Global burden of mesothelioma attributable to occupational asbestos exposure in 204 countries and territories: 1990-2019.

Malignant mesothelioma, a rare and aggressive cancer primarily caused by occupational asbestos exposure, has a poor prognosis. This study leverages the Global Burden of Disease (GBD) 2019 dataset to analyze the burden of mesothelioma linked to occupational asbestos exposure from 1990 to 2019. The analysis includes the number of mesothelioma deaths and disability-adjusted life years (DALYs) attributable to occupational asbestos exposure, focusing on trends in age-standardized mortality rate (ASMR) and age-standardized disability-adjusted life-year rate (ASDR) by year, age, sex, country, region, and Socio-demographic Index (SDI). In 2019, 91.7% of mesothelioma deaths and 85.2% of DALYs were attributable to occupational asbestos exposure, resulting in 26,820 (95% UI 24,312-28,622) deaths and 569,429 (95% UI 509,956-617,484) DALYs. Despite a decline in ASMR and ASDR from 1990 to 2019, the absolute number of deaths and DALYs almost doubled. The United States reported the highest number of mesothelioma deaths, while China had the highest number of DALYs. Age-specific mortality rates and DALYs decreased in the 25-74 age group but increased in the 75+ age group. In conclusion, occupational asbestos exposure remains the primary cause of mesothelioma worldwide, with an increasing number of deaths and DALYs. The highest incidence rates are observed in high-income areas, and rates are rising in low-income areas. It is crucial to raise awareness about the hazards of asbestos to reduce the global burden of mesothelioma linked to occupational exposure.

Global burden of esophageal cancer attributable to high BMI in 204 countries and territories: 1990-2019.

BACKGROUND: Esophageal cancer (EC), a common and fatal disease, includes two histological subtypes; esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (ECA). To aid policymakers in the allocation of resources for the prevention and treatment of EC, updated data on EC deaths and disability-adjusted life years (DALYs) attributable to high body mass index (BMI) are necessary. The objective of this study was to identify trends in EC associated with high BMI between 1990 and 2019 using 2019 Global Burden of Disease data. METHODS: In this observational population-based study, epidemiological data on the association between high BMI and EC were obtained from GBD 2019. The age-standardized mortality rate (ASMRs) and disability-adjusted life year rate (ASDRs) attributable to high BMI-related EC were stratified by year, age, country, and sociodemographic index (SDI). The estimated annual percentage change (EAPC) was calculated to evaluate the temporal trends of the ASMRs and ASDRs between 1990 and 2019. RESULTS: In 2019, the proportion of EC deaths and DALYs attributed to high BMI was 18.1% and 18.9%, respectively, resulting in 89 904 (95% confidence interval [CI]: 27 879-171 255) deaths and 2 202 314 (95% CI: 681 901-4 173 080) DALYs. High BMI-related deaths and DALYs showed a strong upward trend, increasing by more than two-fold since 1990. East Asia and Western Europe showed the highest risk of EC mortality and DALYs attributable to high BMI; China and the USA bear the greatest burden. The ASMR and ASDR increased in five SDI regions. CONCLUSIONS: The incidence of EC is increasing, particularly in developing nations, which may be attributed to the prevalence of high BMI. To mitigate the impact of high BMI on the incidence of EC, it is important to increase awareness of its deleterious effects, which may alleviate the burden of this disease.

The mechanism of Parkinson oscillation in the cortex: Possible evidence in a feedback model projecting from the globus pallidus to the cortex.

The origin, location and cause of Parkinson's oscillation are not clear at present. In this paper, we establish a new cortex-basal ganglia model to study the origin mechanism of Parkinson beta oscillation. Unlike many previous models, this model includes two direct inhibitory projections from the globus pallidus external (GPe) segment to the cortex. We first obtain the critical calculation formula of Parkinson's oscillation by using the method of Quasilinear analysis. Different from previous studies, the formula obtained in this paper can include the self-feedback connection of GPe. Then, we use the bifurcation analysis method to systematically explain the influence of some key parameters on the oscillation. We find that the bifurcation principle of different cortical nuclei is different. In general, the increase of the discharge capacity of the nuclei will cause oscillation. In some special cases, the sharp reduction of the discharge rate of the nuclei will also cause oscillation. The direction of bifurcation simulation is consistent with the critical condition curve. Finally, we discuss the characteristics of oscillation amplitude. At the beginning of the oscillation, the amplitude is relatively small; with the evolution of oscillation, the amplitude will gradually strengthen. This is consistent with the experimental phenomenon. In most cases, the amplitude of cortical inhibitory nuclei (CIN) is greater than that of cortical excitatory nuclei (CEX), and the two direct inhibitory projections feedback from GPe can significantly reduce the amplitude gap between them. We calculate the main frequency of the oscillation generated in this model, which basically falls between 13 and 30 Hz, belonging to the typical beta frequency band oscillation. Some new results obtained in this paper can help to better understand the origin mechanism of Parkinson's disease and have guiding significance for the development of experiments.

Clinical significance of peripheral blood-derived inflammation markers combined with serum eotaxin-2 in human colorectal cancer.

To investigate the value of serum eotaxin-2, neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) in the diagnosis and prognosis of colorectal cancer (CRC). The association between different clinicopathological characteristics and eotaxin-2, NLR, and PLR in different patient groups was evaluated. The combined detection indicator and the combined detection's predictive effect on distant metastasis were examined. The receiver operating characteristic (ROC) curve was drawn to evaluate the efficacy of combined detection. The association between eotaxin-2, inflammation markers, and postoperative complications was assessed. Multivariate analysis to investigate the factors affecting the prognosis of patients with CRC. We detected a marked positive correlation between NLR and PLR (p < 0.05, r= 0.209). The AUC of serum eotaxin-2 combined with inflammation markers was 0.889, which was higher than single diagnosis. Compared with the single eotaxin-2 test, the combined detection of eotaxin-2 and inflammation markers might improve the specificity of CRC assessment. In univariate analysis, age, surgical method, high eotaxin-2, and high NLR were associated with postoperative complications. In multivariate analysis, age (≥ 60 years), high eotaxin-2, and high NLR were independent risk elements influencing postoperative complications of CRC. The distant metastasis, TNM staging -Ⅳ stage, NLR ≥ 3.18, and PLR ≥ 193 were independent factors affecting the prognosis of patients with CRC. The combined detection of eotaxin-2 and inflammatory markers has a particular value in improving the diagnosis of CRC, predicting distant metastasis, and guiding the frequency of reexamination after radical resection of CRC.

Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A.

The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56α is a human tumour suppressor. However, the molecular mechanisms inhibiting PP2A-B56α in cancer are poorly understood. Here, we report molecular level details and structural mechanisms of PP2A-B56α inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56α trimer, CIP2A displaces the PP2A-A subunit and thereby hijacks both the B56α, and the catalytic PP2Ac subunit to form a CIP2A-B56α-PP2Ac pseudotrimer. Further, CIP2A competes with B56α substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56α. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56α stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumour growth. Collectively, we discover a unique multi-step hijack and mute protein complex regulation mechanism resulting in tumour suppressor PP2A-B56α inhibition. Further, the results unfold a structural determinant for the oncogenic activity of CIP2A, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.

miR-21 Negatively Regulates the PTEN-PI3K-Akt-mTOR Signaling Pathway in Crohn's Disease by Altering Immune Tolerance and Epithelial-Mesenchymal Transition.

miR-21 is involved in the mechanisms of inflammatory bowel disease (IBD). It negatively regulates PTEN, which is an upstream regulatory gene of the PI3K/Akt/mTOR signaling pathway. But the relationship between miR-21 and immune tolerance and intestinal epithelial injury, and the mechanism by which miR-21 participates in Crohn's disease (CD) have not been studied. We aimed to address these two questions. The results of the present study showed that the levels of miR-21 and PTEN respectively decreased and increased significantly in the intestinal mucosa from active CD compared with control ones. Transfection with miR-21-5p mimics significantly downregulated the expression of PTEN and upregulated PI3K-Akt-mTOR signaling and the downstream pathway in PBMCs, while transfection with a miR-21-5p inhibitor antagomiR-21had the opposite effect. Moreover, the ratio of Treg/Th1 cells differentiated from peripheral blood mononuclear cells (PBMCs) decreased after being transfected with mimics, and increased with the inhibitor. AntagomiR-21 significantly relieved the lesions in colons of mice with TNBS-induced colitis, accompanied by the upregulation of PTEN and downregulation of mTOR. Inhibition of miR-21 also effectively suppressed the process of epithelial-mesenchymal transition (EMT) in vivo. In conclusion, the level of miR-21 decreased in CD, resulting in an upregulated PI3K-Akt-mTOR signaling pathway, compromised immune tolerance, and elevated inflammation.

Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity.

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor and an important target for cancer immunotherapy. We herein present a potent FcγR-independent GITR agonist IBI37G5 that can effectively activate effector T cells and synergize with anti-programmed death 1 (PD1) antibody to eradicate established tumors. IBI37G5 depends on both antibody bivalency and GITR homo-dimerization for efficient receptor cross-linking. Functional analyses reveal bell-shaped dose responses due to the unique 2:2 antibody-receptor stoichiometry required for GITR activation. Antibody self-competition is observed after concentration exceeded that of 100% receptor occupancy (RO), which leads to antibody monovalent binding and loss of activity. Retrospective pharmacokinetics/pharmacodynamics analysis demonstrates that the maximal efficacy is achieved at medium doses with drug exposure near saturating GITR occupancy during the dosing cycle. Finally, we propose an alternative dose-finding strategy that does not rely on the traditional maximal tolerated dose (MTD)-based paradigm but instead on utilizing the RO-function relations as biomarker to guide the clinical translation of GITR and similar co-stimulatory agonists.

MiR-21 regulates epithelial-mesenchymal transition in intestinal fibrosis of Crohn's disease by targeting PTEN/mTOR.

BACKGROUND: Previous studies suggested miR-21 regulated epithelial-mesenchymal transition (EMT) and fibrosis in organs. The aim of this study was to explore the role and mechanism of miR-21 in EMT process of CD(Crohn's disease)-associated intestinal fibrosis. METHODS: Tissue biopsies from fibrotic and nonfibrotic intestine of CD patients, and non-CD patients were obtained; chronic intestinal fibrosis model established by TNBS was treated with antagonist of miR-21; human intestinal epithelial cell, NCM460, were transfected with miR-21 mimics or inhibitor. The expressions of PTEN and mTOR, EMT-related markers and severity of colitis and fibrosis were examined. RESULTS: Compared to the controls, miR-21 was significantly upregulated in the intestinal tissues from CD patients with fibro stenosis, followed by decreased PTEN expression, increased EMT markers, and mTOR expression, and imbalanced ratio of MMP9(matrix metalloproteinase 9)/TIMP1(tissue inhibitor of metalloproteinase 1). MiR-21 downregulated the expression of PTEN and upregulated mTOR signal in NCM460 cell. Also, knocking miR-21 down reduced EMT in vitro. Inhibiting miR-21 with antagonists reversed TNBS-induced intestinal fibrosis in vivo, through suppressing EMT and balancing MMPs/TIMPs. CONCLUSION: We identified the involvement of miR-21 in EMT during intestinal fibrosis via targeting PTEN and mTOR, and miR-21 inhibition relieved intestinal fibrosis by regulating extracellular matrix (ECM) remodeling . Our results indicated miR-21 as a potential new target for the treatment of fibrosis complication in CD.

Olmesartan Attenuates Single-Lung Ventilation Induced Lung Injury via Regulating Pulmonary Microbiota.

Single-lung ventilation (SLV) associated acute lung injury is similar to ischemia reperfusion (IR) injury which is usually occurred during lung surgery. Olmesartan (Olm), a novel angiotensin receptor blocker (ARB), has been reported to ameliorate organ IR injury. Several recent studies have shown that lung microbiota may be involved in pulmonary diseases, but the effect of pulmonary microbiota in SLV-induced lung injury has not been reported. This study aims to determine the mechanism of how Olm attenuates SLV induced lung injury. Our data showed that 7 days Olm treatment before modeling markedly alleviated SLV-induced lung injury by suppressing inflammation and reactive oxygen species. Bronchoalveolar lavage fluid samples from the injured side were collected for 16S rRNA gene-based sequencing analysis and 53 different bacteria at the genus and species levels were identified. Furthermore, the injured lung samples were collected for metabolomics analysis using liquid chromatography-mass spectrometry analyses to explore differential metabolites. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was applied to analyze the correlation between differential metabolites and lung microbiota. A total of 38 pathways were identified according to differential metabolites and 275 relevant pathways were enriched via analyzing the microbial community, 24 pathways were both identified by analyzing either metabolites or microbiota, including pyrimidine metabolism, purine metabolism, aminoacyl-tRNA biosynthesis and ATP-binding cassette transporter. Besides classical blockage of the renin-angiotensin II system, Olm could also alleviate SLV-induced lung injury by rewiring the interaction between pulmonary microbiota and metabolites.

Dielectric property measurements for the rapid differentiation of thoracic lymph nodes using XGBoost in patients with non-small cell lung cancer: a self-control clinical trial.

Background: One of the important criteria for thoracic surgeons in making surgical strategies is whether the thoracic lymph nodes (LNs) are metastatic. Frozen section (FS) is widely used as an intraoperative diagnostic method, which is time-consuming and expensive. The dielectric property, including permittivity and conductivity, varies with different tissues. The extreme gradient boosting (XGBoost) is a powerful classifier and widely used. Thus, this study aims to develop the rapid differentiation method combining dielectric property and XGBoost, and assess its efficacy on the thoracic LNs in patients with non-small cell lung cancer (NSCLC). Methods: This was a single center self-control clinical trial with paraffin pathology section (PPS) results as gold diagnosis. The LNs from the pathologically diagnosed patients with NSCLC were recruited, which were measured by open-ended coaxial probe for the dielectric property within 1-4,000 MHz after removal from the patients and then were sent to perform FS and PPS diagnosis. The XGBoost combining with dielectric property was developed to differentiate malignant LNs from benign LNs. The classified efficacy was determined using the receiver operator characteristic (ROC) curve and area under the curve (AUC). Results: A total of 204 LNs from 67 NSCLC patients were analyzed. The mean values of the two parameters differed significantly (P<0.001) between benign and malignant LNs. The AUC for permittivity and conductivity were 0.850 [95% confidence interval (CI): 0.786 to 0.915; P<0.001] and 0.887 (95% CI: 0.828 to 0.946; P<0.001), respectively. The AUC was 0.893 (95% CI: 0.834 to 0.951; P<0.001) when the two parameters were combined. After the application of the XGBoost, the AUC was 0.968 (95% CI: 0.918 to 1.000; P<0.001), and the accuracy was 87.80%. Its sensitivity was 58.33% and the specificity was 100%. When the Synthetic Minority Oversampling Technique (SMOTE) algorithm was used, the AUC was 0.954 (95% CI: 0.883 to 1.000; P<0.001) and the accuracy was 92.68%. Its sensitivity was 83.33% and the specificity was 96.55%. Conclusions: This method might be useful for thoracic surgeons during surgery, for its relatively high efficacy in rapid differentiation of LNs for patients with NSCLC.

Overexpression of GSTP1 promotes colorectal cancer cell proliferation, invasion and metastasis by upregulating STAT3.

BACKGROUND: The abnormal expression of glutathione S-transferase P1 (GSTP1) is associated with the progression of several tumor types. However, its role and molecular mechanism in the progression of colorectal cancer (CRC) are largely unknown. OBJECTIVES: To examine the effect of GSTP1 in CRC and determine its possible mechanisms. MATERIAL AND METHODS: In the present study, immunohistochemistry (IHC) and the quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis were used to detect the expression of GSTP1 and signal transducer and activator of transcription 3 (STAT3) in CRC tissues. Western blotting was applied to detect the expression of GSTP1 and proteins of the Janus kinase (JAK)-STAT3 pathway in different CRC cell lines. The interaction and co-localization of GSTP1 and STAT3 were detected using co-immunoprecipitation (co-IP) and immunofluorescence (IF) in the SW620 cell line. RESULTS: A positive correlation was identified between the expression of GSTP1 and STAT3 in human CRC tissues. The overexpression of GSTP1 promoted the proliferation, invasion and metastasis of CRC cells by upregulating STAT3. The GSTP1 and STAT3 can directly bind to and regulate each other. The interaction between them is regulated by the upstream gene called F-box only protein 8 (FBX8). CONCLUSIONS: The present study demonstrated that GSTP1 could enhance the expression of STAT3 to promote the proliferation, invasion and metastasis of CRC cells, which provides a potential therapeutic target for the clinical treatment of CRC.

A Patient With a Foreign Body in Mediastinum That Penetrated Into the Bronchus.

We report the rare case of a patient who had a foreign body in the mediastinum and trachea caused by trauma due to epileptic seizures. A 52-year-old man had an epileptic seizure 3 months before visiting our hospital and had an injury to his neck caused by a broken glass cabinet. Computed tomography scan revealed a foreign body in the mediastinum and trachea. After a detailed discussion among members of the multidisciplinary team, surgery was successfully performed to remove the foreign body. This rare case may help provide a reference for diagnosing and treating a mediastinal and tracheobronchial foreign body.

A teratocyte-specific serpin from the endoparasitoid wasp Cotesia vestalis inhibits the prophenoloxidase-activating system of its host Plutella xylostella.

Many endoparasitoids adopt several parasitic factors, such as venom, polydnavirus and teratocytes, to suppress the immune response of their associated hosts including melanization for successful parasitism. A teratocyte-specific expressed serpin gene, designated as CvT-serpin6, was identified from the parasitoid Cotesia vestalis. The immunoblot result suggested that CvT-serpin6 was secreted into extracellular space. qPCR results showed that CvT-serpin6 was mainly transcribed at later stages of parasitism, and the transcriptional abundance of CvT-serpin6 in teratocytes was significantly increased in response to the challenge of bacteria. Inhibitory assay indicated that recombinant CvT-serpin6 (rCvT-serpin6) could inhibit the activation of Plutella xylostella prophenoloxidase and ultimately resulted in the inhibition of melanization in P. xylostella haemolymph. Furthermore, we confirmed that rCvT-serpin6 could form SDS-stable complexes with activated PxPAP1 and PxPAP3 in a dose-dependent manner. Altogether, our results further shed insight into the molecular mechanisms that teratocytes involved in controlling host immune response.

Ideal Anatomical Landmark Points for Thoracic Esophagus Segmentation in the Chinese Population.

Introduction: The standards of esophagus segmentation remain different between the Japan Esophageal Society (JES) guideline and the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) guideline. This study aimed to present variations in the location of intrathoracic esophageal adjacent anatomical landmarks (EAALs) and determine an appropriate method for segmenting the thoracic esophagus based on the relatively fixed EAALs. Patients and Methods: The distances from the upper incisors to the upper border of the esophageal hiatus, lower border of the inferior pulmonary vein (LPV), tracheal bifurcation, lower border of the azygous vein (LAV), and thoracic inlet were measured in the patients undergoing thoracic surgery. The median distances between the EAALs and the specified starting points, as well as reference value ranges and ratios, were obtained. The variation coefficients of distances and ratios from certain starting points to different EAALs were calculated and compared to determine the relatively fixed landmarks. Results: This study included 305 patients. The average distance from the upper incisors to the upper border of the cardia, the midpoint between the tracheal bifurcation and esophageal hiatus (MTBEH), LPV, LAV, tracheal bifurcation, and thoracic inlet were 41.6, 35.3, 34.8, 29.4, 29.5, and 20.3 cm, respectively. The distances from the upper incisors or thoracic inlet to any intrathoracic EAALs in men were higher than in women. In addition, the height, weight, and body mass index (BMI) were correlated with the distances. The ratio of the distance between the upper incisors and tracheal bifurcation to the distance between the upper incisors and upper border of the cardia and the ratio of the distance between the thoracic inlet and tracheal bifurcation to the distance between the thoracic inlet and upper border of the cardia possessed relatively smaller coefficients of variation. Conclusion: The distances from the EAALs to the upper incisors vary with height, weight, BMI, and gender. Compared with distance, the ratios are more suitable for esophagus segmentation. Tracheal bifurcation and MTBEH are ideal EAALs for thoracic esophagus segmentation, and this is consistent with the JES guideline recommendation.

Cryo-EM structure of human Wntless in complex with Wnt3a.

Wntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A ß-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling.

Classification of Metastatic and Non-Metastatic Thoracic Lymph Nodes in Lung Cancer Patients Based on Dielectric Properties Using Adaptive Probabilistic Neural Networks.

OBJECTIVE: Dielectric properties can be used in normal and malignant tissue identification, which requires an effective classifier because of the high throughput nature of the data. With easy training and fast convergence, probabilistic neural networks (PNNs) are widely applied in pattern classification problems. This study aims to propose a classifier to identify metastatic and non-metastatic thoracic lymph nodes in lung cancer patients based on dielectric properties. METHODS: The dielectric properties (permittivity and conductivity) of lymph nodes were measured using an open-ended coaxial probe. The Synthetic Minority Oversampling Technique method was adopted to modify the dataset. Feature parameters were scored to select the appropriate feature vector using a Statistical Dependency algorithm. The dataset was classified using adaptive PNNs with an optimized smooth factor using the simulated annealing PNN (SA-PNN). The results were compared with traditional Probabilistic, Support Vector Machines, k-Nearest Neighbor and the Classify functions in MATLAB. RESULTS: The conductivity frequencies of 3959, 3958, 3960, 3978, 3510, 3889, 3888, and 3976 MHz were selected as the feature vectors for 219 lymph nodes (178 non-metastatic and 41 metastatic). Compared with the other methods, SA-PNN achieved the highest classification accuracy (92.92%) and the corresponding specificity and sensitivity were 94.72% and 91.11%, respectively. CONCLUSIONS: Compared with the other methods, the SA-PNN proposed in the present study achieved a higher classification accuracy, which provides a new scheme for classification of metastatic and non-metastatic thoracic lymph nodes in lung cancer patients based on dielectric properties.

PRMT5 regulates colorectal cancer cell growth and EMT via EGFR/Akt/GSK3ß signaling cascades.

Emerging evidence shows that type II protein arginine methyltransferase 5 (PRMT5) serves as an oncoprotein and plays a critical role in many types of human cancer. However, the precise role and function of PRMT5 in human colorectal cancer (CRC) growth and epithelial-mesenchymal transition (EMT) are still unclear, and the related molecular mechanism and signaling axis remains largely obscure. Here, we show that PRMT5 is highly expressed in CRC cell lines and tissues. Using PRMT5 stable depletion cell lines and specific inhibitor, we discover that down-regulation of PRMT5 by shRNA or inhibition of PRMT5 activity by specific inhibitor GSK591 markedly suppresses CRC cell proliferation and cell cycle progression, which is closely associated with PRMT5 enzyme activity. Moreover, PRMT5 regulates CRC cell growth and cycle progression via activation of Akt, but not through ERK1/2, PTEN, and mTOR signaling pathway. Further study shows that PRMT5 controls EMT of CRC cells by activation of EGFR/Akt/GSK3ß signaling cascades. Collectively, our results reveal that PRMT5 promotes CRC cell proliferation, cell cycle progression, and EMT via regulation of EGFR/Akt/GSK3ß signaling cascades. Most importantly, our findings also suggest that PRMT5 may be a potential therapeutic target for the treatment of human colorectal cancer.

FBX8 promotes metastatic dormancy of colorectal cancer in liver.

Patients with colorectal cancer (CRC) often develop malignant regrowth of metastatic dormant tumor cells in liver years after primary treatment. FBX8 is involved in suppressing tumor metastasis. Short-term chemotherapy experiments and liver metastasis mice model of orthotopic injection into the cecum were performed to construct the dormant models. GST-pull-down assay, Co-IP and immunofluorescence were used to confirm the bindings among FBX8 and its substrates. FBX8 upregulated the expression of epithelial and stemness markers, while downregulated the expression of mesenchymal and proliferative markers associated with tumor cell dormancy. FBX8 promoted the maintenance of metastatic dormancy of CRC cells. Mechanistically, FBX8 directly bound to HIF-1α, CDK4 and C-myc through its Sec7 domain and led to the ubiquitin degradation of these proteins, thereby inhibiting cell cycle progression, proliferation, angiogenesis, and metastasis. Clinically, FBX8 expression was negatively correlated with the HIF-1α, CDK4, and c-Myc in CRC tissues. Our study reveals a novel mechanism of FBX8 in regulating tumor metastatic dormancy in liver and provides new strategies for the treatment of CRC metastasis.

Selective PP2A Enhancement through Biased Heterotrimer Stabilization.

Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets.