Towards a microfluidic H295R steroidogenesis assay-biocompatibility study and steroid detection on a thiol-ene-based chip.

The development of cell-based microfluidic assays offers exciting new opportunities in toxicity testing, allowing for integration of new functionalities, automation, and high throughput in comparison to traditional well-plate assays. As endocrine disruption caused by environmental chemicals and pharmaceuticals represents a growing global health burden, the purpose of the current study was to contribute towards the miniaturization of the H295R steroidogenesis assay, from the well-plate to the microfluidic format. Microfluidic chip fabrication with the established well-plate material polystyrene (PS) is expensive and complicated; PDMS and thiol-ene were therefore tested as potential chip materials for microfluidic H295R cell culture, and evaluated in terms of cell attachment, cell viability, and steroid synthesis in the absence and presence of collagen surface modification. Additionally, spike-recovery experiments were performed, to investigate potential steroid adsorption to chip materials. Cell aggregation with poor steroid recoveries was observed for PDMS, while cells formed monolayer cultures on the thiol-ene chip material, with cell viability and steroid synthesis comparable to cells grown on a PS surface. As thiol-ene overall displayed more favorable properties for H295R cell culture, a microfluidic chip design and corresponding cell seeding procedure were successfully developed, achieving repeatable and uniform cell distribution in microfluidic channels. Finally, H295R perfusion culture on thiol-ene chips was investigated at different flow rates (20, 10, and 2.5 µL/min), and 13 steroids were detected in eluting cell medium over 48 h at the lowest flow rate. The presented work and results pave the way for a time-resolved microfluidic H295R steroidogenesis assay.

Dermal epidermal junction detection for full-field optical coherence tomography data of human skin by deep learning.

Full-field optical coherence tomography (FF-OCT) has been developed to obtain three-dimensional (3D) OCT data of human skin for early diagnosis of skin cancer. Detection of dermal epidermal junction (DEJ), where melanomas and basal cell carcinomas originate, is an essential step for skin cancer diagnosis. However, most existing DEJ detection methods consider each cross-sectional frame of the 3D OCT data independently, leaving the relationship between neighboring frames unexplored. In this paper, we exploit the continuity of 3D OCT data to enhance DEJ detection. In particular, we propose a method for noise reduction of the training data and a multi-directional convolutional neural network to predict the probability of epidermal pixels in the 3D OCT data, which is more stable than one-directional convolutional neural network for DEJ detection. Our crosscheck refinement method also exploits the domain knowledge to generate a smooth DEJ surface. The average mean error of the entire DEJ detection system is approximately 6 µm.

Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation.

Major limitations of camptothecin anticancer drugs (toxicity, nonselectivity, water insolubility, inactivation by human serum albumin) may be improved by creating glucuronide prodrugs that rely on beta-glucuronidase for their activation. We found that the camptothecin derivative 5,6-dihydro-4H-benzo[de]quinoline-camptothecin (BQC) displays greater cytotoxicity against cancer cells than the clinically used camptothecin derivatives SN-38 and topotecan even in the presence of human serum albumin. We synthesized the prodrug BQC-glucuronide (BQC-G), which was 4000 times more water soluble and 20-40 times less cytotoxic than BQC. Importantly, even in the presence of human serum albumin, BQC-G was efficiently hydrolyzed by beta-glucuronidase and produced greater cytotoxicity (IC50 = 13 nM) than camptothecin, 9-aminocamptothecin, SN-38, or topotecan (IC50 > 3000, 1370, 48, and 28 nM, respectively). BQC-G treatment of mice bearing human colon cancer xenografts with naturally or artificially elevated beta-glucuronidase activity produced significant antitumor activity, showing that BQC-G is a potent prodrug suitable for selective intratumoral drug activation.

Nephrotoxic Polypharmacy and Risk of Contrast Medium-Induced Nephropathy in Hospitalized Patients Undergoing Contrast-Enhanced CT.

OBJECTIVE: For unknown reasons, there is discordance among previous reports with regard to the association of contrast medium (CM) with nephropathy and the incidence of nephropathy after contrast-enhanced CT. This study aimed to determine the frequency of and possible factors related to CM-induced nephropathy in hospitalized patients, with an emphasis on detailing coprescriptions with nephrotoxic potential. MATERIALS AND METHODS: Of 1378 inpatients who underwent CT, 208 (15.1%) met the inclusion criteria: receipt of IV iodinated CM and baseline serum creatinine level obtained within 45 days before and within 2 weeks after CT. Patient demographics, clinical characteristics, comorbidity, nephrotoxic comedications (nine classes of drugs), and type of CM administered were retrospectively reviewed. Relationships between CM-induced nephropathy (serum creatinine level increase ≥ 25% or ≥ 0.5 mg/dL after CT) and risk factors were assessed by stepwise multivariate logistic regression. RESULTS: The cohort of 208 subjects had a high number of comorbidities (mean [± SD], 5.8 ± 3.5 diagnoses) and a high rate of receiving nephrotoxic comedications (45.2%). CM-induced nephropathy was detected in 27 (13.0%) patients. Concurrent use of four nephrotoxic agents (odds ratio [OR], 26.250; 95% CI, 3.673-233.993) was the most influential factor associated with CM-induced nephropathy; other predictors included preexisting renal disease (OR, 8.218; 95% CI, 1.622-42.357), baseline serum creatinine level less than 0.7 or greater than or equal to 1.3 mg/dL (OR, 3.463; 95% CI, 1.341-9.025), and hemoglobin level less than 9.3 g/dL (OR, 3.141; 95% CI, 1.087-8.946). CONCLUSION: Among the known risk factors, such as preexisting renal disease, high serum creatinine level, and low hemoglobin level, a statistically significant association was identified between CM-induced nephropathy and concurrent receipt of four nephrotoxic medications. Relevant preventive measures are warranted for individuals at risk, especially hospitalized patients receiving multiple nephrotoxic medications who require contrast-enhanced CT.

Economic benefits of sponsored clinical trials on pharmaceutical expenditures at a medical center in Taiwan.

Concerns exist regarding the additional cost of patient care when patients are enrolled in clinical trials at hospitals. To assess the avoidance of drug costs by conducting sponsored clinical trials, a retrospective analysis evaluating drug cost avoidance in all sponsored clinical trials was conducted in 2008 at the most prominent medical center in Taiwan. The National Health Insurance (NHI) reimbursement prices of either the investigated drugs or the standardized drug therapy for each specific disease were used to calculate the cost avoidance. Drug cost avoidance from sponsored clinical trials per year, per trial, per patient, in different therapeutic areas, and in different phases was analyzed. Three quarters of the cost avoidance in drug expenditures from 194 sponsored clinical trials were estimated. All cost values are in US Dollars. Around $11.2 million was avoided at the center in 2008. The average value of cost avoidance was $58,000/trial-year or $3,900/participant-year. The early-phase trials and phase III trials accounted for 25% and 56% of all trials, respectively, while they constituted 32% and 49% of the total costs avoided, respectively. The most frequently conducted and highest cost-avoiding trials were those for antineoplastic agents, especially targeted therapy which accounted for 85% of the total cost avoidance of anti-cancer trials. This study demonstrates the profoundly positive economic impact on the healthcare system in Taiwan by sponsored clinical trials. To understand the trend of economic benefits of the trials on pharmaceutical expenditure, it would be important to analyze the cost avoidance of trials regularly in an institution.

Adherence to "Doing-the-month" practices is associated with fewer physical and depressive symptoms among postpartum women in Taiwan.

According to traditional Chinese custom, women should be confined to home and assisted with tasks for 1 month after giving birth to a child. This restrictive regimen is referred to as doing-the-month. The objectives of this study were to describe adherence to doing-the-month practices and to explore the association between adherence to doing-the-month practices and physical symptoms and depression among postpartum women in Taiwan. Participants were 202 women at 4-6 weeks after delivery. Adherence to doing-the-month practices was associated with lower severity of physical symptoms and lower odds of postnatal depression, after adjustment for potential confounders. Adherence to doing-the-month practices was associated with better health status among postpartum women in Taiwan.

SV40 T/t-common polypeptide specifically induces apoptosis in human cancer cells that overexpress HER2/neu.

Previously, we reported that SV40 T/t-common polypeptide, which contains the NH(2)-terminal common domain of SV40 large T and small t antigens, can repress HER2/neu (also known as erbB-2) expression and consequently suppress the tumorigenic potential of the HER2/neu-overexpressing ovarian carcinoma cells. Here we report that T/t-common could specifically induce apoptosis in HER2/neu-overexpressing human cancer cell lines but not in nontransformed cell lines and HER2/neu low-expressing human cancer cell lines. The ability of T/t-common to induce apoptosis in HER2/neu-overexpressing cancer cells was derived from its ability to inhibit HER2/neu because reexpression of a large amount of HER2/neu could block apoptosis induced by T/t-common. T/t-common expression in HER2/neu-overexpressing SK-OV-3 cancer cells led to down-regulation of Bcl-2 and Bcl-X(L), and overexpression of Bcl-2 could inhibit the ability of T/t-common to induce apoptosis in these cells. Therefore, the apoptosis-inducing activity of T/t-common is related to its ability to inhibit Bcl-2 expression in HER2/neu-overexpressing cancer cells. Consistent with the apoptosis-inducing activity of T/t-common, we found that T/t-common could specifically inhibit the soft-agarose colony-forming ability of the HER2/neu-overexpressing human cancer cell lines but not that of the HER2/neu low-expressing human cancer cell lines. Finally, we showed that T/t-common could specifically sensitize HER2/neu-overexpressing human cancer cell lines, but not HER2/neu low-expressing human cancer cell lines, to chemotherapeutic agent etoposide. Together, these data suggest that T/t-common alone or in combination with chemotherapy may provide a new approach for treatment of cancers that overexpress HER2/neu.