-
Cureus May 2024Triple-negative breast cancer poses distinct challenges because it lacks hormone receptors and does not have human epidermal growth factor receptor 2 (HER2)...
Triple-negative breast cancer poses distinct challenges because it lacks hormone receptors and does not have human epidermal growth factor receptor 2 (HER2) amplification. Mutations in BRCA1/2 genes are associated with homologous recombination deficiency tumors, rendering them susceptible to poly (ADP-ribose) polymerase (PARP) inhibitors. Notably, germline BRCA1/2 mutations are linked to distinct clinical features, including an increased risk of triple-negative breast cancer (TNBC) and a younger age of onset. PARP inhibitors such as olaparib and talazoparib have demonstrated efficacy in patients with BRCA mutations, leading to FDA approvals for ovarian and breast cancers. However, there remains limited data on PARP inhibitor response rates in patients with somatic BRCA mutations. This case series demonstrates the use of rucaparib in metastatic breast cancer patients harboring both germline and somatic BRCA1/2 mutations, discussing the advancing landscape of targeted therapies in breast cancer management. In the first case, despite undergoing anthracycline-based chemotherapy followed by hormonal therapy, disease progression ensued. However, transitioning to rucaparib yielded a remarkable complete response lasting over two years, highlighting its efficacy in this clinical setting. Similarly, in the second case, rucaparib demonstrated effectiveness as a maintenance therapy subsequent to achieving a near-complete response to taxane and platinum-based treatment. These findings emphasize the promising role of rucaparib in managing metastatic breast cancer in patients with BRCA1/2 mutations, further contributing to the expanding armamentarium of targeted therapies in breast cancer care.
PubMed: 38910707
DOI: 10.7759/cureus.60963 -
Journal of Experimental & Clinical... Jun 2024
PubMed: 38907260
DOI: 10.1186/s13046-024-03102-y -
Science Advances Jun 2024For decades, there has been debate surrounding the transport of dense metal-rich sulfide liquid in mafic magmas. This topic is crucial to understanding the genesis of...
For decades, there has been debate surrounding the transport of dense metal-rich sulfide liquid in mafic magmas. This topic is crucial to understanding the genesis of valuable resources of nickel, copper, and platinum-group elements, which are essential for a sustainable, emission-free energy future. Recent studies of mineralized mafic magmas suggested that gas bubbles adhere to sulfide globules, reducing their density and favoring upward transport. While this hypothesis may explain sulfide mobility in near-surface magmatic environments, it is at odds with key mineralogic and textural observations and does not explain how long-distance sulfide transport operates. Here, we suggest an alternative hypothesis that builds on previous observations, focusing on the interaction between carbonate melt and sulfide liquid. We demonstrate experimentally that carbonate melt wraps sulfide globules forming a relatively mobile pair that may mediate metal-rich sulfide transport from mantle to crust.
PubMed: 38905350
DOI: 10.1126/sciadv.adl3127 -
Asian Journal of Pharmaceutical Sciences Jun 2024Flare and multiple recurrences pose significant challenges in gouty arthritis. Traditional treatments provide temporary relief from inflammation but fail to promptly...
Flare and multiple recurrences pose significant challenges in gouty arthritis. Traditional treatments provide temporary relief from inflammation but fail to promptly alleviate patient pain or effectively prevent subsequent recurrences. It should also be noted that both anti-inflammation and metabolism of uric acid are necessary for gouty arthritis, calling for therapeutic systems to achieve these two goals simultaneously. In this study, we propose a biomimetic integrated nanozyme, HMPB-Pt@MM, comprising platinum nanozyme and hollow Prussian blue. It demonstrates anti-inflammatory properties by eliminating reactive oxygen species and reducing infiltration of inflammatory macrophages. Additionally, it rapidly targets inflamed ankles through the camouflage of macrophage membranes. Furthermore, HMPB-Pt@MM exhibits urate oxidase-like capabilities, continuously metabolizing locally elevated uric acid concentrations, ultimately inhibiting multiple recurrences of gouty arthritis. In summary, HMPB-Pt@MM integrates ROS clearance with uric acid metabolism, offering a promising platform for the treatment of gouty arthritis.
PubMed: 38903129
DOI: 10.1016/j.ajps.2024.100913 -
Journal of Nanobiotechnology Jun 2024Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection...
BACKGROUND
Cancer recurrence following surgical resection is a major cause of treatment failure. Finding effective methods to prevent postoperative recurrence and wound infection is an important component of successful surgery. With the development of new nanotechnology, more treatment options have been provided for postoperative adjuvant therapy. This study presents an innovative hydrogel system that stimulates tumoricidal immunity after surgical resection of non-small cell lung cancer (NSCLC) and prevents cancer relapse.
RESULTS
The hydrogel system is based on the excellent photothermal conversion performance of single-atom platinum (CN-Pt) along with the delivery and release of the chemotherapy drug, gemcitabine (GEM). The system is coated onto the wound surface after tumor removal with subsequent near-infrared (NIR) photothermal therapy, which efficiently induces necroptosis of residual cancer cells, amplifies the levels of damage-associated molecular patterns (DAMPs), and increases the number of M1 macrophages. The significantly higher levels of phagocytic macrophages enhance tumor immunogenicity and sensitize cancer cells to CD8 + T-cell immunity to control postoperative recurrence, which has been verified using an animal model of postoperative lung cancer recurrence. The CN-Pt-GEM-hydrogel with NIR can also inhibit postoperative wound infection.
CONCLUSIONS
These findings introduce an alternative strategy for supplementing antitumor immunity in patients undergoing resection of NSCLC tumors. The CN-Pt-GEM-hydrogel with the NIR system also exhibits good biosafety and may be adaptable for clinical application in relation to tumor resection surgery, wound tissue filling, infection prevention, and recurrence prevention.
Topics: Animals; Lung Neoplasms; Mice; Deoxycytidine; Hydrogels; Gemcitabine; Humans; Carcinoma, Non-Small-Cell Lung; Necroptosis; Neoplasm Recurrence, Local; Cell Line, Tumor; Immunotherapy; Photothermal Therapy; Wound Infection; Macrophages; Mice, Inbred C57BL; CD8-Positive T-Lymphocytes
PubMed: 38902678
DOI: 10.1186/s12951-024-02568-4 -
MSystems Jun 2024Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis....
Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both and . Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.
PubMed: 38899930
DOI: 10.1128/msystems.01301-23 -
Cancer Medicine Jun 2024Nivolumab was approved for the treatment of advanced gastric cancer in 2017 in Japan. The aim of this study was to assess the impact of nivolumab in a real-world...
BACKGROUND
Nivolumab was approved for the treatment of advanced gastric cancer in 2017 in Japan. The aim of this study was to assess the impact of nivolumab in a real-world clinical setting.
METHODS
This single-institutional retrospective study included patients with advanced gastric or esophagogastric junction adenocarcinoma and a history of first-line chemotherapy with platinum-based doublet or triplet regimens between 2010 and 2020. To assess the impact of nivolumab on survival, the patients were divided based on the year of nivolumab approval into a pre-2017 (2010-2016) group and a post-2017 (2017-2020) group.
RESULTS
From a total of 1918 patients, 1093 were excluded. There were 533 patients in the pre-2017 group and 292 in the post-2017 group. Immune checkpoint inhibitors were used significantly more often in the post-2017 group than in the pre-2017 group (8.6% vs. 47.9%). Median overall survival was significantly longer in the post-2017 group (16.9 vs. 13.9 months; hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.63-0.90; p < 0.01). The proportion of patients transitioning to third-line treatment was higher in the post-2017 group than in the pre-2017 group (56.3% vs. 43.8%, p < 0.01). Median survival outcomes following progression on second-line treatment were significantly longer in the post-2017 group (4.3 vs. 3.2 months; HR 0.70, 95% CI 0.57-0.86; p < 0.01).
CONCLUSION
The proportion of patients transitioning to third-line treatment and survival outcomes following progression on second-line treatment have improved since the approval of nivolumab. This drug might help to prolong overall survival in real-world practice.
Topics: Humans; Stomach Neoplasms; Immune Checkpoint Inhibitors; Male; Female; Aged; Japan; Retrospective Studies; Middle Aged; Nivolumab; Adenocarcinoma; Aged, 80 and over; Adult; Antineoplastic Combined Chemotherapy Protocols; Esophagogastric Junction; Treatment Outcome
PubMed: 38899745
DOI: 10.1002/cam4.7401 -
Cell Death & Disease Jun 2024Platinum-based chemotherapy is the standard postoperative adjuvant treatment for ovarian cancer (OC). Despite the initial response to chemotherapy, 85% of advanced OC...
Platinum-based chemotherapy is the standard postoperative adjuvant treatment for ovarian cancer (OC). Despite the initial response to chemotherapy, 85% of advanced OC patients will have recurrent disease. Relapsed disease and platinum resistance are the major causes of death in OC patients. In this study, we compared the global regulation of alternative polyadenylation (APA) in platinum-resistant and platinum-sensitive tissues of OC patients by analyzing a set of single-cell RNA sequencing (scRNA-seq) data from public databases and found that platinum-resistant patients exhibited global 3' untranslated region (UTR) shortening due to the different usage of polyadenylation sites (PASs). The APA regulator CSTF3 was the most significantly upregulated gene in epithelial cells of platinum-resistant OC. CSTF3 knockdown increased the sensitivity of OC cells to platinum. The lncRNA NEAT1 has two isoforms, short (NEAT1_1) and long (NEAT1_2) transcript, because of the APA processing in 3'UTR. We found that CSTF3 knockdown reduced the usage of NEAT1 proximal PAS to lengthen the transcript and facilitate the expression of NEAT1_2. Downregulation of the expression of NEAT1 (NEAT1_1/_2), but not only NEAT1_2, also increased the sensitivity of OC cells to platinum. Overexpressed NEAT1_1 reversed the platinum resistance of OC cells after knocking down CSTF3 expression. Furthermore, downregulated expression of CSTF3 and NEAT1_1, rather than NEAT1_2, was positively correlated with inactivation of the PI3K/AKT/mTOR pathway in OC cells. Together, our findings revealed a novel mechanism of APA regulation in platinum-resistant OC. CSTF3 directly bound downstream of the NEAT1 proximal PAS to generate the short isoform NEAT1_1 and was conducive to platinum resistance, which provides a potential biomarker and therapeutic strategy for platinum-resistant OC patients.
Topics: Humans; Female; RNA, Long Noncoding; Drug Resistance, Neoplasm; Ovarian Neoplasms; Polyadenylation; Cell Line, Tumor; Cleavage And Polyadenylation Specificity Factor; Gene Expression Regulation, Neoplastic; Animals; Platinum; Mice, Nude; Signal Transduction; Mice
PubMed: 38898019
DOI: 10.1038/s41419-024-06816-1 -
RSC Advances Jun 2024New Pd(ii) (C1), Pt(ii) (C2), and Ag(i) (C3) complexes derived from 3-acetylcoumarin benzoylhydrazone (HL) Schiff base were synthesized and characterized by FTIR, H NMR,...
Palladium(ii), platinum(ii), and silver(i) complexes with 3-acetylcoumarin benzoylhydrazone Schiff base: Synthesis, characterization, biomolecular interactions, cytotoxic activity, and computational studies.
New Pd(ii) (C1), Pt(ii) (C2), and Ag(i) (C3) complexes derived from 3-acetylcoumarin benzoylhydrazone (HL) Schiff base were synthesized and characterized by FTIR, H NMR, UV-visible spectroscopies along with elemental analysis (C, H, N), magnetic, molar conductivity measurements, and DFT calculations. The obtained results suggested that the ligand had different behaviors in the complexes: mono-negative tridentate (C1) and neutral tridentate (C2) as an ONO-donor and neutral bidentate (C3) as an ON-donor. Quantum chemistry calculations were performed to validate the stability of the suggested geometries and indicated that all the complexes possess tetra-coordinated metal ions. The binding affinity of all the compounds toward calf thymus (ctDNA), yeast (tRNA), and bovine serum albumin (BSA) was evaluated by absorption/emission spectral titration studies, which revealed the intercalative binding to ctDNA and tRNA and static binding upon complex formation with BSA. Molecular insights into the binding affinity of the characterized complexes were provided through conducting molecular docking analysis. Moreover, the cytotoxic activity () of the compounds was screened against human cancerous cell lines and a non-cancerous lung fibroblast (WI38) one using cis-platin as a reference drug. The IC and selective index (SI) values indicated the higher cytotoxic activity of all the metal complexes compared to their parent ligand. Among all the compounds, the complex C2 showed the highest activity. These results confirmed the improvement of the anticancer activity of the ligand by incorporating the metal ions. In addition, flow cytometry results showed that complexes C1 and C2 induced cell cycle arrest at S and G1/S, respectively.
PubMed: 38895519
DOI: 10.1039/d4ra02738h -
Frontiers in Oncology 2024Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors,... (Review)
Review
Approximately 50% of tubo-ovarian high-grade serous carcinomas (HGSCs) have functional homologous recombination-mediated (HR) DNA repair, so-called HR-proficient tumors, which are often associated with primary platinum resistance (relapse within six months after completion of first-line therapy), minimal benefit from poly(ADP-ribose) polymerase (PARP) inhibitors, and shorter survival. HR-proficient tumors comprise multiple molecular subtypes including cases with amplification, amplification or alteration, and are often characterized as "cold" tumors with fewer infiltrating lymphocytes and decreased expression of PD-1/PD-L1. Several new treatment approaches aim to manipulate these negative prognostic features and render HR-proficient tumors more susceptible to treatment. Alterations in multiple different molecules and pathways in the DNA damage response are driving new drug development to target HR-proficient cancer cells, such as inhibitors of the CDK or P13K/AKT pathways, as well as ATR inhibitors. Treatment combinations with chemotherapy or PARP inhibitors and agents targeting DNA replication stress have shown promising preclinical and clinical results. New approaches in immunotherapy are also being explored, including vaccines or antibody drug conjugates. Many approaches are still in the early stages of development and further clinical trials will determine their clinical relevance. There is a need to include HR-proficient tumors in ovarian cancer trials and to analyze them in a more targeted manner to provide further evidence for their specific therapy, as this will be crucial in improving the overall prognosis of HGSC and ovarian cancer in general.
PubMed: 38894867
DOI: 10.3389/fonc.2024.1387281