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

Non-Fermi-liquid d-wave metal phase of strongly interacting electrons

Developing a theoretical framework for conducting electronic fluids qualitatively distinct from those described by Landau's Fermi-liquid theory is of central importance to many outstanding problems in condensed matter physics. One such problem is that, above the transition temperature and near optimal doping, high-transition-temperature copper-oxide superconductors exhibit `strange metal' behaviour that is inconsistent with being a traditional Landau Fermi liquid. Indeed, a microscopic theory of a strange-metal quantum phase could shed new light on the interesting low-temperature behaviour in the pseudogap regime and on the d-wave superconductor itself. Here we present a theory for a specific example of a strange metal---the 'd-wave metal'. Using variational wavefunctions, gauge theoretic arguments, and ultimately large-scale density matrix renormalization group calculations, we show that this remarkable quantum phase is the ground state of a reasonable microscopic Hamiltonian---the usual t-J model with electron kinetic energy $t$ and two-spin exchange $J$ supplemented with a frustrated electron `ring-exchange' term, which we here examine extensively on the square lattice two-leg ladder. These findings constitute an explicit theoretical example of a genuine non-Fermi-liquid metal existing as the ground state of a realistic model.Comment: 22 pages, 12 figures: 6 pages, 7 figures of main text + 16 pages, 5 figures of Supplementary Information; this is approximately the version published in Nature, minus various subedits in the main tex

Treatment of bipolar disorder: a complex treatment for a multi-faceted disorder

Background: Manic-depression or bipolar disorder (BD) is a multi-faceted illness with an inevitably complex treatment. Methods: This article summarizes the current status of our knowledge and practice of its treatment. Results: It is widely accepted that lithium is moderately useful during all phases of bipolar illness and it might possess a specific effectiveness on suicidal prevention. Both first and second generation antipsychotics are widely used and the FDA has approved olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole for the treatment of acute mania. These could also be useful in the treatment of bipolar depression, but only limited data exists so far to support the use of quetiapine monotherapy or the olanzapine-fluoxetine combination. Some, but not all, anticonvulsants possess a broad spectrum of effectiveness, including mixed dysphoric and rapid-cycling forms. Lamotrigine may be effective in the treatment of depression but not mania. Antidepressant use is controversial. Guidelines suggest their cautious use in combination with an antimanic agent, because they are supposed to induce switching to mania or hypomania, mixed episodes and rapid cycling. Conclusion: The first-line psychosocial intervention in BD is psychoeducation, followed by cognitive-behavioral therapy. Other treatment options include Electroconvulsive therapy and transcranial magnetic stimulation. There is a gap between the evidence base, which comes mostly from monotherapy trials, and clinical practice, where complex treatment regimens are the rule

Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature

A systematic search of the literature reveals limited evidence to support use of aripiprazole, a second-generation antipsychotic medication, in maintenance therapy of bipolar disorder, despite widespread use

Lithium side effects and toxicity: prevalence and management strategies

Despite its virtually universal acceptance as the gold standard in treating bipolar disorder, prescription rates for lithium have been decreasing recently. Although this observation is multifactorial, one obvious potential contributor is the side effect and toxicity burden associated with lithium. Additionally, side effect concerns assuredly play some role in lithium nonadherence. This paper summarizes the knowledge base on side effects and toxicity and suggests optimal management of these problems. Thirst and excessive urination, nausea and diarrhea and tremor are rather common side effects that are typically no more than annoying even though they are rather prevalent. A simple set of management strategies that involve the timing of the lithium dose, minimizing lithium levels within the therapeutic range and, in some situations, the prescription of side effect antidotes will minimize the side effect burden for patients. In contrast, weight gain and cognitive impairment from lithium tend to be more distressing to patients, more difficult to manage and more likely to be associated with lithium nonadherence. Lithium has adverse effects on the kidneys, thyroid gland and parathyroid glands, necessitating monitoring of these organ functions through periodic blood tests. In most cases, lithium-associated renal effects are relatively mild. A small but measurable percentage of lithium-treated patients will show progressive renal impairment. Infrequently, lithium will need to be discontinued because of the progressive renal insufficiency. Lithium-induced hypothyroidism is relatively common but easily diagnosed and treated. Hyperparathyroidism from lithium is a relatively more recently recognized phenomenon

Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs

MicroRNAs (miRNAs) are 19–22-nucleotide noncoding RNAs that post-transcriptionally regulate mRNA targets. We have identified endogenous miRNA binding sites in mouse embryonic stem cells (mESCs), by performing photo-cross-linking immunoprecipitation using antibodies to Argonaute (Ago2) followed by deep sequencing of RNAs (CLIP-seq). We also performed CLIP-seq in Dicer[superscript −/−] mESCs that lack mature miRNAs, allowing us to define whether the association of Ago2 with the identified sites was miRNA dependent. A significantly enriched motif, GCACUU, was identified only in wild-type mESCs in 3′ untranslated and coding regions. This motif matches the seed of a miRNA family that constitutes ~68% of the mESC miRNA population. Unexpectedly, a G-rich motif was enriched in sequences cross-linked to Ago2 in both the presence and absence of miRNAs. Expression analysis and reporter assays confirmed that the seed-related motif confers miRNA-directed regulation on host mRNAs and that the G-rich motif can modulate this regulation.Leukemia & Lymphoma Society of AmericaUnited States. Public Health Service (Grant R01-GM34277)United States. Public Health Service (Grant R01-CA133404)National Cancer Institute (U.S.) (Grant P01-CA42063)National Cancer Institute (U.S.) Cancer Center Support (Grant P30-CA14051

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications