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Investigative Ophthalmology & Visual... Dec 2023Vitreoretinal lymphoma is a high-grade malignant non-Hodgkin lymphoma with poor prognosis. The objective of this study was to elucidate the proteome profile of the...
PURPOSE
Vitreoretinal lymphoma is a high-grade malignant non-Hodgkin lymphoma with poor prognosis. The objective of this study was to elucidate the proteome profile of the vitreous in patients with vitreoretinal lymphoma (VRL), aiming to advance understanding of the pathophysiology of VRL.
METHODS
Comprehensive proteomic analyses of vitreous humor using liquid chromatography with tandem mass spectrometry were performed for 10 patients with VRL, 10 control patients with idiopathic epiretinal membrane or macular hole, and 10 patients with ocular sarcoidosis. Differentially expressed proteins (DEPs) were identified by comparing VRL with controls and sarcoidosis, and functional pathway analysis was performed. Finally, vitreous concentrations of representative DEPs that were significantly upregulated in proteomics study were measured by ELISA using a separate cohort.
RESULTS
In total, 1594 proteins were identified in the vitreous humor of VRL, control, and sarcoidosis samples. Also, 282 DEPs were detected in VRL, 249 upregulated and 33 downregulated, compared with controls. Enrichment pathway analysis showed alterations in proteasome-related pathways. Compared to controls and sarcoidosis, 14 DEPs in VRL showed significant upregulation. In the validation study, ELISA confirmed significantly higher vitreous concentrations of PSAT1, YWHAG, and 20S/26S proteasome complex in VRL compared with controls and sarcoidosis. Among the upregulated DEPs, vitreous PITHD1 and NCSTN concentrations correlated positively with vitreous IL-10 concentrations.
CONCLUSIONS
This study highlights aberrations in protein expression pattern in the vitreous of patients with VRL. The DEPs identified in this study may play pivotal roles in VRL pathogenesis, providing insights to enhance understanding of VRL pathophysiology and contribute to the development of VRL biomarkers.
Topics: Humans; Vitreous Body; Retinal Neoplasms; Proteomics; Lymphoma, Non-Hodgkin; Sarcoidosis; Proteins; 14-3-3 Proteins
PubMed: 38038618
DOI: 10.1167/iovs.64.15.2 -
Human Vaccines & Immunotherapeutics Dec 2023Coronavirus (COVID-19) vaccines have proved to be effective in the pandemic response but can cause adverse events such as delayed hypersensitivity reactions (DHRs)....
Coronavirus (COVID-19) vaccines have proved to be effective in the pandemic response but can cause adverse events such as delayed hypersensitivity reactions (DHRs). Delayed-reading intradermal tests (IDT) to vaccines are limited by false-positive results and may reflect a cell-mediated rather than IgE-mediated immune response. Lymphocyte transformation test (LTT), which has been utilized in the diagnosis of drug allergy, may be helpful in suspected COVID-19 vaccine and/or its excipient-related DHRs. To investigate the use of LTT in two suspected cases of COVID-19 vaccine-induced DHRs, two patients with suspected DHRs to COVID-19 vaccination were tested by delayed-reading IDT and LTT against vaccines and their excipients. A 47-year-old man developed acute mixed-pattern hepatitis after the second dose of ChAdOx1 vaccine. LTT performed at 2 months post-vaccination revealed reactivity to the ChAdOx1 vaccine, polysorbate 80 and mildly to PEG 2050 but not BNT162b2 vaccine. Delayed-reading IDT returned negative to both vaccines and excipients. He tolerated BNT162b2 vaccination with no adverse events. A 36-year-old woman presented with subacute morbilliform eruption and hepatitis after the first dose of BNT162b2 vaccine. LTT performed 3 months later revealed reactivity to the BNT162b2 but not PEG 2050. Repeat LTT following subsequent natural Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection revealed reactivity to ChAdOx1 and NVX-CoV2373 vaccines but not polysorbate 80. Delayed-reading IDT remained negative. She proceeded with NVX-CoV2373 vaccination with no symptom recurrence. LTT may be a useful tool in suspected COVID-19 vaccine-related DHRs. Further evaluation with a larger patient cohort is required.
Topics: Adult; Female; Humans; Male; Middle Aged; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Excipients; Hypersensitivity, Delayed; Lymphocyte Activation; Polysorbates; SARS-CoV-2; Vaccination
PubMed: 36912718
DOI: 10.1080/21645515.2023.2182527 -
Human Vaccines & Immunotherapeutics Dec 2023Active immunotherapy of cancer with therapeutic vaccines has been the subject of experimental and clinical studies for at least 50 years. Our approach has employed 1)...
Active immunotherapy of cancer with therapeutic vaccines has been the subject of experimental and clinical studies for at least 50 years. Our approach has employed 1) autologous, human cancer cells because of extensive evidence that tumor rejection antigens may differ between multiple tumors of the same histology; 2) the immunopotentiating drug, cyclophosphamide; and 3) haptens, particularly dinitrophenyl. Multiple clinical trials in 455 patients with melanoma and ovarian cancer have shown that administration of haptenized vaccines at the proper dosage-schedule regularly induces T cell-mediated immunity to autologous tumor cells as measured by delayed-type hypersensitivity. Moreover, the vaccine causes changes in the tumor site suggestive of an immune reaction, including inflammation and infiltration with CD8+ T lymphocytes that are activated and produce cytokines. The T cell response is oligoclonal, and dominant Vβ families differ between patients. Studies of measurable metastases show clinically important tumor regression. Commercial development of this technology is clearly feasible.
Topics: Female; Humans; Cancer Vaccines; Melanoma; Antigens, Neoplasm; Inflammation; Dinitrobenzenes
PubMed: 36755486
DOI: 10.1080/21645515.2023.2172925 -
Frontiers in Immunology 2023Sarcoidosis is an inflammatory granulomatous disease of unknown etiology with predominant lung involvement. Organ involvement and disease severity, as well as the nature...
RATIONALE
Sarcoidosis is an inflammatory granulomatous disease of unknown etiology with predominant lung involvement. Organ involvement and disease severity, as well as the nature of immune alterations, vary among patients leading to a range of clinical phenotypes and outcomes. Our objective was to evaluate the association of disease course and immune responses in pulmonary sarcoidosis.
METHODS
In this prospective cohort study of 30 subjects, most of whom were followed for one year, we evaluated 14 inflammatory markers in plasma, 13 Treg/T cell flow cytometry markers and 8 parameters of FOXP3 Treg biology, including suppressive function, epigenetic features and stability.
RESULTS
We identified a set of 13 immunological parameters that differ in sarcoidosis subjects in comparison with healthy donors. Five of those were inversely correlated with suppressive function of Tregs in sarcoidosis, and six (TNFα, TNFR I and II, sCD25, Ki-67 and number of Tregs) were particularly upregulated or increased in subjects with thoracic lymphadenopathy. Treg suppressive function was significantly lower in patients with thoracic lymphadenopathy, and in patients with higher burdens of pulmonary and systemic symptoms. A combination of five inflammatory markers, Ki-67 expression, Treg function, and lung diffusion capacity evaluated at study entry predicted need for therapy at one year follow-up in 90% of cases.
CONCLUSION
Tregs may suppress ongoing inflammation at local and systemic levels, and TNFα, TNFR I and II, sCD25 and Ki-67 emerge as attractive biomarkers for sarcoid inflammatory activity.
Topics: Humans; T-Lymphocytes, Regulatory; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha; Prospective Studies; Ki-67 Antigen; Sarcoidosis; Prognosis; Forkhead Transcription Factors; Lymphadenopathy
PubMed: 38173720
DOI: 10.3389/fimmu.2023.1301991 -
NeuroImage Dec 2023Sensation seeking and delay discounting are strong predictors of various risk-taking behaviors. However, the relationship between sensation seeking and delay discounting...
Sensation seeking and delay discounting are strong predictors of various risk-taking behaviors. However, the relationship between sensation seeking and delay discounting remains elusive. Here, we addressed this issue by examining how high sensation seekers (HSS; N = 40) and low sensation seekers (LSS; N = 40) evaluated immediate and delayed rewards with low and high amounts during a behavioral task and an EEG task of delay discounting. Although HSS and LSS exhibited comparable discounting preference at the behavioral level, HSS relative to LSS was associated with a greater delay discounting effect at the neural level when earned rewards were large. This abnormality of reward magnitude was further corroborated by an electrocortical hypersensitivity to large immediate rewards and a stronger neural coding of reward magnitude for HSS as compared to LSS. Our findings support both the hyperactive approach theory and the optimal arousal theory in sensation seeking and have implications for the prevention and intervention targeting sensation seeking to reduce maladaptive risk-taking behaviors.
Topics: Humans; Reward; Risk-Taking; Sensation; Delay Discounting
PubMed: 37977409
DOI: 10.1016/j.neuroimage.2023.120456 -
Scientific Reports Nov 2023Spatial control over the distribution of therapeutics is a highly desired feature, which could limit the side effects of many drugs. Here we describe a nanoscale agent,...
Spatial control over the distribution of therapeutics is a highly desired feature, which could limit the side effects of many drugs. Here we describe a nanoscale agent, fabricated from a coupled polymer-DNA origami hybrid that exhibits stability in serum and slow diffusion through tissues, in a manner correlating with shape and aspect ratio. Coupling to fragments of polyethylene glycol (PEG) through polyamine electrostatic interactions resulted in marked stability of the agents in-vivo, with > 90% of the agents maintaining structural integrity 5 days following subcutaneous injection. An agent functionalized with aptamers specific for human tumor necrosis factor TNF-alpha, significantly abrogated the inflammatory response in a delayed-type hypersensitivity model in humanized TNF-alpha mice. These findings highlight polymer-DNA hybrid nanostructures as a programmable and pharmacologically viable update to mainstream technologies such as monoclonal antibodies, capable of exerting an additional layer of control across the spatial dimension of drug activity.
Topics: Humans; Animals; Mice; Polymers; Tissue Distribution; Tumor Necrosis Factor-alpha; DNA; Nanostructures
PubMed: 37949918
DOI: 10.1038/s41598-023-46351-1 -
American Journal of Ophthalmology Case... Mar 2024To describe a case of retinal vaso-occlusive vasculitis with associated lid edema and conjunctivitis following intravitreal pegcetacoplan administration in a patient...
PURPOSE
To describe a case of retinal vaso-occlusive vasculitis with associated lid edema and conjunctivitis following intravitreal pegcetacoplan administration in a patient with geographic atrophy (GA).
OBSERVATION
A 78 year old Caucasian woman presented with complaints of lid edema, conjunctival injection, loss of vision, and mild ocular discomfort eleven days after receiving an intravitreal pegcetacoplan injection in the left eye for geographic atrophy. Visual acuity on presentation was decreased to 20/400 from 20/200 previously in that eye. Eyelid edema and conjunctival injection were present with minimal anterior chamber reaction. Dilated fundus examination revealed hemorrhages throughout the retina and signs of retinal vasculitis. The patient subsequently developed hyphema and vitreous hemorrhage. Laboratory evaluations for common infectious and inflammatory causes including aqueous and vitreous cultures for bacteria and Herpes simplex PCR were normal or negative. A delayed hypersensitivity to pegcetacoplan was suspected and was treated with topical, oral subconjunctival and intravitreal steroids.
CONCLUSION
This index report illustrates a case of retinal vaso-occlusive vasculitis associated with intravitreal pegcetacoplan associated with lid edema and conjunctival injection and subsequent hyphema and vitreous hemorrhage. Therapy with steroids topically, systemically, periocularly and intravitreally were used to treat the inflammatory process and prevent further visual loss.
PubMed: 38298266
DOI: 10.1016/j.ajoc.2024.101999 -
Journal of the American Association For... Nov 2023This study compared the therapeutic effects in mice of 3 different formulations of buprenorphine. These formulations were standard buprenorphine hydrochloride (Bup-HCL)...
This study compared the therapeutic effects in mice of 3 different formulations of buprenorphine. These formulations were standard buprenorphine hydrochloride (Bup-HCL) and 2 different extended-release buprenorphine formulations (Bup-ER and Ethiqa-XR [Bup-XR]). Drugs were evaluated based on their ability to attenuate thermal hypersensitivity in a mouse plantar incisional pain model. We hypothesized that Bup-HCL would attenuate postoperative thermal hypersensitivity at 20 min after administration, and that Bup-ER and Bup-XR would attenuate thermal hypersensitivity at 40 min after administration. Male C57BL6/J mice were randomly assigned to 1 of 4 treatment groups: 1) saline, 5 mL/kg SC, once; 2) Bup-HCL, 0.1 mg/kg SC, once; 3) Bup-ER, 1 mg/kg, SC, once; and 4) Bup-XR, 3.25 mg/kg, SC, once. Thermal hypersensitivity was assessed on the day before surgery and again on the day of surgery at 20, 40, 60, 90, and 120 min after drug administration. Thermal hypersensitivity after surgery was not different among the Bup-HCL, Bup-ER and Bup-XR groups at any timepoint. In addition, all buprenorphine treatment groups showed significantly less thermal hypersensitivity after surgery than did the saline group. Subjective observations suggested that mice that received Bup-ER or Bup-XR became hyperactive after drug administration (83 and 75% of mice tested, respectively). Our results indicate that Bup-HCL, Bup-ER, or Bup-XR attenuate thermal hyper- sensitivity related to foot incision by 20 min after administration.
Topics: Animals; Male; Mice; Analgesics, Opioid; Buprenorphine; Delayed-Action Preparations; Drug Compounding; Narcotic Antagonists; Pain
PubMed: 38030144
DOI: 10.30802/AALAS-JAALAS-23-000011 -
Respiratory Research Mar 2024Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with different disease trajectories. Progression (PF-ILD) occurs in up to...
BACKGROUND
Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with different disease trajectories. Progression (PF-ILD) occurs in up to 50% of patients and is associated with increased mortality.
METHODS
The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for disease trajectories in different ILD. The course of disease was classified as significant (absolute forced vital capacity FVC decline > 10%) or moderate progression (FVC decline 5-10%), stable disease (FVC decline or increase < 5%) or improvement (FVC increase ≥ 5%) during time in registry. A second definition for PF-ILD included absolute decline in FVC % predicted ≥ 10% within 24 months or ≥ 1 respiratory-related hospitalisation. Risk factors for progression were determined by Cox proportional-hazard models and by logistic regression with forward selection. Kaplan-Meier curves were utilised to estimate survival time and time to progression.
RESULTS
Within the EXCITING-ILD registry 28.5% of the patients died (n = 171), mainly due to ILD (n = 71, 41.5%). Median survival time from date of diagnosis on was 15.5 years (range 0.1 to 34.4 years). From 601 included patients, progression was detected in 50.6% of the patients (n = 304) with shortest median time to progression in idiopathic NSIP (iNSIP; median 14.6 months) and idiopathic pulmonary fibrosis (IPF; median 18.9 months). Reasons for the determination as PF-ILD were mainly deterioration in lung function (PFT; 57.8%) and respiratory hospitalisations (40.6%). In multivariate analyses reduced baseline FVC together with age were significant predictors for progression (OR = 1.00, p < 0.001). Higher GAP indices were a significant risk factor for a shorter survival time (GAP stage III vs. I HR = 9.06, p < 0.001). A significant shorter survival time was found in IPF compared to sarcoidosis (HR = 0.04, p < 0.001), CTD-ILD (HR = 0.33, p < 0.001), and HP (HR = 0.30, p < 0.001). Patients with at least one reported ILD exacerbation as a reason for hospitalisation had a median survival time of 7.3 years (range 0.1 to 34.4 years) compared to 19.6 years (range 0.3 to 19.6 years) in patients without exacerbations (HR = 0.39, p < 0.001).
CONCLUSION
Disease progression is common in all ILD and associated with increased mortality. Most important risk factors for progression are impaired baseline forced vital capacity and higher age, as well as acute exacerbations and respiratory hospitalisations for mortality. Early detection of progression remains challenging, further clinical criteria in addition to PFT might be helpful.
Topics: Humans; Lung Diseases, Interstitial; Idiopathic Pulmonary Fibrosis; Sarcoidosis; Hospitalization; Registries
PubMed: 38448953
DOI: 10.1186/s12931-024-02731-3 -
BMC Ophthalmology Jul 2023Sarcoidosis is an inflammatory disorder in which patients frequently develop ocular manifestations that precede systemic involvement, sometimes it even presents as an...
BACKGROUND
Sarcoidosis is an inflammatory disorder in which patients frequently develop ocular manifestations that precede systemic involvement, sometimes it even presents as an ocular isolated form of the disease. The purpose of this study is to report the ocular and systemic manifestations of sarcoidosis in a series of Mexican patients, as there is a low incidence of the disease in this population.
METHODS
A retrospective case series of patients with positive classification criteria for sarcoidosis who attended Asociacion Para Evitar la Ceguera en Mexico, IAP between 2011 and 2022. Descriptive statistics were used to report the clinical, laboratory, and imaging findings and treatment. Numerical results were presented using median values and first and third quartiles for distribution.
RESULTS
Fourteen patients were included in this study, 10 of them had definite ocular sarcoidosis (biopsy-proven), 4 had presumed ocular sarcoidosis. The median age of onset was 52 (34; 67), with a predominance of female patients (71.4%). Ten patients (71.4%) debuted with ocular manifestations. The most common forms of ocular involvement were bilateral anterior uveitis (50%) and panuveitis (28.6%). Median follow-up was 24 (13-49) months.
CONCLUSIONS
Sarcoidosis is a rare, underdiagnosed condition in Mexico and ocular involvement can be an early manifestation of the disease. Ophthalmologists should be alert to the signs of ocular sarcoidosis and collaborate with a multidisciplinary team to screen for systemic involvement if suspicion is high.
Topics: Humans; Female; Male; Retrospective Studies; Mexico; Sarcoidosis; Uveitis; Eye; Endophthalmitis
PubMed: 37474932
DOI: 10.1186/s12886-023-03081-2