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Severe cases of COVID-19 pneumonia can lead to acute respiratory distress syndrome (ARDS). Release of interleukin (IL)-33, an epithelial-derived alarmin, and IL-33/ST2 pathway activation are linked with ARDS development in other viral infections. IL-22, a cytokine that modulates innate immunity through multiple regenerative and protective mechanisms in lung epithelial cells, is reduced in patients with ARDS. This study aimed to evaluate safety and efficacy of astegolimab, a human immunoglobulin G2 monoclonal antibody that selectively inhibits the IL-33 receptor, ST2, or efmarodocokin alfa, a human IL-22 fusion protein that activates IL-22 signaling, for treatment of severe COVID-19 pneumonia.Phase 2, double-blind, placebo-controlled study (COVID-astegolimab-IL).Hospitals.Hospitalized adults with severe COVID-19 pneumonia.Patients were randomized to receive IV astegolimab, efmarodocokin alfa, or placebo, plus standard of care. The primary endpoint was time to recovery, defined as time to a score of 1 or 2 on a 7-category ordinal scale by day 28.The study randomized 396 patients. Median time to recovery was 11 days (hazard ratio [HR], 1.01 d; p = 0.93) and 10 days (HR, 1.15 d; p = 0.38) for astegolimab and efmarodocokin alfa, respectively, versus 10 days for placebo. Key secondary endpoints (improved recovery, mortality, or prevention of worsening) showed no treatment benefits. No new safety signals were observed and adverse events were similar across treatment arms. Biomarkers demonstrated that both drugs were pharmacologically active.Treatment with astegolimab or efmarodocokin alfa did not improve time to recovery in patients with severe COVID-19 pneumonia.

The benefit of combined treatment with intravenous thrombolysis before endovascular thrombectomy in patients with acute ischaemic stroke caused by large vessel occlusion remains unclear. We hypothesised that the clinical outcomes of patients with stroke with large vessel occlusion treated with direct endovascular thrombectomy within 4·5 h would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before endovascular thrombectomy).DIRECT-SAFE was an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Adult patients with stroke and large vessel occlusion in the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or basilar artery, confirmed by non-contrast CT and vascular imaging, and who presented within 4·5 h of stroke onset were recruited from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam. Eligible patients were randomly assigned (1:1) via a web-based, computer-generated randomisation procedure stratified by site of baseline arterial occlusion and by geographic region to direct endovascular thrombectomy or bridging therapy. Patients assigned to bridging therapy received intravenous thrombolytic (alteplase or tenecteplase) as per standard care at each site; endovascular thrombectomy was also per standard of care, using the Trevo device (Stryker Neurovascular, Fremont, CA, USA) as first-line intervention. Personnel assessing outcomes were masked to group allocation; patients and treating physicians were not. The primary efficacy endpoint was functional independence defined as modified Rankin Scale score 0-2 or return to baseline at 90 days, with a non-inferiority margin of -0·1, analysed by intention to treat (including all randomly assigned and consenting patients) and per protocol. The intention-to-treat population was included in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03494920, and is closed to new participants.Between June 2, 2018, and July 8, 2021, 295 patients were randomly assigned to direct endovascular thrombectomy (n=148) or bridging therapy (n=147). Functional independence occurred in 80 (55%) of 146 patients in the direct thrombectomy group and 89 (61%) of 147 patients in the bridging therapy group (intention-to-treat risk difference -0·051, two-sided 95% CI -0·160 to 0·059; per-protocol risk difference -0·062, two-sided 95% CI -0·173 to 0·049). Safety outcomes were similar between groups, with symptomatic intracerebral haemorrhage occurring in two (1%) of 146 patients in the direct group and one (1%) of 147 patients in the bridging group (adjusted odds ratio 1·70, 95% CI 0·22-13·04) and death in 22 (15%) of 146 patients in the direct group and 24 (16%) of 147 patients in the bridging group (adjusted odds ratio 0·92, 95% CI 0·46-1·84).We did not show non-inferiority of direct endovascular thrombectomy compared with bridging therapy. The additional information from our study should inform guidelines to recommend bridging therapy as standard treatment.Australian National Health and Medical Research Council and Stryker USA.

This study aimed to determine durability of sustained virologic response (SVR) in hepatitis C virus-infected participants treated with glecaprevir- and/or pibrentasvir-containing regimens.M13-576, a rollover study, evaluated the durability of SVR in a follow-up period of approximately 3 years after hepatitis C virus genotype 1-6-infected participants received a glecaprevir- and/or pibrentasvir-containing regimen in previous phase 2/3 clinical trials. The primary efficacy endpoint was the percentage of participants maintaining SVR and the percentage of participants experiencing relapse or reinfections. Resistance-associated substitutions and safety outcomes related to liver progression were also assessed.Of 384 participants enroled, 377 participants were included in the as-observed population and 287 participants completed the study. In prior studies, 99.7% (376/377) of participants achieved SVR12; of those, an observed 99.5% (374/376) and 100% (286/286) completing the study, maintained SVR. After non-responder imputation of missing data, 286/376 participants (76%) maintained SVR. The participant previously not achieving SVR was a treatment-experienced male with compensated cirrhosis who had NS3 and NS5A substitutions at enrolment, which remained detectable for 12 months. Of the two participants not maintaining SVR, one was re-infected and one experienced late relapse at post-treatment week 60. Five participants (all with a fibrosis stage ≥F3) had hepatocellular carcinoma. No events were deemed related to glecaprevir/pibrentasvir.Glecaprevir/pibrentasvir demonstrated long-term durability of efficacy after SVR12 was achieved. Hepatic-related decompensation events were not seen. Owing to low incidence of virologic failure, conclusions were not drawn on persistence of resistance-associated substitutions.

Background: Right to left shunt (RLS), including patent foramen ovale (PFO), is a recognized risk factor for stroke. RLS/PFO diagnosis can be made by transthoracic echocardiography (TTE) or transcranial Doppler (TCD). A multicenter, prospectively enrolled device trial of robot-assisted TCD (raTCD) vs TTE for RLS detection (BUBL, NCT04604015) was completed. This demonstrated raTCD detecting all and large RLS at approximately 3 times the rate of TTE (primary outcome, any RLS: raTCD 64% vs TTE 20% [absolute difference 43.4% (95% CI 34.3%-52.5%), p < 0.001]). It is unknown if these results are generalizable to routine practice. Methods: We conducted a multi-site retrospective review of prospectively collected “real-world” clinical data of raTCD for RLS diagnosis. All patients referred for a clinical study at the participating sites who underwent raTCD were included. raTCD was performed with standard TCD bubble study technique at all sites. Outcomes included demographics, rate of RLS detection, all and large (Spencer Logarithmic Scale ≥3), as well as “no window” rate. These results were compared to the results of BUBL with descriptive statistics and 2-sample proportion tests. Results: There were 350 patients who underwent clinical raTCD across three participating sites. In this population, the mean age was 56 ± 13 years compared to 59 ± 14 years in BUBL (p = 0.03, 95% CI 0.20-5.49). Both cohorts were 46% female. The clinical population had any RLS on raTCD in 54% (189/350) compared to 64% in BUBL, which was not a significant difference (p= 0.14, 95% CI -0.02-0.18). Large RLS was detected in 26% (91/350) of the clinical population as compared to 28% in BUBL, which was also not a significant difference (p = 0.89, 95% CI -0.08-0.11). The “no window” rate in the clinical population was 5% (18/350), compared to 8% in BUBL (p = 0.39, 95% CI -0.03-0.08). Conclusions: The same raTCD device that was safe and 3 times more likely to diagnose RLS than TTE in a device trial detected all and large RLS in clinical practice at a rate similar to that demonstrated in the device trial. These results further support the notion that raTCD may allow providers to achieve the known sensitivity of TCD for RLS and PFO detection without the need for an experienced operator, even in a “real world” clinical setting.

The mixed cation compounds Na1-xKxAsSe2 (x = 0.8, 0.65, 0.5) and Na0.1K0.9AsS2 crystallize in the polar noncentrosymmetric space group Cc. The AAsQ2 (A = alkali metals, Q = S, Se) family features one-dimensional (1D) 1/∞[AQ2-] chains comprising corner-sharing pyramidal AQ3 units in which the packing of these chains is dependent on the alkali metals. The parallel 1/∞[AQ2-] chains interact via short As···Se contacts, which increase in length when the fraction of K atoms is increased. The increase in the As···Se interchain distance increases the band gap from 1.75 eV in γ-NaAsSe2 to 2.01 eV in Na0.35K0.65AsSe2, 2.07 eV in Na0.2K0.8AsSe2, and 2.18 eV in Na0.1K0.9AsS2. The Na1-xKxAsSe2 (x = 0.8, 0.65) compounds melt congruently at approximately 316 °C. Wavelength-dependent second harmonic generation (SHG) measurements on powder samples of Na1-xKxAsSe2 (x = 0.8, 0.65, 0.5) and Na0.1K0.9AsS2 suggest that Na0.2K0.8AsSe2 and Na0.1K0.9AsS2 have the highest SHG response and exhibit significantly higher laser-induced damage thresholds (LIDTs). Theoretical SHG calculations on Na0.5K0.5AsSe2 confirm its SHG response with the highest value of d33 = 22.5 pm/V (χ333(2) = 45.0 pm/V). The effective nonlinearity for a randomly oriented powder is calculated to be deff = 18.9 pm/V (χeff(2) = 37.8 pm/V), which is consistent with the experimentally obtained value of deff = 16.5 pm/V (χeff(2) = 33.0 pm/V). Three-photon absorption is the dominant mechanism for the optical breakdown of the compounds under intense excitation at 1580 nm, with Na0.2K0.8AsSe2 exhibiting the highest stability.

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR

KRAS mutations occur in 95% of pancreatic ductal adenocarcinomas (PDAC) and are a well-validated driver of PDAC growth. Therefore, anti-KRAS therapies are expected to make a significant impact on the treatment of this deadly cancer, where there are currently no effective targeted therapies. Supporting this premise, early clinical trial results with KRASG12C inhibitors have shown promising disease control rates (84-100%) in KRASG12C-mutant PDAC. Despite these observations, two key issues limit the impact of KRASG12C inhibitors in PDAC. First, KRASG12C(OFF) mutations comprise less than 2% of KRAS mutations in PDAC. Second, patients initially responsive to KRASG12C inhibitors invariably relapse due to treatment-induced resistance. To begin qualifying KRAS inhibitors that target KRAS mutations more frequently found in PDAC, we characterized a RAS inhibitor that targets the multiple KRAS mutations as well as wild-type RAS proteins. We evaluated the impact of this inhibitor on RAS signaling and anti-proliferative activity in KRAS-mutant pancreatic cancer human cell lines and in a panel of RASless MEFs (ras-null mouse embryo fibroblasts) stably expressing exogenous RAS mutant proteins that are commonly found in PDAC. To identify genetic mechanisms of resistance to KRAS inhibition in pancreatic cancer, we applied CRISPR-Cas9 loss-of-function screens to KRASG12C-, KRASG12D-, KRASG12R-, and KRASQ61H-mutant PDAC cells treated with KRAS inhibitors to identify genes that modulate KRAS inhibitor anti-proliferative activity. We identified expected and novel mechanisms of resistance, including those that have been observed in patients treated with KRASG12C inhibitors. Citation Format: Andrew Michael Waters, Wen-Hsuan Chang, Clint Stalnecker, Cole Edwards, Runying Yang, Craig M. Goodwin, Adrienne D. Cox, Channing J. Der. Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1075.

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Coronavirus disease 19 (COVID-19) caused by infection with a novel severe acute respiratory syndrome virus -2 (SARS-CoV2) has evolved into a pandemic and a global public health emergency. The viral genomics, host cellular factors, and interactions are critical for establishing a viral infection and developing a related disease. This paper aims to provide an overview of viral genomics and discuss host cellular factors so far identified to be involved with the disease susceptibility. The novel pathogen is a beta coronavirus and one of seven that cause diseases to humans. It is a single strand positive-sense RNA genome virus that encodes 27 proteins, including the structural Spike protein that binds to host cell surface receptors and is a key for viral entry, and 16 nonstructural proteins play a critical role in viral replication and virulence. While the angiotensin-converting enzyme, ACE2 receptor, and the proteases TMPRSS2 and furin are established as necessary for viral entry, host factors CD147, Cathepsins, DPP4, GRP78, L-SIGN, DC-SIGN, Sialic acid, and Plasmin(ogen) may also play a role in the viral entry. The Spike protein and nonstructural proteins, and various host factors working together may contribute to the infection kinetics, high infectivity, rapid transmission, and a spectrum of clinical manifestations of COVID-19. More importantly, they can serve as potential targets in developing strategies for therapeutical prevention and intervention.

Advances in multimodal characterization methods fuel a generation of increasing immense hyper-dimensional datasets. Color mapping is employed for conveying higher dimensional data in two-dimensiona...

PURPOSE: Men with unfavorable intermediate-risk (UIR-PCa) or high-risk prostate cancer (HR-PCa) are often treated with definitive external beam radiotherapy (EBRT) plus androgen deprivation therapy (ADT). Treatment is frequently intensified by electively treating the pelvic lymph nodes (LN) with whole pelvis radiotherapy (WPRT), but practice patterns and the benefits of WPRT are not well defined. We hypothesized that men treated with WPRT would have improved overall survival (OS) relative to men treated with prostate-only radiotherapy. MATERIALS AND METHODS: National Cancer Database records of men diagnosed between 2008–2015 with UIR-PCa or HR-PCa and treated with prostate EBRT±ADT (72–86.4 Gy) with (n=15,175) or without (n=13,549) WPRT were reviewed. Risk of LN involvement was calculated using the Memorial Sloan Kettering Cancer Center Nomogram. Measured confounders were balanced with inverse probability of treatment weighting and OS hazard ratios (HRs) were generated using multivariable Cox regression. RESULTS: 53% of men received WPRT. Every 1% increase in risk of LN involvement correlated with a 1% increase in risk of death (P

Introduction: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular risk by lowering low-density lipoprotein-cholesterol (LDL-C) levels. AZD8233 is an antisense oligonucleotide in development for the treatment of dyslipidemia. In a single ascending dose study (NCT03593785), AZD8233 was well tolerated and effectively reduced PCSK9 and LDL-C levels in patients with elevated LDL-C. Here, we report results from a multiple ascending dose study of AZD8233. Methods: This was a phase 1, randomized, single-blind, placebo-controlled study (NCT04155645) in patients with dyslipidemia. Participants were receiving statins for ≥ 3 months, had an LDL-C in the range 70-190 mg/dL, and were 18-65 years old. Three cohorts of 11 participants received four subcutaneous injections over an 8-week period (days 1, 8, 29, and 57) of either AZD8233 (15 mg, 30 mg, or 90 mg; n = 8) or placebo (n = 3), and were followed up for 16 weeks post dose. The primary objective was to assess safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD8233; circulating LDL-C was estimated using the Friedewald formula. Results: Overall, 34 patients were randomized and data are available from 33 patients; 15 were male, the mean age was 58 years, and baseline PCSK9 and LDL-C levels were comparable across treatment groups. Treatment with AZD8233 did not result in any clinically relevant safety or tolerability findings. Peak plasma concentrations of AZD8233 were reached within 0.5 to 5 hours post dosing, followed by a biphasic decline. A decrease from baseline in PCSK9 (69.7%, 79.9%, and 95.3%) and LDL-C levels (63.8%, 65.7%, and 83.3%) was observed at 12 weeks for the AZD8233 15 mg, 30 mg, and 90 mg groups, respectively vs placebo ( Figure ). Conclusions: Multiple doses of AZD8233 were generally safe, well tolerated, and reduced PCSK9 and LDL-C levels in a dose-dependent manner in statin-treated patients with dyslipidemia.

Background: \ud In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated.\ud \ud Methods: \ud Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615.\ud \ud Findings: \ud By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60.\ud \ud Interpretation: \ud There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments.\ud \ud Funding: \ud F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

Hoarding disorder was recently recognized as an independent diagnosis; it is characterized by the accumulation of objects causing a functional impairment and is commonly associated with increased risk of injury or death. Limited data exist about deaths of persons found in hoarding environments. This study investigated the characteristics and circumstances surrounding deaths found in "hoarding" environments. Using the electronic record management system, a search for the term "hoard" from 2017 to 2018 identified 138 cases. The mean age was 67 years, 56% were male, 76% were White, and 86% of decedents lived alone. Decomposition was noted in 61% of cases. A full autopsy was performed in 36 cases (26%); natural was the most common manner of death (80%), followed by accident (14%). Cases in which hoarding was thought to be contributory to the cause of death occurred in 5 cases. A qualitative hoard evaluation was done on 29 cases (21%) with available photographs. A hoarding level was assigned using the Clutter Hoarding Scale with an average of 3.39/5. Overall, the analysis showed deaths in pathological hoarding environments appeared to impact all socioeconomic groups and was associated with increased risk of accidental death and being found in a state of decomposition.

Neutrophil extracellular traps formation (NETosis) facilitates thrombosis and contributes to reperfusion resistance - a major challenge encountered during the treatment of acute ischemic stroke. The effect of acute stroke on plasma NETosis biomarkers remains unclear. In this study, young adult C57BL/6 wildtype (WT) mice were subjected to acute brain ischemia-reperfusion (IR) injury. The IR-subjected mice exhibited a drastic increase in plasma citrullinated histone 3 (CitH3) and neutrophil elastase (NE) on day 1 (p

Boron subphthalocyanine chloride is an electron donor material used in small molecule organic photovoltaics with an unusually large molecular dipole moment. Using first-principles calculations, we investigate enhancing the electronic and optical properties of boron subphthalocyanine chloride, by substituting the boron and chlorine atoms with other trivalent and halogen atoms in order to modify the molecular dipole moment. Gas phase molecular structures and properties are predicted with hybrid functionals. Using positions and orientations of the known compounds as the starting coordinates for these molecules, stable crystalline structures are derived following a procedure that involves perturbation and accurate total energy minimization. Electronic structure and photonic properties of the predicted crystals are computed using the GW method and the Bethe-Salpeter equation, respectively. Finally, a simple transport model is use to demonstrate the importance of molecular dipole moments on device performance., 20 pages, 10 figures

Background: Identifying pathways that can be targeted to reduce breast density and breast cancer incidence is an unmet need, especially in premenopausal women. Receptor activator of nuclear factor-κB ligand (RANKL) signaling mediates the major proliferative response of mammary epithelium to progesterone and is positively associated with breast density but there are no clinical trial data on the impact of RANKL inhibition on breast tissue markers in women with dense breasts. We, therefore, determined the impact of RANKL inhibition on breast tissue gene expression in high-risk premenopausal women with dense breasts. Study design: Pilot phase I clinical trial of 9 healthy high-risk pre-menopausal women (≥35 years of age) with dense breasts performed at Washington University School of Medicine, St. Louis, MO from July 2018-December 2018. Fifty-five percent of participants had a positive family history of breast cancer in a first degree relative. Intervention: Participants were given a single dose of subcutaneous RANKL antibody, denosumab (60mg), at baseline (Day 1). On the same day, prior to the denosumab injection, participants had an ultrasound guided core needle biopsy and a blood draw. All study participants returned for repeat core needle biopsy and blood draw after 60 days (Day 60). Outcome Measures: Changes in breast tissue gene expression between Day 1 and Day 60 with a focus on immune/inflammatory and hormone markers. Gene expression was profiled using NanoString nCounter platform. We performed pathway enrichment analysis and used Cell Maker Enrichment library from EnrichR to identify differentially expressed genes. Genes with a p-value Results: Macrophage markers, including CCR5, CD86, CD300A, and CD84 and targets downstream of IRF8: (p-value =4.73e-7), neutrophil degranulation/neutrophil activation in the immune response (p-value=6.0e-21), and the secretory granule membrane pathways (p-value=2.4e-14) were downregulated in breast tissues on Day 60. Pathways involved in progesterone metabolism (p-value=0.0003), estrogen response (p-value=0.0014) and fatty acid metabolism, (p-value=0.0001) were significantly upregulated on Day 60. Specifically, genes involved in steroid hormone metabolism such as DHRS2 (p-value=3.13e-05), and AKR1B15: p-value=4.12e-05) were upregulated on Day 60. Conclusions: A single 60 mg dose of subcutaneous denosumab injection was associated with alterations in pathways involved in hormone, immune and inflammatory signaling in the breast tissues of healthy premenopausal women with dense breasts. Citation Format: Michael Waters, Kay Jayachandran, Debbie Bennet, Jin Zhang, Katherine Weilbaecher, Ian S. Hagemann, Graham A. Colditz, Catherine M. Appleton, Adetunji T. Toriola. Pilot phase I clinical trial of RANKL inhibition and breast tissue gene expression in high-risk premenopausal women with dense breasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2206.