Pretreatment and analysis techniques development of TKIs in biological samples for pharmacokinetic studies and therapeutic drug monitoring

Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways.However,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments,alongside other potential side effects or adverse reactions.Therefore,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different TKIs.This paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(μ-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since 2017.It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electrophoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing techniques.In addition,a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.

Insulin resistance and occurrence and prognosis of ischemic stroke A non-randomized concurrent control and intra-group comparison

BACKGROUND： Clinical evidence has demonstrated that insulin resistance might be an independent risk factor for ischemic stroke, which has not been recognized. At present, insulin resistance has been proven to be an independent risk factor for coronary arteriosclerotic heart disease. However, the relationship between the onset and prognosis of ischemic stroke remains unclear. OBJECTIVE： This study was designed to analyze the relationship between insulin resistance and ischemic stroke and the correlation between insulin resistance and stroke risk factor, and to investigate the relationship between insulin resistance and ischemic stroke prognosis as well as whether insulin resistance is an independent prognostic factor. DESIGN： A non-randomized concurrent control experiment. SETTING： Department of Geriatric Disease, Second Affiliated Hospital of Kunming Medical College. PARTICIPANTS： A total of 106 inpatients with ischemic stroke of the cervical internal carotid artery, who had suffered from the disease within the previous 72 hours, were admitted to the Department of Neurology, First Affiliated Hospital of Kunming Medical College from March to December in 2005 and, recruited for the present study. All 106 inpatients corresponded to the diagnostic criteria of ischemic stroke, formulated at the Fourth National Cerebrovascular Disease Conference in 1995, and were confirmed as having had an ischemic stroke by CT/MRI examinations. The patient group consisted of 54 males and 52 females. An additional 50 healthy individuals, who received health examinations simultaneously, were included as controls. Among the control subjects, there were 26 males and 24 females. Informed consent for laboratory measurements was obtained from all subjects; this study was approved by the Hospital Ethics Committee. METHODS： Following admission, all subjects were inquired of age, gender, previous history, blood pressure, body temperature, admission time, and smoking habits. Meanwhile, they were scored on clinical neurological function deficits. At 24 hours after admission, blood glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels were measured under the fasting condition. The control subjects were subjected to the same examinations and evaluation upon admission. In the two groups, insulin resistance degree was evaluated by the insulin sensitivity index （ISI）. According to the ISI, patients were assigned into severe and mild insulin resistance subgroups. The insulin resistance degree and its correlations to stroke risk factors and stroke prognosis were analyzed separately by t-test, linear correlation analysis and logistic regression analysis. MAIN OUTCOME MEASURES： Comparisons of fasting blood glucose and insulin levels, ISI, blood pressure, and blood lipid level between the two groups; comparisons of neurological function deficit scores, daily living activity scores and complication incidence between the severe and mild insulin resistance patients at 4 weeks after onset. RESULTS： All 106 patients and 50 healthy subjects were included in the final analysis. On admission, in the patient group, the blood glucose and insulin levels were significantly higher, while the ISI was significantly lower, compared with the control group （t = 10.38-12.29, P 〈 0.05）; At 4 weeks after admission, in the patient group, blood glucose level was decreased, but there was no significant difference compared with the control group （P 〉 0.05）, insulin level was decreased, but it was significantly higher compared with the control group （t = 6.46, P 〈 0.05）, and ISI was increased, but it was significantly lower compared with the control group （t = 66, P 〈 0.05）. On admission and at 4 weeks after admission, ISI was negatively correlated with triglyceride level （r = -0.494, -0.459, P 〈 0.05） and positively correlated to high-density lipoprotein cholesterol level （r = 0.448, 0.310, P 〈 0.05）; however, it was not correlated with total cholesterol or high-density lipoprotein cholesterol levels （P 〉 0.05）. In the severe insulin resistance patients, clinical neurological function deficit scores and complication incidence were significantly higher, while daily living activity scores were significantly lower, compared with the mild insulin resistance patients （t = 5.352 9, 4.260 4, 0.070 6, P 〈 0.05）. Logistic regression analysis demonstrated that ISI was finally excluded as an independent prognostic factor. CONCLUSION： Ischemic stroke patients presented with insulin resistance. Insulin resistance was correlated with conventional risk factors for stroke, including hypertension and lipid metabolism disorder. Insulin resistance was correlated with the prognosis of acute cerebral infarction patients, but it was not an independent predictive factor.

深刻把握习近平文化思想的重大意义

习近平文化思想是新时代党领导文化建设实践经验的理论总结,是习近平新时代中国特色社会主义思想的有机组成部分,丰富和发展了马克思主义关于文化建设的理论,为我们在实现第二个百年奋斗目标的征程中,巩固文化自信和建设文化强国提供了根本遵循,在党的宣传思想文化事业发展史上,在马克思主义文化理论中国化时代化发展史上,均具有重要的里程碑意义。

Chromosome-scale genome assembly of sweet cherry(Prunus avium L.)cv.Tieton obtained using long-read and Hi-C sequencing

Sweet cherry(Prunus avium)is an economically significant fruit species in the genus Prunus.However,in contrast to other important fruit trees in this genus,only one draft genome assembly is available for sweet cherry,which was assembled using only Illumina short-read sequences.The incompleteness and low quality of the current sweet cherry draft genome limit its use in genetic and genomic studies.A high-quality chromosome-scale sweet cherry reference genome assembly is therefore needed.A total of 65.05 Gb of Oxford Nanopore long reads and 46.24 Gb of Illumina short reads were generated,representing~190x and 136x coverage,respectively,of the sweet cherry genome.The final de novo assembly resulted in a phased haplotype assembly of 344.29 Mb with a contig N50 of 3.25 Mb.Hi-C scaffolding of the genome resulted in eight pseudochromosomes containing 99.59%of the bases in the assembled genome.Genome annotation revealed that more than half of the genome(59.40%)was composed of repetitive sequences,and 40,338 protein-coding genes were predicted,75.40%of which were functionally annotated.With the chromosomescale assembly,we revealed that gene duplication events contributed to the expansion of gene families for salicylic acid/jasmonic acid carboxyl methyltransferase and ankyrin repeat-containing proteins in the genome of sweet cherry.Four auxin-responsive genes(two GH3s and two SAURs)were induced in the late stage of fruit development,indicating that auxin is crucial for the sweet cherry ripening process.In addition,772 resistance genes were identified and functionally predicted in the sweet cherry genome.The high-quality genome assembly of sweet cherry obtained in this study will provide valuable genomic resources for sweet cherry improvement and molecular breeding.

Automatic Monitoring of Chilling Requirement for Sweet Cherry and Its Application in Protected Cultivation

For sweet cherry, the economic benefit of protected cultivation is much higher than that of open field cultivation. However, problems such as nonuniform germination, aberrant flower, abortion, bad fruit setting and delayed maturation appear frequently due to the inaccurate regulation of chilling requirement. In order to solve the problems, an automatic system for monitoring, selecting and recording of chilling requirement in protected cultivation of sweet cherry was designed and developed. The system, which consisted of temperature detection, effective chilling temperature selection, signal conversion and output and chilling accumulation display, had been continuously used in protected cultivation of sweet cherry for 3 years and good effects had been achieved. The system monitored chilling accumu- lation accurately and made it more reasonable for the time selection of greenhouse covering, thus avoiding risks of nonuniform germination, bad fruit setting and de- layed maturation, etc. Under the coordinate application of this system with other modern measuring and controlling techniques such as automatic detection and alarming of temperature and humidity, the environment in greenhouses was regulated precisely that the uniform fruits were obtained and the expected yield, quality and harvest time were achieved.

论中国题材电影的异语创作与无本回译--以《功夫熊猫3》和真人版《花木兰》为例

中国题材电影的创作,大部分都是中国人自己创作的,语言一般也为汉语,还有一种情况,就是用外语以中国的素材为内容进行创作,创作者一般也为外国人。后者可以称作中国题材电影的异语创作,其实这一现象早已有之。比如,从1923年开始,好莱坞先后拍摄了14部妖魔化中国人形象的“傅满洲”系列电影,1937年,好莱坞拍摄了《大地》,塑造了勤劳、坚韧的中国农民形象。近些年来,《末代皇帝》《花木兰》《功夫之王》《功夫熊猫》等中国题材故事陆续被外国创作团队搬上银幕。

Study protocol:A cross-sectional study on psychology and behavior investigation of Chinese residents,PBICR

Objective:This study protocol identifies the basic research route and framework of psychological and behavioral surveys among Chinese residents,aims establishing a database through a multicenter,large-sample cross-sectional survey in China to provide strong data support for research development in various fields and a more comprehensive and systematic understanding of the physical and mental health status of the public.Method:The study was conducted from June 20,2022 to August 31,2022,using stratified sampling and quota sampling methods,a total of 148 cities,202 districts and counties,390 townships/towns/sub-districts,and 780 communities/villages(excluding Hong Kong,Macao,and Taiwan)from 23 provinces,5 autonomous regions,and 4 municipalities directly under the central government in China were selected.The questionnaire was distributed one-on-one and face-to-face to the public by trained investigators,and the questionnaire included eight aspects:personal basic information,personal health status,family basic information,social environment in which they were located,psychological level scale,behavioral level scale,other scales,and attitude towards social hot issues.Data analysis will be performed after questionnaire return.Results:Data collection is ongoing.These findings will support physical and mental health research and strategy development in China and even globally,guiding policy-makers and health care organizations to reform their programs to ensure the best interests of residents and their families.

Vitreous amyloidosis caused by a Lys55Asn variant in transthyretin: A case report

BACKGROUND Amyloidosis is caused by misfolding of proteins and is characterized by formation of extracellular aggregates of insoluble fibrin.The primary effects in the eye include sharp deterioration of visual acuity as a result of vitreous opacity.According to the local and systemic distribution characteristics of amyloid deposits and their fibrin components,amyloidosis can be classified as primary,secondary or familial.Therefore,we report a typical case of vitreous amyloidosis in hereditary transthyretin amyloidosis(hATTR)to improve ophthalmologists’understanding of the disease and reduce misdiagnosis and recurrence.CASE SUMMARY The patient was a 49-year-old man who complained of progressive visual decline in both eyes over a 2-mo period.No systemic diseases such as diabetes or hypertension were reported,and no obvious family history of disease was identified.The patient’s visual acuity was HM/10 cm in the right eye and 0.06 in the left eye.He had a transparent cornea in both eyes,with a normal anterior depth,clear aqueous humor,no obvious iris abnormalities,round pupils of approximately 3 mm in diameter,normal direct and indirect light reflexes,and normal intraocular pressure.After various examinations,the patient was diagnosed with binocular vitreous amyloidosis secondary to hATTR associated with a Lys55Asn variant in TTR.The binocular visual acuity recovered to 1.0 after binocular vitrectomy.CONCLUSION Vitreous amyloidosis is rare in the clinic and gene testing can assist the diagnosis accurately and effectively.

女性主义视角下动画电影《花木兰》的译介初探

迪士尼动画电影《花木兰》(Mulan)一经推出便在美国本土以至全世界受到了广泛的欢迎,影片取材自中国南北朝时期花木兰替父从军的故事,但却对其进行了较大的再创造与改编。因此,迪士尼的花木兰回归到中国故土伊始,便引起了国内学界全方位的热烈讨论,至今方兴未艾。其中,探讨《花木兰》(Mulan)翻译方面的论述也相当深入和细分。

Light quarkonium and charmonium mass shifts in an unquenched quark model

The unquenched quark model for the light quarkonium and charmonium states is explored in this study.The quark-pair creation operator in the^(3)P_(0) model,which combines the two-quark and four-quark components,is modified by considering the effects of the created quark pair's energy.Furthermore,the separation between the created quark pair and valence quark pair is modified.All the wave functions,including those for the mesons and the relative motion between two mesons,are obtained by solving the corresponding Schrodinger equation using the Gaussian expansion method.The aim of this study is to find a new set of parameters that can accurately describe the mass spectrum of low-lying light quarkonium and charmonium states.Moreover,certain exotic states,such as X(3872),can be described well in the unquenched quark model.

Double-heavy tetraquarks with strangeness in the chiral quark model

Recently,some progress has been made in the experiments on double-heavy tetraquarks,such as T_(cc)reported by the LHCb Collaboration and Xccssreported by the Belle Collaboration.Coming on the heels of our previous work about T_(cc) and T_(bb), we present a study on the bound and resonance states of their companions,QQqs(Q=c,b;q=u,s) tetraquarks with strange flavor in the chiral quark model.Two pictures,meson-meson and diquark-antidiquark ones,and their couplings were considered in our calculations.Isospin violation was neglected herein.Our numerical analysis indicated that the states ccus with 1/2(1^(+)) ald bbus with 1/2(1^(+)) are the most promising stable states against strong interactions.Besides,we found several resonance states for the double-heavy strange tetraquarks with the real scaling method.

Annual variations of black carbon over the Yangtze River Delta from 2015 to 2018

In this study,the black carbon (BC) measurements in the atmosphere of Nanjing,China were continuously conducted from 2015 to 2018 using a Model AE-33 aethalometer.By combining dataset of PM_(2.5),PM_(10),CO,NO_2,SO_2,O_3 and meteorological parameters,the temporal variations and the source apportionment of BC were given in this study.The results showed that the PM_(2.5) mass concentrations decreased in Nanjing,with an average annual rate of variation of 6.50μg/(m^3·year).Differently,the annual average concentrations of BC increased with an average annual variation rate of 214.71 ng/(m^3·year).The seasonal variations showed the pattern of BC mass concentrations in winter>autumn>spring>summer.The diurnal variations of BC mass concentrations showed a double-peak in all four seasons.The first peak occurred at approximately 7:00 in spring,summer and autumn and around 8:00 in winter.The second peak took place after 18:00.The average AAE (absorption ?ngstr?m exponent) was 1.26 with a maximum of 1.35 during wintertime and the lowest(1.12) during summertime.In addition,the AAE was smaller in the daytime than that at night,with a minimum occurring between 13:00 and 14:00.BC and visibility show a good power-function relationship at different humidity levels.The average values of the visibility thresholds of the BC mass concentrations in spring,summer,autumn and winter were 1.326,5.522,1.340 and 0.708μg/m^3,respectively.The greater the relative humidity,the smaller the visibility threshold for the BC mass concentrations was.

In situ self-assembly of near-infrared-emitting gold nanoparticles into body-clearable ID nanostructures with rapid lysosome escape and fast cellular excretion

The integration of strong near-infrared(NIR)emission,rapid lysosome escape,fast cellular excretion,and efficient total body clearance is highly desired for nanoparticles(NPs)to achieve synergistic functions in both molecular imaging and delivery.Herein,using a well-designed cyclopeptide(CP)that can spontaneously assem ble into controllable nanofibers a s template,a facile strategy is reported for in situ self-assembly of NIR-emitting gold NPs(AuNPs)into ordered and well-controlled one-dimensional(1D)nanostructures(AuNPs@CP)with greatly enhanced NIR emission(〜6 fold).Comparing with the unassem bled AuNPs,the AuNPs@CP are observed to enter living cells through endocytosis,escap e from lysosome rapidly,and excrete the cell fast,which shows high gene transfection efficiencies in construction of cell line with-7.5-fold overexpression of p53 protein.Furthermore,the AuNPs@CP exhibit high in vivo diffusibility and total body clearance efficiency with minimized healthy organ retention,which are also demonstrated to be good nanovectors for plasmid complementary deoxyribonucleic acid 3.1(pcDNA3.1)(+)-internal ribosome entry site(IRES)-green fluorescent protein(GFP)-p53 plasmid with efficient p53 gene over-expression in tumor site.This facile in situ strategy in fabricating highly luminescent 1D nanostructures provides a promising approach toward future translatable multifunctional nanostructures for delivering,tracking,and therapy.

Enhancement of endocytic uptake of H IV-1 virions into CD4-negative epithelial cells by HIV-1 gp41 via its interaction with POB1

We previously used recombinant soluble gp41 （rsgp41） as a targetto screen a ntnnan oone marrow cul,~n library by the yeast two-hybrid assay, and we identified an HW-1 gp41-binding protein, human POB1 （the partner of RalBP1）. We found that the gp41- binding site was located at the C-term- inal region （aa462-521） of POB1 and the POBl-binding site was on the N-term- inal heptad repeat （NHR） region of HIV-1 gp41.

X(2900)in a chiral quark model

Recently,the LHCb Collaboration reported their observation of the first two fully open-flavor tetraquark states named X_(0)(2900)and X_(1)(2900)with unknown parity.Inspired by the report,we consider all the possible fourquark candidates for X(2900),which include the molecular structure,diquark structure,and their coupling in a chiral quark model via the Gaussian expansion method.To identify the genuine resonances,the real-scaling method(stabilization method)was employed.Our results show that five possible resonances,R_(0)(2914)withΓ=42 MeV,R_(1)(2906)withΓ=29 MeV,R_(1)(2912)withΓ=10 McV,R_(J)(2920)withΓ=9 MeV,and R_(J)(2842)withΓ=24 MeV,originate in the csqq system.Compared with experimental data,R_(0)(2914)withΓ=42 MeV may be an optimal X_(0)(2900)candidate.However,none of the resonances have a similar width for X_(1)(2900).Hence,further study is required.

The incentive and coordination strategy of sustainable construction supply chain based on robust optimisation

This paper considers the incentive and coordination problem of the construction supply chain consisting of the owner,general contractor,subcontractors and suppliers based on the sustainable development goals under uncertain environment.Firstly,according to the general contract management pattern and the relationships among those participants,we establish an uncertain bi-level nonlinear model in which the owner set the proper intensities to minimise the total cost at first while the general contractor decides its alternative and the limits to subcontractors correspondingly.Then,we convert the primal model into a deterministic bi-level nonlinear programming model based on the concept of relative robustness.Next,a solution procedure combing interactive fuzzy technique and genetic algorithm is designed.Finally,the validity of the model is verified by a numerical example.Our paper provides a method to optimise the construction project management from the perspective of supply chain under the requirement of sustainable development.