The impact of the development of sulfur therapeutics is instrumental to the evolution of the pharmaceutical industry. Sulfur-derived functional groups can be found in a broad range of pharmaceuticals ...and natural products. For centuries, sulfur continues to maintain its status as the dominating heteroatom integrated into a set of 362 sulfur-containing FDA approved drugs (besides oxygen or nitrogen) through the present. Sulfonamides, thioethers, sulfones and Penicillin are the most common scaffolds in sulfur containing drugs, which are well studied both on synthesis and application during the past decades. In this review, these four moieties in pharmaceuticals and recent advances in the synthesis of the corresponding core scaffolds are presented.
Malignant cells support tumor proliferation and progression by adopting to metabolic changes. Tumor cells altered metabolism by increasing glucose uptake and fermentation of glucose to lactate, even ...in the aerobic state and the presence of functioning mitochondria. Glucose metabolism in tumor plasticity has attracted great interests by clinicians and scientists in the past decades. This review discusses the previous and emerging researches on the tumor plasticity altered by changing glucose metabolism in different cancer cells, including cancer stem cells (CSCs). In addition, we summarize the rising applications of glucose metabolism in tumor diagnosis and treatment. Our objective is to direct future investigation on this altered metabolic phenotype and its application in patient care.
Abstract
The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but ...usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu
2+
-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu
2+
into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing
64
Cu
2+
, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an “ideal” PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.
Positron emission tomography (PET) constitutes a functional imaging technique that is harnessed to probe biological processes in vivo. PET imaging has been used to diagnose and monitor the ...progression of diseases, as well as to facilitate drug development efforts at both preclinical and clinical stages. The wide applications and rapid development of PET have ultimately led to an increasing demand for new methods in radiochemistry, with the aim to expand the scope of synthons amenable for radiolabeling. In this work, we provide an overview of commonly used chemical transformations for the syntheses of PET tracers in all aspects of radiochemistry, thereby highlighting recent breakthrough discoveries and contemporary challenges in the field. We discuss the use of biologicals for PET imaging and highlight general examples of successful probe discoveries for molecular imaging with PET - with a particular focus on translational and scalable radiochemistry concepts that have been entered to clinical use.
Fluorine-18 (t½=109.7 min) is the most commonly used isotope to prepare radiopharmaceuticals for molecular imaging by positron emission tomography (PET). Nucleophilic aromatic substitution reactions ...of suitably activated (electron-deficient) aromatic substrates with no-carrier-added (18)Ffluoride ion are routinely carried out in the synthesis of radiotracers in high specific activities. Despite extensive efforts to develop a general (18)F-labelling technique for non-activated arenes there is an urgent and unmet need to achieve this goal. Here we describe an effective solution that relies on the chemistry of spirocyclic hypervalent iodine(III) complexes, which serve as precursors for rapid, one-step regioselective radiofluorination with (18)Ffluoride. This methodology proves to be efficient for radiolabelling a diverse range of non-activated functionalized arenes and heteroarenes, including arene substrates bearing electron-donating groups, bulky ortho functionalities, benzylic substituents and meta-substituted electron-withdrawing groups. Polyfunctional molecules and a range of previously elusive (18)F-labelled building blocks, compounds and radiopharmaceuticals are synthesized.
Colorectal cancer (CRC) incidence has decreased overall in the last several decades, but it has increased among younger adults. Prior studies have characterized this phenomenon in the United States ...(U.S.) using only a small subset of cases. We describe CRC incidence trends using high-quality data from 92% of the U.S. population, with an emphasis on those younger than 50 years.
We obtained 2001 to 2016 data from the U.S. Cancer Statistics database and analyzed CRC incidence for all age groups, with a focus on individuals diagnosed at ages 20 to 49 years (early-onset CRC). We compared incidence trends stratified by age, as well as by race/ethnicity, sex, region, anatomic site, and stage at diagnosis.
We observed 191,659 cases of early-onset and 1,097,765 cases of late-onset CRC during the study period. Overall, CRC incidence increased in every age group from 20 to 54 years. Whites were the only racial group with a consistent increase in incidence across all younger ages, with the steepest rise seen after 2012. Hispanics also experienced smaller increases in incidence in most of the younger age groups. Asians/Pacific Islanders and blacks saw no increase in incidence in any age group in 2016, but blacks continued to have the highest incidence of CRC for every age group. Greater increase in early-onset CRC incidence was observed for males, left-sided tumors, and regional and distant disease.
Early-onset CRC incidence increased overall from 2001 to 2016, but the trends were markedly different for whites, blacks, Asians/Pacific Islanders, and Hispanics. These results may inform future research on the risk factors underlying early-onset CRC.
N-methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptors, mediate a slow component of excitatory synaptic transmission in the central nervous system and play a key role in normal brain ...function and development. Genetic variations in GRIN genes encoding NMDAR subunits that alter the receptor's functional characteristics are associated with a wide range of neurological and neuropsychiatric conditions. Pathological GRIN variants located in the M2 re-entrant loop lining the channel pore cause significant functional changes, the most consequential alteration being a reduction in voltage-dependent Mg
inhibition. Voltage-dependent Mg
block is a unique feature of NMDAR biology whereby channel activation requires both ligand binding and postsynaptic membrane depolarization. Thus, loss of NMDAR Mg
block will have a profound impact on synaptic function and plasticity. Here, we choose 11 missense variants within the GRIN1, GRIN2A, and GRIN2B genes that alter residues located in the M2 loop and significantly reduce Mg
inhibition. Each variant was evaluated for tolerance to genetic variation using the 3-dimensional structure and assessed for functional rescue pharmacology via electrophysiological recordings. Three FDA-approved NMDAR drugs-memantine, dextromethorphan, and ketamine-were chosen based on their ability to bind near the M2 re-entrant loop, potentially rectifying dysregulated NMDAR function by supplementing the reduced voltage-dependent Mg
block. These results provide insight of structural determinants of FDA-approved NMDAR drugs at their binding sites in the channel pore and may further define conditions necessary for the use of such agents as potential rescue pharmacology.
Brown adipose tissue (BAT) is closely associated with thermogenesis and related to numerous diseases, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), and obesity. Using molecular ...imaging technologies to monitor BAT could facilitate etiology elucidation, disease diagnosis, and therapeutics development. Translocator protein (TSPO), an 18 kDa protein that mainly locates on the outer mitochondrial membrane, has been proven as a promising biomarker for monitoring BAT mass. Here, we lay out the steps for imaging BAT with TSPO PET tracer
F-DPA in mouse studies.
Transmission line failures in power systems propagate non-locally, making the control of the resulting outages extremely difficult. In this work, we establish a mathematical theory that characterizes ...the patterns of line failure propagation and localization in terms of network graph structure. It provides a novel perspective on distribution factors that precisely captures Kirchhoff's Law in terms of topological structures. Our results show that the distribution of specific collections of subtrees of the transmission network plays a critical role on the patterns of power redistribution, and motivates the block decomposition of the transmission network as a structure to understand long-distance propagation of disturbances. In Part I of this paper, we present the case when the post-contingency network remains connected after an initial set of lines are disconnected simultaneously. In Part II, we present the case when an outage separates the network into multiple islands.
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