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Biology of the Cell Jul 2024One of the confounding factors in pancreatic cancer (PC) pathogenesis is hyperglycemia. The molecular mechanism by which high glucose (HG) influences PC severity is...
BACKGROUND INFORMATION
One of the confounding factors in pancreatic cancer (PC) pathogenesis is hyperglycemia. The molecular mechanism by which high glucose (HG) influences PC severity is poorly understood. Our investigation delved into the impact of lncRNA highly upregulated in liver cancer (HULC) and its interaction with yes-associated protein (YAP) in regulating the fate of pancreatic ductal adenocarcinoma cells (PDAC) under HG-induced conditions. PDAC cells were cultured under normal or HG conditions. We thereafter measured the effect of HG on the viability of PDAC cells, their migration potential and drug resistance properties. The lncRNAs putatively dysregulated in PC and diabetes were shortlisted by bioinformatics analysis followed by wet lab validation of function.
RESULTS
HG led to enhanced proliferation and drug refractoriness in PDAC cells. HULC was identified as one of the major deregulated lncRNAs following bioinformatics analysis. HULC was found to regulate the expression of the potent transcriptional regulator - YAP through selective histone modifications at the YAP promoter. siRNA-mediated ablation of HULC resulted in a concurrent decrease in YAP transcriptional activity. Importantly, HULC and YAP were found to co-operatively regulate the cellular homeostatic process autophagy, thus inculcating drug resistance and proliferative potential in PDAC cells. Moreover, inhibition of autophagy or YAP led to a decrease in HULC levels, suggesting the existence of an inter-regulatory feedback loop.
CONCLUSIONS
We observed that HG triggers aggressive properties in PDAC cells. Mechanistically, up-regulation of lncRNA HULC resulted in activation of YAP and differential regulation of autophagy coupled to increased proliferation of PDAC cells.
SIGNIFICANCE
Inhibition of HULC and YAP may represent a novel therapeutic strategy for PDAC. Furthermore, this study portrays the intricate molecular interplay between HULC, YAP and autophagy in PDAC pathogenesis.
PubMed: 38949568
DOI: 10.1111/boc.202400034 -
Molecular Imaging and Radionuclide... Jun 2024Neuroendocrine tumors (NETs) of the breast represent 1% of breast carcinomas. Histopathological misinterpretation of breast NET is common. We present the case of a...
Neuroendocrine tumors (NETs) of the breast represent 1% of breast carcinomas. Histopathological misinterpretation of breast NET is common. We present the case of a female patient who had a breast mass diagnosed as invasive ductal carcinoma initially by histopathological examination. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) revealed 2 ametabolic hypodense liver lesions. Subsequently, the patient underwent fibroblast activation protein inhibitor (FAPI)-PET/CT, which did not reveal any FAP expression in the liver lesions, but increased FAP expression was observed in the soft tissue mass of the mesenteric root. Consequently, the pathology of the biopsy taken from the nodule in the right breast was revised, and a diagnosis of grade 2 NET was established. The benefit of FAPI-PET/CT on NETs has been previously investigated. Further prospective studies are required to establish the role of FAPI-PET/CT in NET management.
PubMed: 38949561
DOI: 10.4274/mirt.galenos.2024.89106 -
Journal of Immunology (Baltimore, Md. :... Jul 2024Aberrant activity of NLRP3 has been shown associations with severe diseases. Palmitoylation is a kind of protein post-translational modification, which has been shown to...
Aberrant activity of NLRP3 has been shown associations with severe diseases. Palmitoylation is a kind of protein post-translational modification, which has been shown to regulate cancer development and the innate immune system. Here, we showed that NLRP3 is palmitoylated at Cys419 and that palmitoyltransferase ZDHHC17 is the predominant enzyme that mediates NLRP3 palmitoylation and promotes NLRP3 activation by interacting with NLRP3 and facilitating NIMA-related kinase 7 (NEK7)-NLRP3 interactions. Blockade of NLRP3 palmitoylation by a palmitoylation inhibitor, 2-bromopalmitate, effectively inhibited NLRP3 activation in vitro. Also, in a dextran sulfate sodium-induced colitis model in mice, 2-bromopalmitate application could attenuate weight loss, improve the survival rate, and rescue pathological changes in the colon of mice. Overall, our study reveals that palmitoylation of NLPR3 modulates inflammasome activation and inflammatory bowel disease development. We propose that drugs targeting NLRP3 palmitoylation could be promising candidates in the treatment of NLRP3-mediated inflammatory diseases.
PubMed: 38949555
DOI: 10.4049/jimmunol.2300241 -
Obstetrics and Gynecology Jul 2024To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial. (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
OBJECTIVE
To evaluate maternal and neonatal outcomes by type of antihypertensive used in participants of the CHAP (Chronic Hypertension in Pregnancy) trial.
METHODS
We conducted a planned secondary analysis of CHAP, an open-label, multicenter, randomized trial of antihypertensive treatment compared with standard care (no treatment unless severe hypertension developed) in pregnant patients with mild chronic hypertension (blood pressure 140-159/90-104 mm Hg before 20 weeks of gestation) and singleton pregnancies. We performed three comparisons based on medications prescribed at enrollment: labetalol compared with standard care, nifedipine compared with standard care, and labetalol compared with nifedipine. Although active compared with standard care groups were randomized, medication assignment within the active treatment group was not random but based on clinician or patient preference. The primary outcome was the occurrence of superimposed preeclampsia with severe features, preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The key secondary outcome was small for gestational age (SGA) neonates. We also compared medication adverse effects between groups. Relative risks (RRs) and 95% CIs were estimated with log binomial regression to adjust for confounding.
RESULTS
Of 2,292 participants analyzed, 720 (31.4%) received labetalol, 417 (18.2%) received nifedipine, and 1,155 (50.4%) received no treatment. The mean gestational age at enrollment was 10.5±3.7 weeks; nearly half of participants (47.5%) identified as non-Hispanic Black; and 44.5% used aspirin. The primary outcome occurred in 217 (30.1%), 130 (31.2%), and 427 (37.0%) in the labetalol, nifedipine, and standard care groups, respectively. Risk of the primary outcome was lower among those receiving treatment (labetalol use vs standard adjusted RR 0.82, 95% CI, 0.72-0.94; nifedipine use vs standard adjusted RR 0.84, 95% CI, 0.71-0.99), but there was no significant difference in risk when labetalol was compared with nifedipine (adjusted RR 0.98, 95% CI, 0.82-1.18). There were no significant differences in SGA or serious adverse events between participants receiving labetalol and those receiving nifedipine.
CONCLUSION
No significant differences in predetermined maternal or neonatal outcomes were detected on the basis of the use of labetalol or nifedipine for treatment of chronic hypertension in pregnancy.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT02299414.
Topics: Humans; Pregnancy; Female; Labetalol; Nifedipine; Antihypertensive Agents; Adult; Pregnancy Outcome; Hypertension; Infant, Newborn; Pregnancy Complications, Cardiovascular; Hypertension, Pregnancy-Induced; Administration, Oral; Infant, Small for Gestational Age; Pre-Eclampsia; Chronic Disease
PubMed: 38949541
DOI: 10.1097/AOG.0000000000005613 -
Cancer Epidemiology, Biomarkers &... Jul 2024Two-thirds of global cancer occur in low/middle income countries (LMICs). Northern Central America is the largest LMIC region in the western hemisphere, and lack cancer...
BACKGROUND
Two-thirds of global cancer occur in low/middle income countries (LMICs). Northern Central America is the largest LMIC region in the western hemisphere, and lack cancer registries to guide cancer control. We conducted a gastric cancer (GC) survival study in rural western Honduras, characterized as having among the highest GC incidence rates in Latin America.
METHODS
The cohort of incident GC diagnosed between 2002-2015 was studied with active follow-up, with household visits. The regional gastric cancer registry was primary for case identification, with completeness examination with hospital data and national death certificates. Cox regression models were used for survival calculations.
RESULTS
Survival follow-up was achieved in 741/774 patients (95.7%). Household interviews were conducted in 74.1% (n=549). 65.7% were male, median age at diagnosis was 64 years, 24.5% were <55. 43.9% of tumors had pyloric obstruction. 45.2%, 43.2%, and 7.3% of histology was intestinal, diffuse, and mixed, respectively. 24.7% patients received treatment. 5-year survival rates were 9.9% for both males and females, 7.7% for age <45, and 7.9% for diffuse GC. Median survival time was 4.8 months (95%CI,4.2-5.6). In the final Cox regression model including age, sex, Lauren subtype, and poverty index, only treatment was significantly associated with survival (HR 2.43, 95%CI,1.8-3.2).
CONCLUSIONS
Markedly low gastric cancer 5-year survival rates are observed in rural Central America. The majority of patients present with advanced disease, and a minority have access to therapy.
IMPACT
The findings have implications for cancer control in the Central America LMICs and for U.S. Latino populations.
PubMed: 38949525
DOI: 10.1158/1055-9965.EPI-23-1461 -
Journal of Immunology (Baltimore, Md. :... Jul 2024The Krebs cycle enzyme aconitate decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Previously, we reported that administration of...
The Aconitate Decarboxylase 1/Itaconate Pathway Modulates Immune Dysregulation and Associates with Cardiovascular Disease Markers and Disease Activity in Systemic Lupus Erythematosus.
The Krebs cycle enzyme aconitate decarboxylase 1 (ACOD1) mediates itaconate synthesis in monocytes and macrophages. Previously, we reported that administration of 4-octyl itaconate to lupus-prone mice abrogated immune dysregulation and clinical features. In this study, we explore the role of the endogenous ACOD1/itaconate pathway in the development of TLR7-induced lupus (imiquimod [IMQ] model). We found that, in vitro, ACOD1 was induced in mouse bone marrow-derived macrophages and human monocyte-derived macrophages following TLR7 stimulation. This induction was partially dependent on type I IFN receptor signaling and on specific intracellular pathways. In the IMQ-induced mouse model of lupus, ACOD1 knockout (Acod1-/-) displayed disruptions of the splenic architecture, increased serum levels of anti-dsDNA and proinflammatory cytokines, and enhanced kidney immune complex deposition and proteinuria, when compared with the IMQ-treated wild-type mice. Consistent with these results, Acod1-/- bone marrow-derived macrophages treated in vitro with IMQ showed higher proinflammatory features. Furthermore, itaconate serum levels in systemic lupus erythematosus patients were decreased compared with healthy individuals, in association with disease activity and specific perturbed cardiometabolic parameters. These findings suggest that the ACOD1/itaconate pathway plays important immunomodulatory and vasculoprotective roles in systemic lupus erythematosus, supporting the potential therapeutic role of itaconate analogs in autoimmune diseases.
PubMed: 38949522
DOI: 10.4049/jimmunol.2400241 -
Molecular Imaging and Radionuclide... Jun 2024Epithelial-myoepithelial carcinoma (EMC) is a rare low-grade salivary gland neoplasm. Distant metastasis is rare, and F-fluorodeoxyglucose positron emission...
Epithelial-myoepithelial carcinoma (EMC) is a rare low-grade salivary gland neoplasm. Distant metastasis is rare, and F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) has been used to determine the metastatic disease in EMC. Ga-fibroblast activation protein inhibitors (FAPI) PET/CT is a promising imaging modality for diagnostic and theognostic purposes in various malignancies. Comparison studies with F-FDG have investigated the role of Ga-FAPI PET/CT. Herein, we present F-FDG and Ga-FAPI-04 PET/CT findings of a 51-year-old woman with metastatic EMC arising from ex-pleomorphic adenoma of the parotid.
PubMed: 38949518
DOI: 10.4274/mirt.galenos.2023.83435 -
Journal of Agricultural and Food... Jul 2024Multiprotein bridging factor 1 (MBF1) is a very important transcription factor (TF) in plants, whose members influence numerous defense responses. Our study found that...
Multiprotein bridging factor 1 (MBF1) is a very important transcription factor (TF) in plants, whose members influence numerous defense responses. Our study found that MBF1c in Cucurbitaceae was highly conserved. expression was induced by temperature, salt stress, and abscisic acid (ABA) in cucumber. Overexpressed CsMBF1c enhanced the heat resistance of a cucumber, and the mutant showed decreased resistance to high temperatures (HTs). CsMBF1c played an important role in stabilizing the photosynthetic system of cucumber under HT, and its expression was significantly associated with heat-related TFs and genes related to protein processing in the endoplasmic reticulum (ER). Protein interaction showed that CsMBF1c interacted with dehydration-responsive element binding protein 2 (CsDREB2) and nuclear factor Y A1 (CsNFYA1). Overexpression of CsNFYA1 in improved the heat resistance. Transcriptional activation of CsNFYA1 was elevated by CsMBF1c. Therefore, plays an important regulatory role in cucumber's resistance to high temperatures.
PubMed: 38949485
DOI: 10.1021/acs.jafc.4c02398 -
Internal Medicine Journal Jul 2024This study surveyed South Australian medical oncologists to capture their perceptions, willingness to participate and perceived barriers and motivations to participation...
This study surveyed South Australian medical oncologists to capture their perceptions, willingness to participate and perceived barriers and motivations to participation in voluntary assisted dying (VAD) activities. Approximately 70% of surveyed medical oncologists reported familiarity with VAD legislation. Less than half of physicians (39.1%) reported willingness to participate in any VAD activities, and the rate of conscientious objection was 22%. The top barriers to participation were lack of time and uncertainty given no prior experience. These results demonstrate both a low rate of conscientious objection and a low rate of willingness to participate at the point of VAD implementation in South Australia, and identify barriers to participation that are largely logistical.
PubMed: 38949456
DOI: 10.1111/imj.16448 -
African Journal of Primary Health Care... Jun 2024Clustering of cardiovascular disease (CVD) risk factors have been observed in children and adolescents, but its association with visceral adiposity index (VAI) and...
BACKGROUND
Clustering of cardiovascular disease (CVD) risk factors have been observed in children and adolescents, but its association with visceral adiposity index (VAI) and cardiorespiratory fitness (CRF) in adolescents has rarely been studied.
AIM
This study determines the independent associations of VAI and CRF with the clustering of cardiovascular disease risk (CVDr) among Nigerian adolescents.
SETTING
Adolescents from specific secondary schools in Kogi East, North Central Nigeria participated in the study.
METHODS
A cross-sectional sample of 403 adolescents (202 boys and 201 girls) aged 11 years - 19 years were evaluated for VAI, CRF and CVDr. Using identified risk factors, a clustered CVDr score was generated. The association between VAI, CRF and clustered CVDr was evaluated using regression models that controlled for age, gender and maturity status.
RESULTS
Fitness was negatively associated with CVDr (β = -0.268, p 0.001), while VAI was positively correlated with CVDr (β = 0.379, p 0.001). After CRF or VAI adjustment, the independent association with the dependent variable remained significant. The odds of an adolescent with elevated VAI being at risk of CVD was 4.7 times higher than his peers. Unfit adolescents were 2.1 times more likely to develop CVDr.
CONCLUSION
Both VAI and CRF were independently associated with the clustering of CVDr in Nigerian adolescents. The findings suggest that health promotion efforts focusing on healthy diet and aerobic-type physical activity programmes should be encouraged among the youth to reduce the risk of CVD.Contribution: This study shows that improving visceral adipose tissue and fitness may lower CVD risk factors in adolescents, which is significant for public health.
Topics: Humans; Male; Adolescent; Female; Nigeria; Cross-Sectional Studies; Cardiovascular Diseases; Cardiorespiratory Fitness; Child; Obesity, Abdominal; Heart Disease Risk Factors; Intra-Abdominal Fat; Risk Factors; Young Adult
PubMed: 38949442
DOI: 10.4102/phcfm.v16i1.4474