Studies of Heat Shock Protein A9 (HSPA9/Mortalin/Grp75) Substrate Binding Domain and Anticancer Flex-Hets Interactions Using Nuclear Magnetic Resonance and Molecular Mechanics Tools

Ovarian cancer is the most life-threatening of all gynecologic malignancies with survival rate of about 30% that often has few symptoms prior to late stage diagnosis. Ovarian cancer causes 5 percent of cancer deaths among US women. In 2018 approximately 22,240 new cases of ovarian cancer were diagnosed in the United States and 14,070 died. Cisplatin and taxane drugs usually have unacceptable side effects. SHetA2 is an anticancer compound that has exhibited strong activity against ovarian cancer. It has discriminatory activity against malignant cells versus normal cells and has very low toxicity. SHetA2 is a sulfur containing Flex-Het with the highest anti-cancer activity among the tested Flex-Hets. SHetA2 has been shown effective against all of over 60 cancer cell lines in the US National Cancer Institute. SHetA2 interacts with heat shock protein HSPA9/mortalin. Mortalin was shown to associate with the tumor protein p53 in a concentration-dependent manner and leads to inactivation of p53 apoptotic function in stressed cells. Since p53 has a major role in cell cycle arrest and apoptosis, the loss of p53 function leads to immortalization of cells. Protein p53 is nonfunctional in some tumors by cytoplasmic sequestration of its binding proteins, such as Bcl-2, hsp70/mortalin, Parc, PML, and cytoskeleton proteins. One pathway for the compounds to inhibit the growth of cancer cells in vitro is by displacing p53 from mortalin. Then, p53 migrates to the nucleus and initiates apoptosis. Binding of SHetA2 to mortalin interrupts p53-mortalin interaction, and releases protein p53 to nucleus where it initiates apoptosis. Study of the interactions between mortalin and SHetA2 as well as the interactions between mortalin and SHetA2 analogs is the subject of this study. We used solution state NMR spectroscopy technique (chemical perturbation method) and molecular mechanics approaches (Autodock tools and molecular dynamics via GROMACS) to study protein-ligand interactions. We investigate the binding site and binding affinity using these techniques. Our findings helped designing improved SHetA2 analogs that were tested for their biological activities

A survey on the consumption, knowledge and attitude of pregnant women toward the efects of folic acid on pregnancy outcome in Tabriz

ObjectiveWhile the effects of folic acid are well established in prevention of Neural Tube Defects (NTDs), these diseases have a high prevalence in Iran. In order to encourage folic acid supplement use in pregnancy, it is important to promote the awareness of women of childbearing age regarding folic acid importance in preventing NTDs. The aim of the present study was to study the knowledge and attitude of pregnant women on the effect of folic acid on pregnancy outcome and its use during pregnancy.Materials and MethodsA questionnaire was completed by 400 women from postnatal and prenatal wards/clinics using random sampling. The questionnaire included questions regarding demographic information, folic acid consumption in pregnancy and the attitude and knowledge of the participants on folic acid  supplementation and the source of information on folic acid supplementation.The questions were aimed at subjects' knowledge of folic acid effects on fetal growth and development and prevention of NTDs and not prevention of anemia. Data was analyzed by SPSS software (ver. 13.5).ResultsAbout 89.9% used folic acid supplements at some point of the pregnancy and 53.7% knew it was beneficial for the fetus. Approximately, 25% and 34.8% of those who used folic acid believed that it was most useful when taken preconception and during the first trimester, respectively. Only 15.4% knew itcould prevent NTDs. The most common information sources for folic acid use were physicians.ConclusionAwareness and use of folic acid were most prevalent among Iranian women, especially among educated ones. The results showed areas in which further work could be helpful to improve awareness regarding the benefits of folic acid.Key words: Folic acid;pregnancy; knowledge; neural tube defects (NTD

Structure guided design of improved anticancer compounds

Lew Wentz FoundationPhysic

Site-Agnostic 3D Dose Distribution Prediction with Deep Learning Neural Networks

Typically, the current dose prediction models are limited to small amounts of data and require re-training for a specific site, often leading to suboptimal performance. We propose a site-agnostic, 3D dose distribution prediction model using deep learning that can leverage data from any treatment site, thus increasing the total data available to train the model. Applying our proposed model to a new target treatment site requires only a brief fine-tuning of the model to the new data and involves no modifications to the model input channels or its parameters. Thus, it can be efficiently adapted to a different treatment site, even with a small training dataset

Persistence of earnings and prediction of future cash flows: the role of timely recognition of bad news

Timely recognition of losses and expenses compared to revenues and increased values precipitates future expenses to match with current revenues. Thus, timely recognition of losses acts to reduce the persistence of earnings. However, it is expected that a more timely recognition of negative cash flows, as bad news, increase the power of earnings for predicting future cash flows. This study investigates the effects of the timely recognition of bad news (loss) versus the good news on the decrease of the persistence of earnings, and the effect of negative cash flows on forecasting future cash flows. In this study, two pooling type models and a panel type model have been used to estimate the persistence of earnings and cash flows. Seventy eight firms that were listed in the Tehran Stock Exchange during the period 2003–2010 were duly reviewed. The results of this research proved that the timely recognition of loss does not affect the persistence and the power of earnings for the purpose of forecasting future cash flows. The findings imply that conservatism does not distort persistence of earnings

Minibeam Radiation Therapy Treatment (MBRT): Commissioning and First Clinical Implementation.

BACKGROUND Minibeam radiation therapy (MBRT) is characterized by the delivery of submillimeter wide regions of high "peak" and low "valley" doses throughout a tumor. Preclinical studies have long shown the promise of this technique, and we report here the first clinical implementation of MBRT. METHODS A clinical orthovoltage unit was commissioned for MBRT patient treatments using 3, 4, 5, 8, and 10 cm diameter cones. The 180 kVp output was spatially separated into minibeams using a tungsten collimator with 0.5 mm wide slits spaced 1.1 mm on center. Percentage depth dose (PDD) measurements were obtained using film dosimetry and plastic water for both peak and valley doses. PDDs were measured on central axis for offsets of 0, 0.5, and 1 cm. The peak-to-valley ratio (PVR) was calculated at each depth for all cones and offsets. To mitigate the effects of patient motion on delivered dose, patient-specific 3D printed collimator holders were created. These conformed to the unique anatomy of each patient and affixed the tungsten collimator directly to the body. Two patients were treated with MBRT, both received 2 fractions. RESULTS Peak PDDs decreased gradually with depth. Valley PDDs initially increased slightly with depth, then decreased gradually beyond 2 cm. PVRs were highest at the surface for smaller cone sizes and offsets. In vivo film dosimetry confirmed a distinct delineation of peak and valley doses on both patients treated with MBRT with no dose blurring. Both patients experienced prompt improvement in symptoms and tumor response. CONCLUSIONS We report commissioning results, treatment processes, and the first two patients treated with MBRT using a clinical orthovoltage unit. While demonstrating feasibility of this approach is a crucial first step toward wider translation, clinical trials are needed to further establish safety and efficacy

Effects of Neutralization and Crosslinking Agents on the Morphology of Chitosan Electrospun Scaffolds

Chitosan, a natural polymer derived from chitin by deacetylation process of chitin, has gained an enormous interest in tissue engineering due to its unique features such as antibacterial activity and wound healing properties. Electrospinning of acidified chitosan solution is one of the most widely-used approaches in fabrication of 3D scaffolds. Although there are some reports addressing morphology tailoring of the chitosan nanofibers through solution electrospinning, there is no comparative report concerning the neutralization and stabilization conditions of chitosan electrospun fibers. Therefore, this article compares the effects of different neutralizing agents such as aqueous solutions of sodium carbonate (Na2CO3) and potassium carbonate (K2CO3), and crosslinking reagents including glutaraldehyde (GA) and genipin on morphology of electrospun chitosan fibers. After neutralization and stabilization processes, Fourier transform infrared spectroscopy (FTIR) was employed to investigate the morphology of fibers. Furthermore, the influence of the aforementioned parameters on stability of fibers was probed using scanning electron microscopy. SEM images illustrated that the scaffold resulting from electrospinning of 4 wt% chitosan solution in a mixture of trifluoroacetic acid (TFA) and dichloromethane (DCM) possessed a well-formed nanofibrous structure. Afterwards, different methods for neutralization and stabilization of the electrospun chitosan nanofiber mats were performed. In this respect, aqueous solutions of both Na2CO3 and K2CO3 salts (1M) were employed as neutralization agents and GA and genipin were used as two different crosslinking agents. Based on SEM analysis, the chitosan fibers, crosslinked with genipin, showed better morphology than a scaffold which was crosslinked with glutaraldehyd