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Cancer Cell Apr 2024Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To...
Intratumor morphological heterogeneity of pancreatic ductal adenocarcinoma (PDAC) predicts clinical outcomes but is only partially understood at the molecular level. To elucidate the gene expression programs underpinning intratumor morphological variation in PDAC, we investigated and deconvoluted at single cell level the molecular profiles of histologically distinct clusters of PDAC cells. We identified three major morphological and functional variants that co-exist in varying proportions in all PDACs, display limited genetic diversity, and are associated with a distinct organization of the extracellular matrix: a glandular variant with classical ductal features; a transitional variant displaying abortive ductal structures and mixed endodermal and myofibroblast-like gene expression; and a poorly differentiated variant lacking ductal features and basement membrane, and showing neuronal lineage priming. Ex vivo and in vitro evidence supports the occurrence of dynamic transitions among these variants in part influenced by extracellular matrix composition and stiffness and associated with local, specifically neural, invasion.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Extracellular Matrix; Basement Membrane; Nervous System
PubMed: 38518775
DOI: 10.1016/j.ccell.2024.02.017 -
Small Methods Nov 2023As a highly promising approach to solving the issues of energy and environment, membrane technology has gained increasing attention in various fields including water... (Review)
Review
As a highly promising approach to solving the issues of energy and environment, membrane technology has gained increasing attention in various fields including water treatment, liquid separations, and gas separations, owing to its high energy efficiency and eco-friendliness. Surface segregation, a phenomenon widely found in nature, exhibits irreplaceable advantages in membrane fabrication since it is an in situ method for synchronous modification of membrane and pore surfaces during the membrane forming process. Meanwhile, combined with the development of synthesis chemistry and nanomaterial, the group has developed surface segregation as a versatile membrane fabrication method using diverse surface segregation agents. In this review, the recent breakthroughs in surface segregation methods and their applications in membrane fabrication are first briefly introduced. Then, the surface segregation phenomena and the classification of surface segregation agents are discussed. As the major part of this review, the authors focus on surface segregation methods including free surface segregation, forced surface segregation, synergistic surface segregation, and reaction-enhanced surface segregation. The strategies for regulating the physical and chemical microenvironments of membrane and pore surfaces through the surface segregation method are emphasized. The representative applications of surface segregation membranes are presented. Finally, the current challenges and future perspectives are highlighted.
PubMed: 37668447
DOI: 10.1002/smtd.202300737 -
Biomedicines Feb 2024The nephrotic syndrome holds significant clinical importance and is characterized by a substantial protein loss in the urine. Damage to the glomerular basement membrane... (Review)
Review
The nephrotic syndrome holds significant clinical importance and is characterized by a substantial protein loss in the urine. Damage to the glomerular basement membrane or podocytes frequently underlies renal protein loss. There is an increasing belief in the involvement of the complement system, a part of the innate immune system, in these conditions. Understanding the interactions between the complement system and glomerular structures continually evolves, challenging the traditional view of the blood-urine barrier as a passive filter. Clinical studies suggest that a precise inhibition of the complement system at various points may soon become feasible. However, a thorough understanding of current knowledge is imperative for planning future therapies in nephrotic glomerular diseases such as membranous glomerulopathy, membranoproliferative glomerulonephritis, lupus nephritis, focal segmental glomerulosclerosis, and minimal change disease. This review provides an overview of the complement system, its interactions with glomerular structures, and insights into specific glomerular diseases exhibiting a nephrotic course. Additionally, we explore new diagnostic tools and future therapeutic approaches.
PubMed: 38398059
DOI: 10.3390/biomedicines12020455 -
Journal of Controlled Release :... May 2024My contribution to honoring Professor Kinam Park celebrates and resonates with his scholarly career in drug delivery, his commitment to encouraging the next... (Review)
Review
My contribution to honoring Professor Kinam Park celebrates and resonates with his scholarly career in drug delivery, his commitment to encouraging the next generation(s), and his efforts to keep us focused on clinically effective formulations. To do this I take as my example, niclosamide, a small molecule protonophore that, uniquely, can "target" all cell membranes, both plasma and organelle. As such, it acts upstream of many cell pathways and so has the potential to affect many of the essential events that a cell, and particularly a diseased cell or other entities like a virus, use to stay alive and prosper. Literature shows that it has so far been discovered to positively influence (at least): cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, systemic sclerosis, Parkinson's, and COPD. With such a fundamental action and broad-spectrum activity, I believe that studying niclosamide in all its manifestations, discovering if and to what extent it can contribute positively to disease control (and also where it can't), formulating it as effective therapeutics, and testing them in preclinical and clinical trials is a career builder for our next generation(s). The article is divided into two parts: Part I introduces niclosamide and other proton shunts mainly in cancer and viral infections and reviews an exponentially growing literature with some concepts and physicochemical properties that lead to its proton shunt mechanism. Part II focuses on repurposing by reformulation of niclosamide. I give two examples of "carrier-free formulations", - one for cancer (as a prodrug therapeutic of niclosamide stearate for i.v. and other administration routes, exemplified by our recent work on Osteosarcoma in mice and canine patients), and the other as a niclosamide solution formulation (that could provide the basis for a preventative nasal spray and early treatment option for COVID19 and other respiratory virus infections). My goal is to excite and enthuse, encourage, and motivate all involved in the drug development and testing process in academia, institutes, and industry, to learn more about this interesting molecule and others like it. To enable such endeavors, I give many proposed ideas throughout the document, that have been stimulated and inspired by gaps in the literature, urgent needs in disease, and new studies arising from our own work. The hope is that, by reading through this document and studying the suggested topics and references, the drug delivery and development community will continue our lineage and benefit from our legacy to achieve niclosamide's potential as an effective contributor to the treatment and control of many diseases and conditions.
Topics: Humans; Niclosamide; Animals; Drug Delivery Systems
PubMed: 37544514
DOI: 10.1016/j.jconrel.2023.07.016 -
Materials (Basel, Switzerland) Sep 2023The science related to biomaterials and tissue engineering accounts for a growing part of our knowledge. Surface modifications of biomaterials, their performance in... (Review)
Review
The science related to biomaterials and tissue engineering accounts for a growing part of our knowledge. Surface modifications of biomaterials, their performance in vitro, and the interaction between them and surrounding tissues are gaining more and more attention. It is because we are interested in finding sophisticated materials that help us to treat or mitigate different disorders. Therefore, efficient methods for surface analysis are needed. Several methods are routinely applied to characterize the physical and chemical properties of the biomaterial surface. Mass Spectrometry Imaging (MSI) techniques are able to measure the information about molecular composition simultaneously from biomaterial and adjacent tissue. That is why it can answer the questions connected with biomaterial characteristics and their biological influence. Moreover, this kind of analysis does not demand any antibodies or dyes that may influence the studied items. It means that we can correlate surface chemistry with a biological response without any modification that could distort the image. In our review, we presented examples of biomaterials analyzed by MSI techniques to indicate the utility of SIMS, MALDI, and DESI-three major ones in the field of biomaterials applications. Examples include biomaterials used to treat vascular system diseases, bone implants with the effects of implanted material on adjacent tissues, nanofibers and membranes monitored by mass spectrometry-related techniques, analyses of drug-eluting long-acting parenteral (LAPs) implants and microspheres where MSI serves as a quality control system.
PubMed: 37763619
DOI: 10.3390/ma16186343 -
The Journal of Allergy and Clinical... Jun 2024Nasal obstruction is the subjective perception and objective state of insufficient airflow through the nose. Nasal congestion, conversely, describes a state of not just... (Review)
Review
Nasal obstruction is the subjective perception and objective state of insufficient airflow through the nose. Nasal congestion, conversely, describes a state of not just inadequate airflow or obstructive phenomena but also pressure- and mucus-related states to the patient. Nasal receptors belonging to the transient receptor potential (TRP) protein family mediate the sense of nasal patency via the trigeminal nerve. The transient receptor potential melastatin-8 (TRPM8) responds to temperatures around 8°C to 22°C, and is stimulated by menthol and other cooling agents. The radiant effects of airflow create heat loss to activate these receptors and humans perceive this as nasal patency rather than the direct detection of airflow. The thermovascular state of the mucosa, in conditions such as rhinitis, influence TRPM8 activation. Nasal endoscopy can show signs of rhinitis and should be considered an essential part of the workup of nasal congestion. Efforts to relieve nasal congestion need to manage the mucosal state and surgery needs to ensures that the nasal cavity mucosa is exposed to the cooling effects of airflow rather than simply creating a passage to the nasopharynx.
Topics: Humans; Nasal Obstruction; Nasal Mucosa; TRPM Cation Channels; Endoscopy; Rhinitis
PubMed: 38677589
DOI: 10.1016/j.jaip.2024.04.028 -
Gut Microbes Dec 2023Intestinal microbes impact the health of the intestine and organs distal to the gut. is a human intestinal microbe that promotes normal gut transit, the...
Intestinal microbes impact the health of the intestine and organs distal to the gut. is a human intestinal microbe that promotes normal gut transit, the anti-inflammatory immune system, wound healing, normal social behavior in mice, and prevents bone reabsorption. Oxytocin impacts these functions and oxytocin signaling is required for -mediated wound healing and social behavior; however, the events in the gut leading to oxytocin stimulation and beneficial effects are unknown. Here we report evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, human intestinal organoids produce oxytocin, demonstrating that the intestinal epithelium is sufficient to produce oxytocin. We find that facilitates oxytocin secretion from human intestinal tissue and human intestinal organoids. Finally, we demonstrate that stimulation of oxytocin secretion by is dependent on the gut hormone secretin, which is produced in enteroendocrine cells, while oxytocin itself is produced in enterocytes. Altogether, this work demonstrates that oxytocin is produced and secreted from enterocytes in the intestinal epithelium in response to secretin stimulated by . This work thereby identifies oxytocin as an intestinal hormone and provides mechanistic insight into avenues by which gut microbes promote host health.
Topics: Humans; Animals; Mice; Secretin; Oxytocin; Gastrointestinal Microbiome; Gastrointestinal Hormones; Intestinal Mucosa; Limosilactobacillus reuteri
PubMed: 37698879
DOI: 10.1080/19490976.2023.2256043