Application of computer-aided diagnosis to predict malignancy in BI-RADS 3 breast lesions.

Purpose: To evaluate the ability of computer-aided diagnosis (CAD) system (S-Detect) to identify malignancy in ultrasound (US) -detected BI-RADS 3 breast lesions. Materials and methods: 148 patients with 148 breast lesions categorized as BI-RADS 3 were included in the study between January 2021 and September 2022. The malignancy rate, accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) were calculated. Results: In this study, 143 breast lesions were found to be benign, and 5 breast lesions were malignant (malignancy rate, 3.4 %, 95 % confidence interval (CI): 0.5-6.3). The malignancy rate rose significantly to 18.2 % (4/22, 95 % CI: 2.1-34.3) in the high-risk group with a "possibly malignant" CAD result (p = 0.017). With a "possibly benign" CAD result, the malignancy rate decreased to 0.8 % (1/126, 95 % CI: 0-2.2) in the low-risk group (p = 0.297). The AUC, sensitivity, specificity, accuracy, PPV, and NPV of the CAD system in BI-RADS 3 breast lesions were 0.837 (95 % CI: 77.7-89.6), 80.0 % (95 % CI: 73.6-86.4), 87.4 % (95 % CI: 82.0-92.7), 87.2 % (95 % CI: 81.8-92.6), 18.2 % (95 % CI: 2.1-34.3) and 99.2 % (95 % CI: 97.8-100.0), respectively. Conclusions: CAD system (S-Detect) enables radiologists to distinguish a high-risk group and a low-risk group among US-detected BI-RADS 3 breast lesions, so that patients in the low-risk group can receive follow-up without anxiety, while those in the high-risk group with a significantly increased malignancy rate should actively receive biopsy to avoid delayed diagnosis of breast cancer.

Clinical Application of Computer-Aided Diagnosis System in Breast Ultrasound: A Prospective Multicenter Study.

OBJECTIVES: Ultrasound tends to present very high sensitivity but relatively low specificity and positive predictive value (PPV), which would result in unnecessary breast biopsies. The purpose of this study is to analyze the diagnostic performance of computer-aided diagnosis (CAD) (S-Detect) system in differentiating breast lesions and reducing unnecessary biopsies in non-university hospitals in less-developed regions of China. METHODS: The study was a prospective multicenter study from 8 hospitals. The ultrasound images, and cine, CAD analysis, and BI-RADS were recorded. The accuracy, sensitivity, specificity, PPV, negative predictive value (NPV), and area under the curve (AUC) were analyzed and compared between CAD and radiologists. The Youden Index (YI) was used to determine optimal cut-off for the number of planes to downgrade. RESULTS: A total of 491 breast lesions were included in the study. Less-experienced radiologists combined CAD was superior to less-experienced radiologists alone in AUC (0.878 vs 0.712, p < 0.001), and specificity (81.3% vs 44.6%, p < 0.001). There was no statistical difference in AUC (0.891 vs 0.878, p = 0.346), and specificity (82.3% vs 81.3%, p = 0.791) between experienced radiologists and less-experienced radiologists combined CAD. With CAD assistance, the biopsy rate of less-experienced radiologists was significantly decreased (100.0% vs 25.6%, p < 0.001), and malignant rate of biopsy was significantly increased (15.0% vs 43.9%, p < 0.001). CONCLUSIONS: CAD system can be an effective auxiliary tool in differentiating breast lesions and reducing unnecessary biopsies for radiologists from non-university hospitals in less-developed regions of China.

Association between new plasma inflammatory markers and risk of colorectal neoplasms in individuals over 50 years old.

OBJECTIVE(S): The prognostic value of systemic cytokine profiles and inflammatory markers in colorectal cancer were explored by several studies. We want to know more about inflammatory biomarkers in colorectal adenoma and early cancer. METHOD: The level of 38 inflammatory markers in the plasma of 112 adenoma patients, 72 Tis-T1 staging of colorectal carcinoma patients, 34 T2-T4 staging of colorectal carcinoma patients and 53 normal subjects were detected and compared. RESULT(S): Eight inflammatory biomarkers (Eotaxin, GCSF, IL-4, IL-5, IL-17E, MCP-1, TNF-α and VEGF-A) have higher plasma concentrations in colorectal adenoma and cancer patients compared with normal participants over 50 years old. CONCLUSION(S): Inflammatory markers may have the prognostic value for colorectal adenoma and early-stage carcinoma.

Deep Learning-Based Computer-Aided Diagnosis for Breast Lesion Classification on Ultrasound: A Prospective Multicenter Study of Radiologists Without Breast Ultrasound Expertise.

BACKGROUND. Computer-aided diagnosis (CAD) systems for breast ultrasound interpretation have been primarily evaluated at tertiary and/or urban medical centers by radiologists with breast ultrasound expertise. OBJECTIVE. The purpose of this study was to evaluate the usefulness of deep learning-based CAD software on the diagnostic performance of radiologists without breast ultrasound expertise at secondary or rural hospitals in the differentiation of benign and malignant breast lesions measuring up to 2.0 cm on ultrasound. METHODS. This prospective study included patients scheduled to undergo biopsy or surgical resection at any of eight participating secondary or rural hospitals in China of a breast lesion classified as BI-RADS category 3-5 on prior breast ultrasound from November 2021 to September 2022. Patients underwent an additional investigational breast ultrasound, performed and interpreted by a radiologist without breast ultrasound expertise (hybrid body/breast radiologists, either who lacked breast imaging subspecialty training or for whom the number of breast ultrasounds performed annually accounted for less than 10% of all ultrasounds performed annually by the radiologist), who assigned a BI-RADS category. CAD results were used to upgrade reader-assigned BI-RADS category 3 lesions to category 4A and to downgrade reader-assigned BI-RADS category 4A lesions to category 3. Histologic results of biopsy or resection served as the reference standard. RESULTS. The study included 313 patients (mean age, 47.0 ± 14.0 years) with 313 breast lesions (102 malignant, 211 benign). Of BI-RADS category 3 lesions, 6.0% (6/100) were upgraded by CAD to category 4A, of which 16.7% (1/6) were malignant. Of category 4A lesions, 79.1% (87/110) were downgraded by CAD to category 3, of which 4.6% (4/87) were malignant. Diagnostic performance was significantly better after application of CAD, in comparison with before application of CAD, in terms of accuracy (86.6% vs 62.6%, p < .001), specificity (82.9% vs 46.0%, p < .001), and PPV (72.7% vs 46.5%, p < .001) but not significantly different in terms of sensitivity (94.1% vs 97.1%, p = .38) or NPV (96.7% vs 97.0%, p > .99). CONCLUSION. CAD significantly improved radiologists' diagnostic performance, showing particular potential to reduce the frequency of benign breast biopsies. CLINICAL IMPACT. The findings indicate the ability of CAD to improve patient care in settings with incomplete access to breast imaging expertise.

T cell receptor repertoire as a novel indicator for identification and immune surveillance of patients with severe obstructive sleep apnea.

Background: Obstructive sleep apnea (OSA) is the most prevalent sleep disturbance that affects approximately 936 million people worldwide and leads to extensively increased incidence of cardiovascular disease, metabolic syndrome, neurological disorders, and traffic accidents. Severe OSA patients suffer a significantly higher risk of complications and worse comorbidity outcomes. Notwithstanding, with inadequate access to contact diagnosis based on polysomnography (PSG), numerous patients with severe sleep apnea have not been diagnosed, especially during the pandemic. Moreover, how the T cell immunity is impaired in OSA remains largely unknown. Methods: We primarily investigated the T cell receptor (TCR) repertoires of 50 patients with severe OSA, 23 patients with mild-to-moderate OSA, 23 patients without OSA, and 157 healthy individuals, from their peripheral blood. Firstly, we compared the clinical characteristics, blood cell counts, the ratio of neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and CD4+/CD8+T cell count between groups. Then, we compared the diversity, clonotypes, unique VJ alleles in patients with different disease severity. Furthermore, by identifying a series of disease-associated amino acid sequences, we employed a repeated hold-out machine learning strategy to explore the optimal algorithm for calculating the TCR repertoire characteristic Index (OSA-TCI). We further confirmed its relation with clinical features by linear regression analysis. Moreover, in followup of severe OSA patients who accepted adherent non-invasive ventilation, we assessed the changes of TCR repertoires, OSA-TCI, ESS, NLR, PLR, and CD4+/CD8+T after therapy. Results: We found an unexpected increase in diversity and clonotypes in the TCR repertoire of OSA patients. Furthermore, we successfully developed a novel indicator termed OSA-TCI to summarize the unique repertoire alteration, which provided 90% of sensitivity and 87% of specificity in distinguishing severe OSA. In rationalization, OSA-TCI was found correlated to AHI, BMI, hemoglobin, N1, N2 percentage of sleep, snoring, smoking and lowest oxygen saturation, but only independently related to AHI (R = 0.603) and smoking (R = 0.22). Finally, we observed OSA-TCI in the eight severe patients decreased significantly after home noninvasive ventilation for three months during follow-up, consistently in line with the TCR repertoire improvement. In contrast, NLR, PLR, and the ratio of CD4+/CD8+T cell count were found useless to diagnose and therapeutic surveillance of severe OSA. Conclusions: Our study is the first to unveil the TCR repertoire alteration in OSA, indicates possible insidious autoimmune mechanisms underlying OSA, and suggests that TCR repertoires serve as a convenient peripheral blood biomarker for OSA assessment without long-time contact and facility/instrument occupation. It may shed light on future diagnostic, immunological, pathophysiological, and prognostic research on OSA.

Diabetic endothelial microangiopathy and pulmonary dysfunction.

Type 2 diabetes mellitus (T2DM) is a widespread metabolic condition with a high global morbidity and mortality rate that affects the whole body. Their primary consequences are mostly caused by the macrovascular and microvascular bed degradation brought on by metabolic, hemodynamic, and inflammatory variables. However, research in recent years has expanded the target organ in T2DM to include the lung. Inflammatory lung diseases also impose a severe financial burden on global healthcare. T2DM has long been recognized as a significant comorbidity that influences the course of various respiratory disorders and their disease progress. The pathogenesis of the glycemic metabolic problem and endothelial microangiopathy of the respiratory disorders have garnered more attention lately, indicating that the two ailments have a shared history. This review aims to outline the connection between T2DM related endothelial cell dysfunction and concomitant respiratory diseases, including Coronavirus disease 2019 (COVID-19), asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

Multiple rectal neuroendocrine tumors: An analysis of 15 cases and literature review.

Multiple neuroendocrine tumors (M-NETs) are rare in the rectum and there is no consensus on their characteristics and treatments. Here, we report 15 cases of rectal M-NETs and review the previous literature. We discuss the clinical characteristics, endoscopic features and pathological features of rectal M-NETs, aiming to analyze the treatments and follow-up strategies in combination with these characteristics. We retrospectively reviewed and analyzed the data of 15 patients with rectal M-NETs who were diagnosed and treated at Beijing Friendship Hospital, Capital Medical University. Their clinical data, endoscopic findings, pathological features and treatments were analyzed. Follow-up evaluations and literature review were performed. In all, 14 male (93.3%) and 1 female (6.7%) were recruited. The average age at diagnosis was 55.7 years. The clinical manifestations include asymptomatic in 9 patients (60.0%), defecation habits changes in 2 patients (13.3%), anal distension in 2 patients (13.3%), and abdominal distension in 2 patient (13.3%). The largest tumor diameter ≤10mm was found in 13 patients (86.7%) and >10mm in 2 patients (13.3%). All of the lesions originated from the mucous or submucosa layer. WHO grades were all NET G1. The number of tumors diagnosed by pathology in 13 patients was consistent with that observed by endoscopy, while more lesions were observed by pathology than endoscopy in two patients. Lymph node metastasis occurred in 1 patient (6.7%), and vascular or lymphatic invasion occurred in 9 patients (60.0%). Among the 13 patients with the largest tumor diameter being ≤10mm, lymphovascular invasion occurred in 8 patients (61.5%). And among the 2 patients with the largest tumor diameter of >10mm, lymphovascular invasion occurred in 1 patient (50.0%). 14 patients underwent endoscopic resection and 1 underwent surgical excision. Postoperative follow-up was achieved in 13 patients and no recurrence or metastasis was found. The true number of rectal M-NETs may be more than seen under endoscopy. Rectal M-NETs is associated with a high risk of metastasis; therefore, treatment and surveillance strategies should be more radical than single lesion.

Associations between comorbidities and annual incidence plus frequency of asthma exacerbation hospitalisation during the past year: data from CARN study.

PURPOSE: While asthma comorbidities are associated with higher health care utilisation, lower quality of life and poorer asthma control, the impact of asthma comorbidities on hospitalisation for asthma exacerbation (H-AX) remains less recognised. We aim to analyse the impact of asthma comorbidities on H-AX. METHODS: Based on a national survey on asthma control and disease perception (CARN 2015 study), we analysed the impact of comorbidities on annual incidence and frequency of H-AX in China. Information on demographic characteristics, asthma comorbidities and annual incidence and frequency of H-AX were presented in this study. RESULTS: Among 3875 ambulatory asthma patients, 75.9% (2941/3875) had comorbidities, and 26.4% (1017/3858) experienced H-AX during past year. After adjusting for confounding factors such as demographic data, smoking status and asthma control, COPD [OR = 2.189, 95% CI (1.673, 2.863)] and coronary heart disease [OR = 1.387, 95% CI (1.032, 1.864)] were associated with higher annual incidence, while allergic rhinitis [OR = 0.692, 95% CI (0.588, 0.815)] was associated with lower annual incidence, of H-AX. In terms of frequency, allergic rhinitis [OR = 1.630, 95% CI (1.214, 2.187)], COPD [OR = 1.472, 95% CI (1.021, 2.122)] and anxiety [OR = 2.609, 95% CI (1.051, 6.477)] showed statistically significant correlation with frequent H-AX. CONCLUSIONS: COPD and coronary heart disease were associated with higher annual incidence, while allergic rhinitis was associated with lower annual incidence of H-AX. Allergic rhinitis, COPD and anxiety were associated with frequent H-AX. Comorbidities may have an important role in the risk and frequency of annual hospitalisations due to asthma exacerbation. The goal of asthma control should rely on a multi-disciplinary treatment protocol.

Discovery of novel tubulin inhibitors targeting taxanes site by virtual screening, molecular dynamic simulation, and biological evaluation.

Microtubules play crucial role in process of mitosis and cell proliferation, which have been considered as attractive drug targets for anticancer therapy. The aim of this study was to discover novel and chemically diverse tubulin inhibitors for treatment of cancer. In this investigation, the multilayer virtual screening methods, including common feature pharmacophore model, structure-based pharmacophore model and molecular docking, were developed to screen BioDiversity database with 30,000 compounds. A total of 102 compounds were obtained by the virtual screening, and further filtered by diverse chemical clusters with desired properties and PAINS analysis. Finally, 50 compounds were selected and submitted to the biological evaluation. Among these hits, hits 8 and 30 with novel scaffolds displayed stronger antiproliferative activity on four human tumor cells including Hela, A549, MCF-7, and HepG2. Moreover, the two hits were subsequently submitted to molecular dynamic simulations of 90 ns with the aim of exploring the stability of ligand-protein interactions into the binding pocket, and further probing the mechanism of the interaction between tubulin and hits. The molecular dynamic simulation results revealed there had stronger interactions between tubulin and hits in equilibrium state. Therefore, the hits 8 and 30 have been well characterized as lead compounds for developing new tubulin inhibitors with potential anticancer activity.

Oridonin interferes with simple steatosis of liver cells by regulating autophagy.

Oridonin has significant liver-protective effects, but its effect on liver steatosis has not been reported. We investigated the effects of oridonin on liver steatosis by cell cultures. The optimal experimental concentration of oridonin was determined through cytotoxicity experiments. A simple steatosis liver cell model was induced using free fatty acids (FFA). After adding oridonin to the FFA-induced cell model for 24 h, the lipid droplets and triglyceride (TG) content in the cells were measured by Oil Red O staining and TG kits. The expressions of autophagy-related markers (cyclin dependent kinases inhibitor 1a (p21), Beclin-1, microtubule-associated protein light chain 3 (LC3)-I and LC3-II, protein kinase B (AKT), phosphorylated-AKT (p-AKT), AMP-activated protein kinase (AMPK), and phosphorylated-AMPK (p-AMPK)) were detected by Western blot. Based on the results, the cell model was further treated by autophagy inhibitor 3-methyladenine (3-MA) to determine the degree of steatosis and the expressions of autophagy-related factors. Oridonin at a concentration higher than 10 µmol/L caused cytotoxicity to the cells. Adding 10 µmol/L oridonin to the FFA-induced cell model effectively reduced lipid droplets and TG content in the cells. Oridonin up-regulated p21, Beclin-1 and LC3-II expressions, but down-regulated those of p62 and LC3-I. Also, oridonin increased the ratios of LC3-II/LC3-I and p-AMPK/AMPK, but reduced that of p-AKT/AKT. With the addition of 3-MA, the effect of oridonin on reducing steatosis was partially reversed, and the autophagy was inhibited. This study found that oridonin can activate autophagy, thereby preventing simple steatosis of liver cells.

A Biomimicking Polymeric Cryogel Scaffold for Repair of Critical-Sized Cranial Defect in a Rat Model.

Mineralized polymeric cryogels with interconnective macroporous structure have demonstrated their potential as promising scaffolding material in bone tissue engineering. However, their capability in inducing osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro and osteogenesis in vivo has not been explored yet. In this work, the roles of the mineralized cryogel on osteogenesis are systematically studied. Mineralized macroporous poly(ethylene glycol)-co-2-hydroxyethyl methacrylate cryogel promotes osteogenic differentiation of rat MSCs, particularly in upregulating the activity of alkaline phosphatase (ALP, ∼5.7-folds) and expression of related osteogenic gene markers (ALP ∼16-folds, osteocalcin ∼133-folds) at 14 days. In vivo implantation reveals that mineralized cryogels could promote fast osteogenesis and angiogenesis in critical-sized cranial bone defect of a Sprague-Dawley rat model in 4 weeks. The adsorption, entrapment, and concentration of osteogenic growth factors (bone morphogenetic protein 2) and angiogenesis growth factor (vascular endothelial growth factor [VEGF]) in the matrices in vivo may possibly participate in the process of osteogenesis and angiogenesis. Notably, the adsorption of larger amount of VEGF in nonmineralized cryogels facilitates obvious angiogenesis and comparable osteogenesis in bone defect in 8 weeks. Graphical abstract [Figure: see text] Impact Statement The current work reported the fabrication and characterization of a biomimicking mineralized polymeric cryogel as scaffolding material in bone regeneration. In addition to its three dimensional porous structure and the osteogenic potential, this biomimicking scaffold was also found to enhance the adsorption of biochemical cues, which in turn greatly promoted the angiogenesis as well as the tissue regeneration.

shRNA­mediated knockdown of KNTC1 suppresses cell viability and induces apoptosis in esophageal squamous cell carcinoma.

Kinetochore­associated proteins are critical components of mitotic checkpoints, which are essential for faithful chromosomal segregation and spindle assembly during cell division. Recent advances have demonstrated that kinetochore­associated proteins are upregulated and serve significant roles in the carcinogenesis of numerous types of cancer. However, the effects of kinetochore­associated protein 1 (KNTC1) on human cancer, particularly on esophageal squamous cell carcinoma (ESCC), remain unclear. The present study revealed that KNTC1 was highly expressed in ESCC cell lines. Subsequently, lentivirus­mediated short hairpin RNAs were used to knockdown KNTC1 expression in human ESCC cell lines. Cell growth and viability were measured using multiparametric high­content screening and the MTT assay, respectively. Cell apoptosis was assessed by staining cells with Annexin V­allophycocyanin and was detected using FACScan flow cytometry. The results demonstrated that knockdown of KNTC1 effectively inhibited cell viability and increased apoptosis. In addition, a gene set enrichment analysis of online ESCC datasets indicated that KNTC1 overexpression was associated with increases in the mitotic spindle and hypoxia pathways, and decreases in the DNA repair and mismatch repair pathways. The findings of the present study suggested that KNTC1 may have an essential role in mediating cell viability and apoptosis in human ESCC cells and may serve as a novel therapeutic target for ESCC.

Prevalence and risk factors of asthma in mainland China: The CARE study.

BACKGROUND: There are limited population based data on the prevalence of asthma in China. The China Asthma and Risk factors Epidemiologic (CARE) survey was designed to understand the prevalence and risk factors for asthma in mainland China. OBJECTIVES: The CARE survey aims to demonstrate the prevalence and risk factors of asthma in mainland China among adolescents (age >14 years) and adults. METHODS: The survey was performed between February 2010 and August 2012 in eight provinces/cities of seven areas in mainland China. The inhabitants (age, >14 years) recruited in this survey were through multi-stage cluster random sampling. Asthma diagnosis was based on medical history and lung function tests. Multivariable logistic regression was used to analyzed the risk factors for asthma. RESULTS: The study included 164 215 subjects (men, 79 692 [48.53%]; women, 84 523 [51.47%]). 2034 (1.24%) were asthmatic patients. Among all asthmatic patients, 521 (25.61%) were newly diagnosed. Univariable regression analysis showed that risk factors for asthma included smoking, first-degree relatives with asthma, allergic rhinitis, chronic bronchitis, COPD, pollinosis, allergic pneumonia, concomitant allergic diseases, BMI and raising pets. Multivariable logistic regression indicated that asthma risk factors included women, age stratification, smoking, first-degree relatives suffering from asthma or pollinosis, combined with allergic rhinitis, eczema or GERD. CONCLUSIONS: We speculated that the prevalence of asthma is increasing in mainland China among individuals aged >14 years in the past 10 years. A number of risk factors were identified. The risk factors of asthma would be further elucidated in our future work. CLINICAL IMPLICATIONS: Our CARE study highlights that asthma epidemic in mainland China should be paid more attention.

MiR-27-3p regulates TLR2/4-dependent mouse alveolar macrophage activation by targetting PPARγ.

Activation of alveolar macrophages (AMs) and the release of cytokines play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the mechanisms of AM activation. miRNAs have recently emerged as key regulators of inflammation and as mediators of macrophage activation and polarization. We identified potential miRNAs related to AM activation using miRNA microarray analysis, which showed that miR-27-3p expression was up-regulated in AMs and the lung tissues of mice exposed to cigarette smoke (CS)/lipopolysaccharide (LPS), and found that miR-27-3p regulated proinflammatory cytokine production and AM polarization depending on TLR2/4 intracellular signaling in AMs. We also found that miR-27-3p controlled TLR2/4 signaling in AMs via targetting the 3'-UTR sequences of peroxisome proliferator-activated receptor γ (PPARγ) and inhibiting PPARγ activation. Moreover, we found that PPARγ activation not only inhibited CS/LPS-induced TLR2/4 expression and miR-27-3p-mediated TLR2/4 signaling cascades involving the nuclear factor-κB (NF-κB), c-Jun NH2-terminal kinase (JNK)/p38, and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways in AMs but also ameliorated CS/LPS-induced AM activation and pulmonary inflammation. Our study revealed that miR-27-3p mediated AM activation by the inhibition of PPARγ activation and sensitization of TLR signaling.

Stabilization of Notch1 by the Hsp90 Chaperone Is Crucial for T-Cell Leukemogenesis.

Purpose: Notch1 deregulation is assuming a focal role in T-cell acute lymphoblastic leukemia (T-ALL). Despite tremendous advances in our understanding of Notch1 transcriptional programs, the mechanisms by which Notch1 stability and turnover are regulated remain obscure. The goal of the current study is to identify intracellular Notch1 (ICN1, the activated form of Notch1) binding partner(s) regulating its stability and activity. Experimental Design: We employed immunoaffinity purification to identify ICN1-associating partner(s) and used coimmunoprecipitation to verify the endogenous protein interaction. Pharmacologic or short hairpin RNA-mediated inhibition was applied in loss-of-function assays to assess the role of tentative binding partner(s) in modulating ICN1 protein stability as well as affecting T-ALL cell expansion in vitro and in vivo Mechanistic analysis involved protein degradation and polyubiquitination assays. Results: We identify the Hsp90 chaperone as a direct ICN1-binding partner essential for its stabilization and transcriptional activity. T-ALL cells exhibit constitutive endogenous ICN1-Hsp90 interaction and Hsp90 depletion markedly decreases ICN1 levels. The Hsp90-associated E3 ubiquitin ligase Stub1 mediates the ensuring proteasome-dependent ICN1 degradation. Administration of 17-AAG or PU-H71, two distinct Hsp90 inhibitors, depletes ICN1, inhibits T-ALL cell proliferation, and triggers dramatic apoptotic cell death. Systemic treatment with PU-H71 reduces ICN1 expression and profoundly inhibits murine T-ALL allografts as well as human T-ALL xenografts. Conclusions: Our findings demonstrate Hsp90 blockade leads to ICN1 destabilization, providing an alternative strategy to antagonize oncogenic Notch1 signaling with Hsp90-selective inhibitors. Clin Cancer Res; 23(14); 3834-46. ©2017 AACR.

[Retracted] Production of interleukin­4 in CD133+ cervical cancer stem cells promotes resistance to apoptosis and initiates tumor growth.

Following the publication of this article, an investigation conducted internally within our Department has revealed that the data published in Fig.  5a are not reproducible. Consequently, confidence in the conclusions drawn from the reported results in the paper has been undermined and, as a result, all authors involved have unanimously agreed to the retraction of this article. All authors recognize the seriousness of this issue and apologize unreservedly to the editors, reviewers and readers. We are also in the process of examining other studies in the paper. We sincerely regret that this study has been compromised, and are committed to rapidly correcting the public record and implementing practices to prevent any recurrence of such a situation in the future. [the original article was published in Molecular Medicine Reports 13: 5068-5076, 2016; DOI: 10.3892/mmr.2016.5195].