CD44 and CD221 directed magnetic cubosomes for the targeted delivery of helenalin to rhabdomyosarcoma cells

Confining chemotherapy to tumour sites by means of active targeting nanoparticles(NPs)may increase the treatment effectuality while reducing potential side effects.Cubosomes are one of the next-generation drug delivery nanocarriers by virtue of their biocompatibility and bioadhesion,sizeable payload encapsulation and high thermostability.Herein,an active tumour targeting system towards rhabdomyosarcoma(RMS)cells was evaluated.Cubosomes were loaded with helenalin(a secondary metabolite from Arnica plants),which we have previously shown to induce apoptosis in RMS cells.The functionalization of the cubosomes was accomplished to enable binding to membrane receptors and translocation under a magnetic field.RMS cells overexpress CD44 and CD221 on their membrane surface and,therefore,hyaluronic acid(HA,a ligand for CD44)and antibodies(Abs)against CD221 were coupled to cubosomes via electrostatic attraction and the thiol-Michael reaction,respectively.Magnetization of the cubic phase NPs was achieved by embedding superparamagnetic iron oxide NPs(SPIONPs)into the cubic matrix.Single-function and multi-function cubosomes had Im3m cubic phase structures with well-organized lattice patterns.Conjugation with 2%HA or anti-CD221 half Abs and/or 1%SPIONPs showed significantly higher uptake into RMS cells compared to unfunctionalized cubosomes.CD44 and CD221 directed magnetic(triple-function)cubosomes were capable of internalizing into RMS cells in an energy-independent mechanism.Helenalin-laden triple functionalized cubosomes showed limited impact on the viability of control fibroblast cells,while they induced a high degree cytotoxicity against RMS cells.Profound tumour cell death was observed in both two-dimensional(2D)culture and three-dimensional(3D)tumour spheroids.

Long-Term Temperature Variability and Risk of Dyslipidemia Among Middle-Aged and Elderly Adults:A Prospective Cohort Study-China,2011-2018

Summary What is already known about this topic?Long-term temperature variability(TV)has been examined to be associated with cardiovascular disease(CVD).TV-related dyslipidemia helps us understand the mechanism of how climate change affects CVD.What is added by this report?Based on the China Health and Retirement Longitudinal Study(CHARLS)from 2011 to 2018,this study estimated the long-term effect of TV on dyslipidemia in middle-aged and elderly adults.

Syncytiotrophoblast Derived Extracellular Vesicles in Relation to Preeclampsia

The syncytiotrophoblast,a fused single-cell layer between mother and fetus,constitutively releases extracellular vesicles(STBEV)directly into the maternal circulation.STBEV contain a variety of proteins and RNA which can be targeted to specific cells.In preeclampsia,asymptomatic placental oxidative stress is a precursor to later multi-organ dysfunction in the mother.Increased STBEV release in preeclampsia is considered a manifestation of syncytiotrophoblast stress,which may play a key role in signaling between fetus and mother.STBEV release in preeclampsia changes,both in terms of volume and content.In this review,we outline the latest advances in STBEV isolation and detection.We consider evidence for differential STBEV release,protein cargo and RNA content in preeclampsia,highlighting common pitfalls in study design.We summarise studies to date demonstrating STBEV actions on target cells.Ultimately,we consider how STBEV fit into the pathophysiology of the heterogeneous syndrome of preeclampsia.The key unifying concept in early-and late-onset preeclampsia is syncytiotrophoblast stress.We submit that STBEV are the key stress signal in preeclampsia.We believe that further investigation of STBEV release,content,and actions may offer valuable insights into preeclampsia pathophysiology and potential new clinical diagnostics and therapeutic targets.

Advancing male age differentially alters levels and localization patterns of PLCzeta in sperm and testes from different mouse strains

Sperm-specific phospholipase C zeta(PLCζ)initiates intracellular calcium(Ca2+)transients which drive a series of concurrent events collectively termed oocyte activation.Numerous investigations have linked abrogation and absence/reduction of PLCζwith forms of male infertility in humans where oocyte activation fails.However,very few studies have examined potential relationships between PLCζand advancing male age,both of which are increasingly considered to be major effectors of male fertility.Initial efforts in humans may be hindered by inherent PLCζvariability within the human population,alongside a lack of sufficient controllable repeats.Herein,utilizing immunoblotting,immunofluorescence,and quantitative reverse transcription PCR(qRT-PCR)we examined for the first time PLCζprotein levels and localization patterns in sperm,and PLCζmRNA levels within testes,from mice at 8 weeks,12 weeks,24 weeks,and 36 weeks of age,from two separate strains of mice,C57BL/6(B6;inbred)and CD1(outbred).Collectively,advancing male age generally diminished levels and variability of PLCζprotein and mRNA in sperm and testes,respectively,when both strains were examined.Furthermore,advancing male age altered the predominant pattern of PLCζlocalization in mouse sperm,with younger mice exhibiting predominantly post-acrosomal,and older mice exhibiting both post-acrosomal and acrosomal populations of PLCζ.However,the specific pattern of such decline in levels of protein and mRNA was strain-specific.Collectively,our results demonstrate a negative relationship between advancing male age and PLCζlevels and localization patterns,indicating that aging male mice from different strains may serve as useful models to investigate PLCζin cases of male infertility and subfertility in humans.

Screening for early-onset neonatal sepsis on the Kaiser Permanente sepsis risk calculator could reduce neonatal antibiotic usage by two-thirds

Importance:Effective screening strategies for early-onset neonatal sepsis(EONS)have the potential to reduce high volume parenteral antibiotics(PAb)usage in neonates.Objective:To compare management decisions for EONS,between CG149 National Institute for Health and Care Excellence(NICE)guidelines and those projected through the virtual application of the Kaiser Permanente sepsis risk calculator(SRC)in a level 2 neonatal unit at a district general hospital(DGH).Methods:Hospital records were reviewed for maternal and neonatal risk factors for EONS,neonatal clinical examination findings,and microbial culture results for all neonates born at≥34 weeks’gestation between February and July 2019,who were(1)managed according to CG149-NICE guidelines or(2)received PAb within 72 h following birth at a DGH in Winchester,UK.SRC projections were obtained using its virtual risk estimator.Results:Sixty infants received PAb within the first 72 h of birth during the study period.Of these,19(31.7%)met SRC criteria for antibiotics;20(33.3%)met the criteria for enhanced observations and none had culture-proven sepsis.Based on SRC projections,neonates with’’≥1 NICE clinical indicator and≥1 risk factor’were most likely to have a sepsis risk score(SRS)>3.Birth below 37 weeks’gestation(risk ratio[RR]=2.31,95%confidence interval[CI]:1.02–5.22)and prolonged rupture of membranes(RR=3.14,95%CI:1.16–8.48)increased the risk of an SRS>3.Interpretation:Screening for EONS on the SRC could potentially reduce PAb usage by 68%in term and near-term neonates in level 2 neonatal units.

Greenness and Asthma in the Middle-Aged and Elderly Population in a Prospective Cohort Study—China,2011–2018

Summary What is already known about this topic?Greenness,which refers to the density of vegetated land,has been identified as an essential component of a healthy built environment for human health.Residential environment plays a critical role in the progression of early-onset or late-onset asthma.What is added by this report?Based on the China Health and Retirement Longitudinal Study from 2011 to 2018,this study indicates a negative association between greenness and asthma in the middle-aged and elderly population.