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1.
bioRxiv ; 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39091730

ABSTRACT

Both protein nanoparticle and mRNA vaccines were clinically de-risked during the COVID-19 pandemic. These vaccine modalities have complementary strengths: antigen display on protein nanoparticles can enhance the magnitude, quality, and durability of antibody responses, while mRNA vaccines can be rapidly manufactured and elicit antigen-specific CD4 and CD8 T cells. Here we leverage a computationally designed icosahedral protein nanoparticle that was redesigned for optimal secretion from eukaryotic cells to develop an mRNA-launched nanoparticle vaccine for SARS-CoV-2. The nanoparticle, which displays 60 copies of a stabilized variant of the Wuhan-Hu-1 Spike receptor binding domain (RBD), formed monodisperse, antigenically intact assemblies upon secretion from transfected cells. An mRNA vaccine encoding the secreted RBD nanoparticle elicited 5- to 28-fold higher levels of neutralizing antibodies than an mRNA vaccine encoding membrane-anchored Spike, induced higher levels of CD8 T cells than the same immunogen when delivered as an adjuvanted protein nanoparticle, and protected mice from vaccine-matched and -mismatched SARS-CoV-2 challenge. Our data establish that delivering protein nanoparticle immunogens via mRNA vaccines can combine the benefits of each modality and, more broadly, highlight the utility of computational protein design in genetic immunization strategies.

2.
Polymers (Basel) ; 16(13)2024 Jun 27.
Article in English | MEDLINE | ID: mdl-39000693

ABSTRACT

The development of high-filled 3D printing resin necessitates a bonding protocol for dental indirect restorations to achieve optimal bond strength after cementation. This study evaluates shear bond strengths of high-filler 3D printed materials for permanent restorations with various surface treatments. Rodin Sculpture 1.0 (50% lithium disilicate fillers) and 2.0 Ceramic Nanohybrid (>60% zirconia and lithium disilicate fillers) were tested, with Aelite All-Purpose Body composite resin as control. Samples were prepared, post-cured, and sandblasted with alumina (25 µm). Surface roughness was analyzed using an optical profilometer. Two bonding protocols were compared. First, groups were treated with lithium disilicate silane (Porcelain Primer) or zirconia primer (Z-Prime Plus) or left untreated without a bonding agent. Beam-shaped resin cement (DuoLink Universal) specimens were bonded and stored in a 37 °C water bath. Second, additional sets of materials were coated with a bonding agent (All-Bond Universal), either followed by silane application or left untreated. These sets were then similarly stored alongside resin cement specimens. Shear bond tests were performed after 24 h. SEM images were taken after debonding. One-Way ANOVA and post hoc Duncan were performed for the statistical analysis. Rodin 1.0 exhibited increased adhesive failure with silane or zirconia primer coating, but significantly improved bond strengths with bonding agent application. Rodin 2.0 showed consistent bond strengths regardless of bonding agent application, but cohesive failure rates increased with bonding agent and filler coating. In all groups, except for Rodin 1.0 without bonding agent, silane coating increased cohesive failure rate. In conclusion, optimal shear bond strength for high-filler 3D printing materials can be achieved with silane coating and bonding agent application.

3.
Trauma Violence Abuse ; : 15248380241257957, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39066513

ABSTRACT

Existing measures and theories of intimate partner coercive control largely evaluate men's coercion of women. The extent of knowledge pertaining to intimate relationships among other genders and sexual identities is unclear. Guided by a theoretical framework of intersectionality, we examined and synthesized original studies on coercive control by (perpetration) or against (victimization) Two Spirit, lesbian, gay, bisexual, trans, queer, questioning, intersex, and asexual individuals within intimate partner relationships. We searched eight academic databases for records from 2014 through 2022 and hand-searched review articles' reference lists, supplemented with gray literature and website searches. Using duplicate screening, we identified 1,774 unique documents; 526 met preliminary eligibility criteria and 277 were retained for data extraction in duplicate. Coercive control was more common among minority individuals and was related to mental health challenges. Few studies reported on gender- or sexual-identity specific forms of coercive control, and an intersectional focus was uncommon. This review revealed a lack of agreed definition of coercive control or accepted standard of measurement, and a gap in research with individuals who identify as gender diverse, gender fluid or intersex, or those identifying their sexuality as asexual, pansexual, or sexually diverse.

4.
BMC Cancer ; 24(1): 909, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-39075471

ABSTRACT

BACKGROUND: Advancements in the diagnosis, treatment, and surveillance of castration-resistant prostate cancer (CRPC) have progressed considerably, but a new biomarker that combines existing clinical and pathological data could be useful for a more precise diagnosis and prognosis. Some investigations have found that extracellular vesicle (EV)-derived miRNAs play crucial roles in various types of malignant tumors. The objective of this study was to explore EV miRNA and identify its biologic function as a biomarker for the diagnosis and prognosis of CRPC. METHODS: Plasma samples were collected from five healthy donors (Control, CT) and 17 CRPC patients, categorizing into two groups based on their endocrine treatment response: partial response (PR; n = 10) and progressive disease (PD; n = 7). Candidate extracellular vesicle (EV) miRNAs were identified using miRNA microarray and RT-qPCR. The biological functions of the selected miRNAs were evaluated using the MTT assay, wound healing assay, trans-well assay, and RNA sequencing in CRPC cells after transient miRNA expression. RESULTS: Microarray analysis revealed a significant downregulation of EV-miR-6880-5p in the PD samples compared to both CT and PR samples (p < 0.01). The expression of EV-miR-6880-5p in CRPC patients was decreased compared with that CT group (p = 0.0336) using RT-qPCR. In the PR group, EV-miR-6880-5p was increased at follow-up compared with the baseline (p = 0.2803), while in the PD group, it decreased at follow-up compared with the baseline samples (p = 0.4356). Furthermore, overexpression of miR-6880-5p hampered cell proliferation, migration, and invasion, downregulated pathways associated with tumor progression, and simultaneously upregulated pathways associated with cell growth and apoptosis in CRPC cells. CONCLUSIONS: EV-miR-6880-5p shows promise as a prognostic biomarker in patients with CRPC. Further, prospective validations are necessary to evaluate the potential of these candidate miRNAs.


Subject(s)
Biomarkers, Tumor , Extracellular Vesicles , Gene Expression Regulation, Neoplastic , MicroRNAs , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Extracellular Vesicles/metabolism , Extracellular Vesicles/genetics , MicroRNAs/blood , MicroRNAs/genetics , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Prognosis , Aged , Middle Aged , Cell Line, Tumor , Cell Proliferation , Gene Expression Profiling/methods , Cell Movement/genetics
5.
ACS Appl Mater Interfaces ; 16(29): 37401-37417, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-38981010

ABSTRACT

Continuous monitoring of physiological signals from the human body is critical in health monitoring, disease diagnosis, and therapeutics. Despite the needs, the existing wearable medical devices rely on either bulky wired systems or battery-powered devices needing frequent recharging. Here, we introduce a wearable, self-powered, thermoelectric flexible system architecture for wireless portable monitoring of physiological signals without recharging batteries. This system harvests an exceptionally high open circuit voltage of 175-180 mV from the human body, powering the wireless wearable bioelectronics to detect electrophysiological signals on the skin continuously. The thermoelectric system shows long-term stability in performance for 7 days with stable power management. Integrating screen printing, laser micromachining, and soft packaging technologies enables a multilayered, soft, wearable device to be mounted on any body part. The demonstration of the self-sustainable wearable system for detecting electromyograms and electrocardiograms captures the potential of the platform technology to offer various opportunities for continuous monitoring of biosignals, remote health monitoring, and automated disease diagnosis.


Subject(s)
Wearable Electronic Devices , Wireless Technology , Humans , Wireless Technology/instrumentation , Monitoring, Physiologic/instrumentation , Monitoring, Physiologic/methods , Electric Power Supplies , Electrocardiography/instrumentation , Electromyography/instrumentation , Equipment Design
6.
Adv Sci (Weinh) ; : e2406309, 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39076120

ABSTRACT

Frequent recurrence and metastasis caused by cancer stem cells (CSCs) are major challenges in lung cancer treatment. Therefore, identifying and characterizing specific CSC targets are crucial for the success of prospective targeted therapies. In this study, it is found that upregulated TOR Signaling Pathway Regulator-Like (TIPRL) in lung CSCs causes sustained activation of the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) signaling pathway by binding to CaMKK2, thereby maintaining stemness and survival. CaMKK2-mediated activation of CaM kinase 4 (CaMK4) leads to phosphorylation of cAMP response element-binding protein (CREB) at Ser129 and Ser133, which is necessary for its maximum activation and the downstream constitutive expression of its target genes (Bcl2 and HMG20A). TIPRL depletion sensitizes lung CSCs to afatinib-induced cell death and reduces distal metastasis of lung cancer in vivo. It is determined that CREB activates the transcription of TIPRL in lung CSCs. The positive feedback loop consisting of CREB and TIPRL induces the sustained activation of the CaMKK2-CaMK4-CREB axis as a driving force and upregulates the expression of stemness- and survival-related genes, promoting tumorigenesis in patients with lung cancer. Thus, TIPRL and the CaMKK2 signaling axis may be promising targets for overcoming drug resistance and reducing metastasis in lung cancer.

7.
Nature ; 631(8021): 617-626, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38961298

ABSTRACT

SARS-CoV-2 variants acquire mutations in the spike protein that promote immune evasion1 and affect other properties that contribute to viral fitness, such as ACE2 receptor binding and cell entry2,3. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning4 to measure how more than 9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully affected ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456 and 473; however, the antigenic effects of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however, many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.


Subject(s)
DNA Mutational Analysis , Evolution, Molecular , Genetic Fitness , Immune Evasion , Mutation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Humans , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Binding Sites , COVID-19/immunology , COVID-19/virology , Genetic Fitness/genetics , Immune Evasion/genetics , Neutralization Tests , Protein Binding , Protein Domains/genetics , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/classification , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/immunology , Virus Internalization , HEK293 Cells
8.
Eur J Med Res ; 29(1): 329, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38879517

ABSTRACT

BACKGROUND: Minimizing muscle strain and reducing the risk of musculoskeletal disorders associated with intraoral scanner (IOS) usage require ergonomic awareness, device selection, and workplace adjustments in dental practice. This preliminary clinical study aimed to simulate intraoral scanning tasks using wired and wireless IOSs and assess muscle activation and fatigue for both types. MATERIALS AND METHODS: Fourteen participants performed intraoral scanning tasks using wired and wireless IOSs (i700; MEDIT), with weights of 280 g and 328 g, respectively. The same computer system and software conditions were maintained for both groups (N = 14 per IOS group). Electrodes were placed on arm, neck, and shoulder muscles, and maximal voluntary contraction (MVC) was measured. Surface electromyography (EMG) was performed during the simulation, and EMG values were normalized using MVC. The root mean square EMG (%MVC) and muscle fatigue (%) values were calculated. Statistical comparisons were performed using the Mann-Whitney U and Friedman tests, with the Bonferroni adjustment for multiple comparisons (α = 0.05). RESULTS: Arm (flexor digitorum superficialis) and neck muscles (left sternocleidomastoid and left splenius capitis) showed significantly higher EMG values with wireless IOS (P < 0.05). The neck (left sternocleidomastoid and right levator scapulae) and shoulder muscles (right trapezius descendens) demonstrated significantly higher muscle fatigue with wireless IOS (P < 0.05). CONCLUSIONS: The consecutive use of heavier wireless IOS may increase the risk of muscle activation and fatigue in certain muscles, which may have clinical implications for dentists in terms of ergonomics and musculoskeletal health.


Subject(s)
Electromyography , Humans , Male , Adult , Electromyography/methods , Female , Musculoskeletal Diseases/etiology , Musculoskeletal Diseases/prevention & control , Muscle Fatigue/physiology , Muscle, Skeletal/physiology , Muscle, Skeletal/physiopathology , Ergonomics/methods , Young Adult , Muscle Contraction/physiology
9.
BMC Anesthesiol ; 24(1): 203, 2024 Jun 08.
Article in English | MEDLINE | ID: mdl-38851689

ABSTRACT

BACKGROUND: Ultrasound-guided transversus abdominis plane (TAP) block is commonly used for pain control in laparoscopic cholecystectomy. However, significant pain persists, affecting patient recovery and sleep quality on the day of surgery. We compared the analgesic effect of ultrasound-guided TAP block with or without rectus sheath (RS) block in patients undergoing laparoscopic cholecystectomy using the visual analog scale (VAS) scores. METHODS: The study was registered before patient enrollment at the Clinical Research Information Service (registration number: KCT0006468, 19/08/2021). 88 American Society of Anesthesiologist physical status I-III patients undergoing laparoscopic cholecystectomy were divided into two groups. RS-TAP group received right lateral and right subcostal TAP block, and RS block with 0.2% ropivacaine (30 mL); Bi-TAP group received bilateral and right subcostal TAP block with same amount of ropivacaine. The primary outcome was visual analogue scale (VAS) for 48 h postoperatively. Secondary outcomes included the use of rescue analgesics, cumulative intravenous patient-controlled analgesia (IV-PCA) consumption, patient satisfaction, sleep quality, and incidence of adverse events. RESULTS: There was no significant difference in VAS score between two groups for 48 h postoperatively. We found no difference between the groups in any of the secondary outcomes: the use of rescue analgesics, consumption of IV-PCA, patient satisfaction with postoperative pain control, sleep quality, and the incidence of postoperative adverse events. CONCLUSION: Both RS-TAP and Bi-TAP blocks provided clinically acceptable pain control in patients undergoing laparoscopic cholecystectomy, although there was no significant difference between two combination blocks in postoperative analgesia or sleep quality.


Subject(s)
Abdominal Muscles , Cholecystectomy, Laparoscopic , Nerve Block , Pain, Postoperative , Ropivacaine , Ultrasonography, Interventional , Humans , Cholecystectomy, Laparoscopic/methods , Female , Male , Ultrasonography, Interventional/methods , Nerve Block/methods , Middle Aged , Pain, Postoperative/prevention & control , Pain, Postoperative/drug therapy , Ropivacaine/administration & dosage , Adult , Anesthetics, Local/administration & dosage , Pain Measurement/methods , Rectus Abdominis/innervation , Rectus Abdominis/diagnostic imaging , Patient Satisfaction , Analgesia, Patient-Controlled/methods , Aged
10.
J Pediatr ; 273: 114135, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38848888

ABSTRACT

OBJECTIVE: To describe the characteristics of research training and scholarly activity during pediatrics residency in Canada and identify facilitators and barriers to resident scholarly activity. STUDY DESIGN: We conducted a mixed-methods, cross-sectional survey of pediatrics residents in Canada from April to June 2023. Trainees and medical education experts developed the 55-item survey, pilot tested, and distributed electronically to residents in all 17 Canadian residency programs. Responses were complemented with program-level data from pediatrics residency program directors. RESULTS: Of 644 Canadian pediatrics residents, 230 (36%) responded. Resident respondents conducted various types of scholarly projects, including retrospective clinical study (22%), qualitative research (15%), quality improvement (13%), and medical education research (12%). Discordance between the field of career interests and primary scholarly projects was common. Among respondents, 20% had abstracts accepted at national or international conferences, and 12% had manuscripts submitted to peer-reviewed journals. Resident respondents' self-perceived progress in their scholarly projects were discrepant from their actual progress. Key themes related to barriers and facilitators to scholarly activity included protected time for research, mentorship, and research skills training. CONCLUSIONS: The research training and scholarly activity of pediatrics residents in Canada is variable. Establishing national standards, implementing progress monitoring mechanisms with tailored support, and offering flexible protected research time are important next steps.

11.
J Med Chem ; 67(13): 10601-10621, 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38896548

ABSTRACT

Inflammatory bowel disease (IBD) is characterized by abnormal immune responses, including elevated proinflammatory cytokines, such as tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in the gastrointestinal (GI) tract. This study presents the synthesis and anti-inflammatory evaluation of 2,4,5-trimethylpyridin-3-ol analogues, which exhibit dual inhibition of TNFα- and IL-6-induced inflammation. Analysis using in silico methods, including 3D shape-based target identification, modeling, and docking, identified G protein-coupled estrogen receptor 1 (GPER) as the molecular target for the most effective analogue, 6-26, which exhibits remarkable efficacy in ameliorating inflammation and restoring colonic mucosal integrity. This was further validated by surface plasmon resonance (SPR) assay results, which showed direct binding to GPER, and by the results showing that GPER knockdown abolished the inhibitory effects of 6-26 on TNFα and IL-6 actions. Notably, 6-26 displayed no cytotoxicity, unlike G1 and G15, a well-known GPER agonist and an antagonist, respectively, which induced necroptosis independently of GPER. These findings suggest that the GPER-selective compound 6-26 holds promise as a therapeutic candidate for IBD.


Subject(s)
Inflammatory Bowel Diseases , Receptors, Estrogen , Receptors, G-Protein-Coupled , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolism , Receptors, G-Protein-Coupled/agonists , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/metabolism , Humans , Animals , Receptors, Estrogen/metabolism , Receptors, Estrogen/antagonists & inhibitors , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Interleukin-6/metabolism , Tumor Necrosis Factor-alpha/metabolism , Mice , Molecular Docking Simulation , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Pyridines/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/therapeutic use , Mice, Inbred C57BL , Structure-Activity Relationship
12.
Nat Commun ; 15(1): 5496, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38944664

ABSTRACT

Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S2 subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S2 trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S2 subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S2 trimer elicits broadly reactive sarbecovirus antibodies and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Animals , Mice , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Spike Glycoprotein, Coronavirus/immunology , SARS-CoV-2/immunology , Humans , COVID-19/prevention & control , COVID-19/immunology , COVID-19/virology , Female , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Mice, Inbred BALB C
13.
Article in English | MEDLINE | ID: mdl-38923201

ABSTRACT

AIM: Cholesterol homeostasis is associated with Alzheimer's disease (AD). Despite the multitude of cholesterol metabolites, little is known about which metabolites are directly involved in AD pathogenesis and can serve as its potential biomarkers. METHODS: To identify "hit" metabolites, steroid profiling was conducted in mice with different age, diet, and genotype and also in humans with normal cognition, mild cognitive impairment, and AD using gas chromatography-mass spectrometry. Then, using one of the "hit" molecules (7ß-hydroxycholesterol; OHC), molecular and histopathological experiment and behavioral testing were conducted in normal mice following its intracranial stereotaxic injection to see whether this molecule drives AD pathogenesis and causes cognitive impairment. RESULTS: The serum levels of several metabolites, including 7ß-OHC, were increased by aging in the 3xTg-AD unlike normal mice. Consistently, the levels of 7ß-OHC were increased in the hairs of patients with AD and were correlated with clinical severity. We found that 7ß-OHC directly affects AD-related pathophysiology; intrahippocampal injection of 7ß-OHC induced astrocyte and microglial cell activation, increased the levels of pro-inflammatory cytokines (TNF-alpha, IL-1ß, IL-6), and enhanced amyloidogenic pathway. Mice treated with 7ß-OHC also exhibited deficits in memory and frontal/executive functions assessed by object recognition and 5-choice serial reaction time task, respectively. CONCLUSIONS: Our results suggest that 7ß-OHC could serve as a convenient, peripheral biomarker of AD. As directly involved in AD pathogenesis, 7ß-OHC assay may help actualize personalized medicine in a way to identify an at-risk subgroup as a candidate population for statin-based AD treatment.

14.
Gastroenterology ; 2024 May 23.
Article in English | MEDLINE | ID: mdl-38788861

ABSTRACT

BACKGROUND & AIMS: CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. We aimed to demonstrate superiority of CT-P13 SC vs placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately to severely active CD or UC and inadequate response or intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks 0, 2, and 6. At week 10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until week 54 (maintenance phase) using prefilled syringes. Co-primary end points were clinical remission and endoscopic response (CD) and clinical remission (UC) at week 54 (all-randomized population). RESULTS: Overall, 396 patients with CD and 548 patients with UC received induction treatment. At week 54 in the CD study, statistically significant higher proportions of CT-P13 SC-treated patients vs placebo-treated patients achieved clinical remission (62.3% vs 32.1%; P < .0001) and endoscopic response (51.1% vs 17.9%; P < .0001). In the UC study, clinical remission rates at week 54 were statistically significantly higher with CT-P13 SC vs placebo (43.2% vs 20.8%; P < .0001). Achievement of key secondary end points was significantly higher with CT-P13 SC vs placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSIONS: CT-P13 SC was more effective than placebo as maintenance therapy and was well tolerated in patients with moderately to severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS: gov, Numbers: NCT03945019 (CD) and NCT04205643 (UC).

15.
Infect Immun ; 92(6): e0014124, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38722166

ABSTRACT

The human-specific bacterial pathogen group A Streptococcus (GAS) is a significant cause of morbidity and mortality. Macrophages are important to control GAS infection, but previous data indicate that GAS can persist in macrophages. In this study, we detail the molecular mechanisms by which GAS survives in THP-1 macrophages. Our fluorescence microscopy studies demonstrate that GAS is readily phagocytosed by macrophages, but persists within phagolysosomes. These phagolysosomes are not acidified, which is in agreement with our findings that GAS cannot survive in low pH environments. We find that the secreted pore-forming toxin Streptolysin O (SLO) perforates the phagolysosomal membrane, allowing leakage of not only protons but also large proteins including the lysosomal protease cathepsin B. Additionally, GAS recruits CD63/LAMP-3, which may contribute to lysosomal permeabilization, especially in the absence of SLO. Thus, although GAS does not inhibit fusion of the lysosome with the phagosome, it has multiple mechanisms to prevent proper phagolysosome function, allowing for persistence of the bacteria within the macrophage. This has important implications for not only the initial response but also the overall functionality of the macrophages, which may lead to the resulting pathologies in GAS infection. Our data suggest that therapies aimed at improving macrophage function may positively impact patient outcomes in GAS infection.


Subject(s)
Bacterial Proteins , Lysosomes , Macrophages , Streptococcus pyogenes , Streptolysins , Streptococcus pyogenes/immunology , Humans , Macrophages/microbiology , Macrophages/immunology , Macrophages/metabolism , Lysosomes/metabolism , Lysosomes/microbiology , Streptolysins/metabolism , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Phagosomes/microbiology , Phagosomes/metabolism , THP-1 Cells , Phagocytosis , Streptococcal Infections/immunology , Streptococcal Infections/microbiology , Streptococcal Infections/metabolism , Cathepsin B/metabolism , Hydrogen-Ion Concentration
16.
Cell Rep Med ; 5(6): 101577, 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38761799

ABSTRACT

Descendants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant now account for almost all SARS-CoV-2 infections. The Omicron variant and its sublineages have spike glycoproteins that are highly diverged from the pandemic founder and first-generation vaccine strain, resulting in significant evasion from monoclonal antibody therapeutics and vaccines. Understanding how commonly elicited antibodies can broaden to cross-neutralize escape variants is crucial. We isolate IGHV3-53, using "public" monoclonal antibodies (mAbs) from an individual 7 months post infection with the ancestral virus and identify antibodies that exhibit potent and broad cross-neutralization, extending to the BA.1, BA.2, and BA.4/BA.5 sublineages of Omicron. Deep mutational scanning reveals these mAbs' high resistance to viral escape. Structural analysis via cryoelectron microscopy of a representative broadly neutralizing antibody, CAB-A17, in complex with the Omicron BA.1 spike highlights the structural underpinnings of this broad neutralization. By reintroducing somatic hypermutations into a germline-reverted CAB-A17, we delineate the role of affinity maturation in the development of cross-neutralization by a public class of antibodies.


Subject(s)
Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , COVID-19 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , SARS-CoV-2/immunology , Humans , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/virology , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Antibodies, Neutralizing/immunology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/chemistry , Cross Reactions/immunology , Cryoelectron Microscopy , Neutralization Tests
17.
Am J Speech Lang Pathol ; 33(4): 1952-1964, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38809826

ABSTRACT

PURPOSE: The current study compared temporal and spectral acoustic contrast between vowel segments produced by speakers with dysarthria across three speech tasks-interactive, solo habitual, and solo clear. METHOD: Nine speakers with dysarthria secondary to amyotrophic lateral sclerosis participated in the study. Each speaker was paired with a typical interlocutor over videoconferencing software. The speakers produced the vowels /i, ɪ, ɛ, æ/ in /h/-vowel-/d/ words. For the solo tasks, speakers read the stimuli aloud in both their habitual and clear speaking styles. For the interactive task, speakers produced a target stimulus for their interlocutor to select among the four possibilities. We measured the duration difference between long and short vowels, as well as the F1/F2 Euclidean distance between adjacent vowels, and also determined how well the vowels could be classified based on their acoustic characteristics. RESULTS: Temporal contrast between long and short vowels was higher in the interactive task than in both solo tasks. Spectral distance between adjacent vowel pairs was also higher for some pairs in the interactive task than the habitual speech task. Finally, vowel classification accuracy was highest in the interactive task. CONCLUSIONS: Overall, we found evidence that individuals with dysarthria produced vowels with greater acoustic contrast in structured interactions than they did in solo tasks. Furthermore, the speech adjustments they made to the vowel segments differed from those observed in solo speech.


Subject(s)
Amyotrophic Lateral Sclerosis , Dysarthria , Phonetics , Speech Acoustics , Speech Production Measurement , Humans , Dysarthria/etiology , Dysarthria/physiopathology , Dysarthria/diagnosis , Male , Female , Middle Aged , Aged , Amyotrophic Lateral Sclerosis/complications , Amyotrophic Lateral Sclerosis/physiopathology , Speech Intelligibility , Voice Quality , Preliminary Data , Sound Spectrography , Time Factors , Aged, 80 and over , Acoustics
18.
Br J Radiol ; 97(1158): 1180-1190, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38597871

ABSTRACT

OBJECTIVES: We propose a deep learning (DL) multitask learning framework using convolutional neural network for a direct conversion of single-energy CT (SECT) to 3 different parametric maps of dual-energy CT (DECT): virtual-monochromatic image (VMI), effective atomic number (EAN), and relative electron density (RED). METHODS: We propose VMI-Net for conversion of SECT to 70, 120, and 200 keV VMIs. In addition, EAN-Net and RED-Net were also developed to convert SECT to EAN and RED. We trained and validated our model using 67 patients collected between 2019 and 2020. Single-layer CT images with 120 kVp acquired by the DECT (IQon spectral CT; Philips Healthcare, Amsterdam, Netherlands) were used as input, while the VMIs, EAN, and RED acquired by the same device were used as target. The performance of the DL framework was evaluated by absolute difference (AD) and relative difference (RD). RESULTS: The VMI-Net converted 120 kVp SECT to the VMIs with AD of 9.02 Hounsfield Unit, and RD of 0.41% compared to the ground truth VMIs. The ADs of the converted EAN and RED were 0.29 and 0.96, respectively, while the RDs were 1.99% and 0.50% for the converted EAN and RED, respectively. CONCLUSIONS: SECT images were directly converted to the 3 parametric maps of DECT (ie, VMIs, EAN, and RED). By using this model, one can generate the parametric information from SECT images without DECT device. Our model can help investigate the parametric information from SECT retrospectively. ADVANCES IN KNOWLEDGE: DL framework enables converting SECT to various high-quality parametric maps of DECT.


Subject(s)
Neural Networks, Computer , Radiography, Dual-Energy Scanned Projection , Tomography, X-Ray Computed , Humans , Tomography, X-Ray Computed/methods , Radiography, Dual-Energy Scanned Projection/methods , Deep Learning
19.
Ann Surg Oncol ; 31(8): 5021-5027, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38557912

ABSTRACT

BACKGROUND: For patients with left upper lobe lesions, the functional benefit of left upper division segmentectomy over left upper lobectomy remains controversial. This study evaluated the clinical and functional outcomes after these two procedures. METHODS: This retrospective study included 135 patients with left upper lobe lesions (left upper lobectomy, 110; left upper division segmentectomy, 25). Propensity score matching was used to compare the two groups. Spirometry and computed tomography volume assessments were performed to evaluate bronchus angle and tortuosity. Short-term clinical respiratory symptoms were assessed via medical record reviews. RESULTS: Patients in both groups had similar preoperative characteristics, apart from tumor size (left upper division segmentectomy, 1.6 ± 0.9 cm; left upper lobectomy, 2.8 ± 1.7 cm; p = 0.002). After propensity score matching, both groups had similar preoperative spirometry and pathological results. The postoperative spirometry results were similar; however, the left upper division segmentectomy group had a significantly smaller decrease in left-side computed tomography lung volume compared with that in the left upper lobectomy group (left upper division segmentectomy, 323.6 ± 521.4 mL; left upper lobectomy, 690.7 ± 332.8 mL; p = 0.004). The left main bronchus-curvature index was higher in the left upper lobectomy group (left upper division segmentectomy, 1.074 ± 0.035; left upper lobectomy, 1.097 ± 0.036; p = 0.013), and more patients had persistent cough in the left upper lobectomy group (p = 0.001). CONCLUSIONS: Left upper division segmentectomy may be a promising option for preventing marked bronchial angulation and decreasing postoperative persistent cough in patients with left upper lobe lung cancer.


Subject(s)
Bronchi , Lung Neoplasms , Pneumonectomy , Humans , Male , Female , Pneumonectomy/methods , Retrospective Studies , Lung Neoplasms/surgery , Lung Neoplasms/pathology , Lung Neoplasms/diagnostic imaging , Bronchi/surgery , Bronchi/pathology , Middle Aged , Aged , Follow-Up Studies , Tomography, X-Ray Computed , Prognosis , Carcinoma, Non-Small-Cell Lung/surgery , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Lung/surgery , Lung/diagnostic imaging
20.
Logoped Phoniatr Vocol ; : 1-7, 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38647190

ABSTRACT

BACKGROUND AND AIM: To examine whether the noise components in distress cries of term infants differed from very preterm infants whose cries were collected at a comparable "corrected" gestational age. METHODS: Distress cries were collected from 20 term and 20 preterm infants. The cries were acoustically examined for the occurrence of aperiodic phonatory behavior within and across moments of crying. RESULTS: The findings indicated no significant differences between term and preterm infants at term age in the occurrence of noise. CONCLUSIONS: Distress cries of both term and term-equivalent preterm infants appear to contain high instances of phonatory noise. The high arousal associated with distress crying and associated increase in subglottal pressure appeared to influence both term and term-equivalent preterm infants similarly.

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