Citations

Abstract Background A vast amount of potentially useful information such as description of patient symptoms, family, and social history is recorded as free-text notes in electronic health records (EHRs) but is difficult to reliably extract at scale, limiting their utility in research. This study aims to assess whether an “out of the box” implementation of open-source large language models (LLMs) without any fine-tuning can accurately extract social determinants of health (SDoH) data from free-text clinical notes. Methods We conducted a cross-sectional study using EHR data from the Mass General Brigham (MGB) system, analyzing free-text notes for SDoH information. We selected a random sample of 200 patients and manually labeled nine SDoH aspects. Eight advanced open-source LLMs were evaluated against a baseline pattern-matching model. Two human reviewers provided the manual labels, achieving 93% inter-annotator agreement. LLM performance was assessed using accuracy metrics for overall, mentioned, and non-mentioned SDoH, and macro F1 scores. Results LLMs outperformed the baseline pattern-matching approach, particularly for explicitly mentioned SDoH, achieving up to 40% higher Accuracymentioned. openchat_3.5 was the best-performing model, surpassing the baseline in overall accuracy across all nine SDoH aspects. The refined pipeline with prompt engineering reduced hallucinations and improved accuracy. Conclusions Open-source LLMs are effective and scalable tools for extracting SDoH from unstructured EHRs, surpassing traditional pattern-matching methods. Further refinement and domain-specific training could enhance their utility in clinical research and predictive analytics, improving healthcare outcomes and addressing health disparities.

The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.

Background: Integrin family are known as key gears in focal adhesion for triple-negative breast cancer (TNBC) metastasis. However, the integrin independent factor TLN1 remains vague in TNBC. Methods: Bioinformatics analysis was performed based on TCGA database and Shengjing Hospital cohort. Western blot and RT-PCR were used to detect the expression of TLN1 and integrin pathway in cells. A small-molecule C67399 was screened for blocking TLN1 and integrin β1 through a novel computational screening approach by targeting the protein-protein binding interface. Drug pharmacodynamics were determined through xenograft assay. Results: Upregulation of TLN1 in TNBC samples correlates with metastasis and worse prognosis. Silencing TLN1 in TNBC cells significantly attenuated the migration of tumour cells through interfering the dynamic formation of focal adhesion with integrin β1, thus regulating FAK-AKT signal pathway and epithelial-mesenchymal transformation. Targeting the binding between TLN1 and integrin β1 by C67399 could repress metastasis of TNBC. Conclusions: TLN1 overexpression contributes to TNBC metastasis and C67399 targeting TLN1 may hold promise for TNBC treatment. Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 81872159, 81902607, 81874301), Liaoning Colleges Innovative Talent Support Program (Name: Cancer Stem Cell Origin and Biological Behaviour), Outstanding Scientific Fund of Shengjing Hospital (201803), and Outstanding Young Scholars of Liaoning Province (2019-YQ-10).

Abstract Prostate cancer remains the second leading cause of cancer death among American men. Radiotherapy is a potentially curative treatment for localized prostate cancer, and failure to control localized disease contributes to the majority of prostate cancer deaths. Neuroendocrine differentiation (NED) in prostate cancer, a process by which prostate adenocarcinoma cells transdifferentiate into neuroendocrine-like (NE-like) cells, is an emerging mechanism of resistance to cancer therapies and contributes to disease progression. NED also occurs in response to treatment to promote the development of treatment-induced neuroendocrine prostate cancer (NEPC), a highly aggressive and terminal stage disease. We previously demonstrated that by mimicking clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces prostate cancer cells to undergo NED in vitro and in vivo. Here, we performed transcriptomic analysis and confirmed that FIR-induced NE-like cells share some features of clinical NEPC, suggesting that FIR-induced NED represents a clinically relevant model. Furthermore, we demonstrated that protein arginine methyltransferase 5 (PRMT5), a master epigenetic regulator of the DNA damage response and a putative oncogene in prostate cancer, along with its cofactors pICln and MEP50, mediate FIR-induced NED. Knockdown of PRMT5, pICln, or MEP50 during FIR-induced NED and sensitized prostate cancer cells to radiation. Significantly, PRMT5 knockdown in prostate cancer xenograft tumors in mice during FIR prevented NED, enhanced tumor killing, significantly reduced and delayed tumor recurrence, and prolonged overall survival. Collectively, our results demonstrate that PRMT5 promotes FIR-induced NED and suggests that targeting PRMT5 may be a novel and effective radiosensitization approach for prostate cancer radiotherapy.

Abstract BackgroundThe effect of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEI/ARB) on the COVID-19 remains controversial from clinic evidence. MethodsThis is a retrospective, two-center case series of 198 consecutive COVID-19 patients with a history of hypertension. ResultsAmong 198 patients, 58 (29.3%) and 16 (8.1%) were on were on ARB and ACEI, respectively. Patients who were on ARB or ACEI/ARB had a significantly lower rate of severe illness and ARDS when compared with patients treated with ACEI alone or not receiving and RAAS blocker (P＜0.05). The Kaplan-Meier survival curve showed that patients with ARB in their antihypertensive regimen had a trend towards a higher survival rate when compared with individuals without ARB (adjusted hazard ratio, 0.27; 95% CI, 0.07-1.02; P = 0.054). The Cox-regression analysis to compared ACEI vs. ARB groups showed a significantly lower mortality rate in the ARB group (adjusted hazard ratio, 0.03; 95% CI, 0.00-0.58; P = 0.02). ConclusionsUsing of ARB was associated with a reduced rate of severe illness and ARDS, indicating their potential protective impact in COVID-19.

AIMS To report the major characteristics and clinical outcomes of COVID-19 patients treated with ACE inhibitors and ARBs and compare the different effects of the two drugs for outcomes of COVID-19 patients. METHODS This is a retrospective, two-center case series of 198 consecutive COVID-19 patients with a history of hypertension. RESULTS Among 198 patients, 58 (29.3%) and 16 (8.1%) were on were on ARB and ACEI, respectively. Patients who were on ARB or ACEI/ARB had a significantly lower rate of severe illness and ARDS when compared with patients treated with ACEI alone or not receiving RAAS blocker (P＜0.05). The Kaplan-Meier survival curve showed that patients with ARB in their antihypertensive regimen had a trend towards a higher survival rate when compared with individuals without ARB (adjusted hazard ratio, 0.27; 95% CI, 0.07-1.02; P=0.054). The occurrence rates of severe illness, ARDS, and death were similar in the two groups regardless of receiving ACEI. The Cox-regression analysis to compared ACEI vs. ARB groups showed a significantly lower mortality rate in the ARB group (adjusted hazard ratio, 0.03; 95% CI, 0.00-0.58; P=0.02). CONCLUSIONS Our data may provide some evidence of using ARB, but not ACEI, was associated with a reduced rate of severe illness and ARDS, indicating their potential protective impact in COVID-19. Further large sample sizes and multiethnic populations are warranted to confirm our findings.

AbstractBackgroundGlioblastoma (GBM) represents an aggressive cancer type with a median survival of only 14 months. With fewer than 5% of patients surviving 5 years, comprehensive profiling of these rare patients could elucidate prognostic biomarkers that may confer better patient outcomes. We utilized multiple molecular approaches to characterize the largest patient cohort of isocitrate dehydrogenase (IDH)–wildtype GBM long-term survivors (LTS) to date.MethodsRetrospective analysis was performed on 49 archived formalin-fixed paraffin embedded tumor specimens from patients diagnosed with GBM at the Mayo Clinic between December 1995 and September 2013. These patient samples were subdivided into 2 groups based on survival (12 LTS, 37 short-term survivors [STS]) and subsequently examined by mutation sequencing, copy number analysis, methylation profiling, and gene expression.ResultsOf the 49 patients analyzed in this study, LTS were younger at diagnosis (P = 0.016), more likely to be female (P = 0.048), and MGMT promoter methylated (UniD, P = 0.01). IDH-wildtype STS and LTS demonstrated classic GBM mutations and copy number changes. Pathway analysis of differentially expressed genes showed LTS enrichment for sphingomyelin metabolism, which has been linked to decreased GBM growth, invasion, and angiogenesis. STS were enriched for DNA repair and cell cycle control networks.ConclusionsWhile our findings largely report remarkable similarity between these LTS and more typical STS, unique attributes were observed in regard to altered gene expression and pathway enrichment. These attributes may be valuable prognostic markers and are worth further examination. Importantly, this study also underscores the limitations of existing biomarkers and classification methods in predicting patient prognosis.

Background and Purpose— The prognostic significance of subarachnoid extension of intracerebral hemorrhage was determined in the INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT2) study. Methods— INTERACT2 was an open randomized controlled trial of early intensive compared with guideline-recommended blood pressure lowering in patients with elevated systolic blood pressure within 6 hours of intracerebral hemorrhage. Independent predictors of death or major disability (scores 3–6 on the modified Rankin Scale) at 90 days were analyzed in logistic regression models. Results— Of 2582 participants, 192 (7%) had subarachnoid extension, which was associated with larger hematoma volumes ( P <0.0001) and higher National Institute of Health Stroke Scale score ( P <0.0001). Subarachnoid extension predicted death or major disability at 90 days (71% versus 53%; unadjusted odds ratio, 2.25; 95% confidence interval, 1.63–3.10; P <0.0001). The association remained significant after adjusting for age, region, lipid-lowering therapy, systolic blood pressure, glucose, location of hematoma, intraventricular extension, and randomized treatment (odds ratio, 2.17; 95% confidence interval, 1.50–3.14; P <0.0001), but not after further adjustment for baseline hematoma volume ( P =0.62). Conclusions— Subarachnoid extension of intracerebral hemorrhage is associated with poor prognosis, which is determined by a larger volume of the underlying intraparenchymal hematoma. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00716079.