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The treatment of partial, displaced radial head fractures is determined not only by the type of fracture, but also by patient characteristics such as age, occupation, hand dominance, mechanism of injury, and concomitant injuries and comorbidities. The goal of this study was to employ the Delphi method to achieve consensus on the management of patients with radial head fractures, utilizing the experience of the ASES elbow fracture-dislocation multicenter study group and Mayo Elbow Club surgeons.The initial survey was sent to participants, which included consent to participate in the study and questions about their experience, knowledge, and interest in participating in the Delphi method.We used both open-ended and category-based questions. The second questionnaire generated 76 variables, and individual questions with mean Likert ratings of2.0 or4.0 were deemed significant and merged to form multifactorial clinical scenarios relating to both nonoperative and operative management, respectively.Of surgeons who responded to the questionnaire; 64% were from the United States, while the remainder were from overseas practices. Years in practice on average were 12.4 years (range, 1-40). Seven of the 76 factors met the criteria of a mean Likert score of2.0 or4.0. These factors were; age, block to the range of motion (ROM) after aspiration/injection, crepitation with ROM, tenderness over the distal radioulnar joint (DRUJ) and/or interosseous membrane (dorsal forearm), gap and/or displacement2mm on imaging, complete loss of contact of the head with rest of radius on imaging, fracture head involvement 30% on imaging. 22 (46%) of the 96 clinical scenarios gained90% consensus in favor of surgical treatment, whereas 8 (17%) reached90% consensus in favor of non-operative treatment.Obtaining expert consensus on the treatment of radial head fractures remains challenging. Certain factors such as gap/displacement ≥ 2mm without complete loss of contact, ≥ 30% head involvement with a block to a range of motion regardless of tenderness over DRUJ or interosseous membrane (dorsal forearm) or crepitation when the patient was80 years of age led to a recommendation of operative treatment in 100% of the surveyed surgeons. Patients greater than 80 years of age with no block to ROM after aspiration/injection, no crepitation with ROM, and no tenderness on DRUJ/interosseous membrane (dorsal forearm) were recommended for non-operative treatment regardless of the size of the radial head involvement on imaging.

Elusive intermediates and products were visualized in the conversion of glucose in aqueous barium hydroxide. Competing pathways resembling different biochemical glycolysis pathways were observed in this manner.

Children with obesity frequently have functional impairment after critical illness. Although obesity increases morbidity risk after trauma, the association with functional outcomes in children is unknown.To evaluate the association of weight with functional impairment at hospital discharge in children with serious injuries.This secondary analysis of a multicenter prospective study included children15 years old with a serious injury. Four weight groups, underweight, healthy weight, overweight, and obesity/severe obesity were defined by body mass index z-scores. The functional status scale (FSS) measured impairment across six functional domains before injury and at hospital discharge. New domain morbidity was defined as a change ≥2 points. The association between weight and functional impairment was determined using logistic regression adjusting for demographics, physiological measures, injury details, presence of a severe head injury, and physical abuse.Although most patients discharged with good/unchanged functional status, new domain morbidity occurred in 74 patients (17%). New FSS domain morbidity occurred in 13% of underweight, 14% of healthy weight, 15% of overweight, and 26% of obese/severe obese patients. Compared to healthy weight patients, those with obesity had more frequent new domain morbidity (p = 0.01), while the other weight groups had similar morbidity. However, after adjustment for confounders, weight was not associated with new functional morbidity at discharge.Patients with obesity have greater frequency of new domain morbidity after a serious injury; however, after accounting for injury characteristics, weight group is not independently associated with new functional morbidity at hospital discharge after injury in children.III.

With normal retinal blood flow, cross-sectional optical coherence tomography (OCT) of retinal vessels shows a structured intravascular reflectivity profile, resembling a 'figure-of-8'. Altered profiles have been reported in vascular occlusive and haematological diseases. Giant cell arteritis (GCA) can cause visual loss, usually due to anterior ischaemic optic neuropathy (AION) or retinal artery occlusion. Our aim was to extend the assessment of OCT vascular profiles to patients with suspected GCA and to determine if any abnormalities were related to GCA

Given the ongoing dilemma for college counseling centers to meet steady increases in demand for services, this study outlines the implementation of an adapted stepped care model in a university counseling center. Our adapted model focused, as do other stepped care models, on treatment planning and lower-intensity interventions, with the addition of the intensive therapy option being provided on a weekly basis. We adopted our stepped care model across a large center and hypothesized that after implementation we would be able to serve a similar number of clients as our previous model and that treatment outcomes for these clients would improve. Descriptive data and regression analyses demonstrated support for our hypotheses, including an increased likelihood of clinically significant improvement for clients postimplementation. Implications for adapting service delivery models using practice-based evidence are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Electronic cigarettes (e-cigarettes) are handheld, battery-powered vaporizing devices. It is estimated that more than 25% of youth have used these devices recreationally. While vaping-associated lung injury is an increasingly recognized risk, little is known about the risk of traumatic injuries associated with e-cigarette malfunction.A multi-institutional retrospective study was performed by querying the electronic health records at nine children's hospitals. Patients who sustained traumatic injuries while vaping from January 2016 through December 2019 were identified. Patient demographics, injury characteristics, and the details of trauma management were reviewed.15 children sustained traumatic injuries due to e-cigarette explosion. The median age was 17 y (range 13-18). The median injury severity score was 2 (range 1-5). Three patients reported that their injury coincided with their first vaping experience. Ten patients required hospital admission, three of whom required intensive care unit admission. Admitted patients had a median length of stay of 3 d (range 1-6). The injuries sustained were: facial burns (6), loss of multiple teeth (5), thigh and groin burns (5), hand burns (4), ocular burns (4), a radial nerve injury, a facial laceration, and a mandible fracture. Six children required operative intervention, one of whom required multiple operations for a severe hand injury.In addition to vaping-associated lung injury, vaping-associated traumatic injuries are an emerging and worrisome injury pattern sustained by adolescents in the United States. This report highlights another means by which e-cigarettes pose an increasing risk to a vulnerable youth population.

Methods to improve the fracture toughness of oxide glasses are needed since low fracture toughness is a major bottleneck for their applications. To overcome this, it is critically important to investigate the effect of both short- and medium-range structural features on fracture toughness. Recent work reported a record-high fracture toughness for a bulk lithium aluminoborate glass subjected to hot compression. Here, we further explore the structural origin of this high fracture toughness by subjecting different alkali aluminoborate glasses to hot compression. Through a combination of x-ray total scattering experiments and atomistic simulations, we find that hot compression causes significant changes to both the short- and medium-range order structure of the glasses, e.g., increased coordination numbers (CNs) of network forming species and decreased average size of ring-type structures. To this end, we reveal positive correlations between the pressure-induced increase in fracture toughness and (i) the increase in average CN of network forming species and (ii) the area of the first sharp diffraction peak in the structure factor. Our study thus improves the understanding of which structural features benefit intrinsic toughening of oxide glasses.

With increasing demand for psychotherapy services, clinicians are carrying increasingly large caseloads (Bailey et al., 2020). As the number of new intakes exceeds the number of clinical hours available each week in some settings, psychotherapy is delivered on an attenuated schedule for returning clients (rather than the traditional weekly frequency); there is, however, little support for the efficacy of this practice. The present study explored the effect of session frequency on psychotherapy outcomes using a quasi-randomized controlled design. In a working university counseling center, we assigned therapists to either a treatment-as-usual (TAU) group (attenuated session frequency) or an experimental group (weekly session frequency). Clients were randomly assigned to a therapist in either condition. Using hierarchical linear modeling and survival analyses, we examined psychotherapy outcomes (measured by session-by-session Outcome Questionnaire 45 scores) for 1,322 clients (3,919 individual sessions). We found no differences between groups when examining the full sample, but also found limited fidelity in the experimental group. When identifying individuals who were seen weekly in at least the first three sessions after intake (sensitivity analysis), we found the following: (a) weekly therapy resulted in faster trajectories of change over time, (b) weekly therapy resulted in a greater likelihood of achieving recovery, and (c) weekly therapy resulted in a greater likelihood of achieving recovery sooner. We discuss the importance of including session frequency when considering the dose of therapy, as well as the implication that prioritizing weekly therapy may increase therapy efficacy and efficiency in routine practice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Electrochemical reduction can capture and utilize CO2 through its conversion to small chemicals and fuels. Analytical standard operating procedures for the accurate quantification of short chain acids, aldehydes, and alcohols by HPLC, GC-MS or NMR are not well established. Electrochemical reduction of CO2 produces the smallest conceivable organic compounds, which necessitates slow NMR quantifications due to slow T1 relaxation towards equilibrium magnetization. It is shown that the use of paramagnetic contrast agents or cooling of water/DMSO provides T1-optimized measurements with attractive sensitivity and speed. 1H NMR experiments that are widely used in the study of biological mixtures are found unsuitable for quantitative analyses of T1-optimized samples.

Autism spectrum disorder is an increasingly prevalent neurodevelopmental disorder in the world today, with an estimated 2% of the population being affected in the USA. A major complicating factor in diagnosing, treating, and understanding autism spectrum disorder is that defining the disorder is solely based on the observation of behavior. Thus, recent research has focused on identifying specific biological abnormalities in autism spectrum disorder that can provide clues to diagnosis and treatment. Biomarkers are an objective way to identify and measure biological abnormalities for diagnostic purposes as well as to measure changes resulting from treatment. This current opinion paper discusses the state of research of various biomarkers currently in development for autism spectrum disorder. The types of biomarkers identified include prenatal history, genetics, neurological including neuroimaging, neurophysiologic, and visual attention, metabolic including abnormalities in mitochondrial, folate, trans-methylation, and trans-sulfuration pathways, immune including autoantibodies and cytokine dysregulation, autonomic nervous system, and nutritional. Many of these biomarkers have promising preliminary evidence for prenatal and post-natal pre-symptomatic risk assessment, confirmation of diagnosis, subtyping, and treatment response. However, most biomarkers have not undergone validation studies and most studies do not investigate biomarkers with clinically relevant comparison groups. Although the field of biomarker research in autism spectrum disorder is promising, it appears that it is currently in the early stages of development.

Quality improvement efforts within pediatric trauma centers (PTCs) are robust, but the majority of children do not receive initial postinjury care at PTCs. Disparities in access to quality trauma care remain, particularly for children who initially access the trauma system outside of a PTC. The purpose of this project was to identify unmet needs for injured children within the pediatric emergency care system and to determine national priorities for quality improvement across the continuum of pediatric trauma care.A panel of delegates representing patients and families, prehospital providers, federal funding partners, nurses, and physicians was recruited from 10 national stakeholder organizations. Potential targets were identified using an initial stakeholder meeting followed by a free text response survey. Free text items were coded and condensed as themes and then ranked by the panel using a modified Delphi approach to determine consensus priorities. Items not achieving35% prioritization on a given iteration were dropped from subsequent iterations. Consensus was defined as 75% of members designating an item as a top-four priority.Nineteen themes were identified as potential targets for QI initiatives. Four iterations of panel ranking were used to achieve consensus, with four priorities identified: (1) creation of a toolkit and standard provider training for pediatric trauma triage, shock recognition, and early recognition for need to transfer to higher level of care; (2) development of minimum standards for pediatric trauma resuscitation and stabilization capability in nonpediatric centers; (3) facilitating creation of local nursing and physician champions for pediatric trauma; and (4) development and dissemination of best-practice guidelines to improve imaging practices for injured children.System-level quality improvement priorities for pediatric trauma care should focus resources on developing and implementing minimum pediatric standards for injury care, frontline provider training, stabilization protocols, imaging guidelines, and local pediatric champions.Therapeutic/Care Management; Level IV.

Background: The Tg4-42 mouse model for sporadic Alzheimer’s disease (AD) has unique features, as the neuronal expression of wild type N-truncated Aβ4–42 induces an AD-typical neurological phenotype in the absence of plaques. It is one of the few models developing neuron death in the CA1 region of the hippocampus. As such, it could serve as a powerful tool for preclinical drug testing and identification of the underlying molecular pathways that drive the pathology of AD. Objective: The aim of this study was to use a differential co-expression analysis approach for analyzing a small RNA sequencing dataset from a well-established murine model in order to identify potentially new players in the etiology of AD. Methods: To investigate small nucleolar RNAs in the hippocampus of Tg4-42 mice, we used RNA-Seq data from this particular tissue and, instead of analyzing the data at single gene level, employed differential co-expression analysis, which takes the comparison to gene pair level and thus affords a new angle to the interpretation of these data. Results: We identified two clusters of differentially correlated small RNAs, including Snord55, Snord57, Snord49a, Snord12, Snord38a, Snord99, Snord87, Mir1981, Mir106b, Mir30d, Mir598, and Mir99b. Interestingly, some of them have been reported to be functionally relevant in AD pathogenesis, as AD biomarkers, regulating tau phosphorylation, TGF-β receptor function or Aβ metabolism. Conclusion: The majority of snoRNAs for which our results suggest a potential role in the etiology of AD were so far not conspicuously implicated in the context of AD pathogenesis and could thus point towards interesting new avenues of research in this field.

The ideas of this forum germinated at the Organizational Communication Division’s pre-conference at the 106th annual convention of the National Communication Association (NCA) in 2020. A group of scholar-teachers, committed to addressing various critical social issues, came together to challenge dominant ideas, paradigms, and structures within and beyond organizational communication. We engaged with decolonization and social justice as an ongoing project that cultivates scholarship, pedagogy, and public engagement. Our discussions left us with a sense of urgency and inspiration to work substantively toward thinking differently about organizational communication. Our goal in this forum is to present the collective as a sharp provocation to decenter the spaces of theorizing and pedagogical practices in organizational communication and beyond.

In recent years, concentrating solar collectors have been integrated with several district heating systems with the aim of taking advantage of their low heat losses. The present study investigates the Brønderslev combined heat and power plant, which consists of a 16.6 MW parabolic trough collector field, two biomass boilers, and an organic Rankine cycle system. The study focuses on the solar collector field performance and integration with the district heating network. An in situ characterization of the parabolic solar collector field using the quasi-dynamic test method found that the field had a peak efficiency of 72.7%. Furthermore, a control strategy for supplying a constant outlet temperature to the district heating network was presented and implemented in a TRNSYS simulation model of the solar collector field. The developed simulation model was validated by comparison to measurement data. Subsequently, the simulation model was used to conduct a sensitivity analysis of the influence of the collector row spacing and tracking axis orientation. The results showed that the current suboptimal tracking axis rotation, made necessary by the geography of the location, only reduced the annual power output by 1% compared to the optimal configuration. Additionally, there were only minor improvements in the annual heat output when the row spacing was increased past 15 m (ground cover ratio of 0.38).

Fresnel lenses are used in a wide range of solar energy applications, primarily due to their reduced material usage, low cost, and high optical efficiency. This study presents an investigation of the world’s first full-scale Fresnel lens solar collector field. The collector field consists of 144 two-axis tracking solar collectors manufactured by the Danish company Heliac and supplies heat to the local district heating network in Lendemarke, Denmark. The thermal performance of the solar collector field was determined using the quasi-dynamic test method. It was found that the peak efficiency was 11% lower compared to a brand-new collector and that heat losses from the collectors made up half of the total heat losses of the solar field. The reduction in the peak efficiency was primarily caused by soiling as the collectors were exposed to outdoor conditions for one year without cleaning. Furthermore, the system’s annual performance was determined using a simulation model developed in TRNSYS and validated by comparison to measurement data. For 2020, the heat generation was 373 kWh/m2 (relative to aperture area) when operating with an outlet temperature of 90 °C and inlet temperature of 50 °C. Additionally, a sensitivity analysis of the annual heat generation was performed, varying the ground cover ratio, mean collector temperature, and soiling level. The sensitivity analysis showed that the heat generation was relatively insensitive to changes in the mean collector temperature, demonstrating that the collectors are suitable for generating heat above 100 °C, unlike flat-plate collectors.

In this paper, an open source method for calculating self-shading in fields of two-axis tracking solar collectors of arbitrary geometry was developed and validated. The method was used to investigate the impact of latitude and collector aperture shape on annual shading loss. Simulations were carried out for the entire design space of field layouts by uniformly discretizing the layout parameters, i.e., aspect ratio, offset, rotation, and ground cover ratio. Results showed shading losses generally increase with latitude, and the optimum aspect ratio decreases with distance from the equator. Aperture shape was shown to significantly impact power output; the annual shading loss was lowest for the rectangular collector and highest for the square collector. Also, the impact of sub-optimal rotation of rectangular arrays was presented.

A new manumycin-type natural product named pacificamide (1) and its candidate biosynthetic gene cluster (pac) were discovered from the marine actinobacterium Salinispora pacifica CNT-855. The structure of the compound was determined using NMR, electronic circular dichroism, and bioinformatic predictions. The pac gene cluster is unique to S. pacifica and found in only two of the 119 Salinispora genomes analyzed across nine species. Comparative analyses of biosynthetic gene clusters encoding the production of related manumycin-type compounds revealed genetic differences in accordance with the unique pacificamide structure. Further queries of manumycin-type gene clusters from public databases revealed their limited distribution across the phylum Actinobacteria and orphan diversity that suggests additional products remain to be discovered in this compound class. Production of the known metabolite triacsin D is also reported for the first time from the genus Salinispora. This study adds two classes of compounds to the natural product collective isolated from the genus Salinispora, which has proven to be a useful model for natural product research.

Background Despite improvement in implant design, total elbow arthroplasty (TEA) failures remain a common occurrence with significant patient morbidity. Recent literature points to aseptic loosening as the most common cause of failure. However, investigations of the location of failure are conflicting, and most studies to date have been retrospective reports from single institutions. The aim of this study was to use a national database to investigate the distribution of TEA adverse events according to failure mode and location, with the hypothesis that the aseptic loosening would be the most common cause of TEA failure, and there would be no significant difference between rates of humeral-sided and ulnar-sided failures. Methods The US Food and Drug Administration's Manufacturer and User Facility Device Experience (MAUDE) database is a federally mandated reporting system for implant failures. The MAUDE database was searched for TEA adverse event reports among all loosely linked TEA constructs from 2008 to 2019. TEA failure reports were individually analyzed for failure mode and categorized according to anatomic location. The chi-square test was used to statistically assess differences in categorical data between groups. Results A total of 869 TEA failure reports were included in this study. The most common mode of failure was aseptic loosening (26.8%) followed by component mechanical failure (23.9%), infection (16.1%), and periprosthetic fracture (11.5%). When evaluating TEA failure reports by anatomic location, the majority of aseptic loosening failures occurred at the humeral component as compared to the ulnar component (71.7% vs. 28.3%; P Conclusion TEA failure reports in the large and nationally representative FDA MAUDE database differed from what is represented in current literature, with higher rates of humeral component aseptic loosening than has been previously reported. Understanding TEA failure mechanisms will help direct future design and surgical technical improvements. Level of Evidence Level IV

PURPOSE Artificial intelligence (AI) algorithms improve breast cancer detection on mammography, but their contribution to long-term risk prediction for advanced and interval cancers is unknown. METHODS We identified 2,412 women with invasive breast cancer and 4,995 controls matched on age, race, and date of mammogram, from two US mammography cohorts, who had two-dimensional full-field digital mammograms performed 2-5.5 years before cancer diagnosis. We assessed Breast Imaging Reporting and Data System density, an AI malignancy score (1-10), and volumetric density measures. We used conditional logistic regression to estimate odds ratios (ORs), 95% CIs, adjusted for age and BMI, and C-statistics (AUC) to describe the association of AI score with invasive cancer and its contribution to models with breast density measures. Likelihood ratio tests (LRTs) and bootstrapping methods were used to compare model performance. RESULTS On mammograms between 2-5.5 years prior to cancer, a one unit increase in AI score was associated with 20% greater odds of invasive breast cancer (OR, 1.20; 95% CI, 1.17 to 1.22; AUC, 0.63; 95% CI, 0.62 to 0.64) and was similarly predictive of interval (OR, 1.20; 95% CI, 1.13 to 1.27; AUC, 0.63) and advanced cancers (OR, 1.23; 95% CI, 1.16 to 1.31; AUC, 0.64) and in dense (OR, 1.18; 95% CI, 1.15 to 1.22; AUC, 0.66) breasts. AI score improved prediction of all cancer types in models with density measures ( PLRT values < .001); discrimination improved for advanced cancer (ie, AUC for dense volume increased from 0.624 to 0.679, Δ AUC 0.065, P = .01) but did not reach statistical significance for interval cancer. CONCLUSION AI imaging algorithms coupled with breast density independently contribute to long-term risk prediction of invasive breast cancers, in particular, advanced cancer.

While the field of microbial biogeography has largely focused on the contributions of abiotic factors to community patterns, the potential influence of biotic interactions in structuring microbial communities, such as those mediated by the production of specialized metabolites, remains largely unknown. Here, we examined the relationship between microbial community structure and specialized metabolism at local spatial scales in marine sediment samples collected from the Long-Term Ecological Research (LTER) site in Moorea, French Polynesia. By employing a multi-omic approach to characterize the taxonomic, functional, and specialized metabolite composition within sediment communities, we find that biogeographic patterns were driven by local scale processes (e.g., biotic interactions) and largely independent of dispersal limitation. Specifically, we observed high variation in biosynthetic potential (based on Bray-Curtis dissimilarity) between samples, even within 1 m2 plots, that reflected uncharacterized chemical space associated with site-specific metabolomes. Ultimately, connecting biosynthetic potential to community metabolomes facilitated the in situ detection of natural products and revealed new insights into the complex metabolic dynamics associated with sediment microbial communities. Our study demonstrates the potential to integrate biosynthetic genes and metabolite production into assessments of microbial community dynamics.

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Over one million women in the United States receive biopsy diagnoses of benign breast disease (BBD) each year, which confer a 1.5–4.0-fold increase in breast cancer risk. Studies in the general population suggest that nonsteroidal anti-inflammatory agents (NSAID) lower breast cancer risk; however, associations among women with BBD are unknown. We assessed whether NSAID use among women diagnosed with BBD is associated with lower breast cancer risk. Participants included 3,080 women (mean age = 50.3 ± 13.5 years) in the Mayo BBD surgical biopsy cohort diagnosed between January 1, 1992 and December 31, 2001 who completed breast cancer risk factor questionnaires that assessed NSAID use, and whose biopsies underwent detailed pathology review, masked to outcome. Women were followed from date of BBD biopsy to breast cancer diagnosis (main outcome) or censoring (death, prophylactic mastectomy, reduction mammoplasty, lobular carcinoma in situ or last contact). Median follow-up time was 16.4 ± 6.0 years. Incident breast cancer was diagnosed among 312 women over a median follow-up of 9.9 years. Regular non-aspirin NSAID use was associated with lower breast cancer risk [HR = 0.63; 95% confidence interval (CI) = 0.46–0.85; P = 0.002] with trends of lower risk (highest tertiles of use vs. nonuse) for greater number of years used [HR = 0.55; 95% CI = 0.31–0.97; Ptrend = 0.003), days used per month (HR = 0.51; 95% CI = 0.33–0.80; Ptrend = 0.001) and lifetime number of doses taken (HR = 0.53; 95% CI = 0.31–0.89; Ptrend = 0.003). We conclude that nonaspirin NSAID use is associated with statistically significant lower breast cancer risk after a BBD biopsy, including a dose–response effect, suggesting a potential role for NSAIDs in breast cancer prevention among patients with BBD.

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Supplementary Tables and Figures

Surface-enhanced Raman spectroscopy (SERS) detection of analyte molecules at ultra-low concentrations requires highly-efficient plasmonic nanostructures enabling a high hot-spot density. However, a facile and cost-effective strategy toward large-area fabrication of efficient nanostructures with significant electromagnetic field enhancement remains a great challenge. Further, SERS faces reliability issues with the molecular fingerprint at ultra-low concentrations. This work shows a one-step rapid fabrication technique utilizing glancing angle deposition for growing 3D nanopillars of Ag or Au, which is facile, scalable and cost-effective. The 3D nanopillar substrates can reliably detect analyte molecules with concentrations as low as 10-18 M with a high signal-to-noise ratio molecular fingerprint proven for Cresyl violet, p-aminothiophenol and Rhodamine 6G. The ultra-high enhancement is realized in conjunction with the formation of a high hot-spot density due to localized surface plasmons and surface plasmons at metal/air interface. A portable handheld Raman spectrometer is used to evaluate the potential application of the nanopillars for on-site diagnostics. It avoids the need for sophisticated tabletop instruments yet provides high-precision molecular specificity outside specialized laboratories. The 3D nanopillar substrates show excellent molecular detection limits at 10−15 M concentrations when tested with a handheld Raman spectrometer. The uniqueness of the 3D nanopillar features with the formation of a high density of hot-spots and one-step nanofabrication methods provide a platform to unravel on-site diagnostics with cost-effective approaches.

Activation of p53 by inhibitors of the p53–MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53–MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo. Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2–p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure–response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53–MDM2 inhibitors.Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257–67. ©2018 AACR.

Median of the shRNAs and RSA values. File containing median counts and log fold changes of each gene from Supplementary Data File S1. According significance values of each gene as activator or sensitizer compared to DMSO control (see Methods) are included.

Supplementary Figures S1-S3 from Fyn Is Downstream of the HGF/MET Signaling Axis and Affects Cellular Shape and Tropism in PC3 Cells

Background: Mammographic density (MD) is a strong breast cancer risk factor. We previously reported associations of percent mammographic density (PMD) with larger and node-positive tumors across all ages, and estrogen receptor (ER)–negative status among women ages Methods: Data were pooled from six studies including 4,095 breast cancers and 8,558 controls. DA and NDA were assessed from digitized film-screen mammograms and standardized across studies. Breast cancer odds by density phenotypes and age according to histopathologic characteristics and receptor status were calculated using polytomous logistic regression.Results: DA was associated with increased breast cancer risk [OR for quartiles: 0.65, 1.00 (Ref), 1.22, 1.55; Ptrend Ptrend Ptrend < 0.001) but no differences by nodal status. Among women + versus ER− tumors (Phet = 0.02), while NDA was more strongly associated with decreased risk of ER− versus ER+ tumors (Phet = 0.03).Conclusions: DA and NDA have differential associations with ER+ versus ER− tumors that vary by age.Impact: DA and NDA are important to consider when developing age- and subtype-specific risk models. Cancer Epidemiol Biomarkers Prev; 24(5); 798–809. ©2015 AACR.

Distribution of dense area (DA) and non dense area (NDA) phenotypes prior to standardization. The age effect on DA and NDA as well as the differences in the distribution across the studies observed for breast cancer cases.

Supplementary Video S2 from Fyn Is Downstream of the HGF/MET Signaling Axis and Affects Cellular Shape and Tropism in PC3 Cells