A5088491898- Inflammasome and immune disorders
- Heme Oxygenase-1 and Carbon Monoxide
- Cancer Treatment and Pharmacology
- Metal complexes synthesis and properties
- Advanced Breast Cancer Therapies
- interferon and immune responses
- IL-33, ST2, and ILC Pathways
- Peptidase Inhibition and Analysis
- Streptococcal Infections and Treatments
- Kawasaki Disease and Coronary Complications
- Click Chemistry and Applications
- Crystallization and Solubility Studies
- Cancer therapeutics and mechanisms
- PI3K/AKT/mTOR signaling in cancer
- X-ray Diffraction in Crystallography
- Genetics and Neurodevelopmental Disorders
- Toxin Mechanisms and Immunotoxins
- Immune Response and Inflammation
- Metal-Catalyzed Oxygenation Mechanisms
- Phagocytosis and Immune Regulation
- Gout, Hyperuricemia, Uric Acid
- Burkholderia infections and melioidosis
- HER2/EGFR in Cancer Research
- COVID-19 Clinical Research Studies
- Psoriasis: Treatment and Pathogenesis
Agency for Science, Technology and Research
2016-2024
Hull York Medical School
2024
University of York
2024
City Of Hope National Medical Center
2012-2024
Skin Research Center
2022-2023
Nanyang Technological University
2023
National Skin Centre
2020-2023
Singapore Immunology Network
2021
Institute of Medical Biology
2016-2020
City of Hope
2020
Activating platinum with light: An inert platinum(IV) diazido complex trans, trans,trans-[Pt(N3)2(OH)2(py)2] becomes potently cytotoxic to cancer cells when activated by low doses of visible light. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made available submitted the authors. Please note: The publisher is responsible for content functionality any supporting information supplied...
Abstract Background MicroRNAs (miRNAs) have been recently detected in the circulation of cancer patients, where they are associated with clinical parameters. Discovery profiling circulating small RNAs has not reported breast (BC), and was carried out this study to identify blood-based RNA markers BC outcome. Methods The pre-treatment sera 42 stage II-III locally advanced inflammatory patients who received neoadjuvant chemotherapy (NCT) followed by surgical tumor resection were analyzed for...
Immune sensor proteins are critical to the function of human innate immune system. The full repertoire cognate triggers for sensors is not fully understood. Here, we report that NACHT, LRR, and PYD domains-containing protein 1 (NLRP1) activated by 3C proteases (3Cpros) enteroviruses, such as rhinovirus (HRV). 3Cpros directly cleave NLRP1 at a single site between Glu130 Gly131 This cleavage N-glycine-mediated degradation autoinhibitory N-terminal fragment via cullinZER1/ZYG11B complex, which...
Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin airway epithelium. Here, we report that human senses ultraviolet B (UVB)- toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to direct hyperphosphorylation of a human-specific disordered linker region (NLRP1 DR ) by MAP3K20/ZAKα kinase its downstream effector, p38. Mutating single ZAKα phosphorylation site abrogates UVB- ribotoxin-driven pyroptosis...
Nigericin, an ionophore derived from Streptomyces hygroscopicus , is arguably the most commonly used tool compound to study NLRP3 inflammasome. Recent findings, however, showed that nigericin also activates NLRP1 inflammasome in human keratinocytes. In this study, we resolve mechanistic basis of nigericin-driven activation. multiple nonhematopoietic cell types, rapidly and specifically inhibits elongation stage ribosome cycle by depleting cytosolic potassium ions. This ribotoxic stress...
Abstract Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling activating the inflammasome complex. Closely related sensor NLRP1 CARD8 undergo unique auto-proteolysis-dependent activation are implicated in auto-inflammatory diseases; however, their mechanisms of not understood. Here we report structural basis how domains (FIIND UPA -CARD) self-oligomerize to assemble distinct complexes. Recombinant FIIND -CARD forms a two-layered filament,...
The ZAKα-driven ribotoxic stress response (RSR) is activated by ribosome stalling and/or collisions. Recent work demonstrates that RSR also plays a role in innate immunity activating the human NLRP1 inflammasome. Here, we report ZAKα and sense bacterial exotoxins target elongation factors. One such toxin, diphtheria toxin (DT), causative agent for diphtheria, triggers RSR-dependent inflammasome activation primary keratinocytes. This process requires iron-mediated DT production bacteria, as...
Abstract Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side‐effects. Photoactivatable Pt IV prodrugs offer the potential targeted drug release new mechanisms action. We report synthesis, X‐ray crystallographic spectroscopic properties photoactivatable diazido complexes trans , ‐[Pt(N 3 ) 2 (OH) (MA)(Py)] ( 1 ; MA=methylamine, Py=pyridine) (MA)(Tz)] Tz=thiazole), interpret their photophysical by TD‐DFT modelling....
Abstract Photoactivatable PtIV diazido complexes have unusual photobiologic properties. We show here that trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)] complex 3 is a potent photoactivated cytotoxin toward human cancer cells in culture, with an average IC50 value 13 cell lines of 55 ± 28 μmol/L after 30 minutes (0.12 mW/cm2) photoactivation UVA, although visible light was also effective. Photoactivated noncross-resistant to cisplatin 4 resistant lines. Cell swelling but very little blebbing...
The combination of enobosarm and pembrolizumab was well tolerated showed a modest clinical benefit rate 25% at 16 weeks. Future trials investigating androgen receptor-targeted therapy in with immune checkpoint inhibitors are warranted.Luminal receptor is distinct molecular subtype triple-negative breast cancer (TNBC) defined by overexpression (AR). AR-targeted has shown activity AR-positive (AR+) TNBC. Enobosarm (GTx-024) nonsteroidal selective modulator (SARM) that demonstrates preclinical...
Nucleotide-binding oligomerization domain (NBD), leucine-rich repeat (LRR) containing protein family (NLRs) are intracellular pattern recognition receptors that mediate innate immunity against infections. The endothelium is the first line of defense blood-borne pathogens, but it unclear which NLRs control endothelial cell (EC) intrinsic immunity. Here, we demonstrate human ECs simultaneously activate NLRP1 and CARD8 inflammasomes in response to DPP8/9 inhibitor Val-boro-Pro (VbP)....
Human airway and corneal epithelial cells, which are critically altered during chronic infections mediated by Pseudomonas aeruginosa, specifically express the inflammasome sensor NLRP1. Here, together with a companion study, we report that NLRP1 detects exotoxin A (EXOA), ribotoxin released P. aeruginosa type 2 secretion system (T2SS), infection. Mechanistically, EXOA-driven eukaryotic elongation factor (EEF2) ribosylation covalent inactivation promote ribotoxic stress subsequent activation,...
Dipeptidyl peptidase 9 (DPP9) is a direct inhibitor of NLRP1, but how it affects inflammasome regulation in vivo not yet established. Here, we report three families with immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities that segregate biallelic
Platin mit Licht aktiviert: Der inerte PtIV-Diazidokomplex trans,trans,trans- [Pt(N3)2(OH)2(py)2] verwandelt sich bei der Bestrahlung geringen Dosen sichtbaren Lichts in einen potenten zytotoxischen Wirkstoff gegen Krebszellen. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents peer-reviewed, but not copy-edited or typeset. They made available submitted by the authors. Please note: The publisher is responsible for content...
Abstract Background In this phase II clinical trial, we evaluated the efficacy of nonanthracycline combination carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC). Patients Methods with newly diagnosed II–III TNBC (n = 69) were treated neoadjuvant (area under curve 6) every 28 days for four cycles plus (100 mg/m2) weekly 16 weeks. Pathological complete response (pCR) residual burden (RCB) analyzed germline mutation status, tumor-infiltrating lymphocytes (TILs),...
Objective To evaluate the epidemiology of Candida albicans infection in HIV-infected patients with oral lesions using molecular techniques. Methods Thirty-nine isolates from HIV-positive candidiasis were examined two DNA probes (a Histoplasma capsulatum ribosomal probe that cross-hybridizes C. and a strain-specific derived repetitive sequence DNA). obtained cavity receiving cytotoxic chemotherapy was used as controls. Results Using H. probe, shown to members many distinct classes albicans....
Abstract Background Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin TNBC cell lines and xenograft models. This phase I trial was designed to test safety tolerability combining everolimus patients metastatic TNBC. Methods The primary objective this study evaluate toxicities combination. Patients who had up four prior chemotherapies were enrolled. combination tested using...
Our epithelium represents a battle ground against variety of insults including pathogens and danger signals. It encodes multiple sensors that detect respond to such insults, playing an essential role in maintaining defending tissue homeostasis. One key set defense mechanisms is our inflammasomes which drive innate immune responses including, sensing responding pathogen attack, through the secretion pro‐inflammatory cytokines cell death. Identification physiologically relevant triggers for...