Observations of the 2019 April 4 Solar Energetic Particle Event at the Parker Solar Probe

A solar energetic particle event was detected by the Integrated Science Investigation of the Sun (IS⊙IS) instrument suite on Parker Solar Probe (PSP) on 2019 April 4 when the spacecraft was inside of 0.17 au and less than 1 day before its second perihelion, providing an opportunity to study solar particle acceleration and transport unprecedentedly close to the source. The event was very small, with peak 1 MeV proton intensities of ~0.3 particles (cm² sr s MeV)⁻¹, and was undetectable above background levels at energies above 10 MeV or in particle detectors at 1 au. It was strongly anisotropic, with intensities flowing outward from the Sun up to 30 times greater than those flowing inward persisting throughout the event. Temporal association between particle increases and small brightness surges in the extreme-ultraviolet observed by the Solar TErrestrial RElations Observatory, which were also accompanied by type III radio emission seen by the Electromagnetic Fields Investigation on PSP, indicates that the source of this event was an active region nearly 80° east of the nominal PSP magnetic footpoint. This suggests that the field lines expanded over a wide longitudinal range between the active region in the photosphere and the corona

Integrated Clinical-Molecular Classification of Colorectal Liver Metastases: A Biomarker Analysis of the Phase 3 New EPOC Randomized Clinical Trial

IMPORTANCE: Personalized treatment approaches for patients with oligometastatic colorectal liver metastases are critically needed. We previously defined 3 biologically distinct molecular subtypes of colorectal liver metastases: (1) canonical, (2) immune, and (3) stromal. OBJECTIVE: To independently validate these molecular subtypes in the phase 3 New EPOC randomized clinical trial. DESIGN, SETTING, AND PARTICIPANTS: This retrospective secondary analysis of the phase 3 New EPOC randomized clinical trial included a bi-institutional discovery cohort and multi-institutional validation cohort. The discovery cohort comprised patients who underwent hepatic resection for limited colorectal liver metastases (98% received perioperative chemotherapy) from May 31, 1994, to August 14, 2012. The validation cohort comprised patients who underwent hepatic resection for liver metastases with perioperative chemotherapy (fluorouracil, oxaliplatin, and irinotecan based) with or without cetuximab from February 26, 2007, to November 1, 2012. Data were analyzed from January 18 to December 10, 2021. INTERVENTIONS: Resected metastases underwent RNA sequencing and microRNA (miRNA) profiling in the discovery cohort and messenger RNA and miRNA profiling with microarray in the validation cohort. MAIN OUTCOMES AND MEASURES: A 31-feature (24 messenger RNAs and 7 miRNAs) neural network classifier was trained to predict molecular subtypes in the discovery cohort and applied to the validation cohort. Integrated clinical-molecular risk groups were designated based on molecular subtypes and the clinical risk score. The unique biological phenotype of each molecular subtype was validated using gene set enrichment analyses and immune deconvolution. The primary clinical end points were progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 240 patients were included (mean [range] age, 63.0 [56.3-68.0] years; 151 [63%] male), with 93 in the discovery cohort and 147 in the validation cohort. In the validation cohort, 73 (50%), 28 (19%), and 46 (31%) patients were classified as having canonical, immune, and stromal metastases, respectively. The biological phenotype of each subtype was concordant with the discovery cohort. The immune subtype (best prognosis) demonstrated 5-year PFS of 43% (95% CI, 25%-60%; hazard ratio [HR], 0.37; 95% CI, 0.20-0.68) and OS of 63% (95% CI, 40%-79%; HR, 0.38; 95% CI, 0.17-0.86), which was statistically significantly higher than the canonical subtype (worst prognosis) at 14% (95% CI, 7%-23%) and 43% (95% CI, 32%-55%), respectively. Adding molecular subtypes to the clinical risk score improved prediction (the Gönen and Heller K for discrimination) from 0.55 (95% CI, 0.49-0.61) to 0.62 (95% CI, 0.57-0.67) for PFS and 0.59 (95% CI, 0.52-0.66) to 0.63 (95% CI, 0.56-0.70) for OS. The low-risk integrated group demonstrated 5-year PFS of 44% (95% CI, 20%-66%; HR, 0.38; 95% CI, 0.19-0.76) and OS of 78% (95% CI, 44%-93%; HR, 0.26; 95% CI, 0.08-0.84), superior to the high-risk group at 16% (95% CI, 10%-24%) and 43% (95% CI, 32%-52%), respectively. CONCLUSIONS AND RELEVANCE: In this prognostic study, biologically derived colorectal liver metastasis molecular subtypes and integrated clinical-molecular risk groups were highly prognostic. This novel molecular classification warrants further study as a possible predictive biomarker for personalized systemic treatment for colorectal liver metastases. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN22944367

STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy

BACKGROUND: Traditionally IFN/STAT1 signaling is connected with an anti-viral response and pro-apoptotic tumor-suppressor functions. Emerging functions of a constitutively activated IFN/STAT1 pathway suggest an association with an aggressive tumor phenotype. We hypothesized that tumor clones that constitutively overexpress this pathway are preferentially selected by the host microenvironment due to a resistance to STAT1-dependent cytotoxicity and demonstrate increased metastatic ability combined with increased resistance to genotoxic stress. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that clones of B16F1 tumors grown in the lungs of syngeneic C57BL/6 mice demonstrate variable transcriptional levels of IFN/STAT1 pathway expression. Tumor cells that constitutively overexpress the IFN/STAT1 pathway (STAT1(H) genotype) are selected by the lung microenvironment. STAT1(H) tumor cells also demonstrate resistance to IFN-gamma (IFNgamma), ionizing radiation (IR), and doxorubicin relative to parental B16F1 and low expressors of the IFN/STAT1 pathway (STAT1(L) genotype). Stable knockdown of STAT1 reversed the aggressive phenotype and decreased both lung colonization and resistance to genotoxic stress. CONCLUSIONS: Our results identify a pathway activated by tumor-stromal interactions thereby selecting for pro-metastatic and therapy-resistant tumor clones. New therapies targeted against the IFN/STAT1 signaling pathway may provide an effective strategy to treat or sensitize aggressive tumor clones to conventional cancer therapies and potentially prevent distant organ colonization

Oligo- and Polymetastatic Progression in Lung Metastasis(es) Patients Is Associated with Specific MicroRNAs

Rationale: Strategies to stage and treat cancer rely on a presumption of either localized or widespread metastatic disease. An intermediate state of metastasis termed oligometastasis(es) characterized by limited progression has been proposed. Oligometastases are amenable to treatment by surgical resection or radiotherapy.Methods: We analyzed microRNA expression patterns from lung metastasis samples of patients with ≤5 initial metastases resected with curative intent.Results: Patients were stratified into subgroups based on their rate of metastatic progression. We prioritized microRNAs between patients with the highest and lowest rates of recurrence. We designated these as high rate of progression (HRP) and low rate of progression (LRP); the latter group included patients with no recurrences. The prioritized microRNAs distinguished HRP from LRP and were associated with rate of metastatic progression and survival in an independent validation dataset.Conclusion: Oligo- and poly- metastasis are distinct entities at the clinical and molecular level.</p

Processing of inconsistent emotional information: an fMRI study

Previous studies investigating the anterior cingulate cortex (ACC) have relied on a number of tasks which involved cognitive control and attentional demands. In this fMRI study, we tested the model that ACC functions as an attentional network in the processing of language. We employed a paradigm that requires the processing of concurrent linguistic information predicting that the cognitive costs imposed by competing trials would engender the activation of ACC. Subjects were confronted with sentences where the semantic content conflicted with the prosodic intonation (CONF condition) randomly interspaced with sentences which conveyed coherent discourse components (NOCONF condition). We observed the activation of the rostral ACC and the middle frontal gyrus when the NOCONF condition was subtracted from the CONF condition. Our findings provide evidence for the involvement of the rostral ACC in the processing of complex competing linguistic stimuli, supporting theories that claim its relevance as a part of the cortical attentional circuit. The processing of emotional prosody involved a bilateral network encompassing the superior and medial temporal cortices. This evidence confirms previous research investigating the neuronal network that supports the processing of emotional information

³He-rich Solar Energetic Particle Observations at the Parker Solar Probe and near Earth

The Integrated Science Investigation of the Sun (IS⊙IS) instrument suite on the Parker Solar Probe (PSP) spacecraft is making in situ observations of energetic ions and electrons closer to the Sun than any previous mission. Using data collected during its first two orbits, which reached perihelion distances of 0.17 au, we have searched for ³He-rich solar energetic particle (SEP) events under very quiet solar minimum conditions. On 2019-110–111 (April 20–21), ³He-rich SEPs were observed at energies near 1 MeV nucleon ⁻¹ in association with energetic protons, heavy ions, and electrons. This activity was also detected by the Ultra-Low-Energy Isotope Spectrometer and the Electron, Proton, and Alpha Monitor instruments on the Advanced Composition Explorer (ACE) spacecraft located near Earth, 0.99 au from the Sun. At that time, PSP and ACE were both magnetically connected to locations near the west limb of the Sun. Remote sensing measurements showed the presence of type III radio bursts and also helical jets from this region of the Sun. This combination of observations is commonly associated with ³He-rich SEP acceleration on the Sun. AR 12738, which was located at Carrington coordinates from which numerous X-ray flares were observed over a period of more than 6 months, was identified as the source of the ³He-rich events. This region was also the source of several other SEP events detected at PSP or ACE. Aside from the period in 2019 April, IS⊙IS did not observe any other ³He-rich SEPs during orbits 1 and 2

Observations of the 2019 April 4 Solar Energetic Particle Event at the Parker Solar Probe

A solar energetic particle event was detected by the Integrated Science Investigation of the Sun (IS⊙IS) instrument suite on Parker Solar Probe (PSP) on 2019 April 4 when the spacecraft was inside of 0.17 au and less than 1 day before its second perihelion, providing an opportunity to study solar particle acceleration and transport unprecedentedly close to the source. The event was very small, with peak 1 MeV proton intensities of ~0.3 particles (cm² sr s MeV)⁻¹, and was undetectable above background levels at energies above 10 MeV or in particle detectors at 1 au. It was strongly anisotropic, with intensities flowing outward from the Sun up to 30 times greater than those flowing inward persisting throughout the event. Temporal association between particle increases and small brightness surges in the extreme-ultraviolet observed by the Solar TErrestrial RElations Observatory, which were also accompanied by type III radio emission seen by the Electromagnetic Fields Investigation on PSP, indicates that the source of this event was an active region nearly 80° east of the nominal PSP magnetic footpoint. This suggests that the field lines expanded over a wide longitudinal range between the active region in the photosphere and the corona

Observations of the 2019 April 4 Solar Energetic Particle Event at the Parker Solar Probe

A solar energetic particle event was detected by the Integrated Science Investigation of the Sun (ISOIS) instrument suite on Parker Solar Probe (PSP) on 2019 April 4 when the spacecraft was inside of 0.17 au and less than 1 day before its second perihelion, providing an opportunity to study solar particle acceleration and transport unprecedentedly close to the source. The event was very small, with peak 1 MeV proton intensities of ~0.3 particles (cm^2 sr s MeV)^-1, and was undetectable above background levels at energies above 10 MeV or in particle detectors at 1 au. It was strongly anisotropic, with intensities flowing outward from the Sun up to 30 times greater than those flowing inward persisting throughout the event. Temporal association between particle increases and small brightness surges in the extreme-ultraviolet observed by the Solar TErrestrial RElations Observatory, which were also accompanied by type III radio emission seen by the Electromagnetic Fields Investigation on PSP, indicates that the source of this event was an active region nearly 80 degrees east of the nominal PSP magnetic footpoint. This suggests that the field lines expanded over a wide longitudinal range between the active region in the photosphere and the corona

Expedition Inspiration Fund for Breast Cancer Research Meeting 2003

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44216/1/10549_2004_Article_5139058.pd