tbuckley/cabot-search huggingface dataset:
VCAM-1–targeted MRI Improves Detection of the Tumor-brain Interface
Authors: Vinton W.T. Cheng, Nicholas de Pennington, Rasheed Zakaria, James R. Larkin, Sébastien Serres, Manjima Sarkar, Matthew A. Kirkman, Claire Bristow, Paula Croal, Puneet Plaha, Leticia Campo, Michael A. Chappell, Simon Lord, Michael D. Jenkinson, Mark R. Middleton, Nicola R. Sibson
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI. Experimental Design: Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1–targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression. Results: The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T2*-weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA–enhanced T1-weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI. Conclusions: This work illustrates the potential of VCAM-1–targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.
Abstract P121: Measuring The Impact Of Inaction On Health Disparities In Limb Amputation
Authors: Corey A Kalbaugh, Brian Witrick, Kerry A Howard, Katharine L McGinigle, Catherine R Lesko
Journal: Circulation (2022)

Objective: Peripheral artery disease (PAD) is a common atherosclerotic disorder that reduces blood flow to the lower extremities. There are significant racial disparities in the outcomes of patients with PAD. Ideally, understanding the result of inadequate implementation of proven interventions on health disparities might provoke a policy and culture shift in the provision of care for minoritized persons. We demonstrate a method that leverages knowledge of interventions that we know should be implemented to optimize care for people with PAD, to identify the extent to which disparities might be mitigated by more universal uptake of those interventions. Methods: We compare racial disparities as they exist currently with disparities that would exist under complete uptake of interventions to improve PAD and vascular care. This counterfactual world is modeled by upweighting people who received the proposed interventions to represent the study population at the start of follow-up. It relies on the assumption that we have measured (and adjusted for) all confounders of the intervention (a hypothesized mediator of the observed health disparities) and the outcome. A unique feature of the application of this method to this problem is our ability to demonstrate how, even when guideline-based care appears evenly distributed by race/ethnicity, increasing access to such care may still decrease health disparities. This method was previously proposed for estimating potential reductions in racial disparities for people with HIV. Results: Across 100,579 infrainguinal revascularizations among Black (n=15,442), Hispanic (n=5,506) and White (n=67,651) patients treated for symptomatic PAD, Black (56.5%) and Hispanic patients (57.6%) were slightly less likely than White patients (59.8%) to receive Class I recommended aspirin and statin therapy prior to their procedures. One-year risk of amputation was 2.7% (95% CI: 2.6%,2.8%) in White patients, 5.8% (5.4%,6.2%) in Black patients and 5.6% (5.0%,6.2%) in Hispanic patients. Had all patients received the appropriate anti-ischemic medications, amputation risk would have been lower across all three race-ethnicity groups. However, specifically, the risk difference (RD) for Black vs White patients would have reduced by 8% (-3%,20%) and the RD for Hispanic vs White patients would have reduced by 18% (-1%,36%). Conclusions: Not only is provision of aspirin and statin for infrainguinal revascularization good for all PAD patients, it is also a social justice imperative.
Abstract 11120: Congenitally Corrected Transposition of the Great Arteries - Fetal Diagnosis, Associations and Natural History: A Fetal Heart Society Research Collaborative Study
Authors: Jennifer Cohen, Bhawna Arya, Mary T Donofrio, Jamie K Harrington, Deborah Y Ho, Whitnee J Hogan, Lisa K Hornberger, Stacy A Killen, Erik Michelfelder, Anita J Moon-Grady, Sheetal R Patel, Emilio Quezada, christina ronai, Aura A Sanchez Mejia, David N Schidlow, Shubhika Srivastava
Journal: Circulation (2021)

Introduction: Congenitally corrected transposition of the great arteries (ccTGA) is rare with varied associated cardiac defects and rhythm abnormalities. We aimed to describe the natural history, associated anomalies and prenatal outcome in a cohort of prenatally diagnosed patients in which biventricular repair is anticipated. Methods: A retrospective cohort study was conducted via the Fetal Heart Society Research Collaborative. All fetuses with ccTGA encountered at 15 North American cardiac centers between 1/2004-7/2020 were identified. Fetuses with a hypoplastic ventricle precluding biventricular repair were excluded. Data is presented as median (interquartile range). Results: Inclusion criteria were met in 139 fetuses who were diagnosed with ccTGA at 24 (21-29) weeks. There was a family history of congenital heart disease in 12%. Maternal diabetes was present in 10%. Prenatal genetic testing in 50 pregnancies was normal. Excluding 14 fetuses with heterotaxy, extracardiac anomalies were observed in 9/125 (7.1%). Associated cardiac/extracardiac defects are detailed in table 1. Fetal atrioventricular block (AVB) was present in 17 fetuses (12%), diagnosed at a median of 26 (23-28), range 20-36 weeks. Two fetuses had SVT; 1 self-resolved and 1 during labor. Change occurred during follow-up in 34 fetuses, most commonly in severity of tricuspid regurgitation (6 improved, 4 worsened) and worsening of pulmonary stenosis (n=5). There were 112 live births, 17 terminations, 2 fetal deaths (FD) and 8 lost to follow-up. Both fetuses with FD had AVB, making the intrauterine mortality associated with fetal AVB 11.8% (2/17). Conclusions: This study represents the largest cohort to date of fetuses with ccTGA. Fetal ccTGA is associated with a spectrum of cardiac defects that may evolve, with extracardiac pathology occurring in 7.1%. AVB is found in 12% of fetuses and is a risk factor for FD. This data informs fetal counseling and can aid in delivery planning and perinatal care.
Using autoantibody signatures to define cancer risk in dermatomyositis
Authors: Jessica L. Turnier, J. Michelle Kahlenberg
Journal: Journal of Clinical Investigation (2022)

Dermatomyositis is an idiopathic inflammatory myopathy with a highly heterogeneous disease course. Although there is a known increase in cancer risk surrounding the time of dermatomyositis diagnosis, the mechanisms driving this increased risk are not well understood. Further, there are no current standardized cancer screening guidelines for dermatomyositis patients. In this issue of the JCI, Fiorentino, Mecoli, et al. discovered additional autoantibodies in patients with dermatomyositis and anti–TIF1-γ autoantibodies, a known risk factor for malignancy. They observed a decreased cancer risk with an increasing number of autoantibodies. Importantly, these findings indicate that more detailed autoantibody phenotyping at diagnosis might better predict cancer risk and also suggest that diversity and kinetics of the host immune response might influence cancer development.
Stroke Proteomics: From Discovery to Diagnostic and Therapeutic Applications
Authors: Karin Hochrainer, Wei Yang
Journal: Circulation Research (2022)

Stroke remains a leading cause of death and disability, with limited therapeutic options and suboptimal tools for diagnosis and prognosis. High throughput technologies such as proteomics generate large volumes of experimental data at once, thus providing an advanced opportunity to improve the status quo by facilitating identification of novel therapeutic targets and molecular biomarkers. Proteomics studies in animals are largely designed to decipher molecular pathways and targets altered in brain tissue after stroke, whereas studies in human patients primarily focus on biomarker discovery in biofluids and, more recently, in thrombi and extracellular vesicles. Here, we offer a comprehensive review of stroke proteomics studies conducted in both animal and human specimen and present our view on limitations, challenges, and future perspectives in the field. In addition, as a unique resource for the scientific community, we provide extensive lists of all proteins identified in proteomic studies as altered by stroke and perform postanalysis of animal data to reveal stroke-related cellular processes and pathways.
The Bronchial Circulation in COVID-19 Pneumonia
Authors: Maximilian Ackermann, Paul Tafforeau, Willi L. Wagner, Claire L. Walsh, Christopher Werlein, Mark P. Kühnel, Florian P. Länger, Catherine Disney, Andrew J. Bodey, Alexandre Bellier, Stijn E. Verleden, Peter D. Lee, Steven J. Mentzer, Danny D. Jonigk
Journal: American Journal of Respiratory and Critical Care Medicine (2021)
Continuation of Pembrolizumab with Additional Chemotherapy after Progression with PD-1/PD-L1 Inhibitor Monotherapy in Patients with Advanced NSCLC: A Randomized, Placebo-Controlled Phase II Study
Authors: Hyun Ae Jung, Sehhoon Park, Yoon-La Choi, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Jong-Mu Sun
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Although programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors have shown survival benefits in patients with non–small cell lung cancer (NSCLC), most patients progress. This study evaluated whether continuing pembrolizumab with additional chemotherapy after failure of prior PD-1/PD-L1 inhibitor extends survival. Patients and Methods: This placebo-controlled, double-blind, randomized phase II study enrolled patients with NSCLC who received one or two cytotoxic chemotherapy, including at least one platinum-doublet regimen, and progressed on second- or third-line PD-1/PD-L1 inhibitor monotherapy as the last systemic therapy. Patients were randomized (1:1) to pembrolizumab or placebo plus chemotherapy, stratified by histology and clinical outcomes to prior PD-1/PD-L1 inhibitor. The primary endpoint was progression-free survival (PFS). Results: A total of 98 patients were randomized to the pembrolizumab-chemotherapy (N = 47) and placebo-chemotherapy arm (N = 51). At the median follow-up duration of 10.5 months, there was no statistical difference in PFS [median 4.1 months vs. 5.9 months; HR = 1.06; 95% confidence interval (CI), 0.69–1.62; P = 0.78) and overall survival (median 11.5 months vs. 12.0 months; HR = 1.09; 95% CI, 0.66–1.83; P = 0.73) between the pembrolizumab-chemotherapy and placebo-chemotherapy arms. In a subgroup with PD-L1 expression in ≥50% of tumor cells and favorable clinical outcomes to prior PD-1/PD-L1 inhibitor (partial response or 6 months or longer of stable disease), the pembrolizumab-chemotherapy arm showed a higher 24-month survival rate than the placebo-chemotherapy arm (74% vs. 38%; HR = 0.52; 95% CI, 0.13–2.1; P = 0.34). Conclusions: This study did not show a survival benefit with the continuation of pembrolizumab with chemotherapy in patients whose NSCLC progressed on second- or third-line PD-1/PD-L1 inhibitors. See related commentary by Tseng and Gainor, p. 2206
Abstract P080: Health-related Quality Of Life Predictors Of Exercise Intervention Dropout
Authors: Katherine A Collins, Leanna M Ross, Lucy W Piner, Lori A Bateman, Ilene C Siegler, Kim M Huffman, William E Kraus
Journal: Circulation (2022)

Introduction: Though many individuals know the health benefits of participating in exercise, few report sufficient activity to meet the US 2018 Physical Activity Guidelines. Current research assessing predictors of exercise adherence and dropout has primarily focused on cognitive factors, physiological factors, and demographic characteristics. The purpose of this analysis was to determine if baseline self-rated HrQoL measures are predictive of dropout from an exercise intervention across two STRRIDE trials. Methods: A total of 444 adults with dyslipidemia (STRRIDE AT/RT) or prediabetes (STRRIDE-PD) were randomized to one of seven exercise interventions, ranging from doses of 10-16 kcal/kg/week (KKW); intensities of 50-75% V̇O 2peak ; and durations of 6-9 months. Six groups included aerobic exercise, two groups included resistance training, and one group included dietary intervention (weight loss goal of 7%). Dropout was defined as a participant who did not complete the exercise intervention due to one or more of several reported reasons (e.g., time, motivation, re-occurring injury). Backwards stepwise logistic regression determined significant baseline HrQoL predictors of exercise intervention dropout, while controlling for age, sex, race, and intervention group assignment. Results: A total of 117 individuals were classified as being exercise intervention dropouts (STRRIDE AT/RT: n=55; STRRIDE-PD: n=62). In STRRIDE AT/RT, the logistic regression identified baseline sleep quality, sleep latency, sleep efficiency, sleep disturbance, bodily pain, and social functioning scores as predictors of dropout (R 2 =0.39). In STRRIDE-PD, the logistic regression identified baseline role-emotional, satisfaction with appearance, and physical component scores as predictors of dropout (R 2 =0.08). Conclusion: Among individuals with dyslipidemia, baseline HrQoL measures were able to explain about 39% of the variance in dropout from an exercise intervention, with primarily sleep measures, bodily pain, and social functioning being identified as important predictors of dropout. In contrast, among individuals farther along the disease spectrum, with prediabetes, baseline HrQoL measures only explained about 8% of the variance in dropout, with emotional well-being, perceived appearance, and physical function being important predictors of dropout. Future research should investigate molecular and biological predictors of dropout in combination with HrQoL, physiological, cognitive, and demographic factors to improve predictive power.
Predictive Markers of Response to Neoadjuvant Durvalumab with Nab-Paclitaxel and Dose-Dense Doxorubicin/Cyclophosphamide in Basal-Like Triple-Negative Breast Cancer
Authors: Kim R.M. Blenman, Michal Marczyk, Thomas Karn, Tao Qing, Xiaotong Li, Vignesh Gunasekharan, Vesal Yaghoobi, Yalai Bai, Eiman Y. Ibrahim, Tristen Park, Andrea Silber, Denise M. Wolf, Emily Reisenbichler, Carsten Denkert, Bruno V. Sinn, Mariya Rozenblit, Julia Foldi, David L. Rimm, Sibylle Loibl, Lajos Pusztai
Journal: Clinical Cancer Research (2022)

Abstract Purpose: We examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like triple-negative breast cancer (bTNBC). Experimental Design: Germline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial. Results: Gene set enrichment analysis showed that pathways involved in immunity (adaptive, humoral, innate), JAK–STAT signaling, cancer drivers, cell cycle, apoptosis, and DNA repair were enriched in cases with pathologic complete response (pCR), whereas epithelial–mesenchymal transition, extracellular matrix, and TGFβ pathways were enriched in cases with residual disease (RD). Immune-rich bTNBC with RD was enriched in CCL-3, -4, -5, -8, -23, CXCL-1, -3, -6, -10, and IL1, -23, -27, -34, and had higher expression of macrophage markers compared with immune-rich cancers with pCR that were enriched in IFNγ, IL2, -12, -21, chemokines CXCL-9, -13, CXCR5, and activated T- and B-cell markers (GZMB, CD79A). In the validation cohort, an immune-rich five-gene signature showed higher expression in pCR cases in the durvalumab arm (P = 0.040) but not in the placebo arm (P = 0.923) or in immune-poor cancers. Independent of immune markers, tumor mutation burden was higher, and PI3K, DNA damage repair, MAPK, and WNT/β-catenin signaling pathways were enriched in germline and somatic mutations in cases with pCR. Conclusions: The TGFβ pathway is associated with immune-poor phenotype and RD in bTNBC. Among immune-rich bTNBC RD, macrophage/neutrophil chemoattractants dominate the cytokine milieu, and IFNγ and activated B cells and T cells dominate immune-rich cancers with pCR.
Evolving Role of Prostate-Specific Membrane Antigen-Positron Emission Tomography in Metastatic Hormone-Sensitive Prostate Cancer: More Questions than Answers?
Authors: Maha Hussain, Michael A. Carducci, Noel Clarke, Sarah E. Fenton, Karim Fizazi, Silke Gillessen, Heather Jacene, Michael J. Morris, Fred Saad, Oliver Sartor, Mary-Ellen Taplin, Neha Vapiwala, Scott Williams, Christopher Sweeney
Journal: Journal of Clinical Oncology (2022)

Although most men with metastatic hormone-sensitive prostate cancer (mHSPC) die of prostate cancer (PCa), there remains significant outcome variability, with approximately 18.5% living 10 years or longer. 1 Prognosis and management are determined in part by disease extent detected on conventional imaging (CIM; 99m Tc Bone and computed tomography [CT] scan; Data Supplement, online only).With the advent of multiple new life-prolonging therapies, clinicians can better personalize therapy on the basis of these findings.However, the availability of new imaging modalities with varying performance characteristics has added more variables that affect clinical decision making.Prostate-Specific Membrane Antigen (PSMA)-positron emission tomography (PET) is a more sensitive imaging tool compared with CIM, detecting previously CIM-invisible disease (micrometastases). 2,3PET radiotracers and PSMA-PET development are discussed in the Data Supplement.Several trials demonstrated that PSMA-PET imaging resulted in management changes; 4-6 however, all available clinical trial data guiding the treatment of patients with mHSPC are CIMbased.Integrating PSMA-PET into clinical practice without prospective evidence derived from clinical trials poses significant challenges.In this Comments and Controversy paper, we detail what is known and what remains to be determined for optimal implementation of PSMA-PET imaging and provide opinions generated by an international, multidisciplinary group of PCa experts to help guide decision making until further data are available.
Antitumor Activity of the Novel BTK Inhibitor TG-1701 Is Associated with Disruption of Ikaros Signaling in Patients with B-cell Non–Hodgkin Lymphoma
Authors: Marcelo Lima Ribeiro, Diana Reyes-Garau, Meritxell Vinyoles, Núria Profitós Pelejà, Juliana Carvalho Santos, Marc Armengol, Miranda Fernández-Serrano, Alícia Sedó Mor, Joan J. Bech-Serra, Pedro Blecua, Eva Musulen, Carolina De La Torre, Hari Miskin, Manel Esteller, Francesc Bosch, Pablo Menéndez, Emmanuel Normant, Gaël Roué
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Despite the remarkable activity of BTK inhibitors (BTKi) in relapsed B-cell non–Hodgkin lymphoma (B-NHL), no clinically-relevant biomarker has been associated to these agents so far. The relevance of phosphoproteomic profiling for the early identification of BTKi responders remains underexplored. Experimental Design: A set of six clinical samples from an ongoing phase I trial dosing patients with chronic lymphocytic leukemia (CLL) with TG-1701, a novel irreversible and highly specific BTKi, were characterized by phosphoproteomic and RNA sequencing (RNA-seq) analysis. The activity of TG-1701 was evaluated in a panel of 11 B-NHL cell lines and mouse xenografts, including two NF-κB- and BTKC481S-driven BTKi-resistant models. Biomarker validation and signal transduction analysis were conducted through real-time PCR, Western blot analysis, immunostaining, and gene knockout (KO) experiments. Results: A nonsupervised, phosphoproteomic-based clustering did match the early clinical outcomes of patients with CLL and separated a group of “early-responders” from a group of “late-responders.” This clustering was based on a selected list of 96 phosphosites with Ikaros-pSer442/445 as a potential biomarker for TG-1701 efficacy. TG-1701 treatment was further shown to blunt Ikaros gene signature, including YES1 and MYC, in early-responder patients as well as in BTKi-sensitive B-NHL cell lines and xenografts. In contrast, Ikaros nuclear activity and signaling remained unaffected by the drug in vitro and in vivo in late-responder patients and in BTKC481S, BTKKO, and noncanonical NF-κB models. Conclusions: These data validate phosphoproteomic as a valuable tool for the early detection of response to BTK inhibition in the clinic, and for the determination of drug mechanism of action.
CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins
Authors: Masami Shimizu-Albergine, Debapriya Basu, Jenny E. Kanter, Farah Kramer, Vishal Kothari, Shelley Barnhart, Carissa Thornock, Adam E. Mullick, Noemie Clouet-Foraison, Tomas Vaisar, Jay W. Heinecke, Robert A. Hegele, Ira J. Goldberg, Karin E. Bornfeldt
Journal: Journal of Clinical Investigation (2021)

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.
120P Efficacy of postoperative radiotherapy (PORT) in stage IIIA-N2 non-small cell lung cancer: Meta-analysis of randomized controlled studies
Authors: Y. Ergün, G. Uçar, Y. Açıkgöz, M. Dirikoç, S. Aktürk Esen, M. Bardakçı, C. Karaçin, D. Uncu
Journal: Annals of Oncology (2022)