bluuebunny/crossref_metadata_2025_split huggingface dataset:
P-C1 Development of HIV-1 Immunotherapy with Vacc4x and Vacc-C5
Authors: Smith Peter , Sommerfelt Maja , Stjernholm Grete , Ökvist Mats , Zeldis Jerome , Sorenson Birger , Kvale Dag , Dalgleish Angus 
Published: April 2018

HIV-1 immunotherapy offers an alternative to cART or as a “functional cure” by eliminating reactivated viral reservoirs. Both cellular and antibody mediated immune responses have been identified which are capable of reducing either HIV-1 infection risk or severity of infection. We present data on both T-cell based (Vacc4x) and antibody based (vacc-C5) vaccine antigen under development for HIV-1 immunotherapy.
Vacc4x has undergone phase II trials demonstrating reductions in viral load and sustained anti-HIV-1 T-cell responses. Additional immune modulation, such as that used in cancer immunotherapy, may have utility in HIV-1 Immunotherapy. For this reason we combined Vacc4x with the immune modulator Lenalidomide both in vitro and in a phase I trial of 24 subjects in order to assess the ability of this combination to enhance CD4+ T cell responses. The combination was safe, well tolerated and demonstrated increases in CD4+ T-cell counts after a 2 week vaccine protocol.
We have identified that antibodies specific for a heterodimeric peptide construct comprising the C5501-512 and gp41732-744 regions of the HIV envelope protein (Vacc-C5) are correlated with slow disease progression, lower viral load and markers of immune function in HIV-1 patients and are capable of mediating antibody dependent cytotoxicity. We conducted a phase I/II trial of 36 ART treated patients vaccinated with Vacc-C5 antigen. Vacc-C5 was safe, well tolerated and increased anti-Vacc-C5 titre in a subset of patients.
These data support the continued development of Vacc4x, Lenalidomide and Vacc-C5 in an HIV-1 immunotherapeutic setting.
D-108 Innate-primed alternative signaling pathways enhance functional mucosal mobilization of memory-like NK cells in HIV/SIV infection
Authors: Reeves Keith 
Published: April 2018

Burgeoning evidence indicates a broader functional repertoire for NK cells beyond innate immunity including adaptive functions. Specifically, memory-like NK cells lacking the FcR γ-signaling chain (FcRΔg-NK cells) still require antibody to grant antigen-specificity, but are pre-sensitized for rapid mobilization against viral antigens. Interestingly, FcRΔg-NK cells require innate priming by CMV, but execute memory-like killing against HIV and SIV through poorly understood mechanisms.
Sixty rhCMV−, rhCMV+, and chronically SIV-infected macaques were studied and compared to thirty naive and untreated HIV-infected humans. FcRΔg-NK cells were systemically distributed but, correlating with viral load, increased four-fold in CMV+ and HIV/SIV-subjects, including in the GI tract. Upregulated CD16 and α4β7 suggested memory-like priming is required for both antibody-dependent functions and mucosal homing. FcRΔg-NK cells exhibited two-fold more robust IFN-γ secretion and cytotoxicity in the presence of antibody, but reduced expression of Helios and Eomes—indicative of epigenetic modifications, and clustered independently from traditional NK cells in multidimensional t-SNE. The γ-chain adaptor, Syk was absent or dephosphorylated in FcRΔg-NK cells, but ζ-chain, phosphorylated by adaptor Zap70, was significantly upregulated, indicating use of the alternative ζ-chain/Zap70 pathway to achieve greater functional potency.
Our work presents the first description of a combinatorial mechanism of innate-priming and alternative signaling to explain the memory-like phenomena of NK cells mobilized against HIV/SIV. Future studies harnessing memory-like NK cells could create exciting modalities for both vaccine and curative therapies.
D-109 Defining a potent new class of latency reversing agents devoid of toxicity and detrimental cell activation that enhance CTL/NK cell killing
Authors: Gramatica Andrea , Schwarzer Roland , Montano Mauricio , Herzig Eytan , Packard Thomas , Greene Warner C. 
Published: April 2018

Despite long-term administration of antiretroviral therapy (ART), HIV-1 persists in a broadly distributed latent reservoir mainly comprised of resting CD4+ T cells. Cells harboring latent provirus typically display little to no HIV-1 gene expression and thus remain invisible to the immune system. To achieve a durable sustained viral remission in HIV-infected patients off ART (a functional cure), it will be important to both “reduce the size of the reservoir and to control viral rebound by eliciting an effective immune response capable of restraining viral spread from the smaller reservoir. This approach will likely require the combined use of potent and safe latency-reversing agent (LRA) and a therapeutic HIV vaccine.
Our recent studies have shown that activators of the AKT/mTOR pathway form a promising group of LRAs. Our interest has focused on two small molecules, SB-216763 and Tideglusib that commonly inhibit glycogen synthase kinase-3 (GSK-3). This inhibition triggers a metabolic shift to glycolysis and results in sequential activation of mTORC2, AKT, and mTORC1. Both compounds are known to have high tissue penetration including the brain.
We found that these GSK-3 inhibitors potently activate latent HIV-1 in both a tissue-based model of HIV latency formed in primary CD4 T cells, and in CD4 T cells isolated from HIV-infected patients. In some experiments, these agents are more potent than anti-CD3/anti-CD28 antibodies even though the GSK-3 inhibitors do not appear to induce T cell activation (measured by changes in CD69 and CD25 expression). Finally, in contrast to the undesirable compromise of CTL/NK function associated with many first generation LRAs (PKC activators, HDAC inhibitors), the GSK-3 inhibitors actually enhance CTL and NK cell effector function.
In summary, our findings reveal GSK-3 inhibitors as an interesting new class of potent, safe, non-cell activating LRAs. Next, it will be key to define their activity in vivo using SIV-infected macaques on suppressive ART. The fact that tideglusib is already in phase II human trials for myotonic dystrophy and autism could accelerate its ultimate testing as an LRA in HIV-infected patients.
F-103 Targeting aberrant transcription in pre-cancerous stem cells
Authors: Steidl Ulrich G. 
Published: April 2018

Relapse continues to be the most common cause of death in acute myeloid leukemia (AML) and many other cancers. Recent evidence has shown that the accumulation of stepwise genetic and epigenetic changes in tissue-specific stem cells lead to the formation of pre-cancerous/pre-leukemic stem cells (pre-LSC) that play a pivotal role not only in disease origination but also in relapse. While the existence and essentiality of such pre-cancerous cell states has been demonstrated in mice and humans, still very little is known about the molecular mechanisms driving pre-LSC formation and progression. We have recently performed molecular studies of pre-leukemic cell states in mouse genetic models as well as primary cells from patients, and discovered new transcription factors and regulatory mechanisms in pre-LSC in myelodysplastic syndromes (MDS) and AML. We have uncovered critical roles for several transcription factors in pre-LSC, and found that enhancer haplodeficiency and resulting minimal reduction of key transcription factors can be sufficient to induce pre-LSC formation and subsequent progression to MDS and AML. Such models provide novel tools for mechanistic study of pre-LSC and their progression to overt MDS and AML, and for the development and testing of pharmacological approaches to therapeutically interfere with these processes.
In summary, recent studies have started to shed light on pre-cancerous stem cell states as the earliest origin of various malignancies including MDS and AML, as well as molecular mechanisms driving their formation and progression. These advances provide a basis for the specific therapeutic targeting of pre-cancerous stem cells for the causative treatment of MDS and AML and other cancers.
I-103 The metabolic complications of HIV
Authors: Peters Barry 
Published: April 2018

Some conditions of metabolic origin are, at least in part, considered to be associated or driven by HIV infection or its treatment. These include hyperlipidaemia, lipodystrophy, type 2 diabetes, non-alcoholic fatty liver disease (non-ALFLD), fragility fractures, and some elements of cardiovascular disease.
There are several behavioural factors, particularly diet exercise, alcohol, smoking, and there are some antiretroviral drugs, that contribute to the high incidence of metabolic disease in people living with HIV (PLWH). Some fundamental biological and cellular mechanisms may be important in driving metabolic abnormalities in PLWH. Irisin, a cleaved part of a protein encoded by the FNDC5 (Fibronectin type III domain-containing protein 5) gene, has been correlated in PLWH with adiposity, and inversely correlated with fat free mass and some strength parameters. HIV may disrupt fundamental metabolic host cell processes and further enable a preferential environment for virion assembly. The metabolic syndrome and obesity appear to be key for many cases of liver fibrosis in PLWH with concomitant hepatitis virus infection. The METAFIB study found that adipokines and SCD163 (a soluble form of Cluster of Differentiation receptor163), were significantly associated with fibrosis of the liver.
To improve metabolic health outcomes in PLWH, we need further studies to increase our evidence base and develop better therapies. Therapeutic strategies include the identification of risk factors for metabolic disease in PLWH, such as fatty liver, and screening for diabetes, affording the opportunity to encourage behavioural change such as diet and exercise, and the selection of appropriate antiretroviral medication.
J-104 Geenius HIV 1/2 Supplemental Assay: A Rapid, Reliable and Simple System for the Confirmation and Differentiation of Antibodies to HIV
Authors: Shriver Kathleen , Cardona Muriel , Gadelle Stephane , Sarfati Patrice 
Published: April 2018

INTRODUCTION:
In 2017 Bio-Rad Laboratories completed launching the FDA-approved Geenius HIV-1/HIV-2 Supplemental assay to replace Multispot HIV-1/HIV-2 in the current CDC HIV Diagnostic Algorithm. The Geenius cassette contains antibody-binding protein A, which is conjugated to colloidal gold dye particles; HIV-1 (p31, gp160, p24, gp41) and HIV-2 (gp36, gp140) antigens are bound to the membrane solid phase. Serum, plasma, or whole blood may be tested. Geenius uses an automated cassette reader and proprietary software to interpret HIV-1 and HIV-2 results. We report more recent performance data for this system, as well as an investigational protocol for testing dried blood spot (DBS) specimens.

METHODS:
(1) WHO evaluated the Geenius HIV-1/HIV-2 Supplemental testing system with a panel of 1117 specimens. (2) DBS specimens were tested on Geenius using an investigational procedure (40 μL of DBS eluate and one drop of assay buffer). Samples included established infections (131 HIV-1, 31 HIV-2, one dual), 60 seroconversion specimens, and 106 DBS collected by CDC during HIV surveillance.

RESULTS:
(1) Geenius sensitivity in the WHO evaluation was 100% and specificity was 97.4%. Seroconversion samples were detected +0.875 days vs. the benchmark. All the mixed titer and reference specimens were correctly classified. (2) Geenius DBS correctly detected HIV-1 and HIV-2 DBS with minor exceptions. DBS seroconversions showed slightly reduced sensitivity vs. plasma.

CONCLUSIONS:
(1) The Geenius HIV-1/2 Confirmatory Assay was accepted for the WHO list of prequalified diagnostics (March 17, 2017). (2) Results of an investigational Geenius DBS procedure appear promising for settings without capacity for venipuncture.
P-A1 CBF-1 promotes the establishment and maintenance of HIV latency by recruiting Polycomb repressive complexes, PRC1 and PRC2, at HIV LTR
Authors: Tyagi Mudit , Zicari Sonia , Farley Kalamo , Sun Lin , Simon Gary 
Published: April 2018

The type of chromatin structure around the LTR promoter of integrated HIV provirus provides critical signals that regulate transcription during both productive and latent HIV infections. The C-promoter binding factor-1 (CBF-1) is a potent and specific inhibitor of the HIV-1 transcription, which perform its function after binding to specific sites at HIV LTR. Here we demonstrate that the knockdown of endogenous CBF-1 in latently infected primary CD4+ T cells, using specific small hairpin RNAs (shRNA), resulted in the reactivation of latent HIV proviruses. By performing Chromatin immunoprecipitation (ChIP) assays, using latently infected primary T cells and Jurkat T-cell lines, we demonstrated that CBF-1 induces the establishment and maintenance of HIV latency by recruiting Polycomb Group (PcG/PRC) corepressor complexes or Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Knockdown of CBF-1 resulted in the dissociation of PRCs corepressor complexes and enhanced the recruitment of RNA polymerase II (RNAPII) at HIV LTR. Knockdown of certain components of PRC1 and PRC2 leads to the reactivation of latent proviruses. Similarly, treatment of latently infected primary CD4+ T cells with the EZH2 inhibitor, 3-deazaneplanocin A (DZNep), led to their reactivation.

Importance:
Instead of inhibiting individual enzymes, targeting factors such as CBF-1, which mediate the establishment of multiple repressive epigenetic changes, could be more beneficial in designing strategies to reactivate and subsequently eliminate latent HIV reservoirs.
P-A4 Multimodal theranostic tests for antiretroviral drug delivery
Authors: Kevadiya Bhavesh , Woldstad Christopher , Ottemann Brendan , Dash Prasanta , Sajja Balasrinivasa , Lamberty Benjamin , Morsey Brenda , Kocher Ted 
Published: April 2018

Abstract:
Long acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections and facilitate drug entry into human immunodeficiency viral reservoirs. To speed LASER ART development “multimodal imaging theranostic nanoprobes” were created. These europium (Eu3+) doped cobalt ferrite (CF) dolutegravir (DTG) (EuCF-DTG) nanoparticles were used as platforms for drug-particle biodistribution. After parenteral injection of EuCF-DTG, to rats and rhesus macaques, measured drug and cobalt levels by florescence and magnetic resonance imaging tests were found to be coordinate to iron levels. Moreover, EuCF-DTG was found to be a log order-of-magnitude more sensitive than equivalent amounts of particle encased iron oxide. Folic acid decoration facilitated drug particle cell uptake. We posit that theranostic nanoprobes can facilitate LASER ART drug delivery and be used as part of a precision nanomedicine treatment strategy.
Reliability of Rod Lengthening, Thoracic, and Spino-Pelvic Measurements on Biplanar Stereoradiography in Patients Treated With Magnetically Controlled Growing Rods
Authors: Obid Peter , Yiu Karen Kar Lum , Cheung Kenneth MC , Kwan Kenny , Ruf Michael , Cheung Jason Pui Yin 
Published: April 2018

Study Design.
Cross-sectional study.

Objective.
To assess the inter- and intraobserver reliability of thoracic, spino-pelvic, and rod lengthening measurements made on biplanar spinal stereoradiography (EOS imaging) in children treated with magnetically controlled growing rod (MCGR).

Summary of Background Data.
MCGR treatment aims to gain spine length while gradually correcting the spinal deformity. Monitoring thoracic and spino-pelvic parameters is crucial for successful management. EOS imaging is widely used for diagnosis and monitoring of children with Early Onset Scoliosis. However, there is a paucity of literature on the reliability of thoracic and spino-pelvic parameters on EOS imaging in children treated with MCGR.

Methods.
Three independent reviewers independently read a random assortment of 20 whole spine posteroanterior and lateral radiographs from patients treated with MCGR. The measurements were repeated 4 weeks after the initial read. The following radiological parameters were measured: Cobb angle of the main and compensatory curves, coronal balance, coronal T1-S1 and T1-T12 length, chest width and depth at T6, pelvic inlet width, MCGR distracted lengths, global kyphosis, proximal and distal junctional angle, lordosis, sagittal balance, pelvic incidence, pelvic tilt and sacral slope. Statistical analysis was performed with paired t test and Cronbach alpha for inter- and intraobserver reliability.

Results.
All measurements had good or excellent intra- and interobserver reliability (α>0.8; P < 0.05), except measurements of the proximal junctional angle which showed only poor intra- and interobserver reliability for patients with an upper instrumented vertebra cranial to T4.

Conclusion.
EOS imaging is reliable for diagnosis and monitoring of children with Early Onset Scoliosis treated with MCGR. EOS imaging is particularly excellent for assessment of MCGR lengthening. Diagnosis and interpretation of early proximal junctional kyphosis within the cervicothoracic junction should be made with caution.

Level of Evidence: 3
Alterations in Intramedullary T2-weighted Increased Signal Intensity following Laminoplasty in Cervical Spondylotic Myelopathy Patients
Authors: Machino Masaaki , Ando Kei , Kobayashi Kazuyoshi , Ito Kenyu , Tsushima Mikito , Morozumi Masayoshi , Tanaka Satoshi , Ota Kyotaro , Ito Keigo , Kato Fumihiko , Ishiguro Naoki , Imagama Shiro 
Published: April 2018

Study Design.
A prospective comparative imaging study.

Objective.
This study investigated whether the postoperative classification of and alterations in increased signal intensity (ISI) of the spinal cord reflected the postoperative severity of symptoms and surgical outcomes in cervical spondylotic myelopathy (CSM) patients.

Summary of Background Data.
Although ISI on performing magnetic resonance imaging (MRI) is observed in CSM patients, alterations in ISI have not been investigated. The association of postoperative ISI with surgical outcomes in CSM patients remains controversial.

Methods.
Totally, 505 consecutive CSM patients (311 males) with a mean age of 66.6 (range, 41–91) years were enrolled. All were treated with laminoplasty and underwent MRI scans: preoperatively and after an average of 26.5 months postoperatively (range 12–66 months). ISI was classified pre- and postoperatively into three groups based on sagittal T2-weighted magnetic resonance images: Grade 0, none; Grade 1, light (obscure); and Grade 2, intense (bright). The patients’ pre- and postoperative neurological statuses were evaluated using the Japanese Orthopaedic Association scoring system for cervical myelopathy (JOA score) and other quantifiable tests, including the 10-s grip and release (10-s G&R) test and 10-s step test.

Results.
Preoperatively, 168 patients had Grade 0 ISI, 169 had Grade 1, and 168 had Grade 2; postoperatively, 210 patients had Grade 0 ISI, 94 had Grade 1, and 201 had Grade 2. Patients with postoperative Grade 0 ISI had a better postoperative JOA score, recovery rate, and 10-s G&R and 10-s step test scores than those with other grades. The postoperative ISI grade improved in 66 patients (13.1%), worsened in 57 (11.3%), and remained unchanged in 382 (75.6%).

Conclusion.
Postoperative ISI partially reflects postoperative symptoms and surgical outcomes. Alterations in ISI were observed postoperatively in 123 patients (24.4%) and were not correlated with surgical outcomes.

Level of Evidence: 2
Flexible Versus Restrictive Visiting Policies in ICUs: A Systematic Review and Meta-Analysis*
Authors: Nassar Junior Antonio Paulo , Besen Bruno Adler Maccagnan Pinheiro , Robinson Caroline Cabral , Falavigna Maicon , Teixeira Cassiano , Rosa Regis Goulart 
Published: April 2018

Objectives:
To synthesize data on outcomes related to patients, family members, and ICU professionals by comparing flexible versus restrictive visiting policies in ICUs.

Data Sources:
Medline, Scopus, and Web of Science.

Study Selection:
Observational and randomized studies comparing flexible versus restrictive visiting policies in the ICU and evaluating at least one patient-, family member–, or ICU staff–related outcome.

Data Extraction:
Duplicate independent review and data abstraction.

Data Synthesis:
Of 16 studies identified for inclusion, seven were meta-analyzed. Most studies were rated as having a moderate risk of bias. Among patients, flexible visiting policies were associated with reduced frequency of delirium (odds ratio, 0.39; 95% CI, 0.22–0.69; I
2 = 0%) and lower severity of anxiety symptoms (mean difference, –2.20; 95% CI, –3.80 to –0.61; I
2 = 71%). Flexible visiting policies were not associated with increased risk of ICU mortality (odds ratio, 0.71; 95% CI, 0.38–1.36; I
2 = 86%), ICU-acquired infections (odds ratio, 0.98; 95% CI, 0.68–1.42; I
2 = 11%), or longer ICU stay (mean difference, –0.26 d; 95% CI, –0.57 to 0.05; I
2 = 54%). Among family members, flexible visiting policies were associated with greater satisfaction. Among ICU professionals, flexible visiting policies were associated with higher burnout levels.

Conclusions:
Flexible ICU visiting hours have the potential to reduce delirium and anxiety symptoms among patients and to improve family members’ satisfaction. However, they may be associated with an increased risk of burnout among ICU professionals. These conclusions are based on few studies, with small samples and moderate risk of bias.
Socioeconomic and Tobacco Mediation of Ethnic Inequalities in Mortality over Time
Authors: Blakely Tony , Disney George , Valeri Linda , Atkinson June , Teng Andrea , Wilson Nick , Gurrin Lyle 
Published: April 2018

Background:
Racial/ethnic inequalities in mortality may be reducible by addressing socioeconomic factors and smoking. To our knowledge, this is the first study to estimate trends over multiple decades in (1) mediation of racial/ethnic inequalities in mortality (between Māori and Europeans in New Zealand) by socioeconomic factors, (2) additional mediation through smoking, and (3) inequalities had there never been smoking.

Methods:
We estimated natural (1 and 2 above) and controlled mediation effects (3 above) in census-mortality cohorts for 1981–1984 (1.1 million people), 1996–1999 (1.5 million), and 2006–2011 (1.5 million) for 25- to 74-year-olds in New Zealand, using a weighting of regression predicted outcomes.

Results:
Socioeconomic factors explained 46% of male inequalities in all three cohorts and made an increasing contribution over time among females from 30.4% (95% confidence interval = 18.1%, 42.7%) in 1981–1984 to 41.9% (36.0%, 48.0%). Including smoking with socioeconomic factors only modestly altered the percentage mediated for males, but more substantially increased it for females, for example, 7.7% (5.5%, 10.0%) in 2006–2011. A counterfactual scenario of having eradicated tobacco in the past (but unchanged socioeconomic distribution) lowered mortality for all sex-by-ethnic groups and resulted in a 12.2% (2.9%, 20.8%) and 21.2% (11.6%, 31.0%) reduction in the absolute mortality gap between Māori and Europeans in 2006–2011, for males and females, respectively.

Conclusions:
Our study predicts that, in this high-income country, reducing socioeconomic disparities between ethnic groups would greatly reduce ethnic inequalities in mortality over the long run. Eradicating tobacco would notably reduce ethnic inequalities in absolute but not relative mortality.