Real-time low-complexity diversity combining algorithm for free space coherent optical communication systems over atmospheric turbulence channel.

A novel diversity combining scheme, in conjunction with the complex-valued decision-directed least mean square (CV-DD-LMS) algorithm, is evaluated, and a real-time experimental validation is presented. This proposed scheme employs the CV-DD-LMS algorithm to concurrently perform beam combination and carrier phase recovery (CPR), thereby effectively reducing the overall complexity of digital signal processing. Furthermore, in the numerical simulation, under a low signal-to-noise ratio (SNR), a scheme utilizing the CV-DD-LMS algorithm effectively avoids cycle slips (CS) and outperforms schemes employing independent CPR modules. We experimentally validate this novel scheme by implementing it on an FPGA in a real-time 2.5Gb/s QPSK diversity-receiving system with three inputs. The back-to-back sensitivity is assessed using static received optical power, while the dynamic performance is evaluated by employing variable optical attenuators (VOAs) to simulate a power fluctuation at a frequency of 100kHz. The result proves that the implementation of the CV-DD-LMS algorithm yields stable performance while effectively reducing computational complexity.

Machine learning algorithms to predict intraoperative hemorrhage in surgical patients: a modeling study of real-world data in Shanghai, China.

BACKGROUND: Prediction tools for various intraoperative bleeding events remain scarce. We aim to develop machine learning-based models and identify the most important predictors by real-world data from electronic medical records (EMRs). METHODS: An established database of surgical inpatients in Shanghai was utilized for analysis. A total of 51,173 inpatients were assessed for eligibility. 48,543 inpatients were obtained in the dataset and patients were divided into haemorrhage (N = 9728) and without-haemorrhage (N = 38,815) groups according to their bleeding during the procedure. Candidate predictors were selected from 27 variables, including sex (N = 48,543), age (N = 48,543), BMI (N = 48,543), renal disease (N = 26), heart disease (N = 1309), hypertension (N = 9579), diabetes (N = 4165), coagulopathy (N = 47), and other features. The models were constructed by 7 machine learning algorithms, i.e., light gradient boosting (LGB), extreme gradient boosting (XGB), cathepsin B (CatB), Ada-boosting of decision tree (AdaB), logistic regression (LR), long short-term memory (LSTM), and multilayer perception (MLP). An area under the receiver operating characteristic curve (AUC) was used to evaluate the model performance. RESULTS: The mean age of the inpatients was 53 ± 17 years, and 57.5% were male. LGB showed the best predictive performance for intraoperative bleeding combining multiple indicators (AUC = 0.933, sensitivity = 0.87, specificity = 0.85, accuracy = 0.87) compared with XGB, CatB, AdaB, LR, MLP and LSTM. The three most important predictors identified by LGB were operative time, D-dimer (DD), and age. CONCLUSIONS: We proposed LGB as the best Gradient Boosting Decision Tree (GBDT) algorithm for the evaluation of intraoperative bleeding. It is considered a simple and useful tool for predicting intraoperative bleeding in clinical settings. Operative time, DD, and age should receive attention.

Study on the material basis of Dahuang Zhechong pill of anti-hepatoma effect by promoting vascular normalization.

Dahuang Zhechong Pill (DHZCP) is a traditional Chinese medicine prescription used to treat many diseases especially chronic liver disease accompanied by promotion of vascular normalization. In this work, UPLC-Q-TOF-MS/MS analysis was applied to identify the chemical components absorbed in the blood. HIF-1α, VEGF, Ang2 and Tie2 related to vascular normalization were detected to determine the dynamic changes of pharmacodynamic indicators. Then, the spectrum-effect relationship between the UHPLC fingerprint and pharmacodynamic indicators was evaluated dynamically using partial least squares (PLS). As a result, 103 components were identified from rat serum samples, including 56 original compounds and 47 metabolites. According to the PLS, active constituents of DHZCP acting on HIF-1α, VEGF, Ang2 and Tie2 (8, 15, 17 and 20) were found. In subsequent experiments on cells, 7/11 components of HIF-1α/VEGF were found in HepG2 and HUVEC cells, and 11/14/2 components of HIF-1α/VEGF/Tie2. The main pharmacodynamic components of DHZCP in promoting vascular normalization were successfully identified by the spectrum-effect relationship analysis.

Propofol prevents IL-13-induced epithelial-mesenchymal transition in human colorectal cancer cells.

Accumulating evidence showed that cytokines are involved in the development of cancer. IL-13 was showed to induce epithelial-mesenchymal transition and promote metastasis in colorectal cancer, providing a promising therapeutic target for cancer patients. Interestingly, recent studies showed that propofol, one of most common intravenous anesthetic agent, may have antitumor function in different cancer type. However, the impact of propofol on colorectal cancer and IL-13 induced epithelial-mesenchymal transition remains unknown. Herein, we found that propofol can effectively suppress cell proliferation in colorectal cell lines RKO and SW480 cells by using MTT assay. Furthermore, wound healing assay and migration assay demonstrated that propofol has the ability to inhibit epithelial-mesenchymal transition that induced by IL-13 in RKO and SW480 cells. Mechanistically, we found propofol treatment causes up-regulation of miR-361 and miR-135b, that suppress expression of STAT6 and thereafter leads to the inhibition of IL-13/STAT6/ZEB1 signaling pathway. In conclusion, our data for the first time demonstrated that propofol may serve as a novel therapeutic drug for targeting IL-13. The aggressive function of IL-13/STAT6/ZEB1 axis in colorectal cancer was impaired by propofol through miR-361 and miR-135b.

Update on protease-activated receptor 2 in inflammatory and autoimmune dermatological diseases.

Protease-activated receptor 2 (PAR2) is a cell-surface receptor expressed in various cell types, including keratinocytes, neurons, immune and inflammatory cells. Activation of PAR2, whether via its canonical or biased pathways, triggers a series of signaling cascades that mediate numerous functions. This review aims to highlight the emerging roles and interactions of PAR2 in different skin cells. It specifically summarizes the latest insights into the roles of PAR2 in skin conditions such as atopic dermatitis (AD), psoriasis, vitiligo and melasma. It also considers these roles from the perspective of the cutaneous microenvironment in relation to other inflammatory and autoimmune dermatological disorders. Additionally, the review explores PAR2's involvement in associated comorbidities from both cutaneous and extracutaneous diseases. Therefore, PAR2 may serve as a key target for interactions among various cells within the local skin environment.

Phosphatidylserine improves aging sepsis survival, modulates gut microbiome, and prevents sepsis-associated encephalopathy.

Aged adults are prone to both short- and long-term complications following sepsis due to ineffective therapy. Phosphatidylserine (PS) is a membrane nutrient supplement known to enhance cognition and brain function, but its potential effects in treating sepsis are not well-documented. Our study aimed to explore the potential of PS in improving outcomes in sepsis and sepsis-associated encephalopathy (SAE). Middle-aged mice were administered PS for two months following induction of sepsis by lipopolysaccharides. The results indicated a significant increase in the survival rate of mice treated with PS after sepsis. Surviving mice underwent open field and shuttle box tests 45 days post-sepsis, revealing potential alleviation of neurobehavioral impairments due to PS pretreatment. Analysis at 60 days post-sepsis euthanasia showed reduced cleaved-caspase 3 in neurons and glial cell markers in the PS-treated group compared to the untreated sepsis group. Furthermore, PS administration effectively reduced proinflammatory cytokine gene expression in the hippocampus of mice with SAE, potentially inhibiting the TBK1/NLRP3/ASC signaling pathway. In the gut, PS pretreatment modulated ß-diversity while maintaining jejunal morphology and colon ZO-1 expression, without significantly affecting α-diversity indices. Our findings suggest that PS administration improves survival rates, modulates the gut microbiome, preserves gut integrity, and ameliorates brain pathology in survived mice after sepsis. Importantly, these findings have significant implications for sepsis treatment and cognitive function preservation in aging individuals, providing new insights and sparking further interest and investigation into the potential of PS in sepsis treatment.

Novel EGFR inhibitors against resistant L858R/T790M/C797S mutant for intervention of non-small cell lung cancer.

To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.

Chicoric Acid Alleviates Colitis via Targeting the Gut Microbiota Accompanied by Maintaining Intestinal Barrier Integrity and Inhibiting Inflammatory Responses.

Polyphenols have shown great potential to prevent ulcerative colitis. As a natural plant polyphenol, chicoric acid (CA) has antioxidant and anti-inflammatory properties. This study explored the intervention effects and potential mechanism of CA on dextran sodium sulfate (DSS)-induced colitis mice. The results showed that CA alleviated the symptoms of colitis and maintained the intestinal barrier integrity. CA significantly downregulated the mRNA expression levels of inflammatory factors including IL-6, IL-1ß, TNF-α, IFN-γ, COX-2, and iNOS. In addition, CA modulated the gut microbiota by improving the microbial diversity, reducing the abundance of Gammaproteobacteriaand Clostridium_XI and increasing the abundance ofBarnesiellaandLachnospiraceae. Further fecal microbiota transplantation experiments showed that FM from CA donor mice significantly alleviated the symptoms of colitis, verifying the key role of gut microbiota. These results indicate that CA effectively relieves DSS-induced colitis via targeting gut microbiota along with preserving intestinal barrier function and suppressing inflammatory responses.

Discovery of novel fructose-1,6-bisphosphatase inhibitors bearing benzimidazole scaffold using a dual-ligand molecular docking model.

Fructose-1,6-bisphosphatase (FBPase) is an emerging target in gluconeogenesis, inhibitors of which would be an effective treatment for elevated fasting blood glucose in patients with type 2 diabetes. Based on the lead compound G-1 (FBPase 10 µM inhibition = 64.3 %) and according to the X-ray crystal structure of FBPase, we designed and validated an innovative molecular docking method based on the dual-ligand model to explore the interactions between two identical ligands in neighboring targets. Based on the dual-ligand molecular docking model, a novel compound 45 bearing a benzimidazole scaffold was identified to show increased inhibitory activity against FBPase (IC50, 2.08 µM). An oral pyruvate tolerance test in ICR mice showed that 45 had a potent inhibitory effect on gluconeogenesis similar to that of metformin when administered as a single dose in vivo. Compound 45 did not inhibit the common subtypes of the human cytochrome P450 system, indicating that it may have a reduced propensity for drug-drug interactions. The findings of this study may pave the way for further development of FBPase inhibitors with novel structural features, improved activity, and good druggability.

Dahuang Zhechong pill attenuates hepatic sinusoidal capillarization in liver cirrhosis and hepatocellular carcinoma rat model via the MK/integrin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Dahuang Zhechong pill (DHZCP), a traditional Chinese medicine, was derived from the famous book Unk "Synopsis of Prescriptions of the Golden Chamber" during the Han dynasty. Owing to its ability to invigorate the circulation of blood in Chinese medicine, DHZCP is usually used for treating liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Clinical application have shown that DHZCP exhibits satisfactory therapeutic effects in HCC adjuvant therapy; however, little is known about its underlying mechanisms. AIM OF THE STUDY: We aimed to clarify the mechanism of DHZCP against hepatic sinusoidal capillarization in rats with LC and HCC by inhibiting the MK/integrin signaling pathway of liver sinusoidal endothelial cells (LSECs). MATERIALS AND METHODS: The contents of 29 characteristic components in DHZCP were determined by ultraperformance liquid chromatography-tandem mass spectrometry. DEN (Diethylnitrosamine)-induced LC and HCC rat models were constructed, and DHZCP was administered when the disease entered the LC stage. After 4 or 12 weeks of administration, hematoxylin and eosin staining, Masson staining, Metavir score, and SSCP (Single strand conformation polymorphism) gene mutation detection were used to confirm tissue fibrosis and cancer. The levels of NO, ET-1 and TXA2, which can regulate vasomotor functions and activate the MK/Itgα6/Src signaling pathway were evaluated by using immunohistochemistry, chemiluminescence, immunofluorescence, Western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Similar methods were also used to evaluate the levels of VEGF, VEGFR, Ang-2 and Tie, which can promote pathological angiogenesis and activate the MK/Itgα4/NF-κB signaling pathway. In vitro cell experiments were performed using potential pharmacodynamic molecules targeting integrins in DHZCP were selected by molecular docking, and the effects of these molecules on the function of LSECs were studied by Itgα4+ and Itgα6+ cell models. RESULTS: At the stage of LC, the animal experiments demonstrated that DHZCP mainly inhibited the MK/Itgα6 signaling pathway to increase the number and size of hepatic sinus fenestration, reversed the ET-1/NO and TXA2/NO ratios, regulated hepatic sinus relaxation and contraction balance, reduced the portal vein pressure, and inhibited cirrhotic carcinogenesis. At the HCC stage, DHZCP could also significantly inhibit the MK/Itgα4 signaling pathway, reduce pathological angiogenesis, and alleviate disease progression. The results of the cell experiments showed that Rhein, Naringenin, Liquiritin and Emodin-8-O-ß-D-glucoside (PMEG) were involved in vascular regulation by affecting the MK/integrin signaling pathway. Liquiritin and PMEG mainly blocked the MK/α6 signal, which is important in regulating the vasomotor function of the liver sinus. Naringenin and Rhein mainly acted by blocked the signaling of MK/α4 action signal, which are potent molecules that inhibit pathological angiogenesis. CONCLUSIONS: DHZCP could improve the hepatic sinusoidal capillarization of LC and HCC by inhibiting the MK/Itgα signaling pathway and inhibited disease progression. Rhein, Naringenin, Liquiritin and PMEG were the main active molecules that affected the MK/Itgα signaling pathway.

Exploring drug combinations in genetic interaction network.

BACKGROUND: Drug combination that consists of distinctive agents is an attractive strategy to combat complex diseases and has been widely used clinically with improved therapeutic effects. However, the identification of efficacious drug combinations remains a non-trivial and challenging task due to the huge number of possible combinations among the candidate drugs. As an important factor, the molecular context in which drugs exert their functions can provide crucial insights into the mechanism underlying drug combinations. RESULTS: In this work, we present a network biology approach to investigate drug combinations and their target proteins in the context of genetic interaction networks and the related human pathways, in order to better understand the underlying rules of effective drug combinations. Our results indicate that combinatorial drugs tend to have a smaller effect radius in the genetic interaction networks, which is an important parameter to describe the therapeutic effect of a drug combination from the network perspective. We also find that drug combinations are more likely to modulate functionally related pathways. CONCLUSIONS: This study confirms that the molecular networks where drug combinations exert their functions can indeed provide important insights into the underlying rules of effective drug combinations. We hope that our findings can help shortcut the expedition of the future discovery of novel drug combinations.

Advances in biomaterials as a retinal patch for the repair of rhegmatogenous retinal detachment.

Rhegmatogenous retinal detachment (RRD) is the most common retinological emergency that can cause blindness without surgical treatment. RRD occurs when liquefied vitreous accumulates between the neurosensory retina and the retinal pigment epithelium via retinal breaks, which are caused by the separation of the vitreous from the retina with aging. Currently, the main treatment option is pars plana vitrectomy, which involves surgical removal of the vitreous and laser photocoagulation around retinal breaks to generate firm chorioretinal adhesion, as well as subsequent filling of the vitreous cavity with long-lasting substitutes (expansile gas or silocone oil) to prevent the connection between the subretinal space and the vitreous cavity via the breaks before the chorioretinal adhesion firm enough. However, the postoperative face-down position and the not very satisfactory first retinal reattachment rate place a heavy burden on patients. With the development of technology and materials engineering, researchers have developed biomaterials that can be used as a retinal patch to seal retinal breaks and prevent the connection of subretinal space and vitreous cavity via breaks, thus replacing the long-lasting vitreous substitutes and eliminating the postoperative face-down position. Preclinical studies have demonstrated that biomaterial sealants have enough biocompatibility and efficacy in the in vitro and in vivo experiments. Some sealants have been used in clinical trials on a small scale, and the results indicate promising application prospects of the biomaterial sealants as retinal patches in the repair of RRD. Herein, we review the recent advances in biomaterials as retinal patches for the repair of RRD, focusing on the biomaterial categories, methods, and procedures for sealing retinal breaks, as well as their biocompatibility and efficacy, current limitations, and development perspectives.

In Situ Forming Hydrogel as a Tracer and Degradable Lacrimal Plug for Dry Eye Treatment.

Lacrimal plug is an effective and widely therapeutic strategy to treat dry eye. However, almost all commercialized plugs are fixed in a certain design and associated with many complications, such as spontaneous plug extrusion, epiphora, and granuloma and cannot be traced in the long-term. Herein, a simple in situ forming hydrogel is developed as a tracer and degradable lacrimal plug to achieve the best match with the irregular lacrimal passages. In this strategy, methacrylate-modified silk fibroin (SFMA) is served as a network, and a self-assembled indocyanine green fluorescence tracer nanoparticle (FTN) is embedded as an indicator to develop the hydrogel plug using visible photo-crosslinking. This SFMA/FTN hydrogel plug has excellent biocompatibility and biodegradability, which can be noninvasively monitored by near-infrared light. In vivo tests based on dry eye rabbits show that the SFMA/FTN hydrogel plug can completely block the lacrimal passages and greatly improve the various clinical indicators of dry eye. These results demonstrate that the SFMA/FTN hydrogel is suitable as an injectable and degradable lacrimal plug with a long-term tracking function. The work offers a new approach to the development of absorbable plugs for the treatment of dry eye.

Multi-omics analysis reveals neuroinflammation, activated glial signaling, and dysregulated synaptic signaling and metabolism in the hippocampus of aged mice.

Aging is an intricate biological event that occurs in both vertebrates and invertebrates. During the aging process, the brain, a vulnerable organ, undergoes structural and functional alterations, resulting in behavioral changes. The hippocampus has long been known to be critically associated with cognitive impairment, dementia, and Alzheimer's disease during aging; however, the underlying mechanisms remain largely unknown. In this study, we hypothesized that altered metabolic and gene expression profiles promote the aging process in the hippocampus. Behavioral tests showed that exploration, locomotion, learning, and memory activities were reduced in aged mice. Metabolomics analysis identified 69 differentially abundant metabolites and showed that the abundance of amino acids, lipids, and microbiota-derived metabolites (MDMs) was significantly altered in hippocampal tissue of aged animals. Furthermore, transcriptomic analysis identified 376 differentially expressed genes in the aged hippocampus. A total of 35 differentially abundant metabolites and 119 differentially expressed genes, constituting the top 200 correlations, were employed for the co-expression network. The multi-omics analysis showed that pathways related to inflammation, microglial activation, synapse, cell death, cellular/tissue homeostasis, and metabolism were dysregulated in the aging hippocampus. Our data revealed that metabolic perturbations and gene expression alterations in the aged hippocampus were possibly linked to their behavioral changes in aged mice; we also provide evidence that altered MDMs might mediate the interaction between gut and brain during the aging process.

Immunoregulation in Diabetic Wound Repair with a Photoenhanced Glycyrrhizic Acid Hydrogel Scaffold.

M1 macrophage accumulation and excessive inflammation are commonly encountered issues in diabetic wounds and can fail in the healing process. Hence, hydrogel dressings with immunoregulatory capacity have great promise in the clinical practice of diabetic wound healing. However, current immunoregulatory hydrogels are always needed for complex interventions and high-cost treatments, such as cytokines and cell therapies. In this study, a novel glycyrrhizic acid (GA)-based hybrid hydrogel dressing with intrinsic immunoregulatory properties is developed to promote rapid diabetic wound healing. This hybrid hydrogel consists of interpenetrating polymer networks composed of inorganic Zn2+ -induced self-assembled GA and photo-crosslinked methyl acrylated silk fibroin (SF), realizing both excellent injectability and mechanical strength. Notably, the SF/GA/Zn hybrid hydrogel can regulate macrophage responses in the inflammatory microenvironment, circumventing the use of any additives. The immunomodulatory properties of the hydrogel can be harnessed for safe and efficient therapeutics that accelerate the three phases of wound repair and serve as a promising dressing for the management of diabetic wounds.

Integrated transcriptomics and metabolomics analysis of the hippocampus reveals altered neuroinflammation, downregulated metabolism and synapse in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is an intricated complication of sepsis that brings abnormal emotional and memory dysfunction and increases patients' mortality. Patients' alterations and abnormal function seen in SAE occur in the hippocampus, the primary brain region responsible for memory and emotional control, but the underlying pathophysiological mechanisms remain unclear. In the current study, we employed an integrative analysis combining the RNA-seq-based transcriptomics and liquid chromatography/mass spectrometry (LC-MS)-based metabolomics to comprehensively obtain the enriched genes and metabolites and their core network pathways in the endotoxin (LPS)-injected SAE mice model. As a result, SAE mice exhibited behavioral changes, and their hippocampus showed upregulated inflammatory cytokines and morphological alterations. The omics analysis identified 81 differentially expressed metabolites (variable importance in projection [VIP] > 1 and p < 0.05) and 1747 differentially expressed genes (Foldchange >2 and p < 0.05) were detected in SAE-grouped hippocampus. Moreover, 31 compounds and 100 potential target genes were employed for the Kyoto Encyclopedia of Genes and Genomes (KEGG) Markup Language (KGML) network analysis to explore the core signaling pathways for the progression of SAE. The integrative pathway analysis showed that various dysregulated metabolism pathways, including lipids metabolism, amino acids, glucose and nucleotides, inflammation-related pathways, and deregulated synapses, were tightly associated with hippocampus dysfunction at early SAE. These findings provide a landscape for understanding the pathophysiological mechanisms of the hippocampus in the progression of SAE and pave the way to identify therapeutic targets in future studies.

Anti-melanoma effect and action mechanism of a novel chitosan-based composite hydrogel containing hydroxyapatite nanoparticles.

Hydroxyapatite nanoparticles (HANPs) have been increasingly regarded and reported due to their potential anti-tumor ability. Previously, we found that the rod-like HANPs had good application potential for cutaneous melanoma (CMM). To satisfy the actual requirements in repairing post-operative skin defects and inhibiting CMM recurrence after tumorectomy, we constructed a novel chitosan/alginate (CS/Alg) hydrogel containing the aforementioned HANPs. The in vitro cell experiments confirmed that activated mitochondrial-dependent apoptosis was tightly related to the anti-tumor ability of HANPs. Specifically, we further discovered several target proteins might be involved in abnormal activating Wnt, proteoglycans in cancer, oxidative phosphorylation and p53 signaling pathways. The in vivo animal experiments demonstrated that the HANPs-loaded CS/Alg hydrogel (CS/Alg/HANPs) had a similar effect on inhibiting tumor growth as HANPs, and CS/Alg hydrogel as well as phosphate buffered saline (PBS) group (control) not showed any effect, proving the key role of HANPs. The immunohistochemical staining demonstrated a tumor inhibition via the mitochondria-mediated apoptosis pathway, consistent with the in vitro evaluation. Moreover, CS/Alg/HANPs exhibited no additional biosafety risk to the functions of major organs. Overall, this CS/Alg/HANPs hydrogel has substantial application potential for treating CMM.

CASCADE_SCAN: mining signal transduction network from high-throughput data based on steepest descent method.

BACKGROUND: Signal transduction is an essential biological process involved in cell response to environment changes, by which extracellular signaling initiates intracellular signaling. Many computational methods have been generated in mining signal transduction networks with the increasing of high-throughput genomic and proteomic data. However, more effective means are still needed to understand the complex mechanisms of signaling pathways. RESULTS: We propose a new approach, namely CASCADE_SCAN, for mining signal transduction networks from high-throughput data based on the steepest descent method using indirect protein-protein interactions (PPIs). This method is useful for actual biological application since the given proteins utilized are no longer confined to membrane receptors or transcription factors as in existing methods. The precision and recall values of CASCADE_SCAN are comparable with those of other existing methods. Moreover, functional enrichment analysis of the network components supported the reliability of the results. CONCLUSIONS: CASCADE_SCAN is a more suitable method than existing methods for detecting underlying signaling pathways where the membrane receptors or transcription factors are unknown, providing significant insight into the mechanism of cellular signaling in growth, development and cancer. A new tool based on this method is freely available at http://www.genomescience.com.cn/CASCADE_SCAN/.

CD44(+)/CD24(-) cells are transit progenitors and do not determine the molecular subtypes and clinical parameters in breast carcinomas.

CD44(+)/CD24(-) cells have been associated with breast cancer stem/progenitor cell features. However, the status of this phenotype cells in normal, benign and malignant breast tissues has not been studied, and the clinical correlation of this subpopulation in breast cancer is not fully understood. The present study sought to identify these cells in a series of normal, benign, and malignant breast tissues and explore their correlation to the molecular subtypes of breast carcinoma and conventional pathological features. Double-staining immunohistochemistry (DIHC) of CD44 and CD24 was performed on 30 normal breast tissues, 30 breast fibroadenomas (FA), 60 breast invasive ductal carcinomas (IDC), and 3 breast cancer cell lines (MCF-7, MDA-MB-468, and MDA-MB-231). In the normal breast tissues and FAs, three phenotypes were observed including CD44(+)/CD24(+), CD44(+)/CD24(-), and CD44(-)/CD24(-) cells. In the IDCs, CD44(-)/CD24(+) cells were detected, in addition to the three aforementioned phenotypes. The strong positive rate (+++, incidence >60%) of CD44(+)/CD24(-) was significantly increased from normal breast tissue, FAs to IDCs (0.0%-->6.7%-->21.7%). However, the CD44(+)/CD24(-) cells didn't correlate with ages of patients, lymph node metastasis, tumor size, molecular subtypes, and the expression of ER, PR, HER-2, PS2, Bcl-2, nm23. The proportion of CD44(+)/CD24(-) cells in MCF-7, MDA-MB-468, and MDA-MB-231 was about 1, 5, and 80%, respectively. The results indicate that the CD44(+)/CD24(-) cells are transit progenitors and have no association with the molecular subtypes and clinicopathological parameters in the IDCs.