tbuckley/cabot-search huggingface dataset:
Exploring the role of cytokeratin-17 in skin tumourigenesis and HPV persistence
Authors: Marianne de Brito, Edel A O’Toole
Journal: British Journal of Dermatology (2024)

Journal Article Corrected proof Exploring the role of cytokeratin 17 in skin tumorigenesis and human papillomavirus persistence Get access Marianne de Brito, Marianne de Brito Conceptualization, Data curation, Writing - original draft, Writing - review & editing Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University London https://orcid.org/0000-0002-4156-8634 Search for other works by this author on: Oxford Academic Google Scholar Edel A O'Toole Edel A O'Toole Conceptualization, Data curation, Supervision, Writing - review & editing Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University London Correspondence: Edel A. O'Toole. Email: e.a.otoole@qmul.ac.uk https://orcid.org/0000-0002-4084-4836 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae294, https://doi.org/10.1093/bjd/ljae294 Published: 25 July 2024 Article history Received: 09 July 2024 Accepted: 11 July 2024 Published: 25 July 2024 Corrected and typeset: 20 August 2024
IgG replacement in multiple myeloma
Authors: Alex Wonnaparhown, Talal Hilal, Jacqueline Squire, Catherine Freeman, Rafael Fonseca
Journal: Blood Cancer Journal (2024)

T cell engagers (TCE) such as chimeric antigen receptor (CAR) T cell therapy and bispecific antibodies (BiAbs) for the treatment of multiple myeloma (MM) have significantly improved clinical outcomes, but have also raised awareness for ensuing post-treatment secondary immunodeficiency and hypogammaglobulinemia (HG). As patients with MM live longer, recurrent infections become a significant component of therapy-associated morbidity and mortality. Treatment of HG with immunoglobulin G replacement therapy (IgG-RT) has been a mainstay of the primary immunodeficiency (PI) world, and extrapolation to MM has recently started to show promising clinical outcomes. However, IgG-RT initiation, dosing, route, timing, monitoring, and management in MM has not been standardized in the setting of TCE. Progress in MM treatment will involve greater recognition and screening of underlying secondary immunodeficiency, identification of risk-stratification markers, optimizing IgG-RT management, and implementing other approaches to decrease the risk of infection. In this review, we summarize infection risk, risk of HG, and management strategies for IgG-RT in patients with relapsed MM after TCE.
The m6A methyltransferase METTL14 promotes cell proliferation via SETBP1-mediated activation of PI3K-AKT signaling pathway in myelodysplastic neoplasms
Authors: Lingxu Jiang, Yudi Zhang, Jiejing Qian, Xinping Zhou, Liya Ma, Shuanghong Zhu, Lu Wang, Wei Wang, Wenli Yang, Yingwan Luo, Wei Lang, Gaixiang Xu, Yanling Ren, Chen Mei, Li Ye, Qi Zhang, Xiaozhen Liu, Jie Jin, Jie Sun, Hongyan Tong
Journal: Leukemia (2024)

Abstract N6-methyladenosine (m 6 A) is the most prevalent epitranscriptomic modification in mammalian mRNA. Recent studies have revealed m 6 A is involved in the pathogenesis of various malignant tumors including hematologic neoplasms. Nevertheless, the specific roles of m 6 A modification and m 6 A regulators in myelodysplastic neoplasms (MDS) remain poorly understood. Herein, we demonstrated that m 6 A level and the expression of m 6 A methyltransferase METTL14 were elevated in MDS patients with bone marrow blasts ≥5%. Additionally, m 6 A level and METTL14 expression were upregulated as the disease risk increased and significantly associated with adverse clinical outcomes. Knockdown of METTL14 inhibited cell proliferation and colony formation ability of MDS cells. Moreover, in vivo experiments showed METTL14 knockdown remarkably reduced tumor burden and prolonged the survival of mice. Mechanistically, METTL14 facilitated the m 6 A modification of SETBP1 mRNA by formation of METTL3-METTL14 complex, leading to increased stabilization of SETBP1 mRNA and subsequent activation of the PI3K-AKT signaling pathway. Overall, this study elucidated the involvement of the METTL14/m 6 A/SETBP1/PI3K-AKT signaling axis in MDS, highlighting the therapeutic potential of targeting METTL3-METTL14 complex-mediated m 6 A modification for MDS therapy.
Supervised, structured and individualized exercise in metastatic breast cancer: a randomized controlled trial
Authors: Anouk E. Hiensch, Johanna Depenbusch, Martina E. Schmidt, Evelyn M. Monninkhof, Mireia Pelaez, Dorothea Clauss, Nadira Gunasekara, Philipp Zimmer, Jon Belloso, Mark Trevaskis, Helene Rundqvist, Joachim Wiskemann, Jana Müller, Maike G. Sweegers, Carlo Fremd, Renske Altena, Maciej Gorecki, Rhodé Bijlsma, Lobke van Leeuwen-Snoeks, Daan ten Bokkel Huinink, Gabe Sonke, Ainhara Lahuerta, G. Bruce Mann, Prudence A. Francis, Gary Richardson, Wolfram Malter, Elsken van der Wall, Neil K. Aaronson, Elzbieta Senkus, Ander Urruticoechea, Eva M. Zopf, Wilhelm Bloch, Martijn M. Stuiver, Yvonne Wengstrom, Karen Steindorf, Anne M. May
Journal: Nature Medicine (2024)

Abstract Physical exercise both during and after curative cancer treatment has been shown to reduce side effects. Evidence in the metastatic cancer setting is scarce, and interventions that improve health-related quality of life (HRQOL) are much needed for patients with metastatic breast cancer (MBC). The multinational randomized controlled PREFERABLE-EFFECT trial assessed the effects of exercise on fatigue and HRQOL in patients with MBC. In total, 357 patients with MBC and a life expectancy of ≥6 months but without unstable bone metastases were recruited at eight study centers across five European countries and Australia. Participants were randomly assigned (1:1) to usual care (control group, n = 179) or a 9-month supervised exercise program (exercise group, n = 178). Intervention effects on physical fatigue (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-FA12 scale) and HRQOL (EORTC QLQ-C30 summary score) were determined by comparing the change from baseline to 3, 6 (primary timepoint) and 9 months between groups using mixed models for repeated measures, adjusted for baseline values of the outcome, line of treatment (first or second versus third or higher) and study center. Exercise resulted in significant positive effects on both primary outcomes. Physical fatigue was significantly lower (−5.3 (95% confidence interval (CI), −10.0 to −0.6), Bonferroni–Holm-adjusted P = 0.027; Cohen's effect size, 0.22) and HRQOL significantly higher (4.8 (95% CI, 2.2–7.4), Bonferroni–Holm-adjusted P = 0.0003; effect size, 0.33) in the exercise group than in the control group at 6 months. Two serious adverse events occurred (that is, fractures), but both were not related to bone metastases. These results demonstrate that supervised exercise has positive effects on physical fatigue and HRQOL in patients with MBC and should be recommended as part of supportive care. ClinicalTrials.gov Identifier: NCT04120298 .
Gut microbial features and circulating metabolomic signatures of frailty in older adults
Authors: Yanni Pu, Zhonghan Sun, Hui Zhang, Qingxia Huang, Zhengdong Wang, Zhendong Mei, Peilu Wang, Mengmeng Kong, Wenjun Yang, Chenhao Lin, Xiaofeng Zhou, Shuchun Lin, Qiumin Huang, Lili Huang, Liang Sun, Changzheng Yuan, Qian Xu, Huiru Tang, Xiaofeng Wang, Yan Zheng
Journal: Nature Aging (2024)
Influence of believed AI involvement on the perception of digital medical advice
Authors: Moritz Reis, Florian Reis, Wilfried Kunde
Journal: Nature Medicine (2024)

Abstract Large language models offer novel opportunities to seek digital medical advice. While previous research primarily addressed the performance of such artificial intelligence (AI)-based tools, public perception of these advancements received little attention. In two preregistered studies ( n = 2,280), we presented participants with scenarios of patients obtaining medical advice. All participants received identical information, but we manipulated the putative source of this advice (‘AI’, ‘human physician’, ‘human + AI’). ‘AI’- and ‘human + AI’-labeled advice was evaluated as significantly less reliable and less empathetic compared with ‘human’-labeled advice. Moreover, participants indicated lower willingness to follow the advice when AI was believed to be involved in advice generation. Our findings point toward an anti-AI bias when receiving digital medical advice, even when AI is supposedly supervised by physicians. Given the tremendous potential of AI for medicine, elucidating ways to counteract this bias should be an important objective of future research.
SonicParanoid2: fast, accurate, and comprehensive orthology inference with machine learning and language models
Authors: Salvatore Cosentino, Sira Sriswasdi, Wataru Iwasaki
Journal: Genome biology (2024)

Accurate inference of orthologous genes constitutes a prerequisite for comparative and evolutionary genomics. SonicParanoid is one of the fastest tools for orthology inference; however, its scalability and accuracy have been hampered by time-consuming all-versus-all alignments and the existence of proteins with complex domain architectures. Here, we present a substantial update of SonicParanoid, where a gradient boosting predictor halves the execution time and a language model doubles the recall. Application to empirical large-scale and standardized benchmark datasets shows that SonicParanoid2 is much faster than comparable methods and also the most accurate. SonicParanoid2 is available at https://gitlab.com/salvo981/sonicparanoid2 and https://zenodo.org/doi/10.5281/zenodo.11371108 .
Anti‐TNF therapy impairs both short‐ and long‐term IgG responses after repeated vaccination
Authors: Jana Sophia Buhre, Tamas Pongracz, Ulf Martin Geisen, Mareike Schubert, Wenjun Wang, Jan Nouta, Maureen Obara, Selina Lehrian, Johann Rahmöller, Janina Petry, Florian Tran, Stefan Schreiber, Melike Sümbül, Dennis Berner, Sascha Gerdes, Jan Schirmer, Ann Carolin Longardt, Paula Hoff, Ulrich Kalinke, Ralf J. Ludwig, Yannic C. Bartsch, Bimba F. Hoyer, Manfred Wuhrer, Marc Ehlers
Journal: Allergy (2024)

Recently, it has been questioned whether vaccination of patients with inflammatory (auto)immune diseases under anti-tumor necrosis factor (TNF) treatment leads to impaired vaccine-induced immune responses and protection against breakthrough infections. However, the effects of TNF blockade on short- and long-term immune responses after repeated vaccination remain unclear. Vaccination studies have shown that initial short-term IgG antibodies (Abs) carry highly galactosylated and sialylated Fc glycans, whilst long-term IgG Abs have low levels of galactosylation and sialylation and are most likely generated by long-lived plasma cells (PCs) derived primarily from the germinal center (GC) response. Thus, IgG Fc glycosylation patterns may be applicable to distinguish short- and long-term vaccine responses after repeated vaccination under the influence of anti-TNF treatment. We used COVID-19 vaccination as a model to investigate vaccine-induced IgG subclass levels and Fc glycosylation patterns, B cell subsets, and effector functions of short- and long-term Ab responses after up to three vaccinations in patients on anti-TNF or other immunosuppressive treatments and in healthy individuals. Using TriNetX, a global healthcare database, we determined the risk of SARS-CoV-2 breakthrough infections in vaccinated patients treated with anti-TNF or other immunosuppressive drugs. Anti-TNF treatment reduced the long-term abundance of all anti-S IgG subclasses with low levels of galactosylation and sialylation. Re-activation of potential memory B cells initially generated highly galactosylated and sialylated IgG antibodies, which were progressively reduced after each booster dose in anti-TNF-treated patients, especially in the elderly. The reduced short- and long-term IgG (1) levels in anti-TNF-treated patients correlated with diminished functional activity and an increased risk for the development of COVID-19. The data suggest that anti-TNF treatment reduces both GC-dependent long-lived PCs and GC-dependent memory B cell-derived short-lived PCs, hence both the long- and short-term IgG subclass responses, respectively, after repeated vaccination. We propose that anti-TNF therapy, especially in the elderly, reduces the benefit of booster vaccination.
Immune cell topography of head and neck cancer
Authors: Tara Muijlwijk, Dennis N L M Nijenhuis, Sonja H Ganzevles, Fatima Ekhlas, Carmen Ballesteros-Merino, Laura A N Peferoen, Elisabeth Bloemena, Bernard A Fox, Jos B Poell, C René Leemans, Ruud H Brakenhoff, Rieneke van de Ven
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Approximately 50% of head and neck squamous cell carcinomas (HNSCC) recur after treatment with curative intent. Immune checkpoint inhibitors are treatment options for recurrent/metastatic HNSCC; however, less than 20% of patients respond. To increase this response rate, it is fundamental to increase our understanding of the spatial tumor immune microenvironment (TIME). Methods In total, 53 HNSCC specimens were included. Using a seven-color multiplex immunohistochemistry panel we identified tumor cells, CD163+macrophages, B cells, CD8+T cells, CD4+T helper cells and regulatory T cells (Tregs) in treatment-naive surgical resection specimens (n=29) and biopsies (n=18). To further characterize tumor-infiltrating CD8+T cells, we stained surgical resection specimens (n=12) with a five-color tumor-resident panel including CD103, Ki67, CD8 and pan-cytokeratin. Secretome analysis was performed on matched tumor suspensions (n=11) to measure protein levels. Results Based on CD8+T cell infiltrates, we identified four different immunotypes: fully infiltrated, stroma-restricted, immune-excluded, and immune-desert. We found higher cytokine levels in fully infiltrated tumors compared with other immunotypes. While the highest immune infiltrates were observed in the invasive margin for all immune cells, CD163+macrophages and Tregs had the highest tendency to infiltrate the tumor center. Within the tumor center, especially B cells stayed at the tumor stroma, whereas CD163+macrophages, followed by T cells, were more often localized within tumor fields. Also, B cells were found further away from other cells and often formed aggregates while T cells and CD163+macrophages tended to be more closely located to each other. Across resection specimens from various anatomical sites within the head and neck, oral cavity tumors exhibited the highest densities of Tregs. Moreover, the distance from B cells and T cells to tumor cells was shortest in oral cavity squamous cell carcinoma (OCSCC), suggesting more interaction between lymphocytes and tumor cells. Also, the fraction of T cells within 10 µm of CD163+macrophages was lowest in OCSCC, indicating fewer myeloid/T-cell suppressive interactions in OCSCC. Conclusions We comprehensively described the TIME of HNSCC using a unique data set of resection specimens. We discovered that the composition, as well as the relative localization of immune cells in the TIME, differed in distinct anatomical sites of the head and neck.
Enhanced IL-15-mediated NK cell activation and proliferation by an ADAM17 function-blocking antibody involves CD16A, CD137, and accessory cells
Authors: Anders W Matson, Rob Hullsiek, Kate J Dixon, Sam Wang, Anders J Lindstedt, Ryan R Friess, Shee Kwan Phung, Tanya S Freedman, Martin Felices, Emily N Truckenbrod, Jianming Wu, Jeffrey S Miller, Bruce Walcheck
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Natural killer (NK) cells are being extensively studied as a cell therapy for cancer. These cells are activated by recognition of ligands and antigens on tumor cells. Cytokine therapies, such as IL-15, are also broadly used to stimulate endogenous and adoptively transferred NK cells in patients with cancer. These stimuli activate the membrane protease ADAM17, which cleaves various cell-surface receptors on NK cells as a negative feedback loop to limit their cytolytic function. ADAM17 inhibition can enhance IL-15-mediated NK cell proliferation in vitro and in vivo. In this study, we investigated the underlying mechanism of this process. Methods Peripheral blood mononuclear cells (PBMCs) or enriched NK cells from human peripheral blood, either unlabeled or labeled with a cell proliferation dye, were cultured for up to 7 days in the presence of rhIL-15±an ADAM17 function-blocking antibody. Different fully human versions of the antibody were generated; Medi-1 (IgG1), Medi-4 (IgG4), Medi-PGLALA, Medi-F(ab′) 2 , and TAB16 (anti-ADAM17 and anti-CD16 bispecific) to modulate CD16A binding. Flow cytometry was used to assess NK cell proliferation and phenotypic markers, immunoblotting to examine CD16A signaling, and IncuCyte-based live cell imaging to measure NK cell antitumor activity. Results The ADAM17 function-blocking monoclonal antibody (mAb) Medi-1 markedly increased early NK cell activation by IL-15. By using different engineered versions of the antibody, we demonstrate involvement by CD16A, an activating Fcγ receptor and well-described ADAM17 substrate. Hence, Medi-1 when bound to ADAM17 on NK cells is engaged by CD16A and blocks its shedding, inducing and prolonging its signaling. This process did not promote evident NK cell fratricide or dysfunction. Synergistic signaling by Medi-1 and IL-15 enhanced the upregulation of CD137 on CD16A + NK cells and augmented their proliferation in the presence of PBMC accessory cells or an anti-CD137 agonistic mAb. Conclusions Our data reveal for the first time that CD16A and CD137 underpin Medi-1 enhancement of IL-15-driven NK cell activation and proliferation, respectively, with the latter requiring PBMC accessory cells. The use of Medi-1 represents a novel strategy to enhance IL-15-driven NK cell proliferation, and it may be of therapeutic importance by increasing the antitumor activity of NK cells in patients with cancer.
Merkel cell carcinoma refractory to anti-PD(L)1: utility of adding ipilimumab for salvage therapy
Authors: Tomoko Akaike, Austin J Jabbour, Peter H Goff, Song Y Park, Shailender Bhatia, Paul Nghiem
Journal: Journal for ImmunoTherapy of Cancer (2024)

Merkel cell carcinoma (MCC) incidence has risen to approximately 3,000 cases annually in the USA. Although anti-programmed cell death (ligand) 1 (PD-(L)1) agents are now the first-line treatment for advanced MCC, approximately 50% of such patients do not persistently benefit. In PD-(L)1-refractory cases, ipilimumab (anti-cytotoxic T lymphocyte antigen-4) is often added; however, the extent of the clinical benefit of this combination is controversial. We identified one prospective study, three retrospective studies, and three case reports regarding this combination in refractory MCC. The aggregate response rate from retrospective studies was 32% (13 of 41 patients) with 4 complete responses (CR) and 9 partial responses (PR). In the prospective study, the response rate was very similar at 31% (8 of 26 patients; 4 CR, 4 PR). Response durability was highly variable (range 2 to >43 months), with patients achieving CR having greater durability. Immune-related adverse events (irAEs) were ≥grade III in 29% (retrospective cohort, N=41) and 36% (prospective cohort, N=50). While these aggregate data indicate adding ipilimumab should be considered in this setting, many patients with refractory MCC are ineligible due to comorbidities/irAEs, and approximately 70% will not benefit from this regimen. There is thus a significant unmet need in PD-(L)1-refractory MCC and clinical trials in this setting should be encouraged.
Phase I study of the safety and clinical activity of the interleukin-8 inhibitor AMY109 combined with atezolizumab in patients with advanced solid cancers
Authors: Noboru Yamamoto, Shigehisa Kitano, Takafumi Koyama, Masafumi Ikeda, Hidenori Mizugaki, Takatsugu Narikiyo, Yuki Yamaguchi, Takaaki Ishida, Ryoko Takubo, Chika Ogami, Mayuko Sekiya, Yuki Nakagawa, Yasutoshi Kuboki
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immunosuppressive conditions within the tumor microenvironment (TME) can allow tumors to evade the immune system, including by hampering programmed death ligand 1 (PD-L1) inhibitor activity. Interleukin (IL)-8 contributes to immunosuppression and fibrosis in the TME. AMY109, a humanized anti-IL-8 monoclonal antibody, reduced fibrosis and decreased immunosuppressive cells in tumor tissue in animals. Combining AMY109 with atezolizumab (anti-PD-L1 antibody) may enhance its antitumor effects by making the TME more favorable to PD-L1 inhibition. This multicenter, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and clinical activity of AMY109 plus atezolizumab in patients with previously treated advanced solid tumors and Eastern Cooperative Oncology Group performance status 0 or 1. Patients received AMY109 (2-45 mg/kg) plus atezolizumab (1200 mg) intravenously every 3 weeks in part 1, and AMY109 (15-45 mg/kg) plus atezolizumab (1200 mg) in part 2. Primary endpoints were the dose-limiting toxicity (DLT), safety, and pharmacokinetics of AMY109 and atezolizumab in Part 1, and safety and antitumor activity per investigator-assessed Response Evaluation Criteria in Solid Tumors 1.1 in part 2. Exploratory analyses of peripheral and tumor biomarker were conducted. Overall, 38 patients (18 in part 1 and 20 in part 2) were enrolled. Part 1 showed no DLTs and a dose-proportional increase in AMY109 exposure over 2-45 mg/kg, with no apparent change in mean atezolizumab serum concentrations across AMY109 dosing. Plasma IL-8 concentration accumulation was seen in all dose cohorts after AMY109 initiation. Grade 1-3 treatment-related adverse events (AEs) occurred in 21 of 38 patients (55%). Treatment-related serious AEs occurred in two patients (5%). No AEs led to treatment withdrawal. Partial responses (PRs) occurred in 2 of 38 patients; the confirmed objective response rate was 5%. These patients had uterocervical and pancreatic cancer, respectively, and had been treated for >500 days at the cut-off date: one had received 45 mg/kg of AMY109 throughout, and the other received 30 mg/kg of AMY109 until cycle 5, then 45 mg/kg thereafter. With no DLTs, AMY109 plus atezolizumab was well tolerated in patients with advanced solid tumors, with no new safety signals. AMY109 showed a dose-proportional increase in exposure. The PRs in two patients were durable.
Mitoxantrone Combined with Engineered TRAIL‐Nanovesicles for Enhanced Cancer Immunotherapy Via Converting Apoptosis into Pyroptosis
Authors: Yi Wang, Boning Niu, Yinmei Tian, Hongbing Lan, Zhanhao Zhou, Yang Li, Siyu Zhao, Yu Zhang, Conglian Yang, Li Kong, Zhiping Zhang
Journal: Advanced Healthcare Materials (2024)

Pyroptosis, a highly inflammatory form of programmed cell death, has emerged as a promising target for cancer immunotherapy. However, in the context of pyroptosis execution, while both caspase-3 and GSDME are essential, it is noteworthy that GSDME is frequently under-expressed in cold tumors. To overcome this limitation, engineered cellular nanovesicles (NVs) presenting TRAIL on their membranes (NV
Mast cell responses in a mouse model of food allergy are regulated via a ST2/IL‐4 axis
Authors: Saurav Ranjitkar, Dylan Krajewski, Caitlin Tedeschi, Nicole Maldonado Perez, Nathan Jordan, Kelly Gregory, Sallie S. Schneider, Clinton B. Mathias
Journal: Allergy (2024)

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