Summary of potential research questions.

<p>Summary of potential research questions.</p

Recommended methodological guidelines for future studies.

<p>Recommended methodological guidelines for future studies.</p

Role of cytokines and other determinants in chemotherapy-induced cognitive impairment.

<p>Multiple factors have been postulated as determinants of cognitive changes in cancer patients, including demographical, physiological, psychological, pathological and pharmacological determinants. Recent experimental studies have suggested that pro-inflammatory cytokines may be mediators of chemotherapy-associated cognitive changes.</p

Results of Literature Search.

<p>Results of Literature Search.</p

Summary of methods and results from selected studies (Studies are listed in alphabetical order).

<p>Legend and abbreviations: (listed according to alphabetical order within categories)</p>a<p>Additional data not shown; presented during oral presentation at the International Cognition and Cancer Task Force conference in 2012.</p>b<p>AC: doxorubicin and cyclophosphamide; CAF: cyclophosphamide, doxorubicin and 5-fluorouracil; CMF: cyclophosphamide, methotrexate and 5-fluorouracil; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisolone; MTX: methotrexate; 5-FU: 5- Fluorouracil.</p>c<p>CRP: C-reactive protein; ELISA: enzyme-linked immunosorbent assay; GM-CSF: granulocyte macrophage colony-stimulating factor; IFN: Interferon; IL-: Interleukin-; IL-1RA: interleukin-1 receptor antagonist; MCP-1: monocyte chemotactic protein-1; sTNF-RII: soluble tumor necrosis factor receptor-II; TNF: tumor necrosis factor.</p>d<p>CANTAB: Cambridge Neuropsychological Test Automated Battery; Ctx: chemotherapy treatment; Endo-tx: endocrine treatment; EORTC: European Organization for Research and Treatment of Cancer; FACT-Cog: Functional Assessment of Cancer Therapy – Cognitive Function; M: month; NP: traditional neuropsychological batteries; PET: positron emission tomography.</p>e<p>“√” refers to the authors' observations that cytokine levels were elevated in chemotherapy-receiving study subjects, or the presence of a statistically significant correlation between chemotherapy and cognitive impairment; “X” refers to the authors' observations that cytokine levels were not elevated in chemotherapy-receiving study subjects, or the absence of a statistically significant correlation between chemotherapy and cognitive impairment.</p

Phase I Metabolic Stability and Electrophilic Reactivity of 2‑Phenylaminophenylacetic Acid Derived Compounds

Diclofenac and lumiracoxib are two highly analogous 2-phenylaminophenylacetic acid anti-inflammatory drugs exhibiting occasional dose-limiting hepatotoxicities. Prior data indicate that bioactivation and reactive metabolite formation play roles in the observed toxicity, but the exact chemical influence of the substituents remains elusive. In order to elucidate the role of chemical influence on metabolism related toxicity, metabolic stability and electrophilic reactivity were investigated for a series of structurally related analogues and their resulting metabolites. The resulting analogues embody progressive physiochemical changes through varying halogeno- and aliphatic substituents at two positions and were subjected to <i>in vitro</i> human liver microsomal metabolic stability and cell-based GSH depletion assays (to measure electrophilic reactivity). LC-MS/MS analysis of the GSH trapped reactive intermediates derived from the analogues was then used to identify the putative structures of reactive metabolites. We found that chemical modifications of the structural backbone led to noticeable perturbations of metabolic stability, electrophilic reactivity, and structures and composition of reactive metabolites. With the acquired data, the relationships between stability, reactivity, and toxicity were investigated in an attempt to correlate between Phase I metabolism and <i>in vitro</i> toxicity. A positive correlation was identified between reactivity and <i>in vitro</i> toxicity, indicating that electrophilic reactivity can be an indicator for <i>in vitro</i> toxicity. All in all, the effect of substituents on the structures and reactivity of the metabolites, however subtle the changes, should be taken into consideration during future drug design involving similar chemical features

Systematic Evaluation of the Metabolism and Toxicity of Thiazolidinone and Imidazolidinone Heterocycles

The thiazolidine and imidazolidine heterocyclic scaffolds, i.e., the rhodanines, 2,4-thiazolidinediones, 2-thiohydantoins, and hydantoins have been the subject of debate on their suitability as starting points in drug discovery. This attention arose from the wide variety of biological activities exhibited by these scaffolds and their frequent occurrence as hits in screening campaigns. Studies have been conducted to evaluate their value in drug discovery in terms of their biological activity, chemical reactivity, aggregation-based promiscuity, and electronic properties. However, the metabolic profiles and toxicities have not been systematically assessed. In this study, a series of five-membered multiheterocyclic (FMMH) compounds were selected for a systematic evaluation of their metabolic profiles and toxicities on TAMH cells, a metabolically competent rodent liver cell line and HepG2 cells, a model of human hepatocytes. Our studies showed that generally the rhodanines are the most toxic, followed by the thiazolidinediones, thiohydantoins, and hydantoins. However, not all compounds within the family of heterocycles were toxic. In terms of metabolic stability, 5-substituted rhodanines and 5-benzylidene thiohydantoins were found to have short half-lives in the presence of human liver microsomes (<i>t</i>_1/2 < 30 min) suggesting that the presence of the endocyclic sulfur and thiocarbonyl group or a combination of C5 benzylidene substituent and thiocarbonyl group in these heterocycles could be recognition motifs for P450 metabolism. However, the stability of these compounds could be improved by installing hydrophilic functional groups. Therefore, the toxicities and metabolic profiles of FMMH derivatives will ultimately depend on the overall chemical entity, and a blanket statement on the effect of the FMMH scaffold on toxicity or metabolic stability cannot and should not be made

Gene Detection in Complex Biological Media Using Semiconductor Nanorods within an Integrated Microfluidic Device

The salient optical properties of highly luminescent semiconductor nanocrystals render them ideal fluorophores for clinical diagnostics, therapeutics, and highly sensitive biochip applications. Microfluidic systems allow miniaturization and integration of multiple biochemical processes in a single device and do not require sophisticated diagnostic tools. Herein, we describe a microfluidic system that integrates RNA extraction, reverse transcription to cDNA, amplification and detection within one integrated device to detect histidine decarboxylase (HDC) gene directly from human white blood cells samples. When anisotropic semiconductor nanorods (NRs) were used as the fluorescent probes, the detection limit was found to be 0.4 ng of total RNA, which was much lower than that obtained using spherical quantum dots (QDs) or organic dyes. This was attributed to the large action cross-section of NRs and their high probability of target capture in a pull-down detection scheme. The combination of large scale integrated microfluidics with highly fluorescent semiconductor NRs may find widespread utility in point-of-care devices and multitarget diagnostics

Demographics and clinical information of the patients (N = 125).

<p>Demographics and clinical information of the patients (N = 125).</p

Plasma IL-6 and TNF-α concentrations across the three time-points, after stratifying for the <i>IL6-174</i> and <i>TNF-308</i> genotypes (N = 125)

<p>Plasma IL-6 and TNF-α concentrations across the three time-points, after stratifying for the <i>IL6-174</i> and <i>TNF-308</i> genotypes (N = 125)</p