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Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy–resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). Summary: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.

H3B-5942 in combination with palbocyclib shows synergy in vitro and in vivo

Additional methods provided.

Supplementary Figure from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Supplementary Data from Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer

Enriched GSEA pathways

H3B-6527 response in 40 HCC cell lines and 625 cell lines.

Legends describing each of the supplementary figures and tables

RNA-seq analysis of 24 CCLE HCC cell lines.

Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1–3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999–7013. ©2017 AACR.

Self-assessment of clinical competence is an important tool for effective learning and training for some educational programs. The New York University (NYU) Langone Hospital's Advanced Education in General Dentistry (AEGD) Program has had its residents complete self-assessment of clinical competency evaluations for many years. The evaluation is used to understand the residents' perception of their own clinical skill upon beginning the program and to determine the necessary resources to provide to the residents for them to meet program standards. The same evaluation is completed by the residents 6 months later to determine if they perceived advancement in their clinical performance while in the program. Dental education, along with other fields of education was disrupted by the coronavirus disease 2019 (COVID-19) pandemic. The purpose of this study was to examine the impact of COVID-19 on clinical competency self-assessments among the NYU Langone AEGD residents before and during the pandemic.In this cross-sectional study, data was collected from two AEGD cohorts representing 2019-2020 and 2020-2021 academic years; from July 2019 (n = 196) to January 2020 (n = 189) and July 2020 (n = 202) to January 2021 (n = 184). The self-assessment evaluations were administered via an online residency management platform on the first days of July and January of the academic year. The survey consisted of 48 questions on "clinical skills and performance" as established by CODA standards for postdoctoral general dentistry programs.Survey response rate was 100% for both cohorts. When comparing results, the findings indicate the COVID-19 pandemic had interrupted clinical learning during dental school. However, training through the AEGD program led to improvements in perceived clinical competence by the residents in mid-program evaluation.The self-assessment evaluation can be used as a tool to enhance training as part of the AEGD program's performance improvement plan.

Following airline mergers and network reorganizations aimed at reducing operational costs, consolidated air services at large hub airports have encouraged air travelers to forego use of their smaller local airports to access large hub airports offering superior air services farther away. This study investigates airport leakage in areas of Wisconsin and Michigan served by small airports, where air travelers may leak to neighboring large hubs. Using a proximity-based service area definition, three airports experiencing leakage are identified, and a hierarchical logit airport choice model is applied that accounts for air service characteristics and access distance for travelers coming from these airports’ service areas. Results show that a similar mean number of flight legs at both the local and substitute (large hub) airports will encourage leakage at Dane County Regional and Gerald R. Ford International airports, indicating that adding direct flights alone will not be sufficient to combat leakage. Comparable access distances to local and substitute airports have opposite effects on the local markets of Gerald R. Ford International and Milwaukee Mitchell International airports—promoting leakage at the former but discouraging it at the latter. Furthermore, proportional increases in airfares at local airports lead to uneven losses of markets in investigated service areas. Overall, the study provides empirical evidence of long-distance airport leakage in parts of the U.S. Midwest, and how its implications can be used by small airports seeking to further understand and respond to travelers’ airport choices within their local markets.

The Covid-19 pandemic was a reminder of the importance of increasing connectivity amidst the accelerated rate of changes and disruptive events of our era. The need and the rationale for global citizenship education (GCED) were ever more emphasized by many educational organizations, including UNESCO. This article reviews the GCED discourses conceptualizing global competence as instrumental action and a binary view of global-local relations. In turn, the article proposes the idea of curriculum-as-relations for GCED. Curriculum-as-relations conceptualizes competence as situated praxis and focuses on providing authentic critical-translocal learning. Authentic critical-translocal learning through the strategy of comparison offers an alternative view of global-local relations as "articulated moments created by situated praxis". This new understanding of global-local relations may help different stakeholders to imagine GCED curricula beyond a Tylerian instrumentalist, ends-means orientation of curriculum.

The introductory graphic represents the identity conflict that the author experiences daily. The terms represent labels assigned to the author in the past, the barriers that Autistic people must constantly overcome, and some of the social rules the author has very consciously and intentionally adopted to "fit in" with society. The accompanying experience piece outlines some of the difficulties the author has experienced that suggest that there needs to be more awareness in Canadian society regarding autism and intersectionality. Anecdotally, there appears to be a need for increased access to diagnostic and clinical services across Canada for women across the spectrum, and further investigation into how disability, race, and gender interact.

Laboratory studies show that bisphenol A (BPA) leaches from bisphenol A-glycidyl methacrylate (bisGMA)-based dental materials. We aimed to quantify the extent to which children are exposed to BPA from dental treatment with bisGMA materials, by amount of treatment and type of sedation. We hypothesized that posttreatment urinary BPA (uBPA) concentrations would be higher among patients with more surfaces treated with bisGMA-based materials and among patients receiving general anesthesia compared with pretreatment concentrations. We conducted a prospective cohort study in 211 children, 4 to 12 y old, who had no prior resin-based dental treatment. We measured uBPA concentrations twice before treatment and at 2 d and 1, 4, and 16 wk posttreatment. We abstracted treatment data (surfaces treated) from the chart. We generated descriptive statistics and compared pre- and posttreatment uBPA concentrations using generalized estimating equations. Participants were 51% female, 46% non-White, and 74% publicly insured. The median age was 6 y. The mean number of tooth surfaces exposed to BisGMA materials (composites/sealants) was 7.5 (SD 5.3). Overall, uBPA concentrations were 86% higher (95% confidence interval [CI] 42% to 143%, P < 0.001) at 2 d posttreatment compared with pretreatment concentrations. The uBPA concentrations 2 d posttreatment versus pretreatment tended to be higher (112%, 95% CI 53% to 194%) among those receiving treatment on >4 surfaces than those receiving treatment on ≤4 surfaces (50%, 95% CI −2% to 130%). Two days after treatment, uBPA was significantly higher than pretreatment concentrations in children receiving nitrous oxide but not in those receiving general anesthesia. Among all findings, uBPA concentrations returned to baseline by 4 wk. Children experience short-term increases in BPA from dental treatment. The impact of relatively high, short-term BPA exposure on child health is unknown. Given the widespread use of BisGMA-based dental materials and that chronic low-dose BPA exposure may adversely affect child health, strategies that minimize BPA exposure could potentially improve child health.

Background The conventional guidelines to obtain a safe proximal resection margin (PRM) of 5-6 cm during advanced gastric cancer (AGC) surgery are still applied by many surgeons across the world. Several recent studies have raised questions regarding the need for such extensive resection, but without reaching consensus. This study was designed to prove that the PRM distance does not affect the prognosis of patients who undergo gastrectomy for AGC. Aim To investigate the influence of the PRM distance on the prognosis of patients who underwent gastrectomy for AGC. Methods Electronic medical records of 1518 patients who underwent curative gastrectomy for AGC between June 2004 and December 2007 at Asan Medical Center, a tertiary care center in Korea, were reviewed retrospectively for the study. The demographics and clinicopathologic outcomes were compared between patients who underwent surgery with different PRM distances using one-way ANOVA and Fisher's exact test for continuous and categorical variables, respectively. The influence of PRM on recurrence-free survival and overall survival were analyzed using Kaplan-Meier survival analysis and Cox proportional hazard analysis. Results The median PRM distance was 4.8 cm and 3.5 cm in the distal gastrectomy (DG) and total gastrectomy (TG) groups, respectively. Patient cohorts in the DG and TG groups were subdivided into different groups according to the PRM distance; ≤ 1.0 cm, 1.1-3.0 cm, 3.1-5.0 cm and > 5.0 cm. The DG and TG groups showed no statistical difference in recurrence rate (23.5% vs 30.6% vs 24.0% vs 24.7%, P = 0.765) or local recurrence rate (5.9% vs 6.5% vs 8.4% vs 6.2%, P = 0.727) according to the distance of PRM. In both groups, Kalpan-Meier analysis showed no statistical difference in recurrence-free survival (P = 0.467 in DG group; P = 0.155 in TG group) or overall survival (P = 0.503 in DG group; P = 0.155 in TG group) according to the PRM distance. Multivariate analysis using Cox proportional hazard model revealed that in both groups, there was no significant difference in recurrence-free survival according to the PRM distance. Conclusion The distance of PRM is not a prognostic factor for patients who undergo curative gastrectomy for AGC.

The overlap method is one of the most popular procedures for construction of an esophagojejunostomy and its common entry is usually closed with sutures. This study aimed to report long-term complications and surgical outcomes of the overlap method with stapled closure (OMSC), to compare them with those of laparoscopy-assisted total gastrectomy (LATG), and to analyze a learning curve.Between January 2015 and August 2017, 100 consecutive patients underwent laparoscopic total gastrectomy with OMSC for gastric cancer and the patients' medical records were reviewed. Their clinicopathologic characteristics, surgical outcomes, and long-term complications were investigated and compared with those of the LATG group. A learning curve of OMSC was analyzed using the Exponentially Weighted Moving Average chart.The overall duration of surgery was shorter in the LATG group; however, there was no difference in patients with early gastric cancer. Hospital admission was shorter and the pain scale was lower in the OMSC group. There was no difference in the number of harvested lymph nodes, date of flatus, or incidence of postoperative morbidity. Both groups showed no duodenal stump leakage, anastomosis-related complications, recurrence, or mortality during the follow-up period. Petersen hernia was a notable long-term event following OMSC compared with LATG. At least 27 cases of surgery were required to reach a plateau in terms of surgery duration for OMSC.OMSC is a safe option for the treatment of gastric cancer and has favorable long-term results and surgical outcomes. Closure of mesenteric defects and Petersen space should be considered.

Education buildings, as the third highest consumer of energy in the United States, provides significant opportunities to lower greenhouse gas emissions by increasing energy efficiency (EE). Higher education institutions (HEIs) campuses exhibits multiple favorable but unique attributes, including access to capital, multiple stakeholders involved with differing needs, and control of heterogeneous buildings that are energy intensive, such as laboratories, medical research facilities, sports facilities, and food services. There is a great opportunity to conserve energy by retrofitting these buildings. The decision to retrofit involves many stakeholders and also many factors that are interrelated. This study aims to understand the decision-making processes in EE projects at a higher education institution, particularly the exhaustive list of factors that facilities managers consider when making decision and their interrelationships. Using in-depth semi-structured interviews of facilities managers and secondary data from reports and policy documents, a case study at a large higher education institution is conducted. The content analysis of the data identifies decision factors that are categorized into five major categories: economic feasibility, environmental impact, institutional characteristics, occupant impact, and technical practicality. Interactions among factors are depicted in a causal loop diagram that shows cause-effect relationships. Three main loops highlight the major concerns—economic feasibility, occupant impact, and technical practicality.

Programs to improve the sustainability of building infrastructures often consist of project portfolios that need to be prioritized in an appropriate chronological fashion to maximize the program’s ...

PURPOSE: The aim of this investigation was to document mid- and long-term changes in oral health-related quality of life (OHRQoL) following dental intervention in a sample of restorative treatment-naïve children receiving different levels of care, with and without general anesthesia (GA). METHODS: This prospective cohort study followed 132 children. Parents completed the Pediatric OHRQoL instrument (POQL) before, 16 weeks after (i.e., post-treatment), and 18–45 (mean equals 29.5) months after (i.e., follow-up) child receipt of treatment. Parents provided child demographic and oral health information. Number of restored surfaces and anesthesia type were abstracted from dental records. Mean differences in POQL scores were compared across groups. RESULTS: The sample was 49% female (age range equals four to 12 years; mean±SD equals 5.8±1.8). Overall, from pre-treatment to post-treatment, mean POQL scores decreased by 4.5 points (P

BackgroundThe incidence and costs of medical disputes in Korea are increasing annually. The purpose of this study was to identify the characteristics of medical dispute cases and analyze compensation costs in gastric cancer patients who were admitted for surgery at a single large-volume center. MethodsGastric cancer patients who were admitted for surgery and received compensation after filing medical disputes with the legal affairs team at our center between January 2012 and December 2017 were retrospectively registered for the study. The characteristics of and information on the disputes were reviewed and the amount of awarded compensation was analyzed according to different factors.ResultsThere were 20 cases of medical disputes associated with gastric cancer surgery during the study period. In five cases, evidence of medical negligence was detected. There were 17 morbidity cases and four mortality cases. The mean compensation cost paid for settlement was USD 7,502. Length of hospital stay (p=0.009) and morbidity (p=0.004) were significantly associated with compensation.Conclusion Our results demonstrate foundational information on disputes regarding surgery in gastric cancer patients and the accompanying compensation costs for settlement.

Purpose As the number of gastric cancer survivors is increasing and their quality of life after surgery is being emphasized, single-port surgery is emerging as an alternative to conventional gastrectomy. A novel multi-degree-of-freedom (DOF) articulating device, the ArtiSential® device (LivsMed, Seongnam, Korea), was designed to allow more intuitive and meticulous control for surgeons facing ergonomic difficulties with conventional tools. In this study, we evaluated the feasibility of this new device during single-port laparoscopic distal gastrectomy (SP-LDG) for early gastric cancer (EGC) patients. Materials and Methods Consecutive patients diagnosed with EGC who underwent SP-LDG with ArtiSential® (LivsMed) graspers between April 2018 and August 2020 were enrolled in the study. The clinical outcomes were compared with those of a control group, in which prebent graspers (Olympus Medical Systems Corp) were used for the same procedures. Results Seventeen patients were enrolled in the ArtiSential® group. There was no significant difference in operative time (205.4±6.0 vs. 218.1±9.9 minutes, P= 0.270) or the quality of surgery, in terms of the number of retrieved lymph nodes (49.5±3.5 vs. 45.9±4.0, P=0.473), length of hospital stay (15.4±2.0 vs. 12.4±1.3 days, P=0.588), and postoperative complications (40.0% vs. 41.2%, P=0.595), between the ArtiSential® group and the control group. Conclusions The new multi-DOF articulating grasper is feasible and can be used as an alternative for prebent graspers during SP-LDG.

Indoor environmental quality (IEQ) plays a key role in determining occupants' productivity at work; however, analyses of the interconnected factors among building physical, attitudinal, social and demographic components in one study are lacking. To fill this research gap, this study investigates these interconnected factors' influence on occupants’ IEQ-productivity belief, defined as a personal, subjective evaluation of the linkage between the impacts of five IEQ aspects (the quality of indoor temperature, air, natural and electric lighting, and acoustics) and productivity. A cross-sectional survey data was collected in university offices from six countries (Brazil, Italy, Poland, Switzerland, Taiwan and the U.S.). Results of multiple linear regression models indicate that IEQ satisfaction is the strongest positive predictor of the IEQ-productivity belief and this relationship is stronger in private offices. Country of residence is the second primary predictor. Several attitudinal-behavioral factors, including thermal comfort, perceived ease of controlling indoor environmental features, and attitudes toward sharing controls are all positively associated with IEQ-productivity belief. Interestingly, the level of control accessibility to light switches has the strongest impact as opposed to other controls. On the other hand, group norms and conformity intention are not significant predictors. Regarding demographics, men are more likely than women to perceive the IEQs to have positive impacts on their productivity, without considering other variables in the regression model; however, women are more likely than men to consider all IEQs as having positive impacts on productivity, after considering other variables. Our findings provide suggestions for prioritizing wellness in the workplace since the early design stage.

This paper describes a study undertaken to assess the speed and safety effects of reducing speed limits from 50 to 30 km/h in school zones. Mean speeds and 85th percentile speeds were reduced by 12.2 and 11.6 km/h, respectively. Speed variation was also reduced, and the speed cumulative distributions shifted to the left, indicating further reductions for all speed ranges. The safety evaluation results revealed fatal and injury collisions were significantly reduced by 45.3% and injuries to vulnerable road users were reduced by 55.3%. In fact, for every 1 km/h reduction in mean speed, fatal and injury crashes were reduced by about 4%, which is consistent with findings from previous research. Neither spatial nor temporal collision migration or spillover effects were significant factors in the analysis. Consequently, the results of this study provide strong evidence that reducing speed limits to 30 km/h in school zones can bring significant safety benefits by reducing vehicular speeds and fatal and injury crashes.

The luminous environment affects how office workers perceive their work setting. However, research on how the lighting commissioning process associates with psychosocial variables relevant to office settings is lacking. This case study explored the extent to which employees working on a recently retrofitted floor of an administrative office building believed they could control the new lighting system. It also measured their levels of perceived productivity and affective organizational commitment to examine correlations between these variables and levels of satisfaction with the lighting commissioning process. Satisfaction with the commissioning process did not significantly correlate with perceived productivity, controllability, affective organizational commitment, or the average number of productive work hours reported after the retrofit. However, perceived productivity significantly and positively associated with perceived controllability and affective organizational commitment. Also, controllability and affective organizational commitment both significantly correlated with the number of productive work hours perceived. Results support interdisciplinary studies emphasizing the importance of lighting controllability in improving employees’ perceived performance and satisfaction at work. Results also offer practical suggestions concerning the commissioning process used in the case study.

Weight loss and deterioration in body composition are observed in patients with gastric cancer (GC) following gastrectomy. This study aimed to investigate the impact of residual stomach volume (RSV) on the nutritional status and body composition of patients with GC treated with distal gastrectomy.In total, 227 patients who underwent minimally invasive distal gastrectomy with Billroth 1 anastomosis for stage I GC between February 2015 and May 2018 were enrolled. Clinicodemographic and laboratory data were collected from the GC registry. The RSV, abdominal muscle area, and subcutaneous/visceral fat areas were measured using computed tomography data.A larger RSV was associated with a lower decrease in the nutritional risk index (P=0.004) and hemoglobin level (P=0.003) during the first 3 months after surgery, and better recovery at 12 months. A larger RSV demonstrated an advantage in the preservation of abdominal muscle area (P=0.02) and visceral fat (P=0.04) after surgery, as well as less reduction in weight (P=0.02) and body mass index (P=0.03).Larger RSV was associated with improved nutritional status and better preservation of muscle and fat after distal gastrectomy.

The purpose of this article is to differentially engage in the work of thinking with Indigenous theorists and theories with decolonizing science education research methodologies in mind. As a rejoinder to Tracey McMahon, Emily Griese, and DenYelle Baete Kenyon’s Cultivating Native American scientists: An application of an Indigenous model to an undergraduate research experience, we extend the notion of educationally centering Indigenous processes, pedagogies, and protocols by considering methodology a site in which (neo-)colonial logics often linger. We suggest that (re)designing methodology with Indigenous theorists and theories is an important act of resistance, refusal, and resignification; we demonstrate this significance through braiding together narratives of our engagement in this task and provide insights as to what is produced or producible.