GIScience and cancer: State of the art and trends for cancer surveillance and epidemiology.

Maps are well recognized as an effective means of presenting and communicating health data, such as cancer incidence and mortality rates. These data can be linked to geographic features like counties or census tracts and their associated attributes for mapping and analysis. Such visualization and analysis provide insights regarding the geographic distribution of cancer and can be important for advancing effective cancer prevention and control programs. Applying a spatial approach allows users to identify location-based patterns and trends related to risk factors, health outcomes, and population health. Geographic information science (GIScience) is the discipline that applies Geographic Information Systems (GIS) and other spatial concepts and methods in research. This review explores the current state and evolution of GIScience in cancer research by addressing fundamental topics and issues regarding spatial data and analysis that need to be considered. GIScience, along with its health-specific application in the spatial epidemiology of cancer, incorporates multiple geographic perspectives pertaining to the individual, the health care infrastructure, and the environment. Challenges addressing these perspectives and the synergies among them can be explored through GIScience methods and associated technologies as integral parts of epidemiologic research, analysis efforts, and solutions. The authors suggest GIScience is a powerful tool for cancer research, bringing additional context to cancer data analysis and potentially informing decision-making and policy, ultimately aimed at reducing the burden of cancer.

American BRCA Outcomes and Utilization of Testing (ABOUT) study: a pragmatic research model that incorporates personalized medicine/patient-centered outcomes in a real world setting.

Research to date regarding identification and management of hereditary breast and ovarian cancer syndrome (HBOC) in the U.S. has been confined primarily to academic center-based studies with limited patient engagement. To begin to understand and address the current gaps and disparities in delivery of services for the appropriate identification and optimal risk management of individuals with HBOC, we designed and have initiated the American BRCA Outcomes and Utilization of Testing (ABOUT) Study. ABOUT relies on a collaborative patient advocacy, academic and industry partnership to recruit and engage U.S. individuals who are at increased risk for HBOC and investigate their experiences, decisions and outcomes. It utilizes an extensive research infrastructure, including an interactive web-based data system and electronic interfaces for secure online participation and automated data exchange. We describe the novel recruitment approach that was designed for collaboration with a national commercial health plan partner to identify all individuals for whom a healthcare provider orders a BRCA test and mail to each individual an invitation to participate and study packet. The study packet contains detailed information about the study, a baseline questionnaire and informed consent for participation in the study, for release of relevant medical and health plan records and for ongoing research engagement. This approach employs patient-reported, laboratory-reported and health plan-reported outcomes and facilitates longitudinal engagement. We believe that the type of innovative methodology and collaborative framework we have developed for ABOUT is an ideal foundation for a patient-powered research network. This approach can make substantial contributions to identifying current and best practices in HBOC, leading to improved strategies for clinical care and optimal health outcomes among individuals with high inherited risk for cancer.

A Stability-Indicating HPLC Method for the Determination of Nitrosylcobalamin (NO-Cbl), a Novel Vitamin B12 Analog.

Nitrosylcobalamin (NO-Cbl), a novel vitamin B12 analog and anti-tumor agent, functions as a biologic 'Trojan horse', utilizing the vitamin B12 transcobalamin II transport protein and cell surface receptor to specifically target cancer cells. a stability-indicating HPLC method was developed for the detection of NO-Cbl during forced degradation studies. This method utilized an ascentis® RP-amide (150 mm × 4.6 mm, 5 µm) column at 35 °C with a mobile phase (1.0 mL min-1) combining a gradient of methanol and an acetate buffer at pH 6.0. Detection wavelengths of 450 and 254 nm were used to detect corrin and non-corrin-based products, respectively. NO-Cbl, synthesized from hydroxocobalamin and pure nitric oxide gas, was subjected to degradative stress conditions including oxidation, hydrolysis and thermal and radiant energy challenge. The method was validated by assessing linearity, accuracy, precision, detection and quantitation limits and robustness. The method was applied successfully for purity assessment of synthesized NO-Cbl and for the determination of NO-Cbl during kinetic studies in aqueous solution and in solid-state degradation assessments. This HPLC method is suitable for the separation of cobalamins in aqueous and methanolic solutions, for routine detection of NO-Cbl and for purity assessment of synthesized NO-Cbl. additionally, this method has potential application in identification and monitoring of diseases involving altered nitric oxide homeostasis where vitamin B12 therapy is utilized to scavenge excess nitric oxide, subsequently resulting in the in vivo production of NO-Cbl.

Outcomes of a cancer clinical trial matching service.

The American Cancer Society (ACS) and Coalition of Cancer Cooperative Groups (CCCG) provide a clinical trial (CT) information/matching/eligibility service (Clinical Trials Matching Service [CTMS]). Patients' demographic and clinical data, enrollment status, and self-reported barriers to CT participation were analyzed to assess enrollment rates and determinants of enrollment. During 3 years beginning October 1, 2007, the CTMS served 6,903 patients via the ACS call center. Among the 1,987 patients with follow-up information on enrollment, 219 (11.0%) enrolled in a CT; 48 of these 219 enrollees chose a CT they found via the CTMS. Patients were less likely to enroll if they had poor ECOG performance status (P = 0.032); were African American (P = 0.0003), were uninsured or had Medicaid coverage (P = 0.024), or had lower stage disease (P = 0.018). Enrollment varied by trial type/cancer site/system (P = .026). Several barriers significantly predicted nonenrollment. Broader availability of a CTMS might help improve patient participation in cancer clinical trials.

Manage your online reputation--or someone else will.

In the Internet age, managing one's online "reputation" is a challenging but important task for board-certified plastic surgeons. In this article, the authors discuss the options for ensuring that your Internet presence accurately reflects the quality of your practice.

Cost Effectiveness of Pharmacogenetic Testing for Drugs with Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines: A Systematic Review.

The objective of this study was to evaluate the evidence on cost-effectiveness of pharmacogenetic (PGx)-guided treatment for drugs with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. A systematic review was conducted using multiple biomedical literature databases from inception to June 2021. Full articles comparing PGx-guided with nonguided treatment were included for data extraction. Quality of Health Economic Studies (QHES) was used to assess robustness of each study (0-100). Data are reported using descriptive statistics. Of 108 studies evaluating 39 drugs, 77 (71%) showed PGx testing was cost-effective (CE) (N = 48) or cost-saving (CS) (N = 29); 21 (20%) were not CE; 10 (9%) were uncertain. Clopidogrel had the most articles (N = 23), of which 22 demonstrated CE or CS, followed by warfarin (N = 16), of which 7 demonstrated CE or CS. Of 26 studies evaluating human leukocyte antigen (HLA) testing for abacavir (N = 8), allopurinol (N = 10), or carbamazepine/phenytoin (N = 8), 15 demonstrated CE or CS. Nine of 11 antidepressant articles demonstrated CE or CS. The median QHES score reflected high-quality studies (91; range 48-100). Most studies evaluating cost-effectiveness favored PGx testing. Limited data exist on cost-effectiveness of preemptive and multigene testing across disease states.

Patient-reported outcome measures suitable to assessment of patient navigation.

BACKGROUND: Patient-reported outcomes (PROs) are measures completed by patients to capture outcomes that are meaningful and valued by patients. To help standardize PRO measures in patient navigation research and program evaluation, the Patient-Reported Outcomes Working Group (PROWG) was convened as part of the American Cancer Society's National Patient Navigator Leadership Summit. METHODS: The PROWG consisted of clinicians, researchers, and program managers from a variety of perspectives who developed a set of recommended PRO measures across the cancer continuum (ie, screening, diagnostic follow-up, treatment, survivorship, end of life) as well as those useful for assessing family caregivers. Measures were recommended based on face validity, responsiveness to navigation, reliability, and construct validity in relevant populations. Other considerations included readability, existence of multiple language versions, the existence of norm groups, and respondent burden. RESULTS: The PROWG reached consensus on measures for use in the domains of treatment adherence; perceived barriers to care; satisfaction with cancer care; satisfaction with patient navigation services; working alliance with patient navigator; perceived knowledge/competence/self-efficacy; functional assessment/symptom burden; global quality of life; specific quality-of-life symptoms (eg, depression, anxiety); and perceived cultural competency of the navigator. In domains where validated measures were found lacking, recommendations were made for areas of needed scale development. CONCLUSIONS: These measures should guide research and programmatic evaluation of patient navigation.

Using the internet to understand smokers' treatment preferences: informing strategies to increase demand.

BACKGROUND: Most smokers attempt to quit on their own even though cessation aids can substantially increase their chances of success. Millions of smokers seek cessation advice on the Internet, so using it to promote cessation products and services is one strategy for increasing demand for treatments. Little is known, however, about what cessation aids these smokers would find most appealing or what predicts their preferences (eg, age, level of dependence, or timing of quit date). OBJECTIVE: The objective of our study was to gain insight into how Internet seekers of cessation information make judgments about their preferences for treatments, and to identify sociodemographic and other predictors of preferences. METHODS: An online survey assessing interest in 9 evidence-based cessation products and services was voluntarily completed by 1196 smokers who visited the American Cancer Society's Great American Smokeout (GASO) webpage. Cluster analysis was conducted on ratings of interest. RESULTS: In total, 48% (572/1196) of respondents were "quite a bit" or "very much" interested in nicotine replacement therapy (NRT), 45% (534/1196) in a website that provides customized quitting advice, and 37% (447/1196) in prescription medications. Only 11.5% (138/1196) indicated similar interest in quitlines, and 17% (208/1196) in receiving customized text messages. Hierarchical agglomerative cluster analysis revealed that interest in treatments formed 3 clusters: interpersonal-supportive methods (eg, telephone counseling, Web-based peer support, and in-person group programs), nonsocial-informational methods (eg, Internet programs, tailored emails, and informational booklets), and pharmacotherapy (NRT, bupropion, and varenicline). Only 5% (60/1196) of smokers were "quite a bit" or "very much" interested in interpersonal-supportive methods compared with 25% (298/1196) for nonsocial-informational methods and 33% (399/1196) for pharmacotherapy. Multivariate analyses and follow-up comparisons indicated that level of interest in pharmacotherapy ("quite a bit or "very much" vs. "not at all") varied as a function of education (n = 575, χ(2) (3) =16.6, P = .001), age (n = 528, χ(2) (3) = 8.2, P = .04), smoking level (n = 514, χ(2) (3) = 9.5, P = .02), and when smokers were planning to quit (n = 607, χ(2) (4) = 34.0, P < .001). Surprisingly, greater age was associated with stronger interest in nonsocial-informational methods (n = 367, χ(2) (3) = 10.8, P = .01). Interest in interpersonal-supportive methods was greater if smokers had used a quitline before (n = 259, χ(2) (1) = 18.3, P < .001), or were planning to quit earlier rather than later (n = 148, χ(2) (1) = 4.9, P = .03). CONCLUSIONS: Smokers accessing the Internet for information on quitting appear to differentiate cessation treatments by how much interpersonal interaction or support the treatment entails. Quitting date, smoking level, and sociodemographic variables can identify smokers with varying levels of interest in the 3 classes of cessation methods identified. These results can potentially be used to more effectively target and increase demand for these treatments among smokers searching the Internet for cessation information.

A monolithically-integrated µGC chemical sensor system.

Gas chromatography (GC) is used for organic and inorganic gas detection with a range of applications including screening for chemical warfare agents (CWA), breath analysis for diagnostics or law enforcement purposes, and air pollutants/indoor air quality monitoring of homes and commercial buildings. A field-portable, light weight, low power, rapid response, micro-gas chromatography (µGC) system is essential for such applications. We describe the design, fabrication and packaging of µGC on monolithically-integrated Si dies, comprised of a preconcentrator (PC), µGC column, detector and coatings for each of these components. An important feature of our system is that the same mechanical micro resonator design is used for the PC and detector. We demonstrate system performance by detecting four different CWA simulants within 2 min. We present theoretical analyses for cost/power comparisons of monolithic versus hybrid µGC systems. We discuss thermal isolation in monolithic systems to improve overall performance. Our monolithically-integrated µGC, relative to its hybrid cousin, will afford equal or slightly lower cost, a footprint that is 1/2 to 1/3 the size and an improved resolution of 4 to 25%.

The reflection of a blast wave by a very intense explosion.

We demonstrate that the geometric similarity of Taylor's blast wave persists beyond reflection from an ideal surface. Upon impacting the surface, the spherical symmetry of the blast wave is lost but its cylindrical symmetry endures. As the flow acquires dependence on a second spatial dimension, an analytic solution of the Euler equations becomes elusive. However, the preservation of axisymmetry, geometric similarity and planar symmetry in the presence of a mirror-like surface causes all flow solutions to collapse when scaled by the height of burst (HOB) and the shock arrival time at the surface. The scaled blast volume for any yield, HOB and ambient air density follows a single universal trajectory for all scaled time, both before and after reflection.

Antimicrobial properties of diethylamine NONOate, a nitric oxide donor, against Escherichia coli: a pilot study.

The emergence of SARS-CoV-2, the causative agent of COVID-19, highlights the increasing need for new and effective antiviral and antimicrobial agents. The FDA has recently banned several active ingredients used in hand sanitizers, including triclosan and benzethonium chloride. Nitric oxide (NO) is involved in the innate immune response and is a major component of macrophage-mediated attack on foreign viruses and bacteria. The specific aim of this study was to assess the antibacterial effects of 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NONOate) against Escherichia coli (E. coli). A bacterial growth assay was compared to an adenosine triphosphate (ATP) activity assay at various time points to assess effects of DEA-NONOate on E. coli growth. A UV/Vis spectrophotometer was used to determine concentration of E. coli by measuring optical density (OD) at 630 nm. A luminescent assay was used to measure ATP activity correlating to viable cells. DEA-NONOate at a concentration of 65 mM was able to inhibit the growth of E. coli with the same efficacy as 1 µg ml-1 concentration of ciprofloxacin. Both the OD and ATP assays demonstrated a 99.9% reduction in E. coli. Both a 1 µg ml-1 concentration of ciprofloxacin and a 65 mM concentration of DEA-NONOate achieved 99.9% inhibition of E. coli, verified using both optical density measurement of bacterial cultures in 96 well plates and a luminescent ATP activity assay. The bactericidal effects of DEA-NONOate against E. coli is proof-of-concept to pursue evaluation of nitric oxide-based formulations as antimicrobial and antiviral agents as hand sanitizers.

Anti-tumor effects of nitrosylcobalamin against spontaneous tumors in dogs.

PURPOSE: Given the limited options available to treat canine cancers, the use of companion animals for evaluating new drugs may identify better therapies for veterinary and human oncology. The anti-tumor effects of nitrosylcobalamin (NO-Cbl), an apoptosis-inducing, vitamin B12-based carrier of nitric oxide (NO), was evaluated in four dogs with spontaneous cancer. EXPERIMENTAL DESIGN: (1) A 13 year-old female spayed Giant Schnauzer with inoperable thyroid carcinoma and hypercalcemia. (2) A 6 year-old male neutered Golden Retriever with a malignant peripheral nerve sheath tumor (MPNST). (3) A ten yr-old neutered male Bichon Frise with apocrine gland anal sac adenocarcinoma (AGACA). (4) A 7 year-old female spayed Labrador mix with spinal meningioma following partial surgical resection. Tumor regression was measured by physical exam and verified using ultrasound (case 1) and MRI (case 2-4). Serum chemistries and hematologic parameters were monitored throughout the studies. RESULTS: (1) The Giant Schnauzer demonstrated a 77% reduction in tumor volume after ten weeks of daily NO-Cbl treatment. (2) The Golden Retriever demonstrated a 53% reduction in tumor volume after 15 months of daily NO-Cbl therapy. (3) The Bichon Frise demonstrated a 43% regression of the primary tumor and a 90% regression of an iliac lymph node measured by MRI after 15 months of treatment. After 61 months, the dog currently has stable disease, normal liver enzymes, CBC analysis, and no evidence of toxicity. (4) The Labrador demonstrated complete regression of the residual tumor after 6 months of treatment. CONCLUSION: We have shown previously that NO-Cbl is endocytosed by malignant cells, resulting in intra-tumoral NO release. In this study, we have shown that daily long-term use of NO-Cbl induced responses in all dogs without any signs of toxicity. The use of NO-Cbl capitalizes on the tumor-specific properties of the vitamin B12 receptor and represents a promising anti-cancer therapy.

Social support in smoking cessation: reconciling theory and evidence.

INTRODUCTION: The majority of smokers attempt to quit smoking on their own, but in any given year, only 5% or less are successful. To improve cessation rates, tapping social networks for social support during quitting has been recommended or tested in some interventions. Prior reviews of this research, however, have concluded that there is little to no evidence that partner support interventions are effective. DISCUSSION: Given the theoretical importance of the concept of social support, its demonstrated value in treatments that are implicitly supportive (e.g., telephone counseling), and the general lack of a guiding conceptual framework for research on the effects of peer or partner support for cessation, we describe theoretical models that explicitly incorporate social support constructs in predicting motivation for and success in quitting. CONCLUSION: Better differentiation of support concepts and elucidating causal pathways will lead to studies that demonstrate the value of social relationships in improving smokers' likelihood of cessation.

Nitric Oxide Inhibits NF-κB-mediated Survival Signaling: Possible Role in Overcoming TRAIL Resistance.

BACKGROUND/AIM: Chemoresistance is a major consequence of multicycle chemotherapy and can be attributed to constitutive activation of pro-survival signaling pathways. Nitric oxide is a ubiquitous signaling molecule which has been shown to inhibit several pathways involved with survival signaling in cancer cells. We have previously demonstrated the anti-tumor activity of a nitric oxide-donor, nitrosylcobalamin (NO-Cbl), mediated by increased expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. We also demonstrated that a functional Apo2L/TRAIL receptor is necessary for the induction of cell death by NO-Cbl and the Apo2L/TRAIL death receptor DR4 (TRAIL R1) is S-nitrosylated. The aim of the study was to examine the effects of nitric oxide (NO) on nuclear factor kappa B (NF-κB) and determine whether nitric oxide could sensitize drug-resistant melanomas to Apo2L/TRAIL via inhibition of NF-κB or inhibitor kappa B kinase (IKK). MATERIALS AND METHODS: Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibroblast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by the TUNEL assay. The activation status of NF-κB was established by assaying luciferase reporter activity, the phosphorylation status of IκBα, and in vitro IKK activity. RESULTS: NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL, but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. NO-Cbl suppressed Apo2L/TRAIL- and TNF-α-mediated activation of a transfected NF-κB-driven luciferase reporter. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of IκBα. CONCLUSION: NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of nitric oxide to inhibit NF-κB and potentiate the effects of chemotherapeutic agents, such as Apo2L/TRAIL, represents a promising anti-cancer combination based on recent clinical investigations of anti-TRAIL antibodies for cancer treatment strategies.

Nitrosylcobalamin promotes cell death via S nitrosylation of Apo2L/TRAIL receptor DR4.

We have previously demonstrated that nitrosylcobalamin (NO-Cbl), an analogue of vitamin B12 that delivers nitric oxide (NO), had potent antiproliferative activity against several human cancer cell lines. NO-Cbl induced apoptosis via a death receptor/caspase-8 pathway. In this study, we demonstrate that a functional Apo2L/TRAIL receptor was necessary for the induction of cell death by NO-Cbl. Furthermore, the Apo2L/TRAIL death receptor DR4 (TRAIL R1) was S nitrosylated following NO-Cbl treatment. Human melanoma (A375), renal carcinoma (ACHN), and ovarian carcinoma (NIH-OVCAR-3) cells were treated with NO-Cbl and subjected to the biotin switch assay; S-nitrosylated DR4 was detected in all three cell lines. NO-Cbl treatment did not cause S nitrosylation of DR5. The seven cysteine residues located in the cytoplasmic domain of DR4 were individually point mutated to alanines. NIH-OVCAR-3 cells expressing the DR4 C336A mutation lacked S nitrosylation following NO-Cbl treatment. Overexpression of wild-type DR4 sensitized cells to growth inhibition by NO-Cbl. Cells expressing the DR4 C336A mutant were more resistant to NO-Cbl and Apo2L/TRAIL than were the other six C-A mutations or wild-type cells. The C336A mutant also displayed blunted caspase-8 enzymatic activity following NO-Cbl treatment compared to the other mutants. Thus, DR4 residue C336 becomes S nitrosylated and promotes apoptosis following NO-Cbl treatment.

Interactions of cubilin with megalin and the product of the amnionless gene (AMN): effect on its stability.

Cubilin, a 456 kDa multipurpose receptor lacking in both transmembrane and cytoplasmic domains is expressed in the apical BBMs (brush border membranes) of polarized epithelia. Cubilin interacts with two transmembrane proteins, AMN, a 45-50 kDa protein product of the amnionless gene, and megalin, a 600 kDa giant endocytic receptor. In vitro, three fragments of cubilin, the 113-residue N-terminus and CUB domains 12-17 and 22-27, demonstrated Ca2+-dependent binding to megalin. Immunoprecipitation and immunoblotting studies using detergent extracts of rat kidney BBMs revealed that cubilin interacts with both megalin and AMN. Ligand (intrinsic factor-cobalamin)-affinity chromatography showed that in renal BBMs, functional cubilin exists as a complex with both AMN and megalin. Cubilin and AMN levels were reduced by 80% and 55-60% respectively in total membranes and BBMs obtained from kidney of megalin antibody-producing rabbits. Immunohistochemical analysis and turnover studies for cubilin in megalin or AMN gene-silenced opossum kidney cells showed a significant reduction (85-90%) in cubilin staining and a 2-fold decrease in its half-life. Taken together, these results indicate that three distinct regions of cubilin bind to megalin and its interactions with both megalin and AMN are essential for its intracellular stability.

Dosimetric and anatomic indicators of late rectal toxicity after high-dose intensity modulated radiation therapy for prostate cancer.

We seek to identify dosimetric and anatomic indicators of late rectal toxicity in prostate cancer patients treated with intensity modulated radiation therapy (IMRT). Data from 49 patients sampled from 698 patients treated for clinically localized prostate cancer at the Memorial Sloan-Kettering Cancer Center with IMRT to a dose of 81 Gy were analyzed. The end point of the study was late Grade 2 or worse rectal toxicity within 30 months of treatment. Dosimetric analysis was performed on the rectum surface in three dimensions and on two-dimensional dose maps obtained by flattening the rectum surface using a conformal mapping procedure. Several parameters including the percentage and absolute surface area of the rectum irradiated, mean dose as a function of location on the rectum, planning target volume (PTV) size and rectum size were analyzed for correlation to toxicity. Significance was set at p < 0.05 for a two-sided t-test. Correlation between absolute areas irradiated and toxicity was observed on both the rectum surface and flattened rectum. Patients with toxicity also received a significantly higher mean dose to the superior 25% of the rectum surface and 15% of the flattened rectum. PTV volume, PTV height, rectum surface area and average cross-sectional area were significantly larger in patients with toxicity. The conformal mapping procedure has potential utility for evaluating dose to the rectum and risk of toxicity. Late rectal toxicity was related to the irradiation of the upper part of the rectum and also to the absolute area irradiated, PTV size, and rectum size on the planning computed tomography (CT) scan.