A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/ß-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.

AGFG1 increases cholesterol biosynthesis by disrupting intracellular cholesterol homeostasis to promote PDAC progression.

PURPOSE: Cholesterol metabolism reprograming has been acknowledged as a novel feature of cancers. Pancreatic ductal adenocarcinoma (PDAC) is a cancer with a high demand of cholesterol for rapid growth. The underlying mechanism of how cholesterol metabolism homestasis are disturbed in PDAC is explored. EXPERIMENTAL DESIGN: The relevance between PDAC and cholesterol was confirmed in TCGA database. The expression and clinical association were discovered in TCGA and GEO datasets. Knockdown and overexpression of AGFG1 was adopted to perform function studies. RNA sequencing, cholesterol detection, transmission electron microscope, co-immunoprecipitation, and immunofluorescence et al. were utilized to reveal the underlying mechanism. RESULTS: AGFG1 was identified as one gene positively correlated with cholesterol metabolism in PDAC as revealed by bioinformatics analysis. AGFG1 expression was then found associated with poor prognosis in PDAC. AGFG1 knockdown led to decreased proliferation of tumor cells both in vitro and in vivo. By RNA sequencing, we found AGFG1 upregulated expression leads to enhanced intracellular cholesterol biosynthesis. AGFG1 knockdown suppressed cholesterol biosynthesis and an accumulation of cholesterol in the ER. Mechanistically, we confirmed that AGFG1 interacted with CAV1 to relocate cholesterol for the proceeding of cholesterol biosynthesis, therefore causing disorders in intracellular cholesterol metabolism. CONCLUSIONS: Our study demonstrates the tumor-promoting role of AGFG1 by disturbing cholesterol metabolism homestasis in PDAC. Our study has present a new perspective on cancer therapeutic approach based on cholerstrol metabolism in PDAC.

Elevated expression of Golgi Transport 1B promotes the progression of cervical cancer by activating NF-κB signaling pathway via interaction with TBK1.

As a preventable disease, cervical cancer (cervical squamous cell carcinoma and endocervical adenocarcinoma - CESC) remains a tumor with high morbidity and mortality worldwide, underscoring the pressing need for effective treatment strategies. This research identified Golgi transport 1B (GOLT1B) as a critical gene involved in the development of cervical cancer. Gene Expression Omnibus (GEO) datasets were investigated to determine the upregulation of GOLT1B in cervical cancer tissue compared to normal tissue. Besides, GOLT1B was found to predict poor prognosis in cervical cancer by utilizing Gene Expression Profiling Interactive Analysis (GEPIA). The functional assay indicated that GOLT1B promoted CESC viability and migration in vitro and in vivo. RNA sequencing results suggested that GOLT1B likely influenced NF-κB pathway. The subsequent western blot and dual luciferase reporter assay revealed the interaction between GOLT1B and TBK1, modulating the NF-κB pathway. More importantly, GOLT1B was also found to regulate immune cells infiltration, suggesting its potential role in tumor microenvironment. In conclusion, GOLT1B promotes CESC progression via interaction with TBK1 and augmentation of NF-κB signaling-mediated cancer-associated inflammation, which provides us a new approach to CESC target therapy.

Phase interface engineering enables state-of-the-art half-Heusler thermoelectrics.

In thermoelectric, phase interface engineering proves effective in reducing the lattice thermal conductivity via interface scattering and amplifying the density-of-states effective mass by energy filtering. However, the indiscriminate introduction of phase interfaces inevitably leads to diminished carrier mobility. Moreover, relying on a singular energy barrier is insufficient for comprehensive filtration of low-energy carriers throughout the entire temperature range. Addressing these challenges, we advocate the establishment of a composite phase interface using atomic layer deposition (ALD) technology. This design aims to effectively decouple the interrelated thermoelectric parameters in ZrNiSn. The engineered coherent dual-interface energy barriers substantially enhance the density-of-states effective mass across the entire temperature spectrum while preser carrier mobility. Simultaneously, the strong interface scattering on phonons is crucial for curtailing lattice thermal conductivity. Consequently, a 40-cycles TiO2 coating on ZrNi1.03Sn0.99Sb0.01 achieves an unprecedented zT value of 1.3 at 873 K. These findings deepen the understanding of coherent composite-phase interface engineering.

Phosphorylation of FOXK2 at Thr13 and Ser30 by PDK2 sustains glycolysis through a positive feedback manner in ovarian cancer.

Ovarian cancer is one of the most common gynecological malignant tumors with insidious onset, strong invasiveness, and poor prognosis. Metabolic alteration, particularly aerobic glycolysis, which is tightly regulated by transcription factors, is associated with the malignant behavior of OC. We screened FOXK2 in this study as a key transcription factor that regulates glycolysis in OC. FOXK2 is overly expressed in OC, and poor prognosis is predicted by overexpression. FOXK2 promotes OC cell proliferation both in vitro and in vivo and cell migration in vitro. Further studies showed that PDK2 directly binds to the forkhead-associated (FHA) domain of FOXK2 to phosphorylate FOXK2 at Thr13 and Ser30, thereby enhancing the transcriptional activity of FOXK2. FOXK2 transcriptionally regulates the expression of PDK2, thus forming positive feedback to sustain glycolysis in OC cells.

Nuanced dilute doping strategy enables high-performance GeTe thermoelectrics.

In thermoelectrics, doping is essential to augment the figure of merit. Traditional strategy, predominantly heavy doping, aims to optimize carrier concentration and restrain lattice thermal conductivity. However, this tactic can severely hamper carrier transport due to pronounced point defect scattering, particularly in materials with inherently low carrier mean-free-path. Conversely, dilute doping, although minimally affecting carrier mobility, frequently fails to optimize other vital thermoelectric parameters. Herein, we present a more nuanced dilute doping strategy in GeTe, leveraging the multifaceted roles of small-size metal atoms. A mere 4% CuPbSbTe3 introduction into GeTe swiftly suppresses rhombohedral distortion and optimizes carrier concentration through the aid of Cu interstitials. Additionally, the formation of multiscale microstructures, including zero-dimensional Cu interstitials, one-dimensional dislocations, two-dimensional planar defects, and three-dimensional nanoscale amorphous GeO2 and Cu2GeTe3 precipitates, along with the ensuing lattice softening, contributes to an ultralow lattice thermal conductivity. Intriguingly, dilute CuPbSbTe3 doping incurs only a marginal decrease in carrier mobility. Subsequent trace Cd doping, employed to alleviate the bipolar effect and align the valence bands, yields an impressive figure-of-merit of 2.03 at 623 K in (Ge0.97Cd0.03Te)0.96(CuPbSbTe3)0.04. This leads to a high energy-conversion efficiency of 7.9% and a significant power density of 3.44 W cm-2 at a temperature difference of 500 K. These results underscore the invaluable insights gained into the constructive role of nuanced dilute doping in the concurrent tuning of carrier and phonon transport in GeTe and other thermoelectric materials.

A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

Inhibiting Mg Diffusion and Evaporation by Forming Mg-Rich Reservoir at Grain Boundaries Improves the Thermal Stability of N-Type Mg3 Sb2 Thermoelectrics.

N-type Mg3 Sb2 -based thermoelectric materials show great promise in power generation due to their mechanical robustness, low cost of Mg, and high figure of merit (ZT) over a wide range of temperatures. However, their poor thermal stability hinders their practical applications. Here, MgB2 is introduced to improve the thermal stability of n-type Mg3 Sb2 . Enabled by MgB2 decomposition, extra Mg can be released into the matrix for Mg compensation thermodynamically, and secondary phases of Mg─B compounds can kinetically prevent Mg diffusion along grain boundaries. These synergetic effects inhibit the formation of Mg vacancies at elevated temperatures, thereby enhancing the thermal stability of n-type Mg3 Sb2 . Consequently, the Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 (MgB2 )0.03 sample exhibits negligible variation in thermoelectric performance during the 120-hour continuous measurement at 673 K. Moreover, the ZT of n-type Mg3 Sb2 can be maintained by adding MgB2 , reaching a high average ZT of ≈1.1 within 300-723 K. An eight-pair Mg3 Sb2 -GeTe-based thermoelectric device is also fabricated, achieving an energy conversion efficiency of ≈5.7% at a temperature difference of 438 K with good thermal stability. This work paves a new way to enhance the long-term thermal stability of n-type Mg3 Sb2 -based alloys and other thermoelectrics for practical applications.

Two-step phase manipulation by tailoring chemical bonds results in high-performance GeSe thermoelectrics.

In thermoelectrics, phase engineering serves a crucial function in determining the power factor by affecting the band degeneracy. However, for low-symmetry compounds, the mainstream one-step phase manipulation strategy, depending solely on the valley or orbital degeneracy, is inadequate to attain a high density-of-states effective mass and exceptional zT. Here, we employ a distinctive two-step phase manipulation strategy through stepwise tailoring chemical bonds in GeSe. Initially, we amplify the valley degeneracy via CdTe alloying, which elevates the crystal symmetry from a covalently bonded orthorhombic to a metavalently bonded rhombohedral phase by significantly suppressing the Peierls distortion. Subsequently, we incorporate Pb to trigger the convergence of multivalence bands and further enhance the density-of-states effective mass by moderately restraining the Peierls distortion. Additionally, the atypical metavalent bonding in rhombohedral GeSe enables a high Ge vacancy concentration and a small band effective mass, leading to increased carrier concentration and mobility. This weak chemical bond along with strong lattice anharmonicity also reduces lattice thermal conductivity. Consequently, this unique property ensemble contributes to an outstanding zT of 0.9 at 773 K for Ge0.80Pb0.20Se(CdTe)0.25. This work underscores the pivotal role of the two-step phase manipulation by stepwise tailoring of chemical bonds in improving the thermoelectric performance of p-bonded chalcogenides.

XPOT Disruption Suppresses TNBC Growth through Inhibition of Specific tRNA Nuclear Exportation and TTC19 Expression to Induce Cytokinesis Failure.

Transfer RNAs (tRNAs) impact the development and progression of various cancers, but how individual tRNAs are modulated during triple-negative breast cancer (TNBC) progression remains poorly understood. Here, we found that XPOT (Exportin-T), a nuclear export protein receptor of tRNAs, is associated with poor prognosis in breast cancer and directly orchestrates the nuclear export of a subset of tRNAs, subsequently promoting protein synthesis and proliferation of human TNBC cells. XPOT knockdown inhibited TNBC cell proliferation in vitro, and RNA-seq indicated that XPOT is involved in the completion of cytokinesis in TNBC cells. High-throughput sequencing of tRNA revealed that XPOT specifically influenced a subset of tRNA isodecoders involved in nucleocytoplasmic trafficking, including tRNA-Ala-AGC-10-1. Through codon preferential analysis and protein mass spectrometry, we found that XPOT preferentially transported nuclear tRNA-Ala-AGC-10-1 to the cytoplasm, driving the translation of TPR Repeat Protein 19 (TTC19). TTC19 is also indispensable for cytokinesis and proliferation of TNBC cells. Altogether, these findings provide a novel regulatory translation mechanism for preferential tRNA isodecoder nucleocytoplasmic transport through XPOT, which coordinates the spatial location of specific tRNA and the translation of mRNA to facilitate TNBC proliferation and progression. Targeting XPOT may be a novel therapeutic strategy for treating TNBC.

Gibbs Adsorption and Zener Pinning Enable Mechanically Robust High-Performance Bi2 Te3 -Based Thermoelectric Devices.

Bi2 Te3 -based alloys have great market demand in miniaturized thermoelectric (TE) devices for solid-state refrigeration and power generation. However, their poor mechanical properties increase the fabrication cost and decrease the service durability. Here, this work reports on strengthened mechanical robustness in Bi2 Te3 -based alloys due to thermodynamic Gibbs adsorption and kinetic Zener pinning at grain boundaries enabled by MgB2 decomposition. These effects result in much-refined grain size and twofold enhancement of the compressive strength and Vickers hardness in (Bi0.5 Sb1.5 Te3 )0.97 (MgB2 )0.03 compared with that of traditional powder-metallurgy-derived Bi0.5 Sb1.5 Te3 . High mechanical properties enable excellent cutting machinability in the MgB2 -added samples, showing no missing corners or cracks. Moreover, adding MgB2 facilitates the simultaneous optimization of electron and phonon transport for enhancing the TE figure of merit (ZT). By further optimizing the Bi/Sb ratio, the sample (Bi0.4 Sb1.6 Te3 )0.97 (MgB2 )0.03 shows a maximum ZT of ≈1.3 at 350 K and an average ZT of 1.1 within 300-473 K. As a consequence, robust TE devices with an energy conversion efficiency of 4.2% at a temperature difference of 215 K are fabricated. This work paves a new way for enhancing the machinability and durability of TE materials, which is especially promising for miniature devices.

Mg Compensating Design in the Melting-Sintering Method For High-Performance Mg3 (Bi, Sb)2 Thermoelectric Devices.

N-type Mg3 (Bi, Sb)2 -based thermoelectric (TE) alloys show great promise for solid-state power generation and refrigeration, owing to their excellent figure-of-merit (ZT) and using cheap Mg. However, their rigorous preparation conditions and poor thermal stability limit their large-scale applications. Here, this work develops an Mg compensating strategy to realize n-type Mg3 (Bi, Sb)2 by a facile melting-sintering approach. "2D roadmaps" of TE parameters versus sintering temperature and time are plotted to understand the Mg-vacancy-formation and Mg-diffusion mechanisms. Under this guidance, high weight mobility of 347 cm2  V-1  s-1 and power factor of 34 µW cm-1  K-2 can be obtained for Mg3.05 Bi1.99 Te0.01 , and a peak ZT≈1.55 at 723 K and average ZT≈1.25 within 323-723 K can be obtained for Mg3.05 (Sb0.75 Bi0.25 )1.99 Te0.01 . Moreover, this Mg compensating strategy can also improve the interfacial connecting and thermal stability of corresponding Mg3 (Bi, Sb)2 /Fe TE legs. As a consequence, this work fabricates an 8-pair Mg3 Sb2 -GeTe-based power-generation device reaching an energy conversion efficiency of ≈5.0% at a temperature difference of 439 K, and a one-pair Mg3 Sb2 -Bi2 Te3 -based cooling device reaching -10.7 °C at the cold side. This work paves a facile way to obtain Mg3 Sb2 -based TE devices at low cost and also provides a guide to optimize the off-stoichiometric defects in other TE materials.

SORL1 stabilizes ABCB1 to promote cisplatin resistance in ovarian cancer.

Ovarian cancer (OC) has the worst prognosis among gynecological malignancies. Cisplatin (CDDP) is one of the most commonly used treatments for OC, but recurrence and metastasis are common due to endogenous or acquired resistance. High expression of ATP-binding cassette (ABC) transporters is an important mechanism of resistance to OC chemotherapy, but targeting ABC transporters in OC therapy remains a challenge. The expression of sortilin-related receptor 1 (SORL1; SorLA) in the response of OC to CDDP was determined by analysis of TCGA and GEO public datasets. Immunohistochemistry and western blotting were utilized to evaluate the expression levels of SORL1 in OC tissues and cells that were sensitive or resistant to CDDP treatment. The in vitro effect of SORL1 on OC cisplatin resistance was proven by CCK-8 and cell apoptosis assays. The subcutaneous xenotransplantation model verified the in vivo significance of SORL1 in OC. Finally, the molecular mechanism by which SORL1 regulates OC cisplatin resistance was revealed by coimmunoprecipitation, gene set enrichment analysis and immunofluorescence analysis. This study demonstrated that SORL1 is closely related to CDDP resistance and predicts a poor prognosis in OC. In vivo xenograft experiments showed that SORL1 knockdown significantly enhanced the effect of CDDP on CDDP-resistant OC cells. Mechanistically, silencing of SORL1 inhibits the early endosomal antigen 1 (EEA1) pathway, which impedes the stability of ATP-binding cassette B subfamily member 1 (ABCB1), sensitizing CDDP-resistant OC cells to CDDP. The findings of this study suggest that targeting SORL1 may represent a promising therapeutic approach for overcoming CDDP resistance in OC.

MAOA suppresses the growth of gastric cancer by interacting with NDRG1 and regulating the Warburg effect through the PI3K/AKT/mTOR pathway.

OBJECTIVE: Previous studies have indicated that neurotransmitters play important roles in the occurrence and development of gastric cancer. MAOA is an important catecholamine neurotransmitter-degrading enzyme involved in the degradation of norepinephrine, epinephrine and serotonin. To find a potential therapeutic target for the treatment of gastric cancer, the biological functions of MAOA and the underlying mechanism in gastric cancer need to be explored. METHODS: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets, Kaplan‒Meier (KM) plotter were used to identify the differentially expressed genes, which mainly involved the degradation and synthesis enzymes of neurotransmitters in gastric cancer. We also investigated the expression pattern of MAOA in human and mouse tissues and cell lines by immunohistochemistry and Western blotting analysis. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and a Seahorse experiment were used to identify the molecular mechanism of cancer cell glycolysis. MAOA expression and patient survival were analysed in the Ren Ji cohort, and univariate and multivariate analyses were performed based on the clinicopathological characteristics of the above samples. RESULTS: MAOA expression was significantly downregulated in gastric cancer tissue and associated with poor patient prognosis. Moreover, the expression level of MAOA in gastric cancer tissue had a close negative correlation with the SUXmax value of PET-CT in patients. MAOA suppressed tumour growth and glycolysis and promoted cancer cell apoptosis. We also reported that MAOA can interact with NDRG1 and regulate glycolysis through suppression of the PI3K/Akt/mTOR pathway. MAOA expression may serve as an independent prognostic factor in gastric cancer patients. CONCLUSIONS: MAOA attenuated glycolysis and inhibited the progression of gastric cancer through the PI3K/Akt/mTOR pathway. Loss of function or downregulation of MAOA can facilitate gastric cancer progression. Overexpression of MAOA and inhibition of the PI3K/Akt/mTOR pathway may provide a potential method for gastric cancer treatment in clinical therapeutic regimens.

Nucleolar HEAT Repeat Containing 1 Up-regulated by the Mechanistic Target of Rapamycin Complex 1 Signaling Promotes Hepatocellular Carcinoma Growth by Dominating Ribosome Biogenesis and Proteome Homeostasis.

BACKGROUND & AIMS: Hyperactivation of ribosome biogenesis leads to hepatocyte transformation and plays pivotal roles in hepatocellular carcinoma (HCC) development. We aimed to identify critical ribosome biogenesis proteins that are overexpressed and crucial in HCC progression. METHODS: HEAT repeat containing 1 (HEATR1) expression and clinical correlations were analyzed using The Cancer Genome Atlas and Gene Expression Omnibus databases and further evaluated by immunohistochemical analysis of an HCC tissue microarray. Gene expression was knocked down by small interfering RNA. HEATR1-knockdown cells were subjected to viability, cell cycle, and apoptosis assays and used to establish subcutaneous and orthotopic tumor models. Chromatin immunoprecipitation and quantitative polymerase chain reaction were performed to detect the association of candidate proteins with specific DNA sequences. Endogenous coimmunoprecipitation combined with mass spectrometry was used to identify protein interactions. We performed immunoblot and immunofluorescence assays to detect and localize proteins in cells. The nucleolus ultrastructure was detected by transmission electron microscopy. Click-iT (Thermo Fisher Scientific) RNA imaging and puromycin incorporation assays were used to measure nascent ribosomal RNA and protein synthesis, respectively. Proteasome activity, 20S proteasome foci formation, and protein stability were evaluated in HEATR1-knockdown HCC cells. RESULTS: HEATR1 was the most up-regulated gene in a set of ribosome biogenesis mediators in HCC samples. High expression of HEATR1 was associated with poor survival and malignant clinicopathologic features in patients with HCC and contributed to HCC growth in vitro and in vivo. HEATR1 expression was regulated by the transcription factor specificity protein 1, which can be activated by insulin-like growth factor 1-mammalian target of rapamycin complex 1 signaling in HCC cells. HEATR1 localized predominantly in the nucleolus, bound to ribosomal DNA, and was associated with RNA polymerase I transcription/processing factors. Knockdown of HEATR1 disrupted ribosomal RNA biogenesis and impaired nascent protein synthesis, leading to reduced cytoplasmic proteasome activity and inhibitory-κB/nuclear factor-κB signaling. Moreover, HEATR1 knockdown induced nucleolar stress with increased nuclear proteasome activity and inactivation of the nucleophosmin 1-MYC axis. CONCLUSIONS: Our study revealed that HEATR1 is up-regulated by insulin-like growth factor 1-mammalian target of rapamycin complex 1-specificity protein 1 signaling in HCC and functions as a crucial regulator of ribosome biogenesis and proteome homeostasis to promote HCC development.

METTL3 suppresses pancreatic ductal adenocarcinoma progression through activating endogenous dsRNA-induced anti-tumor immunity.

PURPOSE: Although immunotherapy improves clinical outcomes in several types of malignancies, as an immunologically 'cold' tumor, pancreatic ductal adenocarcinoma (PDAC) is arrantly resistant to immunotherapy. However, the role of N6-methyladenosine (m6A) modification in the immune microenvironment of PDAC is still poorly understood. METHODS: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify differentially expressed m6A related enzymes. The biological role and mechanism of METTL3 in PDAC growth and metastasis were determined in vitro and in vivo. RNA-sequencing and bioinformatics analysis were used to identify signaling pathways involved in METTL3. Western blot, m6A dot blot assays, co-immunoprecipitation, immunofluorescence, and flow cytometry were used to explore the molecular mechanism. RESULTS: Here, we demonstrate that METTL3, the key regulator of m6A modification, is downregulated in PDAC, and negatively correlates with PDAC malignant features. Elevated METTL3 suppresses PDAC growth and overcomes resistance to immune checkpoint blockade. Mechanistically, METTL3 promotes the accumulation of endogenous double-stranded RNA (dsRNA) through protecting m6A-transcripts from further Adenosine-to-inosine (A-to-I) editing. The dsRNA stress activates RIG-I-like receptors (RLRs) to enhance anti-tumor immunity, finally suppressing PDAC progression. CONCLUSION: Our findings indicate that tumor cell-intrinsic m6A modification participates in the regulation of tumor immune landscape. Adjusting the m6A level may be an effective strategy to overcome the resistance to immunotherapy and increase responsiveness to immunotherapy in PDAC.

The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells.

PURPOSE: Gastric cancer (GC) is a malignant tumour with high mortality, and liver metastasis is one of the main causes of poor prognosis. SLIT- and NTRK-like family member 4 (SLITRK4) plays an important role in the nervous system, such as synapse formation. Our study aimed to explore the functional role of SLITRK4 in GC and liver metastasis. METHODS: The mRNA level of SLITRK4 was evaluated using publicly available transcriptome GEO datasets and Renji cohort. The protein level of SLITRK4 in the tissue microarray of GC was observed using immunohistochemistry. Cell Counting Kit-8, colony formation, transwell migration assays in vitro and mouse model of liver metastasis in vivo was performed to investigate the functional roles of SLITRK4 in GC. Bioinformatics predictions and Co-IP experiments were applied to screen and identify SLITRK4-binding proteins. Western blot was performed to detect Tyrosine Kinase receptor B (TrkB)-related signaling molecules. RESULTS: By comparing primary and liver metastases from GC, SLITRK4 was found to be upregulated in tissues of GC with liver metastasis and to be closely related to poor clinical prognosis. SLITRK4 knockdown significantly abrogated the growth, invasion, and metastasis of GC in vitro and in vivo. Further study revealed that SLITRK4 could interact with Canopy FGF Signalling Regulator 3 (CNPY3), thus enhancing TrkB- related signaling by promoting the endocytosis and recycling of the TrkB receptor. CONCLUSION: In conclusion, the CNPY3-SLITRK4 axis contributes to liver metastasis of GC according to the TrkB-related signaling pathway. which may be a therapeutic target for the treatment of GC with liver metastasis.

High Pressure Drives Microstructure Modification and zT Enhancement in Bismuth Telluride-Based Alloys.

Manipulating and integrating the microstructures at different scales is crucial to tune the electrical and thermal properties of a given compound. High-pressure sintering can modify the multiscale microstructures and thus empower the cutting-edge thermoelectric performance. In this work, the high-pressure sintering technique followed by annealing is adopted to prepare Gd-doped p-type (Bi0.2Sb0.8)2(Te0.97Se0.03)3 alloys. First, the high energy of high-pressure sintering promotes the reduction of grain size, thus increasing the content of 2D grain boundaries. Next, high-pressure sintering induces strong interior strain, where 1D dense dislocations are generated near the strain field. More interestingly, the rare-earth element Gd with a high melting temperature is dissolved into the matrix via high-pressure sintering, thus promoting the formation of 0D extrinsic point defects. This concurrently improves the carrier concentration and density-of-state effective mass, resulting in an enhanced power factor. In addition, the integrated 0D point defects, 1D dislocations, and 2D grain boundaries by high-pressure sintering strengthen phonon scattering, thereby achieving a low lattice thermal conductivity of 0.5 Wm-1 K-1 at 348 K. Consequently, a maximum zT value of ∼1.1 at 348 K is achieved in the 0.4 at % Gd-doped (Bi0.2Sb0.8)2(Te0.97Se0.03)3 sample. This work demonstrates that high-pressure sintering enables microstructure modification to enhance the thermoelectric performance of Bi2Te3-based and other bulk materials.

FADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer.

Colonocyte metabolism shapes the microbiome. Metabolites are the main mediators of information exchange between intestine and microbial communities. Arachidonic acid (AA) is an essential polyunsaturated fatty acid and its role in colorectal cancer (CRC) remains unexplored. In this study, we show that AA feeding promotes tumor growth in AOM/DSS and intestinal specific Apc-/- mice via modulating the intestinal microecology of increased gram-negative bacteria. Delta-5 desaturase (FADS1), a rate-limiting enzyme, is upregulated in CRC and effectively mediates AA synthesis. Functionally, FADS1 regulates CRC tumor growth via high AA microenvironment-induced enriched gram-negative microbes. Elimination of gram-negative microbe abolishes FADS1 effect. Mechanistically, gram-negative microbes activate TLR4/MYD88 pathway in CRC cells that contributes FADS1-AA axis to metabolize to prostaglandin E2 (PGE2). Cumulatively, we report a potential cancer-promoting mechanism of FADS1-AA axis in CRC that converts raising synthesized AA to PGE2 via modulating the intestinal microecology of gram-negative.