1,014 research outputs found
Humanin G (HNG) protects age-related macular degeneration (AMD) transmitochondrial ARPE-19 cybrids from mitochondrial and cellular damage.
Age-related macular degeneration (AMD) ranks third among the leading causes of visual impairment with a blindness prevalence rate of 8.7%. Despite several treatment regimens, such as anti-angiogenic drugs, laser therapy, and vitamin supplementation, being available for wet AMD, to date there are no FDA-approved therapies for dry AMD. Substantial evidence implicates mitochondrial damage and retinal pigment epithelium (RPE) cell death in the pathogenesis of AMD. However, the effects of AMD mitochondria and Humanin G (HNG), a more potent variant of the mitochondrial-derived peptide (MDP) Humanin, on retinal cell survival have not been elucidated. In this study, we characterized mitochondrial and cellular damage in transmitochondrial cybrid cell lines that contain identical nuclei but possess mitochondria from either AMD or age-matched normal (Older-normal (NL)) subjects. AMD cybrids showed (1) reduced levels of cell viability, lower mtDNA copy numbers, and downregulation of mitochondrial replication/transcription genes and antioxidant enzyme genes; and (2) elevated levels of genes related to apoptosis, autophagy and ER-stress along with increased mtDNA fragmentation and higher susceptibility to amyloid-β-induced toxicity compared to NL cybrids. In AMD cybrids, HNG protected the AMD mitochondria, reduced pro-apoptosis gene and protein levels, upregulated gp130 (a component of the HN receptor complex), and increased the protection against amyloid-β-induced damage. In summary, in cybrids, damaged AMD mitochondria mediate cell death that can be reversed by HNG treatment. Our results also provide evidence of Humanin playing a pivotal role in protecting cells with AMD mitochondria. In the future, it may be possible that AMD patient's blood samples containing damaged mitochondria may be useful as biomarkers for this condition. In conclusion, HNG may be a potential therapeutic target for treatment of dry AMD, a debilitating eye disease that currently has no available treatment. Further studies are needed to establish HNG as a viable mitochondria-targeting therapy for dry AMD
Subcutaneous Delivery of Nanoconjugated Doxorubicin and Cisplatin for Locally Advanced Breast Cancer Demonstrates Improved Efficacy and Decreased Toxicity at Lower Doses Than Standard Systemic Combination Therapy In Vivo
Background—Combination cytotoxic agents in breast cancer carry dose-limiting toxicities. We
hypothesize that nanocarrier-conjugated doxorubicin and cisplatin will have improved tumor
efficacy with decreased systemic toxicity over standard drugs, even at lower doses.
Methods—Female Nu/Nu mice were injected in the breast with human MDA-MB-468LN cells
and treated with either standard or nanocarrier-conjugated combination therapy (doxorubicin
+cisplatin) at 50% or 75% MTD, and monitored for efficacy and toxicity over 12-weeks.
Results—Efficacy results for mice treated with HA-conjugated doxorubicin/cisplatin at 50%
MTD include:[complete responses(CR)=5, partial responses(PR)=2, and stable disease(SD)=1]and
for HA-conjugated dox/cis at 75% MTD:[CR=7,PR=1; all CR’s confirmed histologically]. In
comparison, mice given standard dox/cis(50% MTD)demonstrated:[progressive disease(PD)=6,
SD=1, and PR=1] and for standard dox/cis(75% MTD):[PD=5,SD=3; p<0.0001 on multivariate
ANOVA]. At 75% MTD, standard drug-treated mice had significant weight loss compared to
nanocarrier drug-treated mice(p<0.001).
Conclusion—Subcutaneous nanocarrier-delivery of doxorubicin and cisplatin demonstrated
significantly improved efficacy with decreased toxicity compared to standard agent combination
therapy at all doses tested achieving complete pathologic tumor response
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Safe use of symbols in handover documentation for medical teams
Concern has been reported about the safe use of medical abbreviations in documents such as handover sheets and medical notes, especially when information is being communicated between staff of different specialties (BBC 2008, Sheppard et al. 2008). This article describes a study to investigate whether the use of symbols in handover documentation that is shared within and between multidisciplinary teams (MDTs) has similar safety implications. We asked 19 healthcare professionals from a range of specialties to identify 45 different combinations of 38 individual symbols. The symbols and combinations of symbols were extracted from 102 handover sheets taken from 6 different healthcare contexts in 4 London hospitals. Three symbols proposed in Microsoft's Common User Interface guidelines for alert symbols were also included. Results reveal that while some symbols are well understood, many others are either ambiguous or unknown. These results have implications for the safe use of symbols in medical documents, including paper and electronic handover documents and Electronic Patient Records (EPRs), especially where teams comprise individuals from different professional backgrounds, i.e. MDTs. We offer initial suggestions for standardisation and further research
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Digit Span Ratio, Joint Laxity, and Muscular Strength as Predisposing Factors for Female ACL Injuries
Females more commonly injure their anterior cruciate ligament (ACL) in
athletics than do males. Despite many studies researching anatomical, neuromuscular,
and hormonal causes, the predisposing risk factors behind this occurrence are currently
unknown. This study compared 5 females who had injured their ACL to 15 healthy
females concentrating on three dependent variables. The first variable measured was
digit span ratio of the second and fourth digits because previous studies suggest that this
ratio is related to prenatal sex hormones that affect visual-spatial abilities. The next
variable was knee joint laxity using an arthrometer to measure the stiffness of the ACL.
The last variable tested was the muscular strength of the quadriceps and hamstrings
using the Biodex dynamometer. The strength of these muscle groups is suggested in the
literature to be a risk factor for ACL injuries because they protect the knee joint. After
analysis, the three variables were not shown to be significantly different between the
two female populations. Further research is needed to determine what factors
predispose females to ACL injuries. Knowing these factors may allow for prediction of
group membership for females who have torn their ACL and for females who have not
Chandra HETGS Multiphase Spectroscopy Of The Young Magnetic O Star Theta(1) Orionis C
We report on four Chandra grating observations of the oblique magnetic rotator theta(1) Ori C (O5.5 V), covering a wide range of viewing angles with respect to the star\u27s 1060 G dipole magnetic field. We employ line-width and centroid analyses to study the dynamics of the X-ray - emitting plasma in the circumstellar environment, as well as line-ratio diagnostics to constrain the spatial location, and global spectral modeling to constrain the temperature distribution and abundances of the very hot plasma. We investigate these diagnostics as a function of viewing angle and analyze them in conjunction with new MHD simulations of the magnetically channeled wind shock mechanism on theta(1) Ori C. This model fits all the data surprisingly well, predicting the temperature, luminosity, and occultation of the X-ray - emitting plasma with rotation phase
Novel C-Terminal Hsp90 Inhibitor for Head and Neck Squamous Cell Cancer (HNSCC) with in vivo Efficacy and Improved Toxicity Profiles Compared with Standard Agents
The final publication is available at Springer via http://dx.doi.org/10.1245/s10434-011-1971-1.Background - Current therapies for HNSCC, especially platinum agents, are limited by their toxicities and drug resistance. This study evaluates a novel C-terminal Hsp90 inhibitor (CT-Hsp90-I) for efficacy and toxicity in vitro and in vivo in an orthotopic HNSCC model. Our hypothesis is that C-terminal inhibitors exhibit improved toxicity/efficacy profiles over standard therapies and may represent a novel group of anticancer agents.
Methods - MDA-1986 HNSCC cells were treated with doses of 17-AAG or KU363 (a CT-Hsp90-I) and compared for antiproliferation by GLO-Titer and trypan blue exclusion and for apoptosis by PARP cleavage and caspase-3 inactivation by Western analysis. In vivo studies in Nu/Nu mice examined an orthotopic model of MDA-1986 cells followed by drug dosing intraperitoneally for a 21-day period (mg/kg/dose: cisplatin = 3.5, low-dose KU363 = 5, high-dose KU363 = 25, 17-AAG = 175). Tumor size, weight, and toxicity (body score) were measured 3Ă—/week.
Results - The IC50 levels for KU363 = 1.2–2 μM in MDA-1986. KU363 induces apoptosis at 1 μM with cleavage of PARP and inactivation of caspase-3 levels after 24 h. Client proteins Akt and Raf-1 were also downregulated at 1–3 μM of drug. In vivo, 100% of controls had progressive disease, while 100% of cisplatin animals showed some response, all with significant systemic toxicity. High-dose KU363 showed 88% of animals responding and low-dose KU363 showed 75% responding. KU363 animals showed significantly less toxicity (P < 0.01) than cisplatin or 17-AAG.
Conclusion - This novel CT-Hsp90-I KU363 manifests potent anticancer activity against HNSCC, showing excellent in vivo efficacy and reduced toxicity compared with standard agents justifying future translational evaluation
Genome-wide sequence and functional analysis of early replicating DNA in normal human fibroblasts
BACKGROUND: The replication of mammalian genomic DNA during the S phase is a highly coordinated process that occurs in a programmed manner. Recent studies have begun to elucidate the pattern of replication timing on a genomic scale. Using a combination of experimental and computational techniques, we identified a genome-wide set of the earliest replicating sequences. This was accomplished by first creating a cosmid library containing DNA enriched in sequences that replicate early in the S phase of normal human fibroblasts. Clone ends were then sequenced and aligned to the human genome. RESULTS: By clustering adjacent or overlapping early replicating clones, we identified 1759 "islands" averaging 100 kb in length, allowing us to perform the most detailed analysis to date of DNA characteristics and genes contained within early replicating DNA. Islands are enriched in open chromatin, transcription related elements, and Alu repetitive elements, with an underrepresentation of LINE elements. In addition, we found a paucity of LTR retroposons, DNA transposon sequences, and an enrichment in all classes of tandem repeats, except for dinucleotides. CONCLUSION: An analysis of genes associated with islands revealed that nearly half of all genes in the WNT family, and a number of genes in the base excision repair pathway, including four of ten DNA glycosylases, were associated with island sequences. Also, we found an overrepresentation of members of apoptosis-associated genes in very early replicating sequences from both fibroblast and lymphoblastoid cells. These data suggest that there is a temporal pattern of replication for some functionally related genes
Restricted Dislocation Motion in Crystals of Colloidal Dimer Particles
At high area fractions, monolayers of colloidal dimer particles form a
degenerate crystal (DC) structure in which the particle lobes occupy triangular
lattice sites while the particles are oriented randomly along any of the three
lattice directions. We report that dislocation glide in DCs is blocked by
certain particle orientations. The mean number of lattice constants between
such obstacles is 4.6 +/- 0.2 in experimentally observed DC grains and 6.18 +/-
0.01 in simulated monocrystalline DCs. Dislocation propagation beyond these
obstacles is observed to proceed through dislocation reactions. We estimate
that the energetic cost of dislocation pair separation via such reactions in an
otherwise defect free DC grows linearly with final separation, hinting that the
material properties of DCs may be dramatically different from those of 2-D
crystals of spheres
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Neurocognitive therapeutics: from concept to application in the treatment of negative attention bias
There is growing interest in the use of neuroimaging for the direct treatment of mental illness. Here, we present a new framework for such treatment, neurocognitive therapeutics. What distinguishes neurocognitive therapeutics from prior approaches is the use of precise brain-decoding techniques within a real-time feedback system, in order to adapt treatment online and tailor feedback to individuals’ needs. We report an initial feasibility study that uses this framework to alter negative attention bias in a small number of patients experiencing significant mood symptoms. The results are consistent with the promise of neurocognitive therapeutics to improve mood symptoms and alter brain networks mediating attentional control. Future work should focus on optimizing the approach, validating its effectiveness, and expanding the scope of targeted disorders
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