Effect of particle size on liver MRI R 2 * relaxometry: Monte Carlo simulation and phantom studies.

PURPOSE: To investigate the effect of particle size on liver R 2 * $$ {\mathrm{R}}_2^{\ast } $$ by Monte Carlo simulation and phantom studies at both 1.5 T and 3.0 T. METHODS: Two kinds of particles (i.e., iron sphere and fat droplet) with varying sizes were considered separately in simulation and phantom studies. MRI signals were synthesized and analyzed for predicting R 2 * $$ {\mathrm{R}}_2^{\ast } $$ , based on simulations by incorporating virtual liver model, particle distribution, magnetic field generation, and proton movement into phase accrual. In the phantom study, iron-water and fat-water phantoms were constructed, and each phantom contained 15 separate vials with combinations of five particle concentrations and three particle sizes. R 2 * $$ {\mathrm{R}}_2^{\ast } $$ measurements in the phantom were made at both 1.5 T and 3.0 T. Finally, differences in R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions or measurements were evaluated across varying particle sizes. RESULTS: In the simulation study, strong linear and positively correlated relationships were observed between R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions and particle concentrations across varying particle sizes and magnetic field strengths ( r ≥ 0.988 $$ r\ge 0.988 $$ ). The relationships were affected by iron sphere size ( p < 0.001 $$ p<0.001 $$ ), where smaller iron sphere size yielded higher predicted R 2 * $$ {\mathrm{R}}_2^{\ast } $$ , whereas fat droplet size had no effect on R 2 * $$ {\mathrm{R}}_2^{\ast } $$ predictions ( p ≥ 0.617 $$ p\ge 0.617 $$ ) for constant total fat concentration. Similarly, the phantom study showed that R 2 * $$ {\mathrm{R}}_2^{\ast } $$ measurements were relatively sensitive to iron sphere size ( p ≤ 0.004 $$ p\le 0.004 $$ ) unlike fat droplet size ( p ≥ 0.223 $$ p\ge 0.223 $$ ). CONCLUSION: Liver R 2 * $$ {\mathrm{R}}_2^{\ast } $$ is affected by iron sphere size, but is relatively unaffected by fat droplet size. These findings may lead to an improved understanding of the underlying mechanisms of R 2 * $$ {\mathrm{R}}_2^{\ast } $$ relaxometry in vivo, and enable improved quantitative MRI phantom design.

miR-769-3p inhibits cellular proliferation of KSHV-infected SH-SY5Y cells through targeting mTOR.

The infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the most common causes of death in AIDS patients. Our studies have found that KSHV can infect SH-SY5Y cells (named SK-RG) in vivo and mTOR was up-regulated, which results in remarkable enhancement of cell proliferation, migration. But the regulatory role of mTOR in KSHV infected neurons has not yet been fully elucidated. Here, we find that miR-769-3p is decreased in SK-RG cells, which can exert anti-KSHV effect through negatively regulating the expression of mTOR. The knockdown of mTOR or overexpress of miR-769-3p decreased the proliferation, migration ability and cell cycle related protein of SK-RG cells, and the expression of KSHV related genes. In contrast, activating mTOR function by 3BDO treatment weakened the cellular behaviors of miR-769-3p overexpressing cells. Meanwhile, overexpressed miR-769-3p and rapamycin showed a shared inhibition trend in the effects on cell proliferation and motility. Our data indicated that miR-769-3p can inhibit cell proliferation and migration by down regulating mTOR in KSHV infected SH-SY5Y cells, and can be a candidate molecule for anti-KSHV therapy.

Diagnostic accuracy and cellular origin of pleural fluid CXCR3 ligands for tuberculous pleural effusion.

BACKGROUND: Pleural biomarkers represent potential diagnostic tools for tuberculous pleural effusion (TPE) due to their advantages of low cost, short turnaround time, and less invasiveness. This study evaluated the diagnostic accuracy of two CXCR3 ligands, C-X-C motif chemokine ligand 9 (CXCL9) and CXCL11, for TPE. In addition, we investigated the cellular origins and biological roles of CXCL9 and CXCL11 in the development of TPE. METHODS: This double-blind study prospectively enrolled patients with undiagnosed pleural effusion from two centers (Hohhot and Changshu) in China. Pleural fluid on admission was obtained and levels of CXCL9 and CXCL11 were measured by an enzyme-linked immunosorbent assay (ELISA). The receiver operating characteristic (ROC) curve and the decision curve analysis (DCA) were used to evaluate their diagnostic accuracy and net benefit, respectively. THP-1 cell-derived macrophages were treated with Bacillus Calmette-Guérin (BCG), and quantitative real-time PCR (qRT-PCR) and ELISA were used to determine the mRNA and protein levels of CXCL9 and CXCL11. The chemoattractant activities of CXCL9 and CXCL11 for T helper (Th) cells were analyzed by a transwell assay. RESULTS: One hundred and fifty-three (20 TPEs and 133 non-TPEs) patients were enrolled in the Hohhot Center, and 58 (13 TPEs and 45 non-TPEs) were enrolled in the Changshu Center. In both centers, we observed increased CXCL9 and CXCL11 in TPE patients. The areas under the ROC curves (AUCs) of pleural CXCL9 and CXCL11 in the Hohhot Center were 0.70 (95 % CI: 0.55-0.85) and 0.68 (95 % CI: 0.52-0.84), respectively. In the Changshu Center, the AUCs of CXCL9 and CXCL11 were 0.96 (95 % CI: 0.92-1.00) and 0.97 (95 % CI: 0.94-1.00), respectively. The AUCs of CXCL9 and CXCL11 decreased with the advancement of age. The decision curves of CXCL9 and CXCL11 showed net benefits in both centers. CXCL9 and CXCL11 were upregulated in BCG-treated macrophages. Pleural fluid from TPE and conditioned medium from BCG-treated macrophages were chemotactic for Th cells. Anti-CXCL9 or CXCL11 neutralizing antibodies could partly block the chemotactic activity. CONCLUSIONS: Pleural CXCL9 and CXCL11 are potential diagnostic markers for TPE, but their diagnostic accuracy is compromised in elderly patients. CXCL9 and CXCL11 can promote the migration of peripheral Th cells, thus representing a therapeutic target for the treatment of TPE.

Pleural fluid carbohydrate antigen 72-4 and malignant pleural effusion: a diagnostic test accuracy study.

BACKGROUND: The prognosis of malignant pleural effusion (MPE) is poor. A timely and accurate diagnosis is the prerequisite for managing MPE patients. Carbohydrate antigen 72-4 (CA72-4) is a diagnostic tool for MPE. OBJECTIVE: We aimed to evaluate the diagnostic accuracy of pleural fluid CA72-4 for MPE. DESIGN: A prospective, preregistered, and double-blind diagnostic test accuracy study. METHODS: We prospectively enrolled participants with undiagnosed pleural effusions from two centers in China (Hohhot and Changshu). CA72-4 concentration in pleural fluid was measured by electrochemiluminescence. Its diagnostic accuracy for MPE was evaluated by a receiver operating characteristic (ROC) curve. The net benefit of CA72-4 was determined by a decision curve analysis (DCA). RESULTS: In all, 153 participants were enrolled in the Hohhot cohort, and 58 were enrolled in the Changshu cohort. In both cohorts, MPE patients had significantly higher CA72-4 levels than benign pleural effusion (BPE) patients. At a cutoff value of 8 U/mL, pleural fluid CA72-4 had a sensitivity, specificity, and area under the ROC curve (AUC) of 0.46, 1.00, and 0.79, respectively, in the Hohhot cohort. In the Changshu cohort, CA72-4 had a sensitivity, specificity, and AUC of 0.27, 0.94, and 0.86, respectively. DCA revealed the relatively high net benefit of CA72-4 determination. In patients with negative cytology, the AUC of CA72-4 was 0.67. CONCLUSION: Pleural fluid CA72-4 helps differentiate MPE and BPE in patients with undiagnosed pleural effusions.

Value of human epididymis secretory protein 4 in differentiating malignant from benign pleural effusion: an analysis of two cohorts.

BACKGROUND: Lung cancer is the most common cause of malignant pleural effusion (MPE). Serum human epididymis secretory protein 4 (HE4) is a useful diagnostic marker for lung cancer. OBJECTIVE: This study aimed to evaluate the diagnostic accuracy of pleural fluid HE4 for MPE. DESIGN: A prospective, double-blind diagnostic test accuracy study. METHODS: Patients with undiagnosed pleural effusion were enrolled in two cohorts (Hohhot and Changshu). Electrochemiluminescence immunoassay was used to detect pleural fluid HE4. The diagnostic accuracy of HE4 was evaluated by a receiver operating characteristic (ROC) curve, and the net benefit of HE4 was assessed by a decision curve analysis (DCA). RESULTS: A total of 66 MPEs and 86 benign pleural effusions (BPEs) were enrolled in the Hohhot cohort. In the Changshu cohort, 26 MPEs and 32 BPEs were enrolled. In both cohorts, MPEs had significantly higher pleural fluid HE4 than BPEs. The area under the ROC curve (AUC) of HE4 was 0.73 (95% CI: 0.64-0.81) in the Hohhot cohort and 0.79 (95% CI: 0.67-0.91) in the Changshu cohort. At a threshold of 1300 pmol/L, HE4 had sensitivities of 0.44 (95% CI: 0.33-0.56) in the Hohhot cohort and 0.54 (95% CI: 0.35-0.73) in the Changshu cohort. The corresponding specificities were 0.90 (95% CI: 0.83-0.95) in the Hohhot cohort and 0.94 (95% CI: 0.84-1.00) in the Changshu cohort. In subgroup analyses, HE4 had an AUC (95% CI) of 0.78 (0.71-0.85) in exudates and an AUC of 0.69 (0.57-0.81) in patients with negative effusion cytology. The DCA revealed that HE4 determination had a net benefit in both cohorts. CONCLUSION: Pleural fluid HE4 has moderate diagnostic accuracy for MPE and has net benefit in pleural effusion patients with unknown etiology.

Computing tensor Z-eigenpairs via an alternating direction method.

Tensor eigenproblems have wide applications in blind source separation, magnetic resonance imaging, and molecular conformation. In this study, we explore an alternating direction method for computing the largest or smallest Z-eigenvalue and corresponding eigenvector of an even-order symmetric tensor. The method decomposes a tensor Z-eigenproblem into a series of matrix eigenproblems that can be readily solved using off-the-shelf matrix eigenvalue algorithms. Our numerical results show that, in most cases, the proposed method converges over two times faster and could determine extreme Z-eigenvalues with 20-50% higher probability than a classical power method-based approach.

Age affects the diagnostic accuracy of the cancer ratio for malignant pleural effusion.

BACKGROUND AND OBJECTIVE: Cancer ratio (CR), which is defined as serum lactate dehydrogenase (LDH) to pleural fluid adenosine deaminase (ADA) ratio, has been reported to be a useful diagnostic marker for malignant pleural effusion (MPE). Whether its diagnostic accuracy is affected by age remains unknown. This study aimed to investigate the effects of age on the diagnostic accuracy of CR. METHODS: The participants in this study were from a prospective cohort (SIMPLE cohort, n = 199) and a retrospective cohort (BUFF cohort, n = 158). All participants were patients with undiagnosed pleural effusion (PE). We used receiver operating characteristic (ROC) curves to evaluate the diagnostic accuracy of CR. The effect of age on the diagnostic accuracy of CR was investigated by adjusting the upper limit of age for participant enrolment. RESULTS: Eighty-eight MPE patients were verified in the SIMPLE cohort, and thirty-five MPE patients were verified in the BUFF cohort. The AUCs of CR in the SIMPLE and BUFF cohorts were 0.60 (95% CI: 0.52-0.68) and 0.63 (95% CI: 0.54-0.71), respectively. In both cohorts, the AUCs of CR decreased with the advancement of age. CONCLUSION: Age can affect the diagnostic accuracy of CR for MPE. CR has limited diagnostic value in older patients. KEY MESSAGE: Cancer ratio is a promising diagnostic marker for malignant pleural effusion. This study revealed that its diagnostic accuracy decreased in older patients. Its diagnostic accuracy is overestimated by previous studies using tuberculosis and pneumonia patients as controls.

Long-term stability of pleural fluid carcinoembryonic antigen and its effect on the diagnostic accuracy for malignant pleural effusion.

BACKGROUND: The in vitro stability assessment is essential for investigating the diagnostic accuracy of pleural biomarkers. This study aimed to investigate the long-term stability of pleural fluid carcinoembryonic antigen (CEA) at -80°C to -70°C. In addition, we analyzed the effects of frozen storage on the diagnostic accuracy of CEA for malignant pleural effusion (MPE). METHODS: Pleural fluid CEA of participants in two prospective cohorts were stored at -80°C to -70°C for 1-3 years. The CEA level in the stored specimen was measured with an immunoassay, and its level in the fresh specimen was extracted from medical records. The Bland-Altman method, Passing-Bablok regression, and Deming regression were used to analyze the agreement of CEA between the fresh and frozen pleural fluid. In addition, we used receiver operating characteristic (ROC) curves to evaluate the diagnostic accuracy of CEA in the fresh and frozen specimens for MPE. RESULTS: A total of 210 participants were enrolled. The median CEA levels in frozen and fresh pleural fluid specimens were similar (frozen, 2.32 ng/mL; fresh, 2.59 ng/mL; p < 0.01). The slopes and intercepts in the Passing-Bablok regression (intercept 0.01, slope 1.04) and Deming regression (intercept 0.65; slope 1.00) were not statistically significant (p > 0.05 for all). No significant difference was observed between the area under the ROC curves of CEA in the fresh and frozen specimens (p > 0.05 for all). CONCLUSION: Pleural fluid CEA is seemingly stable when stored at -80°C to -70°C for 1-3 years. Frozen storage does not significantly affect the diagnostic accuracy of CEA for MPE.

Diagnostic accuracy of pleural fluid to serum carcinoembryonic antigen ratio and delta value for malignant pleural effusion: findings from two cohorts.

BACKGROUND: Pleural fluid (PF) carcinoembryonic antigen (CEA) is a widely used diagnostic marker for malignant pleural effusion (MPE). Recent studies revealed that PF to serum CEA was also a promising diagnostic parameter for MPE. OBJECTIVE: We aimed to investigate whether PF to serum CEA ratio and delta CEA (PF minus serum CEA) provided added value to PF CEA in diagnosing MPE. METHODS: Patients with pleural effusion in a retrospective cohort (BUFF) and a prospective cohort (SIMPLE) were included. The clinical characteristics of the patients were extracted from their medical records. The diagnostic value of CEA ratio and delta CEA was estimated by a receiver operating characteristics (ROC) curve, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: A total of 148 patients in the BUFF cohort and 164 patients in the SIMPLE cohort were enrolled. The BUFF cohort had 46 MPE patients and 102 benign pleural effusion (BPE) patients, and the SIMPLE cohort had 85 MPE patients and 79 BPE patients. In both cohorts, MPE patients had significantly higher PF CEA, serum CEA, CEA ratio, and delta CEA. The area under ROC curves (AUCs) of PF CEA, CEA ratio, and delta CEA were 0.78 (95% CI: 0.67-0.88), 0.80 (95% CI: 0.72-0.89) and 0.83 (95% CI: 0.75-0.91) in the BUFF cohort, and 0.89 (95% CI: 0.83-0.94), 0.86 (95% CI: 0.80-0.92), and 0.84 (95% CI: 0.78-0.91) in the SIMPLE cohort. The differences between the AUCs of PF CEA, CEA ratio, and delta CEA did not reach statistical significance. The continuous NRI and IDI of CEA ratio and delta CEA were <0. CONCLUSION: CEA ratio and delta value cannot provide added diagnostic value to PF CEA. The simultaneous determination of serum and PF CEA should not be adopted in clinical practice.

Pleural fluid soluble Fas ligand and tuberculous pleural effusion: a prospective diagnostic test accuracy study.

Background: The diagnosis of tuberculous pleural effusion (TPE) is challenging for pulmonologists. Adenosine deaminase (ADA), interferon-gamma (IFN-γ), and interleukin-27 (IL-27) have some limitations for diagnosing TPE. Soluble Fas ligand (sFasL) had a high diagnostic value for TPE. However, it remains unknown: (I) whether sFasL has an additional diagnostic value to the traditional markers (e.g., ADA); (II) whether sFasL provides a net benefit in patients with undiagnosed pleural effusion; (III) factors affecting the diagnostic accuracy of sFasL for TPE. This study aimed to evaluate the additional diagnostic value and benefit of pleural fluid sFasL for TPE. Methods: We prospectively enrolled 211 patients with undiagnosed pleural effusion. The concentration of sFasL in pleural fluid was measured by an enzyme-linked immunosorbent assay (ELISA). The diagnostic accuracy and net benefit of sFasL and ADA for TPE were analyzed by a receiver operating characteristic (ROC) curve, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discriminant improvement (IDI). Results: The area under the ROC curves (AUCs) of sFasL and ADA were 0.74 (95% CI: 0.65-0.83) and 0.80 (95% CI: 0.71-0.90), respectively. The decision curve of sFasL revealed net benefit. The continuous NRI and IDI of sFasL were 0.36 (0.00-0.72, P=0.05) and 0.02 (-0.01-0.06, P=0.18), respectively. Conclusions: Pleural fluid sFasL has moderate diagnostic accuracy for TPE.

Diagnostic accuracy of pleural fluid lactate dehydrogenase to adenosine deaminase ratio for tuberculous pleural effusion: an analysis of two cohorts.

BACKGROUND: This study aimed to evaluate the diagnostic accuracy of pleural fluid (PF) lactate dehydrogenase (LDH) to adenosine deaminase (ADA) (LDH/ADA) ratio for tuberculous pleural effusion (TPE). Especially to explore whether the LDH/ADA ratio provides added diagnostic value to ADA. METHODS: The diagnostic accuracy of PF LDH/ADA ratio and ADA for TPE was evaluated in two cohorts, named the BUFF (Biomarkers for patients with Undiagnosed pleural eFFusion) cohort (62 with TPE and 194 with non-TPE) and the SIMPLE (a Study Investigating Markers in PLeural Effusion) cohort (33 with TPE and 177 with non-TPE). Receiver operating characteristic (ROC) curve and decision curve were used to measure the diagnostic accuracy of the PF LDH/ADA ratio. The added diagnostic value of the LDH/ADA ratio to ADA was evaluated with net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: The area under the ROC curves (AUCs) of PF ADA and LDH/ADA ratio in the BUFF cohort were 0.76 and 0.74, respectively. In the SIMPLE cohort, the AUCs of PF ADA and LDH/ADA ratio were 0.80 and 0.85, respectively. The decision curves of PF LDH/ADA and ADA were close in both the BUFF and SIMPLE cohorts. The NRI and IDI analyses did not reveal any added diagnostic value of LDH/ADA to ADA. CONCLUSIONS: PF LDH/ADA ratio has moderate diagnostic accuracy for TPE. It does not provide added diagnostic value beyond ADA. The current evidence does not support LDH/ADA ratio for diagnosing TPE.

Pleural homocysteine for malignant pleural effusion: A prospective and double-blind diagnostic test accuracy study.

OBJECTIVE: To assess the accuracy of pleural fluid homocysteine for discriminating malignant pleural effusion (MPE) and benign pleural effusion (BPE). METHODS: A total of 194 patients from two cohorts (Hohhot and Changshu) with undiagnosed pleural effusion were prospectively enrolled. Their pleural homocysteine was measured, and its diagnostic accuracy and net benefit for MPE were analyzed by receiver operating characteristic (ROC) curve analysis and decision curve analysis, respectively. RESULTS: In the Hohhot cohort (n = 136) and the Changshu cohort (n = 58), MPE patients had significantly higher homocysteine levels than BPE patients. The areas under the ROC curves of homocysteine for the diagnosis of MPE were 0.61 (p = 0.027) and 0.59 (p = 0.247), respectively. The decision curves of homocysteine were close to the reference line in both the Hohhot cohort and the Changshu cohort. CONCLUSION: The diagnostic accuracy of pleural fluid homocysteine for MPE was low.

Evaluation on the generalization of a learned convolutional neural network for MRI reconstruction.

Recently, deep learning approaches with various network architectures have drawn significant attention from the magnetic resonance imaging (MRI) community because of their great potential for image reconstruction from undersampled k-space data in fast MRI. However, the robustness of a trained network when applied to test data deviated from training data is still an important open question. In this work, we focus on quantitatively evaluating the influence of image contrast, human anatomy, sampling pattern, undersampling factor, and noise level on the generalization of a trained network composed by a cascade of several CNNs and a data consistency layer, called a deep cascade of convolutional neural network (DC-CNN). The DC-CNN is trained from datasets with different image contrast, human anatomy, sampling pattern, undersampling factor, and noise level, and then applied to test datasets consistent or inconsistent with the training datasets to assess the generalizability of the learned DC-CNN network. The results of our experiments show that reconstruction quality from the DC-CNN network is highly sensitive to sampling pattern, undersampling factor, and noise level, which are closely related to signal-to-noise ratio (SNR), and is relatively less sensitive to the image contrast. We also show that a deviation of human anatomy between training and test data leads to a substantial reduction of image quality for the brain dataset, whereas comparable performance for the chest and knee dataset having fewer anatomy details than brain images. This work further provides some empirical understanding of the generalizability of trained networks when there are deviations between training and test data. It also demonstrates the potential of transfer learning for image reconstruction from datasets different from those used in training the network.

Effect and mechanism of ethanol extracts of muxiang (Radix Aucklandiae) on gastric ulcers in rats.

OBJECTIVE: To investigate the effect of ethanol extracts of Muxiang (Radix Aucklandiae) (RA) on gastric ulcers in rats and explore the potential mechanisms. METHODS: A model was established by ethanol (0.75 mL/kg). According to body weight, rats were pretreated with RA extracts (2.5 or 5 g/kg). The rats were administered 95% ethanol orally after 1 h. The effects of ethanol were evaluated by measuring the gastric secretion volume, pH, pepsin activity, and ulcer area. Histological analysis and immunohistochemistry were also conducted. Furthermore, the effect of the ethanol extract of RA on transiting activity of the gastrointestinal tract was observed in mice. RESULTS: Intragastric administration of RA extracts protected the gastric mucosa from ethanol-induced gastric ulcers, while reducing submucosal edema and preventing hemorrhagic damage. Moreover, the extracts increased the production of gastric mucus, upregulated Bcl-2, and downregulated Bax expression. Importantly, pretreated rats exhibited no significant change in the gastric secretion volume, gastric juice acidity, or pepsin. Furthermore, pretreatment prominently (P < 0.05) enhanced propulsive movement of the gastrointestinal tract in normal mice and mice with gastrointestinal motility disorders. CONCLUSION: Ethanol extracts of RA ameliorated gastric lesions in the gastric ulcer rat model. The mechanisms of action were related to improvement of gastrointestinal dynamics, maintenance of mucus integrity, and inhibition of apoptosis by downregulating proapoptotic Bax protein and upregulating anti-apoptotic Bcl-2 protein.

A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer.

Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m2) or S-1 (30 mg/m2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71-1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80-2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.

A Drug-Drug Interaction Study to Evaluate the Effect of TAS-303 on CYP3A Activity in the Small Intestine and Liver.

TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride) is a novel selective noradrenaline reuptake inhibitor being developed for the treatment of stress urinary incontinence. An in vitro study and a physiologically based pharmacokinetic model simulation showed that TAS-303 had inhibitory potential against cytochrome P450 (CYP) 3A. This open-label, single-group study investigated the effect of TAS-303 on CYP3A activity by evaluating the pharmacokinetics (PK) of single-dose oral simvastatin 5 mg or intravenous midazolam 1 mg after repeated oral administration of TAS-303 3 mg in 12 healthy participants. TAS-303 plus simvastatin resulted in a 1.326-fold and a 1.420-fold increase of simvastatin in peak plasma concentration and area under the plasma concentration-time curve from time zero to time t, where t is the final time of detection (AUC0-t ), respectively. The addition of midazolam resulted in a 1.090-fold increase in the midazolam AUC0-t . TAS-303 had a weak PK interaction with simvastatin but no apparent interaction with midazolam. TAS-303 at 3 mg/day is a weak inhibitor of intestinal but not hepatic CYP3A activity. No clinically important safety concerns related to TAS-303 were raised.

Safety, Tolerability, Pharmacokinetics, and Food Effects on TAC-302 in Healthy Participants: Randomized, Double-Blind, Placebo-Controlled, Single-Dose and Multiple-Dose Studies.

TAC-302 stimulates neurite outgrowth activity and is expected to restore urinary function in patients with lower urinary tract dysfunction. We conducted 2 phase 1, randomized, placebo-controlled studies to confirm the safety and pharmacokinetics (PK) of TAC-302 in healthy adult Japanese male volunteers. In the first-in-human single-dose study (n = 60), TAC-302 was administered at doses from 100 to 1200 mg after an overnight fast. The effects of a meal on the PK of TAC-302 400 mg were also examined. A multiple-dose study (n = 36) evaluated the effects of meal fat content on the PK of single doses of TAC-302 (100, 200, or 400 mg) and multiple doses of TAC-302 administered for 5 days (100, 200, and 400 mg twice daily). TAC-302 showed linear PK up to doses of 1200 mg in the fasting state, and across the dose range of 100-400 mg in the fed state. No accumulation of TAC-302 was observed. Food, particularly with high fat content, increased TAC-302 plasma concentrations. No differences were observed in the adverse event incidence between the TAC-302 and placebo groups in either study. TAC-302 showed a wide safety margin.

Orthogonal tensor dictionary learning for accelerated dynamic MRI.

A direct application of the compressed sensing (CS) theory to dynamic magnetic resonance imaging (MRI) reconstruction needs vectorization or matricization of the dynamic MRI data, which is composed of a stack of 2D images and can be naturally regarded as a tensor. This 1D/2D model may destroy the inherent spatial structure property of the data. An alternative way to exploit the multidimensional structure in dynamic MRI is to employ tensor decomposition for dictionary learning, that is, learning multiple dictionaries along each dimension (mode) and sparsely representing the multidimensional data with respect to the Kronecker product of these dictionaries. In this work, we introduce a novel tensor dictionary learning method under an orthonormal constraint on the elementary matrix of the tensor dictionary for dynamic MRI reconstruction. The proposed algorithm alternates sparse coding, tensor dictionary learning, and updating reconstruction, and each corresponding subproblem is efficiently solved by a closed-form solution. Numerical experiments on phantom and synthetic data show significant improvements in reconstruction accuracy and computational efficiency obtained by the proposed scheme over the existing method that uses the 1D/2D model with overcomplete dictionary learning. Graphical abstract Fig. 1 Comparison between (a) the traditional method and (b) the proposed method based on dictionary learning for dynamic MRI reconstruction.

Sparsity-promoting orthogonal dictionary updating for image reconstruction from highly undersampled magnetic resonance data.

Image reconstruction from undersampled k-space data accelerates magnetic resonance imaging (MRI) by exploiting image sparseness in certain transform domains. Employing image patch representation over a learned dictionary has the advantage of being adaptive to local image structures and thus can better sparsify images than using fixed transforms (e.g. wavelets and total variations). Dictionary learning methods have recently been introduced to MRI reconstruction, and these methods demonstrate significantly reduced reconstruction errors compared to sparse MRI reconstruction using fixed transforms. However, the synthesis sparse coding problem in dictionary learning is NP-hard and computationally expensive. In this paper, we present a novel sparsity-promoting orthogonal dictionary updating method for efficient image reconstruction from highly undersampled MRI data. The orthogonality imposed on the learned dictionary enables the minimization problem in the reconstruction to be solved by an efficient optimization algorithm which alternately updates representation coefficients, orthogonal dictionary, and missing k-space data. Moreover, both sparsity level and sparse representation contribution using updated dictionaries gradually increase during iterations to recover more details, assuming the progressively improved quality of the dictionary. Simulation and real data experimental results both demonstrate that the proposed method is approximately 10 to 100 times faster than the K-SVD-based dictionary learning MRI method and simultaneously improves reconstruction accuracy.

[The mechanism of inhibition effect of adenovirus-mediated ING4 on human lung adenocarcinoma xenografts in nude mice].

BACKGROUND AND OBJECTIVE: The inhibitor of growth 4 (ING4) is an important tumor suppressive gene.It has been proven that ING4 could inhibite the proliferation of many tumors. e aim of this study is to investigate the inhibitory effect and anti-cancer mechanism of adenovirus-mediated ING4 gene on SPC-A1 human lung adenocarcinoma in nude mice. METHODS: A human lung adenocarcinoma xenograft model was established with SPC-A1 cells in nude mice. A total of 15 tumor-bearing nude mice were randomly divided into three groups, namely, PBS, Ad-GFP, and Ad-ING4. e mice in the three groups were intratumorally injected every other day. Their tumor volumes were continually recorded. The treatment tumors were then removed from the mice and weighed. Tumor inhibition rates were calculated. Cell apoptosis was examined by TUNEL method. Caspase-3, COX-2, Fas, and FasL expressions were investigated by immunohistochemistry SP assay. RESULTS: Both tumor weight and volume in the Ad-ING4 group were significantly decreased. The tumor inhibition rate of the mice in the Ad-ING4 group (33.17% ± 5.24%) was statistically different from that of the mice in the Ad-GFP group (1.31% ± 0.31%; P<0.05). The apoptotic index of the mice in the Ad-ING4 group (69.23% ± 6.53%) was also significantly different from those in PBS (17.04% ± 1.10%) and Ad-GFP groups (18.81% ± 1.93%; P<0.05). Based on immunohistochemistry SP assay, the results showed that Ad-ING4 may not only upregulate the expressions of caspase-3, Fas, and FasL but also downregulate the expression of COX-2. CONCLUSION: ING4 gene elicited a remarkable growth inhibitory e-ect on human lung adenocarcinoma xenografts in nude mice. e mechanism is possibly related to an increase in tumor cell apoptosis.