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As a result of emergency online teaching during the covid-19 pandemic, this study was conducted to determine faculty (n=144) and students’ (n=350) perceptions with their experience in an online teaching and learning environment as well as students’ preferred learning modality. Compared to students, faculty indicated better overall satisfaction with their commitment to teaching and their comfort level with technology prior to emergency online instruction, Wilk’s Λ= .851, F (7,428) = 10.721, p=

This study developed and evaluated DNA metabarcoding to identify the presence of pinniped and cetacean prey DNA in fecal samples of East Greenland (EG) and Southern Beaufort Sea (SB) polar bears Ursus maritimus sampled in the spring of 2015-2019. Prey DNA was detected in half (49/92) of all samples, and when detected, ringed seal Pusa hispida was the predominant prey species, identified in 100% (22/22) of EG and 81% (22/27) of SB polar bear samples with prey DNA detected. Bearded seal Erignathus barbatus DNA was found in 19% (5/27) of SB polar bear samples for which prey DNA was detected. Prey DNA detection frequencies and relative abundances were compared to estimates from quantitative fatty acid signature analysis (QFASA) for a subset of SB polar bears. Ringed seal and bearded seal were the main prey identified by both methods, but QFASA also identified 2 cetacean prey species not found by prey DNA. Differences in DNA metabarcoding vs. QFASA results were likely related to the different dietary timescales captured by each approach, i.e. short-term vs. long-term diet, respectively. Prey DNA detection, sex/age class, and subpopulation significantly explained variation in polar bear gut bacterial composition. Polar bear samples with prey DNA detected were associated with higher abundances of the bacterial classes Clostridia and Bacilli and lower abundances of Negativicutes. Fecal DNA metabarcoding is thus useful for identifying recent prey of polar bears, complementing quantitative and likely longer-term QFASA estimates, and may help understand variation in the polar bear gut microbiome.

Dystrophic epidermolysis bullosa is a rare genetic blistering skin disease caused by mutations inWe conducted a phase 3, double-blind, intrapatient randomized, placebo-controlled trial involving patients 6 months of age or older with genetically confirmed dystrophic epidermolysis bullosa. For each patient, a primary wound pair was selected, with the wounds matched according to size, region, and appearance. The wounds within each pair were randomly assigned in a 1:1 ratio to receive weekly application of either B-VEC or placebo for 26 weeks. The primary end point was complete wound healing of treated as compared with untreated wounds at 6 months. Secondary end points included complete wound healing at 3 months and the change from baseline to weeks 22, 24, and 26 in pain severity during changes in wound dressing, assessed with the use of a visual analogue scale (scores range from 0 to 10, with higher scores indicating greater pain).Primary wound pairs were exposed to B-VEC and placebo in 31 patients. At 6 months, complete wound healing occurred in 67% of the wounds exposed to B-VEC as compared with 22% of those exposed to placebo (difference, 46 percentage points; 95% confidence interval [CI], 24 to 68; P = 0.002). Complete wound healing at 3 months occurred in 71% of the wounds exposed to B-VEC as compared with 20% of those exposed to placebo (difference, 51 percentage points; 95% CI, 29 to 73; P0.001). The mean change from baseline to week 22 in pain severity during wound-dressing changes was -0.88 with B-VEC and -0.71 with placebo (adjusted least-squares mean difference, -0.61; 95% CI, -1.10 to -0.13); similar mean changes were observed at weeks 24 and 26. Adverse events with B-VEC and placebo included pruritus and chills.Complete wound healing at 3 and 6 months in patients with dystrophic epidermolysis bullosa was more likely with topical administration of B-VEC than with placebo. Pruritus and mild systemic side effects were observed in patients treated with B-VEC. Longer and larger trials are warranted to determine the durability and side effects of B-VEC for this disease. (Funded by Krystal Biotech; GEM-3 ClinicalTrials.gov number, NCT04491604.).

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)–negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment.Significance:CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy.This article is highlighted in the In This Issue feature, p. 101

Assessing real-time performance of Artificial Lift Pumps is a prevalent time-series problem to tackle for natural gas operators in Eastern Australia. Multiple physics, data-driven, and hybrid approaches have been investigated to analyse or predict pump performance. However, these methods present a challenge in running compute-heavy algorithms on streaming time-series data. As there is limited research on novel approaches to tackle multivariate time-series analytics for Artificial Lift systems, this paper introduces a human-in-the-loop approach, where petroleum engineers label clustered time-series data to aid in streaming analytics. We rely on our recently developed novel approach of converting streaming time-series data into heatmap images to assist with real-time pump performance analytics. During this study, we were able to automate the labelling of streaming time-series data, which helped petroleum and well surveillance engineers better manage Artificial Lift Pumps through machine learning supported exception-based surveillance. The streaming analytics system developed as part of this research used historical time-series data from three hundred and fifty-nine (359) coal seam gas wells. The developed method is currently used by two natural gas operators, where the operators can accurately detect ten (10) performance-related events and five (5) anomalous events. This paper serves a two-fold purpose; first, we describe a step-by-step methodology that readers can use to reproduce the clustering method for multivariate time-series data. Second, we demonstrate how a human-in-the-loop approach adds value to the proposed method and achieves real-world results.

There is an urgent need for countries to transition their national food and land-use systems toward food and nutritional security, climate stability, and environmental integrity. How can countries satisfy their demands while jointly delivering the required transformative change to achieve global sustainability targets? Here, we present a collaborative approach developed with the FABLE—Food, Agriculture, Biodiversity, Land, and Energy—Consortium to reconcile both global and national elements for developing national food and land-use system pathways. This approach includes three key features: (1) global targets, (2) country-driven multi-objective pathways, and (3) multiple iterations of pathway refinement informed by both national and international impacts. This approach strengthens policy coherence and highlights where greater national and international ambition is needed to achieve global goals (e.g., the SDGs). We discuss how this could be used to support future climate and biodiversity negotiations and what further developments would be needed.

Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis.This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3-4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to15 kg: 200 mg; bodyweight ≥15 kg to30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0-1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434.Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0-1 (23 [28%] vs three [4%], difference 24% [95% CI 13-34]; p0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation.Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults.Sanofi and Regeneron Pharmaceuticals.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Instituto de Salud Carlos III (ISCIII) European Regional Development Fun/European Social Fund (A way to make Europe/Investing in your future). Background Strain measurements have demonstrated to be earlier and more sensitive markers of contractile dysfunction than ejection fraction (EF) alone. Myocardial tagging (MT) is considered the reference standard for CMR strain measurements, but its clinical application is limited because acquisition and analysis are laborious and time consuming. Feature-tracking (FT) CMR allows strain quantification using steady-state in free-precession (SSFP) sequence, which is obtained in routine CMR protocols, being easily applicable in clinical practice. Literature regarding reference strain values in pediatric populations is scarce and, to the best of our knowledge, there are no studies comparing FT and MT in healthy adolescents. Purpose To provide CMR strain reference values in healthy adolescents and compare FT to MT results. Methods A CMR study was performed in healthy adolescents enrolled in the "Early ImaginG Markers of unhealthy lifestyles in Adolescents" (EnIGMA) project using a 3-Tesla CMR scanner between March and October 2021. The imaging protocol included a cine SSFP to provide images for chamber size and function, including FT; and MT acquisitions using spatial modulation of magnetization (SPAMM) technique. Cine acquisitions included the entire left ventricular (LV) short axis and long-axis 4 chamber (4c)- and 2 chamber (2c)-views, while MT acquisitions included three short axis slices (basal, mid and apical) and long-axis 4c-view. Endo- and epicardial borders were manually contoured in the end-diastolic (ED) phase. A non-rigid, elastic algorithm was used for segmentation and registration for strain quantification. If tracking was suboptimal, the software only allowed adaptations of the contours on the ED image. Longitudinal (LS) and circumferential (CS) strains were obtained for the LV and right ventricle (RV). Results CMR scans were performed in 123 adolescents (64 girls, 52.0%) with a mean age of 16.0 years (standard deviation [SD]=0.4), a mean LVEF of 62.5% (SD=4.1) and a mean RVEF of 56.2% (SD=4.6). Reference percentiles (P) 3, 10, 25, 50, 90 and 97 for strain values by sex are provided in Figure 1. FT-measured LVLS and LVCS were higher in girls than in boys (-19.8 vs -17.8%, p Conclusions This study provided CMR derived reference values for left and right ventricle strain in adolescents aged 15 to 18 years. This work suggests that FT is a reasonably valid technique to measure LV and RV strain in this population. This information may be useful for diagnostic and prognostic implications in adolescent patients.

Chromatin organization in theC. elegansgerm line is tightly regulated and critical for germ cell differentiation. While certain germline epigenetic regulatory mechanisms have been identified, how they influence chromatin structure and ultimately gene expression remain unclear, in part because most genomic studies have focused on data collected from whole worms. We therefore analyzed publicly available histone modification and chromatin accessibility data from isolated undifferentiated germ nuclei to define chromatin states. We then correlated these states with overall transcript abundance, spatio-temporal expression patterns, and the function of small RNA pathways. Because the essential role of the germ line is to transmit genetic information to the next generation and establish gene expression in the early embryo, we compared epigenetic and transcriptomic profiles from undifferentiated germ cells, oocytes, and embryos to define the epigenetic changes during this developmental transition. The active histone modification H3K4me3 exhibits particularly dynamic remodeling as germ cells differentiate into oocytes. Our results highlight the dynamism of the chromatin landscape in germ cells, and provide a resource for future investigation into epigenetic regulatory mechanisms.

The piRNA pathway is a conserved germline-specific small RNA pathway that ensures genomic integrity and continued fertility. InC. elegansand other nematodes, Type-I piRNA precursor transcripts are expressed from over 10,000 small, independently regulated genes clustered within two discrete domains of 1.5 and 3.5 MB on Chromosome IV. These large clusters likely play a significant role in promoting germline-specific expression of piRNAs, but the underlying mechanisms are unclear. By examining the chromatin environment specifically in isolated germ nuclei, we demonstrate that piRNA clusters are located in closed chromatin, and confirm the enrichment for the inactive histone modification H3K27me3. We further show that the piRNA biogenesis factor USTC (Upstream Sequence Transcription Complex) plays two roles – it promotes a strong association of nucleosomes throughout the piRNA clusters, and it organizes the local nucleosome environment to direct the exposure of individual piRNA genes. Overall, this work reveals new insight into how chromatin state coordinates transcriptional regulation over large genomic domains, which has implications for understanding global genome organization in the germ line.

Seismic losses due to earthquakes have been shown to have significant economic, social and environmental consequences. Over recent years, research to predict potential economic and social impact due to seismic risk has been increasing. Recognizing that the traditional philosophy of life safety design can lead to extensive damage and demolition which has a large environmental cost, incorporating environmental impacts associated with the expected seismic damage over a building’s life is a key step as the building industry moves towards both sustainable and seismically resilient design. This paper introduces a framework that uses environmental indicators quantifying losses from seismic response that can then be used to advocate for a change in seismic performance objectives. First, existing literature and previously developed approaches for quantifying potential environmental impact due to seismic damage are summarized. Next, performance based earthquake engineering concepts are used to demonstrate a probabilistic approach to quantify potential environmental impacts using a range of environmental and resource use indicators over the life span of a case study building. In addition, a case study is presented to compare different environmental indicators between a Code Minimum building and the same building redesigned for a higher seismic performance. The majority of the composition of the environmental indicator values are from the inclusion of the non-repairable scenario, and from the repair activities, the majority of the impacts are from damage to drift sensitive components including curtains walls, partitions and elevators. For the Code Minimum building the non-repairable scenario contributes to between 8 to 11% the total seismic cost. For the Stronger Stiffer building, the non-repairable scenario contributes around 3% of the initial impact. Neglecting non-repairable scenarios does significantly reduce the potential environmental impacts when analyzing buildings designed for current code minimum structural standards.

Supplemental tables: (1) Subject characteristics. (2) Cytogenetic profiles and high-risk features. (3) Prior treatment exposures and refractoriness. (4) CAR T cell product characteristics. (5) Products that did not meet target dose. (6) Adverse events of grade 3-4. (7) Cytokine release syndrome and ICANS. (8). Maintenance therapy. Supplemental Figures: (1) Study schematic and subject disposition, (2) Correlates of manufacturing success, (3) Hematopoietic recovery, (4) Post-infusion T cell phenotypes, (5) Correlates of in vivo expansion and manufacturing success, (6) Late post-infusion CAR T cell re-expansion, (7) Soluble BCMA, (8) Late-onset clinical responses, (9) MM cell BCMA expression, (10) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA monotherapy patients, (11) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA + huCART19 combination therapy patients, (12) Sustained post-treatment SOX2-specific T-cell responses.

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)–negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment.Significance:CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy.This article is highlighted in the In This Issue feature, p. 101

Supplementary Figure 1. : Representative immunohistochemical staining for Subject 74 with metastatic melanoma; lymph node biopsy. Panel A: pS6 staining prior to infusion; Panel B: pS6 staining at post-infusion biopsy; Panel C: Ki-67 staining prior to infusion; Panel D: Ki-67 staining at post-infusion biopsy.

Supplementary Figure 2: Representative immunohistochemical staining for Subject 27 with metastatic triple-negative breast cancer; lymph node biopsy. Panel A shows CD8 staining prior to infusion and Panel B shows CD8 staining at the time of post-infusion biopsy.

Purpose: Treatments are limited for metastatic melanoma (MM) and triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA- electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET. Patients and Methods: MM or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to 6 infusions (1x10e8 T cells / dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 MM, 4 mTNBC) were treated. Results: Mean age was 50 years (35-64); median ECOG 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade (G) 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue and malaise. One subject had grade 1 cytokine release syndrome. No G 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. Messenger RNA signals corresponding to CAR T cells were detected by RT-PCR in all patients’ blood including in 3 subjects on Day +1 (no infusion administered on this day). Five subjects underwent post-infusion biopsy with no CAR T cell signals seen in tumor. Three subjects had paired tumor tissue; immunohistochemistry showed increases in CD8 and CD3 and decreases in pS6 and Ki67. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible.

Supplementary methods, statistical methods, results, tables, and figures. Supplementary Table 1. CRS grading system. Supplementary Table 2. Samples collected and time points on the trials. Supplementary Table 3. HLH diagnostic criteria. Supplementary Table 4. Timing of severe CRS relative to CRS onset and time from infusion. Supplementary Table 5. Patient demographics and baseline characteristics. Supplementary Table 6. Co-morbid infections. Supplementary Table 7. Median (range) for baseline cytokine values comparing normal subjects and total study population, children on the trials, and adults on the trials. Supplementary Table 8. Median (range) baseline cytokine values comparing baseline disease burden. Supplementary Table 9. Median (range) one-month peak cytokine values in children and adults comparing CRS grades (0-3 vs 4-5). Supplementary Table 10. Time points of target cytokine assessment listed as day since CTL019 infusion, with the acceptable windows provided by the study protocols. Supplementary Table 11. Median (range) day 1-3 peak cytokine values for those with severe (grade 4-5) and without severe (grade 0-3) CRS for total study population, and split into adults and children. Supplementary Table 12. Summary of all predictive models generated by discovery cohort and validated. Supplementary Table 13. Clinical details on the validation cohort. Supplementary Table 14. Therapies used for CRS. Supplementary Table 15. Tocilizumab use by grade and age, as well as, clinical effects of tocilizumab on CRS. Supplementary Table 16. Lee CRS grading scale. Supplementary Table 17. Davila CRS grading scale. Supplementary Table 18. Reclassification of CRS severity by dividing grade 3 into 3a and 3b. Supplementary Table 19. Summary of top predictive models with alternate determination of CRS severity. Supplementary Figure 1. CRP and ferritin are poor early predictors of severe CRS. Supplementary Figure 2. Early increases in IFNγ and sgp130 after CTL019 infusion are associated with development of severe CRS. Supplementary Figure 3. Severity of CRS correlates moderately with CAR T cell expansion but early expansion of CAR T cells does not predict CRS severity. Supplementary Figure 4. Cytokine profiles predict CRS. Supplementary Figure 5. Alternate CRS prediction models.

This position stand aims to provide an evidence-based summary of the energy and nutritional demands of tactical athletes to promote optimal health and performance while keeping in mind the unique challenges faced due to work schedules, job demands, and austere environments. After a critical analysis of the literature, the following nutritional guidelines represent the position of the International Society of Sports Nutrition (ISSN).Nutritional considerations should include the provision and timing of adequate calories, macronutrients, and fluid to meet daily needs as well as strategic nutritional supplementation to improve physical, cognitive, and occupational performance outcomes; reduce risk of injury, obesity, and cardiometabolic disease; reduce the potential for a fatal mistake; and promote occupational readiness.Energy demands should be met by utilizing the Military Dietary Reference Intakes (MDRIs) established and codified in Army Regulation 40-25. Although research is somewhat limited, military personnel may also benefit from caffeine, creatine monohydrate, essential amino acids, protein, omega-3-fatty acids, beta-alanine, and L-tyrosine supplementation, especially during high-stress conditions.Specific energy needs are unknown and may vary depending on occupation-specific tasks. It is likely the general caloric intake and macronutrient guidelines for recreational athletes or the Acceptable Macronutrient Distribution Ranges for the general healthy adult population may benefit first responders. Strategies such as implementing wellness policies, setting up supportive food environments, encouraging healthier food systems, and using community resources to offer evidence-based nutrition classes are inexpensive and potentially meaningful ways to improve physical activity and diet habits. The following provides a more detailed overview of the literature and recommendations for these populations.

Pt and Ir catalysts (3% w/w) supported on Ce0.97Ru0.03O2 were synthesized and successfully tested in a low-temperature CO oxidation process. The CO oxidation was followed in-operation, by FTIR spectroscopy. The catalysts were characterized by SEM-EDS, HTEM, XRD, DRS UV–vis, XPS techniques and BET isotherms. It was found that Pt and Ir nanoparticles on Ce0.97Ru0.03O2 drastically improved the CO oxidation in comparison to CeO2, showing the best performance the Pt/ Ce0.97Ru0.03O2 system. From the FTIR studies, a route for CO oxidation was proposed. The CO oxidation pathway in Ce0.97Ru0.03O2 considers that CO was adsorbed at the Ce and Ru sites, while O2 is adsorbed on the surface oxygen vacancies, being activated by nearby Ru species. Subsequently, the activated oxygen reacts with CO linked to Ce and Ru to produce CO2. Also, Pt and Ir promotes oxygen vacancies, increasing the activation-adsorption of O2 and, consequently, the activity of the catalyst was improved.

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Purpose: To improve the significance of insulin-like growth factor–binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in patients with breast cancer.Experimental Design: Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/insulin receptor (InsR) inhibitor BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 patients with breast cancer to examine correlative associations with invasive tumor fraction and outcome. The use of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts.Results: IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, whereas IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared with pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS.Conclusion: IGFBP-5 expression is a marker of poor outcome in patients with breast cancer. An IGFBP-5/IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R targeting. Clin Cancer Res; 18(6); 1808–17. ©2012 AACR.

Supplementary Legends 1-5 from High SEPT9_v1 Expression in Human Breast Cancer Cells Is Associated with Oncogenic Phenotypes

Supplementary Methods from High SEPT9_v1 Expression in Human Breast Cancer Cells Is Associated with Oncogenic Phenotypes

Supplementary Figures 1-4 from Blockade of CCN6 (WISP3) Activates Growth Factor–Independent Survival and Resistance to Anoikis in Human Mammary Epithelial Cells

Supplementary Tables 1-2 from Histone Methyltransferase EZH2 Induces Akt-Dependent Genomic Instability and BRCA1 Inhibition in Breast Cancer

Supplementary Figures 1-5 from Histone Methyltransferase EZH2 Induces Akt-Dependent Genomic Instability and BRCA1 Inhibition in Breast Cancer

Altered expression of the human septin gene, SEPT9, and its murine homologue, Sept9, has been implicated in neoplasia. However, their role(s) in oncogenesis remains poorly understood. We found amplification of SEPT9 in 67% of breast cancer cells (BCC) when compared with immortalized human mammary epithelial cells (IHMEC) as well as high levels of SEPT9 expression in the majority (61%) of the BCCs studied, unlike IHMECs. Expression profiling of variant SEPT9 transcripts and translated products revealed that high expression of the variant, SEPT9_v1, in contrast to other variants, was widespread in BCCs (55% of the BCCs) but not in IHMECs. High expression of SEPT9_v1 was also observed in primary breast cancer samples by immunohistochemical studies. We subsequently examined the phenotypic consequences of SEPT9_v1 expression in human breast cells. Retroviral expression of SEPT9_v1 in IHMEC cell culture models showed that SEPT9_v1 accelerated growth kinetics, stimulated cell motility, promoted invasion in Matrigel Transwell assays, increased genomic instability with the development of aneuploidy, and stimulated morphologic changes. Significant cytokinesis defects and disruption of tubulin microfilaments were also observed by immunofluorescence when SEPT9_v1 was ectopically expressed in IHMECs. Furthermore, SEPT9_v1 markedly enhanced neoplastic transformation in Hs578T cells, a BCC with no endogenous expression of the SEPT9_v1 isoform. Small interfering RNA–mediated and short hairpin RNA–mediated inhibition of SEPT9_v1 expression in two BCCs with high levels of endogenous SEPT9_v1 expression inhibited neoplastic growth properties of the cells. Taken together, our findings suggest that increased SEPT9_v1 expression contributes to the malignant pathogenesis of some breast tumors. [Cancer Res 2007;67(18):8554–11]

Supplementary Table 1, Figures 1-5 from High SEPT9_v1 Expression in Human Breast Cancer Cells Is Associated with Oncogenic Phenotypes

Stem cell differentiation requires dramatic changes in gene expression and global remodeling of chromatin architecture. How and when chromatin remodels relative to the transcriptional, behavioral, and morphological changes during differentiation remain unclear, particularly in an intact tissue context. Here, we develop a quantitative pipeline which leverages fluorescently-tagged histones and longitudinal imaging to track large-scale chromatin compaction changes within individual cells in a live mouse. Applying this pipeline to epidermal stem cells, we reveal that cell-to-cell chromatin compaction heterogeneity within the stem cell compartment emerges independent of cell cycle status, and instead is reflective of differentiation status. Chromatin compaction state gradually transitions over days as differentiating cells exit the stem cell compartment. Moreover, establishing live imaging of Keratin-10 (K10) nascent RNA, which marks the onset of stem cell differentiation, we find that Keratin-10 transcription is highly dynamic and largely precedes the global chromatin compaction changes associated with differentiation. Together, these analyses reveal that stem cell differentiation involves dynamic transcriptional states and gradual chromatin rearrangement.

Many systemic therapies used for moderate-to-severe atopic dermatitis (AD) have immunosuppressive properties and necessitate laboratory screening and monitoring, adding to the treatment burden. Previous dupilumab studies in adults, adolescents and children aged 6–11 years with moderate-to-severe AD showed no clinically meaningful adverse changes in laboratory parameters. Here we evaluate hematology and chemistry laboratory safety data for dupilumab-treated children aged 6 months to 5 years with moderate-to-severe atopic dermatitis. Patients aged 6 months to 5 years with inadequately controlled moderate-to-severe AD were enrolled in LIBERTY AD PRESCHOOL (NCT03346434 part B), a randomized, double-blind placebo-controlled phase 3 study. 162 patients were randomized to either dupilumab 200/300 mg every 4 weeks (q4w; N = 83; baseline weight ≥5

Qatar Environment and Energy Research Institute (QEERI) hosted a workshop entitled “Impact of Sustainable Buildings in Arid Environment on the Indoor and Outdoor Air Quality,” held in Doha, Qatar, on May 17–19, 2022, co-funded by the Qatar National Research Fund (QNRF), and co-organized by City College of New York (CCNY). The workshop provided a premier interdisciplinary platform for local researchers and enablers to engage and exchange knowledge and experiences with international leading practitioners and subject matter experts in the fields of sustainable buildings, indoor and outdoor air quality, and the urban heat island phenomena. A diverse number of regional partners and stakeholders were represented. The workshop benefitted from a pool of invited international subject experts from various universities and entities. The outcome-driven workshop included breakout sessions where participants actively engaged in brainstorming discussions guided by facilitators. The discussions focused on driving impact in Qatar and beyond by examining the current research landscape and identifying collaborative opportunities. The short-term and long-term outcomes of potential initiatives and project proposals are outlined in this summary. An example of a short-term outcome is the proposed collaborative project to investigate the impact of almost doubling the state of Qatar’s population (over 1.5 million fans are expected to visit the country during the World Cup causing a shock to the system) on vital elements in the city, such as mobility, telecommunication services, and the local environment. In addition, multiple potential research proposals with international collaborations were proposed. A special issue on the subject in the Journal of Engineering for Sustainable Buildings and Cities was recommended as an immediate actionable outcome.

The 2010/2011 Canterbury Earthquake Sequence caused severe economic impacts and community disruption in Christchurch, New Zealand due to damage from liquefaction and strong shaking. Following the earthquake, approximately 7500 dwellings and 1400 commercial properties were demolished, resulting in 4 million tons of building debris. Using the Canterbury event, and the subsequent building demolitions in Christchurch as a case study, this research quantifies the embodied carbon and energy costs associated with the post-earthquake demolition of buildings prior to the end of their intended design life. A building data set consisting of 142 reinforced concrete buildings that were demolished following the event was used to estimate the total amount of structural and non-structural debris resulting from the demolitions. A framework was developed to calculate the global warming potential of the demolished buildings considering embodied CO2 and energy in the building materials, impacts of the processes used in construction of the building, and CO2 emissions of the transport and waste management processes. A life cycle assessment tool was used to calculate the environmental costs in the production and transport module, the spatial distribution of the waste based on the building locations was calculated to determine transport distances to disposal facilities, and the waste disposal and recycling benefits were calculated using values from a life cycle inventory database. The results of the research revealed the demolition of concrete buildings had staggering environmental costs in terms of embodied CO2 and energy, which make the case for both resilient design strategies that reduce waste and pollution following earthquakes, and incorporating environmental impacts into demolition decisions.