tbuckley/cabot-search huggingface dataset:
Response to EGFR/NTRK/MET Co-Inhibition Guided by Paired NGS in Advanced NSCLC With Acquired EGFR L858R/T790M/C797S Mutations
Authors: Xue Yang, Xintong Li, Jiaqi Yan, Yuanxin Liu, Jie Yin, Weikang Shao, You Lu, Jianxin Xue
Journal: Journal of the National Comprehensive Cancer Network (2024)

EGFR tyrosine kinase inhibitors (TKIs) have significantly improved clinical outcomes for patients with non–small cell lung cancer (NSCLC) harboring EGFR-activating mutations. However, resistance to TKI therapy often develops due to secondary EGFR mutations or the activation of bypass signalling pathways. Next-generation sequencing (NGS) can efficiently identify actionable genetic alterations throughout treatment. MET amplification is a well-established off-target resistance mechanism. Additionally, rarer mechanisms, such as NTRK1 gene fusions, have been reported. This report highlights a case of a 58-year-old male diagnosed with bone-metastatic NSCLC harboring the EGFR L858R mutation. After receiving dacomitinib and almonertinib sequentially, plasma-based NGS revealed the emergence of EGFR T790M-trans-C797S mutations, prompting a switch to a combination therapy of almonertinib and gefitinib. Upon disease progression, repeat NGS identified EGFR T790M-cis&amp;trans-C797S mutations and a novel POT1 :: NTRK3 fusion in the blood. The fusion retained a complete NTRK kinase domain without frameshift variants, making it a target for treatment. Larotrectinib was incorporated into the dual EGFR-TKI regimen, forming a triplet therapy. Although this resulted in grade 3 dermatitis, the condition resolved after discontinuing gefitinib. At multiorgan progression, matched tissue- and plasma-based NGS identified MET amplification. Subsequently, the patient was started on a triple-inhibition regimen targeting EGFR, NTRK, and MET, which achieved a partial response with favorable tolerability. This is the first reported case of a novel, targetable POT1 :: NTRK3 fusion as a potential off-target mechanism mediating EGFR-TKI resistance, occurring alongside MET amplification in a patient with NSCLC harboring acquired EGFR L858R/T790M/C797S mutations. Concomitant inhibition of EGFR, NTRK, and MET was safe and resulted in a significant response, underscoring the importance of precision medicine guided by matched NGS.
Superficial circumflex iliac artery (SCIA) perforator flap for shaft-only phalloplasty: Surgical technique and outcomes
Authors: Kristin B. de Haseth, Danny A. Young-Afat, Sterre E. Mokken, Floyd W. S. Timmermans, Marlon E. Buncamper, Matthijs Botman, Brechje L. Ronkes, Garry L. S. Pigot, Mark-Bram Bouman, Wouter B. vd Sluis
Journal: International Journal of Transgender Health (2024)

Background Phalloplasty is the surgical (re)construction of a phallus using pedicled and/or free tissue flaps. The pedicled superficial circumflex iliac artery (SCIA) perforator flap is a novel, up-and-coming technique for phalloplasty. Here, we present our surgical technique and surgical outcomes for pedicled SCIA-based phalloplasty without urethral lengthening (i.e. shaft-only) in transgender men.
Venous Endothelial Cell Transcriptomic Profiling Implicates METAP1 in Preeclampsia
Authors: Maria A. Pabon, Robert M. Weisbrod, Claire Castro, Haobo Li, Peng Xia, Jiayi Kang, Maddalena Ardissino, Katherine E. Economy, Zihui Yang, Yanxi Shi, Eunice Kim, Anna Perillo, Leanne Barrett, Jenifer M. Brown, Sanjay Divakaran, Murat Cetinbas, Ruslan I. Sadreyev, Antonio de Marvao, Malissa J. Wood, Nandita S. Scott, Emily S. Lau, Jennifer E. Ho, Marcelo F. Di Carli, Jason D. Roh, Naomi M. Hamburg, Michael C. Honigberg
Journal: Circulation Research (2024)

BACKGROUND: Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia. METHODS: Venous ECs were isolated from postpartum patients with severe preeclampsia and those with normotensive pregnancy using a J wire–based technique in the antecubital vein followed by CD144 magnetic bead isolation. Venous EC transcriptomes were compared between preeclamptic and normotensive individuals. Differentially expressed genes were carried forward for genetic validation using expression quantitative trait loci from the Genotype-Tissue Expression project as exposures for vascular-specific Mendelian randomization. Functional validation of the top candidate was performed in human umbilical vein ECs using gain- and loss-of-function genetic approaches. RESULTS: Seventeen individuals with preeclampsia and 7 normotensive controls were included. Pairwise analysis yielded 14 protein-coding genes nominally differentially expressed in participants with preeclampsia. Mendelian randomization revealed a significant association between higher genetically predicted METAP1 (methionyl aminopeptidase 1) expression in aortic and tibial arterial tissues and greater risk of preeclampsia. METAP1 overexpression in human umbilical vein ECs decreased angiogenesis, with a 66% decrease in tube formation ( P =7.9×10 −3 ) and 72% decrease in cell proliferation ( P =2.9×10 −2 ). Furthermore, METAP1 overexpression decreased VEGFA expression and increased expression of multiple preeclampsia-related genes, for example, FLT1 , INHBA , and IL1B . Conversely, METAP1 knockdown produced opposite effects on tube formation, cell proliferation, and inflammation-related gene expression. CONCLUSIONS: In a cohort of early postpartum individuals, we observed greater METAP1 expression in venous ECs of women with preeclampsia versus normotensive delivery. Mendelian randomization supported a causal relationship between greater vascular METAP1 expression and higher preeclampsia risk, and functional experiments demonstrated antiangiogenic and proinflammatory effects of METAP1 in human ECs consistent with alterations observed in preeclampsia. Ex vivo EC transcriptomics can identify novel mechanisms underlying preeclampsia pathophysiology, with implications for prevention and treatment.
Breastfeeding and infant gut microbiota: influence of bioactive components
Authors: Dongqing Xu, Fengyi Wan
Journal: Gut Microbes (2024)

Establishment of the gut microbiota during infancy is critical for host health with long-lasting implications. In this orchestrated process, microbial assembly is influenced by an increasing number of genetic and environmental factors, among which breastfeeding is considered as one of the most significant drivers for infant gut microbiota development. As the optimal diet for the infants, maternal milk provides numerous nutritional, microbial, and bioactive components to ensure the most adequate microbial growth and development of a 'healthy' gut microbiota during early life. This review will summarize the available evidence, particularly the recent progress, on how various bioactive compounds supplied in maternal milk affect the establishment of early-life gut microbiota during infancy and promote further interest and investigation in this important area.
Modulation of β secretase and neuroinflammation by biomimetic nanodelivery system for Alzheimer's disease therapy
Authors: Xiaolei Song, Chenchen Wang, Qin Ding, Peng Li, Shihao Sun, Wei Wei, Juan Zhang, Rongli Sun, Lihong Yin, Songqin Liu, Yuepu Pu
Journal: Journal of Controlled Release (2024)
Risk of Major Adverse Cardiovascular Events and Venous Thromboembolic Events Between Patients With Psoriasis or Psoriatic Arthritis on Tumor Necrosis Factor Inhibitors, Interleukin-17 Inhibitors, Interleukin-12/23 Inhibitors and Interleukin-23 Inhibitors: An Emulated Target Trial Analysis
Authors: Tai-Li Chen, Jing-Yang Huang, Hui-Yun Lin, Yun-Ting Chang, Cheng-Yuan Li, James Cheng-Chung Wei
Journal: Journal of the American Academy of Dermatology (2024)
Developmental dynamics mimicking inversely engineered pericellular matrix for articular cartilage regeneration
Authors: Yongkang Yang, Ziheng Xu, Songlin He, Chao Wang, Runmeng Li, Ruiyang Zhang, Jianwei Li, Zhen Yang, Hao Li, Shuyun Liu, Quanyi Guo
Journal: Biomaterials (2024)
THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer
Authors: Xing Zhou, Jiashu Han, Anning Zuo, Yuhao Ba, Shutong Liu, Hui Xu, Yuyuan Zhang, Siyuan Weng, Zhaokai Zhou, Long Liu, Peng Luo, Quan Cheng, Chuhan Zhang, Yukang Chen, Dan Shan, Benyu Liu, Shuaixi Yang, Xinwei Han, Jinhai Deng, Zaoqu Liu
Journal: Molecular Cancer (2024)

Abstract Cancer-associated fibroblasts (CAFs) exert multiple tumor-promoting functions and are key contributors to drug resistance. The mechanisms by which specific subsets of CAFs facilitate oxaliplatin resistance in colorectal cancer (CRC) have not been fully explored. This study found that THBS2 is positively associated with CAF activation, epithelial-mesenchymal transition (EMT), and chemoresistance at the pan-cancer level. Together with single-cell RNA sequencing and spatial transcriptomics analyses, we identified THBS2 specifically derived from subsets of CAFs, termed THBS2 + CAFs, which could promote oxaliplatin resistance by interacting with malignant cells via the collagen pathway in CRC. Mechanistically, COL8A1 specifically secreted from THBS2 + CAFs directly interacts with the ITGB1 receptor on resistant malignant cells, activating the PI3K-AKT signaling pathway and promoting EMT, ultimately leading to oxaliplatin resistance in CRC. Moreover, elevated COL8A1 promotes EMT and contributes to CRC oxaliplatin resistance, which can be mitigated by ITGB1 knockdown or AKT inhibitor. Collectively, these results highlight the crucial role of THBS2 + CAFs in promoting oxaliplatin resistance of CRC by activating EMT and provide a rationale for a novel strategy to overcome oxaliplatin resistance in CRC.
Deciphering a profiling based on multiple post-translational modifications functionally associated regulatory patterns and therapeutic opportunities in human hepatocellular carcinoma
Authors: Yuanxiang Lao, Yirong Jin, Songfeng Wu, Ting Fang, Qiang Wang, Longqin Sun, Beicheng Sun
Journal: Molecular Cancer (2024)

Posttranslational modifications (PTMs) play critical roles in hepatocellular carcinoma (HCC). However, the locations of PTM-modified sites across protein secondary structures and regulatory patterns in HCC remain largely uncharacterized. Total proteome and nine PTMs (phosphorylation, acetylation, crotonylation, ubiquitination, lactylation, N-glycosylation, succinylation, malonylation, and β-hydroxybutyrylation) in tumor sections and paired normal adjacent tissues derived from 18 HCC patients were systematically profiled by 4D-Label free proteomics analysis combined with PTM-based peptide enrichment. We detected robust preferences in locations of intrinsically disordered protein regions (IDRs) with phosphorylated sites and other site biases to locate in folded regions. Integrative analyses revealed that phosphorylated and multiple acylated-modified sites are enriched in proteins containing RRM1 domain, and RNA splicing is the key feature of this subset of proteins, as indicated by phosphorylation and acylation of splicing factor NCL at multiple residues. We confirmed that NCL-S67, K398, and K646 cooperate to regulate RNA processing. Together, this proteome profiling represents a comprehensive study detailing regulatory patterns based on multiple PTMs of HCC.
Hyperglycemia-responsive nitric oxide-releasing biohybrid cryogels with cascade enzyme catalysis for enhanced healing of infected diabetic wounds
Authors: Jiajun Hu, Kairui Duan, Yueming Zhao, Hangbin Xv, Xinxin Ge, Mian Lin, Hu Zhu, Dingze Chen, Hui Deng, Bae Hoon Lee
Journal: Journal of Controlled Release (2024)
Enhancing glioblastoma therapy via intranasal administration of highly potent cell-penetrating peptide decorated nanoparticles
Authors: Jain Koo, Yuseon Shin, Hyewon Jeon, Jaehyun Cheong, Seongmin Cho, Chanho Park, Ee Chan Song, Jacob D Ramsey, Chaemin Lim, Kyung Taek Oh
Journal: Journal of Controlled Release (2025)
The second phase of tumor invasion driven by immune cells: A study on doxorubicin-loaded PLG nanoparticles
Authors: Julia Malinovskaya, Tatyana Kovshova, Pavel Melnikov, Zhuoxuan Li, Namrata Dhakal, Julian Knoll, Marat Valikhov, Yulia Ermolenko, Anastasia Chernysheva, Olga Gurina, Vladimir Chekhonin, Matthias G Wacker, Svetlana Gelperina
Journal: Journal of Controlled Release (2024)
Microglia membrane-mediated trans-blood-brain barrier prodrug micelles enhance phagocytosis for glioblastoma chemo-immunotherapy
Authors: Sufen Li, Jingyan Zhang, Tong Yu, Guangtao Song, Jia Ke, Kai Wang, Yichong Xu, Yiling Hong, Tingting Meng, Yun Hong, Hong Yuan, Fuqiang Hu
Journal: Journal of Controlled Release (2025)
D-peptide hydrogels as a long-acting multipurpose drug delivery platform for combined contraception and HIV prevention
Authors: Sreekanth Pentlavalli, Sophie M Coulter, Yuming An, Emily R Cross, Han Sun, Jessica V Moore, Akmal Bin Sabri, Brett Greer, Lalitkumar Vora, Helen O McCarthy, Garry Laverty
Journal: Journal of Controlled Release (2025)

New multipurpose prevention technology products for use by women, focused on reducing HIV infection and preventing unwanted pregnancies, are a global health priority. Discreet long-acting formulations will empower women with greater choice around their sexual health. This paper outlines the development of a long-acting technology that enables multiple drugs to be incorporated within one injectable platform. This fixed-dose combination product is formed from a phosphorylated D-peptide (naphthalene-2-ly)-acetyl-diphenylalanine-lysine-tyrosine-glycine-OH (Napffky(p)G-OH) that enables the highly hydrophobic drugs MIV-150 (HIV antiretroviral) and etonogestrel (contraceptive) to be solubilized together within aqueous solvents. Upon subcutaneous injection, this D-peptide-drug combination self-assembles in response to phosphatase enzymes present within the skin space to form an in situ forming drug-releasing hydrogel depot. Oscillatory rheology confirmed the formation of hydrogels, which began within ~10 s exposure to 3.98 U/mL phosphatase enzymes and continued for ~198 mins for a Napffk(MIV-150)y(p)G-OH + Napffk(ENG)y(p)G-OH combination (8:2 ratio). Biostability against proteases, an important consideration for long-acting injectables, was demonstrated for at least 28 days in vitro. Covalent attachment of each drug to the D-peptide via an ester linkage enabled sustained release of the drug in an unmodified form via hydrolysis of the D-peptide-drug linker. This significantly reduced the initial drug burst. Low toxicity was also demonstrated in vitro via cell culture (MTS, LHS, Live/Dead®) and within in vivo studies (H&E staining). The fixed dose combination was able to deliver clinically relevant concentrations of each drug to Sprague-Dawley rats for 49 days, providing proof-of-concept for the use of hydrogel-forming D-peptides (Napffky(p)G-OH) as a long-acting injectable platform for the delivery of multiple hydrophobic drugs.
In vivo self-assembled siRNAs within small extracellular vesicles attenuate LRRK2-induced neurodegeneration in Parkinson's disease models
Authors: Li Zhang, Penglu Chen, Tiantian Chen, Lishan Lin, Xiaoyi Ji, Jin Liu, Heng Huang, Tanvikhaa Saravanan, Hannah Fuehrer, Christopher A Ross, Wanli W Smith, Zhong Pei, Xi Chen
Journal: Journal of Controlled Release (2025)

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene play an important role in Parkinson's disease (PD) pathogenesis, and downregulation of LRRK2 has become a promising therapy for PD. Here, we developed a synthetic biology strategy for the self-assembly and delivery of small interfering RNAs (siRNAs) of LRRK2 into the substantia nigra via small extracellular vesicles (sEVs) using a genetic circuit (in the form of naked DNA plasmid) to attenuate PD-like phenotypes in mouse model.
Impact of a national HPV vaccination programme for preadolescent girls on cytology screening performance and CIN2+ incidence: five-year population-based cervical screening results from Slovenia
Authors: Abyan Irzaldy, Tine Jerman, Inge M C M de Kok, Jan A C Hontelez, Harry J de Koning, Erik E L Jansen, Urška Ivanuš
Journal: The Lancet Regional Health - Europe (2024)
Leveraging Old Hepatitis C Therapies
Authors: S Sean Tu, Shyamasundaran Kottilil, T Joseph Mattingly
Journal: New England Journal of Medicine (2024)

Audio Interview Interview with Joey Mattingly on providing widespread access to HCV treatment at the lowest possible price. 12m 16s Download AbstractOlder drugs could potentially advance U.S. hepatitis C elimination efforts. The government could act like a business and use all current and historical market information to its advantage.
Decision-making in feminizing genital gender-affirming surgery – the effect of the introduction of the GenderAid decision-aid
Authors: Irene M. C. Fritschy, Sterre E. Mokken, Margriet G. Mullender, Tim C. van de Grift
Journal: International Journal of Transgender Health (2024)

Introduction Transgender individuals considering feminizing genital gender-affirming surgery (gGAS) face multiple options and potential decisional conflict (DC). Shared decision-making (SDM) between patients and healthcare professionals (HCPs) can support personalized care and improve outcomes. To aid trans women during the decision-making process for gGAS, a decision aid, the GenderAid (GA), was developed.
2D echocardiography video to 3D heart shape reconstruction for clinical application
Authors: Fabian Laumer, Lena Rubi, Michael A Matter, Stefano Buoso, Gabriel Fringeli, François Mach, Frank Ruschitzka, Joachim M Buhmann, Christian M Matter
Journal: Medical Image Analysis (2024)

Transthoracic Echocardiography (TTE) is a crucial tool for assessing cardiac morphology and function quickly and non-invasively without ionising radiation. However, the examination is subject to intra- and inter-user variability and recordings are often limited to 2D imaging and assessments of end-diastolic and end-systolic volumes. We have developed a novel, fully automated machine learning-based framework to generate a personalised 4D (3D plus time) model of the left ventricular (LV) blood pool with high temporal resolution. A 4D shape is reconstructed from specific 2D echocardiographic views employing deep neural networks, pretrained on a synthetic dataset, and fine-tuned in a self-supervised manner using a novel optimisation method for cross-sectional imaging data. No 3D ground truth is needed for model training. The generated digital twins enhance the interpretation of TTE data by providing a versatile tool for automated analysis of LV volume changes, localisation of infarct areas, and identification of new and clinically relevant biomarkers. Experiments are performed on a multicentre dataset that includes TTE exams of 144 patients with normal TTE and 314 patients with acute myocardial infarction (AMI). The novel biomarkers show a high predictive value for survival (area under the curve (AUC) of 0.82 for 1-year all-cause mortality), demonstrating that personalised 3D shape modelling has the potential to improve diagnostic accuracy and risk assessment.
A novel sweat sensor detects inflammatory differential rhythmicity patterns in inpatients and outpatients with cirrhosis
Authors: Brian C. Davis, Kai-Chun Lin, Sarah Shahub, Annapoorna Ramasubramanya, Andrew Fagan, Sriram Muthukumar, Shalini Prasad, Jasmohan S. Bajaj
Journal: npj Digital Medicine (2024)

Abstract Patients with cirrhosis have high systemic inflammation (TNFα, CRP, and IL-6) that is associated with poor outcomes. These biomarkers need continuous non-invasive monitoring, which is difficult with blood. We studied the AWARE sweat-sensor to measure these in passively expressed sweat in healthy people ( N = 12) and cirrhosis ( N = 32, 10 outpatients/22 inpatients) for 3 days. Blood CRP, TNFα, IL6, levels, and liver function and quality of life were measured. We found that CRP, TNFα, and IL6 were correlated in sweat and serum among both groups and were evaluated in inpatients versus outpatients/controls. IL6 is associated with lower transplant-free survival. Sweat monitoring nocturnal CRP/IL6 elevations in cirrhosis versus controls. Outpatients with cirrhosis had inflammation levels that elevated during the evening and peaked towards the early night periods. The levels start to fall much later at night and early morning. These data suggest that further investigation of continuous measurement of sweat biomarkers in cirrhosis is warranted.
High frequency of CTNNB1 variants associated with benign and malignant liver tumors in patients with Congenital Porto-Systemic Shunts
Authors: Athanasios Tyraskis, Yoh Zen, Sandra Strautnieks, Riley Cook, Pierre Foskett, Claudio De Vito, Maesha Deheragoda, Alberto Quaglia, Nigel Heaton, Mark Davenport, Richard J. Thompson
Journal: Liver Cancer (2024)

Introduction Patients born with congenital porto-systemic shunts have been shown to have a high risk of benign and malignant liver tumors in otherwise healthy livers. This study aims to evaluate the genetic landscape of tumors in congenital porto-systemic shunts (CPSS) and correlate sequencing data with histological findings and clinical evolution. Methods Nodules from patients with CPSS and sporadic pediatric focal nodular hyperplasia (FNH) or FNH-like nodules were evaluated histologically and sequenced for a panel of 50 genes using Next-Generation Sequencing. Results Thirty-eight nodules from 17 patients with CPSS were histologically classified as hepatoblastomas (n=2), hepatocellular carcinomas (n=4), HNF-1α inactivated hepatocellular adenomas (HCAs) (n=2), -catenin-activated HCAs (n=5), unclassified HCAs (n=9), and FNH-like nodules (n=16). CTNNB1 variants were detected in of 26/38 nodules (68%) across different histological categories (2/2 hepatoblastomas, 4/4 HCCs, 10/16 HCAs, 10/16 FNH-like nodules), but not in sporadic FNH or FNH-like nodules (0/10). Less frequent variants were identified in APOB, GNAS, HNF1A, SERPINA1, MAML2, PTCH1, G6PC, KMT2C, DICER1, AXIN1, IL6ST and the promoter region of TERT. Germline variants were identified in AXIN1, HFE, SERPINA1, and ZNF521. CTNNB1 variants affecting amino acid positions 32 and 33 are more common in malignant tumors. Mutated regions in background non-tumoral liver were identified in 2 patients. Multiple CTNNB1 variants were identified in 6/7 (86%) of patients with multiple nodules, but no intra-tumoral variation was found. Discussion CPSS is strongly associated with nodules containing variants in CTNNB1, irrespective of the histological category. Areas in background liver containing these variants were also identified, and different variants could be identified in individual patients. The high proportion of CTNNB1 variants may explain the higher malignant potential of benign tumors found in CPSS.