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Current Research in Neurobiology 2024Catamenial epilepsy, defined as a periodicity of seizure exacerbation during the menstrual cycle, affects up to 70 % of epileptic women. Seizures in these patients are...
Catamenial epilepsy, defined as a periodicity of seizure exacerbation during the menstrual cycle, affects up to 70 % of epileptic women. Seizures in these patients are often non-responsive to medication; however, our understanding of the relation between menstrual cycle and seizure generation (i.e. ictogenesis) remains limited. We employed here field potential recordings in the 4-aminopyridine model of epileptiform synchronization in female mice (P60-P130) and found that: (i) the estrous phase favors ictal activity in the entorhinal cortex; (ii) these ictal discharges display an onset pattern characterised by the presence of chirps that are thought to mirror synchronous interneuron firing; and (iii) blocking estrogen receptor β-mediated signaling reduces ictal discharge duration. Our findings indicate that the duration of 4AP-induced ictal discharges, , increases during the estrous phase, which corresponds to the human peri-ovulatory period. We propose that these effects are caused by the presumptive enhancement of interneuron excitability due to increased estrogen receptor β-mediated signaling.
PubMed: 38812499
DOI: 10.1016/j.crneur.2024.100131 -
Journal of Nanobiotechnology May 2024Ulcerative colitis (UC) is one chronic and relapsing inflammatory bowel disease. Macrophage has been reputed as one trigger for UC. Recently, phosphodiesterase 4 (PDE4)...
BACKGROUND
Ulcerative colitis (UC) is one chronic and relapsing inflammatory bowel disease. Macrophage has been reputed as one trigger for UC. Recently, phosphodiesterase 4 (PDE4) inhibitors, for instance roflumilast, have been regarded as one latent approach to modulating macrophage in UC treatment. Roflumilast can decelerate cyclic adenosine monophosphate (cAMP) degradation, which impedes TNF-α synthesis in macrophage. However, roflumilast is devoid of macrophage-target and consequently causes some unavoidable adverse reactions, which restrict the utilization in UC.
RESULTS
Membrane vesicles (MVs) from probiotic Escherichia coli Nissle 1917 (EcN 1917) served as a drug delivery platform for targeting macrophage. As model drugs, roflumilast and MnO were encapsulated in MVs (Rof&MnO@MVs). Roflumilast inhibited cAMP degradation via PDE4 deactivation and MnO boosted cAMP generation by activating adenylate cyclase (AC). Compared with roflumilast, co-delivery of roflumilast and MnO apparently produced more cAMP and less TNF-α in macrophage. Besides, Rof&MnO@MVs could ameliorate colitis in mouse model and regulate gut microbe such as mitigating pathogenic Escherichia-Shigella and elevating probiotic Akkermansia.
CONCLUSIONS
A probiotic-based nanoparticle was prepared for precise codelivery of roflumilast and MnO into macrophage. This biomimetic nanoparticle could synergistically modulate cAMP in macrophage and ameliorate experimental colitis.
Topics: Animals; Aminopyridines; Mice; Cyclic AMP; Probiotics; Cyclopropanes; Manganese Compounds; Benzamides; Oxides; Macrophages; Phosphodiesterase 4 Inhibitors; Colitis; RAW 264.7 Cells; Escherichia coli; Tumor Necrosis Factor-alpha; Mice, Inbred C57BL; Male; Disease Models, Animal
PubMed: 38807127
DOI: 10.1186/s12951-024-02558-6 -
Cancer Letters Jul 2024In patients with ER + metastatic breast cancer (mBC), the first-line treatment involves the combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i)....
In patients with ER + metastatic breast cancer (mBC), the first-line treatment involves the combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). However, a significant group of patients experiences disease progression, emphasizing the urgent clinical need to identify novel anti-tumor therapies. We previously generated breast cancer cells resistant to the combination of fulvestrant (ER downregulator) and abemaciclib (CDK4/6 inhibitor) from MCF7 and T47D (MCF7-FAR and T47D-FAR). RNA-seq-based Gene Set Enrichment Analysis (GSEA) revealed hyper-activation of EGFR, HER2, and AKT signaling in both MCF7-FAR and T47D-FAR. Modulating EGFR or ERBB2 expression through loss- and gain-of-function experiments altered tumor sensitivity to fulvestrant and abemaciclib in parental and FAR spheroids, affecting ERK and AKT/S6 pathways. Cetuximab treatment overcame tumor resistance to fulvestrant and abemaciclib in FAR and EGFR-overexpressing breast cancer spheroids and xenografts. Likewise, patient-derived organoids (PDOs) from individuals with ER + mBC, progressing on palbociclib, exhibited up-regulation of EGFR and HER2 pathways. In conclusion, our findings suggest that inhibiting EGFR and HER2 pathways might overcome resistance to ET + CDK4/6i in selected patients with ER + mBC.
Topics: Humans; Breast Neoplasms; Receptor, ErbB-2; Female; Drug Resistance, Neoplasm; Cyclin-Dependent Kinase 4; Animals; ErbB Receptors; Cyclin-Dependent Kinase 6; Receptors, Estrogen; Mice; Fulvestrant; Protein Kinase Inhibitors; Benzimidazoles; Aminopyridines; Xenograft Model Antitumor Assays; Antineoplastic Agents, Hormonal; MCF-7 Cells; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38788968
DOI: 10.1016/j.canlet.2024.216968 -
Europace : European Pacing,... Jun 2024Human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCM) could be a helpful tool to study the physiology and diseases of the human atrium. To fulfil...
Human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulate contribution of the slowly activating delayed rectifier currents IKs to repolarization in the human atrium.
AIMS
Human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCM) could be a helpful tool to study the physiology and diseases of the human atrium. To fulfil this expectation, the electrophysiology of hiPSC-aCM should closely resemble the situation in the human atrium. Data on the contribution of the slowly activating delayed rectifier currents (IKs) to repolarization are lacking for both human atrium and hiPSC-aCM.
METHODS AND RESULTS
Human atrial tissues were obtained from patients with sinus rhythm (SR) or atrial fibrillation (AF). Currents were measured in human atrial cardiomyocytes (aCM) and compared with hiPSC-aCM and used to model IKs contribution to action potential (AP) shape. Action potential was recorded by sharp microelectrodes. HMR-1556 (1 µM) was used to identify IKs and to estimate IKs contribution to repolarization. Less than 50% of hiPSC-aCM and aCM possessed IKs. Frequency of occurrence, current densities, activation/deactivation kinetics, and voltage dependency of IKs did not differ significantly between hiPSC-aCM and aCM, neither in SR nor AF. β-Adrenoceptor stimulation with isoprenaline did not increase IKs neither in aCM nor in hiPSC-aCM. In tissue from SR, block of IKs with HMR-1556 did not lengthen the action potential duration, even when repolarization reserve was reduced by block of the ultra-rapid repolarizing current with 4-aminopyridine or the rapidly activating delayed rectifier potassium outward current with E-4031.
CONCLUSION
I Ks exists in hiPSC-aCM with biophysics not different from aCM. As in adult human atrium (SR and AF), IKs does not appear to relevantly contribute to repolarization in hiPSC-aCM.
Topics: Humans; Myocytes, Cardiac; Induced Pluripotent Stem Cells; Action Potentials; Heart Atria; Delayed Rectifier Potassium Channels; Atrial Fibrillation; Female; Cells, Cultured; Male; Middle Aged; Kinetics; Aged; Cell Differentiation; Models, Cardiovascular; Potassium Channel Blockers
PubMed: 38788213
DOI: 10.1093/europace/euae140 -
Medicine May 2024To evaluate radiological and clinical features in metastatic anaplastic lymphoma kinase+ non-small cell lung cancer patients and crizotinib efficacy in different lines....
To evaluate radiological and clinical features in metastatic anaplastic lymphoma kinase+ non-small cell lung cancer patients and crizotinib efficacy in different lines. This national, non-interventional, multicenter, retrospective archive screening study evaluated demographic, clinical, and radiological imaging features, and treatment approaches in patients treated between 2013-2017. Totally 367 patients (54.8% males, median age at diagnosis 54 years) were included. Of them, 45.4% were smokers, and 8.7% had a family history of lung cancer. On radiological findings, 55.9% of the tumors were located peripherally, 7.7% of the patients had cavitary lesions, and 42.9% presented with pleural effusion. Pleural effusion was higher in nonsmokers than in smokers (37.3% vs. 25.3%, P = .018). About 47.4% of cases developed distant metastases during treatment, most frequently to the brain (26.2%). Chemotherapy was the first line treatment in 55.0%. Objective response rate was 61.9% (complete response: 7.6%; partial response: 54.2%). The highest complete and partial response rates were observed in patients who received crizotinib as the 2nd line treatment. The median progression-free survival was 14 months (standard error: 1.4, 95% confidence interval: 11.2-16.8 months). Crizotinib treatment lines yielded similar progression-free survival (P = .078). The most frequent treatment-related adverse event was fatigue (14.7%). Adrenal gland metastasis was significantly higher in males and smokers, and pleural involvement and effusion were significantly higher in nonsmokers-a novel finding that has not been reported previously. The radiological and histological characteristics were consistent with the literature data, but several differences in clinical characteristics might be related to population characteristics.
Topics: Humans; Crizotinib; Carcinoma, Non-Small-Cell Lung; Male; Female; Retrospective Studies; Middle Aged; Lung Neoplasms; Anaplastic Lymphoma Kinase; Adult; Aged; Protein Kinase Inhibitors; Antineoplastic Agents; Treatment Outcome
PubMed: 38787994
DOI: 10.1097/MD.0000000000037972 -
Therapeutic Advances in Respiratory... 2024A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still...
BACKGROUND
A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden.
OBJECTIVES
The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden.
DESIGN
The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor.
METHODS
Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed.
RESULTS
Lung function measured as ppFEV1 ( < 0.001), body mass index (BMI) in adults ( < 0.001), and BMI -score in children ( = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of ( = 0.007) and ( < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for ( = 0.009), spp ( = 0.026), and ( < 0.001) shifted from negative to positive.
CONCLUSION
The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for , or , key pathogens in the CF context.
Topics: Humans; Cystic Fibrosis; Male; Prospective Studies; Female; Aminophenols; Benzodioxoles; Child; Adult; Young Adult; Adolescent; Drug Combinations; Aminopyridines; Quinolones; Sweden; Treatment Outcome; Mycoses; Respiratory Tract Infections; Cystic Fibrosis Transmembrane Conductance Regulator; Lung; Chloride Channel Agonists; Time Factors; Fungi; Bacterial Infections
PubMed: 38780228
DOI: 10.1177/17534666241254090 -
Trials May 2024Prostate cancer (PCa) is the most common non-cutaneous malignancy in men and leads to the second most common cause of cancer related mortality in men. Early detection of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Prostate cancer (PCa) is the most common non-cutaneous malignancy in men and leads to the second most common cause of cancer related mortality in men. Early detection of PCa allows for a potentially curative intervention. Most men will live over a decade from the time of their PCa diagnosis. Thus, treatments must balance curative interventions with their impact on quality of life. Radical prostatectomy (RP) is one such potentially curative intervention but often leads to erectile dysfunction (ED) and urinary incontinence (UI). Approximately 90,000 RPs are performed each year in the USA. Post-operative ED and UI is thought to occur in part from traumatic peripheral nerve injury (TPNI) to the neurovascular bundles that surround the prostate. Thus, patients undergoing RP may be a population that would benefit from clinical studies that look at TPNI.
METHODS
The study is a single-institution, double-blinded placebo-controlled, randomized clinical trial in which patients immediately post-RP receive either 4-aminopyrdine (4AP) or placebo in a 1:1 fashion. The primary outcome is evaluation of the efficacy of 4AP in accelerating the early return of baseline erectile and urinary function post-radical prostatectomy.
DISCUSSION
This study is critical as it could reduce the morbidity associated with RP, a commonly performed operation, and identify a patient population that may greatly benefit into further TPNI research.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03701581. Prospectively registered on October 10, 2018.
Topics: Humans; Male; Middle Aged; Double-Blind Method; Erectile Dysfunction; Peripheral Nerve Injuries; Postoperative Complications; Prostatectomy; Prostatic Neoplasms; Recovery of Function; Treatment Outcome; Urinary Incontinence
PubMed: 38773595
DOI: 10.1186/s13063-024-08102-z -
Cancer Medicine May 2024Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth... (Comparative Study)
Comparative Study
Abemaciclib plus endocrine therapy versus chemotherapy after progression on prior palbociclib in HR+/HER2- metastatic breast cancer: A single center real-world study in China.
BACKGROUND
Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib-based ET in Chinese patients with HR+/HER2- MBC.
METHODS
From 414 consecutive patients with HR+/HER2- MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease-free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression-free survival (PFS) compared using the Kaplan-Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group.
RESULTS
The median PFS was 6.0 months (95% confidence interval [CI]: 3.94-8.06) in abemaciclib group and 4.0 months (95% CI, 2.52-5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first-line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd-line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069).
CONCLUSION
Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2- MBC after progression on prior palbociclib-based therapy in addition to chemotherapy.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Piperazines; Pyridines; Antineoplastic Combined Chemotherapy Protocols; Aminopyridines; Receptor, ErbB-2; Benzimidazoles; China; Receptors, Estrogen; Progression-Free Survival; Receptors, Progesterone; Aged; Adult; Retrospective Studies; Disease Progression; Antineoplastic Agents, Hormonal
PubMed: 38770648
DOI: 10.1002/cam4.7249 -
PloS One 2024Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we...
Mechanisms underlying primary and acquired resistance to MET tyrosine kinase inhibitors (TKIs) in managing non-small cell lung cancer remain unclear. In this study, we investigated the possible mechanisms acquired for crizotinib in MET-amplified lung carcinoma cell lines. Two MET-amplified lung cancer cell lines, EBC-1 and H1993, were established for acquired resistance to MET-TKI crizotinib and were functionally elucidated. Genomic and transcriptomic data were used to assess the factors contributing to the resistance mechanism, and the alterations hypothesized to confer resistance were validated. Multiple mechanisms underlie acquired resistance to crizotinib in MET-amplified lung cancer cell lines. In EBC-1-derived resistant cells, the overexpression of SERPINE1, the gene encoding plasminogen activator inhibitor-1 (PAI-1), mediated the drug resistance mechanism. Crizotinib resistance was addressed by combination therapy with a PAI-1 inhibitor and PAI-1 knockdown. Another mechanism of resistance in different subline cells of EBC-1 was evaluated as epithelial-to-mesenchymal transition with the upregulation of antiapoptotic proteins. In H1993-derived resistant cells, MEK inhibitors could be a potential therapeutic strategy for overcoming resistance with downstream mitogen-activated protein kinase pathway activation. In this study, we revealed the different mechanisms of acquired resistance to the MET inhibitor crizotinib with potential therapeutic application in patients with MET-amplified lung carcinoma.
Topics: Humans; Plasminogen Activator Inhibitor 1; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Proto-Oncogene Proteins c-met; Crizotinib; Lung Neoplasms; Cell Line, Tumor; Protein Kinase Inhibitors; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic
PubMed: 38758826
DOI: 10.1371/journal.pone.0300644 -
Signal Transduction and Targeted Therapy May 2024Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate...
Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study.
Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.
Topics: Humans; Male; Female; Middle Aged; Benzamides; Aged; Lymphoma, Extranodal NK-T-Cell; Histone Deacetylase Inhibitors; Antibodies, Monoclonal, Humanized; Adult; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Programmed Cell Death 1 Receptor
PubMed: 38755119
DOI: 10.1038/s41392-024-01825-0