tbuckley/cabot-search huggingface dataset:
Phosphate Restriction Prevents Metabolic Acidosis and Curbs Rise in FGF23 and Mortality in Murine Folic Acid–Induced AKI
Authors: Ahmad Kamal Hamid, Eva Maria Pastor Arroyo, Charlotte Calvet, Timothy D. Hewitson, Maria Lavinia Muscalu, Udo Schnitzbauer, Edward R. Smith, Carsten Alexander Wagner, Daniela Egli-Spichtig
Journal: Journal of the American Society of Nephrology (2024)

Significance Statement Patients with AKI suffer a staggering mortality rate of approximately 30%. Fibroblast growth factor 23 (FGF23) and phosphate (P i ) rise rapidly after the onset of AKI and have both been independently associated with ensuing morbidity and mortality. This study demonstrates that dietary P i restriction markedly diminished the early rise in plasma FGF23 and prevented the rise in plasma P i , parathyroid hormone, and calcitriol in mice with folic acid–induced AKI (FA-AKI). Furthermore, the study provides evidence for P i -sensitive osseous Fgf23 mRNA expression and reveals that P i restriction mitigated calciprotein particles (CPPs) formation, inflammation, acidosis, cardiac electrical disturbances, and mortality in mice with FA-AKI. These findings suggest that P i restriction may have a prophylactic potential in patients at risk for AKI. Background In AKI, plasma FGF23 and P i rise rapidly and are independently associated with disease severity and outcome. Methods The effects of normal (NP) and low (LP) dietary P i were investigated in mice with FA-AKI after 3, 24, and 48 hours and 14 days. Results After 24 hours of AKI, the LP diet curbed the rise in plasma FGF23 and prevented that of parathyroid hormone and calcitriol as well as of osseous but not splenic or thymic Fgf23 mRNA expression. The absence of Pth prevented the rise in calcitriol and reduced the elevation of FGF23 in FA-AKI with the NP diet. Furthermore, the LP diet attenuated the rise in renal and plasma IL-6 and mitigated the decline in renal α -Klotho. After 48 hours, the LP diet further dampened renal IL-6 expression and resulted in lower urinary neutrophil gelatinase-associated lipocalin. In addition, the LP diet prevented the increased formation of CPPs. Fourteen days after AKI induction, the LP diet group maintained less elevated plasma FGF23 levels and had greater survival than the NP diet group. This was associated with prevention of metabolic acidosis, hypocalcemia, hyperkalemia, and cardiac electrical disturbances. Conclusions This study reveals P i -sensitive FGF23 expression in the bone but not in the thymus or spleen in FA-AKI and demonstrates that P i restriction mitigates CPP formation, inflammation, acidosis, and mortality in this model. These results suggest that dietary P i restriction could have prophylactic potential in patients at risk for AKI.
Regulation of mast cells by overlapping but distinct protein interactions of Siglec‐6 and Siglec‐8
Authors: Wouter Korver, Zachary Benet, Alan Wong, Gian Luca Negri, Katherine Chang, Robert Sanchez, John Leung, Naomi De Freitas, Thuy Luu, Julia Schanin, Bradford A. Youngblood
Journal: Allergy (2024)

Abstract Background Sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐6 and Siglec‐8 are closely related mast cell (MC) receptors with broad inhibitory activity, but whose functional differences are incompletely understood. Methods Proteomic profiling using quantitative mass spectrometry was performed on primary mouse MCs to identify proteins associated with Siglec‐6 and Siglec‐8. For functional characterization, each receptor was evaluated biochemically and in ex vivo and in vivo inhibition models of IgE and non‐IgE‐mediated MC activation in Siglec‐6‐ or Siglec‐8‐expressing transgenic mice. Results Siglec‐6 and Siglec‐8 were found in MCs within large complexes, interacting with 66 and 86 proteins, respectively. Strikingly, Siglec‐6 and Siglec‐8 interacted with a large cluster of proteins involved in IgE and non‐IgE‐mediated MC activation, including the high affinity IgE receptor, stem cell factor (SCF) receptor KIT/CD117, IL‐4 and IL‐33 receptors, and intracellular kinases LYN and JAK1. Protein interaction networks revealed Siglec‐6 and Siglec‐8 had overlapping yet distinct MC functions, with a potentially broader regulatory role for Siglec‐6. Indeed, Siglec‐6 preferentially interacted with the mature form of KIT at the cell surface, and treatment with an anti‐Siglec‐6 antibody significantly inhibited SCF‐mediated MC activation more in comparison to targeting Siglec‐8. Conclusion These data demonstrate a central role for Siglec‐6 and Siglec‐8 in controlling MC activation through interactions with multiple activating receptors and key signaling molecules. Our findings suggest that Siglec‐6 has a role distinct from that of Siglec‐8 in regulating MC function and represents a distinct potential therapeutic target in mast cell‐driven diseases.
Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs
Authors: Svenja Müller, Laura Maintz, Thomas Bieber
Journal: Allergy (2024)

Atopic dermatitis (AD) represents the most common skin disease characterized by heterogeneous endophenotypes and a high disease burden. In Europe, six new systemic therapies for AD have been approved: the biologics dupilumab (anti-interleukin-4 receptor (IL-4R) α in 2017), tralokinumab (anti-IL-13 in 2021), lebrikizumab (anti-IL-13 in 2023), and the oral janus kinase (JAK) inhibitors (JAKi) targeting JAK1/2 (baricitinib in 2020 in the EU) or JAK1 (upadacitinib in 2021 and abrocitinib in 2022). Herein, we give an update on new approvals, long-term safety, and efficacy. Upadacitinib and abrocitinib have the highest short-term efficacy among the approved systemic therapies. In responders, dupilumab and tralokinumab catch up regarding long-term efficacy and incremental clinical benefit within continuous use. Recently, the European Medicines Agency has released recommendations for the use of JAKi in patients at risk (cardiovascular and thromboembolic diseases, malignancies, (former) smoking, and age ≥65 years). Furthermore, we give an overview on emerging therapies currently in Phase III trials. Among the topical therapies, tapinarof (aryl hydrocarbon receptor), ruxolitinib (JAK1/2i), delgocitinib (pan-JAKi), asivatrep (anti-transient receptor potential vanilloid), and phosphodiesterase-4-inhibitors (roflumilast, difamilast) are discussed. Among systemic therapies, current data on cord-blood-derived mesenchymal stem cells, CM310 (anti IL-4Rα), nemolizumab (anti-IL-31RA), anti-OX40/OX40L-antibodies, neurokinin-receptor-1-antagonists, and difelikefalin (κ-opioid-R) are reported.
Epidemiology of severe childhood asthma in Japan: A nationwide descriptive study
Authors: Yuya Kimura, Maho Suzukawa, Taisuke Jo, Yohei Hashimoto, Ryosuke Kumazawa, Miho Ishimaru, Hiroki Matsui, Akira Yokoyama, Goh Tanaka, Hideo Yasunaga
Journal: Allergy (2024)

The data that support the findings of this study are available from the Ministry of Health, Labour and Welfare, Japan. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of the Ministry of Health, Labour and Welfare, Japan. Appendix S1. Figure S1. Figure S2. Figure S3. Figure S4. Figure S5. Figure S6. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
The Association of Agent Orange Exposure with the progression of monoclonal gammopathy of undetermined significance to multiple myeloma: a population-based study of Vietnam War Era Veterans
Authors: Lawrence W. Liu, Mei Wang, Nikhil Grandhi, Mark A. Schroeder, Theodore Thomas, Kristin Vargo, Feng Gao, Kristen M. Sanfilippo, Su-Hsin Chang
Journal: Journal of Hematology & Oncology (2024)

Abstract Herbicide and pesticide exposure [e.g., agent orange (AO)] is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). However, it is unclear whether TCDD/AO exposure (AO exposure hereafter) increases the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. We sought to evaluate the association in a nationwide study of US Veterans. A natural language processing algorithm was used to confirm MGUS and progression to MM. We included Veterans who were diagnosed with MGUS from 10/1/1999 to 12/31/2021 and served during the Vietnam War Era from 1/9/1962 to 5/7/1975. AO exposure was stratified according to three TCDD exposure levels: high (1/9/1962–11/30/1965), medium (12/1/1965–12/31/1970), or low (1/1/1971–5/7/1975). The association between AO exposure and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. The analytic cohort included 10,847 Veterans with MGUS, of whom 26.3% had AO exposure and 7.4% progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, high exposure was associated with an increased progression rate (multivariable-adjusted hazard ratio 1.48; 95% confidence interval 1.02–2.16), compared to Veterans with no exposure. This information is critical to inform progression risk in patients diagnosed with MGUS and prior AO exposure. It is also applicable to MGUS patients with occupational TCDD exposure from herbicides and pesticides.
Highlighted research articles
Journal: Blood Cancer Discovery (2024)

In This Issue| January 08 2024 Highlighted research articles Author & Article Information Online ISSN: 2643-3249 Print ISSN: 2643-3230 ©2024 American Association for Cancer Research2024American Association for Cancer Research Blood Cancer Discov (2024) 5 (1): 4. https://doi.org/10.1158/2643-3230.BCD-5-1-ITI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record January 8 2024 Citation Highlighted research articles. Blood Cancer Discov 1 January 2024; 5 (1): 4. https://doi.org/10.1158/2643-3230.BCD-5-1-ITI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Both treatment resistance and toxicities remain risks following CAR T-cell therapy for patients with relapsed/refractory large B-cell lymphoma (LBCL). Utilizing the ZUMA-7 dataset, the largest available for CAR T-cell therapy in second-line LBCL, Filosto, Vardhanabhuti et al. report pharmacokinetics, serum pharmacodynamics, and product and apheresis attributes associated with efficacy or high-grade toxicity among patients treated with axicabtagene ciloleucel (axi-cel), including a naive-like (CCR7+CD45RA+) T-cell phenotype associated with better patient outcomes. These findings have implications on clinical practice, including supporting earlier referral of patients with LBCL for CAR T-cell therapy and informing development of next-generation CAR T-cell products. See article, p. 21. Immunomodulatory imide drugs (IMiD) are a staple of myeloma therapy; however, their efficacy is limited by development of resistance. In this issue, Welsh, Barwick et al uncover mechanisms of resistance and a combinatorial therapy approach. IMiDs act by targeting IKZF1 and IKZF3 for degradation. IKZF1/3 transcription factors recruit... You do not currently have access to this content.
Modeling methyl-sensitive transcription factor motifs with an expanded epigenetic alphabet
Authors: Coby Viner, Charles A. Ishak, James Johnson, Nicolas J. Walker, Hui Shi, Marcela K. Sjöberg-Herrera, Shu Yi Shen, Santana M. Lardo, David J. Adams, Anne C. Ferguson-Smith, Daniel D. De Carvalho, Sarah J. Hainer, Timothy L. Bailey, Michael M. Hoffman
Journal: Genome biology (2024)

Abstract Background Transcription factors bind DNA in specific sequence contexts. In addition to distinguishing one nucleobase from another, some transcription factors can distinguish between unmodified and modified bases. Current models of transcription factor binding tend not to take DNA modifications into account, while the recent few that do often have limitations. This makes a comprehensive and accurate profiling of transcription factor affinities difficult. Results Here, we develop methods to identify transcription factor binding sites in modified DNA. Our models expand the standard /// DNA alphabet to include cytosine modifications. We develop Cytomod to create modified genomic sequences and we also enhance the MEME Suite, adding the capacity to handle custom alphabets. We adapt the well-established position weight matrix (PWM) model of transcription factor binding affinity to this expanded DNA alphabet. Using these methods, we identify modification-sensitive transcription factor binding motifs. We confirm established binding preferences, such as the preference of ZFP57 and C/EBPβ for methylated motifs and the preference of c-Myc for unmethylated E-box motifs. Conclusions Using known binding preferences to tune model parameters, we discover novel modified motifs for a wide array of transcription factors. Finally, we validate our binding preference predictions for OCT4 using cleavage under targets and release using nuclease (CUT&amp;RUN) experiments across conventional, methylation-, and hydroxymethylation-enriched sequences. Our approach readily extends to other DNA modifications. As more genome-wide single-base resolution modification data becomes available, we expect that our method will yield insights into altered transcription factor binding affinities across many different modifications.
Neoadjuvant atezolizumab plus chemotherapy in gastric and gastroesophageal junction adenocarcinoma: the phase 2 PANDA trial
Authors: Yara L. Verschoor, Joris van de Haar, José G. van den Berg, Johanna W. van Sandick, Liudmila L. Kodach, Jolanda M. van Dieren, Sara Balduzzi, Cecile Grootscholten, Marieke E. IJsselsteijn, Alexander A. F. A. Veenhof, Koen J. Hartemink, Marieke A. Vollebergh, Adham Jurdi, Shruti Sharma, Erik Spickard, Emilia C. Owers, Annemarieke Bartels-Rutten, Peggy den Hartog, Noel F. C. C. de Miranda, Monique E. van Leerdam, John B. A. G. Haanen, Ton N. Schumacher, Emile E. Voest, Myriam Chalabi
Journal: Nature Medicine (2024)

Abstract Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors ( n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46–88%) patients, including 9 (45%, 95% confidence interval 23–68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1) + CD8 + T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 .
A pairwise cytokine code explains the organism-wide response to sepsis
Authors: Michihiro Takahama, Ashwini Patil, Gabriella Richey, Denis Cipurko, Katherine Johnson, Peter Carbonetto, Madison Plaster, Surya Pandey, Katerina Cheronis, Tatsuki Ueda, Adam Gruenbaum, Tadafumi Kawamoto, Matthew Stephens, Nicolas Chevrier
Journal: Nature Immunology (2024)

Abstract Sepsis is a systemic response to infection with life-threatening consequences. Our understanding of the molecular and cellular impact of sepsis across organs remains rudimentary. Here, we characterize the pathogenesis of sepsis by measuring dynamic changes in gene expression across organs. To pinpoint molecules controlling organ states in sepsis, we compare the effects of sepsis on organ gene expression to those of 6 singles and 15 pairs of recombinant cytokines. Strikingly, we find that the pairwise effects of tumor necrosis factor plus interleukin (IL)-18, interferon-gamma or IL-1β suffice to mirror the impact of sepsis across tissues. Mechanistically, we map the cellular effects of sepsis and cytokines by computing changes in the abundance of 195 cell types across 9 organs, which we validate by whole-mouse spatial profiling. Our work decodes the cytokine cacophony in sepsis into a pairwise cytokine message capturing the gene, cell and tissue responses of the host to the disease.
Vaccines: a promising therapy for myelodysplastic syndrome
Authors: Kriti Gera, Anjali Chauhan, Paul Castillo, Maryam Rahman, Akash Mathavan, Akshay Mathavan, Elizabeth Oganda-Rivas, Leighton Elliott, John R. Wingard, Elias J. Sayour
Journal: Journal of Hematology & Oncology (2024)

Abstract Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole cell-based vaccines and dendritic cell-based vaccines. These therapeutic vaccines have shown acceptable safety profiles, but consistent clinical responses remain elusive despite robust immunological reactions. Combining vaccines with immunotherapeutic agents holds promise and requires further investigation. Herein, we highlight therapeutic vaccine trials while reviewing challenges and future directions of successful vaccination strategies in MDS.
Toripalimab plus nab-paclitaxel in metastatic or recurrent triple-negative breast cancer: a randomized phase 3 trial
Authors: Zefei Jiang, Quchang Ouyang, Tao Sun, Qingyuan Zhang, Yuee Teng, Jiuwei Cui, Haibo Wang, Yongmei Yin, Xiaojia Wang, Xin Zhou, Yongsheng Wang, Gang Sun, Jingfen Wang, Lili Zhang, Jin Yang, Jun Qian, Min Yan, Xinlan Liu, Tienan Yi, Ying Cheng, Man Li, Aimin Zang, Shusen Wang, Chuan Wang, Xinhong Wu, Jing Cheng, Hui Li, Ying Lin, Cuizhi Geng, Kangsheng Gu, Chunwei Xie, Huihua Xiong, Xiaohong Wu, Junlan Yang, Qingshan Li, Yiding Chen, Fanfan Li, Anqin Zhang, Yongqiang Zhang, Yudong Wu, Jianyun Nie, Qiang Liu, Kun Wang, Xueli Mo, Lilin Chen, Yueyin Pan, Peifen Fu, Helong Zhang, Danmei Pang, Yuan Sheng, Yunwei Han, Hongxia Wang, Shundong Cang, Xianming Luo, Wenbo Yu, Rong Deng, Chaoqiang Yang, Patricia Keegan
Journal: Nature Medicine (2024)
Accelerated demand for interpersonal skills in the Australian post-pandemic labour market
Authors: David Evans, Claire Mason, Haohui Chen, Andrew Reeson
Journal: Nature Human Behaviour (2024)

The COVID-19 pandemic has led to a widespread shift to remote work, reducing the level of face-to-face interaction between workers and changing their modes and patterns of communication. This study tests whether this transformation in production processes has been associated with disruptions in the longstanding labour market trend of increasing demand for interpersonal skills. To address this question, we integrate a skills taxonomy with the text of over 12 million Australian job postings to measure skills demand trends at the aggregate and occupational levels. We find that since the start of the pandemic, there has been an acceleration in the aggregate demand for interpersonal skills. We also find a strong positive association between an occupation's propensity for remote work and the acceleration in interpersonal skills demand for the occupation. Our findings suggest that interpersonal skills continue to grow in importance for employment in the post-pandemic, remote work friendly labour market.
Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance
Authors: Xing Zhang, Xiaofeng Ding, Chunqing Wang, Que Le, Dandan Wu, Anying Song, Guixiang Huang, Liping Luo, Yan Luo, Xin Yang, Aleyah E. Goins, Sharina P. Desai, Chengrui Qiu, Floyd D. Silva, Lily Elizabeth Feldman, Jianlin Zhou, Michael F. Spafford, Nathan H. Boyd, Eric R. Prossnitz, Xuexian O. Yang, Qiong A. Wang, Meilian Liu
Journal: Nature Metabolism (2024)
Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer
Authors: Takahiko Murayama, Jun Nakayama, Xinpei Jiang, Kenichi Miyata, Alexander D. Morris, Kathy Q. Cai, Rahul M. Prasad, Xueying Ma, Andrey Efimov, Neel Belani, Emily R. Gerstein, Yinfei Tan, Yan Zhou, William Kim, Reo Maruyama, Kerry S. Campbell, Lu Chen, Yibin Yang, Siddharth Balachandran, Israel Cañadas
Journal: Cancer Discovery (2024)

Abstract Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry,” has emerged as an effective strategy to convert immunologically “cold” tumors into “hot.” Through a curated CRISPR-based screen of RNA helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLC). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage–derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted a decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune-checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other “cold” tumors in which genomic instability contributes to pathology. Significance: One promising strategy to trigger an immune response within tumors and enhance immunotherapy efficacy is by inducing endogenous “virus-mimetic” nucleic acid accumulation. Here, we identify DHX9 as a viral-mimicry-inducing factor involved in the suppression of double-stranded RNAs and R-loops and propose DHX9 as a novel target to enhance antitumor immunity. See related commentary by Chiappinelli, p. 389. This article is featured in Selected Articles from This Issue, p. 384