tbuckley/cabot-search huggingface dataset:
An Activatable Dual Polymer Nanosystem for Photoimmunotherapy and Metabolic Modulation of Deep‐Seated Tumors
Authors: Gengqi Liu, Jiexin Li, Xiaojie Wang, He Ren, Yumiao Zhang
Journal: Advanced Healthcare Materials (2024)

Abstract Nanomedicine in combination with immunotherapy has shown great potential in the cancer treatment, but phototherapeutic nanomaterials that specifically activate the immunopharmacological effects in deep tumors have rarely been developed due to limited laser penetration depth and tumor immune microenvironment. Herein, this work reports a newly synthesized semiconducting polymer (SP) grafted with imiquimod R837 and indoxmid encapsulated micelle (SPRIN‐micelle) with strong absorption in the second near infrared window (NIR‐II) that can relieve tumor immunosuppression and enhance the photothermal immunotherapy and catabolic modulation on tumors. Immune agonists (Imiquimod R837) and immunometabolic modulators (indoxmid) are covalently attached to NIR‐II SP sensors via a glutathione (GSH) responsive self‐immolation linker and then loaded into Pluronic F127 (F127) micelles by a temperature‐sensitive critical micelle concentration (CMC)‐switching method. Using this method, photothermal effect of SPRIN‐micelles in deep‐seated tumors can be activated, leading to effective tumor ablation and immunogenic cell death (ICD). Meanwhile, imiquimod and indoxmid are tracelessly released in response to the tumor microenvironment, resulting in dendritic cell (DC) maturation by imiquimod R837 and inhibition of both indoleamine 2,3‐dioxygenase (IDO) activity and Treg cell expression by indoxmid. Ultimately, cytotoxic T‐lymphocyte infiltration and tumor metastasis inhibition in deep solid tumors (9 mm) are achieved. In summary, this work demonstrates a new strategy for the combination of photothermal immunotherapy and metabolic modulation by developing a dual functional polymer system including activable SP and temperature‐sensitive F127 for the treatment of deep solid tumors.
A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response
Authors: David Wu, Ashley A. Hailer, Sijia Wang, Michelle Yuan, Jamie Chan, Abdullah El Kurdi, David Han, Hira Ali, Blaize D’Angio, Aaron Mayer, Maha Rahim, Ayano Kondo, Daniel Klufas, Esther Kim, A. Hunter Shain, Jaehyuk Choi, Tina Bhutani, Gregory Simpson, Roy C. Grekin, Roberto Ricardo-Gonzalez, Elizabeth Purdom, Jeffrey P. North, Jeffrey B. Cheng, Raymond J. Cho
Journal: Science Immunology (2024)

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17–producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade–responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of &gt;90% of IL-17–induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.
Mis-spliced transcripts generate de novo proteins in TDP-43–related ALS/FTD
Authors: Sahba Seddighi, Yue A. Qi, Anna-Leigh Brown, Oscar G. Wilkins, Colleen Bereda, Cedric Belair, Yong-Jie Zhang, Mercedes Prudencio, Matthew J. Keuss, Aditya Khandeshi, Sarah Pickles, Sarah E. Kargbo-Hill, James Hawrot, Daniel M. Ramos, Hebao Yuan, Jessica Roberts, Erika Kelmer Sacramento, Syed I. Shah, Mike A. Nalls, Jennifer M. Colón-Mercado, Joel F. Reyes, Veronica H. Ryan, Matthew P. Nelson, Casey N. Cook, Ziyi Li, Laurel Screven, Justin Y. Kwan, Puja R. Mehta, Matteo Zanovello, Martina Hallegger, Anantharaman Shantaraman, Lingyan Ping, Yuka Koike, Björn Oskarsson, Nathan P. Staff, Duc M. Duong, Aisha Ahmed, Maria Secrier, Jernej Ule, Steven Jacobson, Daniel S. Reich, Jonathan D. Rohrer, Andrea Malaspina, Dennis W. Dickson, Jonathan D. Glass, Alessandro Ori, Nicholas T. Seyfried, Manolis Maragkakis, Leonard Petrucelli, Pietro Fratta, Michael E. Ward
Journal: Science Translational Medicine (2024)

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.
Sulfated bile acid is a host-derived ligand for MAIT cells
Authors: Emi Ito, Shinsuke Inuki, Yoshihiro Izumi, Masatomo Takahashi, Yuki Dambayashi, Lisa Ciacchi, Wael Awad, Ami Takeyama, Kensuke Shibata, Shotaro Mori, Jeffrey Y. W. Mak, David P. Fairlie, Takeshi Bamba, Eri Ishikawa, Masamichi Nagae, Jamie Rossjohn, Sho Yamasaki
Journal: Science Immunology (2024)

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize bacterial riboflavin–based metabolites as activating antigens. Although MAIT cells are found in tissues, it is unknown whether any host tissue–derived antigens exist. Here, we report that a sulfated bile acid, cholic acid 7-sulfate (CA7S), binds the nonclassical MHC class I protein MR1 and is recognized by MAIT cells. CA7S is a host-derived metabolite whose levels were reduced by more than 98% in germ-free mice. Deletion of the sulfotransferase 2a family of enzymes ( Sult2a1-8 ) responsible for CA7S synthesis reduced the number of thymic MAIT cells in mice. Moreover, recognition of CA7S induced MAIT cell survival and the expression of a homeostatic gene signature. By contrast, recognition of a previously described foreign antigen, 5-(2-oxopropylideneamino)-6- d -ribitylaminouracil (5-OP-RU), drove MAIT cell proliferation and the expression of inflammatory genes. Thus, CA7S is an endogenous antigen for MAIT cells, which promotes their development and function.
Exosomes miRNA-499a-5p targeted CD38 to alleviate anthraquinone induced cardiotoxicity: experimental research
Authors: Chunhua Ma, Zhaocong Yang, Jing Wang, Han She, Lei Tan, Qing Ye, Fei Wang, Xiaochun Feng, Xuming Mo, Kun Liu, Liangming Liu
Journal: International Journal of Surgery (2024)

Background: The purpose of this study was to investigate the effects of cardiac homing peptide (CHP) engineered bone marrow mesenchymal stem cells (BMMSc) derived exosomes (B-exo) loaded miRNA-499a-5p on doxorubicin (DOX) induced cardiotoxicity. Methods: miRNA chip analysis was used to analyze the differences between DOX induced H9c2 cells and control group. CHP engineering was performed on BMMSc derived exosomes to obtain C-B-exo. miRNA-499a-5p mimic was introduced into C-B-exo by electroporation technology to obtain C-B-exo-miRNA-499a-5p. DOX was used to establish a model of cardiotoxicity to evaluate the effects of C-B-exo- miRNA-499a-5p in vivo and in vitro . Western blot, immunohistochemistry, immunofluorescence, and other molecular biology methods were used to evaluate the role and mechanism of C-B-exo-miRNA-499a-5p on DOX induced cardiotoxicity. Results: miRNA chip analysis revealed that miRNA-499a-5p was one of the most differentially expressed miRNAs and significantly decreased in DOX induced H9c2 cells as compared to the control group. Exo-and B-exo have a double-layer membrane structure in the shape of a saucer. After engineering the CHP of B-exo, the results showed that the delivery of miRNA-499a-5p significantly increased and significantly reached the target organ (heart). The experimental results showed that C-B-exo-miRNA-499a-5p significantly improved electrocardiogram, decreased myocardial enzyme, serum and cardiac cytokines, improved cardiac pathological changes, inhibited CD38/MAPK/NF-κB signal pathway. Conclusions: In this study, C-B-exo-miRNA-499a-5p significantly improved DOX-induced cardiotoxicity via CD38/MAPK/NF-κB signal pathway, providing a new idea and method for the treatment of DOX induced cardiotoxicity.
Intraepithelial Lymphocytes of the Intestine
Authors: Ainsley Lockhart, Daniel Mucida, Angelina M. Bilate
Journal: Annual Review of Immunology (2024)

The intestinal epithelium, which segregates the highly stimulatory lumen from the underlying tissue, harbors one of the largest lymphocyte populations in the body, intestinal intraepithelial lymphocytes (IELs). IELs must balance tolerance, resistance, and tissue protection to maintain epithelial homeostasis and barrier integrity. This review discusses the ontogeny, environmental imprinting, T cell receptor (TCR) repertoire, and function of intestinal IELs. Despite distinct developmental pathways, IEL subsets share core traits including an epithelium-adapted profile, innate-like properties, cytotoxic potential, and limited TCR diversity. IELs also receive important developmental and functional cues through interactions with epithelial cells, microbiota, and dietary components. The restricted TCR diversity of IELs suggests that a limited set of intestinal antigens drives IEL responses, with potential functional consequences. Finally, IELs play a key role in promoting homeostatic immunity and epithelial barrier integrity but can become pathogenic upon dysregulation. Therefore, IELs represent intriguing but underexamined therapeutic targets for inflammatory diseases and cancer.
When I use a word . . . Diphthongs and digraphs
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

A diphthong consists of a set of any number of vowels that together sound like two vowels, in contrast to a monophthong, which sounds like one vowel, and a triphthong, which sounds like three. The numbers of vowels in each form are irrelevant. A digraph, on the other hand, is simply a combination of two letters, which can be consonants or vowels and which, if the latter, can be pronounced as a single vowel or more than one. One of the major differences between British English and American English arises when digraphs such as <i>ae</i> and <i>oe</i>, which are monophthongs and not diphthongs, are replaced by the letter <i>e</i>, in words such as anaemia, anaesthesia, and haematology, oedema, oesophagus, and oestrogen. These changes lead to increased consistency of spelling, but are largely reviled among speakers of British English. Hypercorrection can occur when an <i>e</i> is mistakenly thought to represent <i>ae</i> or <i>oe</i>.
Virus-reactive T cells expanded in aplastic anemia eliminate hematopoietic progenitor cells by molecular mimicry
Authors: Amin Ben Hamza, Carlotta Welters, Serena Stadler, Monika Brüggemann, Kerstin Dietze, Olaf Brauns, Tim H. Brümmendorf, Thomas Winkler, Lars Bullinger, Thomas Blankenstein, Leonie Rosenberger, Matthias Leisegang, Thomas Kammertöns, Wolfgang Herr, Andreas Moosmann, Julian Strobel, Holger Hackstein, Klaus Dornmair, Fabian Beier, Leo Hansmann
Journal: Blood (2024)
A Novel Variant in the <i>WRN</i> Gene Detected in a Case of Early-Onset Severe Insulin Resistance Displaying Some but Not All Hallmarks of Progeroid Werner Syndrome
Authors: Dominik Spira, Susanne Herbst, Sarina Schwartzmann, Véronique Dutrannoy, Elisabeth Steinhagen-Thiessen, Ilja Demuth, Lukas Maurer, Knut Mai, Joachim Spranger, Stefan Mundlos, Thomas Bobbert
Journal: Diabetes Care (2024)

Determining the cause of severe insulin resistance and early-onset diabetes in the case of a young woman in which a wide range of differential diagnoses did not apply.
Artificial Cells and HepG2 Cells in 3D‐Bioprinted Arrangements
Authors: Isabella N. Westensee, Lars J.M.M. Paffen, Stefan Pendlmayr, Paula De Dios Andres, Miguel A. Ramos Docampo, Brigitte Städler
Journal: Advanced Healthcare Materials (2024)

Abstract Artificial cells are engineered units with cell‐like functions for different purposes including acting as supportive elements for mammalian cells. Artificial cells with minimal liver‐like function are made of alginate and equipped with metalloporphyrins that mimic the enzyme activity of a member of the cytochrome P450 family namely CYP1A2. The artificial cells are employed to enhance the dealkylation activity within 3D bioprinted structures composed of HepG2 cells and these artificial cells. This enhancement is monitored through the conversion of resorufin ethyl ether to resorufin. HepG2 cell aggregates are 3D bioprinted using an alginate/gelatin methacryloyl ink, resulting in the successful proliferation of the HepG2 cells. The composite ink made of an alginate/gelatin liquid phase with an increasing amount of artificial cells is characterized. The CYP1A2‐like activity of artificial cells is preserved over at least 35 days, where 6 nM resorufin is produced in 8 h. Composite inks made of artificial cells and HepG2 cell aggregates in a liquid phase are used for 3D bioprinting. The HepG2 cells proliferate over 35 days, and the structure has boosted CYP1A2 activity. The integration of artificial cells and their living counterparts into larger 3D semi‐synthetic tissues is a step towards exploring bottom‐up synthetic biology in tissue engineering.
Systemic Immune Modulation by Gastrointestinal Nematodes
Authors: Darshan N. Kasal, Lindsey M. Warner, Astra S. Bryant, Elia Tait Wojno, Jakob von Moltke
Journal: Annual Review of Immunology (2024)

Gastrointestinal nematode (GIN) infection has applied significant evolutionary pressure to the mammalian immune system and remains a global economic and human health burden. Upon infection, type 2 immune sentinels activate a common antihelminth response that mobilizes and remodels the intestinal tissue for effector function; however, there is growing appreciation of the impact GIN infection also has on the distal tissue immune state. Indeed, this effect is observed even in tissues through which GINs never transit. This review highlights how GIN infection modulates systemic immunity through (
Graded exercise therapy should not be recommended for patients with post-exertional malaise
Authors: Femke Christina Ching-Chuan van Rhijn-Brouwer, Merel Hellemons, Michael Stingl, Kathryn Hoffmann, Joanne VanDerNagel, Todd E. Davenport, Eva Untersmayr, Carmen Scheibenbogen, David Putrino
Journal: Nature Reviews Cardiology (2024)
Multi-omics Analysis Reveals Immune Features Associated with Immunotherapy Benefit in Patients with Squamous Cell Lung Cancer from Phase III Lung-MAP S1400I Trial
Authors: Edwin Roger Parra, Jiexin Zhang, Dzifa Yawa Duose, Edgar Gonzalez-Kozlova, Mary W. Redman, Hong Chen, Ganiraju C. Manyam, Gayatri Kumar, Jianhua Zhang, Xingzhi Song, Rossana Lazcano, Mario L. Marques-Piubelli, Caddie Laberiano-Fernandez, Frank Rojas, Baili Zhang, Len Taing, Aashna Jhaveri, Jacob Geisberg, Jennifer Altreuter, Franziska Michor, James Provencher, Joyce Yu, Ethan Cerami, Radim Moravec, Kasthuri Kannan, Rajyalakshmi Luthra, Gheath Alatrash, Hsin-Hui Huang, Hui Xie, Manishkumar Patel, Kai Nie, Jocelyn Harris, Kimberly Argueta, James Lindsay, Roshni Biswas, Stephen Van Nostrand, Seunghee Kim-Schulze, Jhanelle E. Gray, Roy S. Herbst, Ignacio I. Wistuba, Scott Gettinger, Karen Kelly, Lyudmila Bazhenova, Sacha Gnjatic, J. Jack Lee, Jianjun Zhang, Cara Haymaker
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Identifying molecular and immune features to guide immune checkpoint inhibitor (ICI)-based regimens remains an unmet clinical need. Experimental Design: Tissue and longitudinal blood specimens from phase III trial S1400I in patients with metastatic squamous non–small cell carcinoma (SqNSCLC) treated with nivolumab monotherapy (nivo) or nivolumab plus ipilimumab (nivo+ipi) were subjected to multi-omics analyses including multiplex immunofluorescence (mIF), nCounter PanCancer Immune Profiling Panel, whole-exome sequencing, and Olink. Results: Higher immune scores from immune gene expression profiling or immune cell infiltration by mIF were associated with response to ICIs and improved survival, except regulatory T cells, which were associated with worse overall survival (OS) for patients receiving nivo+ipi. Immune cell density and closer proximity of CD8+GZB+ T cells to malignant cells were associated with superior progression-free survival and OS. The cold immune landscape of NSCLC was associated with a higher level of chromosomal copy-number variation (CNV) burden. Patients with LRP1B-mutant tumors had a shorter survival than patients with LRP1B-wild-type tumors. Olink assays revealed soluble proteins such as LAMP3 increased in responders while IL6 and CXCL13 increased in nonresponders. Upregulation of serum CXCL13, MMP12, CSF-1, and IL8 were associated with worse survival before radiologic progression. Conclusions: The frequency, distribution, and clustering of immune cells relative to malignant ones can impact ICI efficacy in patients with SqNSCLC. High CNV burden may contribute to the cold immune microenvironment. Soluble inflammation/immune-related proteins in the blood have the potential to monitor therapeutic benefit from ICI treatment in patients with SqNSCLC.
Development of a [89Zr]Zr-labeled Human Antibody using a Novel Phage-displayed Human scFv Library
Authors: Abhay K. Singh, Calvin D. Lewis, Cristian A.W.V. Boas, Philipp Diebolder, Prashant N. Jethva, Aaron Rhee, Jong Hee Song, Young Ah Goo, Shunqian Li, Michael L. Nickels, Yongjian Liu, Buck E. Rogers, Vaishali Kapoor, Dennis E. Hallahan
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Tax-interacting protein 1 (TIP1) is a cancer-specific radiation-inducible cell surface antigen that plays a role in cancer progression and resistance to therapy. This study aimed to develop a novel anti-TIP1 human antibody for noninvasive PET imaging in patients with cancer. Experimental Design: A phage-displayed single-chain variable fragment (scFv) library was created from healthy donors’ blood. High-affinity anti-TIP1 scFvs were selected from the library and engineered to human IgG1. Purified Abs were characterized by size exclusion chromatography high-performance liquid chromatography (SEC-HPLC), native mass spectrometry (native MS), ELISA, BIAcore, and flow cytometry. The labeling of positron emitter [89Zr]Zr to the lead Ab, L111, was optimized using deferoxamine (DFO) chelator. The stability of [89Zr]Zr-DFO-L111 was assessed in human serum. Small animal PET studies were performed in lung cancer tumor models (A549 and H460). Results: We obtained 95% pure L111 by SEC-HPLC. Native MS confirmed the intact mass and glycosylation pattern of L111. Conjugation of three molar equivalents of DFO led to the optimal DFO-to-L111 ratio of 1.05. Radiochemical purity of 99.9% and specific activity of 0.37 MBq/μg was obtained for [89Zr]Zr-DFO-L111. [89Zr]Zr-DFO-L111 was stable in human serum over 7 days. The immunoreactive fraction in cell surface binding studies was 96%. In PET, preinjection with 4 mg/kg cold L111 before [89Zr]Zr-DFO-L111 (7.4 MBq; 20 μg) significantly (P &amp;lt; 0.01) enhanced the tumor-to-muscle standard uptake values (SUVmax) ratios on day 5 compared with day 2 postinjection. Conclusions: L111 Ab targets lung cancer cells in vitro and in vivo. [89Zr]Zr-DFO-L111 is a human antibody that will be evaluated in the first in-human study of safety and PET imaging.
Gut Microbiome Mediates Ferroptosis Resistance for Colorectal Cancer Development
Authors: Ruoxi Zhang, Rui Kang, Daolin Tang
Journal: Cancer Research (2024)

Abstract Colorectal cancer is a prevalent cancer type in the United States, affecting both genders and influenced by genetics and environmental factors. The role of the gut microbiome in colorectal cancer development and therapy response is a burgeoning field of study. A recent study uncovered that trans-3-indoleacrylic acid (IDA), a microbial metabolite from P. anaerobius, promotes colorectal cancer by inhibiting ferroptosis, a type of nonapoptotic cell death driven by unrestricted lipid peroxidation and subsequent membrane damage. IDA activates aryl hydrocarbon receptor (AHR), a nuclear transcription factor, leading to the expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3). ALDH1A3, known for aldehyde detoxification, also contributes to ferroptosis resistance by generating reduced nicotinamide adenine dinucleotide (NADH), critical for the synthesis of reduced coenzyme Q10 (COQH10), by apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1). Knocking out AHR, AIFM2, or ALDH1A3 reverses the inhibitory effect of IDA on ferroptosis and IDA-mediated tumor growth. Significantly, P. anaerobius is enriched in patients with colorectal cancer, and supplementing IDA or P. anaerobius accelerates colorectal cancer progression in spontaneous or orthotopic mouse models. Taken together, these findings suggest that targeting P. anaerobius–mediated ferroptosis resistance emerges as a promising strategy to combat colorectal cancer development.