tbuckley/cabot-search huggingface dataset:
An iron-rich subset of macrophages promotes tumor growth through a Bach1-Ednrb axis
Authors: Ian W. Folkert, William A. Molina Arocho, Tsun Ki Jerrick To, Samir Devalaraja, Irene S. Molina, Jason Shoush, Hesham Mohei, Li Zhai, Md Naushad Akhtar, Veena Kochat, Emre Arslan, Alexander J. Lazar, Khalida Wani, William P. Israel, Zhan Zhang, Venkata S. Chaluvadi, Robert J. Norgard, Ying Liu, Ashley M. Fuller, Mai T. Dang, Robert E. Roses, Giorgos C. Karakousis, John T. Miura, Douglas L. Fraker, T.S. Karin Eisinger-Mathason, M. Celeste Simon, Kristy Weber, Kai Tan, Yi Fan, Kunal Rai, Malay Haldar
Journal: The Journal of Experimental Medicine (2024)

We define a subset of macrophages in the tumor microenvironment characterized by high intracellular iron and enrichment of heme and iron metabolism genes. These iron-rich tumor-associated macrophages (iTAMs) supported angiogenesis and immunosuppression in the tumor microenvironment and were conserved between mice and humans. iTAMs comprise two additional subsets based on gene expression profile and location—perivascular (pviTAM) and stromal (stiTAM). We identified the endothelin receptor type B (Ednrb) as a specific marker of iTAMs and found myeloid-specific deletion of Ednrb to reduce tumor growth and vascular density. Further studies identified the transcription factor Bach1 as a repressor of the iTAM transcriptional program, including Ednrb expression. Heme is a known inhibitor of Bach1, and, correspondingly, heme exposure induced Ednrb and iTAM signature genes in macrophages. Thus, iTAMs are a distinct macrophage subset regulated by the transcription factor Bach1 and characterized by Ednrb-mediated immunosuppressive and angiogenic functions.
Influence of Subclinical Atherosclerosis Burden and Progression on Mortality
Authors: Valentin Fuster, Ana García-Álvarez, Ana Devesa, Virginia Mass, Ruth Owen, Antonio Quesada, José J Fuster, Inés García-Lunar, Stuart Pocock, Javier Sánchez-González, Samantha Sartori, Carlos Peyra, Vicente Andres, Pieter Muntendam, Borja Ibanez
Journal: Journal of the American College of Cardiology (2024)
The impact of the massive open online course C19_SPACE during the COVID-19 pandemic on clinical knowledge enhancement: a study among medical doctors and nurses
Authors: Maurizio Cecconi, Anita Barth, Gergő József Szőllősi, Gizella Melania Istrate, Joel Alexandre, Frantisek Duska, Stefan J Schaller, Carole Boulanger, Johannes Mellinghoff, Peter Waldauf, Armand R J Girbes, Lennie Derde, Jan J De Waele, Elie Azoulay, Jozef Kesecioglu
Journal: Intensive Care Medicine (2024)
The transcription regulators ZNF750 and LSD1/KDM1A dampen inflammation on the skin’s surface by silencing pattern recognition receptors
Authors: Ye Liu, Yifang Chen, Uyanga Batzorig, Jingting Li, Celia Fernández-Méndez, Samiksha Mahapatra, Fengwu Li, Shebin Sam, Tatsuya Dokoshi, Seung-Phil Hong, Teruaki Nakatsuji, Richard L Gallo, George L Sen
Journal: Immunity (2024)

The surface of the skin is continually exposed to pro-inflammatory stimuli; however, it is unclear why it is not constantly inflamed due to this exposure. Here, we showed undifferentiated keratinocytes residing in the deep epidermis could trigger a strong inflammatory response due to their high expression of pattern recognition receptors (PRRs) that detect damage or pathogens. As keratinocytes differentiated, they migrated outward toward the surface of the skin and decreased their PRR expression, which led to dampened immune responses. ZNF750, a transcription factor expressed only in differentiated keratinocytes, recruited the histone demethylase KDM1A/LSD1 to silence genes coding for PRRs (TLR3, IFIH1/MDA5, and DDX58/RIG1). Loss of ZNF750 or KDM1A in human keratinocytes or mice resulted in sustained and excessive inflammation resembling psoriatic skin, which could be restored to homeostatic conditions upon silencing of TLR3. Our findings explain how the skin's surface prevents excessive inflammation through ZNF750- and KDM1A-mediated suppression of PRRs.
Radiotherapy and theranostics: a Lancet Oncology Commission
Authors: May Abdel-Wahab, Francesco Giammarile, Mauro Carrara, Diana Paez, Hedvig Hricak, Nayyereh Ayati, Jing Jing Li, Malina Mueller, Ajay Aggarwal, Akram Al-Ibraheem, Sondos Alkhatib, Rifat Atun, Abubakar Bello, Daniel Berger, Roberto C Delgado Bolton, John M Buatti, Graeme Burt, Olivera Ciraj Bjelac, Lisbeth Cordero-Mendez, Manjit Dosanjh, Thomas Eichler, Elena Fidarova, Soehartati Gondhowiardjo, Mary Gospodarowicz, Surbhi Grover, Varsha Hande, Ekaterina Harsdorf-Enderndorf, Ken Herrmann, Michael S Hofman, Ola Holmberg, David Jaffray, Peter Knoll, Jolanta Kunikowska, Jason S Lewis, Yolande Lievens, Miriam Mikhail-Lette, Dennis Ostwald, Jatinder R Palta, Platon Peristeris, Arthur A Rosa, Soha Ahmed Salem, Marcos A Dos Santos, Mike M Sathekge, Shyam Kishore Shrivastava, Egor Titovich, Jean-Luc Urbain, Verna Vanderpuye, Richard L Wahl, Jennifer S Yu, Mohamed Saad Zaghloul, Hongcheng Zhu, Andrew M Scott
Journal: The Lancet Oncology (2024)
Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection ameliorates secondary influenza A virus disease
Authors: Alexander Lercher, Jin-Gyu Cheong, Michael J Bale, Chenyang Jiang, Hans-Heinrich Hoffmann, Alison W Ashbrook, Tyler Lewy, Yue S Yin, Corrine Quirk, Emma J DeGrace, Luis Chiriboga, Brad R Rosenberg, Steven Z Josefowicz, Charles M Rice
Journal: Immunity (2024)
Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition
Authors: Yu Chang, Xiaoju Wang, Jianzhang Yang, Jean Ching-Yi Tien, Rahul Mannan, Gabriel Cruz, Yuping Zhang, Josh N Vo, Brian Magnuson, Somnath Mahapatra, Hanbyul Cho, Saravana Mohan Dhanasekaran, Cynthia Wang, Zhen Wang, Licheng Zhou, Kaijie Zhou, Yang Zhou, Pujuan Zhang, Weixue Huang, Lanbo Xiao, Weihuang Raymond Liu, Rudana Hamadeh, Fengyun Su, Rui Wang, Stephanie J Miner, Xuhong Cao, Yunhui Cheng, Rohit Mehra, Ke Ding, Arul M Chinnaiyan
Journal: Cell Reports Medicine (2024)

Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells. CDK12/13 degradation rapidly triggers gene-length-dependent transcriptional elongation defects, leading to DNA damage and cell-cycle arrest. In vivo, YJ9069 significantly suppresses prostate tumor growth. Modifications of YJ9069 yielded an orally bioavailable CDK12/13 degrader, YJ1206, which exhibits comparable efficacy with significantly less toxicity. To identify pathways synthetically lethal upon CDK12/13 degradation, phosphorylation pathway arrays were performed using cell lines treated with YJ1206. Interestingly, degradation or genetic knockdown of CDK12/13 led to activation of the AKT pathway. Targeting CDK12/13 for degradation, in conjunction with inhibiting the AKT pathway, resulted in a synthetic lethal effect in preclinical prostate cancer models.
Transcriptomic cell-type specificity of local cortical circuits
Authors: Maribel Patiño, Marley A Rossa, Willian Nuñez Lagos, Neelakshi S Patne, Edward M Callaway
Journal: Neuron (2024)

Complex neocortical functions rely on networks of diverse excitatory and inhibitory neurons. While local connectivity rules between major neuronal subclasses have been established, the specificity of connections at the level of transcriptomic subtypes remains unclear. We introduce single transcriptome assisted rabies tracing (START), a method combining monosynaptic rabies tracing and single-nuclei RNA sequencing to identify transcriptomic cell types, providing inputs to defined neuron populations. We employ START to transcriptomically characterize inhibitory neurons providing monosynaptic input to 5 different layer-specific excitatory cortical neuron populations in mouse primary visual cortex (V1). At the subclass level, we observe results consistent with findings from prior studies that resolve neuronal subclasses using antibody staining, transgenic mouse lines, and morphological reconstruction. With improved neuronal subtype granularity achieved with START, we demonstrate transcriptomic subtype specificity of inhibitory inputs to various excitatory neuron subclasses. These results establish local connectivity rules at the resolution of transcriptomic inhibitory cell types.
Human hippocampus and dorsomedial prefrontal cortex infer and update latent causes during social interaction
Authors: Ali Mahmoodi, Shuyi Luo, Caroline Harbison, Payam Piray, Matthew F S Rushworth
Journal: Neuron (2024)

Latent-cause inference is the process of identifying features of the environment that have caused an outcome. This problem is especially important in social settings where individuals may not make equal contributions to the outcomes they achieve together. Here, we designed a novel task in which participants inferred which of two characters was more likely to have been responsible for outcomes achieved by working together. Using computational modeling, univariate and multivariate analysis of human fMRI, and continuous theta-burst stimulation, we identified two brain regions that solved the task. Notably, as each outcome occurred, it was possible to decode the inference of its cause (the responsible character) from hippocampal activity. Activity in dorsomedial prefrontal cortex (dmPFC) updated estimates of association between cause-responsible character-and the outcome. Disruption of dmPFC activity impaired participants' ability to update their estimate as a function of inferred responsibility but spared their ability to infer responsibility.
Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model
Authors: Gillian K Carling, Li Fan, Nessa R Foxe, Kendra Norman, Man Ying Wong, Daphne Zhu, Carlo Corona, Agnese Razzoli, Fangmin Yu, Allan Yarahmady, Pearly Ye, Hao Chen, Yige Huang, Sadaf Amin, Rebecca Sereda, Chloe Lopez-Lee, Emmanouil Zacharioudakis, Xiaoying Chen, Jielin Xu, Feixiong Cheng, Evripidis Gavathiotis, Ana Maria Cuervo, David M Holtzman, Sue-Ann Mok, Subhash C Sinha, Simone Sidoli, Rajiv R Ratan, Wenjie Luo, Shiaoching Gong, Li Gan
Journal: Neuron (2024)

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2
Metaverse in surgery — origins and future potential
Authors: Enrico Checcucci, Alessandro Veccia, Stefano Puliatti, Pieter De Backer, Pietro Piazza, Karl-Friedrich Kowalewski, Severin Rodler, Mark Taratkin, Ines Rivero Belenchon, Loic Baekelandt, Sabrina De Cillis, Alberto Piana, Ahmed Eissa, Juan Gomez Rivas, Giovanni Cacciamani, Francesco Porpiglia
Journal: Nature Reviews Urology (2024)
Automated patient selection and care coaches to increase advance care planning for cancer patients
Authors: Michael F Gensheimer, Winifred Teuteberg, Manali I Patel, Divya Gupta, Mahjabin Noroozi, Xi Ling, Touran Fardeen, Briththa Seevaratnam, Ying Lu, Nina Alves, Brian Rogers, Mary Khay Asuncion, Jan DeNofrio, Jennifer Hansen, Nigam H Shah, Thomas Chen, Elwyn Cabebe, Douglas W Blayney, Alexander D Colevas, Kavitha Ramchandran
Journal: JNCI Journal of the National Cancer Institute (2024)

Advance care planning/serious illness conversations can help clinicians understand patients' values and preferences. There are limited data on how to increase these conversations, and their effect on care patterns. We hypothesized that using a machine learning survival model to select patients for serious illness conversations, along with trained care coaches to conduct the conversations, would increase uptake in cancer patients at high risk of short-term mortality.
Trends in breast cancer specific death by clinical stage at diagnoses between 2000-2017
Authors: Michal Marczyk, Adriana Kahn, Andrea Silber, Mariya Rosenblit, Michael P Digiovanna, Maryam Lustberg, Lajos Pusztai
Journal: JNCI Journal of the National Cancer Institute (2024)

Approximately 40,000 individuals die from metastatic breast cancer each year. We examined what fractions of annual breast cancer-specific death (BCSD) are due to stage I, II, III, IV disease and if these proportions changed over time.
Numerical Flow Simulations of the Shear Stress Forces Arising in Filtration Slits during Glomerular Filtration in Rat Kidney
Authors: Alexander Fuhrmann, Balazs Pritz, Karlhans Endlich, Wilhelm Kriz
Journal: Journal of the American Society of Nephrology (2024)

Background: The flow dynamic forces during glomerular filtration challenging the fixation of podocytes to the GBM are insufficiently understood. Methods: Numerical flow simulations were used to estimate these forces in the rat kidney. Simulations were run with a 3D model of the slit diaphragm as a zipper structure according to Rodewald and Karnovsky 1 . The GBM was modeled as a porous medium. Results: Filtrate flow exerted a mean wall shear stress of 39 Pa with a maximum of 152 Pa on the plasma membrane of foot processes and up to 250 Pa on internal surfaces of the slit diaphragm. The slit diaphragm accounted for 25% of the hydrodynamic resistance of the glomerular filtration barrier. Based on the results of the 3D model, we developed a 2D model that allowed us to perform extensive parameter variations. Reducing the filtration slit width from 40 to 30 nm almost doubled wall shear stress. Furthermore, increasing filtrate flow velocity by 50% increased wall shear stress by 47%. When increasing the viscous resistance of the slit diaphragm, the pressure drop across the slit diaphragm increased to intolerably high values. A lower viscous resistance of the slit diaphragm than that of the GBM accounted for a gradual pressure decline along the filtration barrier. The sub-podocyte space tempered these challenges in circumscribed areas of filtration surface but had only a marginal impact on overall forces. Conclusions: The filtration barrier experiences high levels of shear and pressure stress accounting for the detachment of injured but viable podocytes from the GBM––a hallmark in many glomerular diseases.
Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation
Authors: Laura P Kincer, Ameet Dravid, Mattia Trunfio, Andrea Calcagno, Shuntai Zhou, Riccardo Vercesi, Serena Spudich, Magnus Gisslen, Richard W Price, Paola Cinque, Sarah B Joseph
Journal: Journal of Clinical Investigation (2024)

During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.
Integrated ubiquitomics characterization of hepatocellular carcinomas
Authors: Xiao-Tong Lin, Yuan-Deng Luo, Cui Mao, Yi Gong, Yu Hou, Lei-Da Zhang, Yong-Peng Gu, Di Wu, Jie Zhang, Yu-Jun Zhang, De-Hong Tan, Chuan-Ming Xie
Journal: Hepatology (2024)

Background and Aims: Patients with aggressive hepatocellular carcinoma (HCC) have limited therapeutic options. Therefore, a better understanding of HCC pathogenesis is needed to improve treatment. Genomic studies of HCC have improved our understanding of cancer biology. However, the ubiquitomic characteristics of HCC remain poorly understood. We aimed to reveal the ubiquitomic characteristics of HCC and provide clinical feature biomarkers of the aggressive HCC that may be used for diagnosis or therapy in the clinic. Approach and Results: The comprehensive proteomic, phosphoproteomic, and ubiquitomic analyses were performed on tumors and adjacent normal liver tissues from 85 HCC patients. HCCs displayed overexpression of drugable targets CBR1-S151 and CPNE1-S55. COL4A1, LAMC1 and LAMA4 were highly expressed in the DFS poor patients. Phosphoproteomic and ubiquitomic features of HCC revealed crosstalk in metabolism and metastasis. Ubiquitomics predicted diverse prognosis and clarified HCC subtype-specific proteomic signatures. Expression of biomarkers TUBA1A, BHMT2, BHMT, and ACY1 exhibited differential ubiquitination levels and displayed high prognostic risk scores, suggesting that targeting these proteins or their modified forms may be beneficial for future clinical treatment. We validated that TUBA1A K370 deubiquitination drove severe HCC and labeled an aggressive subtype of HCCs. TUBA1A K370 deubiquitination was at least partly attributed to AKT-mediated USP14 activation in HCC. Notably, targeting AKT-USP14-TUBA1A complex promoted TUBA1A degradation and blocked liver tumorigenesis in vivo . Conclusions: This study expands our knowledge of ubiquitomic signatures, biomarkers, and potential therapeutic targets in HCC.
IFN-γ and YAP lead epithelial cells astray after severe respiratory infection
Authors: Bradley E Hiller, Joseph P Mizgerd
Journal: Journal of Clinical Investigation (2024)

Ineffective recovery from pneumonia can lead to interstitial lung disease characterized by aberrant epithelial cells in fibrotic regions. In this issue of the JCI, Lin et al. define molecular pathways leading to the development and persistence of keratin 5+ (Krt5+) epithelial cells in the alveolar parenchyma when mice struggle to recover from influenza infection. The receptor for IFN-γ on lung epithelium was essential for the formation of aberrant Krt5+ cells and fibrotic lung disease. The transcription factor Yes-associated protein 1 (YAP) was necessary for persistence of these Krt5+ cells, and IFN-γ activated YAP in lung epithelial cells via JAK, focal adhesion kinase (FAK), and Src kinases. These findings establish a targetable pathway underlying some of the pulmonary postacute sequelae of pneumonia.
Viral infection induces inflammatory signals that coordinate YAP regulation of dysplastic cells in lung alveoli
Authors: Xiuyu Lin, Weicheng Chen, Guilin Yang, Jiazhu Zhang, Huilin Wang, Zeyu Liu, Ying Xi, Tao Ren, Bo Liu, Pengfei Sui
Journal: Journal of Clinical Investigation (2024)

Severe viral pneumonia can induce rapid expansion of KRT5+ basal-like cells in small airways and alveoli; this forms a scar-like structure that persists in the injured alveoli and impedes normal alveolar epithelium regeneration. In this study, we investigated the mechanism by which viral infection induced this remodeling response. Through comparing different lung-injury models, we demonstrated that infection induced strong IFN-γ signal-stimulated dysplastic KRT5+ cell formation. Inactivation of interferon receptor 1 (Ifngr1) reduced dysplastic cell formation, ameliorated lung fibrosis, and improved lung-function recovery. Mechanistically, IFN-γ regulated dysplastic cell formation via the focal adhesion kinase (FAK)/Yes-associated protein 1 (YAP) pathway. Inhibiting FAK/Src diminished IFN-γ-induced YAP nuclear translocation and dysplastic cell formation. Inhibiting YAP during viral infection prevented dysplastic cell formation, whereas inhibiting YAP in persistent KRT5+ cells led to their conversion into distal club cells. Importantly, human dysplastic cells exhibited elevated FAK and YAP activity, and IFN-γ treatment promoted the transformation of human alveolar progenitor cells into dysplastic cells. These findings uncover the role of infection-induced inflammatory response in alveolar remodeling and may provide potential therapeutic avenues for the treatment of alveolar remodeling in patients with severe viral pneumonia.
Ciliary localization of GPR75 promotes fat accumulation in mice
Authors: Marcelo Chávez, Anushweta Asthana, Peter K. Jackson
Journal: Journal of Clinical Investigation (2024)

Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands.
Higher proportion of cellulitis in severe lymphoedema
Authors: James Wall, Melanie Sutherland, Nick J Levell, Zoe C Venables, Khaylen Mistry
Journal: British Journal of Dermatology (2024)

We read with interest the article from Burian et al. which discussed the prevalence and risk factors of cellulitis in chronic leg oedema. We conducted a twelve-year service evaluation at the Norfolk and Norwich University Hospital to investigate the applicability of these results in a real-world setting. Our study found that episodes of cellulitis were more common in patients with more severe lymphoedema, reinforcing the findings of Burian et al. and highlighting the importance of controlling lymphatic swelling to reduce cellulitis risk.
Clonal hematopoiesis and hematological malignancy
Authors: William G Dunn, Matthew A McLoughlin, George S Vassiliou
Journal: Journal of Clinical Investigation (2024)

Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.