Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy

RATIONALE: Adjuvant cancer chemotherapy can cause long-lasting, cognitive deficits. It is postulated that these impairments are due to these drugs targeting neural precursors within the adult hippocampus, the loss of which has been associated with memory impairment. OBJECTIVES: The present study investigates the effects of the chemotherapy, methotrexate (MTX) on spatial working memory and the proliferation and survival of the neural precursors involved in hippocampal neurogenesis, and the possible neuroprotective properties of the antidepressant fluoxetine. METHODS: Male Lister hooded rats were administered MTX (75 mg/kg, two i.v. doses a week apart) followed by leucovorin rescue (i.p. 18 h after MTX at 6 mg/kg and at 26, 42 and 50 h at 3 mg/kg) and/or fluoxetine (10 mg/kg/day in drinking water for 40 days). Memory was tested using the novel location recognition (NLR) test. Using markers, cell proliferation (Ki67) and survival (bromodeoxyuridine/BrdU), in the dentate gyrus were quantified. RESULTS: MTX-treated rats showed a cognitive deficit in the NLR task compared with the vehicle and fluoxetine-treated groups. Cognitive ability was restored in the group receiving both MTX and fluoxetine. MTX reduced both the number of proliferating cells in the SGZ and their survival. This was prevented by the co-administration of fluoxetine, which alone increased cell numbers. CONCLUSIONS: These results demonstrate that MTX induces an impairment in spatial working memory and has a negative long-term effect on hippocampal neurogenesis, which is counteracted by the co-administration of fluoxetine. If translatable to patients, this finding has the potential to prevent the chemotherapy-induced cognitive deficits experienced by many cancer survivors

Membrane anchoring stabilizes and favors secretion of New Delhi metallo-β-lactamase

Carbapenems, 'last-resort' β-lactam antibiotics, are inactivated by zinc-dependent metallo-β-lactamases (MBLs). The host innate immune response withholds nutrient metal ions from microbial pathogens by releasing metal-chelating proteins such as calprotectin. We show that metal sequestration is detrimental for the accumulation of MBLs in the bacterial periplasm, because those enzymes are readily degraded in their nonmetallated form. However, the New Delhi metallo-β-lactamase (NDM-1) can persist under conditions of metal depletion. NDM-1 is a lipidated protein that anchors to the outer membrane of Gram-negative bacteria. Membrane anchoring contributes to the unusual stability of NDM-1 and favors secretion of this enzyme in outer-membrane vesicles (OMVs). OMVs containing NDM-1 can protect nearby populations of bacteria from otherwise lethal antibiotic levels, and OMVs from clinical pathogens expressing NDM-1 can carry this MBL and the bla[subscript NDM] gene. We show that protein export into OMVs can be targeted, providing possibilities of new antibacterial therapeutic strategies.Kinship Foundation. Searle Scholars ProgramMassachusetts Institute of Technology. Department of Chemistr

dp53 Restrains Ectopic Neural Stem Cell Formation in the Drosophila Brain in a Non-Apoptotic Mechanism Involving Archipelago and Cyclin E

Accumulating evidence suggests that tumor-initiating stem cells or cancer stem cells (CSCs) possibly originating from normal stem cells may be the root cause of certain malignancies. How stem cell homeostasis is impaired in tumor tissues is not well understood, although certain tumor suppressors have been implicated. In this study, we use the Drosophila neural stem cells (NSCs) called neuroblasts as a model to study this process. Loss-of-function of Numb, a key cell fate determinant with well-conserved mammalian counterparts, leads to the formation of ectopic neuroblasts and a tumor phenotype in the larval brain. Overexpression of the Drosophila tumor suppressor p53 (dp53) was able to suppress ectopic neuroblast formation caused by numb loss-of-function. This occurred in a non-apoptotic manner and was independent of Dacapo, the fly counterpart of the well-characterized mammalian p53 target p21 involved in cellular senescence. The observation that dp53 affected Edu incorporation into neuroblasts led us to test the hypothesis that dp53 acts through regulation of factors involved in cell cycle progression. Our results show that the inhibitory effect of dp53 on ectopic neuroblast formation was mediated largely through its regulation of Cyclin E (Cyc E). Overexpression of Cyc E was able to abrogate dp53′s ability to rescue numb loss-of-function phenotypes. Increasing Cyc E levels by attenuating Archipelago (Ago), a recently identified transcriptional target of dp53 and a negative regulator of Cyc E, had similar effects. Conversely, reducing Cyc E activity by overexpressing Ago blocked ectopic neuroblast formation in numb mutant. Our results reveal an intimate connection between cell cycle progression and NSC self-renewal vs. differentiation control, and indicate that p53-mediated regulation of ectopic NSC self-renewal through the Ago/Cyc E axis becomes particularly important when NSC homeostasis is perturbed as in numb loss-of-function condition. This has important clinical implications

Yoga for breast cancer patients and survivors: a systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Many breast cancer patients and survivors use yoga to cope with their disease. The aim of this review was to systematically assess and meta-analyze the evidence for effects of yoga on health-related quality of life and psychological health in breast cancer patients and survivors.</p> <p>Methods</p> <p>MEDLINE, PsycInfo, EMBASE, CAMBASE, and the Cochrane Library were screened through February 2012. Randomized controlled trials (RCTs) comparing yoga to controls were analyzed when they assessed health-related quality of life or psychological health in breast cancer patients or survivors. Risk of bias was assessed using the Cochrane risk of bias tool. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated.</p> <p>Results</p> <p>Twelve RCTs with a total of 742 participants were included. Seven RCTs compared yoga to no treatment; 3 RCTs compared yoga to supportive therapy; 1 RCT compared yoga to health education; and 1 RCT compared a combination of physiotherapy and yoga to physiotherapy alone. Evidence was found for short-term effects on global health-related quality of life (SMD = 0.62 [95% CI: 0.04 to 1.21]; P = 0.04), functional (SMD = 0.30 [95% CI: 0.03 to 0.57), social (SMD = 0.29 [95% CI: 0.08 to 0.50]; P < 0.01), and spiritual well-being (SMD = 0.41 [95% CI: 0.08; 0.74]; P = 0.01). These effects were, however, only present in studies with unclear or high risk of selection bias. Short-term effects on psychological health also were found: anxiety (SMD = −1.51 [95% CI: -2.47; -0.55]; P < 0.01), depression (SMD = −1.59 [95% CI: -2.68 to −0.51]; P < 0.01), perceived stress (SMD = −1.14 [95% CI:-2.16; -0.12]; P = 0.03), and psychological distress (SMD = −0.86 [95% CI:-1.50; -0.22]; P < 0.01). Subgroup analyses revealed evidence of efficacy only for yoga during active cancer treatment but not after completion of active treatment.</p> <p>Conclusions</p> <p>This systematic review found evidence for short-term effects of yoga in improving psychological health in breast cancer patients. The short-term effects on health-related quality of life could not be clearly distinguished from bias. Yoga can be recommended as an intervention to improve psychological health during breast cancer treatment.</p

Landscape development at Lina myr fen, Eastern Gotland, 9000-2500 cal. yr BP

Using diatoms, pollen, and geochemistry, we explore human habitation around Lina myr, Gotland, in relation to shore displacement. Archeological evidence has shown that Lina myr was an important area for its prehistoric human inhabitants. We investigate if and when Lina myr was connected to the sea and could therefore have been part of an inland water system useful for transport. A chronology was based on 14C AMS dating of terrestrial macrofossils and bulk sediments with dates ranging between 9100 and 2360 cal. yr BP. The initiation of the Littorina transgression was dated to 8500 cal. yr BP. A twofold pattern for the maximum sub-phase of the Littorina Sea is suggested from 8100 to 7500 cal. yr BP and from 6500 to 6000 cal. yr BP. The onset of cultivation and grazing was indicated by the presence of Hordeum and Plantago lanceolata in the pollen record during the Late Neolithic, at about 4580 cal. yr BP. During this time sea level was relatively higher than today and the Lina myr basin was connected with the Littorina Sea, which it continued to be until isostatic uplift caused it to become isolated at about 3820 cal. yr BP. After about 3000 cal. yr BP, human-made landscape changes intensified, grasslands increased, and shrublands decreased. </p