A kilonova as the electromagnetic counterpart to a gravitational-wave source.

Gravitational waves were discovered with the detection of binary black-hole mergers and they should also be detectable from lower-mass neutron-star mergers. These are predicted to eject material rich in heavy radioactive isotopes that can power an electromagnetic signal. This signal is luminous at optical and infrared wavelengths and is called a kilonova. The gravitational-wave source GW170817 arose from a binary neutron-star merger in the nearby Universe with a relatively well confined sky position and distance estimate. Here we report observations and physical modelling of a rapidly fading electromagnetic transient in the galaxy NGC 4993, which is spatially coincident with GW170817 and with a weak, short γ-ray burst. The transient has physical parameters that broadly match the theoretical predictions of blue kilonovae from neutron-star mergers. The emitted electromagnetic radiation can be explained with an ejected mass of 0.04 ± 0.01 solar masses, with an opacity of less than 0.5 square centimetres per gram, at a velocity of 0.2 ± 0.1 times light speed. The power source is constrained to have a power-law slope of -1.2 ± 0.3, consistent with radioactive powering from r-process nuclides. (The r-process is a series of neutron capture reactions that synthesise many of the elements heavier than iron.) We identify line features in the spectra that are consistent with light r-process elements (atomic masses of 90-140). As it fades, the transient rapidly becomes red, and a higher-opacity, lanthanide-rich ejecta component may contribute to the emission. This indicates that neutron-star mergers produce gravitational waves and radioactively powered kilonovae, and are a nucleosynthetic source of the r-process elements.

Branch-Selective and Enantioselective Iridium-Catalyzed Alkene Hydroarylation via Anilide-Directed C-H Oxidative Addition.

Tertiary benzylic stereocenters are accessed in high enantioselectivity by Ir-catalyzed branch selective addition of anilide ortho-C-H bonds across styrenes and α-olefins. Mechanistic studies indicate that the stereocenter generating step is reversible.

Iridium-Catalyzed α-Selective Arylation of Styrenes by Dual C-H Functionalization.

An IrI -system modified with a ferrocene derived bisphosphine ligand promotes α-selective arylation of styrenes by dual C-H functionalization. These studies offer a regioisomeric alternative to the Pd-catalyzed Fujiwara-Moritani reaction.

p-Type Transparent Conducting Oxide/n-Type Semiconductor Heterojunctions for Efficient and Stable Solar Water Oxidation.

Achieving stable operation of photoanodes used as components of solar water splitting devices is critical to realizing the promise of this renewable energy technology. It is shown that p-type transparent conducting oxides (p-TCOs) can function both as a selective hole contact and corrosion protection layer for photoanodes used in light-driven water oxidation. Using NiCo2O4 as the p-TCO and n-type Si as a prototypical light absorber, a rectifying heterojunction capable of light driven water oxidation was created. By placing the charge separating junction in the Si using a np(+) structure and by incorporating a highly active heterogeneous Ni-Fe oxygen evolution catalyst, efficient light-driven water oxidation can be achieved. In this structure, oxygen evolution under AM1.5G illumination occurs at 0.95 V vs RHE, and the current density at the reversible potential for water oxidation (1.23 V vs RHE) is >25 mA cm(-2). Stable operation was confirmed by observing a constant current density over 72 h and by sensitive measurements of corrosion products in the electrolyte. In situ Raman spectroscopy was employed to investigate structural transformation of NiCo2O4 during electrochemical oxidation. The interface between the light absorber and p-TCO is crucial to produce selective hole conduction to the surface under illumination. For example, annealing to produce more crystalline NiCo2O4 produces only small changes in its hole conductivity, while a thicker SiOx layer is formed at the n-Si/p-NiCo2O4 interface, greatly reducing the PEC performance. The generality of the p-TCO protection approach is demonstrated by multihour, stable, water oxidation with n-InP/p-NiCo2O4 heterojunction photoanodes.

Circulating CXCR5+CD4+helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. Recently, a specific highly activated T helper cell subset, follicular helper T (Tfh) cell, has emerged as a key immunoregulator of germinal center (GC) formation and high-affinity antibody production. To identify the pathophysiological role of Tfh cells in SLE patients, we compared the phenotypic and functional properties of circulating Tfh-like cells in lupus patients to GC-Tfh cells, and correlated the percentage of Tfh-like cells with autoantibody production and SLE disease activity. METHODS: Peripheral blood was collected from 29 lupus patients and 25 healthy controls. Tonsils were obtained surgically from non-SLE controls and used as a source of GC-Tfh cells. Tfh cells were defined by their signature surface markers (CXCR5, ICOS, CD57, PD-1 and BTLA) via flow cytometry. IL-21 expression levels from Tfh cells were measured by real-time PCR and intracellular staining. The function of Tfh cells was carried out by co-culture of Tfh cells and autologous B cells in vitro. IgG in the culture supernatant was detected by ELISA. RESULTS: The frequency of circulating Tfh-like cells was significantly increased in SLE patients compared to healthy controls (p < 0.05). The Tfh-like cells not only display similar phenotypes and signature cytokines with GC-Tfh cells, but also are capable of driving B cells to differentiate into IgG-secreting plasma cells in vitro. In addition, the frequency of Tfh-like cells correlated positively with the percentage of circulating plasmablasts, levels of serum anti-dsDNA antibodies and ANA. CONCLUSION: The accumulated circulating Tfh-like cells in lupus patients share phenotypic and functional properties with GC-Tfh cells. Tfh-like cells may serve as perpetuators in the pathogenesis of SLE by enhancing the self-reactive B cell clones to further differentiate into auto antibody-producing plasmablasts, and ultimately cause autoimmunity.

Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Atom and step economical synthesis of acyclic quaternary centers via iridium-catalyzed hydroarylative cross-coupling of 1,1-disubstituted alkenes.

Quaternary benzylic centers are accessed with high atom and step economy by Ir-catalyzed alkene hydroarylation. These studies provide unique examples of the use of non-polarized 1,1-disubstituted alkenes in branch selective Murai-type hydro(hetero)arylations. Detailed mechanistic studies have been undertaken, and these indicate that the first irreversible step is the demanding alkene carbometallation process. Structure-reactivity studies show that the efficiency of this is critically dependent on key structural features of the ligand. Computational studies have been undertaken to rationalize this experimental data, showing how more sterically demanding ligands reduce the reaction barrier via predistortion of the reacting intermediate. The key insight disclosed here will underpin the ongoing development of increasingly sophisticated branch selective Murai hydroarylations.

Radiological physics characteristics of the extracted heavy ion beams of the bevatron.

Studies of the depth-ionization properties and the biological effects of heavy ion beams produced at the bevatron have extended work previously done with less energetic beams from other sources. Results indicate that heavy ion beams are suitable for tumor therapy, studies relating to space biology, and fundamental radiobiology.

Changes in urinary dinor dihydro F(2)-isoprostane metabolite concentrations, a marker of oxidative stress, during and following asthma exacerbations.

To investigate changes in oxidant stress during and following acute asthma exacerbations, this study measured 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (F(2)-IsoP-M), the major urinary metabolite of 15-F(2t)-IsoP, in eight asthmatic adults, during and following an asthma hospitalization. F(2)-IsoP-M concentrations at admission and follow-up were significantly higher than discharge (admission median: 4.12 ng/Cr mg, range 1.89-7.8; follow-up: 2.47 ng/Cr mg (1.56-6.86); discharge: 1.42 ng/Cr mg (0.7-4.44); both p<0.01), but not significantly different between admission and follow-up. F(2)-IsoP-M concentrations at follow-up were higher than a control group with stable asthma (0.68 ng/Cr mg (0.31-1.5), p=0.0008). In conclusion, asthma exacerbations requiring hospitalization are associated with 6-fold higher urinary F(2)-IsoP-M concentrations compared to stable asthmatics. F(2)-IsoP-M concentrations decreased significantly during hospitalization, but significant elevations 3 months following hospitalization suggest ongoing oxidative stress despite clinical improvement. Urinary F(2)-IsoP-M may be a clinically useful, simple non-invasive systemic measure of oxidative stress in asthmatics, providing information not captured by spirometry or symptoms.

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR.

RECK controls breast cancer metastasis by modulating a convergent, STAT3-dependent neoangiogenic switch.

Metastasis is the primary cause of cancer-related death in oncology patients. A comprehensive understanding of the molecular mechanisms that cancer cells usurp to promote metastatic dissemination is critical for the development and implementation of novel diagnostic and treatment strategies. Here we show that the membrane protein RECK (Reversion-inducing cysteine-rich protein with kazal motifs) controls breast cancer metastasis by modulating a novel, non-canonical and convergent signal transducer and activator of transcription factor 3 (STAT3)-dependent angiogenic program. Neoangiogenesis and STAT3 hyperactivation are known to be fundamentally important for metastasis, but the root molecular initiators of these phenotypes are poorly understood. Our study identifies loss of RECK as a critical and previously unknown trigger for these hallmarks of metastasis. Using multiple xenograft mouse models, we comprehensively show that RECK inhibits metastasis, concomitant with a suppression of neoangiogenesis at secondary sites, while leaving primary tumor growth unaffected. Further, with functional genomics and biochemical dissection we demonstrate that RECK controls this angiogenic rheostat through a novel complex with cell surface receptors to regulate STAT3 activation, cytokine signaling, and the induction of both vascular endothelial growth factor and urokinase plasminogen activator. In accordance with these findings, inhibition of STAT3 can rescue this phenotype both in vitro and in vivo. Taken together, our study uncovers, for the first time, that RECK is a novel regulator of multiple well-established and robust mediators of metastasis; thus, RECK is a keystone protein that may be exploited in a clinical setting to target metastatic disease from multiple angles.

Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.

The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.

Normal tissue complication probabilities: variable dose per fraction.

Because of the large amount of data generated by 3D treatment planning, new tools are being developed for the evaluation and optimization of the plans. Estimates of the probability of local control of the tumor and for the probability of specific normal tissue complications are among the new tools. The normal tissue complication probability (NTCP) is based on clinical estimates of the tolerance doses for specific tissues/organs. These tolerance doses are assumed to apply for uniform partial and full volume irradiations delivered at 2 Gy per fraction and 5 fractions per week. A different tolerance dose may apply when the dose is delivered at a different dose per fraction and over a different period of time. This study evaluates the maximum change expected in the NTCP when the normal structure receives the dose at a different dose per fraction than the target volume due to different choices in the delivery of the daily fraction.

Optimization of radiation therapy, III: A method of assessing complication probabilities from dose-volume histograms.

To predict the likelihood of success of a therapeutic strategy, one must be able to assess the effects of the treatment upon both diseased and healthy tissues. This paper proposes a method for determining the probability that a healthy organ that receives a non-uniform distribution of X-irradiation, heat, chemotherapy, or other agent will escape complications. Starting with any given dose distribution, a dose-cumulative-volume histogram for the organ is generated. This is then reduced by an interpolation scheme (involving the volume-weighting of complication probabilities) to a slightly different histogram that corresponds to the same overall likelihood of complications, but which contains one less step. The procedure is repeated, one step at a time, until there remains a final, single-step histogram, for which the complication probability can be determined. The formalism makes use of a complication response function C(D, V) which, for the given treatment schedule, represents the probability of complications arising when the fraction V of the organ receives dose D and the rest of the organ gets none. Although the data required to generate this function are sparse at present, it should be possible to obtain the necessary information from in vivo and clinical studies. Volume effects are taken explicitly into account in two ways: the precise shape of the patient's histogram is employed in the calculation, and the complication response function is a function of the volume.

Optimization of radiation therapy, IV: A dose-volume histogram reduction algorithm.

A general formalism for estimating the complication probability for non-uniform irradiation of a normal tissue structure has been developed and used by the NCI-sponsored committee on "Evaluation of Treatment Planning for Particle Beam Radiotherapy." The approach involves reducing an N-step dose-volume histogram for the tissue (obtained from the 3D treatment plan) to an equivalent (N-1)-step histogram; this procedure is repeated until there remains a single-step histogram, the complication probability of which can readily be determined. This note provides technical details concerning the histogram-reduction algorithm. Results obtained using it are compared with those for two alternative histogram-reduction algorithms.

Heavy charged-particle induced lesions in rabbit cerebral cortex.

Fourteen male rabbits received single doses of 20, 40, and 80 Gy of neon irradiation with an extended Bragg peak. They were sacrificed at 1 day, 1 week, and 6 months post-irradiation. The tissue changes which showed a significant time-dose relationship were leakage of carbon particles from blood vessels, focal arachnoiditis, hemorrhage, cystic necrosis, and a total histopathologic score using a point system of grading. The focal nature of the lesions was clearly demonstrated with 2 mm thick macrotome sections. The transition zone between damaged brain and microscopically normal appearing brain was less than 1 mm and the tissue damage induced was morphologically similar to that of other radiation modalities. These findings may have important therapeutic implications for patients. The sharply demarcated boundaries of heavy charged-particle induced lesions suggest these beams will be useful for obliterating tissue in areas where it is critical that a transition from undamaged to severely damaged tissue must occur over a short distance, such as in the central nervous system.

Heavy charged-particle stereotactic radiosurgery: cerebral angiography and CT in the treatment of intracranial vascular malformations.

A method is described for stereotactic localization of intracranial arteriovenous malformations (AVM) and for calculating treatment plans for heavy charged-particle Bragg peak radiosurgery. A stereotactic frame and head immobilization system is used to correlate the images of multivessel cerebral angiography and computed tomography. The AVM is imaged by angiography, and the frame provides the stereotactic coordinates for transfer of this target to CT images for the calculation of treatment plans. The CT data are used to calculate the residual ranges and compensation for the charged-particle beam required for each treatment port. Three-dimensional coordinates for the patient positioner are calculated, and stereotactic radiosurgery is performed. Verification of the accuracy of the stereotactic positioning is obtained with computer-generated overlays of the vascular malformation, stereotactic fiducial markers, and bony landmarks on orthogonal radiographs immediately prior to treatment. Using these procedures, the accuracy of the repositioning of the patient at each of a series of imaging and treatment procedures is typically within 1 mm in each of three orthogonal planes.

Comparison of different radiation types and irradiation geometries in stereotactic radiosurgery.

Recent interest in stereotactic radiosurgery of intracranial lesions, and the development of stereotactic irradiation techniques has led to the need for a systematic and complete comparison of these methods. A method for conducting these comparisons is proposed and is applied to a set of currently-used stereotactic radiosurgical techniques. Three-dimensional treatment planning calculations are used to compare dose distributions for several different radiation types and irradiation geometries. Calculations were performed using charged particles (H, He, C, and Ne ions) and the irradiation geometry currently used at Lawrence Berkeley Laboratory. Photons in the Gamma Knife configuration and the Heidelberg Linac arc method are used. The 3-dimensional dose distributions were evaluated by means of dose-volume histograms and integral doses to the target volume and to normal brain. The effects of target volume, shape and location are studied. The charged particle dose distributions are more favorable than those of the photon methods. The differences between charged particles and photons increase with increasing target volume. The differences between different charged particle species are small, as are the effects of target shape and location.

Biological response across a ridge filter carbon ion Bragg peak.

The dose distribution of carbon ion beams was modified to cover 14 cm peak width using a ridge filter suitable for clinical application. The results of cell survival as a function of depth of penetration of carbon ions and the mouse skin (foot) response at the proximal-, mid-, and distal-peak positions using four daily fractions are reported. The objective of these studies is to verify whether the dose distribution in the peak region is properly compensated to produce uniform biological effect. The implications of the shape of the dose distribution in the peak region to radiotherapy application are discussed.