tbuckley/cabot-search huggingface dataset:
Metabolic profiling of glioblastoma stem cells reveals pyruvate carboxylase as a critical survival factor and potential therapeutic target
Authors: Ophélie Renoult, Mélanie Laurent--Blond, Hala Awada, Lisa Oliver, Noémie Joalland, Mikaël Croyal, François Paris, Catherine Gratas, Claire Pecqueur
Journal: Neuro-Oncology (2024)

Abstract Background Glioblastoma (GBM) is a highly aggressive tumor with unmet therapeutic needs, which can be explained by extensive intra-tumoral heterogeneity and plasticity. In this study, we aimed to investigate the specific metabolic features of Glioblastoma stem cells (GSC), a rare tumor subpopulation involved in tumor growth and therapy resistance. Methods We conducted comprehensive analyses of primary patient-derived GBM cultures and GSC-enriched cultures of human GBM cell lines using state-of-the-art molecular, metabolic, and phenotypic studies. Results We showed that GSC-enriched cultures display distinct glycolytic profiles compared with differentiated tumor cells. Further analysis revealed that GSC relies on pyruvate carboxylase (PC) activity for survival and self-renewal capacity. Interestingly, inhibition of PC led to GSC death, particularly when the glutamine pool was low, and increased differentiation. Finally, while GSC displayed resistance to the chemotherapy drug etoposide, genetic or pharmacological inhibition of PC restored etoposide sensitivity in GSC, both in vitro and in orthotopic murine models. Conclusions Our findings demonstrate the critical role of PC in GSC metabolism, survival, and escape to etoposide. They also highlight PC as a therapeutic target to overcome therapy resistance in GBM.
SCUBE2 regulates adherens junction dynamics and vascular barrier function during inflammation
Authors: Yuh-Charn Lin, Ya-Jen Chang, Shiang-Shin Gau, Chun-Min Lo, Ruey-Bing Yang
Journal: Cardiovascular Research (2024)

Abstract Aims SCUBE2 (signal peptide-CUB-epidermal growth factor-like domain-containing protein 2) is a secreted or membrane-bound protein originally identified from endothelial cells (ECs). Our previous work showed that SCUBE2 forms a complex with E-cadherin and stabilizes epithelial adherens junctions (AJs) to promote epithelial phenotypes. However, it remains unclear whether SCUBE2 also interacts with vascular endothelial (VE)-cadherin and modulates EC barrier function. In this study, we investigated whether and how SCUBE2 in ECs regulates vascular barrier maintenance. Methods and results We showed that SCUBE2 colocalized and interacted with VE-cadherin and VE-protein tyrosine phosphatase (VE-PTP) within EC AJs. Furthermore, SCUBE2 knockdown disrupted EC AJs and increased EC permeability. Expression of EC SCUBE2 was suppressed at both mRNA and protein levels via the nuclear factor-κB signalling pathway in response to pro-inflammatory cytokines or permeability-inducing agents. In line with these findings, EC-specific deletion of Scube2 (EC-KO) in mice impaired baseline barrier function and worsened vascular leakiness of peripheral capillaries after local injection of histamine or vascular endothelial growth factor. EC-KO mice were also sensitive to pulmonary vascular hyperpermeability and leucocyte infiltration in response to acute endotoxin- or influenza virus-induced systemic inflammation. Meanwhile, EC-specific SCUBE2-overexpressing mice were protected from these effects. Molecular studies suggested that SCUBE2 acts as a scaffold molecule enabling VE-PTP to dephosphorylate VE-cadherin, which prevents VE-cadherin internalization and stabilizes EC AJs. As such, loss of SCUBE2 resulted in hyperphosphorylation of VE-cadherin at tyrosine 685, which led to its endocytosis, thus destabilizing EC AJs and reducing barrier function. All of these effects were exacerbated by inflammatory insults. Conclusion We found that SCUBE2 contributes to vascular integrity by recruiting VE-PTP to dephosphorylate VE-cadherin and stabilize AJs, thereby promoting EC barrier function. Moreover, our data suggest that genetic overexpression or pharmacological up-regulation of SCUBE2 may help to prevent vascular leakage and oedema in inflammatory diseases.
Nanogel-based nitric oxide-driven nanomotor for deep tissue penetration and enhanced tumor therapy
Authors: Jianhong Wang, Junjie Liu, Yiǧitcan Sümbelli, Jingxin Shao, Xiangyang Shi, Jan C M van Hest
Journal: Journal of Controlled Release (2024)

Antitumor agents often lack effective penetration and accumulation to achieve high therapeutic efficacy in treating solid tumors. Nanomotor-based nanomaterials offer a potential solution to address this obstacle. Among them, nitric oxide (NO) based nanomotors have garnered attention for their potential applications in nanomedicine. However, there widespread clinical adoption has been hindered by their complex preparation processes. To address this limitation, we have developed a NO-driven nanomotor utilizing a convenient and scalable nanogel preparation procedure. These nanomotors, loaded with the fluorescent probe / sonosensitizer chlorin e6 (Ce6), were specifically engineered for sonodynamic therapy. Through comprehensive in vitro investigations using both 2D and 3D cell models, as well as in vivo analysis of Ce6 fluorescent signal distribution in solid tumor models, we observed that the self-propulsion of these nanomotors significantly enhances cellular uptake and tumor penetration, particularly in solid tumors. This phenomenon enables efficient access to challenging tumor regions and, in some cases, results in complete tumor coverage. Notably, our nanomotors have demonstrated long-term in vivo biosafety. This study presents an effective approach to enhancing drug penetration and improving therapeutic efficacy in tumor treatment, with potential clinical relevance for future applications.
CBioProfiler: A Web and Standalone Pipeline for Cancer Biomarker and Subtype Characterization
Authors: Xiaoping Liu, Zisong Wang, Hongjie Shi, Sheng Li, Xinghuan Wang
Journal: Genomics Proteomics & Bioinformatics (2024)

Cancer is a leading cause of death worldwide, and the identification of biomarkers and subtypes that can predict the long-term survival of cancer patients is essential for their risk stratification, treatment, and prognosis. However, there are currently no standardized tools for exploring cancer biomarkers or subtypes. In this study, we introduced Cancer Biomarker and subtype Profiler (CBioProfiler), a web server and standalone application that includes two pipelines for analyzing cancer biomarkers and subtypes. The cancer biomarker pipeline consists of five modules for identifying and annotating cancer survival-related biomarkers using multiple survival-related machine learning algorithms. The cancer subtype pipeline includes three modules for data preprocessing, subtype identification using multiple unsupervised machine learning methods, and subtype evaluation and validation. CBioProfiler also includes CuratedCancerPrognosisData, a novel R package that integrates reviewed and curated gene expression and clinical data from 268 studies. These studies cover 43 common blood and solid tumors and draw upon 47,686 clinical samples. The web server is available at https://www.cbioprofiler.com/ and https://cbioprofiler.znhospital.cn/CBioProfiler/, and the standalone app and source code can be found at https://github.com/liuxiaoping2020/CBioProfiler.
Risks of Iodine Excess
Authors: Seo Young Sohn, Kosuke Inoue, Connie M Rhee, Angela M Leung
Journal: Endocrine Reviews (2024)

Abstract Iodine is a micronutrient that is required for thyroid hormone synthesis. The iodide cycle in thyroid hormone synthesis consists of a series of transport, oxidation, organification, and binding/coupling steps in thyroid follicular cells. Common sources of iodine include the consumption of an iodine-rich diet or iodine-fortified foods, the administration of amiodarone, iodine-containing supplements, or iodinated contrast media, and other miscellaneous sources. Methods to assess population iodine status include the measurement of urinary iodine concentrations, blood thyroglobulin levels, prevalence of elevated neonatal thyrotropin levels, and thyroid volume. Although excessive iodine intake or exposure is generally well tolerated, an acute iodine load may result in thyroid dysfunction (hypothyroidism or hyperthyroidism) in certain susceptible individuals due to the failure to escape from the Wolff–Chaikoff effect and to the Jod–Basedow phenomenon, respectively. In this review, we discuss the associations between excessive iodine intake or exposure, with particular focus on iodinated contrast media as a common source of excess iodine in health care settings, and risks of incident thyroid dysfunction. We also summarize the risks of iodine excess in vulnerable populations and review current guidelines regarding the screening and monitoring of iodinated contrast–induced thyroid dysfunction. Finally, we discuss the long-term potential nonthyroidal health risks associated with iodine excess and suggest the need for more data to define safe upper limits for iodine intake, particularly in high-risk populations.
Tightening the purse strings: a stent-free path to a lasting endoscopic gastroenterostomy
Authors: Anam Rizvi, Omar Saab, Sanjay M. Salgado, Mohamed Abu-Hammour, Qais M. Dawod, Reem Z. Sharaiha
Journal: Endoscopy (2024)

A 42-year-old woman presented with epigastric abdominal pain for several years. An extensive workup revealed duodenal compression on esophagogastroduodenoscopy (EGD) and superior mesenteric artery syndrome on imaging ([Fig. 1]). Despite several months of conservative management, the patient remained symptomatic. She deferred surgery and was then offered an endoscopic ultrasound-guided gastroenterostomy (EUS-GE) ([Video 1]).
Prevalence of EGFR Mutations in Patients With Resected Stage I-III NSCLC: Results From the EARLY-EGFR Study
Authors: Ross A. Soo, Thanyanan Reungwetwattana, Herman Andres Perroud, Ullas Batra, Saadettin Kilickap, Luis Fernando Tejado Gallegos, Natalia Donner, Mohamed Alsayed, Reto Huggenberger, Dao Van Tu
Journal: Journal of Thoracic Oncology (2024)

Background:There is limited literature on the prevalence of EGFR mutations in early-stage non-small cell lung cancer (NSCLC).EARLY-EGFR (NCT04742192), a cross-sectional study, determined the prevalence of EGFR mutations in early-stage NSCLC. Methods:This non-interventional, real-world study enrolled consecutive patients with resected stage IA-IIIB (American Joint Committee on Cancer 8 th edition) NSCLC from 14 countries across Asia, Latin America, and Middle East and Africa.The primary endpoint was prevalence of EGFR mutations and secondary endpoints included prevalence of EGFR mutation subtypes and treatment patterns. Results :Of 601 patients (median [range] age: 62.0 [30.0-86.0]years) enrolled, 52.7% were females and 64.2% were non-smokers.The majority had stage IA-IB NSCLC (64.1%) and adenocarcinoma histology (98.7%).Overall prevalence of EGFR mutations was 51.0%; majority reported exon-19 deletions (48.5%) followed by exon-21 L858R mutations (34.0%).Women had a higher EGFR mutation rate than men (64.0%versus 36.4%).Compared with no EGFR mutations, patients with EGFR mutations were more likely to be non-smokers (35.1% versus 60.9%) and have stage I NSCLC compared to stage II and III NSCLC (54.8% versus 47.3% and 35.6%).Systemic adjuvant therapy was planned in 33.8% patients with stage IB to IIIB disease and adjuvant chemoradiotherapy in 6.8% patients.Age ≥60 years, females, and Asians were found to have a significantly (p < 0.05) higher odds of EGFR mutations, while smoking history and stage III disease had lower odds of EGFR mutations.J o u r n a l P r e -p r o o f 5 Conclusion:The EARLY-EGFR study provides an overview of EGFR mutations and subtype prevalence in patients with early-stage NSCLC.The study highlights the limited adherence to treatment guidelines suggesting an unmet need for improved adjuvant therapy.
The Revised Kyoto Criteria and Risk of Malignancy Among Patients With Intraductal Papillary Mucinous Neoplasms
Authors: Tsuyoshi Hamada, Hiroki Oyama, Shuichi Tange, Ryunosuke Hakuta, Kazunaga Ishigaki, Sachiko Kanai, Yoshikuni Kawaguchi, Kensaku Noguchi, Tomotaka Saito, Tatsuya Sato, Tatsunori Suzuki, Naminatsu Takahara, Mariko Tanaka, Kiyoshi Hasegawa, Tetsuo Ushiku, Yousuke Nakai, Mitsuhiro Fujishiro
Journal: Clinical Gastroenterology and Hepatology (2024)
LI-RADS category can be a post-surgical prognostic factor for intrahepatic cholangiocarcinoma in patients with liver cirrhosis or chronic hepatitis B
Authors: Sungeun Park, Boyeon Koo, Boryeong Jeong, Sang Hyun Choi, Jeong Min Lee
Journal: Liver Cancer (2024)

The Liver Imaging Reporting and Data System (LI-RADS) categorization has been proposed as a potential prognostic indicator for primary liver neoplasms in patients with liver cirrhosis or chronic hepatitis B. This multicenter study aimed to determine whether LI-RADS categorization can offer additional post-surgical prognostic value for intrahepatic cholangiocarcinoma (ICCA) when used in conjunction with the American Joint Committee on Cancer (AJCC) guidelines.
Prognostic Efficacy of the Albumin-Bilirubin Score and Treatment Outcomes in Hepatocellular Carcinoma: A Large-Scale, Multi-Center Real-World Database Study
Authors: Kyu-Pyo Kim, Kang Mo Kim, Baek-Yeol Ryoo, Won-Mook Choi, Won Chul Cha, Mira Kang, Dong Hyun Sinn, Myung Ji Goh, Do Young Kim, Min Ji Lee, Subin Lim, DongKyu Kim, Kyoungdae Baek, Joohyun Kim, Eui Jun Choi, Doik Lee, Jung-Ae Kim, Ki-Hun Kim
Journal: Liver Cancer (2024)

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with treatment outcomes closely tied to liver function. This study evaluates the prognostic utility of the albumin-bilirubin (ALBI) score compared to the traditional Child-Pugh (CP) grading, leveraging real-world evidence from a large-scale, multi-center database.
AI based PD-L1 CPS quantifier software to identify more patients for checkpoint therapy in gastric cancer at pathologist-level interobserver concordance.
Authors: Sunil S Badve, George Louis Kumar, Tobias Lang, David Mulder, Diego Calvopiña, Patrick Frey, Maria Karasarides
Journal: Journal of Clinical Oncology (2024)

2633 Background: To determine whether gastric cancer (GC) patients are eligible for immunotherapy, PD-L1 expression is analyzed by immunohistochemistry (IHC) using the “Combined Positive Score” (CPS). This requires quantification of PD-L1 stained tumor and tumor-associated immune cells as well as all viable tumor cells. However, manual CPS scoring on whole-slide images (WSIs) is time-consuming and prone to error as evidenced by low interobserver concordance. While the use of artificial intelligence (AI) holds the promise to ameliorate this key challenge in clinical practice, AI models have not yet met the required accuracy thresholds for PD-L1 CPS scoring on GC biopsies. Methods: We investigated the use of an AI-based PD-L1 CPS quantifier software to support pathologists in standardized PD-L1 IHC assessment on GC biopsies.An AI software for automated PD-L1 CPS scoring was deployed on WSIs from GC biopsies (n = 97) stained for PD-L1 with the 28-8 pharmDx assay and scanned on a 3DHistech P1000 scanner. Manual CPS scores from 12 pathologists on all 97 slides were available for comparison. Pairwise correlation was calculated for continuous values using Lin’s concordance correlation coefficient (CCC). Pairwise concordance was measured for scores binarized at the clinically relevant positivity cutoff of CPS ≥ 5 using unweighted Cohen’s kappa. Results: For continuous CPS scores, the CCC between AI scores and pathologists’ scores was higher (0.59) than the mean correlation among pathologists (0.56). In the majority of cases, the AI scores were found to be within the range of all pathologists, but slightly above the pathologist median. At a cutoff of CPS≥5, the concordance between AI scores and pathologists’ manual scores (κ=0.45) was higher than the mean concordance among pathologists’ manual scores (κ=0.39) (p&lt;0.05). Substantial variability is seen among pathologists when categorizing patients as positive (CPS≥5), with approximately 30.3 ±5.0 patients classified as positive on average by manual scoring and 46 patients (&gt;50% more) categorized as positive by the AI model. Conclusions: An AI model for the assessment of PD-L1 expression in GC using CPS was applied successfully without human intervention. The correlation in continuous CPS scores as well as the concordance in clinical categories with all pathologists was higher for the AI model than for individual pathologists on average, while at the same time, the AI model found more positive patients. This shows that by using AI more positive patients eligible for PD-L1 targeted treatment might be identified while simultaneously ensuring a level of concordance that is non-inferior to pathologists.
Mn(II)‐Aloe‐Emodin Nanoscale Coordination Polymer Enhances Ferroptosis by Synergistically Enhancing Reactive Oxygen Species Generation via the Nrf2–GPX4 Axis
Authors: Xiaoxin Yang, Chang Li, Mengjun Ge, Xiaoying Li, Wei Zhao, Hu Guo, Hemin Nie, Jun Liu
Journal: Advanced Healthcare Materials (2024)

Ferroptosis induction is particularly promising for cancer therapy when the apoptosis pathway is compromised. Current strategies in nanomedicine for inducing ferroptosis primarily focus on promoting the accumulation of reactive oxygen species (ROS). However, the presence of intracellular antioxidants, such as nuclear factor erythroid 2-related factor 2 (Nrf2), can limit the effectiveness of such therapy by activating detoxification systems and eliminating ROS. To overcome this challenge, we developed a synergistic ferroptosis-inducing agent by modifying manganese (Mn
Evaluation of the tumor microenvironment in African American and non-Hispanic White patients with non-small cell lung cancer associated with PD-L1 expression or the presence of tertiary lymphoid structures.
Authors: Matthew Raymond Trendowski, Donovan Watza, Chrissy Lusk, Fulvio Lonardo, Valerie Ratliff, Angela Wenzlaff, Hirva Mamdani, Christine Neslund-Dudas, Julie Boerner, Ann G. Schwartz, Heather M Gibson
Journal: Journal of Clinical Oncology (2024)

2627 Background: African Americans have higher incidence and mortality from lung cancer than non-Hispanic Whites, but investigations into differences in the tumor microenvironment and treatment response have been minimal. Due to the increasing utility of immunotherapy in the treatment of non-small cell lung cancer (NSCLC), we compared the immune cell composition and transcriptomic signature in the tumor microenvironment among African American and non-Hispanic White patients based on PD-L1 or tertiary lymphocyte structure (TLS) status to determine if there were differences of translational relevance. Methods: Using a cohort of 280 NSCLC patients from the INHALE study (non-Hispanic White: n = 155; African American: n = 125) with whole transcriptome microarray data, we determined the PD-L1 tumor proportion score (&lt; 1% vs. ≥ 1%) and TLS status (presence/absence) within tumor tissue sections by immunohistochemistry. TLS were defined as dense aggregates of CD20 stained cells with a minimum diameter of 150 µm. Immune cell distribution within the tumor microenvironment was evaluated relative to differential gene expression. Results: Tumors from African Americans had a higher proportion of plasma cell signatures within the tumor microenvironment than tumors from non-Hispanic Whites. In addition, gene expression patterns in African American PD-L1 positive samples suggest these tumors contained significantly greater numbers of γδ T-cells and resting dendritic cells, along with fewer CD8 + T-cells compared to PD-L1 negative samples after adjusting for stage and histology. We also identified 22 genes that were differentially expressed between PD-L1 positive and negative tumors, along with 37 genes that were differentially expressed between TLS positive and negative tumors. Investigation of differential expression of B-cell/plasma cell related genes between the two patient populations revealed that four immunoglobulin genes in African Americans ( IGHA1, IGHD, IGKV2-29, and IGLL5) were associated with decreased mortality risk, while none of these genes were associated with overall survival in the non-Hispanic White population. Conclusions: In the first known race-stratified analysis of tumor microenvironment in lung cancer based on PD-L1 expression or TLS status, differences within the immune cell composition and transcriptomic signature were identified among non-Hispanic White and African American patients that may have therapeutic implications. Future investigation of these unique aspects within the tumor microenvironment will make advances in immunotherapy more equitable, thereby reducing the health disparities African Americans currently experience.
Primary analysis of a phase 1/2 study of LM-101: An anti-SIRPα antibody as a single agent in patients with advanced malignancies.
Authors: Yi Xia, Fuling Zhou, Liang Kong, Da Fei, Tian Bai, Xia Qin, Xiaojie Fang, Dongmei Ji, Qingqing Cai
Journal: Journal of Clinical Oncology (2024)

2640 Background: LM-101 is a humanized monoclonal antibody which binds to both V1 and V2 isoforms of SIRPα that expressed on macrophages and dendritic cells and enables phagocytosis of tumor cells. LM-101 has shown optimal pre-clinical safety profiles and promising anti-tumor activity in animal models. Here we report the primary analysis of the single agent dose escalation results of a phase 1/2 study (NCT05615974). Methods: This is an open-label, phase 1/2, first-in-human, multicenter dose escalation study with dose expansion evaluating safety and clinical activity of LM-101 as a single agent in patients with advanced malignancies. Eligible patients were aged ≥ 18 years with advanced solid tumors or relapsed/refractory lymphoma who had progressed on standard therapy, or intolerable to the available standard therapy, or had no available standard therapy for treatment. In the dose escalation part, enrolled patients were administered with LM-101 intravenously every three weeks at dose levels of 3 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, and 40 mg/kg as per traditional 3+3 design. The objectives for this dose escalation part included safety and clinical activity as per RECIST v1.1 criteria or Lugano 2014 criteria. Results: As of January 24, 2024, 17 patients were enrolled in the single agent dose escalation part. No DLT was observed at all dose levels and MTD for single agent was not reached. The most frequent adverse event (AE) related to the study drug was lymphocyte counts decreased. Two patients experienced grade ≥ 3 AEs which were related to LM-101. Out of 16 patients from single agent dose-escalation groups who had at least one time tumor assessment post treatment, one patient achieved complete response (CR), one patient achieved partial response (PR) and five patients achieved stable disease (SD). Conclusions: LM-101 monotherapy showed excellent safety profile and promising anti-tumor activity in patients with advanced malignancies. Further investigation of LM-101 as a single agent and in combination with other anti-tumor agents are ongoing. Clinical trial information: NCT05615974 .