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Renal cell carcinoma (RCC) is a common cancer in the USA. Up to 30% of patients with RCC are in an advanced stage of disease at diagnosis. RCC is difficult to cure, with an 11% chance of survival after 5 years for patients with advanced RCC. A recent clinical study showed that nivolumab plus cabozantinib (NC) had a greater benefit in patients with advanced RCC than sunitinib. The US FDA approved NC for advanced RCC, but NC is relatively expensive. This study explored the cost–effectiveness of NC for advanced RCC versus sunitinib for a US payer using two cost–effectiveness models developed based on the results of the aforementioned clinical study. The results showed that to gain an additional year in perfect health, NC costs an average of US$555,663 or $531,748 more versus sunitinib, which is more than a US payer is willing to pay for an additional year in perfect health ($150,000). Therefore, NC for advanced RCC is not cost-effective versus sunitinib for a US payer at current prices.

Background The health levels of young elderly individuals are generally low due to multiple factors. This study sought to analyze factors that affect the health of the young elderly to provide a reference for improving their level of health. Methods We used cluster sampling to survey 1,000 young elderly residents aged between 60 and 69 and living in Town P, District M, Shanghai. Health levels were assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), Social Support Rate Score (SSRS), General Self-Efficacy Scale (GSES), and Health Promoting Lifestyle Profile II (HPLP II) instruments. Demographic characteristics were compared based on the SF-36 score and coupled with one-way analysis and stepwise regression analysis, to determine factors affecting health. Results The young elderly in this community have a high morbidity of chronic disease and score low in the SF-36, SSRS, GSES, and HPLP II. One-way analysis reveals that gender, education, marriage, current work, total social support score, total general self-efficacy score, and total health promoting score are factors affecting the scoring of the SF-36 and the results of stepwise regression analysis. Marriage, current working condition, age, total score of social support, total score of health promotion behavior, type of work, presence of chronic disease, and the number of children are positively correlated with the SF-36 score and can predict it. Conclusions To improve the health of community living elderly young it is necessary to adopt appropriate health promotion measures which motivate their self-efficacy and health responsibility. Such measures include increasing interactions between the young elderly and medical resources and offering them public participation opportunities to ensure that they receive adequate social support.

Epithelial plasticity, reversible modulation of a cell's epithelial and mesenchymal features, is associated with tumor metastasis and chemoresistance, leading causes of cancer mortality. Although different master transcription factors and epigenetic modifiers have been implicated in this process in various contexts, the extent to which a unifying, generalized mechanism of transcriptional regulation underlies epithelial plasticity remains largely unknown. Here, through targeted CRISPR/Cas9 screening, we discovered two histone-modifying enzymes involved in the writing and erasing of H3K36me2 that act reciprocally to regulate epithelial-to-mesenchymal identity, tumor differentiation, and metastasis. Using a lysine-to-methionine histone mutant to directly inhibit H3K36me2, we found that global modulation of the mark is a conserved mechanism underlying the mesenchymal state in various contexts. Mechanistically, regulation of H3K36me2 reprograms enhancers associated with master regulators of epithelial-to-mesenchymal state. Our results thus outline a unifying epigenome-scale mechanism by which a specific histone modification regulates cellular plasticity and metastasis in cancer. Significance: Although epithelial plasticity contributes to cancer metastasis and chemoresistance, no strategies exist for pharmacologically inhibiting the process. Here, we show that global regulation of a specific histone mark, H3K36me2, is a universal epigenome-wide mechanism that underlies epithelial-to-mesenchymal transition and mesenchymal-to-epithelial transition in carcinoma cells. These results offer a new strategy for targeting epithelial plasticity in cancer. This article is highlighted in the In This Issue feature, p. 747

The overall architectural complexity of autonomous underwater vehicles continuous to increase, enlarging the probability of fault occurrence in subsystems. Estimating the thrust loss by particle filter provided a useful method to detect the fault in propeller subsystem. In order to detect the fault in propellers as early as possible, the particle filter direct prediction method could amplify the fault trend and detect the fault earlier, but at the same time increase the possibility of false diagnosis. Therefore, a more accurate fault diagnosis method was required to discover the fault early and decrease the occurrence of false diagnosis. In this paper, an improved particle filter prediction method was proposed, combining the advantage of grey prediction to forecast the motion state, reducing the uncertainty in particle filter direct prediction process. Besides, the Gaussian kernel function was applied to judge the credibility of the prediction result, decreasing the possibility of the false diagnosis. In the experiments with simulated working conditions data and a section of actual sea trial data with propeller fault, the proposed method detected the fault earlier compared with the original particle filter method, and reduced the false diagnosis rate compared with the particle filter direct prediction method. The results show that the proposed method is effective in detecting the fault early with low false diagnosis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a 5-year survival rate of only 10%. One hallmark of PDAC’s tumor microenvironment is dense desmoplasia, due to abnormal accumulation of extracellular matrix and proliferative fibroblasts. During tumorigenesis, pancreatic stellate cells (PSCs) obtain myofibroblast-like signatures and contribute to the fibrotic environment of PDAC. Desmoplasia-induced hypovascularity severely limits oxygen and nutrient delivery. Our laboratory revealed that hypoxia is prominent even at the pancreatic intraepithelial neoplasia (PanIN) stage, a dominant precursor lesion of PDAC. Hypoxia inhibits oxygen-dependent metabolic processes. For example, unsaturated lipid biosynthesis relies on oxygen to maintain desaturase enzymatic activities. Hypoxia also stimulates lipid uptake. Previous studies demonstrated that RAS-transformed cells preferentially import unsaturated lysophosphatidylcholines (LPCs) from culture media. However, in a nutrient-limited fibrotic environment, the potential source of lipids is unclear. Interestingly, a lipidomic study of a PSC secretome displayed a significant amount of LPCs, suggesting that PSCs are the potential lipid source in the PDAC microenvironment. Our data indicate that exogenous unsaturated lipids sustain PDAC cell viability under hypoxia and nutrient deficiency. Moreover, we find PDAC cell survival under tumor-like stress is enhanced in PSC conditioned medium, but not in delipidated conditioned medium. Strikingly, we show that cancer-associated fibroblasts do not experience hypoxic stress as much as adjacent malignant epithelium cells in vivo, suggesting cancer-associated fibroblasts provide unsaturated (and other) lipids to PDAC cells. Based on our lipidomic mass spectra of PSC conditioned medium, we determined that LPCs are actively utilized by PDAC cells for phosphatidylcholine and triglyceride regeneration. To discover novel therapeutic strategies, we performed small molecule screens to identify potential drugs that disrupt LPC uptake and metabolism by PDAC cells. Our overall hypothesis is that activated PSCs (and potentially other fibroblasts) support PDAC cell survival by providing lipids, particularly LPCs, and inhibition of LPC utilization by cancer cells or unsaturated lipid synthesis by PSCs induces PDAC cell death under metabolically challenging conditions. In summary, this project aims to demonstrate metabolic crosstalk between fibroblasts and PDAC cells under stress conditions. The key advance of my research is that activated PSCs suppress PDAC cell death by supplying tumor cells with unsaturated LPCs for the maintenance of lipid homeostasis, in a hypoxic and nutrient-poor environment. If true, our findings will reveal novel metabolic targets for developing combinatorial therapy of PDAC. Citation Format: Xu Han, Michelle Burrows, Yanqing Jiang, Clementina Mesaros, David Schultz, Brian Keith, Celeste Simon. Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR024.

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death with a five-year survival rate of 10%. The complex genetic makeup and heterogeneity of its microenvironment make PDAC difficult to treat. Desmoplasia, a major feature of PDAC’s TME, are dense fibrotic and inflammatory stromal regions. Desmoplastic reaction results in poor intratumoral perfusion and elevated interstitial fluid pressure, creating regions with severe oxygen and nutrient deprivation. One result is a deficiency in unsaturated fatty acids (uFAs) because the de novo synthesis of uFAs requires oxygen. Our results indicate that PDAC cells experience endoplasmic reticulum (ER) stress and trigger subsequent ER stress responses under uFA limited conditions in vitro. The ER stress responses are governed by three major stress sensors: Inositol-requiring enzyme 1𝛼 (IRE1𝛼), PKR-like ER kinase (PERK) and activating transcription factor 6𝛼 (ATF6𝛼). We hypothesize that ER stress responses are tumor promoting in PDAC and used as a survival strategy under uFA deprivation. In addition, previous studies showed that MYC-driven cancer cells are highly reliant on the ER stress response pathways. Therefore, we hypothesize that the two major PDAC transcriptional subtypes “Classical” and “Basal-like” have distinct dependencies on ER stress response pathways, with the basal-like subtype being more dependent due to an enrichment of MYC gene signatures. Our results suggest that opposite to cancer cell promoting, ER stress responses mediated by IRE1𝛼, PERK and ATF6𝛼 are cytotoxic in vitro under uFA deprived conditions. By analyzing the published bulk RNA-seq from patient samples, we found that the basal-like PDAC subtype is enriched with an ER stress gene signature. To avoid contamination from other cell populations, we are currently analyzing a published scRNA-seq dataset from 15 independent patient samples. We will investigate whether the ER stress signature is also enhanced in basal-like cells. Basal-like PDAC cells are usually more mesenchymal; we therefore created isogenic “epithelial” and “mesenchymal” lines to mimic PDAC subtypes. However, we did not see signaling preferences between the lines. One caveat is that the basal-like subtype have many more features than being mesenchymal, and our isogenic system might not be a faithful modeling of the subtypes. We are studying whether hypoxic PDAC cells experience ER stress in vivo due to a deprivation in uFAs using multiplex fluorescent imaging, stimulated Raman microscopy and/or mass spectrometry. We are evaluating the role of ER stress responses in vivo and see whether inhibiting ER stress response alone or in combination with other reagents gives rise to potential therapeutic opportunities. This project will provide a better understanding of the role ER stress responses play under uFA deprivation and will also enable us to further understand PDAC subtypes in terms of how they utilize ER stress responses. Citation Format: Yanqing (Christine) Jiang, Xu Han, Mai Wang, Raymond Ng, Pamela Burgess-Jones, John Tobias, Nathan Coffey, Andrew Hu, Brian Keith, Celeste Simon. Investigating endoplasmic reticulum stress responses in pancreatic ductal adenocarcinoma under lipid imbalance [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B010.

Accumulating evidence has shown that chronic injection of D-galactose (D-gal) can mimic natural ageing and induce liver and kidney injury. Previous studies showed that D-gal increased uric acid (UA) levels in mice. The increase in UA levels caused inflammation, accelerated oxidative stress, and aggravated liver and kidney injury. Oxidative stress and inflammation play vital roles in the ageing process. Therefore, reducing the levels of UA in ageing mice improved liver and kidney injury. Glucose transporter 9 (GLUT9) is responsible for the reabsorption of UA in the body, and its inhibition helps downregulate UA levels. The present study investigated the UA-lowering activity of the GLUT9 inhibitor resveratrol (RSV) using the patch clamping technique established in our laboratory

In this paper we empirically examine the possible effects of regional infrastructure investment on regional per capita income growth and regional total factor productivity (TFP) growth. We first pr...

Changes in gravity and buoyancy of a Full Ocean Depth Autonomous Underwater Vehicle (FOD-AUV) during its descending and ascending process must be considered very carefully compared with a Human Occupied Vehicle (HOV) or a Remotely Pperated Vehicle (ROV) whose activities rely on human decision. We firstly designed a two-step weight dropping pattern to achieve a high descending and ascending efficiency and a gravity-buoyancy balance at designed depth. The static equations showed that gravity acceleration, seawater density and displacement are three key aspects affecting the balance. Secondly, we try our best to analysis the gravity and buoyancy changing according to the previous known scientific information, such as anomaly of gravity acceleration, changing of seawater states. Finally, we drew conclusion that gravity changes little (no more than 0.1kgf, it is impossible to give a accurate value). A density-depth relationship at the Challenger Deep was acquired and the displacement changing of the FOD-AUV was calculated preciously. Keywords: Autonomous underwater vehicle, Full ocean depth, Statics variation analysis, Challenger deep, Gravity and buoyancy

Although immunotherapy has revolutionized cancer care, patients with pancreatic ductal adenocarcinoma (PDA) rarely respond to these treatments, a failure that is attributed to poor infiltration and activation of T cells in the tumor microenvironment (TME). We performed an in vivo CRISPR screen and identified lysine demethylase 3A (KDM3A) as a potent epigenetic regulator of immunotherapy response in PDA. Mechanistically, KDM3A acts through Krueppel-like factor 5 (KLF5) and SMAD family member 4 (SMAD4) to regulate the expression of the epidermal growth factor receptor (EGFR). Ablation of KDM3A, KLF5, SMAD4, or EGFR in tumor cells altered the immune TME and sensitized tumors to combination immunotherapy, whereas treatment of established tumors with an EGFR inhibitor, erlotinib, prompted a dose-dependent increase in intratumoral T cells. This study defines an epigenetic–transcriptional mechanism by which tumor cells modulate their immune microenvironment and highlights the potential of EGFR inhibitors as immunotherapy sensitizers in PDA.Significance:PDA remains refractory to immunotherapies. Here, we performed an in vivo CRISPR screen and identified an epigenetic–transcriptional network that regulates antitumor immunity by converging on EGFR. Pharmacologic inhibition of EGFR is sufficient to rewire the immune microenvironment. These results offer a readily accessible immunotherapy-sensitizing strategy for PDA.This article is highlighted in the In This Issue feature, p. 521

In this article, the three-dimensional trajectory tracking control of an autonomous underwater vehicle is addressed. The vehicle is assumed to be underactuated and the system parameters and the external disturbances are unknown. First, the five degrees of freedom kinematics and dynamics model of underactuated autonomous underwater vehicle are acquired. Following this, reduced-order linear extended state observers are designed to estimate and compensate for the uncertainties that exist in the model and the external disturbances. A backstepping active disturbance rejection control method is designed with the help of a time-varying barrier Lyapunov function to constrain the position tracking error. Furthermore, the controller system can be proved to be stable by employing the Lyapunov stability theory. Finally, the simulation and comparative analyses demonstrate the usefulness and robustness of the proposed controller in the presence of internal parameter uncertainties and external time-varying disturbances.