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BioRxiv : the Preprint Server For... Jun 2023Microfluidics have enabled significant advances in molecular biology , synthetic chemistry , diagnostics , and tissue engineering . However, there has long been a...
Microfluidics have enabled significant advances in molecular biology , synthetic chemistry , diagnostics , and tissue engineering . However, there has long been a critical need in the field to manipulate fluids and suspended matter with the precision, modularity, and scalability of electronic circuits . Just as the electronic transistor enabled unprecedented advances in the control of electricity on an electronic chip, a microfluidic analogue to the transistor could enable improvements in the complex, scalable control of reagents, droplets, and single cells on an autonomous microfluidic chip. Prior works on creating a microfluidic analogue to the electronic transistor could not replicate the transistor's saturation behavior, which is crucial to perform analog amplification and is fundamental to modern circuit design . Here we exploit the fluidic phenomenon of to develop a microfluidic element with flow-pressure characteristics completely analogous to the current-voltage characteristics of the electronic transistor. As this microfluidic transistor successfully replicates all of the key operating regimes of the electronic transistor (linear, cut-off and saturation), we are able to directly translate a variety of fundamental electronic circuit designs into the fluidic domain, including the amplifier, regulator, level shifter, logic gate, and latch. Finally, we demonstrate a "smart" particle dispenser that senses single suspended particles, performs liquid signal processing, and accordingly controls the movement of said particles in a purely fluidic system without electronics. By leveraging the vast repertoire of electronic circuit design, microfluidic transistor-based circuits are easy to integrate at scale, eliminate the need for external flow control, and enable uniquely complex liquid signal processing and single-particle manipulation for the next generation of chemical, biological, and clinical platforms.
PubMed: 37398240
DOI: 10.1101/2023.05.31.543146 -
AJR. American Journal of Roentgenology Aug 2021Theranostics have shown great promise for delivering precision medicine, particularly in neuroendocrine tumors (NETs). The clinical applications of radiolabeled... (Review)
Review
Theranostics have shown great promise for delivering precision medicine, particularly in neuroendocrine tumors (NETs). The clinical applications of radiolabeled somatostatin analogues in imaging and radionuclide therapy have been rapidly increasing over the past 2 decades and are currently integrated into the management guidelines of NETs. This article summarizes the available literature on different somatostatin receptor-targeting radiopharmaceuticals with theranostic potential in NETs, pheochromocytomas, and paragangliomas. We discuss the clinical application, administration, and toxicity of recent FDA-approved radionuclide therapies, including Lu-DOTATATE in advanced gastroenteropancreatic NETs and I-MIBG in advanced paragangliomas and pheochromocytomas. Several studies support the safety and clinical efficacy of peptide receptor radionuclide therapies in disease control and quality-of-life improvement in patients with NETs and report potential benefits of combined radionuclide treatment approaches. The utility and pitfalls of functional imaging in therapy response assessment and surveillance of NETs remain to be established.
Topics: 3-Iodobenzylguanidine; Humans; Iodine Radioisotopes; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pheochromocytoma; Precision Medicine; Radiopharmaceuticals
PubMed: 34076455
DOI: 10.2214/AJR.20.23349 -
Frontiers in Pharmacology 2022Glaucoma is the main cause of irreversible visual loss worldwide, and comprises a group of progressive, age-related, and chronic optic neuropathies. Prostaglandin... (Review)
Review
Glaucoma is the main cause of irreversible visual loss worldwide, and comprises a group of progressive, age-related, and chronic optic neuropathies. Prostaglandin analogs are considered a first-line treatment in the management of glaucoma and have the best efficacy in reducing intraocular pressure. When comparing these therapeutic agents between them, long-term therapy with 0.03% bimatoprost is the most effective followed by treatment with 0.005% latanoprost and 0.004% travoprost. The prevalence of adverse events is lower for latanoprost than for other prostaglandin analogs. However, some patients do not respond to the treatment with prostaglandin analogs (non-responders). Intraocular pressure-lowering efficacy differs significantly between individuals partly owing to genetic factors. Rs1045642 in , rs4241366 in , rs9503012 in , rs10306114 in , rs11568658 in , rs10786455 and rs6686438 in were reported to be positive with the response to prostaglandin analogs in patients with glaucoma. A negative association was found between single nucleotide polymorphisms of (rs11578155 and rs6672484) and the response to prostaglandin analogs in patients with glaucoma. The current review is an analysis of the information relevant to prostaglandin analog treatments based on previous literatures. It describes in detail the clinical pharmacology and pharmacogenetics of drugs belonging to this therapeutical class to provide a sound pharmacological basis for their proper use in ophthalmological clinical practice.
PubMed: 36313286
DOI: 10.3389/fphar.2022.1015338 -
Journal of the American Chemical Society Jun 2022Since the advent of organotransuranium chemistry six decades ago, structurally verified complexes remain restricted to π-bonded carbocycle and σ-bonded hydrocarbyl...
Since the advent of organotransuranium chemistry six decades ago, structurally verified complexes remain restricted to π-bonded carbocycle and σ-bonded hydrocarbyl derivatives. Thus, transuranium-carbon multiple or dative bonds are yet to be reported. Here, utilizing diphosphoniomethanide precursors we report the synthesis and characterization of transuranium-carbene derivatives, namely, diphosphonio-alkylidene- and -heterocyclic carbene-neptunium(III) complexes that exhibit polarized-covalent σπ multiple and dative σ single transuranium-carbon bond interactions, respectively. The reaction of [NpI(THF)] with [Rb(BIPMH)] (BIPMH = {HC(PPhNSiMe)}) affords [(BIPMH)Np(I)(THF)] () in situ, and subsequent treatment with the -heterocyclic carbene {C(NMeCMe)} (I) allows isolation of [(BIPMH)Np(I)(I)] (). Separate treatment of in situ prepared with benzyl potassium in 1,2-dimethoxyethane (DME) affords [(BIPM)Np(I)(DME)] (, BIPM = {C(PPhNSiMe)}). Analogously, addition of benzyl potassium and I to gives [(BIPM)Np(I)(I)] (). The synthesis of - was facilitated by adopting a scaled-down prechoreographed approach using cerium synthetic surrogates. The thorium(III) and uranium(III) analogues of these neptunium(III) complexes are currently unavailable, meaning that the synthesis of - provides an example of experimental grounding of 5f- vs 5f- and 5f- vs 4f-element bonding and reactivity comparisons being led by nonaqueous transuranium chemistry rather than thorium and uranium congeners. Computational analysis suggests that these Np═C bonds are more covalent than U═C, Ce═C, and Pm═C congeners but comparable to analogous U═C bonds in terms of bond orders and total metal contributions to the M═C bonds. A preliminary assessment of Np═C reactivity has introduced multiple bond metathesis to transuranium chemistry, extending the range of known metallo-Wittig reactions to encompass actinide oxidation states III-VI.
PubMed: 35609882
DOI: 10.1021/jacs.2c02152 -
Current Drug Metabolism 2018Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue (SSA) developed as the successor of the first-generation SSAs. Currently, pasireotide is... (Review)
Review
BACKGROUND
Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue (SSA) developed as the successor of the first-generation SSAs. Currently, pasireotide is recommended for the treatment of patients with Cushing's disease in whom surgery was unsuccessful, and patients with acromegaly who either remain uncontrolled after surgical therapy or in whom tumor resection is not possible.
METHODS AND RESULTS
Phase II and III clinical trials have shown pasireotide efficacy in these diseases, with a similar rate of adverse events when compared with first-line SSA, although higher incidence of hyperglycemia has been observed.
CONCLUSION
Pasireotide therapy provides biochemical control, tumor volume reduction, and improves the quality of life in patients with those disorders. Furthermore, pasireotide might be considered as second-line therapy in patients with metastatic neuroendocrine tumors, and it also might be effective in other neoplasms with a high expression of somatostatin receptors. In addition, therapy with this novel agent has been effective in prevention of postoperative complications after pancreatectomy. However, considering the diversified responsiveness to this drug in vivo, future studies should identify factors predicting better clinical response to pasireotide.
Topics: Acromegaly; Animals; Gastrointestinal Neoplasms; Humans; Neuroendocrine Tumors; Pituitary ACTH Hypersecretion; Somatostatin
PubMed: 29595102
DOI: 10.2174/1389200219666180328113801 -
Mini Reviews in Medicinal Chemistry 2023Five-membered heterocycles, including furan and thiophene, play a prominent role in drug design as structural units of bioactive molecules. This review is intended to... (Review)
Review
Five-membered heterocycles, including furan and thiophene, play a prominent role in drug design as structural units of bioactive molecules. This review is intended to demonstrate the importance of the furan-2-yl, furan-3-yl, thien-2-yl and thien-3-yl substituents in the medicinal chemistry of purine and pyrimidine nucleobases, nucleosides and selected analogues. Data presented in the article are limited to compounds containing heteroaromatic ring connected through a bond and not fused to other systems. The impact of bioisosteric replacement of aryl substituents with heteroaryl ones on activities was assessed by comparison of the title compounds with their aryl counterparts. A total of 135 heteroaryl-substituted and 35 aryl-substituted derivatives are mentioned in the text and shown in the figures. The following classes of compounds are included in the article: (i) 5-heteroaryl-2'-deoxyuridines and related compounds; (ii) 8-heteroaryl- 2,9-disubstituted adenine derivatives; (iii) O-(heteroarylmethyl)guanines; (iv) 6-heteroaryl tricyclic guanine analogues; (v) 6-heteroaryl-9-benzylpurines and analogous compounds; (vi) N- furfurylcytosine, N-furfuryladenine, their derivatives and analogues; (vii) 6-heteroaryl purine and 7- deazapurine ribonucleosides; (viii) 7-heteroaryl-7-deazaadenosines, their derivatives and analogues; (ix) 4-heteroaryl fused 7-deazapurine nucleosides. In most cases various modifications of the lead compound structure performed in order to obtain the most favorable activity and selectivity are briefly discussed. The reviewed structure-activity relationship studies exemplify the search for compounds with optimized antiviral, antitumor, antimycobacterial or antiparkinsonian action.
Topics: Nucleosides; Purines; Ribonucleosides; Structure-Activity Relationship; Antiviral Agents
PubMed: 35959910
DOI: 10.2174/1389557522666220812125205 -
International Journal of Molecular... Jul 2018The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D₃, which is a central regulator of mineral homeostasis: excessive administration leads to... (Review)
Review
The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D₃, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D₃ is important to decision-making by cells, driving many cell types to growth arrest, differentiate and undergo apoptosis. 1α,25-Dihydroxyvitamin D₃ regulates gene transcription by binding to a single known receptor, the vitamin D receptor. Rapid intracellular signals are also elicited in vitro by 1α,25-dihydroxyvitamin D₃ that are independent of transcription. There are many aspects of the multiple actions of 1α,25-dihydroxyvitamin D₃ that we do not fully understand. These include how a single receptor and provoked rapid events relate to the different actions of 1α,25-dihydroxyvitamin D₃, its calcemic action per se, and whether a large number of genes are activated directly, via the vitamin D receptor, or indirectly. A strategy to resolving these issues has been to generate synthetic analogues of 1α,25-dihydroxyvitamin D₃: Some of these separate the anti-proliferative and calcemic actions of the parent hormone. Crystallography is important to understanding how differences between 1α,25-dihydroxyvitamin D₃- and analogue-provoked structural changes to the vitamin D receptor may underlie their different activity profiles. Current crystallographic resolution has not revealed such information. Studies of our new analogues have revealed the importance of the A-ring adopting the chair β-conformation upon interaction with the vitamin D receptor to receptor-affinity and biological activity. Vitamin D analogues are useful probes to providing a better understanding of the physiology of vitamin D.
Topics: Animals; Cell Differentiation; Humans; Receptors, Calcitriol; Structure-Activity Relationship; Vitamin D
PubMed: 30037036
DOI: 10.3390/ijms19072119 -
Current Opinion in Virology Apr 2019Recent outbreaks of SARS-Coronavirus and MERS-Coronavirus (CoV) have heightened awareness about the lack of vaccines or antiviral compounds approved for prevention or... (Review)
Review
Recent outbreaks of SARS-Coronavirus and MERS-Coronavirus (CoV) have heightened awareness about the lack of vaccines or antiviral compounds approved for prevention or treatment of human or potential zoonotic CoVs. Anti-CoV drug development has long been challenged by the activity of a 3' to 5' proofreading exoribonuclease unique to CoVs. Recently, a promising nucleoside analogue with broad-spectrum activity against CoVs has been identified. This review will discuss progress made in the development of antiviral nucleoside and nucleotide analogues targeting viral RNA synthesis as effective therapeutics against CoV infections and propose promising strategies for combination therapy.
Topics: Animals; Antiviral Agents; Coronavirus; Coronavirus Infections; Drug Therapy, Combination; Exoribonucleases; Humans; Middle East Respiratory Syndrome Coronavirus; Nucleosides; Severe acute respiratory syndrome-related coronavirus; Virus Replication
PubMed: 31125806
DOI: 10.1016/j.coviro.2019.04.002 -
Critical Reviews in Oncology/hematology Apr 2017The vitamin D receptor (VDR) is a member of the thyroid-steroid family of nuclear transcription factors. Following binding of the active form of vitamin D, i.e.,... (Review)
Review
The vitamin D receptor (VDR) is a member of the thyroid-steroid family of nuclear transcription factors. Following binding of the active form of vitamin D, i.e., 1,25(OH)D3 (also known as calcitriol) and interaction with co-activators and co-repressors, VDR regulates the expression of several different genes. Although relatively little work has been carried out on VDR in human cancers, several epidemiological studies suggest that low circulating levels of vitamin D are associated with both an increased risk of developing specific cancer types and poor outcome in patients with specific diagnosed cancers. These associations apply especially in colorectal and breast cancer. Consistent with these findings, calcitriol as well as several of its synthetic analogues have been shown to inhibit tumor cell growth in vitro and in diverse animal model systems. Indeed, some of these vitamin D analogues with low calcemic inducing activity (e.g., EB1089, inecalcitol, paricalcitol) have progressed to clinical trials in patients with cancer. Preliminary results from these trials suggest that these vitamin D analogues have minimal toxicity, but clear evidence of efficacy remains to be shown. Although evidence of efficacy for mono-treatment with vitamin D analogues is currently lacking, several studies have reported that supplementation with calcitriol or the presence of high endogenous circulating levels of vitamin D enhances response to standard therapies.
Topics: Animals; Humans; Neoplasms; Vitamin D
PubMed: 28325259
DOI: 10.1016/j.critrevonc.2017.02.015 -
International Journal of Molecular... Jun 2015Trehalose (α-D-glucopyranosyl α-D-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting... (Review)
Review
Trehalose (α-D-glucopyranosyl α-D-glucopyranoside) is a non-reducing sugar with unique stabilizing properties due to its symmetrical, low energy structure consisting of two 1,1-anomerically bound glucose moieties. Many applications of this beneficial sugar have been reported in the novel food (nutricals), medical, pharmaceutical and cosmetic industries. Trehalose analogues, like lactotrehalose (α-D-glucopyranosyl α-D-galactopyranoside) or galactotrehalose (α-D-galactopyranosyl α-D-galactopyranoside), offer similar benefits as trehalose, but show additional features such as prebiotic or low-calorie sweetener due to their resistance against hydrolysis during digestion. Unfortunately, large-scale chemical production processes for trehalose analogues are not readily available at the moment due to the lack of efficient synthesis methods. Most of the procedures reported in literature suffer from low yields, elevated costs and are far from environmentally friendly. "Greener" alternatives found in the biocatalysis field, including galactosidases, trehalose phosphorylases and TreT-type trehalose synthases are suggested as primary candidates for trehalose analogue production instead. Significant progress has been made in the last decade to turn these into highly efficient biocatalysts and to broaden the variety of useful donor and acceptor sugars. In this review, we aim to provide an overview of the latest insights and future perspectives in trehalose analogue chemistry, applications and production pathways with emphasis on biocatalysis.
Topics: Biocatalysis; Glucosyltransferases; Prebiotics; Trehalose
PubMed: 26084050
DOI: 10.3390/ijms160613729