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Purpose: Patients who inherit a pathogenic loss-of-function genetic variant involving one of the four succinate dehydrogenase (SDH) subunit genes have up to an 86% chance of developing one or more cancers by the age of 50. If tumors are identified and removed early in these high-risk patients, they have a higher potential for cure. Unfortunately, many alterations identified in these genes are variants of unknown significance (VUS), confounding the identification of high-risk patients. If we could identify misclassified SDH VUS as benign or pathogenic SDH mutations, we could better select patients for cancer screening procedures and remove tumors at earlier stages.Experimental Design: In this study, we combine data from clinical observations, a functional yeast model, and a computational model to determine the pathogenicity of 22 SDHA VUS. We gathered SDHA VUS from two primary sources: The OHSU Knight Diagnostics Laboratory and the literature. We used a yeast model to identify the functional effect of a VUS on mitochondrial function with a variety of biochemical assays. The computational model was used to visualize variants' effect on protein structure.Results: We were able to draw conclusions on functional effects of variants using our three-prong approach to understanding VUS. We determined that 16 (73%) of the alterations are actually pathogenic, causing loss of SDH function, and six (27%) have no effect upon SDH function.Conclusions: We thus report the reclassification of the majority of the VUS tested as pathogenic, and highlight the need for more thorough functional assessment of inherited SDH variants. Clin Cancer Res; 23(21); 6733–43. ©2017 AACR.

TIFF file for supplemental figure 1

TIFF file for supplemental figure 1

Video for Biochemical, molecular, and clinical characterization of SDHA VUS from Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance

Supplemental tables 1 and 2, supplemental figure legends, supplemental video legend

Background: Although patients (pts) with hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently experience disease response to neoadjuvant therapy, fewer than 10% achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an unmet need. HER2 is expressed at a low level (IHC 1+ or 2+) in approximately 60-70% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved in the US for HER2-positive and HER2-low metastatic BC (with boxed warnings for interstitial lung disease). However, the efficacy of T-DXd in the neoadjuvant setting is not known. The primary objective of TALENT (TRIO-US B-12, NCT04553770) is to evaluate the clinical activity and safety of neoadjuvant T-DXd alone or in combination with endocrine therapy in pts with HR+/HER2-low early BC. Methods: Men and women with previously untreated, operable invasive early stage, non-recurrent, HR+, HER2-low (IHC 1+ or 2+/ISH- by local or central review) BC measuring > 2 cm were eligible. In stage 1 of clinical trial, participants were randomized 1:1 to receive T-DXd (5.4 mg/kg IV q21 days) alone, Arm A, or in combination with anastrozole AI (1 mg PO QD), Arm B. Originally 6 cycles (cy) were given but in 02/2022, an amendment increased the number of treatment cy from 6 to 8 for newly enrolled pts, or those who had not yet had surgery. Men and pre/peri-menopausal women randomized to Arm B also received a GnRH agonist. Stratification factors were HER2 expression (1+ vs. 2+) and menopausal status (men as postmenopausal). Tumor tissue collected at baseline, cy 1 day 17-21, and at surgery. Breast imaging performed at baseline, cy 2 and pre-surgery/EOT. Primary endpoint is pCR rate (ypT0/is ypN0) at surgery. In stage 1, intent was to randomize 58 pts (if at least 2 pCR occurred in an arm, arm progresses to Stage 2 and an additional 15 pts to be enrolled). Other endpoints include safety, objective response rate (ORR), changes in Ki67 expression, Residual Cancer Burden index, exploratory biomarker analysis, and health-related quality of life. Here we present results from stage 1 of the trial. Results: From 09/21/2020 to 10/13/2022, 58 pts were enrolled and treated (29 Arm A, 29 Arm B) in stage 1 of trial. Five pts came off study before completing study therapy (2 after cy 1, 2 after cy 2, 1 after cy 3). As of data cut-off (10/05/2022), 33 pts completed study treatment and have had surgery (17 Arm A, 16 Arm B), 13 are on treatment and 7 are pending surgery; 27 pts completed 6 cy and 13 completed 8 cy. Baseline characteristics were balanced between arms. 19/58 pts were Stage IIA, 26/58 Stage IIB, 12/58 Stage IIIA, and 1/58 Stage IIIB at baseline. 46/58 pts had baseline HER2 expression (from central review) of 1+, 4/58 were 0, 6/58 were 2+, 1/58 had multicentric lesion 1+ and 2+, and 1/58 had a single lesion with 1+ and 2+. In Arm A, 1/17 pt had pCR after 8 cy, 2/17 pts had RCB-I after 6 cy (17.6% RCB 0/1). In Arm B, 1/16 pt had RCB-I after 8 cy (6.3%). The ORR for response-evaluable pts in Arm A was 75% (12/16, 1 CR, 11 PR) and in Arm B was 63.2% (12/19, 2 CR, 10 PR); 1 patient (Arm B) had PD. ILD occurred in 1 pt (1.7%), Gr 2 and resolved 11 days after stopping therapy. Most common treatment-related Grade ≥ 3 AEs in Arms A and B, respectively, include hypokalemia (1.7%, 5.2%), diarrhea (3.4%, 3.4%), neutropenia (3.4%, 1.7%), fatigue (1.7%, 3.4%), headache (3.4%, 1.7%), vomiting (3.4%, 1.7%), dehydration (1.7%, 1.7%) and nausea (3.4%, 0%). Conclusions: This is the first report of a trial evaluating neoadjuvant T-DXd in HER2 low breast cancer. T-DXd +/- endocrine therapy demonstrates promising clinical activity for pts with HR+ BC. Updated study results will be provided at the time of presentation. Citation Format: Aditya Bardia, Sara Hurvitz, Michael F. Press, Lisa S. Wang, Nicholas P. McAndrew, David Chan, Vu Phan, Deborah Villa, Merry L. Tetef, Erin Chamberlain, Nihal Abdulla, Thomas Lomis, Laura M. Spring, Steven Applebaum, Shaker Dakhil, Brian DiCarlo, David D. Kim, Evangelia Kirimis, William E. Lawler, Aashini K. Master, Kelly McCann, Edwin Hayashi, Christine Kivork, James Chauv. GS2-03 TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-03.

BACKGROUND Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community. OBJECTIVE Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute–designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community. METHODS We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated the TB discussions into concise, non–case-based Q&As on theMednet. Answers were peer reviewed and disseminated in email newsletters to registered oncologists. Reach and engagement were measured. Following each Q&A, a survey question asked how the TB Q&As impacted the readers’ practice. RESULTS A total of 23 breast, thoracic, gastrointestinal, and genitourinary programs from 16 NCI-CCC sites participated. Between December 2016 and July 2021, the faculty highlighted 368 questions from their TBs. Q&As were viewed 147,661 times by 7381 oncologists at 3515 institutions from all 50 states. A total of 277 (75%) Q&As were viewed every month. Of the 1063 responses to a survey question on how the Q&A affected clinicians’ practices, 646 (61%) reported that it confirmed their current practice, 163 (20%) indicated that a Q&A would change their future practice, and 214 (15%) reported learning something new. CONCLUSIONS Through an online Q&A platform, academics at the NCI-CCCs share knowledge outside the walls of academia with oncologists across the United States. Access to up-to-date expert knowledge can reassure clinicians’ practices, significantly impact patient care in community practices, and be a source of new knowledge and education.

While existing research documents the effectiveness of summer reading programs, little is know about how and to what degree children actually read the books that are sent home or how families engage with these texts. We took this opportunity to dive in and explore what happened when books were sent home to low-income, culturally diverse families. Specifically, my doctoral students and I used home visits and interviews to better understand how students and family members engaged with summer reading books. By the end of the summer, we had a gained an expanded understanding of how our summer reading program both built upon and extended families’ existing literacy practices.

Being able to identify the lymphocytes, monocytes, and neutrophils (granuolcytes) subpopulations in murine spleen and peripheral blood is an important step of the analysis of the immune system. Conventionally, this task is accomplished by performing immunofluorescence staining of specific cell surface markers. However, given the distinct morphology of each of these subpopulations as well as the cell imageries obtained using the Image Stream technology, we attempt to identify 3cell types in the spleen and peripheral blood samples of C57BL/6 and BALB/c mice based solely on the Bright Field (BF), Side Scatter (SSC) and nuclear images without using any specific markers for the cell types. We will then compare the results obtained using this novel method with that obtained using immunofluorescence. We hope that the results will serve to both validate our methodology and highlight the value offered by this objective, automated, and quantitative approach towards other murine immune cell analysis, particularly in those situations where immunofluorescence based subpopulation detections are either unfeasible(due to fluorochrome conflicts) or impractical (due to high sample sizes).

Employees’ affective responses to their work have increasingly been linked to their subjective well-being and their quality of life (QOL) overall. One source of subjective well-being for individuals is the credit they receive for organizational successes and the blame they receive for failures. This chapter presents two ethical dilemmas involving blame and credit attributions. In determining how to address these dilemmas, we review the research literature on responsibility assignments, integrate recent research on blame contagion, describe how this process can affect employees’ willingness to take risks and report errors, and examines how these processes can impact an organization’s capacity to learn. We finally integrate these findings in a model of blame assignment in organizations, proposing structural and cultural interventions that may help to address some of the problematic outcomes of blame and credit attributions for QWL.

A genome-wide screen in Saccharomyces cerevisiae identified LSM1 as a new gene affecting sensitivity to ultraviolet (UV) radiation. Lsmlp is a member of a cytoplasmic complex composed of Lsmlp-7p that interacts with the yeast mRNA degradation machinery. To investigate the potential role of Lsmlp in response to UV radiation, we constructed double mutant strains in which LSM1 was deleted in combination with a representative gene from each of three known yeast DNA repair pathways. Our results show that lsm1delta increases the UV-radiation sensitivity of the rad1delta and rad51delta mutants, but not the radl8delta mutant, placing LSM1 within the post-replication repair/damage tolerance pathway (PRR). When combined with other deletions affecting PRR, lsm1delta increases the UV-radiation sensitivity of the rev3delta, rad30delta and pol30-K164R mutants but not rad5delta. Furthermore, the UV-radiation sensitivity phenotype of lsmldelta is partially rescued by mutations in genes involved in 3' to 5' mRNA degradation, and mutations predicted to function in RNA interactions confer the most UV-radiation sensitivity. Together, these results suggest that Lsmlp may confer protection against UV-radiation damage by protecting the 3' ends of mRNAs from exosome-dependent 3' to 5' degradation as part of a novel RAD5-mediated, PCNA-K164 ubiquitylation-independent subpathway of PRR.

Objectives: Misplaced ECG electrodes can cause changes in ECG recordings, which could have an impact on clinical decisions. We aimed to determine the inter-rater reliability of ECG electrode placement by senior clinical staff in the ED. Methods: A prospective observational study was conducted in adult patients undergoing an ECG as part of their routine ED care. Adhesive electrodes were left in place after an ECG had been performed by the treating nurse, and subsequently each patient was assessed by two of the three investigators. Each investigator independently recorded the location of the chest electrodes relative to the recommended standard positions. Displacement of the electrodes from the standard positions was measured in the vertical and horizontal planes. The age, sex, weight, height and chest circumference was also recorded. Comparisons were made between investigators to determine variability in assessment of the standard positions. Results: Measurement of horizontal and vertical displacement for each of the six chest leads in the 77 patients resulted in 924 paired measurements. There was substantial inter-rater variation in the measurement of both vertical (mean 13.5 mm, range 0–105 mm) and horizontal (mean 16.5 mm, range 0–120 mm) displacement. This variation was greater in the lateral chest leads and was more marked in women than in men, especially in the vertical plane (lead V6: men 14.5 mm vs women 27.0 mm, P

We report select outcomes from an evaluation of Project Wall Talk, a community-based, peer-led HIV prevention education program implemented in 36 Texas State prison units. Peer educators completed questionnaires prior to receipt of a 40-hour intensive training (N = 590) and at 9-month follow-up (N = 257). Students (N = 2506) completed questionnaires pre- and post-receipt of peer educator-led HIV education sessions. Peer educators and their students showed significant increases in HIV-related knowledge. Peer educators showed significant increases in assessment of their skills as educators. For both peer educators and students, significant differences in HIV-related knowledge were indicated across categories of prior educational level attained and race/ethnicity; no such differences were indicated at follow-up. Compared with baseline, a significantly greater proportion of peer educators reported ever having had an HIV test. After receiving peer-led education, a significantly smaller proportion of students reported they knew their HIV status and more indicated plans to take an HIV test. Additionally, in months 12 and 18 following program implementation, the numbers of HIV tests at the five units that implemented the peer education program were roughly twice that of five, matched comparison units without the peer education program. Based on peer educator reports, we projected that peer educators (N = 257) may have as many as 84,000 or more annual opportunities to share HIV-related knowledge with other prisoners outside the classroom.

Motivation: Genotype–phenotype modeling problems are often overcomplete, or ill-posed, since the number of potential predictors—genes, proteins, mutations and their interactions—is large relative to the number of measured outcomes. Such datasets can still be used to train sparse parameter models that generalize accurately, by exerting a principle similar to Occam's Razor: When many possible theories can explain the observations, the most simple is most likely to be correct. We apply this philosophy to modeling the drug response of Type-1 Human Immunodeficiency Virus (HIV-1). Owing to the decreasing expense of genetic sequencing relative to in vitro phenotype testing, a statistical model that reliably predicts viral drug response from genetic data is an important tool in the selection of antiretroviral therapy (ART). The optimization techniques described will have application to many genotype–phenotype modeling problems for the purpose of enhancing clinical decisions. Results: We describe two regression techniques for predicting viral phenotype in response to ART from genetic sequence data. Both techniques employ convex optimization for the continuous subset selection of a sparse set of model parameters. The first technique, the least absolute shrinkage and selection operator, uses the l1 norm loss function to create a sparse linear model; the second, the support vector machine with radial basis kernel functions, uses the ε-insensitive loss function to create a sparse non-linear model. The techniques are applied to predict the response of the HIV-1 virus to 10 reverse transcriptase inhibitor and 7 protease inhibitor drugs. The genetic data are derived from the HIV coding sequences for the reverse transcriptase and protease enzymes. When tested by cross-validation with actual laboratory measurements, these models predict drug response phenotype more accurately than models previously discussed in the literature, and other canonical techniques described here. Key features of the methods that enable this performance are the tendency to generate simple models where many of the parameters are zero, and the convexity of the cost function, which assures that we can find model parameters to globally minimize the cost function for a particular training dataset. Availability: Results, tables and figures are available at Contact: mrabinowitz@genesecurity.net Supplementary information: An Appendix to accompany this article is available at Bioinformatics online.