evidence that Andrographolide play a role in inhibiting the risk of certain cancers. Objective: Our aim was to evaluate the chemopreventive efficacy of the Andrographolide in the AOM induced rat model. Methods: To evaluate inhibitory properties of andrographolide on colonic aberrant crypt foci (ACF), five groups of 7-week-old male rats were used. Group 1 (control group) were fed with 10% Tween 20 once a day, Group 2 (cancer control) rats were intra-peritoneally injected with 15 mg/kg Azoxymethan, Gropu 3 (drug control) rats were injected with 15 mg/kg azoxymethan and 5-Flourouracil, Group 4 and 5 (experimental groups) were fed with 10 and 20 mg/kg andrographolide each once a day. After 1 week, the treatment group rats received subcutaneous injections of azoxymethane, 15 mg/kg body weight, once weekly for 2 weeks. Control rats were continued on Tween 20 feeding once a day and experimental groups 10 and 20 mg/kg andrographolide feeding once a day for 8 weeks. All rats were sacrificed 8 weeks after the azoxymethane treatment. Colons were evaluated grossly and histopathologically for ACF. Results: Administration of 10 mg/kg and 20 mg/kg andrographolide were found to be effectively chemoprotective, as evidenced microscopily and biochemically. Andrographolide suppressed total colonic ACF formation up to 40% to 60%, respectively, when compared with control group. Pre-treatment with andrographolide, significantly reduced the impact of AOM toxicity on plasma protein and urea levels as well as on plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and gamma-glutamyl transpeptidase (GGT) activities. Grossly, colorectal specimens revealed that andrographolide treatments decreased the mean score of number of crypts in AOM-treated rats. Importantly, rats fed andrographolide showed 75% inhibition of foci containing four or more aberrant crypts. The results also showed a significant increase in glutathione (GSH), superoxide dismutase (SOD), nitric oxide (NO), and Prostaglandin E2 (PGE2) activities and a decrease in malondialdehyde (MDA) level. Histologically all treatment groups showed a significant decrease of dysplasia as compared to control group. Immunohistochemical staining showed up-regulation of Hsp70 and down-regulation of Bax proteins. Conclusion: The current study demonstrated that Andrographolide reduce the number of ACF. According to these data, Andrographolide might be a promising chemoprotective activity, in a model of AOM-induced in ACF.

Keywords: chemopreventive, andrographolide, colon cancer, aberrant crypt foci (ACF)

Procedia PDF Downloads 418

Authors: Manjusha R. Vagal, Shyam K. Shrivastava, Umesh Mahantshetty, Sudeep Gupta, Supriya Chopra, Reena Engineer, Amita Maheshwari, Atul Buduk

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Vaginal stenosis is a common side effect associated with pelvic radiotherapy in cervical cancer patients which contributes negatively to woman’s health and prevents adequate vaginal/cervical examination. Vaginal dilation with a dilator is routine practice and is internationally advocated as a prophylactic measure to preserve vaginal patency. This retrospective study was carried out with the aim to know the usefulness of vaginal dilation following pelvic radiation therapy in cervical cancer patients in India. Data from medical records of 183 cervical cancer patients, which met the study criteria, were collected related to the stage of the disease, treatment received, commencement period of dilation post radiation therapy, sexual status and side effects associated to dilation practice. Data related to vaginal dimensions as per the length of insertion of a small, medium and large dilator were collected on regular follow-ups until 36 months and/or more. Vaginal dimensions as measured with the length of medium dilator insertion were used for analysis of dilation therapy results using paired t-test. Patients who underwent vaginal dilation with dilator maintained vaginal patency, also the mean vaginal length significantly increased, from 8.02 cm ± 2.69 to 9.96 ± 2.89 cm with a p value <0.001. There was no significant difference found on vaginal patency with different intervals of initiation of dilation therapy. At the third year and more following dilation therapy, significant increase in vaginal length observed with a p value of 0.0001 in both sexually active and inactive patients. Compilation of vaginal dosage during brachytherapy was inadequate, and hence, the secondary objective of the study to determine the effect of radiotherapy on the outcome of rehabilitation intervention was not studied in detail. This retrospective study has found that dilation therapy with vaginal dilators post pelvic radiotherapy is effective in preventing vaginal stenosis and improving vaginal patency and cannot be substituted with vaginal intercourse. Sexual quality of life assessment in the Indian population needs much attention.

Keywords: dilator, sexually active, vaginal dilation, vaginal stenosis

Procedia PDF Downloads 188

Authors: Nouha Bouayed Abdelmoula, Rim Louati, Nawel Abdellaoui, Balkiss Abdelmoula, Oldez Kaabi, Walid Smaoui, Samir Aloulou

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Background and Aims: Cardiofaciocutaneous syndrome (CFC) is an autosomal dominant disorder with the vast majority of cases arising by a new mutation of BRAF, MEK1, MEK2, or rarely, KRAS genes. Here, we report a rare Tunisian case of CFC syndrome for whom we identify SOS1 mutation. Methods: Genomic DNA was obtained from peripheral blood collected in an EDTA tube and extracted from leukocytes using the phenol/chloroform method according to standard protocols. High resolution melting (HRM) analysis for screening of mutations in the entire coding sequence of PTPN11 was conducted first. Then, HRM assays to look for hot spot mutations coding regions of the other genes of the RAS-MAPK pathway (RAt Sarcoma viral oncogene homolog Mitogen-Activated Protein Kinases Pathway): SOS1, SHOC2, KRAS, RAF1, KRAS, NRAS, CBL, BRAF, MEK1, MEK2, HRAS, and RIT1, were applied. Results: Heterozygous SOS1 point mutation clustered in exon 10, which encodes for the PH domain of SOS1, was identified: c.1655 G > A. The patient was a 9-year-old female born from a consanguineous couple. She exhibited pulmonic valvular stenosis as congenital heart disease. She had facial features and other malformations of Noonan syndrome, including macrocephaly, hypertelorism, ptosis, downslanting palpebral fissures, sparse eyebrows, a short and broad nose with upturned tip, low-set ears, high forehead commonly associated with bitemporal narrowing and prominent supraorbital ridges, short and/or webbed neck and short stature. However, the phenotype is also suggestive of CFC syndrome with the presence of more severe ectodermal abnormalities, including curly hair, keloid scars, hyperkeratotic skin, deep plantar creases, and delayed permanent dentition with agenesis of the right maxillary first molar. Moreover, the familial history of the patient revealed recurrent brain malignancies in the paternal family and epileptic disease in the maternal family. Conclusions: This case report of an overlapping RASopathy associated with SOS1 mutation and familial history of brain tumorigenesis is exceptional. The evidence suggests that RASopathies are truly cancer-prone syndromes, but the magnitude of the cancer risk and the types of cancer partially overlap.

Keywords: cardiofaciocutaneous syndrome, CFC, SOS1, brain cancer, germline mutation

Procedia PDF Downloads 139

Authors: Khalid A. Salman, Shereen Wagih, Tariq Munshi, Musaed Almalki, Safwan Zatari, Zahid Khan

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Aim: To measure exposure levels to family members and caregivers of Saudi patients treated with low dose I131 therapy, and household radiation exposure rate to predict different factors that can affect radiation exposure. Patients and methods: All adult self dependent patients with hyperthyroidism or cancer thyroid referred for low dose radioactive I131 therapy on outpatient basis are included. Radiation protection procedures are given to the participant and family members in details. TLD’s were dispensed to each participant in sufficient quantity for his/her family members living in the household. TLD’s are collected at fifth days post-dispense from patients who agreed to have a home visit during which the household is inspected and level of radiation contamination of surfaces was measured. Results: Thirty-two patients were enrolled in the current study, with a mean age of 43.1± 17.1 years Out of them 25 patients (78%) are females. I131 therapy was given in twenty patients (63%) for cancer thyroid of and for toxic goiter in the remaining twelve patients (37%), with an overall mean I131 dose of 24.1 ± 7.5mCi that is relatively higher in the former. The overall number of household family members and helpers of patients are 139, out of them77 are females (55.4%) & 62 are males (44.6%) with a mean age of 29.8± 17.6. The mean period of contact with the patient is 7.6 ±5.6hours. The cumulative radiation exposure shows that radiation exposure to all family members is below the exposure constraint (1mSv), with a range of 109 to 503uSv, and a mean value of 220.9±91 uSv. Numerical data shows a little higher exposure rate for family members of those who receive higher dose of I131 (patients with thyroid cancer) and household members who spent longer time with the patient, yet, the difference is statistically insignificant (P>0.05). Besides, no significant correlation was found between the degree of cumulative exposure of the family members to their gender, age, socioeconomic standard, educational level and residential factors. In the 21 home visits all data from bedrooms, reception areas and kitchens are below hazardous limits (0.5uSv/h) apart from bathrooms that give a slightly higher reading of 0.57±0.39 uSv/h in those with cancer thyroid who receive a higher radiation dose. A statistically significant difference was found between radiation exposure rate in bathrooms used by the patient versus those used by family members only, with a mean value of exposure rate of 0.701±0.21 uSv/h and 0.17±0.82 uSv/h respectively, with a p-value of 0.018 (<0.05). Conclusion: Family members of patients treated with low dose I131 on outpatient basis have a good compliance to radiation protection instruction if given properly with a cumulative radiation exposure rate evidently beyond the radiation exposure constraints of 1 mSv. Given I131 dose, hours spent with the patient, age, gender, socioeconomic standard, educational level and residential factors have no significant correlation with the cumulative radiation exposure. The patient bathroom exhibits more radiation exposure rate, needing more strict instructions for patient bathroom use and health hygiene.

Keywords: family members, radiation exposure, radioactive iodine therapy, radiation safety

Procedia PDF Downloads 259

Authors: Abdul Musaweer Habib, Habibul Hasan Mazumder, Saiful Islam, Sohel Sikder, Omar Faruk Sikder

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The plethora of genome sequence information of bacteria in recent times has ushered in many novel strategies for antibacterial drug discovery and facilitated medical science to take up the challenge of the increasing resistance of pathogenic bacteria to current antibiotics. In this study, we adopted subtractive genomics approach to analyze the whole genome sequence of the Fusobacterium nucleatum, a human oral pathogen having association with colorectal cancer. Our study divulged 1499 proteins of Fusobacterium nucleatum, which has no homolog in human genome. These proteins were subjected to screening further by using the Database of Essential Genes (DEG) that resulted in the identification of 32 vitally important proteins for the bacterium. Subsequent analysis of the identified pivotal proteins, using the KEGG Automated Annotation Server (KAAS) resulted in sorting 3 key enzymes of F. nucleatum that may be good candidates as potential drug targets, since they are unique for the bacterium and absent in humans. In addition, we have demonstrated the 3-D structure of these three proteins. Finally, determination of ligand binding sites of the key proteins as well as screening for functional inhibitors that best fitted with the ligands sites were conducted to discover effective novel therapeutic compounds against Fusobacterium nucleatum.

Keywords: colorectal cancer, drug target, Fusobacterium nucleatum, homology modeling, ligands

Procedia PDF Downloads 367

Authors: Naila Sher, Mushtaq Ahmed, Nadia Mushtaq, Rahmat Ali Khan

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In cancer therapy, nanoparticles (NPs) shall be applied possibly by inoculation in the veins of humans. This action will connect them with white (WBCs) and red blood cells (RBCs) in the bloodstream before they reach their main targeted cancer cells. However, possible effects of silver, gold, and silver/gold bimetallic NPs (Ag, Au, and Ag/Au BNPs) on baby hamster kidney-21 (BHK-21) cells were studied by MTT assay. Here, Ag, Au, and their Ag/Au BNPs (bimetallic nanoparticles) were synthesized by using Hippeastrum hybridum (HH) extract. These NPs were characterized by UV-visible spectroscopy, FT-IR, XRD, and EDX, and SEM analysis. XRD analysis conferring the crystal structure with an average size of 13.3, 10.72, and 8.34nm of Ag, Au, and Ag/Au BNPs, respectively. SEM showed that Ag, Au, and Ag/Au BNPs had irregular morphologies, with nano measures calculated sizes of 40, 30, and 20 nm respectively. EDX spectrometers confirmed the presence of elemental Ag signal of the AgNPs with 22.75%, Au signal of the AuNPs with 48.08%, Ag signal with 12%, and Au signal with 38.26% of the Ag/Au BNPs. The BHK-21cells were incubated in the existence of doxorubicin, plant extract, Ag, Au, and Ag/Au BNPs. The cytotoxic effects could be observed in a dose-dependent mode; doxorubicin and Ag/Au BNPs were more toxic than plant extract, Ag, and Au NPs. It is demonstrated that NPs interact with BHK-21cells and significantly reduce cell viability in a concentration-dependent manner. However, to reduce the potential threats of NPs further studies are recommended.

Keywords: hippeastrum hybridum, nanoparticle, BHK-21cells

Procedia PDF Downloads 113

Authors: Spira A., Marabelle A., Kientop D., Moser E., Mumm J.

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Background: Both interleukin-2 (IL-2) and interleukin-10 (IL-10) have been extensively studied for their stimulatory function on T cells and their potential to obtain sustainable tumor control in RCC, melanoma, lung, and pancreatic cancer as monotherapy, as well as combination with PD-1 blockers, radiation, and chemotherapy. While approved, IL-2 retains significant toxicity, preventing its widespread use. The significant efforts undertaken to uncouple IL-2 toxicity from its anti-tumor function have been unsuccessful, and early phase clinical safety observed with PEGylated IL-10 was not met in a blinded Phase 3 trial. Deka Biosciences has engineered a novel molecule coupling wild-type IL-2 to a high affinity variant of Epstein Barr Viral (EBV) IL-10 via a scaffold (scFv) that binds to epidermal growth factor receptors (EGFR). This patented molecule, termed DK210 (EGFR), is retained at high levels within the tumor microenvironment for days after dosing. In addition to overlapping and non-redundant anti-tumor function, IL-10 reduces IL-2 mediated cytokine release syndrome risks and inhibits IL-2 mediated T regulatory cell proliferation. Methods: DK210 (EGFR) is being evaluated in an open-label, dose-escalation (Phase 1) study with 5 (0.025-0.3 mg/kg) monotherapy dose levels and (expansion cohorts) in combination with PD-1 blockers, or radiation or chemotherapy in patients with advanced solid tumors overexpressing EGFR. Key eligibility criteria include 1) confirmed progressive disease on at least one line of systemic treatment, 2) EGFR overexpression or amplification documented in histology reports, 3) at least a 4 week or 5 half-lives window since last treatment, and 4) excluding subjects with long QT syndrome, multiple myeloma, multiple sclerosis, myasthenia gravis or uncontrolled infectious, psychiatric, neurologic, or cancer disease. Plasma and tissue samples will be investigated for pharmacodynamic and predictive biomarkers and genetic signatures associated with IFN-gamma secretion, aiming to select subjects for treatment in Phase 2. Conclusion: Through successful coupling of wild-type IL-2 with a high affinity IL-10 and targeting directly to the tumor microenvironment, DK210 (EGFR) has the potential to harness IL-2 and IL-10’s known anti-cancer promise while reducing immunogenicity and toxicity risks enabling safe concomitant cytokine treatment with other anti-cancer modalities.

Keywords: cytokine, EGFR over expression, interleukine-2, interleukine-10, clinical trial

Procedia PDF Downloads 67

Authors: Iman Nazari, Behrouz Shaabani, Ali Ramouz

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Regarding to the dramatic rise of cancer prevalence of cancers in Iran and also base on the investigations around environmental factors which causes cancer, The air and water pollution is in high level in Iran’s capital city this issue motivated us to start an investigation on concentration of heavy metals and nitrate in Tehran’s Tap water, additionally we investigated the effects of this contaminations on public health, it is clear that heavy metals and also nitrate are causes cancers directly and indirectly, we divided the city to four districts: (1) North, (2) East, (3) West, (4) South and totally collected over 30 samples from noted districts, we obvious difference in concentrations, after a study we founded the reasons of this difference, the old distribution system, non-standard sewage disposal system, travel up from contaminated rains, releasing industrial wastes waters without any pretreatment, the most important one is the old distribution system, Tehran is an old city hence distribution system is old too we know that the old water pipes were built from alloys which containing several of this harmful heavy metals, releasing of this heavy metals from pipes to the tap water is one of the most Important reasons, as the result we presented the concentrations by districts and the alternatives to decreasing the level of this contaminations.

Keywords: water quality, heavy metals, drinking water, environmental toxinology

Procedia PDF Downloads 271

Authors: Hussein Alahmer, Amr Ahmed

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Liver cancer is one of the common diseases that cause the death. Early detection is important to diagnose and reduce the incidence of death. Improvements in medical imaging and image processing techniques have significantly enhanced interpretation of medical images. Computer-Aided Diagnosis (CAD) systems based on these techniques play a vital role in the early detection of liver disease and hence reduce liver cancer death rate.  This paper presents an automated CAD system consists of three stages; firstly, automatic liver segmentation and lesion’s detection. Secondly, extracting features. Finally, classifying liver lesions into benign and malignant by using the novel contrasting feature-difference approach. Several types of intensity, texture features are extracted from both; the lesion area and its surrounding normal liver tissue. The difference between the features of both areas is then used as the new lesion descriptors. Machine learning classifiers are then trained on the new descriptors to automatically classify liver lesions into benign or malignant. The experimental results show promising improvements. Moreover, the proposed approach can overcome the problems of varying ranges of intensity and textures between patients, demographics, and imaging devices and settings.

Keywords: CAD system, difference of feature, fuzzy c means, lesion detection, liver segmentation

Procedia PDF Downloads 304

Authors: Christos Lampropoulos, Maria Konsta, Ifigenia Apostolou, Vicky Dradaki, Tamta Sirbilatze, Irini Dri, Christina Kordali, Vaggelis Lambas, Kostas Argyros, Georgios Mavras

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Objectives: Mediterranean diet has been associated with lower incidence of cardiovascular disease and cancer. The purpose of our study was to examine the hypothesis that Mediterranean diet may protect against mortality and reduce admission duration in elderly, hospitalized patients. Methods: Sample population included 150 patients (78 men, 72 women, mean age 80±8.2). The following data were taken into account in analysis: anthropometric and laboratory data, dietary habits (MedDiet score), patients’ nutritional status [Mini Nutritional Assessment (MNA) score], physical activity (International Physical Activity Questionnaires, IPAQ), smoking status, cause and duration of current admission, medical history (co-morbidities, previous admissions). Primary endpoints were mortality (from admission until 6 months afterwards) and duration of admission, compared to national guidelines for closed consolidated medical expenses. Logistic regression and linear regression analysis were performed in order to identify independent predictors for mortality and admission duration difference respectively. Results: According to MNA, nutrition was normal in 54/150 (36%) of patients, 46/150 (30.7%) of them were at risk of malnutrition and the rest 50/150 (33.3%) were malnourished. After performing multivariate logistic regression analysis we found that the odds of death decreased 30% per each unit increase of MedDiet score (OR=0.7, 95% CI:0.6-0.8, p < 0.0001). Patients with cancer-related admission were 37.7 times more likely to die, compared to those with infection (OR=37.7, 95% CI:4.4-325, p=0.001). According to multivariate linear regression analysis, admission duration was inversely related to Mediterranean diet, since it is decreased 0.18 days on average for each unit increase of MedDiet score (b:-0.18, 95% CI:-0.33 - -0.035, p=0.02). Additionally, the duration of current admission increased on average 0.83 days for each previous hospital admission (b:0.83, 95% CI:0.5-1.16, p<0.0001). The admission duration of patients with cancer was on average 4.5 days higher than the patients who admitted due to infection (b:4.5, 95% CI:0.9-8, p=0.015). Conclusion: Mediterranean diet adequately protects elderly, hospitalized patients against mortality and reduces the duration of hospitalization.

Keywords: Mediterranean diet, malnutrition, nutritional status, prognostic factors for mortality

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Authors: AliAkbar Hafezi, Jamshid Abedi, Jalal Taherian, Behnam Kadkhodaei, Mahsa Elahi

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Background. Peripheral neuropathy is a common side effect of the administration of neurotoxic chemotherapy agents. This adverse effect is a major dose-limiting factor of many commonly used chemotherapy drugs. Currently, there are no Food and Drug Administration (FDA) approved medications for the prevention or treatment of chemotherapy-induced peripheral neuropathy. Therefore, this study was performed to investigate the efficacy and safety of metformin on paclitaxel-induced peripheral neuropathy (PIPN). Methods. In this randomized clinical trial, cancer patients who were candidates for chemotherapy with paclitaxel referred to the radiation oncology departments in Iran from 2022 to 2023 were studied. Patients were randomly divided into two groups; 1- Case group (n = 30) received metformin 500 mg orally twice a day after meals during chemotherapy with paclitaxel, and 2- Control group (30 people) received chemotherapy without metformin or any additional medication. Patients were visited in terms of numbness or other neurological symptoms two weeks before chemotherapy, 1-2 days before and weekly during chemotherapy, and at the end of the study. They were assessed by nerve conduction study (NCS) before intervention and one week after the end of chemotherapy. The primary outcome was the efficacy in reducing PIPN and the secondary outcome was adverse effects. Eventually, the outcomes were compared between the two groups of patients. Results. A total of 60 female cancer patients receiving chemotherapy with paclitaxel were evaluated in two groups. The groups were matched in terms of age, body mass index, fasting blood sugar, smoking, pathologic stage, and creatinine levels. The results showed that 18 patients (60.0 %) in the case group and 23 patients (76.6 %) in the control group had PIPN clinically (P = 0.267), and NCS showed 11 patients (36.6 %) in the case group and 15 patients (50.0 %) in the control group suffered from PIPN which no significant difference was observed between the two groups (P = 0.435). Diarrhea (n = 3; 10.0 %) and nausea (n = 3; 10.0 %) were the most common side effects of metformin in the case group and no serious side effects (lactic acidosis and anemia) were found in these patients. Conclusion. This study indicated that metformin did not significantly prevent PIPN in cancer patients receiving chemotherapy, although the frequency of peripheral neuropathy in the case group was lower than in the control group. The use of metformin in the patients had acceptable safety and no serious side effects were reported.

Keywords: peripheral neuropathy, chemotherapy, paclitaxel, metformin

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Authors: A. A. Dehpour, B. Eslami, S. Rezaie, S. F. Hashemian, F. Shafie, M. Kiaie

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The aims of study were investigation on chemical composition essential oil and the effect of extract of Coronilla varia on antimicrobial and cytotoxicity activity. The essential oils of Coronilla varia is obtained by hydrodistillation and analyzed by (GC/MS) for determining their chemical composition and identification of their components. Antibacterial activity of plant extract was determined by disc diffusion method. The effect of hydroalcolic extracts from Cornilla varia investigated on MCF7 cancer cell line by MTT assay. The major components were Caryophyllene Oxide (60.19%), Alphacadinol (4.13%) and Homoadantaneca Robexylic Acid (3.31%). The extracts from Coronilla varia had interesting activity against Proteus mirabilis in the concentration of 700 µg/disc and did not show any activity against Staphylococus aureus, Bacillus subtillis, Klebsiella pneumonia and Entrobacter cloacae. The positive control, Ampicillin, Chloramphenicol and Cenphalothin had shown zone of inhibition resistant all bacteria. Corohilla varia ethanol extract could inhibit the proliferation of MCF7 cell line in RPMI 1640 medium. IC50 5(mg/ml) was the optimum concentration of extract from Coronilla varia inhibition of cell line growth. The MCF7 cancer cell line and Proteus mirabilis were more sensitive to Coronilla varia ethanol extract.

Keywords: Coronilla varia, essential oil, antibacterial, anticancer, hela cell line

Procedia PDF Downloads 377

Authors: Alvaro L. Ronco

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Background and purpose: Although our country is a developing one, it has a typical Western meat-rich dietary style. Based on estimates of heme and nonheme iron contents in representative foods, we carried out the present epidemiologic study, with the aim of accurately analyzing dietary iron and its role on CRC risk. Subjects/methods: Patients (611 CRC incident cases and 2394 controls, all belonging to public hospitals of our capital city) were interviewed through a questionnaire including socio-demographic, reproductive and lifestyle variables, and a food frequency questionnaire of 64 items, which asked about food intake 5 years before the interview. The sample included 1937 men and 1068 women. Controls were matched by sex and age (± 5 years) to cases. Food-derived nutrients were calculated from available databases. Total dietary iron was calculated and classified by heme or nonheme source, following data of specific Dutch and Canadian studies, and additionally adjusted by energy. Odds Ratios (OR) and 95% confidence intervals were calculated through unconditional logistic regression, adjusting for relevant potential confounders (education, body mass index, family history of cancer, energy, infusions, and others). A heme/nonheme (H/NH) ratio was created and the interest variables were categorized into tertiles, for analysis purposes. Results: The following risk estimations correspond to the highest tertiles. Total iron intake showed no association with CRC risk neither among men (OR=0.83, ptrend =.18) nor among women (OR=1.48, ptrend =.09). Heme iron was positively associated among men (OR=1.88, ptrend < .001) and for the overall sample (OR=1.44, ptrend =.002), however, it was not associated among women (OR=0.91, ptrend =.83). Nonheme iron showed an inverse association among men (OR=0.53, ptrend < .001) and the overall sample (OR=0.78, ptrend =.04), but was not associated among women (OR=1.46, ptrend =.14). Regarding H/NH ratio, risks increased only among men (OR=2.12, ptrend < .001) but lacked of association among women (OR=0.81, ptrend =.29). Conclusions. We have observed different types of associations between CRC risk and high dietary heme, nonheme and H/NH iron ratio. Therefore, the source of the available iron might be of importance as a link to colorectal carcinogenesis, perhaps pointing to reconsider the animal/plant proportions of this vital mineral within diet. Nevertheless, the different associations observed for each sex, demand further studies in order to clarify these points.

Keywords: chelation, colorectal cancer, heme, iron, nonheme

Procedia PDF Downloads 155

Authors: Corina Muscurel, Irina Stoian, Laura Gaman, Valeriu Atanasiu

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Chronic inflammation predisposes cells to neoplastic transformation and is associated with angiogenesis. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) give rise to anti-inflammatory metabolites and decrease some inflammatory cytokines. The aim of the study was to analyze the effect of n-3 PUFAs intake on patients with tumors in early-stage (without regional or distant metastasis). There were two groups of patients: one group with colon tumors and one group with lung tumors. All patients took for 60 days daily supplements from fish-oil containing 600 mg eicosapentaenoic acid and 400 mg docosahexaenoic acid. The plasma markers were evaluated before and after PUFAs intake: ceruloplasmin (using p-phenylenediamine oxidase method), plasma total thiol groups (using dithiobis-nitrobenzoic acid method) and CEA (carcinoembryonic antigen using electrochemiluminescent immunoassay). The results reflect ceruloplasmin decrease (p < 0.05), plasma total thiol groups increase (not statistically significant) and CEA decrease (p < 0.05) after n-3 PUFAs intake. Conclusions: n-3 PUFAs intake is favorable in premalignant lesions or in early tumor stage and dietary fish-oil has anti-inflammatory effects and can contribute to reduce cancer progression.

Keywords: cancer, fish-oil, inflammation, n-3 polyunsaturated fatty acids

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Authors: Abdul Hafeez, Samiya Shehzadi

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This research paper presents a different approach towards eco-friendly textile design by developing a sustainable composite fabric from orange peel for ladies' undergarments. The research focuses on utilizing orange peel to develop a unique orange leather/composite (fabric) through a process involving heating, extracting, and subsequent sun-drying to obtain the composite. The sustainable composite fabric shows properties that are favorable to the development of environmentally friendly undergarments, which not only offer UV protection but also possess healing properties for the skin. Through comprehensive testing and analysis, it has been determined that the orange peel composite fabric has zero harmful effects on the skin, making it a safe and desirable material for intimate wear. Furthermore, the research suggests that the orange peel composite fabric has the potential to reduce the rate of cancer cell growth. While the exact mechanisms and factors contributing to this effect require further investigation, the initial findings indicate promising aspects of the fabric in terms of potential cancer-preventive properties. Research contribution to the field of sustainable textile design by introducing a usual and eco-friendly approach utilizing orange peel waste. This work opens up avenues for further exploration and development of innovative materials that are both sustainable and beneficial for human health.

Keywords: sustainability, composite textiles, extracting, undergarments, eco-friendly, orange peels

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Authors: Aoxue Yang, Weili Tian, Haikun Liu

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Brain tumor stem cells (BTSCs) are resistant to therapy and give rise to recurrent tumors. These rare and elusive cells are likely to disseminate during cancer progression, and some may enter dormancy, remaining viable but not increasing. The identification of dormant BTSCs is thus necessary to design effective therapies for glioblastoma (GBM) patients. Glucocorticoids (GCs) are used to treat GBM-associated edema. However, glucocorticoids participate in the physiological response to psychosocial stress, linked to poor cancer prognosis. This raises concern that glucocorticoids affect the tumor and BTSCs. Identifying markers specifically expressed by brain tumor stem cells (BTSCs) may enable specific therapies that spare their regular tissue-resident counterparts. By ribosome profiling analysis, we have identified that glycerol-3-phosphate dehydrogenase 1 (GPD1) is expressed by dormant BTSCs but not by NSCs. Through different stress-induced experiments in vitro, we found that only dexamethasone (DEXA) can significantly increase the expression of GPD1 in NSCs. Adversely, mifepristone (MIFE) which is classified as glucocorticoid receptors antagonists, could decrease GPD1 protein level and weaken the proliferation and stemness in BTSCs. Furthermore, DEXA can induce GPD1 expression in tumor-bearing mice brains and shorten animal survival, whereas MIFE has a distinct adverse effect that prolonged mice lifespan. Knocking out GR in NSC can block the upregulation of GPD1 inducing by DEXA, and we find the specific sequences on GPD1 promotor combined with GR, thus improving the efficiency of GPD1 transcription from CHIP-Seq. Moreover, GR and GPD1 are highly co-stained on GBM sections obtained from patients and mice. All these findings confirmed that GR could regulate GPD1 and loss of GPD1 Impairs Multiple Pathways Important for BTSCs Maintenance GPD1 is also a critical enzyme regulating glycolysis and lipid synthesis. We observed that DEXA and MIFE could change the metabolic profiles of BTSCs by regulating GPD1 to shift the transition of cell dormancy. Our transcriptome and lipidomics analysis demonstrated that cell cycle signaling and phosphoglycerides synthesis pathways contributed a lot to the inhibition of GPD1 caused by MIFE. In conclusion, our findings raise concern that treatment of GBM with GCs may compromise the efficacy of chemotherapy and contribute to BTSC dormancy. Inhibition of GR can dramatically reduce GPD1 and extend the survival duration of GBM-bearing mice. The molecular link between GPD1 and GR may give us an attractive therapeutic target for glioblastoma.

Keywords: cancer stem cell, dormancy, glioblastoma, glycerol-3-phosphate dehydrogenase 1, glucocorticoid receptor, dexamethasone, RNA-sequencing, phosphoglycerides

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Authors: Shenlun Chen, Leonard Wee

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Tumor grading is an essential reference for colorectal cancer (CRC) staging and survival prognostication. The widely used World Health Organization (WHO) grading system defines histological grade of CRC adenocarcinoma based on the density of glandular formation on whole slide images (WSI). Tumors are classified as well-, moderately-, poorly- or un-differentiated depending on the percentage of the tumor that is gland forming; >95%, 50-95%, 5-50% and <5%, respectively. However, manually grading WSIs is a time-consuming process and can cause observer error due to subjective judgment and unnoticed regions. Furthermore, pathologists’ grading is usually coarse while a finer and continuous differentiation grade may help to stratifying CRC patients better. In this study, a deep learning based automatic differentiation grading algorithm was developed and evaluated by survival analysis. Firstly, a gland segmentation model was developed for segmenting gland structures. Gland regions of WSIs were delineated and used for differentiation annotating. Tumor regions were annotated by experienced pathologists into high-, medium-, low-differentiation and normal tissue, which correspond to tumor with clear-, unclear-, no-gland structure and non-tumor, respectively. Then a differentiation prediction model was developed on these human annotations. Finally, all enrolled WSIs were processed by gland segmentation model and differentiation prediction model. The differentiation grade can be calculated by deep learning models’ prediction of tumor regions and tumor differentiation status according to WHO’s defines. If multiple WSIs were possessed by a patient, the highest differentiation grade was chosen. Additionally, the differentiation grade was normalized into scale between 0 to 1. The Cancer Genome Atlas, project COAD (TCGA-COAD) project was enrolled into this study. For the gland segmentation model, receiver operating characteristic (ROC) reached 0.981 and accuracy reached 0.932 in validation set. For the differentiation prediction model, ROC reached 0.983, 0.963, 0.963, 0.981 and accuracy reached 0.880, 0.923, 0.668, 0.881 for groups of low-, medium-, high-differentiation and normal tissue in validation set. Four hundred and one patients were selected after removing WSIs without gland regions and patients without follow up data. The concordance index reached to 0.609. Optimized cut off point of 51% was found by “Maxstat” method which was almost the same as WHO system’s cut off point of 50%. Both WHO system’s cut off point and optimized cut off point performed impressively in Kaplan-Meier curves and both p value of logrank test were below 0.005. In this study, gland structure of WSIs and differentiation status of tumor regions were proven to be predictable through deep leaning method. A finer and continuous differentiation grade can also be automatically calculated through above models. The differentiation grade was proven to stratify CAC patients well in survival analysis, whose optimized cut off point was almost the same as WHO tumor grading system. The tool of automatically calculating differentiation grade may show potential in field of therapy decision making and personalized treatment.

Keywords: colorectal cancer, differentiation, survival analysis, tumor grading

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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: 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: 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: Oluwatosin M. A. Jesuyon

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In order to propose a simpler tool that eliminates the age-long problems associated with the traditional index method for selection of multiple traits in broilers, the Barttlet factor regression equation is being proposed as an alternative selection tool. 100 day-old chicks each of Arbor Acres (AA) and Annak (AN) broiler strains were obtained from two rival hatcheries in Ibadan Nigeria. These were raised in deep litter system in a 56-day feeding trial at the University of Ibadan Teaching and Research Farm, located in South-west Tropical Nigeria. The body weight and body dimensions were measured and recorded during the trial period. Eight (8) zoometric measurements namely live weight (g), abdominal circumference, abdominal length, breast width, leg length, height, wing length and thigh circumference (all in cm) were recorded randomly from 20 birds within strain, at a fixed time on the first day of the new week respectively with a 5-kg capacity Camry scale. These records were analyzed and compared using completely randomized design (CRD) of SPSS analytical software, with the means procedure, Factor Scores (FS) in stepwise Multiple Linear Regression (MLR) procedure for initial live weight equations. Bartlett Factor Score (BFS) analysis extracted 2 factors for each strain, termed Body-length and Thigh-meatiness Factors for AA, and; Breast Size and Height Factors for AN. These derived orthogonal factors assisted in deducing and comparing trait-combinations that best describe body conformation and Meatiness in experimental broilers. BFS procedure yielded different body conformational traits for the two strains, thus indicating the different economic traits and advantages of strains. These factors could be useful as selection criteria for improving desired economic traits. The final Bartlett Factor Regression equations for prediction of body weight were highly significant with P < 0.0001, R2 of 0.92 and above, VIF of 1.00, and DW of 1.90 and 1.47 for Arbor Acres and Annak respectively. These FSR equations could be used as a simple and potent tool for selection during poultry flock improvement, it could also be used to estimate selection index of flocks in order to discriminate between strains, and evaluate consumer preference traits in broilers.

Keywords: alternative selection tool, Bartlet factor regression model, consumer preference trait, linear and body measurements, live body weight

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

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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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