Probing the energetic particle environment near the Sun.

NASA's Parker Solar Probe mission1 recently plunged through the inner heliosphere of the Sun to its perihelia, about 24 million kilometres from the Sun. Previous studies farther from the Sun (performed mostly at a distance of 1 astronomical unit) indicate that solar energetic particles are accelerated from a few kiloelectronvolts up to near-relativistic energies via at least two processes: 'impulsive' events, which are usually associated with magnetic reconnection in solar flares and are typically enriched in electrons, helium-3 and heavier ions2, and 'gradual' events3,4, which are typically associated with large coronal-mass-ejection-driven shocks and compressions moving through the corona and inner solar wind and are the dominant source of protons with energies between 1 and 10 megaelectronvolts. However, some events show aspects of both processes and the electron-proton ratio is not bimodally distributed, as would be expected if there were only two possible processes5. These processes have been very difficult to resolve from prior observations, owing to the various transport effects that affect the energetic particle population en route to more distant spacecraft6. Here we report observations of the near-Sun energetic particle radiation environment over the first two orbits of the probe. We find a variety of energetic particle events accelerated both locally and remotely including by corotating interaction regions, impulsive events driven by acceleration near the Sun, and an event related to a coronal mass ejection. We provide direct observations of the energetic particle radiation environment in the region just above the corona of the Sun and directly explore the physics of particle acceleration and transport.

Mediation of the solar wind termination shock by non-thermal ions.

Broad regions on both sides of the solar wind termination shock are populated by high intensities of non-thermal ions and electrons. The pre-shock particles in the solar wind have been measured by the spacecraft Voyager 1 (refs 1-5) and Voyager 2 (refs 3, 6). The post-shock particles in the heliosheath have also been measured by Voyager 1 (refs 3-5). It was not clear, however, what effect these particles might have on the physics of the shock transition until Voyager 2 crossed the shock on 31 August-1 September 2007 (refs 7-9). Unlike Voyager 1, Voyager 2 is making plasma measurements. Data from the plasma and magnetic field instruments on Voyager 2 indicate that non-thermal ion distributions probably have key roles in mediating dynamical processes at the termination shock and in the heliosheath. Here we report that intensities of low-energy ions measured by Voyager 2 produce non-thermal partial ion pressures in the heliosheath that are comparable to (or exceed) both the thermal plasma pressures and the scalar magnetic field pressures. We conclude that these ions are the >0.028 MeV portion of the non-thermal ion distribution that determines the termination shock structure and the acceleration of which extracts a large fraction of bulk-flow kinetic energy from the incident solar wind.

Future Exploration of the Outer Heliosphere and Very Local Interstellar Medium by Interstellar Probe.

A detailed overview of the knowledge gaps in our understanding of the heliospheric interaction with the largely unexplored Very Local Interstellar Medium (VLISM) are provided along with predictions of with the scientific discoveries that await. The new measurements required to make progress in this expanding frontier of space physics are discussed and include in-situ plasma and pick-up ion measurements throughout the heliosheath, direct sampling of the VLISM properties such as elemental and isotopic composition, densities, flows, and temperatures of neutral gas, dust and plasma, and remote energetic neutral atom (ENA) and Lyman-alpha (LYA) imaging from vantage points that can uniquely discern the heliospheric shape and bring new information on the interaction with interstellar hydrogen. The implementation of a pragmatic Interstellar Probe mission with a nominal design life to reach 375 Astronomical Units (au) with likely operation out to 550 au are reported as a result of a 4-year NASA funded mission study.

Venular amyloid accumulation in transgenic Fischer 344 Alzheimer's disease rats.

Strong evidence demonstrates a significant association between cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). For this reason, interest in understanding the underlying vascular pathologies that contribute to AD remain. CAA research has primarily focused on arterioles and capillaries, overlooking the draining venules. Therefore, this study sought to examine venular amyloid pathology and its relationship to arteriolar amyloidosis throughout AD progression in the TgF344-AD rat model. Antibodies targeting the amyloid-beta peptide (Aß) sequence suggest morphological differences between arteriolar and venular amyloid. Mass spectrometric analyses of isolated cortical parenchymal plaques, arteriolar and venular amyloid demonstrated presence of Aß in all three samples, as well as proteins known to be associated with AD. Histopathological analysis indicates a significant age effect for both arteriolar and venular amyloid accumulation, with accumulation initiated in the somatosensory cortex followed by the motor and cingulate cortex. Lastly, significant arteriolar amyloid accumulates relative to venular amyloid deposition in AD progression. Overall, understanding venular and arteriolar amyloid pathology provides insight into the complex connection between CAA and AD.

Anomalous Cosmic Rays and Heliospheric Energetic Particles.

We present a review of Anomalous Cosmic Rays (ACRs), including the history of their discovery and recent insights into their acceleration and transport in the heliosphere. We focus on a few selected topics including a discussion of mechanisms of their acceleration, escape from the heliosphere, their effects on the dynamics of the heliosheath, transport in the inner heliosphere, and their solar cycle dependence. A discussion concerning their name is also presented towards the end of the review. We note that much is known about ACRs and perhaps the term Anomalous Cosmic Ray is not particularly descriptive to a non specialist. We suggest that the more-general term: "Heliospheric Energetic Particles", which is more descriptive, for which ACRs and other energetic particle species of heliospheric origin are subsets, might be more appropriate.

Voyager 1 exited the solar wind at a distance of approximately 85 Au from the Sun.

The outer limit of the Solar System is often considered to be at the distance from the Sun where the solar wind changes from supersonic to subsonic flow. Theory predicts that a termination shock marks this boundary, with locations ranging from a few to over 100 au (1 Au approximately 1.5 x 10(8) km, the distance from Earth to the Sun). 'Pick-up ions' that originate as interstellar neutral atoms should be accelerated to tens of MeV at the termination shock, generating anomalous cosmic rays. Here we report a large increase in the intensity of energetic particles in the outer heliosphere, as measured by an instrument on the Voyager 1 spacecraft. We argue that the spacecraft exited the supersonic solar wind and passed into the subsonic region (possibly beyond the termination shock) on about 1 August 2002 at a distance of approximately 85 Au (heliolatitude approximately 34 degrees N), then re-entered the supersonic solar wind about 200 days later at approximately 87 au from the Sun. We show that the composition of the ions accelerated at the putative termination shock is that of anomalous cosmic rays and of interstellar pick-up ions.

Color, composition, and thermal environment of Kuiper Belt object (486958) Arrokoth.

The outer Solar System object (486958) Arrokoth (provisional designation 2014 MU69) has been largely undisturbed since its formation. We studied its surface composition using data collected by the New Horizons spacecraft. Methanol ice is present along with organic material, which may have formed through irradiation of simple molecules. Water ice was not detected. This composition indicates hydrogenation of carbon monoxide-rich ice and/or energetic processing of methane condensed on water ice grains in the cold, outer edge of the early Solar System. There are only small regional variations in color and spectra across the surface, which suggests that Arrokoth formed from a homogeneous or well-mixed reservoir of solids. Microwave thermal emission from the winter night side is consistent with a mean brightness temperature of 29 ± 5 kelvin.

The geology and geophysics of Kuiper Belt object (486958) Arrokoth.

The Cold Classical Kuiper Belt, a class of small bodies in undisturbed orbits beyond Neptune, is composed of primitive objects preserving information about Solar System formation. In January 2019, the New Horizons spacecraft flew past one of these objects, the 36-kilometer-long contact binary (486958) Arrokoth (provisional designation 2014 MU69). Images from the flyby show that Arrokoth has no detectable rings, and no satellites (larger than 180 meters in diameter) within a radius of 8000 kilometers. Arrokoth has a lightly cratered, smooth surface with complex geological features, unlike those on previously visited Solar System bodies. The density of impact craters indicates the surface dates from the formation of the Solar System. The two lobes of the contact binary have closely aligned poles and equators, constraining their accretion mechanism.

Pluto's Interaction With Energetic Heliospheric Ions.

Pluto energies of a few kiloelectron volts and suprathermal ions with tens of kiloelectron volts and above. We measure this population using the Pluto Energetic Particle Spectrometer Science Investigation (PEPSSI) instrument on board the New Horizons spacecraft that flew by Pluto in 2015. Even though the measured ions have gyroradii larger than the size of Pluto and the cross section of its magnetosphere, we find that the boundary of the magnetosphere is depleting the energetic ion intensities by about an order of magnitude close to Pluto. The intensity is increasing exponentially with distance to Pluto and reaches nominal levels of the interplanetary medium at about 190R P distance. Inside the wake of Pluto, we observe oscillations of the ion intensities with a periodicity of about 0.2 hr. We show that these can be quantitatively explained by the electric field of an ultralow-frequency wave and discuss possible physical drivers for such a field. We find no evidence for the presence of plutogenic ions in the considered energy range.

A radiation belt of energetic protons located between Saturn and its rings.

Saturn has a sufficiently strong dipole magnetic field to trap high-energy charged particles and form radiation belts, which have been observed outside its rings. Whether stable radiation belts exist near the planet and inward of the rings was previously unknown. The Cassini spacecraft's Magnetosphere Imaging Instrument obtained measurements of a radiation belt that lies just above Saturn's dense atmosphere and is decoupled from the rest of the magnetosphere by the planet's A- to C-rings. The belt extends across the D-ring and comprises protons produced through cosmic ray albedo neutron decay and multiple charge-exchange reactions. These protons are lost to atmospheric neutrals and D-ring dust. Strong proton depletions that map onto features on the D-ring indicate a highly structured and diverse dust environment near Saturn.

Mutations of the epidermal growth factor receptor in non-small cell lung cancer -- search and destroy.

The targeting of the ATP binding pocket of the epidermal growth factor receptor (EGFR) tyrosine kinase, by the small molecule drugs gefitinib and erlotinib, represents a promising new therapeutic strategy in non-small cell lung cancer. However, it is now apparent that only a subset of patients responds to such treatment. Two publications in early 2004 reported the presence of activating mutations in the EGFR tyrosine kinase gene conferring exquisite sensitivity to these drugs. Several publications have since reported prospective data consistent with this finding. This brief review summarises the mutation data from 15 such studies in terms of mutation frequency by clinicopathological features and correlation with response to tyrosine kinase inhibition. A new paradigm for the routine detection of such mutations is needed to facilitate patient selection for treatment and further studies.

The "Puck" energetic charged particle detector: Design, heritage, and advancements.

Energetic charged particle detectors characterize a portion of the plasma distribution function that plays critical roles in some physical processes, from carrying the currents in planetary ring currents to weathering the surfaces of planetary objects. For several low-resource missions in the past, the need was recognized for a low-resource but highly capable, mass-species-discriminating energetic particle sensor that could also obtain angular distributions without motors or mechanical articulation. This need led to the development of a compact Energetic Particle Detector (EPD), known as the "Puck" EPD (short for hockey puck), that is capable of determining the flux, angular distribution, and composition of incident ions between an energy range of ~10 keV to several MeV. This sensor makes simultaneous angular measurements of electron fluxes from the tens of keV to about 1 MeV. The same measurements can be extended down to approximately 1 keV/nucleon, with some composition ambiguity. These sensors have a proven flight heritage record that includes missions such as MErcury Surface, Space ENvironment, GEochemistry, and Ranging and New Horizons, with multiple sensors on each of Juno, Van Allen Probes, and Magnetospheric Multiscale. In this review paper we discuss the Puck EPD design, its heritage, unexpected results from these past missions and future advancements. We also discuss high-voltage anomalies that are thought to be associated with the use of curved foils, which is a new foil manufacturing processes utilized on recent Puck EPD designs. Finally, we discuss the important role Puck EPDs can potentially play in upcoming missions.

Pluto's interaction with its space environment: Solar wind, energetic particles, and dust.

The New Horizons spacecraft carried three instruments that measured the space environment near Pluto as it flew by on 14 July 2015. The Solar Wind Around Pluto (SWAP) instrument revealed an interaction region confined sunward of Pluto to within about 6 Pluto radii. The region's surprisingly small size is consistent with a reduced atmospheric escape rate, as well as a particularly high solar wind flux. Observations from the Pluto Energetic Particle Spectrometer Science Investigation (PEPSSI) instrument suggest that ions are accelerated and/or deflected around Pluto. In the wake of the interaction region, PEPSSI observed suprathermal particle fluxes equal to about 1/10 of the flux in the interplanetary medium and increasing with distance downstream. The Venetia Burney Student Dust Counter, which measures grains with radii larger than 1.4 micrometers, detected one candidate impact in ±5 days around New Horizons' closest approach, indicating an upper limit of <4.6 kilometers(-3) for the dust density in the Pluto system.

Elimination of glucagon-like peptide 1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action.

Leptin and glucagon-like peptide 1 (GLP-1) exhibit opposing actions in the endocrine pancreas. GLP-1 stimulates insulin biosynthesis, secretion, and islet growth, whereas leptin inhibits glucose-dependent insulin secretion and insulin gene transcription. In contrast, GLP-1 and leptin actions overlap in the central nervous system, where leptin has been shown to activate GLP-1 circuits that inhibit food intake. To determine the physiological importance of GLP-1 receptor (GLP-1R)-leptin interactions, we studied islet function and feeding behavior in ob/ob:GLP-1R(-/-) mice. Although GLP-1R actions are thought to be essential for glucose-dependent insulin secretion, the levels of fasting glucose, glycemic excursion after glucose loading, glucose-stimulated insulin, and pancreatic insulin RNA content were similar in ob/ob:GLP-1R(+/+) versus ob/ob:GLP-1R(-/-) mice. Despite evidence linking GLP-1R signaling to the regulation of islet neogenesis and proliferation, ob/ob:GLP-1R(-/-) mice exhibited significantly increased islet numbers and area and an increase in the number of large islets compared with GLP-1R(+/+) or (-/-) mice (P < -0.01 to 0.05). Similarly, growth rates and both shortand long-term control of food intake were comparable in ob/ob:GLP-1R(+/+) versus ob/ob:GLP-1R4(-/-) mice. Furthermore, leptin produced a similar inhibition of food intake in GLP-1R(-/-), ob/ob:GLP-1R(+/+), and ob/ob:GLP1R4(-/-) mice. These findings illustrate that although leptin and GLP-1 actions overlap in the brain and endocrine pancreas, disruption of GLP-1 signaling does not modify the response to leptin or the phenotype of leptin deficiency in the ob/ob mouse, as assessed by long-term control of body weight or the adaptive beta-cell response to insulin resistance in vivo.

Essential requirement for Pax6 in control of enteroendocrine proglucagon gene transcription.

The primary function of islet A cells is the synthesis and secretion of glucagon, an essential hormonal regulator of glucose homeostasis. The proglucagon gene is also expressed in enteroendocrine L cells of the intestinal epithelium, which produce glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2), regulators of insulin secretion and intestinal growth, respectively. We show here that Pax6, a critical determinant of islet cell development and proglucagon gene expression in islet A cells, is also essential for glucagon gene transcription in the small and large intestine. Pax6 is expressed in enteroendocrine cells, binds to the G1 and G3 elements in the proglucagon promoter, and activates proglucagon gene transcription. The dominant negative Pax6 allele, SEYNeu, represses proglucagon gene transcription in enteroendocrine cells. Mice homozygous for the SEYNeu mutation exhibit markedly reduced levels of proglucagon mRNA transcripts in the small and large intestine, and GLP-1 or GLP-2-immunopositive enteroendocrine cells were not detected in the intestinal mucosa. These findings implicate an essential role for Pax6 in the development and function of glucagon-producing cells in both pancreatic and intestinal endodermal lineages.

Surgery plus chemotherapy or chemotherapy alone for primary intermediate- and high-grade gastric non-Hodgkin's lymphoma: the Royal Marsden Hospital experience.

Primary gastric lymphomas (PGL) have traditionally been treated with surgery followed by chemotherapy or radiotherapy. Surgery was thought to improve staging, optimise local disease control and reduce risk of perforation or bleeding, but recent studies question its role. In this study, patients with intermediate- or high-grade PGL who received chemotherapy from 1985 to 1996 at the Royal Marsden Hospital were identified using a prospectively accrued database. A total of 37 patients (6 with low-grade mucosa-associated lymphoid tissue lymphoma (MALT-L), 9 with high-grade MALT-L, 20 with diffuse large B-cell (DLBC) lymphoma and 2 other histologies), 17 of whom had localised disease, were treated with either surgery plus chemotherapy or chemotherapy alone. 5-year overall survival for localised and advanced PGL was 94 and 50%, respectively, with no differences between the two treatments over a 53 months median follow-up. No perforations or serious bleeding occurred. Surgery is associated with important morbidity and we detected no benefit of surgery prior to chemotherapy in this limited series of patients.

Baseline quality of life predicts survival in patients with advanced colorectal cancer.

The aim of this study was to investigate the influence of baseline quality of life (QoL) on survival in patients with advanced colorectal cancer. From 1992 to 1998, four randomised clinical trials in advanced colorectal cancer were conducted at this institution. The European Organization for Research and Treatment of Cancer-Quality of Life Core 30 (EORTC-QLQ-C30) questionnaire was completed prior to the commencement of chemotherapy. Analyses were performed on median-dichotomised baseline Quality of Life (QoL) and clinical prognostic factors. Baseline QoL questionnaires were completed by 501 patients. One-year survival was 38.3 and 72.5% (P<0.0001) for patients with global QoL scores below and above the median (67), respectively. Other than cognitive functioning, fatigue, appetite, constipation, diarrhoea and financial domains, all QoL scales were significant independent predictors of survival (P<0.035). In the final model, the global QoL score remained highly significant as an independent predictor of survival (P<0.0001). Baseline QoL is a strong independent predictor of survival in patients with advanced colorectal cancer. Measurements should be routinely recorded in clinical trials to stratify cohorts and aid in trial comparison.

A randomised study of protracted venous infusion of 5-fluorouracil (5-FU) with or without bolus mitomycin C (MMC) in patients with carcinoma of unknown primary.

No standard regimen has been identified for patients with a carcinoma of unknown primary (CUP). This study compared protracted venous infusion 5-fluorouracil (PVI 5-FU) with or without mitomycin C (MMC) in patients with CUP in a multicentre, prospectively randomised study. 88 patients were randomised to PVI 5-FU (300 mg/m(2)/day for a maximum of 24 weeks) +/-MMC (7 mg/m(2) 6 weekly for four courses). The overall response rate was 11.6% for PVI 5-FU alone compared with 20.0% for PVI 5-FU plus MMC (P=0.29). Median failure-free survival (FFS) was 4.1 months for PVI 5-FU and 3.6 months for PVI 5-FU plus MMC (P=0.78) with an equivalent overall survival (OS) (6.6 versus 4.7 months, P=0.60). Symptomatic benefit was observed in most patients in each arm. PVI 5-FU is a well tolerated outpatient treatment regimen for patients with CUP, although the addition of MMC provides little extra benefit. PVI 5-FU may be a potential reference regimen in randomised trials with newer chemotherapy agents in patients with CUP.

Combining platinum, paclitaxel and anthracycline in patients with advanced gynaecological malignancy.

Two meta-analyses have suggested that the addition of an anthracycline to platinum-based chemotherapy may improve survival in advanced ovarian cancer, and two randomised trials have demonstrated superiority of paclitaxel over cyclophosphamide in platinum combinations. A combination of platinum, anthracycline and paclitaxel would, therefore, be a reasonable experimental arm of any future randomised trial in patients with epithelial ovarian carcinoma (EOC). Patients who required chemotherapy for EOC but were ineligible for standard trials or had other gynaecological tumours that required similar platinum-based chemotherapy were considered for this pilot. The platinum/anthracycline/paclitaxel regimen (G-CAT) was given 3-weekly and consisted of doxorubicin 50 mg/m(2) or epirubicin 60 mg/m(2) intravenously (i.v.) bolus, paclitaxel 175 mg/m(2) (i.v.) over 3 h and either cisplatin 75 mg/m(2) (i.v.) or carboplatin AUC 6, with granulocyte colony-stimulating factor (G-CSF) at the neutrophil nadir. Different combinations were used in order to determine the least toxic regimen. Toxicity and response were assessed according to CTC and WHO criteria, respectively. 26 patients entered the study, 13 with EOC and 13 with other gynaecological cancers (peritoneal, fallopian tube, mixed Mullerian). Median age was 49 years (range: 27-67). 8 patients received carboplatin/doxorubicin/paclitaxel, 8 cisplatin/doxorubicin/paclitaxel and 10 carboplatin/epirubicin/paclitaxel. A total of 135 cycles of chemotherapy were delivered, with a median of 6 cycles per patient (range: 2-6). 54 (40%) cycles required G-CSF support and 17 (65%) patients required at least one dose reduction. All patients experienced grade 4 neutropenia and 13 (50%) patients developed grade 3-4 thrombocytopenia (12 of whom had received carboplatin). There were 4 (15%) patients with grade 3/4 infections but no septic deaths. Non-haematological toxicities were manageable, lethargy occurred in 75% of cisplatin-treated patients. Grade 1/2 cardiotoxicity, as assessed pre- and post-treatment by left ventricular ejection fraction, was observed in 6/13 (46%) patients who had received doxorubicin and 2/7 (29%) epirubicin-treated patients. No clinically detectable cardiac toxicity was encountered. The response rate in 25 evaluable patients was 76% (12 CR, 7 PR). Dose intensity was highest in the carboplatin/epirubicin/paclitaxel combination. G-CAT shows high activity and can be administered safely, but only very fit patients are suitable for this regimen as it is associated with considerable toxicity. Carboplatin/epirubicin/paclitaxel was the best tolerated regimen overall.

Are 18fluorodeoxyglucose positron emission tomography and magnetic resonance imaging useful in the prediction of relapse in lymphoma residual masses?

Treatment of both Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) frequently results in a residual mass visible radiologically. Such patients may receive radiotherapy unnecessarily because the residual mass may represent benign fibrotic tissue rather than residual active lymphoma. Radiotherapy has been shown to have significant short and more worrying long-term toxicity. Refining the criteria for its use would be a major advance. A number of clinical investigations have been evaluated to more accurately determine the nature of such lesions, including erythrocyte sedimentation rate (ESR), magnetic resonance imaging (MRI) and high-dose gallium-67 scanning (HDGS) but none has proven utility. 18[F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is an imaging technique that has been shown to be useful in distinguishing fibrosis from residual active disease in solid tumours. The aim of this study was to compare FDG PET and MRI in the assessment of residual masses following treatment for lymphoma. Patients with NHL/HD who had a residual mass following chemotherapy were eligible for this study. Patients had a combination of MRI and/or PET. All scans were completed within 5 months of the end of treatment. Patients were followed-up for relapse. 56 patients had an MRI scan, 24 had a PET scan and 22 patients had both investigations. Overall sensitivity and specificity, respectively, were for MRI 45% and 74%, PET 50% and 69%, and PET/MRI concurring 50% and 67%. There was a trend for improved relapse-free survival (RFS) with a negative result of both MRI and PET, but this was not statistically significant. The predictive value for both tests failed to reach statistical significance. Subgroup analysis suggests that PET may be better at predicting relapse in patients with NHL, especially those with masses above the diaphragm. There is no convincing evidence that either MRI or PET or the combination can reliably predict relapse within residual masses after treatment for lymphoma. A negative PET scan however appears to be more informative than a positive result and may well aid clinical decision making. There are a number of factors that may produce false-positive results, including post-treatment inflammatory changes, the sensitivity of the test in the setting of minimal residual disease and the heterogeneity of the histological subtypes studied. A negative PET (or MRI) result in lymphoma residual masses following therapy may negate the necessity for further therapy such as chemotherapy or radiotherapy and their concomitant toxicities.