tbuckley/cabot-search huggingface dataset:
Cardiovascular toxicities associated with bispecific T-cell engager therapy
Authors: Ahmed Sayed, Malak Munir, Sanam M Ghazi, Mussammat Ferdousi, Satyam Krishan, Adnan Shaaban, Alma Habib, Onaopepo Kola-Kehinde, Patrick Ruz, Sarah Khan, Sneha Sharma, Alexa Meara, Syed Mahmood, Stephanie Feldman, Eric H Yang, Jiwon Kim, Narendranath Epperla, Daniel Addison
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Bispecific T-cell engagers (BTEs) are novel agents used to treat hematological malignancies. Early trials were underpowered to define cardiovascular adverse events (CVAE) and no large-scale studies systematically examined the CVAEs associated with BTEs. Methods Leveraging the US Food and Drug Administration’s Adverse Event Reporting System-(FAERS), we identified the relative frequency of CVAEs after initiation of five BTE products approved by the Food and Drug Administration between 2014 and 2023 for the treatment of hematological malignancies. Adjusted reporting ORs (aROR) were used to identify disproportionate reporting of CVAEs with BTEs compared with background rates in the database. Fatality rates and risk ratios (RRs) for each adverse event (AE) were calculated. Results From 3668 BTE-related cases reported to FAERS, 747 (20.4%) involved CVAEs. BTEs as a class were associated with fatal CVAEs (aROR 1.29 (95% CI 1.12 to 1.50)), an association mainly driven by teclistamab (aROR 2.44 (95% CI 1.65 to 3.60)). Teclistamab was also associated with a disproportionate risk of myocarditis (aROR 25.70 (95% CI 9.54 to 69.23)) and shock (aROR 3.63 (95% CI 2.30 to 5.74)), whereas blinatumomab was associated with a disproportionate risk of disseminated intravascular coagulation (aROR 3.02 (95% CI 1.98 to 4.60)) and hypotension (aROR 1.59 (95% CI 1.25 to 2.03)). CVAEs were more fatal compared with non-CVAEs (31.1% vs 17.4%; RR 1.76 (95% CI 1.54 to 2.03)). Most CVAEs (83.3%) did not overlap with cytokine release syndrome. Conclusion In the first postmarketing surveillance study of BTEs, CVAEs were involved in approximately one in five AE reports and carried a significant mortality risk.
Overcoming Barriers to Discovery and Implementation of Equitable Pharmacogenomic Testing in Oncology
Authors: Sharon P. Shriver, Devon Adams, Brittany Avin McKelvey, Jeannine S. McCune, Dale Miles, Victoria M. Pratt, Kristine Ashcraft, Howard L. McLeod, Hannah Williams, Mark E. Fleury
Journal: Journal of Clinical Oncology (2024)

Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.
Author correction to ‘VEGFR2-targeted antibody fused with IFNamut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity’ [Acta Pharm Sin B 11 (2021) 420–433]
Authors: Pengzhao Shang, Rui Gao, Yijia Zhu, Xiaorui Zhang, Yang Wang, Minji Guo, Hui Peng, Min Wang, Juan Zhang
Journal: Acta Pharmaceutica Sinica B (2024)

[This corrects the article DOI: 10.1016/j.apsb.2020.09.008.].
Impact of socioeconomic disparities on outcomes in adults undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia
Authors: Daniel J Olivieri, Megan Othus, Corentin Orvain, Eduardo Rodríguez-Arbolí, Filippo Milano, Brenda M Sandmaier, Irum Khan, Chris Davis, Ryan S Basom, Frederick R Appelbaum, Roland B Walter
Journal: Leukemia (2024)
Oral Delivery of the Vancomycin Derivative FU002 by a Surface‐Modified Liposomal Nanocarrier
Authors: Julia Werner, Florian Umstätter, Tobias Hertlein, Eric Mühlberg, Barbro Beijer, Sabrina Wohlfart, Stefan Zimmermann, Uwe Haberkorn, Knut Ohlsen, Gert Fricker, Walter Mier, Philipp Uhl
Journal: Advanced Healthcare Materials (2024)

Abstract Oral delivery of peptide therapeutics faces multiple challenges due to their instability in the gastrointestinal tract and low permeation capability. In this study, the aim is to develop a liposomal nanocarrier formulation to enable the oral delivery of the vancomycin‐peptide derivative FU002. FU002 is a promising, resistance‐breaking, antibiotic which exhibits poor oral bioavailability, limiting its potential therapeutic use. To increase its oral bioavailability, FU002 is incorporated into tetraether lipid‐stabilized liposomes modified with cyclic cell‐penetrating peptides on the liposomal surface. This liposomal formulation shows strong binding to Caco‐2 cells without exerting cytotoxic effects in vitro. Pharmacokinetics studies in vivo in rats reveal increased oral bioavailability of liposomal FU002 when compared to the free drug. In vitro and in vivo antimicrobial activity of FU002 are preserved in the liposomal formulation. As a highlight, oral administration of liposomal FU002 results in significant therapeutic efficacy in a murine systemic infection model. Thus, the presented nanotechnological approach provides a promising strategy for enabling oral delivery of this highly active vancomycin derivative.
Solar-powered O2 delivery for the treatment of children with hypoxaemia in Uganda: a stepped-wedge, cluster randomised controlled trial
Authors: Nicholas Conradi, Robert O Opoka, Qaasim Mian, Andrea L Conroy, Laura L Hermann, Olaro Charles, Jackson Amone, Juliet Nabwire, Bonita E Lee, Abdullah Saleh, Piush Mandhane, Sophie Namasopo, Michael T Hawkes
Journal: The Lancet (2024)
Long-term Radiological and Pulmonary Function Abnormalities at 3-year post COVID-19 Hospitalization: A Longitudinal Cohort Study
Authors: Xiaoyu Han, Lu Chen, Liyan Guo, Linxia Wu, Osamah Alwalid, Jie Liu, Yuting Zheng, Leqing Chen, Wenlong Wu, Hanting Li, Qinyue Luo, Huangxuan Zhao, Lijie Zhang, Yaowei Bai, Bo Sun, Tao Sun, Yuxi Gui, Tong Nie, Lei Chen, Fan Yang, Yanqing Fan, Heshui Shi, Chuansheng Zheng
Journal: European Respiratory Journal (2024)

Background This study aimed to evaluate the longitudinal progression of residual lung abnormalities (ground-glass opacities, reticulation and fibrotic-like changes) and pulmonary function at 3 years following coronavirus disease 2019 (COVID-19). Methods This prospective, longitudinal cohort study enrolled COVID-19 survivors who exhibited residual lung abnormalities upon discharge from two hospitals. Follow-up assessments were conducted at 6 months, 12 months, 2 years and 3 years post-discharge, and included pulmonary function tests, 6-min walk distance (6MWD), chest computed tomography (CT) scans and symptom questionnaires. Non-COVID-19 controls were retrospectively recruited for comparative analysis. Results 728 COVID-19 survivors and 792 controls were included. From 6 months to 3 years, there was a gradual improvement in reduced diffusing capacity of the lung for carbon monoxide ( D LCO &lt;80% predicted: 49% versus 38%; p=0.001), 6MWD (496 versus 510 m; p=0.002) and residual lung abnormalities (46% versus 36%; p&lt;0.001), regardless of disease severity. Patients with residual lung abnormalities at 3 years more commonly had respiratory symptoms (32% versus 16%; p&lt;0.001), lower 6MWD (494 versus 510 m; p=0.003) and abnormal D LCO (57% versus 27%; p&lt;0.001) compared with those with complete resolution. Compared with controls, the proportions of D LCO impairment (38% versus 17%; p&lt;0.001) and respiratory symptoms (23% versus 2.2%; p&lt;0.001) were significantly higher in the matched COVID-19 survivors at the 3-year follow-up. Conclusions Most patients exhibited improvement in radiological abnormalities and pulmonary function over time following COVID-19. However, more than a third continued to have persistent lung abnormalities at the 3-year mark, which were associated with respiratory symptoms and reduced diffusion capacity.
Inhibitory CARs fail to protect from immediate T cell cytotoxicity
Authors: Maximilian A. Funk, Gerwin Heller, Petra Waidhofer-Söllner, Judith Leitner, Peter Steinberger
Journal: Molecular Therapy (2024)

Chimeric antigen receptors (CARs) equipped with an inhibitory signaling domain (iCARs) have been proposed as strategy to increase on-tumor specificity of CAR-T cell therapies. iCARs inhibit T cell activation upon antigen recognition and thereby program a Boolean NOT gate within the CAR-T cell. If cancer cells do not express the iCAR target antigen while it is highly expressed on healthy tissue, CAR/iCAR coexpressing T cells are supposed to kill cancer cells but not healthy cells expressing the CAR antigen. In this study, we employed a well-established reporter cell system to demonstrate high potency of iCAR constructs harboring BTLA-derived signaling domains. We then created CAR/iCAR combinations for the clinically relevant antigen pairs B7-H3/CD45 and CD123/CD19 and show potent reporter cell suppression by iCARs targeting CD45 or CD19. In primary human T cells αCD19-iCARs were capable of suppressing T cell proliferation and cytokine production. Surprisingly, the iCAR failed to veto immediate CAR-mediated cytotoxicity. Likewise, T cells overexpressing PD-1 or BTLA did not show impaired cytotoxicity toward ligand-expressing target cells, indicating that inhibitory signaling by these receptors does not mediate protection against cytotoxicity by CAR-T cells. Future approaches employing iCAR-equipped CAR-T cells for cancer therapy should therefore monitor off-tumor reactivity and potential CAR/iCAR-T cell dysfunction. Chimeric antigen receptors (CARs) equipped with an inhibitory signaling domain (iCARs) have been proposed as strategy to increase on-tumor specificity of CAR-T cell therapies. iCARs inhibit T cell activation upon antigen recognition and thereby program a Boolean NOT gate within the CAR-T cell. If cancer cells do not express the iCAR target antigen while it is highly expressed on healthy tissue, CAR/iCAR coexpressing T cells are supposed to kill cancer cells but not healthy cells expressing the CAR antigen. In this study, we employed a well-established reporter cell system to demonstrate high potency of iCAR constructs harboring BTLA-derived signaling domains. We then created CAR/iCAR combinations for the clinically relevant antigen pairs B7-H3/CD45 and CD123/CD19 and show potent reporter cell suppression by iCARs targeting CD45 or CD19. In primary human T cells αCD19-iCARs were capable of suppressing T cell proliferation and cytokine production. Surprisingly, the iCAR failed to veto immediate CAR-mediated cytotoxicity. Likewise, T cells overexpressing PD-1 or BTLA did not show impaired cytotoxicity toward ligand-expressing target cells, indicating that inhibitory signaling by these receptors does not mediate protection against cytotoxicity by CAR-T cells. Future approaches employing iCAR-equipped CAR-T cells for cancer therapy should therefore monitor off-tumor reactivity and potential CAR/iCAR-T cell dysfunction.
Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of <i>MYC</i> Paralogs
Authors: Shreoshi Pal Choudhuri, Luc Girard, Jun Yi Stanley Lim, Jillian F. Wise, Braeden Freitas, Di Yang, Edmond Wong, Seth Hamilton, Victor D. Chien, Yoon Jung Kim, Collin Gilbreath, Jun Zhong, Sarah Phat, David T. Myers, Camilla L. Christensen, Hanieh Mazloom-Farsibaf, Marcello Stanzione, Kwok-Kin Wong, Yin P. Hung, Anna F. Farago, Catherine B. Meador, Nicholas J. Dyson, Michael S. Lawrence, Sihan Wu, Benjamin J. Drapkin
Journal: Cancer Discovery (2024)

Abstract Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a preclinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC. Significance: SCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications of MYC paralogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC. This article is featured in Selected Articles from This Issue, p. 695
Skin‐Attached Arrayed Piezoelectric Sensors for Continuous and Safe Monitoring of Oculomotor Movements
Authors: Nam‐In Kim, Jie Chen, Weijie Wang, Ja‐Yeon Kim, Min‐Ki Kwon, Mina Moradnia, Sara Pouladi, Jae‐Hyun Ryou
Journal: Advanced Healthcare Materials (2024)

Abstract Abnormal oculomotor movements are known to be linked to various types of brain disorders, physical/mental shocks to the brain, and other neurological disorders, hence its monitoring can be developed into a simple but effective diagnostic tool. To overcome the limitations in the current eye‐tracking system and electrooculography, a piezoelectric arrayed sensor system is developed using single‐crystalline III‐N thin‐film transducers, which offers advantages of mechanical flexibility, biocompatibility, and high electromechanical conversion, for continuous monitoring of oculomotor movements by skin‐attachable, safe, and highly sensitive sensors. The flexible piezoelectric eye movement sensor array (F‐PEMSA), consisting of three transducers, is attached to the face temple area where it can be comfortably wearable and can detect the muscles’ activity associated with the eye motions. Output voltages from upper, mid, and lower sensors (transducers) on different temple areas generate discernable patterns of output voltage signals with different combinations of positive/negative signs and their relative magnitudes for the various movements of eyeballs including 8 directional (lateral, vertical, and diagonal) and two rotational movements, which enable various types of saccade and pursuit tests. The F‐PEMSA can be used in clinical studies on the brain‐eye relationship to evaluate the functional integrity of multiple brain systems and cognitive processes.
Axon-like aligned conductive CNT/GelMA hydrogel fibers combined with electrical stimulation for spinal cord injury recovery
Authors: Shenglian Yao, Yongdong Yang, Chenyu Li, Kaitan Yang, Xin Song, Chuanhong Li, Zheng Cao, He Zhao, Xing Yu, Xiumei Wang, Lu-Ning Wang
Journal: Bioactive Materials (2024)

Rehabilitation and regenerative medicine are two promising approaches for spinal cord injury (SCI) recovery, but their combination has been limited. Conductive biomaterials could bridge regenerative scaffolds with electrical stimulation by inducing axon regeneration and supporting physiological electrical signal transmission. Here, we developed aligned conductive hydrogel fibers by incorporating carbon nanotubes (CNTs) into methacrylate acylated gelatin (GelMA) hydrogel via rotating liquid bath electrospinning. The electrospun CNT/GelMA hydrogel fibers mimicked the micro-scale aligned structure, conductivity, and soft mechanical properties of neural axons. For
MicroRNA-targeting nanomedicines for the treatment of intervertebral disc degeneration
Authors: Hussein H. Genedy, Paul Humbert, Bilel Laoulaou, Brian Le Moal, Marion Fusellier, Catherine Passirani, Catherine Le Visage, Jérôme Guicheux, Élise Lepeltier, Johann Clouet
Journal: Advanced Drug Delivery Reviews (2024)
Selective DRD2 antagonist and ClpP agonist ONC201 in a recurrent non-midline H3 K27M-mutant glioma cohort
Authors: Yazmin Odia, Matthew D Hall, Timothy Francis Cloughesy, Patrick Y Wen, Isabel Arrillaga-Romany, Doured Daghistani, Minesh P Mehta, Rohinton S Tarapore, Samuel C Ramage, Joshua E Allen
Journal: Neuro-Oncology (2024)

Abstract Background Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumors Classification defined H3 K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist, and ClpP agonist associated with durable responses in recurrent H3 K27M-mutant DMG. Activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas has not been reported. Methods Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas treated with ONC201 were enrolled in 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma, Karnofsky/Lansky performance score ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR). Results Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for 2, however, 1 deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness. Conclusions H3 K27M-mutant diffuse gliomas occasionally occur in non-midline cerebrum. ONC201 exhibits activity in H3 K27M-mutant gliomas irrespective of CNS location.
Clinical care of childhood sexual abuse: a systematic review and critical appraisal of guidelines from European countries
Authors: Gabriel Otterman, Ulugbek B. Nurmatov, Ather Akhlaq, Laura Korhonen, Alison M. Kemp, Aideen Naughton, Martin Chalumeau, Andreas Jud, Mary Jo Vollmer Sandholm, Eva Mora-Theuer, Sarah Moultrie, Diogo Lamela, Nara Tagiyeva-Milne, Joanne Nelson, Jordan Greenbaum
Journal: The Lancet Regional Health - Europe (2024)

<h2>Summary</h2><h3>Background</h3> The clinical management of Child sexual abuse (CSA) demands specialised skills from healthcare professionals due to its sensitivity, legal implications, and serious physical health and mental health effects. Standardised, comprehensive clinical practice guidelines (CPGs) may be pivotal. In this systematic review, we examined existing CSA national CPGs (NCPGs) from European countries to assess their quality and reporting. <h3>Methods</h3> We systematically searched six international databases and multiple grey literature sources, reporting by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Eligible guidelines were CSA guidance from national health agencies or societies in 34 COST Action 19106 Network Countries (CANC), published between January 2012 and November 2022. Two independent researchers searched, screened, reviewed, and extracted data. NCPGs were compared for completeness with reference WHO 2017 and 2019 guidelines. We used the Appraisal of Guidelines for Research and Evaluation (AGREE II) to appraise quality and reporting. <b>PROSPERO</b>: CRD42022320747. <h3>Findings</h3> Of 2919 records identified by database searches, none met inclusion criteria. Of 4714 records identified by other methods, 24 NCPGs from 17 (50%) of CANC countries were included. In 17 (50%) of eligible countries, no NCPGs were found. Content varied significantly within and between countries. NCPGs lacked many components in state-of-the art clinical practice compared to WHO reference standards, particularly in safety and risk assessment, interactions with caregivers, and mental health interventions. Appraisal by AGREE II revealed shortcomings in NCPG development, regarding scientific rigour, stakeholder involvement, implementation and evaluation. <h3>Interpretation</h3> A notable number of European countries lack an NCPG; existing NCPGs often fall short. The healthcare response to CSA in Europe requires a coordinated approach to develop and implement high-quality CPGs. We advocate for a multidisciplinary team to develop a pan-European CSA guideline to ensure quality care for survivors. <h3>Funding</h3> Funding was provided by the International Centre for Missing and Exploited Children.
First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial
Authors: Yelena Y. Janjigian, Jaffer A. Ajani, Markus Moehler, Lin Shen, Marcelo Garrido, Carlos Gallardo, Lucjan Wyrwicz, Kensei Yamaguchi, James M. Cleary, Elena Elimova, Michalis Karamouzis, Ricardo Bruges, Tomasz Skoczylas, Arinilda Bragagnoli, Tianshi Liu, Mustapha Tehfe, Thomas Zander, Ruben Kowalyszyn, Roberto Pazo-Cid, Michael Schenker, Kynan Feeny, Rui Wang, Ming Lei, Clara Chen, Raheel Nathani, Kohei Shitara
Journal: Journal of Clinical Oncology (2024)

JCO
Systematic Review of Interventions Addressing Racial and Ethnic Disparities in Cancer Care and Health Outcomes
Authors: Shakira J. Grant, Juan Yanguela, Olufeyisayo Odebunmi, Alyssa A. Grimshaw, Smith Giri, Stephanie B. Wheeler
Journal: Journal of Clinical Oncology (2024)

Cancer health disparities result from complex interactions among socioeconomic, behavioral, and biological factors, disproportionately affecting marginalized racial and ethnic groups. The objective of this review is to synthesize existing evidence on interventions addressing racial or ethnic disparities in cancer-related health care access and clinical outcomes.
Paediatric, maternal, and congenital mpox: a systematic review and meta-analysis
Authors: Nuria Sanchez Clemente, Charlotte Coles, Enny S Paixao, Elizabeth B Brickley, Elizabeth Whittaker, Tobias Alfven, Stephen Rulisa, Nelson Agudelo Higuita, Paul Torpiano, Priyesh Agravat, Emma V Thorley, Simon B Drysdale, Kirsty Le Doare, Jean-Jacques Muyembe Tamfum
Journal: The Lancet Global Health (2024)

Although mpox has been detected in paediatric populations in central and west Africa for decades, evidence synthesis on paediatric, maternal, and congenital mpox, and the use of vaccines and therapeutics in these groups, is lacking. A systematic review is therefore indicated to set the research agenda.