Peptides and proteins play an important role in skin health and well-being. They are also found to contribute to skin aging and melanogenesis. Microneedles have been shown to substantially enhance ...skin penetration and may offer an effective means of peptide delivery enhancement. The aim of this investigation was to assess the influence of microneedles on the skin penetration of peptides using fluorescence imaging to determine skin distribution. In particular the effect of peptide chain length (3, 4, 5 amino acid chain length) on passive and MN facilitated skin penetration was investigated. Confocal laser scanning microscopy was used to image fluorescence intensity and the area of penetration of fluorescently tagged peptides. Penetration studies were conducted on excised full thickness human skin in Franz type diffusion cells for 1 and 24 hours. A 2 to 22 fold signal improvement in microneedle enhanced delivery of melanostatin, rigin and pal-KTTKS was observed. To our knowledge this is the first description of microneedle enhanced skin permeation studies on these peptides.
Abstract Background SF1126 is a peptidic pro-drug inhibitor of pan-PI3K/mTORC. A first-in-human study evaluated safety, dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics ...(PK), pharmacodynamics (PD) and efficacy of SF1126, in patients with advanced solid and B-cell malignancies. Patients and methods SF1126 was administered IV days 1 and 4, weekly in 28 day-cycles. Dose escalation utilised modified Fibonacci 3+3. Samples to monitor PK and PD were obtained. Results Forty four patients were treated at 9 dose levels (90–1110 mg/m2 /day). Most toxicity was grade 1 and 2 with a single DLT at180 mg/m2 (diarrhoea). Exposure measured by peak concentration (Cmax ) and area under the time-concentration curve (AUC0-t ) was dose proportional. Stable disease (SD) was the best response in 19 of 33 (58%) evaluable patients. MTD was not reached but the maximum administered dose (MAD) was 1110 mg/m2 . The protocol was amended to enrol patients with CD20+ B-cell malignancies at 1110 mg/m2 . A CLL patient who progressed on rituximab R achieved SD after 2 months on SF1126 alone but in combination with R achieved a 55% decrease in absolute lymphocyte count and a lymph node response. PD studies of CLL cells demonstrated SF1126 reduced p-AKT and increased apoptosis indicating inhibition of activated PI3K signalling. Conclusion SF1126 is well tolerated with SD as the best response in patients with advanced malignancies.
We report a measurement of the B mode polarization power spectmm in the cosmic microwave background (CMB) using the Polarbear experiment in Chile. The faint B mode polarization signature carries ...information about the universe's entire history of gravitational structure formation, and the cosmic inflation that may have occurred in the very early universe. Our measurement covers the angular multipole range 500 < l < 2100 and is based on observations of an effective sky area of 25 deg super(2) with 3'5 resolution at 150 GHz. On these angular scales, gravitational lensing of the CMB by intervening structure in the universe is expected to be the dominant source of B mode polarization. Including both systematic and statistical uncertainties, the hypothesis of no B mode polarization power from gravitational lensing is rejected at 97.2% confidence. The band powers are consistent with the standard cosmological model. Fitting a single lensing amplitude parameter A sub(BB) to the measured band powers, A sub(BB) = 1 12 + or - O 61(stat) super(+0 04) sub(-0 12)(sys) + or - 0 07(multi), where A sub(BB) = 1 is the fiducial WMAP 9 LambdaCDM value. In this expression, "stat" refers to the statistical uncertainty, "sys" to the systematic uncertainty associated with possible biases from the instrument and astrophysical foregrounds, and "multi" to the calibration uncertainties that have a multiplicative effect on the measured amplitude A sub(BB)
Current knowledge about the dynamics of antigen presentation to T cells during viral infection is very poor despite being of fundamental importance to our understanding of anti-viral immunity. Here ...we use an advanced mass spectrometry method to simultaneously quantify the presentation of eight vaccinia virus peptide-MHC complexes (epitopes) on infected cells and the amounts of their source antigens at multiple times after infection. The results show a startling 1000-fold range in abundance as well as strikingly different kinetics across the epitopes monitored. The tight correlation between onset of protein expression and epitope display for most antigens provides the strongest support to date that antigen presentation is largely linked to translation and not later degradation of antigens. Finally, we show a complete disconnect between the epitope abundance and immunodominance hierarchy of these eight epitopes. This study highlights the complexity of viral antigen presentation by the host and demonstrates the weakness of simple models that assume total protein levels are directly linked to epitope presentation and immunogenicity.
Tremor is one of the clinical manifestations of dystonia; however, there are no specific therapeutic trials evaluating the efficacy of treatments for dystonic tremor (DT), tremor associated with ...dystonia or primary writing tremor (PWT). We systematically reviewed the literature available up to July 2013 on the treatment of these tremors and retrieved the data of 487 patients published in 43 papers detailing the effects of given interventions on tremor severity. Treatment outcome was highly variable, depending on the specific type of intervention and tremor distribution. No specifically designed studies were available for the treatment of tremor associated with dystonia. As for the other tremors, drug efficacy was generally disappointing and a moderate effect was only found with anticholinergics, tetrabenazine, clonazepam, β-blockers and primidone; levodopa was only efficacious on tremor due to dopa-responsive dystonia. The largest amount of data was available for botulinum toxin injections, which provided a marked improvement, particularly for the management of axial tremors (head or vocal cords). In refractory DTs, deep brain stimulation of several targets was attempted. Deep brain stimulation of globus pallidus internus, thalamus or subthalamic area led to a marked improvement of dystonic axial or appendicular tremors in most cases refractory to other treatments. Few other non-invasive treatments, for example, orthotic device in PWT, have been used with anecdotal success. In conclusion, considering the lack of good-quality studies, future randomised controlled trials are needed. In absence of evidence-based guidelines, we propose an algorithm for the treatment of DT based on currently available data.
The emergence of antibiotic-resistance genes (ARGs) by means of integrons in multidrug-resistant Acinetobacter baumannii (MDR A. baumannii) has become a significant challenge in the management of ...infections from this pathogen. In this paper, we report on the variable region of class 1 and 2 integrons observed in MDR A. baumanni isolates recovered from rivers in the Eastern Cape Province, South Africa. Class 1 and 2 integrons with their variable regions were evaluated with polymerase chain reaction techniques followed by sequencing. Antibiotic sensitivity testing, checkerboard assay, time-kill independent assay, and Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR) were carried out using standard microbiological techniques. A total of fifty-six (56) isolates were examined, among which 45 (79%) tested positive for class 1 integron, and 7 (12.3%) had class 2 integron. None was found to be class 3 integron positive among the isolates. The variable region contained aadA1, aadA5, and aadA2 genes, which confer resistance against streptomycin and spectinomycin, aac(6')-Ib against amikacin/ tobramycin and dfrA17 genes against trimethoprim. The minimum inhibitory concentrations of the antimicrobials for one of the tested organisms were resistant against meropenem, colistin sodium methanesulfonate, tetracycline, ceftazidime, and ciprofloxacin (16, > 16, > 8, > 256, and 128 ug/mL respectively). The impact of colistin combined with quinolones (ciprofloxacin), with the FICIs (0.31) indicated synergistic effects against MDR A baumanni. However, when colistin was combined with meropenem and ceftazidime, additive effects with fractional inhibitory concentration (FIC) index ranging from 0.52 to 1 were observed. No antagonistic effect was evaluated among the examined isolates. ERIC-PCR analyses of A. baumanni isolates revealed significant genetic diversity, suggesting various sources of environmental contamination. We conclude that A. baumanni harbouring class 1 integrons in aquatic milieus are a significant source of ARGs and can transmit these elements to other organisms and consequently to man with significant public health implications.
Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less ...well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312.
•Chromosomal abnormalities predict outcome after relapse in BCP-ALL, and high-risk cytogenetics takes precedence over clinical risk factors.•Patients with mutations or deletions targeting TP53, NR3C1, BTG1, and NRAS were associated with clinical high risk and an inferior outcome.
In more than 30% of B-cell precursor acute lymphoblastic leukaemia (B-ALL), chromosome 21 sequence is overrepresented through aneuploidy or structural rearrangements, exemplified by intrachromosomal ...amplification of chromosome 21 (iAMP21). Although frequent, the mechanisms by which these abnormalities promote B-ALL remain obscure. Intriguingly, we found copy number neutral loss of heterozygosity (CN-LOH) of 12q was recurrent in iAMP21-ALL, but never observed in B-ALL without some form of chromosome 21 gain. As a consequence of CN-LOH 12q, mutations or deletions of the adaptor protein, SH2B3, were converted to homozygosity. In patients without CN-LOH 12q, bi-allelic abnormalities of SH2B3 occurred, but only in iAMP21-ALL, giving an overall incidence of 18% in this sub-type. Review of published data confirmed a tight association between overrepresentation of chromosome 21 and both CN-LOH 12q and SH2B3 abnormalities in B-ALL. Despite relatively small patient numbers, preliminary analysis linked 12q abnormalities to poor outcome in iAMP21-ALL (p = 0.03). Homology modelling of a leukaemia-associated SH2 domain mutation and in vitro analysis of patient-derived xenograft cells implicated the JAK/STAT pathway as one likely target for SH2B3 tumour suppressor activity in iAMP21-ALL.
Abstract
We have observed the
z
= 4.3 protocluster SPT2349−56 with the Australia Telescope Compact Array (ATCA) with the aim of detecting radio-loud active galactic nuclei (AGNs) among the ∼30 ...submillimeter (submm) galaxies (SMGs) identified in the structure. We detect the central complex of submm sources at 2.2 GHz with a luminosity of
L
2.2
= (4.42 ± 0.56) × 10
25
W Hz
−1
. MeerKAT and the Australian Square Kilometre Array Pathfinder also detect the source at 816 MHz and 888 MHz, respectively, constraining the radio spectral index to
α
= −1.45 ± 0.16, implying
L
1.4,rest
= (2.2 ± 0.2) × 10
26
W Hz
−1
. The radio observations do not have sufficient spatial resolution to uniquely identify one of the three Atacama Large Millimeter/submillimeter Array (ALMA) galaxies as the AGN, however the ALMA source properties themselves suggest a likely host. This radio luminosity is ∼100× higher than expected from star formation, assuming the usual far-infrared–radio correlation, indicating an AGN driven by a forming brightest cluster galaxy. None of the SMGs in SPT2349−56 show signs of AGNs in any other diagnostics available to us, highlighting the radio continuum as a powerful probe of obscured AGNs. We compare these results to field samples of radio sources and SMGs, along with the 22 gravitationally lensed SPT-SMGs also observed in the ATCA program, as well as powerful radio galaxies at high redshifts. The (3.3 ± 0.7) × 10
38
W of power from the radio-loud AGN sustained over 100 Myr is comparable to the binding energy of the gas mass of the central halo, and similar to the instantaneous energy injection from supernova feedback from the SMGs in the core region. The SPT2349−56 radio-loud AGNs may be providing strong feedback on a nascent intracluster medium.
Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the ...treatment with this drug should be initiated.
In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week.
A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4 points in the early-start group and 29.3±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0±13.1 points and -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval CI, -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04±0.23 in the early-start group and 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups.
Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).
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