Superior Therapeutic Efficacy of Nanoparticle Albumin Bound Paclitaxel Over Cremophor-Bound Paclitaxel in Experimental Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is the fastest growing cancer in the western world and the overall 5 year survival rate of EAC is below 20%. Most patients with EAC present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Therefore, new therapeutic approaches are urgently needed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel albumin-stabilized, cremophor-free and water soluble nanoparticle formulation of paclitaxel, and the potential role of nab-paclitaxel has not been tested yet in experimental EAC. Here we tested the antiproliferative and antitumor efficacy with survival advantage of nab-paclitaxel as monotherapy and in combinations in in-vitro, and in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Nab-paclitaxel significantly inhibited in-vitro cell proliferation with higher in-vivo antitumour efficacy and survival benefit compared to paclitaxel or carboplatin treatments both in mono- and combination therapies. Nab-paclitaxel treatment increased expression of mitotic-spindle associated phospho-stathmin, decreased expression of proliferative markers and enhanced apoptosis. This study demonstrates that nab-paclitaxel had stronger antiproliferative and antitumor activity in experimental EAC than the current standard chemotherapeutic agents which supports the rationale for its clinical use in EAC.     

Digitonin-Permeabilized Cells Are Exocytosis Competent

Release of norepinephrine from PC12 cells can be stimulated by free Ca2+ in micromolar concentrations after permeabilization with 10 micrograms/ml of digitonin. This release is time and temperature dependent, half-maximal at 0.3 microM Ca2+, and, after washing out of endogenous ATP, half-maximal at about 0.5 mM MgATP when exogenously added. Similar results were obtained with bovine adrenal chromaffin cells using the same protocol. Support for the idea that the mechanism of release from both permeabilized cell types is still exocytosis is demonstrated at the electron microscopic level by immunolabeling chromaffin granule membrane antigens that were introduced into the plasma membrane following stimulation. Electron micrographs furthermore demonstrate that chromaffin granules retain typical dense cores after permeabilization, indicating that leakiness of catecholamines from the granules was not a major factor. Pores, formed by digitonin in the plasma membranes, were utilized to introduce antibodies into such exocytosis-competent cells. Anti-actin and anti-chromaffin granule membrane antibodies show a staining pattern similar to conventionally fixed and stained preparations. Our results demonstrate that pores formed by digitonin do not impair the process of exocytosis although they are big enough to allow macromolecules to pass in both directions. The digitonin-permeabilized cell is therefore an ideal in vitro system with which to study the fusion process between chromaffin granules and the plasma membrane.     

Limited recovery following a massive seagrass decline in subarctic eastern Canada

Over the last few decades, there has been an increasing recognition for seagrasses' contribution to the functioning of nearshore ecosystems and climate change mitigation. Nevertheless, seagrass ecosystems have been deteriorating globally at an accelerating rate during recent decades. In 2017, research into the condition of eelgrass (Zostera marina) along the eastern coast of James Bay, Canada, was initiated in response to reports of eelgrass decline by the Cree First Nations of Eeyou Istchee. As part of this research, we compiled and analyzed two decades of eelgrass cover data and three decades of eelgrass monitoring data (biomass and density) to detect changes and assess possible environmental drivers. We detected a major decline in eelgrass condition between 1995 and 1999, which encompassed the entire east coast of James Bay. Surveys conducted in 2019 and 2020 indicated limited changes post-decline, for example, low eelgrass cover (<25%), low aboveground biomass, smaller shoots than before 1995, and marginally low densities persisted at most sites. Overall, the synthesized datasets show a 40% loss of eelgrass meadows with >50% cover in eastern James Bay since 1995, representing the largest scale eelgrass decline documented in eastern Canada since the massive die-off event that occurred in the 1930s along the North Atlantic coast. Using biomass data collected since 1982, but geographically limited to the sector of the coast near the regulated La Grande River, generalized additive modeling revealed eelgrass meadows are affected by local sea surface temperature, early ice breakup, and higher summer freshwater discharge. Our results caution against assuming subarctic seagrass ecosystems have avoided recent global declines or will benefit from ongoing climate warming.     

Food Resource Characteristics in Two Nocturnal Lemurs with Different Social Behavior: Avahi occidentalis and Lepilemur edwardsi

I present results from a comparative field study on the feeding behavior of the gregarious Avahi occidentalis and the solitary-but-social Lepilemur edwardsi to evaluate hypotheses relating to social organization and food resources. While Avahi and Lepilemur are both nocturnal, have comparable body weights and positional behaviors, and are both folivorous, they differ in their social organization. Therefore, they present an ideal model for assessing food resource characteristics through comparisons of food selection in both species with regard to forest composition. The monogamous Avahi tend to select under-represented resources. They are repeatedly exploited, which suggests that their location must be known. It is worthwhile and probably imperative to defend those resources. Such defense imposes ranging limitations on male Avahi. Females may prefer familiar mates that will share their knowledge of resource location and defend the resources. A stable monogamous pattern could be the optimal strategy. In contrast, food selection by Lepilemur is based on common resources to a higher degree, but they show a lower degree of exploitation. Lepilemur males would be less restricted and could potentially opt for a different strategy, e.g., a dispersed harem. It is unclear whether this strategy is realized or not. I discuss other possible correlates of monogamy—infanticide protection, predation avoidance—but the gregarious pattern in Avahi may best be seen as a retention, and its nocturnal activity as a secondary adaptation.     

Nitrogen Metabolism in Senescing Leaves

Leaf senescence is a highly organized process and not a passive decay. Photosynthesizing mesophyll cells lose their functions in an early phase, while the epidermal layer with the stomates and the phloem remains functional throughout senescence. The subcellular compartmentation is maintained and allows the cooperation of different organelles in the remobilization of constituents. Nitrogen metabolism changes at the onset of senescence from assimilation to remobilization. Enzymes involved in nitrate reduction are lost, while some enzymes of intermediary nitrogen metabolism are maintained longer, and some catabolic enzymes reach highest activities during senescence. Chloroplasts are dismantled early, but mitochondria remain active and may fuel remobilization processes. Chloroplast proteins are degraded, and this nitrogen fraction can be translocated via the phloem from senescing leaves to sinks within the same plant. In contrast, chlorophyll is degraded, fragments produced reach the vacuole, and catabolites accumulate there. Nuclear DNA is maintained until a very late phase. The export of nitrogen from senescing plant parts is important for the economic use of this macronutrient. The regulation of senescence at the whole plant level as well as at the molecular level is only rudimentarily known, although interesting new aspects have been presented recently.