M6A RNA methylation-mediated dysregulation of AGAP2-AS1 promotes trastuzumab resistance of breast cancer.

INTRODUCTION: Trastuzumab is commonly used in the treatment of human epidermal growth factor receptor-2 positive (HER-2+) breast cancer patients, but its efficacy is often limited by chemotherapy resistance. Recent studies indicate that long noncoding RNAs (lncRNAs) play important roles in tumor progression and response to therapy. However, the regulatory mechanism of lncRNAs in trastuzumab resistance is still unknown to date. METHODS: qPCR was performed to detect the expression of related genes. Western blot and immunofluorescence assays were used for the evaluation of protein expression levels. A series of gain- or loss-functional assays confirmed the function of AGAP2-AS1 in trastuzumab resistance, both in vitro and in vivo. RNA immunoprecipitation and pulldown analysis was conducted to verify the interaction between METTL3/YTHDF2 and lncRNA AGAP2-AS1. , Results: AGAP2-AS1 was upregulated in trastuzumab-resistant cells and SKBR-3R-generated xenograft in nude mice. Silence of AGAP2-AS1 significantly decreased trastuzumab-induced cell cytotoxicity both in vitro and in vivo. The m6A methylation of AGAP2-AS1 was found to be reduced in trastuzumab resistant cells compared to parental cells. In addition, METTL3 increased the m6A methylation of AGAP2-AS1, which finally induced the suppression of AGAP2-AS1 expression. Moreover, YTHDF2 was essential for METTL3-mediated m6A methylation of AGAP2-AS1. Functionally, AGAP2-AS1 regulated trastuzumab resistance via inducing autophagy and increasing ATG5 protein level. CONCLUSION: Taken together, we proved that METTL3/YTHDF2-mediated m6A methylation indued the increased expression AGAP2-AS1, which could promote the trastuzumab resistance of breast cancer. In addition, AGAP2-AS1 also regulates trastuzumab resistance via inducing autophagy. Therefore, AGAP2-AS1 may be promising predictive biomarker and therapeutic target breast cancer patients.

Numerical Study on Combustion Characteristics of Biogas Cocombustion in a 300MW Coal-Fired Boiler Furnace.

To further explore cocombustion technology with biogas and coal, a series of numerical simulations have been carried out to analyze the effects of the cocombustion ratio ξ, height of biogas nozzle HGN, and tilt angle of burner θBN on combustion characteristics in a 300 MW four-corner tangential boiler furnace. Three types of biogas are gasified from straw, sawdust, and raw wood when air serves as the gasification agent. The velocity field, temperature field, and NO emissions have been comprehensively analyzed when the values of ξ, HGN, and θBN range, respectively, from 0.02 to 0.12, from 17.3 to 20.3 m, and from -15° to +15°. Results showed that the NO concentration at the furnace outlet monotonously decreased with ξ. The injection of biogas reduces both the peak temperature of the entire boiler furnace and the NO concentration at the furnace outlet. The NO emission concentration decreases with the increased ξ value for all types of biogases. The cocombustion with sawdust biogas indicates the least NO emission at a fixed cocombustion ratio. Furthermore, reducing the furnace height at HGN = 17.3 m or titling down the burner at θBN = -15° contributed to a greater NO concentration at the furnace outlet.

In vitro digestion and fermentation behaviors of polysaccharides from Choerospondias axillaris fruit and its effect on human gut microbiota.

Choerospondias axillaris fruit has attracted more and more attention due to its various pharmacological activities, which are rich in polysaccharides. This study investigated the in vitro saliva-gastrointestinal digestion and fecal fermentation behaviors of polysaccharides from Choerospondias axillaris fruit (CAP), as well as its impact on human gut microbiota. The results showed that CAP could be partially degraded during the gastrointestinal digestion. The FT-IR spectra of the digested CAP didn't change significantly, however, the morphological feature of SEM changed to disordered flocculent and rod-like structures. 16S rRNA sequencing analysis found that after in vitro fermentation, CAP could increase the relative abundances of beneficial bacteria including Megasphaera, Megamonas and Bifidobacterium to produce short-chain fatty acids (SCFAs), while it can also reduce the abundances of harmful bacteria of Collinsella, Gemmiger, Klebsiella and Citrobacter, suggesting that CAP could modulate the composition and abundance of gut microbiota. These results implied that CAP can be developed as a potential prebiotic in the future.

Nonclassical crystallization of goethite nanorods in limpet teeth by self-assembly of silica-rich nanoparticles reveals structure-mechanical property relations.

The intricate organization of goethite nanorods within a silica-rich matrix makes limpet teeth the strongest known natural material. However, the mineralization pathway of goethite in organisms under ambient conditions remains elusive. Here, by investigating the multi-level structure of limpet teeth at different growth stages, it is revealed that the growth of goethite crystals proceeds by the attachment of amorphous nanoparticles, a nonclassical crystallization pathway widely observed during the formation of calcium-based biominerals. Importantly, these nanoparticles contain a high amount of silica, which is gradually expelled during the growth of goethite. Moreover, in mature teeth of limpet, the content of silica correlates with the size of goethite crystals, where smaller goethite crystals are densely packed in the leading part with higher content of silica. Correspondingly, the leading part exhibits higher hardness and elastic modulus. Thus, this study not only reveals the nonclassical crystallization pathway of goethite nanorods in limpet teeth, but also highlights the critical roles of silica in controlling the hierarchical structure and the mechanical properties of limpet teeth, thus providing inspirations for fabricating biomimetic materials with excellent properties.

Short-term supplementation with uncoated and encapsulated Enterococcus faecium affected growth performance, gut microbiome and intestinal barrier integrity in broiler chickens.

Enterococcus faecium (E. faecium) is an alternative to antibiotics, while the probiotic effect of short-term application in mature broiler chickens remains unclear. In the current study, 48 Arbor Acres male broilers were chosen to investigate the effects of E. faecium on growth performance, the gut microbiome and intestinal health during the finishing period. Forty-eight birds were randomly allocated to 4 treatment groups that were fed a corn-soybean meal basal diet (Con), a basal diet supplemented with 1 g/kg amoxicillin (ABX), 5×106 CFU/g encapsulated E. faecium (cEF), or 5×106 CFU/g uncoated E. faecium (EF) from d 33 to 42. The results showed that 10 d of antibiotic treatment decreased the growth performance of the broilers (P < 0.05). The feed conversion ratio of the cEF and EF groups were lower than that of the Con group by 0.13 and 0.07, respectively (P > 0.05). The abundance of viable ileal and cecal E. faecium in the cEF group was greater than that in the EF group (P < 0.05), and both groups were markedly greater than those in the Con and ABX groups (P < 0.05). The ABX treatment decreased the Shannon and Chao1 indices of the cecal microbiota, while the dietary E. faecium treatment resulted in significant differences in the ß diversity of the ileal and cecal microbiota (P < 0.05). Mantel correlation revealed that the ileal microbiota at the genus level was significantly correlated with the growth performance of broilers, with Lactobacillus, Bacillus and Escherichia-Shigella showing positive and strong correlations (P < 0.05). In the ileum, the crypt depth was lower in the cEF group than in the Con group, but the villi height-to-crypt depth ratio was greater in the cEF group than in the other groups (P = 0.037). However, the expression of the ZO-2 and Occludin genes was downregulated in the E. faecium-fed birds (P < 0.05). In the cecum, the acetate, butyrate and total SCFA levels were greater in the EF group (P < 0.05), while the propionate, isobutyrate and isovalerate levels were lower in the ABX group (P < 0.05). In summary, 10 d of dietary supplementation with E. faecium markedly increased colonization in mature broilers and potentially improved growth performance by modulating the ileal microbiota. Encapsulation techniques could enable a slow release of E. faecium in the intestine, thereby reducing the negative impacts of rapid expansion of E. faecium on the intestinal epithelium.

Analysis of mild and severe neonatal enterovirus infections in a Chinese neonatal tertiary center: a retrospective case-control study.

PURPOSE: To compare the clinical characteristics, virus serotype, and outcome in cases of mild and severe enteroviral infection at a tertiary neonatal intensive care unit in China. METHODS: A retrospective analysis of cases hospitalized between June and August 2019. Samples (stool or throat swabs) were examined using reverse transcription polymerase chain reaction. Positive cases were divided into two groups: mild infection and severe infection. RESULTS: A total of 149 cases were assigned to one of two groups: mild infection (n = 104) and severe infection (n = 45). There were no significant differences between the groups in terms of sex, gestational age, birth weight, mode of delivery, and onset within 7 days. Clinical symptoms in both groups mostly resembled sepsis (fever, rash, poor feeding, and lethargy); however, there were significant variations in concomitant symptoms such as hepatitis, thrombocytopenia, encephalitis, coagulopathy, and myocarditis. Severe cases were more likely to have abnormal complete blood counts, biochemical parameters, and cerebrospinal fluid markers. The predominant serotypes implicated in neonatal enterovirus infections were echoviruses and Coxsackievirus B. Invasive ventilation, intravenous immunoglobulin, vasoactive medications, and blood product transfusions were often required, with high mortality rates among severe cases. CONCLUSION: We found significant differences between mild and severe cases of neonatal enterovirus infection with respect to complications, laboratory findings, and enterovirus serotypes. It is crucial to exercise caution when newborns exhibit symptoms of sepsis, during an enterovirus outbreak. Anemia, thrombocytopenia, abnormal liver function, and coagulation dysfunction should be monitored closely as they could indicate the presence of a severe enteroviral infection.

ZnMo-MOF as anti-CO hydrogen electrocatalyst enhance microbial electrosynthesis for CO/CO2 conversion.

Microbial electrosynthesis (MES) is an electrically driven technology that can be used for converting CO/CO2 into chemicals. The unique electronic and substrate properties of CO make it an important research target for MES. However, CO can poison the cathode and increase the overpotential of hydrogen evolution reaction (HER), thus reducing the electron transfer rate via H2. This work evaluated the effect of an anti-CO HER catalyst on the performance of MES for CO/CO2 conversion. ZnMo-metal-organic framework (MOF) materials with different calcination temperatures were synthesized. ZnMo-MOF-800 with Mo2C nanoparticles as active centers exhibited excellent resistance to CO toxicity. It also obtained the highest hydrogen evolution and enhanced electron transfer rate in CO atmosphere. MES with ZnMo-MOF-800 cathode and Clostridium ljungdahlii as biocatalyst obtained 0.31 g L-1 d-1 acetate yield, 0.1 g L-1 d-1 butyrate yield, and 0.09 g L-1 d-1 2,3-butanediol yield in CO/CO2, while Pt/C only get 0.076 g L-1 d-1 acetate yield, 0.05 g L-1 d-1 butyrate yield and 0.02 g L-1 d-1 2,3-butanediol yield. ZnMo-MOF-800 was conducive to biofilm formation, enabling it to better resist CO toxicity. This work provides new opportunities for constructing a highly efficient cathode with an anti-CO hydrogen evolution catalyst to enhance CO/CO2 conversion in MES.

Unique Advantages of Dendrimers-Structured Mesoporous Silica Nanoparticles over Traditional Hollow Ones in Delivering Bcl2-Functional Converting Peptide for Multidrug Resistant Cancer Treatment.

Innovative silica nanomaterials have made the significant advancements in curative therapy against cancers with multidrug resistance (MDR). The study on different-nanostructured mesoporous silica nanoparticles (MSNs) with discrepant pore sizes affecting biomacromolecules in resisting cancer MDR hasn't been reported yet. In this study, a systematic comparison of 6 nm-pore sized hollow-structured MSNs (HMSNs) and 10 nm-pore sized dendrimers-structured MSNs (LMSNs) for delivering Bcl-2-functional converting peptide (N9) or doxorubicin (DOX) to overcome cancer MDR is comprehensively carried out both in in vitro and in vivo resistant tumor models. The results show that both LMSNs and HMSNs exert no significant difference in delivering DOX to treat drug-resistant cancers. However, compared with N9@HMSNs, N9@LMSNs display the increased loading efficiency, the improved cell-penetrative capability, the higher cancer cell apoptosis effect, the enhanced tumor accumulation and retention efficiency, and the final elevated tumor inhibition efficiency. Unexpectedly, naked LMSNs without surface modification especially at high dosage produce relatively more serious toxicity than HMSNs whatever in cells, zebrafish embryo or mice models. Collectively, the data provide the sufficient theoretical evidence that LMSNs might be a better choice for delivering biomacromolecules to treat resistant cancers after appropriate surface functionalization such as with PEGylation to weaken its intrinsic toxicity.

In Situ Construction of Inorganics-Rich Cathode-Electrolyte Interface toward Long-Life Prussian White Cathode.

Prussian white (PW) is one of the most promising candidates as a cathode for sodium-ion batteries (SIBs) because of its high theoretical capacity, excellent rate performance, and low production cost. However, PW materials suffer severe capacity decay during long-term cycling. In this work, a robust cathode electrolyte interface (CEI) is designed on the PW cathode by employing cresyl diphenyl phosphate (CDP) and adiponitrile (ADN) as electrolyte additives. CDP and ADN possess higher highest occupied molecular orbital energy levels (HOMO) than other solvents, leading to the preferential decomposition of CDP and ADN to construct an inorganics-rich CEI layer in situ on the PW cathode. Benefiting from this CEI layer, the degradation of PW is effectively inhibited during the long cycling. The Na||PW cell achieves an excellent cycling performance with a capacity retention of 85.62% after 1400 cycles. This work presented here provides a feasible strategy for improving the cycling performance of PW by electrolyte modification.

Computational Discovery of High-Temperature Ferromagnetic Semiconductor Monolayer H-MnN2.

In the past few years, two-dimensional (2D) high-temperature ferromagnetic semiconductor (FMS) materials with novelty and excellent properties have attracted much attention due to their potential in spintronics applications. In this work, using first-principles calculations, we predict that the H-MnN2 monolayer with the H-MoS2-type structure is a stable intrinsic FMS with an indirect band gap of 0.79 eV and a high Curie temperature (Tc) of 380 K. The monolayer also has a considerable in-plane magnetic anisotropy energy (IMAE) of 1005.70 µeV/atom, including a magnetic shape anisotropy energy induced by the dipole-dipole interaction (shape-MAE) of 168.37 µeV/atom and a magnetic crystalline anisotropy energy resulting from spin-orbit coupling (SOC-MAE) of 837.33 µeV/atom. Further, based on the second-order perturbation theory, its in-plane SOC-MAE of 837.33 µeV/atom is revealed to mainly derive from the couplings of Mn-dxz,dyz and Mn-dx2-y2,dxy orbitals through Lz in the same spin channel. In addition, the biaxial strain and carrier doping can effectively tune the monolayer's magnetic and electronic properties. Such as, under the hole and few electrons doping, the transition from semiconductor to half-metal can be realized, and its Tc can go up to 520 and 620 K under 5% tensile strain and 0.3 hole doping, respectively. Therefore, our research will provide a new, promising 2D FMS for spintronics devices.

A nanoparticle-based sonodynamic therapy reduces Helicobacter pylori infection in mouse without disrupting gut microbiota.

Infection by Helicobacter pylori, a prevalent global pathogen, currently requires antibiotic-based treatments, which often lead to antimicrobial resistance and gut microbiota dysbiosis. Here, we develop a non-antibiotic approach using sonodynamic therapy mediated by a lecithin bilayer-coated poly(lactic-co-glycolic) nanoparticle preloaded with verteporfin, Ver-PLGA@Lecithin, in conjunction with localized ultrasound exposure of a dosage permissible for ultrasound medical devices. This study reveals dual functionality of Ver-PLGA@Lecithin. It effectively neutralizes vacuolating cytotoxin A, a key virulence factor secreted by H. pylori, even in the absence of ultrasound. When coupled with ultrasound exposure, it inactivates H. pylori by generating reactive oxygen species, offering a potential solution to overcome antimicrobial resistance. In female mouse models bearing H. pylori infection, this sonodynamic therapy performs comparably to the standard triple therapy in reducing gastric infection. Significantly, unlike the antibiotic treatments, the sonodynamic therapy does not negatively disrupt gut microbiota, with the only major impact being upregulation of Lactobacillus, which is a bacterium widely used in yogurt products and probiotics. This study presents a promising alternative to the current antibiotic-based therapies for H. pylori infection, offering a reduced risk of antimicrobial resistance and minimal disturbance to the gut microbiota.

Newly discovered variants in unexplained neonatal encephalopathy.

BACKGROUND: The genetic background of neonatal encephalopathy (NE) is complicated and early diagnosis is beneficial to optimizing therapeutic strategy for patients. METHODS: NE Patients with unclear etiology received regular clinical tests including ammonia test, metabolic screening test, amplitude-integrated electroencephalographic (aEEG) monitoring, brain Magnetic Resonance Imaging (MRI) scanning, and genetic test. The protein structure change was predicted using Dynamut2 and RoseTTAFold. RESULTS: 15 out of a total of 113 NE Patients were detected with newly reported pathogenic variants. In this sub-cohort, (1) seizure was the primary initial symptoms; (2) four patients had abnormal metabolic screening results, and two of them were also diagnosed with excessive blood ammonia concentration; (3) the brain MRI results were irregular in three infants and the brain waves were of moderate-severe abnormality in about a half of the patients. The novel pathogenic variants discovered in this study belonged to 12 genes, and seven of them were predicted to introduce a premature translation termination. In-silicon predictions showed that four variants were destructive to the protein structure of KCNQ2. CONCLUSION: Our study expands the mutation spectrum of genes associated with NE and introduces new evidence for molecular diagnosis in this newborn illness.

Comprehensive assessment of immune context and immunotherapy response via noninvasive imaging in gastric cancer.

BACKGROUNDThe tumor immune microenvironment can provide prognostic and therapeutic information. We aimed to develop noninvasive imaging biomarkers from computed tomography (CT) for comprehensive evaluation of immune context and investigate their associations with prognosis and immunotherapy response in gastric cancer (GC).METHODSThis study involved 2,600 patients with GC from 9 independent cohorts. We developed and validated 2 CT imaging biomarkers (lymphoid radiomics score [LRS] and myeloid radiomics score [MRS]) for evaluating the IHC-derived lymphoid and myeloid immune context respectively, and integrated them into a combined imaging biomarker [LRS/MRS: low(-) or high(+)] with 4 radiomics immune subtypes: 1 (-/-), 2 (+/-), 3 (-/+), and 4 (+/+). We further evaluated the imaging biomarkers' predictive values on prognosis and immunotherapy response.RESULTSThe developed imaging biomarkers (LRS and MRS) had a high accuracy in predicting lymphoid (AUC range: 0.765-0.773) and myeloid (AUC range: 0.736-0.750) immune context. Further, similar to the IHC-derived immune context, 2 imaging biomarkers (HR range: 0.240-0.761 for LRS; 1.301-4.012 for MRS) and the combined biomarker were independent predictors for disease-free and overall survival in the training and all validation cohorts (all P < 0.05). Additionally, patients with high LRS or low MRS may benefit more from immunotherapy (P < 0.001). Further, a highly heterogeneous outcome on objective response ​rate was observed in 4 imaging subtypes: 1 (-/-) with 27.3%, 2 (+/-) with 53.3%, 3 (-/+) with 10.2%, and 4 (+/+) with 30.0% (P < 0.0001).CONCLUSIONThe noninvasive imaging biomarkers could accurately evaluate the immune context and provide information regarding prognosis and immunotherapy for GC.

Effect of non-starch components on the structural properties, physicochemical properties and in vitro digestibility of waxy highland barley starch.

Highland barley (HB) endosperm with an amylose content of 0-10 % is called waxy HB (WHB). WHB is a naturally slow-digesting grain, and the interaction between its endogenous non-starch composition and the WHB starch (WHBS) has an important effect on starch digestion. This paper focuses on the mechanisms by which the components of ß-glucan, proteins and lipids affect the molecular, granular, crystalline structure and digestive properties of WHBS. After eliminating the main nutrients except for starch, the estimated glycemic index (eGI) of the samples rose from 62.56 % to 92.93 %, and the rapidly digested starch content increased from 60.81 % to 98.56 %, respectively. The resistant starch (RS) content, in contrast, dropped from 38.61 % to 0.13 %. Comparatively to lipids, ß-glucan and protein contributed more to the rise in eGI and decline in RS content. The crystalline characteristics of starch were enhanced in the decomposed samples. The samples' gelatinization properties improved, as did the order of the starch molecules. Protein and ß-glucan form a dense matrix on the surface of WHBS particles to inhibit WHBS digestion. In summary, this study revealed the mechanism influencing the digestibility of WHBS from the perspective of endogenous non-starch composition and provided a theoretical basis to develop slow-digesting foods.

Imaging mRNA in vitro and in vivo with nanofirecracker probes via intramolecular hybridization chain reaction.

Hybridization chain reaction (HCR) based enzyme-free amplification techniques have recently been developed for the visualization of intracellular messenger RNA (mRNA). However, the slow kinetics and potential interference with the intricate biological environments hinder its application in the clinic and in vivo. Herein, we designed a nanofirecracker probe-based strategy using intramolecular hybridization chain reaction (IHCR) amplifier for rapid, efficient, sensitive, specific detection and imaging of survivin mRNA both in vitro and vivo. Two probes, HP1 and HP2, in IHCR were simultaneously incorporated into a DNA nanowire scaffolds to bring HP1 and HP2 to close proximity on the assembled nanowire scaffolds. Empowered by the DNA nanowire scaffolds and spatial confinement effect, the nanofirecracker probe-based IHCR sensing system exhibited improved biostability, accelerated reaction kinetics, and enhanced signal amplification. This new strategy has been successfully applied to imaging mRNA in both cultured cells and in mice. Importantly, this novel sensing method was capable of detecting survivin mRNA in clinical blood samples from subjects with colorectal cancer. Thus, this novel nanofirecracker probe-based IHCR strategy holds great potential in advancing both biomedical research and in molecular diagnostics.

LILRB3 Supports Immunosuppressive Activity of Myeloid Cells and Tumor Development.

The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the immune system to treat solid tumors. Here, we report that galectin-4 and galectin-7 induce activation of LILRB3 and that LILRB3 is functionally expressed on immunosuppressive myeloid cells. In some samples from patients with solid cancers, blockade of LILRB3 signaling by an antagonistic antibody inhibited the activity of immunosuppressive myeloid cells. Anti-LILRB3 also impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent manner. LILRB3 blockade may prove to be a novel approach for immunotherapy of solid cancers.

Effects of Phytase Source and Dose on Its Stability during Pelleting Process under Different Conditioning Temperatures.

Phytase activity can be impaired during pelleting because of extreme thermal conditions. This study investigated the effects of dose and source of phytase on phytase activity during the conditioning, pelleting, and cooling process. A split-plot design was used in two experiments, with five phytase doses (Exp. 1; 7560, 14310, 33830, 43590 and 61500 FTU/kg) or eight phytase sources (Exp. 2) as the main plot and steam conditioning temperatures (Exp. 1 and 2; 75 and 85 °C) as the subplot. Each treatment processed four batches, one batch per replicate. The results of Exp. 1 showed phytase dose in diets had no effect (p > 0.05) on the recovery rate of phytase activity after the conditioning, pelleting, or cooling process. The recovery rate of phytase activity in each process was higher (p < 0.05) at 75 °C than that at 85 °C for both Exp. 1 and 2. The phytase source significantly affected (p < 0.05) the recovery rate of phytase activity and had varied appearances of structure. In conclusion, the structure, phytase activity, and phytase recovery after steam conditioning-pelleting significantly varied across sources, but the stability of phytase was not affected by dose.

Phase separation underlies signaling activation of oncogenic NTRK fusions.

NTRK (neurotrophic tyrosine receptor kinase) gene fusions that encode chimeric proteins exhibiting constitutive activity of tropomyosin receptor kinases (TRK), are oncogenic drivers in multiple cancer types. However, the underlying mechanisms in oncogenesis that involve various N-terminal fusion partners of NTRK fusions remain elusive. Here, we show that NTRK fusion proteins form liquid-like condensates driven by their N-terminal fusion partners. The kinase reactions are accelerated in these condensates where the complexes for downstream signaling activation are also concentrated. Our work demonstrates that the phase separation driven by NTRK fusions is not only critical for TRK activation, but the condensates formed through phase separation serve as organizational hubs for oncogenic signaling.