Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients

Background: Volume of distribution is an important pharmacokinetic property that indicates the extent of a drug's distribution in the body tissues. This paper addresses the problem of how to estimate the apparent volume of distribution at steady state (Vss) of chemical compounds in the human body using decision tree-based regression methods from the area of data mining (or machine learning). Hence, the pros and cons of several different types of decision tree-based regression methods have been discussed. The regression methods predict Vss using, as predictive features, both the compounds' molecular descriptors and the compounds' tissue:plasma partition coefficients (Kt:p) - often used in physiologically-based pharmacokinetics. Therefore, this work has assessed whether the data mining-based prediction of Vss can be made more accurate by using as input not only the compounds' molecular descriptors but also (a subset of) their predicted Kt:p values. Results: Comparison of the models that used only molecular descriptors, in particular, the Bagging decision tree (mean fold error of 2.33), with those employing predicted Kt:p values in addition to the molecular descriptors, such as the Bagging decision tree using adipose Kt:p (mean fold error of 2.29), indicated that the use of predicted Kt:p values as descriptors may be beneficial for accurate prediction of Vss using decision trees if prior feature selection is applied. Conclusions: Decision tree based models presented in this work have an accuracy that is reasonable and similar to the accuracy of reported Vss inter-species extrapolations in the literature. The estimation of Vss for new compounds in drug discovery will benefit from methods that are able to integrate large and varied sources of data and flexible non-linear data mining methods such as decision trees, which can produce interpretable models. Figure not available: see fulltext. © 2015 Freitas et al.; licensee Springer

Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism

Inflammasomes are cytosolic caspase-1-activation complexes that sense intrinsic and extrinsic danger signals, and trigger inflammatory responses and pyroptotic cell death. Homotypic interactions among Pyrin domains and caspase recruitment domains (CARDs) in inflammasome-complex components mediate oligomerization into filamentous assemblies. Several cytosolic proteins consisting of only interaction domains exert inhibitory effects on inflammasome assembly. In this study, we determined the structure of the human caspase-1 CARD domain (caspase-1[superscript CARD]) filament by cryo-electron microscopy and investigated the biophysical properties of two caspase-1-like CARD-only proteins: human inhibitor of CARD (INCA or CARD17) and ICEBERG (CARD18). Our results reveal that INCA caps caspase-1 filaments, thereby exerting potent inhibition with low-nanomolar K[subscript i] on caspase-1[superscript CARD] polymerization in vitro and inflammasome activation in cells. Whereas caspase-1[superscript CARD] uses six complementary surfaces of three types for filament assembly, INCA is defective in two of the six interfaces and thus terminates the caspase-1 filament

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Measurement of Trilinear Gauge Couplings in e+e−e^+ e^- Collisions at 161 GeV and 172 GeV

Trilinear gauge boson couplings are measured using data taken by DELPHI at 161~GeV and 172~GeV. Values for $WWV$ couplings ($V=Z, \gamma$) are determined from a study of the reactions \eeWW\ and \eeWev, using differential distributions from the $WW$ final state in which one $W$ decays hadronically and the other leptonically, and total cross-section data from other channels. Limits are also derived on neutral $ZV\gamma$ couplings from an analysis of the reaction \eegi

The impact of paratracheal lymph node metastasis in squamous cell carcinoma of the hypopharynx

The aim of this study was to analyze the prevalence and prognostic importance of paratracheal lymph nodes in squamous cell carcinoma of the hypopharynx. A retrospective review of 64 previously untreated patients with squamous cell carcinoma (SCC) of the hypopharynx that underwent surgery was performed. Ipsilateral paratracheal lymph node metastases occurred in 22% (14 out of 64) and the mean number of paratracheal lymph nodes dissected per side was 2.3 (range 1–6). Contralateral paratracheal lymph node metastases were present in 2% (1 out of 42). Sixty-seven percent with postcricoid SCC and 22% with pyriform sinus SCC developed clinical node-positive ipsilateral paratracheal lymph node metastases, whereas 11% with posterior pharyngeal wall SCC developed paratracheal metastases. There was a significant correlation between paratracheal lymph node metastasis and cervical metastasis (p = 0.005), and the primary tumor site (postcricoid, 57.1%; pyriform sinus, 20.0%; posterior pharyngeal wall, 8.3%) (p = 0.039). Patients with no evidence of paratracheal lymph node metastasis may have a survival benefit (5-year disease-specific survival rate, 60 vs. 29%). However, this result did not reach statistical significance (p = 0.071). The patients with SCC of the postcricoid and/or pyriform sinus were at risk for ipsilateral paratracheal lymph node metastasis; furthermore, patients with paratracheal node metastasis had a high frequency of cervical metastasis and a poorer prognosis. Therefore, routine ipsilateral paratracheal node dissection is recommended during the surgical treatment of patients with SCC of the postcricoid and/or pyriform sinus with clinical node metastases

Characterisation of a Novel White Laccase from the Deuteromycete Fungus Myrothecium verrucaria NF-05 and Its Decolourisation of Dyes

A novel ‘white’ laccase was purified from the deuteromycete fungus, Myrothecium verrucaria NF-05, which was a high laccase-producing strain (40.2 U·ml−1 on the thirteenth day during fermentation). SDS-PAGE and native-PAGE revealed a single band with laccase activity corresponding to a molecular weight of approximately 66 kDa. The enzyme had three copper and one iron atoms per protein molecule determined by ICP-AES. Furthermore, both UV/visible and EPR spectroscopy remained silence, indicating the enzyme a novel laccase with new metal compositions of active centre and spectral properties. The N-terminal amino acid sequence of the purified protein was APQISPQYPM. Together with MALDI-TOF analysis, the protein revealed a high homology of the protein with that from reported M. verrucaria. The highest activity was detected at pH 4.0 and at 30°C. The enzyme activity was significantly enhanced by Na+, Mn2+, Cu2+ and Zn2+ while inhibited by DTT, NaN3 and halogen anions. The kinetic constant (Km) showed the enzyme was more affinitive to ABTS than other tested aromatic substrates. Twelve structurally different dyes could be effectively decolourised by the laccase within 10 min. The high production of the strain and novel properties of the laccase suggested its potential for biotechnological applications

Predicting septic shock in obstructive pyelonephritis associated with ureteral stones A retrospective study

To identify the best combination of potential predictors of septic shock in patients with obstructive acute pyelonephritis associated with ureteral stones (OAPN-US) according to Sepsis-3 criteria. Patients who underwent percutaneous nephrostomy (PCN) with OAPN-US were retrospectively evaluated. Recursive feature elimination (RFE) was applied to patients with and without septic shock to identify factors associated with the prediction of progression to septic shock. We compared combinations of the selected features based on area under the receiver operating curve (AUROC) to determine which combination was most effective. This study included 81 patients who were treated with PCN due to OAPN-US. A comparison was made between 37 patients with septic shock (SS) and 44 patients without septic shock (NSS). SS group had a higher age, poorer Eastern Cooperative Oncology Group status, and significantly higher levels of positivity in urine cultures and blood cultures. There were also differences in laboratory tests between the 2 groups. Procalcitonin (PCT), international normalized ratio (INR), and absolute lymphocyte count (ALC) were selected based on RFE. We compared the predictive power for SS when each marker was used alone, when 2 markers were combined, and when all 3 markers were combined. Among these combinations, using all 3 variables together yielded the highest AUROC of 0.942. Of the 3 variables, PCT had the highest Gini importance score, indicating that it was the most influential factor. Clinical characteristics were different between the SS and the NSS groups. In patients with OAPN-US, the combination of PCT, ALC, and INR was an excellent predictor of septic shock

The Role of Age in Predicting the Outcome of Caustic Ingestion in Adults: A Retrospective Analysis

<p>Abstract</p> <p>Background</p> <p>Although the outcomes of caustic ingestion differ between children and adults, it is unclear whether such outcomes differ among adults as a function of their age. This retrospective study was performed to ascertain whether the clinical outcomes of caustic ingestion differ significantly between elderly and non-elderly adults.</p> <p>Methods</p> <p>Medical records of patients hospitalized for caustic ingestion between June 1999 and July 2009 were reviewed retrospectively. Three hundred eighty nine patients between the ages of 17 and 107 years were divided into two groups: non-elderly (< 65 years) and elderly (≥ 65 years). Mucosal damage was graded using esophagogastroduodenoscopy (EGD). Parameters examined in this study included gender, intent of ingestion, substance ingested, systemic and gastrointestinal complications, psychological and systemic comorbidities, severity of mucosal injury, and time to expiration.</p> <p>Results</p> <p>The incidence of psychological comorbidities was higher for the non-elderly group. By contrast, the incidence of systemic comorbidities, the grade of severity of mucosal damage, and the incidence of systemic complications were higher for the elderly group. The percentages of ICU admissions and deaths in the ICU were higher and the cumulative survival rate was lower for the elderly group. Elderly subjects, those with systemic complications had the greatest mortality risk due to caustic ingestion.</p> <p>Conclusions</p> <p>Caustic ingestion by subjects ≥65 years of age is associated with poorer clinical outcomes as compared to subjects < 65 years of age; elderly subjects with systemic complications have the poorest clinical outcomes. The severity of gastrointestinal tract injury appears to have no impact on the survival of elderly subjects.</p