Design and Optimization of a Nanoparticulate Pore Former as a Multifunctional Coating Excipient for pH Transition-Independent Controlled Release of Weakly Basic Drugs for Oral Drug Delivery.

Bioavailability of weakly basic drugs may be disrupted by dramatic pH changes or unexpected pH alterations in the gastrointestinal tract. Conventional organic acids or enteric coating polymers cannot address this problem adequately because they leach out or dissolve prematurely, especially during controlled release applications. Thus, a non-leachable, multifunctional terpolymer nanoparticle (TPN) made of cross-linked poly(methacrylic acid) (PMAA)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) was proposed to provide pH transition-independent release of a weakly basic drug, verapamil HCl (VER), by a rationally designed bilayer-coated controlled release bead formulation. The pH-responsive PMAA and cross-linker content in the TPN was first optimized to achieve the largest possible increase in medium uptake alongside the smallest decrease in drug release rate at pH 6.8, relative to pH 1.2. Such TPNs maintained an acidic microenvironmental pH (pHm) when loaded in ethylcellulose (EC) films, as measured using pH-indicating dyes. Further studies of formulations revealed that with the 1:2 VER:TPN ratio and 19% coating weight gain, bilayer-coated beads maintained a constant release rate over the pH transition and exhibited extended release up to 18 h. These results demonstrated that the multifunctional TPN as a pHm modifier and pH-dependent pore former could overcome the severe pH-dependent solubility of weakly basic drugs.

Protodioscin inhibits bladder cancer cell migration and growth, and promotes apoptosis through activating JNK and p38 signaling pathways.

Bladder cancer is one of the most common malignancies of the male genitourinary urinary system. Protodioscin is a steroidal saponin with anti-cancer effects on several types of cancers; however, the anti-cancer activities of protodioscin on bladder cancer have not yet been investigated. Therefore, we aimed to examine the anti-cancer effects of protodioscin on bladder cancer. Two types of bladder cancer cell lines, non-muscle-invasive 5637 cells and muscle-invasive T24 cells, were used to evaluate the effects of protodioscin on cell growth, migration, invasion and epithelial-mesenchymal transition(EMT) marker expressions. Transcriptome analysis was performed by RNA-seq and validated using real-time PCR and western blot; additionally, an in vivo xenograft animal model was established and the anti-tumor effects of protodioscin were tested. Our results demonstrated that protodioscin inhibited cell proliferation, migration, motility and invasion on 5637 and T24 cells. Additionally, protodioscin also induced cell apoptosis and arrested the progression of cell cycle at G2 phase in bladder cancer cells. Moreover, protodioscin inhibited EMT through increased protein expression of E-cadherin and decreased protein expression of N-cadherin and vimentin. RNA-seq analysis indicated that protodioscin regulated mitogen-activated protein kinase(MAPK) and phosphoinositide 3-kinases(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR) signaling pathways as further verified by Western blot. Furthermore, protodioscin significantly inhibited tumor growth in vivo. Our results indicated that protodioscin inhibits cell growth, migration and invasion and induces apoptosis and G2 phase cell cycle arrest by activated p38 and JNK signaling pathways in bladder cancer cells, suggesting that protodioscin could be an effective agent for bladder cancer treatment.

A clinical observational study of effectiveness of a solid coupling medium in extracorporeal shock wave lithotripsy.

This study aimed to investigate clinical effectiveness of stone disintegration by using isolation coupling pad ("icPad") as coupling medium to reduce trapped air pockets during extracorporeal shock wave lithotripsy (ESWL). Patients underwent ESWL between Oct. 2017 and May 2018 were enrolled in this clinical observational study. An electromagnetic lithotripter (Dornier MedTech Europe GmbH Co., Germany) was used in this study. Patients were divided into icPad group P1, P2 and semi-gel group C by different coupling medium. The energy level and total number of shock wave (SW) for group P1 and C was set at level 2 and 3000 and group P2 at level 3 and 2500. The successful stone disintegration rate (SSDR) was determined to evaluate the treatment outcome. All patients were evaluated by KUB film and ultrasonography after 90 days. Complications during ESWL were recorded. A total of 300 patients satisfied the inclusion criteria. There were no significant differences in characteristics of patients and stone among three groups. The corresponding SSDRs for patients in group P1, P2 and C was 73.0%, 73.2% and 55.3%, respectively. The SSDR in group P1 was statistically higher than Group C. Comparing to semi-liquid gel, coupling medium using by icPad could achieve better treatment outcome of stone disintegration in ESWL.

Congenital collagenopathies increased the risk of inguinal hernia developing and repair: analysis from a nationwide population-based cohort study.

Herein, we aimed to explore whether male patients with congenital collagen diseases had a higher risk of inguinal herniation than patients without these diseases. Data were retrospectively collected from the National Health Insurance Research Database of Taiwan. The study cohort included 1,801 male patients diagnosed with congenital collagen diseases based on the ICD-9 CM diagnostic codes; after propensity score matching, the control group comprised 6,493 men without congenital collagen diseases. The primary endpoint was inguinal hernia repair during the observation period. During a median follow-up period of 133.9 months, the risk of inguinal herniation in the collagen group was significantly higher than that in the control group (HR = 2.237, 95% CI 1.646-3.291, p < 0.001). This phenomenon was observed in patients younger than 18 years (HR: 3.040, 95% CI 1.819-5.083, p < 0.001) and in those aged 18-80 years (HR: 1.909, 95% CI 1.186-3.073, p < 0.001). Asian men with congenital collagen diseases are at a high risk of developing inguinal hernias, regardless of age. Detailed physical examination and patient education should be performed for these patients to prevent inguinal herniation.

Genetic Analysis Reveals the Prognostic Significance of the DNA Mismatch Repair Gene MSH2 in Advanced Prostate Cancer.

DNA damage repair is frequently dysregulated in advanced prostate cancer and has been linked to cancer susceptibility and survival outcomes. The aim of this study is to assess the influence of genetic variants in DNA damage repair pathways on the prognosis of prostate cancer. Specifically, 167 single nucleotide polymorphisms (SNPs) in 18 DNA damage repair pathway genes were assessed for association with cancer-specific survival (CSS), overall survival (OS), and progression-free survival (PFS) in a cohort of 630 patients with advanced prostate cancer receiving androgen deprivation therapy. Univariate analysis identified four SNPs associated with CSS, four with OS, and two with PFS. However, only MSH2 rs1400633 C > G showed a significant association upon multivariate analysis and multiple testing adjustments (hazard ratio = 0.75, 95% confidence interval = 0.63-0.90, p = 0.002). Furthermore, rs1400633 risk allele C increased MSH2 expression in the prostate and other tissues, which correlated with more aggressive prostate cancer characteristics. A meta-analysis of 31 gene expression datasets revealed significantly higher MSH2 expression in prostate cancer than in normal tissues (p < 0.001), and this high expression was associated with a poor prognosis of prostate cancer (p = 0.002). In summary, we identified MSH2 rs1400633 as an independent prognostic biomarker for prostate cancer survival, and the association of MSH2 with cancer progression lends relevance to our findings.

Structural break-aware pairs trading strategy using deep reinforcement learning.

Pairs trading is an effective statistical arbitrage strategy considering the spread of paired stocks in a stable cointegration relationship. Nevertheless, rapid market changes may break the relationship (namely structural break), which further leads to tremendous loss in intraday trading. In this paper, we design a two-phase pairs trading strategy optimization framework, namely structural break-aware pairs trading strategy (SAPT), by leveraging machine learning techniques. Phase one is a hybrid model extracting frequency- and time-domain features to detect structural breaks. Phase two optimizes pairs trading strategy by sensing important risks, including structural breaks and market-closing risks, with a novel reinforcement learning model. In addition, the transaction cost is factored in a cost-aware objective to avoid significant reduction of profitability. Through large-scale experiments in real Taiwan stock market datasets, SAPT outperforms the state-of-the-art strategies by at least 456% and 934% in terms of profit and Sortino ratio, respectively.

Mannosylation of pH-sensitive liposomes promoted cytoplasmic delivery of protein to macrophages: green fluorescent protein (GFP) performed as an endosomal escape tracer.

Conventional non-pH-sensitive liposomes for cytoplasmic delivery of protein suffer from poor efficiency. Here we investigated mannosylated pH-sensitive liposomes (MAN-PSL) for cytoplasmic delivery of protein to macrophages RAW 264.7 using PSL and non-pH-sensitive liposomes for comparison. We characterised the pH-dependent fluorescence of green fluorescent protein (GFP) and encapsulated it in liposomes as an intracellular trafficking tracer. GFP showed a reversed 'S'-shaped pH-fluorescence curve with a dramatic signal loss at acidic pH. GFP stored at 4 °C with light protection showed a half-life of 10 days (pH 5-8). The entrapment efficiency of GFP was dominated by the volume ratio of intraliposomal core to external medium for thin-film hydration. Mannosylation did not affect the pH-responsiveness of PSL. Confocal microscopy elucidated that mannosylation promoted the cellular uptake of PSL. For both these liposomes, the strongest, homogeneously distributed GFP fluorescence in the cytoplasm was found at 3 h, confirming efficient endosomal escape of GFP. Conversely, internalisation of non-pH-sensitive liposomes was slow (peaked at 12 h) and both Nile Red and GFP signals remained weak and punctuated in the cytosol. In conclusion, GFP performed as a probe for endosome escape of liposomal cargo. Mannosylation facilitated the internalisation of PSL without compromising their endosomal escape ability.

Appetitive Motivation and Regulatory Processes in Adolescent Ketamine Users.

BACKGROUND: Ketamine has remained the most commonly used illicit drug among adolescents in Taiwan. A dual process model proposes that addictive behaviors develop in adolescents as a result of an imbalance between an appetitive, approach-oriented system (implicit and explicit attitudes) and a regulatory executive system (cool and hot executive functions). We aimed to examine the appetitive and regulatory processes in adolescent ketamine users in comparison to matched healthy adolescents. Method: The participants were 30 adolescent ketamine users and 32 nondrug controls, matched with gender, age, education years, and education systems. Both groups completed the affective priming task (APT), the stop-signal task (SST), an Iowa Gambling Task (IGT), and finally a Drug Use Disorders Identification Test: Extended (DUDIT-E). Results: The controls had higher positive and negative outcome expectancy with respect to using ketamine compared to the adolescent ketamine users. There was no significant between-group performance difference in APT. The adolescent ketamine users may have shown marginally poorer performance compared to the controls in hot executive functions (IGT), but their cold executive functions (SST) remained intact. Conclusion: The current study reported that the adolescent ketamine users may not have imbalanced dual processes (biased appetitive motivation and impaired regulatory executive process). A different therapeutic focus on adolescent ketamine users may be developed accordingly. More advocacies on ketamine's aversive outcomes are needed, particularly on campus in order to reduce substance misuse.

Extraperitoneal laparoscopic repair of huge inguinoscrotal bladder hernia: A case report and literature review.

Inguinal herniation of urinary bladder is a rare condition which might associated with significant complication. Exact pre-operative diagnosis is extremely important. We reported a case of huge inguinoscrotal bladder hernia, associated with bilateral hydronephrosis and kidney injuries, managed by laparoscopy technique.

Distal ureteral stone in an ileal conduit: A case treated by antegrade flexible ureteroscopic lithotripsy.

Antegrade flexible URSL is a minimal invasive option for treating distal ureteral stones in patient after urinary diversion.

A novel mechanism of gland formation in zebrafish involving transdifferentiation of renal epithelial cells and live cell extrusion.

Transdifferentiation is the poorly understood phenomenon whereby a terminally differentiated cell acquires a completely new identity. Here, we describe a rare example of a naturally occurring transdifferentiation event in zebrafish in which kidney distal tubule epithelial cells are converted into an endocrine gland known as the Corpuscles of Stannius (CS). We find that this process requires Notch signalling and is associated with the cytoplasmic sequestration of the Hnf1b transcription factor, a master-regulator of renal tubule fate. A deficiency in the Irx3b transcription factor results in ectopic transdifferentiation of distal tubule cells to a CS identity but in a Notch-dependent fashion. Using live-cell imaging we show that CS cells undergo apical constriction en masse and are then extruded from the tubule to form a distinct organ. This system provides a valuable new model to understand the molecular and morphological basis of transdifferentiation and will advance efforts to exploit this rare phenomenon therapeutically.

Investigation of a new pH-responsive nanoparticulate pore former for controlled release enteric coating with improved processability and stability.

Water-soluble polymers are often used as pore formers to tailor permeability of film-forming hydrophobic polymers on coated dosage forms. However, their addition to a coating formulation could significantly increase the viscosity thus making the coating process difficult. Moreover, the dissolution of pore formers after oral administration could compromise film integrity resulting in undesirable, inconsistent release profiles. Therefore, a non-leaching, pH-responsive nanoparticulate pore former is proposed herein to preserve film integrity and maintain pH-dependent permeability. Poly(methacrylic acid)-polysorbate 80-grafted-starch terpolymer nanoparticles (TPNs) were incorporated within an ethylcellulose (EC) film (TPN-EC) by casting or spray coating. TPNs at 10%wt (pore former level) only increased viscosity of EC coating suspension slightly while conventional pore formers increased the viscosity by 490-11,700%. Negligible leaching of TPNs led to superior mechanical properties of TPN-EC films compared to Eudragit® L-EC films. As pH increased from 1.2 to 6.8, TPN-EC films with 10% pore former level exhibited an 8-fold higher diltiazem permeability compared to Eudragit® L-EC films. The pH-dependent drug release kinetics of diltiazem HCl beads coated with TPN-EC films was tunable by adjusting the pore former level. These results suggest that the TPNs are promising pH-sensitive nanoparticulate pore formers in EC-coated dosage forms.

The diabetic rat kidney mediates inosituria and selective urinary partitioning of D-chiro-inositol.

Diabetic nephropathy is a serious complication of diabetes mellitus with a pressing need for effective metabolic markers to detect renal impairment. Of potential significance are the inositol compounds, myo-inositol (MI), and the less abundant stereoisomer, D-chiro-inositol (DCI), which are excreted at increased levels in the urine in diabetes mellitus, a phenomenon known as inosituria. There is also a selective urinary excretion of DCI compared to MI. As the biological origins of altered inositol metabolism in diabetes mellitus are unknown, the aim of this study was to determine whether the diabetic kidney was directly responsible. Kidneys isolated from four-week streptozotocin-induced diabetic rats were characterized by a 3-fold reduction in glomerular filtration rate (GFR) compared to matched non-diabetic kidneys. When perfused with fixed quantities of MI (50 µM) and DCI (5 µM) under normoglycemic conditions (5 mM glucose), GFR-normalized urinary excretion of MI was increased by 1.7-fold in diabetic vs. non-diabetic kidneys. By comparison, GFR-normalized urinary excretion of DCI was increased by 4-fold. Perfusion conditions replicating hyperglycemia (20 mM glucose) potentiated DCI but not MI urinary excretion in both non-diabetic and diabetic kidneys. Overall, there was a 2.4-fold increase in DCI urinary excretion compared to MI in diabetic kidneys that was independent of glucose ambience. This increased urinary excretion of DCI and MI in diabetic kidneys occurred despite increased renal expression of the inositol transporters, sodium myo-inositol transporter subtype 1 and 2 (SMIT1 and SMIT2). These findings show that the diabetic kidney primarily mediates inosituria and altered urinary partitioning of MI and DCI. Urinary inositol levels might therefore serve as an indicator of impaired renal function in diabetes mellitus with wider implications for monitoring chronic kidney disease.

Isolated perfused rat kidney: a technical update.

The isolated perfused kidney is commonly utilized as a screening tool for renal clearance and metabolism, and to correlate renal drug deposition to renal function. Here, we report on several aspects of this procedure that will facilitate a higher experimental success rate and lead to a reduction in animal use. First, we investigated the utility of inulin and creatinine as commonly used markers to measure glomerular filtration rate. For inulin, in the presence of either 20 mM glucose or 4.5% dextran in the buffer, significant interference was observed using an anthrone-based colorimetric assay. These findings suggest that caution needs to be exercised when using glucose or dextran and when inulin is quantitated using this method. Under these circumstances the use of alternative methods of inulin quantitation such as fluorescently tagged inulin is preferred. Second, we optimized bovine serum albumin (BSA) and BSA/dextran compositions that are routinely recommended as oncotic agents in the perfusion buffer and found that a 4% BSA/1.67% dextran composition had the best viability of kidney biomarkers in accordance with recommended threshold parameters. These considerations will be of particular relevance to researchers utilizing the isolated perfused kidney as a screening tool to measure renal biology and drug metabolism as well as applications to investigate diabetic nephropathy.