St John's Wort (Hypericum perforatum L.) photomedicine: hypericin-photodynamic therapy induces metastatic melanoma cell death

Hypericin, an extract from St John's Wort ( Hypericum perforatum L. ), is a promising photosensitizer in the context of clinical photodynamic therapy due to its excellent photosensitizing properties and tumoritropic characteristics. Hypericin-PDT induced cytotoxicity elicits tumor cell death by various mechanisms including apoptosis, necrosis and autophagy-related cell death. However, limited reports on the efficacy of this photomedicine for the treatment of melanoma have been published. Melanoma is a highly aggressive tumor due to its metastasizing potential and resistance to conventional cancer therapies. The aim of this study was to investigate the response mechanisms of melanoma cells to hypericin-PDT in an in vitro tissue culture model. Hypericin was taken up by all melanoma cells and partially co-localized to the endoplasmic reticulum, mitochondria, lysosomes and melanosomes, but not the nucleus. Light activation of hypericin induced a rapid, extensive modification of the tubular mitochondrial network into a beaded appearance, loss of structural details of the endoplasmic reticulum and concomitant loss of hypericin co-localization. Surprisingly the opposite was found for lysosomal-related organelles, suggesting that the melanoma cells may be using these intracellular organelles for hypericin-PDT resistance. In line with this speculation we found an increase in cellular granularity, suggesting an increase in pigmentation levels in response to hypericin-PDT. Pigmentation in melanoma is related to a melanocyte-specific organelle, the melanosome, which has recently been implicated in drug trapping, chemotherapy and hypericin-PDT resistance. However, hypericin-PDT was effective in killing both unpigmented (A375 and 501mel) and pigmented (UCT Mel-1) melanoma cells by specific mechanisms involving the externalization of phosphatidylserines, cell shrinkage and loss of cell membrane integrity. In addition, this treatment resulted in extrinsic (A375) and intrinsic (UCT Mel-1) caspase-dependent apoptotic modes of cell death, as well as a caspase-independent apoptotic mode that did not involve apoptosis-inducing factor (501 mel). Further research is needed to shed more light on these mechanisms

Comparison of Aquatic-Insect Habitat and Diversity Above and Below Road Crossings in Low-Order Streams

The effects of road crossings on fish communities have been extensively studied; yet little attention has been given to macroinvertebrate communities. This study evaluated physical stream characteristics, water quality, and aquatic-insect richness from above and below road crossings of low-order streams in the Ouachita National Forest in Arkansas. Fifteen road crossings were sampled during October and November 2005. Erosion was significantly higher below road crossings than above. Sites downstream of road crossings had significantly lower pH and significantly higher turbidity than sites upstream of road crossings. Despite differences in water quality and habitat, there was no apparent difference in aquatic-insect richness from above and below road crossings based on the EPT index, suggesting that road crossings did not act as barriers to insect movement. The water-quality differences observed were well within acceptable limits and likely not biologically important

Heat shock proteins are essential components in transformation and tumor progression: Cancer cell intrinsic pathways and beyond

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.Fil: Lang, Benjamin J.. Harvard Medical School; Estados UnidosFil: Guerrero Gimenez, Martin Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Prince, Thomas L.. Geisinger Medical Center; Estados UnidosFil: Ackerman, Andrew. Geisinger Medical Center; Estados UnidosFil: Bonorino, Cristina. Universidade Federal de Ciências da Saúde de Porto Alegre; Brasil. University of California; Estados UnidosFil: Calderwood, Stuart K.. Harvard Medical School; Estados Unido

The Panchromatic Hubble Andromeda Treasury. Progression of Large-Scale Star Formation across Space and Time in M31

We investigate the clustering of early-type stars younger than 300 Myr on galactic scales in M31. Based on the stellar photometric catalogs of the Panchromatic Hubble Andromeda Treasury program that also provides stellar parameters derived from the individual energy distributions, our analysis is focused on the young stars in three star-forming regions, located at galactocentric distances of about 5, 10, and 15 kpc, corresponding to the inner spiral arms, the ring structure, and the outer arm, respectively. We apply the two-point correlation function to our selected sample to investigate the clustering behavior of these stars across different time- and length-scales. We find that young stellar structure survives across the whole extent of M31 longer than 300 Myr. Stellar distribution in all regions appears to be self-similar, with younger stars being systematically more strongly clustered than the older, which are more dispersed. The observed clustering is interpreted as being induced by turbulence, the driving source for which is probably gravitational instabilities driven by the spiral arms, which are stronger closer to the galactic centre.Comment: 10 pages, 5 figures. To appear in "LESSONS FROM THE LOCAL GROUP - A Conference in Honour of David Block and Bruce Elmegreen" eds. Freeman, K.C., Elmegreen, B.G., Block, D.L. & Woolway, M. (Springer: New York

Witnessing Bell violations through probabilistic negativity

Bell's theorem shows that no local hidden-variable model can explain the measurement statistics of a quantum system shared between two parties, thus ruling out a classical (local) understanding of nature. In this paper we demonstrate that by relaxing the positivity restriction in the hidden-variable probability distribution it is possible to derive quasiprobabilistic Bell inequalities whose sharp upper bound is written in terms of a negativity witness of said distribution. This provides an analytic solution for the amount of negativity necessary to violate the Clauser-Horne-Shimony-Holt inequality by an arbitrary amount, therefore revealing the amount of negativity required to emulate the quantum statistics in a Bell test

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

Heat shock factor 1 (HSF1) is the primary component for initiation of the powerful heat shock response (HSR) in eukaryotes. The HSR is an evolutionarily conserved mechanism for responding to proteotoxic stress and involves the rapid expression of heat shock protein (HSP) molecular chaperones that promote cell viability by facilitating proteostasis. HSF1 activity is amplified in many tumor contexts in a manner that resembles a chronic state of stress, characterized by high levels of HSP gene expression as well as HSF1-mediated non-HSP gene regulation. HSF1 and its gene targets are essential for tumorigenesis across several experimental tumor models, and facilitate metastatic and resistant properties within cancer cells. Recent studies have suggested the significant potential of HSF1 as a therapeutic target and have motivated research efforts to understand the mechanisms of HSF1 regulation and develop methods for pharmacological intervention. We review what is currently known regarding the contribution of HSF1 activity to cancer pathology, its regulation and expression across human cancers, and strategies to target HSF1 for cancer therapy.Fil: Prince, Thomas L.. Geisinger Clinic. Department of Molecular Functional Genomics; Estados UnidosFil: Lang, Benjamin J.. Harvard Medical School; Estados UnidosFil: Guerrero Gimenez, Martin Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fernandez Muñoz, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Ackerman, Andrew. Geisinger Clinic. Department of Molecular Functional Genomics; Estados UnidosFil: Calderwood, Stuart K.. Harvard Medical School; Estados Unido

Do Low Preoperative Vitamin D Levels Reduce the Accuracy of Quick Parathyroid Hormone in Predicting Postthyroidectomy Hypocalcemia?

BACKGROUND: Although some studies have suggested that low preoperative 25-hydroxyvitamin D (25-OHD) levels may increase the risk of hypocalcemia and decrease the accuracy of single quick parathyroid hormone in predicting hypocalcemia after total thyroidectomy, the literature remains scarce and inconsistent. Our study aimed to address these issues. METHODS: Of the 281 consecutive patients who underwent a total/completion total thyroidectomy, 244 (86.8 %) did not require any oral calcium and/or calcitriol supplements (group 1), while 37 (13.2 %) did (group 2) at hospital discharge. 25-OHD level was checked 1 day before surgery, and postoperative quick parathyroid hormone (PTH) was checked at skin closure (PTH-SC). Postoperative serum calcium was checked regularly. Hypocalcemia was defined by the presence of symptoms or adjusted calcium of <1.90 mmol/L. Significant factors for hypocalcemia were determined by univariate and multivariate analyses. The accuracy of PTH-SC in predicting hypocalcemia was measured by area under a receiver operating characteristic curve (AUC), and the AUC of PTH-SC was compared between patients with preoperative 25-OHD <15 and ≥15 ng/mL via bootstrapping. RESULTS: Preoperative 25-OHD level was not significantly different between groups 1 and 2 (13.1 vs. 12.5 ng/mL, p = 0.175). After adjusting for other significant factors, PTH-SC (odds ratio 2.49, 95 % confidence interval 1.52–4.07, p < 0.001) and parathyroid autotransplantation (odds ratio 3.23, 95 % confidence interval 1.22–8.60, p = 0.019) were the two independent factors for hypocalcemia. The AUC of PTH-SC was similar between those with 25-OHD <15 and ≥15 ng/mL (0.880 vs. 0.850, p = 0.61) CONCLUSIONS: Low 25-OHD was not a significant factor for hypocalcemia and did not lower the accuracy of quick PTH in predicting postthyroidectomy hypocalcemia