cssi/SciSciGPT-SciSciNet huggingface dataset:
Escherichia coliLipopolysaccharide Downregulates Soluble Guanylate Cyclase in Pulmonary Artery Smooth Muscle

The soluble isoform of guanylate cyclase (sGC) is activated by nitric oxide (NO) to form guanosine 3′:5′-cyclic monophosphate (cGMP). Cyclic GMP levels cause smooth muscle relaxation and regulate vascular tone to various vascular beds, including the lung. Under conditions of cytokine excess the inducible synthesis of NO may result in cGMP overproduction, generalized vasodilation, and septic shock. In the pulmonary bed the opposite response may occur, pulmonary hypertension. We hypothesized that sGC activity becomes downregulated in the face ofEscherichia colilipopolysaccharide (LPS). We tested the effects of LPS on α1-subunit sGC mRNA abundance, Western analysis, and enzyme activity in cultured rat pulmonary artery smooth muscle cells. LPS increased extracellular cGMP production by pulmonary artery smooth muscle cells, with increased levels being first detectable at 3–6 h (10 μg/ml LPS) and exceeding 140 pmol/ml by 24 h (P< 0.05). The response was inhibited by 0.05 mMl-NG-monomethyl-l-arginine (l-NMA) and, in turn, restored by 1 mMl-arginine, indicating a NO synthase-dependent response. Pretreating cells with LPS for ≥ 3 h inhibited subsequent cGMP synthesis in response to 10−4M SNAP for 60 min. Coincubating cells with 0.05 mMl-NMA also reversed this effect. Soluble GC enzyme activity in cells exposed to basal medium alone measured 0.74 pmol cGMP/ml per minute; activity in cells exposed to 10 μg/ml LPS for 24 h decreased to 0.04 pmol cGMP/ml per minute (P< 0.05). LPS pretreatment decreased sGC mRNA abundance and protein mass, but did not totally eliminate them. It is concluded that LPS affects cGMP synthesis at the level of enzyme activity, enzyme mass, and mRNA abundance. Over the short term (<24 h) LPS causes the synthesis of large amounts of cGMP. As the duration of exposure progresses (≥3 h), mechanisms come into play that decrease cGMP production significantly and include decreases in mRNA abundance, enzyme mass, and enzyme activity.
The global climatology of an interannually varying air–sea flux data set

The air–sea fluxes of momentum, heat, freshwater and their components have been computed globally from 1948 at frequencies ranging from 6-hourly to monthly. All fluxes are computed over the 23 years from 1984 to 2006, but radiation prior to 1984 and precipitation before 1979 are given only as climatological mean annual cycles. The input data are based on NCEP reanalysis only for the near surface vector wind, temperature, specific humidity and density, and on a variety of satellite based radiation, sea surface temperature, sea-ice concentration and precipitation products. Some of these data are adjusted to agree in the mean with a variety of more reliable satellite and in situ measurements, that themselves are either too short a duration, or too regional in coverage. The major adjustments are a general increase in wind speed, decrease in humidity and reduction in tropical solar radiation. The climatological global mean air–sea heat and freshwater fluxes (1984–2006) then become 2 W/m2 and −0.1 mg/m2 per second, respectively, down from 30 W/m2 and 3.4 mg/m2 per second for the unaltered data. However, decadal means vary from 7.3 W/m2 (1977–1986) to −0.3 W/m2 (1997–2006). The spatial distributions of climatological fluxes display all the expected features. A comparison of zonally averaged wind stress components across ocean sub-basins reveals large differences between available products due both to winds and to the stress calculation. Regional comparisons of the heat and freshwater fluxes reveal an alarming range among alternatives; typically 40 W/m2 and 10 mg/m2 per second, respectively. The implied ocean heat transports are within the uncertainty of estimates from ocean observations in both the Atlantic and Indo-Pacific basins. They show about 2.4 PW of tropical heating, of which 80% is transported to the north, mostly in the Atlantic. There is similar good agreement in freshwater transport at many latitudes in both basins, but neither in the South Atlantic, nor at 35°N.
Corporate plant location under uncertainty: Divergence between the interests of ownership and management

This paper expands current knowledge of location decision-making under uncertainty by analyzing instances where the corporate goal of profit maximization diverges from the managerial decision-maker's goal of maximizing personal profit. With illustrations based on alternative decision-making criteria, the paper demonstrates that a corporate manager acting in his own self interest may select a plant site that does not maximize corporate profits. The trend for US corporations to select suburban locations, despite the cost advantages of older urban areas, is illustrative of this divergence between the objectives of ownership and management.
Measures of Obesity Are Associated With Vascular Stiffness in Young and Older Adults

Obesity has reached epidemic levels and carries a risk for cardiovascular disease. Obesity's effects on the vascular systems of young adults and African Americans have not been well characterized. The aim of this study was to assess the association between measures of obesity and aortic stiffness in 186 young adults (20 to 40 years, 50% African American) and 177 older adults (41 to 70 years, 33% African American). Aortic stiffness was measured by aortic pulse-wave velocity. The median pulse-wave velocity value was 468 cm/s for young adults and 627 cm/s for older adults (P 30) had a mean pulse-wave velocity value 47 cm/s higher than did nonobese individuals (P<0.001). Obesity measures were among the strongest independent predictors of pulse-wave velocity overall and for both age groups. Results were consistent by race. In conclusion, excess body weight is associated with higher aortic stiffness in whites and African Americans as young as 20 to 30 years. The strength of the association, the early age at which it appears, and the prevalence of obesity among the young warn of substantially increased cardiovascular disease incidence as this cohort ages.
Digital Video and Digital TV

This paper presents an overview of the recently emerged development and current work into all digital High Definition Television systems based on the MPEG-2 compression scheme. It explores the advantages and disadvantages of Japan's MUSE, European DVB, and U.S. all digital HDTV systems, examines the global HDTV standardization process, and provides a comprehensive and technical survey of HDTV in Asia, Europe and the U.S. It also analyzes the consumer acceptance and market potential of all digital High Definition Television, and predicts the future merge of broadcast video and computers.
Ventricular Pacing With Premature Excitation for Treatment of Hypertensive-Cardiac Hypertrophy With Cavity-Obliteration

Background—Hypertensive left ventricular hypertrophy with supranormal systolic ejection and distal cavity obliteration (HHCO) can result in debilitating exertional fatigue and dyspnea. Dual-chamber pacing with ventricular preactivation generates discoordinate contraction, which can limit cavity obliteration and thereby increase potential ejection reserve. Accordingly, we hypothesized that pacing may improve exercise tolerance long-term in this syndrome. Methods and Results—Dual-chamber pacemakers were implanted in 9 patients with exertional dyspnea caused by HHCO. Intrinsic atrial rate was sensed, and ventricular preactivation was achieved by shortening the atrial-ventricular delay. Pacing was on or off for successive 3-month periods (randomized, double-blind, crossover design), followed by 6 additional pacing-on months. Metabolic exercise testing, quality-of-life assessment, and rest and dobutamine-stress echocardiographic/Doppler data were obtained. After 3 months of pacing-on, exercise duration rose fr...
Orthotopic liver transplantation (OLT) for fulminant hepatic failure (FHF) induced by a dietary supplement lipokinetix

Orthotopic liver transplantation (OLT) for fulminant hepatic failure (FHF) induced by a dietary supplement lipokinetix
The Fundamental Constraint on the evolution of culture

This paper argues that there is a general constraint on the evolution of culture. This constraint – what I am calling the Fundamental Constraint – must be satisfied in order for a cultural system to be adaptive. The Fundamental Constraint is this: for culture to be adaptive there must be a positive correlation between the fitness of cultural variants and their fitness impact on the organisms adopting those variants. Two ways of satisfying the Fundamental Constraint are introduced, structural solutions and evaluative solutions. Because of the limitations on these solutions, this constraint helps explain why there is not more culture in nature, why the culture that does exist has the form it has, and why complex, cumulative culture is restricted to the human species.
Recovery of vacuum switching gaps

Laser-induced fluorescence imaging was used to characterize the spatial distribution of post-discharge switch vapors. It is shown that in short-pulse switching gaps, even at relatively low current levels, energy coupling into the anode drives the vapor production. This is consistent with the fact that there is a strong turn-on transient in short-pulse gaps which does not die before the recovery phase begins. In 60 Hz applications, the turn-on transient might not be so severe, any turn-on transient that does exist is substantially decoupled from the recovery phase by a long intervening conduction period. In gaps carrying long and relatively low-amplitude current pulses, bulk heating of the electrodes can occur, thus ensuring that post discharge vapors are emitted more or less uniformly from the electrode surfaces. In these switches, recovery models based on vapor emission from a multitude of small particles might be appropriate. In short-pulse switching gaps, on the other hand, the high-power turn-on dominates other processes during the recovery phase. >
Radiofrequency Ablation for Stage I Non-Small Cell Lung Cancer: Management of Locoregional Recurrence

Background This study characterizes the management of locoregional recurrence (LRR) in patients with high-risk stage I non-small cell lung cancer (NSCLC) treated with lung radiofrequency ablation (RFA). Methods Consecutive patients with biopsy-proven stage I NSCLC underwent computed tomography-guided lung RFA from December 2003 to 2010. All patients were deemed medically inoperable or refused an operation. RFA was performed with curative intent. Results Fifty-five ablations were performed in 45 patients (age, 51 to 89 years) with stage I NSCLC. At a median follow-up of 32 months, LRR occurred in 21 (38%) within a mean of 12 ± 10 (range, 1–44) months from RFA. Recurrence was observed locally in the tumor bed in 18 (33%), in regional nodes in 4 (7%), and distant in 2 (4%). The mean maximal tumor diameter was 2.3 ± 1.3 (range, 0.7 to 4.5) cm. In tumors exceeding 3 cm, 10 (80%) were associated with LRR. Recurrent lesions were treated with repeat RFA (5), radiotherapy (8), chemoradiotherapy (5), and chemotherapy (2). Local control was achieved by repeat RFA in 2 of 5 (40%) or by radiotherapy in 8 lesions (100%), with 2 regional nodal failures (median follow-up, 40 ± 13 months). Overall survival among patients who did or did not experience LRR was similar (32% to 35%). Repeat RFA was not associated with any significant complications or procedure-related 30-day mortality. Conclusions Lung RFA is associated with increased rates of local failure in tumors exceeding 3 cm and in contact with larger segmental vessels. Patients with local failure can be promptly salvaged with SBRT or repeat RFA, without detriment to overall survival.
Effect of Sealing of the Shell and Holding Temperature on Hatchability of Hens’ Eggs

Abstract WHILE numerous studies have been made on the relation of temperature to changes in the hatchability of eggs, knowledge concerning the effects of sealing of eggshell on hatchability are noticeably lacking. This series of experiments was undertaken with the particular object in mind of determining the effect on hatchability of the sealing of eggshells and submerging eggs in distilled water previous to incubation. In addition, data were also secured on eggs held in air. Romanoff and Romanoff (1933) have presented a complete review of the work of other investigators who submerged eggs in water or sealed eggshells by the use of oil, varnish, or other substances and observed early embryo development. Retardation in development was observed as the area of the eggshell treated was increased. Fere (1893) reported that the injection of 1 c.c. of distilled water in an egg did not retard development up to 96 hours. Lippincott and . . .
Social suppression of cortisol in female marmoset monkeys: role of circulating ACTH levels and glucocorticoid negative feedback

Behaviorally subordinate female common marmoset monkeys (Callithrix jacchus) exhibit pronounced, chronic reductions of circulating cortisol levels. Cortisol suppression in these animals is mediated in part by adrenocortical hyporesponsiveness to adrenocorticotropic hormone (ACTH). In addition, we hypothesized that social subordination may activate a central, neurally mediated mechanism to further inhibit hypothalamo-pituitary-adrenal function. In this study, therefore, we evaluated basal plasma cortisol and ACTH concentrations, as well as cortisol and ACTH responses to dexamethasone (DEX), in dominant and subordinate females to initially characterize such a mechanism. Morning plasma cortisol and ACTH levels were determined before, and 1, 2, and 3 days following administration of DEX (0.5, 1.0, or 5.0 mg/kg, IM) or saline. Baseline cortisol concentrations prior to DEX treatment were significantly lower in subordinate females than in dominants, as previously reported. However, ACTH concentrations in the same blood samples did not differ between the two groups. Furthermore, dominant and subordinate females showed similar cortisol and ACTH responses to DEX. These results indicate that reduced circulating cortisol levels in subordinate females are not associated with either altered circulating ACTH concentrations or enhanced responsiveness to glucocorticoid negative feedback. However, the finding that basal ACTH levels are not elevated in subordinate females as compared to dominants, in spite of low circulating cortisol concentrations, suggests that ACTH secretion in subordinate females is restrained by a steroid-independent inhibitory mechanism operating at the level of the brain or pituitary.
Adaptive interference suppression for joint acquisition and demodulation of direct-sequence CDMA signals

It has shown that adaptive interference suppression methods for the demodulation of CDMA signals provide immunity to the near-far problem, and perform much better than the conventional matched filter receiver even with perfect power control. Demodulation must, however, be preceded by acquisition of the timing of the desired signal, and conventional methods for acquisition are interference-limited and vulnerable to the near-far problem to the same extent as conventional demodulation. We present two interference suppression schemes for the joint acquisition and demodulation of direct sequence CDMA signals. Roughly speaking, the idea is to run several adaptive demodulation algorithms serially or in parallel, each under a different hypothesis regarding the desired transmission's timing, and to choose the one that gives the best performance. Thus, our schemes have the unique feature that the output of the acquisition process is not merely the timing of the desired transmission, but a near-far resistant demodulator which implicitly takes into account the timing and amplitudes of all transmissions in order to achieve interference suppression. Our acquisition schemes are amenable to efficient decentralized or centralized implementations, and are near-far resistant by virtue of the near-far resistance of the demodulation schemes on which they are based.
Application of an innovative, autonomous, creative teaching modality through service-learning in a community-health nursing course

Nursing faculty continue to find themselves challenged to meet student needs by the increasing student enrollment numbers and increasing faculty workloads without simultaneously increasing resources. The responsibility to meet student needs rests on the nursing faculty. It is therefore increasingly important that nursing faculty implement teaching modalities to meet student and patient needs. This article demonstrates faculty’s use of service-learning as an effective, innovative teaching modality to meet increasing student, patient, and community needs without additional resources. The authors seek to differentiate between service learning and contracted clinical experiences in order to enable nurse educators to use service learning as a teaching modality. The authors describe the process of using service learning with nursing process in this course. Nursing assessment is built into the project as a “windshield survey”. A literature review was conducted seeking to understand other uses of service learning in education and validate the authors’ experiences. This three-credit hour lecture and one credit hour clinical course has yielded unique and interesting service learning projects that positively impact their communities. The students work with cohorts of all races, ethnicities and cultures throughout the lifespan. Service-learning opportunities assist in the availability and accessibility of health care to safety net facilities and vulnerable populations who may not otherwise receive health care screening or treatment. Faculty in nursing and other health disciplines will likely appreciate the innovation, creativity, and autonomy afforded this modality of outreach.
Hierarchical clustering and visualization of aggregate cyber data

Most commercial intrusion detections systems (IDS) can produce a very high volume of alerts, and are typically plagued by a high false positive rate. The approach described here uses Splunk to aggregate IDS alerts. The aggregated IDS alerts are retrieved from Splunk programmatically and are then clustered using text analysis and visualized using a sunburst diagram to provide an additional understanding of the data. The equivalent of what the cluster analysis and visualization provides would require numerous detailed queries using Splunk and considerable manual effort.
Reverse-alignment surgical skills assessment.

Background During the course of certain laparoscopic procedures, a surgeon may encounter circumstances where the camera and working instruments are not aligned along the same axis. When the alignment is off by 180°, the laparoscope is pointed directly at the surgeon and a mirror image of the operative field is created. Under reverse alignment conditions, surgeons often become disoriented and task performance may be degraded. The aim of this study is to measure the degree to which reverse alignment conditions impair the performance of operators of varying laparoscopic surgical skill and experience.
Short-term lifestyle modification alters circulating biomarkers of endothelial health in sedentary, overweight adults

Obesity and inactivity are associated with endothelial dysfunction that may contribute to the development of atherosclerosis. We examined the effects of a short-term lifestyle intervention on circu...
Rate‐Controlled Technique for Calcining and Drying

To control ceramic drying and calcining operations, an approach that ensures uniform gas evolution was developed to prevent cracking on sudden release of gas. Instead of increasing temperature according to a present schedule, the output signal from a thermogravimetric analysis apparatus is used as input to a computer system which varies temperature as required to cause mass loss to follow a preselected schedule. Materials that cracked when processed conventionally were prepared crack-free by this procedure. 14 references, 2 figures.
MP3 resistant oblivious steganography

Robustness to compression is a basic requirement for any data hiding scheme. We concentrate on MP3 resistant oblivious data hiding. First the MP3 compression algorithm is briefly introduced. We then propose three effective data hiding schemes, where the message is embedded in amplitude, DFT phase domain, and noisy components, respectively. All these schemes demonstrate robustness to MP3 compression.
ON CONDITIONS FOR MIXTURES OF INCREASING FAILURE RATE DISTRIBUTIONS TO HAVE AN INCREASING FAILURE RATE

Consider a family of distributions with survival distributions that are log concave and stochastically increasing in a parameter over which it will be mixed. It is shown that a necessary and sufficient condition for a mixture over any such family to have an increasing failure rate is that the mixing distribution have an increasing failure rate. Some observations are given on generalizing this result as well as weakening the conditions on Prekopa's Theorem.
Relating peptide presentation and biological response through supported films of peptide amphiphiles

The focus of this project is to understand how the secondary structure of a peptide ligand influences cell behavior. Accordingly, model surfaces upon which the surface density, organization, and presentation of the peptide can be controlled are required. To accomplish this, we synthesized a series of peptide amphiphiles (Fig. 1) that have hydrocarbon tails and head groups that contain RGD (Arg-Gly-Asp) or GRGDSP (Gly-Arg-Gly-Asp-SerPro) peptides [1]. The versatility of this protocol allows several variations of these adhesive peptide amphiphiles to be synthesized. The peptide may be linear or cyclic and may be attached to the hydrocarbon tails at either the N-terminus or both Nand C-termini. These peptide amphiphiles are synthesized in order to produce thin films for surface modifications. The peptide amphiphiles are ordered at the air-water interface, and their assembly analyzed with Langmuir isotherms and, when applicable, by Fourier transform infrared spectroscopy (FTIR). Using the Langmuir-Blodgett technique, a condensed monolayer of the RGD amphiphiles is deposited onto a hydrophobic substrate using a downstroke. The Langmuir-Blodgett technique has been selected because the resultant film presents the peptide uniformly at the interface. We control the surface density of the peptide and manipulate the spatial organization of the monolayer by mixing the peptide amphiphile with an inert background amphiphile. The bioactive film is then used as the substrate for short term (1 h) adhesion assays involving human umbilical vein endothelial cells (HUVECs) or M14#5 human melanoma cells. The adhesive activity of the peptide amphiphiles is evaluated by measuring the size and shape of the cells after they have been fixed and stained.
Advancements and Application of Microsecond Synchrotron X-ray Footprinting at the Advanced Light Source

The method of synchrotron X-ray protein footprinting (XF-MS) is used to determine protein conformational changes, folding, protein-protein and protein-ligand interactions, providing information which is often difficult to obtain using X-ray crystallography and other common structural biology methods [1–3]. The technique uses comparative in situ labeling of solvent-accessible side chains by highly reactive hydroxyl radicals (•OH) in buffered aqueous solution under different assay conditions. In regions where a protein is folded or binds a partner, these •OH susceptible sites are inaccessible to solvent, and therefore protected from labeling. The •OH are generated by the ionization of water using high-flux-density X-rays. High-flux density is a key factor for XF-MS labeling because obtaining an adequate steady-state concentration of hydroxyl radical within a short irradiation time is necessary to minimize radiation-induced secondary damage and also to overcome various scavenging reactions that reduce the yi...
S -allele sequence diversity in natural populations of Solanum carolinense (Horsenettle)

S-allele diversity in Solanum carolinense was surveyed in two natural populations, located in Tennessee and North Carolina, with a molecular assay to determine the genotype of individual plants. A total of 13 different S-alleles were identified and sequenced. There is high overlap between the two populations sampled, with 10 alleles shared in common, one allele found only in Tennessee, and two found only in North Carolina. The number of alleles in this species appears to be extremely low compared with other species with gametophytic self-incompatibility. Sequence comparisons show that most alleles are extremely different one from another in their primary sequence and a phylogenetic analysis indicates extensive trans-specific evolution of S-lineages. In addition, some alleles appear to be derived much more recently. The implications of these observations are discussed in the light of recent theoretical results on S-allele population diversity and persistence.
Fate of Escherichia coli O157:H7 and Salmonella on whole strawberries and blueberries of two maturities under different storage conditions.

Strawberries and blueberries harvested at or near full-ripe maturity tend to be less firm and more susceptible to bruising during harvest and transport. The objective of this research was to determine the fate of Escherichia coli O157:H7 and Salmonella on bruised and intact surfaces of whole strawberries and blueberries at shipping (2°C) and retail display (15.5°C) temperatures. Strawberries and blueberries were either purchased from a supermarket or were harvested immediately prior to use; they were bruised using established protocols, were spot inoculated, and were incubated at 2 and 15.5°C. Strawberries, subjected to modified atmospheres, were further transferred to bags and were sealed in with an initial atmosphere of ca. 10% CO2 and 5% O2. Strawberries were sampled at 0, 2, 5, and 24 h and on days 3 and 7; blueberries were sampled on days 0, 1, 3, and 7. After stomaching, samples were enumerated on nonselective and selective media, and populations were recorded as log CFU per berry. At both storage t...
Abundance and distribution of Marbled and Kittlitz's Murrelets in Southcentral and Southeast Alaska

We used small boats to survey Marbled, Brachyramphus marmoratus, and Kittlitz's Murrelets, B. brevirostris (Brachyramphus murrelets) in Lower Cook Inlet, Prince William Sound, and Southeast Alaska. We estimated (± 95% CI) that there were 58,227 ± 16,058 (4.2 birds km -2 ) murrelets in Lower Cook Inlet in summer and 11,627 ± 7,410 (3.1 birds km -2 ) murrelets in the eastern half during winter. We estimated a mean of 113,652 ± 25,900 (12.7 birds km -2 ) murrelets in Prince William Sound in four summers and a mean of 24,979 ± 11,710 (2.8 birds km -2 ) murrelets in four winters. An estimated 687,061 ± 201,162 (19.4 birds km -2 ) murrelets were in Southeast Alaska in summer 1994. The summer population of all three areas was estimated to be between 655,482 and 1,062,398 murrelets. Winter abundance for the eastern portion of Lower Cook Inlet and Prince William Sound ranged from 22,646 to 50,164. Brachyramphus murrelets were distributed in low densities throughout each of the three study areas, although abundance was not uniform; there were areas of high densities within each study area. The largest densities were found in Southeast Alaska.
Vaccination Status of Immunization Program in Chengdu,2009-2012

Objective To know the vaccination status after the implement of national expanded immunization program in Chengdu during 2009- 2012 and thus to evaluate the quality of immunization. Methods Multistage cluster random sampling was conducted yearly from 2009 to 2012,and the data were statistically analyzed. Results Totally 16,490 children were investigated. The rates of immunization card and certificates established were respectively 99. 97% and 99. 85%; the compatible card-certificate rate was 97. 49%; the rate of BCG scar was 90. 21%. The qualified coverage for the primary doses of 5 vaccines( BCG,OPV,DPT,MV, HepB) all reached over 95%; the qualified coverage of 4 vaccines was 96. 61%; the timely coverage for first-dose of HepB was 98. 50%; the qualified coverage of MenA1,MenA2,JEV,HepA were respectively 97. 61%,92. 56%,94. 00% and 93. 13%. The qualified coverage for the booster of OPV,DPT,MV / MM / MMR,DT,JEV,MenA + C1,MenA+C2were respectively 97. 29%,97. 15%,96. 80%,95. 17%, 93. 70%,94. 18% and 91. 19%. The reason of non-qualified immunization was mainly attributed to overdue vaccination( 79. 41%) and the proportion increased from 67. 86% in 2009 to 89. 13% in 2012. The reasons of non-immunization were mainly attributed to the other( 35. 97%) and children getting sick( 24. 61%). Conclusion The qualified coverage rates of 5 vaccines and the timely coverage for first-dose of HepB stays at a high level; the proportion of overdue vaccination in the reasons of non-qualified immunization are rising year by year.
Application of Extended FCM Algorithm in Contextual Ads Keywords Extraction

With the high-speed development of Internet,contextual Ads of IM software is attracted more and more researchers.Chat text is different from article text,which only used TFIDF algorithm to extract keywords is not performs well.In this paper,a EFCM based clustering algorithm is introduced to improve the performance of TFIDF in chat text.
Abstract B52: Overcoming phenotypic heterogeneity and plasticity in basal-like breast cancer through targeting adaptive pathway use

The use of small-molecule kinase inhibitors is a promising therapeutic strategy for the management of breast cancer. Positive responses to these agents, however, are often transient, and acquired resistance arises in the course of weeks to months. Recent studies have demonstrated that phenotypic plasticity in cancer cell populations can provide adaptive resistance to small-molecule kinase inhibitors, whereby cancer cells transition to drug-tolerant phenotypic states, reliant on compensatory survival and proliferative signaling pathways. Drug combinations and sequences can prevent this adaptive resistance to targeted therapy, however, nominating effective drug pairs is challenging. In this study, we seek to identify such drug combinations through first identifying single agent therapeutics that reduce phenotypic heterogeneity and enrich distinct cell-states with common pathway reliance. To do so, we focus on phenotypic heterogeneity in tumor-cell lineage-state; using immunofluorescent staining against markers of the luminal, basal, and mesenchymal lineages, we combine high-throughput drug screening with high-content imaging and pursue small-molecule inhibitors that reduce phenotypic heterogeneity and promote the accumulation of particular lineage-states in residual cell populations. We observe pronounced lineage-state heterogeneity in Triple-Negative tumors and Basal-Like breast cancer cell lines, and find that the lineage-state distributions are greatly influenced by numerous therapeutics. MEK and PI3K/mTOR inhibitors in particular induce robust time- and dose-dependent alterations is lineage-state distribution in residual cell populations, selecting for a cell population enriched in, or depleted of a basal lineage-state, respectively. Through gene expression profiling and master-regulator analysis of active transcriptional states in the residual cell populations, we are able to identify compensatory-signaling pathways. We demonstrate that combining MEK and PI3K/mTOR inhibitors with agents targeting these compensatory pathways induces synergistic antiproliferative effects. Citation Format: Tyler Risom, Ellen Langer, Juha Rantala, Mariano Alvarez, Katie Johnson-Camacho, Carl Pelz, Nicholas Wang, Paul Spellman, Andrea Califano, Joe Gray, Rosalie Sears. Overcoming phenotypic heterogeneity and plasticity in basal-like breast cancer through targeting adaptive pathway use. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B52.
Indoor Air Pollution/Developing Countries

Almost three billion people worldwide use biomass and coal as their primary source of energy for cooking, heating, and other household needs. Combustion of biomass and coal emits hundreds of health-damaging pollutants, at concentrations several fold higher than common health guidelines, especially when used in open or poorly enclosed and ventilated stoves. An estimated 1.8 million annual deaths and 3% of the total global burden of disease are due to exposure to indoor air pollution from solid fuels, mainly among young children and adult women. There is a need for ambitious R&D on alternative technologies for clean and accessible energy, and on economic and regulatory institutions required for large-scale dissemination of these technologies.
An Exploration of Supervisory and Therapeutic Relationships and Client Outcomes

The authors explored the connection between the facilitative conditions present within the supervisory relationship, the therapeutic relationship, and client outcomes. A correlational research design was used with a sample of 55 counselors-in-training and 88 clients. Results indicated a significant positive relationship between the therapeutic relationship and client outcomes and a significant negative relationship between the supervisory relationship and client outcomes.
Validation of PROMIS emotional distress short form scales for cervical cancer trials.

6633 Background: PROMIS is an NIH-sponsored effort to standardize the measurement of common symptoms and functional concerns of people with chronic conditions. The purpose of this study is to valid...
Die bedeutsamsten Gefahrenfaktoren in der Lebensversicherung, insbesondere der plötzliche Herztod (Kranzadertod)

Wenn man die Sterblichkeitstafeln der deutschen Bevolkerung aus den letzten 50 Jahren durchmustert, so findet man an der Spitze aller Todesursachen immer wieder drei grose Gruppen: Die Infektionskrankheiten mit der Tuberkulose, den Krebs und die Herz- und Kreislaufkrankheiten. Naturgemas wirken sich diese Gruppen auch in der Lebensversicherung als die erheblichsten Gefahrenfaktoren aus. Jahrzehntelang stand die gefurchtete Tuberkulose an erster Stelle, auch heute noch macht sie die Halfte aller Infektionen aus; aber ein Blick auf diese Kurve zeigt Ihnen den starken Ruckgang im Laufe von 40 Jahren, ein sichtbares Zeichen der groszugigen staatlichen Die bedeutsamsten Gefahrenfaktoren in der Lebensversicherung. 107 Tuberkulosebekampfung. Der gewaltige Kampf der medizinischen Wissenschaft gegen die Infektionskrankheiten spiegelt sich am deutlichsten darin wieder, das innerhalb dieser funf Jahrzehnte die mittlere Lebenserwartung um rund 22 Jahre angestiegen ist. Mit dieser Erhohung der mittleren Lebensdauer steigt aber gleichzeitig die Zahl der hoheren Altersklassen, und damit nehmen naturgemas auch die Sterbefalle an den dem hoheren Lebensalter eigentumlichen Krankheiten zu. Von der sogenannten „Altersschwache“ sehe ich ab; sie ist ein sehr dehnbarer Begriff, hinter dem sich meist eine andere Todesursache verbirgt und die als reine „Verlegenheitsdiagnose“ aufzufassen ist. Einen hohen Prozentsatz unserer Gefahrenfaktoren nimmt aber dann der Krebs ein. Im Gegensatz zur Tuberkulose zeigen die Krebssterbefalle eine dauernde Zunahme. Wenn noch 1892 auf 10 000 Lebende 6,1, 1910 8,8 Todesfalle kamen, so waren es 1920 schon 9,6 und 1931 bereits 13,7. Und auch von da ab haben wir, wie Sie aus der folgenden Kurve ersehen, eine langsam steigende Tendenz bis auf 15 im Jahre 1935.
Dasatinib blocks the growth, migration, and invasion of breast cancer cells through inhibition of Src family kinases

5415 Src family tyrosine kinases (SFK) control essential properties of cancerous cells, such as cell cycle progression, survival, and metastasis. Specific, small molecule inhibitors of SFK are currently in pre-clinical and clinical trials. The FDA has recently approved dasatinib (BMS-354825), an orally available, dual Src/Abl inhibitor, for imatinib-resistant, BCR-ABL+ leukemia. Because dasatinib also has activity against receptor tyrosine kinases such as Platelet-Derived Growth Factor Receptor (PDGFR), c-kit, and the Ephrin receptors, its multi-kinase effects suggest a therapeutic role for solid tumors. We determined the efficacy and mechanism of dasatinib in inhibiting the proliferation and migration/invasion of a panel of breast cancer cell lines chosen for their contrasting migratory and invasive capabilities as well as expression of endogenous Src family members. We studied three breast cancer cell lines: MDA-MB-231 (strongly invasive), and MCF-7 and T-47D (both weakly invasive). Dasatinib inhibits the growth of MDA-MB-231, MCF-7, and T-47D cells with calculated GI50 values of 0.7 uM, 1.6 uM, and 0.9 uM, respectively. Dasatinib caused cell cycle arrest in the G1 phase, but it does not induce apoptosis or cell death, as determined by viability assays and flow cytometry with annexin V and propidium iodide staining. Most strikingly, dasatinib treatment blocked cytoskeletal rearrangement. MDA-MB-231 cells, the most invasive line in our panel, undergo a dramatic contraction of the actin and tubulin cytoskeleton upon treatment with 0.1 uM dasatinib. Treated cells showed a dose-responsive loss of the well-organized dendritic processes that are normally present in untreated cells. These cells became much more round, suggesting a loss of adhesion points, but did not fully detach from the culture surface. With 0.1uM of dasatinib treatment, there was a 90% inhibition of MDA-MB-231 invasiveness through a Matrigel matrix when compared to a DMSO control (p=0.007). Migration of MDA-MB-231 cells in wound healing assays was also greatly reduced (74% below DMSO control). In support of our in vitro data, our studies of mouse xenograft models of MCF-7 cell growth demonstrate that dasatinib treatment reduces the establishment and growth of solid tumors. Since most patients die from metastatic disease, our data provide rationale for therapeutic targeting of Src by dasatinib in women with advanced breast cancer.
Absorptive Dissolution Testing of Supersaturating Systems: Impact of Absorptive Sink Conditions on Solution Phase Behavior and Mass Transport.

One of the most commonly used formulation development tools is dissolution testing. However, for solubility enhancing formulations, a simple closed compartment conventional dissolution apparatus operating under sink conditions often fails to predict oral bioavailability and differentiate between formulations. Hence, increasing attention is being paid to combined dissolution–absorption testing. The currently available mass transport apparatuses, however, have certain limitations, the most important being the small membrane surface area, which results in slow mass transfer. In this study, a novel high surface area, flow-through absorptive dissolution testing apparatus was developed and tested on a weakly basic model drug, nevirapine. Following optimization of the experimental parameters, the mass transfer attained for a nevirapine solution was 30 times higher in 60 min as compared to a side-by-side diffusion cell. To further evaluate the system, nevirapine powder and commercial tablets were first dissolved ...
Natural Indices for the Chemical Hardness/Softness of Metal Cations and Ligands

Quantitative understanding of reactivity and stability for a chemical species is fundamental to chemistry. The concept has undergone many changes and additions throughout the history of chemistry, stemming from the ideas such as Lewis acids and bases. For a given complexing ligand (Lewis base) and a group of isovalent metal cations (Lewis acids), the stability constants of metal–ligand (ML) complexes can simply correlate to the known properties of metal ions [ionic radii (rMn+), Gibbs free energy of formation (ΔG°f,Mn+), and solvation energy (ΔG°s,Mn+)] by 2.303RT log KML = (α*MLΔG°f,Mn+ – β*MLrMn+ + γ*MLΔG°s,Mn+ – δ*ML), where the coefficients (α*ML, β*ML, γ*ML, and intercept δ*ML) are determined by fitting the equation to the existing experimental data. Coefficients β*ML and γ*ML have the same sign and are in a linear relationship through the origin. Gibbs free energies of formation of cations (ΔG°f,Mn+) are found to be natural indices for the softness or hardness of metal cations, with positive values ...
Examination of the effect of blowing on the near-surface flow structure over a dimpled surface

The near surface flow over a dimpled surface with flow injection through it was documented using time-resolved particle image velocimetry. The instantaneous flow structure, time-averaged statistics, and results from snapshot proper orthogonal decomposition were used to examine the coherent structures forming near the dimpled surface. In particular, the modifications made to the flow structures by the addition of flow injection through the surface were studied. It was observed that without flow injection, inclined flow structures with alternating vorticity from neighboring dimples are generated by the dimples and advect downstream. This behavior is coupled with fluid becoming entrained inside the dimples, recirculating and ejecting away from the surface. When flow injection was introduced through the surface, the flow structures became more disorganized, but some of the features of the semi-periodic structures observed without flow injection were preserved. The structures with flow injection appear in multiple wall-normal layers, formed from vortical structures shed from upstream dimples, with a corresponding increase in the size of the advecting structures. As a result of the more complex flow field observed with flow injection, there was an increase in turbulent kinetic energy and Reynolds shear stress, with the Reynolds shear stress representing an increase in vertical transport of momentum by sweeping and ejecting motions that were not present without flow injection.
Vitamin D in Pregnancy and Lactation: Moving Into the Future

Abstract Pregnancy and lactation both represent a time of rapid bodily change, which include physical proportions, physiology, and responsibility. Arguably, nothing during these times changes more than the requirement and metabolism of vitamin D, although from current Institute of Medicine (IOM) recommendations, one would never surmise this fact. Do the current recommendations for the requirements of vitamin D during these critical time periods reflect emerging data? Sadly, no. The minimal recommendations by the IOM and the zero recommendation by the World Health Organization, which was echoed by a recent Cochrane Review, stating that there are simply no requirement for vitamin D during pregnancy, are contrary to expanding published data (later reviewed in this chapter) that suggest otherwise. Why these recommendations continue to be made remains unclear, but clearly not recognizing a problem exists suggests that one does not need to address the “problem.”
Nesting Biologies and Mature Larvae of Oxaeine Bees (Apoidea: Andrenidae)

ABSTRACT This study encompasses a number of field encounters by the author and others with nests of representatives of three of the four genera of the little-known New World andrenid subfamily Oxaeinae. Species treated include Protoxaea gloriosa Fox, Oxaea flavescens Klug, O. austera Gerstaecker, and Mesoxaea nigerrima (Friese), leaving the nesting biology of only the monotypic genus Notoxaea completely unknown. Nests, all subterranean, are described and diagrammed, and each is reported to consist of a moderately to very deep main burrow with vertical cells occurring at the lower end attached to the main burrow by subhorizontal lateral tunnels, each of which is closed immediately after egg deposition. To the extent known, eggs, mature larvae, and pupae are described. Two known cleptoparasites of the subfamily are reported: Triepeolus kathrynae Rozen, hosted by P. gloriosa, and Thalestria spinosa (Fabricius) (= T. smaragdina Smith), which attacks nests of both O. flavescens and O. austera. The mature larva...
Measurement of Vibrational and Rotational-Translational Temperatures Independently from Pure Rotational Raman Spectra

We show here that rotational Raman lines in vibrationally-excited gases consist of distinct components that arise from molecules in different vibrational states. These components create a line structure that can be observed and used to determine vibrational temperature.
Effect of Chemical Cleaning Agents and Commercial Sanitizers on ATP Bioluminescence Measurements

Nine chemical cleaning agents at three concentrations were studied to determine the effect on ATP bioluminescence measurements from pure ATP (PATP) and ATP from chicken exudate (CJATP). The nine commercial cleaning and sanitizing chemicals were concentrated foaming acid (FA), acid sanitizer (AS), iodine cleaner-disinfectant (ZI), alkaline cleaner-degreaser (PC), chlorinated alkaline cleaner (CA), chlorinated sanitizer (CS), quaternary ammonium (QA), antibiofilm agent (AB), and acidic peroxygen sanitizer (HP). Effect was reported as a percent change from the log10 relative light unit (LRLU) measurements of the control groups. All cleaners and sanitizers were tested at one-tenth of the manufacturer's recommended level (MRL), MRL, and two times MRL. FA, PC, and CA at all three concentrations significantly decreased PATP and CJATP LRLU. AS decreased PATP and CJATP LRLU at 200 and 400 ppm quaternary ammonium. ZI decreased PATP LRLU at MRL or greater, while CJATP LRLU were decreased by all concentrations of ZI tested. CS decreased PATP LRLU in a dose-dependent manner; however, for CJATP, LRLU decreased slightly at the two lower concentrations but were not affected by 1,200 ppm CS. QA at MRL or above for PATP or at all concentrations for CJATP significantly increased LRLU. AB decreased LRLU at all concentrations tested for PATP or at MRL or greater for CJATP. HPA at MRL or greater for PATP or at all concentrations for CJATP significantly reduced LRLU. These results demonstrate that commercial sanitizers and cleansers may squelch or increase LRLU measurements when the chemical comes into direct contact with the ATP bioluminescence reagents. Hence, when using ATP bioluminescence as a means of determining sanitary quality of food-processing equipment, it is essential to consider the type and concentration of chemical cleaner or sanitizer being used on the equipment prior to testing.
Estimating Phenytoin Concentrations by the Sheiner-Tozer Method in Adults with Pronounced Hypoalbuminemia

Objective:To assess the performance of the Sheiner-Tozer equation when used to evaluate total phenytoin concentrations in patients with pronounced hypoalbuminemia.Design:Patients with phenytoin concentrations drawn at least 5 days after initiation of therapy and with serum albumin concentrations of less than 25 g/L were identified during routine daily monitoring. Phenytoin samples were frozen at −30 °C, batched, and later thawed for total and free phenytoin assay. Separation of free phenytoin concentration was performed at 37 °C using a Centrifree micropartition filter.Setting:A 400-bed university teaching hospital.Patients:Twenty-nine adults with hypoalbuminemia receiving phenytoin therapy. Patients receiving drugs known to displace phenytoin, or those with renal failure, abnormal liver enzymes, or increased bilirubin concentrations were excluded.Main Outcome Measure:Precision and bias of the normalized result using the Sheiner-Tozer equation were assessed with respect to observed phenytoin concentration...