Advanced cancer patients in a randomized clinical trial of night-simulating eyeglasses observed to have a normal 24-h circadian rhythm during chemotherapy.

Objectives: Cancer patients routinely exhibit dysfunctional circadian organization. Indeed, a dysfunctional circadian organization is a hallmark of advanced cancer. A cohort of advanced cancer patients undergoing chemotherapy was recruited to investigate whether manipulating exposure to blue light could restore or ameliorate their circadian organization. Methods: Thirty advanced metastatic cancer patients participated in a randomized crossover trial to evaluate whether blue light-blocking night-simulating eyeglasses could ameliorate a disrupted circadian organization better than sham eyeglasses. Circadian organization was evaluated by actigraphy and patients' self-reports of sleep, fatigue, and quality of life. Kruskal-Wallis tests compared patients' outcomes in circadian organization with a cohort of non-cancer, disease-free individuals with normal sleep as a negative control, and with advanced cancer patients with disrupted circadian organization as a positive control. Quality-of-life outcomes of the patients were compared with population-based controls (negative controls) and with cohorts of advanced cancer patients (positive controls). Results: Actigraphy measurements, self-reported sleep, fatigue levels, and quality-of-life outcomes of trial participants were similar to those of negative controls with a normal circadian organization, in spite of the trial patients' concurrent chemotherapy. Night-simulating glasses did not improve circadian organization. The 24-h correlation of day-to-day rhythms of rest and activity was 0.455 for the experimental eyeglasses and 0.476 for the sham eyeglasses (p = 0.258). Actigraphic and patient-reported outcomes compared favorably to outcomes of positive controls. Conclusion: The circadian organization of patients in this study unexpectedly resembled that of healthy controls and was better than comparison populations with disrupted circadian organization. The study clinic implements chronomodulated chemotherapy and a systematic, supportive integrative treatment protocol. Results suggest a need for further research on interventions for circadian rhythm. Although the study intervention did not benefit the participants, this work highlights the value of supporting circadian time structure in advanced cancer patients.

The effect of renewable energy incorporation on power grid stability and resilience.

Contemporary proliferation of renewable power generation is causing an overhaul in the topology, composition, and dynamics of electrical grids. These low-output, intermittent generators are widely distributed throughout the grid, including at the household level. It is critical for the function of modern power infrastructure to understand how this increasingly distributed layout affects network stability and resilience. This paper uses dynamical models, household power consumption, and photovoltaic generation data to show how these characteristics vary with the level of distribution. It is shown that resilience exhibits daily oscillations as the grid's effective structure and the power demand fluctuate. This can lead to a substantial decrease in grid resilience, explained by periods of highly clustered generator output. Moreover, the addition of batteries, while enabling consumer self-sufficiency, fails to ameliorate these problems. The methodology identifies a grid's susceptibility to disruption resulting from its network structure and modes of operation.

Integrative Treatment for Colorectal Cancer: A Comprehensive Approach.

A comprehensive approach to integrative treatment of colorectal cancer (CRC) patients involves three spheres of intervention: lifestyle, biology, and conventional treatment. Individualization of treatment is emphasized. The lifestyle sphere includes nutritional therapies, biobehavioral strategies with circadian interventions, and physical care modalities. The biology sphere comprises six host factors in the patient's internal biochemical environment or "terrain": inflammation, glycemia, oxidative stress, immune dysregulation, coagulopathy, and stress chemistries. Laboratory testing of these factors guides integrative lifestyle and supplement recommendations. The conventional treatment sphere includes individualized lifestyle recommendations, and supplements or drugs used to enhance tolerability or effectiveness of conventional treatments. Innovative strategies are implemented, including chronomodulated chemotherapy, chemosensitivity testing, and using results of molecular genomic testing to guide nutritional infusions and supplement recommendations. In the lifestyle sphere, substantial evidence from cohort studies supports recommendations for a diet that emphasizes plant and fish proteins, healthful fats in amounts that are tailored to the clinical circumstance of the patient, and carbohydrates based on unrefined whole grains, vegetables and whole fruits. High glycemic diets and refined carbohydrates, especially sugar-sweetened beverages, should be avoided. Biobehavioral strategies include practice of the relaxation response and related approaches. In addition, specific strategies to promote robust circadian organization (CO) are used to combat quality of life concerns and worsened survival that accompany disrupted CO. Physical activity, including aerobic activity and muscle strengthening, is recommended at all disease stages. In the biology sphere, supplements and lifestyle recommendations for inflammation and glycemia are discussed. In the conventional treatment sphere, supplements and innovative and complementary therapies that may remedy treatment toxicities are reviewed. Approaching CRC treatment with a comprehensive, individualized intervention enables safe and beneficial outcomes in this patient population, which can vary widely in individual biology, treatment toxicities, and disease complications. Further research in integrative therapies for CRC patients is needed.

Sensory optimization of crackers developed from high-quality cassava flour, starch, and prawn powder.

Crackers produced from high-quality cassava flour (HQCF), cassava starch, and prawn powder were optimized based on sensory preference testing. Ten different formulations of crackers were produced using mixture design. These were subjected to sensory evaluation using attributes such as taste, crispiness, puffiness, and acceptability on a 7-point hedonic scale. A mean score of 4.7, 5.6, 5.2, and 5.2 was obtained correspondingly for taste, crispiness, puffiness, and acceptability. Scores for these attributes indicated that the crackers were acceptable. Mixture regression models were used to generate contour plots for the sensory attributes and these were superimposed to obtain an optimal region, from where an optimum formulation was chosen. Verification of the optimal formulation with acceptability studies confirmed that the newly developed snack had a likeness score of 6.3 and was highly acceptable to consumers. The study demonstrates the suitability of HQCF in processing value added snack products.

Periodicity in the autocorrelation function as a mechanism for regularly occurring zero crossings or extreme values of a Gaussian process.

The problem of zero crossings is of great historical prevalence and promises extensive application. The challenge is to establish precisely how the autocorrelation function or power spectrum of a one-dimensional continuous random process determines the density function of the intervals between the zero crossings of that process. This paper investigates the case where periodicities are incorporated into the autocorrelation function of a smooth process. Numerical simulations, and statistics about the number of crossings in a fixed interval, reveal that in this case the zero crossings segue between a random and deterministic point process depending on the relative time scales of the periodic and nonperiodic components of the autocorrelation function. By considering the Laplace transform of the density function, we show that incorporating correlation between successive intervals is essential to obtaining accurate results for the interval variance. The same method enables prediction of the density function tail in some regions, and we suggest approaches for extending this to cover all regions. In an ever-more complex world, the potential applications for this scale of regularity in a random process are far reaching and powerful.

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

Integrative therapies in cancer: modulating a broad spectrum of targets for cancer management.

Integrative medicine is an approach to health and healing that "makes use of all appropriate therapeutic approaches, health care professionals, and disciplines to achieve optimal health and healing." A comprehensive integrative medicine intervention for cancer patients typically includes nutritional counseling, biobehavioral strategies, and promotion of physical activity, as well as dietary supplements including herbs, nutraceuticals, and phytochemicals. A broad-spectrum intervention of this type may contribute uniquely to improvement in cancer outcomes through its impact on a wide variety of relevant molecular targets, including effects on multiple cancer hallmarks. Hallmarks that may be particularly affected include genetic instability, tumor-promoting inflammation, deregulated metabolism, and immune system evasion. Because of their susceptibility to manipulation by diet, exercise, and supplementation, these may be characterized as metabolic hallmarks. Research on the use of comprehensive integrative approaches can contribute to the development of systems of multitargeted treatment regimens and would help clarify the combined effect of these approaches on cancer outcomes.

A Case of Complete and Durable Molecular Remission of Chronic Lymphocytic Leukemia Following Treatment with Epigallocatechin-3-gallate, an Extract of Green Tea.

We report the case of a 48-year-old man who achieved a complete molecular remission 20 years after a diagnosis of chronic lymphocytic leukemia while using epigallicatechin-3-gallate, an extract of green tea. The patient presented at age 28 with lymphocytosis, mild anemia, mild thrombocytopenia, and massive splenomegaly, for which a splenectomy was performed. He was then followed expectantly. Over the next two decades, he suffered two symptomatic chronic lymphocytic leukemia-related events. The first occurred twelve years after diagnosis (at age 40) when the patient developed fevers, night sweats, and moderate anemia. He was diagnosed with autoimmune hemolytic anemia secondary to chronic lymphocytic leukemia. The patient declined conventional therapy in favor of a diet, exercise, and supplement regimen, and recovered from the autoimmune hemolytic anemia though the underlying chronic lymphocytic leukemia remained evident. This is the first published case report of "spontaneous" recovery from secondary autoimmune hemolytic anemia in an adult.  Over the second decade following chronic lymphocytic leukemia diagnosis, serial bone marrow biopsies demonstrated increasing lymphocytosis, with minimal peripheral lymphocytosis. However, twenty years after diagnosis, peripheral lymphocytosis accelerated, with white blood cell counts rising to 55,000/µL. Because the patient continued to refuse conventional therapy, he was treated instead with a supplement regimen that included high doses of epigallocatechin-3-gallate, a green tea extract. Peripheral lymphocytosis resolved. More remarkably, a bone marrow examination, including flow cytometry, showed no evidence of a malignant clone. Two years later (at age 51), the peripheral blood and bone marrow were without molecular evidence of chronic lymphocytic leukemia or any malignancy. The patient remains well at age 52.

Cross-cultural acceptance of a traditional yoghurt-like product made from fermented cereal.

BACKGROUND: Akpan is a traditional ready-to-drink fermented yoghurt-like cereal beverage consumed in urban and rural areas in Benin. With the aim of adapting the product to new local and export markets, this work maps African and European consumer preferences for different types of Akpan. RESULTS: A sensory profile of Akpan was created and consumer tests were conducted with 103 consumers of African origin and 74 consumers of European origin. Consumer acceptance was significantly correlated with fermented odour (r = -0.94) and milky taste (r = 0.92-0.97) attributes. Cluster analysis revealed different behaviour by African and European consumers with respect to acceptability of Akpan; European consumers did not like the sour taste and African consumers liked an intense sweet milky taste. CONCLUSION: This study provides information on how Akpan, and other fermented yoghurt-type cereal products, could be adapted to African and European consumer preferences.

Reprogramming the mechanism of action of chlorambucil by coupling to a G-quadruplex ligand.

The nitrogen mustard Chlorambucil (Chl) generates covalent adducts with double-helical DNA and inhibits cell proliferation. Among these adducts, interstrand cross-links (ICLs) are the most toxic, as they stall replication by generating DNA double strand breaks (DSBs). Conversely, intrastrand cross-links generated by Chl are efficiently repaired by a dedicated Nucleotide Excision Repair (NER) enzyme. We synthesized a novel cross-linking agent that combines Chl with the G-quadruplex (G4) ligand PDS (PDS-Chl). We demonstrated that PDS-Chl alkylates G4 structures at low µM concentrations, without reactivity toward double- or single-stranded DNA. Since intramolecular G4s arise from a single DNA strand, we reasoned that preferential alkylation of such structures might prevent the generation of ICLs, while favoring intrastrand cross-links. We observed that PDS-Chl selectively impairs growth in cells genetically deficient in NER, but did not show any sensitivity to the repair gene BRCA2, involved in double-stranded break repair. Our findings suggest that G4 targeting of this clinically important alkylating agent alters the overall mechanism of action. These insights may inspire new opportunities for intervention in diseases specifically characterized by genetic impairment of NER, such as skin and testicular cancers.

Targeting a c-MYC G-quadruplex DNA with a fragment library.

We report here on the screening of a fragment library against a G-quadruplex element in the human c-MYC promoter. The ten fragment hits had significant concordance between a biophysical assay, in silico modelling and c-MYC expression inhibition, highlighting the feasibility of applying a fragment-based approach to the targeting of a quadruplex nucleic acid.

Relationships between anthocyanins and other compounds and sensory acceptability of Hibiscus drinks.

Chemical composition of Hibiscus drinks (Koor and Vimto varieties, commercial and traditional, infusions and syrups) (n=8) was related to sensory evaluation and acceptance. Significant correlations between chemical composition and sensory perception of drinks were found (i.e. anthocyanin content and Hibiscus taste) (p<0.05). Consumers (n=160) evaluated drink acceptability on a 9-point verbal hedonic scale. Three classes of behaviour were identified: (a) those who preferred syrup (43% of consumers); (b) those who preferred infusion (36%); and (c) those who preferred all of the samples (21%). Acceptability of 'syrup likers' was positively correlated to sweet taste, reducing sugar content and inversely correlated to acidic taste and titratable acidity (p<0.10). Acceptability of 'infusion likers' was positively correlated to the taste of Hibiscus drink and anthocyanin content. The study showed that the distinctions between the acceptability groups are very clear with respect to the chemical composition and rating of sensory attributes.

Case report: concurrent herpesviral and presumptive iridoviral infection associated with disease in cultured shortnose sturgeon, Acipenser brevirostrum (L.), from the Atlantic coast of Canada.

Approximately 8 weeks after a chlorine insult associated with the city water supply, shortnose sturgeon, Acipenser brevirostrum (L.), from one group presented with small (3-4 mm) irregular foci of cutaneous pallor that involved the dorsocranial integument with progressive ulceration of the nascent lesions. Various bacterial organisms were isolated from the cutaneous lesions, but not from the internal viscera. Histologically, the nuclei of the intralesional and perilesional epidermal cells often exhibited margination of the chromatin that resulted in a homogenous, pale, amphophilic, tinctorial quality of the nucleoplasm consistent with a herpesvirus infection. In addition, rare lamellar epithelial cells were prominently enlarged due to an abundant, dense, basophilic cytoplasm characteristic of an iridovirus infection. Inoculation of cutaneous lesion and kidney, spleen, liver sample pools from affected shortnose sturgeon onto white sturgeon spleen (WSS-2) cell line induced cytopathic effect characterized by syncytia formation. Ultrastructural analysis of infected WSS-2 cells revealed viral particles with a characteristic herpesvirus morphology. Intranuclear hexagonal capsids had a diameter of 95-108 nm, and enveloped particles present in the cytoplasm of infected cells had a diameter of 176-196 nm. This is the first report of a herpesvirus and a possible iridovirus-like infection in shortnose sturgeon.