Preclinical pharmacokinetic characterization of amdizalisib, a novel PI3Kδ inhibitor for the treatment of hematological malignancies.

Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized in vitro and in vivo to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using in vitro experiments. In vivo PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and Vss) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized in vivo, and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC50 values of 30.4 and 10.7 µM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.

Effect of different metastasis patterns on the prognosis of patients with stage III high-grade serous ovarian cancer.

To investigate the effect of different metastatic patterns of stage III high-grade serous ovarian cancer on the patient prognosis. The clinical data of 134 patients with Stage III, high-grade serous ovarian cancer diagnosed in The Affiliated Hospital of Qingdao University from January 2018 to April 2020 were retrospectively collected, and the patients were grouped according to metastasis mode. Patients with simple lymph node metastasis (SLNM) were included in the SLNM group, and patients with simple abdominal implantation alone and patients with abdominal metastasis combined with lymph node metastasis were all in the abdominal metastasis (AM) group. The prognosis of the two groups was analyzed. Of the 134 enrolled patients, complete datasets from 128 were successfully collected. There were 20 cases of SLNM (15.63%) and 108 cases of AM (84.37%). Initial CA125, initial HE4, and whether neoadjuvant chemotherapy was used were compared between the two groups (P < 0.05). According to the chemotherapy results, patients was divided into two groups: chemotherapy remission and uncontrolled, including 111 patients with chemotherapy remission and 17 patients with uncontrolled chemotherapy. According to the criteria of relapse after complete completion of chemotherapy and clinical remission, 91 cases relapsed, 20 cases did not relapse, of which 78 cases were platinum-sensitive, and 13 were platinum-resistant relapses. There were 4 recurrence cases in SLNM group (4.40%) and 87 recurrence cases (95.60%) in AM group (P < 0.05). The recurrence sites of 91 patients were analyzed, including 52 cases (57.14%) in the peritoneum, 11 cases (12.09%) in distant regions, 9 cases (9.89%) in lymph nodes, 19 cases (20.88%) in the peritoneum and lymph nodes. Significant differences were noted in the two groups' peritoneum, lymph node, and distance (P < 0.05). The two groups had significant differences in progression-free survival, overall survival, and 3-year survival (all P < 0.05). Initial HE4 levels, chemotherapy sensitivity, and SLNM are independent prognostic factors for Stage III high-grade serous ovarian cancer patients. Initial HE4 level < 233.7 pmol/l and chemotherapy sensitivity were protective factors, indicating a good prognosis. Patients in the SLNM group had lower initial CA125 and HE4 levels and higher survival rates. Initial HE4 levels and chemotherapy sensitivity are independent factors affecting prognosis in Stage III high-grade serous ovarian cancer patients.

Removal of pollutants and accumulation of high-value cell inclusions in a batch reactor containing Rhodopseudomonas for treating real heavy oil refinery wastewater.

Treating wastewater using purple non-sulfur bacteria (PNSB) is an environmentally friendly technique that can simultaneously remove pollutants and lead to the accumulation of high-value cell inclusions. However, no PNSB system for treating heavy oil refinery wastewater (HORW) and recovering high-value cell inclusions has yet been developed. In this study, five batch PNSB systems dominated by Rhodopseudomonas were used to treat real HORW for 186 d. The effects of using different hydraulic retention times (HRT), sludge retention times (SRT), trace element solutions, phosphate loads, and influent loads were investigated, and the bacteriochlorophyll, carotenoid, and coenzyme Q10 concentrations were determined. The community structure and quantity of Rhodopseudomonas in the systems were determined using a high-sequencing technique and quantitative polymerase chain reaction technique. The long-term results indicated that phosphate was the limiting factor for treating HORW in the PNSB reactor. The soluble chemical oxygen demand (SCOD) removal rates were 67.03% and 85.26% without and with phosphate added, respectively, and the NH4+-N removal rates were 32.18% and 89.22%, respectively. The NO3--N concentration in the effluent was stable at 0-3 mg/L with or without phosphate added. Adding phosphate increased the Rhodopseudomonas relative abundance and number by 13.21% and 41.61%, respectively, to 57.35% and 8.52 × 106 gene copies/µL, respectively. The SRT was the limiting factor for SCOD removal, and the bacteria concentration was the limiting factor for nitrogen removal. Once the inflow load had been increased, the total nitrogen (TN) removal rate increased as the HRT increased. Maximum TN removal rates of 64.46%, 68.06%, 73.89%, 82.15%, and 89.73% were found at HRT of 7, 10, 13, 16, and 19 d, respectively. The highest bacteriochlorophyll, carotenoid, and coenzyme Q10 concentrations were 2.92, 4.99, and 4.53 mg/L, respectively. This study provided a simple and efficient method for treating HORW and reutilizing resources, providing theoretical support and parameter guidance for the application of Rhodopseudomonas in treating HORW.

77 % Photothermal Conversion in Blatter-Type Diradicals: Photophysics and Photodynamic Applications.

Diradicals based on the Blatter units and connected by acetylene and alkene spacers have been prepared. All the molecules show sizably large diradical character and low energy singlet-triplet gaps. Their photo-physical properties concerning their lowest energy excited state have been studied in detail by steady-state and time-resolved absorption spectroscopy. We have fully identified the main optical absorption band and full absence of emission from the lowest energy excited state. A computational study has been also carried out that has helped to identify the presence of a conical intersection between the lowest energy excited state and the ground state which produces a highly efficient light-to-heat conversion of the absorbed radiation. Furthermore, an outstanding photo-thermal conversion 77.23 % has been confirmed, close to the highest in the diradicaloid field. For the first time, stable diradicals are applied to photo-thermal therapy of tumor cells with good stability and satisfactory performance at near-infrared region.

FLASHlab@PITZ: New R&D platform with unique capabilities for electron FLASH and VHEE radiation therapy and radiation biology under preparation at PITZ.

At the Photo Injector Test facility at DESY in Zeuthen (PITZ), an R&D platform for electron FLASH and very high energy electron radiation therapy and radiation biology is being prepared (FLASHlab@PITZ). The beam parameters available at PITZ are worldwide unique. They are based on experiences from 20 + years of developing high brightness beam sources and an ultra-intensive THz light source demonstrator for ps scale electron bunches with up to 5 nC bunch charge at MHz repetition rate in bunch trains of up to 1 ms length, currently 22 MeV (upgrade to 250 MeV planned). Individual bunches can provide peak dose rates up to 1014 Gy/s, and 10 Gy can be delivered within picoseconds. Upon demand, each bunch of the bunch train can be guided to a different transverse location, so that either a "painting" with micro beams (comparable to pencil beam scanning in proton therapy) or a cumulative increase of absorbed dose, using a wide beam distribution, can be realized at the tumor. Full tumor treatment can hence be completed within 1 ms, mitigating organ movement issues. With extremely flexible beam manipulation capabilities, FLASHlab@PITZ will cover the current parameter range of successfully demonstrated FLASH effects and extend the parameter range towards yet unexploited short treatment times and high dose rates. A summary of the plans for FLASHlab@PITZ and the status of its realization will be presented.

Monitoring physiological and biochemical indices in the systematic training of sprinters / Monitoramento de índices fisiológicos e bioquímicos no treino sistemático de velocistas / Monitoreo de los índices fisiológicos y bioquímicos en el entrenamiento sistemático de velocistas

ABSTRACT Introduction This paper studies physiological and biochemical indicators in the systematic training of sprinters. This paper analyzes the data measured during the athletes' training process and studies the detailed data of their physical functions. Objective This study aimed to find a link between exercise data and biochemical indicator data in sprinter athletes. By analyzing the data from this article, the researchers were able to find the optimal training program for the athletes. Methods High-intensity aerobic training tests were performed with statistical analysis of various physiological and biochemical indicators. Results Hemoglobin data were shown to be highly sensitive to intensity. The researchers found that long-term high-load training in athletes can lead to physical fatigue. This fatigue production is positively correlated with the intensity of the training load. Conclusion There is a strong positive correlation between biochemical and physiological indicators on performance levels in sprinter athletes. Evidence Level II; Therapeutic Studies - Investigating the results.

RESUMO Introdução Este artigo estuda o monitoramento de indicadores fisiológicos e bioquímicos no treino sistemático de velocistas. Este documento analisa os dados medidos durante o processo de treino das atletas e estuda os dados detalhados de suas funções físicas. Objetivo O objetivo deste estudo foi encontrar uma ligação entre os dados de exercício e os dados de indicadores bioquímicos nas atletas velocistas. Ao analisar as informações deste artigo, os pesquisadores conseguiram encontrar um programa de treino ideal para as atletas. Métodos Foram empegadas experiências de treino aeróbico de alta intensidade, com análise estatística de vários indicadores fisiológicos e bioquímicos. Resultados Os dados de hemoglobina mostraram-se altamente sensíveis à intensidade. Os pesquisadores descobriram que o treino a longo prazo de alta carga em atletas pode acarretar numa fadiga física. Essa produção de fadiga está positivamente correlacionada com a intensidade da carga de treino. Conclusão Há uma forte correlação positiva entre indicadores bioquímicos e fisiológicos nos níveis de desempenho em atletas velocistas. Nível de evidência II; Estudos Terapêuticos - Investigação de Resultados.

RESUMEN Introducción Este trabajo estudia el seguimiento de los indicadores fisiológicos y bioquímicos en el entrenamiento sistemático de los velocistas. Este artículo analiza los datos medidos durante el proceso de entrenamiento de los atletas y estudia los datos detallados de sus funciones físicas. Objetivo El objetivo de este estudio fue encontrar una relación entre los datos del ejercicio y los datos de los indicadores bioquímicos en los atletas velocistas. Al analizar las informaciones de este artículo, los investigadores pudieron encontrar un programa de entrenamiento óptimo para los atletas. Métodos Se realizaron pruebas de entrenamiento aeróbico de alta intensidad con análisis estadístico de varios indicadores fisiológicos y bioquímicos. Resultados Los datos de la hemoglobina se mostraron muy sensibles a la intensidad. Los investigadores descubrieron que el entrenamiento de alta carga a largo plazo en los atletas puede conducir a la fatiga física. Esta producción de fatiga está positivamente correlacionada con la intensidad de la carga de entrenamiento. Conclusión Existe una fuerte correlación positiva entre los indicadores bioquímicos y fisiológicos en los niveles de rendimiento de los atletas velocistas. Nivel de evidencia II; Estudios terapéuticos - Investigación de resultados.

Enhanced pollutants removal and high-value cell inclusions accumulation with Fe2+ in heavy oil refinery treatment system using Rhodopseudomonas and Pseudomonas.

Metal ions has been widely used as a method of improving pollutant removal efficiency in wastewater biological treatment system. In order to enhance pollutants removal and high-value cell inclusions accumulation in heavy oil refinery wastewater treatment systems using PSB, different reactors were built feeding with different Fe2+ concentrations respectively, and run with enriching Rhodopseudomonas and Pseudomonas in the reactors. Solute chemical oxygen demand (SCOD), ammonia (NH4+-N), nitrate nitrogen (NO3--N), nitrous nitrogen (NO2--N), Fe2+, and related cell inclusions were all detected, moreover, microbial community structure and the quantity of Rhodopseudomonas and Pseudomonas were also detected. The results showed that at the optimal dosage of Fe2+ with 20 mg/L, the corresponding removal ratios of solute chemical oxygen demand and ammonia were 73.51% and 92.26%, respectively. The yields of carotenoid, bacteriochlorophyll, and coenzyme Q10 were 11.18, 6.75, and 9.84 mg/g-DCW respectively. Furthermore, with 20 mg/L Fe2+ dosage, the relative abundance and gene number of Rhodopseudomonas were the highest in the system, which were 91.57% and 1.843 × 106 gene copies/µL, while Fe2+ had no obvious effect on the growth of Pseudomonas. The results showed that adding Fe2+ has improved the removal of pollutants and accumulation of high-value cells inclusions, also provided theoretical guidance for the treatment of heavy oil refinery wastewater using PSB.

Optimization of extraction for Anemarrhena asphodeloides Bge. using silica gel-based vortex-homogenized matrix solid-phase dispersion and rapid identification of antioxidant substances.

A novel and simple method was established for the extraction and determination of seven compounds in Anemarrhena asphodeloides Bge. using silica gel-based vortex-homogenized matrix solid-phase dispersion and ultra-high performance liquid chromatography quadrupole-time of-flight mass spectrometer. The conditions for the extraction were optimized. Silica gel was used as the dispersant, 50% methanol-water was selected as an elution solvent and the grinding time was 3 min. Compared with the traditional ultrasonic-assisted extraction, the developed method was rapid and efficient. In order to screen potential antioxidants, extract dealing with the optimized method was applied to a polyamide chromatography column and a D-101 macroporous resin column. Fr.2.2 showed the highest antioxidant activities with the most content of flavonoid. A total of 25 peaks were identified from the active fraction. A 2,2'-diphenyl-1-picrylhydrazyl ultra-high performance liquid chromatography coupled with mass spectrometry approach was adopted for the rapid and exact screening and identification of antioxidant compounds. It indicated that flavonoids exhibited potential antioxidant activities. The antioxidant activities of nine monomeric compounds in vivo were tested. Structure-activity relationships were discussed. Five flavonoids with the concentration of 500 µg/mL would reduce the oxidative stress of PC12 cells that were induced with 2,2'-azobis[2-methylpropionamidine] dihydrochloride.

Relationship between oxidative stress and inflammation in hyperuricemia: Analysis based on asymptomatic young patients with primary hyperuricemia.

The average age of hyperuricemia patients has gradually decreased, but young patients with primary hyperuricemia often do not exhibit clinical symptoms and have not received sufficient attention. However, a lack of symptoms with primary hyperuricemia does not mean that high serum uric acid (UA) levels cannot lead to pathological effects, such as oxidative stress and inflammation, and the specific damage is still unclear. We aimed to determine the relationship between oxidative stress and inflammation to explore the possible role of pathological damage in asymptomatic young patients with primary hyperuricemia.A total of 333 participants were enrolled in our study: 158 asymptomatic young patients with primary hyperuricemia and 175 healthy persons from a health check-up population. Malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and general biochemical markers were measured.We found no differences in biochemical markers (fasting glucose, TG, TC, LDL-C, HDL-C, SCr, BUN, AST, and ALT) between the patients and healthy persons. Subsequent analyses of oxidative stress and inflammation revealed that the serum levels of MDA, IL-6, and TNF-α in the patients were significantly higher than those in the healthy control group (P < .001), and the SOD activity was significantly lower (P < .001). As the UA levels increased, MDA increased significantly and SOD decreased significantly; likewise, IL-6 and TNF-α increased significantly as the UA level increased. MDA showed a significant positive correlation with IL-6 (r = 0.367, P < .001) and TNF-α (r = 0.319, P < .001), and SOD was negatively correlated with IL-6 (r = -0.241, P < .01) and TNF-α (r = -0.308, P < .001). Multivariable logistic regression analysis showed that UA (OR: 2.379, 95% CI: 1.698-3.286, P < .001; OR: 3.261, 95% CI: 1.729-3.857, P < .001; for IL-6 and TNF-α, respectively) and MDA (OR: 1.836, 95% CI: 1.283-2.517, P < .01; OR: 2.532, 95% CI: 1.693-3.102, P < .001; for IL-6 and TNF-α, respectively) were risk factors for high IL-6 and TNF-α and that SOD (OR: 0.517, 95% CI: 0.428-0.763, P < .01; OR: 0.603, 95% CI: 0.415-0.699, P < .001; for IL-6 and TNF-α, respectively) was a protective factor.In our study, some abnormal pathological effects were found in asymptomatic young patients with hyperuricemia, suggesting that in young hyperuricemia patients, oxidative stress, inflammation and the inflammatory response may be related to the oxidative stress induced by UA. Therefore, we should pay more attention to the pathological damage caused by these alterations.

Improved bioautographic assay on TLC layers for qualitative and quantitative estimation of xanthine oxidase inhibitors and superoxide scavengers.

A new agar-free bioautographic assay for xanthine oxidase (XO) inhibitors and superoxide scavengers on TLC layers was developed and validated. Compared to the first version of TLC bioautographic agar overlay method, our bioautographic assay greatly improved the sensitivity and quantification ability. The limit of detection (LOD) of this assay was 0.017ng for allopurinol. Quantitative estimation of XO inhibitors and superoxide scavengers was achieved by densitometry scanning, expressed as allopurinol equivalents in millimoles on a per sample weight basis. This assay has acceptable accuracy (95.37-99.23%), intra-day and inter-day precisions (RSD, 2.56-6.69%), as well as intra-plate and inter-plate precisions (RSD, 2.93-9.62%). Six pure compounds and three herbal extracts were evaluated for their potential XO inhibitory and superoxide scavenging activity by this bioautographic assay on TLC layers. Four active components were separated, located and identified in Astragalus membranaceus var. mongholicus extract by the bioautographic assay after TLC separation. The developed method is rapid, simple, sensitive and stable for screening and estimation of the potential XO inhibitors and superoxide scavengers.

Distribution and genetic diversity of the microorganisms in the biofilter for the simultaneous removal of arsenic, iron and manganese from simulated groundwater.

A biofilter was developed in this study, which showed an excellent performance with the simultaneous removal of AsIII from 150 to 10mg L(-1) during biological iron and manganese oxidation. The distribution and genetic diversity of the microorganisms along the depth of the biofilter have been investigated using DGGE. Results suggested that Iron oxidizing bacteria (IOB, such as Gallionella, Leptothrix), Manganese oxidizing bacteria (MnOB, such as Leptothrix, Pseudomonas, Hyphomicrobium, Arthrobacter) and AsIII-oxidizing bacteria (AsOB, such as Alcaligenes, Pseudomonas) are dominant in the biofilter. The spatial distribution of IOB, MnOB and AsOB at different depths of the biofilter determined the removal zone of FeII, MnII and AsIII, which site at the depths of 20, 60 and 60cm, respectively, and the corresponding removal efficiencies were 86%, 84% and 87%, respectively. This process shows great potential to the treatment of groundwater contaminated with iron, manganese and arsenic due to its stable performance and significant cost-savings.

Molecular characterization of microbial populations in full-scale biofilters treating iron, manganese and ammonia containing groundwater in Harbin, China.

In iron and manganese-containing groundwater treatment for drinking water production, biological filter is an effective process to remove such pollutants. Until now the exact microbial mechanism of iron and manganese removal, especially coupled with other pollutants, such as ammonia, has not been clearly understood. To assess this issue, the performance of a full-scale biofilter located in Harbin, China was monitored over four months. Microbial populations in the biofilter were investigated using T-RFLP and clone library technique. Results suggested that Gallionella, Leptothrix, Nitrospira, Hyphomicrobium and Pseudomonas are dominant in the biofilter and play major roles in the removal of iron, manganese and ammonia. The spatial distribution of microbial populations along the depth of the biofilter demonstrated the stratification of the removal of iron, manganese and ammonia. Additionally, the absence of ammonia-oxidizing bacteria in the biofilter implicated that ammonia-oxidizing archaea might be responsible for the oxidation of ammonia to nitrite.

Isolation of a new meroterpene and inhibitors of nitric oxide production from Psoralea corylifolia fruits guided by TLC bioautography.

A new meroterpene, psoracorylifol F (1), was isolated from Psoralea corylifolia fruits, along with two known meroterpenes (2 and 3), guided by TLC bioautography against O(2)(-) radicals. The structure of 1 was elucidated by means of NMR, HRESIMS, and X-ray crystallographic analysis. All the three metroterpenes possessed potential inhibitory activity against LPS-induced NO production in RAW 264.7 cells with IC(50) values ranging from 7.71 to 27.63µM.

Phosphorus accumulation by bacteria isolated from a continuous-flow two-sludge system.

In this article, polyphosphate-accumulating organisms (PAOs) from a lab-scale continuous-flow two-sludge system was isolated and identified, the different phosphorus accumulation characteristics of the isolates under anoxic and aerobic conditions were investigated. Two kinds of PAOs were both found in the anoxic zones of the two-sludge system, one of them utilized only oxygen as electron acceptor, and the other one utilized either nitrate or oxygen as electron acceptor. Of the total eight isolates, five isolates were capable of utilizing both nitrate and oxygen as electron acceptors to uptake phosphorus to some extent. And three of the five isolates showed good phosphorus accumulative capacities both under anoxic or aerobic conditions, two identified as Alcaligenes and one identified as Pseudomonas. Streptococcus was observed weak anoxic phosphorus accumulation because of its weak denitrification capacity, but it showed good phosphorus accumulation capacity under aerobic conditions. One isolates identified as Enterobacteriaceae was proved to be a special species of PAOs, which could only uptake small amounts of phosphorus under anoxic conditions, although its denitrification capacity and aerobic phosphorus accumulation capacity were excellent.