-
Science Immunology Sep 2023About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration...
About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (ā„50%). Single-cell analysis of 17,158 CD8 T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8 tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX) and expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTXCD8 TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103PD-1CD8 T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of CTX TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting CTX TILs is a major mechanism of response in the immediate postneoadjuvant setting.
Topics: Humans; Neoadjuvant Therapy; CD8-Positive T-Lymphocytes; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Antineoplastic Agents; Tumor Microenvironment
PubMed: 37683037
DOI: 10.1126/sciimmunol.adf4968 -
Circulation Research Sep 2023Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
BACKGROUND
Using proteomics, we aimed to reveal molecular types of human atherosclerotic lesions and study their associations with histology, imaging, and cardiovascular outcomes.
METHODS
Two hundred nineteen carotid endarterectomy samples were procured from 120 patients. A sequential protein extraction protocol was employed in conjunction with multiplexed, discovery proteomics. To focus on extracellular proteins, parallel reaction monitoring was employed for targeted proteomics. Proteomic signatures were integrated with bulk, single-cell, and spatial RNA-sequencing data, and validated in 200 patients from the Athero-Express Biobank study.
RESULTS
This extensive proteomics analysis identified plaque inflammation and calcification signatures, which were inversely correlated and validated using targeted proteomics. The inflammation signature was characterized by the presence of neutrophil-derived proteins, such as S100A8/9 (calprotectin) and myeloperoxidase, whereas the calcification signature included fetuin-A, osteopontin, and gamma-carboxylated proteins. The proteomics data also revealed sex differences in atherosclerosis, with large-aggregating proteoglycans versican and aggrecan being more abundant in females and exhibiting an inverse correlation with estradiol levels. The integration of RNA-sequencing data attributed the inflammation signature predominantly to neutrophils and macrophages, and the calcification and sex signatures to smooth muscle cells, except for certain plasma proteins that were not expressed but retained in plaques, such as fetuin-A. Dimensionality reduction and machine learning techniques were applied to identify 4 distinct plaque phenotypes based on proteomics data. A protein signature of 4 key proteins (calponin, protein C, serpin H1, and versican) predicted future cardiovascular mortality with an area under the curve of 75% and 67.5% in the discovery and validation cohort, respectively, surpassing the prognostic performance of imaging and histology.
CONCLUSIONS
Plaque proteomics redefined clinically relevant patient groups with distinct outcomes, identifying subgroups of male and female patients with elevated risk of future cardiovascular events.
Topics: Female; Humans; Male; Proteomics; Sex Characteristics; Versicans; alpha-2-HS-Glycoprotein; Atherosclerosis; Calcinosis
PubMed: 37646165
DOI: 10.1161/CIRCRESAHA.123.322590 -
JAMA Pediatrics Jan 2024Intensive interventions are provided to young children with unilateral cerebral palsy (UCP), classically focused on the upper extremity despite the frequent impairment... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Intensive interventions are provided to young children with unilateral cerebral palsy (UCP), classically focused on the upper extremity despite the frequent impairment of gross motor function. Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) effectively improves manual dexterity and gross motor function in school-aged children.
OBJECTIVE
To verify if HABIT-ILE would improve manual abilities in young children with UCP more than usual motor activity.
DESIGN, SETTING, AND PARTICIPANTS
This prospective randomized clinical trial (November 2018 to December 2021), including 2 parallel groups and a 1:1 allocation, recruitment took place at European university hospitals, cerebral palsy specialized centers, and spontaneous applications at 3 sites: Brussels, Belgium; Brest, France; and Pisa, Italy. Matched (age at inclusion, lesion type, cause of cerebral palsy, and affected side) pairs randomization was performed. Young children were assessed at baseline (T0), 2 weeks after baseline (T1), and 3 months after baseline (T2). Health care professionals and assessors of main outcomes were blinded to group allocation. At least 23 young children (in each group) aged 12 to 59 months with spastic/dyskinetic UCP and able to follow instructions were needed. Exclusion criteria included uncontrolled seizures, scheduled botulinum toxin injections, orthopedic surgery scheduled during the 6 months before or during the study period, severe visual/cognitive impairments, or contraindications to magnetic resonance imaging.
INTERVENTIONS
Two weeks of usual motor activity including usual rehabilitation (control group) vs 2 weeks (50 hours) of HABIT-ILE (HABIT-ILE group).
MAIN OUTCOMES AND MEASURES
Primary outcome: Assisting Hand Assessment (AHA); secondary outcomes: Gross Motor Function Measure-66 (GMFM-66), Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), and Canadian Occupational Performance Measure (COPM).
RESULTS
Of 50 recruited young children (26 girls [52%], median age; 35.3 months for HABIT-ILE group; median age, 32.8 months for control group), 49 were included in the final analyses. Change in AHA score from T0 to T2 was significantly greater in the HABIT-ILE group (adjusted mean score difference [MD], 5.19; 95% CI, 2.84-7.55; Pā<ā.001). Changes in GMFM-66 (MD, 4.72; 95% CI, 2.66-6.78), PEDI-CAT daily activities (MD, 1.40; 95% CI, 0.29-2.51), COPM performance (MD, 3.62; 95% CI, 2.91-4.32), and satisfaction (MD, 3.53; 95% CI, 2.70-4.36) scores were greater in the HABIT ILE group.
CONCLUSIONS AND RELEVANCE
In this clinical trial, early HABIT-ILE was shown to be an effective treatment to improve motor performance in young children with UCP. Moreover, the improvements had an impact on daily life activities of these children.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04020354.
Topics: Female; Child; Humans; Child, Preschool; Cerebral Palsy; Prospective Studies; Physical Therapy Modalities; Canada; Upper Extremity; Lower Extremity
PubMed: 37930692
DOI: 10.1001/jamapediatrics.2023.4809 -
Biology Aug 2023The suprachiasmatic nuclei (SCN) of the hypothalamus contain the circadian pacemaker that coordinates mammalian rhythms in tune with the day-night cycle. Understanding... (Review)
Review
The suprachiasmatic nuclei (SCN) of the hypothalamus contain the circadian pacemaker that coordinates mammalian rhythms in tune with the day-night cycle. Understanding the determinants of the intrinsic rhythmicity of this biological clock, its outputs, and resetting by environmental cues, has been a longstanding goal of the field. Integrated techniques of neurophysiology, including lesion studies and in vivo multi-unit electrophysiology, have been key to characterizing the rhythmic nature and outputs of the SCN in animal models. In parallel, reduced ex vivo and in vitro approaches have permitted us to unravel molecular, cellular, and multicellular mechanisms underlying the pacemaker properties of the SCN. New questions have emerged in recent years that will require combining investigation at a cell resolution within the physiological context of the living animal: What is the role of specific cell subpopulations in the SCN neural network? How do they integrate various external and internal inputs? What are the circuits involved in controlling other body rhythms? Here, we review what we have already learned about the SCN from in vivo studies, and how the recent development of new genetically encoded tools and cutting-edge imaging technology in neuroscience offers chronobiologists the opportunity to meet these challenges.
PubMed: 37627020
DOI: 10.3390/biology12081136 -
Journal of the Korean Society of... Mar 2024MRI plays an important role in abdominal imaging because of its ability to detect and characterize focal lesions. However, MRI examinations have several challenges, such... (Review)
Review
MRI plays an important role in abdominal imaging because of its ability to detect and characterize focal lesions. However, MRI examinations have several challenges, such as comparatively long scan times and motion management through breath-holding maneuvers. Techniques for reducing scan time with acceptable image quality, such as parallel imaging, compressed sensing, and cutting-edge deep learning techniques, have been developed to enable problem-solving strategies. Additionally, free-breathing techniques for dynamic contrast-enhanced imaging, such as extra-dimensional-volumetric interpolated breath-hold examination, golden-angle radial sparse parallel, and liver acceleration volume acquisition Star, can help patients with severe dyspnea or those under sedation to undergo abdominal MRI. We aimed to present various advanced abdominal MRI techniques for reducing the scan time while maintaining image quality and free-breathing techniques for dynamic imaging and illustrate cases using the techniques mentioned above. A review of these advanced techniques can assist in the appropriate interpretation of sequences.
PubMed: 38617869
DOI: 10.3348/jksr.2023.0067