tbuckley/cabot-search huggingface dataset:
Evolutionary and functional analysis of caspase-8 and ASC interactions to drive lytic cell death, PANoptosis
Authors: Sivakumar Prasanth Kumar, Eswar Kumar Nadendla, R K Subbarao Malireddi, Syed Asfarul Haque, Raghvendra Mall, Andrew F Neuwald, Thirumala-Devi Kanneganti
Journal: Molecular Biology and Evolution (2025)

Abstract Caspases are evolutionarily conserved proteins essential for driving cell death in development and host defense. Caspase-8, a key member of the caspase family, is implicated in apoptosis, a non-lytic form of cell death, as well as lytic forms of cell death. Recently, caspase-8 has been identified as an integral component of PANoptosomes, multi-protein complexes formed in response to innate immune sensor activation. Several innate immune sensors can nucleate this caspase-8–containing PANoptosome complex to drive inflammatory lytic cell death, PANoptosis. However, how the evolutionarily conserved and diverse functions of caspase-8 drive PANoptosis remains unclear. To address this, we performed evolutionary, sequence, structural, and functional analyses to decode caspase-8’s complex-forming abilities and its interaction with the PANoptosome adaptor ASC. Our study distinguished distinct subgroups within the death domain superfamily based on their evolutionary and functional relationships, identified homotypic traits among sub-family members, and captured key events in caspase evolution. We also identified critical residues defining the heterotypic interaction between caspase-8’s death effector domain and ASC’s pyrin domain, validated through cross-species analyses, dynamic simulations, and in vitro experiments. Overall, our study elucidated recent evolutionary adaptations of caspase-8 that allowed it to interact with ASC, improving our understanding of critical molecular associations in PANoptosome complex formation and the underlying PANoptotic responses in host defense and inflammation. These findings have implications for understanding mammalian immune responses and developing new therapeutic strategies for inflammatory diseases.
Trametinib as a promising therapy for Darier disease: case report
Authors: Diego Soto-García, Paula Dávila-Seijo, Carlota González-Moure, Ana Pampín, Ander Zulaica, Francisco Allegue, Ignacio García-Doval
Journal: British Journal of Dermatology (2025)

Darier disease is a rare autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene, which encodes sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2). This leads to impaired intercellular adhesion and epidermal blistering. We report the case of a 25-year-old male with severe Darier disease who demonstrated a positive response to trametinib after multiple unsuccessful therapies.
Nerve- and airway-associated interstitial macrophages mitigate SARS-CoV-2 pathogenesis via type I interferon signaling
Authors: Stephen T Yeung, Payal Damani-Yokota, Sara A Thannickal, Eric Bartnicki, Eduardo D Bernier, Clea R Barnett, Camille Khairallah, Ralf Duerr, Maria G Noval, Leopoldo N Segal, Kenneth A Stapleford, Kamal M Khanna
Journal: Immunity (2025)
Transposable elements drive regulatory and functional innovation of F-box genes
Authors: Miguel Vasconcelos Almeida, Zixin Li, Pedro Rebelo-Guiomar, Alexandra Dallaire, Lukáš Fiedler, Jonathan L Price, Jan Sluka, Xiaodan Liu, Falk Butter, Christian Rödelsperger, Eric A Miska
Journal: Molecular Biology and Evolution (2025)

Abstract Protein domains of transposable elements (TEs) and viruses increase the protein diversity of host genomes by recombining with other protein domains. By screening 10 million eukaryotic proteins, we identified several domains that define multi-copy gene families and frequently co-occur with TE/viral domains. Among these, a Tc1/Mariner transposase helix-turn-helix (HTH) domain was captured by F-box genes in the Caenorhabditis genus, creating a new class of F-box genes. For specific members of this class, like fbxa-215, we found that the HTH domain is required for diverse processes including germ granule localisation, fertility, and thermotolerance. Furthermore, we provide evidence that Heat Shock Factor 1 (HSF-1) mediates the transcriptional integration of fbxa-215 into the heat-shock response by binding to Helitron TEs directly upstream of the fbxa-215 locus. The interactome of HTH-bearing F-box factors suggests roles in post-translational regulation and proteostasis, consistent with established functions of F-box proteins. Based on AlphaFold2 multimer proteome-wide screens, we propose that the HTH domain may diversify the repertoire of protein substrates that F-box factors regulate post-translationally. We also describe an independent capture of a TE domain by F-box genes in zebrafish. In conclusion, we identify two independent TE domain captures by F-box genes in eukaryotes and provide insights into how these novel proteins are integrated within host gene regulatory networks.
T–B cell cooperation in ectopic lymphoid follicles propagates CNS autoimmunity
Authors: Anna Kolz, Clara de la Rosa, Isabel J. Syma, Sarah McGrath, Vladyslav Kavaka, Rosa Schmitz, Anna S. Thomann, Martin Kerschensteiner, Eduardo Beltran, Naoto Kawakami, Anneli Peters
Journal: Science Immunology (2025)

Meningeal ectopic lymphoid follicle (eLF)–like structures have been described in multiple sclerosis, but their role in central nervous system (CNS) autoimmunity is unclear. Here, we used a T helper 17 (T H 17) adoptive transfer experimental autoimmune encephalomyelitis model featuring formation of eLFs. Single-cell RNA sequencing revealed that clusters of activated B cells and B1/marginal zone–like B cells were overrepresented in the CNS and identified B cells poised for undergoing germinal center reactions and clonal expansion in the CNS. Using intravital imaging to directly visualize T H 17–B cell interactions, we demonstrated that T and B cells form long-lasting antigen-specific contacts in meningeal eLFs that result in reactivation of autoreactive T cells. CNS T cells depended on CNS B cells to maintain a proinflammatory cytokine profile. Our study reveals that extensive T–B cell cooperation occurs in meningeal eLFs, promoting both B cell differentiation and T cell reactivation, and may thereby propagate smoldering inflammation in the CNS.
Clone tracking through repeated malaria identifies high-fidelity memory CD4 T cell responses
Authors: Jason Nideffer, Florian Bach, Felistas Nankya, Kenneth Musinguzi, Šimon Borna, Michelle Mantilla, Maato Zedi, Aracely Garcia Romero, Chloe Gerungan, Nora Yang, Soyeon Kim, Kattria van der Ploeg, Kylie Camanag, Luis Lopez, Evelyn Nansubuga, Joaniter I. Nankabirwa, Emmanuel Arinaitwe, Potchara Boonrat, Steven Strubbe, Alma-Martina Cepika, Saki Takahashi, Grant Dorsey, Bryan Greenhouse, Isabel Rodriguez-Barraquer, Moses R. Kamya, Rosa Bacchetta, Isaac Ssewanyana, Ashraful Haque, Maria Grazia Roncarolo, Prasanna Jagannathan
Journal: Science Immunology (2025)

Few studies have tracked human CD4 + T cell clones through repeated infections. We used longitudinal single-cell RNA and T cell receptor (TCR) tracking to study the functional stability and memory potential of CD4 + T cell clonotypes during repeated Plasmodium falciparum ( Pf ) infections in Ugandan children and adults. Nearly all clonotypes displayed a strong preference for one of seven CD4 + subsets. This phenomenon of “clonal fidelity” was influenced by clonal expansion, linking T cell polarization and proliferation in vivo. Using clone tracking, we characterized subset-specific activation trajectories and identified antigen-specific clones. Type 1 regulatory T (T R 1) cells accounted for nearly 90% of Pf -specific CD4 + T cells in blood. Tracking these clones longitudinally for hundreds of days, we observed malaria-induced expansion of T R 1 effectors, long-term persistence of T R 1 memory cells, and high-fidelity recall responses after reinfection. This work establishes clonal fidelity as a natural phenomenon and demonstrates the stable, long-term memory potential of T R 1 cells.
Redistribution of ancestral functions underlies the evolution of venom production in marine predatory snails
Authors: Giulia Zancolli, Maria Vittoria Modica, Nicolas Puillandre, Yuri Kantor, Agneesh Barua, Giulia Campli, Marc Robinson-Rechavi
Journal: Molecular Biology and Evolution (2025)

Abstract Venom-secreting glands are highly specialised organs evolved throughout the animal kingdom to synthetise and secrete toxins for predation and defence. Venom is extensively studied for its toxin components and application potential; yet, how animals become venomous remains poorly understood. Venom systems therefore offer a unique opportunity to understand the molecular mechanisms underlying functional innovation. Here, we conducted a multi-species multi-tissue comparative transcriptomics analysis of 12 marine predatory gastropod species, including species with venom glands and species with homologous non-venom producing glands, to examine how specialised functions evolve through gene expression changes. We found that while the venom gland specialised for the mass production of toxins, its homologous glands retained the ancestral digestive functions. The functional divergence and specialisation of the venom gland was achieved through a redistribution of its ancestral digestive functions to other organs, specifically the oesophagus. This entailed concerted expression changes and accelerated transcriptome evolution across the entire digestive system. The increase in venom gland secretory capacity was achieved through the modulation of an ancient secretory machinery, particularly genes involved in endoplasmic reticulum stress and unfolded protein response. This study shifts the focus from the well-explored evolution of toxins to the lesser-known evolution of the organ and mechanisms responsible for venom production. As such, it contributes to elucidating the molecular mechanisms underlying organ evolution at a fine evolutionary scale, highlighting the specific events that lead to functional divergence.
Clinical phenotype and pathophysiological mechanisms underlying qualitative Low VWF
Authors: Ferdows Atiq, Robin Blok, Calvin van Kwawegen, Anne-Marije Hulshof, Dearbhla Doherty, Michelle Lavin, Johanna G van der Bom, Niamh M O'Connell, Joke de Meris, Kevin Ryan, Saskia E.M. Schols, Waander L. van Heerde, Mairead M Doyle, Mary B Byrne, Floor C.J.I. Heubel-Moenen, Karin P.M. van Galen, Roger J.S. Preston, Marjon H. Cnossen, Karin Fijnvandraat, Ross Ian Baker, Karina Meijer, Paula D. James, Jorge Di Paola, Jeroen C.J. Eikenboom, Frank W.G. Leebeek, James S. O'Donnell
Journal: Blood (2025)

Previous reports have highlighted that some low VWF patients with significant bleeding were diagnosed based upon an isolated but persistent reduction in plasma VWF activity levels in the 30-50 IU/dL range. These patients had plasma VWF:Ag levels &amp;gt; 50 IU/dL and thus had 'qualitative' rather than 'quantitative' low VWF. Although the clinical importance of functional VWF defects in type 2 VWD is well recognized, the translational implications of mild functional defects in patients with qualitative low VWF (low VWF-QL) have not been defined. To address this clinically important question, we combined low VWF datasets from the low VWF in Ireland cohort and the low VWF in Erasmus MC studies. Overall, we observed that low VWF-QL was common and accounted for approximately 50% of our combined low VWF cohort. Importantly, our findings demonstrate that many of these patients with mild isolated functional VWF defects in the 30-50 IU/dl range had significant bleeding phenotypes, even though their plasma VWF:Ag levels were within the normal range. In addition, we further show that low VWF-QL is a distinct clinic-pathological entity compared to type 2 VWD. Finally, our studies highlight that low VWF-QL is predominantly due to abnormalities in VWF biosynthesis within endothelial cells that are occurring largely independent of identifiable pathological VWF sequence variants. Cumulatively, these novel observations have important clinical implications for the diagnosis and management of patients with mild functional VWF defects.
A phase 2 randomized study of modakafusp alfa as a single agent in patients with relapsed/refractory multiple myeloma
Authors: Sarah A Holstein, Shebli Atrash, Hira Mian, Meletios Athanasios Dimopoulos, Fredrik Schjesvold, Rakesh Popat, Nishi Shah, Moshe E Gatt, Christian B. Gocke, Laurent Frenzel, Cyrille Touzeau, Meral Beksac, Salomon Manier, Hila Magen, Patrick Travis, Omar Nadeem, Kaveri Suryanarayan, Cheryl Li, Shuli Li, Allison Nelson, Dasha Cherepanov, Xavier Parot, Dan T Vogl
Journal: Blood (2025)

Modakafusp alfa is a first-in-class immunocytokine directing interferon-α to CD38-positive cells. Our previous phase 1/2 trial identified two potential phase 2 doses of modakafusp alfa in patients with relapsed/refractory multiple myeloma (RRMM): 1.5 or 3 mg/kg every 4 weeks (Q4W). The overall response rate (ORR) among 30 patients treated at 1.5 mg/kg was 43%. This phase 2 dose optimization study (NCT03215030) randomized 147 patients with triple-class refractory disease and ≥3 prior lines of therapy 1:1 to modakafusp alfa 120 mg (n = 71) or 240 mg (n = 75) Q4W (fixed-dose equivalents of 1.5 and 3 mg/kg Q4W). Patients had received a median of 6 prior lines of therapy; 66% were penta-exposed and 45% anti-BCMA-exposed. Modakafusp alfa development was discontinued for strategic reasons by the sponsor and the study was terminated early. At median follow-ups of 7.3 and 7.6 months in the 120 and 240 mg arms, ORRs were 32% and 41%; median progression-free survival was 4.1 and 5.3 months, respectively. ORRs were higher in patients who had not received prior-BCMA therapy (46% vs 29%). The most common treatment-related adverse events (TEAEs) in the 120 and 240 mg arms were thrombocytopenia (75% and 84%; grade ≥3, 55% and 61%) and neutropenia (68% and 73%; grade ≥3, 56% and 68%); 90% and 96% of patients experienced grade ≥3 TEAEs; 39% and 44% experienced serious TEAEs. Pharmacokinetic studies showed a ~2-fold greater exposure with 240 vs 120 mg. Our results confirm the efficacy of single-agent modakafusp alfa in patients with RRMM.
68Ga FAPI-04 PET/MRI for Detecting Metastatic Bone Lesions of Esophageal Cancer in Patients With G-CSF Administration, Missed by 18F FDG PET/CT
Authors: Jingxuan Miao, Xiaoyu Su, Alei Xu, Lei Yao, Hui Wang
Journal: Clinical Nuclear Medicine (2025)

We report a patient who underwent surgery for esophageal cancer, in whom 18 F FDG PET/CT showed diffuse skeletal uptake, while 68 Ga FAPI-04 PET/MRI revealed significantly higher uptake in bone metastatic lesions. Bone lesions were visible after granulocyte-colony stimulating factor(G-CSF) administration due to lower 68 Ga FAPI-04 background uptake, suggesting its superior potential for detecting bone metastases in esophageal cancer patients after G-CSF treatment.
Fluciclovine-PET Uptake in Microcystic Meningioma Mimicking High-grade Glioma: A Case Report
Authors: Junki Takenaka, Kenji Hirata, Shiro Watanabe, Yukitomo Ishi, Kohsuke Kudo
Journal: Clinical Nuclear Medicine (2025)

A 69-year-old asymptomatic woman underwent magnetic resonance imaging (MRI), revealing a left parietal lobe tumor suspected to be a high-grade glioma (HGG). [ 18 F]Fluciclovine-positron emission tomography (PET), which reflects amino acid metabolism, showed moderate uptake [SUVmax 1.4, tumor-to-normal ratio (TNR) 1.9], consistent with HGG, whereas [ 18 F]fluorodeoxyglucose-PET findings demonstrated low uptake (SUVmax 2.5, TNR 0.22), which is atypical for HGG. Surgical and pathologic investigations confirmed the diagnosis of microcystic meningioma, a rare subtype classified as grade 1. Microcystic meningiomas mimic HGG on magnetic resonance imaging and [ 18 F]fluciclovine-PET due to l -amino acid transporter expression, complicating diagnosis.
PET/CT Findings of a Solid Pseudopapillary Tumor Mimicking Adrenocortical Carcinoma
Authors: Zhenpeng Jiang, Huimin Shan, Jingfa Li, Yayi Xiao, Xusheng Zhu
Journal: Clinical Nuclear Medicine (2025)

Solid pseudopapillary tumor (SPT) is a rare low-grade malignant neoplasm originating predominantly in the pancreas. Extra-pancreatic SPTs are exceedingly rare clinical entities. The 18 F-FDG PET/CT imaging features of extra-pancreatic SPTs remain poorly characterized in the current literature. We present a diagnostically challenging case of left adrenal SPT demonstrating MRI and 18 F-FDG PET/CT features indistinguishable from adrenocortical carcinoma, ultimately resulting in preoperative misdiagnosis.
Redistribution of Intraspinal and Muscular 18F-FDG Uptake after the Epidural Electrical Stimulation Treatment in Spinal Cord Injury Individuals
Authors: Qingyu Yao, Boyang Zhang, Feng Zhang, Xi Zhang, Xuesong Luo, Luming Li
Journal: Clinical Nuclear Medicine (2025)

Purpose: This study investigates the redistribution of resting 18 F-Fluorodeoxyglucose ( 18 F-FDG) uptake in both spinal cord and lower limb muscles following 6 months of epidural electrical stimulation (EES) treatment in spinal cord injury (SCI) individuals, examining potential implications for metabolic and functional recovery. Materials and Methods: A clinical trial (NCT04969042) was conducted to improve lower limb motor function using EES. Resting 18 F-FDG Positron Emission Tomography–Computed Tomography (PET/CT) was performed before EES implantation and after 6 months of EES treatment. Metabolic changes were assessed in both the spinal cord and lower limb muscles. Results: After 6 months of EES treatment, the motor function of the lower limbs gradually recovers. EES can synergistically activate the muscles to form a rhythmic gait. Increased intraspinal 18 F-FDG uptake was observed in the EES-implanted region, while a decrease was noted in nonstimulated segments, indicating a redistribution of spinal cord 18 F-FDG uptake. In addition, muscle cross-sectional total glycolysis (TLG) increased in the lower limbs. The TLG increased by 19.84% in the psoas major, by 30.67% in the iliacus muscle, and by 9.78% in the thigh muscles. Conclusions: EES promotes localized 18 F-FDG uptake at stimulated intraspinal region and lower limb muscles, suggesting potential as a targeted metabolic intervention for motor recovery in SCI and related metabolic dysfunctions.
Excellent Response of Glioblastoma Multiforme to [177Lu] Lu-PSMA Therapy
Authors: Tahereh Ghaedian, Abdolmajid Alipour, Abbas Rakhsha, Hamid Nasrollahi, Mehrnaz Ghaedian, Susan Andalibi, Arash Saffarian
Journal: Clinical Nuclear Medicine (2025)

The application of PSMA theranostic pairs in the glioblastoma multiform (GBM) has gained attention recently due to reports of PSMA radiotracer uptake in these tumors. The presented case is a 42-year-old man who had a known case of GBM with no response to standard-of-care therapy. However, 6 doses of 100-150 mCi 177 Lu-PSMA-617 therapy with short intervals of 4–5 weeks revealed excellent response on both MRI and 99m Tc-HYNIC-PSMA-11 scintigraphy. Though more dedicated studies are warranted, this case highlighted the potential efficacy of the 177 Lu-PSMA therapy in recurrent refractory GBM.
Comparison of Al18F-NOTA-FAPI-74 and 18F-FDG PET/CT in the Evaluation and Staging of Hepatobiliary Malignancies
Authors: Guozhu Hou, Xin Cheng, Yuanyuan Jiang, Yi Yang, Bo Chen, Zhen Huang, Zhuo Li, Aiping Zhou, Xiaoyuan Chen, Rong Zheng, Hong Zhao, Jingjing Zhang, Xuejuan Wang
Journal: Clinical Nuclear Medicine (2025)

Background: Accurate diagnosis and staging are crucial for the management of patients with hepatobiliary malignancies. Here, we investigated the efficacy of Al 18 F-NOTA-FAPI-74 PET/CT in detecting hepatobiliary malignancies and compared the results with 18 F-FDG PET/CT. Patients and Methods: Participants with hepatobiliary malignancies were prospectively enrolled and underwent paired Al 18 F-NOTA-FAPI-74 and 18 F-FDG PET/CT from April 2023 to March 2024. Histopathology and/or follow-up imaging served as the reference standard. The SUVmax of the primary and metastatic lesions between Al 18 F-NOTA-FAPI-74 and 18 F-FDG PET/CT were compared using the Wilcoxon signed-rank test. The association between Al 18 F-NOTA-FAPI-74 uptake intensity and immunohistochemical FAP expression was analyzed with Spearman r correlation. Results: Our cohort comprised of 28 patients with hepatobiliary malignancies, including 12 with hepatocellular carcinoma, 13 with intrahepatic cholangiocarcinoma (ICC), 2 with perihilar cholangiocarcinoma, and 1 with gallbladder carcinoma. Of these 28 patients, 13 underwent PET/CT for initial staging and 15 for restaging. Al 18 F-NOTA-FAPI-74 PET/CT showed higher sensitivity than 18 F-FDG PET/CT for detecting primary tumors [100% (13/13) vs 92.3% (12/13)], lymph node metastases [79.2% (42/53) vs 54.7% (29/53)], and bone and visceral metastases [97.6% (164/168) vs 69.0% (116/168)]. Al 18 F-NOTA-FAPI-74 PET/CT findings led to upstaging or restaging in 6 of 28 patients compared with the 18 F-FDG PET/CT-based stage. In addition, Al 18 F-NOTA-FAPI-74 PET/CT detected tumor-related obstructive inflammation in 7 patients, while 18 F-FDG PET/CT detected it in only 1 patient (25% vs 3.6%). All these 7 patients suffered from cholangiocarcinomas, including 5 with ICC and 2 with perihilar cholangiocarcinomas. The SUVmax of obstructive inflammation on Al 18 F-NOTA-FAPI-74 PET/CT was significantly lower than that of tumor (median SUVmax, 4.0 vs 8.8; P = 0.008). A positive correlation was found between FAPI uptake and FAP expression ( r = 0.730, P = 0.04). Conclusions: In patients with hepatobiliary malignancies, Al 18 F-NOTA-FAPI-74 PET/CT outperformed 18 F-FDG PET/CT in detecting primary tumors and metastatic lesions, resulting in more accurate staging or restaging. In addition, Al 18 F-NOTA-FAPI-74 PET/CT showed good detection efficacy for tumor-related obstructive inflammation, which was only found in cholangiocarcinoma, thus rendering Al 18 F-NOTA-FAPI-74 the potential to differentiate ICC from hepatocellular carcinoma.
Vertebral Artery Microcalcification Detected by 18F-NaF PET/CT
Authors: Shiv Patil, Nirmal Patel, Eric Teichner, Thomas Werner, Poul Flemming Høilund-Carlsen, Abass Alavi
Journal: Clinical Nuclear Medicine (2025)

Intracranial atherosclerosis is a leading cause of stroke and cognitive dysfunction. Calcification of intracranial atherosclerotic plaques is commonly observed on noncontrast CT, yet structural imaging alone cannot visualize active microcalcifications characteristic of progressive atheroma. 18 F-NaF is an emerging PET radiotracer of vascular microcalcification that may enable the detection of such pathophysiology. In this report, we present molecular microcalcification of the left vertebral artery incidentally found on 18 F-NaF PET/CT of a 64-year-old man with risk factors for intracranial atherosclerosis.
Cervical Paraganglioma Negative on Both 68Ga-DOTATATE and 18F-FDG PET/CT Studies
Authors: Lixiang Yang, Yuheng Zou, Rong Tian
Journal: Clinical Nuclear Medicine (2025)

A 66-year-old woman with a nodule between the bladder and the vagina underwent both 68 Ga-DOTATATE and 18 F-FDG PET/CT. Neither study showed increased activity in the nodule. Cervical paraganglioma was diagnosed from the pathologic examination.