expHRD: an individualized, transcriptome-based prediction model for homologous recombination deficiency assessment in cancer.

BACKGROUND: Homologous recombination deficiency (HRD) stands as a clinical indicator for discerning responsive outcomes to platinum-based chemotherapy and poly ADP-ribose polymerase (PARP) inhibitors. One of the conventional approaches to HRD prognostication has generally centered on identifying deleterious mutations within the BRCA1/2 genes, along with quantifying the genomic scars, such as Genomic Instability Score (GIS) estimation with scarHRD. However, the scarHRD method has limitations in scenarios involving tumors bereft of corresponding germline data. Although several RNA-seq-based HRD prediction algorithms have been developed, they mainly support cohort-wise classification, thereby yielding HRD status without furnishing an analogous quantitative metric akin to scarHRD. This study introduces the expHRD method, which operates as a novel transcriptome-based framework tailored to n-of-1-style HRD scoring. RESULTS: The prediction model has been established using the elastic net regression method in the Cancer Genome Atlas (TCGA) pan-cancer training set. The bootstrap technique derived the HRD geneset for applying the expHRD calculation. The expHRD demonstrated a notable correlation with scarHRD and superior performance in predicting HRD-high samples. We also performed intra- and extra-cohort evaluations for clinical feasibility in the TCGA-OV and the Genomic Data Commons (GDC) ovarian cancer cohort, respectively. The innovative web service designed for ease of use is poised to extend the realms of HRD prediction across diverse malignancies, with ovarian cancer standing as an emblematic example. CONCLUSIONS: Our novel approach leverages the transcriptome data, enabling the prediction of HRD status with remarkable precision. This innovative method addresses the challenges associated with limited available data, opening new avenues for utilizing transcriptomics to inform clinical decisions.

Variations in Student Approaches to Problem Solving in Undergraduate Biology Education.

Existing research has investigated student problem-solving strategies across science, technology, engineering, and mathematics; however, there is limited work in undergraduate biology education on how various aspects that influence learning combine to generate holistic approaches to problem solving. Through the lens of situated cognition, we consider problem solving as a learning phenomenon that involves the interactions between internal cognition of the learner and the external learning environment. Using phenomenography as a methodology, we investigated undergraduate student approaches to problem solving in biology through interviews. We identified five aspects of problem solving (including knowledge, strategy, intention, metacognition, and mindset) that define three qualitatively different approaches to problem solving; each approach is distinguishable by variations across the aspects. Variations in the knowledge and strategy aspects largely aligned with previous work on how the use or avoidance of biological knowledge informed both concept-based and nonconcept-based strategies. Variations in the other aspects revealed intentions spanning complete disengagement to deep interest with the course material, different degrees of metacognitive reflections, and a continuum of fixed to growth mindsets. We discuss implications for how these characterizations can improve instruction and efforts to support development of problem-solving skills.

Novel Glucose Metric "Latest Spike Time" Correlated with Weight Loss at Six Months in People with Obesity Using the Signos System.

Introduction: The rise of digital health applications utilizing continuous glucose monitoring (CGM) allows for novel assessments of glucose management and weight changes in people without diabetes. The Signos System incorporates a digital health app paired with a CGM to provide information and prompts aimed to help people without diabetes to manage weight. Objectives: The primary objective of this study was to determine whether the average timing of the latest chronological glucose excursion ("spike") was correlated with amount of weight loss. Methods: This was a retrospective analysis of prospectively obtained glucose and weight data from people without diabetes who enrolled in the Signos System from November 2021 to August 2023. Participants were provided CGMs as well as encouraged to use the Signos app with personalized advice and logging capabilities for weight, food, physical activity, heart rate, sleep, and activities. "Latest spike time" (LST) was retrospectively derived from CGM data and compared with weight changes at 6 months. Results: Nine hundred and twenty-six subjects met the inclusion criteria including sufficient days wearing a CGM and a weight log within 15 days of 6 months from their first weight log. There was a strong correlation between an earlier spike time and increased weight loss. The top quintile of subjects, with an average LST before 5:41 PM, lost over three times as much weight as the bottom quintile of users, with LST after 8:40 PM; this separation was predictable within 1 month of data. Conclusion: In a large population of obese people without diabetes, continuous glucose data, specifically a novel metric "LST," was highly correlated with percentage of total body weight loss at 6 months. This research suggests that for people attempting weight loss, review and alteration of behaviors relating to later glucose excursions may be of specific benefit.

The art of specimen orientation: Two-dimensional maps for oropharynx squamous cell carcinoma.

The goal of surgical treatment for oropharynx squamous cell carcinoma (SCCa) is resection to negative margins. Current methods of orienting resection specimens often do not give a comprehensive view, especially in oropharynx SCCa where specimens can lack anatomic landmarks. We created standardized two-dimensional maps of oropharynx anatomy drawn to scale to improve communication between surgeons and pathologists. Notes regarding surgery including anatomic landmarks, areas of concern, additional margins, and relevant clinical information were added to the map. The maps guided pathology work-up, and the pathologist could communicate details back to the surgeon on how the specimen was sectioned or locations of microscopic foci to direct future treatment and clinical monitoring. The use of two-dimensional maps for oropharynx SCCa specimens offers a standardized solution to address the challenges of anatomic orientation. These maps summarized key pathological information, preserved clinical details from the specimens, and guided multidisciplinary conferences when planning adjuvant treatment.

Effect of Hormone Therapy on Lipoprotein Subfractions in Early and Late Postmenopausal Women.

CONTEXT: The Early vs Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced atherosclerosis progression among early but not late postmenopausal women (PMW). OBJECTIVE: Determined by time-since-menopause (1) HT effects on lipids and lipoprotein particle subfractions (LPs), (2) associations of estradiol (E2) level with lipids and LPs, (3) associations of lipids and LPs with atherosclerosis progression. DESIGN: Randomized controlled trial stratified by time-since-menopause. SETTING: Academic institution. PARTICIPANTS: Healthy postmenopausal women. INTERVENTION: Oral E2 with/without sequential vaginal progesterone. MAIN OUTCOME MEASURES: Standard lipids and 21 LPs quantitated by ion mobility every 6 months. RESULTS: Among 562 PMW (240 early, 322 late), HT significantly increased total triglycerides (TG), high-density lipoprotein (HDL) cholesterol, small low-density lipoproteins (LDL), large HDL, and TG/C ratio in LDL and HDL and decreased LDL-cholesterol, total very low density lipoproteins (VLDL), small VLDL, intermediate-density lipoproteins, large LDL, and LDL peak diameter. HT showed no lipid or LP differences between time-since-menopause. Associations of E2 level with lipids and LPs explained the HT effects. Despite the nonsignificant P interaction by time-since-menopause, we observed that very small LDL and total HDL LPs were associated with atherosclerosis progression in late PMW. CONCLUSION: HT effects on standard lipids and LPs are consistent with the literature. HT has similar effect on lipids and LPs in early and late PMW. Novel findings include discordant effects of HT on TG and VLDL particles, which can be explained by increased catabolism of atherogenic remnants of TG-rich lipoproteins. Our findings extend the well-known HT effects on standard lipids and LPs that may contribute to the beneficial effects on atherosclerosis progression in PMW.

The EPA Ecosystem Services Tool Selection Portal.

The dynamics of an environmental decision-making context can be complicated. The use of decision support tools can help better facilitate restoring and maintaining ecosystems that provide environmental benefits (ecosystem services) to people. Although an ecosystem services assessment tool is designed for specific purposes, having access to a comprehensive suite of tools offers the user additional insight and resources to help in decision making. A range of approaches exist to connect ecosystem services to a given decision context ranging from less to more complex: using the best professional judgment; applying examples from other efforts; testing individual tool applications; and using a systematic, decision-tree approach to navigate among relevant tools and frameworks. The U.S. Environmental Protection Agency developed a decision-tree approach for a user to navigate the question of how to choose among a suite of ecosystem services assessment tools for three decision contexts: (1) ecological risk assessments; (2) cleanup of contaminated sites; (3) and generic structured decision-making processes. This tool selection navigator was developed with/for the intended user, including developing crosswalks between tool functionality and the user's language for what they require in a tool. To navigate the tool, the user first chooses one of three decision contexts. Second, the user selects among the different phases of the decision process. Third, the user selects among a few ecosystem-services related tasks relevant to the decision context chosen to identify potential tools. The tool uses simple language to navigate the decision pathways and provides the user with a suite of potential ES resources and tools for their given decision context.

Assessing Adherence to US LI-RADS Follow-up Recommendations in Vulnerable Patients Undergoing Hepatocellular Carcinoma Surveillance.

Purpose To assess adherence to the US Liver Imaging Reporting and Data System (LI-RADS) recommendations for hepatocellular carcinoma (HCC) surveillance and associated patient-level factors in a vulnerable, diverse patient sample. Materials and Methods The radiology report database was queried retrospectively for patients who underwent US LI-RADS-based surveillance examinations at a single institution between June 1, 2020, and February 28, 2021. Initial US and follow-up liver imaging were included. Sociodemographic and clinical data were captured from electronic medical records. Adherence to radiologist recommendation was defined as imaging (US, CT, or MRI) follow-up in 5-7 months for US-1, imaging follow-up in 3-6 months for US-2, and CT or MRI follow-up in 2 months for US-3. Descriptive analysis and multivariable modeling that adjusted for age, sex, race, and time since COVID-19 pandemic onset were performed. Results Among 936 patients, the mean age was 59.1 years; 531 patients (56.7%) were male and 544 (58.1%) were Asian or Pacific Islander, 91 (9.7%) were Black, 129 (13.8%) were Hispanic, 147 (15.7%) were White, and 25 (2.7%) self-reported as other race. The overall adherence rate was 38.8% (95% CI: 35.7, 41.9). The most common liver disease etiology was hepatitis B (60.6% [657 of 936 patients]); 19.7% of patients (183 of 936) had current or past substance use disorder, and 44.8% (416 of 936) smoked. At adjusted multivariable analysis, older age (odds ratio [OR], 1.20; P = .02), male sex (OR, 1.62; P = .003), hepatology clinic attendance (OR, 3.81; P < .001), and recent prior US examination (OR, 2.44; P < .001) were associated with full adherence, while current smoking (OR, 0.39; P < .001) was negatively associated. Conclusion Adherence to HCC imaging surveillance was suboptimal, despite US LI-RADS implementation. Keywords: Liver, Ultrasound, Screening, Abdomen/GI, Cirrhosis, Metabolic Disorders, Socioeconomic Issues Supplemental material is available for this article. © RSNA, 2024.

TXNIP-mediated crosstalk between oxidative stress and glucose metabolism.

Thioredoxin-interacting protein (TXNIP) has emerged as a key player in cancer and diabetes since it targets thioredoxin (TRX)-mediated redox regulation and glucose transporter (GLUT)-mediated metabolism. TXNIP consists of two arrestin (ARR, N-ARR and C-ARR) domains at its amino-terminus and two PPxY (PY) motifs and a di-leucine (LL) motif for endocytosis at its carboxyl-terminus. Here, we report that TXNIP shuffles between TRX and GLUTs to regulate homeostasis of intracellular oxidative stress and glucose metabolism. While TXNIP functions as a gatekeeper of TRX by default, it robustly interacted with class I GLUTs through its C-ARR domain upon increase of intracellular reactive oxygen species. This interaction prompted the surface expression downregulation and lysosomal degradation of GLUTs by its carboxyl-terminal LL endocytic signaling motif to attenuate glucose uptake. Consequently, TXNIP expression significantly limited glucose uptake, leading to the suppression of glycolysis, hexosamine biosynthesis, and the pentose phosphate pathway. Our findings establish a fundamental link between ROS and glucose metabolism through TXNIP and provide a promising target for the drug development against GLUT-related metabolic disorders.