tbuckley/cabot-search huggingface dataset:
Cancer Therapy and Exercise Intolerance: The Heart Is but a Part
Authors: Hayley T. Dillon, Stephen J. Foulkes, Alan H. Baik, Jessica M. Scott, Rhian M. Touyz, Joerg Herrmann, Mark J. Haykowsky, André La Gerche, Erin J. Howden
Journal: JACC CardioOncology (2024)

The landscape of cancer therapeutics is continually evolving, with successes in improved survivorship and reduced disease progression for many patients with cancer. Improved cancer outcomes expose competing comorbidities, some of which may be exacerbated by cancer therapies. The leading cause of disability and death for many early-stage cancers is cardiovascular disease (CVD), which is often attributed to direct or indirect cardiac injury from cancer therapy. In this review, the authors propose that toxicities related to conventional and novel cancer therapeutics should be considered beyond the heart. The authors provide a framework using the oxygen pathway to understand the impact of cancer treatment on peak oxygen uptake, a marker of integrative cardiopulmonary function and CVD risk. Peripheral toxicities and the impact on oxygen transport are discussed. Consideration for the broad effects of cancer therapies will improve the prediction and identification of cancer survivors at risk for CVD, functional disability, and premature mortality and those who would benefit from therapeutic intervention, ultimately improving patient outcomes.
Macrophage-derived FGFR1 drives atherosclerosis through PLCγ-mediated activation of NF-κB inflammatory signalling pathway
Authors: Lintao Wang, Wu Luo, Suya Zhang, Junsheng Zhang, Lu He, Yifan Shi, Li Gao, Baochuan Wu, Xiaoyan Nie, Chenghong Hu, Xue Han, Chaoyong He, Biao Xu, Guang Liang
Journal: Cardiovascular Research (2024)

Abstract Aims Atherosclerosis (AS) is a leading cause of cardiovascular morbidity and mortality. Atherosclerotic lesions show increased levels of proteins associated with the fibroblast growth factor receptor (FGFR) pathway. However, the functional significance and mechanisms governed by FGFR signalling in AS are not known. In the present study, we investigated fibroblast growth factor receptor 1 (FGFR1) signalling in AS development and progression. Methods and results Examination of human atherosclerotic lesions and aortas of Apoe−/− mice fed a high-fat diet (HFD) showed increased levels of FGFR1 in macrophages. We deleted myeloid-expressed Fgfr1 in Apoe−/− mice and showed that Fgfr1 deficiency reduces atherosclerotic lesions and lipid accumulations in both male and female mice upon HFD feeding. These protective effects of myeloid Fgfr1 deficiency were also observed when mice with intact FGFR1 were treated with FGFR inhibitor AZD4547. To understand the mechanistic basis of this protection, we harvested macrophages from mice and show that FGFR1 is required for macrophage inflammatory responses and uptake of oxidized LDL. RNA sequencing showed that FGFR1 activity is mediated through phospholipase-C-gamma (PLCγ) and the activation of nuclear factor-κB (NF-κB) but is independent of FGFR substrate 2. Conclusion Our study provides evidence of a new FGFR1–PLCγ–NF-κB axis in macrophages in inflammatory AS, supporting FGFR1 as a potentially therapeutic target for AS-related diseases.
Coronary coding in dTGA pre- and post-ASO - verification and necessary corrections following adult CMR
Authors: Hedwig H Hövels-Gürich, Corinna Lebherz, Rosalia Dettori, Andreas Pütz, Anca Racolta, Katharina Linden, Annemarie Kirschfink, Ertunc Altiok, André Rüffer, Nikolaus Marx, Ulrike Herberg, Michael Frick
Journal:  (2024)

In adult patients with transposition of the great arteries (dTGA) after arterial switch operation (ASO), the coronary artery circulation after neonatal surgical transfer remains a major culprit for long-term sequelae, including myocardial ischaemia and sudden cardiac death. As coronary imaging in paediatric age is often incomplete and classification mainly relies on the surgeon's description in the operation report, we intended to develop a systematic, understandable pattern of the coronary status for each young patient, combining unambiguous coding with non-invasive imaging.
Spatially informed gene signatures for response to immunotherapy in melanoma
Authors: Thazin N. Aung, Jonathan Warrell, Sandra Martinez-Morilla, Niki Gavrielatou, Ioannis Vathiotis, Vesal Yaghoobi, Harriet M. Kluger, Mark Gerstein, David L. Rimm
Journal: Clinical Cancer Research (2024)

Abstract Purpose: We aim to improve the prediction of response or resistance to immunotherapies in patients with melanoma. This goal is based on the hypothesis that current gene signatures predicting immunotherapy outcomes show only modest accuracy due to the lack of spatial information about cellular functions and molecular processes within tumors and their microenvironment. Experimental Design: We collected gene expression data spatially from three cellular compartments defined by CD68+ macrophages, CD45+ leukocytes, and S100B+ tumor cells in 55 immunotherapy-treated melanoma specimens using Digital Spatial Profiling–Whole Transcriptome Atlas. We developed a computational pipeline to discover compartment-specific gene signatures and determine if adding spatial information can improve patient stratification. Results: We achieved robust performance of compartment-specific signatures in predicting the outcome of immune checkpoint inhibitors in the discovery cohort. Of the three signatures, the S100B signature showed the best performance in the validation cohort (N = 45). We also compared our compartment-specific signatures with published bulk signatures and found the S100B tumor spatial signature outperformed previous signatures. Within the eight-gene S100B signature, five genes (PSMB8, TAX1BP3, NOTCH3, LCP2, and NQO1) with positive coefficients predict the response, and three genes (KMT2C, OVCA2, and MGRN1) with negative coefficients predict the resistance to treatment. Conclusions: We conclude that the spatially defined compartment signatures utilize tumor and tumor microenvironment–specific information, leading to more accurate prediction of treatment outcome, and thus merit prospective clinical assessment.
Imaging α-synuclein pathologies in animal models and patients with Parkinson’s and related diseases
Authors: Hironobu Endo, Maiko Ono, Yuhei Takado, Kiwamu Matsuoka, Manami Takahashi, Kenji Tagai, Yuko Kataoka, Kosei Hirata, Keisuke Takahata, Chie Seki, Naomi Kokubo, Masayuki Fujinaga, Wakana Mori, Yuji Nagai, Koki Mimura, Katsushi Kumata, Tatsuya Kikuchi, Aki Shimozawa, Sushil K. Mishra, Yoshiki Yamaguchi, Hiroshi Shimizu, Akiyoshi Kakita, Hiroyuki Takuwa, Hitoshi Shinotoh, Hitoshi Shimada, Yasuyuki Kimura, Masanori Ichise, Tetsuya Suhara, Takafumi Minamimoto, Naruhiko Sahara, Kazunori Kawamura, Ming-Rong Zhang, Masato Hasegawa, Makoto Higuchi
Journal: Neuron (2024)

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while in vivo detection of α-synuclein pathologies in these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing α-synuclein deposits in the brains of living subjects. In vivo optical and positron emission tomography (PET) imaging of mouse and marmoset models demonstrated that C05-05 captured a dynamic propagation of fibrillogenesis along neural pathways, followed by disruptions of these structures. High-affinity binding of 18F-C05-05 to α-synuclein aggregates in human brain tissues was also proven by in vitro assays. Notably, PET-detectable 18F-C05-05 signals were intensified in the midbrains of PD and DLB patients as compared with healthy controls, providing the first demonstration of visualizing α-synuclein pathologies in these illnesses. Collectively, we propose a new imaging technology offering neuropathology-based translational assessments of PD and allied disorders toward diagnostic and therapeutic research and development.
In vivo selection in non-human primates identifies AAV capsids for on-target CSF delivery to spinal cord
Authors: Killian S. Hanlon, Ming Cheng, Roberto Montoro Ferrer, Jae Ryun Ryu, Boram Lee, Demitri De La Cruz, Nikita Patel, Paula Espinoza, Miguel C. Santoscoy, Yi Gong, Carrie Ng, Diane M. Nguyen, Josette Nammour, Sean W. Clark, Vivi M. Heine, Woong Sun, Karen Kozarsky, Casey A. Maguire
Journal: Molecular Therapy (2024)

Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal (IT) delivery of AAV vectors into cerebral spinal fluid can avoid many issues, although distribution of the vector throughout the spinal cord is limited, and vector entry to the periphery sometimes initiates hepatotoxicity. Here we performed biopanning in non-human primates (NHPs) with an IT injected AAV9 peptide display library. We identified top candidates by sequencing inserts of AAV DNA isolated from whole tissue, nuclei, or nuclei from transgene-expressing cells. These barcoded candidates were pooled with AAV9 and compared for biodistribution and transgene expression in spinal cord and liver of IT injected NHPs. Most candidates displayed increased retention in spinal cord compared with AAV9. Greater spread from the lumbar to the thoracic and cervical regions was observed for several capsids. Furthermore, several capsids displayed decreased biodistribution to the liver compared with AAV9, providing a high on-target/low off-target biodistribution. Finally, we tested top candidates in human spinal cord organoids and found them to outperform AAV9 in efficiency of transgene expression in neurons and astrocytes. These capsids have potential to serve as leading-edge delivery vehicles for spinal cord-directed gene therapies.
Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice
Authors: Diego Acuña-Catalán, Samah Shah, Cameron Wehrfritz, Mitsunori Nomura, Alejandro Acevedo, Cristina Olmos, Gabriel Quiroz, Hernán Huerta, Joanna Bons, Estibaliz Ampuero, Ursula Wyneken, Magdalena Sanhueza, Felipe Arancibia, Darwin Contreras, Julio César Cárdenas, Bernardo Morales, Birgit Schilling, John C. Newman, Christian González-Billault
Journal: Cell Reports Medicine (2024)

Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age.
A CD36-dependent non-canonical lipid metabolism program promotes immune escape and resistance to hypomethylating agent therapy in AML
Authors: He-Zhou Guo, Rui-Xue Feng, Yan-Jie Zhang, Ye-Hua Yu, Wei Lu, Jia-Jia Liu, Shao-Xin Yang, Chong Zhao, Zhao-Li Zhang, Shan-He Yu, Hui Jin, Si-Xuan Qian, Jian-Yong Li, Jiang Zhu, Jun Shi
Journal: Cell Reports Medicine (2024)

Environmental lipids are essential for fueling tumor energetics, but whether these exogenous lipids transported into cancer cells facilitate immune escape remains unclear. Here, we find that CD36, a transporter for exogenous lipids, promotes acute myeloid leukemia (AML) immune evasion. We show that, separately from its established role in lipid oxidation, CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway, and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MYD88 palmitoylation. Subsequently, NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably, high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling, leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression.
Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Non-smokers and Tobacco Smokers
Authors: Bhavik Dalal, Takeshi Tada, Daxesh P. Patel, Sharon R. Pine, Mohammed Khan, Takahiro Oike, Yasuyuki Kanke, Amelia L. Parker, Majda Haznadar, Leila Toulabi, Kristopher W. Krausz, Ana I. Robles, Elise D. Bowman, Frank J. Gonzalez, Curtis C. Harris
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Nonsmokers account for 10% to 13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose CT (LDCT). Experimental Design: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified using liquid chromatography–mass spectrometry to determine if nonsmoker cases can be distinguished from sex and age-matched controls in comparison with tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening. Results: Urinary levels of CR and NANA were significantly higher and comparable in nonsmokers and tobacco smoker cases than population controls in both cohorts. Receiver operating characteristic analysis for combined CR and NANA levels in nonsmokers of the exploratory cohort resulted in better predictive performance with the AUC of 0.94, whereas the validation cohort nonsmokers had an AUC of 0.80. Kaplan–Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in nonsmokers as well as tobacco smoker cases in both cohorts. Conclusions: Measuring CR and NANA in urine liquid biopsies could identify nonsmokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.
Association Between Microvascular Disease and Cardiorespiratory Fitness Among Adults With Type 2 Diabetes
Authors: Arnaud D. Kaze, Prasanna Santhanam, Rexford S. Ahima, Alain G. Bertoni, Justin B. Echouffo-Tcheugui
Journal: Diabetes Care (2024)

Little is known about the extent to which microvascular disease is associated with cardiorespiratory fitness (CRF) among individuals with type 2 diabetes.
Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery
Authors: Yi Wang, Jing-Song Yang, Min Zhao, Jia-Qi Chen, Hai-Xin Xie, Hao-Yuan Yu, Na-Hui Liu, Zi-Juan Yi, Hui-Lin Liang, Lei Xing, Hu-Lin Jiang
Journal: Advanced Drug Delivery Reviews (2024)
Enhancing efficacy and reducing toxicity: Therapeutic optimization in locoregionally advanced nasopharyngeal carcinoma
Authors: Wei Jiang, Jia Wei Lv, Ling Long Tang, Ying Sun, Yu Pei Chen, Jun Ma
Journal: Cell Reports Medicine (2024)

When applied as the standard therapeutic modality, intensity-modulated radiotherapy (IMRT) improves local control and survival rates in patients with nasopharyngeal carcinoma (NPC). However, distant metastasis continues to be the leading cause of treatment failure. Here, we review the most recent optimization strategies for combining chemotherapy with IMRT in high-risk patients with locoregionally advanced NPC. We focus on major clinical trials on induction chemotherapy and metronomic adjuvant chemotherapy, emphasizing their efficacy in mitigating distant metastasis and prognosis. We also highlight innovations in reducing toxicity in low-risk patients, particularly through approaches of excluding chemotherapy, adopting equivalent low-toxicity drugs, or selectively exempting lymph nodes with low metastatic risk from irradiation. These approaches have provided positive treatment outcomes and significantly enhanced patients' quality of life. Finally, we provide an overview of the evolving immunotherapy landscape, with a focus on the ongoing trials and future potential of immune checkpoint inhibitors in advanced NPC treatment.
An Analysis of <i>PIK3CA</i> Hotspot Mutations and Response to Neoadjuvant Therapy in Patients with Breast Cancer from Four Prospective Clinical Trials
Authors: Paul Jank, Thomas Karn, Marion van Mackelenbergh, Judith Lindner, Denise Treue, Jens Huober, Knut Engels, Christine Solbach, Kurt Diebold, Frederik Marmé, Volkmar Müller, Andreas Schneeweiss, Hans-Peter Sinn, Tanja Fehm, Christian Schem, Elmar Stickeler, Peter Fasching, Jan Budczies, Bärbel Felder, Valentina Nekljudova, Johannes Holtschmidt, Michael Untch, Carsten Denkert, Sibylle Loibl
Journal: Clinical Cancer Research (2024)

The PI3K signaling pathway is frequently dysregulated in breast cancer, and mutations in PIK3CA are relevant for therapy resistance in HER2-positive (HER2pos) breast cancer. Mutations in exons 9 or 20 may have different impacts on response to neoadjuvant chemotherapy-based treatment regimens.
Glycoengineering-based anti-PD-1-iRGD peptide conjugate boosts antitumor efficacy through T cell engagement
Authors: Yunfeng Pan, Qi Xue, Yi Yang, Tao Shi, Hanbing Wang, Xueru Song, Yuting Luo, Wenqi Liu, Shiji Ren, Yiran Cai, Yang Nie, Zhentao Song, Baorui Liu, Jie P. Li, Jia Wei
Journal: Cell Reports Medicine (2024)

Despite the important breakthroughs of immune checkpoint inhibitors in recent years, the objective response rates remain limited. Here, we synthesize programmed cell death protein-1 (PD-1) antibody-iRGD cyclic peptide conjugate (αPD-1-(iRGD)2) through glycoengineering methods. In addition to enhancing tissue penetration, αPD-1-(iRGD)2 simultaneously engages tumor cells and PD-1+ T cells via dual targeting, thus mediating tumor-specific T cell activation and proliferation with mild effects on non-specific T cells. In multiple syngeneic mouse models, αPD-1-(iRGD)2 effectively reduces tumor growth with satisfactory biosafety. Moreover, results of flow cytometry and single-cell RNA-seq reveal that αPD-1-(iRGD)2 remodels the tumor microenvironment and expands a population of "better effector" CD8+ tumor infiltrating T cells expressing stem- and memory-associated genes, including Tcf7, Il7r, Lef1, and Bach2. Conclusively, αPD-1-(iRGD)2 is a promising antibody conjugate therapeutic beyond antibody-drug conjugate for cancer immunotherapy.
Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma
Authors: Ao Chen, Vanilla Xin Zhang, Qingyang Zhang, Karen Man-Fong Sze, Lu Tian, Hongyang Huang, Xia Wang, Eva Lee, Jingyi Lu, Xueying Lyu, Man-Fong Joyce Lee, Chun Ming Wong, Daniel Wai-Hung Ho, Irene Oi-Lin Ng
Journal: Gut (2024)

Fat mass and obesity-associated protein (FTO), an eraser of
Risk of colorectal neoplasia after removal of conventional adenomas and serrated polyps: a comprehensive evaluation of risk factors and surveillance use
Authors: Georgios Polychronidis, Ming-Ming He, Mathew Vithayathil, Markus D Knudsen, Kai Wang, Mingyang Song
Journal: Gut (2024)

Surveillance colonoscopy after polyp removal is recommended to prevent subsequent colorectal cancer (CRC). It is known that advanced adenomas have a substantially higher risk than non-advanced ones, but optimal intervals for surveillance remain unclear.
Effectiveness of mailed outreach and patient navigation to promote HCC screening process completion: a multicentre pragmatic randomised clinical trial
Authors: Amit G Singal, Manasa Narasimman, Darine Daher, Sruthi Yekkaluri, Yan Liu, MinJae Lee, Vanessa Cerda, Aisha Khan, Karim Seif El Dahan, Jennifer Kramer, Purva Gopal, Caitlin Murphy, Ruben Hernaez
Journal: Gut (2024)

Background Hepatocellular carcinoma (HCC) is plagued by failures across the cancer care continuum, leading to frequent late-stage diagnoses and high mortality. We evaluated the effectiveness of mailed outreach invitations plus patient navigation to promote HCC screening process completion in patients with cirrhosis. Methods Between April 2018 and September 2021, we conducted a multicentre pragmatic randomised clinical trial comparing mailed outreach plus patient navigation for HCC screening (n=1436) versus usual care with visit-based screening (n=1436) among patients with cirrhosis at three US health systems. Our primary outcome was screening process completion over a 36-month period, and our secondary outcome was the proportion of time covered (PTC) by screening. All patients were included in intention-to-screen analyses. Results All 2872 participants (median age 61.3 years; 32.3% women) were included in intention-to-screen analyses. Screening process completion was observed in 6.6% (95% CI: 5.3% to 7.9%) of patients randomised to outreach and 3.3% (95% CI: 2.4% to 4.3%) of those randomised to usual care (OR 2.05, 95% CI: 1.44 to 2.92). The intervention increased HCC screening process completion across most subgroups including age, sex, race and ethnicity, Child-Turcotte-Pugh class and health system. PTC was also significantly higher in the outreach arm than usual care (mean 37.5% vs 28.2%; RR 1.33, 95% CI: 1.31 to 1.35). Despite screening underuse, most HCC in both arms were detected at an early stage. Conclusion Mailed outreach plus navigation significantly increased HCC screening process completion versus usual care in patients with cirrhosis, with a consistent effect across most examined subgroups. However, screening completion remained suboptimal in both arms, underscoring a need for more intensive interventions. Trial registration number NCT02582918 .
Value doctors or see NHS crisis worsen, BMA warns in manifesto for next government
Authors: Zosia Kmietowicz
Journal: BMJ (2024)

The next government has no hope of improving the nation's health or providing high quality healthcare if it doesn't look after and retain doctors, the BMA has said in its general election manifesto.1 The result will be an ever deepening NHS crisis. Health must be the first priority of the incoming government, says the association, and it must commit to five key areas:
Sacubitril/Valsartan in Patients With Heart Failure and Deterioration in eGFR to &lt;30 mL/min/1.73 m2
Authors: Safia Chatur, Iris E. Beldhuis, Brian L. Claggett, Finnian R. McCausland, Brendon L. Neuen, Akshay S. Desai, Jean L. Rouleau, Michael R. Zile, Milton Packer, Marc A. Pfeffer, Martin P. Lefkowitz, John J.V. McMurray, Scott D. Solomon, Muthiah Vaduganathan
Journal: JACC Heart Failure (2024)