Mass Balance, Metabolic Pathways, Absolute Bioavailability, and Pharmacokinetics of Giredestrant in Healthy Subjects.

Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [14C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [14C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; n = 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP (n = 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. SIGNIFICANCE STATEMENT: This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, a high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

Dendrocandin U from Dendrobium officinale Kimura et Migo Inhibits M1 Polarization in Alveolar Macrophage by Suppressing NF-κB Signaling Pathway.

Dendrobium officinale Kimura et Migo is a valuable and homologous medicine and food traditional Chinese medicine. Currently there are few studies on the anti-inflammatory activity of lipophilic components. The aim of this study was to explore the anti-inflammatory effect and mechanism of the lipophilic compounds in Dendrobium officinale. Six compounds were isolated and identified, including three bibenzyl compounds, dendrocandin U, dendronbibisline B, erianin, and three lignans, (-)-syringaresinol, (+)-syringaresinol-O-ß-D-glucopyranoside, 5-methoxy-(+)-isolariciresinol. Among them, dendronbibisline B and 5-methoxy-(+)-isolariciresinol were isolated from Dendrobium officinale for the first time. Besides, we found dendrocandin U, dendronbibisline B and (-)-syringaresinol exhibited the anti-inflammation to inhibit nitric oxide secretion induced by lipopolysaccharide (LPS)/interferon (IFN-γ) in MH-S cells. Furthermore, dendrocandin U could inhibit the expression of tumor necrosis factor-α (TNF-α), Cluster of Differentiation 86 (CD86), and reduce inflammatory morphological changes of macrophages. Meanwhile, we confirmed that the anti-inflammation mechanism of dendrocandin U was to inhibit M1 polarization by suppressing toll-like receptor 4 (TLR4)/recombinant myeloid differentiation factor 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. In this paper, dendrocandin U with significant anti-inflammatory activity was found from Dendrobium officinale, which could provide a basis for the study of its anti-inflammatory drugs.

Schisandrin A ameliorates increased pulmonary capillary endothelial permeability accompanied with sepsis through inhibition of RhoA/ROCK1/MLC pathways.

BACKGROUND: Sepsis is a systemic inflammatory response, and vascular leakage associated with acute lung injury (ALI) is an important pathophysiological process during sepsis. Schisandrin A (SchA) is a bioactive lignan which has been reported to have the anti-inflammatory effects in many studies, while whether SchA can ameliorate ALI-related vascular leakage caused by sepsis is unknown. OBJECTIVE: To evaluate the role and the underlying mechanism of SchA in increase of pulmonary vascular permeability induced by sepsis. METHODS: The effect of SchA on pulmonary vascular permeability was examined in rat acute lung injury model. The effect of SchA on skin vascular permeability of mice was investigated through Miles assay. MTT assay was performed to detect the cell activity, and transwell assay was used to detect the effect of SchA on cell permeability. The effects of SchA on junction proteins and RhoA/ROCK1/MLC signaling pathway were manifested by immunofluorescence staining and western blot. RESULTS: The administration of SchA alleviated rat pulmonary endothelial dysfunction, relieved increased permeability in the mouse skin and HUVECs induced by lipopolysaccharide (LPS). Meanwhile, SchA inhibited the formation of stress fibers, reversed the decrease of expression of ZO-1 and VE-cadherin. Subsequent experiments confirmed that SchA inhibited RhoA/ROCK1/MLC canonical pathway in rat lungs and HUVECs induced by LPS. Moreover, overexpression of RhoA reversed the inhibitory effect of SchA in HUVECs, which suggested that SchA protected the pulmonary endothelial barrier by inhibiting RhoA/ROCK1/MLC pathway. CONCLUSION: In summary, our results indicate that SchA ameliorates the increase of pulmonary endothelial permeability induced by sepsis through inhibition of RhoA/ROCK1/MLC pathway, providing a potentially effective therapeutic strategy for sepsis.

Absorption, Metabolism, and Excretion of Taselisib (GDC-0032), a Potent ß-Sparing PI3K Inhibitor in Rats, Dogs, and Humans.

Taselisib (also known as GDC-0032) is a potent and selective phosphoinositide 3-kinase (PI3K) inhibitor that displays greater selectivity for mutant PI3Kα than wild-type PI3Kα To better understand the absorption, distribution, metabolism, and excretion properties of taselisib, mass balance studies were conducted following single oral doses of [14C]taselisib in rats, dogs, and humans. Absolute bioavailability (ABA) of taselisib in humans was determined by oral administration of taselisib at the therapeutic dose followed by intravenous dosing of [14C]taselisib as a microtracer. The ABA in humans was 57.4%. Absorption of taselisib was rapid in rats and dogs and moderately slow in humans. The recovery of radioactivity in excreta was high (>96%) in the three species where feces was the major route of excretion. Taselisib was the major circulating component in the three species with no metabolite accounting for >10% of the total drug-derived material. The fraction absorbed of taselisib was 35.9% in rats and 71.4% in dogs. In rats, absorbed drug underwent moderate to extensive metabolism and biliary excretion of taselisib was minor. In dog, biliary excretion and metabolism were major clearance pathways. In humans, 84.2% of the dose was recovered as the parent drug in excreta indicating that metabolism played a minor role in the drug's clearance. Major metabolism pathways were oxidation and amide hydrolysis in the three species while methylation was another prominent metabolism pathway in dogs. The site of methylation was identified on the triazole moiety. In vitro experiments characterized that the N-methylation was dog-specific and likely mediated by a thiol methyltransferase. SIGNIFICANCE STATEMENT: This study provides a comprehensive description of the absorption, distribution, and metabolism and pharmacokinetic properties of taselisib in preclinical species and humans. This study demonstrated the importance of oral bioavailability results for understanding taselisib's clearance pathways. The study also describes the identification and characterization of a unique dog-specific N-methylation metabolite of taselisib and the enzyme mediating N-methylation in vitro.

Prediction of COVID-19 Data Using Hybrid Modeling Approaches.

A major emphasis is the dissemination of COVID-19 across the country's many regions and provinces. Using the present COVID-19 pandemic as a guide, the researchers suggest a hybrid model architecture for analyzing and optimizing COVID-19 data during the complete country. The analysis of COVID-19's exploration and death rate uses an ARIMA model with susceptible-infectious-removed and susceptible-exposed-infectious-removed (SEIR) models. The logistic model's failure to forecast the number of confirmed diagnoses and the snags of the SEIR model's too many tuning parameters are both addressed by a hybrid model method. Logistic regression (LR), Autoregressive Integrated Moving Average Model (ARIMA), support vector regression (SVR), multilayer perceptron (MLP), Recurrent Neural Networks (RNN), Gate Recurrent Unit (GRU), and long short-term memory (LSTM) are utilized for the same purpose. Root mean square error, mean absolute error, and mean absolute percentage error are used to show these models. New COVID-19 cases, the number of quarantines, mortality rates, and the deployment of public self-protection measures to reduce the epidemic are all outlined in the study's findings. Government officials can use the findings to guide future illness prevention and control choices.

Phthalates in house dust in Chinese urban residences: Concentrations, partition, origin and determinants.

Exposure to phthalates poses adverse health impacts to human beings. In this study, we analyzed 7 phthalates in dust samples, which were collected with vacuum cleaner from 40 to 31 residences in Beijing in summer and winter, respectively. The major phthalates (median concentration in the summer and winter, respectively) were DiBP (55 and 40 ng/mg), DnBP (99 and 30 ng/mg) and DEHP (795 and 335 ng/mg). The concentrations were significantly influenced by season and residence time of house dust. The concentrations of phthalates in dust on plastic surfaces were highest, followed by those on wooden and fabric surfaces. The dust-air partition coefficients (Kd) were calculated: the median values were 0.13, 0.02 and 5.62 m3/mg in the summer and 0.06, 0.018 and 0.76 m3/mg in the winter for DiBP, DnBP and DEHP, respectively. A comparison with Kd* at equilibrium state suggested that partition between air and dust deviated from equilibrium state in both seasons. The results also revealed that dust-phthalates in the summer may completely originate from source materials via direct transfer and external physical process; while dust-phthalates in the winter may come from both air (via partition) and source material (via direct transfer and external physical process). The influence of temperature on dust-phthalate concentrations differed by season, owing to different origin of dust-phthalates in two seasons. Polar organic components in dust, which are products of reactions between O3 and unsaturated hydrocarbons in dust, likely played an important role in fate and transport of phthalates. The presence of them resulted in the significant associations between dust-phthalate concentrations and air humidity in the summer. Moreover, the impacts of indoor PM2.5 concentrations, traffic conditions surrounding residence, household lifestyle and number of occupants were also observed. The mechanisms behind those observations were discussed.

Estimates of emission strengths of 43 VOCs in wintertime residential indoor environments, Beijing.

There are many sources of volatile organic compounds (VOCs) in indoor environments, leading to much higher total indoor VOC concentrations than outdoor counterparts. Given the potential health hazards associated with VOC exposure, it is necessary to estimate the indoor VOC emission strengths. In this study, the indoor and outdoor concentrations of 43 VOCs were concurrently measured in 8 urban residences, Beijing. The indoor/outdoor concentration ratio was used to screen out 36 species having significant indoor sources. A one-compartment steady-state model was developed to estimate the indoor emission strengths of these VOCs, in which ventilation and reaction with ozone were included as sink routes. The order of VOCs in terms of indoor emission strength was d-limonene (a median value of 1.05 g/h), α-pinene (82.50 mg/h), styrene (24.12 mg/h), ß-pinene (9.70 mg/h), formaldehyde (1.97 mg/h), n-dodecane (1.82 mg/h), n-pentadecane (1.66 mg/h), n-hexadecane (1.62 mg/h), n-undecane (1.20 mg/h), acetaldehyde (1.05 mg/h) and 1, 4-dichlorobenzene (0.80 mg/h). The sum of estimates of those VOCs accounted for >95% of total emission strength. Specific indoor sources of those VOCs in the tested homes were identified. Air exchange rate, indoor temperature and air humidity were found to pose significant impacts to the indoor emission strengths of VOCs.

[Application of continuous monitoring of intracranial pressure and brain oxygen partial pressure in the treatment of patients with severe craniocerebral injury].

OBJECTIVE: To investigate the effects of continuous monitoring intracranial pressure (ICP) and brain oxygen partial pressure (PbtO2) on the prognosis of patients with severe craniocerebral injury. METHODS: A prospective randomized controlled trial was conducted. Seventy patients with severe craniocerebral injury with a Glasgow coma score (GCS) 4-8 admitted to the neurosurgical intensive care unit (NICU) of the People's Hospital of Inner Mongolia Autonomous Region from January 2017 to May 2020 were enrolled, and they were divided into ICP monitoring group and ICP+PbtO2 monitoring group by random number table. Patients in ICP monitoring group received ICP monitoring and were given traditional treatment of controlling ICP and cerebral perfusion pressure (CPP), the therapeutic target was ICP < 20 mmHg (1 mmHg = 0.133 kPa) and CPP > 60 mmHg. Patients in ICP+PbtO2 monitoring group were given ICP and PbtO2 monitoring at the same time, and oxygen flow was adjusted on the basis of controlling ICP and CPP to maintain the PbtO2 > 20 mmHg, and the therapeutic target of ICP and CPP was the same as the ICP monitoring group. ICP and PbtO2 values were recorded during monitoring in the two groups, the results of CPP, GCS and arterial blood gas analysis were recorded, and the prognosis at 3 months and 6 months after injury was compared by Glasgow outcome scale (GOS) score between the two groups. GOS score > 3 was considered as good prognosis. Kaplan-Meier survival curve was drawn, and the 3-month and 6-month cumulative survival rates of the two groups were analyzed. Linear regression analysis was used to further evaluate the relationship between PbtO2 and GOS score. RESULTS: Finally, a total of 70 patients with severe craniocerebral injury were enrolled in the analysis, 34 patients received ICP combined with PbtO2 monitoring and guided therapy, and 36 patients received ICP monitoring alone. The average ICP of ICP+PbtO2 monitoring group was significantly lower than that of ICP monitoring group (mmHg: 13.4±3.2 vs. 18.2±8.3, P < 0.01). Although the CPP in both groups was great than 60 mmHg, the average CPP of ICP+PbtO2 monitoring group was significantly higher than that of ICP monitoring group (mmHg: 82.1±10.5 vs. 74.5±11.6, P < 0.01). No significant difference was found in average GCS score or arterial partial pressure of carbon dioxide (PaCO2) between the ICP+PbtO2 monitoring group and ICP monitoring group [GCS score: 5.3±2.3 vs. 5.2±2.2, PaCO2 (mmHg): 33.5±4.8 vs. 32.6±5.2, both P > 0.05]. The average arterial partial pressure of oxygen (PaO2) of ICP+PbtO2 monitoring group was obviously higher than that of ICP monitoring group (mmHg: 228.4±93.6 vs. 167.3±81.2, P < 0.01). Compared with the ICP monitoring group, the good outcome rates of 3 months and 6 months after injury in the ICP+PbtO2 monitoring group were significantly higher (3 months: 67.6% vs. 38.9%, 6 months: 70.6% vs. 41.7%, both P < 0.05). Kaplan-Meier survival curve showed that the 3-month and 6-month cumulative survival rates of ICP+PbtO2 monitoring group were significantly higher than those of ICP monitoring group (3 months: 85.3% vs. 61.1%, Log-Rank test: χ2 = 5.171, P = 0.023; 6 months: 79.4% vs. 55.6%, Log-Rank test: χ2 = 4.511, P = 0.034). Linear regression analysis showed that PbtO2 was significantly correlated with GOS score at 3 months and 6 months after injury in patients with severe craniocerebral injury (r values were 0.951 and 0.933, both P < 0.01). CONCLUSIONS: PbtO2 compared with ICP monitoring guiding therapy is valuable in improving the prognosis of patients with severe craniocerebral injury. It can improve the prognosis at 3-6 months after injury.

A supramolecular complex based on a Gd-containing polyoxometalate and food-borne peptide for MRI/CT imaging and NIR-triggered photothermal therapy.

A multifunctional supramolecular complex is reported for the integrated multiple magnetic resonance imaging/computed X-ray tomography (MRI/CT) imaging and photothermal therapy, wherein a gadolinium-substituted paramagnetic polyoxometalate cluster and food-borne antioxidant peptides identified from the trepang protein hydrolysates are introduced. The as-prepared complex maintained an uniform particle size and much better biocompatibility, and is an ideal candidate for the in vivo applications. The complex allows for T1-weighted MR imaging and a high Hounsfield unit value for enhanced CT imaging. Interestingly, we demonstrate that the complex possesses outstanding photothermal cancer-killing effects due to its high photothermal conversion efficiency under the exposure of an NIR laser and enhanced antibacterial activity to avoid bacterial infection from the thermal therapeutic process. These results indicate that the supramolecular complex platform exhibit potential for accurate medical diagnosis at an early stage and effective eradication of the tumor cells.

Superhydrophobic and Antioxidative Film Based on Edible Materials for Food Packaging.

Significant wastage of the food deterioration in the food preserving process and residual liquid in a container has become a major concern for scientists and the whole society. In this study, an edible multifunctional film integrated superhydrophobicity and antioxidant ability is constructed by chitosan, tea polyphenol, carnauba wax material that is food and drug administration (FDA)-approved for food packaging. The formed edible packaging materials that exhibit great antioxidant property and extremely low water-absorbing quality, was thus proven to display excellent fresh beef preservation effect during storage of 14 days. Importantly, the formed edible multifunctional interface was also demonstrated to perform excellent superhydrophobicity due to the carnauba wax and exhibited large contact angles for various liquid foods, which could effectively reduce the liquid residue. Moreover, the formed edible multifunctional packaging materials showed good thermostability and biocompatibility, which has the potential to be applied as a functional packaging material.

Airborne phthalates in indoor environment: Partition state and influential built environmental conditions.

Exposure to phthalates has recently become a major public health concern. The information of indoor airborne phthalates and their air-particle partition in real indoor environmental condition is still limited. In this study, the gas- and PM2.5-concentrations of 7 phthalates in 40 residences were concurrently measured in summer and winter. The major phthalates (median concentration in the summer and winter, respectively) in indoor air were DMP (2442.3 and 2403.4 ng/m3), DiBP (801.0 and 640.0 ng/m3) and DnBP (5173.2 and 1379.6 ng/m3), whereas the major phthalates in PM2.5 were DiBP (1055.1 and 585.9 ng/m3) and DnBP (1658.5 and 1517.0 ng/m3) and DEHP (215.1 and 344.9 ng/m3). Air-PM2.5 partition coefficients (Kp) of DiBP, DnBP and DEHP were calculated: the summer and winter median values (m3/µg) were 0.053 and 0.011 for DiBP, 0.010 and 0.004 for DnBP, 0.021 and 0.025 for DEHP, respectively. Air-PM2.5 partition of DiBP and DnBP approached equilibrium, while that of DEHP did not reach equilibrium in either season. The impacts of built environmental conditions on phthalate concentrations were characterized. Elevated temperature resulted in accumulation of airborne phthalates. Higher air humidity led to more water absorption of aerosols in summer, facilitated mass transfer of phthalates from air to PM2.5, and resulted in greater Kp of DiBP and DnBP in the summer. Any factors such as proximity to local traffic highway and indoor smoking activities, which can increase indoor PM2.5 concentrations, resulted in significantly higher airborne phthalate concentrations. Improving ventilation was not an effective measure to reduce indoor airborne phthalate concentrations.

Transcriptome analysis of differentially expressed unigenes involved in flavonoid biosynthesis during flower development of Chrysanthemum morifolium 'Chuju'.

Chrysanthemum morifolium is an ornamentally and medicinally important plant species. Up to date, molecular and genetic investigations have largely focused on determination of flowering time in the ornamental species. However, little is known about gene regulatory networks for the biosynthesis of flavonoids in the medicinal species. In the current study, we employed the high-throughput sequencing technology to profile the genome-wide transcriptome of C. morifolium 'Chuju', a famous medicinal species in traditional Chinese medicine. A total of 63,854 unigenes with an average length of 741 bp were obtained. Bioinformatic analysis has identified a great number of structural and regulatory unigenes potentially participating in the flavonoid biosynthetic pathway. According to the comparison of digital gene expression, 8,370 (3,026 up-regulated and 5,344 down-regulated), 1,348 (717 up-regulated and 631 down-regulated) and 944 (206 up-regulated and 738 down-regulated) differentially expressed unigenes (DEUs) were detected in the early, middle and mature growth phases, respectively. Among them, many DEUs were implicated in controlling the biosynthesis and composition of flavonoids from the budding to full blooming stages during flower development. Furthermore, the expression patterns of 12 unigenes involved in flavonoid biosynthesis were generally validated by using quantitative real time PCR. These findings could shed light on the molecular basis of flavonoid biosynthesis in C. morifolium 'Chuju' and provide a genetic resource for breeding varieties with improved nutritional quality.

LC-MS Differential Analysis for Fast and Sensitive Determination of Biotransformation of Therapeutic Proteins.

Therapeutic biologics have become a fast-growing segment within the pharmaceutical industry during the past 3 decades. Although the metabolism of biologics is more predictable than small molecule drugs, biotransformation can significantly affect the activity of biologics. Unfortunately, there are only a limited number of published studies on the biotransformation of biologics, most of which are focused on one or a few types of modifications. In this study, an untargeted LC-MS-based differential analysis approach was developed to rapidly and precisely determine the universal biotransformation profile of biologics with the assistance of bioinformatic tools. A human monoclonal antibody (mAb) was treated with t-butyl hydroperoxide and compared with control mAb using a bottom-up proteomics approach. Thirty-seven types of post-translational modifications were identified, and 38 peptides were significantly changed. Moreover, although all modifications were screened and detected, only the ones related to the treatment process were revealed by differential analysis. Other modifications that coexist in both groups were filtered out. This novel analytical strategy can be effectively applied to study biotransformation-mediated protein modifications, which will streamline the process of biologic drug discovery and development.

Decompressive Craniectomy With Bifrontal Coronal Incision in the Management of Fronto-Temporal Contusion and Laceration for Early Cranioplasty.

The present study aims to explore the effectiveness of decompressive craniectomy with bifrontal coronal incision in the management of severe contusion and laceration of bilateral fronto-temporal lobes, as well as the outcomes of early cranioplasty. The authors performed the bifrontal decompressive craniectomy on 56 patients with contusion and laceration of bilateral frontal and temporal lobes, and their follow-up treatment outcomes were tracked within 6 months using Glasgow Outcome Scale. The results showed that 33 patients (out of 56, 58.9%) have recovered, 12 patients (out of 56, 21.4%) have moderate defects, 5 patients (out of 56, 8.9%) have severe defects, 3 patients (out of 56, 5.3%) stayed in persistent vegetative status, and the remaining 3 patients (out of 56, 5.3%) have been dead. There was no persistent temporal hollowing. No patients required revision surgery with modified titanium mesh in this study. Particularly, 28 patients have successfully accepted the early cranioplasty with bone flap or computer-assisted design titanium mesh, and showed good recovery. These results together indicated that the decompressive craniectomy with bifrontal coronal incision in the management of severe contusion and laceration of bilateral fronto-temporal lobes can significantly relieve the comorbidity of intracranial hypertension, and improve the prognosis obviously, thus finally increasing the probability of successful rescue and decreasing the probability of mortality and disability.

NADPH Oxidase Activation Contributes to Heavy Ion Irradiation-Induced Cell Death.

Increased oxidative stress plays an important role in heavy ion radiation-induced cell death. The mechanism involved in the generation of elevated reactive oxygen species (ROS) is not fully illustrated. Here we show that NADPH oxidase activation is closely related to heavy ion radiation-induced cell death via excessive ROS generation. Cell death and cellular ROS can be greatly reduced in irradiated cancer cells with the preincubation of diphenyleneiodium, an inhibitor of NADPH oxidase. Most of the NADPH oxidase (NOX) family proteins (NOX1, NOX2, NOX3, NOX4, and NOX5) showed increased expression after heavy ion irradiation. Meanwhile, the cytoplasmic subunit p47phox was translocated to the cell membrane and localized with NOX2 to form reactive NADPH oxidase. Our data suggest for the first time that ROS generation, as mediated by NADPH oxidase activation, could be an important contributor to heavy ion irradiation-induced cell death.

Biotransformation of Daclatasvir In Vitro and in Nonclinical Species: Formation of the Main Metabolite by Pyrrolidine δ-Oxidation and Rearrangement.

Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2-67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)-supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection.

Early channel transurethral resection of the prostate for patients with urinary retention after brachytherapy.

OBJECTIVE: It is recommended that transurethral resection of the prostate (TURP) after brachytherapy should not be performed at an early stage after implantation. Herein we report our experiences and the results of channel TURP (cTURP) within six months post-implant for patients with refractory urinary retention. METHODS: One hundred and ninety patients with localized prostate cancer of clinical stages T1c to T2c were treated by brachytherapy as monotherapy at our institution from February 2009 to July 2013. Nine patients who developed refractory urinary retention and underwent cTURP within six months after brachytherapy were retrospectively reviewed and analyzed. RESULTS: The median interval between prostate brachytherapy and cTURP was three months (range 1.5 to 5.0 months). There were no intraoperative or postoperative complications and no incontinence resulting from the surgery. All urinary retention was relieved per the American Brachytherapy Society urinary symptom score. With a mean follow-up time of 16 months (range 6 to 26 months) after cTURP, no patient experienced biochemical recurrence. The mean serum prostate-specific antigen (PSA) of the patients who underwent cTURP was 0.42 ng/ml (range 0.08 to 0.83 ng/ml) at the end of their follow-up. CONCLUSIONS: Early cTURP was found to be safe and effective in relieving urinary retention after brachytherapy and could be performed without compromising its therapeutic efficacy.

Assessment of vandetanib as an inhibitor of various human renal transporters: inhibition of multidrug and toxin extrusion as a possible mechanism leading to decreased cisplatin and creatinine clearance.

Vandetanib was evaluated as an inhibitor of human organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion (MATE1 and MATE2K) transfected (individually) into human embryonic kidney 293 cells (HEK293). Although no inhibition of OAT1 and OAT3 was observed, inhibition of OCT2-mediated uptake of 1-methyl-4-phenylpyridinium (MPP(+)) and metformin was evident (IC(50) of 73.4 ± 14.8 and 8.8 ± 1.9 µM, respectively). However, vandetanib was an even more potent inhibitor of MATE1- and MATE2K-mediated uptake of MPP(+) (IC(50) of 1.23 ± 0.05 and 1.26 ± 0.06 µM, respectively) and metformin (IC(50) of 0.16 ± 0.05 and 0.30 ± 0.09 µM, respectively). Subsequent cytotoxicity studies demonstrated that transport inhibition by vandetanib (2.5 µM) significantly decreased the sensitivity [right shift in concentration of cisplatin giving rise to 50% cell death; IC(50(CN))] of MATE1-HEK and MATE2K-HEK cells to cisplatin [IC(50(CN)) of 1.12 ± 0.13 versus 2.39 ± 0.44 µM; 0.85 ± 0.09 versus 1.99 ± 0.16 µM; P < 0.05), but not OCT2-HEK cells (1.36 ± 0.19 versus 1.47 ± 0.24 µM) versus vandetanib untreated cells and Mock-HEK cells [IC(50(CN)) of 2.34 ± 0.31 µM]. In summary, the results show that vandetanib is a potent inhibitor of MATE1 and MATE2K (versus OCT2). Inhibition of the two transporters may explain why there are reports of decreased creatinine clearance, and increased cisplatin nephrotoxicity (reduced cisplatin clearance), in some subjects receiving vandetanib therapy.

Correlation between the optical loss and crystalline quality in erbium-doped GaN optical waveguides.

Erbium-doped GaN (GaN:Er) epilayers were synthesized by metal organic chemical vapor deposition. GaN:Er waveguides were fabricated based on four different GaN:Er layer structures: GaN:Er/GaN/Al2O3, GaN:Er/GaN/AlN/Al2O3, GaN:Er/GaN/Al(0.75)Ga(0.25)N/AlN/Al2O3, and GaN/GaN:Er/GaN/Al2O3. Optical loss at 1.54 µm in these waveguide structures has been measured. It was found that the optical attenuation coefficient of the GaN:Er waveguide increases almost linearly with the GaN (002) x-ray rocking curve linewidth. The lowest measured loss was ~6 dB/cm.

Transcriptome-based discovery of pathways and genes related to resistance against Fusarium head blight in wheat landrace Wangshuibai.

BACKGROUND: Fusarium head blight (FHB), caused mainly by Fusarium graminearum (Fg) Schwabe (teleomorph: Gibberellazeae Schwble), brings serious damage to wheat production. Chinese wheat landrace Wangshuibai is one of the most important resistance sources in the world. The knowledge of mechanism underlying its resistance to FHB is still limited. RESULTS: To get an overview of transcriptome characteristics of Wangshuibai during infection by Fg, a high-throughput RNA sequencing based on next generation sequencing (NGS) technology (Illumina) were performed. Totally, 165,499 unigenes were generated and assigned to known protein databases including NCBI non-redundant protein database (nr) (82,721, 50.0%), Gene Ontology (GO) (38,184, 23.1%), Swiss-Prot (50,702, 30.6%), Clusters of orthologous groups (COG) (51,566, 31.2%) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) (30,657, 18.5%), as determined by Blastx search. With another NGS based platform, a digital gene expression (DGE) system, gene expression in Wangshuibai and its FHB susceptible mutant NAUH117 was profiled and compared at two infection stages by inoculation of Fg at 24 and 48 hour, with the aim of identifying genes involved in FHB resistance. CONCLUSION: Pathogen-related proteins such as PR5, PR14 and ABC transporter and JA signaling pathway were crucial for FHB resistance, especially that mediated by Fhb1. ET pathway and ROS/NO pathway were not activated in Wangshuibai and may be not pivotal in defense to FHB. Consistent with the fact that in NAUH117 there presented a chromosome fragment deletion, which led to its increased FHB susceptibility, in Wangshuibai, twenty out of eighty-nine genes showed changed expression patterns upon the infection of Fg. The up-regulation of eight of them was confirmed by qRT-PCR, revealing they may be candidate genes for Fhb1 and need further functional analysis to confirm their roles in FHB resistance.