The combined cardiovascular effects of hemorrhagic shock and mechanical brain injury were modeled in five groups of pigs. Standard and hypertonic saline resuscitation of hypotension were evaluated. ...Changes in mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), intracranial pressure (ICP), and brain water were measured. Brain injury (BI) was produced with a fluid percussion device that generated an extradural pressure of 3.5 × 105 N/m2 for 400 msec. Shock was caused by bleeding to a MAP of 60 mm Hg for 60 minutes and then resuscitated with shed blood only or shed blood plus 0.9% or 1.8% saline. Brain-injured only and shocked-only pigs served as controls.
We found that brain injury alone caused refractory hypotension. Less shed blood was required to produce shock in brain injured animals (p <. 05). Shock accompanied by brain injury was not reversed with crystalloid solutions. Volumes of saline required to restore blood pressure were large (>6 L in 3 hours). 1.8% saline produced less rise in ICP than 0.9% saline but was less effective in restoring blood pressure. Brain edema was not decreased with 1.8% saline. Brain injury altered vascular compensation to hemorrhage and made accepted resuscitative measures ineffective.
DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the ...intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.
Background
We completed a large genetic analysis of resilience to cognitive decline in Alzheimer’s Disease (AD) and discovered novel variants, genes, and complex traits associated with better‐than or ...worse‐than‐expected cognitive performance given an individual’s age, sex, and APOE genotype.
Method
Leveraging 15,933 non‐Hispanic white participants across four longitudinal cohort studies of aging and AD (Figure 1), our group determined the effects of genetic variants on resilience metrics using mixed‐effects regressions. Models adjusted for age, sex, APOE ε4 allele count, presence of the APOE ε2 allele and all covariate interactions with interval (years from baseline). The outcomes of interest were residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function, and language), and combined resilience, summarized as the covariance of educational attainment with residual cognitive resilience. Post‐GWAS analyses included gene tests using MAGMA and estimates of genetic correlation with 65 complex traits using GNOVA.
Result
We observed genome‐wide significant associations at multiple established AD loci, including BIN1 and CR1 (Figure 2). We observed a novel association with combined resilience on chromosome 13 (top SNP: rs11838654, MAF = 0.06, P = 4.7×10−8; Figure 3) and a novel signal on chromosome 1 approaching significance (top SNP: rs2817183, MAF = 0.41, P = 5.1×10−8). Interestingly, rs11838654 is an eQTL for four genes in hippocampus (WBP4, COG6, MRPS31, and NHLRC3I; Braineac database). We also observed an association with residual cognitive resilience on chromosome 5 that approached genome‐wide significance (top SNP: rs4482935, MAF = 0.25, P = 5.5×10−8; Figure 2). Gene‐level tests identified associations of CD2AP (P.fdr = 0.027) and ZNF146 (P.fdr = 0.049) with residual cognitive resilience and combined resilience, respectively. Additionally, we identified negative genetic correlations of combined resilience with ischemic stroke and coronary artery disease (all P.fdr<2.5×10−2; Figure 4).
Conclusion
Compared to models of resilience that regress out the effects of AD neuropathology on cognition, the present models benefit from larger sample size at the cost of molecular precision. Although the genetic architecture of resilience from these less precise models more closely resembles that of clinical AD, we uncovered novel genetic drivers of resilience through this approach. Such findings will require future replication but suggest a trajectory‐based definition of resilience holds substantial promise for discovery.
A physical map of the human genome McPherson, J D; Marra, M; Waterston, R H ...
Nature (London),
02/2001, Letnik:
409, Številka:
6822
Journal Article
Recenzirano
Odprti dostop
The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium ...constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Two-dimensional materials are promising for a range of applications, as well as testbeds for probing the physics of low-dimensional systems. Tungsten disulfide (WS
) monolayers exhibit a direct band ...gap and strong photoluminescence (PL) in the visible range, opening possibilities for advanced optoelectronic applications. Here, we report the realization of two-dimensional nanometer-size pores in suspended monolayer WS
membranes, allowing for electrical and optical response in ionic current measurements. A focused electron beam was used to fabricate nanopores in WS
membranes suspended on silicon-based chips and characterized using PL spectroscopy and aberration-corrected high-resolution scanning transmission electron microscopy. It was observed that the PL intensity of suspended WS
monolayers is ∼10-15 times stronger when compared to that of substrate-supported monolayers, and low-dose scanning transmission electron microscope viewing and drilling preserves the PL signal of WS
around the pore. We establish that such nanopores allow ionic conductance and DNA translocations. We also demonstrate that under low-power laser illumination in solution, WS
nanopores grow slowly in size at an effective rate of ∼0.2-0.4 nm/s, thus allowing for atomically controlled nanopore size using short light pulses.
The D/H ratio in cometary water is believed to be an important indicator of the conditions under which icy planetesimals formed and can provide clues to the contribution of comets to the delivery of ...water and other volatiles to Earth. Available measurements suggest that there is isotopic diversity in the comet population. The Herschel Space Observatory revealed an ocean-like ratio in the Jupiter-family comet 103P/Hartley 2, whereas most values measured in Oort-cloud comets are twice as high as the ocean D/H ratio. We present here a new measurement of the D/H ratio in the water of an Oort-cloud comet. HDO, H2O, and \hbox{$\mathrm{H}_2^{18}\mathrm{O}$}H218O lines were observed with high signal-to-noise ratio in comet C/2009 P1 (Garradd) using the Herschel HIFI instrument. Spectral maps of two water lines were obtained to constrain the water excitation. The D/H ratio derived from the measured H216O and HDO production rates is (2.06 ± 0.22) × 10-4. This result shows that the D/H in the water of Oort-cloud comets is not as high as previously thought, at least for a fraction of the population, hence the paradigm of a single, archetypal D/H ratio for all Oort-cloud comets is no longer tenable. Nevertheless, the value measured in C/2009 P1 (Garradd) is significantly higher than the Earth’s ocean value of 1.558 × 10-4. The measured 16O/18O ratio of 523 ± 32 is, however, consistent with the terrestrial value.
We report on the initial analysis of Herschel/HIFI carbon monoxide (CO) observations of the Martian atmosphere performed between 11 and 16 April 2010. We selected the (7–6) rotational transitions of ...the isotopes 13CO at 771 GHz and C18O and 768 GHz in order to retrieve the mean vertical profile of temperature and the mean volume mixing ratio of carbon monoxide. The derived temperature profile agrees within less than 5 K with general circulation model (GCM) predictions up to an altitude of 45 km, however, show about 12–15 K lower values at 60 km. The CO mixing ratio was determined as 980 ± 150 ppm, in agreement with the 900 ppm derived from Herschel/SPIRE observations in November 2009.
Abstract
Checkpoint inhibitor therapies (CPI) have shown great promise, however in a limited percentage of patients. One of the key mechanisms behind the limited efficacy of CPI therapy is immune ...resistance mediated by immunosuppressive myeloid cells at the tumor microenvironment (TME), namely M2 macrophages and myeloid-derived suppressor cells (MDSC). Multiple therapeutic interventions are being developed to target these cell types with the intention of reshaping the TME and enhancing the effector functions of the infiltrating cytotoxic T cells.Molecules containing pathogen associated molecular patterns (PAMPS) are one of the unique combination partners that can sensitize tumors to respond to CPI. Imprime PGG (Imprime), an intravenously administered soluble yeast β-1,3/1,6 glucan PAMP, is being clinically developed in combination with tumor-targeting antibodies, anti-angiogenics, and CPI. Imprime has shown promising results in two randomized phase 2 studies in non-small cell lung cancer. Mechanistic studies have shown Imprime to repolarize M2 macrophages and MDSC in in vitro human systems as well as multiple xenograft models. The objective of this study was to evaluate Imprime’s ability to counteract immunosuppression and thereby influence the effector functions of T cells in a syngeneic tumor model. To this end, we first evaluated the anti-tumor efficacy of Imprime in combination with anti-PD-1 or anti-PD-L1 antibody in the MC-38 colon cancer model and found that both combinations repressed tumor growth more effectively than either single agent. Flow cytometric evaluation of single cell suspensions of spleen and tumor tissue after one week of Imprime dosing revealed that the tumor associated macrophages showed a shift to an M1-like phenotype with increased expression of PD-L1, CD86, inducible nitric oxide synthase, MHC class II and downmodulation of Arginase-1. qRT-PCR analyses also demonstrated an increase in transcripts for M1 markers (Il12b p35, Ifng, Tnfa) with a coincident decrease in transcripts for M2 markers (VEGF, Fizz1, CCL17). Adaptive immune resistance, increased PD-L1 expression on the tumor cells as a result of immune activation was observed. In the spleen, the monocytic MDSC also showed increased expression of M1 markers. Furthermore, increased number of CD8 cells in the spleen were of effector memory phenotype with enhanced expression of PD-1, granzyme B, and Ki-67. At the tumor site, the CD8 cells from Imprime treated mice demonstrated increased proliferative and cytokine producing capabilities (IL-2, IFNg, and TNFa) in response to CD3/CD28 stimulation. Collectively, these data show that Imprime’s ability to remold the TME such that the myeloid cells are less suppressive and the cytotoxic T cells are more functionally active can have a tremendous impact on overcoming resistance to CPI therapy.
Citation Format: Adria B. Jonas, Anissa SH Chan, Xiaohong Qiu, Kathryn Fraser, Nadine Ottoson, Takashi Kangas, Richard Walsh, Steven M. Leonardo, Ross Fulton, Keith Gorden, Mark Uhlik, Jeremy Graff, Nandita Bose. Imprime PGG modulates immunosuppressive myeloid components of the tumor microenvironment and drives enhanced antitumor efficacy in combination with checkpoint inhibitor therapies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-199. doi:10.1158/1538-7445.AM2017-LB-199
Neural ectopic rewiring in retinal degeneration such as retinitis pigmentosa (RP) may form functional synapses between cones and rod bipolar cells that cause atypical signal processing. In this ...study, the multifocal electroretinograms (mfERGs) of a large animal model of RP, the rhodopsin P347L transgenic (Tg) pig, were measured to examine the sources and nature of altered signal processing.
mfERG responses from a 6-week-old Tg pig were recorded before and after sequential application of tetrodotoxin (TTX), N-methyl-D-aspartate (NMDA), 2-amino-4-phosphonobutyric acid (APB), and cis-2,3-piperidinedicarboylic acid (PDA), to identify contributions to the retinal signal from inner retinal neurons, the ON-pathway, the OFF-pathway, and photoreceptors. The mfERG response contributions from different retinal components of in the Tg eyes were estimated and compared with control data from eyes of age-matched wild-type (WT) pigs.
There was a prominent difference in the estimates of the inner retinal response and ON-bipolar cell pathway contribution between the Tg and WT mfERG responses. In particular, the early components of the inner retinal contribution were obviously altered in the Tg mfERG. The inner retinal components at approximately 24 and 40 ms appeared to be inverted. Differences in the estimates of OFF-bipolar cell pathway contributions were minimal. There was no change in cone cell responses in the Tg mfERG.
In Tg retinas, ectopic synapses formed between cones and rod bipolar cells probably altered signal processing of the ON-bipolar cell pathway. In response to the altered visual signal input from the outer retina, signal processing in inner retinal neurons was also modified.
We use the SPIRE Fourier-transform spectrometer (FTS) on-board the ESA Herschel Space Observatory to analyse the submillimetre spectrum of the Ultra-compact HII region G29.96-0.02. Spectral lines ...from species including 13CO, CO, CI, and NII are detected. A sparse map of the NII emission shows at least one other HII region neighbouring the clump containing the UCHII. The FTS spectra are combined with ISO SWS and LWS spectra and fluxes from the literature to present a detailed spectrum of the source spanning three orders of magnitude in wavelength. The quality of the spectrum longwards of 100 μm allows us to fit a single temperature greybody with temperature 80.3±0.6 K and dust emissivity index 1.73±0.02, an accuracy rarely obtained with previous instruments. We estimate a mass of 1500 $M_\odot$ for the clump containing the HII region. The clump's bolometeric luminosity of 4×106 $L_\odot$ is comparable to, or slightly greater than, the known O-star powering the UCHII region.
PDF
