bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Cross-Clade Characterization of Antibody-Mediated Recognition, Complement-Mediated Lysis, and Cell-Mediated Cytotoxicity of HIV-1 Envelope-Specific Antibodies toward Eradication of the HIV-1 Reservoir
Authors: Mujib Shariq , Liu Jun , Rahman A. K. M. Nur-ur , Schwartz Jordan A. , Bonner Phil , Yue Feng Yun , Ostrowski Mario A. 
Published: June 2017

ABSTRACTImmunotherapy with passive administration of broadly neutralizing HIV-1 envelope-specific antibodies (bnAbs) in the setting of established infectionin vivohas yielded mixed results. The contribution of different antibodies toward the direct elimination of infected cells is poorly understood. In this study, we determined the ability of 12 well-characterized anti-HIV-1 neutralizing antibodies to recognize and eliminate primary CD4 T cells infected with HIV-1 belonging to clades A, B, C, and D, via antibody-dependent complement-mediated lysis (ADCML) and antibody-dependent cell-mediated cytotoxicity (ADCC),in vitro. We further tested unique combinations of these antibodies to determine the optimal antibody cocktails to be tested in future clinical trials. We report that antibody binding to infected CD4 T cells is highly variable and correlates with ADCML and ADCC processes. Particularly, antibodies targeting the envelope glycan shield (2G12) and V1/V2 site (PG9, PG16, and PGT145) are best at recognizing HIV-1-infected CD4 T cells. However, only PG9 and PG16 and their combinations with other bnAbs sufficiently induced the elimination of HIV-1-infected CD4 T cells by ADCML, ADCC, or both. Notably, CD4 binding site antibodies VRC01, 3BNC117, and NIH45-46 G54W did not exhibit recognition of infected cells and were unable to induce their killing. Future trials geared toward the development of a cure for HIV/AIDS should incorporate V1/V2 antibodies for maximal clearance of infected cells. With the use of only primary immune cells, we conducted a comprehensive cross-clade physiological analysis to aid the direction of antibodies as therapeutics toward the development of a cure for HIV/AIDS.IMPORTANCESeveral antibodies capable of neutralizing the majority of circulating HIV-1 strains have been identified to date and have been shown to prevent infection in animal models. However, the use of combinations of such broadly neutralizing antibodies (bnAbs) for the treatment and eradication of HIV-1 in infected humans remains uncertain. In this study, we tested the ability of bnAbs to directly recognize and eliminate primary human CD4 T cells infected with diverse HIV-1 strains representative of the global epidemic by antibody-dependent pathways. We also tested several combinations of bnAbs in our assays in order to maximize the clearance of infected cells. We show that the ability of bnAbs to identify and kill infected cells is highly variable and that only a few of them are able to exert this function. Our data will help guide the formulation of bnAbs to test in future human trials aimed at the development of a cure.
HIV-1 Epitope Variability Is Associated with T Cell Receptor Repertoire Instability and Breadth
Authors: Balamurugan Arumugam , Claiborne Deon , Ng Hwee L. , Yang Otto O. 
Published: June 2017

ABSTRACT

Mutational escape of HIV-1 from HIV-1-specific CD8
+
T lymphocytes (CTLs) is a major barrier for effective immune control. Each epitope typically is targeted by multiple clones with distinct T cell receptors (TCRs). While the clonal repertoire may be important for containing epitope variation, determinants of its composition are poorly understood. We investigate the clonal repertoire of 29 CTL responses against 23 HIV-1 epitopes longitudinally in nine chronically infected untreated subjects with plasma viremia of <3,000 RNA copies/ml over 17 to 179 weeks. The composition of TCRs targeting each epitope varied considerably in stability over time, although clonal stability (Sorensen index) was not significantly time dependent within this interval. However, TCR stability inversely correlated with epitope variability in the Los Alamos HIV-1 Sequence Database, consistent with TCR evolution being driven by epitope variation. Finally, a robust inverse correlation of TCR breadth against each epitope versus epitope variability further suggested that this variability drives TCR repertoire diversification. In the context of studies demonstrating rapidly shifting HIV-1 sequences
in vivo
, our findings support a variably dynamic process of shifting CTL clonality lagging in tandem with viral evolution and suggest that preventing escape of HIV-1 may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways.

IMPORTANCE
Mutational escape of HIV-1 from HIV-1-specific CD8
+
T lymphocytes (CTLs) is a major barrier to effective immune control. The number of distinct CTL clones targeting each epitope is proposed to be an important factor, but the determinants are poorly understood. Here, we demonstrate that the clonal stability and number of clones for the CTL response against an epitope are inversely associated with the general variability of the epitope. These results show that CTLs constantly lag epitope mutation, suggesting that preventing HIV-1 escape may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways.
Role of Autophagy in HIV-1 Matrix Protein p17-Driven Lymphangiogenesis
Authors: Mazzuca Pietro , Marsico Stefania , Schulze Kai , Mitola Stefania , Pils Marina C. , Giagulli Cinzia , Guzman Carlos A. , Caruso Arnaldo , Caccuri Francesca 
Published: June 2017

ABSTRACT

AIDS-related lymphomas (ARLs) are expected to increase in the future since combined antiretroviral therapy (cART) enhances the life expectancy of HIV-1-infected (HIV
+
) patients but does not affect the occurrence of ARLs to the same extent as that of other tumors. Lymphangiogenesis is essential in supporting growth and metastatic spreading of ARLs. HIV-1 does not infect the neoplastic B cells, but HIV-1 proteins have been hypothesized to play a key role in sustaining a prolymphangiogenic microenvironment in lymphoid organs. The HIV-1 matrix protein p17 is detected in blood and accumulates in the germinal centers of lymph nodes of HIV
+
patients under successful cART. The viral protein displays potent lymphangiogenic activity
in vitro
and
in vivo
. This is, at least in part, mediated by the secretion of the lymphangiogenic factor endothelin-1, suggesting that activation of a secretory pathway sustains the lymphangiogenic activity of p17. Here, we show that the p17 lymphangiogenic activity occurs on human lymph node-derived lymphatic endothelial cells (LN-LECs) under stress conditions only and relies entirely on activation of an autophagy-based pathway. In fact, induction of autophagy by p17 promotes lymphangiogenesis, whereas pharmacological and genetic inhibition of autophagy inhibits p17-triggered lymphangiogenesis. Similarly, the vasculogenic activity of p17 was totally inhibited in autophagy-incompetent mice. Our findings reveal a previously unrecognized role of autophagy in lymphangiogenesis and open the way to identify novel treatment strategies aimed at inhibiting aberrant tumor-driven lymphangiogenesis in HIV
+
patients.

IMPORTANCE
AIDS-related lymphomas (ARLs) are the most common malignancies in HIV-1-infected (HIV
+
) patients after the introduction of combined antiretroviral therapy (cART). Lymphangiogenesis is of critical importance in sustaining growth and metastasis of ARLs. Indeed, enhanced lymphangiogenesis occurs in the lymph nodes of HIV
+
patients under successful cART. The HIV-1 matrix protein p17 is detected in blood and accumulates in the lymph node germinal centers even in the absence of virus replication. Several findings suggest a key role for p17 as a microenvironmental factor capable of promoting lymphangiogenesis. Here, we show that p17 promotes lymphangiogenesis of human lymph node-derived lymphatic endothelial cells (LN-LECs). The lymphangiogenic activity of p17 is sustained by an autophagy-based pathway that enables LN-LECs to release prolymphangiogenic factors into the extracellular microenvironment. Our findings indicate that specific targeting of autophagy may provide an important new tool for treating ARLs.
Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs
Authors: Harding Alfred T. , Heaton Brook E. , Dumm Rebekah E. , Heaton Nicholas S. 
Published: June 2017

ABSTRACT
Influenza virus vaccine production is currently limited by the ability to grow circulating human strains in chicken eggs or in cell culture. To facilitate cost-effective growth, vaccine strains are serially passaged under production conditions, which frequently results in mutations of the major antigenic protein, the viral hemagglutinin (HA). Human vaccination with an antigenically drifted strain is known to contribute to poor vaccine efficacy. To address this problem, we developed a replication-competent influenza A virus (IAV) with an artificial genomic organization that allowed the incorporation of two independent and functional HA proteins with different growth requirements onto the same virion. Vaccination with these viruses induced protective immunity against both strains from which the HA proteins were derived, and the magnitude of the response was as high as or higher than vaccination with either of the monovalent parental strains alone. Dual-HA viruses also displayed remarkable antigenic stability; even when using an HA protein known to be highly unstable during growth in eggs, we observed high-titer virus amplification without a single adaptive mutation. Thus, the viral genomic design described in this work can be used to grow influenza virus vaccines to high titers without introducing antigenic mutations.

IMPORTANCE
Influenza A virus (IAV) is a major public health threat, and vaccination is currently the best available strategy to prevent infection. While there have been many advances in influenza vaccine production, the fact that we cannot predict the growth characteristics of a given strain under vaccine production conditions
a priori
introduces fundamental uncertainty into the process. Clinically relevant IAV strains frequently grow poorly under vaccine conditions, and this poor growth can result in the delay of vaccine production or the exchange of the recommended strain for one with favorable growth properties. Even in strains that grow to high titers, adaptive mutations in the antigenic protein hemagglutinin (HA) that make it antigenically dissimilar to the circulating strain are common. The genomic restructuring of the influenza virus described in this work offers a solution to the problem of uncertain or unstable growth of IAV during vaccine production.
Pituitary abscess
Authors: Al salman Jameela Mohammed , Al Agha Rawan Al Muataz Billa , Helmy Mohamed 
Published: June 2017

Pituitary abscess is an uncommon pituitary lesion. Its clinical diagnosis can be difficult to distinguish from other pituitary lesions. This pathology is characterised by vague symptoms of headaches, generalised tiredness and hypopituitarism manifestations. A history of recent meningitis, paranasal sinusitis or head surgery can be a suggestive of the source of infection.A 20-year-old man was admitted to neurosurgery department with complain of headache, fatigue, polyuria, polydipsia, blurred vision and sexual dysfunction. MRI of the head revealed a suprasellar mass that was centrally hyperintense lesion on T2-weighted images with peripheral hypointensity and isointense centrally on T1 images with peripheral hyperintensity images. Treatment of this lesion pituitary abscess was surgical drainage of the pituitary area through a trans-sphenoidal approach and broad spectrum antibiotic therapy with ceftriaxone, metronidazole and vancomycin for 6 weeks. The patient continues to have pituitary insufficiency and treated with oral hydrocortisone.Although pituitary abscess is a rare condition, it should always be kept in mind when evaluating a patient with hypopituitarism. After the diagnosis, the surgery and antibiotics should be commenced rapidly. The outcome is usually good with proper treatment.
Bacterial meningitis in Finland, 1995–2014: a population-based observational study
Authors: Polkowska Aleksandra , Toropainen Maija , Ollgren Jukka , Lyytikäinen Outi , Nuorti J. Pekka 
Published: June 2017

ObjectivesBacterial meningitis remains an important cause of morbidity and mortality worldwide. Its epidemiological characteristics, however, are changing due to new vaccines and secular trends. Conjugate vaccines againstHaemophilus influenzaetype b andStreptococcus pneumoniae(10-valent) were introduced in 1986 and 2010 in Finland. We assessed the disease burden and long-term trends of five common causes of bacterial meningitis in a population-based observational study.MethodsA case was defined as isolation ofS. pneumoniae,Neisseria meningitidis,Streptococcus agalactiae,Listeria monocytogenesorH. influenzaefrom cerebrospinal fluid and reported to national, population-based laboratory surveillance system during 1995–2014. We evaluated changes in incidence rates (Poisson or negative binomial regression), case fatality proportions (χ2) and age distribution of cases (Wilcoxon rank-sum).ResultsDuring 1995–2014,S. pneumoniaeandN. meningitidisaccounted for 78% of the total 1361 reported bacterial meningitis cases.H. influenzaeaccounted for 4% of cases (92% of isolates were non-type b). During the study period, the overall rate of bacterial meningitis per 1 00 000 person-years decreased from 1.88 cases in 1995 to 0.70 cases in 2014 (4% annual decline (95% CI 3% to 5%). This was primarily due to a 9% annual reduction in rates ofN. meningitidis(95% CI 7% to 10%) and 2% decrease inS. pneumoniae(95% CI 1% to 4%). The median age of cases increased from 31 years in 1995–2004 to 43 years in 2005–2014 (p=0.0004). Overall case fatality proportion (10%) did not change from 2004 to 2009 to 2010–2014.ConclusionsSubstantial decreases in bacterial meningitis were associated with infant conjugate vaccination against pneumococcal meningitis and secular trend in meningococcal meningitis in the absence of vaccination programme. Ongoing epidemiological surveillance is needed to identify trends, evaluate serotype distribution, assess vaccine impact and develop future vaccination strategies.
A systematic review of alcohol screening and assessment measures for young people: a study protocol
Authors: Toner Paul , Böhnke Jan R , McCambridge Jim 
Published: June 2017

IntroductionAlcohol consumption creates a significant public health burden, and young people who drink alcohol place themselves at risk of harm. Expert guidance and reviews have highlighted the pressing need for reliable and valid, age-appropriate alcohol screening and assessment measures for young people. The proposed systematic review will evaluate existing alcohol screening and assessment measures for young people aged 24 and under.Methods and analysisSix electronic databases will be searched for published and grey literature. In addition, reverse and forward citation searching and consultation with experts will be performed. Three sets of search terms will be combined, including alcohol use/problems, young people and validation studies. The titles and abstracts of reports from the searches will be screened, and potentially relevant full-text reports will be retrieved and independently assessed for inclusion by two reviewers based on prespecified criteria. Discrete validation studies within included reports will then be assessed for eligibility. There will be an a priori basic quality threshold for predictive validity, internal and test–retest for studies to warrant full data extraction. Studies above the quality threshold will be assessed for quality using the modified consensus-based standards for the selection of health measurement instruments checklist and a quality assessment tool for diagnostic accuracy studies.DisseminationThis review will highlight the best performing measures both for screening and assessment based on their psychometric properties and the quality of the validation studies supporting their use. Providing clear guidance on which existing measures perform best to screen and assess alcohol use and problems in young people will inform policy, practice and decision-making, and clarify the need for further research.Trial registration numberInternational Prospective Register of Systematic Reviews, CRD42016053330.
Alcohol-flavoured tobacco products
Authors: Jackler Robert K , VanWinkle Callie K , Bumanlag Isabela M , Ramamurthi Divya 
Published: June 2017

BackgroundIn 2009, the Food and Drug Administration (FDA) banned characterising flavours in cigarettes (except for menthol) due to their appeal to teen starter smokers. In August 2016, the agency deemed all tobacco products to be under its authority and a more comprehensive flavour ban is under consideration.ObjectivesTo determine the scope and scale of alcohol-flavoured tobacco products among cigars & cigarillos, hookahs and electronic cigarettes (e-cigarettes).MethodsAlcohol-flavoured tobacco products were identified by online search of tobacco purveyors’ product lines and via Google search cross-referencing the various tobacco product types versus a list of alcoholic beverage flavours (eg, wine, beer, appletini, margarita).Results48 types of alcohol-flavoured tobacco products marketed by 409 tobacco brands were identified. Alcohol flavours included mixed drinks (n=25), spirits (11), liqueurs (7) and wine/beer (5). Sweet and fruity tropical mixed drink flavours were marketed by the most brands: piña colada (96), mojito (66) and margarita (50). Wine flavours were common with 104 brands. Among the tobacco product categories, brands offering alcohol-flavoured e-cigarettes (280) were most numerous, but alcohol-flavoured products were also marketed by cigars & cigarillos (88) and hookah brands (41). Brands by major tobacco companies (eg, Philip Morris, Imperial Tobacco) were well represented among alcohol-flavoured cigars & cigarillos with five companies offering a total of 17 brands.ConclusionsThe widespread availability of alcohol-flavoured tobacco products illustrates the need to regulate characterising flavours on all tobacco products.
Extracting aerobic system dynamics during unsupervised activities of daily living using wearable sensor machine learning models
Authors: Beltrame Thomas , Amelard Robert , Wong Alexander , Hughson Richard L. 
Published: June 2017

Physical activity levels are related through algorithms to the energetic demand, with no information regarding the integrity of the multiple physiological systems involved in the energetic supply. Longitudinal analysis of the oxygen uptake (V̇o2) by wearable sensors in realistic settings might permit development of a practical tool for the study of the longitudinal aerobic system dynamics (i.e., V̇o2 kinetics). This study evaluated aerobic system dynamics based on predicted V̇o2 data obtained from wearable sensors during unsupervised activities of daily living (μADL). Thirteen healthy men performed a laboratory-controlled moderate exercise protocol and were monitored for ≈6 h/day for 4 days (μADL data). Variables derived from hip accelerometer (ACCHIP), heart rate monitor, and respiratory bands during μADL were extracted and processed by a validated random forest regression model to predict V̇o2. The aerobic system analysis was based on the frequency-domain analysis of ACCHIP and predicted V̇o2 data obtained during μADL. Optimal samples for frequency domain analysis (constrained to ≤0.01 Hz) were selected when ACCHIP was higher than 0.05 g at a given frequency (i.e., participants were active). The temporal characteristics of predicted V̇o2 data during μADL correlated with the temporal characteristics of measured V̇o2 data during laboratory-controlled protocol ([Formula: see text] = 0.82, P < 0.001, n = 13). In conclusion, aerobic system dynamics can be investigated during unsupervised activities of daily living by wearable sensors. Although speculative, these algorithms have the potential to be incorporated into wearable systems for early detection of changes in health status in realistic environments by detecting changes in aerobic response dynamics. NEW & NOTEWORTHY The early detection of subclinical aerobic system impairments might be indicative of impaired physiological reserves that impact the capacity for physical activity. This study is the first to use wearable sensors in unsupervised activities of daily living in combination with novel machine learning algorithms to investigate the aerobic system dynamics with the potential to contribute to models of functional health status and guide future individualized health care in the normal population.
Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia
Authors: Braamskamp Marjet J.A.M. , Langslet Gisle , McCrindle Brian W. , Cassiman David , Francis Gordon A. , Gagne Claude , Gaudet Daniel , Morrison Katherine M. , Wiegman Albert , Turner Traci , Miller Elinor , Kusters D. Meeike , Raichlen Joel S. , Martin Paul D. , Stein Evan A. , Kastelein John J.P. , Hutten Barbara A. 
Published: June 2017

Background:
Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis manifested by increased carotid intima-media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in children with HeFH.

Methods:

Children with HeFH (age, 6–<18 years) and low-density lipoprotein cholesterol >4.9 mmol/L or >4.1 mmol/L in combination with other risk factors received rosuvastatin for 2 years, starting at 5 mg once daily, with uptitration to 10 mg (age, 6–<10 years) or 20 mg (age, 10–<18 years). Carotid IMT was assessed by ultrasonography at baseline and 12 and 24 months in all patients and in age-matched unaffected siblings. Carotid IMT was measured at 3 locations (common carotid artery, carotid bulb, internal carotid artery) in both the left and right carotid arteries. A linear mixed-effects model was used to evaluate differences in carotid IMT between children with HeFH and the unaffected siblings.
P
values were adjusted for age, sex, carotid artery site, and family relations.

Results:

At baseline, mean±SD carotid IMT was significantly greater for the 197 children with HeFH compared with the 65 unaffected siblings (0.397±0.049 and 0.377±0.045 mm, respectively;
P
=0.001). During 2 years of follow-up, the change in carotid IMT was 0.0054 mm/y (95% confidence interval, 0.0030–0.0082) in children with HeFH and 0.0143 mm/y (95% confidence interval, 0.0095–0.0192) in unaffected siblings (
P
=0.002). The end-of-study difference in mean carotid IMT between children with HeFH and unaffected siblings after 2 years was no longer significant (0.408±0.043 and 0.402±0.042 mm, respectively;
P
=0.2).

Conclusions:
In children with HeFH who were ≥6 years of age, carotid IMT was significantly greater at baseline compared with unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid IMT in children with HeFH than untreated unaffected siblings. As a result, no difference in carotid IMT could be detected between the 2 groups after 2 years of rosuvastatin. These findings support the value of early initiation of statin treatment for low-density lipoprotein cholesterol reduction in children with HeFH.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01078675.