Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote ...PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH). In contrast, pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss, indicating a potential therapeutic window for inhibiting SOAT1 in PDAC.
Radiation treatment patterns in patients with brain metastases from non-small cell lung cancer (NSCLC) have not been well elucidated. The National Cancer Database (NCDB) was used to evaluate trends ...in the use of whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) for brain metastasis from NSCLC.
This NCDB study included patients > 18 years old with metastatic NSCLC treated with single-fraction SRS or WBRT between 2004 and 2014. Chi-square, t-test, and multivariable logistic regression analyses were used to identify predictors of SRS versus WBRT.
Of 40,803 patients, 34,183 (83.8%) received WBRT and 6,620 (16.2%) received SRS. SRS utilization increased from 7% (157 cases) in 2004 to 37% (1,346 cases) in 2014 (p < .001). SRS was utilized more by academic than community facilities (22% versus 13%, p < .001). The strongest independent predictors of SRS included year of diagnosis in 2010-2014 versus 2004-2009 (odds ratio OR 2.62, 95% CI 2.46-2.79, p < .0001), metropolitan versus rural (OR 2.26, CI 1.79-2.85, p < .0001), distance from cancer-reporting facility of ≥ 30 versus < 30 miles (OR 2.36, CI 2.18-2.56, p < .0001), private insurance versus non-insured patients (OR 1.96, CI 1.68-2.29, p < .0001), and academic versus community facility (OR 1.76, CI 1.66-1.87, p < .0001).
SRS for NSCLC brain metastases has steadily increased in the United States; however, WBRT remains the most commonly used. Wide geographic and socioeconomic variations exist in the utilization of SRS and WBRT for this patient population.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs ...are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment.
We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC.
We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression.
Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.
The optimal therapeutic response in cancer patients is highly dependent upon the differentiation state of their tumours. Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer that harbours ...distinct phenotypic subtypes with preferential sensitivities to standard therapies. This study aimed to investigate intratumour heterogeneity and plasticity of cancer cell states in PDA in order to reveal cell state-specific regulators.
We analysed single-cell expression profiling of mouse PDAs, revealing intratumour heterogeneity and cell plasticity and identified pathways activated in the different cell states. We performed comparative analysis of murine and human expression states and confirmed their phenotypic diversity in specimens by immunolabeling. We assessed the function of phenotypic regulators using mouse models of PDA, organoids, cell lines and orthotopically grafted tumour models.
Our expression analysis and immunolabeling analysis show that a mucus production programme regulated by the transcription factor SPDEF is highly active in precancerous lesions and the classical subtype of PDA - the most common differentiation state. SPDEF maintains the classical differentiation and supports PDA transformation
. The SPDEF tumour-promoting function is mediated by its target genes AGR2 and
/IRE1β that regulate mucus production, and inactivation of the SPDEF programme impairs tumour growth and facilitates subtype interconversion from classical towards basal-like differentiation.
Our findings expand our understanding of the transcriptional programmes active in precancerous lesions and PDAs of classical differentiation, determine the regulators of mucus production as specific vulnerabilities in these cell states and reveal phenotype switching as a response mechanism to inactivation of differentiation states determinants.
Practically, Deepfake technology has given people access to generate fake videos that look like real content using neural networks, and can further create misconceptions and deceit about the ...innocuous elements of society. This technology can prove fatal not only to national security but on an international level. Existing methodologies that apply deep learning to automatically extract salient and discriminative features to detect Deepfakes based on typical CNN-LSTM models tend to have their shortcomings. Having said that, we propose a system that extracts Spatio-Temporal features and achieves Real-Time Deepfake detection using Transformers. For the end user, a web application was developed, which with utmost simplicity allows the uploading of a video that will be further authenticated within the application and, at the same time, features the authentication of live meetings.
Accurate estimation of travel times is an important step in smart transportation and smart building systems. Poor estimation of travel times results in both frustrated users and wasted resources. ...Current methods that estimate travel times usually only return point estimates, losing important distributional information necessary for accurate decision-making. We propose using neural network-based mixture distributions to predict a user's travel times given their origin and destination coordinates. We show that our method correctly estimates the travel time distribution, maximizes utility in a downstream elevator scheduling task, and is easy to retrain—making it a versatile and an inexpensive-to-maintain module when deployed in smart crowd management systems.
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