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Frontiers in Oncology 2024Pre-clinical studies showed the anti-tumor mechanisms of PARP inhibitors (PARPi) and platinum have some crossover and overlap in the DNA damage repair pathway, patients...
BACKGROUND
Pre-clinical studies showed the anti-tumor mechanisms of PARP inhibitors (PARPi) and platinum have some crossover and overlap in the DNA damage repair pathway, patients who respond to platinum-based chemotherapy are also more likely to be sensitive to PARPi. This real-world study mainly aimed to evaluate whether TRAE (treatment-related adverse event) between platinum based chemotherapy (PBC) and niraparib are also associated.
METHODS
Patients received niraparib as maintenance treatment or salvage therapy for advanced ovarian cancer at the First Affiliated Hospital of Gannan Medical University from January 2020 to August 2023 were included. Survival data of niraparib treatment and adverse events occurred during the last platinum-based chemotherapy cycle before starting niraparib treatment and during niraparib treatment are documented. Fisher's exact test were used for correlation analysis.
RESULTS
1. 40 patients treated with niraparib were included in the analysis, including 31 patients treated with niraparib for 1st-line maintenance therapy, 6 patients for PSR (platinum-sensitive recurrence) maintenance therapy, and 3 patients for salvage therapy. The overall median follow-up time was 15.0 months (ranged from 2.2 months to 32.1 months). 2. Overall grade≥3 TRAE (40% vs 70%, p=0.012) including anemia (20% vs 45%, p=0.041) and neutrophil count decreased (17.5% vs 57.5%, p<0.001) was significantly lower during niraparib treatment compared to during chemotherapy. 3. Any grade TRAE (75% vs 100%, p=0.002) including white blood cell count decreased (47.5% vs 87.5%, p<0.001), red blood cell count decreased (57.5% vs 92.5%, p<0.001), anemia (55% vs 87.5%, p<0.001) and neutrophil count decreased (35% vs 85%, p<0.001) were also significantly lower in niraparib treatment group compared with chemotherapy group. No new safety signals were identified.
CONCLUSION
1. In this real-world practice, we observed that patients with advanced ovarian cancer who experienced any grade and grade ≥3 TRAE during chemotherapy were well tolerated when treated with niraparib, particularly the incidence of any grade and grade ≥3 anemia, and neutrophil count decreased during niraparib treatment were significantly lower compared with that during chemotherapy. 2. For patients with ovarian cancer who have experienced grade ≥3 hematological adverse reactions during prior platinum-based chemotherapy, greater attention should be paid to the monitoring and management of hematological adverse reactions during subsequent treatment with niraparib.
PubMed: 38952544
DOI: 10.3389/fonc.2024.1390820 -
Scientific Reports Jul 2024The objective of this study was to assess the potential for recovering precious metals from technological solutions using an ion-exchange dynamic method. Precious metals...
The objective of this study was to assess the potential for recovering precious metals from technological solutions using an ion-exchange dynamic method. Precious metals like platinum, palladium, rhodium, and gold are essential materials in various industries such as: automotive, electronics, pharmaceuticals, and jewellery. Due to their limited occurrence in primary sources, there is a growing trend in the market to extract these metals from secondary sources. The research involved conducting sorption and elution tests under different parameters to investigate their impact on the process in dynamic conditions. Additionally, an attempt was made to calculate the operational and total capacity of the resins, which has not been done previously for industrial solutions. The results showed that using Puromet MTS9200, Puromet MTS9850, and Lewatit MonoPlus MP600 resins, the sorption process could be effectively carried out in dynamic conditions with a contact time of 5 min between the technological solution and the resin bed. For optimal elution, the contact time between the eluent solution and the bed should range between 10 and 30 min. To improve rhodium sorption efficiency, it was found that neutralizing the technological solution to a pH of approximately 7 and using Lewatit MonoPlus MP600 resin could be beneficial.
PubMed: 38951606
DOI: 10.1038/s41598-024-66086-x -
Mikrochimica Acta Jul 2024A dual-recognition strategy is reported to construct a one-step washing and highly efficient signal-transduction tag system for high-sensitivity colorimetric detection...
A dual-recognition strategy is reported to construct a one-step washing and highly efficient signal-transduction tag system for high-sensitivity colorimetric detection of Staphylococcus aureus (S. aureus). The porous (gold core)@(platinum shell) nanozymes (Au@PtNEs) as the signal labels show highly efficient peroxidase mimetic activity and are robust. For the sake of simplicity the detection involved the use of a vancomycin-immobilized magnetic bead (MB) and aptamer-functionalized Au@PtNEs for dual-recognition detection in the presence of S. aureus. In addition, we designed a magnetic plate to fit the 96-well microplate to ensure consistent magnetic properties of each well, which can quickly remove unreacted Au@PtNEs and sample matrix while avoiding tedious washing steps. Subsequently, Au@PtNEs catalyze hydrogen peroxide (H2O2) to oxidize 3,3',5,5'-tetramethylbenzidine (TMB) generating a color signal. Finally, the developed Au@PtNEs-based dual-recognition washing-free colorimetric assay displayed a response in the range of S. aureus of 5 × 10-5 × 10 CFU/mL, and the detection limit was 40 CFU/mL within 1.5 h. In addition, S. aureus-fortified samples were analyzed to further evaluate the performance of the proposed method, which yielded average recoveries ranging from 93.66 to 112.44% and coefficients of variation (CVs) within the range 2.72-9.01%. These results furnish a novel horizon for the exploitation of a different mode of recognition and inexpensive enzyme-free assay platforms as an alternative to traditional enzyme-based immunoassays for the detection of other Gram-positive pathogenic bacteria.
Topics: Staphylococcus aureus; Colorimetry; Gold; Platinum; Limit of Detection; Porosity; Benzidines; Hydrogen Peroxide; Aptamers, Nucleotide; Metal Nanoparticles; Vancomycin; Biosensing Techniques; Catalysis; Humans
PubMed: 38951285
DOI: 10.1007/s00604-024-06460-8 -
Zhonghua Fu Chan Ke Za Zhi Jun 2024To investigate the effect of DNA methylation of laminin α3 (LAMA3) on the prognosis of platinum-resistant epithelial ovarian cancer (EOC) and its possible mechanism....
To investigate the effect of DNA methylation of laminin α3 (LAMA3) on the prognosis of platinum-resistant epithelial ovarian cancer (EOC) and its possible mechanism. (1) The relationship between DNA methylation of LAMA3 and platinum resistance in EOC was evaluated by bioinformatics. (2) A total of 67 EOC patients treated at Guangxi Medical University Cancer Hospital from January 2000 to December 2012 were selected to detect the levels of LAMA3 DNA methylation in EOC tissues using pyrophosphate sequencing technology to explore its diagnostic efficacy for platinum resistance and prognosis in EOC patients. Furthermore, its impact on chemotherapy efficacy and prognosis of platinum resistant EOC patients were also analyzed. (1) Ten proteins highly interacting with LAMA3 were screened from the Gene Interaction Retrieval Platform (STRING) database, including laminin β (LAMB) 3, laminin γ (LAMC) 3, integrin α (ITGA) 6, intestine protein β4 (ITGB4), ITGA3, LAMC1,LAMB2, dystrophin associated glycoprotein 1 (DAG1), LAMB1 and cytochrome P450c17α (COL17A1) protein; kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that LAMA3 and its related interacting proteins participate in the regulation of malignant tumor occurrence and development through signaling pathways such as apoptosis, cell cycle, DNA damage response, epithelial mesenchymal transition (EMT), androgen receptor (AR), estrogen receptor (ER), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt), RAS/mitogen activated protein kinase (MAPK), receptor tyrosine kinase (RTK), tuberous sclerosis protein complex (TSC)/mammalian target of rapamycin (mTOR), and their expression levels were related to the sensitivity of chemotherapy drugs such as cisplatin in EOC. (2) Our clinical data analysis found that the LAMA3 DNA methylation level in EOC tissue of the platinum-sensitive group (35 cases) was 71% (25/35), which was higher than 69% (22/32) in the platinum-resistant group (32 cases), with statistically insignificant difference (=0.057, =0.811). The area under the curve (AUC) of LAMA3 DNA methylation level for assessing platinum resistance in EOC was 0.601, and the AUC for predicting EOC patient prognosis was 0.686. The chemotherapy efficacy of EOC patients with high methylation of LAMA3 DNA was worse than that of patients with low methylation, 50% (12/24) vs 15/15, with statistically significant difference (=10.833, =0.001). The level of LAMA3 DNA methylation had a significant impact on the progression free survival and overall survival of EOC patients (both <0.05). The level of LAMA3 DNA methylation has certain diagnostic and predictive value for platinum resistance and prognosis in EOC patients, which may be closely related to the regulatory mechanism, platinum resistance and prognosis of EOC.
Topics: Humans; Female; Laminin; DNA Methylation; Drug Resistance, Neoplasm; Computational Biology; Carcinoma, Ovarian Epithelial; Prognosis; Ovarian Neoplasms; Gene Expression Regulation, Neoplastic; Antineoplastic Agents; Platinum; Signal Transduction
PubMed: 38951081
DOI: 10.3760/cma.j.cn112141-20240201-00069 -
International Journal of Gynecological... Jul 2024To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study.
METHODS
In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, /homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021).
RESULTS
Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with - and -mutated/homologous recombination-deficient tumors or wild-type/not determined/homologous recombination-deficient tumors (vs wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions).
CONCLUSIONS
The hypothesis-generating results of this analysis suggest that mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy.
TRIAL REGISTRATION NUMBER
NCT02655016.
Topics: Humans; Female; Indazoles; Piperidines; Progression-Free Survival; Ovarian Neoplasms; Middle Aged; Poly(ADP-ribose) Polymerase Inhibitors; Adult; Aged
PubMed: 38950925
DOI: 10.1136/ijgc-2024-005356 -
International Journal of Gynecological... Jun 2024Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique... (Review)
Review
Low-grade serous ovarian cancer was previously thought to be a subtype of high-grade serous ovarian cancer, but it is now recognized as a distinct disease with unique clinical and molecular behaviors. The disease may arise de novo or develop from a serous borderline ovarian tumor. Although it is more indolent than high-grade serous ovarian cancer, most patients have advanced metastatic disease at diagnosis and recurrence is common. Recurrent low-grade serous ovarian cancer is often resistant to standard platinum-taxane chemotherapy, making it difficult to treat with the options currently available. New targeted therapies are needed, but their development is contingent on a deeper understanding of the specific biology of the disease. The known molecular drivers of low-grade tumors are strong hormone receptor expression, mutations in the mitogen-activated protein kinase (MAPK) pathway (, , and ), and in genes related to the MAPK pathway (, and ). However, MAPK inhibitors have shown only modest clinical responses. Based on the discovery of mutations in low-grade serous ovarian cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are now being tested in clinical trials in combination with hormone therapy. Additional mutations seen in a smaller population of low-grade tumors include , and but no specific therapies targeting them have been tested clinically. This review summarizes the clinical, pathologic, and molecular features of low-grade serous ovarian cancer as they are now understood and introduces potential therapeutic targets and new avenues for research.
PubMed: 38950921
DOI: 10.1136/ijgc-2024-005305 -
Cancer Research Communications Jul 2024Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by...
Myristoylation is a type of protein acylation by which the fatty acid myristate is added to the N-terminus of target proteins, a process mediated by N-myristoyltransferases. Myristoylation is emerging as a promising cancer therapeutic target, however the molecular determinants of sensitivity to N-myristoyltransferase inhibition or the mechanism by which it induces cancer cell death are not completely understood. We report that N-myristoyltransferases are a novel therapeutic target in lung carcinoma cells with LKB1 and/or KEAP1 mutations in a KRAS mutant background. Inhibition of myristoylation decreases cell viability in vitro and tumor growth in vivo. Inhibition of myristoylation causes mitochondrial ferrous iron overload, oxidative stress, elevated protein poly (ADP)-ribosylation and death by parthanatos. Furthermore, NMT inhibitors sensitized lung carcinoma cells to platinum-based chemotherapy. Unexpectedly, the mitochondrial transporter Translocase of Inner Mitochondrial Membrane 17 homologue A (TIM17A) is a critical target of myristoylation inhibitors in these cells. TIM17A silencing recapitulated the effects of NMT inhibition at inducing mitochondrial ferrous iron overload and parthanatos. Furthermore, sensitivity of lung carcinoma cells to myristoylation inhibition correlated with their dependency on TIM17A. This study reveals the unexpected connection between protein myristoylation, the mitochondrial import machinery, and iron homeostasis. It also uncovers myristoylation inhibitors as novel inducers of parthanatos in cancer, and the novel axis N-myristoyltransferase-TIM17A as a potential therapeutic target in highly aggressive lung carcinomas.
PubMed: 38949950
DOI: 10.1158/2767-9764.CRC-23-0428 -
Environmental Monitoring and Assessment Jun 2024We assessed the hydrochemistry of 15 watersheds in the Halton Region, southern Ontario, in high resolution (n > 500 samples across n > 40 streams) to...
We assessed the hydrochemistry of 15 watersheds in the Halton Region, southern Ontario, in high resolution (n > 500 samples across n > 40 streams) to characterize water quality dynamics and governing controls on major and trace element concentrations in this rapidly urbanizing region. In 2022, major water quality parameters were generally in line with historic monitoring data yet significantly different across catchments, e.g., in specific conductance, turbidity, phosphate and chloride, and trace element concentrations. Distinct hydrochemical signatures were observed between urban and rural creeks, with urban stream sections and sites near the river mouths close to Lake Ontario having consistently higher chloride (up to 700 mg/L) and occasional enrichment in nutrients levels (up to 8 and 20 mg/L phosphate and nitrate, respectively). Particularly upper reaches exhibited hydrochemical signatures that were reflective of the catchment surface lithologies, for instance through higher dissolved Ca to Mg ratios. Unlike for chloride and phosphate, provincial water quality guidelines for trace elements and heavy metals were seldom surpassed (on < 10 occasions for copper, zinc, cadmium, and uranium). Concentrations of other trace elements (e.g., platinum group elements or rare earth elements) were expectedly low (< 0.3 µg/L) but showed spatiotemporal concentration patterns and concentration-discharge dynamics different from those of the major water quality parameters. Our results help improve the understanding of surface water conditions within Halton's regional Natural Heritage Systems and demonstrate how enhanced environmental monitoring can deliver actionable information for watershed decision-making.
Topics: Environmental Monitoring; Ontario; Water Pollutants, Chemical; Water Quality; Rivers; Trace Elements; Metals, Heavy; Chlorides; Water Pollution, Chemical
PubMed: 38949676
DOI: 10.1007/s10661-024-12833-6 -
Several common methods of making vesicles (except an emulsion method) capture intended lipid ratios.BioRxiv : the Preprint Server For... Jun 2024Researchers choose different methods of making giant unilamellar vesicles in order to satisfy different constraints of their experimental designs. A challenge of using a...
UNLABELLED
Researchers choose different methods of making giant unilamellar vesicles in order to satisfy different constraints of their experimental designs. A challenge of using a variety of methods is that each may produce vesicles of different lipid compositions, even if all vesicles are made from a common stock mixture. Here, we use mass spectrometry to investigate ratios of lipids in vesicles made by five common methods: electroformation on indium tin oxide slides, electroformation on platinum wires, gentle hydration, emulsion transfer, and extrusion. We made vesicles from either 5-component or binary mixtures of lipids chosen to span a wide range of physical properties: di(18:1)PC, di(16:0)PC, di(18:1)PG, di(12:0)PE, and cholesterol. For a mixture of all five of these lipids, ITO electroformation, Pt electroformation, gentle hydration, and extrusion methods result in only minor shifts (≤ 5 mol%) in lipid ratios of vesicles relative to a common stock solution. In contrast, emulsion transfer results in ∼80% less cholesterol than expected from the stock solution, which is counterbalanced by a surprising overabundance of saturated PC-lipid relative to all other phospholipids. Experiments using binary mixtures of some of the lipids largely support results from the 5-component mixture. Exact values of lipid ratios variations likely depend on the details of each method, so a broader conclusion is that experiments that increment lipid ratios in small steps will be highly sensitive to the method of lipid formation and to sample-to-sample variations, which are low (roughly ±2 mol% in the 5-component mixture and either scale proportionally with increasing mole fraction or remain low). Experiments that increment lipid ratios in larger steps or that seek to explain general trends or new phenomena will be less sensitive to the method used.
SIGNIFICANCE STATEMENT
Small changes to the amounts and types of lipids in membranes can drastically affect the membrane's behavior. Unfortunately, it is unknown whether (or to what extent) different methods of making vesicles alter the ratios of lipids in membranes, even when identical stock solutions are used. This presents challenges for researchers when comparing data with colleagues who use different methods. Here, we measure ratios of lipid types in vesicle membranes produced by five methods. We assess each method's reproducibility and compare resulting vesicle compositions across methods. In doing so, we provide a quantitative basis that the scientific community can use to estimate whether differences between their results can be simply attributed to differences between methods or to sample-to-sample variations.
PubMed: 38948736
DOI: 10.1101/2024.02.21.581444 -
Frontiers in Pharmacology 2024Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that... (Review)
Review
Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that treated patients have a high risk of disease recurrence. Moreover, ovarian cancer is very diverse in terms of molecular, histological features and mutations. Many patients may also develop platinum resistance, resulting in poor response to subsequent lines of treatment. To improve the prognosis of patients with ovarian cancer, it is expected to make better existing and implement new, promising treatment methods. Targeted therapies seem very promising. Currently, bevacizumab - a VEGF inhibitor and therapy with olaparib - a polyADP-ribose polymerase inhibitor are approved. Other methods worth considering in the future include: folate receptor α, immune checkpoints or other immunotherapy methods. To improve the treatment of ovarian cancer, it is also important to ameliorate the determination of molecular features to describe and understand which group of patients will benefit most from a given treatment method. This is important because a larger group of patients treated for ovarian cancer can have a greater chance of surviving longer without recurrence.
PubMed: 38948462
DOI: 10.3389/fphar.2024.1416555