Effects of Radiotherapy Upon Bone Structure-Strength Relationships Vary With Sex and Fractionation of Dosing.

Background: Radiotherapy for tumor treatment in or near bones often causes osteopenia and/or osteoporosis, and the resulting increased bone fragility can lead to pathologic fractures. Bone mineral density (BMD) is often used to screen for fracture risk, but no conclusive relationship has been established between BMD and the microstructural/ biomechanical changes in irradiated bone. Understanding the effects of radiation dosing regimen on the bone structure-strength relationship would improve the ability to reduce fracture-related complications resulting from cancer treatment.

Manipulation of Redox Metabolism Using Pharmacologic Ascorbate Opens a Therapeutic Window for Radio-Sensitization by ATM Inhibitors in Colorectal Cancer.

Purpose: Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH; intravenous administration achieving mM plasma concentrations) selectively enhances HO-induced oxidative stress and radiosensitization in tumors while acting as an antioxidant and mitigating radiation damage in normal tissues including the bowel. We hypothesized that P-AscH could enhance the therapeutic index of ATM inhibitor-based chemoradiation by simultaneously enhancing the intended effects of ATM inhibitors in tumors and mitigating off-target effects in adjacent normal tissues.

Combining Medication Adherence Support Plus Long-Acting Injectable Antipsychotic Medication: A Post-Hoc Analysis of 3 Pilot Studies.

Patients with severe mental illness (SMI) who do not adhere to treatment have a lower quality of life, with more hospitalizations, interpersonal relationship conflict, homelessness, substance use problems, and incarceration compared to patients who adhere to treatment. Nonadherence to psychiatric medications has been studied for over a decade in patients diagnosed with bipolar, schizoaffective, and schizophrenia disorders with long-acting injectable antipsychotics (LAI) becoming a mainstay of adherence-focused treatment. Previous studies have shown that LAI treatment can be further optimized with the inclusion of the behavioral intervention, Customized Adherence Enhancement (CAE).

Extracellular biomolecular free radical formation during injury.

Determine if oxidative damage increases in articular cartilage as a result of injury and matrix failure and whether modulation of the local redox environment influences this damage. Osteoarthritis is an age associated disease with no current disease modifying approaches available. Mechanisms of cartilage damage in vitro suggest tissue free radical production could be critical to early degeneration, but these mechanisms have not been described in intact tissue.

Sex-based differences in the severity of radiation-induced arthrofibrosis.

As cancer survivorship increases, so does the number of patients that suffer from the late effects of radiation therapy. This includes arthrofibrosis, the development of stiff joints near the field of radiation. Previous reports have concentrated on skin fibrosis around the joint but largely ignored the deeper tissues of the joint.

Ketogenic Diet with Concurrent Chemoradiation in Head and Neck Squamous Cell Carcinoma: Preclinical and Phase 1 Trial Results.

Ketogenic diets (KD) are high in fat and low in carbohydrates, forcing cells to utilize mitochondrial fatty acid oxidation for energy production. Since cancer cells demonstrate increased mitochondrial oxidative stress relative to normal cells, we hypothesized that a KD may selectively enhance metabolic oxidative stress in head and neck cancer cells, sensitizing them to radiation and platinum-based chemotherapy without causing increased toxicity in surrounding normal tissues. This hypothesis was tested in preclinical murine xenografts and in a phase 1 clinical trial (NCT01975766).

Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide.

Avasopasem manganese (AVA or GC4419), a selective superoxide dismutase mimetic, is in a phase 3 clinical trial (NCT03689712) as a mitigator of radiation-induced mucositis in head and neck cancer based on its superoxide scavenging activity. We tested whether AVA synergized with radiation via the generation of hydrogen peroxide, the product of superoxide dismutation, to target tumor cells in preclinical xenograft models of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma. Treatment synergy with AVA and high dose per fraction radiation occurred when mice were given AVA once before tumor irradiation and further increased when AVA was given before and for 4 days after radiation, supporting a role for oxidative metabolism.

Neoadjuvant Radiotherapy-Related Wound Morbidity in Soft Tissue Sarcoma: Perspectives for Radioprotective Agents.

Historically, patients with localized soft tissue sarcomas (STS) of the extremities would undergo limb amputation. It was subsequently determined that the addition of radiation therapy (RT) delivered prior to (neoadjuvant) or after (adjuvant) a limb-sparing surgical resection yielded equivalent survival outcomes to amputation in appropriate patients. Generally, neoadjuvant radiation offers decreased volume and dose of high-intensity radiation to normal tissue and increased chance of achieving negative surgical margins-but also increases wound healing complications when compared to adjuvant radiotherapy.

Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper.

Therapies for lung cancer patients initially elicit desirable responses, but the presence of hypoxia and drug resistant cells within tumors ultimately lead to treatment failure. Disulfiram (DSF) is an FDA approved, copper chelating agent that can target oxidative metabolic frailties in cancer vs. normal cells and be repurposed as an adjuvant to cancer therapy.

Augmentation of intracellular iron using iron sucrose enhances the toxicity of pharmacological ascorbate in colon cancer cells.

Pharmacological doses (> 1mM) of ascorbate (a.k.a.

Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials.

Ketogenic diets are low in carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Relative to normal cells, cancer cells are believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a ketogenic diet concurrent with radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung cancer (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes.

D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via HO-mediated oxidative stress.

D-penicillamine (DPEN), a copper chelator, has been used in the treatment of Wilson's disease, cystinuria, and rheumatoid arthritis. Recent evidence suggests that DPEN in combination with biologically relevant copper (Cu) concentrations generates HO in cancer cell cultures, but the effects of this on cancer cell responses to ionizing radiation and chemotherapy are unknown. Increased steady-state levels of HO were detected in MB231 breast and H1299 lung cancer cells following treatment with DPEN (100µM) and copper sulfate (15µM).

Enhancement of Radiation Response in Breast Cancer Stem Cells by Inhibition of Thioredoxin- and Glutathione-Dependent Metabolism.

The goal of this study was to determine if depletion of glutathione (GSH) and inhibition of thioredoxin (Trx) reductase (TrxR) activity could enhance radiation responses in human breast cancer stem cells by a mechanism involving thiol-dependent oxidative stress. The following were used to inhibit GSH and Trx metabolism: buthionine sulfoximine (BSO), a GSH synthesis inhibitor; sulfasalazine (SSZ), an inhibitor of x cysteine/glutamate antiporter; auranofin (Au), a thioredoxin reductase inhibitor; or 2-AAPA, a GSH-reductase inhibitor. Clonogenic survival, Matrigel assays, flow cytometry cancer stem cell assays (CD44CD24ESA or ALDH1) and human tumor xenograft models were used to determine the antitumor activity of drug and radiation combinations.

Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor β-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells.

Transforming growth factor β-activated kinase 1 (TAK1) is critical for survival of many KRAS mutated colorectal cancer cells, and TAK1 inhibition with 5Z-7-oxozeaenol has been associated with oxidative stress leading to tumor cell killing. When SW 620 and HCT 116 human colon cancer cells were treated with 5µM 5Z-7-oxozeaenol, cell viability, growth, and clonogenic survival were significantly decreased. Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress, 10mM N-acetylcysteine (NAC) partially reversed the growth inhibitory effects of 5Z-7-oxozeaenol.

Core temperature circdian rhythm during 35 days of horizontal bed rest.

The present study evaluated whether the previously reported alterations in core temperature circadian rhythm associated with bed rest might be attributable to increased heat loss from the skin. Infra-red thermograms were obtained at weekly intervals during 5 weeks of bed rest and after 4 weeks of active recovery. Tympanic temperature (Tty) was measured at hourly intervals from 0800 to 2300 hrs on similar occasions during bed rest.

Influence of active recovery following prolonged bed rest on static exercise pressor response.

The present study investigated the effect of active recovery, following 35 days of horizontal bed rest, on the magnitude and time course of the pressor and heart rate responses to sustained 90 minute submaximal isometric contraction of unilateral knee extensor muscles. Ten healthy male subjects were tested immediately post bed rest (Post BR) and again after 4 weeks of active recovery (Recovery). In both trials subjects sustained an absolute force equal to 30% of Post BR maximal voluntary contraction (MVC).