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Endocrinology, Diabetes & Metabolism... Dec 2022Large-cell neuroendocrine carcinoma (LCNEC) is a rare neuroendocrine prostatic malignancy. It usually arises after androgen deprivation therapy (ADT), while de novo...
SUMMARY
Large-cell neuroendocrine carcinoma (LCNEC) is a rare neuroendocrine prostatic malignancy. It usually arises after androgen deprivation therapy (ADT), while de novo cases are even more infrequent, with only six cases described. The patient was a 78-year-old man with no history of ADT who presented with cervical lymphadenopathy. Diagnostic approaches included PET/CT, MRI, CT scans, ultrasonography, biopsies, and cytological and immunohistochemical evaluations. Results showed a poorly differentiated carcinoma in the thyroid gland accompanied by cervical lymph node enlargement. Thyroid surgery revealed LCNEC metastasis to the thyroid gland. Additional metastases were identified in both the adrenal glands. Despite appropriate treatment, the patient died of the disease. De novo LCNEC of the prostate is a rare, highly aggressive tumor with a poor prognosis. It is resistant to most therapeutic agents, has a high metastatic potential, and is usually diagnosed at an advanced stage. Further studies are required to characterize this tumor.
LEARNING POINTS
De novo LCNECs of the prostate gland can metastasize almost anywhere in the body, including the thyroid and adrenal glands. LCNECs of the prostate are usually associated with androgen-depriving therapy, but de novo cases are also notable and should be accounted for. Further studies are required to fully understand and treat LCNECs more effectively.
PubMed: 36511447
DOI: 10.1530/EDM-22-0301 -
Molecular Metabolism Nov 2021Sphingolipid-mediated signalling pathways are described as important players in the normal functioning of neurons and nonneuronal cells in the central nervous system... (Review)
Review
BACKGROUND
Sphingolipid-mediated signalling pathways are described as important players in the normal functioning of neurons and nonneuronal cells in the central nervous system (CNS).
SCOPE OF REVIEW
This review aims to show role of de novo ceramide synthesis in the CNS in controling key physiological processes, including food intake, energy expenditure, and thermogenesis. The corollary is a condition that leads to a dysfunction in ceramide metabolism in these central regions that can have major consequences on the physiological regulation of energy balance.
MAJOR CONCLUSIONS
Excessive hypothalamic de novo ceramide synthesis has been shown to result in the establishment of central insulin resistance, endoplasmic reticulum stress, and inflammation. Additionally, excessive hypothalamic de novo ceramide synthesis has also been associated with changes in the activity of the autonomic nervous system. Such dysregulation of hypothalamic de novo ceramide synthesis forms the key starting point for the initiation of pathophysiological conditions such as obesity - which may or may not be associated with type 2 diabetes.
Topics: Animals; Ceramides; Humans; Hypothalamus; Metabolic Diseases; Obesity
PubMed: 34273578
DOI: 10.1016/j.molmet.2021.101298 -
Life (Basel, Switzerland) Mar 2021De novo protein design is a powerful methodology used to study natural functions in an artificial-protein context. Since its inception, it has been used to reproduce a... (Review)
Review
De novo protein design is a powerful methodology used to study natural functions in an artificial-protein context. Since its inception, it has been used to reproduce a plethora of reactions and uncover biophysical principles that are often difficult to extract from direct studies of natural proteins. Natural proteins are capable of assuming a variety of different structures and subsequently binding ligands at impressively high levels of both specificity and affinity. Here, we will review recent examples of de novo design studies on binding reactions for small molecules, nucleic acids, and the formation of protein-protein interactions. We will then discuss some new structural advances in the field. Finally, we will discuss some advancements in computational modeling and design approaches and provide an overview of some modern algorithmic tools being used to design these proteins.
PubMed: 33802210
DOI: 10.3390/life11030225 -
Development (Cambridge, England) May 2023De novo root regeneration (DNRR) is a developmental process that regenerates adventitious roots from wounded tissues. Phytohormone signaling pathways involved in...
De novo root regeneration (DNRR) is a developmental process that regenerates adventitious roots from wounded tissues. Phytohormone signaling pathways involved in microbial resistance are mobilized after cutting and influence de novo root regeneration. Microbes may positively or negatively influence the development and stress responses of a plant. However, most studies on the molecular mechanisms of de novo organogenesis are performed in aseptic conditions. Thus, the potential crosstalk between organ regeneration and biotic stresses is underexplored. Here, we report the development of a versatile experimental system to study the impact of microbes on DNRR. Using this system, we found that bacteria inhibited root regeneration by activation of, but not limited to, pathogen-associated molecular pattern (PAMP)-triggered immunity. Sensing bacteria-derived flagellin 22 peptide (flg22) inhibited root regeneration by interfering with the formation of an auxin maximum at the wound site. This inhibition relies on the receptor complex that recognizes microbial patterns but may bypass the requirement of salicylic acid signaling.
Topics: Arabidopsis Proteins; Arabidopsis; Plant Growth Regulators; Indoleacetic Acids; Plant Roots; Gene Expression Regulation, Plant
PubMed: 37073949
DOI: 10.1242/dev.201485 -
Frontiers in Nutrition 2022Fructose consumption is a potential risk factor for hyperuricemia because uric acid (UA) is a byproduct of fructose metabolism caused by the rapid consumption of...
BACKGROUND
Fructose consumption is a potential risk factor for hyperuricemia because uric acid (UA) is a byproduct of fructose metabolism caused by the rapid consumption of adenosine triphosphate and accumulation of adenosine monophosphate (AMP) and other purine nucleotides. Additionally, a clinical experiment with four gout patients demonstrated that intravenous infusion of fructose increased the purine synthesis rate, which implied fructose-induced hyperuricemia might be related to purine nucleotide synthesis. Moreover, the mechanistic (mammalian) target of rapamycin (mTOR) is a key protein both involved in fructose metabolism and purine synthesis. The present study was conducted to elucidate how fructose influences mTOR and purine synthesis in a hepatic cell line and livers of mice.
MATERIALS AND METHODS
RNA-sequencing in NCTC 1469 cells treated with 0- and 25-mM fructose for 24 h and metabolomics analysis on the livers of mice fed with 0- and 30-g/kg fructose for 2 weeks were assessed. Gene and protein expression of phosphoribosyl pyrophosphate synthase (PRPSAP1), Glutamine PRPP aminotransferase (PPAT), adenyl succinate lyase (ADSL), adenyl succinate synthetase isozyme-1 (Adss1), inosine-5'-monophosphate dehydrogenase (IMPDH), and guanine monophosphate synthetase (GMPS) was measured. The location of PRPSAP1 and PPAT in the liver was assessed by an immunofluorescence assay.
RESULTS
Metabolite profiling showed that the level of AMP, adenine, adenosine, hypoxanthine, and guanine was increased significantly. RNA-sequencing showed that gene expression of phosphoribosyl pyrophosphate synthase (PRPS2), phosphoribosyl glycinamide formyl transferase (GART), AICAR transformylase (ATIC), ADSL, Adss1, and IMPDH were raised, and gene expression of adenosine monophosphate deaminase 3 (AMPD3), adenosine deaminase (ADA), 5',3'-nucleotidase, cytosolic (NT5C), and xanthine oxidoreductase (XOR) was also increased significantly. Fructose increased the gene expression, protein expression, and fluorescence intensity of PRPSAP1 and PPAT in mice livers by increasing mTOR expression. Fructose increased the expression and activity of XOR, decreased the expression of uricase, and increased the serum level of UA.
CONCLUSION
This study demonstrated that the increased purine synthesis may be a crucial mechanism for fructose-induced hyperuricemia.
PubMed: 36601078
DOI: 10.3389/fnut.2022.1045805 -
World Journal of Hepatology Dec 2021Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new acronym adopted from the consensus of international experts. Given the increasing prevalence of... (Review)
Review
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new acronym adopted from the consensus of international experts. Given the increasing prevalence of MAFLD in pre-transplant settings, and recurrent graft steatosis/MAFLD are common in post-transplant settings. The impact of graft steatosis on long-term outcomes is unclear. The current knowledge of incidence rate, risk factors, diagnosis, long-term outcomes, and management of graft steatosis (both and recurrent) is discussed in this review.
PubMed: 35070003
DOI: 10.4254/wjh.v13.i12.1991 -
Biology Jan 2023Protein therapeutics have been widely used to treat hematological disorders. With the advent of de novo protein design, protein therapeutics are not limited to... (Review)
Review
Protein therapeutics have been widely used to treat hematological disorders. With the advent of de novo protein design, protein therapeutics are not limited to ameliorating natural proteins but also produce novel protein sequences, folds, and functions with shapes and functions customized to bind to the therapeutic targets. De novo protein techniques have been widely used biomedically to design novel diagnostic and therapeutic drugs, novel vaccines, and novel biological materials. In addition, de novo protein design has provided new options for treating hematological disorders. Scientists have designed protein switches called Colocalization-dependent Latching Orthogonal Cage-Key pRoteins (Co-LOCKR) that perform computations on the surface of cells. De novo designed molecules exhibit a better capacity than the currently available tyrosine kinase inhibitors in chronic myeloid leukemia therapy. De novo designed protein neoleukin-2/15 enhances chimeric antigen receptor T-cell activity. This new technique has great biomedical potential, especially in exploring new treatment methods for hematological disorders. This review discusses the development of de novo protein design and its biological applications, with emphasis on the treatment of hematological disorders.
PubMed: 36829445
DOI: 10.3390/biology12020166 -
Proceedings of the National Academy of... Oct 2022De novo protein design enables the exploration of novel sequences and structures absent from the natural protein universe. De novo design also stands as a stringent test...
De novo protein design enables the exploration of novel sequences and structures absent from the natural protein universe. De novo design also stands as a stringent test for our understanding of the underlying physical principles of protein folding and may lead to the development of proteins with unmatched functional characteristics. The first fundamental challenge of de novo design is to devise "designable" structural templates leading to sequences that will adopt the predicted fold. Here, we built on the TopoBuilder (TB) de novo design method, to automatically assemble structural templates with native-like features starting from string descriptors that capture the overall topology of proteins. Our framework eliminates the dependency of hand-crafted and fold-specific rules through an iterative, data-driven approach that extracts geometrical parameters from structural tertiary motifs. We evaluated the TopoBuilder framework by designing sequences for a set of five protein folds and experimental characterization revealed that several sequences were folded and stable in solution. The TopoBuilder de novo design framework will be broadly useful to guide the generation of artificial proteins with customized geometries, enabling the exploration of the protein universe.
Topics: Models, Molecular; Protein Engineering; Protein Folding; Proteins
PubMed: 36252041
DOI: 10.1073/pnas.2206111119 -
Cancers Oct 2023De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since... (Review)
Review
De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities for de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have modified the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as a predictive biomarker requires further validation, and it remains to be ascertained how the genomic variants detected in mHSPC, which are regarded as predictive in the castration-resistant disease, can be exploited in the mHSPC setting.
PubMed: 37894312
DOI: 10.3390/cancers15204945 -
Prostate International Sep 2021Probably, patients with de novo (synchronous) and recurrent (metachronous) oligometastatic hormone-sensitive prostate cancer have different oncologic outcomes. Thus, we... (Review)
Review
Probably, patients with de novo (synchronous) and recurrent (metachronous) oligometastatic hormone-sensitive prostate cancer have different oncologic outcomes. Thus, we are challenged with different scenarios in clinical practice, where different treatment options may apply. In the last years, several prospective studies have focused on the treatment of patients with de novo oligometastatic hormone-sensitive prostate cancer. Not only the addition of systemic therapeutic treatments, such as chemotherapy with docetaxel, abiraterone, enzalutamide, and apalutamide, next to androgen deprivation therapy, demonstrated to improve outcomes in these patients but also local therapy of the primary has been demonstrated to improve outcomes of low-volume metastatic disease. Next to radiotherapy, also radical prostatectomy has been reported as a feasible and safe treatment option. Additional metastasis-directed therapy in de novo metastatic disease is currently examined by four trials. In the recurrent metastatic setting, less data are available, and it remains uncertain if patients can be treated in the same way as synchronous oligometastatic disease. Metastasis-directed therapy has demonstrated to prolong outcomes, while data on survival are still missing.
PubMed: 34692582
DOI: 10.1016/j.prnil.2020.12.003