Value and Diagnostic Accuracy of Ultrasound-Guided Full Core Needle Biopsy in the Diagnosis of Lymphadenopathy: A Retrospective Evaluation of 793 Cases.

Objectives: Whole surgical lymph node excision (SNE) is considered the standard diagnostic method in the primary diagnosis of lymphadenopathy (LA) suspected of malignancy. Ultrasound-guided full core needle biopsy (UFCNB) offers an alternative method to SNE. This study examined the accuracy of UFCNB in the diagnosis of unexplained LA in 793 cases.

Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression.

Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases that bind vitamin K-dependent endogenous ligands, Protein S (ProS), and growth arrest-specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radioresistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment that can suppress host antitumor immunity. In the present study, we utilized TAM-IFNγR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity.

Discovery of a β-Hairpin Octapeptide, c[Pro-Arg-Phe-Phe-Dap-Ala-Phe-DPro], Mimetic of Agouti-Related Protein(87-132) [AGRP(87-132)] with Equipotent Mouse Melanocortin-4 Receptor (mMC4R) Antagonist Pharmacology.

Agouti-related protein (AGRP) is a potent orexigenic peptide that antagonizes the melanocortin-3 and -4 receptors (MC3R and MC4R). While the C-terminal domain of AGRP, AGRP(87-132), is equipotent to the full-length peptide, further truncation decreases potency at the MC3R and MC4R. Herein, we report AGRP-derived peptides designed to mimic the active β-hairpin secondary structure that contains the hypothesized Arg-Phe-Phe pharmacophore.

Synthesis, biophysical, and pharmacological evaluation of the melanocortin agonist AST3-88: modifications of peptide backbone at Trp 7 position lead to a potent, selective, and stable ligand of the melanocortin 4 receptor (MC4R).

The melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors are expressed in the brain and are implicated in the regulation of food intake and energy homeostasis. The endogenous agonist ligands for these receptors (α-, β-, γ-MSH and ACTH) are linear peptides with limited receptor subtype selectivity and metabolic stability, thus minimizing their use as probes to characterize the overlapping pharmacological and physiological functions of the melanocortin receptor subtypes. In the present study, an engineered template, in which the peptide backbone was modified by a heterocyclic reverse turn mimetic at the Trp(7) residue, was synthesized using solid phase peptide synthesis and characterized by a β-galactosidase cAMP based reporter gene assay.

Site-specific Labeling of a Protein Lysine Residue By Novel Kinetic Labeling Combinatorial Libraries.

The first example of a kinetic labeling library designed to enable the discovery of affinity labels is presented. Each library component (1) consists of a variable peptidyl component linked to a biotinyl moiety by a 4-mercaptobenzoyl linker in thioester format. We demonstrate that an affinity label can be uncovered by measuring reaction rates between library pools and the protein target, human serum albumin (HSA) and identifying significant outliers.

Incorporation of a bioactive reverse-turn heterocycle into a peptide template using solid-phase synthesis to probe melanocortin receptor selectivity and ligand conformations by 2D 1H NMR.

By use of a solid-phase synthetic approach, a bioactive reverse turn heterocycle was incorporated into a cyclic peptide template to probe melanocortin receptor potency and ligand structural conformations. The five melanocortin receptor isoforms (MC1R-MC5R) are G-protein-coupled receptors (GPCRs) that are regulated by endogenous agonists and antagonists. This pathway is involved in pigmentation, weight, and energy homeostasis.

(1R, 3S)-(-)-trans-PAT: a novel full-efficacy serotonin 5-HT2C receptor agonist with 5-HT2A and 5-HT2B receptor inverse agonist/antagonist activity.

The serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C) G protein-coupled receptors signal primarily through G alpha(q) to activate phospholipase C (PLC) and formation of inositol phosphates (IP) and diacylglycerol. The human 5-HT(2C) receptor, expressed exclusively in the central nervous system, is involved in several physiological and psychological processes. Development of 5-HT(2C) agonists that do not also activate 5-HT(2A) or 5-HT(2B) receptors is challenging because transmembrane domain identity is about 75% among 5-HT(2) subtypes.

Peptide and small molecules rescue the functional activity and agonist potency of dysfunctional human melanocortin-4 receptor polymorphisms.

The melanocortin pathway, specifically the melanocortin-4 receptor and the cognate endogenous agonist and antagonist ligands, have been strongly implicated in the regulation of energy homeostasis and satiety. Genetic studies of morbidly obese human patients and normal weight control patients have resulted in the discovery of over 70 human melanocortin-4 receptor (MC4R) polymorphisms observed as both heterozygous and homozygous forms. A number of laboratories have been studying these hMC4R polymorphisms attempting to understand the molecular mechanism(s) that might explain the obese human phenotype.

[The outcome of pregnancy and delivery in primigravid pregnancy with Kearn-Sayre's syndrome].

The Kearn-Sayre's syndrome is an uncommon, non-hereditary disease which belongs to the group of mitochondrial myopathy. The characteristic symptoms of this syndrome often appear before the age of 20. In this report we describe the outcome of primigravid pregnancy of a 33 year old woman with early diagnosed Kearn-Sayre's syndrome.

[Total and ionized magnesium concentration in the blood plasma and erythrocytic magnesium concentration of women in the third trimester of pregnancy with imminent preterm labor].

Objectives: There are some data concerning magnesium concentration influence on the risk of preterm labor. The estimation of magnesium concentration changes may be useful in prevention of preterm labor.

Design: Therefore the aim of our study was to find out the correlation between magnesium concentration and the risk of preterm labor.

Current trends in the structure-activity relationship studies of the endogenous agouti-related protein (AGRP) melanocortin receptor antagonist.

Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin-3 and -4 (MC3R and MC4) G-protein coupled receptors. The 87-132 amino acid C-terminal domain of hAGRP possesses five disulfide bridges and a well-defined three-dimensional structure that displays full biological activity as compared to the full-length protein. Based on the NMR structure of the C-terminal AGRP(87-132), a novel mini-protein, referred to as "Mini-AGRP" was designed that exhibited receptor binding affinity and antagonism similar to that of the parent hAGRP(87-132) protein.

Structure-activity relationships of the unique and potent agouti-related protein (AGRP)-melanocortin chimeric Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH2 peptide template.

The melanocortin receptor system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. Herein, we report the structure-activity relationship (SAR) of a new chimeric hAGRP-melanocortin agonist peptide template Tyr-c[beta-Asp-His-DPhe-Arg-Trp-Asn-Ala-Phe-Dpr]-Tyr-NH(2) that was characterized using amino acids previously reported in other melanocortin agonist templates. Twenty peptides were examined in this study, and six peptides were selected for (1)H NMR and computer-assisted molecular modeling structural analysis.

Progress in the development of melanocortin receptor selective ligands.

The melanocortin pathway consists of endogenous agonists, antagonists, G-protein coupled receptors (GPCRs), and auxiliary proteins. This pathway has been identified to participate physiologically in numerous biological pathways including energy homeostasis, pigmentation, sexual function, inflammation, cardiovascular function, adrenal function, sebaceous gland lipid production, just to list a few. During this past decade, a clear link between the melanocortin-4 receptor (MC4R) and obesity, in both mice and humans via the regulation of food intake and energy homeostasis, has made this pathway the target of many academic and industrial research endeavors in attempts to develop potent and selective MC4R small molecules as anti-obesity therapeutic agents.

Structural characterization and pharmacology of a potent (Cys101-Cys119, Cys110-Cys117) bicyclic agouti-related protein (AGRP) melanocortin receptor antagonist.

Agouti-related protein (AGRP) is one of two known naturally occurring antagonists of G-protein coupled receptors. AGRP is synthesized in the brain and is an antagonist of the melanocortin-3 and -4 receptors (MC3R, MC4R). These three proteins are involved in the regulation of energy homeostasis and obesity in both mice and humans.

Threonine at position 6 is not essential for the immunosuppressive activity of HLA-DQ(beta164-172)-hexapeptide.

It has been previously found that the nonapeptide fragment of human leukocyte antigen (HLA)-DQ molecule, located in the beta chain 164-172 with the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr sequence, suppresses the immune response. The hexapeptide: Arg-Gly-Asp-Val-Tyr-Thr was the shortest fragment of HLA-DQ showing both cellular and humoral immunosuppressive activity, while the analog deprived of the last amino acid (Arg-Gly-Asp-Val-Tyr) showed very weak stimulatory activity with respect to the humoral immune response. This suggested that the threonine residue in the hexapeptide plays an essential role in immunosuppression.

Immunosuppressory activity of ubiquitin fragments containing retro-RGD sequence.

A peptide fragment corresponding to the ubiquitin(50-59) sequence (LEDGRTLSDY) (U50-59) possesses a very high immunosuppressory activity, comparable to that of cyclosporine, both in the cellular and humoral immune responses. We found that the pentapeptide DGRTL (U52-56) is the shortest, effective immunosuppressory fragment of ubiquitin, although its potency is weaker than that of U50-59. Replacement of each consecutive residue with alanine in U52-56 allowed identification of essential amino acids involved in the immunosuppression.

Chimeric NDP-MSH and MTII melanocortin peptides with agouti-related protein (AGRP) Arg-Phe-Phe amino acids possess agonist melanocortin receptor activity.

Agouti-related protein (AGRP) is one of only two known endogenous antagonists of G-protein coupled receptors (GPCRs). Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis, regulation of feeding behavior, and obesity. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these receptors.

Identification of putative agouti-related protein(87-132)-melanocortin-4 receptor interactions by homology molecular modeling and validation using chimeric peptide ligands.

Agouti-related protein (AGRP) is one of only two naturally known antagonists of G-protein-coupled receptors (GPCRs) identified to date. Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these melanocortin receptors.

Design, synthesis and biological evaluation of a new bridged immunosuppressor.

A bridged peptide with the sequence: H-Thr-Pro-Gln-Arg-Gly-Asp-Val-gamma-Abu-Asn-Asp-Gln-Glu-Glu-Thr-Thr-Gly-Val-Val-Ser-Thr-Pro-Leu-Ile-Arg-Asn-Gly-OH was designed to mimic the discontinuous epitope of the HLA-DQ molecule that might interact with CD4. The bridged peptide revealed distinct suppressory effect in the humoral immune response. This result supports our suggestion that the 164-172 region of the HLA-DQ molecule may enhance its interactions with coreceptors, possibly with CD4.

New conformationally restricted analog of the immunosuppressory mini-domain of HLA-DQ and its biological properties.

Our previous studies revealed that the nonapeptide fragment of HLA-DQ located in the beta 164-172 loop of the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr sequence suppresses the immune humoral and cellular responses [30]. Based on the crystal structure of HLA-class II molecules we designed and synthesized a cyclic analog with restricted conformation, cyclo(Suc-Thr-Pro-Gln-Arg-Gly-Asp-Val-Lys)-Thr-OH (Suc = succinyl) by reacting a Lys side chain with a succinylated N-terminus. The cyclization product more potently suppresses the cellular immune response than its linear counterparts and is efficiently cleaved by trypsin.

Immunosuppressory mini-regions of HLA-DP and HLA-DR.

Our previous studies showed, that the,TPQRGDVYT, QRGDVYT and RGDVYT fragments, located in the beta164-172 loop of HLA-DQ, strongly suppress the humoral and cellular immune response, while their shorter analogs, RGDV, RGDVY, and QRGDVY, show only weak stimulatory activity in respect to humoral immunological response. The fragments contain the RGDVY sequence that is analogous to thymopentin (pentapeptide RKDVY, an immune system activator) as well as the RGD sequence, known for its importance for cellular association phenomena. Based on the crystal structure of HLA-DR1, we also designed and synthesized a cyclic analog C*RGDVYC* (where C* indicates Cys participating in disulfide bridge) with restricted conformation, which strongly suppresses both humoral and cellular immune response.

Further investigations on thymopentin-like fragments of HLA-DQ and their analogs.

Recently we showed that the fragments of HLA-DQ with the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr and Gln-Arg-Gly-Asp-Val-Tyr-Thr sequences strongly suppress the immune response, while their shorter analogs, Arg-Gly-Asp-Val, Arg-Gly-Asp-Val-Tyr and Gln-Arg-Gly-Asp-Val-Tyr, show very weak stimulatory activity with respect to humoral immunological response. The fragments contain the sequence which is very similar to thymopentin (pentapeptide Arg-Lys-Asp-Val-Tyr, an active fragment (32-36) of thymopoietin, an immune system activator produced in thymi), and at the same time contains the Arg-Gly-Asp (RGD) sequence, known as an inhibitor of adhesion processes. In the present study we found that a hexapeptide: Arg-Gly-Asp-Val-Tyr-Thr is the smallest size fragment of HLA-DQ having both cellular and humoral immunosuppressive activity.

The immunosuppressory and adhesive miniregion of the human major histocompatibility protein, human leukocyte antigen DQ.

Our previous studies showed that the nonapeptide fragment of human leukocyte antigen DQ with the TPQRGDVYT sequence strongly suppresses the immune response [Z. Szewczuk, I. Z.