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.

The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors.

Digestive system tumors include malignancies of the stomach, pancreas, colon, rectum, and the esophagus, and are associated with high morbidity and mortality. Aberrant epigenetic modifications play a vital role in the progression of digestive system tumors. The aberrant transcription of key oncogenes is driven by super-enhancers (SEs), which are characterized by large clusters of enhancers with significantly high density of transcription factors, cofactors, and epigenetic modulatory proteins. The SEs consist of critical epigenetic regulatory elements, which modulate the biological characteristics of digestive system tumors including tumor cell identity and differentiation, tumorigenesis, environmental response, immune response, and chemotherapeutic resistance. The core transcription regulatory loop of the digestive system tumors is complex and a high density of transcription regulatory complexes in the SEs and the crosstalk between SEs and the noncoding RNAs. In this review, we summarized the known characteristics and functions of the SEs in the digestive system tumors. Furthermore, we discuss the oncogenic roles and regulatory mechanisms of SEs in the digestive system tumors. We highlight the role of SE-driven genes, enhancer RNAs (eRNAs), lncRNAs, and miRNAs in the digestive system tumor growth and progression. Finally, we discuss clinical significance of the CRISPR-Cas9 gene editing system and inhibitors of SE-related proteins such as BET and CDK7 as potential cancer therapeutics.

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors.

Transcriptional deregulation, a cancer cell hallmark, is driven by epigenetic abnormalities in the majority of brain tumors, including adult glioblastoma and pediatric brain tumors. Epigenetic abnormalities can activate epigenetic regulatory elements to regulate the expression of oncogenes. Superenhancers (SEs), identified as novel epigenetic regulatory elements, are clusters of enhancers with cell-type specificity that can drive the aberrant transcription of oncogenes and promote tumor initiation and progression. As gene regulators, SEs are involved in tumorigenesis in a variety of tumors, including brain tumors. SEs are susceptible to inhibition by their key components, such as bromodomain protein 4 and cyclin-dependent kinase 7, providing new opportunities for antitumor therapy. In this review, we summarized the characteristics and identification, unique organizational structures, and activation mechanisms of SEs in tumors, as well as the clinical applications related to SEs in tumor therapy and prognostication. Based on a review of the literature, we discussed the relationship between SEs and different brain tumors and potential therapeutic targets, focusing on glioblastoma.

Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery.

Gliomas are central nervous system tumors originating from glial cells, whose incidence and mortality rise in coming years. The current treatment of gliomas is surgery combined with chemotherapy or radiotherapy. However, developing therapeutic resistance is one of the significant challenges. Recent research suggested that small interfering RNA (siRNA) has excellent potential as a therapeutic to silence genes that are significantly involved in the manipulation of gliomas' malignant phenotypes, including proliferation, invasion, metastasis, therapy resistance, and immune escape. However, it is challenging to deliver the naked siRNA to the action site in the cells of target tissues. Therefore, it is urgent to develop delivery strategies to transport siRNA to achieve the optimal silencing effect of the target gene. However, there is no systematic discussion about siRNAs' clinical potential and delivery strategies in gliomas. This review mainly discusses siRNAs' delivery strategies, especially nanotechnology-based delivery systems, as a potential glioma therapy. Moreover, we envisage the future orientation and challenges in translating these findings into clinical applications.

Therapeutic Drug Monitoring of Ceftazidime-Avibactam Concentrations in Carbapenem-Resistant K. pneumoniae-Infected Patients With Different Kidney Statuses.

Aims: Carbapenem-resistant K. pneumoniae (CRKP) is the most common carbapenem-resistant Enterobacteriaceae with high mortality. Ceftazidime-avibactam (CAZ-AVI) has exhibited excellent in vitro activity in vivo against CRKP. However, the efficacy of CAZ-AVI in KPC-producing CRKP-infected patients with different kidney statuses varies, such as renal insufficiency, normal renal function, and augmented renal clearance (ARC). We explored the use of therapeutic drug monitoring (TDM) to evaluate the concentration and efficacy of CAZ-AVI in CRKP-infected patients with different kidney statuses. Methods: Serum concentrations for CAZ and AVI were determined by the high-performance liquid chromatography method. Bacterial identification, routine susceptibility testing, renal function index, and others were performed in standard protocols in the hospital's clinical laboratories. Results: In the two patients with ARC, in case 1, CAZ-AVI 2.5g q6h was used with good efficacy, and the concentrations were up to the pharmacokinetics/pharmacodynamics targets. In Case 2, 2.5 g q8h was used with invalid effectiveness, and AVI Cmin was only 0.797 mg/l, which is lower than the PK/PD target. Case 3 was renal insufficiency using CAZ-AVI 1.25 q8h, and case 4 was normal renal function using 2.5 g q8h. Their concentrations were both up to the PK/PD targets. Conclusion: TDM results demonstrated that CAZ-AVI steady-state plasma concentration varies among patients with different kidney statuses, providing evidence for the utility of TDM of CAZ-AVI in individualized drug dose adjustment. ARC patients may need more CAZ-AVI daily doses than the standard dose.

Polymyxin B-Associated Nephrotoxicity and Its Predictors: A Retrospective Study in Carbapenem-Resistant Gram-Negative Bacterial Infections.

Polymyxin B (PMB), a kind of polymyxin, was widely used in carbapenem-resistant Gram-negative bacterial (CR-GNB) infections. However, adverse reactions such as nephrotoxicity and neurotoxicity limit its use in clinical practice. The aim of this study was to explore PMB associated with nephrotoxicity and its predictors. Patients who received PMB intravenous drip for more than 72 h were eligible for the study. Characteristics of patients, concomitant nephrotoxic agents, underlying disease, and antimicrobial susceptibility were submitted for descriptive analysis. Univariate analysis and binary logistic regression were used to assess the factors leading to acute kidney injury (AKI). AKI was assessed with serum creatinine variations according to the classification of risk (stage R), injury (stage I), failure (stage F), loss, and end-stage of kidney disease. Among 234 patients with CR-GNB infections who used PMB in our study, 67 (28.63%) patients developed AKI, including 31 (14.25%) patients in stage R, 15 (6.41%) patients in stage I, and 21 (8.97%) patients in stage F. The incident rate of PMB-related nephrotoxicity in patients with normal renal function was 32.82% (43/131). The higher risk factors of AKI include males [odds ratio (OR) = 3.237; 95% confidence interval (95%CI) = 1.426-7.350], digestive system diseases [OR = 2.481 (1.127-5.463)], using furosemide (>20 mg/day) [OR = 2.473 (1.102-5.551)], and baseline serum creatinine [OR = 0.994 (0.990-0.999)]. Nonparametric tests of K-independent samples showed that baseline serum creatinine and the PMB maintenance dose were associated with the severity of nephrotoxicity (both p < 0.05). Male, digestive system diseases, using furosemide (>20 mg/day), and high baseline serum creatinine were the independent risk factors of PMB-associated AKI development. The maintenance dose of PMB may be related to the severity of AKI. These risk factors should be taken into consideration when initiating PMB-based therapy. The serum creatinine value should be closely monitored when using PMB.

Nephrotoxicity and Efficacy Assessment of Polymyxin B Use in Renal Transplant Patients.

PURPOSE: This study investigates the nephrotoxicity and efficacy assessment of polymyxin B (PMB) use in renal transplant patients. PATIENTS AND METHODS: This retrospective study included adult (>18 years of age) renal transplant patients who received PMB intravenous drip for more than 72 hours. Efficacy assessment of PMB included clinical treatment efficacy, microbiological efficacy at the end of PMB treatment, and in-hospital all-cause mortality. Nephrotoxicity of PMB was evaluated for further group comparison. RESULTS: We enrolled 235 renal transplant patients in our study. After PMB treatment, 45 patients occurred PMB-nephrotoxicity, and the nephrotoxicity rate was 19.15%. Among them, 44 patients were RIFLE R stage, and one patient was RIFLE I stage. The dose of PMB used in patients was 40.0 (40.0-50.0) mg q12h with a loading dose of 41.8±9.8 mg. Multivariate logistic regression analysis showed that ICU admission, vasoactive agents, aminoglycosides, creatinine clearance rate before PMB use, and mean total hospital stay were independent risk factors of PMB-nephrotoxicity in kidney transplant patients. The clinical effective rate was 97.9%, and the microbiological clean rate was 66.7%. CONCLUSION: Our study demonstrated that PMB low dose regimens might achieve good efficacy and less nephrotoxicity in renal transplant patients. We should evaluate the severity of the infection and renal function of patients, avoid the combined use of other nephrotoxic drugs, and minimize the course of use to reduce the occurrence of PMB-nephrotoxicity.

Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance.

Although new developments of surgery, chemotherapy, radiotherapy, and immunotherapy treatments for cancer have improved patient survival, the emergence of chemoresistance in cancer has significant impacts on treatment effects. The development of chemoresistance involves several polygenic, progressive mechanisms at the molecular and cellular levels, as well as both genetic and epigenetic heterogeneities. Chemotherapeutics induce epigenetic reprogramming in cancer cells, converting a transient transcriptional state into a stably resistant one. Super-enhancers (SEs) are central to the maintenance of identity of cancer cells and promote SE-driven-oncogenic transcriptions to which cancer cells become highly addicted. This dependence on SE-driven transcription to maintain chemoresistance offers an Achilles' heel for chemoresistance. Indeed, the inhibition of SE components dampens oncogenic transcription and inhibits tumor growth to ultimately achieve combined sensitization and reverse the effects of drug resistance. No reviews have been published on SE-related mechanisms in the cancer chemoresistance. In this review, we investigated the structure, function, and regulation of chemoresistance-related SEs and their contributions to the chemotherapy via regulation of the formation of cancer stem cells, cellular plasticity, the microenvironment, genes associated with chemoresistance, noncoding RNAs, and tumor immunity. The discovery of these mechanisms may aid in the development of new drugs to improve the sensitivity and specificity of cancer cells to chemotherapy drugs.

Clinical Analysis of Metagenomic Next-Generation Sequencing Confirmed Chlamydia psittaci Pneumonia: A Case Series and Literature Review.

INTRODUCTION: Chlamydia psittaci infection is a zoonotic infectious disease, which mainly inhaled through the lungs when exposed to the secretions of poultry that carry pathogenic bacteria. The traditional respiratory specimens or serological antibody testing is slow, and the false-negative rate is high. Metagenomic next-generation sequencing (mNGS) gives a promising rapid diagnosis tool. METHODS: We retrospectively summarized the clinical characteristics of five C. psittaci pneumonia patients diagnosed by mNGS, conducted a literature review summarizing the clinical characteristics of patients with C. psittaci pneumonia reported since 2010. RESULTS: Five C. psittaci pneumonia patients confirmed by mNGS aged from 36 to 66 years with three males. About 60% of patients had a history of contact with avian or poultry. All patients had a high fever over 38.5 °C, cough, hypodynamia, hypoxemia, and dyspnea on admission. Two patients had invasive ventilator support and extracorporeal membrane oxygenation support. Inflammatory index levels on admission and follow-up were all higher than normal values. Doxycycline or moxifloxacin and their combination therapy were used in patients. Four patients improved and were discharged, and one patient died due to multiple organ failures and disseminated intravascular coagulation. We summarized 19 articles including 69 C. psittaci pneumonia patients and patients in 11 publications were identified by mNGS, and most patients are treated with tetracycline and quinolone with good outcomes. CONCLUSION: mNGS is a promising rapid diagnosis tool, which may increase the detection rate and shorten the diagnosis time of C. psittaci pneumonia. Further case-control studies are needed to confirm.

A Comparative Study of the Microbiological Efficacy of Polymyxin B on Different Carbapenem-Resistant Gram-Negative Bacteria Infections.

Objective: The emergence of carbapenem-resistant gram-negative bacteria (CR-GNB) has brought great challenges to clinical anti-infection treatment around the world. Polymyxins are often considered as the last line of defense in the treatment of CR-GNB infections. In this study, we explored the microbiological efficacy of Polymyxin B (PMB) on different CR-GNB infections as well as the factors influencing microbiological efficacy. Methods: CR-GNB infected patients with PMB-based regimens were enrolled. Clinical and microbiological data were collected from the medical electronic record system of the Second Xiangya hospital. The efficacy of PMB on different CR-GNB was evaluated by the clearance rate at 7-days and within the course of treatment, as well as the 30-day mortality rate. Results: A total of 294 CR-GNB infected patients were enrolled: 154 CR-Acinetobacter baumannii (CRAB), 55 CR-Klebsiella pneumoniae (CRKP), and 85 CR-Pseudomonas aeruginosa (CRPA). The CRAB group had the highest 7-day bacterial clearance rate [(CRAB: 39.0%) vs. (CRKP: 29.4%) vs. (CRPA: 14.5%), P = 0.003] and total bacterial clearance rate [(CRAB: 49.0%) vs. (CRKP: 39.8%) vs. (CRPA: 18.2%), P < 0.001] among the three groups, while the bacterial clearance rate of the CRPA group was the lowest. Multivariate logistic regression showed that the differences among the three groups were multiple CR-GNB infections (P = 0.004), respiratory infections (P = 0.001), PMB resistance (P < 0.001), and the combination of tigecycline (P < 0.001). Binary logistic regression showed that multiple CR-GNB infection [(7-day bacterial clearance: P = 0.004) & (total bacterial clearance: P = 0.011)] and bacterial species [(7-day bacterial clearance: P < 0.001) & (total bacterial clearance: P < 0.001)] were independent risk factors for microbiological efficacy. Conclusion: PMB exhibited differential microbiological efficacy on different types of CR-GNB infections; it had the best effect on CRAB, followed by CRKP and CRPA. Multiple CR-GNB infections and bacterial species were independent risk factors for microbiological efficacy.