Nomogram using intratumoral and peritumoral radiomics for the preoperative prediction of visceral pleural invasion in clinical stage IA lung adenocarcinoma.

BACKGROUND: Accurate prediction of visceral pleural invasion (VPI) in lung adenocarcinoma before operation can provide guidance and help for surgical operation and postoperative treatment. We investigate the value of intratumoral and peritumoral radiomics nomograms for preoperatively predicting the status of VPI in patients diagnosed with clinical stage IA lung adenocarcinoma. METHODS: A total of 404 patients from our hospital were randomly assigned to a training set (n = 283) and an internal validation set (n = 121) using a 7:3 ratio, while 81 patients from two other hospitals constituted the external validation set. We extracted 1218 CT-based radiomics features from the gross tumor volume (GTV) as well as the gross peritumoral tumor volume (GPTV5, 10, 15), respectively, and constructed radiomic models. Additionally, we developed a nomogram based on relevant CT features and the radscore derived from the optimal radiomics model. RESULTS: The GPTV10 radiomics model exhibited superior predictive performance compared to GTV, GPTV5, and GPTV15, with area under the curve (AUC) values of 0.855, 0.842, and 0.842 in the three respective sets. In the clinical model, the solid component size, pleural indentation, solid attachment, and vascular convergence sign were identified as independent risk factors among the CT features. The predictive performance of the nomogram, which incorporated relevant CT features and the GPTV10-radscore, outperformed both the radiomics model and clinical model alone, with AUC values of 0.894, 0.828, and 0.876 in the three respective sets. CONCLUSIONS: The nomogram, integrating radiomics features and CT morphological features, exhibits good performance in predicting VPI status in lung adenocarcinoma.

Enhancing the Catalytic Activity of Laccase@Copper-Metal-Organic Framework Nanofractal Microspheres: Synergistic Contribution of the Mass Transfer and Electron Transfer Pathway.

Metal-organic frameworks (MOFs) are limited by small pores and buried active sites, and their enzyme-like catalytic activity is still very low. Herein, laccase was employed as the organic component to construct laccase@Cu3(BTC)2 nanofractal microspheres. During the preparation process, laccase adsorbed Cu2+ by electrostatic attractive interaction, then combined with Cu2+ by coordination interaction, and finally induced the in situ growth of H3BTC2 in multiple directions by electrostatic repulsion. Interestingly, electrostatic repulsion was tuned efficiently by adjusting the Cu2+ concentration to obtain laccase@Cu3(BTC)2 nanofractal microspheres (nanosheet microspheres, nanorod microspheres, and nanoneedle microspheres). Laccase@Cu3(BTC)2 nanorod microspheres exhibited the highest catalytic efficiency, which was 14-fold higher than that of smooth microspheres. The mechanism of the improvement of catalytic activity in the degradation of BPA was proposed for the first time. The enhanced catalytic activity depended on the adsorption effect of the nanorod framework and dual cycle synergistic catalysis of Cu+/Cu2+ active sites, which accelerated substrate diffusion and electron transfer. The catalytic mechanism of enzyme@MOF nanofractal microspheres not only deepens our understanding of enzyme and MOF synergistic catalysis but also provides new insights into the design of catalysts.

Prognostic utility of the geriatric nutritional risk index for head and neck cancer: Systematic review and meta-analysis.

We conducted a systematic review of the literature to assess the potential prognostic utility of geriatric nutritional risk index (GNRI) for head and neck cancer (HNC). We selected studies and extracted data after searching the Cochrane Library, EMBASE, and PubMed databases. The associations between GNRI and survival outcomes were explored by calculating hazard ratios (HRs) and 95% confidence intervals (CIs) through a random-effects meta-analysis. We included 11 studies that involved 2887 patients with HNC. The combined HR demonstrated significant associations of low GNRI with unfavorable progression-free survival (HR = 1.87, 95% CI = 1.32-2.65, p < 0.001) and overall survival (HR = 3.04, 95% CI = 2.30-4.03, p < 0.001). The association between the GNRI and overall survival persisted across various subgroups. The GNRI could serve as a valuable prognostic biomarker for patients with HNC. Low GNRI scores are significantly associated with unfavorable survival outcomes.

A Case of Squamous Cell Carcinoma Arising in Disseminated Superficial Porokeratosis.

Porokeratosis (PK), characterized by keratotic lesions with an atrophic center and a prominent peripheral ridge, with a typical histological hallmark, namely, the cornoid lamella, has two forms: disseminated and localized. While PK often converts into squamous cell carcinoma (SCC), conversion from disseminated superficial porokeratosis (DSP) alone is rarely reported except for one case in which DSP and LP coexisted and converted to SCC. Here, we report the case of a patient with SCC converted from DSP alone, presenting with coin-sized macules on the bottom right of his waist that developed into an ulcer at the center. The patient underwent radiation therapy, which effectively treated the SCC but did not resolve the PK. This article highlights regular follow-up and undergo comprehensive diagnosis, both of which are beneficial to enable early detection and management of DSP that has converted to into SCC; in addition, standardized medical treatment may help improve the treatment therapeutic effect of in similar diseases.

Impact of the Early COVID-19 Pandemic on Incidence and Outcomes of Hepatocellular Carcinoma in the United States.

OBJECTIVES: Access to hepatocellular carcinoma (HCC) surveillance and treatments were disrupted during the COVID-19 pandemic. We aimed to characterize the impact of the pandemic on HCC incidence and mortality rates, treatment and outcomes in the U.S. METHODS: Two nationwide databases, the United States Cancer Statistics and the National Vital Statistics System, were used to investigate HCC incidence and mortality between 2001-2020. Trends in age-adjusted incidence (aIR) and mortality (aMR) rates were assessed using joinpoint analysis. The 2020 aIR and aMR were projected based on the pre-pandemic data and compared to actual values to assess the extent of underdiagnosis. We assessed differences in HCC characteristics, treatment and overall survival (OS) between 2020 and 2018-2019. RESULTS: The aIR of HCC in 2020 was significantly reduced compared to 2019 (5.22 vs 6.03/100K PY), representing a 12.2% decrease compared to the predicted aIR in 2020 (5.94/100K PY). The greatest extent of underdiagnosis was observed in Black (-14.87%) and Hispanic (-14.51%) individuals and those with localized HCC (-15.12%). Individuals staged as regional or distant HCC were also less likely to receive treatment in 2020. However, there was no significant difference in short-term OS in 2020 compared to 2018-2019, with HCC mortality rates remaining stable (aMR: 2.76 vs 2.73/100K PY in 2020 vs 2019). CONCLUSIONS: The COVID-19 pandemic resulted in underdiagnosis of HCC, particularly early-stage disease and racial ethnic minorities, and underuse of HCC-directed treatment. Longer follow-up is needed to determine the impact of the COVID-19 pandemic on HCC-related mortality.

Polyphenols as Potential Antioxidants for the Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is a common musculoskeletal system disease, which is one of the most important causes of low back pain. Despite the high prevalence of IDD, current treatments are limited to relieving symptoms, and there are no effective therapeutic agents that can block or reverse the progression of IDD. Oxidative stress, the result of an imbalance between the production of reactive oxygen species (ROS) and clearance by the antioxidant defense system, plays an important role in the progression of IDD. Polyphenols are antioxidant compounds that can inhibit ROS production, which can scavenge free radicals, reduce hydrogen peroxide production, and inhibit lipid oxidation in nucleus pulposus (NP) cells and IDD animal models. In this review, we discussed the antioxidant effects of polyphenols and their regulatory role in different molecular pathways associated with the pathogenesis of IDD, as well as the limitations and future prospects of polyphenols as a potential treatment of IDD.

The involvement and application potential of exosomes in breast cancer immunotherapy.

Breast cancer has a high incidence and a heightened propensity for metastasis. The absence of precise targets for effective intervention makes it imperative to devise enhanced treatment strategies. Exosomes, characterized by a lipid bilayer and ranging in size from 30 to 150 nm, can be actively released by various cells, including those in tumors. Exosomes derived from distinct subsets of immune cells have been shown to modulate the immune microenvironment within tumors and influence breast cancer progression. In addition, tumor-derived exosomes have been shown to contribute to breast cancer development and progression and may become a new target for breast cancer immunotherapy. Tumor immunotherapy has become an option for managing tumors, and exosomes have become therapeutic vectors that can be used for various pathological conditions. Edited exosomes can be used as nanoscale drug delivery systems for breast cancer therapy, contributing to the remodeling of immunosuppressive tumor microenvironments and influencing the efficacy of immunotherapy. This review discusses the regulatory role of exosomes from different cells in breast cancer and the latest applications of exosomes as nanoscale drug delivery systems and immunotherapeutic agents in breast cancer, showing the development prospects of exosomes in the clinical treatment of breast cancer.

Case report: Prone positioning in the improvement of severe post-operative hypoxia following aortic dissection.

Postoperative hypoxemia after aortic dissection surgery presents a considerable clinical challenge, and acute respiratory distress syndrome (ARDS) is a common etiology. Prone positioning treatment has emerged as a potential intervention for improving respiratory function in this context. We report the case of a 27-year-old male who developed severe hypoxemia complicated by pulmonary embolism after aortic dissection surgery. He was diagnosed with postoperative hypoxemia combined with pulmonary embolism following aortic dissection. His respiratory status continued to deteriorate despite receiving standard postoperative care, thereby necessitating an alternative approach. Implementation of prone positioning treatment led to a substantial amelioration in his oxygenation and overall respiratory health, with a consistent hemodynamic state observed throughout the treatment. This technique resulted in significant relief in symptoms and improvement in respiratory parameters, facilitating successful extubation and, ultimately, discharge. This case underlines the possible efficacy of prone positioning therapy in managing severe hypoxia complicated by pulmonary embolism following aortic dissection surgery, warranting more thorough research to explore the potential of this treatment modality.

ICU Nurses' Perception of Sensitive Indicators of Quality of Care for ECMO Patients in Guizhou Province, China: A Cross-Sectional Study.

Purpose: This study aimed to investigate the cognitive evaluation level of ICU nurses in Guizhou Province, China, on the sensitivity indicators of nursing quality for ECMO patients. Patients and Methods: This was a cross-sectional observational study conducted in Guizhou Province, China, from May to July 2023, 259 ICU nurses were surveyed. Objective sampling method was used to select the participants from 10 hospitals in Guizhou Province that carried out ECMO. Data were collected through questionnaire survey. Two researchers checked and recorded Epidata 3.1. SPSS 25.0 was used for statistical analysis of the data, and frequency, mean and component ratio were used for descriptive statistical analysis. The importance rating was used to reflect the degree of nurses' agreement with the indicators. Results: The results of this study showed that 79.1% of the 253 ICU nurses in Guizhou Province, China, had not participated in training and courses related to indicators of quality of care evaluation for ECMO patients. The main way for ICU nurses to acquire knowledge related to indicators of quality of care sensitivity for ECMO patients was departmental training, which accounted for 87.4%. And the other ways, in descending order, were public, the matic lectures or academic conferences, journals and magazines; their evaluation scores of the importance of most of the quality of care sensitivity indicators for ECMO patients was moderate, with the scores ranging from 73 to 150. Among them, the range of importance evaluation scores for each indicator was 4.01 ~ 4.48. Conclusion: The overall cognitive evaluation of ICU nurses in Guizhou Province, China, on most sensitivity indicators of quality of care for ECMO patients was moderate, and there is a general lack of systematic courses and training on the knowledge related to ECMO care quality sensitive indicators.

CircVIRMA enhances cell malignant behavior by governing the miR-452-5p/CREBRF pathway in cervical cancer.

Our current study aimed to investigate the role and mechanism of circVIRMA in cervical cancer (CC) progression. CircVIRMA, microRNA-452-5p (miR-452-5p) and CREB3 regulatory factor (CREBRF) mRNA levels were examined in CC via quantitative real-time PCR (qRT-PCR). The protein level of CREBRF in CC was checked by Western blot. Cell Counting Kit-8 (CCK-8), colony formation, 5-Ethynyl-2'-deoxyuridine (EdU) staining, cell cycle, flow cytometry and transwell assays were conducted to estimate the effects of circVIRMA on malignant phenotypes of CC tumors. Western blot was used to measure related marker protein levels. The interaction between miR-452-5p and circVIRMA or CREBRF was predicted by bioinformatics analysis and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) assays. Xenograft assay was used to assess the effect of circVIRMA on tumor growth in vivo. Immunohistochemistry (IHC) assay was performed to detect Ki-67 expression in tissues of mice. CircVIRMA and CREBRF levels were upregulated, while miR-452-5p was downregulated in CC tissues and cells. CircVIRMA silencing restrained CC cell proliferation, migration and invasion whereas induced apoptosis in vitro. In addition circVIRMA knockdown markedly attenuated xenograft tumor growth in vivo. circVIRMA was an efficient molecular sponge for miR-452-5p, and negatively regulated miR-452-5p expression. circVIRMA regulated CREBRF expression to modulate CC progression via miR-452-5p. MiR-452-5p downregulation reversed the effects of circVIRMA knockdown on CC progression. MiR-452-5p directly targeted CREBRF, and CREBRF overexpression partly restored the impact of miR-452-5p mimics on CC progression. circVIRMA mediated CC progression via regulating miR-452-5p/CREBRF axis, providing a novel therapeutic target for CC treatment.

Perceptions of metabolic syndrome management utilization in relation to patient experience and health-related quality of life.

Background: One factor for the poor health outcomes among adult people with metabolic syndrome (MetS) is poor utilization of disease management resources, which may be attributable to prior experience with pharmacists (PEwP) and perceptions of disease management resource utilization (PMU). Therefore, understanding patients' experience could be critical to improving their perceptions and promoting health outcomes. Objectives: The study explored the influence of PEwP and PMU on the health-related quality of life (HRQoL) of people with MetS. Methods: Data on perceptions of healthcare, medication, and pharmacy services utilization, PEwP, and HRQoL were collected using validated tools via an electronic survey. Chi-square and ordinal regression tests were used to predict the association between PMU, PEwP, and HRQoL. Also, mediation analysis through Haye's model 4 explored the direct and indirect relationship of PMU and PEwP on HRQoL. Results: A total of 706 completed surveys were collected and used for analyses. On average, respondents reported three comorbidities. Of the respondents, 72.0% had good PEwP, while 32.6% had good PMU. Comparatively, 38.4% of those with good PEwP had good PMU, compared to 17.3% of those with poor PEwP. Also, 47.0% of those with good PMU had good HRQoL compared to 35.3% with poor PMU. The odds of having fair or good PMU were nearly triple (OR = 2.97, p < 0.001) among those with good PEwP compared to those with poor PEwP. Also, respondents with good PMU had 58% (OR = 1.58, p = 0.008) higher odds of having fair or good HRQoL. Analysis through bootstrap indicated a significant relationship (BootCI = -0.072, -0.022) between PEwP and HRQoL via respondents' PMU. Conclusions: MetS individuals with good experience and PMU were more likely to have good HRQoL. Prior experience with pharmacists influenced PMU and indirectly impacted HRQoL. Therefore, pharmacists must consider patients' experience and management utilization perceptions to promote health outcome among people with MetS, while implementing interventions.

Vapochromic separation of toluene and pyridine azeotropes using adaptive macrocycle co-crystals.

The separation of toluene (Tol) and pyridine (Py) azeotropes is significant in the chemical industry. Herein, we present a new method for the energy-efficient separation of Tol and Py using pillar[5]arene-based adaptive macrocycle co-crystals (MCCs) that can selectively separate Py from a Py/Tol equimolar mixture with 99.2% purity, accompanied by vapochromic behavior from white to yellow.

Solvent-Free Enzymatic Synthesis of Ethyl 3-Oxobutyrate Derivative: Characterization and Optimization of Reaction Condition.

It was first found that porcine pancreatic lipase (PPL) could catalyze the Knoevenagel condensation of aromatic aldehydes and ethyl acetoacetate under solvent-free conditions in this paper. Under solvent-free conditions, the highest yield of PPL catalytic reaction was 99.38%, and the Z/E selectivity of the product was 3.93. In addition, the reaction conditions were optimized, and the factors affecting the product structure were studied.

Efficacy and Safety of Snap Needles in the Treatment of Postoperative Hemorrhoidal Pain: A Systematic Review and Meta-Analysis.

Purpose: The aim of this study is to evaluate the efficacy and safety of Snap Needles (SN) in the management of Postoperative Hemorrhoidal Pain (POHP). Patients and Methods: A systematic search was conducted in various databases, including EMBASE, Web of Science, PubMed, WanFang database, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), and China Science and Technology Journal Database (VIP), spanning from their inception to August 2023, to identify relevant randomized controlled trials (RCTs) on SN for POHP. The primary outcome measure was the Visual Analog Scale (VAS), while secondary outcomes encompassed the Total Effective Rate (TER), Wound Healing Time (WHT), Pain Relief Time (PRT), Pain Disappearance Time (PDT), and Adverse Events (AEs). The Cochrane Risk of Bias Tool was employed to assess the quality of individual studies. A meta-analysis was conducted using RevMan 5.4.1 software. Results: The meta-analysis included 11 RCTs involving 1188 POHP patients, with an overall assessment of study quality ranging from very low to moderate. The findings revealed that the SN group exhibited significant improvements in treatment outcomes when compared to the control group (CG). These improvements were reflected in reduced VAS scores (mean difference [MD] = -1.10, 95% confidence interval [CI]: -1.31, -0.89, P < 0.05), shorter WHT (MD = -2.55, 95% CI: -3.02, -2.09, P < 0.05), quicker PRT (MD = -7.99, 95% CI: -8.48, -7.49, P < 0.05), fewer AEs (risk ratio [RR] = 0.38, 95% CI: 0.22, 0.67, P < 0.05), improved TER (RR = 1.18, 95% CI: 1.09, 1.27, P < 0.05), and faster PDT (MD = 19.24, 95% CI: 14.17, 24.31, P < 0.05). Conclusion: The use of SN appears to yield favorable outcomes in the treatment of POHP, and is potentially an alternative therapy to western drug therapy.

ß-Lactoglobulin-based aerogels: Facile preparation and sustainable removal of organic contaminants from water.

Economically and efficiently removing organic pollutants from water is still a challenge in wastewater treatment. Utilizing environmentally friendly and readily available protein-based natural polymers to develop aerogels with effective removal performance and sustainable regeneration capability is a promising strategy for adsorbent design. Here, a robust and cost-effective method using inexpensive ß-lactoglobulin (BLG) as raw material was proposed to fabricate BLG-based aerogels. Firstly, photocurable BLG-based polymers were synthesized by grafting glycidyl methacrylate. Then, a cross-linking reaction, including photo-crosslinking and salting-out treatment, was applied to prepared BLG-based hydrogels. Finally, the BLG-based aerogels with high porosity and ultralight weight were obtained after freeze-drying. The outcomes revealed that the biocompatible BLG-based aerogels exhibited effective removal performance for a variety of organic pollutants under perfectly quiescent conditions, and could be regenerated and reused many times via a simple and rapid process of acid washing and centrifugation. Overall, this work not only demonstrates that BLG-based aerogels are promising adsorbents for water purification but also provides a potential way for the sustainable utilization of BLG.

Astaxanthin Alleviates Autoimmune Hepatitis by Modulating CD8+ T Cells: Insights From Mass Cytometry and Single-Cell RNA Sequencing Analyses.

Astaxanthin (ASX) is an oxygen-containing non-vitamin A carotenoid pigment. However, the role of ASX in autoimmune hepatitis (AIH) remains unclear. In this study, a mouse model of AIH is established induced by concanavalin A (ConA). Mass cytometry and single-cell RNA sequencing (scRNA-seq) are used to analyze the potential role of ASX in regulating the immune microenvironment of AIH. ASX treatment effectively alleviated liver damage induced by ConA and downregulated pro-inflammatory cytokines production in mice. Mass cytometry and scRNA-seq analyses revealed a significant increase in the number of CD8+ T cells following ASX treatment. Functional markers of CD8+ T cells, such as CD69, MHC II, and PD-1, are significantly downregulated. Additionally, specific CD8+ T cell subclusters (subclusters 4, 13, 24, and 27) are identified, each displaying distinct changes in marker gene expression after ASX treatment. This finding suggests a modulation of CD8+ T cell function by ASX. Finally, the key transcription factors for four subclusters of CD8+ T cells are predicted and constructed a cell-to-cell communication network based on receptor-ligand interactions probability. In conclusion, ASX holds the potential to ameliorate liver damage by regulating the number and function of CD8+ T cells.

WonderFlow: Narration-Centric Design of Animated Data Videos.

Creating an animated data video with audio narration is a time-consuming and complex task that requires expertise. It involves designing complex animations, turning written scripts into audio narrations, and synchronizing visual changes with the narrations. This paper presents WonderFlow, an interactive authoring tool, that facilitates narration-centric design of animated data videos. WonderFlow allows authors to easily specify semantic links between text and the corresponding chart elements. Then it automatically generates audio narration by leveraging text-to-speech techniques and aligns the narration with an animation. WonderFlow provides a structure-aware animation library designed to ease chart animation creation, enabling authors to apply pre-designed animation effects to common visualization components. Additionally, authors can preview and refine their data videos within the same system, without having to switch between different creation tools. A series of evaluation results confirmed that WonderFlow is easy to use and simplifies the creation of data videos with narration-animation interplay.

Deep learning system for malignancy risk prediction in cystic renal lesions: a multicenter study.

OBJECTIVES: To develop an interactive, non-invasive artificial intelligence (AI) system for malignancy risk prediction in cystic renal lesions (CRLs). METHODS: In this retrospective, multicenter diagnostic study, we evaluated 715 patients. An interactive geodesic-based 3D segmentation model was created for CRLs segmentation. A CRLs classification model was developed using spatial encoder temporal decoder (SETD) architecture. The classification model combines a 3D-ResNet50 network for extracting spatial features and a gated recurrent unit (GRU) network for decoding temporal features from multi-phase CT images. We assessed the segmentation model using sensitivity (SEN), specificity (SPE), intersection over union (IOU), and dice similarity (Dice) metrics. The classification model's performance was evaluated using the area under the receiver operator characteristic curve (AUC), accuracy score (ACC), and decision curve analysis (DCA). RESULTS: From 2012 to 2023, we included 477 CRLs (median age, 57 [IQR: 48-65]; 173 men) in the training cohort, 226 CRLs (median age, 60 [IQR: 52-69]; 77 men) in the validation cohort, and 239 CRLs (median age, 59 [IQR: 53-69]; 95 men) in the testing cohort (external validation cohort 1, cohort 2, and cohort 3). The segmentation model and SETD classifier exhibited excellent performance in both validation (AUC = 0.973, ACC = 0.916, Dice = 0.847, IOU = 0.743, SEN = 0.840, SPE = 1.000) and testing datasets (AUC = 0.998, ACC = 0.988, Dice = 0.861, IOU = 0.762, SEN = 0.876, SPE = 1.000). CONCLUSION: The AI system demonstrated excellent benign-malignant discriminatory ability across both validation and testing datasets and illustrated improved clinical decision-making utility. CRITICAL RELEVANCE STATEMENT: In this era when incidental CRLs are prevalent, this interactive, non-invasive AI system will facilitate accurate diagnosis of CRLs, reducing excessive follow-up and overtreatment. KEY POINTS: The rising prevalence of CRLs necessitates better malignancy prediction strategies. The AI system demonstrated excellent diagnostic performance in identifying malignant CRL. The AI system illustrated improved clinical decision-making utility.

Deficiency of ADAR2 ameliorates metabolic-associated fatty liver disease via AMPK signaling pathways in obese mice.

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.