IMPACT OF SODIUM DICHLOROACETATE ALONE AND IN COMBINATION THERAPIES ON LUNG TUMOR GROWTH AND METASTASIS

Lung cancer is the second most common form of cancer with the highest mortality rate worldwide in 2020 despite the advances in targeted- and immuno-therapies. Metabolic reprogramming has been recognized as an essential emerging cancer hallmark in which altered metabolic pathways represent an attractive therapeutic target. Sodium Dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, effect has been investigated in various tumors. Building on the already published data, this pre-clinical study aims to explore the anticancer potential of DCA in lung cancer alone and in combination with chemo- and targeted therapies using two non-small cell lung cancer (NSCLC) cell lines namely, A549 and LNM35. This project was addressed through the investigation of the impact of DCA on lung cancer cell viability, migration, invasion, and colony growth in-vitro and on tumor growth and metastasis using the chick embryo chorioallantoic membrane (CAM) and the nude mice models in-vivo. The anti-angiogenic potential of DCA, its safety profile, and the impact of its combination with the proposed chemotherapy and first-generation EGFR tyrosine kinase inhibitors (EGFR-TKi) were also investigated. This study demonstrated that DCA causes a concentration- and time-dependent decrease in the viability of A549 and LNM35 cells and the growth of their colonies in-vitro. Similarly, DCA slow-down the growth of A549 and LNM35 tumor xenografts in both the chick embryo CAM and nude mice models in-vivo. DCA decreases the angiogenic capacity of human umbilical vein endothelial cells (HUVECs) in-vitro by decreasing HUVECs tube formation and sprouting, suggesting the inhibition of tumor angiogenesis as a potential mechanism behind its anti-tumor growth effect. On the other hand, DCA did not inhibit the in-vitro migration and invasion and the in-vivo incidence and growth of lymph nodes metastases in nude mice xenografted with the highly metastatic lung cancer cells LNM35. Treatment with DCA did not show any significant side effects on the chick embryos viability or on the nude mice weight and survival. In addition, blood, kidney, and liver function tests showed no toxicity with DCA when compared to the control group. Finally, DCA significantly enhanced the anticancer effect of cisplatin in LNM35, gefitinib and erlotinib in both cell lines. In summary, these findings demonstrate that DCA is a safe and promising therapeutic agent for lung cancer and pave the way for further pre-clinical studies validating the impact of DCA in combination with not only the first generation but also the second and third generation of EGFR-Tki in-vivo

Modeling Agreement between Binary Classifications of Multiple Raters in R and SAS

Cancer screening and diagnostic tests often are classified using a binary outcome such as diseased or not diseased. Recently large-scale studies have been conducted to assess agreement between many raters. Measures of agreement using the class of generalized linear mixed models were implemented efficiently in four recently introduced R and SAS packages in large-scale agreement studies incorporating binary classifications. Simulation studies were conducted to compare the performance across the packages and apply the agreement methods to two cancer studies

Superconductivity in undoped T' cuprates with Tc over 30 K

Undoped cuprates have long been considered to be antiferromagnetic insulators. In this article, however, we report that superconductivity is achieved in undoped T'-RE2CuO4 (RE = Pr, Nd, Sm, Eu, and Gd). Our discovery was performed by using metal-organic decomposition (MOD), an inexpensive and easy-to-implement thin-film process. The keys to prepare the superconducting films are firing with low partial-pressure of oxygen and reduction at low temperatures. The highest Tc of undoped T'-RE2CuO4 is over 30 K, substantially higher than "electron-doped" analogs. Remarkably, Gd2CuO4, even the derivatives of which have not shown superconductivity so far, gets superconducting with Tconset as high as ~ 20 K. The implication of our discovery is briefly discussed.Comment: 22 pages, 5 figures, submitted to Physical Review Letter

Potentiation of raloxifene cytotoxicity against MCF-7 breast cancer cell lines via transdermal delivery and loading on self-emulsifying nanoemulsions

Purpose: To enhance raloxifene (RLX) delivery and cytotoxicity against breast cancer (MCF-7) cell lines. Methods: This was a solubility study of RLX in different oils, surfactants, and co-surfactants. Twelve formulae were tested to reach the smallest  globular size, and hydroxypropyl methylcellulose, (HPMC), and Carbopol 947 polymers were tested for formation of transdermal films. The formula  with the lowest size was compared with raw RLX in diffusion studies using a Franz diffusion cell. Finally, a cytotoxicity study against MCF-7 breast cancer cell lines was conducted. Results: The maximum solubility of RLX was in Tween 80, peppermint oil, and PEG 200; therefore, these were the main components of the 12 formulations. The release of RLX loaded on the selfnanoemulsion drug delivery system (SNEDDS) was increased 3-fold compared with raw RLX.Cytotoxicity results revealed that RLX SNEDDs decreased MCF-7 cell survival by approximately 40 %, compared with raw RLX (control), which augmented the RLX suppression of breast cancer cell lines. Conclusion: Improvement in RLX cytotoxicity is a novel strategy to suppress breast cancer. Keywords: Raloxifene, Osteoporosis, Bioavailability, Nanoemulsion, Nanoparticle

Constraints on the origin of the ultra-high energy cosmic-rays using cosmic diffuse neutrino flux limits: An analytical approach

Astrophysical neutrinos are expected to be produced in the interactions of ultra-high energy cosmic-rays with surrounding photons. The fluxes of the astrophysical neutrinos are highly dependent on the characteristics of the cosmic-ray sources, such as their cosmological distributions. We study possible constraints on the properties of cosmic-ray sources in a model-independent way using experimentally obtained diffuse neutrino flux above 100 PeV. The semi-analytic formula is derived to estimate the cosmogenic neutrino fluxes as functions of source evolution parameter and source extension in redshift. The obtained formula converts the upper-limits on the neutrino fluxes into the constraints on the cosmic-ray sources. It is found that the recently obtained upper-limit on the cosmogenic neutrinos by IceCube constrains the scenarios with strongly evolving ultra-high energy cosmic-ray sources, and the future limits from an 1 km^3 scale detector are able to further constrain the ultra-high energy cosmic-rays sources with evolutions comparable to the cosmic star formation rate.Comment: 9 pages, 3 figures and 1 table. Accepted by Phys. Rev.

Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer

SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials

Epidemiology and risk factors of atopic dermatitis among children in Basrah, Iraq

Atopic dermatitis is a major public health problem, especially among children and has an economic burden at family and community levels. The present research aimed to study the frequency, distribution and determinants of atopic dermatitis in Basrah city, Iraq. A cross-sectional study was carried out between December 2020 and March 2021 at the dermatology outpatient clinic of Alfayhaa Hospital in Basrah, Iraq. The overall prevalence of the disease among children was 21.3 %. The age-specific prevalence rate among infantile, childhood and adolescent groups were 40.7%, 21.7%, and 12.1%, respectively. One hundred Four children who attended the dermatology outpatient clinic were diagnosed with Atopic dermatitis. The mean age of the patients was 6.6±2.8 years. In 87.5% of the cases, the onset of disease was before two years of age. Using objective scoring atopic dermatitis (SCORAD), the disease was classified into mild, moderate and severe with a percentage of 10.6, 83.6, and 5.8, respectively. There was no significant association between the severity of atopic dermatitis with early-onset, positive family history of atopy, nor a high body mass index (BMI). We recommend further large-scale and community-based studies to estimate the real burden of the disease with emphasis on preventive measures