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1.
Mol Biol Rep ; 51(1): 865, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-39073611

ABSTRACT

BACKGROUND: Treating Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) is difficult due to high relapse rates and drug resistance. Tumorigenesis is largely dependent on disruption of the cell cycle progression. While the role of Cell Division Cycle 27 (CDC27) in the anaphase-promoting complex/cyclosome is well-known, its significance in the pathophysiology of acute leukemia and its potential as a biomarker are less well understood. METHODS AND RESULTS: This case-control study used samples from 100 leukemia patients (50 with ALL and 50 with AML) at Shariati Hospital in Tehran, Iran, along with 50 healthy individuals. The expression of CDC27 was analyzed using quantitative real-time PCR (RQ-PCR). Statistical analysis was done using the nonparametric Mann-Whitney U test. The results showed that AML and ALL patients had significantly higher levels of CDC27 expression compared to the control group. Although a weak correlation between CDC27 expression and hematological parameters was found, there was no significant correlation with sample type, demographics, clinical variables or prognosis. CONCLUSIONS: This study highlights the potential of CDC27 as an oncogene, as well as a possible prognostic and diagnostic marker in acute leukemias. It suggests that CDC27 could be a valuable biomarker or therapeutic target in the treatment of AML and ALL.


Subject(s)
Biomarkers, Tumor , Leukemia, Myeloid, Acute , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Male , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Female , Adult , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Case-Control Studies , Middle Aged , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Adolescent , Prognosis , Young Adult , Iran , Gene Expression Regulation, Leukemic , Aged , Child , Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
2.
Expert Opin Ther Pat ; 34(9): 733-757, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38958471

ABSTRACT

INTRODUCTION: COX-2 is a crucial enzyme in the manufacture of prostaglandins. The enzyme's metabolites might have an important function as regulators of the inflammatory response and other medical conditions such as cancer. Selective COX-2 inhibitors are believed to enhance or reverse the response of cancer chemotherapeutics. AREAS COVERED: This study addresses the chemical structures as well as the antitumor activity of new COX-2 inhibitors produced in the recent five years, aiming to provide an insight into the mechanism of COX-2 induced PGE2 powerful signal in cancer development. EXPERT OPINION: The significance of selective COX-2 inhibitors as an efficient superfamily of compounds with anti-inflammatory, anti-Alzheimer's, anti-Parkinson's disease, and anticancer properties has piqued the passion of academics in the field of drug development. Long-term usage of selective COX-2 inhibitors, such as celecoxib has been proven in clinical trials to lower the incidence of several human malignancies. Furthermore, celecoxib has the potential to greatly increase the effectiveness of chemotherapy. Our extensive understanding of selective COX-2 inhibitor SAR may aid in the development of safer and more effective selective COX-2 inhibitors as cancer chemopreventive agents. This review focuses on the different structural classes of selective COX-2 inhibitors, with a particular emphasis on their SAR.


Subject(s)
Antineoplastic Agents , Cyclooxygenase 2 Inhibitors , Cyclooxygenase 2 , Drug Development , Neoplasms , Patents as Topic , Humans , Cyclooxygenase 2 Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/enzymology , Animals , Cyclooxygenase 2/metabolism , Cyclooxygenase 2/drug effects , Structure-Activity Relationship , Dinoprostone/metabolism , Drug Design
3.
Curr Opin Virol ; 67: 101412, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38838550

ABSTRACT

Mucosal-associated invariant T (MAIT) cells are an unconventional T cell population that are highly abundant in humans. They possess a semi-invariant T cell receptor (TCR) that recognises microbial metabolites formed during riboflavin biosynthesis, presented on a nonpolymorphic MHC-like molecule MR1. MAIT cells possess an array of effector functions, including type 1, type 17, and tissue repair activity. Deployment of these functions depends on the stimuli they receive through their TCR and/or cytokine receptors. Strong cytokine signalling, such as in response to vaccination, can bypass TCR triggering and provokes a strong proinflammatory response. Although data are still emerging, multiple aspects of MAIT cell biology are associated with modulation of immunity induced by the coronavirus disease 2019 mRNA and adenovirus vector vaccines. In this review, we will address how MAIT cells may play a role in immunogenicity of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and how these cells can be harnessed as cellular adjuvants.


Subject(s)
COVID-19 Vaccines , COVID-19 , Mucosal-Associated Invariant T Cells , SARS-CoV-2 , Humans , Mucosal-Associated Invariant T Cells/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , SARS-CoV-2/immunology , Immunogenicity, Vaccine , Animals , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Cytokines/immunology , Cytokines/metabolism
4.
Mikrochim Acta ; 191(3): 171, 2024 Mar 02.
Article in English | MEDLINE | ID: mdl-38430344

ABSTRACT

This paper focuses on 3D printing using digital light processing (DLP) to create microchannel devices with inner diameters of 100, 200, and 500 µm and cater flow-through applications within the realm of analytical chemistry, in particular high-pressure liquid chromatographic separations. Effects of layer thickness and exposure time on channel dimensions and surface roughness were systematically investigated. Utilizing a commercially accessible 3D printer and acrylate resin formulation, we fabricated 100-500 µm i.d. squared and circular channel designs minimizing average surface roughness (< 20%) by applying a 20-µm layer thickness and exposure times ranging from 1.1 to 0.7 s. Pressure resistance was measured by encasing microdevices in an aluminum chip holder that integrated flat-bottom polyetheretherketon (PEEK) nanoports allowing to establish the micro-to-macro interface to the HPLC instrument. After thermal post-curing and finetuning the clamping force of the chip holder, a maximum pressure resistance of 650 bar (1.5% RSD) was reached (n = 3). A polymer monolithic support structure was successfully synthesized in situ with the confines of a 500 µm i.d. 3D printed microchannel. A proof-of-concept of a reversed-phase chromatographic gradient separation of intact proteins is demonstrated using an aqueous-organic mobile-phase with isopropanol as organic modifier.

5.
Br Dent J ; 2024 Feb 07.
Article in English | MEDLINE | ID: mdl-38326460

ABSTRACT

Introduction This study aims to assess if the COVID-19 pandemic impacted upon oral cancer staging in a single centre in the UK.Materials and methods Data were collected from the head and neck cancer database of a teaching hospital in London. Oral cancer diagnosis and staging in the peak period of the pandemic (March 2020-2021) were assessed against the one-year period (March 2019-2020) before the pandemic.Results In total, 25 cases of oral cancer were diagnosed in the pre-COVID-19 group compared to 26 in the COVID-19 cohort. Referrals from dentists accounted for 30% of cases of confirmed oral cancer in the COVID-19 class in comparison to 48% the year prior. Higher rates of overall TNM (tumour, lymph node, metastasis) staging at level 4a and above were observed in the COVID-19 cohort at 68% in comparison to 48% the year before.Conclusion Marginal non-statistically significant differences were noted of worsening stages of oral cancer presentations in the first year of the COVID-19 pandemic in this unit. Long-term studies on the outcomes of those diagnosed with oral cancer during the pandemic at a regional and national level will facilitate greater analysis on the impact the pandemic had on this cohort.

6.
Cell Commun Signal ; 22(1): 105, 2024 02 08.
Article in English | MEDLINE | ID: mdl-38331801

ABSTRACT

The current scientific literature has extensively explored the potential role of proteasome inhibitors (PIs) in the NF-κB pathway of leukemia and lymphoma. The ubiquitin-proteasome system (UPS) is a critical component in regulating protein degradation in eukaryotic cells. PIs, such as BTZ, are used to target the 26S proteasome in hematologic malignancies, resulting in the prevention of the degradation of tumor suppressor proteins, the activation of intrinsic mitochondrial-dependent cell death, and the inhibition of the NF-κB signaling pathway. NF-κB is a transcription factor that plays a critical role in the regulation of apoptosis, cell proliferation, differentiation, inflammation, angiogenesis, and tumor migration. Despite the successful use of PIs in various hematologic malignancies, there are limitations such as resistant to these inhibitors. Some reports suggest that PIs can induce NF-κB activation, which increases the survival of malignant cells. This article discusses the various aspects of PIs' effects on the NF-κB pathway and their limitations. Video Abstract.


Subject(s)
Hematologic Neoplasms , Leukemia , Lymphoma , Humans , Proteasome Inhibitors/pharmacology , Proteasome Inhibitors/therapeutic use , NF-kappa B/metabolism , Proteasome Endopeptidase Complex/metabolism , Leukemia/drug therapy , Lymphoma/drug therapy , Apoptosis
7.
Mol Divers ; 28(1): 419-435, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37847467

ABSTRACT

The development of transition metal-free 2-isocyanobiaryl-based reactions has received much attention due to the widespread presence of phenanthidine frameworks as products in pharmacological chemistry and materials science. This review article focuses on the achievements from 2013 until now in various metal-free catalyzed reactions and discusses challenging mechanisms and features of the transformations.


Subject(s)
Metals , Transition Elements , Cyclization , Phenanthridines
8.
bioRxiv ; 2023 Dec 07.
Article in English | MEDLINE | ID: mdl-38106155

ABSTRACT

In this study we report a naturally evolved temperature-sensing electrical regulator in the cytochrome c oxidase of the Devil Worm, Halicephalobus mephisto. This extremophile metazoan was isolated 1.3 km underground in a South African goldmine, where it adapted to heat and potentially to hypoxia, making its mitochondrial sequence a likely target of adaptational change. We obtained the full mitochondrial genome sequence of this organism, and show through dN/dS analysis statistically robust evidence of positive selection in H. mephisto cytochrome c oxidase subunits. Seventeen of these positively-selected amino acid substitutions were localized in proximity to the H- and K-pathway proton channels of the complex. Surprisingly, the H. mephisto cytochrome c oxidase proton pump completely shuts down at low temperatures (20°C) leading to approximately a 4.8-fold reduction in the transmembrane proton gradient voltage (ΔΨm) compared to optimal temperature (37°C). Direct measurement of oxygen consumption found a corresponding 4.7-fold drop at 20°C compared to 37°C. Correspondingly, the lifecycle of H. mephisto takes four-fold longer at the low temperature compared to higher. This elegant evolutionary adaptation creates a finely-tuned mitochondrial temperature sensor, allowing this ectothermic organism to maximize its reproductive success in varying environmental temperatures. Our study shows that evolutionary innovation may remodel core metabolism to make it more accurately map onto environmental variation.

9.
Lab Chip ; 23(22): 4868-4875, 2023 11 07.
Article in English | MEDLINE | ID: mdl-37867384

ABSTRACT

A diagnostic test based on microfluidic image cytometry and machine learning has been designed and applied for accurate classification of erythrocytes and leukocytes, including a unique fully-automated 5-part quantitative differentiation into neutrophils, lymphocytes, monocytes, eosinophils, and basophils, using minute amounts of whole blood in a single counting chamber. A low-cost disposable multilayer microdevice for microfluidic image cytometry was developed that comprises a 1 mm × 22 mm × 70 µm (w × l × h) rectangular microchannel, allowing the analysis of trace volume of blood (20 µL) for each assay. Automated analysis of digitized binary images applying a border following algorithm was performed allowing the qualitative analysis of erythrocytes. Bright-field imaging was used for the detection of erythrocytes and fluorescence imaging for 5-part differentiation of leukocytes after acridine orange staining, applying a convolutional neural network enabling unparalleled speed for identification and automated morphology classification yielding 98.57% accuracy. Blood samples were obtained from 30 volunteers and count values did not significantly differ from data obtained using a commercial automated hematology analyzer.


Subject(s)
Leukocytes , Microfluidics , Humans , Erythrocytes , Machine Learning , Image Cytometry
10.
Nat Immunol ; 24(9): 1565-1578, 2023 09.
Article in English | MEDLINE | ID: mdl-37580605

ABSTRACT

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize microbial metabolites through a semi-invariant T cell receptor (TCR). Major questions remain regarding the extent of human MAIT cell functional and clonal diversity. To address these, we analyzed the single-cell transcriptome and TCR repertoire of blood and liver MAIT cells and developed functional RNA-sequencing, a method to integrate function and TCR clonotype at single-cell resolution. MAIT cell clonal diversity was comparable to conventional memory T cells, with private TCR repertoires shared across matched tissues. Baseline functional diversity was low and largely related to tissue site. MAIT cells showed stimulus-specific transcriptional responses in vitro, with cells positioned along gradients of activation. Clonal identity influenced resting and activated transcriptional profiles but intriguingly was not associated with the capacity to produce IL-17. Overall, MAIT cells show phenotypic and functional diversity according to tissue localization, stimulation environment and clonotype.


Subject(s)
Mucosal-Associated Invariant T Cells , Humans , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , Clone Cells/metabolism , Lymphocyte Activation/genetics , Single-Cell Analysis
11.
J Chromatogr A ; 1692: 463842, 2023 Mar 15.
Article in English | MEDLINE | ID: mdl-36745962

ABSTRACT

Digital light processing (DLP) 3D printing is rapidly advancing and has emerged as a powerful additive manufacturing approach to fabricate analytical microdevices. DLP 3D-printing utilizes a digital micromirror device to direct the projected light and photopolymerize a liquid resin, in a layer-by-layer approach. Advances in vat and lift design, projector technology, and resin composition, allow accurate fabrication of microchannel structures as small as 18 × 20 µm. This review describes the latest advances in DLP 3D-printing technology with respect to instrument set-up and resin formulation and highlights key efforts to fabricate microdevices targeting emerging (bio-)analytical chemistry applications, including colorimetric assays, extraction, and separation.


Subject(s)
Microfluidics , Printing, Three-Dimensional , Lab-On-A-Chip Devices , Drug Delivery Systems
12.
Neurochem Res ; 48(3): 885-894, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36383324

ABSTRACT

Ivermectin (IVM) is an antiparasitic drug that primarily works by the activation of GABAA receptors. The potential pharmacological pathways behind the anti-convulsant effect of IVM haven't yet been identified. In this study, intravenous injection of pentylenetetrazole (PTZ)-induced clonic seizure in mice was investigated in order to assess the possible influence of IVM on clonic seizure threshold (CST). We also look at the function of the Opioidergic and nitrergic pathways in IVM anticonvulsant action on clonic seizure threshold. IVM (0.5, 1, 5, and 10 mg/kg, i.p.) raised the PTZ-induced CST, according to our findings. Furthermore, the ineffective dose of nitric oxide synthase inhibitors (L-NAME 10 mg/kg, i.p.), and (7-NI 30 mg/kg, i.p.) or opioidergic system agonist (morphine 0.25 mg/kg, i.p.) were able to amplify the anticonvulsive action of IVM (0.2 mg/kg, i.p.). Moreover, the anticonvulsant effect of IVM was reversed by an opioid receptor antagonist (naltrexone 1 mg/kg, i.p.). Furthermore, the combination of the ineffective dose of morphine as an opioid receptor agonist with either L-NAME (2 mg/kg, i.p.) or 7-NI (10 mg/kg, i.p.) and with an ineffective dose of IVM (0.2 mg/kg, i.p.) had a significant anticonvulsant effect. Taken together, IVM has anticonvulsant activity against PTZ-induced clonic seizures in mice, which may be mediated at least in part through the interaction of the opioidergic system and the nitric oxide pathway.


Subject(s)
Anticonvulsants , Pentylenetetrazole , Mice , Animals , Pentylenetetrazole/toxicity , Anticonvulsants/adverse effects , Ivermectin/adverse effects , NG-Nitroarginine Methyl Ester/pharmacology , Seizures/chemically induced , Seizures/drug therapy , Morphine/pharmacology , Dose-Response Relationship, Drug , Nitric Oxide/metabolism , Disease Models, Animal
13.
Cell Rep ; 42(1): 111903, 2023 01 31.
Article in English | MEDLINE | ID: mdl-36586406

ABSTRACT

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused successive global waves of infection. These variants, with multiple mutations in the spike protein, are thought to facilitate escape from natural and vaccine-induced immunity and often increase in affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor-binding domain (RBD). Here, we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared with BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection, which may explain the rapid spread in India, where where there is a high background of Delta infection. ACE2 affinity appears to be prioritized over greater escape.


Subject(s)
COVID-19 , Hepatitis D , Humans , Angiotensin-Converting Enzyme 2 , SARS-CoV-2 , Antibodies
14.
Cell ; 185(12): 2116-2131.e18, 2022 06 09.
Article in English | MEDLINE | ID: mdl-35662412

ABSTRACT

Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.


Subject(s)
Antibodies, Monoclonal , COVID-19 Vaccines/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Viral , COVID-19 , COVID-19 Vaccines/administration & dosage , Epitopes , Humans , Neutralization Tests , SARS-CoV-2/classification , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry
15.
Br J Haematol ; 198(4): 668-679, 2022 08.
Article in English | MEDLINE | ID: mdl-35655410

ABSTRACT

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.


Subject(s)
COVID-19 Vaccines , COVID-19 , Hematopoietic Stem Cell Transplantation , Age Factors , Antibodies, Viral/immunology , BNT162 Vaccine/immunology , BNT162 Vaccine/therapeutic use , Bone Marrow Transplantation/adverse effects , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19 Vaccines/pharmacology , COVID-19 Vaccines/therapeutic use , ChAdOx1 nCoV-19/immunology , ChAdOx1 nCoV-19/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/immunology , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Seroconversion , Transplantation, Homologous/adverse effects , Vaccination/adverse effects
16.
Cell ; 185(14): 2422-2433.e13, 2022 07 07.
Article in English | MEDLINE | ID: mdl-35772405

ABSTRACT

The Omicron lineage of SARS-CoV-2, which was first described in November 2021, spread rapidly to become globally dominant and has split into a number of sublineages. BA.1 dominated the initial wave but has been replaced by BA.2 in many countries. Recent sequencing from South Africa's Gauteng region uncovered two new sublineages, BA.4 and BA.5, which are taking over locally, driving a new wave. BA.4 and BA.5 contain identical spike sequences, and although closely related to BA.2, they contain further mutations in the receptor-binding domain of their spikes. Here, we study the neutralization of BA.4/5 using a range of vaccine and naturally immune serum and panels of monoclonal antibodies. BA.4/5 shows reduced neutralization by the serum from individuals vaccinated with triple doses of AstraZeneca or Pfizer vaccine compared with BA.1 and BA.2. Furthermore, using the serum from BA.1 vaccine breakthrough infections, there are, likewise, significant reductions in the neutralization of BA.4/5, raising the possibility of repeat Omicron infections.


Subject(s)
COVID-19 , Viral Vaccines , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , Neutralization Tests , SARS-CoV-2/genetics , South Africa
17.
Clin Exp Immunol ; 209(1): 90-98, 2022 07 22.
Article in English | MEDLINE | ID: mdl-35522978

ABSTRACT

T-cell responses to SARS-CoV-2 following infection and vaccination are less characterized than antibody responses, due to a more complex experimental pathway. We measured T-cell responses in 108 healthcare workers (HCWs) using the commercialized Oxford Immunotec T-SPOT Discovery SARS-CoV-2 assay service (OI T-SPOT) and the PITCH ELISpot protocol established for academic research settings. Both assays detected T-cell responses to SARS-CoV-2 spike, membrane, and nucleocapsid proteins. Responses were significantly lower when reported by OI T-SPOT than by PITCH ELISpot. Four weeks after two doses of either Pfizer/BioNTech BNT162b or ChAdOx1 nCoV-19 AZD1222 vaccine, the responder rate was 63% for OI T-SPOT Panels 1 + 2 (peptides representing SARS-CoV-2 spike protein excluding regions present in seasonal coronaviruses), 69% for OI T-SPOT Panel 14 (peptides representing the entire SARS-CoV-2 spike), and 94% for the PITCH ELISpot total spike. The two OI T-SPOT panels correlated strongly with each other showing that either readout quantifies spike-specific T-cell responses, although the correlation between the OI T-SPOT panels and the PITCH ELISpot total spike was moderate. The standardization, relative scalability, and longer interval between blood acquisition and processing are advantages of the commercial OI T-SPOT assay. However, the OI T-SPOT assay measures T-cell responses at a significantly lower magnitude compared to the PITCH ELISpot assay, detecting T-cell responses in a lower proportion of vaccinees. This has implications for the reporting of low-level T-cell responses that may be observed in patient populations and for the assessment of T-cell durability after vaccination.


Subject(s)
BNT162 Vaccine , COVID-19 , ChAdOx1 nCoV-19 , T-Lymphocytes , Antibodies, Viral , BNT162 Vaccine/immunology , COVID-19/prevention & control , ChAdOx1 nCoV-19/immunology , Health Personnel , Humans , Peptides , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , T-Lymphocytes/immunology , Vaccination
18.
Biophys J ; 121(4): 629-643, 2022 02 15.
Article in English | MEDLINE | ID: mdl-34999131

ABSTRACT

Tissue and cell mechanics are crucial factors in maintaining homeostasis and in development, with aberrant mechanics contributing to many diseases. During the epithelial-to-mesenchymal transition (EMT), a highly conserved cellular program in organismal development and cancer metastasis, cells gain the ability to detach from their original location and autonomously migrate. While a great deal of biochemical and biophysical changes at the single-cell level have been revealed, how the physical properties of multicellular assemblies change during EMT, and how this may affect disease progression, is unknown. Here we introduce cell monolayer deformation microscopy (CMDM), a new methodology to measure the planar mechanical properties of cell monolayers by locally applying strain and measuring their resistance to deformation. We employ this new method to characterize epithelial multicellular mechanics at early and late stages of EMT, finding the epithelial monolayers to be relatively compliant, ductile, and mechanically homogeneous. By comparison, the transformed mesenchymal monolayers, while much stiffer, were also more brittle, mechanically heterogeneous, displayed more viscoelastic creep, and showed sharp yield points at significantly lower strains. Here, CMDM measurements identify specific biophysical functional states of EMT and offer insight into how cell aggregates fragment under mechanical stress. This mechanical fingerprinting of multicellular assemblies using new quantitative metrics may also offer new diagnostic applications in healthcare to characterize multicellular mechanical changes in disease.


Subject(s)
Epithelial-Mesenchymal Transition , Microscopy , Stress, Mechanical
19.
Cell ; 185(3): 467-484.e15, 2022 02 03.
Article in English | MEDLINE | ID: mdl-35081335

ABSTRACT

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

20.
Eur J Immunol ; 52(5): 835-837, 2022 05.
Article in English | MEDLINE | ID: mdl-34958459

ABSTRACT

Vδ2+ γδT cells are unconventional T cells that can be activated by cytokines without TCR signaling. Adenovirus vaccine vectors activated Vδ2+ γδT cells in an interleukin 18-, TNF-, and type I interferon-dependent manner. This stimulatory capacity was associated with adenovirus vectors of non-species C origin, including the ChAdOx1 vaccine platform.


Subject(s)
Interferon Type I , T-Lymphocyte Subsets , Adenoviridae/genetics , Cytokines , Interleukin-18 , Receptors, Antigen, T-Cell, gamma-delta/genetics
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