-
Cancer Medicine Jun 2024With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled...
INTRODUCTION
With locally advanced pancreatic cancer (LAPC), uncontrolled local tumor growth frequently leads to mortality. Advancements in radiotherapy (RT) techniques have enabled conformal delivery of escalated-dose RT (EDR), which may have potential local control and overall survival (OS) benefits based on retrospective and early prospective studies. With evidence for EDR emerging, we characterized the adoption of EDR across the United States and its associated outcomes.
METHODS
We searched the National Cancer Database for nonsurgically managed LAPC patients diagnosed between 2004 and 2019. Pancreas-directed RT with biologically effective doses (BED) ≥39 and ≤70 Gy was labeled conventional-dose RT (CDR), and BED >70 and ≤132 Gy was labeled EDR. We identified associations of EDR and OS using logistic and Cox regressions, respectively.
RESULTS
Among the definitive therapy subset (n = 54,115) of the entire study cohort (n = 91,493), the most common treatments were chemotherapy alone (69%), chemotherapy and radiation (29%), and RT alone (2%). For the radiation therapy subset (n = 16,978), use of pancreas-directed RT remained between 13% and 17% over the study period (p > 0.999). Using multivariable logistic regression, treatment at an academic/research facility (adjusted odds ratio [aOR] 1.46, p < 0.001) and treatment between 2016 and 2019 (aOR 2.54, p < 0.001) were associated with greater receipt of EDR, whereas use of chemotherapy (aOR 0.60, p < 0.001) was associated with less receipt. Median OS estimates for EDR and CDR were 14.5 months and 13.0 months (p < 0.0001), respectively. For radiation therapy subset patients with available survival data (n = 13,579), multivariable Cox regression correlated EDR (adjusted hazard ratio 0.85, 95% confidence interval 0.80-0.91; p < 0.001) with longer OS versus CDR.
DISCUSSION AND CONCLUSIONS
Utilization of EDR has increased since 2016, but overall utilization of RT for LAPC has remained at less than one in five patients for almost two decades. These real-world results additionally provide an estimate of effect size of EDR for future prospective trials.
Topics: Humans; Pancreatic Neoplasms; Male; Female; United States; Aged; Middle Aged; Radiotherapy Dosage; Retrospective Studies; Aged, 80 and over
PubMed: 38923407
DOI: 10.1002/cam4.7434 -
Metabolites Jun 2024Obesity is a systemic and chronic inflammation, which seriously endangers people's health. People tend to diet to control weight, and the short-term effect of dieting in... (Review)
Review
Obesity is a systemic and chronic inflammation, which seriously endangers people's health. People tend to diet to control weight, and the short-term effect of dieting in losing weight is significant, but the prognosis is limited. With weight loss and recovery occurring frequently, people focus on weight cycling. The effect of weight cycling on a certain tissue of the body also has different conclusions. Therefore, this article systematically reviews the effects of body weight cycling on the body and finds that multiple weight cycling (1) increased fat deposition in central areas, lean mass decreased in weight loss period, and fat mass increased in weight recovery period, which harms body composition and skeletal muscle mass; (2) enhanced the inflammatory response of adipose tissue, macrophages infiltrated into adipose tissue, and increased the production of pro-inflammatory mediators in adipocytes; (3) blood glucose concentration mutation and hyperinsulinemia caused the increase or decrease in pancreatic β-cell population, which makes β-cell fatigue and leads to β-cell failure; (4) resulted in additional burden on the cardiovascular system because of cardiovascular rick escalation. Physical activity combined with calorie restriction can effectively reduce metabolic disease and chronic inflammation, alleviating the adverse effects of weight cycling on the body.
PubMed: 38921478
DOI: 10.3390/metabo14060344 -
Current Oncology (Toronto, Ont.) Jun 2024Despite the advancements made in oncology in recent years, the treatment of pancreatic cancer remains a challenge. Five-year survival rates for this cancer do not exceed... (Review)
Review
Despite the advancements made in oncology in recent years, the treatment of pancreatic cancer remains a challenge. Five-year survival rates for this cancer do not exceed 10%. Among the reasons contributing to poor treatment outcomes are the oligosymptomatic course of the tumor, diagnostic difficulties due to the anatomical location of the organ, and the unique biological features of pancreatic cancer. The mainstay of treatment for resectable cancer is surgery and adjuvant chemotherapy. For unresectable and metastatic cancers, chemotherapy remains the primary method of treatment. At the same time, for about thirty years, there have been attempts to improve treatment outcomes by using radiotherapy combined with systemic treatment. Unlike chemotherapy, radiotherapy has no established place in the treatment of pancreatic cancer. This paper addresses the topic of radiotherapy in pancreatic cancer as a valuable method that can improve treatment outcomes alongside chemotherapy.
Topics: Humans; Pancreatic Neoplasms; Chemoradiotherapy
PubMed: 38920733
DOI: 10.3390/curroncol31060250 -
Cells Jun 2024Serine/threonine kinase AKT isoforms play a well-established role in cell metabolism and growth. Most pancreatic adenocarcinomas (PDACs) harbor activation mutations of...
Serine/threonine kinase AKT isoforms play a well-established role in cell metabolism and growth. Most pancreatic adenocarcinomas (PDACs) harbor activation mutations of KRAS, which activates the PI3K/AKT signaling pathway. However, AKT inhibitors are not effective in the treatment of pancreatic cancer. To better understand the role of AKT signaling in mutant-KRAS pancreatic tumors, this study utilized proteolysis-targeting chimeras (PROTACs) and CRISPR-Cas9-genome editing to investigate AKT proteins. The PROTAC down-regulation of AKT proteins markedly slowed the growth of three pancreatic tumor cell lines harboring mutant KRAS. In contrast, the inhibition of AKT kinase activity alone had very little effect on the growth of these cell lines. The concurrent genetic deletion of all AKT isoforms (AKT1, AKT2, and AKT3) in the KPC (; ; ) pancreatic cancer cell line also dramatically slowed its growth in vitro and when orthotopically implanted in syngeneic mice. Surprisingly, insulin-like growth factor-1 (IGF-1), but not epidermal growth factor (EGF), restored KPC cell growth in serum-deprived conditions, and the IGF-1 growth stimulation effect was AKT-dependent. The RNA-seq analysis of AKT1/2/3-deficient KPC cells suggested that reduced cholesterol synthesis may be responsible for the decreased response to IGF-1 stimulation. These results indicate that the presence of all three AKT isoforms supports pancreatic tumor cell growth, and the pharmacological degradation of AKT proteins may be more effective than AKT catalytic inhibitors for treating pancreatic cancer.
Topics: Proto-Oncogene Proteins c-akt; Pancreatic Neoplasms; Animals; Cell Line, Tumor; Mice; Humans; Down-Regulation; Proto-Oncogene Proteins p21(ras); Mutation; Cell Proliferation; Signal Transduction; Gene Expression Regulation, Neoplastic
PubMed: 38920688
DOI: 10.3390/cells13121061 -
Journal of Biosciences 2024Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an... (Review)
Review
Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that facilitates transportation of water and salts across epithelial cell membranes through the conductance of Cl and other anions. A dysfunctional CFTR due to abnormalities in the gene causes CF, which is believed to be a rare disease in India mainly due to mis/underdiagnosis. Although numerous diagnostic methods and treatment options are available for CF globally, most of these are unaffordable for developing countries like India. Currently, CF symptoms are managed with mucolytics, antibiotics, anti-inflammatory drugs, and various CFTR modulators based on the type of defect. While a definitive cure for CF remains elusive, advancements in stem cell and gene therapies hold promise for permanent cure in the near future. In this review, we discuss the prevalence of CF cases in India, affordable diagnostic methods, and treatment options amenable for developing countries. We further emphasize the scope for the universal newborn screening programme.
Topics: Cystic Fibrosis; Humans; India; Cystic Fibrosis Transmembrane Conductance Regulator; Developing Countries; Genetic Therapy; Neonatal Screening; Infant, Newborn; Mutation
PubMed: 38920104
DOI: No ID Found -
Frontiers in Immunology 2024The transitory emergence of myeloid-derived suppressor cells (MDSCs) in infants is important for the homeostasis of the immune system in early life. The composition and...
The transitory emergence of myeloid-derived suppressor cells (MDSCs) in infants is important for the homeostasis of the immune system in early life. The composition and functional heterogeneity of MDSCs in newborns remain elusive, hampering the understanding of the importance of MDSCs in neonates. In this study, we unraveled the maturation trajectory of polymorphonuclear (PMN)-MDSCs from the peripheral blood of human newborns by performing single-cell RNA sequencing. Results indicated that neonatal PMN-MDSCs differentiated from self-renewal progenitors, antimicrobial PMN-MDSCs, and immunosuppressive PMN-MDSCs to late PMN-MDSCs with reduced antimicrobial capacity. We also established a simple framework to distinguish these distinct stages by CD177 and CXCR2. Importantly, preterm newborns displayed a reduced abundance of classical PMN-MDSCs but increased late PMN-MDSCs, consistent with their higher susceptibility to infections and inflammation. Furthermore, newborn PMN-MDSCs were distinct from those from cancer patients, which displayed minimum expression of genes about antimicrobial capacity. This study indicates that the heterogeneity of PMN-MDSCs is associated with the maturity of human newborns.
Topics: Humans; Myeloid-Derived Suppressor Cells; Infant, Newborn; Single-Cell Analysis; Receptors, Interleukin-8B; Gene Expression Profiling; Transcriptome; Neutrophils; GPI-Linked Proteins; Cell Differentiation; Female; Male; Isoantigens; Receptors, Cell Surface
PubMed: 38919617
DOI: 10.3389/fimmu.2024.1367230 -
World Journal of Surgical Oncology Jun 2024Prior research exploring the correlation between the XRCC3 Thr241Met polymorphism and the susceptibility to pancreatic cancer has yielded conflicting outcomes. To date,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Prior research exploring the correlation between the XRCC3 Thr241Met polymorphism and the susceptibility to pancreatic cancer has yielded conflicting outcomes. To date, there has been a notable absence of studies examining this polymorphism. The primary aim of the current investigation is to elucidate the potential role of the XRCC3 Thr241Met polymorphism as a risk factor in the development of pancreatic cancer.
METHODS
The comprehensive literature search was meticulously conducted across primary databases, including PubMed, Embase, and CNKI (China National Knowledge Infrastructure), spanning from the inception of each database through January 2024. To synthesize the data, a meta-analysis was performed using either a fixed or random-effects model, as appropriate, to calculate the odds ratios (ORs) and their corresponding 95% confidence intervals (CIs).
RESULTS
The analysis revealed significant associations between the XRCC3 Thr241Met polymorphism and an increased risk of pancreatic cancer. This was evidenced through various genetic model comparisons: allele contrast (T vs. C: OR = 0.77, 95% CI = 0.70-0.86, P < 0.001), homozygote comparison (TT vs. CC: OR = 0.71, 95% CI = 0.58-0.88, P = 0.001), heterozygote comparison (TC vs. CC: OR = 0.67, 95% CI = 0.52-0.87, P = 0.003), and a dominant genetic model (TT/TC vs. CC: OR = 0.68, 95% CI = 0.57-0.81, P < 0.001). Additionally, subgroup analyses based on ethnicity disclosed that these associations were particularly pronounced in the Caucasian population, with all genetic models showing significance (P < 0.05).
CONCLUSIONS
The XRCC3 Thr241Met polymorphism has been identified as contributing to a reduced risk of pancreatic cancer in the Caucasian population. This finding underscores the need for further research to validate and expand upon our conclusions, emphasizing the urgency for continued investigations in this domain.
Topics: Humans; Pancreatic Neoplasms; Genetic Predisposition to Disease; DNA-Binding Proteins; Polymorphism, Single Nucleotide; Prognosis; Risk Factors; DNA Repair; Case-Control Studies
PubMed: 38918791
DOI: 10.1186/s12957-024-03450-1 -
Scientific Reports Jun 2024Type 2 diabetes (T2D) is the fastest growing non-infectious disease worldwide. Impaired insulin secretion from pancreatic beta-cells is a hallmark of T2D, but the...
Type 2 diabetes (T2D) is the fastest growing non-infectious disease worldwide. Impaired insulin secretion from pancreatic beta-cells is a hallmark of T2D, but the mechanisms behind this defect are insufficiently characterized. Integrating multiple layers of biomedical information, such as different Omics, may allow more accurate understanding of complex diseases such as T2D. Our aim was to explore and use Machine Learning to integrate multiple sources of biological/molecular information (multiOmics), in our case RNA-sequening, DNA methylation, SNP and phenotypic data from islet donors with T2D and non-diabetic controls. We exploited Machine Learning to perform multiOmics integration of DNA methylation, expression, SNPs, and phenotypes from pancreatic islets of 110 individuals, with ~ 30% being T2D cases. DNA methylation was analyzed using Infinium MethylationEPIC array, expression was analyzed using RNA-sequencing, and SNPs were analyzed using HumanOmniExpress arrays. Supervised linear multiOmics integration via DIABLO based on Partial Least Squares (PLS) achieved an accuracy of 91 ± 15% of T2D prediction with an area under the curve of 0.96 ± 0.08 on the test dataset after cross-validation. Biomarkers identified by this multiOmics integration, including SACS and TXNIP DNA methylation, OPRD1 and RHOT1 expression and a SNP annotated to ANO1, provide novel insights into the interplay between different biological mechanisms contributing to T2D. This Machine Learning approach of multiOmics cross-sectional data from human pancreatic islets achieved a promising accuracy of T2D prediction, which may potentially find broad applications in clinical diagnostics. In addition, it delivered novel candidate biomarkers for T2D and links between them across the different Omics.
Topics: Humans; Diabetes Mellitus, Type 2; Machine Learning; DNA Methylation; Islets of Langerhans; Polymorphism, Single Nucleotide; Male; Female; Middle Aged; Biomarkers; Adult; Aged
PubMed: 38918439
DOI: 10.1038/s41598-024-64846-3 -
Nature Communications Jun 2024Artificial intelligence transforms drug discovery, with phenotype-based approaches emerging as a promising alternative to target-based methods, overcoming limitations...
Artificial intelligence transforms drug discovery, with phenotype-based approaches emerging as a promising alternative to target-based methods, overcoming limitations like lack of well-defined targets. While chemical-induced transcriptional profiles offer a comprehensive view of drug mechanisms, inherent noise often obscures the true signal, hindering their potential for meaningful insights. Here, we highlight the development of TranSiGen, a deep generative model employing self-supervised representation learning. TranSiGen analyzes basal cell gene expression and molecular structures to reconstruct chemical-induced transcriptional profiles with high accuracy. By capturing both cellular and compound information, TranSiGen-derived representations demonstrate efficacy in diverse downstream tasks like ligand-based virtual screening, drug response prediction, and phenotype-based drug repurposing. Notably, in vitro validation of TranSiGen's application in pancreatic cancer drug discovery highlights its potential for identifying effective compounds. We envisage that integrating TranSiGen into the drug discovery and mechanism research holds significant promise for advancing biomedicine.
Topics: Drug Discovery; Humans; Deep Learning; Phenotype; Drug Repositioning; Pancreatic Neoplasms; Transcriptome; Gene Expression Profiling; Antineoplastic Agents; Artificial Intelligence
PubMed: 38918369
DOI: 10.1038/s41467-024-49620-3 -
Endoscopy Dec 2024
Topics: Humans; Stents; Pancreatitis, Acute Necrotizing; Male; Middle Aged; Drainage
PubMed: 38917979
DOI: 10.1055/a-2335-6707