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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 -
Communications Biology Jun 2024AMPK is a well-known energy sensor regulating cellular metabolism. Metabolic disorders such as obesity and diabetes are considered detrimental factors that reduce...
AMPK is a well-known energy sensor regulating cellular metabolism. Metabolic disorders such as obesity and diabetes are considered detrimental factors that reduce fecundity. Here, we show that pharmacologically induced in vitro activation (by metformin) or inhibition (by dorsomorphin) of the AMPK pathway inhibits or promotes activation of ovarian primordial follicles in cultured murine ovaries and human ovarian cortical chips. In mice, activation of primordial follicles in dorsomorphin in vitro-treated ovaries reduces AMPK activation and upregulates Wnt and FOXO genes, which, interestingly, is associated with decreased phosphorylation of β-catenin. The dorsomorphin-treated ovaries remain of high quality, with no detectable difference in reactive oxygen species production, apoptosis or mitochondrial cytochrome c oxidase activity, suggesting safe activation. Subsequent maturation of in vitro-treated follicles, using a 3D alginate cell culture system, results in mature metaphase eggs with protruding polar bodies. These findings demonstrate that the AMPK pathway can safely regulate primordial follicles by modulating Wnt and FOXO genes, and reduce β-catenin phosphorylation.
Topics: Animals; Female; Mice; Ovarian Follicle; AMP-Activated Protein Kinases; Pyrimidines; Pyrazoles; Humans; Up-Regulation; Forkhead Transcription Factors; Wnt Proteins; beta Catenin; Phosphorylation; Mice, Inbred C57BL; Metformin; Wnt Signaling Pathway
PubMed: 38902324
DOI: 10.1038/s42003-024-06418-9 -
Nature Communications Jun 2024Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9...
Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.
Topics: Pancreatic Neoplasms; Humans; Animals; CRISPR-Cas Systems; Mice; Cell Line, Tumor; Ubiquitin-Specific Proteases; Mutation; Gene Expression Regulation, Neoplastic; Deoxycytidine; Gemcitabine
PubMed: 38902237
DOI: 10.1038/s41467-024-49450-3 -
Cell Death & Disease Jun 20245-Fluorouracil (5-FU) is the primary treatment option for advanced gastric cancer. However, the current challenge lies in the absence of validated biomarkers to...
5-Fluorouracil (5-FU) is the primary treatment option for advanced gastric cancer. However, the current challenge lies in the absence of validated biomarkers to accurately predict the efficacy and sensitivity of 5-FU in individual patients. It has been confirmed that 5-FU can regulate tumor progression by promoting gasdermin E (GSDME, encoded by DFNA5) cleavage to induce pyroptosis. Lysine demethylase ALKBH4 has been shown to be upregulated in a variety of tumors to promote tumor progression. However, its role in gastric cancer is not clear. In this study, we observed a significant upregulation of ALKBH4 expression in gastric cancer tissues compared to adjacent normal tissues, indicating its potential as a predictor for the poor prognosis of gastric cancer patients. On the contrary, GSDME exhibits low expression levels in gastric cancer and demonstrates a negative correlation with poor prognosis among patients diagnosed with gastric cancer. In addition, we also found that high expression of ALKBH4 can inhibit pyroptosis and promote the proliferation of gastric cancer cells. Mechanistically, ALKBH4 inhibits GSDME activation at the transcriptional level by inhibiting H3K4me3 histone modification in the GSDME promoter region, thereby reducing the sensitivity of gastric cancer cells to 5-FU treatment. These findings provide further insight into the regulatory mechanisms of ALKBH4 in the progression of gastric cancer and underscore its potential as a prognostic marker for predicting the sensitivity of gastric cancer cells to 5-FU treatment.
Topics: Humans; Stomach Neoplasms; Pyroptosis; Fluorouracil; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Animals; Mice; Male; Histones; Mice, Nude; Female; Drug Resistance, Neoplasm; Prognosis; Gasdermins
PubMed: 38902235
DOI: 10.1038/s41419-024-06832-1 -
Epigenetics Dec 2024Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia (SCA) caused by a polyglutamine expansion in the ataxin-3 protein, which initiates a cascade...
Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia (SCA) caused by a polyglutamine expansion in the ataxin-3 protein, which initiates a cascade of pathogenic events, including transcriptional dysregulation. Genotype-phenotype correlations in MJD are incomplete, suggesting an influence of additional factors, such as epigenetic modifications, underlying the MJD pathogenesis. DNA methylation is known to impact the pathophysiology of neurodegenerative disorders through gene expression regulation and increased methylation has been reported for other SCAs. In this work we aimed to analyse global methylation in MJD carriers. Global 5-mC levels were quantified in blood samples of 33 MJD mutation carriers (patients and preclinical subjects) and 33 healthy controls, matched by age, sex, and smoking status. For a subset of 16 MJD subjects, a pilot follow-up analysis with two time points was also conducted. No differences were found in median global 5-mC levels between MJD mutation carriers and controls and no correlations between methylation levels and clinical or genetic variables were detected. Also, no alterations in global 5-mC levels were observed over time. Our findings do not support an increase in global blood methylation levels associated with MJD.
Topics: Humans; Machado-Joseph Disease; DNA Methylation; Male; Female; Adult; Middle Aged; Mutation; Heterozygote; Case-Control Studies; Ataxin-3; 5-Methylcytosine; Aged; Epigenesis, Genetic
PubMed: 38900099
DOI: 10.1080/15592294.2024.2368995 -
The New England Journal of Medicine Jun 2024The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but...
BACKGROUND
The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown.
METHODS
We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.
RESULTS
In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of and or (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.
CONCLUSIONS
Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Female; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Sulfonamides; Aged; Male; Bridged Bicyclo Compounds, Heterocyclic; Lenalidomide; Piperidines; Adult; Antibodies, Monoclonal, Humanized; Prednisone; Adenine; Aged, 80 and over; Recurrence; Pyrazoles; Pyrimidines; Molecular Targeted Therapy; Progression-Free Survival
PubMed: 38899693
DOI: 10.1056/NEJMoa2401532 -
BMJ (Clinical Research Ed.) Jun 2024To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Nab-paclitaxel, cisplatin, and capecitabine versus cisplatin and gemcitabine as first line chemotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma: randomised phase 3 clinical trial.
OBJECTIVE
To compare the effectiveness and safety of nab-paclitaxel, cisplatin, and capecitabine (nab-TPC) with gemcitabine and cisplatin as an alternative first line treatment option for recurrent or metastatic nasopharyngeal carcinoma.
DESIGN
Phase 3, open label, multicentre, randomised trial.
SETTING
Four hospitals located in China between September 2019 and August 2022.
PARTICIPANTS
Adults (≥18 years) with recurrent or metastatic nasopharyngeal carcinoma.
INTERVENTIONS
Patients were randomised in a 1:1 ratio to treatment with either nab-paclitaxel (200 g/m on day 1), cisplatin (60 mg/m on day 1), and capecitabine (1000 mg/m twice on days 1-14) or gemcitabine (1 g/m on days 1 and 8) and cisplatin (80 mg/m on day 1).
MAIN OUTCOME MEASURES
Progression-free survival was evaluated by the independent review committee as the primary endpoint in the intention-to-treat population.
RESULTS
The median follow-up was 15.8 months in the prespecified interim analysis (31 October 2022). As assessed by the independent review committee, the median progression-free survival was 11.3 (95% confidence interval 9.7 to 12.9) months in the nab-TPC cohort compared with 7.7 (6.5 to 9.0) months in the gemcitabine and cisplatin cohort. The hazard ratio was 0.43 (95% confidence interval 0.25 to 0.73; P=0.002). The objective response rate in the nab-TPC cohort was 83% (34/41) versus 63% (25/40) in the gemcitabine and cisplatin cohort (P=0.05), and the duration of response was 10.8 months in the nab-TPC cohort compared with 6.9 months in the gemcitabine and cisplatin cohort (P=0.009). Treatment related grade 3 or 4 adverse events, including leukopenia (4/41 (10%) 13/40 (33%); P=0.02), neutropenia (6/41 (15%) 16/40 (40%); P=0.01), and anaemia (1/41 (2%) 8/40 (20%); P=0.01), were higher in the gemcitabine and cisplatin cohort than in the nab-TPC cohort. No deaths related to treatment occurred in either treatment group. Survival and long term toxicity are still being evaluated with longer follow-up.
CONCLUSION
The nab-TPC regimen showed a superior antitumoural efficacy and favourable safety profile compared with gemcitabine and cisplatin for recurrent or metastatic nasopharyngeal carcinoma. Nab-TPC should be considered the standard first line treatment for recurrent or metastatic nasopharyngeal carcinoma. Longer follow-up is needed to confirm the benefits for overall survival.
TRIAL REGISTRATION
Chinese Clinical Trial Registry ChiCTR1900027112.
Topics: Humans; Cisplatin; Male; Middle Aged; Female; Gemcitabine; Nasopharyngeal Carcinoma; Deoxycytidine; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Adult; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Paclitaxel; Albumins; Aged; Progression-Free Survival; China; Neoplasm Metastasis
PubMed: 38897625
DOI: 10.1136/bmj-2023-077890 -
Science Advances Jun 2024Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells....
Pancreatic adenocarcinoma is the fourth leading cause of malignancy-related deaths, with rapid development of drug resistance driven by pancreatic cancer stem cells. However, the mechanisms sustaining stemness and chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we demonstrate that Bicaudal C homolog 1 (BICC1), an RNA binding protein regulating numerous cytoplasmic mRNAs, facilitates chemoresistance and stemness in PDAC. Mechanistically, BICC1 activated tryptophan catabolism in PDAC by up-regulating indoleamine 2,3-dioxygenase-1 (IDO1) expression, a tryptophan-catabolizing enzyme. Increased levels of tryptophan metabolites contribute to NAD synthesis and oxidative phosphorylation, leading to a stem cell-like phenotype. Blocking BICC1/IDO1/tryptophan metabolism signaling greatly improves the gemcitabine (GEM) efficacy in several PDAC models with high BICC1 level. These findings indicate that BICC1 is a critical tryptophan metabolism regulator that drives the stemness and chemoresistance of PDAC and thus a potential target for combinatorial therapeutic strategy against chemoresistance.
Topics: Tryptophan; Humans; Drug Resistance, Neoplasm; Neoplastic Stem Cells; Pancreatic Neoplasms; Cell Line, Tumor; Animals; Mice; Gene Expression Regulation, Neoplastic; Carcinoma, Pancreatic Ductal; Gemcitabine; Deoxycytidine; RNA-Binding Proteins; Indoleamine-Pyrrole 2,3,-Dioxygenase
PubMed: 38896624
DOI: 10.1126/sciadv.adj8650 -
Applied Microbiology and Biotechnology Jun 2024Chinese hamster ovary (CHO) cells are popular in the pharmaceutical industry for their ability to produce high concentrations of antibodies and their resemblance to...
Chinese hamster ovary (CHO) cells are popular in the pharmaceutical industry for their ability to produce high concentrations of antibodies and their resemblance to human cells in terms of protein glycosylation patterns. Current data indicate the relevance of CHO cells in the biopharmaceutical industry, with a high number of product commendations and a significant market share for monoclonal antibodies. To enhance the production capabilities of CHO cells, a deep understanding of their cellular and molecular composition is crucial. Genome sequencing and proteomic analysis have provided valuable insights into the impact of the bioprocessing conditions, productivity, and product quality. In our investigation, we conducted a comparative analysis of proteomic profiles in high and low monoclonal antibody-producing cell lines and studied the impact of tunicamycin (TM)-induced endoplasmic reticulum (ER) stress. We examined the expression levels of different proteins including unfolded protein response (UPR) target genes by using label-free quantification techniques for protein abundance. Our results show the upregulation of proteins associated with protein folding mechanisms in low producer vs. high producer cell line suggesting a form of ER stress related to specific protein production. Further, Hspa9 and Dnaja3 are notable candidates activated by the mitochondria UPR and play important roles in protein folding processes in mitochondria. We identified significant upregulation of Nedd8 and Lgmn proteins in similar levels which may contribute to UPR stress. Interestingly, the downregulation of Hspa5/Bip and Pdia4 in response to tunicamycin treatment suggests a low-level UPR activation. KEY POINTS: • Proteome profiling of recombinant CHO cells under mild TM treatment. • Identified protein clusters are associated with the unfolded protein response (UPR). • The compared cell lines revealed noticeable disparities in protein expression levels.
Topics: CHO Cells; Cricetulus; Tunicamycin; Animals; Antibodies, Monoclonal; Proteomics; Endoplasmic Reticulum Stress; Unfolded Protein Response; Proteome; Cricetinae
PubMed: 38896138
DOI: 10.1007/s00253-024-13223-1 -
Clinical Cardiology Jun 2024Statins are lipid-lowering drugs with favorable anti-inflammatory effects. This study aimed to explore different statin-based lipid-lowering strategies to reduce... (Comparative Study)
Comparative Study
BACKGROUND
Statins are lipid-lowering drugs with favorable anti-inflammatory effects. This study aimed to explore different statin-based lipid-lowering strategies to reduce high-sensitivity C-reactive protein (hs-CRP).
HYPOTHESIS
The hypothesis is that different statin-based lipid-lowering strategies might reduce hs-CRP.
METHODS
This retrospective study included 3653 patients who underwent percutaneous coronary intervention (PCI). Three statin-based lipid-lowering strategies were investigated, including different types of statins (atorvastatin vs. rosuvastatin), statin combined with ezetimibe therapy (vs. without), and intensive statin therapy (vs. regular). The hs-CRP levels and blood lipid indicators were measured at baseline and after 1-month lipid-lowering therapy. Multivariable linear regression analysis and structural equation mode analysis were conducted to verify the association between different lipid-lowering strategies, Δhs-CRP (%) and ΔLDL-C (%).
RESULTS
Totally, 3653 patients were enrolled with an average age of 63.81 years. Multivariable linear regression demonstrated that statin combined with ezetimibe therapy was significantly associated with decreased Δhs-CRP (%) (β = -0.253, 95% CI: [-0.501 to -0.005], p = 0.045). The increased ΔLDL-C (%) was an independent predictor of elevated levels of Δhs-CRP (%) (β = 0.487, 95% CI: [0.15-0.824], p = 0.005). Furthermore, structural equation model analysis proved that statin combined with ezetimibe therapy (β = -0.300, p < 0.001) and intensive statin therapy (β = -0.032, p = 0.043) had an indirect negative effect on Δhs-CRP via ΔLDL-C.
CONCLUSIONS
Compared with routine statin use, statin combined with ezetimibe therapy and intensive statin therapy could further reduce hs-CRP levels.
Topics: Humans; Male; Retrospective Studies; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; C-Reactive Protein; Coronary Artery Disease; Middle Aged; Biomarkers; Treatment Outcome; Percutaneous Coronary Intervention; Ezetimibe; Drug Therapy, Combination; Aged; Rosuvastatin Calcium; Atorvastatin; Cholesterol, LDL; Anticholesteremic Agents; Dyslipidemias
PubMed: 38895772
DOI: 10.1002/clc.24301