IL6. Two-step model of ultrafast interfacial electron transfer in dye-semiconductor assemblies

Interfacial electron transfer (IET) is one of the steps in light-harvesting process that occurs in various assemblies for solar energy conversion, such as dye-sensitized solar cells or dye-sensitized photoelectrosynthesis cells. This work investigates IET in a model pyridine-TiO2 assembly, with the goals to assess the validity of the Fermi\u27s golden rule for calculation of the IET rates, understand the importance of conformational sampling in modeling the IET process, and establish an approach to rapid computational screening of dye-sensitizers that undergo fast IET into the semiconductor. Our results suggest that IET is a two-step process, in which the electron is first transferred into the semiconductor surface states, followed by the diffusion of the electron into the nanoparticle bulk states. Furthermore, while Fermi\u27s golden rule and related approaches are appropriate for predicting the initial IET rate (i.e., initial transfer of electron from dye into the semiconductor surface states), they are not reliable for prediction of the overall IET rate. Inclusion of the conformational sampling at room temperature into the model offers a more complete picture of the IET process, leading to a distribution of IET rates with the median rate faster than that of the IET rate obtained for the fully-optimized structure at 0 K. Finally, the two most important criteria for determination of the initial IET rate are the percent of electron density on linker in the excited state as well as the number of the semiconductor acceptor states available at the energy of the excited state. Both of these can be obtained from relatively simple electronic structure calculations either at ab initio or semiempirical levels of theory and can be thus used for rapid screening of dyes with desired properties. Elena Jakubikova, North Carolina State University Chang Liu, North Carolina State Universit

Misreporting of energy and micronutrient intake estimated by food records and 24 hour recalls, control and adjustment methods in practice

In order to assess nutritional adequacy, valid estimates of nutrient intake are required. One of the main errors in dietary assessment is misreporting. The objective was to review the extent, nature and determinants of misreporting in dietary assessment, how this affects reported intakes of micronutrients and how this is identified and measured, and to identify the best ways of dealing with misreporting when interpreting results. A systematic literature search was conducted for studies of misreporting of dietary intake in adults by 24 hour recalls or by estimated or weighed food records, published up to March 2008. Thirty-seven relevant studies were identified. Possible causes of misreporting were identified. Methods most used to identify misreporting were the Goldberg cut-off (46 % studies) and the doubly labelled water technique (24 % studies). The magnitude of misreporting of energy intake was similar in all three dietary assessment methods. The percentage of under-reporters was about 30 % and energy intake was underestimated by approximately 15 %. Seven papers presented usable data for micronutrient intake. Absolute intakes of Fe, Ca and vitamin C (the three micronutrients addressed in all papers) were on average 30 % lower in low-energy reporters (LER) than that in non-LER and, although results were not consistent, there was a tendency for micronutrient density to be higher in LER. Excluding underreporters or using energy adjustment methods for micronutrient intakes is discussed. Residual method of energy adjustment seems to be a good tool for practice to decrease an influence of misreporting when interpreting results of studies based on food records and 24 hour recall

Wpływ zapalenia tarczycy Hashimoto, stężenia TSH oraz dodatniego wyniku obecności przeciwciał przeciwtarczycowych na występowanie zróżnicowanego raka tarczycy

  Introduction: The relationship between Hashimoto’s thyroiditis (HT) and thyroid cancer (TC) is controversial. While most surgical studies report a high incidence of malignancy among patients with HT, cytological studies do not. The role of autoantibodies in the incidence of malignancy is unclear. Material and methods: A single-centre retrospective observational study was conducted in patients evaluated for thyroid nodules by US-guided fine-needle aspiration cytology (FNAC) and, if indicated, by surgery. The levels of thyroid-stimulating hormone (TSH) and anti-thyroid antibodies were measured at the time of FNAC. Results: Of 4947 patients, 599 (12.1%) were diagnosed with HT. A malignant/suspicious cytological result was found in 14.2% of the patients with HT and in 15.2% of the others. The odds ratio (OR) for malignancy in HT was 0.921 (0.716–1.183, p = 0.51). Of 1603 patients who underwent surgery, differentiated thyroid carcinoma was found in 29.5% of the HT patients and in 15.2% of the others (OR 2.33, 95% confidence interval CI, 1.403–3.854, p < 0,001). Low TSH (< 0.4 mIU/L) decreased the malignancy rate in the entire patient population, both when considering the cytological results and the surgical results. This was not confirmed in the subgroup diagnosed with HT. No relationship was observed between autoantibodies against thyroid peroxidase (ATP) or thyroglobulin (ATG) and malignancy rate. Conclusions: No association between HT and thyroid cancer was observed cytologically; a positive relationship in histological series was caused by selection bias. Low TSH levels decreased the risk of TC in patients with nodular goitre, but this has not been proven in patients with HT. (Endokrynol Pol 2016; 67 (1): 48–53)    Wstęp: Związek pomiędzy zapaleniem tarczycy Hashimoto (HT) i rakiem tarczycy (TC) jest uważany za kontrowersyjny. Podczas gdy większość badań nad operacjami dokumentuje wysoką częstotliwość występowania guzów wśród pacjentów z HT, badania cytologiczne tego nie potwierdzają. Rola autoprzeciwciał w częstotliwości występowania guzów nie jest do końca jasna. Materiał i metody: Wśród pacjentów, u których stwierdzono guzki tarczycy przeprowadzono jednoośrodkowe, retrospektywne badanie obserwacyjne poprzez aspiracyjną cytologię cienkoigłową (FNAC) pod kontrolą USG oraz operacyjnie, jeśli takie było wskazanie. Stężenia tyreotropiny (TSH) oraz przeciwciał przeciwtarczycowych zmierzono podczas przeprowadzania FNAC. Wyniki: Z 4947 pacjentów, u 599 (12,1%) zdiagnozowano HT. Zły/podejrzany wynik cytologii stwierdzono u 14,2% pacjentów z HT oraz u 15,2% innych pacjentów. Iloraz szans (OR) dla guza przy HT wynosił 0,921 (0,716–1,183, p = 0,51). Z 1603 pacjentów, których poddano operacji, zróżnicowanego raka tarczycy wykryto u 29,5% pacjentów z HT i u 15,2% innych pacjentów (OR 2,33; 95% CI; 1,403–3,854, p < 0,001). Niski poziom TSH (< 0,4 mIU/l) obniża wskaźnik występowania guza w całej populacji pacjentów, zarówno gdy bierze się pod uwagę wyniki cytologiczne, jak i operacyjne. Nie zostało to potwierdzone w podgrupie, u której zdiagnozowano HT. Nie zaobserwowano związku pomiędzy autoprzeciwciałami przeciw peroksydazie tarczycowej (ATP) lub tyreoglobulinie (ATG) i wskaźnikiem występowania guzów. Wnioski: Nie zaobserwowano cytologicznego związku pomiędzy HT i rakiem tarczycy; dodatni związek w seriach histologicznych spowodowany był stronniczością selekcji. Niskie stężenie TSH obniżył ryzyko TC u pacjentów z wolem guzkowym, lecz nie zostało to udowodnione u pacjentów z HT. (Endokrynol Pol 2016; 67 (1): 48–53)

Can sulforaphane prevent the onset or slow the progression of osteoarthritis?

Osteoarthritis (OA) is a degenerative joint disease characterised in part by destruction of articular cartilage. There are currently no disease-modifying drugs to treat OA, with joint replacement the only treatment offered to patients at end-stage disease. With age the major risk factor for OA, the number of patients is predicted to double by 2030. An understanding of the role of bioactive molecules from the habitual diet on joint health offers a novel way in which to prevent the onset or slow the progression of OA. Our research has indicated that sulforaphane (SFN), gained from the consumption of cruciferous vegetables, particularly broccoli, could impact upon articular cartilage in laboratory models of OA because (1) it decreased the cytokine-induced expression of cartilage-degrading proteinases from chondrocytes (cartilage cells); (2) it prevented the cytokine-induced degradation of cartilage explants; and (3) it attenuated cartilage destruction in a murine model of OA. The major mechanism of action for SFN in human articular chondrocytes was inhibition of NFB, not activation of Nrf2 nor inhibition of histone deacetylases. A proof-of-principle human trial was performed to measure uptake of SFN, or its metabolites, in the human knee joint following a broccoli-rich diet, and the expression or levels of several genes and proteins in cartilage, fat and synovial fluid were also measured. Data from this trial are about to be published. Overall, these findings support the utility of SFN in the prevention or treatment of OA. The proof of this requires an appropriately designed clinical trial of pain and function which we are currently pursuing

Lenalidomide for the Treatment of Relapsed and Refractory Multiple Myeloma

Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy

Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint

Rational combination treatment with histone deacetylase inhibitors and immunomodulatory drugs in multiple myeloma

Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide (Len) and pomalidomide trigger anti-tumor activities in multiple myeloma (MM) by targetting cereblon and thereby impacting IZF1/3, c-Myc and IRF4. Histone deacetylase inhibitors (HDACi) also downregulate c-Myc. We therefore determined whether IMiDs with HDACi trigger significant MM cell growth inhibition by inhibiting or downregulating c-Myc. Combination treatment of Len with non-selective HDACi suberoylanilide hydroxamic acid or class-I HDAC-selective inhibitor MS275 induces synergic cytotoxicity, associated with downregulation of c-Myc. Unexpectedly, we observed that decreased levels of cereblon (CRBN), a primary target protein of IMiDs, was triggered by these agents. Indeed, sequential treatment of MM cells with MS275 followed by Len shows less efficacy than simultaneous treatment with this combination. Importantly ACY1215, an HDAC6 inhibitor with minimal effects on class-I HDACs, together with Len induces synergistic MM cytotoxicity without alteration of CRBN expression. Our results showed that only modest class-I HDAC inhibition is able to induce synergistic MM cytotoxicity in combination with Len. These studies may provide the framework for utilizing HDACi in combination with Len to both avoid CRBN downregulation and enhance anti-MM activities

Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development

Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAF- mutant lineage becomes a cancerized lineage. The TgCreERT2; BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution

A novel 3D mesenchymal stem cell model of the multiple myeloma bone marrow niche : biologic and clinical applications

Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system. In the 3D model, MSC with conserved phenotype (CD73+CD90+CD105+) formed compact clusters with active fibrous connections, and retained lineage differentiation capacity. Extracellular matrix molecules, integrins, and niche related molecules including N-cadherin and CXCL12 are expressed in 3D MSC model. Furthermore, activation of osteogenesis (MMP13, SPP1, ADAMTS4, and MGP genes) and osteoblastogenic differentiation was confirmed in 3D MSC model. Co-culture of patient-derived BM mononuclear cells with either autologous or allogeneic MSC in 3D model increased proliferation of MM cells, CXCR4 expression, and SP cells. We carried out immune profiling to show that distribution of immune cell subsets was similar in 3D and 2D MSC model systems. Importantly, resistance to novel agents (IMiDs, bortezomib, carfilzomib) and conventional agents (doxorubicin, dexamethasone, melphalan) was observed in 3D MSC system, reflective of clinical resistance. This 3D MSC model may therefore allow for studies of MM pathogenesis and drug resistance within the BM niche. Importantly, ongoing prospective trials are evaluating its utility to inform personalized targeted and immune therapy in MM

Taste and flavour perceptions of glucosinolates, isothiocyanates, and related compounds

Brassicaceae plants are renowned for their taste, aroma and trigeminal characteristics; predominantly bitter taste, sulfurous aroma and pungency. Compounds responsible for these sensations include the glucosinolates (GSLs) and their hydrolysis products, particularly isothiocyanates (ITCs), but also sulfur‐containing volatile compounds. This article reviews the relative importance of taste and flavour perceptions resulting from such compounds; collating evidence from papers where findings are based on sensory analytical correlations, and those that have extracted specific compounds prior to sensory evaluation. Where specific GSLs impart bitterness and many ITCs impart pungency, this is clearly not true for all GSLs and ITCs. Designing crop improvement strategies for sensory traits based on total GSL content would be flawed, as it does not consider the relative differences in sensory characteristics of different GSLs and ITCs, nor contribution from other GSL hydrolysis products. In addition, some Brassicaceae plants are consumed raw, whilst others are cooked; this affects not only the hydrolysis of GSLs, but also the generation and release of sulfides. Therefore, in breeding new plant varieties it is prudent to consider the individual GSLs, the typical cooking conditions the plant is subjected to, enzyme stability, and resultant composition of both GSL hydrolysis products (including ITCs) and sulfides