Citations

Abstract Post-translational modifications (PTM) of tau are implicated in Alzheimer disease (AD) progression and are established biomarkers in cerebrospinal fluid and plasma; however, the labor-intensive nature of conventional proteomics limits their investigation in histology-specific contexts. We describe the findings of an artificial intelligence-guided laser capture microdissection (LCM) pipeline for harvesting neurofibrillary tangles (NFTs) by maturation level into pretangles (pre-NFTs), mature tangles (iNFTs), and ghost tangles (eNFTs) using 38 cases obtained from 2 independent biobanks. We evaluated the performance characteristics of proprietary machine learning algorithms for the subclassification of these NFT categories in anti-pTau217-stained whole slide images of entorhinal cortex, hippocampus, frontal, and parietal cortex sections. Overall precision/recall/F1 scores were highest for Classifier A (0.6/0.46/0.5). The best performing algorithm was used to guide LCM capture and inform NFT enrichment. Targeted proteomics on tau signature peptides (pTau181, pTau217, and TauMTBR) was performed on approximately 1250 NFT collections. The results demonstrated that their abundance increased from pretangles to mature tangles (∼2-11-fold increase), and that this was followed by a sharp reduction in ghost tangles (∼3-116-fold decrease), with pTau217 showing the most drastic change. Pathologist-trained NFT classifiers represent an objective albeit imperfect means to enrich specific morphologic forms permitting coupled LCM-MS (mass spectrometry) to investigate AD-associated PTM.

Abstract Rationale High-attenuation area (HAA) is a computed tomography (CT) tool that correlates with lung inflammation and fibrosis. Systemic molecular correlates of HAA (e.g., plasma proteins) may inform biological processes involved in interstitial lung disease. Objectives To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). Methods Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; N = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; N = 1,781). Linear regression models identified HAA-associated proteins after adjustment for demographic and socioeconomic factors, CT scanner parameters, study center, and batch. Associations of HAA-related proteins with new-onset fibrotic or subpleural ILAs were examined in MESA participants with ILA assessments on full-lung CT 10 years later. Immunohistochemical staining of select proteins was performed in lung tissue from pulmonary fibrosis cases. Measurements and Main Results There were 75 proteins detected that were significantly associated with HAA in MESA and SPIROMICS. Gene Ontology analysis of these proteins identified processes involved in immune cell chemotaxis and cellular growth and apoptosis. Seven proteins were associated with a higher probability of new-onset fibrotic or subpleural ILAs in MESA, and two of these, junctional adhesion molecule-like protein and GTP cyclohydrolase 1 feedback regulatory protein, stained in areas of fibrosis in lung tissue from patients with interstitial lung disease. Conclusions Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.

Abstract Taxanes are frontline chemotherapeutics that stabilize microtubules, induce mitotic arrest, and drive tumor remission. However, their off-target effects in healthy tissues, most notably cutaneous axon degeneration underlying chemotherapy-induced peripheral neuropathy (CIPN), remain poorly understood. Here, we show that paclitaxel induces microtubule fasciculation in epidermal keratinocytes through the mitotic kinesin Eg5, thereby initiating CIPN. Mechanistically, paclitaxel enhances Eg5-dependent fasciculation of detyrosinated (stabilized) microtubules, which constrict and breach the nuclear lamina. This deformation triggers tension-dependent NADPH oxidase-mediated nuclear ROS (X-ROS) formation upstream of mmp13 transcription, a pathway we previously demonstrated drives sensory axon degeneration. Employing a cross-species framework spanning zebrafish, mice, human skin biopsies, and a breast adenocarcinoma cell line, we uncover a conserved paclitaxel–Eg5 mechanism leading to fasciculation of stable microtubules in both healthy epidermis and cancer cells. These findings highlight the dualistic nature of paclitaxel action and underscore the challenge of preserving anticancer efficacy while preventing neurotoxic side effects.

Abstract The effectiveness of T cell–based immunotherapy depends on durable T-cell responses that can efficiently eliminate tumor cells. NKG7 was discovered three decades ago as a protein associated with lytic granules. However, only studies published over the past 5 years have contributed substantially to our understanding of NKG7 in T-cell biology. NKG7 has been recognized as an important T-cell functional marker in responses to immune checkpoint inhibitor therapy and in the prognosis of certain cancers. Besides its role in the generation, trafficking, and release of lytic granules, which is critical for efficient T-cell cytotoxicity against tumor cells, NKG7 has been identified as a key negative regulator of mTORC1 activity. By restraining mTORC1 activity, NKG7 promotes T-cell longevity and memory generation after infection. Importantly, NKG7 upregulation has demonstrated therapeutic potential in preclinical T-cell therapy for cancer. Collectively, NKG7 is emerging as a promising biomarker and therapeutic addition to T cell–based immunotherapies.

Abstract Background Acamprosate is an FDA-approved medication for the treatment of alcohol use disorder (AUD), however, only about 50% of patients will respond to acamprosate. Previously, we conducted an acamprosate trial (n=442), which is one of the largest acamprosate clinical studies ever conducted and currently the only study with multi-omics data. To date, no biological measures are utilized to predict response to acamprosate treatment. Aims & Objectives We set out to apply our established pharmaco-omics informed genomics strategy to identify potential biomarkers associated with acamprosate treatment response. Method Our open-label acamprosate clinical trial recruited 442 patients with AUD, all of whom were treated with acamprosate for three months. The primary outcomes were 1) relapse to alcohol use and 2) relapse to heavy drinking. Alcohol consumption was measured using the self-reported timeline follow back method. Plasma protein levels were measured using Olink proximity extension immunoassays. Results Our established “Pharmaco-Omics-informed genome-wide association study (GWAS)” research strategy identified 12 proteins, including interleukin-17 receptor B (IL17RB), that were associated with acamprosate treatment response. A GWAS for IL17RB concentrations identified several genome-wide significant signals. Specifically, the top hit single nucleotide polymorphism (SNP) rs6801605 with a minor allele frequency of 38% in the European American population mapped 4 kilobase (Kb) upstream of IL17RB, and intron 1 of the choline dehydrogenase (CHDH) gene on chromosome 3 (p: 4.8E-20). The variant genotype (AA) for the SNP rs6801605 was associated with lower IL17RB protein expression. In addition, we identified a series of genetic variants in IL17RB that were associated with acamprosate treatment outcomes. Furthermore, the variant genotypes for all of those IL17RB SNPs were protective against alcohol relapse. Finally, we demonstrated that the basal level of mRNA expression of IL17RB was inversely correlated with those of nuclear factor-κB (NF-κB) subunits, and a significantly higher expression of NF-κB subunits was observed in AUD patients who relapsed to alcohol use. Discussion & Conclusions This study illustrates that IL17RB genetic variants might contribute to acamprosate treatment outcomes. This series of studies represents an important step toward generating functional hypotheses that could be tested to gain insight into mechanisms underlying variation in acamprosate treatment response phenotypes.

ABSTRACT Background and Objectives The relevance of Cochrane systematic reviews depends on timely completion and updates. This study aimed to empirically assess the lifecycles of Cochrane reviews published from 2003 to 2024, including transitions from protocol to review, update patterns, and withdrawals. Methods We extracted data from Cochrane Library publications between 2003 and 2024. Each review topic was identified using a unique six‐digit DOI‐based ID. We recorded protocol publication, review publication, updates, and withdrawals (i.e., removed from the Cochrane Library for editorial or procedural reasons), calculating time intervals between stages and conducting subgroup analyses by review type. Results Of 8137 protocols, 71.9% progressed to reviews (median 25.7 months), 2.4% were updated during the protocol stage, and 10.0% were withdrawn. Among 8477 reviews, 64.3% were never updated by the time of our analysis; for those updated at least once, the median interval between updates was 57.2 months. Withdrawal occurred in 2.5% of reviews (median 67.6 months post‐publication). Subgroup analyses showed variation across review types; diagnostic and qualitative reviews tended to have longer protocol‐to‐review times than other types of reviews. Conclusions Cochrane reviews show long development and update intervals, with variation by review type. Greater use of automation and targeted support may improve review efficiency and timeliness.

Background: Lung cancer ranks as the leading cause of cancer-related mortality worldwide. The complexity of tumor delineation, crucial for radiation therapy, requires expertise often unavailable in resource-limited settings. Artificial Intelligence (AI), particularly with advancements in deep learning (DL) and natural language processing (NLP), offers potential solutions yet is challenged by high false positive rates. Purpose: The Oncology Contouring Copilot (OCC) system is developed to leverage oncologist expertise for precise tumor contouring using textual descriptions, aiming to increase the efficiency of oncological workflows by combining the strengths of AI with human oversight. Methods: Our OCC system initially identifies nodule candidates from CT scans. Employing Language Vision Models (LVMs) like GPT-4V, OCC then effectively reduces false positives with clinical descriptive texts, merging textual and visual data to automate tumor delineation, designed to elevate the quality of oncology care by incorporating knowledge from experienced domain experts. Results: The deployment of the OCC system resulted in a 35.0% reduction in the false discovery rate, a 72.4% decrease in false positives per scan, and an F1-score of 0.652 across our dataset for unbiased evaluation. Conclusions: OCC represents a significant advance in oncology care, particularly through the use of the latest LVMs, improving contouring results by (1) streamlining oncology treatment workflows by optimizing tumor delineation and reducing manual processes; (2) offering a scalable and intuitive framework to reduce false positives in radiotherapy planning using LVMs; (3) introducing novel medical language vision prompt techniques to minimize LVM hallucinations with ablation study; and (4) conducting a comparative analysis of LVMs, highlighting their potential in addressing medical language vision challenges.

ImportanceIdentification of factors associated with variation in outpatient surgery may further quality improvement efforts to safely reduce postoperative hospital length of stay nationally.ObjectivesTo explore variation in the use of outpatient surgery, incorporating patient, geographic, and hospital factors.Design, Setting, and ParticipantsThis retrospective cross-sectional study used deidentified administrative claims data from OptumLabs Data Warehouse. Participants included adults who underwent 1 of 10 general, urological, or gynecological operations between January 1, 2015, and June 30, 2021, in the US. Patients who underwent combined procedures or reoperations or had at least 15 Elixhauser comorbidities were excluded. Data were analyzed from July 26 to December 16, 2023.ExposureInpatient or outpatient surgical procedures.Main Outcomes and MeasuresMultilevel logistic regression assessed variation in the use of outpatient surgery rates by hospital characteristics (bed size, presence of trainees, and rural referral center status) and hospital census division, adjusting for patient factors (age, sex, number of Elixhauser comorbidities, year, and rural-urban commuting area). This multilevel model allowed for the sources of variability to be quantitatively attributed to patient characteristics, geography, and hospital characteristics.ResultsA total of 330 424 (72.3%) of 456 954 included patients underwent outpatient surgery. The median age was 54 (IQR, 41-67) years, and of those with data available, most patients were female (268 692 of 414 193 [64.9%]). The likelihood of outpatient surgery varied significantly by hospital census division for all 10 operations (eg, MIS salpingo-oophorectomy range, 29.6%-58.8%; P < .001). Variation in hospital census division contributed most to outpatient surgery for 8 of 10 operations compared with other patient and hospital characteristics. Hospital census division contributed the greatest degree to the variation in outpatient simple mastectomy (20.6%) and the least to outpatient open ventral hernia repair (0.7%). Multivariable analysis showed that the odds of outpatient surgery for patients from metropolitan areas were higher for minimally invasive salpingo-oophorectomy (odds ratio [OR], 1.62; 95% CI, 1.34-1.95) and open ventral hernia repair (OR, 1.16; 95% CI, 1.09-1.24). Hospitals with 400 or more beds were independently associated with decreased odds of outpatient surgery compared with hospitals with 50 to 199 beds for 4 of 7 operations (MIS paraesophageal hernia repair [OR, 0.58; 95% CI, 0.47-0.71; P < .001]; MIS cholecystectomy [OR, 0.73; 95% CI, 0.68-0.78; P < .001]; open ventral hernia [OR, 0.51; 95% CI, 0.46-0.57; P < .001]; MIS ventral hernia repair [OR, 0.66; 95% CI, 0.56-0.77; P < .001]). The presence of a residency training program was independently associated with increased odds of outpatient surgery for simple mastectomy (OR, 1.35; 95% CI, 1.16-1.58; P < .001) and mastectomy with reconstruction (OR, 1.50; 95% CI, 1.27-1.77; P < .001) and decreased odds of outpatient surgery for minimally invasive cholecystectomy (OR, 0.96; 95% CI, 0.92-1.00; P = .04), open ventral hernia repair (OR, 0.93; 95% CI, 0.86-1.00; P = .04), and total thyroidectomy (OR, 0.84; 95% CI, 0.71-1.00; P = .04).Conclusions and RelevanceIn this cross-sectional study, significant variation existed in the use of outpatient surgery in the US and appeared to be driven primarily by hospital geography. Addressing these variations may improve the use of resources.