The Burgeoning Significance of Liquid-Liquid Phase Separation in the Pathogenesis and Therapeutics of Cancers.

Liquid-liquid phase separation (LLPS) is a physiological phenomenon that parallels the mixing of oil and water, giving rise to compartments with diverse physical properties. Biomolecular condensates, arising from LLPS, serve as critical regulators of gene expression and control, with a particular significance in the context of malignant tumors. Recent investigations have unveiled the intimate connection between LLPS and cancer, a nexus that profoundly impacts various facets of cancer progression, including DNA repair, transcriptional regulation, oncogene expression, and the formation of critical membraneless organelles within the cancer microenvironment. This review provides a comprehensive account of the evolution of LLPS from the molecular to the pathological level. We explore the mechanisms by through which biomolecular condensates govern diverse cellular physiological processes, encompassing gene expression, transcriptional control, signal transduction, and responses to environmental stressors. Furthermore, we concentrate on potential therapeutic targets and the development of small-molecule inhibitors associated with LLPS in prevalent clinical malignancies. Understanding the role of LLPS and its interplay within the tumor milieu holds promise for enhancing cancer treatment strategies, particularly in overcoming drug resistance challenges. These insights offer innovative perspectives and support for advancing cancer therapy.

Personalized application of antimicrobial drugs in pediatric patients with augmented renal clearance: a review of literature.

The effect of renal functional status on drug metabolism is a crucial consideration for clinicians when determining the appropriate dosage of medications to administer. In critically ill patients, there is often a significant increase in renal function, which leads to enhanced drug metabolism and potentially inadequate drug exposure. This phenomenon, known as augmented renal clearance (ARC), is commonly observed in pediatric critical care settings. The findings of the current study underscore the significant impact of ARC on the pharmacokinetics and pharmacodynamics of antimicrobial drugs in critically ill pediatric patients. Moreover, the study reveals a negative correlation between increased creatinine clearance and blood concentrations of antimicrobial drugs. The article provides a comprehensive review of ARC screening in pediatric patients, including its definition, risk factors, and clinical outcomes. Furthermore, it summarizes the dosages and dosing regimens of commonly used antibacterial and antiviral drugs for pediatric patients with ARC, and recommendations are made for dose and infusion considerations and the role of therapeutic drug monitoring. CONCLUSION:  ARC impacts antimicrobial drugs in pediatric patients. WHAT IS KNOWN: • ARC is inextricably linked to the failure of antimicrobial therapy, recurrence of infection, and subtherapeutic concentrations of drugs. WHAT IS NEW: • This study provides an updated overview of the influence of ARC on medication use and clinical outcomes in pediatric patients. • In this context, there are several recommendations for using antibiotics in pediatric patients with ARC: 1) increase the dose administered; 2) prolonged or continuous infusion administration; 3) use of TDM; and 4) use alternative drugs that do not undergo renal elimination.

Corrigendum: Bibliometric analysis of evolutionary trends and hotspots of super-enhancers in cancer.

[This corrects the article DOI: 10.3389/fphar.2023.1192855.].

Individualized antibiotic dosage regimens for patients with augmented renal clearance.

Objectives: Augmented renal clearance (ARC) is a state of enhanced renal function commonly observed in 30%-65% of critically ill patients despite normal serum creatinine levels. Using unadjusted standard dosing regimens of renally eliminated drugs in ARC patients often leads to subtherapeutic concentrations, poor clinical outcomes, and the emergence of multidrug-resistant bacteria. We summarized pharmaceutical, pharmacokinetic, and pharmacodynamic research on the definition, underlying mechanisms, and risk factors of ARC to guide individualized dosing of antibiotics and various strategies for optimizing outcomes. Methods: We searched for articles between 2010 and 2022 in the MEDLINE database about ARC patients and antibiotics and further provided individualized antibiotic dosage regimens for patients with ARC. Results: 25 antibiotic dosage regimens for patients with ARC and various strategies for optimization of outcomes, such as extended infusion time, continuous infusion, increased dosage, and combination regimens, were summarized according to previous research. Conclusion: ARC patients, especially critically ill patients, need to make individualized adjustments to antibiotics, including dose, frequency, and method of administration. Further comprehensive research is required to determine ARC staging, expand the range of recommended antibiotics, and establish individualized dosing guidelines for ARC patients.

Bibliometric analysis of evolutionary trends and hotspots of super-enhancers in cancer.

Introduction: In the past decade, super-enhancer (SE) has become a research hotspot with increasing attention on cancer occurrence, development, and prognosis. To illustrate the hotspots of SE in cancer research and its evolutionary tendency, bibliometric analysis was carried out for this topic. Methods: Literature published before Dec 31, 2022, in WOSCC, was systematically classified, and Citespace, bibliometric.com/app, and GraphPad Prism analyzed the data. Results: After screening out inappropriate documents and duplicate data, 911 publications were selected for further bibliometric analysis. The top five research areas were Oncology (257, 28.211%), Cell Biology (210, 23.052%), Biochemistry Molecular Biology (209, 22.942%), Science Technology Other Topics (138, 15.148%), and Genetics Heredity (132, 14.490%). The United States of America (United States) has the highest number of documents (462, 50.71%), followed by China (303, 33.26%). Among the most productive institutions, four of which are from the United States and one from Singapore, the National University of Singapore. Harvard Medical School (7.68%) has the highest percentage of articles. Young, Richard A, with 32 publications, ranks first in the number of articles. The top three authors came from Whitehead Institute for Biomedical Research as a research team. More than two-thirds of the research are supported by the National Institutes of Health of the United States (337, 37.654%) and the United States Department of Health Human Services (337, 37.654%). And "super enhancer" (525), "cell identity" (258), "expression" (223), "cancer" (205), and "transcription factor" (193) account for the top 5 occurrence keywords. Discussion: Since 2013, SE and cancer related publications have shown a rapid growth trend. The United States continues to play a leading role in this field, as the top literature numbers, affiliations, funding agencies, and authors were all from the United States, followed by China and European countries. A high degree of active cooperation is evident among a multitude of countries. The role of SEs in cell identity, gene transcription, expression, and inhibition, as well as the relationship between SEs and TFs, and the selective inhibition of SEs, have received much attention, suggesting that they are hot issues for research.

[Distribution Characteristics and Source Apportionment of Perfluoroalkyl Substances in Surface Soils of the Northeast Tibetan Plateau].

Surface soil samples collected at 18 sites from the northeast Tibetan Plateau were used to analyze perfluoroalkyl substances (PFASs) via ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to study the concentration levels and sources of PFASs. The results showed that 11 PFASs were detected in the soil, and the ω(Σ11PFASs) ranged from 0.043-1.573 ng·g-1 with an average concentration of 0.398 ng·g-1. PFBA displayed the highest concentration level with a mean content of 0.164 ng·g-1, whereas PFHxA was at the lowest level (0.005 ng·g-1). The concentrations of the other PFASs were similar to each other (0.011-0.057 ng·g-1). Generally, PFASs contents in the west and north were higher than that in the southeast, and the alpine condensation effect existed for PFBA. The principal component analysis showed that PFASs in surface soils in the northeast Tibetan Plateau region mainly originated from the atmospheric transport of PFASs and their precursors. Few areas were affected by direct emissions of point source pollution, and the main sources were the industrial production of metals/minerals and other human activities.

[Pollution Characteristics of Organophosphate Esters in Frozen Soil on the Eastern Edge of Qinghai-Tibet Plateau].

In this study, soil samples were collected from the eastern edge of the Qinghai Tibet Plateau in December 2019. The level and distribution characteristics of organophosphate esters (OPEs) in seasonal frozen soil were analyzed, and their sources were discussed. The results showed that the target analytes including tri-n-butyl phosphate (TnBP), tris(2-ethylhexyl) phosphate (TEHP), tributoxyethyl phosphate (TBEP), triphenyl phosphate (TPhP), tri(2-chloroethyl) phosphate (TCEP), trichloropropyl phosphate (TCPP), and tris-(2,3-dichloropropyl) phosphate (TDCPP) were detected with 100% frequency. Levels of Σ7OPEs in topsoil (0-10 cm) and sub topsoil (10-20 cm) were 146.7-348.7 ng·g-1 (mean:231.1 ng·g-1) and 206.5-333.2 ng·g-1 (mean:260.2 ng·g-1), respectively. The Σ7OPEs content level is comparable to that of urban soil,which is worthy of attention. TBEP and TDCPP were the most abundant compounds in the plateau soil. Point source emissions have significant influence on the spatial distribution of OPEs, and regional deposition of OPEs contributes to all sampling sites. The migration ability of different OPE compounds in soil was different. Stronger migration ability was observed for aromatic OPEs (TPhP) than chlorinated OPEs. Principal component analysis showed that the main sources of OPEs in plateau soil were atmospheric wet and dry deposition, manufactured consumer materials, and the release of OPEs from automobile interior decoration.

High-efficiency removal capacities and quantitative adsorption mechanisms of Cd2+ by thermally modified biochars derived from different feedstocks.

Adsorption characteristics of Cd2+ on the three biochars modified by pyrolysis and calcination were investigated that were derived from rice straw (TRSB), chicken manure (TCMB) and sewage sludge (TSSB). The pH effect, adsorption kinetics, isotherms and thermodynamics, and desorption were determined, and qualitative analysis of adsorption mechanisms was performed by SEM, XRD, FTIR and XPS. Maximum adsorption capacities reached 177.28, 96.03 and 74.04 mg/g for TCMB, TRSB and TSSB, respectively, which were higher than that of many previously reported biochars. Even after five adsorption-desorption cycles, TCMB showed the strongest reusability without losing significantly adsorption capacity. This suggested that thermally modified biochars, particularly TCMB, could be a preferred adsorbent for Cd2+. Relative distribution of adsorption mechanisms was examined by direct and indirect calculation, in which the precipitation and cation-exchange dominated the whole chemisorption process, jointly accounting for 84% (TRSB) to 95% (TCMB) of total adsorption. While the complexation was of minor importance in total adsorption accounting for 5%-16%. The relationship of each mechanism with the properties of biochar was also discussed. These provided new insights on the adsorption effectiveness and mechanisms for Cd2+ in the aqueous solution that was critical for evaluating the application of modified biochars.

[Distribution and Sources of OPEs in Plants and Snow in Hailuogou].

In order to study the effects of atmospheric transport and the wet/dry deposition on the content and distribution of organophosphate esters (OPEs) in remote areas, seven types of OPEs including tri-n-butyl phosphate (TnBP), tri (2-chloroethyl) phosphate (TCEP), trichloropropyl phosphate (TCPP), tridichloropropyl phosphate (TDCPP), triphenyl phosphate (TPhP), tributoxyethyl phosphate (TBEP), and tris (2-ethylhexyl) phosphate (TEHP) were analyzed in plants and snow samples in Hailuogou using gas chromatography-mass spectrometry. The results showed that the pollution levels of the seven OPEs (∑7OPEs) in the plant samples ranged from 43.1 ng·g-1 to 1050.8 ng·g-1. TBEP and TPhP were the main pollutants, accounting for 36%-70% and 24%-80% of the ∑7OPEs, respectively. The main pollutants in the snow in Hailuogou were the same as those in the plants, with TBEP dominating the profile of the ∑7OPEs at 47%, followed by TPhP at 24%. The analysis results of the grid analysis display system (Grads), backward trajectory model, and historical wind data of Hailuogou indicate that the OPEs in this region are affected mainly by atmospheric transmission from Chengdu and the junction of Yunnan Zhaotong and Yibin, Luzhou, and Xichang. The environment of Hailuogou has obviously been disturbed by human activities. It is necessary to conduct thorough investigations of its environmental behavior and to strengthen urban pollution control measures.

Optical coherence tomography with or without enhanced depth imaging for peripapillary retinal nerve fiber layer and choroidal thickness.

AIM: To assess peripapillary retinal nerve fiber layer (RNFL) and choroidal thickness obtained with enhanced depth imaging (EDI) mode compared with those obtained without EDI mode using Heidelberg Spectralis optical coherence tomography (OCT). METHODS: Fifty eyes of 25 normal healthy subjects and 32 eyes of 20 patients with different eye diseases were included in the study. All subjects underwent 3.4 mm diameter peripapillary circular OCT scan centered on the optic disc using both the conventional and the EDI OCT protocols. The visualization of RNFL and choroidoscleral junction was assessed using an ordinal scoring scale. The paired t-test, intraclass correlation coefficient (ICC), 95% limits of agreement (LoA), and Bland and Altman plots were used to test the agreement of measurements. RESULTS: The visibility score of RNFL obtained with and without EDI was of no significant difference (P=0.532), the visualization of choroidoscleral junction was better using EDI protocol than conventional protocol (P<0.001). Peripapillary RNFL thickness obtained with EDI was slightly thicker than that obtained without EDI (103.25±9.42 µm vs 101.87±8.78 µm, P=0.010). The ICC of the two protocols was excellent with the value of 0.867 to 0.924, the 95% LoA of global RNFL thickness was between -10.0 to 7.4 µm. Peripapillary choroidal thickness obtained with EDI was slightly thinner than that obtained without EDI (147.23±51.04 µm vs 150.90±51.84 µm, P<0.001). The ICC was also excellent with the value of 0.960 to 0.987, the 95% LoA of global choroidal thickness was between -12.5 to 19.8 µm. CONCLUSION: Peripapillary circular OCT scan with or without EDI mode shows comparable results in the measurement of peripapillary RNFL and choroidal thickness.

[Research and progress on diagnosis and treatment of intervertebral space infection].

As the disc surgery were extensively developed, the incidence of intervertebral space infection was significantly increased. Due to a lack of specificity, early diagnosis is difficult and it is prone to misdiagnose. Intervertebral disc puncture sampling microorganism culture is a gold standard of antibiotic selection, but the positive detection rate needs to be improved. At present, different medical institutions have different opinious in epidemiology, treatment experiences, the choice of antibiotic treatment, the course of treatment and the way of operation. In recent years, magnetic resonance imaging, fluorine deoxidization glucose positron emission computed tomography scanning, the imaging application mediated percutaneous intervertebral disc, spinal puncture percutaneous endoscopic debridement and lavage drainage and percutaneous internal fixation combined with anterior posterior incision provide more choices for early diagnosis and treatment. Intervertebral infection should attract more attention to the prevention, early diagnosis, early specific pathogens. Doctors' experience and patients' actual situation should be considered when choosing a appropriate treatment. During the treatment, we should be closely monitored laboratory indexes and timely adjust plan of the treatment, and shorten the treatment time and prevent other complications through the auxiliary treatment.

Confinement effects on the kinetics and thermodynamics of protein dimerization.

In the cell, protein complexes form by relying on specific interactions between their monomers. Excluded volume effects due to molecular crowding would lead to correlations between molecules even without specific interactions. What is the interplay of these effects in the crowded cellular environment? We study dimerization of a model homodimer when the mondimers are free and when they are tethered to each other. We consider a structured environment: Two monomers first diffuse into a cavity of size L and then fold and bind within the cavity. The folding and binding are simulated by using molecular dynamics based on a simplified topology based model. The confinement in the cell is described by an effective molecular concentration C approximately L(-3). A two-state coupled folding and binding behavior is found. We show the maximal rate of dimerization occurred at an effective molecular concentration C(op) approximately = 1 mM, which is a relevant cellular concentration. In contrast, for tethered chains the rate keeps at a plateau when C < C(op) but then decreases sharply when C > C(op). For both the free and tethered cases, the simulated variation of the rate of dimerization and thermodynamic stability with effective molecular concentration agrees well with experimental observations. In addition, a theoretical argument for the effects of confinement on dimerization is also made.

Structure-based optimization of protein tyrosine phosphatase 1B inhibitors: from the active site to the second phosphotyrosine binding site.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from the enzyme active site into the second phosphotyrosine binding site is described. Medicinal chemistry, guided by X-ray complex structure and molecular modeling, has yielded low nanomolar PTP1B inhibitors in an efficient manner. Compounds from this chemical series were found to be actively transported into hepatocytes. This active uptake into target tissues could be one of the possible avenues to overcome the poor membrane permeability of PTP1B inhibitors.

Folding behavior of chaperonin-mediated substrate protein.

Chaperonin-mediated protein folding is complex. There have been diverse results on folding behavior, and the chaperonin molecules have been investigated as enhancing or retarding the folding rate. To understand the diversity of chaperonin-mediated protein folding, we report a study based on simulations using a simplified Go-type model. By considering effects of affinity between the substrate protein and the chaperonin wall and spatial confinement of the chaperonin cavity, we study the thermodynamics and kinetics of folding of an unfrustrated substrate protein encapsulated in a chaperonin cavity. The affinity makes the hydrophobic residues of the protein bind to the chaperonin wall, and a strong (or weak) affinity results in a large (or small) effect of binding. Compared with the folding in bulk, the folding in chaperonin cavity with different strengths of affinity shows two kinds of behaviors: one with less dependence on the affinity but more reliance on the spatial confinement effect and the other relying strongly on the affinity. It is found that the enhancement or retardation of the folding rate depends on the competition between the spatial confinement and the affinity due to the chaperonin cavity, and a strong affinity produces a slow folding while a weak affinity induces a fast folding. The crossover between two kinds of folding behaviors happens in the case that the favorable effect of confinement is balanced by the unfavorable effect of the affinity, and a critical affinity strength is roughly defined. By analyzing the contacts formed between the residues of the protein and the chaperonin wall and between the residues of the protein themselves, the role of the affinity in the folding processes is studied. The binding of the residues with the chaperonin wall reduces the formation of both native contacts and nonnative contact or mis-contacts, providing a loose structure for further folding after allosteric change of the chaperonin cavity. In addition, 15 single-site-mutated mutants are simulated in order to test the validity of our model and to investigate the importance of affinity. Inspiringly, our results of the folding rates have a good correlation with those obtained from experiments. The folding rates are inversely correlated with the strength of the binding interactions, i.e., the weaker the binding, the faster the folding. We also find that the inner hydrophobic residues have larger effects on the folding kinetics than those of the exterior hydrophobic residues. We suggest that, besides the confinement effect, the affinity acts as another important factor to affect the folding of the substrate proteins in chaperonin systems, providing an understanding of the folding mechanism of the molecular chaperonin systems.