bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stimulation of Natural Killer Cell–Mediated Tumor Immunity by an IL15/TGFβ–Neutralizing Fusion Protein
Authors: Ng Spencer , Deng Jiusheng , Chinnadurai Raghavan , Yuan Shala , Pennati Andrea , Galipeau Jacques 
Published: August 2016

AbstractThe clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGFβ. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T-cell–stimulatory cytokine IL15, the sushi domain of IL15Rα and a TGFβ ligand trap, can overcome immunosuppressive TGFβ to effectively stimulate the proliferation and activation of natural killer (NK) and CD8+ T cells with potent antitumor properties. FIST15-treated NK and CD8+ T cells produced more IFNγ and TNFα compared with treatment with IL15 and a commercially available TGFβ receptor-Fc fusion protein (sTβRII) in the presence of TGFβ. Murine B16 melanoma cells, which overproduce TGFβ, were lysed by FIST15-treated NK cells in vitro at doses approximately 10-fold lower than NK cells treated with IL15 and sTβRII. Melanoma cells transduced to express FIST15 failed to establish tumors in vivo in immunocompetent murine hosts and could only form tumors in beige mice lacking NK cells. Mice injected with the same cells were also protected from subsequent challenge by unmodified B16 melanoma cells. Finally, mice with pre-established B16 melanoma tumors responded to FIST15 treatment more strongly compared with tumors treated with control cytokines. Taken together, our results offer a preclinical proof of concept for the use of FIST15 as a new class of biological therapeutics that can coordinately neutralize the effects of immunosuppressive TGFβ in the tumor microenvironment while empowering tumor immunity. Cancer Res; 76(19); 5683–95. ©2016 AACR.
Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate
Authors: Limani Perparim , Linecker Michael , Kachaylo Ekaterina , Tschuor Christoph , Kron Philipp , Schlegel Andrea , Ungethuem Udo , Jang Jae Hwi , Georgiopoulou Stavroula , Nicolau Claude , Lehn Jean-Marie , Graf Rolf , Humar Bostjan , Clavien Pierre-Alain 
Published: August 2016

Abstract
Purpose: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.
Experimental Design: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential.
Results: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by &lt;30%, whereas ITPP combined with FOLFOX extended survival by &gt;140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure.
Conclusions: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887–97. ©2016 AACR.
Dialect Interference in Lexical Processing: Effects of Familiarity and Social Stereotypes
Authors: Clopper Cynthia 
Published: August 2016

Abstract
Background/Aims: The current study explored the roles of dialect familiarityand social stereotypes in dialect interference effects in a speeded lexical classification task. Methods: Listeners classified the words bad and bed or had and head produced by local Midland and non-local Northern talkers and the words sod and side or rod and ride produced by non-local, non-stereotyped Northern and nonlocal, stereotyped Southern talkers in single- and mixed-talker blocks. Results: Lexical classification was better for the local dialect than for the non-local dialects, and for the stereotyped non-local dialect than for the non-stereotyped non-local dialect. Dialect interference effects were observed for all three dialects, although the patterns of interference differed. For the local dialect, dialect interference was observed for response times, whereas for the non-local dialects, dialect interference was observed primarily for accuracy. Conclusion: These findings reveal complex interactions between indexical and lexical information in speech processing.
Normalization of NAD
+
Redox Balance as a Therapy for Heart Failure
Authors: Lee Chi Fung , Chavez Juan D. , Garcia-Menendez Lorena , Choi Yongseon , Roe Nathan D. , Chiao Ying Ann , Edgar John S. , Goo Young Ah , Goodlett David R. , Bruce James E. , Tian Rong 
Published: August 2016

Background:
Impairments of mitochondrial function in the heart are linked intricately to the development of heart failure, but there is no therapy for mitochondrial dysfunction.

Methods:

We assessed the reduced/oxidized ratio of nicotinamide adenine dinucleotide (NADH/NAD
+
ratio) and protein acetylation in the failing heart. Proteome and acetylome analyses were followed by docking calculation, mutagenesis, and mitochondrial calcium uptake assays to determine the functional role of specific acetylation sites. The therapeutic effects of normalizing mitochondrial protein acetylation by expanding the NAD
+
pool also were tested.

Results:

Increased NADH/NAD
+
and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, also are present in human failing hearts as well as in mouse hearts with pathologic hypertrophy. Elevation of NAD
+
levels by stimulating the NAD
+
salvage pathway suppressed mitochondrial protein hyperacetylation and cardiac hypertrophy, and improved cardiac function in responses to stresses. Acetylome analysis identified a subpopulation of mitochondrial proteins that was sensitive to changes in the NADH/NAD
+
ratio. Hyperacetylation of mitochondrial malate-aspartate shuttle proteins impaired the transport and oxidation of cytosolic NADH in the mitochondria, resulting in altered cytosolic redox state and energy deficiency. Furthermore, acetylation of oligomycin-sensitive conferring protein at lysine-70 in adenosine triphosphate synthase complex promoted its interaction with cyclophilin D, and sensitized the opening of mitochondrial permeability transition pore. Both could be alleviated by normalizing the NAD
+
redox balance either genetically or pharmacologically.

Conclusions:

We show that mitochondrial protein hyperacetylation due to NAD
+
redox imbalance contributes to the pathologic remodeling of the heart via 2 distinct mechanisms. Our preclinical data demonstrate a clear benefit of normalizing NADH/NAD
+
imbalance in the failing hearts. These findings have a high translational potential as the pharmacologic strategy of increasing NAD
+
precursors are feasible in humans.
Understanding Orographic Effects on Surface Observations at Macquarie Island
Authors: Wang Zhan , Belusic Danijel , Huang Yi , Siems Steven T. , Manton Michael J. 
Published: August 2016

AbstractThe meteorological observations on Macquarie Island have become of increasing value for efforts to understand the unique nature of atmospheric processes over the Southern Ocean. While the island is of modest elevation (peak altitude of 410 m), the orographic effects on observations on this island are still not clear. High-resolution numerical simulations [Weather Research and Forecasting (WRF) Model] with and without terrain have been used to identify orographic effects for four cases representing common synoptic patterns at Macquarie Island: a cold front, a warm front, postfrontal drizzle, and a midlatitude cyclone. Although the simulations cannot capture every possible feature of the precipitation, preliminary results show that clouds and precipitation can readily be perturbed by the island with the main enhancement of precipitation normally in the lee in accordance with the nondimensional mountain height being much less than 1. The weather station is located at the far north end of the island and is only in the lee to southerly and southwesterly winds, which are normally associated with drizzle. The station is on the upwind side for strong northwesterly winds, which are most common and can bring heavier frontal precipitation. Overall the orographic effect on the precipitation record is not found to be significant, except for the enhancement of drizzle found in southwesterly winds. Given the strong winds over the Southern Ocean and the shallow height of the island, the 3D nondimensional mountain height is smaller than 1 in 93.5% of the soundings. As a result, boundary layer flow commonly passes over the island, with the greatest impact in the lee.
Trends and Variability in Droughts in the Pacific Islands and Northeast Australia
Authors: McGree Simon , Schreider Sergei , Kuleshov Yuriy 
Published: August 2016

AbstractDrought is a recurrent climate feature of the Pacific Islands and northeast Australia with meteorological and socioeconomic impacts documented from early European settlement. In this study, precipitation records for 21 countries and territories in the Pacific for the period 1951 to 2010 have been examined to identify trends in drought occurrence, duration, and magnitude. The strength of the relationships between the main climate drivers in the Pacific—El Niño–Southern Oscillation (ENSO), the interdecadal Pacific oscillation (IPO), and the Pacific decadal oscillation (PDO)—and precipitation has been also examined. Station-scale drought trends are largely positive, but the majority are statistically nonsignificant with the significant trends mainly in the subtropics. Spatially, trend patterns are largely heterogeneous. A significant relationship between the oceanic component of ENSO and precipitation is confirmed for a large part of the Pacific Islands and eastern Australia with a strong lagged relationship in the year after the El Niño onset at locations southwest of the South Pacific convergence zone (SPCZ) and north of the intertropical convergence zone (ITCZ). Similarly, a strong relationship was found with the IPO and PDO at most locations. Drought was found to be longer and more severe southwest of the SPCZ and north of the ITCZ during the positive phases of the IPO and PDO.
Tracing Airline Travelers for a Public Health Investigation
Authors: Regan Joanna J. , Jungerman M. Robynne , Lippold Susan A. , Washburn Faith , Roland Efrosini , Objio Tina , Schembri Christopher , Gulati Reena , Edelson Paul J. , Alvarado-Ramy Francisco , Pesik Nicki , Cohen Nicole J. 
Published: August 2016

Objective. CDC routinely conducts contact investigations involving travelers on commercial conveyances, such as aircrafts, cargo vessels, and cruise ships. Methods. The agency used established systems of communication and partnerships with other federal agencies to quickly provide accurate traveler contact information to states and jurisdictions to alert contacts of potential exposure to two travelers with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) who had entered the United States on commercial flights in April and May 2014. Results. Applying the same process used to trace and notify travelers during routine investigations, such as those for tuberculosis or measles, CDC was able to notify most travelers of their potential exposure to MERS-CoV during the first few days of each investigation. Conclusion. To prevent the introduction and spread of newly emerging infectious diseases, travelers need to be located and contacted quickly.
Continuum of Care Among People Living with Perinatally Acquired HIV Infection in New York City, 2014
Authors: Xia Qiang , Shah Dipal , Gill Balwant , Torian Lucia V. , Braunstein Sarah L. 
Published: August 2016

Objective. The HIV care continuum outlines the steps from HIV infection to diagnosis, linkage to care, and viral suppression among people living with HIV. We examined data for steps along the HIV care continuum among people living with perinatally acquired infection in New York City using surveillance data. Methods. This study included data for people who acquired HIV infection perinatally and lived in New York City as of December 31, 2014. We defined “in care” as having ≥1 CD4 or viral load test in 2014, “in continuous care” as having ≥2 CD4 or viral load tests ≥3 months apart in 2014, and “virally suppressed” as having a viral load of ≤200 copies per milliliter in the most recent test in 2014. We estimated factors associated with viral suppression from a weighted log-binomial regression model that included sex, race/ethnicity, age, and country of birth as independent variables. Results. As of December 31, 2014, an estimated 1,596 people were living with perinatally acquired HIV infection in New York City. All were diagnosed, 96% were in care, 80% were in continuous care, and 61% were virally suppressed. The multivariable analysis showed significant differences in viral suppression by race/ethnicity and age. Black patients (59%, 534/907) were the least likely of all racial/ethnic groups examined to have a suppressed viral load. By age, compared with 73% (80/109) of children aged 0–12 years who were virally suppressed, 58% (568/987) of adults aged 20–29 years and 56% (54/96) of adults aged 30–39 years were virally suppressed; the adjusted prevalence ratio was 0.80 (95% confidence interval [CI] 0.69, 0.92) for those aged 20–29 years and 0.79 (95% CI 0.63, 0.99) for those aged 30–39 years. Conclusion. The low level of viral suppression among people living with perinatally acquired infection found in this study warrants further exploration to identify the best management strategies to improve viral suppression in this population, especially those transitioning from pediatric to adult health care.
Oliver Sacks and migraine
Authors: Haan Joost , Kaptein Ad A , ter Meulen Bastiaan C 
Published: August 2016

Background Oliver Sacks (1933–2015) published a large number of books on a variety of neurological topics. Of these, numerous copies have been sold and they probably serve as the only or main source of information on neurological diseases for many persons without a medical background. His first book was on migraine and in his subsequent books many descriptions of migraine can be found, mainly those of auras. Methods We explored the descriptions of migraine in Sacks’ work in order to evaluate the image of migraine offered to the readers. Conclusion Oliver Sacks gave wonderful descriptions of migraine auras, but hardly any of migraine headache. Furthermore, he described rare auras such as ‘amusia’ and olfactory auras. Overall, this makes his descriptions of migraine not very useful to serve as medical information for laypersons. Oliver Sacks, however, wrote great literature.
Alcoholic liver disease on the intensive care unit – Outcomes and prognostication
Authors: Beck James I , Staicu Anca , Everett Simon M , Jackson Phil 
Published: August 2016

Background Hospital admissions with decompensated chronic alcoholic liver disease have been increasing, leading to increased pressure on intensive care unit services. We aimed to determine the outcome and prognostic factors for patients with alcoholic liver disease requiring admission to intensive care unit. Methods This was a retrospective study over 5 years (January 2006–December 2010) of all intensive care unit admissions with alcoholic liver disease to either of the two Leeds Teaching Hospitals NHS Trust general intensive care units. A detailed case note review was conducted based on a pre-established proforma. Eighty-two patients included. Primary outcome was hospital mortality. Results The overall intensive care unit and hospital mortality were 46% and 67%, respectively. Hospital mortality in patients successfully discharged from intensive care unit with the intent of recovery remained high at 21%. Variceal bleed was the only indicator that had a mortality <60%. Factors which suggested a poor outcome included sepsis (86% mortality) and hepato-renal syndrome (86% mortality). A Sequential Organ Failure Assessment score of greater than 10 on intensive care unit admission was associated with 97% hospital mortality. Sequential Organ Failure Assessment score increased from a mean of 10.9–12.5 in those that did not survive hospital. Patients with first alcoholic liver disease related admission had poorer outcomes. Conclusion These results are similar to previous studies with no significant improvement in outcomes. Alcoholic liver disease is not a contra-indication to intensive care unit admission but assessment of the individual patient is required. The most appropriate objective factors to guide prognostication are the presenting intensive care unit diagnosis and Sequential Organ Failure Assessment score. First presentation of alcoholic liver disease is not a positive prognostic indicator.
Zebrafish P54 RNA helicases are cytoplasmic granule residents that are required for development and stress resilience
Authors: Zampedri Cecilia , Tinoco-Cuellar Maryana , Carrillo-Rosas Samantha , Diaz-Tellez Abigail , Ramos-Balderas Jose Luis , Pelegri Francisco , Maldonado Ernesto 
Published: August 2016

ABSTRACTStress granules are cytoplasmic foci that directly respond to the protein synthesis status of the cell. Various environmental insults, such as oxidative stress or extreme heat, block protein synthesis; consequently, mRNA will stall in translation, and stress granules will immediately form and become enriched with mRNAs. P54 DEAD box RNA helicases are components of RNA granules such as P-bodies and stress granules. We studied the expression, in cytoplasmic foci, of both zebrafish P54 RNA helicases (P54a and P54b) during development and found that they are expressed in cytoplasmic granules under both normal conditions and stress conditions. In zebrafish embryos exposed to heat shock, some proportion of P54a and P54b helicases move to larger granules that exhibit the properties of genuine stress granules. Knockdown of P54a and/or P54b in zebrafish embryos produces developmental abnormalities restricted to the posterior trunk; further, these embryos do not form stress granules, and their survival upon exposure to heat-shock conditions is compromised. Our observations fit the model that cells lacking stress granules have no resilience or ability to recover once the stress has ended, indicating that stress granules play an essential role in the way organisms adapt to a changing environment.
An in vitro model of granuloma-like cell aggregates substantiates early host immune responses against Mycobacterium massiliense infection
Authors: Je Sungmo , Quan Hailian , Na Yirang , Cho Sang-Nae , Kim Bum-Joon , Seok Seung Hyeok 
Published: August 2016

ABSTRACT
Mycobacterium massiliense (M. mass), belonging to the M. abscessus complex, is a rapidly growing mycobacterium that is known to cause tuberculous-like lesions in humans. To better understand the interaction between host cells and M. mass, we used a recently developed in vitro model of early granuloma-like cell aggregates composed of human peripheral blood mononuclear cells (PBMCs). PBMCs formed granuloma-like, small and rounded cell aggregates when infected by live M. mass. Microscopic examination showed monocytes and macrophages surrounded by lymphocytes, which resembled cell aggregation induced by M. tuberculosis (M. tb). M. mass-infected PBMCs exhibited higher expression levels of HLA-DR, CD86 and CD80 on macrophages, and a significant decrease in the populations of CD4+ and CD8+ T cells. Interestingly, low doses of M. mass were sufficient to infect PBMCs, while active host cell death was gradually induced with highly increased bacterial loads, reflecting host destruction and dissemination of virulent rapid-growing mycobacteria (RGM). Collectively, this in vitro model of M. mass infection improves our understanding of the interplay of host immune cells with mycobacteria, and may be useful for developing therapeutics to control bacterial pathogenesis.
The Place of Modern Cooperative Forms of the Organization in the Small Entrepreneurship Development
Authors: Лебедева  , Lebedeva I. , Лебедев  , Lebedev V. 
Published: August 2016

In the article the actual directions of development of small business in Russia
are considered. Results of the analysis of the main economic indicators
characterizing the provision of small business are given. The characteristic of
the main measures of the state support of small business at the present stage
in comparison with international experience of state regulation in this sphere is
given. Possibilities of development of small enterprises within cooperative
organizational forms are revealed. Features of the organization of cooperative
forms of integration of small enterprises are considered.
The use of FloSeal haemostatic sealant in the management of epistaxis: a prospective clinical study and literature review
Authors: Wakelam OC , Dimitriadis PA , Stephens J 
Published: August 2016

INTRODUCTION It is standard practice in the UK that if conservative measures or chemical cautery fail to control epistaxis, patients receive nasal packing which is often uncomfortable, requires admission and has well documented associated morbidity. Our study aims to evaluate the use of FloSeal haemostatic sealant in managing patients with epistaxis. MATERIALS AND METHODS Patients were identified from those referred with active epistaxis. A successful outcome was defined as complete haemostasis with FloSeal alone, with no further significant bleeding requiring admission or further interventions in the subsequent 7 days. Patients reported satisfaction using a ten-point visual analogue scale. Ear, nose and throat doctors recorded patient demographics, time to prepare FloSeal, length of stay, need for further treatment and adverse events on an electronic database. RESULTS 30 patients were enrolled in the study. The mean time to prepare FloSeal was 5 minutes. The success rate of FloSeal was 90%. The mean length of stay was 2.75 hours. The mean patient satisfaction with FloSeal was 8.4/10. No adverse events occurred. DISCUSSION FloSeal was found to be effective in controlling anterior epistaxis. There was a single case of posterior epistaxis which required operative management. The literature largely supports FloSeal in anterior epistaxis, but indicates sphenopalatine artery ligation as the definitive management of posterior epistaxis. CONCLUSIONS Our data support the use of FloSeal in patients with anterior epistaxis not controlled with conservative measures or chemical cautery. It was found to be easy to use, is well tolerated by patients and is efficient in financial terms.