Can We `Feel' the Temperature of Knowledge? Modelling Scientific Popularity Dynamics via Thermodynamics

Just like everything in the nature, scientific topics flourish and perish. While existing literature well captures article's life-cycle via citation patterns, little is known about how scientific popularity and impact evolves for a specific topic. It would be most intuitive if we could `feel' topic's activity just as we perceive the weather by temperature. Here, we conceive knowledge temperature to quantify topic overall popularity and impact through citation network dynamics. Knowledge temperature includes 2 parts. One part depicts lasting impact by assessing knowledge accumulation with an analogy between topic evolution and isobaric expansion. The other part gauges temporal changes in knowledge structure, an embodiment of short-term popularity, through the rate of entropy change with internal energy, 2 thermodynamic variables approximated via node degree and edge number. Our analysis of representative topics with size ranging from 1000 to over 30000 articles reveals that the key to flourishing is topics' ability in accumulating useful information for future knowledge generation. Topics particularly experience temperature surges when their knowledge structure is altered by influential articles. The spike is especially obvious when there appears a single non-trivial novel research focus or merging in topic structure. Overall, knowledge temperature manifests topics' distinct evolutionary cycles

Palbociclib with Letrozole in Postmenopausal Women with ER+/HER2- Advanced Breast Cancer: Hematologic Safety Analysis of the Randomized PALOMA-2 Trial.

BackgroundPALOMA-2 confirmed that first-line palbociclib + letrozole improved progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.46-0.72) in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This analysis evaluated palbociclib-associated hematologic adverse events (AEs) and provides insight on managing these AEs.Materials and methodsPostmenopausal women with ER+/HER2- ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC).ResultsPALOMA-2 randomized 666 women to palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression-free survival was similar between patients who experienced grade ≥ 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with palbociclib + letrozole was 15 (12-700) days (grade ≥ 3, 28.0 [12-854] days); median duration of each neutropenia episode grade ≥ 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with palbociclib (p < .001).ConclusionPalbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2- ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ≥ 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427) IMPLICATIONS FOR PRACTICE: Palbociclib demonstrated an acceptable safety profile in PALOMA-2 in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) receiving first-line palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, palbociclib-related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting palbociclib + letrozole as a first-line treatment for ER+/HER2- ABC

Pharmacokinetic study of isoquercitrin in rat plasma after intravenous administration at three different doses

O objetivo deste estudo é desenvolver um método simples e específico de HPLC usando vitexina como padrão interno para investigar a farmacocinética do isoquercitrina (ISOQ) após três doses diferentes administradas por via intravenosa a ratos. Os parâmetros farmacocinéticos foram calculados pelas abordagens compartimental e não compartimental. Os resultados mostraram que ISOQ se encaixa no modelo de três compartimentos. Os valores de AUC aumentaram proporcionalmente na faixa de 5-10 mg·kg-1. Além disso, a meia-vida, b meia-vida, ªCL, MRT0-t and MRT0→∞ de ISOQ em ratos mostraram diferenças significativas entre 20 mg·kg-1 e outras doses, o que significa que ISOQ apresenta farmacocinética dose-dependente no intervalo de 5-10 mg·kg-1 e farmacocinética não linear em doses mais elevadas.The aim of this study is to develop a simple and specific HPLC method using vitexin as the internal standard to investigate the pharmacokinetics of isoquercitrin (ISOQ) after three different doses administrated intravenously to rats. The pharmacokinetic parameters were calculated by both compartmental and non-compartmental approaches. The results showed that ISOQ fitted a three-compartment open model. The values of AUC increased proportionally within the range of 5-10 mg·kg-1. Moreover, a half-life, b half-life, ªCL, MRT0-t and MRT0→∞ of ISOQ in rats showed significant differences between 20 mg·kg-1 and other doses, indicating that ISOQ presented dose-dependent pharmacokinetics in the range of 5-10 mg·kg-1 and non-linear pharmacokinetics at higher doses

Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer.

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent

Integrating Strategies of Herbal Metabolomics, Network Pharmacology, and Experiment Validation to Investigate Frankincense Processing Effects

In-depth research on processing can promote the globalization of processed herbs. The purpose of this study is to propose an improved strategy for processing effect investigation. Frankincense and processed frankincense were used as research subjects. First, high-speed countercurrent chromatography (HSCCC) and preparation high-performance liquid chromatography (PHPLC) techniques were used for major compounds isolation and minor compounds concentration. Processed frankincense was subjected to two stepwise solvent systems, namely, n-hexane:ethanol:water (6:5:1) and n-hexane:methyl-acetate:acetonitrile:water (4:4:3:4), to yield 12 fractions, and 18 compounds were further separated. Second, a comprehensive metabolomic analysis conducted by ultrahigh-performance liquid-chromatography/electrospray-ionization mass spectrometry (UHPLC-Qtof-MS) coupled with multivariate statistics was performed to fully characterize the chemical components and discover the potential biomarkers between frankincense and processed frankincense. In total, 81 metabolites, including the 18 separated compounds, were selected as potential biomarkers between frankincense and processed frankincense among 153 detected compounds for their VIP values of greater than one. The tirucallane-type compounds and components with 9,11-dehydro structures clearly occurred at high levels in the processed frankincense, while lupine-type compounds and those with 11-keto structures were significantly higher in frankincense. Then, a network pharmacology model was constructed to decipher the potential mechanisms of processing. Intestinal absorption properties prediction indicated the possibility of processing-related absorption enhancement. A systematic analysis of the constructed networks showed that the C-T network was constructed with 18 potential biomarkers and 69 targets. TNF and IL-1β were among the top-ranked and were linked by 8 and 7 pathways, which were mainly involved in inflammation. The arachidonic acid metabolism pathway exhibited the highest number of target connections. Finally, the prediction was validated experimentally by an intestinal permeability and efficacy assay. The experiments provided convincing evidence that processed frankincense harbored stronger inhibition effects toward TNF-α-, IL-1β- and arachidonic acid-induced platelet aggregation. The processing procedure leads to changes of the chemical metabolites, which triggers the enhancement of absorption and cure efficiency. The global change of the metabolites, absorption and pharmacological effects of processing were depicted in a systematic manner

Evaluation of the Bacterial Diversity in the Human Tongue Coating Based on Genus-Specific Primers for 16S rRNA Sequencing

The characteristics of tongue coating are very important symbols for disease diagnosis in traditional Chinese medicine (TCM) theory. As a habitat of oral microbiota, bacteria on the tongue dorsum have been proved to be the cause of many oral diseases. The high-throughput next-generation sequencing (NGS) platforms have been widely applied in the analysis of bacterial 16S rRNA gene. We developed a methodology based on genus-specific multiprimer amplification and ligation-based sequencing for microbiota analysis. In order to validate the efficiency of the approach, we thoroughly analyzed six tongue coating samples from lung cancer patients with different TCM types, and more than 600 genera of bacteria were detected by this platform. The results showed that ligation-based parallel sequencing combined with enzyme digestion and multiamplification could expand the effective length of sequencing reads and could be applied in the microbiota analysis

Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models

Immunotherapy using chimeric antigen receptor (CAR) T cells is a rapidly emerging modality that engineers T cells to redirect tumor-specific cytotoxicity. CAR T cells have been well characterized for their efficacy against B cell malignancies, and rigorously studied in other types of tumors. Preclinical evaluation of CAR T cell function, including direct tumor killing, cytokine production, and memory responses, is crucial to the development and optimization of CAR T cell therapies. Such comprehensive examinations are usually performed in different types of models. Model establishment should focus on key challenges in the clinical setting and the capability to generate reliable data to indicate CAR T cell therapeutic potency in the clinic. Further, modeling the interaction between CAR T cells and tumor microenvironment provides additional insight for the future endeavors to enhance efficacy, especially against solid tumors. This review will summarize both in vitro and in vivo models for CAR T cell functional evaluation, including how they have evolved with the needs of CAR T cell research, the information they can provide for preclinical assessment of CAR T cell products, and recent technology advances to test CAR T cells in more clinically relevant models