Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, and diseased ...states. Phagocytosis is a highly complex process that is specialized for the uptake and removal of opsonized and non-opsonized targets, such as pathogens, apoptotic cells, and cellular debris. While the role of phagocytosis in mediating classical innate and adaptive immune responses has been known for decades, it is now appreciated that phagocytosis is also critical throughout early neural development, homeostasis, and initiating repair mechanisms. As such, modulating phagocytic processes has provided unexplored avenues with the intent of developing novel therapeutics that promote repair and regeneration in the CNS. Here, we review the functional consequences that phagocytosis plays in both the healthy and diseased CNS, and summarize how phagocytosis contributes to overall pathophysiological mechanisms involved in brain injury and repair.
Recapitulation of the tumor microenvironment is critical for probing mechanisms involved in cancer, and for evaluating the tumor-killing potential of chemotherapeutic agents, targeted therapies and ...immunotherapies. Microfluidic devices have emerged as valuable tools for both mechanistic studies and for preclinical evaluation of therapeutic agents, due to their ability to precisely control drug concentrations and gradients of oxygen and other species in a scalable and potentially high throughput manner. Most existing
in vitro
microfluidic cancer models are comprised of cultured cancer cells embedded in a physiologically relevant matrix, collocated with vascular-like structures. However, the recent emergence of immune checkpoint inhibitors (ICI) as a powerful therapeutic modality against many cancers has created a need for preclinical
in vitro
models that accommodate interactions between tumors and immune cells, particularly for assessment of unprocessed tumor fragments harvested directly from patient biopsies. Here we report on a microfluidic model, termed EVIDENT (
ex vivo
immuno-oncology dynamic environment for tumor biopsies), that accommodates up to 12 separate tumor biopsy fragments interacting with flowing tumor-infiltrating lymphocytes (TILs) in a dynamic microenvironment. Flow control is achieved with a single pump in a simple and scalable configuration, and the entire system is constructed using low-sorption materials, addressing two principal concerns with existing microfluidic cancer models. The system sustains tumor fragments for multiple days, and permits real-time, high-resolution imaging of the interaction between autologous TILs and tumor fragments, enabling mapping of TIL-mediated tumor killing and testing of various ICI treatments
versus
tumor response. Custom image analytic algorithms based on machine learning reported here provide automated and quantitative assessment of experimental results. Initial studies indicate that the system is capable of quantifying temporal levels of TIL infiltration and tumor death, and that the EVIDENT model mimics the known
in vivo
tumor response to anti-PD-1 ICI treatment of flowing TILs relative to isotype control treatments for syngeneic mouse MC38 tumors.
A system for perfusing and interacting tumor fragments and immune cells and testing drug response with image analytics is reported.
Aims
Among people with diabetes, 10–25% will experience a foot ulcer. Research has shown that supplementation with arginine, glutamine and β‐hydroxy‐β‐methylbutyrate may improve wound repair. This ...study tested whether such supplementation would improve healing of foot ulcers in persons with diabetes.
Methods
Along with standard of care, 270 subjects received, in a double‐blinded fashion, (twice per day) either arginine, glutamine and β‐hydroxy‐β‐methylbutyrate or a control drink for 16 weeks. The proportion of subjects with total wound closure and time to complete healing was assessed. In a post‐hoc analysis, the interaction of serum albumin or limb perfusion, as measured by ankle–brachial index, and supplementation on healing was investigated.
Results
Overall, there were no group differences in wound closure or time to wound healing at week 16. However, in subjects with an albumin level of ≤ 40 g/l and/or an ankle–brachial index of < 1.0, a significantly greater proportion of subjects in the arginine, glutamine and β‐hydroxy‐β‐methylbutyrate group healed at week 16 compared with control subjects (P = 0.03 and 0.008, respectively). Those with low albumin or decreased limb perfusion in the supplementation group were 1.70 (95% CI 1.04–2.79) and 1.66 (95% CI 1.15–2.38) times more likely to heal.
Conclusions
While no differences in healing were identified with supplementation in non‐ischaemic patients or those with normal albumin, addition of arginine, glutamine and β‐hydroxy‐β‐methylbutyrate as an adjunct to standard of care may improve healing of diabetic foot ulcers in patients with risk of poor limb perfusion and/or low albumin levels. Further investigation involving arginine, glutamine and β‐hydroxy‐β‐methylbutyrate in these high‐risk subgroups might prove clinically valuable.
What's new?
This manuscript constitutes, to our knowledge, the first multi‐centre, multinational, randomized trial evaluating the potential efficacy of oral nutritional supplementation on wound healing in diabetes.
The sensitivity curve of a canonical pulsar timing array is calculated for two types of source: a monochromatic wave and a stochastic background. These calculations are performed in both a Bayesian ...and frequentist framework, using both analytical and numerical methods. These calculations are used to clarify the interpretation of the sensitivity curves and to illustrate the sometimes overlooked fact that the sensitivity curve depends not only on the properties of the pulse time-of-arrival data set but also on the properties of the source being observed. The Bayesian and frequentist frameworks were found to give consistent results and the analytic and numerical calculations were also found to be in good agreement.
The flyby of Pluto and Charon by the New Horizons spacecraft provided high-resolution images of cratered surfaces embedded in the Kuiper belt, an extensive region of bodies orbiting beyond Neptune. ...Impact craters on Pluto and Charon were formed by collisions with other Kuiper belt objects (KBOs) with diameters from ~40 kilometers to ~300 meters, smaller than most KBOs observed directly by telescopes. We find a relative paucity of small craters ≲13 kilometers in diameter, which cannot be explained solely by geological resurfacing. This implies a deficit of small KBOs (≲1 to 2 kilometers in diameter). Some surfaces on Pluto and Charon are likely ≳4 billion years old, thus their crater records provide information on the size-frequency distribution of KBOs in the early Solar System.
We report on a terrestrial gamma ray flash (TGF) that occurred on 15 August 2014 coincident with an altitude‐triggered lightning at the International Center for Lightning Research and Testing (ICLRT) ...in North Central Florida. The TGF was observed by a ground‐level network of gamma ray, close electric field, distant magnetic field, Lightning Mapping Array (LMA), optical, and radar measurements. Simultaneous gamma ray and LMA data indicate that the upward positive leader of the triggered lightning flash induced relativistic runaway electron avalanches when the leader tip was at about 3.5 km altitude, resulting in the observed TGF. Channel luminosity and electric field data show that there was an initial continuous current (ICC) pulse in the lightning channel to ground during the time of the TGF. Modeling of the observed ICC pulse electric fields measured at close range (100–200 m) indicates that the ICC pulse current had both a slow and fast component (full widths at half maximum of 235 μs and 59 μs) and that the fast component was more or less coincident with the TGF, suggesting a physical association between the relativistic runaway electron avalanches and the ICC pulse observed at ground. Our ICC pulse model reproduces moderately well the measured close electric fields at the ICLRT as well as three independent magnetic field measurements made about 250 km away. Radar and LMA data suggest that there was negative charge near the region in which the TGF was initiated.
Key Points
Best documented TGF observed at ground
Second TGF induced by triggered lightning
An ICC pulse occurred simultaneously (within 20 μs) of the TGF
Intrahepatic cholestasis of pregnancy (ICP) has a complex aetiology with a significant genetic component. ABCB11 encodes the bile salt export pump (BSEP); mutations cause a spectrum of cholestatic ...disease, and are implicated in the aetiology of ICP.
ABCB11 variation in ICP was investigated by screening for five mutant alleles (E297G, D482G, N591S, D676Y and G855R) and the V444A polymorphism (c.1331T>C, rs2287622) in two ICP cohorts (n = 333 UK, n = 158 continental Europe), and controls (n = 261) for V444A. PCR primers were used to amplify and sequence patient and control DNA. The molecular basis for the observed phenotypes was investigated in silico by analysing the equivalent residues in the structure of the homologous bacterial transporter Sav1866.
E297G was observed four times and D482G once. N591S was present in two patients; D676Y and G855R were not observed. The V444A polymorphism was associated with ICP (allelic analysis for C vs T: OR 1.7 (95% CI 1.4 to 2.1, p<0.001)). In addition, CC homozygotes were more likely to have ICP than TT homozygotes: OR 2.8 (95% CI 1.7 to 4.4 p<0.0001). Structural analyses suggest that E297G and D482G destabilize the protein fold of BSEP. The molecular basis of V444A and N591S was not apparent from the Sav1866 structure.
Heterozygosity for the common ABCB11 mutations accounts for 1% of European ICP cases; these two mutants probably reduce the folding efficiency of BSEP. N591S is a recurrent mutation; however, the mechanism may be independent of protein stability or function. The V444A polymorphism is a significant risk factor for ICP in this population.
Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated ...cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas.
Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1–6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10–18 mg/kg) (Regimen B).
Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders.Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab.
Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing.
NCT01148849.
Following a major upgrade, the two advanced detectors of the Laser Interferometer Gravitational-wave Observatory (LIGO) held their first observation run between September 2015 and January 2016. With ...a strain sensitivity of 10^{-23}/sqrtHz at 100 Hz, the product of observable volume and measurement time exceeded that of all previous runs within the first 16 days of coincident observation. On September 14, 2015, the Advanced LIGO detectors observed a transient gravitational-wave signal determined to be the coalescence of two black holes B. P. Abbott et al., Phys. Rev. Lett. 116, 061102 (2016), launching the era of gravitational-wave astronomy. The event, GW150914, was observed with a combined signal-to-noise ratio of 24 in coincidence by the two detectors. Here, we present the main features of the detectors that enabled this observation. At full sensitivity, the Advanced LIGO detectors are designed to deliver another factor of 3 improvement in the signal-to-noise ratio for binary black hole systems similar in mass to GW150914.
The LIGO Scientific and Virgo Collaborations have announced the event GW170817, the first detection of gravitational waves from the coalescence of two neutron stars. The merger rate of binary neutron ...stars estimated from this event suggests that distant, unresolvable binary neutron stars create a significant astrophysical stochastic gravitational-wave background. The binary neutron star component will add to the contribution from binary black holes, increasing the amplitude of the total astrophysical background relative to previous expectations. In the Advanced LIGO-Virgo frequency band most sensitive to stochastic backgrounds (near 25 Hz), we predict a total astrophysical background with amplitude Ω_{GW}(f=25 Hz)=1.8_{-1.3}^{+2.7}×10^{-9} with 90% confidence, compared with Ω_{GW}(f=25 Hz)=1.1_{-0.7}^{+1.2}×10^{-9} from binary black holes alone. Assuming the most probable rate for compact binary mergers, we find that the total background may be detectable with a signal-to-noise-ratio of 3 after 40 months of total observation time, based on the expected timeline for Advanced LIGO and Virgo to reach their design sensitivity.
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