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Focused lung ultrasound (FLUS) has high diagnostic accuracy in many common conditions seen in a variety of emergency settings. Competencies are essential for diagnostic success and patient safety but can be challenging to acquire in clinical environments. Immersive virtual reality (IVR) offers an interactive risk-free learning environment and is progressing as an educational tool. First, this study explored the educational impact of novice FLUS users participating in a gamified or non-gamified IVR training module in FLUS by comparing test scores using a test with proven validity evidence. Second, the learning effect was assessed by comparing scores of each group with known test scores of novices, intermediates and experienced users in FLUS. A total of 48 participants were included: 24 received gamified and 24 received non-gamified IVR training. No significant difference was found between gamified (mean = 15.5 points) and non-gamified (mean = 15.2 points), indicating that chosen gamification elements for our setup did not affect learning outcome (p = 0.66). The mean scores of both groups did not significantly differ from those of known intermediate users in FLUS (gamified p = 0.63, non-gamified p = 0.24), indicating that both IVR modules could be used as unsupervised out-of-hospital training for novice trainees in FLUS.

The angle between the rotation and orbital axes of stars in binary systems -- the obliquity -- is an important indicator of how these systems form and evolve but few such measurements exist. We combine the sample of astrometric orbital inclinations from Gaia DR3 with a sample of solar-like oscillators in which rotational inclinations have been measured using asteroseismology. We supplement our sample with one binary whose visual orbit has been determined using speckle interferometry and present the projected spin-orbit alignments in five systems. We find that each system, and the overall sample, is consistent with alignment but there are important caveats. First, the asteroseismic rotational inclinations are fundamentally ambiguous and, second, we can only measure the projected (rather than true) obliquity. If rotational and orbital inclinations are independent and isotropically-distributed, however, the likelihood of drawing our data by chance is less than a few per cent. Though small, our data set argues against uniformly random obliquities in binary systems. We speculate that dozens more measurements could be made using data from NASA's TESS mission, mostly in red giants. ESA's PLATO mission will likely produce hundreds more spin-orbit measurements in systems with main-sequence and subgiant stars., Comment: Accepted for publication in MNRAS. 4 pages, 3 figures, 1 table. Scripts to reproduce Figs 1 & 2 and data in Table 1 are available at https://gitlab.com/warrickball/kepler-gaia-spin-orbit

Objective: We investigated the association between new-onset atrial fibrillation (AF) and risk of stroke and myocardial infarction (MI) in patients with abdominal aortic aneurysmal (AAA) disease.Methods: Observational crossover study using Danish nationwide data, including patients with AAA and incident AF between 1997 and 2018. We estimated the 1-year risk of stroke and MI and the within-individual odds ratios (ORs) of ischemic events before and after an AF diagnosis, stratified by year of AF diagnosis (1997-2010 and 2011-2018), and supplemented with analyses on changes in use of antithrombotic therapy.Results: A total of 3,035 AAA patients were included: 1,040 diagnosed during 1997 to 2010, and 1,995 during 2011 to 2018 (22.2% females, median age 78 years; median CHA2DS2-VASc score 4; interquartile range: 3-5). One-year risk of ischemic events after AF was 5.9% (confidence interval [CI] 95%: 4.6-7.5%) and 4.5% (CI 95%: 3.7-5.5%) for stroke and 5.4% (CI 95%: 4.2-6.9%) and 4.0% (CI 95%: 3.2-4.9%) for MI during 1997 to 2010 and 2011 to 2018, respectively. The OR of ischemic stroke before and after incident AF was 2.8 (CI 95%: 1.6-5.2) during 1997 to 2010; and 2.4 (CI 95%: 1.5 to 3.9) during 2011 to 2018, and 3.5 (CI 95%: 1.7-7.5) and 1.5 (CI 95%: 0.9-2.4) for MI. One-year proportion of prescription claims for oral anticoagulants after AF changed from 66.1% in 1997 to 2010 to 82.6% in 2011 to 2018, while antiplatelet prescription claims changed from 80.8 to 60.9%.Conclusion: Cardiovascular prognosis has improved in patients with prevalent AAA disease and new-onset AF in concordance with optimization of antithrombotic therapy over time. A diagnosis of AF conferred residual risk of stroke and MI. Objective: We investigated the association between new-onset atrial fibrillation (AF) and risk of stroke and myocardial infarction (MI) in patients with abdominal aortic aneurysmal (AAA) disease.Methods: Observational crossover study using Danish nationwide data, including patients with AAA and incident AF between 1997 and 2018. We estimated the 1-year risk of stroke and MI and the within-individual odds ratios (ORs) of ischemic events before and after an AF diagnosis, stratified by year of AF diagnosis (1997-2010 and 2011-2018), and supplemented with analyses on changes in use of antithrombotic therapy.Results: A total of 3,035 AAA patients were included: 1,040 diagnosed during 1997 to 2010, and 1,995 during 2011 to 2018 (22.2% females, median age 78 years; median CHA2DS2-VASc score 4; interquartile range: 3-5). One-year risk of ischemic events after AF was 5.9% (confidence interval [CI] 95%: 4.6-7.5%) and 4.5% (CI 95%: 3.7-5.5%) for stroke and 5.4% (CI 95%: 4.2-6.9%) and 4.0% (CI 95%: 3.2-4.9%) for MI during 1997 to 2010 and 2011 to 2018, respectively. The OR of ischemic stroke before and after incident AF was 2.8 (CI 95%: 1.6-5.2) during 1997 to 2010; and 2.4 (CI 95%: 1.5 to 3.9) during 2011 to 2018, and 3.5 (CI 95%: 1.7-7.5) and 1.5 (CI 95%: 0.9-2.4) for MI. One-year proportion of prescription claims for oral anticoagulants after AF changed from 66.1% in 1997 to 2010 to 82.6% in 2011 to 2018, while antiplatelet prescription claims changed from 80.8 to 60.9%.Conclusion: Cardiovascular prognosis has improved in patients with prevalent AAA disease and new-onset AF in concordance with optimization of antithrombotic therapy over time. A diagnosis of AF conferred residual risk of stroke and MI.

Background We previously reported developing 2 anticapsular monoclonal antibodies (mAbs) as a novel therapy for Acinetobacter baumannii infections. We sought to determine whether a bispecific mAb (bsAb) could improve avidity and efficacy while maximizing strain coverage in one molecule. Methods Humanized mAb 65 was cloned into a single-chain variable fragment and attached to humanized mAb C8, combining their paratopes into a single bsAb (C73). We tested bsAb C73’s strain coverage, binding affinity, ex vivo opsonic activity, and in vivo efficacy compared to each mAb alone and combined. Results The bsAb demonstrated strain coverage, binding affinity, opsonization, and in vivo efficacy superior to either original mAb alone or combined. Conclusions A humanized bsAb targeting distinct A. baumannii capsule moieties enabled potent and effective coverage of disparate A. baumannii clinical isolates. The bsAb enhances feasibility of development by minimizing the number of components of a promising novel therapeutic for these difficult-to-treat infections.

Non-ionic polar side chains are leveraged in the molecular design of conjugated polymers to create stable surfactant-free polymer nanoparticle dispersions. An organic electronic device is prepared by processing the nanoparticles directly from water.

Background & Aim: To assess consonant proficiency and velopharyngeal function in 10-year-old children born with unilateral cleft lip and palate (UCLP) within the Scandcleft project.Methods & Procedures: Three parallel group, randomized, clinical trials were undertaken as an international multicentre study by nine cleft teams in five countries. Three different surgical protocols for primary palate repair (Arm B–Lip and soft palate closure at 3–4 months, hard palate closure at 36 months, Arm C–Lip closure at 3–4 months, hard and soft palate closure at 12 months, and Arm D–Lip closure at 3–4 months combined with a single-layer closure of the hard palate using a vomer flap, soft palate closure at 12 months) were tested against a common procedure (Arm A–Lip and soft palate closure at 3–4 months followed by hard palate closure at 12 months) in the total cohort of 431 children born with a non-syndromic UCLP. Speech audio and video recordings of 399 children were available and perceptually analysed. Percentage of consonants correct (PCC) from a naming test, an overall rating of velopharyngeal competence (VPC) (VPC-Rate), and a composite measure (VPC-Sum) were reported.Outcomes & Results: The mean levels of consonant proficiency (PCC score) in the trial arms were 86–92% and between 58% and 83% of the children had VPC (VPC-Sum). Only 50–73% of the participants had a consonant proficiency level with their peers. Girls performed better throughout. Long delay of the hard palate repair (Arm B) indicated lower PCC and simultaneous hard and soft palate closure higher (Arm C). However, the proportion of participants with primary VPC (not including velopharyngeal surgeries) was highest in Arm B (68%) and lowest in Arm C (47%).Conclusions & Implications: The speech outcome in terms of PCC and VPC was low across the trials. The different protocols had their pros and cons and there is no obvious evidence to recommend any of the protocols as superior. Aspects other than primary surgical method, such as time after velopharyngeal surgery, surgical experience, hearing level, language difficulties and speech therapy, need to be thoroughly reviewed for a better understanding of what has affected speech outcome at 10 years.

BACKGROUND: Thrombosis is common among patients with cancer. Primary thromboprophylaxis guided by the Khorana score is endorsed by guidelines but recommendations rely mainly on data from patients treated with chemotherapy.OBJECTIVES: To explore if the Khorana score could risk stratify patients with cancer treated with immune checkpoint inhibitors according to risk of venous and arterial thrombosis.PATIENTS/METHODS: The study population and Khorana score were defined using administrative Danish health registries. The primary outcome was 6-month risk of venous thromboembolism after initiation of checkpoint inhibitor treatment. Secondary outcomes were arterial thrombosis and any thromboembolic event. Death was considered a competing risk event.RESULTS: Among 3946 patients with cancer initiating checkpoint inhibitor treatment without other indications for anticoagulation, the overall 6-month incidence of venous thromboembolism was 2.6% (95% confidence interval [CI]: 2.1-3.1). Risks were 2.1% (95% CI: 1.5-3.0), 2.6% (95% CI: 2.0-3.4), and 3.7% (95% CI: 2.1-5.9) in low (score 0), intermediate (score 1-2), and high risk (score ≥3) Khorana categories, respectively. Among patients eligible for primary thromboprophylaxis according to guidelines (Khorana score ≥2), risk of venous thromboembolism was 4.1% (95% CI: 3.1-5.4). Higher Khorana risk category was also associated with higher 6-month risk of both arterial thrombosis and any thromboembolic events.CONCLUSIONS: The Khorana score was able to risk stratify patients with cancer treated with immune checkpoint inhibitors according to 6-month risk of thromboembolic events. Risks of venous thromboembolism were lower than in randomized thromboprophylaxis trials, thus questioning the absolute benefit of routine primary thromboprophylaxis in an unselected population of patients treated with immune checkpoint inhibitors.

Long-term weight loss can reduce the risk of type 2 diabetes for people living with obesity and reduce complications for patients diagnosed with type 2 diabetes. We investigated whether a telehealth lifestyle-coaching program (Liva) leads to long-term (24 months) weight loss compared to usual care. In a randomized controlled trial, n = 340 participants living with obesity with or without type 2 diabetes were enrolled and randomized via an automated computer algorithm to an intervention group ( n = 200) or to a control group ( n = 140). The telehealth lifestyle-coaching program comprised of an initial one-hour face-to-face motivational interview followed by asynchronous telehealth coaching. The behavioural change techniques used were enabled by individual live monitoring. The primary outcome was a change in body weight from baseline to 24 months. Data were assessed for n = 136 participants (40%), n = 81 from the intervention group and n = 55 from the control group, who completed the 24-month follow-up. After 24 months mean body weight and body mass index were reduced significantly for completers in both groups, but almost twice as much was registered for those in the intervention group which was not significant between groups −4.4 (CI −6.1; −2.8) kg versus −2.5 (CI −3.9; −1.1) kg, P = 0.101. Haemoglobin A1c was significantly reduced in the intervention group −3.1 (CI −5.0; −1.2) mmol/mol, but not in the control group −0.2 (CI −2.4; −2.0) mmol/mol without a significant between group difference ( P = 0.223). Low completion was partly due to coronavirus disease 2019. Telehealth lifestyle coaching improve long-term weight loss (> 24 months) for obese people with and without type 2 diabetes compared to usual care.

As sediment accumulation indicates basin subsidence, erosion often is understood as tectonic uplift, but the amplitude and timing may be difficult to determine because the sedimentary record is missing. Quantification of erosion therefore requires indirect evidence, for example thermal indicators such as temperature, vitrinite reflectance and fission tracks in apatite. However, as always, the types and quality of data and the choice of models are important to the results. For example, considering only the thermal evolution of the sedimentary section discards the thermal time constant of the lithosphere and essentially ignores the temporal continuity of the thermal structure. Furthermore, the types and density of thermal indicators determine the solution space of deposition and erosion, the quantification of which calls for the use of inverse methods, which can only be successful when all models are mutually consistent. Here, we use integrated basin modelling and Markov Chain Monte Carlo inversion of four deep boreholes to show that the erosional pattern along the Sorgenfrei–Tornquist Zone (STZ) in the eastern North Sea is consistent with a tectonic model of tectonic inversion based on compression and relaxation of an elastic plate. Three wells in close proximity SW of the STZ have different data and exhibit characteristic differences in erosion estimates but are consistent with the formation of a thick chalk sequence, followed by minor Cenozoic erosion during relaxation inversion. The well on the inversion ridge requires ca. 1.7 km Jurassic-Early Cretaceous sedimentation followed by Late Cretaceous–Palaeocene erosion during inversion. No well demands thick Cenozoic sedimentation followed by equivalent significant Neogene exhumation. When data are of high quality and models are consistent, the thermal indicator method yields significant results with important tectonic and geodynamic implications.

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings ( P -8 ). Among them, a rare intergenic variant at novel locus, LOC100506274 , was associated with lower systolic blood pressure in stage-1 (beta [SE]=−32.6 [6.0]; P =4.99×10 -8 ) but not stage-2 analysis ( P =0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=−0.36 [0.07]; P =4.18×10 -7 ) and attained genome-wide significance in stage-2 (beta [SE]=−0.29 [0.03]; P =7.28×10 -23 ). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings ( P -6 and P -4 , respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The LOOP Study was funded by Innovation Fund Denmark [grant number 12-1352259], The Research Foundation for the Capital Region of Denmark, The Danish Heart Foundation [grant number 11-04-R83-A3363-22625], Aalborg University Talent Management Program, Arvid Nilssons Fond, Skibsreder Per Henriksen, R og Hustrus Fond, the European Union’s Horizon 2020 program [grant number 847770], Læge Sophus Carl Emil Friis og hustru Olga Doris Friis’ Legat, and an unrestricted grant from Medtronic. Background It is well known that atrial fibrillation (AF) confers a substantially increased risk of ischemic stroke, but data on health benefits from AF screening are scarce. The newly proposed MVP risk score combining the duration, voltage and morphology of P-wave has been demonstrated to be predictive of AF and might therefore also be useful in risk-stratifying individuals for AF screening and subsequent treatment. Purpose The present study sought to examine MVP risk score and its P-wave components for prediction of AF screening effects. Methods The LOOP Study randomized AF-naïve individuals aged 70-90 years with additional stroke risk factors to either continuous AF screening with implantable loop recorder (ILR) and subsequent anticoagulation initiation upon detection of AF episode ≥6 minutes, or usual care. In this secondary analysis, the LOOP participants with a baseline 12-lead electrocardiogram (ECG) suitable for P-wave measurement were included. Results Of 5759 participants included, 265 (4.6%) had had ischemic stroke during follow-up: 213 (4.9%) of 4311 in the control group versus 64 (3.6%) of 1448 in the ILR group. Among the participants in the control group, a significantly increased risk of ischemic stroke was observed for MVP score 5-6 versus score 0-2 (hazard ratio (HR) 1.66 [95% confidence interval (CI): 1.01-2.75]) and for the presence of interatrial block (IAB) versus no IAB (HR 1.85 [95% CI: 1.19-2.86]), whereas a P-wave voltage in lead I (PWVI) 110 versus ≤110 ms). Compared with usual care, ILR screening did not significantly reduce the stroke risk regardless of MVP risk score, PWD, PWVI, or IAB pattern at baseline. Conclusions In an elderly population with additional stroke risk factors, both the P-wave parameters and the combined MVP risk score based on 12-lead ECG were associated with ischemic stroke, but these did not successfully demonstrate an association with effects of AF screening on stroke prevention.

Geological observations reveal that earthquakes nucleate, propagate, and arrest in complex fault zones whose structural heterogeneity depends on the tectonic loading, geometry, lithology, rheology, presence of fluids, and strain localization processes. These fault zones can host a wide range of fault slip behaviors (e.g., creep, aseismic- and slow-slip events, afterslip, and earthquakes). This implies that the environment in which earthquakes occur is diverse, and that different physical and chemical processes can be involved during the coseismic dynamic rupture.Earthquakes are generated by rupture propagation and slip within fault cores and dissipate the stored elastic and gravitational strain energy in fracture and frictional processes in the fault zone (from microscale - less than a millimeter - to macroscale - centimeters to kilometers) and in radiated seismic waves. Understanding this energy partitioning is fundamental in earthquake mechanics to describe dynamic fault weakening and causative rupture processes operating over different spatial and temporal scales.The energy dissipated in earthquake rupture propagation is commonly called fracture energy (G) or breakdown work (Wb). Here we discuss these two parameters, and we review fracture energy estimates from seismological, modeling, geological, and experimental studies and show that fracture energy scales with fault slip and earthquake size. Our analysis confirms that seismological estimates of fracture energy and breakdown work are comparable and scale with seismic slip. The inferred scaling laws show modest deviations explained in terms of epistemic uncertainties. The original collection of fracture energy estimates from laboratory experiments confirms the scaling with slip over a slip range of more than 10 decades. Fracture energy associated with breaking of intact rocks is larger than for precut specimens and might suggest differences between the role of fracture and friction, or a different size of the rupture front zone. It is important to recall that fault products after deformation in the laboratory correspond to fault products observed in nature, and acoustic emissions recorded in the laboratory can be processed as seismic waves on a natural fault. We conclude that although material-dependent constant fracture energies are important at the microscale for fracturing grains of the fault zone, they are negligible with respect to the macroscale processes governing rupture propagation on natural faults.In this study we discuss the scaling of fracture energy and breakdown work with slip, and we propose different interpretations relying on different processes characterizing complex fault zones. Our results suggest that, for earthquake ruptures in natural faults, the estimates of G and Wb are consistent with a macroscale description of the causative processes.Reconciling observations and results from laboratory experiments and numerical modeling with geological observations can be done, provided that we accept the evidence that earthquakes can occur in a variety of geological settings and fault zone structures governed by different physical and chemical processes.

Background It is not clearly known how well Danes estimate their chances of reaching the average life expectancy and whether identifiable population subgroups misestimate their life expectancy, and potentially also investments and savings in health and pensions. Therefore, in this study, we examined on the individual level whether subjective life expectancy is in line with the statistically calculated chance of reaching age 85, and further explored the psychological and behavioral factors associated with under or overestimation. Methods We opted for a cross-sectional survey design based on a sample of 5,379 Danish citizens aged 50–70 years, returning a web-based questionnaire with socio-demographic data supplemented from a national registry. Average participant estimates of their chance of reaching age 85 for each age range and sex group were compared with actuarial data. We then performed multiple linear regression analyses to examine factors associated with the subjective expectancy of reaching age 85 years. Results We found that 32% of females and 23% of males reported 100% certainty of reaching age 85, and average expected survival chance exceeded the statistically predicted survival chance for 23% of males and 16% for females in age-ranges 50–60 and 61–70. Our multivariable analysis found that health literacy, internal health locus of control, willingness to take health risks, self-rated health, and health and life satisfaction all showed a significant positive association with expectation of reaching age 85. Moreover, those on daily medications, ex- or current smokers, and heavy drinkers were significantly less optimistic about reaching age 85. Conclusions Particularly for the population groups with inaccurate life expectancies, the significant associations with psychological and behavioral factors open a way for initiatives based on behavior change theories to reach a better agreement between subjective and statistical life expectancy.

Western blots and quantification of time course of HRG-stimulated signaling (pAKT-S473, pERK1/2) in NCI-N87, SKBR3, OVCAR8, and HCC1937 control cell lines.

Table showing indication, specific PIK3CA and PTEN mutations, as well as ErbB2 amplification status.

PDF file, 450KB, Biphasic distribution of the increase in binding affinity for conversion from monovalent to bivalent forms for antibodies with different intrinsic affinities.

Supplementary Methods, Figures S1-S11, and Table Legends. Supplementary Methods: description of methods used in the Supplementary figures, expanded description of ELISA assays, and description of the computational model of multiple EGFR ligand antagonists. Supplementary Figure S1: Monoclonal EGFR antibodies poorly block signal amplification by high-affinity EGFR ligands. Supplementary Figure S2: Hierarchical clustering of EGFR ligand expression in primary colon, head and neck, and lung tumors. Supplementary Figure S3: Trends observed in EGFR ligand expression in TCGA data set are similarly apparent in primary colorectal samples analyzed by RT-qPCR. Supplementary Figure S4: Relative expression of EGFR ligands varies across cancer indications. Supplementary Figure S5: Simulated activity of a combination of two ligand antagonists versus single antagonists as a function of ligand affinity. Supplementary Figure S6: MM-151 antibodies have non-overlapping epitopes and can simultaneously engage the same EGF receptor molecule. Supplementary Figure S7: MM-151 elicits superior ligand antagonism. Supplementary Figure S8: MM-151 promotes potent down-regulation of EGFR that is dependent upon the oligoclonal combination of bivalent antibodies. Supplementary Figure S9: MM-151 promotes both antibody-dependent cell-mediated (ADCC) and complement-dependent (CDC) cytotoxicity. Supplementary Figure S10: Cell proliferation stimulated by high-affinity ligands is partially or completely resistant to cetuximab treatment but still sensitive to MM-151 treatment. Supplementary Figure S11: MM-151 overcomes signal amplification driven by high-affinity ligand. Legends for Supplementary Tables S1-S8.

PDF file, 95KB, Comparison of cell-binding curves for low and high affinity anti-EGFR IgG antibodies at the experimental incubation time and a hypothetical time.

Supplementary Tables S2, S3, S4. Structure of the computational model of multiple ligand antagonists: species (Table S2), parameters (Table S3), and Reactions (Table S4).

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PDF - 111K, Additional details on the implementation and training of the mechanistic model.

Figure legends describing supplemental data.

Supplementary Figures S1-S6. Supplementary Fig. S1. The effect of cyclophosphamide on liposome delivery is dose dependent, requires a predose rather than a co-injection, and is not mediated by changes in blood clearance. Supplementary Fig. S2. Cyclophosphamide induces DNA-damage and tumor cell apoptosis. Supplementary Fig. S3. Effects of cyclophosphamide, ifosfamide, paclitaxel and eribulin on HER2-tPLD delivery, stromal cell density, total cell density, and interstitial space area. Supplementary Fig. S4. Pretreatment of tumors with cyclophosphamide significantly enhances nuclear delivery of doxorubicin following HER2-tPLD injection. Supplementary Fig. S5. Pretreatment of tumors with cyclophosphamide enhances the delivery of HER2-tPLD in multiple tumor models. Supplementary Fig. S6. The combination of a cyclophosphamide predose with HER2-tPLD results in synergistic anti-tumor activity.

Supplementary Table S1. Cell lines and cell culture conditions

PDF file, 52KB, Comparison of measured apparent IgG affinities vs affinities calculated by using a mathematical model on cells of different EGFR density (A431, MDAMB468, and MDAMB231).

Although inhibition of the insulin-like growth factor (IGF) signaling pathway was expected to eliminate a key resistance mechanism for EGF receptor (EGFR)-driven cancers, the effectiveness of IGF-I receptor (IGF-IR) inhibitors in clinical trials has been limited. A multiplicity of survival mechanisms are available to cancer cells. Both IGF-IR and the ErbB3 receptor activate the PI3K/AKT/mTOR axis, but ErbB3 has only recently been pursued as a therapeutic target. We show that coactivation of the ErbB3 pathway is prevalent in a majority of cell lines responsive to IGF ligands and antagonizes IGF-IR–mediated growth inhibition. Blockade of the redundant IGF-IR and ErbB3 survival pathways and downstream resistance mechanisms was achieved with MM-141, a tetravalent bispecific antibody antagonist of IGF-IR and ErbB3. MM-141 potency was superior to monospecific and combination antibody therapies and was insensitive to variation in the ratio of IGF-IR and ErbB3 receptors. MM-141 enhanced the biologic impact of receptor inhibition in vivo as a monotherapy and in combination with the mTOR inhibitor everolimus, gemcitabine, or docetaxel, through blockade of IGF-IR and ErbB3 signaling and prevention of PI3K/AKT/mTOR network adaptation. Mol Cancer Ther; 13(2); 410–25. ©2013 AACR.

Supplementary Tables S5, S6, S7, S8. mRNA expression data for EGFR ligands as measured by RNAseq from The Cancer Genome Atlas (TCGA) across 14 cancer indications or by RT-qPCR of colorectal cancer FFPE samples. Table S5: Summary of TCGA datasets included in the analysis. Table S6: Raw and normalized expression data from TCGA. Table S7: EGFR ligand expression measured by RT-qPCR on commercially-obtained colorectal cancer FFPE samples. Table S8: Pairwise correlations of EGFR ligands across four TCGA indications.

PDF file, 56KB, Kinetic parameters used in the computational model of antibody binding.

Given the bulky nature of nanotherapeutics relative to small molecules, it is hypothesized that effective tumor delivery and penetration are critical barriers to their clinical activity. HER2-targeted PEGylated liposomal doxorubicin (MM-302, HER2-tPLD) is an antibody–liposomal drug conjugate designed to deliver doxorubicin to HER2-overexpressing cancer cells while limiting uptake into nontarget cells. In this work, we demonstrate that the administration and appropriate dose sequencing of cyclophosphamide can improve subsequent MM-302 delivery and enhance antitumor activity in preclinical models without negatively affecting nontarget tissues, such as the heart and skin. We demonstrate that this effect is critically dependent on the timing of cyclophosphamide administration. Furthermore, the effect was found to be unique to cyclophosphamide and related analogues, and not shared by other agents, such as taxanes or eribulin, under the conditions examined. Analysis of the cyclophosphamide-treated tumors suggests that the mechanism for improved MM-302 delivery involves the induction of tumor cell apoptosis, reduction of overall tumor cell density, substantial lowering of interstitial fluid pressure, and increasing vascular perfusion. The novel dosing strategy for cyclophosphamide described herein is readily translatable to standard clinical regimens, represents a potentially significant advance in addressing the drug delivery challenge, and may have broad applicability for nanomedicines. This work formed the basis for clinical evaluation of cyclophosphamide for improving liposome deposition as part of an ongoing phase I clinical trial of MM-302 in HER2-positive metastatic breast cancer. Mol Cancer Ther; 14(9); 2060–71. ©2015 AACR.

PDF - 711K, Supplemental Figure S1. Schematic representation of components of IGF-1R/ErbB3 merged mechanistic signaling model. Supplemental Table S1. Mean ligand-stimulated pAKT (S473) levels (A) or simulated levels (B) in BxPC-3, AdRr and MCF7 cells that were used to generate 3D contour plots in Figure 1A. Supplemental Figure S2. Western blots used to generate bar graphs in Figures 1, 3, & 4. Supplemental Figure S3. MM-141 is selective for IGF-1R and ErbB3, and is cross-reactive to relevant toxicology species. Supplemental Table S2. MM-141 is more potent than monospecific antibodies at inhibition of single ligand-induced pAKT (Ser473) signaling. Supplemental Figure S4. MM-141 does not promote basal signaling. Supplemental Figure S5. Generation of isogenic BxPC-3 cell lines with stable knockdown of IGF-1R or ErbB3. Supplemental Table S3. Mean pAKT (S473) levels in engineered BxPC-3 cells that were used to generate 3D contour plots in Figure 3A. Supplemental Figure S6. MM-141 maintains activity over a broad range of receptor profiles. Supplemental Figure S7. Mechanistic model can recapitulate signal inhibition properties of MM-141. Supplemental Figure S8. Pharmacokinetic properties of MM-141. Supplemental Figure S9. MM-141 controls gemcitabine-induced network adaptation. Supplemental Figure S10. MM-141 controls expression of IGF-1R and ErbB3-interacting RTKs.

Growth rates of engineered OVCAR8 cells grown as spheroids.

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Supplementary Tables S1-S3. Supplementary Table S1: Changes in tumor deposition in the control and cyclophosphamide-treated groups as measured by PET/CT. Supplementary Table S2: Effects of cyclophosphamide on HER2 expression, collagen type I deposition and vascular parameters in BT474-M3 tumors. Supplementary Table S3. Reagents for immunofluorescence on FFPE and frozen tumor sections

PDF - 91K, Supplementary Figure Legends.

Supplementary Materials and Methods. This file contains information on the reagents, methods for the evaluation of cell viability, preparation of liposomes and details on the image analysis.

Table showing raw values of tumor sizes of OVCAR8 EV-neg, H1047R-neg, and H1047R-ErbB3 expressing xenografts.

Growth rates of control (GFP/EV) or PIK3CA- (WT or H1047R mutant) expressing NCI-N87, SKBR3, OVCAR8, and HCC1937 cells grown in 3D culture.

Aims Abdominal aortic aneurysmal disease is associated with increased risk of cardiovascular morbidity and death, which potentially can be reduced with cardioprotective medical therapy. The aim of this study was to observe temporal trends in prevalence and incidence of cardiovascular comorbidity as well as use of medical cardioprotective treatment in patients diagnosed with abdominal aortic aneurysmal disease. Methods and results This was a population-based cohort study based on data from national health registries, including all patients diagnosed with abdominal aortic aneurysms between 1998 and 2018. Data were stratified into four time periods (1999–2003, 2004–2008, 2009–2013, and 2014–2018) to illustrate trends over time. Outcome measures were (i) cardiovascular comorbidity and medical cardioprotective therapy at time of diagnosis, (ii) new admissions for atherosclerotic cardiovascular disease, and (iii) all-cause mortality after 2-year follow-up. The study cohort included 33 296 individuals. Mean age was 74 years. Prevalence of atherosclerotic cardiovascular comorbidity at diagnosis decreased from 41.5 to 32.6%. Use of statins increased from 17.9 to 66.9%, antiplatelets from 45.6 to 63.3%, and combined therapy with both antiplatelets and statins from 11.3 to 44.8%, and from 12.1 to 50.7% when anticoagulant therapy was included. Developments in medication use plateaued after 2013. Prevalence and incidence of atherosclerotic cardiovascular disease decreased through all four time periods. The same applied to all-cause mortality, which decreased from 24.3 to 12.4 deaths (per 100 person-years). Conclusion In patients diagnosed with abdominal aortic aneurysm, cardiovascular comorbidity at diagnosis, risk of future cardiovascular events, and all-cause mortality is decreasing. Nevertheless, cardiovascular burden and mortality rates remain substantial, and medical cardioprotective therapy can be further improved.

We propose a physics-based combustion simulation method for computer graphics that extends the mathematical models of previous efforts to automatically capture more realistic flames as well as temperature and soot distributions. Our method includes mathematical models for the thermodynamic properties of real-world fuels which enables, for example, the prediction of adiabatic flame temperatures. We couple this with a model of heat transfer that includes convection, conduction as well as both radiative cooling and heating. This facilitates among other things ignition at a distance without heating up the intermediate air. We model the combustion as infinitely fast chemistry and couple this with the thin flame model, spatially varying laminar burning velocities based on local species and empirical measurements, physically validated soot formation and oxidation as well as water vapor production and condensation. We implement this on adaptive octree-like grids with collocated state variables, a new SBDF2-derived semi-Lagrangian time integrator for velocity, and a multigrid scheme used for multiple solver components. In combination, these models enable us to simulate deflagration phenomena ranging from small scale premixed and diffusion flames to fireballs and subsonic explosions which we demonstrate by several examples. In addition, we validate several of the results based on reference footage and measurements and discuss the relation of prevalent heuristic techniques arising in visual effects production to some of the physics-based models we propose.

Thermal treatment is often employed in food processing to tailor product properties by manipulating the ingredient functionality, but these elevated temperatures may accelerate oxidation and nutrient loss. Here, oxidation of different whey protein systems [α-lactalbumin (α-LA), β-lactoglobulin (β-LG), a mix of α-LA and β-LG (whey model), and a commercial whey protein isolate (WPI)] was investigated during heat treatment at 60–90 °C and a UHT-like treatment by LC-MS-based proteomic analysis. The relative modification levels of each oxidation site were calculated and compared among different heat treatments and sample systems. Oxidation increased significantly in protein systems after heating at ≥90 °C but decreased in systems with higher complexity [pure protein (α-LA > β-LG) > whey model > WPI]. In α-LA, Cys, Met, and Trp residues were found to be most prone to oxidation. In β-LG-containing protein systems, Cys residues were suggested to scavenge most of the reactive oxidants and undergo an oxidation-mediated disulfide rearrangement. The rearranged disulfide bonds contributed to protein aggregation, which was suggested to provide physical protection against oxidation. Overall, limited loss of amino acid residues was detected after acidic hydrolysis followed by UHPLC analysis, which showed only a minor effect of heat treatment on protein oxidation in these protein systems.

Context Falling insulin requirements often lead to considerations of whether a pregnancy can continue safely or if delivery is indicated. Objective To evaluate prevalence and predictors of falling insulin requirements in pregnant women with preexisting diabetes delivering preterm and to explore the relationship to fetal asphyxia and neonatal morbidity. Methods A prospective cohort study of 101 consecutive singleton pregnant women with preexisting diabetes delivering preterm Results In total, 27% (27/101) experienced falling insulin requirements of median 30% (interquartile range 24-40) before delivery. In all women with type 1 diabetes, the prevalence was 37% (25/68), whereas it was 43% (24/56) in those with indicated preterm delivery and 6% (2/33) among women with type 2 diabetes. In women with type 1 diabetes and indicated preterm delivery, falling insulin requirements were first identified at 34 + 5 (33 + 6-35 + 4) weeks + days and delivery occurred 3 (1-9) days later. Gestational age at delivery, prevalence of suspected fetal asphyxia, and neonatal morbidity were similar in women with and without falling insulin requirements. Neither glycemic control, nausea, or preeclampsia was associated with falling insulin requirement. Conclusion Falling insulin requirements often preceded preterm delivery in women with type 1 diabetes, foremost when preterm delivery was indicated, but was not related to fetal asphyxia or neonatal morbidity. Whether falling insulin requirements in late pregnancy are a warning sign of placental insufficiency or mainly reflects variations in normal physiology needs further investigation.