tbuckley/cabot-search huggingface dataset:
Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined With Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies
Authors: Jason J. Luke, Karen Gelmon, Lillian L. Siu, Victor Moreno, Jayesh Desai, Carlos A. Gomez-Roca, Matteo S. Carlino, Russell K. Pachynski, Rasha Cosman, Quincy Siu-Chung. Chu, Silvia Damian, Giuseppe Curigliano, Rachel Tam, Xianling Wang, Chandrika Jeyamohan, Lily Wang, Li Zhu, Julia Santucci-Pereira, Danielle M. Greenawalt, Josep Tabernero
Journal: Clinical Cancer Research (2024)

Abstract Purpose: To evaluate linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies. Patients and Methods: In this phase 1/2 study, patients received once-daily (QD) linrodostat (part 1 [escalation], 25-400 mg; part 2 [expansion], 100 or 200 mg) plus nivolumab (480 mg every [Q] 4 weeks [W] or 240 mg Q2W) or triplet therapy (part 3, linrodostat 20-100 mg QD; nivolumab 360 mg Q3W or 480 mg Q4W; ipilimumab 1 mg/kg Q6W or Q8W). Endpoints included safety and efficacy (co-primary; parts 2, 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1). Results: Fifty-five, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1%-63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naive patients. Kynurenine decreased with linrodostat + nivolumab, regardless of response. In contrast, interferon gamma (IFN-γ) gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase (TDO2) gene expression plus high IFN-γ signature was associated with response. Conclusions: Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported IDO1 pathway inhibition but did not correlate with response. A composite biomarker of low TDO2 expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.
Complete remissions of HER2-positive trastuzumab-resistant xenografts using a potent [225Ac]Ac-labeled anti-HER2 antibody-drug radioconjugate
Authors: Jessica Pougoue Ketchemen, Fabrice Ngoh Njotu, Hanan Babeker, Alissar Monzer, Emmanuel Nwangele, Anjong Florence Tikum, Nikita Henning, Nava Hassani, Sarah Frye, Randy Perron, Chris Byrne, Candice Didychuk, Qi Qi, Laura Bannister, Alireza Doroudi, Humphrey Fonge
Journal: Clinical Cancer Research (2024)

Abstract Purpose: There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted alpha therapies. Antibody-drug conjugates (ADCs) are highly cytotoxic. Combining [225Ac]Ac with ADC to develop an antibody-drug radioconjugate (ADR) [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1, is expected to be more effective than its ADC (trastuzumab-PEG6-DM1) against breast cancer (BC). Experimental design: [89Zr]Zr-DFO-trastuzumab-PEG6-DM1 (imaging) and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 (radiotherapy) were developed. Biodistribution and safety evaluation of [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 were carried out in non-tumor bearing Balb/C mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO-trastuzumab-PEG6-DM1, and radiotherapy using [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 was carried-out in athymic Balb/C nude mice bearing trastuzumab-resistant HCC1954 and T-DM1/trastuzumab resistant JIMT-1 tumor bearing mice. Results: After 7-days (d) of incubation at 37ºC, [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 was stable in both human serum (89.2 ± 0.9%) and phosphate buffered saline (82.8 ± 0.4%). Trastuzumab-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 (3 x 18 kBq) administered separately in non-tumor bearing mice, 10-d apart was well tolerated biochemically and haematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO-trastuzumab-PEG6-DM1 in tumor-bearing mice at 120 h post injection: 38.1 ± 2.8% IA/g (HCC1954) and 14.6 ± 1% IA/g (JIMT-1). In HCC1954-tumor bearing mice, all treatment groups had complete remission (8/8 CR) indicative of the responsiveness of the xenograft to T-DM1-based treatments, while for JIMT-1 xenograft (having 1/8 CR) at 23-d post treatment, tumor volumes were 332.1 ± 77.5 vs 244.6 ± 63 vs 417.9 ± 62.1 vs 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), trastuzumab-PEG6-DM1 and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1, respectively. Conclusion: [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 is more potent than ADC against trastuzumab-resistant BC and necessitates clinical translation.
The Presence and Pathogenic Roles of M(<scp>IL</scp>‐33 + <scp>IL</scp>‐2) Macrophages in Allergic Airway Inflammation
Authors: Han Guo, Yang Zhao, Zhaoqi Zhang, Yanan Xu, Yifang Chen, Tong Lei, Yong Zhao
Journal: Allergy (2024)

Macrophages, one of the most abundant immune cells in the lung, have drawn great attention in allergic asthma. Currently, most studies emphasize alternative activated (M2) polarization bias. However, macrophage function in allergic asthma is still controversial. Interleukin (IL)-9 contributes to the development and pathogenesis of allergic airway inflammation. We sought to investigate the IL-9-producing macrophage and its role in allergic asthma.
Next generation sequencing-based MSI scoring predict benefit in mismatch repair deficient tumors treated with nivolumab: follow-up on NCI-MATCH arm Z1D
Authors: Jonathan D. Schoenfeld, Nilofer S. Azad, Jacob Gross, Li Chen, Michael J. Overman, Katrina Kao, Latifa F. Jackson, Donna Brunnquell, Xiangning Bu, Christina Coppola, Ping Guan, Jennifer Lee, David Sims, Rebecca Fuchs, Jason L. Weirather, Kathleen L. Pfaff, Lauren Gunasti, Srin Ranasinghe, Stanley R. Hamilton, Victoria Wang, Peter J. O'Dwyer, Catherine J. Wu, Scott J. Rodig, David R. Patton, Lyndsay Harris
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Mismatch repair deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment. Experimental Design: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-MATCH arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with non-colorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples. Results: In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS was associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included interferon signaling, antigen processing and PI3K-AKT-mTOR signaling, while hedgehog signaling was found to be enriched in subjects lacking clinical benefit. Conclusions: These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS based measures of MSI could serve as biomarkers of immunotherapy response.
TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacology
Authors: Jing Lu, Ying Zhang, Chunyan Yan, Jingwen Liu, Dan Qi, Yue Zhou, Qinwen Wang, Juechen Yang, Jing Jiang, Benhao Wu, Meiling Yang, Weiwei Zhang, Xin Zhang, Xiaoyu Shi, Yan Zhang, Kun Liu, Yongcai Liang, Chaoyang Wang, Hanyu Yang, Yuqing Gao, Yuping Sun, Ronghu Ke, Jason H Huang, Min Wu, Hongbo Wang, Chunlei Li, Shuang Zhou, Bin Guo, Erxi Wu, Guoying Zhang
Journal: Bioactive Materials (2024)
Comment on “A Practical Guide to Using Oral JAK Inhibitors for Atopic Dermatitis from the International Eczema Council”- A case of Rhabdomyolysis Induced by Upadacitinib
Authors: Edoardo Mortato, Marina Talamonti, Claudia Paganini, Alfredo Belcastro, Luca Bianchi, Marco Galluzzo
Journal: British Journal of Dermatology (2024)

Rapid response to the recent publication in BJD “A Practical Guide to Using Oral JAK Inhibitors for Atopic Dermatitis from the International Eczema Council”
Comment on ‘Oncogenic alterations in <i>KIR3DL1</i> in cutaneous acral CD8+ lymphoproliferative disorder’ by Wobser <i>et al</i>
Authors: Baptiste Louveau, Fanélie Jouenne, Caroline Ram-Wolff, Maxence Mancini, Adèle De Masson, Samia Mourah, Maxime Battistella
Journal: British Journal of Dermatology (2024)

Identifying pathognomonic features that differentiate primary cutaneous acral CD8+ T-cell lymphoproliferative disorder (TLPD) from other CD8+ aggressive lymphomas is a major concern. Doing so can facilitate diagnosis and allow clinicians to optimize clinical management. In this context, we read with great interest the article from Wobser et al., which proposed a molecular characterization of five cutaneous acral CD8+ TLPDs and identified KIR3DL1 alterations in addition to PIK3R1 alterations. To broaden this spectrum, we propose genomic profiling of six cutaneous acral CD8+ TLPDs from our database and identify alterations related to oncogenic pathways such as the AKT pathway and the Janus kinase–signal transducer and activator of transcription protein pathway. We also confirm the decreased mRNA expression of KIR3DL1 in this setting.
A new frontier in drug discovery for skin cancer through electronic medical records
Authors: Lea Dousset, Kiarash Khosrotehrani
Journal: British Journal of Dermatology (2024)

Journal Article Accepted manuscript A new frontier in drug discovery for skin cancer through electronic medical records Get access Lea Dousset, Lea Dousset Frazer Institute, The University of Queensland, Dermatology Research Centre, Experimental Dermatology Group, Brisbane, Australia Search for other works by this author on: Oxford Academic Google Scholar Kiarash Khosrotehrani Kiarash Khosrotehrani Frazer Institute, The University of Queensland, Dermatology Research Centre, Experimental Dermatology Group, Brisbane, AustraliaDepartment of Dermatology, Princess Alexandra Hospital, Brisbane, Australia Correspondence: Kiarash Khosrotehrani Email:[email protected] Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, ljae489, https://doi.org/10.1093/bjd/ljae489 Published: 13 December 2024 Article history Received: 06 December 2024 Accepted: 11 December 2024 Published: 13 December 2024
Mpox in people with haematological cancers
Authors: RP Gale, A. Hochhaus
Journal: Leukemia (2024)

Mpox (formerly monkeypox) is a virus infection caused by Monkeypox virus, a double-stranded DNA orthopoxvirus related to variola, vaccinia, cowpox and Borealpox viruses.There are 2 main Mpox clades: Clade I, endemic to Central Africa and Clade II, to West Africa.Clade I is associated with more severe and Clade II with less severe disease.In 2022 cases of Mpox Clade II were reported in North America and Europe.More recently, Clade I cases are reported in Europe and the US.Clade II Mpox is now reported in >100 countries with >100,000 cases worldwide and >500 deaths.The World Health Organization (WHO) has declared Mpox a Public Health Emergency of International Concern (PHEIC).Human-to-human transmission of Mpox is the most common route outside Africa.Transmission occurs by contact with skin of an infected, usually symptomatic person.However, transmission can also occur via clothing, bedding, towels, dishes, cutlery and by saliva.There is also transmission via sexual contact among people who are gay or b-isexual.Diagnosis of Mpox infection is by polymerase chain reaction (PCR)-testing with virus-specific DNA primers and probes.Persons with a positive orthopoxvirus virus PCR test should have additional testing to exclude related infections such as coxpox and Borealpox.Symptoms of Mpox infection are protean including a painful rash which starts as raised spots turning into ulcers and liquidfilled blisters which eventually form desquamating scabs, fever, headache, myalgias, enlarged lymph nodes, rigors, fatigue and arthralgias.Pharyngitis and proctitis may be presenting symptoms.Clade II cases are typically self-limited but this is not so of Clade I infections which may require medical intervention with anti-virals such as tecovirimat and cidofovir.Smallpox vaccination may attenuate severity of Mpox infections and is recommended in health care workers and others likely to be in close contact with Mpox-infected persons.Isolation of known or suspected cases is critical.Currently, there is no vaccine.It is important to report all suspected and proven cases to local and national Health Authorities.
Tuberculosis in adult migrants in Europe: a TBnet consensus statement
Authors: Heinke Kunst, Berit Lange, Olga Hovardovska, Annabelle Bockey, Dominik Zenner, Aase B Andersen, Sally Hargreaves, Manish Pareek, Jon S Friedland, Chrsitain Wejse, Graham Bothamley, Lorenzo Guglielmetti, Dima Chesov, Simon Tiberi, Alberto Matteelli, Anna M Mandalakas, Jan Heyckendorf, Johannes Eimer, Akanksha Malhotra, Javier Zamora, Anca Vasiliu, Christoph Lange
Journal: European Respiratory Journal (2024)

Introduction Global migration has increased in recent decades due to war, conflict, persecutions, and natural disasters, but also secondary to increased opportunities related to work or study. Migrants’ risk of tuberculosis (TB) differs by reasons for migration, socioeconomic status, mode of travel and TB risk in transit, TB incidence and healthcare provision in country of origin. Despite advances in TB care for migrants and new treatment strategies, decisions for the management of migrants at risk of TB often rely on expert opinions, rather than clinical evidence. Methods A systematic literature search was conducted, studies were mapped to different recommendation groups and included studies were synthesized by meta-analysis where appropriate. Current evidence on diagnosis of active TB in migrants entering the European Union /European Economic Area (EU/EEA) &amp;UK including the clinical presentation and diagnostic delay, treatment outcomes of drug susceptible TB, prevalence and treatment outcomes of multidrug/rifampicin-resistant (MDR/RR)-TB and TB/HIV co-infection was summarised. A consensus process was used based on the evidence. Results We document a higher vulnerability of migrants for TB, including an increased risk of extrapulmonary TB, MDR/RR-TB, TB/HIV co-infection and worse TB treatment outcomes compared to host populations. Consensus recommendations include screening of migrants for TB/ latent TB infection (LTBI) according to country data; a minimal package for TB care in drug susceptible and MDR/RR-TB; implementation of migrant-sensitive strategies; free healthcare and preventive treatment for migrants with HIV co-infection. Conclusion Dedicated care for TB prevention and treatment in migrant populations within the EU/EEA &amp;UK is essential.
Intervention accelerator to prevent and respond to abuse of older people: insights from key promising interventions
Authors: Laura Campo-Tena, Aresya Farzana, David Burnes, Titus A Chan, Wan Yuen Choo, Mélanie Couture, Fatemeh Estebsari, Minying He, Jeffrey H Herbst, Christelle Sibdou Liliane Kafando, Joshua Lachs, George Rouamba, Marie-Madeleine Simbreni, Louis To, Hau Yan Wan, Elsie Yan, Yongjie Yon, Christopher Mikton
Journal: The Lancet Healthy Longevity (2024)
Simultaneous intracranial recordings of interacting brains reveal neurocognitive dynamics of human cooperation
Authors: Jiaxin Wang, Fangang Meng, Cuiping Xu, Yanyang Zhang, Kun Liang, Chunlei Han, Yuan Gao, Xinguang Yu, Zizhou Li, Xiaoyu Zeng, Jun Ni, Huixin Tan, Jiaxin Yang, Yina Ma
Journal: Nature Neuroscience (2024)
Efficient circular RNA synthesis for potent rolling circle translation
Authors: Yifei Du, Philipp Konrad Zuber, Huajuan Xiao, Xueyan Li, Yuliya Gordiyenko, V. Ramakrishnan
Journal: Nature Biomedical Engineering (2024)

Abstract Circular RNA (circRNA) is a candidate for next-generation messenger RNA therapeutics owing to its remarkable stability. Here we describe trans -splicing-based methods for the synthesis of circRNAs over 8,000 nucleotides. The methods are independent of bacterial sequences, outperform the permuted intron–exon method and allow for the incorporation of RNA modifications. The resulting unmodified circRNAs, which incorporate sequences from human 28S ribosomal RNA, display low immunogenicity and are translated more efficiently than permuted intron–exon-derived circRNAs. Additionally, by using viral internal ribosomal entry sites for rolling circle translation, we show that ribosomes can efficiently read through highly structured internal ribosomal entry sites, enhancing the efficiency of rolling circle translation by over 7,000-fold with respect to previous constructs. The efficient and reliable production of circRNA may facilitate its therapeutic use.
Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+
Authors: Lena E. Høyland, Magali R. VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J. Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F. Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K. N. Pettersen, Karl J. Tronstad, Svein A. Mjøs, Faisal Hayat, Mikhail V. Makarov, Marie E. Migaud, Ines Heiland, Mathias Ziegler
Journal: Nature Metabolism (2024)
The CALERIE Genomic Data Resource
Authors: C. P. Ryan, D. L. Corcoran, N. Banskota, C. Eckstein Indik, A. Floratos, R. Friedman, M. S. Kobor, V. B. Kraus, W. E. Kraus, J. L. MacIsaac, M. C. Orenduff, C. F. Pieper, J. P. White, L. Ferrucci, S. Horvath, K. M. Huffman, D. W. Belsky
Journal: Nature Aging (2024)
Nuvaxovid NVX-CoV2373 vaccine safety profile: real-world data evidence after 100,000 doses, Australia, 2022 to 2023
Authors: Hazel J Clothier, Claire Parker, John H Mallard, Paul Effler, Lauren Bloomfield, Dale Carcione, Jim P Buttery
Journal: Eurosurveillance (2024)

Introduction Nuvaxovid became available in Australia from February 2022, a year after the first COVID-19 vaccines. This protein-based vaccine was an alternative for people who had had an adverse event to and/or were hesitant to receive an mRNA or adenovirus-based COVID-19 vaccine. Although safety from clinical trials was reassuring, small trial populations, low administration rates and limited post-licensure intelligence meant potential rare adverse events were underinformed. Aim We aimed to describe Nuvaxovid’s safety profile in a real-world setting. Methods We conducted a retrospective observational analysis of adverse events following immunisation (AEFI) spontaneously reported to SAFEVAC, the integrated vaccine safety surveillance system in Victoria and Western Australia. Reports from 14 February 2022 to 30 June 2023 were analysed by vaccinee demographics, reported reactions and COVID-19 vaccine dose, and compared as reporting rates (RR) per 100,000 doses administered. Results We received 356 AEFI reports, following 102,946 Nuvaxovid doses administered. Rates were higher after dose 1 than dose 2 (rate ratio: 1.5, p = 0.0008), primary series than booster (rate ratio: 2.4, p &lt; 0.0001), and in females vs males (rate ratio: 1.4, p = 0.004). Clinically confirmed serious AEFI included 94 cases of chest pain (RR = 91.3), two myocarditis (RR = 1.9) and 20 pericarditis (RR = 19.4). Guillain–Barré syndrome or thrombosis with thrombocytopaenia syndromes were not reported, nor deaths attributable to vaccination. Conclusion SAFEVAC’s collaborative data model enabled pooling of clinically reviewed data across jurisdictions, increasing the safety profile evidence for Nuvaxovid and improving the odds for identification and description of rare events. This analysis affirmed the safety profile of Nuvaxovid.
Direct and indirect effects of the COVID-19 pandemic on mortality: an individual-level population-scale analysis using linked electronic health records, Wales, United Kingdom, 2016 to 2022
Authors: Rhiannon K Owen, James D van Oppen, Jane Lyons, Ashley Akbari, Gareth Davies, Fatemeh Torabi, Keith R Abrams, Ronan A Lyons
Journal: Eurosurveillance (2024)

Background The COVID-19 pandemic resulted in increased mortality directly and indirectly associated with COVID-19. Aim To assess the impact of the COVID-19 pandemic on all-cause and disease-specific mortality and explore potential health inequalities associated with area-level deprivation in Wales. Methods Two population-based cohort studies were derived from multi-sourced, linked demographic, administrative and electronic health record data from 2016 to 2019 (n = 3,113,319) and 2020 to 2022 (n = 3,571,471). Data were analysed using generalised linear models adjusting for age, sex, area-level deprivation and time at risk. Results COVID-19 deaths peaked in January 2021 (54.9/100,000 person-months, 95% confidence interval (CI): 52.4–57.5). The pandemic indirectly affected deaths, with higher than expected maximum relative mortality rates (RR) related to cancer (RR: 1.24, 95% CI: 1.13–1.36), infectious diseases (excluding respiratory infections) (RR: 2.09, 95% CI: 1.27– 3.43), circulatory system (RR: 1.41, 95% CI: 1.28–1.56), trauma (RR: 2.04, 95% CI: 1.57– 2.65), digestive system (RR: 1.54, 95% CI: 1.25–1.91), nervous system (RR: 1.63; 95% CI: 1.34–2.00) and mental and behavioural disorders (RR: 1.85, 95% CI: 1.58–2.16). Mortality associated with respiratory diseases (unrelated to COVID-19) were lower than expected (minimum RR: 0.52, 95% CI: 0.45–0.60). All-cause mortality was lower in least deprived communities compared with most deprived (RR: 0.61, 95% CI: 0.60–0.62), and the magnitude of this effect increased during the pandemic. Conclusions All-cause and disease-specific mortality directly and indirectly associated with COVID-19 increased during the COVID-19 pandemic. Socioeconomic disparities were exacerbated during this time.
An outbreak of influenza A(H1N1)pdm09 antigenic variants exhibiting cross-resistance to oseltamivir and peramivir in an elementary school in Japan, September 2024
Authors: Emi Takashita, Kohei Shimizu, Shuzo Usuku, Ryuichi Senda, Ichiro Okubo, Hiroko Morita, Shiho Nagata, Seiichiro Fujisaki, Hideka Miura, Noriko Kishida, Kazuya Nakamura, Masayuki Shirakura, Masataka Ichikawa, Yoko Matsuzaki, Shinji Watanabe, Yoshimasa Takahashi, Hideki Hasegawa
Journal: Eurosurveillance (2024)

An outbreak of influenza A(H1N1)pdm09 viruses exhibiting cross-resistance to oseltamivir and peramivir occurred in Yokohama, Japan, in September 2024. Among 24 students in a class, 11 were diagnosed with influenza or influenza-like illness, and viruses harbouring the NA H275Y and HA Q210H substitutions were isolated from four. Deep sequencing analysis confirmed the clonal spread of these mutants. Antigenic analysis revealed differences from the vaccine strain. Continued monitoring is crucial to assess the potential for further spread of these mutant viruses.