Macropinocytosis confers resistance to therapies targeting cancer anabolism.

Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals that necrocytosis provides not only amino acids, but sugars, fatty acids and nucleotides for biosynthesis, conferring resistance to therapies targeting anabolic pathways. Indeed, necrotic cell debris allow macropinocytic breast and prostate cancer cells to proliferate, despite fatty acid synthase inhibition. Standard therapies such as gemcitabine, 5-fluorouracil (5-FU), doxorubicin and gamma-irradiation directly or indirectly target nucleotide biosynthesis, creating stress that is relieved by scavenged nucleotides. Strikingly, necrotic debris also render macropinocytic, but not non-macropinocytic, pancreas and breast cancer cells resistant to these treatments. Selective, genetic inhibition of macropinocytosis confirms that necrocytosis both supports tumor growth and limits the effectiveness of 5-FU in vivo. Therefore, this study establishes necrocytosis as a mechanism for drug resistance

Data requirements for in-flight synthesis and multiple blender studies

Data requirements for in-flight synthesis and multiple blender studies to improve stability and control of large flexible booster

Defective autophagy leads to cancer

AbstractCellular proteins are degraded within two distinct compartments: the proteasome and the lysosome. Alterations in proteasomal degradation can contribute to carcinogenesis. In contrast, alterations in autophagic protein degradation through the lysosome have not been linked to cancer. Now two reports demonstrate that the autophagic gene, Beclin 1, is a haploinsufficient tumor suppressor gene. These new data suggest that autophagic degradation provides an important mechanism to prevent cellular transformation

Saturn 5/Voyager load relief study Final report

Load relief control system to improve launch probability of Saturn 5 booster with Voyager payloa

Saturn 5/Voyager load relief study Data base report

Saturn 5/Voyager load relief control syste

3α-Androstanediol, but Not Testosterone, Attenuates Age-Related Decrements in Cognitive, Anxiety, and Depressive Behavior of Male Rats

Some hippocampally-influenced affective and/or cognitive processes decline with aging. The role of androgens in this process is of interest. Testosterone (T) is aromatized to estrogen, and reduced to dihydrotestosterone (DHT), which is converted to 5α-androstane, 3α, 17α-diol (3α-diol). To determine the extent to which some age-related decline in hippocampally-influenced behaviors may be due to androgens, we examined the effects of variation in androgen levels due to age, gonadectomy, and androgen replacement on cognitive (inhibitory avoidance, Morris water maze) and affective (defensive freezing, forced swim) behavior among young (4 months), middle-aged (13 months), and aged (24 months) male rats. Plasma and hippocampal levels of androgens were determined. In experiment 1, comparisons were made between 4-, 13-, and 24-month-old rats that were intact or gonadectomized (GDX) and administered a T-filled or empty silastic capsule. There was age-related decline in performance of the inhibitory avoidance, water maze, defensive freezing, and forced swim tasks, and hippocampal 3α-diol levels. Chronic, long-term (1–4 weeks) T-replacement reversed the effects of GDX in 4- and 13-month-old, but not 24-month-old, rats in the inhibitory avoidance task. Experiments 2 and 3 assessed whether acute subcutaneous T or 3α-diol, respectively, could reverse age-associated decline in performance. 3α-diol, but not T, compared to vehicle, improved performance in the inhibitory avoidance, water maze, forced swim, and defensive freezing tasks, irrespective of age. Thus, age is associated with a decrease in 3α-diol production and 3α-diol administration reinstates cognitive and affective performance of aged male rats

Ariel - Volume 4 Number 6

Editors David A. Jacoby Eugenia Miller Tom Williams Associate Editors Paul Bialas Terry Burt Michael Leo Gail Tenikat Editor Emeritus and Business Manager Richard J. Bonnano Movie Editor Robert Breckenridge Staff Richard Blutstein Mary F. Buechler J.D. Kanofsky Rocket Weber David Maye

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The consensus sleep diary: Standardizing prospective sleep self-monitoring

Study Objectives: To present an expert consensus, standardized, patient-informed sleep diary. Methods and Results: Sleep diaries from the original expert panel of 25 attendees of the Pittsburgh Assessment Conference1 were collected and reviewed. A smaller subset of experts formed a committee and reviewed the compiled diaries. Items deemed essential were included in a Core sleep diary, and those deemed optional were retained for an expanded diary. Secondly, optional items would be available in other versions. A draft of the Core and optional versions along with a feedback questionnaire were sent to members of the Pittsburgh Assessment Conference. The feedback from the group was integrated and the diary drafts were subjected to 6 focus groups composed of good sleepers, people with insomnia, and people with sleep apnea. The data were summarized into themes and changes to the drafts were made in response to the focus groups. The resultant draft was evaluated by another focus group and subjected to lexile analyses. The lexile analyses suggested that the Core diary instructions are at a sixth-grade reading level and the Core diary was written at a third-grade reading level. Conclusions: The Consensus Sleep Diary was the result of collaborations with insomnia experts and potential users. The adoption of a standard sleep diary for insomnia will facilitate comparisons across studies and advance the field. The proposed diary is intended as a living document which still needs to be tested, refined, and validate

BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells.

B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner