tbuckley/cabot-search huggingface dataset:
GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review
Authors: Paula Rodriguez-Otero, Niels W. C. J. van de Donk, Kodandaram Pillarisetti, Ingrid Cornax, Deeksha Vishwamitra, Kathleen Gray, Brandi Hilder, Jaszianne Tolbert, Thomas Renaud, Tara Masterson, Christoph Heuck, Colleen Kane, Raluca Verona, Philippe Moreau, Nizar Bahlis, Ajai Chari
Journal: Blood Cancer Journal (2024)

Abstract Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein–coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell–redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell–redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell–redirecting agents have shown promising efficacy and manageable safety profiles, including lower infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell–redirecting agents in combination with other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes.
Effect of a transitional care model following hospitalization for heart failure: 3‐year outcomes of the Patient‐Centered Care Transitions in Heart Failure (PACT‐HF) randomized controlled trial
Authors: Tauben Averbuch, Shun Fu Lee, Brandon Zagorski, Alexandre Mebazaa, Gregg C. Fonarow, Lehana Thabane, Harriette G.C. Van Spall
Journal: European Journal of Heart Failure (2024)

Abstract Aims Patients are at high risk of death or readmission following hospitalization for heart failure (HF). We tested the effect of a transitional care model that included month‐long nurse‐led home visits and long‐term heart function clinic visits ‐ with services titrated to estimated risk of clinical events ‐ on 3‐year outcomes following hospitalization. Methods and results In a pragmatic, stepped‐wedge cluster randomized trial, 10 hospitals were randomized to the intervention versus usual care. The primary outcome was a composite of all‐cause death, readmission, or emergency department (ED) visit. Secondary outcomes included components of the primary composite outcomes, HF readmissions and healthcare resource utilization. There were 2494 patients (50.4% female) with mean age of 77.7 years. The primary outcome was reached in 1040 (94.2%) patients in the intervention and 1314 (94.5%) in the usual care group at 3 years. The intervention did not reduce the risk of the primary composite outcome (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.81–1.05) nor the component outcomes overall, although numerically reduced the risk of ED visits in women but not men (HR 0.79, 95% CI 0.63–1.00 vs. HR 0.98, 95% CI 0.80–1.19; sex‐treatment interaction p = 0.23). The uptake of guideline‐directed medical therapy was no different with the intervention than with usual care, with the exception of sacubitril/valsartan, which increased with the intervention (3.3% vs 1.5%; relative risk 6.2, 95% CI 1.92–20.06). Conclusions More than 9 of 10 patients hospitalized for HF experienced all‐cause death, readmission, or ED visit at 3 years. A transitional care model with services titrated to risk did not improve the composite of these endpoints, likely because there were no major differences in uptake of medical therapies between the groups. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02112227.
Exercise is also medicine for iron homeostasis
Authors: Abel Plaza-Florido, Alejandro Lucia, Carmen Fiuza-Luces
Journal: Trends in Endocrinology and Metabolism (2024)

High-intensity interval training (HIIT) is gaining popularity as an effective exercise modality to improve cardiometabolic health. Combining high-throughput/sensitivity proteome analyses in subcutaneous adipose tissue with biochemical blood measures, Larsen et al. recently provided mechanistic insights into a potential beneficial role of this exercise modality on iron homeostasis at the whole-body level.
Pharmacological interventions in human aging
Authors: Michael Angelo Petr, Frida Matiyevskaya, Brenna Osborne, Magnus Berglind, Simon Reves, Bin Zhang, Michael Ben Ezra, Lina Maria Carmona-Marin, Muhammad Farraz Syadzha, Marta Cortés Mediavilla, Guido Keijzers, Daniela Bakula, Garik V Mkrtchyan, Morten Scheibye-Knudsen
Journal: Ageing Research Reviews (2024)
Smart Design of ZnFe and ZnFe@Fe Nanoparticles for MRI‐Tracked Magnetic Hyperthermia Therapy: Challenging Classical Theories of Nanoparticles Growth and Nanomagnetism
Authors: Carlos Caro, Cinzia Guzzi, Irene Moral‐Sánchez, Jesús David Urbano‐Gámez, Ana M. Beltrán, Maria Luisa García‐Martín
Journal: Advanced Healthcare Materials (2024)

Abstract Iron Oxide Nanoparticles (IONPs) hold the potential to exert significant influence on fighting cancer through their theranostics capabilities as contrast agents (CAs) for magnetic resonance imaging (MRI) and as mediators for magnetic hyperthermia (MH). In addition, these capabilities can be improved by doping IONPs with other elements. In this work, the synthesis and characterization of single‐core and alloy ZnFe novel magnetic nanoparticles (MNPs), with improved magnetic properties and more efficient magnetic‐to‐heat conversion, are reported. Remarkably, the results challenge classical nucleation and growth theories, which cannot fully predict the final size/shape of these nanoparticles and, consequently, their magnetic properties, implying the need for further studies to better understand the nanomagnetism phenomenon. On the other hand, leveraging the enhanced properties of these new NPs, successful tumor therapy by MH is achieved following their intravenous administration and tumor accumulation via the enhanced permeability and retention (EPR) effect. Notably, these results are obtained using a single low dose of MNPs and a single exposure to clinically suitable alternating magnetic fields (AMF). Therefore, as far as the authors are aware, for the first time, the successful application of intravenously administered MNPs for MRI‐tracked MH tumor therapy in passively targeted tumor xenografts using clinically suitable conditions is demonstrated.
Feminizing genital gender affirmation surgery: Patient-reported outcomes of urethral flap and classical penile inversion techniques
Authors: Barbara Mijuskovic, Salome Niggli, Kathrin Bausch, David Garcia Nuñez, Dirk J. Schaefer, Antje Feicke
Journal: International Journal of Transgender Health (2024)

Introduction: Although more and more transgender individuals are receiving gender-affirming medical interventions, there are limited data on patient-reported outcome measures (PROMs). We assessed PROMs in patients who received genital gender affirmation surgery (gGAS) with vaginoplasty by conventional penile inversion (PI) or urethral flap (UF). Methods: Consecutive patients undergoing vaginoplasty by PI or UF between 2015 and 2021 were candidates for this questionnaire-based cohort study. PROMs including satisfaction with body image and overall quality of life, esthetic, sensory, and functional parameters, including urological and sexual outcomes, and decision for surgery were assessed by using the Gender Congruence and Life Satisfaction scale, the Hamburg Body Drawing Scale, the Inclusive Sexual Function Inventory, and additional questions, and responses from PI and UF groups were compared. Results: With a response rate of 64%, total 41 patients were included in the study. Overall, patients reported high satisfaction with body image and quality of life after PI and UF. Patients with UF were significantly more comfortable being naked in front of a sexual partner compared to those with PI, but satisfaction with esthetics was high in both groups. The UF group had a significantly higher frequency of sanguineous discharge from the neovagina. Functional urological problems were rare in both groups, but urgency was reported more frequently in PI than in UF. Both groups reported generally high interest in sexual activity, and both frequently needed lubrication for neovaginal penetration. There were few regrets about the decision to undergo gGAS in either group. Conclusion: Patient satisfaction regarding body image, quality of life, functionality, sexuality, and decision for surgery was reasonably high, and UF seems to be a valid alternative to PI.
Bordetella pertussis isolates in Finland after acellular vaccination: serotype change and biofilm formation
Authors: Vili Niinikoski, Alex-Mikael Barkoff, Jussi Mertsola, Qiushui He
Journal: Clinical Microbiology and Infection (2024)

In Finland, whole cell pertussis vaccine (wP) was introduced in 1952 and was replaced by acellular pertussis vaccine (aP) without fimbrial (FIM) antigen in 2005. We aimed to analyse the changes in serotypes of circulating Bordetella pertussis before and after acellular vaccination and to explore the relationship between biofilm formation and serotype diversity after the introduction of aP vaccine.
Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency
Authors: Moritz Jakab, Ki Hong Lee, Alexey Uvarovskii, Svetlana Ovchinnikova, Shubhada R. Kulkarni, Sevinç Jakab, Till Rostalski, Carleen Spegg, Simon Anders, Hellmut G. Augustin
Journal: Nature Cancer (2024)

In metastasis, cancer cells travel around the circulation to colonize distant sites. Due to the rarity of these events, the immediate fates of metastasizing tumor cells (mTCs) are poorly understood while the role of the endothelium as a dissemination interface remains elusive. Using a newly developed combinatorial mTC enrichment approach, we provide a transcriptional blueprint of the early colonization process. Following their arrest at the metastatic site, mTCs were found to either proliferate intravascularly or extravasate, thereby establishing metastatic latency. Endothelial-derived angiocrine Wnt factors drive this bifurcation, instructing mTCs to follow the extravasation-latency route. Surprisingly, mTC responsiveness towards niche-derived Wnt was established at the epigenetic level, which predetermined tumor cell behavior. Whereas hypomethylation enabled high Wnt activity leading to metastatic latency, methylated mTCs exhibited low activity and proliferated intravascularly. Collectively the data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche.
Natural products as IL‐6 inhibitors for inflammatory diseases: Synthetic and SAR perspective
Authors: Dipesh S. Harmalkar, Aneesh Sivaraman, Hossam Nada, Joohan Lee, Hyeseul Kang, Yongseok Choi, Kyeong Lee
Journal: Medicinal Research Reviews (2024)

Interleukin-6 (IL-6), a pleiotropic cytokine, plays a pivotal role in the pathophysiology of various diseases including diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. The signaling pathways associated with IL-6 offer promising targets for therapeutic interventions in inflammatory diseases and IL-6-dependent tumors. Although certain anti-IL-6 monoclonal antibodies are currently employed clinically, their usage is hampered by drawbacks such as high cost and potential immunogenicity, limiting their application. Thus, the imperative arises to develop novel small non-peptide molecules acting as IL-6 inhibitors. Various natural products derived from diverse sources have been investigated for their potential to inhibit IL-6 activity. Nevertheless, these natural products remain inadequately explored in terms of their structure-activity relationships. In response, our review aims to provide syntheses and structure activity perspective of natural IL-6 inhibitors. The comprehensive amalgamation of information presented in this review holds the potential to serve as a foundation for forthcoming research endeavors by medicinal chemists, facilitating the design of innovative IL-6 inhibitors to address the complexities of inflammatory diseases.
HIV coinfection exacerbates HBV-induced liver fibrogenesis through a HIF-1α- and TGF-β1-dependent pathway
Authors: Min Xu, Charlotte Warner, Xiaoqiong Duan, Zhimeng Cheng, Andre J. Jeyarajan, Wenting Li, Yongtao Wang, Tuo Shao, Shadi Salloum, Pei-Jer Chen, Xu Yu, Raymond T. Chung, Wenyu Lin
Journal: Journal of Hepatology (2024)

Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-β1 signaling.
Etiology, pathogenesis and treatment of peri‐implantitis: A European perspective
Authors: Tord Berglundh, Andrea Mombelli, Frank Schwarz, Jan Derks
Journal: Periodontology 2000 (2024)

Abstract Peri‐implantitis is a plaque‐associated pathological condition occurring in tissues around dental implants. It is characterized by inflammation in the peri‐implant mucosa and progressive loss of supporting bone. Over the last 30 years, peri‐implantitis has become a major disease burden in dentistry. An understanding of the diagnosis, etiology and pathogenesis, epidemiology, and treatment of peri‐implantitis must be a central component in undergraduate and postgraduate training programs in dentistry. In view of the strong role of European research in periodontology and implant dentistry, the focus of this review was to address peri‐implantitis from a European perspective. One component of the work was to summarize new and reliable data on patients with dental implants to underpin the relevance of peri‐implantitis from a population perspective. The nature of the peri‐implantitis lesion was evaluated through results presented in preclinical models and evaluations of human biopsy material together with an appraisal of the microbiological characteristics. An overview of strategies and outcomes presented in clinical studies on nonsurgical and surgical treatment of peri‐implantitis is discussed with a particular focus on end points of therapy and recommendations presented in the S3 level Clinical Practice Guideline for the prevention and treatment of peri‐implant diseases.
Deep simulated annealing for the discovery of novel dental anesthetics with local anesthesia and anti-inflammatory properties
Authors: Yihang Hao, Haofan Wang, Xianggen Liu, Wenrui Gai, Shilong Hu, Wencheng Liu, Zhuang Miao, Yu Gan, Xianghua Yu, Rongjia Shi, Yongzhen Tan, Ting Kang, Ao Hai, Yi Zhao, Yihang Fu, Yaling Tang, Ling Ye, Jin Liu, Xinhua Liang, Bowen Ke
Journal: Acta Pharmaceutica Sinica B (2024)

Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects. The primary challenge is to integrate diverse pharmacophores within a single-molecule framework. To address this, we introduced DeepSA, a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine, a well-known local anesthetic. DeepSA integrates deep neural networks into metaheuristics, effectively constraining molecular space during compound generation. This framework employs a sophisticated objective function that accounts for scaffold preservation, anti-inflammatory properties, and covalent constraints. Through a sequence of local editing to navigate the molecular space, DeepSA successfully identified AT-17, a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models. Mechanistic insights into AT-17 revealed its dual mode of action: selective inhibition of NaV1.7 and 1.8 channels, contributing to its prolonged local anesthetic effects, and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway. These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery, particularly within stringent chemical constraints.
CpG Island Definition and Methylation Mapping of the T2T-YAO Genome
Authors: Ming Xiao, Rui Wei, Jun Yu, Chujie Gao, Fengyi Yang, Le Zhang
Journal: Genomics Proteomics & Bioinformatics (2024)

Precisely defining and mapping all cytosine (C) positions and their clusters, known as CpG islands (CGIs), as well as their methylation status, are pivotal for genome-wide epigenetic studies, especially when population-centric reference genomes are ready for timely application. Here, we first align the two high-quality reference genomes, T2T-YAO and T2T-CHM13, from different ethnic backgrounds in a base-by-base fashion and compute their genome-wide density-defined and position-defined CGIs. Second, by mapping some representative genome-wide methylation data from selected organs onto the two genomes, we find that there are about 4.7%-5.8% sequence divergency of variable categories depending on quality cutoffs. Genes among the divergent sequences are mostly associated with neurological functions. Moreover, CGIs associated with the divergent sequences are significantly different with respect to CpG density and observed CpG/expected CpG (O/E) ratio between the two genomes. Finally, we find that the T2T-YAO genome not only has a greater CpG coverage than that of the T2T-CHM13 genome when whole-genome bisulfite sequencing (WGBS) data from the European and American populations are mapped to each reference, but also shows more hyper-methylated CpG sites as compared to the T2T-CHM13 genome. Our study suggests that future genome-wide epigenetic studies of the Chinese populations rely on both acquisition of high-quality methylation data and subsequent precision CGI mapping based on the Chinese T2T reference.
<i>ERBB3</i> Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature
Authors: Jordan E. Vellky, Brenna J. Kirkpatrick, Lisa C. Gutgesell, Mathias Morales, Ryan M. Brown, Yaqi Wu, Mark Maienschein-Cline, Lucia D. Notardonato, Michael S. Weinfeld, Ryan H. Nguyen, Eileen Brister, Maria Sverdlov, Li Liu, Ziqiao Xu, Steven Kregel, Larisa Nonn, Donald J. Vander Griend, Natalie M. Reizine
Journal: Clinical Cancer Research (2024)

Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies.
School Vaccine Coverage and Medical Exemption Uptake After the New York State Repeal of Nonmedical Vaccination Exemptions
Authors: John W. Correira, Rhiannon Kamstra, Nanqing Zhu, Margaret K. Doll
Journal: JAMA Network Open (2024)

Importance Although New York State (NYS) recently adopted legislation eliminating nonmedical vaccination exemption options from school-entry requirements, the implications of the law for school vaccine coverage and medical vaccine exemption uptake have not been examined. Objective To evaluate the implications of the repeal of school-entry nonmedical vaccination exemptions for vaccine coverage and medical exemption uptake at NYS schools outside of New York City (NYC). Design, Setting, and Participants This cohort study had an interrupted time-series design and used generalized estimating equation models to examine longitudinal school immunization compliance data from the 2012 to 2013 through 2021 to 2022 school years. The cohort comprised NYS public and nonpublic schools, excluding NYC schools, with any students enrolled in kindergarten to 12th grade. Eligible schools had enrollment and immunization data before and after the implementation of the Senate Bill 2994A legislation. Data analyses were conducted in July 2023. Exposure Senate Bill 2994A was passed in June 2019, eliminating school-entry nonmedical vaccination exemptions. Since compliance with the law was evaluated for most students during the next school year, the 2019 to 2020 school year was considered to be the law’s effective date. Main Outcomes and Measures The primary outcomes were school vaccine coverage (defined as the percentage of students at each school who completed grade-appropriate requirements for all required vaccines) and medical exemption uptake (defined as the percentage of students at each school who received a medical exemption). Results Among the 3821 eligible schools, 3632 (95.1%) were included in the analysis, representing 2794 (96.9% of eligible) public schools and 838 (89.2% of eligible) nonpublic schools. The implementation of Senate Bill 2994A was associated with absolute increases in mean vaccine coverage of 5.5% (95% CI, 4.5%-6.6%) among nonpublic schools and 0.9% (95% CI, 0.7%-1.1%) among public schools, with additional annual increases in vaccine coverage observed through the 2021 to 2022 school year. The law’s implementation was also associated with a 0.1% (95% CI, 0.0%-0.1%) mean absolute decrease in medical vaccination exemption uptake at both public and nonpublic schools, and small but significant mean annual decreases in medical vaccination exemptions (0.02%; 95% CI, 0.01%-0.03%) through the end of the study period. Conclusions and Relevance Results of this cohort study suggested that repeal of school-entry nonmedical vaccination exemptions was associated with increased vaccine coverage at NYS schools outside of NYC. Coverage gains were not replaced by increases in medical vaccination exemptions.
Corrigendum to “Tick-borne encephalitis: Acute clinical manifestations and severity in 581 cases from Germany, 2018-2020” [J Infect 86 (2023) 369-375]
Authors: Teresa M. Nygren, Antonia Pilic, Merle M. Böhmer, Christiane Wagner-Wiening, Simone-Beatrice Went, Ole Wichmann, Wiebke Hellenbrand
Journal: Journal of Infection (2024)

The authors regret that an extra affiliation was missed out during publication of this article. The affiliation relates to author Teresa M. Nygren. This affiliation is 'Charité – Universitätsmedizin Berlin, Berlin, Germany'. The authors would like to apologise for any inconvenience caused. DOI of original article: https://doi.org/10.1016/j.jinf.2023.02.018. Tick-borne encephalitis: Acute clinical manifestations and severity in 581 cases from Germany, 2018–2020Journal of InfectionVol. 86Issue 4PreviewTick-borne encephalitis (TBE) is a growing public health problem with an average of 361 cases notified annually to Germany's passive surveillance system since 2001. We aimed to assess clinical manifestations and identify covariates associated with severity. Full-Text PDF