Challenges and improvements in HER2 scoring and histologic evaluation: insights from a national proficiency testing scheme for breast cancer diagnosis in China.

BACKGROUND: In 2022, our team launched the pioneering national proficiency testing (PT) scheme for the pathological diagnosis of breast cancer, rapidly establishing its credibility throughout China. Aiming to continuously monitor and improve the proficiency of Chinese pathologists in breast pathology, the second round of the PT scheme was initiated in 2023, which will expand the number of participating institutions, and will conduct a nationwide investigation into the interpretation of HER2 0, 1+, and 2+/FISH- categories in China. METHODS: The methodology employed in the current round of PT scheme closely mirrors that of the preceding cycle in 2022, which is designed and implemented according to the "Conformity assessment-General requirements for proficiency testing"(GB/T27043-2012/ISO/IEC 17043:2010). More importantly, we utilized a statistics-based method to generate assigned values to enhance their robustness and credibility. RESULTS: The final PT results, published on the website of the National Quality Control Center for Cancer ( http://117.133.40.88:3927 ), showed that all participants passed the testing. However, a few institutions demonstrated systemic biases in scoring HER2 0, 1+, and 2+/FISH- with accuracy levels below 59%, considered unsatisfactory. Especially, the concordance rate for HER2 0 cases was only 78.1%, indicating challenges in distinguishing HER2 0 from low HER2 expression. Meanwhile, areas for histologic type and grade interpretation improvement were also noted. CONCLUSIONS: Our PT scheme demonstrated high proficiency in diagnosing breast cancer in China. But it also identified systemic biases in scoring HER2 0, 1+, and 2+/FISH- at some institutions. More importantly, our study highlighted challenges in the evaluation at the extreme lower end of the HER2 staining spectrum, a crucial area for further research. Meanwhile, it also revealed the need for improvements in interpreting histologic types and grades. These findings strengthened the importance of robust quality assurance mechanisms, like the nationwide PT scheme conducted in this study, to maintain high diagnostic standards and identify areas requiring further training and enhancement.

Determination of succinic acid and lactic acid in pigs' serum, intestinal contents, and meat by ultrahigh-performance liquid chromatography-tandem mass spectrometry.

RATIONALE: Succinic acid and lactic acid have been associated with diarrhea in weaned piglets. The level of succinic acid and lactic acid in serum, meat, and intestinal contents is important to elucidate the mechanism of diarrhea in weaned piglets. METHODS: A facile method was developed for the quantification of succinic acid and lactic acid in pigs' serum, intestinal contents, and meat using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC/MS/MS). The serum samples underwent protein precipitation with methanol. The meat and intestinal contents were freeze-dried and homogenized using a tissue grinding apparatus. Methanol-water mixture (80:20, v/v) was used for homogenizing the meat, while water was used for homogenizing the intestinal contents. An additional step of protein precipitation with acetonitrile was required for the intestinal contents. The resulting solution was diluted with water before being analyzed by UHPLC/MS/MS. Separation of succinic acid and lactic acid could be achieved within 3 min using a Kinetic XB-C18 column. RESULTS: The coefficients of variation for peak areas of succinic acid and lactic acid were less than 5.0%. The established method demonstrated good linearity as indicated by correlation coefficients exceeding 0.996. Additionally, satisfactory recoveries ranging from 88.58% to 108.8% were obtained. The detection limits (RS/N = 3) for succinic acid and lactic acid were determined to be 0.75 ng/mL and 0.02 µg/mL, respectively. CONCLUSION: This method exhibited high sensitivity, simplicity in operation, and small sample weight, making it suitable for quantitative determination of succinic acid and lactic acid in pigs' serum, intestinal contents, and meat. The method developed will provide valuable technical support in studying the metabolic mechanisms of succinic acid and lactic acid in pigs.

Development and implementation of evidence-based, nurse-leading early warning model and healthcare quality improvement project for transplant-associated thrombotic microangiopathy: a mixed-methods, before-and-after study.

OBJECTIVE: The early identification and diagnosis of transplant-associated thrombotic microangiopathy (TA-TMA) are essential yet difficult in patients underwent hematopoietic stem cell transplantation (HSCT). To develop an evidence-based, nurse-leading early warning model for TA-TMA, and implement the healthcare quality review and improvement project. METHODS: This study was a mixed-methods, before-and-after study. The early warning model was developed based on quality evidence from literature search. The healthcare quality review and improvement project mainly included baseline investigation of nurse, improvement action and effectiveness evaluation. The awareness and knowledge of early parameter of TA-TMA among nurses and the prognosis of patients underwent HSCT were compared before and after the improvement. RESULTS: A total of 1 guideline, 1 evidence synthesis, 4 expert consensuses, 10 literature reviews, 2 diagnostic studies, and 9 case series were included in the best evidence. The early warning model including warning period, high-risk characteristics and early manifestation of TA-TMA was developed. The improvement action, including staff training and assessment, suspected TA-TMA identification and patient education, was implemented. The awareness and knowledge rate of early parameter of TA-TMA among nurses significantly improved after improvement action (100% vs. 26.7%, P < 0.001). The incidence of TA-TMA was similar among patients underwent HSCT before and after improvement action (2.8% vs. 1.2%, P = 0.643), while no fall event occurred after improvement action (0 vs. 1.2%, P < 0.001). CONCLUSION: The evidence-based early warning model and healthcare quality improvement project could enhance the awareness and knowledge of TA-TMA among healthcare providers and might improve the prognosis of patients diagnosed with TA-TMA.

Transcriptomics and Metabolomics for Co-Exposure to a Cocktail of Neonicotinoids and the Synergist Piperonyl Butoxide.

Here, the transcriptomics and metabolomics on a model of exposure to a cocktail of neonicotinoids (Neo) containing seven commercial compounds and a synergist piperonyl butoxide (PBO) were established. The results showed that Neo and PBO disrupted mRNA and metabolite levels in a dose-dependent manner. Neo caused tryptophan pathway-related neurotoxicity, reduced lipolysis, and promoted fat mass accumulation in the liver, while PBO induced an increase in inflammatory factors and damage to intercellular membranes. Co-exposure enhanced Neo-induced liver steatosis, focal necrosis, and oxidative stress by inhibiting oxidative phosphorylation (OXPHOS). Furthermore, diglycerides and metabolic biomarkers demonstrated that the activation of insulin signaling is associated with restricted OXPHOS, which commonly leads to a high risk of non-alcoholic fatty liver disease (NAFLD) and Alzheimer's disease (AD) as the result of over-synthesis of lipids, low energy supply, and high thermogenesis. The study demonstrates that chronic disease can be induced by Neo and the synergist PBO at the molecular level.

An SSL-PUF Based Access Authentication and Key Distribution Scheme for the Space-Air-Ground Integrated Network.

The Space-Air-Ground Integrated Network (SAGIN) expands cyberspace greatly. Dynamic network architecture, complex communication links, limited resources, and diverse environments make SAGIN's authentication and key distribution much more difficult. Public key cryptography is a better choice for terminals to access SAGIN dynamically, but it is time-consuming. The semiconductor superlattice (SSL) is a strong Physical Unclonable Function (PUF) to be the hardware root of security, and the matched SSL pairs can achieve full entropy key distribution through an insecure public channel. Thus, an access authentication and key distribution scheme is proposed. The inherent security of SSL makes the authentication and key distribution spontaneously achieved without a key management burden and solves the assumption that excellent performance is based on pre-shared symmetric keys. The proposed scheme achieves the intended authentication, confidentiality, integrity, and forward security, which can defend against masquerade attacks, replay attacks, and man-in-the-middle attacks. The formal security analysis substantiates the security goal. The performance evaluation results confirm that the proposed protocols have an obvious advantage over the elliptic curve or bilinear pairings-based protocols. Compared with the protocols based on the pre-distributed symmetric key, our scheme shows unconditional security and dynamic key management with the same level performance.

A Secure Scheme Based on a Hybrid of Classical-Quantum Communications Protocols for Managing Classical Blockchains.

Blockchain technology affords data integrity protection and building trust mechanisms in transactions for distributed networks, and, therefore, is seen as a promising revolutionary information technology. At the same time, the ongoing breakthrough in quantum computation technology contributes toward large-scale quantum computers, which might attack classic cryptography, seriously threatening the classic cryptography security currently employed in the blockchain. As a better alternative, a quantum blockchain has high expectations of being immune to quantum computing attacks perpetrated by quantum adversaries. Although several works have been presented, the problems of impracticality and inefficiency in quantum blockchain systems remain prominent and need to be addressed. First, this paper develops a quantum-secure blockchain (QSB) scheme by introducing a consensus mechanism-quantum proof of authority (QPoA) and an identity-based quantum signature (IQS)-wherein QPoA is used for new block generation and IQS is used for transaction signing and verification. Second, QPoA is developed by adopting a quantum voting protocol to achieve secure and efficient decentralization for the blockchain system, and a quantum random number generator (QRNG) is deployed for randomized leader node election to protect the blockchain system from centralized attacks like distributed denial of service (DDoS). Compared to previous work, our scheme is more practical and efficient without sacrificing security, greatly contributing to better addressing the challenges in the quantum era. Extensive security analysis demonstrates that our scheme provides better protection against quantum computing attacks than classic blockchains. Overall, our scheme presents a feasible solution for blockchain systems against quantum computing attacks through a quantum strategy, contributing toward quantum-secured blockchain in the quantum era.

Sex-Dependent Environmental Health Risk Analysis of Flupyradifurone.

Pesticides are used in agricultural production worldwide, resulting in widespread environmental pollution. Many diseases are closely related to exposure to pesticide residues. In this study, the association between exposure to the pesticide flupyradifurone (FPF), a substitute for neonicotinoids, and sex-dependent thyroid dysfunction was explored for the first time. Exposure using rat models revealed that the FPF metabolism is sex-dependent, with males preferring N-dealkylation and hydrolytic metabolism and females preferring hydroxylation. In particular, novel chloropyridine-site hydroxylation I and II metabolic pathways of FPF were discovered. More importantly, differential metabolic pathways of FPF induced sex-based dysregulation of the hypothalamic-pituitary-thyroid axis, in which females exhibited subclinical hyperthyroidism, while males displayed abnormal hypothyroidism. This may be attributed to the potential agonistic or antagonistic effect of FPF sex-dependent metabolites on liver thyroid hormone receptors. Furthermore, FPF exposure further mediated sex-specific dysregulation of cellular lipid homeostasis, with abnormal fatty acid ß-oxidation and excessive energy expenditure in females and the risk of excessive accumulation of triglycerides in males. These results illustrate the potential risk of sex-related thyroid metabolic diseases caused by FPF and provide an important basis and support for further studies of FPF on human health and as an environmental pollutant.

Passively Mode-Locked Er-Doped Fiber Laser Based on Sb2S3-PVA Saturable Absorber.

In this paper, antimony trisulfide (Sb2S3) was successfully prepared with the liquid phase exfoliation method and embedded into polyvinyl alcohol (PVA) as a saturable absorber (SA) in a passively mode-locked Er-doped fiber laser for the first time. Based on Sb2S3-PVA SA with a modulation depth of 4.0% and a saturable intensity of 1.545 GW/cm2, a maximum average output power of 3.04 mW and maximum peak power of 325.6 W for the stable mode-locked pulses was achieved with slope a efficiency of 0.87% and maximum single pulse energy of 0.81 nJ at a repetition rate of 3.47 MHz under a pump power of 369 mW. A minimum pulse width value of 2.4 ps with a variation range less than 0.1 ps, and a maximum signal to noise ratio (SNR) of 54.3 dB indicated reliable stability of mode-locking, revealing promising potentials of Sb2S3 as a saturable absorber in ultrafast all-fiber lasers.

A Dead Reckoning Calibration Scheme Based on Optimization with an Adaptive Quantum-Inspired Evolutionary Algorithm for Vehicle Self-Localization.

Parameter calibration is critical for self-localization based on dead reckoning in the control of intelligent vehicles such as autonomous driving. Most traditional calibration methods for robotics control based on dead reckoning rely on data collection with specially designed paths. For the calibration of parameters in the control of intelligent vehicles, the design of such paths is considered impossible due to the complexity of road conditions. To solve this problem, an optimization-based dead reckoning calibration scheme is introduced in this research using the differential global positioning system to obtain the actual positions of the intelligent vehicle. In this scheme, the difference between the positions obtained through dead reckoning and the positions obtained through the differential global positioning system is selected as the optimization objective function to be minimized. An adaptive quantum-inspired evolutionary algorithm is developed to improve the quality and efficiency of optimization. Experiments with an intelligent vehicle were also conducted to demonstrate the effectiveness of the developed calibration scheme. In addition, the newly introduced adaptive quantum-inspired evolutionary algorithm is compared with the classic genetic algorithm and the classic quantum-inspired evolutionary algorithm using eight benchmark test functions considering computation quality and efficiency.

Vasectomy and prostate cancer risk: a meta-analysis of prospective studies.

Epidemiological cohort studies investigating the association between vasectomy and prostate cancer risk have yielded inconsistent results. The aim of the present meta-analysis is to update the evidence on the association between vasectomy and prostate cancer. A comprehensively literature search of relevant studies was performed in December 2019 using PubMed. A DerSimonian and Laird random-effects model was used to calculate the summary relative risk (RR) and its 95% confidence interval (CI). A total of 15 eligible cohort studies (16 data sets) with more than four million of participants were eventually included in this meta-analysis. There was a statistically significant higher risk of prostate cancer among men who underwent vasectomy (RR: 1.09, 95% CI: 1.04-1.13) with obvious heterogeneity among included studies (P < 0.001, I2 = 64.2%). Vasectomy was also associated with the risk of advanced prostate cancer (RR: 1.07, 95% CI: 1.02-1.13), which is less likely to be affected from detection bias. In conclusion, findings from this meta-analysis of prospective studies indicate that vasectomy may be positively associated with the risk of prostate cancer. Further large prospective studies with long follow-up are warranted to verify the findings from this meta-analysis. In addition, the potential underlying molecular mechanism needed further exploration with in vitro and animal studies.

Vascular endothelial cell-derived exosomal miR-30a-5p inhibits lung adenocarcinoma malignant progression by targeting CCNE2.

This study tried to explore the molecular mechanism underlying progression of lung adenocarcinoma (LUAD) and discuss the extracellular communication between cancer cells and vascular endothelial cells. Roughly, differential analysis was carried out to note that miR-30a-5p was lowly expressed in LUAD, whereas CCNE2 was highly expressed. Cell functional experiments demonstrated that overexpressed miR-30a-5p led to suppressed cell abilities in proliferation, migration and invasion. Dual-luciferase reporter gene assay and RNA immunoprecipitation verified the binding of miR-30a-5p and CCNE2, as well as decreased mRNA and protein expression of CCNE2 with miR-30a-5p overexpression. Simultaneous up-regulation of miR-30a-5p and CCNE2 reversed the promotion of CCNE2 on malignant behaviors of LUAD cells. In vivo mice experiments exhibited that high miR-30a-5p expression hindered tumor growth. Additionally, miR-30a-5p was localized on the Extracellular Vesicles microRNA (EVmiRNA) database. MiR-30a-5p was abundant in exosomes derived from vascular endothelial cells. To validate that miR-30a-5p could be delivered to LUAD cells via exosomes and then make an effect, exosomes from vascular endothelial cells were first extracted and identified by transmission electron microscopy and detection of exosomal marker proteins (Alix, CD63, TSG101). Sequentially, the extracted exosomes were labeled with DIO to note that exosomes could be internalized by cancer cells. Further experiments indicated that miR-30a-5p was increased in cancer cells co-cultured with exosomes, which in turn suppressed cell malignant behaviors and made cell cycle arrest. In all, our findings clarified that exosomes derived from vascular endothelial cells delivered miR-30a-5p to LUAD cells to affect tumor malignant progression via the miR-30a-5p/CCNE2 axis.

Potential Environmental Health Risk Analysis of Neonicotinoids and a Synergist.

The extensive use of neonicotinoid pesticides has led to their widespread presence in the environment, resulting in considerable safety risks to the ecosystem and human health. In this study, we investigated the biotransformation behavior of a cocktail of multiple neonicotinoids and piperonyl butoxide (PBO) synergist in vivo and their potential environmental health risk. It was found that neonicotinoids with a cyano group, such as acetamiprid and thiacloprid, tended to accumulate in liver and spleen tissues, while others with nitro groups (imidacloprid, thiamethoxam, clothianidin, dinotefuran, and nitenpyram) were mostly excreted in urine. In the presence of the synergist PBO, the metabolism of neonicotinoids in vivo changed, mainly through the nitro reduction pathway, while a low abundance of related metabolites was observed in the conventional hydroxylation and demethylation metabolic pathways, due to inhibition of CYP450 enzymes by the synergist. Furthermore, DNA methylation damage in vivo was exacerbated by the induction of hydroxylamine metabolites formed in the intermediate process of neonicotinoid metabolism with the synergistic effect of PBO, which resulted in a higher level of the O6-methyldeoxyguanosine (O6-medG) biomarker in the liver. Therefore, during the comprehensive evaluation of pesticide environmental risks, attention should be paid not only to the co-exposure mode under real environmental conditions but also to the potential risks of intermediate metabolism and related intermediate metabolites. This study provides a referential strategy and theoretical support for the health risk assessment of co-exposure of chemicals.

Development and verification of a nomogram for prediction of recurrence-free survival in clear cell renal cell carcinoma.

Nowadays, gene expression profiling has been widely used in screening out prognostic biomarkers in numerous kinds of carcinoma. Our studies attempt to construct a clinical nomogram which combines risk gene signature and clinical features for individual recurrent risk assessment and offer personalized managements for clear cell renal cell carcinoma. A total of 580 differentially expressed genes (DEGs) were identified via microarray. Functional analysis revealed that DEGs are of fundamental importance in ccRCC progression and metastasis. In our study, 338 ccRCC patients were retrospectively analysed and a risk gene signature which composed of 5 genes was obtained from a LASSO Cox regression model. Further analysis revealed that identified risk gene signature could usefully distinguish the patients with poor prognosis in training cohort (hazard ratio [HR] = 3.554, 95% confidence interval [CI] 2.261-7.472, P < .0001, n = 107). Moreover, the prognostic value of this gene-signature was independent of clinical features (P = .002). The efficacy of risk gene signature was verified in both internal and external cohorts. The area under receiver operating characteristic curve of this signature was 0.770, 0.765 and 0.774 in the training, testing and external validation cohorts, respectively. Finally, a nomogram was developed for clinicians and did well in the calibration plots. This nomogram based on risk gene signature and clinical features might provide a practical way for recurrence prediction and facilitating personalized managements of ccRCC patients after surgery.

Cell active and functionally-relevant small-molecule agonists of calcitonin receptor.

The natural calcitonin (CT) receptor and its peptide agonists are considered validated targets for drug discovery. A small molecule agonist, SUN-B8155, has previously been shown to efficiently activate cellular CTR. Herein, we report the synthesis of a series of compounds (S8155 1-9) derived from SUN-B8155, and investigate the structural-functional relationship, bias properties and their cellular activity profile. We discover that the N-hydroxyl group from the pyridone ring is required for G protein activity and its affinity to the CT receptor. Among the compounds studied, S8155-7 exhibits improved G protein activity while S8155-4 displays a significant ß-arrestin-2 signaling bias. Finally, we show that both S8155-4 and S8155-7 inhibit tumour cell invasion through CTR activation. These two compounds are anticipated to find extensive applications in chemical biology research as well drug development efforts targeting CT receptor.

Profiling and Identification of Biocatalyzed Transformation of Sulfoxaflor In Vivo.

In the present study, we investigated the biotransformation of the neonicotinoid pesticide sulfoxaflor and the metabolic responses in Sprague-Dawley rats. Sulfoxaflor transformation was catalyzed by cytochrome P450 while five phase I and four phase II metabolites were identified for the first time in vivo. The experimental results demonstrated that sulfoxaflor brought about the metabolic profiling disturbances in liver and bile. Exposure to sulfoxaflor caused dysregulation of bile acid synthesis and reabsorption by the expression of farnesoid X receptor (FXR). Our data provided insights into biotransformation of chemicals while enabling the implementation of a new toolbox for the design of sulfoximine compounds.

Circ-AKT3 inhibits clear cell renal cell carcinoma metastasis via altering miR-296-3p/E-cadherin signals.

BACKGROUND: Circular RNA (circRNA) is a type of circular endogenous RNA produced by special selective splicing and participates in progression of diverse diseases. However, the role of circRNA in clear cell renal cell carcinoma (ccRCC) is still rarely reported. METHODS: We detected lower circ-AKT3 expression in ccRCC using the circular RNA microarray. Then, qPCR array was applied to verify the expression of circ-AKT3 in between 60 ccRCC tissues and adjacent normal tissues, as well as ccRCC cell lines and human normal kidney cell (HK-2). We investigated the function of circ-AKT3 in ccRCC in vitro and in vivo and detected underlying mechanisms by Western blotting, bioinformatic analysis, RNA pull-down assay and luciferase reporter assay. RESULTS: Circ-AKT3 was verified significantly downregulated in ccRCC. Knockdown of circ-AKT3 promoted ccRCC migration and invasion, while overexpression of circ-AKT3 suppressed ccRCC metastasis. Further, circ-AKT3/miR-296-3p/E-cadherin axis was shown responsible for circ-AKT3 inhibiting ccRCC metastasis. CONCLUSION: Circ-AKT3 suppresses ccRCC metastasis by enforcing E-cadherin expression through competitively binding miR-296-3p. Circ-AKT3 may therefore serve as a novel therapeutic to better suppress ccRCC metastasis.

Testicular orphan receptor 4 promotes tumor progression and implies poor survival through AKT3 regulation in seminoma.

Seminoma is the most common testicular germ cell tumor worldwide and mainly occurs in 15-35-year-old young men. Early studies have indicated that testicular nuclear receptor 4 (TR4) first cloned from testis is involved in the invasion and metastasis of several human tumors; however, little attention is paid to the function of TR4 in seminoma. Our immunohistochemical (IHC) staining results showed that patients with advanced stage tumors tended to have higher expression of TR4. Importantly, there was a significant association between elevated TR4 expression and reduced overall survival in seminoma patients. In vitro MTS, western blot and transwell assays, after manipulating TR4 expression in Tcam-2 cells, revealed that TR4 induced epithelial-to-mesenchymal transition (EMT) and promoted Tcam-2 cell proliferation and invasion. Mechanism dissection demonstrated that AKT3, a critical component in the signaling pathway, played a crucial role in mediating TR4-promoted Tcam-2 cell proliferation and invasion. We further revealed that TR4 modulated AKT3 at the transcriptional level via chromatin immunoprecipitation and luciferase assays. Meanwhile, addition of the AKT3 siRNA blocked the function of TR4. Overall, these findings first elucidate that TR4 is a novel prognostic marker and plays a critical role in the metastatic capacity of Tcam-2 cells by EMT regulation and, consequently, targeting TR4-AKT3 pathway may serve as a potential therapeutic approach for seminoma.

Quadrant response model and error analysis of four-quadrant detectors related to the non-uniform spot and blind area.

In the system of tracking and detection based on the four-quadrant detector (4-QD), the energy distribution of the incident spot and the blind area of the photosensitive surface will affect the location accuracy. The current model of the spot is based on the ideal circular Gauss spot, which makes the error caused by the spot shape easily ignored. In this paper, the model of the spot energy distribution is improved, which can adapt to the elliptical Gauss distribution. The width of the blind area is also added to the response models of the detector so that the output of each quadrant and the error of the localization algorithm can be calculated more accurately. The simulation results show that the measurement accuracy of 4-QD decreases with the increase of the blind area, the shape, and the inclination of the light spot. In the experiment, we first verify the correctness and practicability of the improved model of the spot energy distribution, and then the improved model is proved to be able to make the response and error calculation more accurate.

Integrated gene expression profiling and chromatin immunoprecipitation followed by sequencing: Analysis of the C-terminal binding protein in breast cancer.

AIM: This study explored the possible mechanisms of the transcriptional regulatory activities of C-terminal binding protein (CtBP) and the role of CtBP in the pathogenesis of breast cancer. METHODS: Microarray data of GSE36529, including three CtBP-knockdown breast cancer MCF-7 cell samples, three control knockdown samples and data of CtBP binding profile in MCF-7 cells, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened between CtBP-knockdown MCF-7 cell samples and controls. Newly developed chromatin immunoprecipitation followed by sequencing technology was used to identify the CtBP binding regions. The direct target genes of CtBP were identified using ChIP-Array software and a regulatory network was constructed, followed by gene ontology (GO) enrichment analysis of all identified DEGs and DEGs targeted by CtBP. RESULTS: In total, 404 DEGs were identified in CtBP-knockdown MCF-7 cell samples. These DEGs were enriched in different GO terms, such as cellular response to stress and cell cycle, endoplasmic reticulum and nucleotide binding. Additionally, 143 DEGs were identified as potential direct targets of CtBP in the regulatory network. CtBP target genes such as hypoxia up-regulated 1, BTG family member 2 and endothelin 1 were mainly related to response to hypoxia and regulation of cell proliferation. CONCLUSIONS: Hypoxia up-regulated 1, BTG family member 2 and endothelin 1 may be associated with the progression of breast cancer through interaction with CtBP in different biological processes. CtBP may be a therapeutic target for the treatment of breast cancer.

A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts.

The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer.