Smart exosomes enhance PDAC targeted therapy.

Exosomes continue to attract interest as a promising nanocarrier drug delivery technology. They are naturally derived nanoscale extracellular vesicles with innate properties well suited to shuttle proteins, lipids, and nucleic acids between cells. Nonetheless, their clinical utility is currently limited by several major challenges, such as their inability to target tumor cells and a high proportion of clearance by the mononuclear phagocyte system (MPS) of the liver and spleen. To overcome these limitations, we developed "Smart Exosomes" that co-display RGD and CD47p110-130 through CD9 engineering (ExoSmart). The resultant ExoSmart demonstrates enhanced binding capacity to αvß3 on pancreatic ductal adenocarcinoma (PDAC) cells, resulting in amplified cellular uptake in in vitro and in vivo models and increased chemotherapeutic efficacies. Simultaneously, ExoSmart significantly reduced liver and spleen clearance of exosomes by inhibiting macrophage phagocytosis via CD47p110-130 interaction with signal regulatory proteins (SIRPα) on macrophages. These studies demonstrate that an engineered exosome drug delivery system increases PDAC therapeutic efficacy by enhancing active PDAC targeting and prolonging circulation times, and their findings hold tremendous translational potential for cancer therapy while providing a concrete foundation for future work utilizing novel peptide-engineered exosome strategies.

Nanoparticles loaded withß-Lapachone and Fe3+exhibit enhanced chemodynamic therapy by producing H2O2through cascaded amplification.

The rapid, irreversible change of active Fe2+to inactive Fe3+after the Fenton reaction occurring reduces the chemodynamic therapeutic (CDT) effect. Therefore, manipulation of the tumor microenvironment to provide sufficient hydrogen peroxide (H2O2) while maintaining metal ion catalyst activity is critical for effective CDT. Here,ß-Lapachone (LPC) was loaded by mesoporous silica nanoparticles (MSNs) and coated with polydopamine (PDA) to further chelate Fe3+and link aptamer AS1411, and a pH-controlled released, chemotherapy-photothermal therapy (PTT)-enhanced CDT-small molecule therapy combination drug delivery system with passive and active tumor targeting was engineered (designated asß-LPC@MSN@PDA/Fe3+-AS1411, LMPFA). The results showed that LFMPA nanoparticles massively accumulated in tumor tissues to achieve tumor targeting through AS1411 mediating and enhanced permeability and retention (EPR) effect. Subsequently, PDA released Fe3+and LPC through acid response to exhibited CDT and chemotherapeutic therapy. Meanwhile, the photothermal effect of PDA promoted the release of LPC from the pores of MSN. LPC exerted chemotherapy effect and cyclically producing of H2O2by the catalysis of NQO1, which enhanced the CDT activated by Fe3+. In addition, while serving as a targeted ligand, AS1411 could also exhibit a small molecule therapeutic effect by binding to nucleoli of tumor cells. This unique nano delivery system achieved the combination of chemotherapy, PTT, enhanced CDT and small molecule therapy, and fought against malignant tumors synergistically through multi-target and multi-dimension.

A preoperative CT-based deep learning radiomics model in predicting the stage, size, grade and necrosis score and outcome in localized clear cell renal cell carcinoma: A multicenter study.

BACKGROUND AND PURPOSE: The Stage, Size, Grade and Necrosis (SSIGN) score is the most commonly used prognostic model in clear cell renal cell carcinoma (ccRCC) patients. It is a great challenge to preoperatively predict SSIGN score and outcome of ccRCC patients. The aim of this study was to develop and validate a CT-based deep learning radiomics model (DLRM) for predicting SSIGN score and outcome in localized ccRCC. METHODS: A multicenter 784 (training cohort/ test 1 cohort / test 2 cohort, 475/204/105) localized ccRCC patients were enrolled. Radiomics signature (RS), deep learning signature (DLS), and DLRM incorporating radiomics and deep learning features were developed for predicting SSIGN score. Model performance was evaluated with area under the receiver operating characteristic curve (AUC). Kaplan-Meier survival analysis was used to assess the association of the model-predicted SSIGN with cancer-specific survival (CSS). Harrell's concordance index (C-index) was calculated to assess the CSS predictive accuracy of these models. RESULTS: The DLRM achieved higher micro-average/macro-average AUCs (0.913/0.850, and 0.969/0.942, respectively in test 1 cohort and test 2 cohort) than the RS and DLS did for the prediction of SSIGN score. The CSS showed significant differences among the DLRM-predicted risk groups. The DLRM achieved higher C-indices (0.827 and 0.824, respectively in test 1 cohort and test 2 cohort) than the RS and DLS did in predicting CSS for localized ccRCC patients. CONCLUSION: The DLRM can accurately predict the SSIGN score and outcome in localized ccRCC.

Association of Resting Heart Rate Trajectories With Cardiovascular Disease and Mortality in Patients With Diabetes Mellitus.

CONTEXT: Longitudinal patterns of resting heart rate (RHR) in patients with diabetes mellitus and their association with health outcomes are not well-characterized. OBJECTIVE: We sought to explore the RHR trajectories in patients with diabetes mellitus and their association with cardiovascular disease (CVD) and all-cause mortality. DESIGN: The Kailuan Study is a prospective cohort study. Participants underwent health examinations biennially starting in 2006 and were followed until December 31, 2020. SETTING: General community. PARTICIPANTS: A total of 8218 diabetic participants who attended at least 3 of the examinations conducted in 2006, 2008, 2010, and 2012 were included. MAIN OUTCOME MEASURES: CVD and all-cause mortality. RESULTS: We identified 4 RHR trajectories in participants with diabetes mellitus between 2006 and 2012: low-stable (range, 66.83-64.91 beats/min; n = 1705), moderate-stable (range, 76.30-76.95 beats/min; n = 5437), high-decreasing (mean decreased from 92.14 to 85.60 beats/min; n = 862), and high-increasing (mean increased from 84.03 to 111.62 beats/min; n = 214). During an average follow-up of 7.25 years, 977 cases of CVD and 1162 deaths were identified. Compared with the low-stable trajectory, adjusted hazard ratios (HRs) for CVD were 1.48 (95% CI, 1.02-2.14; P = .04) for the high-increasing trajectory, adjusted HRs for all-cause mortality were 1.34 (95% CI, 1.14-1.58; P < .01) for the moderate-stable trajectory, 1.68 (95% CI, 1.35-2.10; P < .01) for the high-decreasing trajectory, and 2.47 (95% CI, 1.85-3.31; P < .01) for the high-increasing trajectory. CONCLUSIONS: RHR trajectories were associated with the subsequent risks of CVD and all-cause mortality in patients with diabetes mellitus.

Effects of a ketogenic diet on reproductive and metabolic phenotypes in mice with polycystic ovary syndrome†.

Polycystic ovary syndrome (PCOS) is one of the most common female reproductive and metabolic disorders. The ketogenic diet (KD) is a diet high in fat and low in carbohydrate. The beneficial effects of KD intervention have been demonstrated in obese women with PCOS. The underlying mechanisms, however, remain unknown. The aim of the present study was to investigate the effects of a KD on both reproductive and metabolic phenotypes of dehydroepiandrosterone (DHEA)-induced PCOS mice. Female C57BL/6 mice were divided into three groups, designated Control, DHEA, and DHEA+KD groups. Mice of both Control and DHEA groups were fed the control diet, whereas DHEA+KD mice were fed a KD with 89%(kcal) fat for 1 or 3 weeks after PCOS mouse model was completed. At the end of the experiment, both reproductive and metabolic characteristics were assessed. Our data show that KD treatment significantly increased blood ketone levels, reduced body weight and random and fasting blood glucose levels in DHEA+KD mice compared with DHEA mice. Glucose tolerance, however, was impaired in DHEA+KD mice. Ovarian functions were improved in some DHEAmice after KD feeding, especially in mice treated with KD for 3 weeks. In addition, inflammation and cell apoptosis were inhibited in the ovaries of DHEA+KD mice. Results from in vitro experiments showed that the main ketone body ß-hydroxybutyrate reduced inflammation and cell apoptosis in DHEA-treated KGN cells. These findings support the therapeutic effects of KD and reveal a possible mechanism by which KD improves ovarian functions in PCOS mice.

Predicting the grade of meningiomas by clinical-radiological features: A comparison of precontrast and postcontrast MRI.

Objectives: Postcontrast magnetic resonance imaging (MRI) is important for the differentiation between low-grade (WHO I) and high-grade (WHO II/III) meningiomas. However, nephrogenic systemic fibrosis and cerebral gadolinium deposition are major concerns for postcontrast MRI. This study aimed to develop and validate an accessible risk-scoring model for this differential diagnosis using the clinical characteristics and radiological features of precontrast MRI. Methods: From January 2019 to October 2021, a total of 231 meningioma patients (development cohort n = 137, low grade/high grade, 85/52; external validation cohort n = 94, low-grade/high-grade, 60/34) were retrospectively included. Fourteen types of demographic and radiological characteristics were evaluated by logistic regression analyses in the development cohort. The selected characteristics were applied to develop two distinguishing models using nomograms, based on full MRI and precontrast MRI. Their distinguishing performances were validated and compared using the external validation cohort. Results: One demographic characteristic (male), three precontrast MRI features (intratumoral cystic changes, lobulated and irregular shape, and peritumoral edema), and one postcontrast MRI feature (absence of a dural tail sign) were independent predictive factors for high-grade meningiomas. The area under the receiver operating characteristic (ROC) curve (AUC) values of the two distinguishing models (precontrast-postcontrast nomogram vs. precontrast nomogram) in the development cohort were 0.919 and 0.898 and in the validation cohort were 0.922 and 0.878. DeLong's test showed no statistical difference between the AUC values of the two distinguishing models (p = 0.101). Conclusions: An accessible risk-scoring model based on the demographic characteristics and radiological features of precontrast MRI is sufficient to distinguish between low-grade and high-grade meningiomas, with a performance equal to that of a full MRI, based on radiological features.

Oxidative Stress as a Contributor to Insulin Resistance in the Skeletal Muscles of Mice with Polycystic Ovary Syndrome.

Polycystic ovarian syndrome (PCOS) is a reproductive, endocrine, and metabolic disorder. Circulating markers of oxidative stress are abnormal in women with PCOS. There is a close relationship between oxidative stress and insulin resistance (IR). However, little information is available about oxidative stress in the skeletal muscles of those affected by PCOS. In this study, PCOS was induced in prepubertal C57BL/6J mice by injection with dehydroepiandrosterone. Oxidative stress biomarkers were then measured in both serum and skeletal muscles. The underlying mechanisms were investigated in C2C12 myotubes treated with testosterone (T). We discovered increased oxidative biomarkers, increased ROS production, and damaged insulin sensitivity in the skeletal muscles of mice with PCOS. High levels of T caused mitochondrial dysfunction and increased ROS levels through the androgen receptor (AR)-nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) signaling pathway in C2C12 cells. Treatment of C2C12 cells with an antioxidant N-acetylcysteine (NAC) decreased T-induced ROS production, improved mitochondrial function, and reversed IR. Administration of NAC to mice with PCOS improved insulin sensitivity in the skeletal muscles of the animals. Hyperandrogenism caused mitochondrial dysfunction and redox imbalance in the skeletal muscles of mice with PCOS. We discovered that oxidative stress contributed to skeletal muscle IR in PCOS. Reducing ROS levels may improve the insulin sensitivity of skeletal muscles in patients with PCOS.

Cost-Effectiveness of Intensive Versus Standard Blood Pressure Treatment in Older Patients With Hypertension in China.

BACKGROUND: In the STEP trial (Strategy of Blood Pressure Intervention in older Hypertensive Patients), the risk of cardiovascular events is significantly lower in patients who received intensive systolic blood psressure (BP) treatment than in those who received standard treatment. This study compared the lifetime health benefits and medical costs of intensive BP treatment with those of standard BP treatment. METHODS: A microsimulation model included 10 000 hypothetical samples of Chinese adults aged 60 to 80 years old with baseline systolic BP higher than 140 mm Hg. Primary outcome was the incremental cost-effectiveness ratio from a payer's perspective. Secondary outcome was cardiovascular events, including acute coronary syndrome, stroke, acute decompensated heart failure, atrial fibrillation, and death from cardiovascular causes. RESULTS: The model simulated that cardiovascular events occurred in 36.88% of the patients in the intensive treatment group, as compared to 41.28% of the patients in the standard treatment group over the lifetime horizon. The mean number of quality-adjusted life-years would be 0.16 higher in patients who received intensive treatment than in those who received standard treatment and would cost Chinese yuan 12 614 (International dollars 3018) more per quality-adjusted life-year gained. Most simulation results indicated that intensive treatment would be cost-effective (82%-95% below the willingness-to-pay threshold of Chinese yuan 72 000 [1× the gross domestic product per capita in China in 2020]). Sensitivity analyses showed that these conclusions were robust. CONCLUSIONS: In this study, intensive BP treatment prevented cardiovascular events among older patients with hypertension in China and was cost-effective in most scenarios. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03015311.

A Double-Chamber "Dandelion" Appearance Sequential Drug Delivery System for Synergistic Treatment of Malignant Tumors.

Introduction: During the combined treatment of tumors, the non-interfering transportation of drugs with different solubilities and the controllable sequential release are the main challenges. Here, we reported a double-chamber "Dandelion" -like sequential drug delivery system to realize the sequential release of different drugs for treating malignant tumors synergistically. Methods: After synthesizing mesoporous silica nanoparticles (MSN) by template method, a hydrophilic chemotherapy drug doxorubicin (DOX) was loaded into the channels of mesoporous silica (MSN) and locked with polydopamine (PDA) coating. Next, ß-cyclodextrin (ß-CDs) was decorated on PDA by Michael addition reaction, and the hydrophobic photosensitizer chlorin e6 (Ce6) was encapsulated into the hydrophobic chambers of ß-CDs. Finally, AS1411 was modified on the surface of PDA and obtained DOX@MSN@PDA-ß-CD/Ce6-AS1411 nanoparticles (DMPCCA) through which orthogonal loading and effective controlled release of different drugs were realized. Results: Under the sequential irradiations of 808 nm and 660 nm near-infrared (NIR) laser, PDA promoted the extensive release of Ce6 firstly while playing the effect of photothermal therapy (PTT), further to achieve the effect of photodynamic therapy (PDT) of Ce6. Meanwhile, the rapid release of DOX loaded in MSN channels showed a time lag of about 5 h after Ce6 release, through which it maximized the chemotherapeutic effect. Besides, the present drug loading nano-platform combined passive tumor-targeting effect given by EPR and active tumor-targeting effect endowed by AS1411 realized PTT-PDT-chemotherapy triple mode synergistic combination. Conclusion: We offer a general solution to address the key limitations for the delivery and sequential release of different drugs with different solubilities.

Aptamer-mediated DNA concatemer functionalized magnetic nanoparticles for reversible capture and release of circulating tumor cells.

Effectively capturing, releasing, and reanalyzing circulating tumor cells (CTCs) are critical in cancer diagnosis and individualized treatment. Traditional immunomagnetic separation has disadvantages of low sensitivity and specificity, and is time-consuming and costly in CTCs capture. It is also easily disturbed by the microenvironment in releasing and analyzing CTCs. Here, we proposed an aptamer-mediated DNA concatemer functionalized magnetic nanoparticles (MNPs-AMDC) for the reversible capture and release of CTCs. In this study, aptamers were used both for efficiently capturing CTCs without complicated assembly steps and stimulus-response switch for releasing CTCs with little influence on cellular activity. The MNPs-AMDC was demonstrated to effectively capture (83%) and release CTCs with a good viability rate (92%). Moreover, this device was also tested in clinical blood samples, which would provide a universal tool for diagnosing cancer and treating individuals.

Aptamer-functionalized quercetin thermosensitive liposomes for targeting drug delivery and antitumor therapy.

Chemo-thermotherapy, as a promising cancer combination therapy strategy, has attracted widespread attention. In this study, a novel aptamer functionalized thermosensitive liposome encapsulating hydrophobic drug quercetin was fabricated as an efficient drug delivery system. This aptamer-functionalized quercetin thermosensitive liposomes (AQTSL) combined the merits of high-loading yield, sustained drug release, long-term circulation in the body of PEGylated liposomes, passive targeting provided by 100-200 nm nanoparticles, active targeting and improved internalization effects offered by AS1411 aptamer, and temperature-responsive of quercetin release. In addition, AQTSL tail vein injection combined with 42 °C water bath heating on tumor site (AQTSL + 42 °C)treatment inhibited the tumor growth significantly compared with the normal saline administration (p< 0.01), and the inhibition rate reached 75%. Furthermore, AQTSL + 42 °C treatment also slowed down the tumor growth significantly compared with QTSL combined with 42 °C administration (p< 0.05), confirming that AS1411 decoration on QTSL increased the active targeting and internalization effects of the drug delivery system, and AS1411 aptamer itself might also contribute to the tumor inhibition. These data indicate that AQTSL is a potential carrier candidate for different hydrophobic drugs and tumor targeting delivery, and this kind of targeted drug delivery system combined with temperature responsive drug release mode is expected to achieve an ideal tumor therapy effect.

Layered and orthogonal assembly of hydrophilic drugs and hydrophobic photosensitizers for enhanced cancer therapy.

Combinatorial tumor therapy including chemotherapy and photodynamic therapy (PDT) can compensate for the limitations of each other and significantly increase the therapeutic effect. However, considering the differences of water-soluble characteristics between chemotherapeutic drugs and photosensitizers for photodynamic therapy, simply loading these substances into the same cavities of nanocarriers is rather difficult, leading to the reduced drug loading efficiency. Here, we reported a layered and orthogonal assembly of hydrophilic drugs doxorubicin (Dox) and hydrophobic photosensitizers Chlorin e6 (Ce6) for enhancing the effect of synergistic therapeutics. The assembly was based on polydopamine (PDA) modified with ß-cyclodextrin (ß-CD) through the addition reaction of -HS in HS-ß-CD and-C=C in PDA, then DOX and Ce6 were loaded on the PDA and in the hydrophobic cavities of ß-CDs respectively with superior drug loading efficiencies (38.8 ± 0.8% and 5.4 ± 0.3% for DOX and Ce6). PDA was hydrolyzed completely under the lysosomal acidic condition, leading to the controlled release of DOX. Under NIR irradiations, DOX-based chemotherapy was successfully integrated with PDA-based photothermal and Ce6-based photodynamic therapy. Tumor specific aptamer AS1411-modified assembly provides ideal antitumor effects in vitro and in vivo with excellent biocompatibility. Collectively, this layered and orthogonal assembly offers a generalizable solution for delivering matters with distinct aqueous solubility would find broad applications not only in drug delivery but also in bio-nanotechnology.

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases.

Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia.

Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.

Clinical value of CT-guided percutaneous fine-needle aspiration biopsy for peritoneal lesions.

BACKGROUND: To investigate the clinical value of CT-guided percutaneous fine-needle aspiration biopsy for peritoneal lesions of unknown nature. METHODS: A retrospective analysis was conducted of 84 patients with peritoneal thickening for unknown reasons. There were 26 males and 58 females who underwent CT-guided percutaneous fine-needle aspiration biopsy for peritoneal lesions. RESULT: Among these 84 patients, no definite pathologic diagnosis was made in 3 patients, who were lost to the follow-up. The accuracy rate of CT-guided percutaneous fine-needle aspiration biopsy was 95.1% (77/81). Sixty lesions were pathologically-diagnosed with malignancies (74.1%), including 55 with peritoneal metastases, 4 with malignant mesotheliomas, and 1 with a lymphoma. Twenty-four patients (33.8%) were diagnosed as benign lesions, including 11 with tuberculosis and 13 with inflammatory lesions. The complications of CT-guided percutaneous fine-needle aspiration biopsy included bleeding in 1 patient and ascites leakage in 2 patients. CONCLUSION: CT-guided percutaneous fine-needle aspiration biopsy is a safe and effective method for diagnosing peritoneal lesions.

Exploratory Study of a CT Radiomics Model for the Classification of Small Cell Lung Cancer and Non-small-Cell Lung Cancer.

Background: Radiomics can quantify tumor phenotypic characteristics non-invasively by applying feature algorithms to medical imaging data. In this study, we investigated the association between radiomics features and the tumor histological subtypes, and we aimed to establish a nomogram for the classification of small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Methods: This was a retrospective single center study. In total, 468 cases including 202 patients with SCLC and 266 patients with NSCLC were enrolled in our study, and were randomly divided into a training set (n = 327) and a validation set (n = 141) in a 7:3 ratio. The clinical data of the patients, including age, sex, smoking history, tumor maximum diameter, clinical stage, and serum tumor markers, were collected. All patients underwent enhanced computed tomography (CT) scans, and all lesions were pathologically confirmed. A radiomics signature was generated from the training set using the least absolute shrinkage and selection operator algorithm. Independent risk factors were identified by multivariate logistic regression analysis, and a radiomics nomogram based on the radiomics signature and clinical features was constructed. The capability of the nomogram was evaluated in the training set and validated in the validation set. Results: Fourteen of 396 radiomics parameters were screened as important factors for establishing the radiomics model. The radiomics signature performed well in differentiating SCLC and NSCLC, with an area under the curve (AUC) of 0.86 (95% CI: 0.82-0.90) in the training set and 0.82 (95% CI: 0.75-0.89) in the validation set. The radiomics nomogram had better predictive performance [AUC = 0.94 (95% CI: 0.90-0.98) in the validation set] than the clinical model [AUC = 0.86 (95% CI: 0.80-0.93)] and the radiomics signature [AUC = 0.82 (95% CI: 0.75-0.89)], and the accuracy was 86.2% (95% CI: 0.79-0.92) in the validation set. Conclusion: The enhanced CT radiomics signature performed well in the classification of SCLC and NSCLC. The nomogram based on the radiomics signature and clinical factors has better diagnostic performance for the classification of SCLC and NSCLC than the simple application of the radiomics signature.

Transcriptome sequencing analysis reveals unique and shared antitumor effects of three statins in pancreatic cancer.

Statins, a class of commonly prescribed cholesterol­lowering medications, have been revealed to influence the risk of multiple types of cancer. However, the antitumor effects of statins on pancreatic cancer and their differential efficacy among a variety of statins are not currently well­defined. The aim of the present study was therefore to identify and compare the genes and related biological pathways that were affected by each individual statin on pancreatic cancer. Two human pancreatic cancer cell lines, MiaPaCa2 and PANC1, were exposed to three statins, lovastatin, fluvastatin and simvastatin. The inhibitory effect of statins on pancreatic cancer cell proliferation was first validated. Next, RNA­seq analysis was used to determine the gene expression alterations in either low (2 µM) or high (20 µM) statin concentration­treated cancer cells. Marked differences in gene transcription profiles of both pancreatic cancer cell lines exposed to high concentration statins were observed. Notably, the high concentration statins significantly suppressed core­gene CCNA2­associated cell cycle and DNA replication pathways and upregulated genes involved in ribosome and autophagy pathways. However, the low concentration statin­induced gene expression alterations were only detected in MiaPaCa2 cells. In conclusion, a marked difference in the intra and inter cell­type performance of pancreatic cancer cells exposed to a variety of statins at low or high concentrations was reported herein, which may provide insights for the potential clinical use of statins in future pancreatic cancer therapeutics.

Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma.

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.

Preliminary analysis of serum electrolytes and body mass index in patients with and without urolithiasis.

OBJECTIVES: To compare body mass index (BMI); serum parameters; and urine parameters between patients with and without urolithiasis. METHODS: Data from 1164 patients admitted to our Department of Urology from January 2011 to July 2013 were retrospectively reviewed; 714 patients (age, 5-87 years; male:female ratio, 1.8:1) exhibited urolithiasis, and 450 patients (age, 12-94 years; male:female ratio, 3.8:1) did not. Blood and urine were collected from patients the morning after hospital admission. Serum and urine parameters were checked by an automatic biochemistry analyzer. Statistical analysis included the Mann-Whitney U test and binary logistic regression. RESULTS: Serum sodium, potassium, chloride, calcium, phosphorus, and carbon dioxide combining power significantly differed between groups. In male patients, serum sodium, calcium, and phosphorus levels were higher in the urolithiasis group, whereas serum potassium and urine pH levels were lower. In female patients, serum sodium was higher in the urolithiasis group. BMI was higher in the urolithiasis group in all patients, male and female. Respective ß-values of serum sodium and BMI in male patients were 0.077 and 0.084; in female patients, these values were 0.119 and 0.102. CONCLUSIONS: Changes in serum sodium and BMI may be involved in the pathogenesis and treatment of urolithiasis.