High-Dose Upadacitinib Therapy for Refractory Metastatic Crohn Disease.

This case report describes 2 patients with metastatic Crohn disease who were treated with upadacitinib.

Peptides as multifunctional players in cancer therapy.

Peptides exhibit lower affinity and a shorter half-life in the body than antibodies. Conversely, peptides demonstrate higher efficiency in tissue penetration and cell internalization than antibodies. Regardless of the pros and cons of peptides, they have been used as tumor-homing ligands for delivering carriers (such as nanoparticles, extracellular vesicles, and cells) and cargoes (such as cytotoxic peptides and radioisotopes) to tumors. Additionally, tumor-homing peptides have been conjugated with cargoes such as small-molecule or chemotherapeutic drugs via linkers to synthesize peptide-drug conjugates. In addition, peptides selectively bind to cell surface receptors and proteins, such as immune checkpoints, receptor kinases, and hormone receptors, subsequently blocking their biological activity or serving as hormone analogs. Furthermore, peptides internalized into cells bind to intracellular proteins and interfere with protein-protein interactions. Thus, peptides demonstrate great application potential as multifunctional players in cancer therapy.

Steady-state memory-phenotype conventional CD4+ T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis.

Memory-phenotype (MP) CD4+ T cells are a substantial population of conventional T cells that exist in steady-state mice, yet their immunological roles in autoimmune disease remain unclear. In this work, we unveil a unique phenotype of MP CD4+ T cells determined by analyzing single-cell transcriptomic data and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+ T cells in the spleen were composed of heterogeneous effector subpopulations and existed regardless of germ and food antigen exposure. Distinct subpopulations of MP CD4+ T cells were specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells exerted TCR-independent bystander effector functions similar to innate lymphoid cells. In particular, CCR6high subpopulation of MP CD4+ T cells were major responders to IL-23 and IL-1ß without MOG35-55 antigen reactivity, which gave them pathogenic Th17 characteristics and allowed them to contribute to autoimmune encephalomyelitis. We identified that Bhlhe40 in CCR6high MP CD4+ T cells as a key regulator of GM-CSF expression through IL-23 and IL-1ß signaling, contributing to central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal the clearly distinct effector-like heterogeneity of MP CD4+ T cells in the steady state and indicate that CCR6high MP CD4+ T cells exacerbate autoimmune neuroinflammation via the Bhlhe40/GM-CSF axis in a bystander manner.

Diagnostic accuracy of general dermatologists and supportive oncodermatologists for biopsied cutaneous immune-related adverse events.

PURPOSE: Supportive oncodermatology has been shown to improve several aspects of care for patients with cancer, but research showing improved diagnostic accuracy as a benefit of supportive oncodermatology is largely lacking. We thus aimed to evaluate different dermatologist groups' diagnostic accuracy for heterogenous cutaneous toxicities, using cutaneous immune-related adverse events (cirAEs) from immune checkpoint inhibitors (ICIs) as a test model. METHODS: Billing/requisition codes were used to identify patients who initiated programmed death-1/ligand-1 (PD-1/PD-L1) ICIs between 2010 and 2019 at Dana-Farber Cancer Institute/Brigham and Women's Hospital/Massachusetts General Hospital and underwent a subsequent skin biopsy. For each biopsied cirAE, pre-biopsy clinical diagnoses and post-biopsy clinico-pathologic diagnoses were retrospectively obtained from the medical record. Each biopsy-ordering dermatology provider was categorized as a general dermatologist or supportive oncodermatologist on the basis of providing clinical care within a cancer-center or attending on a hospital/clinic service dedicated to anti-cancer drug-related skin toxicities. RESULTS: Of 4,183 patients who initiated anti-PD-1/PD-L1 therapy between 2010 and 2019, 101 (2.4%) patients collectively had 104 biopsied cirAEs. In more than one-third of all reviewed biopsied cirAEs (n = 39, 37.5%), histopathology results frequently led to revision of the pre-biopsy clinical diagnosis. The rate of initial cirAE misclassification amongst supportive oncodermatologists was significantly lower than that amongst general dermatologists (18/66, 27.3% vs. 21/38, 55.3%; Fischer's-exact-test p = 0.006). CONCLUSION: Experienced supportive oncodermatologists may benefit patient care through increased diagnostic accuracy for skin toxicities from ICIs. Collectively, these results underscore that both skin biopsy from any dermatology provider and oncodermatology referral (where available) are valuable resources that should be integrated into supportive cancer care.

Thermoplastic elastomers containing antimicrobial and antiviral additives for mobility applications.

The transmission of the SARS-CoV-2 coronavirus has been shown through droplets generated by infected people when coughing, sneezing, or talking in close contact. These droplets either reach the next person directly or land on nearby surfaces. The objective of this study is to develop a novel, durable, and effective disinfecting antimicrobial (antiviral, antibacterial, and antifungal) styrene-ethylene/butylene-styrene (SEBS) based thermoplastic elastomers (TPE). TPE incorporated with six different formulations was investigated for mechanical and antiviral performance. The formulations consist of a combination of zinc pyrithione (ZnPT), sodium pentaborate pentahydrate (NaB), disodium octaborate tetrahydrate (DOT), and chlorhexidine (CHX). ZnPT and DOT incorporated TPE showed a reduction of microbes such as bacteria by up to 99.99%, deactivated Adenovirus, Poliovirus, Norovirus, and reduced a strain of the coronavirus family by 99.95% in 60 min on TPE samples. Control samples had higher tensile strengths among all formulations and tensile strength decreased by around 14%, 21% and 27% for ZnPT and DOT combinations compared to control samples. The elongation at break decreased by around 7%, 9% and 12% with ZnPT and DOT combinations, where it reached minimum values of 720%, 702% and 684%, respectively. The 100% Modulus and 300% Modulus slightly increased with ZnPT and NaB combination (reaching values from 1.6 to 1.9 MPa and 2.6-2.9 MPa respectively) in comparison with control samples. The MFI also decreased with antimicrobial and antiviral additives (decreasing values from 64.8 to 43.3 g/10 min). ZnPT and NaB combination showed the lowest MFI (43.3 g/10 min) and reduced the MFI of control sample by around 33%. TPE samples containing ZnPT and DOT combination showed biocidal activity against the microorganisms tested and can be used to develop antimicrobial products for multiple touchpoints within a vehicle and micro-mobility.

Patterns of Cutaneous and Noncutaneous Immune-Related Adverse Events Among Patients With Advanced Cancer.

Importance: Cutaneous immune-related adverse events (cirAEs) are some of the earliest toxic reactions to emerge following immune-checkpoint inhibitor (ICI) initiation. As an early indicator of robust inflammatory response, cirAEs may be associated with patterns of immune-mediated toxic effects, but associations between these events and noncutaneous immune-related adverse events (irAEs) remain underexplored. Objectives: To characterize patterns of cirAEs and irAEs across care settings and examine associations between the features of first cirAE, overall irAE risk, and risk of specific irAE subtypes. Design, Setting, and Participants: A retrospective cohort study was conducted at a single academic medical center. The cohort included 358 patients with cancer who initiated anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 ICI therapy between January 1, 2016, and March 8, 2019, and developed 1 or more cirAEs, identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and confirmed via manual medical record review. All relevant information documented before March 31, 2020, was included. Exposures: Anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 therapy. Main Outcomes and Measures: Associations between specific cirAE morphologic classes and patterns of irAEs (occurrence, timeline, organ class, and specific toxic effects). Given the potential that shared underlying factors are associated with the risk of both noncutaneous and cutaneous toxic effects, the presence of observed positive associations between certain cirAE and irAE subtypes was hypothesized. Results: Of the 358 patients, 213 were men (59.5%); median age was 65 years (interquartile range, 55-73 years). Nearly half of the patients (177 [49.4%]) with cirAE also developed a noncutaneous irAE. Most patients (128 [72.3%]) experienced their first cirAE before developing any irAE. Several cirAE morphologic classes were found to be associated with overall, organ-based, and specific irAEs. More specifically, mucositis was found to be associated with overall irAE risk (odds ratio [OR], 5.28; 95% CI, 1.11-24.26; P = .04), gastrointestinal irAEs (OR, 5.70; 95% CI, 1.11-29.40; P = .04), and the specific diagnosis of gastroenterocolitis (OR, 6.80; 95% CI, 1.24-37.39; P = .03). In addition, psoriasis was associated with an increased risk of endocrine irAEs (OR, 4.54; 95% CI, 1.21-17.04; P = .03). Conclusions and Relevance: In this cohort study, these findings underscore the risk of multisystem toxic effects in patients experiencing cirAEs and highlight potential opportunities for dermatologists in the management of noncutaneous toxic effects.

Factors that influence the thymic selection of CD8αα intraepithelial lymphocytes.

Thymocytes bearing αß T cell receptors (TCRαß) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8αα-expressing intraepithelial lymphocytes (CD8αα IELs). The factors that influence the choice between negative selection versus CD8αα IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8αα IEL development, we show that the affinity threshold for CD8αα IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.

A role for phagocytosis in inducing cell death during thymocyte negative selection.

Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, using a murine thymic slice model in which thymocytes undergo negative selection in situ, we demonstrate that phagocytosis promotes negative selection, and provide evidence for the escape of autoreactive CD8 T cells to the periphery when phagocytosis in the thymus is impaired. We also show that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a model for negative selection in which the death process initiated following strong TCR signaling is facilitated by phagocytosis. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.

Controlled microstructuring of janus particles based on a multifunctional poly(ethylene glycol).

A novel water insoluble, multifunctional poly(ethylene glycol), poly(hydrazide ethylene glycol-co-benzyl glycidyl ether) (P(HZ-co-BnGE)), is synthesized via thiol-ene click reaction of poly(allyl glycidyl ether-co-benzyl glycidyl ether) (P(AGE-co-BnGE)). The base polymer P(AGE-co-BnGE) is previously prepared by anionic ring-opening copolymerization of the corresponding monomers. To demonstrate utility, bicompartmental microspheres and microcylinders containing P(HZ-co-BnGE) in one of the compartments are prepared via electrohydrodynamic (EHD) co-jetting. Next, spatially controlled surface reactivity toward sugars is demonstrated by selective binding of 2α-mannobiose to the P(HZ-co-BnGE) compartment only, as confirmed by a carbohydrate-lectin-binding assay. These sugar-reactive hydrazide-presenting microparticles have potential applications for glyco-targeted drug delivery.