Summary
VRC‐HIVMAB060‐00‐AB (VRC01) is a broadly neutralizing HIV‐1 monoclonal antibody (mAb) isolated from the B cells of an HIV‐infected patient. It is directed against the HIV‐1 CD4 binding site ...and is capable of potently neutralizing the majority of diverse HIV‐1 strains. This Phase I dose‐escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose‐limiting toxicities. Mean 28‐day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28‐day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5–40 mg/kg i.v. dose range (n = 18), the clearance was 0·016 l/h and terminal half‐life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti‐VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half‐life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV‐1 prevention efficacy studies.
Gene expression data are accumulating exponentially in public repositories. Reanalysis and integration of themed collections from these studies may provide new insights, but requires further human ...curation. Here we report a crowdsourcing project to annotate and reanalyse a large number of gene expression profiles from Gene Expression Omnibus (GEO). Through a massive open online course on Coursera, over 70 participants from over 25 countries identify and annotate 2,460 single-gene perturbation signatures, 839 disease versus normal signatures, and 906 drug perturbation signatures. All these signatures are unique and are manually validated for quality. Global analysis of these signatures confirms known associations and identifies novel associations between genes, diseases and drugs. The manually curated signatures are used as a training set to develop classifiers for extracting similar signatures from the entire GEO repository. We develop a web portal to serve these signatures for query, download and visualization.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55–200 CGG repeats) of the fragile X ...mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67–87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).
We report observations of turbulent dissipation and particle acceleration from large‐amplitude electric fields (E) associated with strong magnetic field (B) fluctuations in the Earth's plasma sheet. ...The turbulence occurs in a region of depleted density with anti‐earthward flows followed by earthward flows suggesting ongoing magnetic reconnection. In the turbulent region, ions and electrons have a significant increase in energy, occasionally >100 keV, and strong variation. There are numerous occurrences of |E| >100 mV/m including occurrences of large potentials (>1 kV) parallel to B and occurrences with extraordinarily large J · E (J is current density). In this event, we find that the perpendicular contribution of J · E with frequencies near or below the ion cyclotron frequency (fci) provide the majority net positive J · E. Large‐amplitude parallel E events with frequencies above fci to several times the lower hybrid frequency provide significant dissipation and can result in energetic electron acceleration.
Plain Language Summary
The Magnetospheric Multiscale mission is able to examine dissipation associated with magnetic reconnection with unprecedented accuracy and frequency response. The observations show that roughly 80% of the dissipation is from the perpendicular currents and electric fields. However, large‐amplitude parallel electric fields appear to play a strong role in turbulent dissipation into electrons and in electron acceleration.
Key Points
MMS observations reveal characteristics of turbulent dissipation and particle acceleration associated with magnetic reconnection
Perpendicular electric fields and large‐amplitude parallel electric fields structures have dominant roles in turbulent dissipation
Turbulent electric fields in a magnetic structure is shown to play a key role in accelerating electrons to greater than 100 keV energies
The etiology of endometriosis is not well understood. Limited evidence suggests that dietary factors influence risk, but prospective data related to carbohydrate, fiber, and gluten consumption are ...scarce. Despite this, recommendations concerning fiber, gluten intake, and endometriosis are pervasive in the lay literature.
We aimed to investigate the associations of carbohydrate quality glycemic index (GI) and glycemic load (GL), fiber intake (total, legume, vegetable, cruciferous vegetable, fruit, cereal), and gluten intake with incident laparoscopically confirmed endometriosis.
This was a prospective cohort study using data collected from 81,961 premenopausal women in the Nurses' Health Study II (mean age = 36 y in 1991). Diet was assessed with a validated FFQ every 4 y. Cox proportional hazards models were used to calculate rate ratios (RRs) and 95% CIs.
A total of 3810 incident cases of laparoscopically confirmed endometriosis were reported over 24 y of follow-up. Women in the highest quintile of GI had 12% (95% CI: 1.01, 1.23; Ptrend = 0.03) higher risk of endometriosis diagnosis than those in the lowest quintile. Total vegetable and cruciferous vegetable fiber intakes were also associated with higher risk (highest compared with lowest quintile RR: 1.13; 95% CI: 1.02, 1.24; Ptrend = 0.004 and RR: 1.17; 95% CI: 1.06, 1.29; Ptrend = 0.02, respectively). Higher intake of fruit fiber was associated with lower risk of endometriosis but the association was not significant after adjusting for the Alternative Healthy Eating Index. Gluten intake was also associated with lower risk (highest compared with lowest quintile RR: 0.91; 95% CI: 0.80, 1.02; Ptrend = 0.01), but these results were not consistent in direction nor statistical significance across sensitivity analyses. No association was observed for GL or total, legume, or cereal fiber intake.
Our findings suggest that carbohydrate quality and specific types of fiber-total vegetable and cruciferous vegetable fiber-are associated with endometriosis diagnosis in premenopausal women. These results also indicate it is unlikely that gluten intake is a strong factor in the etiology or symptomatology of endometriosis.
The high use of antibiotics in human and veterinary medicine has led to a wide spread of antibiotics and antimicrobial resistance into the environment. In recent years, various studies have shown ...that antibiotic residues, resistant bacteria and resistance genes, occur in aquatic environments and that clinical wastewater seems to be a hot spot for the environmental spread of antibiotic resistance. Here a representative statistical analysis of various sampling points is presented, containing different proportions of clinically influenced wastewater. The statistical analysis contains the calculation of the odds ratios for any combination of antibiotics with resistant bacteria or resistance genes, respectively. The results were screened for an increased probability of detecting resistant bacteria, or resistance genes, with the simultaneous presence of antibiotic residues. Positive associated sets were then compared, with regards to the detected median concentration, at the investigated sampling points. All results show that the sampling points with the highest proportion of clinical wastewater always form a distinct cluster concerning resistance. The results shown in this study lead to the assumption that ciprofloxacin is a good indicator of the presence of multidrug resistant P. aeruginosa and extended spectrum β-lactamase (ESBL)-producing Klebsiella spec., Enterobacter spec. and Citrobacter spec., as it positively relates with both parameters. Furthermore, a precise relationship between carbapenemase genes and meropenem, regarding the respective sampling sites, could be obtained. These results highlight the role of clinical wastewater for the dissemination and development of multidrug resistance.
•Clinically influenced wastewater differs from municipal wastewater (WW).•Statistical associations between antibiotics and resistant bacteria are observed.•Ciprofloxacin seems to be an indicator for the presence of ESBL-producing bacteria.•P. aeruginosa, resistant against 3rd gen. cephalosporins, were mainly in clinical WW.
Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 ...(alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor.
This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1–d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design.
Seventy-two patients were enrolled at 24 sites 12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3–4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%).
Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising.
NCT01653028.
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