A5001720875- Synthesis and Biological Evaluation
- Synthesis and biological activity
- Cancer Immunotherapy and Biomarkers
- Lung Cancer Treatments and Mutations
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Nitric Oxide and Endothelin Effects
- Immune cells in cancer
- Platelet Disorders and Treatments
- Bioactive Compounds and Antitumor Agents
- Click Chemistry and Applications
- Classical Philosophy and Thought
- Peptidase Inhibition and Analysis
- Receptor Mechanisms and Signaling
- Antiplatelet Therapy and Cardiovascular Diseases
- Adenosine and Purinergic Signaling
- RNA modifications and cancer
- Cancer-related Molecular Pathways
- Hepatocellular Carcinoma Treatment and Prognosis
- Ferroptosis and cancer prognosis
- Pain Mechanisms and Treatments
- PI3K/AKT/mTOR signaling in cancer
- Inflammasome and immune disorders
- Cell Image Analysis Techniques
- Ion channel regulation and function
Northwestern Memorial Hospital
2022-2025
The Francis Crick Institute
2017-2024
Indiana University School of Medicine
2022-2024
Indiana University
2024
Northwestern University
2006-2022
Christiana Care Health System
2022
E Ink (South Korea)
2022
Indiana University – Purdue University Indianapolis
2022
Augusta University Health
2022
Queen Alexandra Hospital
2010-2021
The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. relative importance tumor microenvironment cancer cell-intrinsic signaling regulation expression remains unclear. We report that oncogenic RAS can upregulate cell through a mechanism involving increases mRNA stability via modulation AU-rich element-binding tristetraprolin (TTP). TTP negatively regulates elements 3′ UTR mRNA. MEK downstream leads phosphorylation inhibition...
Combined targeting of KRAS-G12C, mTOR, and IGF1R enhances extends the response to recently developed KRAS-G12C inhibitors in lung cancer models.
Recently developed KRAS G12C inhibitory drugs are beneficial to lung cancer patients harboring mutations, but drug resistance frequently develops. Because of the immunosuppressive nature signaling network controlled by oncogenic KRAS, these can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how inhibition reverses immunosuppression driven in number preclinical models varying levels...
The CATERPILLER (CLR, also NOD and NLR) proteins share structural similarities with the nucleotide binding domain (NBD)-leucine-rich repeat (LRR) superfamily of plant disease-resistance (R) are emerging as important immune regulators in animals. CLR contain NBD-LRR motifs linked to a limited number distinct N-terminal domains including transactivation, CARD (caspase activation recruitment), pyrin (PyD). gene, Monarch-1/Pypaf7, is expressed by resting primary myeloid/monocytic cells, its...
Highlights•Inducible disruption of PI3-kinase p110α interaction with RAS was modeled in mice•Blocking RAS/p110α established lung tumors causes partial regression•Blocking binding has effects similar to deletion on tumor regression•Coordinate MEK inhibition is required for major regression Kras mutant cancerSummaryRAS proteins directly activate PI3-kinases. Mice bearing a germline mutation the domain subunit PI3-kinse are resistant development RAS-driven tumors. However, it unknown whether...
RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study role of RAC1P29S melanoma development reveal that activates PAK, AKT, a gene expression program initiated by SRF/MRTF transcriptional pathway, which results melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous from endogenous locus develop lymphoma. When expressed only melanocytes, cooperates oncogenic or NF1-loss promote tumorigenesis. also drives...
Radioembolization (yttrium-90 [Y90]) is used in hepatocellular carcinoma (HCC) as a bridging well downstaging liver-directed therapy to curative liver transplantation (LT). In this study, we report long-term outcomes of LT for patients with HCC who were bridged/downstaged by Y90.Patients undergoing following Y90 between 2004 and 2018 included, staging United Network Organ Sharing (UNOS) tumor-node-metastasis criteria at baseline pre-Y90 pre-LT. Post-Y90 toxicities recorded. Histopathological...
Abstract Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection mechanisms through chemical and genetic manipulations that not feasible the clinical setting. In tumour microenvironment (TME), multiplexed imaging methods can provide a rich source information. However, application such technologies mouse tissues is still its infancy. Here we present workflow for studying TME using mass cytometry with panel 27 antibodies on frozen tissues. We optimise validate...
Abstract Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins tumor regression but ultimately fail to elicit cures. As result, there is an intense interest how best combine targeted therapies with other treatments, immunotherapies. However, preclinical systems for studying the interaction tumors host immune system are inadequate, part due low mutational burden genetically engineered mouse models. Here we set out develop models...
Abstract Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of contents into the cytosol affects function cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile triggers a cell death independent proteolytic remodelling mitochondrial proteome macrophages. Mitochondrial metabolic reprogramming required cathepsins was mitophagy, mitoproteases proteasome degradation. In an vivo...
ABSTRACT This case study presents the first reported instance of cytarabine-induced hyperbilirubinemia in a pregnant patient undergoing treatment acute myeloid leukemia. Despite experiencing direct during induction therapy, exhibited no other signs liver dysfunction. Lowering cytarabine dose subsequent cycles resulted milder bilirubin elevations without compromising efficacy. The gave birth to healthy baby at term between cycles, underscoring benign nature this effect on both maternal and...
We describe a case of delayed onset, acute demyelinating neuropathy secondary to novel SARS-CoV-2 infection. A previously healthy 46-year-old man presented with bilateral leg pain and loss sensation in his feet 53 days after having COVID-19 pneumonitis. He developed painful sensory symptoms followed by rapidly progressive lower motor neuron weakness involving all limbs, face respiratory muscles, needing ventilatory support. In keeping diagnosis Guillain-Barré syndrome, cerebrospinal fluid...
Abstract Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic drives evasion is needed identify approaches that could sensitize KRAS-mutant lung cancer immunotherapy. In vivo CRISPR–Cas9 screening in an immunogenic murine model identified promotes evasion, most notably via upregulation immunosuppressive COX2 cells. potently induced both mouse...
Introduction: We compared the efficacy of ALBI (albumin–bilirubin) score to established Child–Pugh (CP) grade in hepatocellular carcinoma (HCC) patients treated with yttrium-90 radioembolization (Y90). further assessed individual contributions albumin and bilirubin survival prediction. Methods: 1000 consecutive HCC Y90 were included. Overall (OS) was using Kaplan Meier analysis. Sub-stratification analyses performed CP subgroups determined by United Network for Organ Sharing (UNOS) or...
Summary Nitric oxide (NO) regulates both vascular tone and platelet function. Since thrombotic diseases their animal models consist of components, the functional mechanisms by which NO endothelial nitric synthase (eNOS) regulate events are unclear. Experiments were conducted measuring collagen-induced aggregation freely circulating radio-labelled platelets in pulmonary vasculature anaesthetised mice via external detection probes. In addition, cardiac haemodynamic function was assessed...
Abstract Mutant selective drugs targeting the inactive, GDP-bound form of KRAS G12C have been approved for use in lung cancer, but resistance develops rapidly. Here we an inhibitor, (RMC-4998) that targets RAS its active, GTP-bound form, to treat mutant cancer various immune competent mouse models. pathway reactivation after RMC-4998 treatment could be delayed using combined with a SHP2 which not only impacts tumour cell signalling also remodels microenvironment less immunosuppressive. In...
Although exogenous nitric oxide (NO) clearly modifies platelet function, the role and source of endogenous NO in vivo remain undefined. In addition, endothelial synthase (NOS-3) critically regulates vessel tone but its modulating function is unclear. this paper we have investigated roles NOS-3 regulating determined functional contribution made by platelet-derived NO.We used a mouse model for directly assessing responses situ presence an intact vascular endothelium with supporting vitro...
RSK4 promotes invasiveness and drug resistance in lung bladder cancer inhibition of this kinase shows therapeutic potential.
Summary Identifying and evaluating new therapeutic targets in platelets requires advanced animal models which platelet responses can be measured directly situ.This is important because function strongly influenced by external factors such as those originating from the vascular endothelium. Our objectives were to record graded, non-lethal thromboembolic agonists situ mouse demonstrate an inhibitory effect of aspirin our model. Radiolabelled infused into anaesthetized mice ADP, collagen...
Article16 July 2020Open Access Source DataTransparent process Combined targeting of G protein-coupled receptor and EGF signaling overcomes resistance to PI3K pathway inhibitors in PTEN-null triple negative breast cancer Davide Zecchin Oncogene Biology, Francis Crick Institute, London, UK Search for more papers by this author Christopher Moore Fanourios Michailidis Stuart Horswell Computational Sareena Rana Lung Cancer Group, Institute Research, Michael Howell High Throughput Screening...