APC loss affects DNA damage repair causing doxorubicin resistance in breast cancer cells

Chemoresistance is one of the leading causes of cancer-related deaths in the United States. Triple negative breast cancer (TNBC), a subtype lacking the known breast cancer receptors used for targeted therapy, is reliant on chemotherapy as the standard of care. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 70% of sporadic breast cancers with APC-deficient tumors resembling the TNBC subtype. Using mammary tumor cells from the ApcMin/+ mouse model crossed to the Polyoma middle T antigen (PyMT) transgenic model, we previously showed that APC loss decreased sensitivity to doxorubicin (DOX). Understanding the molecular basis for chemoresistance is essential for the advancement of novel therapeutic approaches to ultimately improve patient outcomes. Resistance can be caused via different methods, but here we focus on the DNA repair response with DOX treatment. We show that MMTV-PyMT;ApcMin/+ cells have decreased DNA damage following 24 hour DOX treatment compared to MMTV-PyMT;Apc+/+ cells. This decreased damage is first observed 24 hours post-treatment and continues throughout 24 hours of drug recovery. Activation of DNA damage response pathways (ATM, Chk1, and Chk2) are decreased at 24 hours DOX-treatment in MMTV-PyMT;ApcMin/+ cells compared to control cells, but show activation at earlier time points. Using inhibitors that target DNA damage repair kinases (ATM, ATR, and DNA-PK), we showed that ATM and DNA-PK inhibition increased DOX-induced apoptosis in the MMTV-PyMT;ApcMin/+ cells. In the current work, we demonstrated that APC loss imparts resistance through decreased DNA damage response, which can be attenuated through DNA repair inhibition, suggesting the potential clinical use of DNA repair inhibitions as combination therapy

No barrier to emergence of bathyal king crabs on the Antarctic shelf

Cold-water conditions have excluded durophagous (skeleton-breaking) predators from the Antarctic seafloor for millions of years. Rapidly warming seas off the western Antarctic Peninsula could now facilitate their return to the continental shelf, with profound consequences for the endemic fauna. Among the likely first arrivals are king crabs (Lithodidae), which were discovered recently on the adjacent continental slope. During the austral summer of 2010‒2011, we used underwater imagery to survey a slope-dwelling population of the lithodid Paralomis birsteini off Marguerite Bay, western Antarctic Peninsula for environmental or trophic impediments to shoreward expansion. The population density averaged ∼4.5 individuals × 1,000 m(−2) within a depth range of 1,100‒1,500 m (overall observed depth range 841–2,266 m). Images of juveniles, discarded molts, and precopulatory behavior, as well as gravid females in a trapping study, suggested a reproductively viable population on the slope. At the time of the survey, there was no thermal barrier to prevent the lithodids from expanding upward and emerging on the outer shelf (400- to 550-m depth); however, near-surface temperatures remained too cold for them to survive in inner-shelf and coastal environments (<200 m). Ambient salinity, composition of the substrate, and the depth distribution of potential predators likewise indicated no barriers to expansion of lithodids onto the outer shelf. Primary food resources for lithodids—echinoderms and mollusks—were abundant on the upper slope (550–800 m) and outer shelf. As sea temperatures continue to rise, lithodids will likely play an increasingly important role in the trophic structure of subtidal communities closer to shore

Detailed Analysis of a Contiguous 22-Mb Region of the Maize Genome

Most of our understanding of plant genome structure and evolution has come from the careful annotation of small (e.g., 100 kb) sequenced genomic regions or from automated annotation of complete genome sequences. Here, we sequenced and carefully annotated a contiguous 22 Mb region of maize chromosome 4 using an improved pseudomolecule for annotation. The sequence segment was comprehensively ordered, oriented, and confirmed using the maize optical map. Nearly 84% of the sequence is composed of transposable elements (TEs) that are mostly nested within each other, of which most families are low-copy. We identified 544 gene models using multiple levels of evidence, as well as five miRNA genes. Gene fragments, many captured by TEs, are prevalent within this region. Elimination of gene redundancy from a tetraploid maize ancestor that originated a few million years ago is responsible in this region for most disruptions of synteny with sorghum and rice. Consistent with other sub-genomic analyses in maize, small RNA mapping showed that many small RNAs match TEs and that most TEs match small RNAs. These results, performed on ∼1% of the maize genome, demonstrate the feasibility of refining the B73 RefGen_v1 genome assembly by incorporating optical map, high-resolution genetic map, and comparative genomic data sets. Such improvements, along with those of gene and repeat annotation, will serve to promote future functional genomic and phylogenomic research in maize and other grasses

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Deterrence and Escalation in Competition with Russia (Executive Summary)

The deterrence of armed conflict has been studied intensively for decades, as have escalation dynamics along the path to such conflicts. The deterrence of forms of aggression below the level of armed conflict -- such hostile measures as economic coercion, political subversion, and military intimidation -- has received much less attention.In this report, the authors investigate how the United States might use its military posture in Europe (specifically, ground forces) as part of a strategy to deter these Russian malign activities.The authors identify how forward posture could deter hostile measures through signaling the United States' commitment to its allies and partners, providing irregular capabilities for those partners and allies threatened with political subversion, providing conventional capabilities to neutralize hostile powers' coercion attempts, and providing support for other instruments of U.S. power, such as sanctions. However, forward posture can also lead to an escalation in competitor activities, increasing their sense of threat, incentivizing partners to undertake aggression at levels below armed conflict, and incentivizing third parties to act in ways that increase the likelihood of confrontation. The authors propose ways to calibrate U.S. forward posture to minimize such risks while enhancing deterrence

Discovery of a recent, natural whale fall on the continental slope off Anvers Island, western Antarctic Peninsula

Whale falls provide a substantial, nutrient-rich resource for opportunistic species in areas of the ocean that may otherwise be largely devoid of food. We report the discovery of a natural whale fall at 1430 m depth in the cold waters of the continental slope off the western Antarctic Peninsula. This is the highest latitude whale fall reported to date. The section of the carcass we observed—the tail fluke—was more complete than any previously reported natural whale fall from the deep sea and in the early stages of decomposition. We estimate the entire cetacean to measure 5 to 8 m in length. The flesh remained almost intact on the carcass but the skin had been removed from the entire section except for the end of the fluke, clearly exposing blubber and soft tissue. The absence of skin indicates rapid and homogenous removal by scavengers. The dominant macrofauna present were crustaceans, including most prominently the lithodid crab Paralomis birsteini, and zoarcid fish typical of the ‘mobile-scavenger’ successional stage. The density of mobile macrofauna was greatest on the carcass and declined to background levels within 100 m, indicating that they were attracted to the whale fall. This whale fall offers an important opportunity to examine the decomposition of a carcass under deep-sea conditions at polar latitudes