Physics-Informed Neural Networks Integrating Compartmental Model for Analyzing COVID-19 Transmission Dynamics.

Modelling and predicting the behaviour of infectious diseases is essential for early warning and evaluating the most effective interventions to prevent significant harm. Compartmental models produce a system of ordinary differential equations (ODEs) that are renowned for simulating the transmission dynamics of infectious diseases. However, the parameters in compartmental models are often unknown, and they can even change over time in the real world, making them difficult to determine. This study proposes an advanced artificial intelligence approach based on physics-informed neural networks (PINNs) to estimate time-varying parameters from given data for the compartmental model. Our proposed PINNs method captures the complex dynamics of COVID-19 by integrating a modified Susceptible-Exposed-Infectious-Recovered-Death (SEIRD) compartmental model with deep neural networks. Specifically, we modelled the system of ODEs as one network and the time-varying parameters as another network to address significant unknown parameters and limited data. Such structure of the PINNs method is in line with the prior epidemiological correlations and comprises the mismatch between available data and network output and the residual of ODEs. The experimental findings on real-world reported data data have demonstrated that our method robustly and accurately learns the dynamics and forecasts future states. Moreover, as more data becomes available, our proposed PINNs method can be successfully extended to other regions and infectious diseases.

Antibiotic Resistance Patterns and Molecular Characterization of Streptococcus suis Isolates from Swine and Humans in China.

Streptococcus suis is a zoonotic pathogen that causes disease in humans after exposure to infected pigs or pig-derived food products. In this study, we examined the serotype distribution, antimicrobial resistance phenotypes and genotypes, integrative and conjugative elements (ICEs), and associated genomic environments of S. suis isolates from humans and pigs in China from 2008 to 2019. We identified isolates of 13 serotypes, predominated by serotype 2 (40/96; 41.7%), serotype 3 (10/96; 10.4%), and serotype 1 (6/96; 6.3%). Whole-genome sequencing analysis revealed that these isolates possessed 36 different sequence types (STs), and ST242 and ST117 were the most prevalent. Phylogenetic analysis revealed possible animal and human clonal transmission, while antimicrobial susceptibility testing indicated high-level resistance to macrolides, tetracyclines, and aminoglycosides. These isolates carried 24 antibiotic resistance genes (ARGs) that conferred resistance to 7 antibiotic classes. The antibiotic resistance genotypes were directly correlated with the observed phenotypes. We also identified ICEs in 10 isolates, which were present in 4 different genetic environments and possessed differing ARG combinations. We also predicted and confirmed by PCR analysis the existence of a translocatable unit (TU) in which the oxazolidinone resistance gene optrA was flanked by IS1216E elements. One-half (5/10) of the ICE-carrying strains could be mobilized by conjugation. A comparison of the parental recipient with an ICE-carrying transconjugant in a mouse in vivo thigh infection model indicated that the ICE strain could not be eliminated with tetracycline treatment. S. suis therefore poses a significant challenge to global public health and requires continuous monitoring, especially for the presence of ICEs and associated ARGs that can be transferred via conjugation. IMPORTANCE S. suis is a serious zoonotic pathogen. In this study, we investigated the epidemiological and molecular characteristics of 96 S. suis isolates from 10 different provinces of China from 2008 to 2019. A subset of these isolates (10) carried ICEs that were able to be horizontally transferred among isolates of different S. suis serotypes. A mouse thigh infection model revealed that ICE-facilitated ARG transfer promoted resistance development. S. suis requires continuous monitoring, especially for the presence of ICEs and associated ARGs that can be transferred via conjugation.

METTL14 promotes fibroblast-like synoviocytes activation via the LASP1/SRC/AKT axis in rheumatoid arthritis.

The objective of this study is to explore the specific roles of a crucial N6-methyladenosine (m6A) methyltransferase, methyltransferase-like 14 (METTL14), in fibroblast-like synoviocytes (FLSs) activation of rheumatoid arthritis (RA). RA rat model was induced by administering intraperitoneally collagen antibody alcohol. Primary fibroblast-like synoviocytes (FLSs) were isolated from joint synovium tissues in rats. shRNA transfection tools were used to downregulate METTL14 expression in vivo and vitro. The injury of joint synovium was shown by hematoxylin and eosin (HE) staining. The cell apoptosis of FLSs was determined by flow cytometry. The levels of IL-6, IL-18, and C-X-C motif chemokine ligand (CXCL)10 in serum and culture supernatants were measured by ELISA kits. The expressions of LIM and SH3 domain protein 1 (LASP1), p-SRC/SRC, and p-AKT/AKT in FLSs and joint synovium tissues were determined by Western blots. The expression of METTL14 was greatly induced in the synovium tissues of RA rats compared with normal control rats. Compared with sh-NC-treated FLSs, METTL14 knockdown significantly increased cell apoptosis, inhibited cell migration and invasion, and suppressed the production of IL-6, IL-18, and CXCL10 induced by TNF-α. METTL14 silencing suppresses the expression of LASP1 and the activation of Src/AKT axis induced by TNF-α in FLSs. METTL14 improves the mRNA stability of LASP1 through m6A modification. In contrast, these were reversed by LASP1 overexpression. Moreover, METTL14 silencing clearly alleviates FLSs activation and inflammation in a RA rat model. These results suggested that METTL14 promotes FLSs activation and related inflammatory response via the LASP1/SRC/AKT signaling pathway and identified METTL14 as a potential target for treating RA.

Experimental Study on the Mechanical Behaviors of Aeolian Sand Treated by Microbially Induced Calcite Precipitation (MICP) and Basalt Fiber Reinforcement (BFR).

Aeolian sand flow is a major cause of land desertification, and it is prone to developing into a dust storm coupled with strong wind and thermal instability. The microbially induced calcite precipitation (MICP) technique can significantly improve the strength and integrity of sandy soils, whereas it easily leads to brittle destruction. To effectively inhibit land desertification, a method coupled with MICP and basalt fiberreinforcement (BFR) was put forward to enhance the strength and toughness of aeolian sand. Based on a permeability test and an unconfined compressive strength (UCS) test, the effects of initial dry density (ρd), fiber length (FL), and fiber content (FC) on the characteristics of permeability, strength, and CaCO3 production were analyzed, and the consolidation mechanism of the MICP-BFR method was explored. The experiments indicated that the permeability coefficient of aeolian sand increased first, then decreased, and subsequently increased with the increase in FC, whereas it exhibited a tendency to decrease first and then increase with the increase in FL. The UCS increased with the increase in the initial dry density, while it increased first and then decreased with the increase in FL and FC. Furthermore, the UCS increased linearly with the increase in CaCO3 generation, and the maximum correlation coefficient reached 0.852. The CaCO3 crystals played the roles of providing bonding, filling, and anchoring effects, and the spatial mesh structure formed by the fibers acted as a bridge effect to enhance the strength and brittle damage of aeolian sand. The findings could supply a guideline for sand solidification in desert areas.

Epi-DNNs: Epidemiological priors informed deep neural networks for modeling COVID-19 dynamics.

Differential equations-based epidemic compartmental models and deep neural networks-based artificial intelligence (AI) models are powerful tools for analyzing and fighting the transmission of COVID-19. However, the capability of compartmental models is limited by the challenges of parameter estimation, while AI models fail to discover the evolutionary pattern of COVID-19 and lack explainability. This paper aims to provide a novel method (called Epi-DNNs) by integrating compartmental models and deep neural networks (DNNs) to model the complex dynamics of COVID-19. In the proposed Epi-DNNs method, the neural network is designed to express the unknown parameters in the compartmental model and the Runge-Kutta method is implemented to solve the ordinary differential equations (ODEs) so as to give the values of the ODEs at a given time. Specifically, the discrepancy between predictions and observations is incorporated into the loss function, then the defined loss is minimized and applied to identify the best-fitted parameters governing the compartmental model. Furthermore, we verify the performance of Epi-DNNs on the real-world reported COVID-19 data on the Omicron epidemic in Shanghai covering February 25 to May 27, 2022. The experimental findings on the synthesized data have revealed its effectiveness in COVID-19 transmission modeling. Moreover, the inferred parameters from the proposed Epi-DNNs method yield a predictive compartmental model, which can serve to forecast future dynamics.

Synthesis, biological evaluation and preliminary mechanisms of 6-amino substituted harmine derivatives as potential antitumor agents.

To explore the effect of the introduction of the amino and substituted amino groups on the antitumor activity of harmine, twenty-five novel 6-amino substituted harmine derivatives (3a-3j and 5a-5o) were synthesized and evaluated for anti-proliferative activity on a panel of cancer cell lines. Compounds 3i and 5n exhibited the most potent antiproliferative activity with IC50 values lower than 2.2 µM. Especially, compound 5n possessed extremely potent antitumor activity with IC50 values of 0.34 µM and 0.65 µM against HL-60 and A549 cell lines, respectively. Further, the preliminary studies of mechanisms showed that compound 5n could significantly induce cell apoptosis in a dose-dependent manner, cause cell cycle arrest at the G2/M phase and intercalate into ct-DNA via the competition with EB, while displaying very weak topoisomerase I (Topo I) inhibition activity. More importantly, 5n showed mild cytotoxicity against human normal lung epithelial cells BEAS-2B. Based on these considerations, 5n may be a good antitumor candidate compound for further exploration.

Comparison of PK/PD Targets and Cutoff Values for Danofloxacin Against Pasteurella multocida and Haemophilus parasuis in Piglets.

Danofloxacin is a synthetic fluoroquinolone with broad-spectrum activity developed for use in veterinary medicine. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) targets, PK/PD cutoff values and the optimum doses of danofloxacin against P. multocida and H. parasuis in piglets. Single dose serum pharmacokinetics was determined in piglets after intravenous and intramuscular administration of 2.5 mg/kg. Danofloxacin was well absorbed and fully bioavailable (95.2%) after intramuscular administration of 2.5 mg/kg. The epidemiological cutoff (ECOFF) values of danofloxacin from 931 P. multocida isolates and 263 H. parasuis isolates were 0.03 and 4 mg/L, respectively. Danofloxacin MICs determined in porcine serum were markedly lower than those measured in artificial broth, with a broth/serum ratio of 4.33 for H. parasuis. Compared to P. multocida, danofloxacin exhibited significantly longer post-antibiotic effects (3.18-6.60 h) and post-antibiotic sub-MIC effects (7.02-9.94 h) against H. parasuis. The mean area under the concentration-time curve/MIC (AUC24h/MIC) targets of danofloxacin in serum associated with the static and bactericidal effects were 32 and 49.8, respectively, for P. multocida, whereas they were 14.6 and 37.8, respectively, for H. parasuis. Danofloxacin AUC24h/MIC targets for the same endpoints for P. multocida were higher than those for H. parasuis. At the current dose of 2.5 mg/kg, the PK/PD cutoff (COPD) values of danofloxacin against P. multocida and H. parasuis were calculated to be 0.125 and 0.5 mg/L, respectively, based on Monte Carlo simulations. The predicted optimum doses of danofloxacin for a probability of target attainment (PTA) of > 90% to cover the overall MIC population distributions of P. multocida and H. parasuis in this study were 2.38 and 13.36 mg/kg, respectively. These PK/PD-based results have potential relevance for the clinical dose optimization and evaluation of susceptibility breakpoints for danofloxacin in the treatment of swine respiratory tract infections involving these pathogens.

Urban sediment pollutants alternate human cell essential behaviour through promoting oxidative damage.

The main objective of this study was to establish a human cell-based platform to assess the effects of sediment toxicity on oxidative damage and cell essential behaviour. Since sediment pollution has increased as a consequence of including but not limited to industrialisation, the contaminants accumulated in sediments have already led to human health concerns. The Hsinchu Science Park is one of the most prominent semiconductor manufacturing centres in the world, and the Ke-Ya River flows through Hsinchu Science Park and the Hsinchu urban district. Because semiconductor wastes potentially contribute to higher-than-normal rates of cancers, birth defects, and serious diseases, the quality assessment of the Ke-Ya River has prompted widespread concerns. While previous studies have shown an association between the degradation of fish populations and sediment pollutants, very little is known about the issues on human health. Herein, the effects of sediment from three sediment sampling sites of the Ke-Ya River on 11 different human cell lines were directly evaluated. The upstream represents the undeveloped zone, the middle-stream represents the household/industrial wastewater zone, and the downstream represents the accumulation zone. Our results indicated that the sediment pollution of the downstream Ke-Ya River was more cytotoxic than that of the middle stream and upstream. Downstream sediment extract (DSE) significantly increased reactive oxygen species (ROS) levels across all cell types. Accordingly, oxidative stress can trigger redox-sensitive pathways and alter essential biological processes such as cell viability, cell adhesion, and cell motility. Importantly, the MTT assay indicated that DSE significantly decreased the viability of brain, oral, lung, breast, liver, pancreatic, cervical, prostate, and colorectal cells. Furthermore, the adhesive ability and wound healing ability of most cells were greatly reduced in the presence of DSE compared to other conditions. Thus, this study shows the results of the first analyses completed on the sediment cytotoxicity in human cells, and stimulated ROS levels are crucial for cellular life. In future research, the detailed cause and effect mechanisms of the abundant ROS generated in DSE will be further investigated. We sincerely hope that our study provides a scientific basis for further investigations with a global perspective on public health challenges.

A longitudinal analysis of collapsibility with predictions over the southeastern Loess Plateau in China.

Loess presents very unique collapsible behaviour due to its special under-compactness, weak cementation and porousness. Many environmental issues and geological hazards including subgrade subsidences, slope collapses or failures, building cracking and so on are directly caused by the collapsible deformation of loess. Such collapsible behaviour may also severe accidents due to sinkholes, underground caves or loess gullies. Moreover, with the increasing demand of construction and development in the loess areas, an in-depth research towards effective evaluation of loess collapsibility is urged. Currently no studies have made attempts to explore a rather complete and representative area of Loess Plateau. This paper thus provides a novel approach on spatial modelling over Jin-Shan Loess Plateau as an extension to experimental studies. The in-lab experiment results have shown that shown that the porosity ratio and collapsibility follow a Gaussian distribution and a Gamma distribution respectively for both sampling areas: Yan'an and Lv Liang. This establishes the prior intuition towards spatial modelling which provides insights of potential influential factors on loess collapsibility and further sets a potential direction of the loess studies by considering an extra dimension of spatial correlation. Such modelling allows robust predictions taken into account of longitudinal information as well as structural parameters and basic physical properties. Water contents, dry densities, pressure levels and elevations of samples are determined to be statistically significant factors which affect the loess collapsibility. All regions in Lv Liang area are at risk of high collapsibility with average around 0.03, out of which roughly a third of them are predicted to be at high risk. Clear spatial patterns of higher expected collapsibility in the southwest comparing to the northeast are shown adjusting for influential covariates. On reference guidelines for potential policy makings, county-level regions with the highest expected loess collapsibility are also identified.

3D printing guide plate for accurate hemicortical bone tumor resection in metaphysis of distal femoral: a technical note.

BACKGROUND: Surgical resection and reconstruction for low-grade bone sarcoma in the metaphysis of the distal femur remain challenging. We hypothesized that 3D printing osteotomy guide plate could assist to accurately resect the tumor lesion and save the joint function. METHODS: From January 2017 to August 2019, five patients diagnosed with low-grade bone sarcoma in the metaphysis of the distal femur were treated with hemicortical resection using 3D printing guide plate. Autologous bone graft was inactivated in a high-temperature water bath and re-implanted in situ fixed with plate and screw. Patients were followed up from 17 to 33 months. The Musculoskeletal Tumor Society Score was used to evaluate the joint function. X-ray was used to evaluate the bone union. RESULTS: One patient was paracorticular osteosarcoma, and four cases had highly differentiated chondrosarcoma. All cases were involved in the metaphysis of the distal femur. Patients were followed up from 13 to 33 months, with an average of 23.6 months. There was neither post-operation infection, internal fixation loosening, nor fracture occurrence in any of the patients. The Musculoskeletal Tumor Society Score averaged at 28.1, while the International Society of Limb Salvage imaging score examination averaged 89.8%. CONCLUSIONS: Here, we demonstrate that the 3D printing osteotomy guide plate-assisted hemicortical bone resection is a beneficial strategy to effectively resect the primary low-grade malignant bone tumors in the metaphysis of the distal femur and retained satisfied joint function.

The near-infrared fluorescent dye IR-780 was coupled with cabazitaxel for castration-resistant prostate cancer imaging and therapy.

A new drug, Caba-780, was synthesized by chemical coupling of the heptamethyl phthalocyanine near-infrared fluorescent (NIRF) dye IR-780 and the paclitaxel-based chemotherapeutic drug cabazitaxel. Then, the potential value of Caba-780 in the diagnosis and treatment of castration-resistant prostate cancer (CRPC) was evaluated. The CRPC cell lines DU145 and PC-3, as well as the normal human prostate stromal cell line WPMY-1, were used to evaluate the uptake of Caba-780 and its antitumor effect in vitro. The distribution, antitumor effect, and safety of Caba-780 were also evaluated in tumor-bearing mouse xenograft models. Our results showed that Caba-780 was efficiently absorbed by DU145 and PC-3 cells and that the cytotoxicity of Caba-780 was significantly stronger than that of IR-780 and cabazitaxel. In addition, Caba-780 inhibited the migration and invasion of DU145 and PC-3 cells and promoted apoptosis by prolonging the G2 phase of the cell cycle. Further analysis indicated that Caba-780 could be used to effectively image tumor xenografts. At the same time, this drug inhibited the growth of tumors in vivo. Therefore, the new synthetic drug Caba-780 has potential applications in the diagnosis and treatment of CRPC.

Construction and validation of a novel prognostic nomogram for patients with sarcomatoid renal cell carcinoma: a SEER-based study.

OBJECTIVE: The only one established prognostic nomogram for patients with sarcomatoid renal cell carcinoma (sRCC) was based on a small sample-sized study without external validation, and a nomogram can be applied to western sRCC patients has not yet been developed. Therefore, our study aimed to construct and validate an effective nomogram to predict overall survival (OS) for these patients. METHODS: The independent predictors for OS were identified and the nomogram was constructed on the basis of a retrospective study of a training cohort consisted of 428 non-Hispanic white sRCC patients registered in the Surveillance, Epidemiology and End Results (SEER) database from January 2010 to December 2015. Then, the discriminative performance of the nomogram was assessed by the concordance index (C-index). OS calibrations of the nomogram were also performed by comparing the nomogram-predicted probability to the observed survival rate. Furthermore, our nomogram was externally validated using two independent cohorts consisted of 71 non-Hispanic black patients and 82 Hispanic patients, respectively. RESULTS: Age at diagnosis, T stage, N stage, bone metastases, liver metastases, lung metastases and nephrectomy were identified as independent predictors for OS. In the training cohort and two validation cohorts, the C-indexes of the nomogram were 0.737, 0.801 and 0.764, respectively. Besides, excellent agreements between the nomogram prediction and the actual observation were achieved in all cohorts. CONCLUSIONS: The current study constructed and validated an effective prognostic nomogram for patients with sRCC, which can be used to perform accurate predictions of the 0.5-, 1-, and 2-year possibilities of OS.

The RNA-binding protein QKI suppresses tumorigenesis of clear cell renal cell carcinoma by regulating the expression of HIF-1α.

Backgrounds: A number of genetic and biological phenomena imply that tumorigenesis of clear cell renal cell carcinoma (ccRCC) is highly correlated with hypoxia-induced factor-1a (HIF-1α). Recently, research focusing on the post-transcriptional regulation of HIF-1α has provided a new perspective for ccRCC therapy. In this study, we observed the expression pattern of the RNA-binding protein QKI, which could regulate HIF expression in ccRCC both in vitro and in vivo. Methods: Tissue microarraywas subjected to immunohistochemistry and tumour cell lines and nude mice were used for in vitro and in vivo assays. QKI overexpression or knockdown was assessed in renal cancer cells. Results: The overexpression of QKI inhibited the proliferation of the 786-0 and caki-1 cells, blocked the cells' entry into the S phase, and promoted apoptosis. In ectopic-implantation nude mice model, QKI depletion significantly increased tumor sizes and initiation rates. Tissue microarrays showed that the expression of QKI genes, and especially QKI-6, was significantly decreased in tumor tissues compared with these in normal kidney tissues. Moreover, decreased QKI expression was closely correlated with high tumor grade, poor differentiation, and poor survival. Conclusions: QKI may be useful as a novel, independent diagnostic and biological marker for ccRCC.

The tumor suppressor NDRG2 cooperates with an mTORC1 inhibitor to suppress the Warburg effect in renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the most common malignancies worldwide, and metabolic reprogramming has a profound effect on RCC tumorigenesis. mTORC1 inhibitors are widely used in RCC treatment, yet some types of RCC cells are resistant to these compounds. Thus, clarification of the metabolic mechanism of mTORC1 inhibitors and exploration of new therapeutic approaches are urgently needed. In this study, we found that the mTORC1 pathway was hyperactive in RCC. Immunohistochemistry and western blot analysis showed that phosphorylation of the mTORC1 substrate 4EBP1 at threonine 37/46 increased in RCC tissues compared with that in normal renal tissues. It was also found that mTORC1 inhibitor everolimus suppressed glucose consumption, lactate production, and multiple catalytic enzymes involved in glycolysis in 786-O and ACHN cells, but the accumulation of HIF1α induced by CoCl2 blocked the inhibitory effect of everolimus on aerobic glycolysis. Interestingly, western blot and metabolite analysis showed that the tumor suppressor NDRG2 (N-Myc downstream regulated gene 2) was able to inhibit mTORC1 activity and cooperate with an mTOR inhibitor to decrease aerobic glycolysis in 786-O and ACHN cells. These results demonstrate that NDRG2 may potentially synergize with mTORC1 inhibitors to suppress malignant phenotype of RCC. Taken together, these data provided preclinical evidence that the combination of NDRG2 and mTORC1 inhibitors might be a promising strategy for RCC therapy.

Development and validation of a prognostic nomogram for patients with intravesical recurrence after radical nephroureterectomy for non-metastatic upper tract urothelial carcinoma.

PURPOSE: To develop and validate a prognostic nomogram for patients with intravesical recurrence (IVR) after radical nephroureterectomy (RNU) for non-metastatic upper tract urothelial carcinoma (UTUC). METHODS: The clinical data of 468 patients registered in the surveillance, epidemiology and end results database between 2010 and 2015 were retrospectively analyzed. Multivariate analysis using the Cox proportional hazard model was used to determine independent prognostic factors for the development of a nomogram to predict the 1-, 3-, and 5-year probability of individual cancer-specific survival (CSS). Moreover, the nomogram was internally validated using receiver operating characteristic curves and calibration plots. RESULTS: Age at IVR > 80 years, UTUC stage ≥ T3, bladder cancer (BC) stage T1, and muscle-invasive BC (stage ≥ T2) were identified as independent risk factors for CSS in patients with IVR after RNU, whereas a time interval of > 24 months between UTUC and BC was an independent protective factor. The 1-, 3-, and 5-year predictive accuracies of our nomogram were 0.74, 0.70, and 0.71, respectively. Additionally, 1-, 3-, and 5-year calibration curves demonstrated perfect agreement between the nomogram-predicted and the actual CSS. CONCLUSIONS: This study developed and internally validated the first nomogram to date to predict individual prognosis in patients with IVR after RUN for UTUC. This nomogram can be used for patient counseling and for designing clinical trials.

Development and validation of a SEER-based prognostic nomogram for patients with bone metastatic prostate cancer.

Controversies exist between the previous two prognostic nomograms for patients with bone metastatic prostate cancer (PCa), and a nomogram applied to western patients has yet to be established. Thus, we aimed to build a reliable and generic nomogram to individualize prognosis.The independent prognostic factors were identified in a retrospective study of 1556 patients with bone metastatic PCa registered in the Surveillance, Epidemiology and End Results (SEER) database. Besides, the prognostic nomogram was developed using R software according to the result of multivariable Cox regression analysis. Then, the discriminative ability of the nomogram was assessed by analyses of receiver operating characteristic curves (ROC curves). We also performed 1-, 2-, and 3-year calibrations of the nomogram by comparing the predicted survival to the observed survival. Furthermore, the model was externally validated using the data of 711 patients diagnosed at different times enrolled in the SEER database.Age ≥70 years, Gleason score ≥8, PSA value of 201 to 900 ng/ml, stage T4, stage N1, with liver metastases, and Asian/Pacific ethnicity were identified as independent prognostic factors. In the primary cohort, 1-, 2-, and 3-year area under the ROC curve (AUC) of the nomogram for predicting cancer-specific survival (CSS) were 0.71, 0.70, and 0.70, respectively. Besides 1-, 2-, and 3-year AUC were 0.70, 0.68, and 0.69, respectively, in the external validation cohort. Moreover, calibration curves presented perfect agreements between the nomogram-predicted and actual 1-, 2-, and 3-year CSS rate in both the primary and external validation cohorts. In other words, our nomogram has great predictive accuracy and reliability in predicting 1-, 2-, and 3-year CSS for patients with bone metastatic prostate cancer.This study established and validated a prognostic nomogram applied to not only Asian patients but western patients with bone metastatic PCa, which will be useful for patients' counseling and clinical trial designing.

Combined Aberrant Expression of NDRG2 and LDHA Predicts Hepatocellular Carcinoma Prognosis and Mediates the Anti-tumor Effect of Gemcitabine.

The Warburg effect is one of the important hallmarks of cancer. The activation of oncogene and inactivation of tumor suppressor gene contribute to the enhancement of glycolytic enzymes and the Warburg effect. The N-myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene and is frequently lost in various types of cancer. However, little is known about glycolytic function and therapeutic value of NDRG2 in hepatocellular carcinoma (HCC). In this study, we found that NDRG2 and lactate dehydrogenase A (LDHA) were aberrantly expressed in HCC and were closely related to the Warburg effect. The correlation between NDRG2 and LDHA expression predicted HCC prognosis and the clinical response to chemotherapy. NDRG2 expression was significantly decreased while LDHA expression was increased in HCC specimens. NDRG2 and LDHA expression was significantly correlated with differentiation status, vascular invasion, and TNM stage of HCC. NDRG2 inhibited LDHA expression, the Warburg effect and the growth of HCC cells. Furthermore, NDRG2 mediated gemcitabine-induced inhibition of LDHA expression and the Warburg effect in HCC cells. Taken together, our data suggest that NDRG2 plays an important role in inhibiting the Warburg effect and the malignant growth of HCC via LDHA. NDRG2 combined with LDHA might be powerful prognostic biomarkers and targets for chemotherapy treatment of HCC.

Deletion of discoidin domain receptor 2 attenuates renal interstitial fibrosis in a murine unilateral ureteral obstruction model.

Background: Renal interstitial fibrosis is a common pathway of chronic kidney disease to end-stage renal disease, which is characterized by an imbalance between the synthesis and degradation of the collagen-rich extracellular matrix (ECM). While, discoidin domain receptor 2 (DDR2) can be activated when it binds to some types of collagen. Therefore, we hypothesized that DDR2 may be a major player in renal interstitial fibrosis. Methods: Renal histologic analysis, real-time PCR analyses and hydroxyproline assay were performed in DDR2-deficient mice and wild-type mice after unilateral ureteral obstruction; C57 mice were randomly divided into sham operation group (Sham group, n = 4), renal interstitial fibrosis model group (UUO group, n = 4), and calcium dobesilate treatment group (CDT group, n = 4), preparation of renal interstitial fibrosis model by unilateral ureteral obstruction (UUO), CDT Group was treated with calcium dobesilate orally, Sham group and UUO group were given double distilled water, HE staining, Masson staining, real-time quantitative PCR were detected after 14 days of UUO in mice to observe the renal interstitial fibrosis degree. Results: DDR2 expression was dramatically increased in the obstructed kidney; In contrast to wild-type mice that developed severe interstitial fibrosis, the DDR2-deficient mice displayed only moderate fibrotic changes; Compared with the UUO group, the degree of renal interstitial fibrosis in CDT group was relieved after operation 14 day. Conclusion: DDR2 might play an important role in the development of RIF; Calcium dobesilate can affect the expression of DDR2 and improve the renal interstitial fibrosis in mice.

MiR-9 promotes synovial sarcoma cell migration and invasion by directly targeting CDH1.

BACKGROUND: Invasion and metastasis of synovial sarcoma is the leading cause of death in patients. Epithelial mesenchymal transition (EMT) accelerates tumor cell invasion and metastasis. MiR-9 promotes tumor metastasis by inducing EMT. However, the role of miR-9 in synovial sarcoma is still not clear. METHODS: Overexpression or knockdown of miR-9 in human synovial sarcoma (HSS) cell lines was carried out by miR-9 mimics or miR-9 inhibitors transfection. Cell proliferation, apoptosis, migration and invasion were detected using MTS and colony formation assays, flow cytometry, wound healing and transwell assays, respectively. Luciferase reporter assay was applied to study the interaction between miR-9 and CDH1. Nude mice xenograft model was established, and immunohistochemistry staining assessed Ki-67 level. The related mRNA and protein expression levels were evaluated by qRT-PCR and Western blotting. RESULTS: The bioinformatics analyses and luciferase reporter assay showed that miR-9 can target CDH1 3'-UTR. Moreover, miR-9 could induce EMT of HSS cells via targeting CDH1. The negative regulation of miR-9 on CDH1 expression was also confirmed in a mouse xenograft model of synovial sarcoma. Furthermore, miR-9 was observed to induce HSS cell proliferation, migration and invasion and inhibit apoptosis. MAPK/ERK and Wnt/ß-catenin signal pathways were activated by the miR-9 overexpression in HSS cells, and then further enhancing tumorigenesis of HSS, which was further confirmed in the mouse model. CONCLUSION: MiR-9 induces EMT by targeting CDH1, and activates MAPK/ERK and Wnt/ß-catenin signal pathways, thus promoting HSS tumorigenesis.

Effect of PTEN loss on metabolic reprogramming in prostate cancer cells.

The tumor suppressor gene PTEN is one of the most often deleted genes in human prostate cancer. Loss of PTEN is an important event in prostate carcinogenesis. Metabolic reprogramming induced by PTEN loss fuels malignant growth and proliferation of prostate cancer cells. Targeted metabolomics analysis was used to investigate the effects of PTEN loss on intracellular metabolic pathways in prostate cancer cells. DU-145 cells were transfected with PTEN siRNAs (siRNA-1 and siRNA-2) for 48 h, and endogenous PTEN expression was monitored by western blotting. Changes in intracellular metabolites were determined by liquid chromatography-tandem mass chromatography (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS). Most intracellular metabolites involved in glycolysis and glutaminolysis were increased in PTEN knockdown prostate cancer cells. In addition, most intracellular metabolites involved in fatty acid de novo synthesis, fatty acid beta oxidation and branched chain amino acid catabolism were also increased in PTEN knockdown prostate cancer cells. These results revealed that PTEN loss induced the metabolic reprogramming of prostate cancer cells and promoted the malignant proliferation of prostate cancer cells. The present metabolomics analysis indicates that tumor suppressor gene PTEN mutation or deletion can induce metabolic reprogramming in prostate cancer cells and tumorigenesis by altering the metabolic flux of glycolysis, glutaminolysis, fatty acid metabolism and branched chain amino acid catabolism pathways. Metabolic reprogramming is one of the contributors to PTEN-loss driven prostate cancer.