tbuckley/cabot-search huggingface dataset:
High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation
Authors: Yu Fan, Jincai Wang, Jingyi Jian, Yalei Wen, Jiahao Li, Hao Tian, Jacques Crommen, Wei Bi, Tingting Zhang, Zhengjin Jiang
Journal: Acta Pharmaceutica Sinica B (2024)

Human monoamine oxidase B (hMAO-B) has emerged as a pivotal therapeutic target for Parkinson's disease. Due to adverse effects and shortage of commercial drugs, there is a need for novel, highly selective, and reversible hMAO-B inhibitors with good blood-brain barrier permeability. In this study, a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma, which resulted in the discovery of 75 active compounds, including phenolic acids, volatile oils, and phthalides, two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent, selective, reversible and had good blood‒brain permeability. Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism. Sedanolide (IC50 = 103 nmol/L; SI = 645) and neocnidilide (IC50 = 131 nmol/L; SI = 207) demonstrated their excellent potential as hMAO-B inhibitors. They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline. In SH-SY5Y cell assays, sedanolide (EC50 = 0.962 μmol/L) and neocnidilide (EC50 = 1.161 μmol/L) exhibited significant neuroprotective effects, comparable to the positive drugs rasagiline (EC50 = 0.896 μmol/L) and safinamide (EC50 = 1.079 μmol/L). These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.
Interim FDG-PET improves treatment failure prediction in primary central nervous system lymphoma: An LOC network prospective multicentric study
Authors: Laura Rozenblum, Caroline Houillier, Amandine Baptiste, Carole Soussain, Véronique Edeline, Philippe Naggara, Marine Soret, Valérie Causse-Lemercier, Lise Willems, Sylvain Choquet, Renata Ursu, Damien Galanaud, Lisa Belin, Khê Hoang-Xuan, Aurélie Kas
Journal: Neuro-Oncology (2024)

The purpose of our study was to assess the predictive and prognostic role of 2-18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/MRI during high-dose methotrexate-based chemotherapy (HD-MBC) in de novo primary central nervous system lymphoma (PCNSL) patients aged 60 and above. This prospective multicentric ancillary study included 65 immunocompetent patients who received induction HD-MBC as part of the BLOCAGE01 phase III trial. FDG-PET/MRI were acquired at baseline, post 2 cycles (PET/MRI2), and posttreatment (PET/MRI3). FDG-PET response was dichotomized with "positive" indicating persistent tumor uptake higher than the contralateral mirroring brain region. Performances of FDG-PET and International PCNSL Collaborative Group criteria in predicting induction response, progression-free survival (PFS), and overall survival (OS) were compared. Of the 48 PET2 scans performed, 9 were positive and aligned with a partial response (PR) on MRI2. Among these, 8 (89%) progressed by the end of the induction phase. In contrast, 35/39 (90%) of PET2-negative patients achieved complete response (CR). Among the 18 discordant responses at interim (PETCR/MRIPR), 83% ultimately achieved CR. Eighty-seven percent of the PET2-negative patients were disease free at 6 months versus 11% of the PET2-positive patients (P < .001). The MRI2 response did not significantly differentiate patients based on their PFS, regardless of whether they were in CR or PR. Both PET2 and MRI2 independently predicted OS in multivariate analysis, with PET2 showing a stronger association. Our study highlights the potential of interim FDG-PET for early management of PCNSL patients. Response-driven treatment based on PET2 may guide future clinical trials. LOCALYZE, NCT03582254, ancillary of phase III clinical trial BLOCAGE01, NCT02313389 (Registered July 10, 2018-retrospectively registered) https://clinicaltrials.gov/ct2/show/NCT03582254?term=LOCALYZE&draw=2&rank=1.
Solving the antibacterial resistance in Europe: the multipronged approach of the COST Action CA21145 EURESTOP
Authors: Carole Seguin-Devaux, Tomislav Mestrovic, Jacobus J. Arts, Didem Sen Karaman, Cristina Nativi, Dana Reichmann, Priyanka Sahariah, Younes Smani, Patricia Rijo, Mattia Mori
Journal: Drug Resistance Updates (2024)
Immune response to post-translationally modified proteins in rheumatoid arthritis: what makes it special?
Authors: Diane van der Woude, René E M Toes
Journal: Annals of the Rheumatic Diseases (2024)

Rheumatoid arthritis (RA) exhibits common characteristics with numerous other autoimmune diseases, including the presence of susceptibility genes and the presence of disease-specific autoantibodies. Anti-citrullinated protein antibodies (ACPA) are the hallmarking autoantibodies in RA and the anti-citrullinated protein immune response has been implicated in disease pathogenesis. Insight into the immunological pathways leading to anti-citrullinated protein immunity will not only aid understanding of RA pathogenesis, but may also contribute to elucidation of similar mechanisms in other autoantibody-positive autoimmune diseases. Similarly, lessons learnt in other human autoimmune diseases might be relevant to understand potential drivers of RA. In this review, we will summarise several novel insights into the biology of the anti-citrullinated protein response and their clinical associations that have been obtained in recent years. These insights include the identification of glycans in the variable domain of ACPA, the realisation that ACPA are polyreactive towards other post-translational modifications on proteins, as well as new awareness of the contributing role of mucosal sites to the development of the ACPA response. These findings will be mirrored to emerging concepts obtained in other human (autoimmune) disease characterised by disease-specific autoantibodies. Together with an updated understanding of genetic and environmental risk factors and fresh perspectives on how the microbiome could contribute to antibody formation, these advancements coalesce to a progressively clearer picture of the B cell reaction to modified antigens in the progression of RA.
Nanotechnology and nano-sized tools: Newer approaches to circumvent oncolytic adenovirus limitations
Authors: Maryam Mashhadi Abolghasem Shirazi, Tayebeh Azam Saedi, Zahra Samadi Moghaddam, Mahnaz Nemati, Reza Shiri, Babak Negahdari, Nasser Hashemi Goradel
Journal: Pharmacology & Therapeutics (2024)
Comparing venetoclax in combination with hypomethylating agents to hypomethylating agent-based therapies for treatment naive TP53-mutated acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND)
Authors: Talha Badar, Ahmad Nanaa, Ehab Atallah, Rory M. Shallis, Sacchi de Camargo Correia Guilherme, Aaron D. Goldberg, Antoine N. Saliba, Anand Patel, Jan P. Bewersdorf, Adam S. DuVall, Danielle Bradshaw, Yasmin Abaza, Guru Subramanian Guru Murthy, Neil Palmisiano, Amer M. Zeidan, Vamsi Kota, Mark R. Litzow
Journal: Blood Cancer Journal (2024)
99mTc-HYNIC-FAPI-46 SPECT/CT Uptake in Lactating Breasts
Authors: Bentolhoda Hadad, Kamran Aryana, Hassan Kamali, Emran Askari
Journal: Clinical Nuclear Medicine (2024)

Abstract A 36-year-old woman with a history of medullary thyroid carcinoma was referred for 99m Tc-HYNIC-FAPI-46 scan. Her calcitonin levels gradually increased after external beam radiation therapy, whereas her CEA levels were stable. A few suspicious tumoral lymphadenopathies were localized to the superior mediastinum. Interestingly, bilateral physiologic breast uptake was noticed, which was presumed to be due to lactation in the past 18 months. To our knowledge, physiologic breast uptake in 99m Tc-HYNIC-FAPI imaging has not been previously reported.
RAS-MAPK Pathway Mutations in Congenital Pulmonary Airway Malformations
Authors: Jonas Windrich, Peter Braubach, Florian Länger, Jens Dingemann, Nicolaus Schwerk, Martin Wetzke, Diane M. Renz, Martin Zenker, Denny Schanze, Christian P. Kratz
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
Comparison of 18F-FAPI and 18F-FDG PET/CT in a Patient With Fibrous Dysplasia
Authors: Xingyu Mu, Zuguo Li, Jie Qin, Zhenzhen Wang, Wei Fu
Journal: Clinical Nuclear Medicine (2024)

Abstract A 16-year-old woman presented with an acute headache on the left side. A head CT scan revealed bone destruction in the skull. Subsequent 18 F-FDG and 18 F-FAPI PET/CT scans were performed within a week. The 18 F-FDG PET/CT indicated mild uptake in the regions of bone destruction, whereas the 18 F-FAPI PET/CT displayed significant tracer accumulation. The patient was ultimately diagnosed with fibrous dysplasia.
FDG Uptake Caused by Right Varicocele
Authors: Jia Deng, Yuanyuan Sun, Renjie He, Liang Cai, Yue Chen
Journal: Clinical Nuclear Medicine (2024)

Abstract A 67-year-old man underwent 18 F-FDG PET/CT for lung cancer staging. Interestingly, the PET scan revealed strip-shaped FDG uptake in the right inguinal contoured area, which was later confirmed as a right varicocele through ultrasound imaging.
Hypomethylating agents plus venetoclax compared with intensive induction chemotherapy regimens in molecularly defined secondary AML
Authors: Shai Shimony, Jan Philipp Bewersdorf, Rory M Shallis, Yiwen Liu, Eva J Schaefer, Amer M Zeidan, Aaron D Goldberg, Eytan M Stein, Guido Marcucci, R Coleman Lindsley, Evan C Chen, Jorge Ramos Perez, Anthony Stein, Daniel J DeAngelo, Donna S Neuberg, Richard M Stone, Brian Ball, Maximilian Stahl
Journal: Leukemia (2024)
Forskolin-driven conversion of human somatic cells into induced neurons through regulation of the cAMP-CREB1-JNK signaling
Authors: Guodong Wang, Dandan Zhang, Liangshan Qin, Quanhui Liu, Wenkui Tang, Mingxing Liu, Fan Xu, Fen Tang, Leping Cheng, Huiming Mo, Xiang Yuan, Zhiqiang Wang, Ben Huang
Journal: Theranostics (2024)

Human somatic cells can be reprogrammed into neuron cell fate through regulation of a single transcription factor or application of small molecule cocktails.Methods: Here, we report that forskolin efficiently induces the conversion of human somatic cells into induced neurons (FiNs).Results: A large population of neuron-like phenotype cells was observed as early as 24-36 h post-induction.There were >90% TUJ1-, >80% MAP2-, and >80% NEUN-positive neurons at 5 days post-induction.Multiple subtypes of neurons were present among TUJ1-positive cells, including >60% cholinergic, >20% glutamatergic, >10% GABAergic, and >5% dopaminergic neurons.FiNs exhibited typical neural electrophysiological activity in vitro and the ability to survive in vitro and in vivo more than 2 months.Mechanistically, forskolin functions in FiN reprogramming by regulating the cAMP-CREB1-JNK signals, which upregulates cAMP-CREB1 expression and downregulates JNK expression.Conclusion: Overall, our studies identify a safer and efficient single-small-molecule-driven reprogramming approach for induced neuron generation and reveal a novel regulatory mechanism of neuronal cell fate acquisition.
BitterDB database analysis plus cell stiffness screening identify flufenamic acid as the most potent TAS2R14-based relaxant of airway smooth muscle cells for therapeutic bronchodilation
Authors: Kai Ni, Bo Che, Rong Gu, Chunhong Wang, Hongyang Xu, Huiduo Li, Shiyan Cen, Mingzhi Luo, Linhong Deng
Journal: Theranostics (2024)

Rationale: Bitter taste receptors (TAS2Rs) are abundantly expressed in airway smooth muscle cells (ASMCs), which have been recognized as promising targets for bitter agonists to initiate relaxation and thereby prevent excessive airway constriction as the main characteristic of asthma.However, due to the current lack of tested safe and potent agonists functioning at low effective concentrations, there has been no clinically approved TAS2R-based drug for bronchodilation in asthma therapy.This study thus aimed at exploring TAS2R agonists with bronchodilator potential by BitterDB database analysis and cell stiffness screening.Methods: Bitter compounds in the BitterDB database were retrieved and analyzed for their working subtype of TAS2R and effective concentration.Compounds activating TAS2R5, 10, and 14 at < 100 μM effective concentration were identified and subsequently screened by cell stiffness assay using optical magnetic twisting cytometry (OMTC) to identify the most potent to relax ASMCs.Then the compound identified was further characterized for efficacy on various aspects related to relaxation of ASMCs, incl.but not limited to traction force by Fourier transform traction force microscopy (FTTFM), [Ca 2+ ]i signaling by Fluo-4/AM intensity, cell migration by scratch wound healing, mRNA expression by qPCR, and protein expressing by ELISA.The compound identified was also compared to conventional β-agonist (isoproterenol and salbutamol) for efficacy in reducing cell stiffness of cultured ASMCs and airway resistance of ovalbumin-treated mice.Results: BitterDB analysis found 18 compounds activating TAS2R5, 10, and 14 at < 100 μM effective concentration.Cell stiffness screening of these compounds eventually identified flufenamic acid (FFA) as the most potent compound to rapidly reduce cell stiffness at 1 μM.The efficacy of FFA to relax ASMCs in vitro and abrogate airway resistance in vivo was equivalent to that of conventional β-agonists.The FFA-induced effect on ASMCs was mediated by TAS2R14 activation, endoplasmic reticulum Ca 2+ release, and large-conductance Ca 2+ -activated K + (BKCa) channel opening.FFA also attenuated lipopolysaccharide-induced inflammatory response in cultured ASMCs.Conclusions: FFA as a potent TAS2R14 agonist to relax ASMCs while suppressing cytokine release might be a favorite drug agent for further development of TAS2R-based novel dual functional medication for bronchodilation and anti-inflammation in asthma therapy.
Terbium radionuclides for theranostic applications in nuclear medicine: from atom to bedside
Authors: Camille Van Laere, Michel Koole, Christophe M. Deroose, Michiel Van de Voorde, Kristof Baete, Thomas E. Cocolios, Charlotte Duchemin, Maarten Ooms, Frederik Cleeren
Journal: Theranostics (2024)

Terbium features four clinically interesting radionuclides for application in nuclear medicine: terbium-149, terbium-152, terbium-155, and terbium-161.Their identical chemical properties enable the synthesis of radiopharmaceuticals with the same pharmacokinetic character, while their distinctive decay characteristics make them valuable for both imaging and therapeutic applications.In particular, terbium-152 and terbium-155 are useful candidates for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging, respectively; whereas terbium-149 and terbium-161 find application in α-and β --/Auger electron therapy, respectively.This unique characteristic makes the terbium family ideal for the "matched-pair" principle of theranostics.In this review, the advantages and challenges of terbium-based radiopharmaceuticals are discussed, covering the entire chain from radionuclide production to bedside administration.It elaborates on the fundamental properties of terbium, the production routes of the four interesting radionuclides and gives an overview of the available bifunctional chelators.Finally, we discuss the preclinical and clinical studies as well as the prospects of this promising development in nuclear medicine.
Unplanned Index Limb Revascularization With Rivaroxaban Versus Placebo in Patients With Critical Limb-Threatening Ischemia After Endovascular and Surgical Treatment: Insights From VOYAGER PAD
Authors: Shea E. Hogan, Eike Sebastian Debus, Mark R. Nehler, Manesh R. Patel, Sonia S. Anand, Eva Muehlhofer, Lloyd P. Haskell, Scott D. Berkowitz, Rupert M. Bauersachs, Marc P. Bonaca
Journal: Circulation (2024)
Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography
Authors: George Joy, Luis R. Lopes, Matthew Webber, Alessandra M. Ardissino, James Wilson, Fiona Chan, Iain Pierce, Rebecca K. Hughes, Konstantinos Moschonas, Hunain Shiwani, Robert Jamieson, Paula P. Velazquez, Ramya Vijayakumar, Erica Dall’Armellina, Peter W. Macfarlane, Charlotte Manisty, Peter Kellman, Rhodri H. Davies, Maite Tome, Vladan Koncar, Xuyuan Tao, Christoph Guger, Yoram Rudy, Alun D. Hughes, Pier D. Lambiase, James C. Moon, Michele Orini, Gabriella Captur
Journal: Journal of the American College of Cardiology (2024)

Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)–guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]−), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G−LVH+) and structural phenotype. This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH−, 104 LVH+ (51 G+/53 G−), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH− from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G−LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.
Vertical tumor-positive resection margins and the risk of residual neoplasia after endoscopic resection of Barrett’s neoplasia: a nationwide cohort with pathology reassessment
Authors: Laurelle van Tilburg, Eva Verheij, Steffi Elisabeth Maria van de Ven, Sanne van Munster, Bas Weusten, Lorenza Alvarez Herrero, Wouter B Nagengast, Erik J Schoon, Alaa Alkhalaf, Jacques Bergman, Roos E. Pouw, Lindsey Oudijk, Sybren L Meijer, Marnix Jansen, Michael Doukas, Arjun Dave Koch
Journal: Endoscopy (2024)

Background This study evaluated the proportion of patients with residual neoplasia after endoscopic resection (ER) for Barrett’s neoplasia with confirmed tumor-positive vertical resection margin (R1v). Methods This retrospective cohort study included patients undergoing ER for Barrett’s neoplasia with histologically documented R1v since 2008 in the Dutch Barrett Expert Centers. We defined R1v as cancer cells touching vertical resection margins and Rx as nonassessable margins. Reassessment of R1v specimens was performed by experienced pathologists until consensus was reached regarding vertical margins. Results 101/110 included patients had macroscopically complete resections (17 T1a, 84 T1b), and 99/101 (98%) ER specimens were histologically reassessed, with R1v confirmed in 74 patients (75%), Rx in 16%, and R0 in 9%. Presence/absence of residual neoplasia could be assessed in 66/74 patients during endoscopic reassessment (52) and/or in the surgical resection specimen (14), and 33/66 (50%) had residual neoplasia. Residual neoplasia detected during endoscopy was always endoscopically visible and biopsies from a normal-appearing ER scar did not detect additional neoplasia. Of 25 patients who underwent endoscopic follow-up (median 37 months [interquartile range 12–50]), 4 developed local recurrence (16.0%), all detected as visible abnormalities. Conclusions After ER with R1v, 50% of patients had no residual neoplasia. Histological evaluation of ER margins appears challenging, as in this study 75% of documented R1v cases were confirmed during reassessment. Endoscopic reassessment 8–12 weeks after ER seems to accurately detect residual neoplasia and can help to determine the most appropriate strategy for patients with R1v.
Activatable prodrug for controlled release of an antimicrobial peptide via the proteases overexpressed in <i>Candida albicans</i> and <i>Porphyromonas gingivalis</i>
Authors: Lubna Amer, Maurice Retout, Jesse V. Jokerst
Journal: Theranostics (2024)

Candida albicans and Porphyromonas gingivalis are prevalent in the subgingival area where the frequency of fungal colonization increases with periodontal disease.Candida's transition to a pathogenic state and its interaction with P. gingivalis exacerbate periodontal disease severity.However, current treatments for these infections differ, and combined therapy remains unexplored.This work is based on an antimicrobial peptide that is therapeutic and induces a color change in a nanoparticle reporter.Methods: We built and characterized two enzyme-activatable prodrugs to treat and detect C. albicans and P. gingivalis via the controlled release of the antimicrobial peptide.The zwitterionic prodrug quenches the antimicrobial peptide's activity until activation by a protease inherent to the pathogens (SAP9 for C. albicans and RgpB for P. gingivalis).The toxicity of the intact prodrugs was evaluated against fungal, bacterial, and mammalian cells.Therapeutic efficacy was assessed through microscopy, disk diffusion, and viability assays, comparing the prodrug to the antimicrobial peptide alone.Finally, we developed a colorimetric detection system based on the aggregation of plasmonic nanoparticles.Results: The intact prodrugs showed negligible toxicity to cells absent a protease trigger.The therapeutic impact of the prodrugs was comparable to that of the antimicrobial peptide alone, with a minimum inhibitory concentration of 3.1 -16 µg/mL.The enzymatic detection system returned a detection limit of 10 nM with gold nanoparticles and 3 nM with silver nanoparticles.Conclusion: This approach offers a convenient and selective protease sensing and protease-induced treatment mechanism based on bioinspired antimicrobial peptides.
A commentary on ‘Local excision as a viable alternative to hysterectomy for early-stage cervical cancer in women of reproductive age: a population-based cohort study’
Authors: Jianxia Zhang, Huiling Qiu, Yinxia Qing, Yanxia Hu, Huaxiang Deng
Journal: International Journal of Surgery (2024)

Zhang, Jianxia; Qiu, Huiling; Qing, Yinxia; Hu, Yanxia; Deng, Huaxiang Author Information