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ESMO Open Jun 2024The PENELOPE-B study demonstrated that the addition of 1-year post-neoadjuvant palbociclib to endocrine therapy (ET) in patients with high-risk early breast cancer (BC)... (Randomized Controlled Trial)
Randomized Controlled Trial
Palbociclib combined with endocrine treatment in hormone receptor-positive, HER2-negative breast cancer patients with high relapse risk after neoadjuvant chemotherapy: subgroup analyses of premenopausal patients in PENELOPE-B.
BACKGROUND
The PENELOPE-B study demonstrated that the addition of 1-year post-neoadjuvant palbociclib to endocrine therapy (ET) in patients with high-risk early breast cancer (BC) did not improve invasive disease-free survival (iDFS) compared to placebo. Here, we report results for premenopausal women.
PATIENTS AND METHODS
Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative BC at high risk of relapse [defined as no pathological complete response after neoadjuvant chemotherapy and a clinical, pathological stage, estrogen receptor, grading (CPS-EG) score ≥3 or 2/ypN+] were randomized to receive 13 cycles of palbociclib or placebo + standard ET. Ovarian function (OF) was evaluated by centrally assessed estradiol, follicle-stimulating hormone and anti-Müllerian hormone serum levels.
RESULTS
Overall, 616 of 1250 randomized patients were premenopausal; of these, 30.0% were <40 years of age, 47.4% had four or more metastatic lymph nodes, and 58.2% had a CPS-EG score ≥3. 66.1% of patients were treated with tamoxifen alone, and 32.9% received ovarian function suppression (OFS) in addition to either tamoxifen or aromatase inhibitor (AI). After a median follow-up of 42.8 months (97.2% completeness) no difference in iDFS between palbociclib and placebo was observed [hazard ratio = 0.95, 95% confidence interval (CI) 0.69-1.30, P = 0.737]. The estimated 3-year iDFS rate was marginally higher in the palbociclib arm (80.6% versus 78.3%). Three year iDFS was higher in patients receiving AI than tamoxifen plus OFS or tamoxifen alone (86.0% versus 78.6% versus 78.0%). Patients receiving tamoxifen plus OFS showed a favorable iDFS with palbociclib (83.0% versus 74.1%, hazard ratio = 0.52, 95% CI 0.27-1.02, P = 0.057). Hematologic adverse events were more frequent with palbociclib (76.1% versus 1.9% grade 3-4, P < 0.001). Palbociclib seems not to negatively impact the OF throughout the treatment period.
CONCLUSIONS
In premenopausal women, who received tamoxifen plus OFS as ET, the addition of palbociclib to ET results in a favorable iDFS. The safety profile seems favorable and in contrast to chemotherapy palbociclib does not impact OF throughout the treatment period.
Topics: Humans; Female; Breast Neoplasms; Piperazines; Pyridines; Adult; Premenopause; Neoadjuvant Therapy; Receptor, ErbB-2; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Receptors, Estrogen; Disease-Free Survival
PubMed: 38838498
DOI: 10.1016/j.esmoop.2024.103466 -
Water Research X Jan 2024The performance of partial nitritation (PN)-moving bed biofilm reactor (MBBR) in removal of antibiotics in the sidestream wastewater has not been investigated so far. In...
The performance of partial nitritation (PN)-moving bed biofilm reactor (MBBR) in removal of antibiotics in the sidestream wastewater has not been investigated so far. In this work, the removal of ciprofloxacin was assessed under varying free nitrous acid (FNA) levels and different trophic modes. For the first time, a positive correlation was observed between ciprofloxacin removal and FNA levels, either in the autotrophic PN-MBBR or in the mixotrophic PN-MBBR, mainly ascribed to the FNA-stimulating effect on heterotrophic bacteria (HB)-induced biodegradation. The maximum ciprofloxacin removal efficiency (∼98 %) and removal rate constant (0.021 L g SS h) were obtained in the mixotrophic PN-MBBR at an average FNA level of 0.056 mg-N L, which were 5.8 and 51.2 times higher than the corresponding values in the autotrophic PN-MBBR at 0 mg FNA-N L. Increasing FNA from 0.006 to 0.056 mg-N L would inhibit ammonia oxidizing bacteria (AOB)-induced cometabolism and metabolism from 10.2 % and 6.9 % to 6.2 % and 6.4 %, respectively, while HB-induced cometabolism and metabolism increased from 31.2 % and 22.7 % to 41.9 % and 34.5 %, respectively. HB-induced cometabolism became the predominant biodegradation pathway (75.9 %-85.8 %) in the mixotrophic mode. Less antimicrobial biotransformation products without the piperazine or fluorine were newly identified to propose potential degradation pathways, corresponding to microbial-induced metabolic types and FNA levels. This work shed light on enhancing antibiotic removal via regulating both FNA accumulation and organic carbon addition in the PN-MBBR process treating sidestream wastewater.
PubMed: 38831973
DOI: 10.1016/j.wroa.2024.100216 -
Molecular Cancer Jun 2024Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is...
Triple negative breast cancer (TNBC) remains exceptionally challenging to treat. While CDK4/6 inhibitors have revolutionized HR + breast cancer therapy, there is limited understanding of their efficacy in TNBC and meaningful predictors of response and resistance to these drugs remain scarce. We conducted an in vivo genome-wide CRISPR screen using palbociclib as a selection pressure in TNBC. Hits were prioritized using microarray data from a large panel of breast cancer cell lines to identify top palbociclib sensitizers. Our study defines TGFβ3 as an actionable determinant of palbociclib sensitivity that potentiates its anti-tumor effects. Mechanistically, we show that chronic palbociclib exposure depletes p21 levels, contributing to acquired resistance, and that TGFβ3 treatment can overcome this. This study defines TGFβ3 as an actionable biomarker that can be used to improve patient stratification for palbociclib treatment and exploits the synergistic interaction between CDK4/6 and TGFβ3 to propose a new combinatorial treatment for TNBC.
Topics: Humans; Piperazines; Triple Negative Breast Neoplasms; Pyridines; Drug Resistance, Neoplasm; Female; Biomarkers, Tumor; Cell Line, Tumor; Mice; Animals; Transforming Growth Factor beta3; CRISPR-Cas Systems; Xenograft Model Antitumor Assays; Protein Kinase Inhibitors; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression Regulation, Neoplastic
PubMed: 38831405
DOI: 10.1186/s12943-024-02029-4 -
Scientific Reports Jun 2024Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients...
Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients are limited. This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while the reason in the niraparib was thrombocytopenia. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity was challenging. In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Ovarian Neoplasms; Middle Aged; Aged; Japan; Retrospective Studies; Piperidines; Phthalazines; Piperazines; Indazoles; Adult; Aged, 80 and over; Thrombocytopenia; East Asian People
PubMed: 38824213
DOI: 10.1038/s41598-024-63600-z -
International Journal of Cardiology Sep 2024The comparative efficacy and safety of adjusted- and standard-dose prasugrel in East Asian patients with acute myocardial infarction (AMI) undergoing percutaneous... (Comparative Study)
Comparative Study
BACKGROUND
The comparative efficacy and safety of adjusted- and standard-dose prasugrel in East Asian patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) remain unclear. This study aimed to comparatively assess the ischaemic and bleeding outcomes of adjusted-dose (maintenance dose: 3.75 mg) and standard-dose (maintenance dose: 10 mg) prasugrel in East Asian patients with AMI undergoing PCI.
METHODS
From a combined dataset sourced from nationwide AMI registries in Japan and South Korea (n = 17,118), patients treated with either adjusted- or standard-dose prasugrel were identified. Patients who did not undergo emergent PCI, those on oral anticoagulants, and those meeting the criteria of contraindication of prasugrel in South Korea (age ≥ 75 years, body weight < 60 kg, or history of stroke) were excluded. Major adverse cardiovascular events (MACE) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding events were compared between the adjusted-dose (n = 1160) and standard-dose (n = 1086) prasugrel groups.
RESULTS
Within the propensity-matched cohort (n = 702 in each group), no significant difference was observed in the in-hospital MACE between the adjusted- and standard-dose prasugrel groups (1.85% vs. 2.71%, odds ratio [OR] 0.68, 95% confidence interval [CI] 0.33-1.38, p = 0.286). However, the incidence of in-hospital major bleeding was significantly lower in the adjusted-dose prasugrel group than in the standard-dose group (0.43% vs. 1.71%, OR 0.25, 95% CI 0.07-0.88, p = 0.031). The cumulative 12-month incidence of MACE was equivalent in both groups (4.70% vs. 4.70%, OR 1.00, 95% CI 0.61-1.64, p = 1.000).
CONCLUSIONS
Among East Asian patients with AMI undergoing PCI, those administered adjusted-dose prasugrel exhibited a lower risk of in-hospital bleeding events than those administered standard-dose prasugrel, while maintaining a comparable 1-year incidence of MACE.
Topics: Aged; Female; Humans; Male; Middle Aged; Cohort Studies; Dose-Response Relationship, Drug; East Asian People; Hemorrhage; Japan; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Registries; Republic of Korea; Treatment Outcome
PubMed: 38823533
DOI: 10.1016/j.ijcard.2024.132197 -
Scientific Reports May 2024Binding affinity is an important factor in drug design to improve drug-target selectivity and specificity. In this study, in silico techniques based on molecular docking...
Binding affinity is an important factor in drug design to improve drug-target selectivity and specificity. In this study, in silico techniques based on molecular docking followed by molecular dynamics (MD) simulations were utilized to identify the key residue(s) for CSF1R binding affinity among 14 pan-tyrosine kinase inhibitors and 15 CSF1R-specific inhibitors. We found tryptophan at position 550 (W550) on the CSF1R binding site interacted with the inhibitors' aromatic ring in a π-π way that made the ligands better at binding. Upon W550-Alanine substitution (W550A), the binding affinity of trans-(-)-kusunokinin and imatinib to CSF1R was significantly decreased. However, in terms of structural features, W550 did not significantly affect overall CSF1R structure, but provided destabilizing effect upon mutation. The W550A also did not either cause ligand to change its binding site or conformational changes due to ligand binding. As a result of our findings, the π-π interaction with W550's aromatic ring could be still the choice for increasing binding affinity to CSF1R. Nevertheless, our study showed that the increasing binding to W550 of the design ligand may not ensure CSF1R specificity and inhibition since W550-ligand bound state did not induce significantly conformational change into inactive state.
Topics: Tryptophan; Ligands; Binding Sites; Humans; Molecular Dynamics Simulation; Protein Binding; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Molecular Docking Simulation; Protein Kinase Inhibitors; Imatinib Mesylate; Receptor, Macrophage Colony-Stimulating Factor
PubMed: 38822100
DOI: 10.1038/s41598-024-63505-x -
Blood Cancer Journal May 2024Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the...
Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo BCR::ABL1AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were ASXL1, RUNX1 and NPM1. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo BCR::ABL1AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no ABL1 mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50-91). Four out of five patients who were not transplanted did not relapse. Comparison of BCR::ABL1AML, CML-BP, 2017 ELN intermediate (n = 643) and adverse-risk patients (n = 863) showed that patients with BCR::ABL1AML had a significant better outcome than intermediate and adverse-risk patients. BCR::ABL1AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.
Topics: Humans; Male; Female; Middle Aged; Adult; Imatinib Mesylate; Aged; Leukemia, Myeloid, Acute; Translocation, Genetic; Registries; Chromosomes, Human, Pair 22; Fusion Proteins, bcr-abl; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 9; Young Adult; Nucleophosmin
PubMed: 38821940
DOI: 10.1038/s41408-024-01069-9 -
Journal of Pharmaceutical and... Aug 2024Recently, pharmaceutical research has been focused on the design of new antibacterial drugs with higher selectivity towards several strains. Major issues concern the...
Recently, pharmaceutical research has been focused on the design of new antibacterial drugs with higher selectivity towards several strains. Major issues concern the possibility to obtain compounds with fewer side effects, at the same time effectively overcoming the problem of antimicrobial resistance. Several solutions include the synthesis of new pharmacophores starting from piperazine or morpholine core units. Mass spectrometry-based techniques offer important support for the structural characterization of newly synthesized compounds to design safer and more effective drugs for various medical conditions. Here, two new piperazine derivatives and four new morpholine derivatives were synthesized and structurally characterized through a combined approach of Fourier transform-ion cyclotron resonance (FT-ICR) and Linear Trap Quadrupole (LTQ) mass spectrometry. The support of both high-resolution and low-resolution mass spectrometric data namely accurate mass measurements, isotopic distribution and MS spectra, was crucial to confirm the success of the synthesis. These compounds were further evaluated for inhibitory activity against a total of twenty-nine Gram-positive and Gram-negative bacteria to determine the action spectrum and the antimicrobial effectiveness. Results demonstrated compounds' antimicrobial activity against many tested bacterial species, providing an inhibitory effect linked to different chemical structure and suggesting that the new-synthesized derivatives could be considered as promising antimicrobial agents.
Topics: Morpholines; Anti-Bacterial Agents; Microbial Sensitivity Tests; Piperazines; Gram-Negative Bacteria; Mass Spectrometry; Gram-Positive Bacteria; Structure-Activity Relationship; Piperazine
PubMed: 38820833
DOI: 10.1016/j.jpba.2024.116202 -
Free Radical Biology & Medicine Aug 2024Despite of yet unknown mechanism, microvascular deposition of oligomeric Tau (oTau) has been implicated in alteration of the Blood-Brain Barrier (BBB) function in...
Despite of yet unknown mechanism, microvascular deposition of oligomeric Tau (oTau) has been implicated in alteration of the Blood-Brain Barrier (BBB) function in Alzheimer's disease (AD) brains. In this study, we employed an in vitro BBB model using primary mouse cerebral endothelial cells (CECs) to investigate the mechanism underlying the effects of oTau on BBB function. We found that exposing CECs to oTau induced oxidative stress through NADPH oxidase, increased oxidative damage to proteins, decreased proteasome activity, and expressions of tight junction (TJ) proteins including occludin, zonula occludens-1 (ZO-1) and claudin-5. These effects were suppressed by the pretreatment with Fasudil, a RhoA/ROCK signaling inhibitor. Consistent with the biochemical alterations, we found that exposing the basolateral side of CECs to oTau in the BBB model disrupted the integrity of the BBB, as indicated by an increase in FITC-dextran transport across the model, and a decrease in trans endothelial electrical resistance (TEER). oTau also increased the transmigration of peripheral blood mononuclear cells (PBMCs) in the BBB model. These functional alterations in the BBB induced by oTau were also suppressed by Fasudil. Taken together, our findings suggest that targeting the RhoA/ROCK pathway can be a potential therapeutic strategy to maintain BBB function in AD.
Topics: Animals; rho-Associated Kinases; Mice; Blood-Brain Barrier; Endothelial Cells; rhoA GTP-Binding Protein; Signal Transduction; Oxidative Stress; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; tau Proteins; Humans; Alzheimer Disease; Cells, Cultured; Tight Junctions; Zonula Occludens-1 Protein
PubMed: 38815773
DOI: 10.1016/j.freeradbiomed.2024.05.044 -
Turkish Journal of Medical Sciences 2023People living with human immunodeficiency virus (PLWH) are getting older. Age-related comorbidities in PLWH result in polypharmacy and increase the risk for potential...
BACKGROUND/AIM
People living with human immunodeficiency virus (PLWH) are getting older. Age-related comorbidities in PLWH result in polypharmacy and increase the risk for potential drug-drug interactions (pDDIs). This study aimed to evaluate how the rate of pDDIs would change if the treatment of patients receiving different combined antiretroviral therapies (ARTs) were theoretically changed with dolutegravir/lamivudine (DTG+3TC) or cabotegravir/rilpivirine (CAB+RPV).
MATERIALS AND METHODS
This study was conducted at the infectious disease outpatient clinic of a university hospital as a follow-up of a previous study. The data of PLWH receiving at least 1 comedication other than antiretrovirals (ARVs) were retrospectively reviewed and analyzed. The Drugs.com/Drug Interactions Checker and University of Liverpool HIV Drug Interactions Checker databases were used to identify pDDIs and their severities.
RESULTS
A total of 75 PLWH, of whom 83% were male, with a mean age (± standard deviation) of 46.5 (±12.98) years were included. Polypharmacy was observed in 59 (79%) of the participants; however, with dual ARV options, the probability of polypharmacy was 35 (47%) (p < 0.001). In the Drugs.com database, no significant difference was found in terms of pDDIs between the treatment of current ARTs (64%) and DTG/3TC (%44) (p = 0.06) or CAB/RPV (%64) (p = 0.521). However, in the University of Liverpool database, the current rate of pDDIs (55%) was significantly higher compared to the theoretical treatment of DTG/3TC (40%) (p = 0.029), oral CAB/RPV (48%) (p = 0.003), and injectable CAB/RPV (31%) use (p = 0.006).
CONCLUSION
The results suggest that dual treatment regimens can reduce pDDIs, resulting in better tolerance and probably higher quality of life among PLWH.
Topics: Humans; Drug Interactions; Retrospective Studies; Male; Female; Middle Aged; HIV Infections; Adult; Polypharmacy; Anti-HIV Agents; Lamivudine; Pyridones; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; Oxazines; Anti-Retroviral Agents; Piperazines
PubMed: 38813033
DOI: 10.55730/1300-0144.5718