Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy

Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-173 (PI3K inhibitor) are identified as a novel combination that synergistically enhance toxicity and induce immunogenic cell death both in vitro and in vivo in a CRC model. These inhibitors were co-encapsulated in a polymer micelle to overcome solubility limitations while minimizing off-target toxicity. Mice bearing syngeneic colorectal tumors (CT26) were administered these therapeutic micelles in combination with X-ray irradiation and anti-CTLA-4 immunotherapy. This combination led to enhanced efficacy demonstrated by improved tumor control and increased tumor infiltrating lymphocytes. This report represents the first investigation of DNA damage repair inhibition combined with radiation to potentiate anti-CTLA-4 immunotherapy in a CRC model.Peer reviewe

A maximum rupture model for the central and southern Cascadia subduction zone—reassessing ages for coastal evidence of megathrust earthquakes and tsunamis

A new history of great earthquakes (and their tsunamis) for the central and southern Cascadia subduction zone shows more frequent (17 in the past 6700 yr) megathrust ruptures than previous coastal chronologies. The history is based on along-strike correlations of Bayesian age models derived from evaluation of 554 radiocarbon ages that date earthquake evidence at 14 coastal sites. We reconstruct a history that accounts for all dated stratigraphic evidence with the fewest possible ruptures by evaluating the sequence of age models for earthquake or tsunami contacts at each site, comparing the degree of temporal overlap of correlated site age models, considering evidence for closely spaced earthquakes at four sites, and hypothesizing only maximum-length megathrust ruptures. For the past 6700 yr, recurrence for all earthquakes is 370–420 yr. But correlations suggest that ruptures at ∼1.5 ka and ∼1.1 ka were of limited extent (<400 km). If so, post-3-ka recurrence for ruptures extending throughout central and southern Cascadia is 510–540 yr. But the range in the times between earthquakes is large: two instances may be ∼50 yr, whereas the longest are ∼550 and ∼850 yr. The closely spaced ruptures about 1.6 ka may illustrate a pattern common at subduction zones of a long gap ending with a great earthquake rupturing much of the subduction zone, shortly followed by a rupture of more limited extent. The ruptures of limited extent support the continued inclusion of magnitude-8 earthquakes, with longer ruptures near magnitude 9, in assessments of seismic hazard in the region

The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health–Centers for Disease Control and Prevention Multidisciplinary Workshop

The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed

Rapid Surface Rupture Mapping from Satellite Data: The 2023 Kahramanmaraş, Turkey (Türkiye), Earthquake Sequence

The 6 February 2023 Kahramanmaraş, Turkey (Türkiye), earthquake sequence produced > 500 km of surface rupture primarily on the left-lateral East Anatolian (~345 km) and Çardak (~175 km) faults. Constraining the length and magnitude of surface displacement on the causative faults is critical for loss estimates, recovery efforts, rapid identification of impacted infrastructure, and fault displacement hazard analysis. To support these efforts, we rapidly mapped the surface rupture from satellite data with support from remote sensing and field teams, and released the results to the public in near-real time. Detailed surface rupture mapping commenced on 7 February and continued as high-resolution (< 1.0 m/pixel) optical images from WorldView satellites (2023 Maxar) became available. We interpreted the initial simplified rupture trace from subpixel offset fields derived from Advanced Land Observation Satellite2 and Sentinel-1A synthetic aperture radar image pairs available on 8 and 10 February, respectively. The mapping was released publicly on 10 February, with frequent updates, and published in final form four months postearthquake (Reitman, Briggs, et al., 2023). This publicly available, rapid mapping helped guide fieldwork and constrained U.S. Geological Survey finite-fault and loss estimate models, as well as stress change estimates and dynamic rupture models

Activating KRAS mutations are characteristic of oncocytic sinonasal papilloma and associated sinonasal squamous cell carcinoma

Oncocytic sinonasal papillomas (OSPs) are benign tumours of the sinonasal tract, a subset of which are associated with synchronous or metachronous sinonasal squamous cell carcinoma (SNSCC). Activating EGFR mutations were recently identified in nearly 90% of inverted sinonasal papillomas (ISPs) â a related tumour with distinct morphology. EGFR mutations were, however, not found in OSP, suggesting that different molecular alterations drive the oncogenesis of these tumours. In this study, tissue from 51 cases of OSP and five cases of OSPâ associated SNSCC was obtained retrospectively from six institutions. Tissue was also obtained from 50 cases of ISP, 22 cases of ISPâ associated SNSCC, ten cases of exophytic sinonasal papilloma (ESP), and 19 cases of SNSCC with no known papilloma association. Using targeted nextâ generation and conventional Sanger sequencing, we identified KRAS mutations in 51/51 (100%) OSPs and 5/5 (100%) OSPâ associated SNSCCs. The somatic nature of KRAS mutations was confirmed in a subset of cases with matched germline DNA, and four matched pairs of OSP and concurrent associated SNSCC had concordant KRAS genotypes. In contrast, KRAS mutations were present in only one (5%) SNSCC with no known papilloma association and none of the ISPs, ISPâ associated SNSCCs, or ESPs. This is the first report of somatic KRAS mutations in OSP and OSPâ associated SNSCC. The presence of identical mutations in OSP and concurrent associated SNSCC supports the putative role of OSP as a precursor to SNSCC, and the high frequency and specificity of KRAS mutations suggest that OSP and OSPâ associated SNSCC are biologically distinct from other similar sinonasal tumours. The identification of KRAS mutations in all studied OSP cases represents an important development in our understanding of the pathogenesis of this disease and may have implications for diagnosis and therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/133586/1/path4750.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/133586/2/path4750_am.pd

How similar was the 1983 Mw 6.9 Borah Peak earthquake rupture to its surface-faulting predecessors along the northern Lost River fault zone (Idaho, USA)?

We excavated trenches at two paleoseismic sites bounding a trans-basin bedrock ridge (the Willow Creek Hills) along the northern Lost River fault zone to explore the uniqueness of the 1983 Mw 6.9 Borah Peak earthquake compared to its prehistoric predecessors. At the Sheep Creek site on the southernmost Warm Springs section, two earthquakes occurred at 9.8–14.0 ka (95% confidence) and 6.5–7.1 ka; each had ~1.9 m of vertical displacement. About 4 km to the southeast, across the Willow Creek Hills, two ruptures at the Arentson Gulch site on the northernmost Thousand Springs section occurred at 9.0–14.7 ka and 6.1–7.5 ka with ~1.9 m of vertical displacement each. We synthesize these and previous paleoseismic results into a model of five postglacial (<15 ka) ruptures along a ~65 km reach of the northern Lost River fault zone. Our results show that the Borah Peak earthquake (34 km; 0.9 m mean displacement) was unique compared to previous ruptures that had both longer and shorter rupture lengths (~25–38 km), more displacement (mean of ~1.3–1.4 m), and equal or greater magnitude (Mw 6.9–7.1) than that in the 1983 earthquake. These ruptures support a hypothesis of variable rupture length and displacement on the northern Lost River fault zone and show that predecessors to the 1983 rupture have passed unimpeded through the Willow Creek Hills. Our work demonstrates that normal faults are capable of producing variable spatial-temporal patterns of rupture that, together with comparisons of fault geometry and historical rupture length, improve our understanding of fault segmentation and help inform models of earthquake rupture probability.This project was supported by the U.S. Geological Survey Earthquake Hazards Program