-
Small (Weinheim An Der Bergstrasse,... Apr 2024Nanomaterials have revolutionized medicine by enabling control over drugs' pharmacokinetics, biodistribution, and biocompatibility. However, most nanotherapeutic batches... (Review)
Review
Nanomaterials have revolutionized medicine by enabling control over drugs' pharmacokinetics, biodistribution, and biocompatibility. However, most nanotherapeutic batches are highly heterogeneous, meaning they comprise nanoparticles that vary in size, shape, charge, composition, and ligand functionalization. Similarly, individual nanotherapeutics often have heterogeneously distributed components, ligands, and charges. This review discusses nanotherapeutic heterogeneity's sources and effects on experimental readouts and therapeutic efficacy. Among other topics, it demonstrates that heterogeneity exists in nearly all nanotherapeutic types, examines how nanotherapeutic heterogeneity arises, and discusses how heterogeneity impacts nanomaterials' in vitro and in vivo behavior. How nanotherapeutic heterogeneity skews experimental readouts and complicates their optimization and clinical translation is also shown. Lastly, strategies for limiting nanotherapeutic heterogeneity are reviewed and recommendations for developing more reproducible and effective nanotherapeutics provided.
Topics: Humans; Animals; Nanoparticles; Nanostructures; Nanomedicine
PubMed: 38050951
DOI: 10.1002/smll.202307502 -
Cancer Letters Jan 2022Tumor heterogeneity plays a key role in prostate cancer prognosis, therapy selection, relapse, and acquisition of treatment resistance. Prostate cancer presents a... (Review)
Review
Tumor heterogeneity plays a key role in prostate cancer prognosis, therapy selection, relapse, and acquisition of treatment resistance. Prostate cancer presents a heterogeneous diversity at inter- and intra-tumor and inter-patient levels which are influenced by multiple intrinsic and/or extrinsic factors. Recent studies have started to characterize the complexity of prostate tumors and these different tiers of heterogeneity. In this review, we discuss the most common factors that contribute to tumoral diversity. Moreover, we focus on the description of the in vitro and in vivo approaches, as well as high-throughput technologies, that help to model intra-tumoral diversity. Further understanding tumor heterogeneities and the challenges they present will guide enhanced patient risk stratification, aid the design of more precise therapies, and ultimately help beat this chameleon-like disease.
Topics: Drug Resistance, Neoplasm; Genetic Heterogeneity; Humans; Male; Mutation; Neoplasm Recurrence, Local; Prostatic Neoplasms
PubMed: 34688843
DOI: 10.1016/j.canlet.2021.10.012 -
Chronic Stress (Thousand Oaks, Calif.) 2020Genome-wide association studies (GWAS) have been performed for many psychiatric disorders and revealed a complex polygenic architecture linking mental and physical... (Review)
Review
Genome-wide association studies (GWAS) have been performed for many psychiatric disorders and revealed a complex polygenic architecture linking mental and physical health phenotypes. Psychiatric diagnoses are often heterogeneous, and several layers of trait heterogeneity may contribute to detection of genetic risks per disorder or across multiple disorders. In this review, we discuss these heterogeneities and their consequences on the discovery of risk loci using large-scale genetic data. We primarily highlight the ways in which sex and diagnostic complexity contribute to risk locus discovery in schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, autism spectrum disorder, posttraumatic stress disorder, major depressive disorder, obsessive-compulsive disorder, Tourette's syndrome and chronic tic disorder, anxiety disorders, suicidality, feeding and eating disorders, and substance use disorders. Genetic data also have facilitated discovery of clinically relevant subphenotypes also described here. Collectively, GWAS of psychiatric disorders revealed that the understanding of heterogeneity, polygenicity, and pleiotropy is critical to translate genetic findings into treatment strategies.
PubMed: 32518889
DOI: 10.1177/2470547020924844 -
Biomedicines Jun 2023The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated nucleophosmin 1 () is the largest of the genetically... (Review)
Review
The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated nucleophosmin 1 () is the largest of the genetically defined groups, involving about 30% of adult AMLs and is currently recognized as a distinct entity in the actual AML classifications. AML usually occurs in de novo AML and is associated predominantly with a normal karyotype and relatively favorable prognosis. However, AMLs are genetically, transcriptionally, and phenotypically heterogeneous. Furthermore, is a clinically heterogenous group. Recent studies have in part clarified the consistent heterogeneities of these AMLs and have strongly supported the need for an additional stratification aiming to improve the therapeutic response of the different subgroups of AML patients.
PubMed: 37509445
DOI: 10.3390/biomedicines11071805 -
Nanomaterials (Basel, Switzerland) Jul 2022As the demands for improved performance of integrated circuit (IC) chips continue to increase, while technology scaling driven by Moore's law is becoming extremely... (Review)
Review
As the demands for improved performance of integrated circuit (IC) chips continue to increase, while technology scaling driven by Moore's law is becoming extremely challenging, if not impractical or impossible, heterogeneous integration (HI) emerges as an attractive pathway to further enhance performance of Si-based complementary metal-oxide-semiconductor (CMOS) chips. The underlying basis for using HI technologies and structures is that IC performance goes well beyond classic logic functions; rather, functionalities and complexity of smart chips span across the full information chain, including signal sensing, conditioning, processing, storage, computing, communication, control, and actuation, which are required to facilitate comprehensive human-world interactions. Therefore, HI technologies can bring in more function diversifications to make system chips smarter within acceptable design constraints, including costs. Over the past two decades or so, a large number of HI technologies have been explored to increase heterogeneities in materials, technologies, devices, circuits, and system architectures, making it practically impossible to provide one single comprehensive review of everything in the field in one paper. This article chooses to offer a topical overview of selected HI structures that have been validated in CMOS platforms, including a stacked-via vertical magnetic-cored inductor structure in CMOSs, a metal wall structure in the back end of line (BEOL) of CMOSs to suppress global flying noises, an above-IC graphene nano-electromechanical system (NEMS) switch and nano-crossbar array electrostatic discharge (ESD) protection structure, and graphene ESD interconnects.
PubMed: 35889564
DOI: 10.3390/nano12142340 -
Mathematical Biosciences and... Mar 2019Circadian rhythms have been observed in behavioral and physiological activities of living things exposed to the natural 24 h light-darkness cycle. Interestingly, even... (Review)
Review
Circadian rhythms have been observed in behavioral and physiological activities of living things exposed to the natural 24 h light-darkness cycle. Interestingly, even under constant darkness, living organisms maintain a robust endogenous circadian rhythm suggesting the existence of an endogenous clock. In mammals, the endogenous clock is located in the suprachiasmatic nucleus (SCN) which is composed of about 20,000 neuronal oscillators. These neuronal oscillators are heterogeneous in their properties, including the intrinsic period, intrinsic amplitude, light information sensitivity, cellular coupling strength, intrinsic amplitudes and the topological links. In this review, we introduce the influence of the heterogeneity of these properties on the two main functions of the SCN, i.e. the free running rhythm in constant darkness and entrainment to the external cycle, based on mathematical models where heterogeneous neuronal oscillators are coupled to form a network. Our findings show that the heterogeneities can alter the free running periods under constant darkness and the entrainment ability to the external cycle for the SCN by controlling a fine balance between flexibility and robustness of the clock. These findings can explain experimental observation, e.g., why the free running periods and entrainment abilities are different between species, and shed light on the heterogeneity of the SCN network.
Topics: Algorithms; Animals; Circadian Clocks; Circadian Rhythm; Computer Simulation; Darkness; Hormones; Humans; Models, Neurological; Neurons; Oscillometry; Suprachiasmatic Nucleus
PubMed: 31137191
DOI: 10.3934/mbe.2019092 -
Journal of Proteomics Feb 2019Renal diseases are driven by alterations in the entity of proteins within the kidney, at the level of single cells, nephron subunits (such as glomerulus and tubule),... (Review)
Review
Renal diseases are driven by alterations in the entity of proteins within the kidney, at the level of single cells, nephron subunits (such as glomerulus and tubule), tissues and body fluids. Histologically, kidney diseases are extremely heterogeneous. Mass-spectrometry based proteomics provides a unique opportunity to interrogate heterogeneity and dynamics of various proteome layers within the kidney to better understand physiology and pathophysiology, and to translate signaling networks into therapies. Yet, the success of this endeavor will largely depend on improving proteomic data acquisition methods toward increased reproducibility. Here, we provide an overview of targeted proteomics studies in renal tissue and their insights into major renal diseases such as diabetic nephropathy, acute kidney injury and chronic kidney disease. The technical approaches currently include antibody-based and mass spectrometry based approaches, range from single-cells to single-nephrons to bulk tissue proteomic acquisitions, and are applied to physiological studies and translational approaches in biomarker discovery. Within this context, we identify key challenges in proteomics of kidney biopsies. We also suggest that novel models of translational nephrology have increased need for targeted acquisition of proteomics data with focus on primary urinary cells, organoids and induced renal epithelial cells (IRECs). In conclusion, targeted proteomics will be very beneficial to identify heterogenic disease mechanisms that drive renal disease and further emerge as an important tool in translational kidney research. SIGNIFICANCE: Improved targeted proteomics technologies will be an important cornerstone of renal systems medicine in order to identify and tackle the heterogenic disease mechanisms driving renal disease.
Topics: Acute Kidney Injury; Diabetic Nephropathies; Humans; Kidney; Mass Spectrometry; Proteome; Proteomics
PubMed: 29522878
DOI: 10.1016/j.jprot.2018.03.001 -
Progress in Biophysics and Molecular... Dec 2016Heterogeneous distribution of electrophysiological behavior across the heart is essential for normal cardiac function. If this heterogeneity becomes excessive it may... (Review)
Review
Heterogeneous distribution of electrophysiological behavior across the heart is essential for normal cardiac function. If this heterogeneity becomes excessive it may contribute to arrhythmogenesis and sudden cardiac death. Controversy exists regarding the localization of activation and repolarization gradients in the diseased heart and how these heterogeneities contribute to arrhythmogenesis. In this review we focus on the genesis and existence of transmural heterogeneity in activation and repolarization. We will describe a possible embryonic origin of these heterogeneities and address the question how heterogeneities contribute to the genesis of the electrocardiogram and how they may cause reentrant arrhythmias. This review subsequently concentrates on several pathologies in which transmural heterogeneities are thought to play a role.
Topics: Animals; Arrhythmias, Cardiac; Electrocardiography; Electrophysiological Phenomena; Heart Ventricles; Humans
PubMed: 27221779
DOI: 10.1016/j.pbiomolbio.2016.05.009 -
Seminars in Cell & Developmental Biology Apr 2017Precision medicine is becoming considerably critical in colorectal cancer therapy. Particularly for targeted therapies, the response to anti-EGFR therapy largely varies... (Review)
Review
Precision medicine is becoming considerably critical in colorectal cancer therapy. Particularly for targeted therapies, the response to anti-EGFR therapy largely varies among individual patients. The mechanisms of anti-EGFR-based regimens resistance have been revealed, for instance, mutations in KRAS, BRAF, and PIK3CA. It is well known that colorectal cancer is a heterogeneous disease, massive evidences indicate that there are intertumour and intratumour heterogeneities in colorectal cancer. Recently, the integrative factor of the genetic, epigenetic and microenvironmental alterations that attribute to CRC heterogeneity is associated with the response to targeted therapies. We review here the possible mechanisms of heterogeneity that influence the anti-EGFR therapy, and mainly focus on the enhancive biomarkers detection to predict the therapy efficiency and select appropriate patients who are most likely to benefit from special targeted therapies, and take advantage of simultaneously blocked the multiple molecules involved in activation of independent of ligands induced EGFR signaling pathway to overcome the resistance to anti-EGFR therapies.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; Drug Resistance, Neoplasm; Genetic Heterogeneity; Humans; Models, Biological; Molecular Targeted Therapy
PubMed: 27578007
DOI: 10.1016/j.semcdb.2016.08.033 -
Herzschrittmachertherapie &... Mar 2018In the healthy heart, physiological heterogeneities in structure and in electrical and mechanical activity are crucial for normal, efficient excitation and pumping.... (Review)
Review
In the healthy heart, physiological heterogeneities in structure and in electrical and mechanical activity are crucial for normal, efficient excitation and pumping. Alterations of heterogeneity have been linked to arrhythmogenesis in various cardiac disorders such as long QT syndrome (LQTS). This inherited arrhythmia disorder is caused by mutations in different ion channel genes and is characterized by (heterogeneously) prolonged cardiac repolarization and increased risk for ventricular tachycardia, syncope and sudden cardiac death. Cardiac electrical and mechanical function are not independent of each other but interact in a bidirectional manner by electromechanical and mechano-electrical coupling. Therefore, changes in either process will affect the other. Recent experimental and clinical evidence suggests that LQTS, which is primarily considered an "electrical" disorder, also exhibits features of disturbed mechanical function and heterogeneity, which in turn appears to correlate with the risk of arrhythmia in the individual patient. In this review, we give a short overview of the current knowledge about physiological and pathological, long QT-related electrical and mechanical heterogeneity in the heart. Also, their respective roles for future risk prediction approaches in LQTS are discussed.
Topics: Biomechanical Phenomena; DNA Mutational Analysis; Death, Sudden, Cardiac; Electrocardiography; Electrophysiological Phenomena; Humans; Ion Channels; Long QT Syndrome; Myocardial Contraction; Risk Assessment; Syncope; Tachycardia, Ventricular
PubMed: 29234865
DOI: 10.1007/s00399-017-0544-9