-
In Vivo (Athens, Greece) 2024Patients with pneumonia after prolonged neutropenia are at increased risk for acute respiratory distress syndrome (ARDS). The key molecule of endothelial barrier...
BACKGROUND/AIM
Patients with pneumonia after prolonged neutropenia are at increased risk for acute respiratory distress syndrome (ARDS). The key molecule of endothelial barrier breakdown in sepsis is lipopolysaccharide (LPS), which is a component of the outer membrane of gram-negative bacterial cell walls. Maintaining increased cyclic adenosine monophosphate (cAMP) levels in endothelial cells is effective in preventing endothelial dysfunction and microvascular permeability. The aim of this study was to elucidate whether roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, is effective in LPS-induced acute lung injury (ALI) during neutropenia recovery in a murine model.
MATERIALS AND METHODS
To induce neutropenia, all mice were administered intraperitoneal cyclophosphamide. On day 2 after neutropenia, mice were administered LPS by intra-tracheal instillation. In the prevention group, roflumilast was given orally on day 0, when neutropenia was induced. In the treatment group, roflumilast was administered orally 1 hour after LPS injection.
RESULTS
Roflumilast attenuated histopathological changes associated with LPS-induced lung injury. The accumulation of neutrophils and the concentrations of inflammatory cytokines IL-1β, TNF-α, and IL-6 in bronchoalveolar lavage fluids were inhibited effectively by roflumilast. Also, MMP-9 and TGF-β expression was attenuated in the roflumilast group.
CONCLUSION
Roflumilast significantly attenuated LPS-induced ALI during neutropenia recovery.
Topics: Animals; Aminopyridines; Cyclopropanes; Acute Lung Injury; Lipopolysaccharides; Mice; Benzamides; Neutropenia; Disease Models, Animal; Phosphodiesterase 4 Inhibitors; Cytokines; Male; Bronchoalveolar Lavage Fluid; Neutrophils
PubMed: 38688656
DOI: 10.21873/invivo.13547 -
Journal of Cancer Research and... Apr 2024This study aimed to investigate BVD-523 (ulixertinib), an adenosine triphosphate (ATP)-dependent extracellular signal-regulated kinases 1/2 inhibitor, for its antitumor...
OBJECTIVE
This study aimed to investigate BVD-523 (ulixertinib), an adenosine triphosphate (ATP)-dependent extracellular signal-regulated kinases 1/2 inhibitor, for its antitumor potential in thyroid cancer.
MATERIALS AND METHODS
Ten thyroid cancer cell lines known to carry mitogen-activated protein kinase (MAPK)-activated mutations, including v-Raf murine sarcoma viral oncogene homolog B (BRAF) and rat sarcoma virus (RAS) mutations, were examined. Cells were exposed to a 10-fold concentration gradient ranging from 0 to 3000 nM for 5 days. The half-inhibitory concentration was determined using the Cell Counting Kit-8 assay. Following BVD-523 treatment, cell cycle analysis was conducted using flow cytometry. In addition, the impact of BVD-523 on extracellular signal-regulated kinase (ERK)- dependent ribosomal S6 kinase (RSK) activation and the expression of cell cycle markers were assessed through western blot analysis.
RESULTS
BVD-523 significantly inhibited thyroid cancer cell proliferation and induced G1/S cell cycle arrest dose-dependently. Notably, cell lines carrying MAPK mutations, especially those with the BRAF V600E mutation, exhibited heightened sensitivity to BVD-523's antitumor effects. Furthermore, BVD-523 suppressed cyclin D1 and phosphorylated retinoblastoma protein expression, and it robustly increased p27 levels in an RSK-independent manner.
CONCLUSION
This study reveals the potent antitumor activity of BVD-523 against thyroid cancer cells bearing MAPK-activating mutations, offering promise for treating aggressive forms of thyroid cancer.
Topics: Humans; Thyroid Neoplasms; Cell Proliferation; Cell Line, Tumor; Protein Kinase Inhibitors; Pteridines; Proto-Oncogene Proteins B-raf; Mitogen-Activated Protein Kinase 3; Antineoplastic Agents; Mitogen-Activated Protein Kinase 1; Mutation; MAP Kinase Signaling System; Aminopyridines; Pyrroles
PubMed: 38687926
DOI: 10.4103/jcrt.jcrt_1504_23 -
International Journal of Clinical... Jul 2024Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a new entity considered a biologically distinct subtype from HER2-zero BC. However, the...
AIMS AND OBJECTIVES
Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a new entity considered a biologically distinct subtype from HER2-zero BC. However, the importance of HER2 low expression on the activity of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) remains unclear.
METHODS/MATERIALS
We conducted a single-center retrospective study including hormone receptor-positive (HR +) /HER2- metastatic BC (mBC) patients treated with CDK4/6i plus endocrine treatment (ET) as first-line therapy. Clinical outcomes were analyzed according to HER2 expression.
RESULTS
258 women were analyzed with a median follow-up of 25.4 months; 39.9% had HER2 low, and 60.1% had HER2 zero BC. Median progression-free survival (mPFS) in the HER2-low group was 27.6 months compared with 44.3 months in the HER2-zero group (p = 0.341). In patients receiving ribociclib, the mPFS in the HER2-low group was 24.2 months compared with 53.1 months in the HER2-zero group (multivariate-adjusted HR: 1.981, 95 Cl 1.094-3.586; p = 0.024). The survival probabilities at 24, 36 and 48 months for the HER2 low and HER2 zero groups were 82%, 69%, 69% and 83%, 75% and 69%, respectively (p = 0.336). Objective response rate (p = 0.179) and disease control rate (p = 0.338) did not significantly differ between HER-2-low and HER-2-zero groups.
CONCLUSIONS
The mPFS in the Her2-zero group was almost twice that of the Her2-low group, but the difference was not statistically significant. mPFS was significantly longer in the HER2-zero group compared to the HER2-low group in patients receiving ribociclib. More prospective studies are needed to understand the actual consequences of this biomarker.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Middle Aged; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Retrospective Studies; Aged; Adult; Protein Kinase Inhibitors; Purines; Aminopyridines; Progression-Free Survival; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38687407
DOI: 10.1007/s10147-024-02528-w -
Advanced Materials (Deerfield Beach,... Apr 2024Recovering platinum group metals from secondary resources is crucial to meet the growing demand for high-tech applications. Various techniques are explored, and...
Recovering platinum group metals from secondary resources is crucial to meet the growing demand for high-tech applications. Various techniques are explored, and adsorption using porous materials has emerged as a promising technology due to its efficient performance and environmental beingness. However, the challenge lies in effectively recovering and separating individual platinum group metals (PGMs) given their similar chemical properties. Herein, a breakthrough approach is presented by sophisticatedly tailoring the coordination micro-environment in a series of aminopyridine-based porous organic polymers, which enables the creation of platinum-specific nanotraps for efficient separation of binary PGMs (platinum/palladium). The newly synthesized POP-o2NH-Py demonstrates record uptakes and selectivity toward platinum over palladium, with the amino groups adjacent to the pyridine moieties being vital in improving platinum binding performance. Further breakthrough experiments underline its remarkable ability to separate platinum and palladium. Spectroscopic analysis reveals that POP-o2NH-Py offers a more favorable coordination fashion to platinum ions compared to palladium ions owing to the greater interaction between N and Pt and stronger intramolecular hydrogen bonding between the amino groups and four coordinating chlorines at platinum. These findings underscore the importance of fine-tuning the coordination micro-environment of nanotraps through subtle modifications that can greatly enhance the selectivity toward the desired metal ions.
PubMed: 38685565
DOI: 10.1002/adma.202313747 -
Scientific Reports Apr 2024Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the standard agents for treating patients with estrogen receptor-positive and human epidermal growth factor...
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the standard agents for treating patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer (ER + HER2 - ABC). However, markers predicting the outcomes of CDK4/6i treatment have yet to be identified. This study was a single-center retrospective cohort study. We retrospectively evaluated 101 patients with ER + HER2 - ABC receiving CDK4/6i in combination with endocrine therapy at Fukuyama City Hospital between November 2017 and July 2021. We investigated the clinical outcomes and the safety of CDK4/6i treatment, and the absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) as predictive markers for CDK4/6i. We defined the cut-off values as 1000/μL for ALC and 3 for NLR, and divided into "low" and "high" groups, respectively. We evaluated 43 and 58 patients who received abemaciclib and palbociclib, respectively. Patients with high ALC and low NLR had significantly longer overall survival than those with low ALC and high NLR (high vs. low; ALC: HR 0.29; 95% CI 0.12-0.70; NLR: HR 2.94; 95% CI 1.21-7.13). There was no significant difference in efficacy between abemaciclib and palbociclib and both had good safety profiles. We demonstrated that ALC and NLR might predict the outcomes of CDK4/6i treatment in patients with ER + HER2 - ABC.
Topics: Humans; Female; Breast Neoplasms; Cyclin-Dependent Kinase 4; Neutrophils; Cyclin-Dependent Kinase 6; Middle Aged; Lymphocytes; Lymphocyte Count; Retrospective Studies; Protein Kinase Inhibitors; Aged; Adult; Pyridines; Piperazines; Aminopyridines; Benzimidazoles; Aged, 80 and over; Receptor, ErbB-2; Treatment Outcome
PubMed: 38684839
DOI: 10.1038/s41598-024-60101-x -
EJNMMI Research Apr 20244-Aminopyridine (4AP) is a medication for the symptomatic treatment of multiple sclerosis. Several 4AP-based PET tracers have been developed for imaging demyelination....
BACKGROUND
4-Aminopyridine (4AP) is a medication for the symptomatic treatment of multiple sclerosis. Several 4AP-based PET tracers have been developed for imaging demyelination. In preclinical studies, [C]3MeO4AP has shown promise due to its high brain permeability, high metabolic stability, high plasma availability, and high in vivo binding affinity. To prepare for the translation to human studies, we developed a cGMP-compatible automated radiosynthesis protocol and evaluated the whole-body biodistribution and radiation dosimetry of [C]3MeO4AP in non-human primates (NHPs).
METHODS
Automated radiosynthesis was carried out using a GE TRACERlab FX-C Pro synthesis module. One male and one female adult rhesus macaques were used in the study. A high-resolution CT from cranial vertex to knee was acquired. PET data were collected using a dynamic acquisition protocol with four bed positions and 13 passes over a total scan time of ~ 150 min. Based on the CT and PET images, volumes of interest (VOIs) were manually drawn for selected organs. Non-decay corrected time-activity curves (TACs) were extracted for each VOI. Radiation dosimetry and effective dose were calculated from the integrated TACs using OLINDA software.
RESULTS
Fully automated radiosynthesis of [C]3MeO4AP was achieved with 7.3 ± 1.2% (n = 4) of non-decay corrected radiochemical yield within 38 min of synthesis and purification time. [C]3MeO4AP distributed quickly throughout the body and into the brain. The organs with highest dose were the kidneys. The average effective dose of [C]3MeO4AP was 4.0 ± 0.6 μSv/MBq. No significant changes in vital signs were observed during the scan.
CONCLUSION
A cGMP-compatible automated radiosynthesis of [C]3MeO4AP was developed. The whole-body biodistribution and radiation dosimetry of [C]3MeO4AP was successfully evaluated in NHPs. [C]3MeO4AP shows lower average effective dose than [F]3F4AP and similar average effective dose as other carbon-11 tracers.
PubMed: 38683467
DOI: 10.1186/s13550-024-01092-8 -
Cancer Research Communications May 2024Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in...
PURPOSE
Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) is a potent and reversible small-molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases.
MATERIALS AND METHODS
We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a sample size of 25 patients and an initial evaluation of efficacy after 13 patients.
RESULTS
From April 2018 to April 2019, 13 patients were enrolled. Patients were predominantly female (69%) with a median age of 64 years (34-76). Sites of metastases included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with ERK inhibitors and included liver function test (LFT) elevation, hyponatremia, pruritis, amylase elevation, anemia, and rash. The best response, per RECIST 1.1, was stable disease in 4 patients, and disease progression in 7 patients. Two patients were unevaluable for response due to withdrawal from study. Median time to progression was 2.0 months. There were eight deaths due to disease progression with a median overall survival of 6.9 months.
CONCLUSIONS
ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed were consistent with what would be expected with MAPK pathway inhibition.
SIGNIFICANCE
Uveal melanoma is a difficult to treat disease with minimal therapy options. The majority of uveal melanomas have mutations in GNAQ or GNA11 leading to activation of the MAPK pathway. Efforts to target MEK in uveal melanoma has had mixed results. This phase II trial of ERK inhibition with BVD-523 examined the potential role of this agent in uveal melanoma therapy.
Topics: Humans; Uveal Neoplasms; Melanoma; Female; Middle Aged; Male; Aged; Adult; Protein Kinase Inhibitors; Aminopyridines; Pyrroles
PubMed: 38683104
DOI: 10.1158/2767-9764.CRC-24-0036 -
Journal of Pharmacological Sciences Jun 2024Microglia are the residential immune cells in the central nervous system. Their roles as innate immune cells and regulators of synaptic remodeling are critical to the...
Microglia are the residential immune cells in the central nervous system. Their roles as innate immune cells and regulators of synaptic remodeling are critical to the development and the maintenance of the brain. Numerous studies have depleted microglia to elucidate their involvement in healthy and pathological conditions. PLX3397, a blocker of colony stimulating factor 1 receptor (CSF1R), is widely used to deplete mouse microglia due to its non-invasiveness and convenience. Recently, other small rodents, including Syrian hamsters (Mesocricetus auratus) and Mongolian gerbils (Meriones unguiculatus), have been recognized as valuable animal models for studying brain functions and diseases. However, whether microglia depletion via PLX3397 is feasible in these species remains unclear. Here, we administered PLX3397 orally via food pellets to hamsters and gerbils. PLX3397 successfully depleted gerbil microglia but had no effect on microglial density in hamsters. Comparative analysis of the CSF1R amino acid sequence in different species hints that amino acid substitutions in the juxtamembrane domain may potentially contribute to the inefficacy of PLX3397 in hamsters.
Topics: Animals; Cricetinae; Administration, Oral; Aminopyridines; Brain; Gerbillinae; Mesocricetus; Microglia; Models, Animal; Pyrroles; Pyrrolidines; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Species Specificity
PubMed: 38677783
DOI: 10.1016/j.jphs.2024.03.003 -
Drug and Alcohol Dependence Jun 2024As nicotine dependence represents a longstanding major public health issue, new nicotine cessation pharmacotherapies are needed. Administration of N-oleoyl glycine...
BACKGROUND
As nicotine dependence represents a longstanding major public health issue, new nicotine cessation pharmacotherapies are needed. Administration of N-oleoyl glycine (OlGly), an endogenous lipid signaling molecule, prevents nicotine-induced conditioned place preference (CPP) through a peroxisome proliferator-activated receptor-alpha (PPARα) dependent mechanism, and also ameliorated withdrawal signs in nicotine-dependent mice. Pharmacological evidence suggests that the methylated analog of OlGly, N-oleoyl alanine (OlAla), has an increased duration of action and may offer translational benefit. Accordingly, OlAla was assessed in nicotine CPP and dependence assays as well as its pharmacokinetics compared to OlGly.
METHODS
ICR female and male mice were tested in nicotine-induced CPP with and without the PPARα antagonist GW6471. OlAla was also assessed in nicotine-dependent mice following removal of nicotine minipumps: somatic withdrawal signs, thermal hyper-nociception and altered affective behavior (i.e., light/dark box). Finally, plasma and brain were collected after administration of OlGly or OlAla and analyzed by high-performance liquid chromatography tandem mass spectrometry.
RESULTS
OlAla prevented nicotine-induced CPP, but this effect was not blocked by GW6471. OlAla attenuated somatic and affective nicotine withdrawal signs, but not thermal hyper-nociception in nicotine-dependent mice undergoing withdrawal. OlAla and OlGly showed similar time-courses in plasma and brain.
CONCLUSIONS
The observation that both molecules showed similar pharmacokinetics argues against the notion that OlAla offers increased metabolic stability. Moreover, while these structurally similar lipids show efficacy in mouse models of reward and dependence, they reduce nicotine reward through distinct mechanisms.
Topics: Animals; Substance Withdrawal Syndrome; Mice; Male; Nicotine; Reward; Female; Mice, Inbred ICR; Tobacco Use Disorder; PPAR alpha; Alanine; Oleic Acids; Glycine; Aminopyridines; Brain; Oxazoles; Tyrosine
PubMed: 38676968
DOI: 10.1016/j.drugalcdep.2024.111276 -
Lung Cancer (Amsterdam, Netherlands) May 2024
Topics: Humans; Anaplastic Lymphoma Kinase; Lung Neoplasms; Protein Kinase Inhibitors; Adenocarcinoma of Lung; Oncogene Proteins, Fusion; Adenocarcinoma; Receptor Protein-Tyrosine Kinases; Female; Male; Crizotinib; Middle Aged
PubMed: 38669726
DOI: 10.1016/j.lungcan.2024.107797