Cell Communication Network factor 4 promotes tumor-induced immunosuppression in melanoma.

Cell Communication Network factor 4 (CCN4/WISP1) is a matricellular protein secreted by cancer cells that promotes metastasis by inducing the epithelial-mesenchymal transition. While metastasis limits survival, limited anti-tumor immunity also associates with poor patient outcomes with recent work linking these two clinical correlates. Motivated by increased CCN4 correlating with dampened anti-tumor immunity in primary melanoma, we test for a direct causal link by knocking out CCN4 (CCN4 KO) in the B16F0 and YUMM1.7 mouse melanoma models. Tumor growth is reduced when CCN4 KO melanoma cells are implanted in immunocompetent but not in immunodeficient mice. Correspondingly, CD45+ tumor-infiltrating leukocytes are significantly increased in CCN4 KO tumors, with increased natural killer and CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC). Among mechanisms linked to local immunosuppression, CCN4 suppresses IFN-gamma release by CD8+ T cells and enhances tumor secretion of MDSC-attracting chemokines like CCL2 and CXCL1. Finally, CCN4 KO potentiates the anti-tumor effect of immune checkpoint blockade (ICB) therapy. Overall, our results suggest that CCN4 promotes tumor-induced immunosuppression and is a potential target for therapeutic combinations with ICB.

Identification of clinical prognostic factors and analysis of ferroptosis-related gene signatures in the bladder cancer immune microenvironment.

BACKGROUND: Bladder cancer (BLCA) is a prevalent malignancy affecting the urinary system and poses a significant burden in terms of both incidence and mortality rates on a global scale. Among all BLCA cases, non-muscle invasive bladder cancer constitutes approximately 75% of the total. In recent years, the concept of ferroptosis, an iron-dependent form of regulated cell death marked by the accumulation of lipid peroxides, has captured the attention of researchers worldwide. Nevertheless, the precise involvement of ferroptosis-related genes (FRGs) in the anti-BLCA response remains inadequately elucidated. METHODS: The integration of BLCA samples from the TCGA and GEO datasets facilitated the quantitative evaluation of FRGs, offering potential insights into their predictive capabilities. Leveraging the wealth of information encompassing mRNAsi, gene mutations, CNV, TMB, and clinical features within these datasets further enriched the analysis, augmenting its robustness and reliability. Through the utilization of Lasso regression, a prediction model was developed, enabling accurate prognostic assessments within the context of BLCA. Additionally, co-expression analysis shed light on the complex relationship between gene expression patterns and FRGs, unraveling their functional relevance and potential implications in BLCA. RESULTS: FRGs exhibited increased expression levels in the high-risk cohort of BLCA patients, even in the absence of other clinical indicators, suggesting their potential as prognostic markers. GSEA revealed enrichment of immunological and tumor-related pathways specifically in the high-risk group. Furthermore, notable differences were observed in immune function and m6a gene expression between the low- and high-risk groups. Several genes, including MYBPH, SOST, SPRR2A, and CRNN, were found to potentially participate in the oncogenic processes underlying BLCA. Additionally, CYP4F8, PDZD3, CRTAC1, and LRTM1 were identified as potential tumor suppressor genes. Significant discrepancies in immunological function and m6a gene expression were observed between the two risk groups, further highlighting the distinct molecular characteristics associated with different prognostic outcomes. Notably, strong correlations were observed among the prognostic model, CNVs, SNPs, and drug sensitivity profiles. CONCLUSIONS: FRGs are associated with the onset and progression of BLCA. A FRGs signature offers a viable alternative to predict BLCA, and these FRGs show a prospective research area for BLCA targeted treatment in the future.

Tunable Ordered Nanostructured Phases by Co-assembly of Amphiphilic Polyoxometalates and Pluronic Block Copolymers.

The assembly of polyoxometalate (POM) metal-oxygen clusters into ordered nanostructures is attracting a growing interest for catalytic and sensing applications. However, assembly of ordered nanostructured POMs from solution can be impaired by aggregation, and the structural diversity is poorly understood. Here, we present a time-resolved small-angle X-ray scattering (SAXS) study of the co-assembly in aqueous solutions of amphiphilic organo-functionalized Wells-Dawson-type POMs with a Pluronic block copolymer over a wide concentration range in levitating droplets. SAXS analysis revealed the formation and subsequent transformation with increasing concentration of large vesicles, a lamellar phase, a mixture of two cubic phases that evolved into one dominating cubic phase, and eventually a hexagonal phase formed at concentrations above 110 mM. The structural versatility of co-assembled amphiphilic POMs and Pluronic block copolymers was supported by dissipative particle dynamics simulations and cryo-TEM.

Optimization of cold plasma combined treatment process and its effect on the quality of Asian sea bass (Lates calcarifer) during refrigerated storage.

BACKGROUND: Cold plasma exhibits broad applicability in the realm of fish sterilization and preservation. The combination process of plasma-activated water and dielectric barrier discharge (PAW-DBD) was optimized, and its disinfection effects on bass fillets were studied. RESULTS: The best conditions for disinfection of PAW-DBD were as follows. Bass fillets were soaked in PAW for 150 s, and then treated by DBD system at 160 kV for 180 s. The total viable count (TVC) reduced by 1.68 log CFU g-1 . On the 15th day of refrigerated storage, TVC of PAW-DBD group was 7.01 log CFU g-1 , while the PAW and DBD group exhibited a TVC of 7.02 and 7.01 log CFU g-1 on day 12; the TVC of the control group was 7.13 log CFU g-1 on day 6. The sensory score, water-holding capacity, and 2-thiobarbituric acid reactive substance values of the PAW-DBD group were significantly higher than those of PAW and DBD group (P < 0.05), whereas the TVC, Pseudomonas spp. count, and pH of the group were significantly lower (P < 0.05) during refrigerated storage. CONCLUSION: PAW-DBD treatment can enhance the disinfection effect, maintain good quality, and extend the storage period of bass fillets. © 2023 Society of Chemical Industry.

Trace Fluorinated Carbon dots driven Li-Garnet Solid-State Batteries.

Garnet solid-state electrolyte Li6.5La3Zr1.5Ta0.5O12 (LLZTO) holds significant promise. However, the practical utilization has been seriously impeded by the poor contact of Li|garnet and electron leakage. Herein, one new type garnet-based solid-state batteries is prososed with high-performance  through the disparity in interfacial energy, induced by the reaction between trace fluorinated carbon dots (FCDs) and Li. The work of adhesion of Li|garnet is increased by the acquired Li-FCD composite, which facilitates an intimate Li|garnet interface with the promoted uniform Li+ deposition, revealed by density functional theory (DFT) calculations. It is futher validated that a concentrated C-Li2O-LiF component at the Li|garnet interface is spontaneously constructed, due to the the significant disparity in interfacial energy between C-Li2O-LiF|LLZTO and C-Li2O-LiF|Li. Furthermore, The electron transport and Li dendrites penetration are effectively hindered by the formed Li2O and LiF. The Li-FCD|LLZTO|Li-FCD symmetrical cells demonstrate stable cycling performance for over 3000 hours at 0.3 mA cm-2 and 800 hours at 0.5 mA cm-2. Furthermore, the LFP|garnet|Li-FCD full cell exhibit remarkable cycling performance (91.6% capacity retention after 500 cycles at 1 C). Our research has revealed a novel approach to establish a dendrite-free Li|garnet interface, laying the groundwork for future advancements in garnet-based solid-state batteries.

Confined Element Distribution with Structure-driven Energy Coupling for Enhanced Prussian Blue Analogue Cathode.

The structural failure of Na2Mn[Fe(CN)6] could not be alleviated with traditional modification strategies through the adjustable composition property of Prussian blue analogues (PBAs), considering that the accumulation and release of stress derived from the MnN6 octahedrons are unilaterally restrained. Herein, a novel application of adjustable composition property, through constructing a coordination competition relationship between chelators and [Fe(CN)6]4- to directionally tune the enrichment of elements, is proposed to restrain structural degradation and induce unconventional energy coupling phenomenon. The non-uniform distribution of elements at the M1 site of PBAs (NFM-PB) is manipulated by the sequentially precipitated Ni, Fe, and Mn according to the Irving-William order. Electrochemically active Fe is operated to accompany Mn, and zero-strain Ni is modulated to enrich at the surface, synergistically mitigating with the enrichment and release of stress and then significantly improving the structural stability. Furthermore, unconventional energy coupling effect, a fusion of the electrochemical behavior between FeLS and MnHS, is triggered by the confined element distribution, leading to the enhanced electrochemical stability and anti-polarization ability. Consequently, the NFM-PB demonstrates superior rate performance and cycling stability. These findings further exploit potentialities of the adjustable composition property and provide new insights into the component design engineering for advanced PBAs.

Interfacial Mo-S-C Bond with High Reversibility for Advanced Alkali-Ion Capacitors: Strategies for High-Throughput Production.

The high-throughput scalable production of low-cost and high-performance electrode materials that work well under high power densities required in industrial application is full of challenges for the large-scale implementation of electrochemical technologies. Here, motivated by theoretical calculation that Mo-S-C heterojunction and sulfur vacancies can reduce the energy band gap, decrease the migration energy barrier, and improve the mechanical stability of MoS2 , the scalable preparation of inexpensive MoS2-x @CN is contrived by employing natural molybdenite as precursor, which is characteristic of high efficiency in synthesis process and energy conservation and the calculated costs are four orders of magnitude lower than MoS2 /C in previous work. More importantly, MoS2- x @CN electrode is endowed with impressive rate capability even at 5 A g-1 , and ultrastable cycling stability during almost 5000 cycles, which far outperform chemosynthesis MoS2 materials. Obtaining the full SIC cell assembled by MoS2- x @CN anode and carbon cathode, the energy/power output is high up to 265.3 W h kg-1 at 250 W kg-1 . These advantages indicate the huge potentials of the designed MoS2- x @CN and of mineral-based cost-effective and abundant resources as anode materials in high-performance AICs.

Interfacial Interaction of Multifunctional GQDs Reinforcing Polymer Electrolytes For All-Solid-State Li Battery.

Solid-state polymer electrolytes are highly anticipated for next generation lithium ion batteries with enhanced safety and energy density. However, a major disadvantage of polymer electrolytes is their low ionic conductivity at room temperature. In order to enhance the ionic conductivity, here, graphene quantum dots (GQDs) are employed to improve the poly (ethylene oxide) (PEO) based electrolyte. Owing to the increased amorphous areas of PEO and mobility of Li+ , GQDs modified composite polymer electrolytes achieved high ionic conductivity and favorable lithium ion transference numbers. Significantly, the abundant hydroxyl groups and amino groups originated from GQDs can serve as Lewis base sites and interact with lithium ions, thus promoting the dissociation of lithium salts and providing more ion pathways. Moreover, lithium dendrite is suppressed, associated with high transference number, enhanced mechanical properties and steady interface stability. It is further observed that all solid-state lithium batteries assembled with GQDs modified composite polymer electrolytes display excellent rate performance and cycling stability.

Trapping Lithium Selenides with Evolving Heterogeneous Interfaces for High-Power Lithium-Ion Capacitors.

Transition metal selenides anodes with fast reaction kinetics and high theoretical specific capacity are expected to solve mismatched kinetics between cathode and anode in Li-ion capacitors. However, transition metal selenides face great challenges in the dissolution and shuttle problem of lithium selenides, which is the same as Li-Se batteries. Herein, inspired by the density functional theory calculations, heterogeneous can enhance the adsorption of Li2 Se relative to single component selenide electrodes, thus inhibiting the dissolution and shuttle effect of Li2 Se. A heterostructure material (denoted as CoSe2 /SnSe) with the ability to evolve continuously (CoSe2 /SnSe→Co/Sn→Co/Li13 Sn5 ) is successfully designed by employing CoSnO3 -MOF as a precursor. Impressively, CoSe2 /SnSe heterostructure material delivers the ultrahigh reversible specific capacity of 510 mAh g-1 after 1000 cycles at the high current density of 4 A g-1 . In situ XRD reveals the continuous evolution of the interface based on the transformation and alloying reactions during the charging and discharging process. Visualizations of in situ disassembly experiments demonstrate that the continuously evolving interface inhibits the shuttle of Li2 Se. This research proposes an innovative approach to inhibit the dissolution and shuttling of discharge intermediates (Li2 Se) of metal selenides, which is expected to be applied to metal sulfides or Li-Se and Li-S energy storage systems.

High Voltage Ga-Doped P2-Type Na2/3 Ni0.2 Mn0.8 O2 Cathode for Sodium-Ion Batteries.

Ni/Mn-based oxide cathode materials have drawn great attention due to their high discharge voltage and large capacity, but structural instability at high potential causes rapid capacity decay. How to moderate the capacity loss while maintaining the advantages of high discharge voltage remains challenging. Herein, the replacement of Mn ions by Ga ions is proposed in the P2-Na2/3 Ni0.2 Mn0.8 O2 cathode for improving their cycling performances without sacrificing the high discharge voltage. With the introduction of Ga ions, the relative movement between the transition metal ions is restricted and more Na ions are retained in the lattice at high voltage, leading to an enhanced redox activity of Ni ions, validated by ex situ synchrotron X-ray absorption spectrum and X-ray photoelectron spectroscopy. Additionally, the P2-O2 phase transition is replaced by a P2-OP4 phase transition with a smaller volume change, reducing the lattice strain in the c-axis direction, as detected by operando/ex situ X-ray diffraction. Consequently, the Na2/3 Ni0.21 Mn0.74 Ga0.05 O2 electrode exhibits a high discharge voltage close to that of the undoped materials, while increasing voltage retention from 79% to 93% after 50 cycles. This work offers a new avenue for designing high-energy density Ni/Mn-based oxide cathodes for sodium-ion batteries.

Electrochemically Engineering a Single-Crystal Nickel-Rich Layered Cathode.

Nickel-rich layered electrode material has been attracting significant attention owing to its high specific capacity as a cathode for lithium-ion batteries. Generally, the high-nickel ternary precursors obtained by traditional coprecipitation methods are micron-scale. In this work, the submicrometer single-crystal LiNi0.8Co0.1Mn0.1O2 (NCM) cathode is efficiently prepared by electrochemically anodic oxidation followed by a molten-salt-assisted reaction without the need of extreme alkaline environments and complex processes. More importantly, when prepared under optimal voltage (10 V), single-crystal NCM exhibits a moderate particle size (∼250 nm) and strong metal-oxygen bonds due to reasonable and balanced crystal nucleation/growth rate, which are conducive to greatly enhancing the Li+ diffusion kinetics and structure stability. Given that a good discharge capacity of 205.7 mAh g-1 at 0.1 C (1 C = 200 mAh g-1) and a superior capacity retention of 87.7% after 180 cycles at 1 C are obtained based on the NCM electrode, this strategy is effective and flexible for developing a submicrometer single-crystal nickel-rich layered cathode. Besides, it can be adopted to elevate the performance and utilization of nickel-rich cathode materials.

Advanced NASICON-Type Na4Fe3(PO4)2(P2O7) Cathode for High-Performance Na+/Li+ Batteries.

Na4Fe3(PO4)2(P2O7) (NFPP) is an attractive candidate for Na+ batteries (SIBs) and Li+ batteries (LIBs). However, the real implementation of NFPP has been critically restrained by the inferior intrinsic electronic conductivity. Herein, in situ carbon-coated mesoporous NFPP, obtained via freeze drying and heat treatment, demonstrates highly reversible insertion/extraction of Na+/Li+. Mechanically, the electronic transmission and structural stabilities of NFPP are significantly enhanced by the graphitized carbon coating layer. Chemically, the porous nanosized structure shortens Na+/Li+ diffusion paths and increases the contact area between the electrolyte and NFPP, ultimately rendering fast ion diffusion. Greatly, long-lasting cyclability (88.5% capacity retention for over 5000 cycles), decent thermal stability at 60 °C, and impressive electrochemical performances are demonstrated in LIBs. The insertion/extraction mechanisms of NFPP in both SIBs and LIBs are systematically investigated, confirming its small volume expansion and high reversibility. The superior electrochemical performances and the insertion/extraction mechanism investigation confirm the feasibility of utilizing NFPP as a cathode material for Na+/Li+ batteries.

Reconstructing Hydrogen Bond Network Enables High Voltage Aqueous Zinc-Ion Supercapacitors.

High-voltage aqueous rechargeable energy storage devices with safety and high specific energy are hopeful candidates for the future energy storage system. However, the electrochemical stability window of aqueous electrolytes is a great challenge. Herein, inspired by density functional theory (DFT), polyethylene glycol (PEG) can interact strongly with water molecules, effectively reconstructing the hydrogen bond network. In addition, N, N-dimethylformamide (DMF) can coordinate with Zn2+ , assisting in the rapid desolvation of Zn2+ and stable plating/stripping process. Remarkably, by introducing PEG400 and DMF as co-solvents into the electrolyte, a wide electrochemical window of 4.27 V can be achieved. The shift in spectra indicate the transformation in the number and strength of hydrogen bonds, verifying the reconstruction of hydrogen bond network, which can largely inhibit the activity of water molecule, according well with the molecular dynamics simulations (MD) and online electrochemical mass spectroscopy (OEMS). Based on this electrolyte, symmetric Zn cells survived up to 5000 h at 1 mA cm-2 , and high voltage aqueous zinc ion supercapacitors assembled with Zn anode and activated carbon cathode achieved 800 cycles at 0.1 A g-1 . This work provides a feasible approach for constructing high-voltage alkali metal ion supercapacitors through reconstruction strategy of hydrogen bond network.

Disease mechanisms of X-linked cone dystrophy caused by missense mutations in the red and green cone opsins.

Cone photoreceptors are responsible for the visual acuity and color vision of the human eye. Red/green cone opsin missense mutations N94K, W177R, P307L, R330Q, and G338E have been identified in subjects with congenital blue cone monochromacy or color-vision deficiency. Studies on disease mechanisms due to these cone opsin mutations have been previously carried out exclusively in vitro, and the reported impairments were not always consistent. Here we expressed these mutants via AAV specifically in vivo in M-opsin knockout mouse cones to investigate their subcellular localization, the pathogenic effects on cone structure, function, and cone viability. We show that these mutations alter the M-opsin structure, function, and localization. N94K and W177R mutants appeared to be misfolded since they localized exclusively in cone inner segments and endoplasmic reticulum. In contrast, P307L, R330Q, and G338E mutants were detected predominately in cone outer segments. Expression of R330Q and G338E, but not P307L opsins, also partially restored expression and correct localization of cone PDE6α' and cone transducin γ and resulted in partial rescue of M-cone-mediated light responses. Expression of W177R and P307L mutants significantly reduced cone viability, whereas N94K, R330Q, and G338E were only modestly toxic. We propose that although the underlying biochemical and cellular defects caused by these mutants are distinct, they all seem to exhibit a dominant phenotype, resembling autosomal dominant retinitis pigmentosa associated with the majority of rhodopsin missense mutations. The understanding of the molecular mechanisms associated with these cone opsin mutants is fundamental to developing targeted therapies for cone dystrophy/dysfunction.

Crystalline Hydrate Dehydration Sensing Based on Integrated Terahertz Whispering Gallery Mode Resonators.

Water molecules play a very important role in the hydration and dehydration process of hydrates, which may lead to distinct physical and chemical properties, affecting their availability in practical applications. However, miniaturized, integrated sensors capable of the rapid, sensitive sensing of water molecules in the hydrate are still lacking, limiting their proliferation. Here, we realize the high-sensitivity sensing of water molecules in copper sulfate pentahydrate (CuSO4·5H2O), based on an on-chip terahertz whispering gallery mode resonator (THz-WGMR) fabricated on silicon material via CMOS-compatible technologies. An integrated THz-WGMR with a high-Q factor of 3305 and a resonance frequency of 410.497 GHz was proposed and fabricated. Then, the sensor was employed to distinguish the CuSO4·xH2O (x = 5, 3, 1). The static characterization from the CuSO4·5H2O to the copper sulfate trihydrate (CuSO4·3H2O) experienced blueshifts of 0.55 GHz/µmol, whereas the dehydration process of CuSO4·3H2O to copper sulfate monohydrate (CuSO4·H2O) exhibited blueshifts of 0.21 GHz/µmol. Finally, the dynamic dehydration processes of CuSO4·5H2O to CuSO4·3H2O at different temperatures were monitored. We believe that our proposed THz-WGMR sensors with highly sensitive substance identification capabilities can provide a versatile and integrated platform for studying the transformation between substances, contributing to hydrated/crystal water-assisted biochemical applications.

Solid Solution Metal Chalcogenides for Sodium-Ion Batteries: The Recent Advances as Anodes.

The sodium-ion battery (SIB) has attracted ever growing attention as a promising alternative of the lithium-ion battery (LIB). Constructing appropriate anode materials is critical for speeding up the application of SIB. This review aims at guiding anode design from the material's perspective, and specifically focusing on solid solution metal chalcogenide anode. The sodium ion storage mechanisms of a solid solution metal chalcogenide anode is overviewed on basis of the elements it is composed of, and discusses how the solid solution character alters the electrochemical performances through diffusion and surface-controlled processes. In addition, by classifying solid solution metal chalcogenide as cation and anion, their recent applications are updated, and understanding the roles of guest elements in improving the electrochemical behaviors of a solid solution metal chalcogenide is carried out. After that, discussion of possible strategies to further optimize these anode materials in the future, flowing from crystal structure design to morphology control and finally to the intimacy improvement between conductive matrix and solid solution metal chalcogenide are also provided.

High-power Si-Ge photodiode assisted by doping regulation.

High-power silicon-based photodiodes are key components in many silicon photonics systems, such as microwave photonics systems, an optical interconnection system with multi-level modulation formats, etc. Usually, the saturation power of the silicon-germanium (Si-Ge) photodiode is limited by the space-charge screening (SCS) effect and the feasibility of the fabrication process. Here, we propose a high saturation power Si-Ge photodiode assisted by doping regulation. Through alleviating the SCS effect of the photodiode, we successfully demonstrate an 85.7% improvement on the saturation power and a 57% improvement on the -1 dB compression photocurrent. The proposed high-power Si-Ge photodiode requires no specific fabrication process and will promote the low-cost integrated silicon photonics systems for more applications.

WNT1-inducible signaling pathway protein 1 (WISP1/CCN4) stimulates melanoma invasion and metastasis by promoting the epithelial-mesenchymal transition.

Besides intrinsic changes, malignant cells also release soluble signals that reshape their microenvironment. Among these signals is WNT1-inducible signaling pathway protein 1 (WISP1), a secreted matricellular protein whose expression is elevated in several cancers, including melanoma, and is associated with reduced survival of patients diagnosed with primary melanoma. Here, we found that WISP1 knockout increases cell proliferation and represses wound healing, migration, and invasion of mouse and human melanoma cells in multiple in vitro assays. Metastasis assays revealed that WISP1 knockout represses tumor metastasis of B16F10 and YUMM1.7 melanoma cells in both C57BL/6Ncrl and NOD-scid IL2Rγnull (NSG) mice. WT B16F10 cells having an invasion phenotype in a transwell assay possessed a gene expression signature similar to that observed in the epithelial-mesenchymal transition (EMT), including E-cadherin repression and fibronectin and N-cadherin induction. Upon WISP1 knockout, expression of these EMT signature genes went in the opposite direction in both mouse and human cell lines, and EMT-associated gene expression was restored upon exposure to media containing WISP1 or to recombinant WISP1 protein. In vivo, Wisp1 knockout-associated metastasis repression was reversed by the reintroduction of either WISP1 or snail family transcriptional repressor 1 (SNAI1). Experiments testing EMT gene activation and inhibition with recombinant WISP1 or kinase inhibitors in B16F10 and YUMM1.7 cells suggested that WISP1 activates AKT Ser/Thr kinase and that MEK/ERK signaling pathways shift melanoma cells from proliferation to invasion. Our results indicate that WISP1 present within the tumor microenvironment stimulates melanoma invasion and metastasis by promoting an EMT-like process.

Interleukin-12 elicits a non-canonical response in B16 melanoma cells to enhance survival.

BACKGROUND: Oncogenesis rewires signaling networks to confer a fitness advantage to malignant cells. For instance, the B16F0 melanoma cell model creates a cytokine sink for Interleukin-12 (IL-12) to deprive neighboring cells of this important anti-tumor immune signal. While a cytokine sink provides an indirect fitness advantage, does IL-12 provide an intrinsic advantage to B16F0 cells? METHODS: Acute in vitro viability assays were used to compare the cytotoxic effect of imatinib on a melanoma cell line of spontaneous origin (B16F0) with a normal melanocyte cell line (Melan-A) in the presence of IL-12. The results were analyzed using a mathematical model coupled with a Markov Chain Monte Carlo approach to obtain a posterior distribution in the parameters that quantified the biological effect of imatinib and IL-12. Intracellular signaling responses to IL-12 were compared using flow cytometry in 2D6 cells, a cell model for canonical signaling, and B16F0 cells, where potential non-canonical signaling occurs. Bayes Factors were used to select among competing signaling mechanisms that were formulated as mathematical models. Analysis of single cell RNAseq data from human melanoma patients was used to explore generalizability. RESULTS: Functionally, IL-12 enhanced the survival of B16F0 cells but not normal Melan-A melanocytes that were challenged with a cytotoxic agent. Interestingly, the ratio of IL-12 receptor components (IL12RB2:IL12RB1) was increased in B16F0 cells. A similar pattern was observed in human melanoma. To identify a mechanism, we assayed the phosphorylation of proteins involved in canonical IL-12 signaling, STAT4, and cell survival, Akt. In contrast to T cells that exhibited a canonical response to IL-12 by phosphorylating STAT4, IL-12 stimulation of B16F0 cells predominantly phosphorylated Akt. Mechanistically, the differential response in B16F0 cells is explained by both ligand-dependent and ligand-independent aspects to initiate PI3K-AKT signaling upon IL12RB2 homodimerization. Namely, IL-12 promotes IL12RB2 homodimerization with low affinity and IL12RB2 overexpression promotes homodimerization via molecular crowding on the plasma membrane. CONCLUSIONS: The data suggest that B16F0 cells shifted the intracellular response to IL-12 from engaging immune surveillance to favoring cell survival. Identifying how signaling networks are rewired in model systems of spontaneous origin can inspire therapeutic strategies in humans. Interleukin-12 is a key cytokine that promotes anti-tumor immunity, as it is secreted by antigen presenting cells to activate Natural Killer cells and T cells present within the tumor microenvironment. Thinking of cancer as an evolutionary process implies that an immunosuppressive tumor microenvironment could arise during oncogenesis by interfering with endogenous anti-tumor immune signals, like IL-12. Previously, we found that B16F0 cells, a cell line derived from a spontaneous melanoma, interrupts this secreted heterocellular signal by sequestering IL-12, which provides an indirect fitness advantage. Normally, IL-12 signals via a receptor comprised of two components, IL12RB1 and IL12RB2, that are expressed in a 1:1 ratio and activates STAT4 as a downstream effector. Here, we report that B16F0 cells gain an intrinsic advantage by rewiring the canonical response to IL-12 to instead initiate PI3K-AKT signaling, which promotes cell survival. The data suggest a model where overexpressing one component of the IL-12 receptor, IL12RB2, enables melanoma cells to shift the functional response via both IL-12-mediated and molecular crowding-based IL12RB2 homodimerization. To explore the generalizability of these results, we also found that the expression of IL12RB2:IL12RB1 is similarly skewed in human melanoma based on transcriptional profiles of melanoma cells and tumor-infiltrating lymphocytes. Additional file 6: Video abstract. (MP4 600 kb).

Incidence and risk factors of postoperative ileus after hysterectomy for benign indications.

PURPOSE: Postoperative ileus (POI) after abdominal surgery is associated with prolonged hospital stay and increased costs. The aim of this study is to investigate the incidence of, risk factors for, and outcomes associated with POI in patients undergoing hysterectomy for benign indications. METHODS: A retrospective review of 1017 consecutive patients undergoing benign hysterectomy over the period 2012-2017 in a single center was performed. POI was predefined as absence of flatus and defecation for more than 2 days with the presence of one or more of the following symptoms: nausea, vomiting, and abdominal distention. The association between perioperative variables and the risk of POI was evaluated by univariate analysis. Independent risk factors were identified by multivariate logistic regression analysis. RESULTS: Overall incidence of POI was 9.2%. Incidence of POI did not differ significantly among three different surgical approaches (abdominal hysterectomy, 10.6%; laparoscopic hysterectomy, 7.8%; vaginal hysterectomy, 11.3%; P = 0.279). Independent risk factors of POI identified by multivariate analysis included anesthesia technique (odds ratio [OR] 2.662, 95% interval [CI] 1.533-4.622, P = 0.001), adhesiolysis (odds ratio [OR] 1.818, 95% interval [CI] 1.533-4.622, P = 0.011), duration of operation (odds ratio [OR] 1.005, 95% interval [CI] 0.942-6.190, P = 0.029), previous cancer (odds ratio [OR] 4.789, 95% interval [CI] 1.232-18.626, P = 0.024), and dysmenorrhea (odds ratio [OR] 1.859, 95% interval [CI] 1.182-2.925, P = 0.007). CONCLUSION: POI is a common complication after hysterectomy. This study identified risk factors of POI specifically for gynecologic patients. Patients exposed to these factors should be monitored closely for the development POI.