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.

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.

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.

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.

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.

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.

Fast and accurate protein structure search with Foldseek.

As structure prediction methods are generating millions of publicly available protein structures, searching these databases is becoming a bottleneck. Foldseek aligns the structure of a query protein against a database by describing tertiary amino acid interactions within proteins as sequences over a structural alphabet. Foldseek decreases computation times by four to five orders of magnitude with 86%, 88% and 133% of the sensitivities of Dali, TM-align and CE, respectively.

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.

New Biomarkers for Cardiovascular Disease.

Cardiovascular disease is the leading cause of death and disability worldwide. Early detection and treatment of cardiovascular disease are crucial for patient survival and long-term health. Despite advances in cardiovascular disease biomarkers, the prevalence of cardiovascular disease continues to increase worldwide as the global population ages. To address this problem, novel biomarkers that are more sensitive and specific to cardiovascular diseases must be developed and incorporated into clinical practice. Exosomes are promising biomarkers for cardiovascular disease. These small vesicles are produced and released into body fluids by all cells and carry specific information that can be correlated with disease progression. This article reviews the advantages and limitations of existing biomarkers for cardiovascular disease, such as cardiac troponin and cytokines, and discusses recent evidence suggesting the promise of exosomes as cardiovascular disease biomarkers.

Self-assembling Gn head ferritin nanoparticle vaccine provides full protection from lethal challenge of Dabie bandavirus in aged ferrets.

IMPORTANCE: Dabie bandavirus (DBV) is an emerging tick-borne virus that causes severe fever with thrombocytopenia syndrome (SFTS) in infected patients. Human SFTS symptoms progress from fever, fatigue, and muscle pain to the depletion of white blood cells and platelets with fatality rates up to 30%. The recent spread of its vector tick to over 20 states in the United States increases the potential for outbreaks of the SFTS beyond the East Asia. Thus, the development of vaccine to control this rapidly emerging virus is a high priority. In this study, we applied self-assembling ferritin (FT) nanoparticle to enhance the immunogenicity of DBV Gn head domain (GnH) as a vaccine target. Mice immunized with the GnH-FT nanoparticle vaccine induced potent antibody responses and cellular immunity. Immunized aged ferrets were fully protected from the lethal challenge of DBV. Our study describes the GnH-FT nanoparticle vaccine candidate that provides protective immunity against the emerging DBV infection.

Viatorr Stent Migration and Retrieval during Transjugular Intrahepatic Portosystemic Shunt Revision.

Transjugular intrahepatic portosystemic shunt (TIPS) is an important interventional option for the treatment of complications related to cirrhosis and portal hypertension. Emergent TIPS placement can be a life-saving measure in patients with uncontrolled variceal hemorrhage. After TIPS placement, patients may benefit from additional interventions for clinical optimization including stent dilation, stent extension, and embolization of varices. Here, we describe a case of emergent TIPS placement and revision which resulted in TIPS stent migration requiring stent removal and replacement. We discuss our technique and review previously reported methods for the management of migrated TIPS stents.

DNA methylation biomarkers distinguishing early-stage prostate cancer from benign prostatic hyperplasia.

Background: DNA methylation markers are considered robust diagnostic features in various cancer types, as epigenetic marks are commonly altered during cancer progression. Differentiation between benign prostatic hyperplasia (BPH) and early-stage prostate cancer (PCa) is clinically difficult, relying on the information of the patient's symptoms or levels of prostate-specific antigen. Methods: A total of 42 PCa patients and 11 BPH patients were recruited. Genomic DNA was purified from tissues and used for the library preparation of the target-enriched methylome with enzymatic conversion and a Twist 85 Mbp EM-seq panel. Paired-end sequencing (150 bp) was performed using NovaSeq 6000 or NextSeq 550. After quality control, including adapter trimming and de-duplication of raw sequencing data, differential methylation patterns were analyzed between the BPH and PCa groups. Results: We report DNA methylation patterns existing between BPH and PCa. The major finding is that broad hypermethylation occurred at genic loci in PCa tissues as compared to the BPH. Gene ontology analysis suggested that hypermethylation of genic loci involved in chromatin and transcriptional regulation is involved in cancer progression. We also compared PCa tissues with high Gleason scores to tissues with low Gleason scores. The high-Gleason PCa tissues showed hundreds of focal differentially methylated CpG sites corresponding to genes functioning in cancer cell proliferation or metastasis. This suggests that dissecting early-to-advanced-grade cancer stages requires an in-depth analysis of differential methylation at the single CpG site level. Conclusions: Our study reports that enzymatic methylome sequencing data can be used to distinguish PCa from BPH and advanced PCa from early-stage PCa. The stage-specific methylation patterns in this study will be valuable resources for diagnostic purposes as well as further development of liquid biopsy approaches for the early detection of PCa.

Sequential Imaging of a Rapidly Progressive Rheumatoid Vasculitis: A Unique Depiction.

Rheumatoid vasculitis is a clinically heterogenous complication of rheumatoid arthritis (RA), primarily affecting small- and medium-sized vessels.1 A 63-year-old man with long-standing seropositive erosive RA presented to our emergency department with abdominal pain and diarrhea.

Lung-specific MCEMP1 functions as an adaptor for KIT to promote SCF-mediated mast cell proliferation.

Lung mast cells are important in host defense, and excessive proliferation or activation of these cells can cause chronic inflammatory disorders like asthma. Two parallel pathways induced by KIT-stem cell factor (SCF) and FcεRI-immunoglobulin E interactions are critical for the proliferation and activation of mast cells, respectively. Here, we report that mast cell-expressed membrane protein1 (MCEMP1), a lung-specific surface protein, functions as an adaptor for KIT, which promotes SCF-mediated mast cell proliferation. MCEMP1 elicits intracellular signaling through its cytoplasmic immunoreceptor tyrosine-based activation motif and forms a complex with KIT to enhance its autophosphorylation and activation. Consequently, MCEMP1 deficiency impairs SCF-induced peritoneal mast cell proliferation in vitro and lung mast cell expansion in vivo. Mcemp1-deficient mice exhibit reduced airway inflammation and lung impairment in chronic asthma mouse models. This study shows lung-specific MCEMP1 as an adaptor for KIT to facilitate SCF-mediated mast cell proliferation.

Glucosylceramide is essential for Heartland and Dabie bandavirus glycoprotein-induced membrane fusion.

Due to climate changes, there has been a large expansion of emerging tick-borne zoonotic viruses, including Heartland bandavirus (HRTV) and Dabie bandavirus (DBV). As etiologic agents of hemorrhagic fever with high fatality, HRTV and DBV have been recognized as dangerous viral pathogens that likely cause future wide epidemics. Despite serious health concerns, the mechanisms underlying viral infection are largely unknown. HRTV and DBV Gn and Gc are viral surface glycoproteins required for early entry events during infection. Glycosphingolipids, including galactosylceramide (GalCer), glucosylceramide (GlcCer) and lactosylceramide (LacCer), are a class of membrane lipids that play essential roles in membrane structure and viral lifecycle. Here, our genome-wide CRISPR/Cas9 knockout screen identifies that glycosphingolipid biosynthesis pathway is essential for HRTV and DBV infection. The deficiency of UDP-glucose ceramide glucosyltransferase (UGCG) that produces GlcCer resulted in the loss of infectivity of recombinant viruses pseudotyped with HRTV or DBV Gn/Gc glycoproteins. Conversely, exogenous supplement of GlcCer, but not GalCer or LacCer, recovered viral entry of UGCG-deficient cells in a dose-dependent manner. Biophysical analyses showed that GlcCer targeted the lipid-head-group binding pocket of Gc to form a stable protein-lipid complex, which allowed the insertion of Gc protein into host lysosomal membrane lipid bilayers for viral fusion. Mutagenesis showed that D841 residue at the Gc lipid binding pocket was critical for GlcCer interaction and thereby, viral entry. These findings reveal detailed mechanism of GlcCer glycosphingolipid in HRTV and DBV Gc-mediated membrane fusion and provide a potential therapeutic target for tickborne virus infection.

Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor-Induced Hypophysitis.

Context: Hypophysitis is a known immune-related adverse event (irAE) of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and less often with PD-1/PD-L1 inhibitors. Objective: We aimed to determine clinical, imaging, and HLA characteristics of CPI-induced hypophysitis (CPI-hypophysitis). Methods: We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary, and association with HLA type in patients with CPI-hypophysitis. Results: Forty-nine patients were identified. Mean age was 61.3 years, 61.2% were men, 81.6% were Caucasian, 38.8% had melanoma, and 44.5% received PD-1/PD-L1 inhibitor monotherapy while the remainder received CTLA-4 inhibitor monotherapy or CTLA-4/PD-1 inhibitor combination therapy. A comparison of CTLA-4 inhibitor exposure vs PD-1/PD-L1 inhibitor monotherapy revealed faster time to CPI-hypophysitis (median 84 vs 185 days, P < .01) and abnormal pituitary appearance on MRI (odds ratio 7.00, P = .03). We observed effect modification by sex in the association between CPI type and time to CPI-hypophysitis. In particular, anti-CTLA-4 exposed men had a shorter time to onset than women. MRI changes of the pituitary were most common at the time of hypophysitis diagnosis (55.6% enlarged, 37.0% normal, 7.4% empty or partially empty) but persisted in follow-up (23.8% enlarged, 57.1% normal, 19.1% empty or partially empty). HLA typing was done on 55 subjects; HLA type DQ0602 was over-represented in CPI-hypophysitis relative to the Caucasian American population (39.4% vs 21.5%, P = 0.01) and CPI population. Conclusion: The association of CPI-hypophysitis with HLA DQ0602 suggests a genetic risk for its development. The clinical phenotype of hypophysitis appears heterogenous, with differences in timing of onset, changes in thyroid function tests, MRI changes, and possibly sex related to CPI type. These factors may play an important role in our mechanistic understanding of CPI-hypophysitis.

AlphaFold2 reveals commonalities and novelties in protein structure space for 21 model organisms.

Deep-learning (DL) methods like DeepMind's AlphaFold2 (AF2) have led to substantial improvements in protein structure prediction. We analyse confident AF2 models from 21 model organisms using a new classification protocol (CATH-Assign) which exploits novel DL methods for structural comparison and classification. Of ~370,000 confident models, 92% can be assigned to 3253 superfamilies in our CATH domain superfamily classification. The remaining cluster into 2367 putative novel superfamilies. Detailed manual analysis on 618 of these, having at least one human relative, reveal extremely remote homologies and further unusual features. Only 25 novel superfamilies could be confirmed. Although most models map to existing superfamilies, AF2 domains expand CATH by 67% and increases the number of unique 'global' folds by 36% and will provide valuable insights on structure function relationships. CATH-Assign will harness the huge expansion in structural data provided by DeepMind to rationalise evolutionary changes driving functional divergence.