Analysis of functional germline polymorphisms for prediction of response to anthracycline-based neoadjuvant chemotherapy in breast cancer

To elucidate the role of predictive factors on individual's drug response, based on genetic variation, we examined the association between eight germline polymorphisms in genes involved in protection against oxidative stress, apoptosis, oncogenic transformation, proliferation, immune response and DNA repair (TP53, NQO1, IL6, TLR4 and XRCC1) and the pathological response to anthracycline-based neoadjuvant chemotherapy in 70 patients with breast cancer. The DNA was genotyped for eight polymorphisms in five genes (TP53, NQO1, IL6, TLR4 and XRCC1) by 5'-exonuclease (TaqMan?) technology. Fisher's exact test was used to evaluate the association between genotype, clinicopathological parameters and pathological response. A good pathological response, defined as a pathological complete response or residual isolated invasive tumor cells, was found significantly more frequently for estrogen (ER) and progesterone receptor (PR) negative breast carcinomas compared to ER and PR positive and ER or PR positive carcinomas, respectively (43.5 vs. 37.5 and 10.3?%, p?=?0.006), and was significantly associated with high tumor grade (G3) (p?=?0.002). A non-significant trend towards a good pathological response was shown in patients carrying the Arg/Arg or Arg/Pro TP53 codon 72 gene variant compared to those harboring the Pro/Pro variant (17.6 or 37.9?% vs. 0; p?=?0.071). No association was found between NQO1 Pro187Ser, IL6 -174G>C, TLR4 Asp299Gly and Thr399Ile, and XRCC1 Arg194Trp, Arg399Gln and Arg280His and pathological response. The present study shows hormone receptor status and tumor grade as predictors for pathological response to neoadjuvant anthracycline-based chemotherapy. Among various functional germline polymorphisms, a potential predictive value was only found for the TP53 Arg72Pro gene variant.     

TIMING DEEP DIVERGENCE EVENTS IN CALCAREOUS DINOFLAGELLATES1

Based on morphological and molecular data, calcareous dinoflagellates (Thoracosphaeraceae, Peridiniales) are a monophyletic group comprising the three major clades Ensiculifera/Pentapharsodinium, Thoracosphaera/Pfiesteria, and Scrippsiella sensu lato. We used stratigraphically well‐documented first occurrences of particular archeopyle types to constrain relaxed Bayesian molecular clocks applied to nuclear rRNA sequences of 18 representatives of the three main clades. By comparing divergence estimates obtained in differently calibrated clocks with first stratigraphic occurrences of taxa not themselves used as constraints, we identified plausible divergence times for several subclades of calcareous dinoflagellates. The initial diversification of extant calcareous dinoflagellates probably took place in the Late Jurassic, with the three main clades all established by the Cretaceous. The two mesoepicystal operculum types observed in calcareous dinoflagellates probably evolved independently from simple apical archeopyles. Based on our taxon sample, the K/T boundary had relatively little effect on the diversity of the group, with several lineages dating to before 65 mya (million years ago). The first stratigraphic occurrences of key taxa, such as Thoracosphaera and Calciodinellum (not themselves used as constraints), are in agreement with the molecular time estimates. Conflicts that involve “Calciodinellum”levantinum, Leonella, Pentapharsodinium, Pernambugia, and the Scrippsiella trochoidea species complex may be due to inaccurate assignment of fossils because of high morphological homoplasy and insufficient knowledge of the extant diversity of calcareous dinoflagellates.     

The challenge of CT and MRI imaging of obese individuals who present to the emergency department: a national survey

The objective of this study was to estimate the availability of large weight capacity computed tomography (CT) and magnetic resonance imaging (MRI) equipment in US hospitals with emergency departments (EDs) and to evaluate animal facilities as alternate sources of imaging. We conducted a telephone survey of radiology technicians from a random sample of all the US hospitals with EDs (n = 262) and all 136 primary hospitals of academic EDs, 145 zoos, and 28 veterinary schools. We measured the prevalence of large weight capacity (>450 lb) CT and MRI, stratified by hospital characteristics. Response rates were 94-100% across samples. Nationally, 10% (95% confidence interval, 7-15) of hospitals with EDs had large weight capacity CT and 8% (95% confidence interval, 5-13) had large weight capacity MRI. In academic hospitals, access to large capacity equipment was better for CT (28%), but similar for MRI (10%) (P < 0.001 and 0.51, respectively). Few rural (5%) and critical-access hospitals (3%) had large capacity CT. In addition, 34% of trauma centers, 23% of stroke centers, and 21% of bariatric surgery centers of excellence had large capacity CT. Only two zoos (1%) had CT scanners; both would not image human patients. Among veterinary schools, 16 (57%) had large weight capacity CT equipment, but only 4 (14%) would consider imaging human patients. Further, 23 (82%) veterinary schools reported policies that specifically prohibited imaging humans. For patients who weigh >450 lb, access to emergent CT and MRI is limited, even at academic and bariatric surgery centers. Animal facilities are not a viable alternative for diagnostic imaging of human patients.     

Molecular dynamics of postsynaptic receptors and scaffold proteins

The activity of neurotransmitter receptors determines the strength of synaptic transmission. Therefore, the clustering of receptors at synapses is an important mechanism underlying synaptic plasticity. The dynamic exchange of receptors between synaptic and extrasynaptic membranes is dependent on their interaction with synaptic scaffold proteins. Here, we review the recent advances and emerging concepts related to the dynamics of synaptic proteins at inhibitory and excitatory synapses. These include the imaging techniques that enable the study of protein dynamics in cells, the differences and similarities of receptor dynamics at excitatory and inhibitory synapses, the relationship between the exchange of receptor and scaffold proteins, as well as the role of receptor fluxes in the modulation of synaptic strength.     

Interleukin-12 increases bispecific-antibody-mediated natural killer cell cytotoxicity against human tumors

 The combination of CD16/CD30 bispecific monoclonal antibodies (bi-mAb) and unstimulated human resting natural killer (NK) cells can cure about 50% of mice with severe combined immunodeficiency (SCID) bearing subcutaneously growing established Hodgkin’s lymphoma. As interleukin-2 (IL-2) and IL-12 have been shown to increase NK cell activity, we tested the capacity of these cytokines to increase bi-mAb-mediated NK cell cytotoxicity against two types of human tumors (Hodgkin’s disease and colorectal carcinoma). Unstimulated NK cells needed a three- to five-times higher antibody concentration than cytokine-stimulated NK cells to exert similar levels of bi-mAb-mediated cytotoxicity. The augmented tumor cell lysis was achieved with IL-12 at considerably lower concentrations than with IL-2 and was associated with a significantly increased bi-mAb-mediated intracellular Ca²⁺ mobilization. The efficiency of IL-12 in this setting together with its low toxicity make it the ideal candidate for a combination therapy with NK-cell-activating bi-mAb in human tumors that are resistant to standard treatment. Received: 26 July 1995 / Accepted: 16 November 1995     

Effects of pentachlorophenol and some of its known and possible metabolites on different species of bacteria

The antibacterial activity of pentachlorophenol and 35 of its known or possible metabolites against 30 different species of bacteria was tested. In comparison with pentachlorophenol, no increase of inhibitory activity was found for any of the chlorinated anisoles tested (except for pentachloroanisole against Streptomyces spp.), 2-chlorophenol, 2,6-dichlorophenol, 2,3,6- and 2,4,6-trichlorophenol, 2,3,5,6-tetrachlorophenol, tetrachloro-1,4- and -1,3-benzenediol (except for the 1,3-isomer against Streptomyces spp.), tetrachloro-1,3-dimethoxybenzene, and tetrachloro-1,3-benzenediol diacetate. Two chlorophenols, five dichlorophenols, four trichlorophenols, two tetrachlorophenols, and tetrachloro-1,2-benzenediol were more active than pentachlorophenol against some, but not all, of the strains tested.     

Reproductive ecology of <Emphasis Type="Italic">Agave colorata</Emphasis>: the importance of nectar-feeding bats and the germination consequences of self-pollination

Agave colorata is a paniculate agave distributed along the migratory route of the nectar-feeding bat Leptonycteris yerbabuenae. In this paper, we evaluate the importance of nectar-feeding bats in the reproduction of A. colorata in a population in Sonora, Mexico, and describe the germination consequences of self-pollination. We estimated abundance using five plots and set pollination treatments to evaluate the importance of bats. We recorded 14.8?±?6.8 plants/400 m², with a bimodal size distribution. Flowers are protandrous and visited mainly (>?20 visits/plant/30 min) by L. yerbabuenae. Pollination exclusion experiments showed that flowers excluded from diurnal visitors had maximum fruit set values (0.49?±?0.42), while the autonomous self-pollination treatment had the lowest value (0.03?±?0.06). Similarly, the greatest number of viable seeds per fruit was recorded in the diurnal exclusion treatment, while the greatest number of empty seeds was observed in the self-pollination treatment. Fruit set values among untreated plants varied from 32 to 54%, with a mean value of 41.8%. Seeds derived from self-pollination had a narrower window of opportunity for germination compared to seeds derived from nocturnal pollination. Self-pollinated seeds had lower germination, rate of germination or lag time in response to light, osmotic potential and heat shock treatments, compared to other pollination treatments, revealing an inbreeding cost. Overall, our results show that L. yerbabuenae is the likely major pollinator of the studied A. colorata population. However, under pollinator limitation A. colorata may produce seeds by autonomous self-pollination, at a cost expressed as lower germination.     

From mesophilic to thermophilic conditions: one-step temperature increase improves the methane production of a granular sludge treating agroindustrial effluents

Objectives

To assess the effect of one-step temperature increase, from 35 to 55 °C, on the methane production of a mesophilic granular sludge (MGS) treating wine vinasses and the effluent of a hydrogenogenic upflow anaerobic sludge blanket (UASB) reactor.

Results

One-step temperature increase from mesophilic to thermophilic conditions improved methane production regardless of the substrate tested. The biomethane potentials obtained under thermophilic conditions were 1.8–2.9 times higher than those obtained under mesophilic conditions. The MGS also performed better than an acclimated thermophilic digestate, producing 2.2–2.5 times more methane than the digestate under thermophilic conditions. Increasing the temperature from 35 to 55 °C also improved the methane production rate of the MGS (up to 9.4 times faster) and reduced the lag time (up to 1.9 times). Although the temperature increase mediated a decrease in the size of the sludge granules, no negative effects on the performance of the MGS was observed under thermophilic conditions.

Conclusions

More methane is obtained from real agroindustrial effluents at thermophilic conditions than under mesophilic conditions. One-step temperature increase (instead of progressive sequential increases) can be used to implement the thermophilic anaerobic digestion processes with MGS.

     

Anaerobic biotransformation of hexachlorocyclohexane isomers by <Emphasis Type="Italic">Dehalococcoides</Emphasis> species and an enrichment culture

The biotransformation of hexachlorocyclohexane isomers (HCH) by two Dehalococcoides mccartyi strains (195 and BTF08) and an enrichment culture was investigated and compared to conversion by the obligate anaerobic strain Clostridium pasteurianum strain DSMZ 525. The D. mccartyi strains preferentially transformed γ-HCH over α-HCH and δ-HCH isomers while β-HCH biotransformation was not significant. In case of the enrichment culture, γ-HCH was preferentially transformed over the δ-HCH, β-HCH and α-HCH isomers. Major observed metabolites in both cases were tetrachlorocyclohexene and as end products monochlorobenzene (MCB) and benzene. Dechlorination of the γ-HCH isomer was linked to an increase in cell numbers for strain 195. γ-HCH transformation was linked to considerable carbon stable isotope fractionation with the enrichment factor ε_c?=???5.5?±?0.8‰ for D. mccartyi strain 195, ε_c?=???3.1?±?0.4‰ for the enrichment culture and ε_c?=???4.1?±?0.6‰ for co-metabolic transformation by C. pasteurianum.