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Journal of Molecular Modeling Jun 2024Breast cancer stem cells (BCSCs) are a small subset of cells within breast tumors with characteristics similar to normal stem cells. Despite advancements in chemotherapy...
CONTEXT
Breast cancer stem cells (BCSCs) are a small subset of cells within breast tumors with characteristics similar to normal stem cells. Despite advancements in chemotherapy and targeted therapy for breast cancer, the prognosis for breast cancer patients has remained poor due to drug resistance, reoccurrence, and metastasis. Growing evidence suggests that deregulation of the self-renewal pathways, like the Wnt signaling pathway mediated by β-catenin, plays a crucial role in the survival of breast cancer stem cells. Targeting the Wnt signaling pathway in breast cancer stem cells offers a promising avenue for developing effective therapeutic strategies targeting these cells, potentially leading to improved patient outcomes and reduced tumor recurrence.
METHODS
For this purpose, we have screened a 1615 FDA-approved drug library against our target protein, β-catenin, which is involved in the Wnt signaling pathway using molecular docking analysis, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations.
RESULTS
Molecular docking studies showed that the Lumacaftor- β-catenin complex had the lowest docking score of - 8.7 kcal/mol towards β-catenin protein than the reference inhibitor. Molecular dynamic simulations and MM/PBSA calculations were also performed for the Lumacaftor-β-catenin complex to establish the stability of the interactions involved. Considering its promising attributes and encouraging results, Lumacaftor holds significant potential as a novel therapeutic option to target BCSCs. This study opens avenues for further investigation and may pave the way for developing therapeutic potential in breast cancer treatment. Further confirmation is warranted through in vitro and clinical studies to validate the findings of this study.
Topics: Neoplastic Stem Cells; Humans; Breast Neoplasms; Molecular Docking Simulation; Female; Molecular Dynamics Simulation; Benzodioxoles; beta Catenin; Wnt Signaling Pathway; Drug Repositioning; Aminopyridines; Antineoplastic Agents
PubMed: 38913211
DOI: 10.1007/s00894-024-05990-5 -
The Canadian Journal of Urology Jun 2024Drug-induced nephrolithiasis represents only 1%-2% of stone cases. Here we focus on drugs capable of crystallizing and forming stone, specifically phenazopyridine...
Drug-induced nephrolithiasis represents only 1%-2% of stone cases. Here we focus on drugs capable of crystallizing and forming stone, specifically phenazopyridine (Pyridium/Azo). This is a case of a patient who presented with a stone conglomerate in the right proximal ureter and underwent definitive treatment. Interestingly, the stone had a purple hue with FTIR spectroscopy showing stone composition of calcium oxalate (monohydrate and dihydrate) and a material resembling phenazopyridine. We retrospectively learned that she used multiple extended courses of phenazopyridine over 3 months.
Topics: Humans; Phenazopyridine; Female; Kidney Calculi; Middle Aged
PubMed: 38912947
DOI: No ID Found -
Inorganic Chemistry Jun 2024Four Ag(I) complexes with mefenamato and nitrogen heterocyclic ligands, [Ag(2-apy)(mef)] (), [Ag(3-apy)(mef)] (), [Ag(tmpyz)(mef)] (), and...
Four Ag(I) complexes with mefenamato and nitrogen heterocyclic ligands, [Ag(2-apy)(mef)] (), [Ag(3-apy)(mef)] (), [Ag(tmpyz)(mef)] (), and {[Ag(4,4'-bipy)(mef)](CHCN)(HO)} (), (mef = mefenamato, 2-apy = 2-aminopyridine, 3-apy = 3-aminopyridine, tmpyz = 2,3,5,6-tetramethylpyrazine, 4,4'-bipy = 4,4'-bipyridine), were synthesized and characterized. The interactions of these complexes with BSA were investigated by fluorescence spectroscopy, which indicated that these complexes quench the fluorescence of BSA by a static mechanism. The fluorescence data also indicated that the complexes showed good affinity for BSA, and one binding site on BSA was suitable for the complexes. The cytotoxicity of the four complexes against human cancer cell lines (MCF-7, HepG-2, A549, and MDA-MB-468) and one normal cell line (HTR-8) was evaluated by the MTT assay. Complex displayed high cytotoxic activity against A549 cells. Further studies revealed that complex could enhance the intracellular levels of ROS (reactive oxygen species) in A549 cells, cause cell cycle arrest in the G0/G1 phase, and induce apoptosis in A549 cells in a dose-dependent manner.
PubMed: 38910548
DOI: 10.1021/acs.inorgchem.4c01766 -
Journal of Translational Medicine Jun 2024In the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and...
BACKGROUND
In the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and subsequent therapeutic approaches for ALK-positive (ALK) non-small cell lung cancer (NSCLC).
METHODS
Patients with advanced ALK NSCLC were retrospectively selected from our center. Cohort 1 consisted of patients who experienced disease progression after receiving first-line alectinib treatment (n = 20), while Cohort 2 included patients who progressed following sequential treatment with crizotinib and second-generation ALK-TKIs (n = 53). Oligo-progression was defined as the occurrence of disease progression in no more than three lesions. Symptomatic progression was determined when patients developed new symptoms or experienced worsening of pre-existing symptoms during radiological progression.
RESULTS
The incidence of central nervous system (CNS) progression and symptomatic CNS progression was significantly lower in Cohort 1 compared to patients treated with crizotinib, with rates of 15.0% vs. 56.6% (p = 0.002) and 5.0% vs. 32.1% (p = 0.016), respectively. A total of 60.3% (44/73) patients underwent repeated biopsy and next-generation sequencing subsequent to the second-generation ALK-TKI resistance, with secondary mutation in ALK kinase domain emerging as the predominant mechanism of resistance (56.8%). Local therapy was applied to 50% of oligo-progression cases. Subsequent ALK-TKIs demonstrated significantly prolonged progression-free survival (PFS) (8.6 m vs. 2.7 m, p = 0.021, HR = 0.43, 95%CI: 0.15-0.85) and long-term overall survival (OS) (NA vs. 11.9 m, p = 0.132, HR = 0.50, 95%CI: 0.18-1.25) in patients harboring ALK resistance mutations, compared to those without such mutations. For patients without ALK-resistant mutations following progression on second-generation ALK-TKIs, there was no statistically significant difference in survival outcomes between subsequent chemotherapy or alternative ALK-TKI treatments.
CONCLUSIONS
First-line alectinib demonstrated superior efficacy in protecting the CNS compared to crizotinib. For patients with ALK-resistant mutations following the resistance to second-generation ALK-TKIs, appropriate sensitive ALK-TKI should be administered; for those without such mutations, the selection of chemotherapy or third-generation ALK-TKI should be based on the patient's overall physical health and personal preferences.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Anaplastic Lymphoma Kinase; Protein Kinase Inhibitors; Male; Female; Middle Aged; Lung Neoplasms; Drug Resistance, Neoplasm; Disease Progression; Aged; Adult; Crizotinib; Retrospective Studies; Mutation
PubMed: 38902768
DOI: 10.1186/s12967-024-05388-0 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Breast Neoplasms; Purines; Female; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents, Hormonal
PubMed: 38899707
DOI: 10.1056/NEJMc2404917 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Breast Neoplasms; Female; Purines; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents, Hormonal; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase 4
PubMed: 38899706
DOI: 10.1056/NEJMc2404917 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Breast Neoplasms; Female; Purines; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents, Hormonal; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase 4
PubMed: 38899705
DOI: 10.1056/NEJMc2404917 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Breast Neoplasms; Female; Purines; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents, Hormonal; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase 4
PubMed: 38899704
DOI: 10.1056/NEJMc2404917 -
Journal of Neurologic Physical Therapy... Jun 2024Individuals with downbeat nystagmus (DBN) syndrome present with DBN, dizziness, blurred vision, and unsteady gait. Pharmacological intervention with 4-aminopyridine...
BACKGROUND AND PURPOSE
Individuals with downbeat nystagmus (DBN) syndrome present with DBN, dizziness, blurred vision, and unsteady gait. Pharmacological intervention with 4-aminopyridine (4-AP) may be effective in improving oculomotor function, but there is minimal evidence to date that it improves gait. This suggests the possible benefit of combining pharmacotherapy with physical therapy to maximize outcomes. This case report documents improvements in gait and balance after physical therapy and aminopyridine (AP) in an individual with DBN syndrome.
CASE DESCRIPTION
The patient was a 70-year-old man with a 4-year history of worsening dizziness and imbalance, diagnosed with DBN syndrome. He demonstrated impaired oculomotor function, dizziness, and imbalance, which resulted in falls and limited community ambulation.
INTERVENTION
The patient completed a customized, tapered course of physical therapy over 6 months. Outcome measures included the 10-meter walk test, the Timed Up and Go (TUG), the Dynamic Gait Index (DGI), and the modified clinical test of sensory integration and balance.
OUTCOMES
Improvements exceeding minimal detectable change were demonstrated on the TUG and the DGI. Gait speed on the 10-meter walk test did not change significantly, but the patient was able to use a cane to ambulate in the community and reported no further falls.
DISCUSSION
Controlled studies are needed to explore the potential for AP to augment physical therapy in people with DBN syndrome. Physical therapists are encouraged to communicate with referring medical providers about the use of AP as pharmacotherapy along with physical therapy for individuals with DBN syndrome.
PubMed: 38898545
DOI: 10.1097/NPT.0000000000000485 -
ACS Medicinal Chemistry Letters Jun 2024Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Na1.8 sodium channel. Parallel library synthesis,...
Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Na1.8 sodium channel. Parallel library synthesis, guided by predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and efficacy of these compounds will be discussed.
PubMed: 38894930
DOI: 10.1021/acsmedchemlett.4c00103