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ESMO Open Jun 2024Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a...
BACKGROUND
Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
PATIENTS AND METHODS
Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
RESULTS
Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
CONCLUSIONS
The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
Topics: Humans; Paclitaxel; Female; Middle Aged; Aged; Neoplasms; Male; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Taxoids; Maximum Tolerated Dose; Syk Kinase
PubMed: 38914452
DOI: 10.1016/j.esmoop.2024.103486 -
Epigenetics Dec 2024Lung cancer is one familiar cancer that threatens the lives of humans. circCTNNB1 has been disclosed to have regulatory functions in some diseases. However, the...
Lung cancer is one familiar cancer that threatens the lives of humans. circCTNNB1 has been disclosed to have regulatory functions in some diseases. However, the functions and related regulatory mechanisms of circCTNNB1 in lung cancer remain largely indistinct. The mRNA and protein expression levels were examined through real-time polymerase chain reaction (RT-qPCR) and western blot. The cell proliferation was tested through CCK-8 assay. The cell migration and invasion were confirmed through Transwell assays. The cell senescence was evaluated through SA-β-gal assay. The binding ability between miR-186-5p and circCTNNB1 (or YY1) was verified through luciferase reporter and RIP assays. In this study, the higher expression of circCTNNB1 was discovered in lung cancer tissues and cell lines and resulted in poor prognosis. In addition, circCTNNB1 facilitated lung cancer cell proliferation, migration, invasion, and suppressed cell senescence. Knockdown of circCTNNB1 retarded the Wnt pathway. Mechanism-related experiments revealed that circCTNNB1 combined with miR-186-5p to target YY1. Through rescue assays, YY1 overexpression could rescue decreased cell proliferation, migration, invasion, increased cell senescence, and retarded Wnt pathway mediated by circCTNNB1 suppression. Furthermore, YY1 acts as a transcription factor that can transcriptionally activate circCTNNB1 to form YY1/circCTNNB1/miR-186-5p/YY1 positive loop. Through in vivo assays, circCTNNB1 accelerated tumour growth in vivo. All findings revealed that a positive loop YY1/circCTNNB1/miR-186-5p/YY1 aggravated lung cancer progression by modulating the Wnt pathway.
Topics: YY1 Transcription Factor; Humans; MicroRNAs; Lung Neoplasms; Wnt Signaling Pathway; Cell Proliferation; Animals; Cell Line, Tumor; RNA, Circular; Cell Movement; Mice; Gene Expression Regulation, Neoplastic; Mice, Nude; Male; Disease Progression; Female; A549 Cells
PubMed: 38913848
DOI: 10.1080/15592294.2024.2369006 -
PloS One 2024Pulmonary fibrosis (PF) is a common interstitial pneumonia disease, also occurred in post-COVID-19 survivors. The mechanism underlying the anti-PF effect of Qing Fei Hua...
BACKGROUND
Pulmonary fibrosis (PF) is a common interstitial pneumonia disease, also occurred in post-COVID-19 survivors. The mechanism underlying the anti-PF effect of Qing Fei Hua Xian Decotion (QFHXD), a traditional Chinese medicine formula applied for treating PF in COVID-19 survivors, is unclear. This study aimed to uncover the mechanisms related to the anti-PF effect of QFHXD through analysis of network pharmacology and experimental verification.
METHODS
The candidate chemical compounds of QFHXD and its putative targets for treating PF were achieved from public databases, thereby we established the corresponding "herb-compound-target" network of QFHXD. The protein-protein interaction network of potential targets was also constructed to screen the core targets. Furthermore, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to predict targets, and pathways, then validated by in vivo experiments.
RESULTS
A total of 188 active compounds in QFHXD and 50 target genes were identified from databases. The key therapeutic targets of QFHXD, such as PI3K/Akt, IL-6, TNF, IL-1β, STAT3, MMP-9, and TGF-β1 were identified by KEGG and GO analysis. Anti-PF effects of QFHXD (in a dose-dependent manner) and prednisone were confirmed by HE, Masson staining, and Sirius red staining as well as in vivo Micro-CT and immunohistochemical analysis in a rat model of bleomycin-induced PF. Besides, QFXHD remarkably inhibits the activity of PI3K/Akt/NF-κB and TGF-β1/Smad2/3.
CONCLUSIONS
QFXHD significantly attenuated bleomycin-induced PF via inhibiting inflammation and epithelial-mesenchymal transition. PI3K/Akt/NF-κB and TGF-β1/Smad2/3 pathways might be the potential therapeutic effects of QFHXD for treating PF.
Topics: Pulmonary Fibrosis; Drugs, Chinese Herbal; Animals; Rats; Male; Network Pharmacology; Protein Interaction Maps; Bleomycin; Transforming Growth Factor beta1; Rats, Sprague-Dawley; Signal Transduction; Humans; COVID-19; Epithelial-Mesenchymal Transition; Medicine, Chinese Traditional; COVID-19 Drug Treatment
PubMed: 38913698
DOI: 10.1371/journal.pone.0305903 -
PloS One 2024Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Stroke stands as a significant macrovascular complication among individuals with Type 2 diabetes mellitus (T2DM), often resulting in the primary cause of mortality and disability within this patient demographic. Presently, numerous studies have been conducted to investigate the underlying causes of stroke in individuals with T2DM, yet the findings exhibit inconsistencies.
OBJECTIVE
This paper aims to consolidate and summarize the available evidence concerning the influential factors contributing to stroke among patients diagnosed with T2DM.
METHODS
We conducted a comprehensive search across multiple databases, including Cochrane Library, PubMed, Web Of Science, Embase, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Weipu up to August 2023. Google Scholar was also searched to retrieve gray literature. We calculated odds ratios (OR) and 95% confidence intervals (CI) using Stata software.
RESULTS
Our analysis encompassed 43 observational studies, exploring factors across sociodemographic, biochemical, complications, and hypoglycemic agent categories. The findings identified several risk factors for stroke in patients with T2DM: age, gender, T2DM duration, hypertension, body-mass index (BMI), smoking, Glycated hemoglobin (HbA1c), estimated Glomerular Filtration Rate (eGFR), albuminuria, Triglycerides (TG), Low density lipoprotein cholesterol (LDL-C), Coronary heart disease (CHD), Atrial fibrillation (AF), diabetic retinopathy (DR), Peripheral vascular disease (PVD), and carotid plaque. Conversely, exercise, High density lipoprotein cholesterol (HDL-C), metformin (MET), pioglitazone, and metformin combination therapy emerged as protective factors.
CONCLUSION
This study underscores the multitude of influencing factors contributing to stroke in people with T2DM patients, among which the microvascular complications of T2DM play an most important role. Therefore, we emphasize the importance of screening for microvascular complications in patients with T2DM. However, due to limitations arising from the number of articles reviewed, there remain areas where clarity is lacking. Further research efforts are warranted to expand upon and reinforce our current findings.
Topics: Diabetes Mellitus, Type 2; Humans; Stroke; Risk Factors; Hypoglycemic Agents; Glycated Hemoglobin
PubMed: 38913694
DOI: 10.1371/journal.pone.0305954 -
PloS One 2024Non-alcoholic fatty liver disease (NAFLD) is independently associated with atrial fibrillation (AF) risk. The uric acid (UA) to high-density lipoprotein cholesterol...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is independently associated with atrial fibrillation (AF) risk. The uric acid (UA) to high-density lipoprotein cholesterol (HDL-C) ratio (UHR) has been shown to be closely associated with cardiovascular disease (CVD) and NAFLD. The aim of this study is to clarify whether elevated UHR is associated with the occurrence of AF in patients with NAFLD and to determine whether UHR predicted AF.
METHODS
Patients diagnosed with NAFLD in the Department of Cardiovascular Medicine of the Second Hospital of Shanxi Medical University from January 1, 2020, to December 31, 2021, were retrospectively enrolled in this study. The study subjects were categorized into AF group and non-AF group based on the presence or absence of combined AF. Logistic regression was performed to evaluate the correlation between UHR and AF. Sensitivity analysis and subgroup interaction analysis were performed to verify the robustness of the study results. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff value for UHR to predict the development of AF in patients with NAFLD.
RESULTS
A total of 421 patients with NAFLD were included, including 171 in the AF group and 250 in the non-AF group. In the univariate regression analysis, NAFLD patients with higher UHR were more likely to experience AF, and the risk of AF persisted after confounding factors were adjusted for (OR: 1.010, 95%CI: 1.007-1.013, P<0.001). AF risk increased with increasing UHR quartile (P for trend < 0.001). Despite normal serum UA and HDL-C, UHR was still connected with AF in patients with NAFLD. All subgroup variables did not interact significantly with UHR in the subgroup analysis. The ROC curve analysis showed that the areas under the curve for UA, HDL-C, and UHR were 0.702, 0.606, and 0.720, respectively, suggesting that UHR has a higher predictive value for AF occurrence in NAFLD patients compared to HDL-C or UA alone.
CONCLUSION
Increased UHR level was independently correlated with a high risk of AF in NAFLD patients.
Topics: Humans; Uric Acid; Atrial Fibrillation; Non-alcoholic Fatty Liver Disease; Male; Female; Cholesterol, HDL; Middle Aged; Retrospective Studies; ROC Curve; Risk Factors; Aged; Adult
PubMed: 38913677
DOI: 10.1371/journal.pone.0305952 -
PloS One 2024Tick-borne encephalitis (TBE) is usually diagnosed based on the presence of TBE virus (TBEV)-specific IgM and IgG antibodies in serum. However, antibodies induced by...
Tick-borne encephalitis (TBE) is usually diagnosed based on the presence of TBE virus (TBEV)-specific IgM and IgG antibodies in serum. However, antibodies induced by vaccination or cross-reactivity to previous flavivirus infections may result in false positive TBEV serology. Detection of TBEV RNA may be an alternative diagnostic approach to detect viral presence and circumvent the diagnostic difficulties present when using serology. Viral RNA in blood is commonly detectable only in the first viremic phase usually lasting up to two weeks, and not in the second neurologic phase, when the patients contact the health care system and undergo diagnostic work-up. TBEV RNA has previously been detected in urine in a few retrospective TBE cases in the neurologic phase, and furthermore RNA of other flaviviruses has been detected in patient saliva. In this study, blood, saliva and urine were collected from 31 hospitalised immunocompetent patients with pleocytosis and symptoms of aseptic meningitis and/or encephalitis, suspected to have TBE. We wanted to pursue if molecular testing of TBEV RNA in these patient materials may be useful in the diagnostics. Eleven of the 31 study patients were diagnosed with TBE based on ELISA detection of TBEV specific IgG and IgM antibodies. None of the study patients had TBEV RNA detectable in any of the collected patient material.
Topics: Humans; Encephalitis, Tick-Borne; Encephalitis Viruses, Tick-Borne; Saliva; RNA, Viral; Male; Female; Middle Aged; Adult; Aged; Immunoglobulin M; Immunoglobulin G; Antibodies, Viral; Aged, 80 and over; Immunocompetence; Hospitalization
PubMed: 38913668
DOI: 10.1371/journal.pone.0305603 -
PloS One 2024The efficacy of rosuvastatin in reducing allergic inflammation has been established. However, its potential to reduce airway remodeling has yet to be explored. This...
The efficacy of rosuvastatin in reducing allergic inflammation has been established. However, its potential to reduce airway remodeling has yet to be explored. This study aimed to evaluate the efficacy of rosuvastatin in reducing airway inflammation and remodeling in a mouse model of chronic allergic asthma induced by sensitization and challenge with OVA. Histology of the lung tissue and the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) showed a marked decrease in airway inflammation and remodeling in mice treated with rosuvastatin, as evidenced by a decrease in goblet cell hyperplasia, collagen deposition, and smooth muscle hypertrophy. Furthermore, levels of inflammatory cytokines, angiogenesis-related factors, and OVA-specific IgE in BALF, plasma, and serum were all reduced upon treatment with rosuvastatin. Western blotting was employed to detect AMPK expression, while immunohistochemistry staining was used to observe the expression of remodeling signaling proteins such as α-SMA, TGF-β, MMP-9, and p-AMPKα in the lungs. It was found that the activity of 5'-adenosine monophosphate-activated protein kinase alpha (AMPKα) was significantly lower in the lungs of OVA-induced asthmatic mice compared to Control mice. However, the administration of rosuvastatin increased the ratio of phosphorylated AMPK to total AMPKα, thus inhibiting the formation of new blood vessels, as indicated by CD31-positive staining mainly in the sub-epithelial region. These results indicate that rosuvastatin can effectively reduce airway inflammation and remodeling in mice with chronic allergic asthma caused by OVA, likely due to the reactivation of AMPKα and a decrease in angiogenesis.
Topics: Animals; Asthma; Rosuvastatin Calcium; AMP-Activated Protein Kinases; Signal Transduction; Airway Remodeling; Mice; Disease Models, Animal; Ovalbumin; Female; Mice, Inbred BALB C; Bronchoalveolar Lavage Fluid; Chronic Disease; Inflammation; Lung; Immunoglobulin E
PubMed: 38913666
DOI: 10.1371/journal.pone.0305863 -
PloS One 2024The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder...
Cannabinoid receptor 1 positive allosteric modulator ZCZ011 shows differential effects on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice.
The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the therapeutic potential of CB1R by direct activation is limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating the CB1R by utilizing positive allosteric modulators (PAMs). Studies have shown that CB1R PAMs (ZCZ011 and GAT211) are effective in mouse models of Huntington's disease and neuropathic pain, and hence, we assess the therapeutic potential of ZCZ011 in a well-established mouse model of neuroHIV. The current study investigates the effect of chronic ZCZ011 treatment (14 days) on various behavioral paradigms and the endocannabinoid system in HIV-1 Tat transgenic female and male mice. Chronic ZCZ011 treatment (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless of sex or genotype. However, differential effects were noted in hot plate latency, motor coordination, and recognition memory in female mice only, with ZCZ011 treatment increasing hot plate latency and improving motor coordination and recognition memory. Only minor effects or no alterations were seen in the endocannabinoid system and related lipids except in the cerebellum, where the effect of ZCZ011 was more pronounced in female mice. Moreover, AEA and PEA levels in the cerebellum were positively correlated with improved motor coordination in female mice. In summary, these findings indicate that chronic ZCZ011 treatment has differential effects on antinociception, motor coordination, and memory, based on sex and HIV-1 Tat expression, making CB1R PAMs potential treatment options for HAND without the psychoactive side effects.
Topics: Animals; Female; Male; Mice, Transgenic; Endocannabinoids; Receptor, Cannabinoid, CB1; Mice; tat Gene Products, Human Immunodeficiency Virus; HIV-1; Allosteric Regulation; Behavior, Animal; Motor Activity; Disease Models, Animal
PubMed: 38913661
DOI: 10.1371/journal.pone.0305868 -
PloS One 2024Obstructive sleep apnea (OSA) is characterized by cyclic normoxic and hypoxic conditions (intermittent hypoxia, IH) induced by the repeated closure of the upper-airway...
Obstructive sleep apnea (OSA) is characterized by cyclic normoxic and hypoxic conditions (intermittent hypoxia, IH) induced by the repeated closure of the upper-airway respiratory tract. As a pathomechanism of OSA, IH results in various comorbidities via chronic inflammation and related pathways. However, the role of other inflammatory cells, such as lymphocytes, has not been well-explored. This study aimed to examine the effects of IH on the distribution and balance of T cell subsets and other related cytokines, and mechanisms in the immune system. We modified OSA mouse model (male C57BL/6N male) using our customized chamber that controls specific sleep and oxygenic cycles. To induce hypoxia, the IH group was repeatedly exposed to 5% O2 and 21% O2 lasting for 120 s each for 7 h daily for 4 weeks. Mice were then subjected to a recovery period of 4 weeks, in which IH stimulation was ceased. T cells and related cytokines were analyzed using flow cytometry and immunohistochemistry. Compared with the control group, the IH group had significantly lower levels of CD4+CD25+Foxp3+ regulatory T cells but higher levels of Th 17, IL-4, HIF-1, and inflammatory cytokines. After the recovery period, these altered changes in the immune cells were recovered, and we found no significant difference in their levels between the control and recovery groups. This study revealed that the Th17/Treg ratio is increased by intermittent hypoxia, and this imbalance can explain immune-related diseases, including recently reported allergies, autoimmune, and even cancer diseases, arising from OSA.
Topics: Animals; Sleep Apnea, Obstructive; T-Lymphocytes, Regulatory; Male; Hypoxia; Th17 Cells; Mice; Disease Models, Animal; Mice, Inbred C57BL; Cytokines; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-4
PubMed: 38913648
DOI: 10.1371/journal.pone.0305230 -
PloS One 2024This study aimed to evaluate the effects of sarcopenia and inflammation on the prognosis of patients with pancreatic cancer after pancreaticoduodenectomy.
BACKGROUND
This study aimed to evaluate the effects of sarcopenia and inflammation on the prognosis of patients with pancreatic cancer after pancreaticoduodenectomy.
METHODS
Eighty patients who had undergone pancreaticoduodenectomy for pancreatic cancer between July 2010 and December 2023 were included in this study. The psoas muscle index was used to assess sarcopenia. The C-reactive protein-to-albumin ratio, prognostic nutritional index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were used to calculate the preoperative inflammatory marker levels. The prognostic factors for overall survival were determined using Cox regression analysis.
RESULTS
Twenty-four patients were diagnosed with sarcopenia. Sarcopenia showed a significant association with advanced tumor stage. Univariate analysis revealed a significant reduction in overall survival in patients with a prognostic nutritional index of <45, C-reactive protein-to-albumin ratio of ≥0.047, cancer antigen 19-9 levels of ≥130 U/mL, sarcopenia, lymph node metastasis, and vascular invasion. Multivariate analysis revealed that a C-reactive protein-to-albumin ratio of ≥0.047 (hazards ratio, 3.383; 95% confidence interval: 1.384-8.689; p< 0.001), cancer antigen 19-9 levels of ≥130 U/mL (hazards ratio, 2.720; 95% confidence interval: 1.291-6.060; p = 0.008), sarcopenia (hazards ratio, 3.256; 95% confidence interval: 1.535-7.072; p = 0.002) and vascular invasion (hazards ratio, 2.092; 95% confidence interval: 1.057-4.170; p = 0.034) were independent predictors of overall survival. Overall survival in the sarcopenia and high C-reactive protein-to-albumin ratio groups was significantly poorer than that in the non-sarcopenia and low C-reactive protein-to-albumin ratio and sarcopenia or high C-reactive protein-to-albumin ratio groups.
CONCLUSION
Sarcopenia and a high C-reactive protein-to-albumin ratio are independent prognostic factors in patients with pancreatic cancer after pancreaticoduodenectomy. Thus, sarcopenia may have a better prognostic value when combined with the C-reactive protein-to-albumin ratio.
Topics: Humans; Sarcopenia; Pancreatic Neoplasms; Pancreaticoduodenectomy; Male; Female; Middle Aged; Aged; Prognosis; C-Reactive Protein; Inflammation; Retrospective Studies; Biomarkers, Tumor
PubMed: 38913646
DOI: 10.1371/journal.pone.0305844