A rheological equation of state for blood at low shear rates

In this work a new rheological equation of state is presented and its application to blood is studied. The equation considered is a linear combination of Newtonian and non-Newtonian contributions to the apparent viscosity. The general form of the equation is Tij =-(A + Be-1/C|(.5)Δi/j:Δj/i|1/2)Δij Data from the literature were used to test the equation by generating curves of measured torque (T/L) versus applied shear rate (Ω) that would characterize the behavior of blood at all red cell concentrations and all shear rates in the Gilinson, Dauwalter and Merrill viscometer. The constants for the equation were obtained by appropriate curve-fitting using the Least- Squares Estimation of Non-Linear Parameters procedure of Marquardt and functions in terms of hematocrit were determined to represent this behavior. Comparisons of the predicted results with those from the literature indicate considerable deviations at the lowest shear rates. However, it is believed that with more data in the very low shear region (less than 0.5 sec.-1) to determine the correct values of the constants, better correlation with experimental data may be obtained. The results presented in this work were found to correlate well for shear rates in the intermediate region and low region (greater than 5 sec. -1 and less than 50 sec. -1)

Atomic Force Microscopy Investigation of Radiation-Induced DNA Double Strand Breaks

We have used atomic force microscopy (AFM) to study radiation-induced DNA double strand breaks. Double-stranded plasmid DNA was irradiated with 18-MeV electrons in aqueous buffer, using a medical linear accelerator. Doses of 50, 100, 150, and 200 Gy were delivered to DNA samples, and atomic force microscopy was used to measure the length of each DNA fragment. From these measurements, we obtained the average length of the irradiated DNA for each sample and found a linear-quadratic relationship between the average length and radiation dose

Radiation-Induced Neoplastic Transformation of Human Cells

Ionizing radiation can induce cancers in humans and animals and can cause in vitro neoplastic transformation of various rodent cell systems. However, numerous attempts to achieve neoplastic transformation of human cells by radiation have generally proven unsuccessful. Neoplastic transformation of immortalized human epidermal keratinocytes by X-ray irradiation has recently been reported. The carcinogenic effect of radiation on cultured human cells will be briefly reviewed. The current state-of-the-art in radiation-induced transformation of human cells in culture is presented. This will provide insight into the molecular and cellular mechanisms in the conversion of normal cells to a neoplastic state of growth

Rationale for Stereotactic Body Radiation Therapy in Treating Patients with Oligometastatic Hormone-Naïve Prostate Cancer

Despite advances in treatment for metastatic prostate cancer, patients eventually progress to castrate-resistant disease and ultimately succumb to their cancer. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer and has been shown to improve median time to progression and median survival time. Research suggests that castrate-resistant clones may be present early in the disease process prior to the initiation of ADT. These clones are not susceptible to ADT and may even flourish when androgen-responsive clones are depleted. Stereotactic body radiation therapy (SBRT) is a safe and efficacious method of treating clinically localized prostate cancer and metastases. In patients with a limited number of metastatic sites, SBRT may have a role in eliminating castrate-resistant clones and possibly delaying progression to castrate-resistant disease

Improved Irritative Voiding Symptoms 3 Years after Stereotactic Body Radiation Therapy for Prostate Cancer

Background: Irritative voiding symptoms are common in elderly men and following prostate radiotherapy. The impact of hypofractionated treatment on irritative voiding symptoms has not been determined. This study sought to evaluate urgency, frequency and nocturia following SBRT for prostate cancer. Methods: Patients treated with SBRT monotherapy for localized prostate cancer from August 2007 to July 2011 at Georgetown University Hospital were included in this study. Treatment was delivered using the CyberKnife® with doses of 35 Gy-36.25 Gy in 5 fractions. Patient-reported urinary symptoms were assessed using the International Prostate Symptom Score (IPSS) before treatment and at 1, 3, 6, 9, 12 months post-treatment and every 6 months thereafter.Results: 204 patients at a median age of 69 years received SBRT with a median follow-up of 4.8 years. Prior to treatment, 50.0% of patients reported moderate to severe lower urinary track symptoms and 17.7% felt that urinary frequency was a moderate to big problem. The mean prostate volume was 39 cc and 8% had prior procedures for benign prostatic hyperplasia (BPH). A mean baseline IPSS-irritative score of 4.8 significantly increased to 6.5 at 1 month (p 8) at baseline, the mean IPSS-I decreased from a baseline score of 6.8 to 4.9 at three years post-SBRT. This decrease was both statistically (p < 0.0001) and clinically significant (MID = 1.45). Only 14.6% of patients felt that urinary frequency was a moderate to big problem at three years post-SBRT (p = 0.23).Conclusions: Treatment of prostate cance

The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells.

The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer

Individual patient oesophageal cancer 3D models for tailored treatment

Background: A model to predict chemotherapy response would provide a marked clinical benefit, enabling tailored treatment of oesophageal cancer, where less than half of patients respond to the routinely administered chemotherapy. Methods: Cancer cells were established from tumour biopsies taken from individual patients about to undergo neoadjuvant chemotherapy. A 3D-tumour growth assay (3D-TGA) was developed, in which cancer cells were grown with or without supporting mesenchymal cells, then subjected to chemo-sensitivity testing using the standard chemotherapy administered in clinic, and a novel emerging HDAC inhibitor, Panobinostat. Results: Individual patient’s cancer cells could be expanded and screened within a clinically applicable timescale of 3 weeks. Incorporating mesenchymal support within the 3D-TGA significantly enhanced both the growth and drug resistance profiles of the patient’s cancer cells. The ex vivo drug response in the presence, but not absence, of mesenchymal cells accurately reflected clinical chemo-sensitivity, as measured by tumour regression grade. Combination with Panobinostat enhanced response and proved efficacious in otherwise chemo-resistant tumours. Conclusions: This novel method of establishing individual patient oesophageal cancers in the laboratory, from small endoscopic biopsies, enables clinically-relevant chemo-sensitivity testing, and reduces use of animals by providing more refined in vitro models for pre-screening of drugs. The 3D-TGA accurately predicted chemo-sensitivity in patients, and could be developed to guide tailored patient treatment. The incorporation of mesenchymal cells as the stromal cell component of the tumour micro-environment had a significant effect upon enhancing chemotherapy drug resistance in oesophageal cancer, and could prove a useful target for future drug development