Prior Exposure to Coxsackievirus A21 Does Not Mitigate Oncolytic Therapeutic Efficacy.

Oncolytic viruses (OVs) are being developed as a type of immunotherapy and have demonstrated durable tumor responses and clinical efficacy. One such OV, Coxsackievirus A21 (CVA21), exhibited therapeutic efficacy in early phase clinical trials, demonstrating the ability to infect and kill cancer cells and stimulate anti-tumor immune responses. However, one of the major concerns in using this common cold virus as a therapeutic is the potential for innate and adaptive immune responses to mitigate the benefits of viral infection, particularly in individuals that have been exposed to coxsackievirus prior to treatment. In this study, we assess melanoma responses to CVA21 in the absence or presence of prior exposure to the virus. Melanomas were transplanted into naïve or CVA21-immunized C57BL6 mice and the mice were treated with intratumoral (IT) CVA21. We find that prior exposure to CVA21 does not dramatically affect tumor responses, nor does it alter overall survival. Our results suggest that prior exposure to coxsackievirus is not a critical determinant of patient selection for IT CVA21 interventions.

Physical Activity Level and Perception of Exercise in Cystic Fibrosis.

BACKGROUND: More patients with cystic fibrosis (CF) are living longer, and lifestyle-related behavior is becoming increasingly important for improving morbidity and mortality. Declining levels of exercise leads to low cardiorespiratory fitness, which is a strong, independent predictor of mortality in patients with CF. As a result, exercise training has become a commonly accepted form of treatment for patients with CF. The purpose of this study was to determine physical activity levels and perception of exercise in adult patients with CF. METHODS: Adult patients from an in-patient CF unit were recruited to participate. A structured interview and self-report questionnaires were used to collect information on levels of physical activity and exercise perception including preferences, readiness, and barriers. RESULTS: Forty-six adult patients with CF consented to participate in the interview and completed self-report questionnaires. Subjects self-reported that the majority (84%) of their time was spent performing physical activity at a moderate level, with mean ± SD of 11.8 ± 12.2 h per week of moderate physical activity. Vigorous physical activity was described as hard and very hard physical activity, with a mean ± SD of 1.8 ± 4.6 h (13%) and 0.4 ± 1.6 h (3%), respectively. Most of the adult subjects with CF preferred walking, and 65% of them felt that exercise was very important. Lack of energy, lack of good health, lack of self-discipline, and lack of time were noted as the most frequent barriers to exercise. CONCLUSIONS: In this study, adult subjects with CF self-reported performing an adequate amount of moderate physical activity, although only a small proportion of time was spent at a vigorous level of physical activity. Clinicians providing rehabilitation have an opportunity to improve adherence to prescribed exercise by understanding the impact that physiological and psychological factors have on patients with CF. Further, motivating patients with CF to engage in more vigorous physical activity may provide a stimulus that improves clinical outcomes and potentially survival.

A phase I trial of azacitidine and nanoparticle albumin bound paclitaxel in patients with advanced or metastatic solid tumors.

BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein, is downregulated by hypermethylation in many cancers. Hypomethylating agents such as azacitidine can upregulate SPARC in tumors, which may enhance the accumulation of albumin-bound drugs at tumor site. The objectives of this phase I trial was to determine the safety and maximum tolerated dose and to assess any clinical activity of the combination of azacytidine and weekly nanoparticle-albumin-bound (nab®) paclitaxel. METHODS: Patients received escalating azacytidine doses daily for 5 days, followed by nab-paclitaxel at the standard 100mg/m2 weekly dose for 3 weeks in 4-week cycles. Dose-limiting toxicities (DLTs) were monitored during the first cycle. Serum was obtained at baseline, during and after treatment for correlative study. RESULTS: All sixteen total patients enrolled were evaluable for toxicity, while 13 patients were evaluable for response. Two of five patients treated with 100mg/m2 of azacytidine had DLT of prolonged grade 4 neutropenia. Therefore, the MTD of azacitidine in this regimen is 75 mg/m2. Three additional patients were treated with no grade 4 toxicity in cycle 1. Clinical activity included 1 complete response (CR) in refractory DLBCL, 2 CR in ovarian cancer, 4 partial responses (PR) in ovarian and endometrial cancer, 4 stable diseases (SD) in lung, sarcoma and pancreatic cancer, 1 unconfirmed PR in breast cancer, and 1 progression of disease in CLL/SLL. CONCLUSIONS: Priming with azacitidine 75 mg/m2 daily for 5 days, followed by weekly nab-paclitaxel 100 mg/m2 weekly was well tolerated and results in dramatic responses pre-treated cancer patients.

Perception of Exercise-Induced Bronchoconstriction in College Athletes.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) can lead to long-term respiratory illness and even death. EIB prevalence rates are both high and variable in college athletes. Also, prevalence rates may be underestimated due to ineffective screening. The purpose of this study is to investigate the prevalence of EIB and the perceived impact of EIB in college athletes via a self-report questionnaire. METHODS: A self-report EIB questionnaire was administered to college athletes on 8 different sports teams. Information collected was used to identify athletes who self-reported: (1) a history of EIB and/or asthma, (2) respiratory symptoms during exercise, (3) medication use, and (4) concern about EIB. RESULTS: Results showed that 56 of 196 athletes (28.6%) self-reported a history of EIB or asthma. Over half (52%) reported a history of EIB/asthma or current EIB symptoms. Forty-six of the 140 athletes (32.9%) who did not report a history of EIB or asthma indicated symptoms of EIB during sports, training, or exercise. Fourteen of 56 athletes (25%) self-reporting a history of EIB or asthma did not report the use of a respiratory medication. Nineteen of 196 athletes (9.7%) reported being concerned that EIB was adversely affecting their sports performance. CONCLUSIONS: College athletes self-report a high prevalence of EIB or asthma. Although college athletes may not report a history of EIB or asthma, they indicate symptoms of EIB. A majority of athletes reported a history or current symptoms related to EIB or asthma. Many athletes with a history of EIB or asthma are not taking any asthma medication. Last, athletes report concern about EIB adversely affecting their sports performance. More work is needed using a combination of a screening questionnaire and standardized EIB testing to develop a validated tool for accurately screening and diagnosing EIB in college athletes.

Prevalence of Exercise-Induced Bronchoconstriction Measured by Standardized Testing in Healthy College Athletes.

BACKGROUND: Exercise-induced bronchoconstriction (EIB) can lead to long-term respiratory illness and even death. EIB prevalence rates are both high and variable in college athletes. Prevalence rates may be underestimated due to ineffective testing and screening. The purpose of this study was to investigate the prevalence of EIB in college athletes by a standardized EIB test that can be used on many college campuses. In addition, we assessed the usefulness of self-reporting EIB/asthma (1) history, (2) symptoms, and (3) respiratory medication obtained from a simple screening questionnaire for predicting an EIB-positive athlete. METHODS: A standardized EIB test and self-report questionnaire were administered to college athletes on 10 different sports teams. Information collected included pulmonary function (spirometry), expired gas analysis (maximal oxygen uptake), CO2 production, minute ventilation, EIB/asthma history, current symptoms, and medication use. RESULTS: Results showed that 34 of 80 athletes (42.5%) were EIB-positive by standardized exercise testing. The majority (76.5 and 58.8%) of the 34 athletes who tested positive self-reported a negative history or no symptoms, respectively. Also, 79.4% of the athletes who tested positive for EIB reported not using a respiratory medication. There were no significant differences in a positive EIB test when assessing interactions for history (P = .93), current symptoms (P = .12), or respiratory medication use (P = .66). CONCLUSIONS: A high proportion of college athletes tested positive for EIB when using a standardized test. Positive history, current symptoms of EIB/asthma, and respiratory medication use were not predictive of a positive test. Many EIB-positive athletes are not using a respiratory medication. More work is needed to develop an effective screening tool and improve education for EIB in college athletes.

The depletion of DNA methyltransferase-1 and the epigenetic effects of 5-aza-2'deoxycytidine (decitabine) are differentially regulated by cell cycle progression.

5-Aza-2'-deoxycytidine (decitabine) is a drug targeting the epigenetic abnormalities of tumors. The basis for its limited efficacy in solid tumors is unresolved, but may relate to their indolent growth, their p53 genotype or both. We report that the primary molecular mechanism of decitabine-depletion of DNA methyltransferase-1 following its "suicide" inactivation-is not absolutely associated with cell cycle progression in HCT 116 colon cancer cells, but is associated with their p53 genotype. Control experiments affirmed that the secondary molecular effects of decitabine on global and promoter-specific CpG methylation and MAGE-A1 mRNA expression were S-phase dependent, as expected. Secondary changes in CpG methylation occurred only in growing cells ~24-48 h after decitabine treatment; these epigenetic changes coincided with p53 accumulation, an index of DNA damage. Conversely, primary depletion of DNA methyltransferase-1 began immediately after a single exposure to 300 nM decitabine and it progressed to completion within ~8 h, even in confluent cells arrested in G 1 and G 2/M. Our results suggest that DNA repair and remodeling activity in arrested, confluent cells may be sufficient to support the primary molecular action of decitabine, while its secondary, epigenetic effects require cell cycle progression through S-phase.

Fiberoptic resonance Raman spectroscopy to measure carotenoid oxidative breakdown in live tissues.

Based on compelling epidemiologic and corroboratory in vitro studies, carotenoids are thought to have great potential as dietary prevention against cancer. Yet, carotenoid-based chemopreventive trials have found very contradictory results. Definitive conclusions from these trials are hampered by an inability to accurately and safely measure carotenoids in specific tissues at risk of cancer development. Raman spectroscopy has been proposed as an optical technology with which to analyze various molecules in live tissues. One major obstacle that impedes the clinical use of this powerful technology is the lack of a fiberoptic Raman probe suitable for endoscopic tissue evaluation. A single-fiber resonance Raman Spectroscope capable of noninvasive "optical biopsies" to measure carotenoid concentrations in live tissues has been developed. The accuracy of this Raman instrument was confirmed by comparison with more standard methods of spectrophotometry and high-pressure liquid chromatography using solubilized beta-carotene (BC) and BC-loaded cells before use in a small patient cohort. This Raman instrument detected intact BC as well as BC oxidative breakdown as a decrement of its Raman signal in cells. Use of the Raman instrument in our small cohort study showed its feasibility for measuring human tissues and raised some potentially intriguing possibilities about BC tissue pharmacokinetics and oxidative biology. Based on these results, our newly developed single fiberoptic resonance Raman instrument may provide a very useful method of measuring carotenoids and their oxidative breakdown within live tissue during future carotenoid chemopreventive trials. This proof-of-concept study provides the foundation to justify future validation of our Raman prototype.

The kinetics and redox state of nitric oxide determine the biological consequences in lung adenocarcinoma.

Few studies have explored the mechanistic basis for the apparent paradoxical effects of nitric oxide and its interrelated redox species (NO(X)) in cancer biology. Our aim was to determine the differential effects of the redox state and kinetics of nitrosative species on the key cancer processes of apoptosis. Therefore, a murine lung adenocarcinoma cell line was exposed to various NO(X) donor compounds differing in redox state and delivery kinetics. DNA strand breaks (DSBs) were measured by the alkaline single-cell gel electrophoresis assay (the COMET assay) and correlated with cell viability by the MTT and soft agar colony assays, while caspase enzymatic activity was measured using an in vitro fluorogenic caspase assay. Finally, cDNA microarrays defined apoptosis-related gene expression alterations resultant from these NO(X) donors. Exogenous NO(X) differentially influences DSBs, and apoptosis-related cell death and expression based on the redox state and kinetics of NO(X) delivery. In our murine lung adenocarcinoma model we have demonstrated differential effects of NO(X) based on the mode of delivery and redox state. These data suggest that the development of NO(X)-based cancer chemotherapy must consider the redox state and kinetics of delivery into their logical design.