In Situ Reactive Printing of Aluminum Matrix Composite with Ultra-High Volume Fraction Reinforcement.

Additive manufacturing (AM) can fabricate intricate structures that are infeasible or uneconomical for conventional manufacturing methods. Its unique capabilities have motivated emergence of several printing technologies and extensive research in material adoption in particular ferrous-, Ti-, and Ni-based alloys. Meanwhile, the large freezing range and high reflectivity of aluminum, a lightweight structural material, greatly reduce aluminum's compatibility with AM. The incompatibility roots from aluminum's unstable behavior in the rapid cyclic thermal conditions in AM and its poor interaction with laser. This hinders the development of laser-based aluminum AM and deteriorates the existing lack of lightweight structural materials in the intermediate temperature range. Aluminum matrix composites (AMCs) have great potential to serve as thermally stable lightweight structural materials, combining lightweight nature of aluminum matrix and strength of reinforcement phases. However, fabrication of AMC largely uses conventional methods, achieving only moderate volume fraction of reinforcement while having limited part complexity compared with AM. To address these challenges, in situ reactive printing (IRP) is adopted as a novel AM method, harnessing the reaction product of dissimilar elemental powder mix to fabricate AMC with an ultra-high volume fraction of intermetallic reinforcement. In this study, the effect of titanium addition to elemental aluminum feedstock powder is systematically studied on different aspects, including material processability, microstructural features, and mechanical performances. The results show that IRP can overcome the incompatibility between AM and aluminum and produce AMC with exceptional volume fraction of reinforcements and outstanding stiffness enhancement when compared with existing AM aluminum alloys and other AMCs.

Motility and tumor infiltration are key aspects of invariant natural killer T cell anti-tumor function.

Dysfunction of invariant natural killer T (iNKT) cells contributes to immune resistance of tumors. Most mechanistic studies focus on their static functional status before or after activation, not considering motility as an important characteristic for antigen scanning and thus anti-tumor capability. Here we show via intravital imaging, that impaired motility of iNKT cells and their exclusion from tumors both contribute to the diminished anti-tumor iNKT cell response. Mechanistically, CD1d, expressed on macrophages, interferes with tumor infiltration of iNKT cells and iNKT-DC interactions but does not influence their intratumoral motility. VCAM1, expressed by cancer cells, restricts iNKT cell motility and inhibits their antigen scanning and activation by DCs via reducing CDC42 expression. Blocking VCAM1-CD49d signaling improves motility and activation of intratumoral iNKT cells, and consequently augments their anti-tumor function. Interference with macrophage-iNKT cell interactions further enhances the anti-tumor capability of iNKT cells. Thus, our findings provide a direction to enhance the efficacy of iNKT cell-based immunotherapy via motility regulation.

Elucidating Interfacial Dynamics of Ti-Al Systems Using Molecular Dynamics Simulation and Markov State Modeling.

Due to their remarkable mechanical and chemical properties, Ti-Al-based materials are attracting considerable interest in numerous fields of engineering, such as automotive, aerospace, and defense. With their low density, high strength, and resistance to corrosion and oxidation, these intermetallic alloys and metal-compound composites have found diverse applications. However, additive manufacturing and heat treatment of Ti-Al alloys frequently lead to brittleness and severe formation of defects. The present study delves into the interfacial dynamics of these Ti-Al systems, particularly focusing on the behavior of Ti and Al atoms in the presence of TiAl3 grain boundaries under experimental heat treatment conditions. Using a combination of molecular dynamics and Markov state modeling, we scrutinize the kinetic processes involved in the formation of TiAl3. The molecular dynamics simulation indicates that at the early stage of heat treatment, the predominating process is the diffusion of Al atoms toward the Ti surface through the TiAl3 grain boundaries. Markov state modeling identifies three distinct dynamic states of Al atoms within the Ti/Al mixture that forms during the process, each exhibiting a unique spatial distribution. Using transition time scales as a qualitative measure of the rapidness of the dynamics, it is observed that the Al dynamics is significantly less rapid near the Ti surface compared to the Al surface. Put together, the results offer a comprehensive understanding of the interfacial dynamics and reveal a three-stage diffusion mechanism. The process initiates with the premelting of Al, proceeds with the prevalent diffusion of Al atoms toward the Ti surface, and eventually ceases as the Ti concentration within the mixture progressively increases. The insights gained from this study could contribute significantly to the control and optimization of manufacturing processes for these high-performing Ti-Al-based materials.

O2 plasma-modified carbon nanotube for sulfamethoxazole degradation via peroxymonosulfate activation: Synergism of radical and non-radical pathways boosting water decontamination and detoxification.

Sulfamethoxazole (SMX), a widely used antibiotic, has triggered increasing attention due to its extensive detection in wastewater effluent, causing serious ecological threats. Herein, a carbon-based heterogeneous catalyst was developed by the O2 plasma-etching process, regulating oxygen-containing functional groups (OFGs) and defects of carbon nanotubes (O-CNT) to activate peroxymonosulfate (PMS) for highly efficient SMX abatement. Through adjusting the etching time, the desired active sites (i.e., C=O and defects) could be rationally created. Experiments collectively suggested that the degradation of SMX was owing to the contribution of synergism by radical (•OH (17.3%) and SO4•- (39.3%)) and non-radical pathways (1O2, 43.4%), which originated from PMS catalyzed by C=O and defects. In addition, the possible degradation products and transformation pathways of SMX in the system were inferred by combining the Fukui function calculations and the LC-MS/MS analysis. And the possible degradation pathway was effective in reducing the environmental toxicity of SMX, as evidenced by the T.E.S.T. software and the micronucleus experiment on Vicia faba root tip. Also, the catalytic system exhibited excellent performance for different antibiotics removal, such as amoxicillin (AMX), carbamazepine (CBZ) and isopropylphenazone (PRP). This study is expected to provide an alternative strategy for antibiotics removal in water decontamination and detoxification.

Antigen Priming Induces Functional Reprogramming in iNKT Cells via Metabolic and Epigenetic Regulation: An Insight into iNKT Cell-Based Antitumor Immunotherapy.

Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their antitumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses upon restimulation but constitutive high cytotoxicity. Mechanistically, impaired oxidative phosphorylation (OXPHOS) in antigen-primed iNKT cells inhibited T-cell receptor signaling, as well as elevation of glycolysis, upon restimulation via reducing mTORC1 activation, and thus led to impaired cytokine production. However, the metabolic reprogramming in antigen-primed iNKT cells was uncoupled with their enhanced cytotoxicity; instead, epigenetic remodeling explained their high expression of granzymes. Notably, intratumoral iNKT cells shared similar metabolic reprogramming and functional reprogramming with antigen-primed iNKT cells due to endogenous antigen priming in tumors, and thus recovery of OXPHOS in intratumoral iNKT cells by ZLN005 successfully enhanced their antitumor responses. Our study deciphers the influences of antigen priming-induced metabolic reprogramming and epigenetic remodeling on functionality of intratumoral iNKT cells, and proposes a way to enhance efficacy of iNKT cell-based antitumor immunotherapy by targeting cellular metabolism.

HIVEP3 inhibits fate decision of CD8+ invariant NKT cells after positive selection.

CD8+ invariant natural killer T (iNKT) cells are functionally different from other iNKT cells and are enriched in human but not in mouse. To date, their developmental pathway and molecular basis for fate decision remain unclear. Here, we report enrichment of CD8+ iNKT cells in neonatal mice due to their more rapid maturation kinetics than CD8- iNKT cells. Along developmental trajectories, CD8+ and CD8- iNKT cells separate at stage 0, following stage 0 double-positive iNKT cells, and differ in HIVEP3 expression. HIVEP3 is lowly expressed in stage 0 CD8+ iNKT cells and negatively controls their development, whereas it is highly expressed in stage 0 CD8- iNKT cells and positively controls their development. Despite no effect on IFN-γ, HIVEP3 inhibits granzyme B but promotes interleukin-4 production in CD8+ iNKT cells. Together, we reveal that, as a negative regulator for CD8+ iNKT fate decision, low expression of HIVEP3 in stage 0 CD8+ iNKT cells favors their development and T helper 1-biased cytokine responses as well as high cytotoxicity.

Robust and Effective: A Deep Matrix Factorization Framework for Classification.

For complex data, high dimension and high noise are challenging problems, and deep matrix factorization shows great potential in data dimensionality reduction. In this article, a novel robust and effective deep matrix factorization framework is proposed. This method constructs a dual-angle feature for single-modal gene data to improve the effectiveness and robustness, which can solve the problem of high-dimensional tumor classification. The proposed framework consists of three parts, deep matrix factorization, double-angle decomposition, and feature purification. First, a robust deep matrix factorization (RDMF) model is proposed in the feature learning, to enhance the classification stability and obtain better feature when faced with noisy data. Second, a double-angle feature (RDMF-DA) is designed by cascading the RDMF features with sparse features, which contains the more comprehensive information in gene data. Third, to avoid the influence of redundant genes on the representation ability, a gene selection method is proposed to purify the features by RDMF-DA, based on the principle of sparse representation (SR) and gene coexpression. Finally, the proposed algorithm is applied to the gene expression profiling datasets, and the performance of the algorithm is fully verified.

Proteomic Profiling of Extracellular Matrix Components from Patient Metastases Identifies Consistently Elevated Proteins for Developing Nanobodies That Target Primary Tumors and Metastases.

Metastases are hard to detect and treat, and they cause most cancer-related deaths. The relative lack of therapies targeting metastases represents a major unmet clinical need. The extracellular matrix (ECM) forms a major component of the tumor microenvironment in both primary and metastatic tumors, and certain ECM proteins can be selectively and abundantly expressed in tumors. Nanobodies against ECM proteins that show selective abundance in metastases have the potential to be used as vehicles for delivery of imaging and therapeutic cargoes. Here, we describe a strategy to develop phage-display libraries of nanobodies against ECM proteins expressed in human metastases, using entire ECM-enriched preparations from triple-negative breast cancer (TNBC) and colorectal cancer metastases to different organs as immunogens. In parallel, LC-MS/MS-based proteomics were used to define a metastasis-associated ECM signature shared by metastases from TNBC and colorectal cancer, and this conserved set of ECM proteins was selectively elevated in other tumors. As proof of concept, selective and high-affinity nanobodies were isolated against an example protein from this signature, tenascin-C (TNC), known to be abundant in many tumor types and to play a role in metastasis. TNC was abundantly expressed in patient metastases and widely expressed across diverse metastatic sites originating from several primary tumor types. Immuno-PET/CT showed that anti-TNC nanobodies bind TNBC tumors and metastases with excellent specificity. We propose that such generic nanobodies against tumors and metastases are promising cancer-agnostic tools for delivery of therapeutics to tumor and metastatic ECM. SIGNIFICANCE: Nanobodies specific for extracellular matrix markers commonly expressed in primary tumors and metastases are promising agents for noninvasive detection of tumors and metastases and potential tools for targeted therapy.

Dual-Encoder VAE-GAN With Spatiotemporal Features for Emotional EEG Data Augmentation.

The current data scarcity problem in EEG-based emotion recognition tasks leads to difficulty in building high-precision models using existing deep learning methods. To tackle this problem, a dual encoder variational autoencoder-generative adversarial network (DEVAE-GAN) incorporating spatiotemporal features is proposed to generate high-quality artificial samples. First, EEG data for different emotions are preprocessed as differential entropy features under five frequency bands and divided into segments with a 5s time window. Secondly, each feature segment is processed in two forms: the temporal morphology data and the spatial morphology data distributed according to the electrode position. Finally, the proposed dual encoder is trained to extract information from these two features, concatenate the two pieces of information as latent variables, and feed them into the decoder to generate artificial samples. To evaluate the effectiveness, a systematic experimental study was conducted in this work on the SEED dataset. First, the original training dataset is augmented with different numbers of generated samples; then, the augmented training datasets are used to train the deep neural network to construct the sentiment model. The results show that the augmented datasets generated by the proposed method have an average accuracy of 97.21% on all subjects, which is a 5% improvement compared to the original dataset, and the similarity between the generated data and the original data distribution is proved. These results demonstrate that our proposed model can effectively learn the distribution of raw data to generate high-quality artificial samples, which can effectively train a high-precision affective model.

Aging-related features predict prognosis and immunotherapy efficacy in hepatocellular carcinoma.

The aging microenvironment serves important roles in cancers. However, most studies focus on circumscribed hot spots such as immunity and metabolism. Thus, it is well ignored that the aging microenvironment contributes to the proliferation of tumor. Herein, we established three prognosis-distinctive aging microenvironment subtypes, including AME1, AME2, and AME3, based on aging-related genes and characterized them with "Immune Exclusion," "Immune Infiltration," and "Immune Intermediate" features separately. AME2-subtype tumors were characterized by specific activation of immune cells and were most likely to be sensitive to immunotherapy. AME1-subtype tumors were characterized by inhibition of immune cells with high proportion of Catenin Beta 1 (CTNNB1) mutation, which was more likely to be insensitive to immunotherapy. Furthermore, we found that CTNNB1 may inhibit the expression of C-C Motif Chemokine Ligand 19 (CCL19), thus restraining immune cells and attenuating the sensitivity to immunotherapy. Finally, we also established a robust aging prognostic model to predict the prognosis of patients with hepatocellular carcinoma. Overall, this research promotes a comprehensive understanding about the aging microenvironment and immunity in hepatocellular carcinoma and may provide potential therapeutic targets for immunotherapy.

Metastasis to lymph nodes at the contralateral entrance point to the recurrent laryngeal nerve in unilateral thyroid papillary carcinoma: a case report and literature review.

Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. PTC is slow growing, and prognosis after surgery is excellent. However, PTC is associated with a high incidence of cervical lymph node metastasis, and usually metastasizes from the central lymph nodes to the ipsilateral cervical and mediastinal lymph nodes. Anatomic studies have shown that the thyroid gland and surrounding tissue have an abundant lymphatic network that facilitates tumor dissemination and lymph node metastasis, there may be many ways to connect lymph nodes on both sides of the neck of patients, which needs further research and discussion. Case Description: We report the case of a 45-year-old female who was diagnosed with thyroid cancer of the right lobe and right lateral lymph node metastasis by fine-needle aspiration (FNA). During surgery, 0.2 mL of carbon nanoparticle (CN) suspension was injected into the right lobe of the thyroid gland, which resulted in black staining of a lymph node at the contralateral entrance point to the recurrent laryngeal nerve (LN-epRLN). The black-stained lymph node was resected, and the pathology results revealed lymph node metastasis from thyroid cancer. The left lobe of the thyroid was benign. Conclusions: Retro-tracheal periesophageal lymph node metastasis may be a rare metastatic pathway in thyroid cancer.

Vam6 reduces iNKT cell function in tumor via modulating AMPK/mTOR pathways.

Activation of mTORC1 is essential for anti-tumor function of iNKT cells. The mechanisms underlying impaired mTORC1 activation in intratumoral iNKT cells remain unclear. Via generating Vam6+/- mice and using flow cytometry, image approach, and RNA sequencing, we studied the role of Vam6 in controlling mTORC1 activation and intratumoral iNKT cell functions. Here, we find that increased Vam6 expression in intratumoral iNKT cells leads to impaired mTORC1 activation and IFN-γ production. Mechanistically, Vam6 in iNKT cells is essential for Rab7a-Vam6-AMPK complex formation and thus for recruitment of AMPK to lysosome to activate AMPK, a negative regulator of mTORC1. Additionally, Vam6 relieves inhibitory effect of VDAC1 on Rab7a-Vam6-AMPK complex formation at mitochondria-lysosome contact site. Moreover, we report that lactic acid produced by tumor cells increases Vam6 expression in iNKT cells. Given the key roles of increased Vam6 in promoting AMPK activation in intratumoral iNKT cells, reducing Vam6 expression signifificantly enhances the mTORC1 activation in intratumoral iNKT cells as well as their anti-tumor effificacy. Together, we propose Vam6 as a target for iNKT cell-based immunotherapy.

Repulsive guidance molecule acts in axon branching in Caenorhabditis elegans.

Repulsive guidance molecules (RGMs) are evolutionarily conserved proteins implicated in repulsive axon guidance. Here we report the function of the Caenorhabditis elegans ortholog DRAG-1 in axon branching. The axons of hermaphrodite-specific neurons (HSNs) extend dorsal branches at the region abutting the vulval muscles. The drag-1 mutants exhibited defects in HSN axon branching in addition to a small body size phenotype. DRAG-1 expression in the hypodermal cells was required for the branching of the axons. Although DRAG-1 is normally expressed in the ventral hypodermis excepting the vulval region, its ectopic expression in vulval precursor cells was sufficient to induce the branching. The C-terminal glycosylphosphatidylinositol anchor of DRAG-1 was important for its function, suggesting that DRAG-1 should be anchored to the cell surface. Genetic analyses suggested that the membrane receptor UNC-40 acts in the same pathway with DRAG-1 in HSN branching. We propose that DRAG-1 expressed in the ventral hypodermis signals via the UNC-40 receptor expressed in HSNs to elicit branching activity of HSN axons.

iNKT subsets differ in their developmental and functional requirements on Foxo1.

Invariant natural killer T (iNKT) cells play important roles in regulating immune responses. Based on cytokine profiling and key transcriptional factors, iNKT cells are classified into iNKT1, iNKT2, and iNKT17 subsets. However, whether the development and functions of these subsets are controlled by distinct mechanisms remains unclear. Here, we show that forkhead box protein O1 (Foxo1) promotes differentiation of iNKT1 and iNKT2 cells but not iNKT17 cells because of its distinct contributions to IL7R expression in these subsets. Nuclear Foxo1 is essential for Il7r expression in iNKT1 and iNKT2 cells at early stages of differentiation but is dispensable in iNKT17 cells. RORγt, instead of Foxo1, promotes IL7R expression in iNKT17 cells. Additionally, Foxo1 is required for the effector function of iNKT1 and iNKT2 cells but not iNKT17 cells. Cytoplasmic Foxo1 promotes activation of mTORC1 in iNKT1 and iNKT2 cells through inhibiting TSC1-TSC2 interaction, whereas it is dispensable for mTORC1 activation in iNKT17 cells. iNKT17 cells display distinct metabolic gene expression patterns from iNKT1 and iNKT2 cells that match their different functional requirements on Foxo1. Together, our results demonstrate that iNKT cell subsets differ in their developmental and functional requirements on Foxo1.

Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells.

Pancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.

Agaricus blazei polypeptide exerts a protective effect on D-galactose-induced aging mice via the Keap1/Nrf2/ARE and P53/Trim32 signaling pathways.

This experiment mainly optimized the extraction technology of Agaricus blazei polypeptide (ABp) and evaluated its protective effect on aging mice. In this study, a novel single component, the M is 3 kD, was isolated and purified from Agaricus blazei. An aging mouse model was established using D-galactose. After the administration of ABp, the contents of total antioxidant capacity (T-AOC), malondialdehyde (MDA), catalase (CAT), and reactive oxygen species were significantly changed. Through immunofluorescence staining, it was observed that ABp can reduce changes in brain tissue. The differential expression of genes was analyzed by RNA-seq. A total of 295 differentially expressed genes were screened out in the ABp group.RT-qPCR verified important genes and showed that the mRNA expression levels of Hsph1, Trim32, HK1, Hnrnpa1, and Grik5 were significantly increased, and those of ApoE, Atp1a3, Stxbp1, and Mapk8ip1 was significantly decreased. Western blotting showed that the protein expression levels of Keap1 and p53 were significantly lower, while the protein expression levels of Nrf2, HO-1, Hsph1, and Trim32 were significantly higher in the ABP group. ABp played an anti-aging role in an aging mouse model. The specific mechanism of action may be related to the regulation of the expression of the Keap1/Nrf2/P53 signaling pathway and related factors. PRACTICAL APPLICATIONS: The research may contribute to the development of ABp as functional foods or dietary supplements for anti-aging in the future.

Cancer Cell-Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma.

The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell-derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell-derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell-derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. SIGNIFICANCE: This study provides insights into the biological roles of cancer cell-derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

The scaffold protein IQGAP1 is crucial for extravasation and metastasis.

IQGAP1 is a scaffold protein involved in a range of cellular activities, including migration, invasion, adhesion and proliferation. It is also oncogenic in a variety of cancers, promoting primary tumor growth and invasiveness. However, the role of IQGAP1 in tumor progression and metastasis remains unclear. In this study, we use both knockdown and knockout of IQGAP1 to investigate its role in the metastatic cascade of both melanoma and breast cancer cells in vivo. We find that reduction of IQGAP1 expression decreases the formation of both spontaneous and experimental metastases, without limiting primary or metastatic tumor growth. Furthermore, IQGAP1 knockout significantly inhibits extravasation of tumor cells from circulation, possibly involving invadopodial function. By expressing mutant forms of IQGAP1 in a knockout context, we also determine that IQGAP1's pro-metastatic functions are dependent on multiple domains and functions. These data demonstrate that IQGAP1 is crucial for metastasis in vivo through regulation of extravasation and suggest that it may represent a valid therapeutic target for inhibiting metastasis.

Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells.

Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.

Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells.

Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular matrix (ECM) that compromises treatments yet cannot be nonselectively disrupted without adverse consequences. ECM of PDAC, despite the recognition of its importance, has not been comprehensively studied in patients. In this study, we used quantitative mass spectrometry (MS)-based proteomics to characterize ECM proteins in normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and PDAC-bearing pancreas from both human patients and mouse genetic models, as well as chronic pancreatitis patient samples. We describe detailed changes in both abundance and complexity of matrisome proteins in the course of PDAC progression. We reveal an early up-regulated group of matrisome proteins in PanIN, which are further up-regulated in PDAC, and we uncover notable similarities in matrix changes between pancreatitis and PDAC. We further assigned cellular origins to matrisome proteins by performing MS on multiple lines of human-to-mouse xenograft tumors. We found that, although stromal cells produce over 90% of the ECM mass, elevated levels of ECM proteins derived from the tumor cells, but not those produced exclusively by stromal cells, tend to correlate with poor patient survival. Furthermore, distinct pathways were implicated in regulating expression of matrisome proteins in cancer cells and stromal cells. We suggest that, rather than global suppression of ECM production, more precise ECM manipulations, such as targeting tumor-promoting ECM proteins and their regulators in cancer cells, could be more effective therapeutically.