tbuckley/cabot-search huggingface dataset:
Targeting aging with urolithin A in humans: A systematic review
Authors: Ajla Hodzic Kuerec, Xuan K. Lim, Anderson LY. Khoo, Elena Sandalova, Lihuan Guan, Lei Feng, Andrea B. Maier
Journal: Ageing Research Reviews (2024)

Urolithin A (UA) is a gut metabolite derived from ellagic acid. This systematic review assesses the potential geroprotective effect of UA in humans. In five studies including 250 healthy individuals, UA (10-1000 mg/day) for a duration ranging from 28 days to 4 months, showed a dose-dependent anti-inflammatory effect and upregulated some mitochondrial genes, markers of autophagy, and fatty acid oxidation. It did not affect mitochondrial maximal adenosine triphosphate production, biogenesis, dynamics, or gut microbiota composition. UA increased muscle strength and endurance, however, had no effect on anthropometrics, cardiovascular outcomes, and physical function. Unrelated adverse events were mild or moderate. Further research across more physiological systems and longer intervention periods is required.
Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: A randomized, double-blind, placebo-controlled study
Authors: Stephen A. Harrison, Sarah K. Browne, John J. Suschak, Shaheen Tomah, Julio A. Gutierrez, Jay Yang, M. Scot Roberts, M. Scott Harris
Journal: Journal of Hepatology (2024)

Background & AimsThis was a randomized, double-blind, placebo-controlled study to assess the effects of pemvidutide, a glucagon-like peptide-1 (GLP-1)/glucagon dual receptor agonist, on liver fat content (LFC) in subjects with metabolic dysfunction-associated steatotic liver disease (MASLD).MethodsSubjects with a BMI ≥28.0 kg/m2 and LFC ≥10% by magnetic resonance imaging-proton density fat fraction were randomized 1:1:1:1 to pemvidutide at 1.2 mg, 1.8 mg, or 2.4 mg, or placebo administered subcutaneously once weekly for 12 weeks. Participants were stratified according to a diagnosis of type 2 diabetes mellitus (T2DM). The primary efficacy endpoint was relative reduction (%) from baseline in LFC after 12 weeks of treatment.Results94 subjects were randomized and dosed. Median baseline BMI and LFC across the study population were 36.2 kg/m2 and 20.6%; 29% of subjects had T2DM. At Week 12, relative reductions in LFC from baseline were (1.2 mg) 46.6% [95% CI -63.7 to -29.6], (1.8 mg) 68.5% [95% CI -84.4 to -52.5], and (2.4 mg) 57.1% [95% CI -76.1 to -38.1] versus 4.4% [95% CI -20.2 to 11.3] in placebo subjects (p <0.001 vs. placebo, all treatment groups), with 94.4% and 72.2% of subjects achieving 30% and 50% reductions in LFC and 55.6% achieving normalization (≤5% LFC) at the 1.8 mg dose. Maximal responses for weight loss (-4.3%; p <0.001), alanine aminotransferase (-13.8 IU/L; p = 0.029), and corrected cT1 (-75.9 ms; p = 0.002) were all observed at the 1.8 mg dose. Pemvidutide was well-tolerated at all doses with no severe or serious adverse events.ConclusionsIn subjects with MASLD, weekly pemvidutide treatment yielded significant reductions in LFC, markers of hepatic inflammation, and body weight compared to placebo.Impact and implicationsMASLD, and MASH, are strongly associated with overweight and obesity and it is believed that the excess liver fat associated with obesity is an important driver of these diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonists elicit weight loss through centrally and peripherally mediated effects on appetite. Unlike GLP-1R agonists, glucagon receptor (GCGR) agonists act directly on the liver to stimulate fatty acid oxidation and inhibit lipogenesis, potentially providing a more potent mechanism for liver fat content (LFC) reduction than weight loss alone. This study demonstrated the ability of once-weekly treatment with pemvidutide, a dual GLP-1R/GCGR agonist, to significantly reduce LFC, hepatic inflammatory activity, and body weight, suggesting that pemvidutide may be an effective treatment for both MASH and obesity.Clinical Trial NumberNCT05006885.
Detection of Bordetella spp. in children with pertussis-like illness from 2018 to 2024 in China
Authors: Yahong Hu, Wei Shi, Qinghong Meng, Lin Yuan, Wei Gao, Lei Wang, Kaihu Yao
Journal: Journal of Infection (2024)

To evaluate the role of Bordetella pertussis (B. pertussis), B. parapertussis, B. holmesii, and B. bronchiseptica on pertussis resurgence in China, particularly the sharp rise since the latest winter.
Infection history imprints prolonged changes to the epigenome, transcriptome and function of Kupffer cells
Authors: Mohamed Amer Musrati, Benoit Stijlemans, Abdulkader Azouz, Daliya Kancheva, Sarah Mesbahi, Eva Hadadi, Els Lebegge, Leen Ali, Karen De Vlaminck, Isabelle Scheyltjens, Niels Vandamme, Maida Zivalj, Naela Assaf, Yvon Elkrim, Ilham Ahmidi, Camille Huart, Mohamed Lamkanfi, Martin Guilliams, Patrick De Baetselier, Stanislas Goriely, Kiavash Movahedi, Jo A. Van Ginderachter
Journal: Journal of Hepatology (2024)

Background and aimsLiver macrophages fulfill various homeostatic functions and represent an essential line of defense against pathogenic insults. However, it remains unclear whether a history of infectious disease in the liver instructs long-term alterations to the liver macrophage compartment.MethodsWe utilized a curable model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of fate mapping, single cell CITE-sequencing, single nuclei multiome analysis, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection.ResultsWe show that T. b. brucei infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages engraft in the liver, assume a Kupffer cell (KC)-like profile and co-exist with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted an altered transcriptional program on post-resolution KCs that was underpinned by an epigenetic remodeling of KC chromatin landscapes and a shift in KC ontogeny, along with transcriptional and epigenetic alterations in their niche cells. This reprogramming altered KC functions and was associated with increased resilience to a subsequent bacterial infection.ConclusionOur study demonstrates that a prior exposure to a parasitic infection induces trained immunity in KCs, reshaping their identity and function in the long-term.Impact And ImplicationsAlthough the liver is frequently affected during infections, and despite housing a major population of resident macrophages known as Kupffer cells (KCs), it is currently unclear whether infections can durably alter KCs and their niche cells. Our study provides a comprehensive investigation into the long-term impact of a prior, cured parasitic infection, unveiling long-lasting ontogenic, epigenetic, transcriptomic and functional changes to KCs as well as KC niche cells, which may contribute to KC remodeling. Our data suggest that infection history may continuously reprogram KCs throughout life with potential implications for subsequent disease susceptibility in the liver, influencing preventive and therapeutic approaches.
Comparison of 68Ga-FAPI-04 and 18F-FDG PET/CT in Fumarate Hydratase-Deficient Renal Cell Carcinoma
Authors: Shuhui Huang, Haoyang Liu, Hongyuan Dai, Mengfang Qi, Minggang Su, Hao Zeng, Rui Huang
Journal: Clinical Nuclear Medicine (2024)

Fumarate hydratase-deficient renal cell cancer (FHRCC) is a rare and aggressive form of renal cell carcinoma. The diagnostic value of 68 Ga-FAPI PET/CT for FHRCC remains unexplored. Therefore, we compared the potential value of 68 Ga-FAPI-04 and 18 F-FDG PET/CT in FHRCC.
A phase 1/2 dose escalation and expansion study of sonodynamic therapy with SONALA-001 in combination with Exablate 4000 Type 2.0 MR-guided focused ultrasound in patients with progressive or recurrent glioblastoma (rGBM).
Authors: Dimitris Placantonakis, Matthew Grabowski, Terry C. Burns, Nicholas A. Butowski, Peter Fenn, Ryan Clanton, Lenora Henry, Wyatt Potter, Corina Andresen, Stuart Marcus, Ely Benaim
Journal: Journal of Clinical Oncology (2024)

TPS2101 Background: Recurrent glioblastoma (rGBM) is a lethal brain tumor with no effective therapy and an extremely poor prognosis (median survival 6 to 8 months after first recurrence). Sonodynamic therapy (SDT) is a non-invasive combination treatment that utilizes a drug, aminolevulinic acid HCL (SONALA-001), and a device, the Exablate 4000 Type 2.0, to deliver non-ablative MR-guided focused ultrasound (MRgFUS) to tumor. Preclinical studies have shown that SDT-induced sonoluminescence activates protoporphyrin IX (PpIX), which in turn generates reactive oxygen species that lead to tumor cell death and improved survival in animal glioma models. A first-in-human Phase 0 trial (NCT04559685) indicated that SONALA-001 SDT was well-tolerated and not associated with off-target cellular or radiographic effects, and provided direct evidence of reactive oxygen species formation and targeted tumor cell death in recurrent high-grade glioma (rHGG). Methods: SDT-202 is a Phase 1/2 multicenter, open-label, dose escalation and expansion study (NCT05370508) of 10 mg/kg iv SONALA-001 in combination with MRgFUS for SDT in patients with progressive or recurrent GBM. Treatments take place every 4 weeks. In phase 1, sonication energy escalation utilizes an accelerated titration design with a single subject for dose level 1, followed by cohorts 2 and 3 with 3+3 design for additional dose escalation. SONALA-001 is administered 6 to 12 hours prior to MRgFUS treatment. Once the RP2D is determined, Phase 2 dose expansion will enroll approximately 36 additional subjects to assess safety and efficacy of repeated cycles of SONALA-001 SDT at the optimized RP2D. Endpoints of this study are safety evaluation, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and determination of pharmacokinetic (PK) parameters. The Phase 2 portion will further characterize safety of RP2D along with evaluation of efficacy with PFS6 (mRANO), ORR, CBR, DOR, DOCR, TTR, and OS. Clinical trial information: NCT05370508 .
A multicenter, randomized controlled phase 2b trial of survivin vaccine SurVaxM plus adjuvant temozolomide for newly diagnosed glioblastoma (SURVIVE).
Authors: Manmeet Singh Ahluwalia, Michael J Ciesielski, David A. Reardon, Nicholas A. Butowski, Robert Aiken, Vyshak Venur, Ajay Prakash Abad, Laszlo Mechtler, David M. Peereboom, Yazmin Odia, Kaylyn Sinicrope, John A Boockvar, Andrew J. Brenner, Marissa Barbaro, Ahmad Ozair, Ahmed Belal, Jing-Xin Qiu, Atulya Aman Khosla, Danielle M. Casucci, Robert Alan Fenstermaker
Journal: Journal of Clinical Oncology (2024)

TPS2099 Background: Newly-diagnosed glioblastoma (nGBM) has a dismal prognosis with a median overall survival (OS) of nearly 16 months. nGBM cells have high expression of tumor-associated survivin protein. Survivin, localized to the cell surface through presentation by MHC class I molecules, is recognized by antibodies and cytotoxic T-lymphocytes (CTLs). A phase 2a trial (NCT02455557) demonstrated a median OS of 25.9 months in nGBM from a 15-amino acid-peptide-conjugate vaccine (SurVaxM), which also stimulated production of survivin-directed antibodies and anti-tumor CTL. This phase 2b randomized controlled trial (RCT) aims to further investigate the efficacy and safety of SurVaxM and adjuvant temozolomide for nGBM. Methods: This multicenter, placebo-controlled, investigator- and patient-blinded, in-progress RCT randomizes nGBM patients receiving standard of care to either SurVaxM (arm A) or saline placebo (arm B) in a 3:2 ratio at 11 sites. Included patients have age ≥18 years, normal organ function, Karnofsky Performance Status (KPS) ≥70, receiving surgical resection with residual MRI contrast enhancement of ≤1 cm 3 within 72 hours of resection, and adjuvant temozolomide (TMZ) therapy. Patients with recurrent, multicentric, brainstem- or cerebellar-origin GBM are excluded, as well as patients on tumor-treating fields or other immunotherapies. All patients undergo 3 phases: (1) vaccine priming (VP) phase, starting within 4 weeks after completion of chemoradiation, where 4 doses of SurVaxM or Placebo are administered every 2 weeks; (2) adjuvant TMZ phase, started after ≥1 VP dose; and (3) vaccine maintenance phase, started 8 weeks after VP, with SurVaxM or placebo given every 8 weeks. TMZ phase overlaps with VP and VM phases. The primary endpoint is median OS. Assuming a 1-year survival rate of 75% in the SurVaxM arm, comparable to median OS in early phase trials, and 60% in the control arm, the required sample size consists of 137 in the SurVaxM arm and 91 in the control arm for a total sample size of 228. Accounting for dropout, the study aims to enroll 246 patients. A log-rank test stratified by KPS (70-80 and 90-100), MGMT status (methylated and unmethylated), and IDH status (mutant and wild-type) will be used for analysis. Secondary endpoints per study arm are survival at 15, 18, and 24 months, median progression-free survival, toxicity, and progression-free survival at 3, 6, and 12 months. A single sequential OS-driven interim analysis is planned when 50% of OS events (deaths) occur. 205 patients have been enrolled as of January 2024. Clinical trial information: NCT05163080 .
Phase 1 dose-finding study to evaluate safety and tolerability of CVGBM in patients with newly diagnosed and surgically resected MGMT-unmethylated glioblastoma.
Authors: Ghazaleh Tabatabai, Louisa Von Baumgarten, Martin J. Van Den Bent, Michael C Burger, Pierre Freres, Martin Glas, Peter Hau, Ulrich Herrlinger, Iris Mildenberger, Bart Neyns, Henning Sebastian Schafer, Clemens Seidel, Rachel Galot, Antje Wick, Martin H. Falk, Laura Leticia de Freitas Chama, Peter Kelemen, Sven D Koch, Paula Romer Roche, Senta Ulrike Gnad-Vogt
Journal: Journal of Clinical Oncology (2024)

TPS2095 Background: Glioblastoma (GBM) is characterized by a low mutational burden limiting the number of neoantigen targets for cancer vaccines. Vaccination against tumor-associated antigens over-presented via MHC class I and II in GBM is an alternative that has shown promise in previous trials. A previous cancer vaccine containing peptides presented by HLA-A*02:01 (class I) and some DR alleles (class II), showed evidence of peripheral and intratumoral vaccine-induced immune response against these peptides in patients with GBM. Our study will assess the safety and immunogenicity of the messenger ribonucleic acid (mRNA)-based multiepitope vaccine CVGBM, an investigational therapeutic mRNA vaccine, encoding eight of these peptides that have demonstrated immunogenicity as peptide vaccines. CVGBM consists of a mRNA with unmodified nucleotides formulated with lipid nanoparticles. Methods: CV-GBLM-001 (NCT05938387) is a first-in-human, open-label, international, dose-escalation phase 1 trial. HLA-A*02:01-positive patients with newly diagnosed MGMT-unmethylated GBM (CNS WHO Grade 4), including IDH-wildtype astrocytoma with a molecular signature of unmethylated glioblastoma who have had a gross total or partial resection and who completed post-surgery radiotherapy with or without chemotherapy, are eligible to receive CVGBM. The trial comprises a dose-escalation part (Part A) followed by a dose-expansion part (Part B). In Part A, mRNA dose levels between 12 and 100 µg are being investigated and dose escalation is guided by a Bayesian logistic regression model. Patients will receive 7 doses of CVGBM by intramuscular injection on Days 1, 8, 15, 29, 43, 57, and 71, followed by 6 optional doses at 6-week intervals, up to 1 year after the first dose or until disease progression or intolerable toxicity. An independent Data and Safety Monitoring Board will recommend the dose for expansion in Part B and about 20 patients will be enrolled. Biomarkers and vaccine-induced innate and adaptive immunogenicity, including, but not limited to, systemically induced cytokines and chemokines and antigen-specific CD4 + and CD8 + T cells, will be monitored in the blood, and optionally in vaccine-draining lymph nodes and progressive tumors. In addition to the primary safety objectives, secondary objectives of efficacy (progression-free survival, overall survival) and patient-reported quality of life outcomes will be assessed. Trial sponsor: CureVac SE, Germany. Clinical trial information: NCT05938387 .
A phase I/II study to assess safety and preliminary evidence of a therapeutic effect of azeliragon combined with stereotactic radiation therapy in patients with brain metastases (ADORATION).
Authors: Rupesh Kotecha, Yazmin Odia, Zhijian Chen, Amy K. Starosciak, Muni Rubens, Alonso La Rosa, Susana Herrera, Miguel A. Ramirez Menendez, Cristina I. Pow-Sang, Suyen Ramos, Jennifer Perez, Manmeet Singh Ahluwalia, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2024)

TPS2093 Background: The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor which stimulates proliferation, invasion, resistance to chemotherapy and radiotherapy, and metastatic spread when activated. One of the RAGE ligands preferentially associated with brain metastasis, S100A9, has been recently identified as a specific mediator of radiotherapy resistance. RAGE also mediates neuroinflammatory pathways in the brain associated with peri-tumoral edema and cancer-related cognitive decline. Azeliragon is an oral small molecule agent that crosses the blood-brain barrier and inhibits RAGE interactions with its ligands, including S100A9. Consequently, the purpose of this study is to evaluate a new treatment paradigm with Azeliragon + stereotactic radiosurgery (SRS) for patients with brain metastasis to evaluate the safety and tolerability of the combined approach with the goal of minimizing the use of peri-procedural corticosteroids (loading dose [LD] and corticosteroid taper [CT]) as well was evaluating the potential radiosensitizing efficacy of this therapeutic combination. Methods: ADORATION is a single center, open-label, phase I/II cohort expansion trial to determine if azeliragon can be substituted for peri-procedural corticosteroids in patients undergoing SRS for brain metastasis. Eligible adults will have a confirmed cancer diagnosis in the last 5 years, a maximum tumor diameter of the largest brain metastasis ≤ 2 cm, and have discontinued corticosteroids at least 5 days prior to SRS. In phase I (n=up to 9), participants are enrolled into sequential cohorts, starting with azeliragon + SRS + LD. Depending on dose-limiting toxicities (DLTs) within 28 days of SRS, the next cohort will receive azeliragon + SRS alone or azeliragon + SRS + LD + CT. The phase II expansion cohort (n=up to 40 including the phase I cohort) will subsequently open with a primary endpoint of response rate. Azeliragon dosing includes a loading dose for 6 days followed by a continuous dose for at least 8 weeks, and SRS within 7 days of starting drug. Safety endpoints include number of DLTs and number of CNS treatment-related adverse events. Response endpoints include early brain metastasis response at 8 weeks, intracranial response at 6 and 12 months, and lesion specific local control. Neurocognitive batteries, symptom inventories, and quality-of-life questionnaires will also be administered. Three participants have been enrolled in the starting cohort and are pending DLT assessment. Clinical trial information: NCT05789589 .
Phase 1 study of multiple intracerebral doses of a neural stem cell-based oncolytic virotherapy for treatment of recurrent high-grade gliomas.
Authors: Jana Portnow, Behnam Badie, Suzette Blanchard, Massimo D'Apuzzo, Aritro Nath, Timothy W. Synold, Floris Barthel, Rachael Mooney, Gary Ngai, Boris Minev, Antonio F. Santidrian, Karen S. Aboody
Journal: Journal of Clinical Oncology (2024)

TPS2102 Background: Oncolytic virotherapy is a promising cancer treatment that can directly lyse tumor cells as well as induce anti-tumor immune responses. However, clinical efficacy has been limited by rapid immune-mediated clearance of oncolytic viruses (OVs). Neural stem cell (NSC) carriers are tumor tropic and can protect OVs, allowing time for viral amplification and better distribution throughout tumors. HB1.F3.CD.21 is an immortalized, clonal human NSC line with demonstrated stability, scalability, and safety in humans (NCT01172964, NCT02015819). This NSC line was genetically modified to produce a tumor-selective, conditionally replicating adenovirus (CRAd; NSC-CRAd-S-pk7). A first-in-human clinical trial (NCT03072134) in newly diagnosed high grade glioma patients showed safety of a single intracerebral dose of NSC-CRAd-S-pk7 and determined the maximum feasible dose (MFD). Here we describe the next early phase clinical trial for development of this new NSC-based oncolytic virotherapy. Methods: This phase 1 study is evaluating the safety and feasibility of intracerebrally administering up to 4 weekly doses of NSC-CRAd-S-pk7 in patients with recurrent high grade gliomas. Study participants initially undergo resection of tumor followed by manual injection of the first dose of study agent into the wall of the resection cavity. Two Rickham catheters are also placed: one in the surgical cavity for subsequent administration of weekly doses of NSC-CRAd-S-pk7 and the other in the lateral ventricle to obtain serial CSF samples for correlative immunologic and safety studies. Two weeks after receiving the last dose of NSC-CRAd-S-pk7, participants undergo a second surgical procedure to remove the Rickham catheters and obtain post-treatment tissue samples. All participants are treated with the same dose of NSC-CRAd-S-pk7: 150 x 10 6 NSCs/1.875 x 10 11 viral particles, which is the MFD that was determined in the first-in-human study. A multi-cycle toxicity equivalence range design is used to define the escalation and de-escalation rules for evaluating the four treatment schedules. Once the maximum tolerated number of weekly cycles is determined, an expansion cohort will be assessed. The study’s secondary objectives include assessing the biologic activity, biodistribution, immunogenicity, safety, and preliminary clinical efficacy of NSC-CRAd-S-pk7. The estimated study sample size is 24-30 participants. Progress: The first patient began study treatment in May 2023. We are currently enrolling participants to Treatment Schedule 4. Multi-center sites for enrolling patients to the expansion cohort include City of Hope, Stanford University, Wake Forest University, and Northwestern University. Clinical trial information: NCT05139056 .