Can Machine Learning Models Detect and Predict Lymph Node Involvement in Prostate Cancer? A Comprehensive Systematic Review.

(1) Background: Recently, Artificial Intelligence (AI)-based models have been investigated for lymph node involvement (LNI) detection and prediction in Prostate cancer (PCa) patients, in order to reduce surgical risks and improve patient outcomes. This review aims to gather and analyze the few studies available in the literature to examine their initial findings. (2) Methods: Two reviewers conducted independently a search of MEDLINE databases, identifying articles exploring AI's role in PCa LNI. Sixteen studies were selected, and their methodological quality was appraised using the Radiomics Quality Score. (3) Results: AI models in Magnetic Resonance Imaging (MRI)-based studies exhibited comparable LNI prediction accuracy to standard nomograms. Computed Tomography (CT)-based and Positron Emission Tomography (PET)-CT models demonstrated high diagnostic and prognostic results. (4) Conclusions: AI models showed promising results in LN metastasis prediction and detection in PCa patients. Limitations of the reviewed studies encompass retrospective design, non-standardization, manual segmentation, and limited studies and participants. Further research is crucial to enhance AI tools' effectiveness in this area.

A rare cause of right-upper quadrant abdominal pain: Epiploic appendagitis of the hepatic flexure.

Epiploic appendagitis (EA) is an uncommon cause of acute abdominal pain that may mimic other causes of acute abdomen. Epiploic appendages are outpouching of fat tissue located on the external wall of the colon, being more numerous in the descending and sigmoid colon that account for up to 80% of EA cases. We present the case of a 59-year-old woman with right upper quadrant pain. Abdominal ultrasound and contrast-enhanced computed tomography suggested the diagnosis of epiploic appendagitis of the right colonic flexure. Our case highlights the fact that epiploic appendagitis may occur in unusual locations and must be included in the differential diagnosis of acute abdominal pain, in order to avoid unnecessary medical and surgical treatment.

Ionic strength effects on the critical micellar concentration of ionic and nonionic surfactants: the binding model.

We have recently investigated the aggregation behavior of zwitterionic n-dodecyl phosphocholine in the presence of high salt. As double logarithmic Corrin-Harkins plots of the critical micellar concentration versus the salt concentration were not linear, here we re-examine those data in the context of the binding model of surfactant aggregation, as previously developed by us for ionic surfactants. We have also re-examined plenty of data available in the literature on the salt-dependent aggregation of neutral surfactants. The use of double-logarithmic plots allowed us to show that the binding model is of general applicability. Indeed, it permits unified treatment of ionic and uncharged aggregation without requiring the introduction of linear terms in the salt concentration, as needed in the empirical Corrin-Harkins treatment of nonionic surfactants. The use of this model could be of help in a broad range of surfactant-based applications in the presence of high salt.

Structural determinants of protein translocation in bacteria: conformational flexibility of SecA IRA1 loop region.

Bacteria employ the SecA motor protein to push unfolded proteins across the cytoplasmic membrane through the SecY protein-conducting channel complex. The crystal structure of the SecA-SecY complex shows that the intramolecular regulator of ATPase1 (IRA1) SecA domain, made up of two helices and the loop between them, is partly inserted into the SecY conducting channel, with the loop between the helices as the main functional region. A computational analysis suggested that the entire IRA1 domain is structurally autonomous, and was the basis to synthesize peptide analogs of the SecA IRA1 loop region, to the aim of investigating its conformational preferences. Our study indicates that the loop region populates a predominantly flexible state, even in the presence of structuring agent. This provides indirect evidence that the SecA loop-SecY receptor docking involves loop-mediated opening of the SecY channel.

Effective critical micellar concentration of a zwitterionic detergent: a fluorimetric study on n-dodecyl phosphocholine.

We have investigated the effect of ionic strength on the aggregation behavior of n-dodecyl phosphocholine. On the basis of the classical Corrin-Harkins relation, the critical micellar concentration of this detergent decreases with a biphasic trend on lithium chloride addition. It is nearly constant below 150 mM salt, with a mean value of 0.91 mM, whereas it undergoes a dramatic 80-fold decrease in 7 M LiCl. Such a drop in the critical micellar concentration could be explained by the effect of salting out and the implication of phosphocholine head groups on the organization of surrounding water. Knowledge of the effective critical micellar concentration of n-dodecyl phosphocholine could be useful in the purification of membrane proteins in non-denaturing conditions.

Antiapoptotic seminal vesicle protein IV induces histamine release from human FcepsilonRI+ cells.

BACKGROUND: Seminal vesicle protein number 4 (SV-IV) is a small, basic, multifunctional, intrinsically disordered secretory protein synthesized in large amounts by rat seminal vesicle epithelium under androgen transcriptional control. SV-IV-immunorelated proteins occur in other rat tissues and in humans. METHODS: The in vitro effect of SV-IV on human FcepsilonRI+ cells was investigated by standard immunologic, biochemical and molecular biology procedures. RESULTS: SV-IV-induced histamine release from human basophils and lung mast cells without any influence on leukotriene C(4) release and cell migration. The histamine release rate was slower compared with that induced by anti-IgE, the temperature dependence of the event being similar. SV-IV-induced histamine release was Ca2+-dependent, suggesting a physiological interaction of the protein with FcepsilonRI+ cells. SV-IV and anti-IgE acted synergistically on the histamine release. SV-IV did not induce de novo synthesis of cytokines and growth factors (transforming growth factor-beta(1), interleukin-10, interleukin-13, tumor necrosis factor-alpha, vascular endothelial growth factor A) in FcepsilonRI+ cells. CONCLUSIONS: SV-IV protein induces in human FcepsilonRI+ cells the release of histamine, a proinflammatory, antiapoptotic and immunosuppressive biogenic amine. These data: (1) are consistent with the antiapoptotic and immunosuppressive properties of SV-IV; (2) confirm a regulatory feature of SV-IV on mammal inflammatory reactivity by either inhibiting the arachidonate cascade pathway or stimulating proinflammatory cytokine release from lymphocyte/monocytes and histamine from FcepsilonRI+ cells; (3) raise the possibility of a protective role of SV-IV on implanting hemiallogenic blastocysts against maternal reactive oxygen species and immunological attacks at the uterine implantation site.

Homocysteine disulphides and vascular disease.

The total plasma concentration of homocysteine is a marker of this amino acid's atherogenic potential. However, the homocysteine pool exists almost entirely as oxidized homocysteine equivalents (OHcyE), composed of homocystine and cysteine-homocysteine disulphides (20-30%), and protein-bound disulphide (70-80%). We have noticed that the total concentration of OHcyE in injured coronary artery tissue is higher than the aqueous solubility of homocystine (approximately 1.4-1.5 x 10;{-3} mol kg;{-1} versus approximately 0.6 mol kg;{-1}). Based on the measurement of the solubility of homocystine in a plasma-mimetic condition (0.17 mol kg;{-1} NaCl at 37 degrees C), we have estimated that OHcyE may really reach their saturation limit in the vascular tissue (0.93-1.02 x 10{-3} mol kg;{-1}), above which their deposition as solid phase may occur. This means that significant leakage of intracellular fluid can promote OHcyE crystallization in tissue fluids, which may serve to initiate inflammation. We speculate that deposition of OHcyE crystals could damage blood vessels and act as a primer of homocysteine-triggered inflammation, thus being along the causal pathway that leads to vascular dysfunction.

A thermodynamic approach to the conformational preferences of the 180-195 segment derived from the human prion protein alpha2-helix.

On consideration that intrinsic structural weakness could affect the segment spanning the alpha2-helical residues 173-195 of the PrP, we have investigated the conformational stabilities of some synthetic Ala-scanned analogs of the peptide derived from the 180-195 C-terminal sequence, using a novel approach whose theoretical basis originates from protein thermodynamics. Even though a quantitative comparison among peptides could not be assessed to rank them according to the effect caused by single amino acid substitution, as a general trend, all peptides invariably showed an appreciable preference for an alpha-type organization, consistently with the fact that the wild-type sequence is organized as an alpha-helix in the native protein. Moreover, the substitution of whatever single amino acid in the wild-type sequence reduced the gap between the alpha- and the beta-propensity, invariably enhancing the latter, but in any case this gap was larger than that evaluated for the full-length alpha2-helix-derived peptide. It appears that the low beta-conformation propensity of the 180-195 region depends on the simultaneous presence of all of the Ala-scanned residues, indirectly confirming that the N-terminal 173-179 segment could play a major role in determining the chameleon conformational behavior of the entire 173-195 region in the PrP.

Structural characterization of a neurotoxic threonine-rich peptide corresponding to the human prion protein alpha 2-helical 180-195 segment, and comparison with full-length alpha 2-helix-derived peptides.

The 173-195 segment corresponding to the helix 2 of the globular PrP domain is a good candidate to be one of the several 'spots' of intrinsic structural flexibility, which might induce local destabilization and concur to protein transformation, leading to aggregation-prone conformations. Here, we report CD and NMR studies on the alpha2-helix-derived peptide of maximal length (hPrP[180-195]) that is able to exhibit a regular structure different from the prevalently random arrangement of other alpha2-helix-derived peptides. This peptide, which has previously been shown to be affected by buffer composition via the ion charge density dependence typical of Hofmeister effects, corresponds to the C-terminal sequence of the PrP(C) full-length alpha2-helix and includes the highly conserved threonine-rich 188-195 segment. At neutral pH, its conformation is dominated by beta-type contributions, which only very strong environmental modifications are able to modify. On TFE addition, an increase of alpha-helical content can be observed, but a fully helical conformation is only obtained in neat TFE. However, linking of the 173-179 segment, as occurring in wild-type and mutant peptides corresponding to the full-length alpha2-helix, perturbs these intrinsic structural propensities in a manner that depends on whether the environment is water or TFE. Overall, these results confirm that the 180-195 parental region in hPrP(C) makes a strong contribution to the chameleon conformational behavior of the segment corresponding to the full-length alpha2-helix, and could play a role in determining structural rearrangements of the entire globular domain.

Abundance of intrinsic disorder in SV-IV, a multifunctional androgen-dependent protein secreted from rat seminal vesicle.

The potent immunomodulatory, anti-inflammatory and procoagulant properties of protein no. 4 secreted from the rat seminal vesicle epithelium (SV-IV) have previously been found to be modulated by a supramolecular monomer-trimer equilibrium. More structural details that integrate experimental data into a predictive framework have recently been reported. Unfortunately, homology modelling and fold-recognition strategies were not successful in creating a theoretical model of the structural organization of SV-IV. It was inferred that the global structure of SV-IV is not similar to that of any protein of known three-dimensional structure. Reversing the classical approach to the sequence-structure-function paradigm, in this paper we report novel information obtained by comparing the physicochemical parameters of SV-IV with two datasets composed of intrinsically unfolded and ideally globular proteins. In addition, we analyse the SV-IV sequence by several publicly available disorder-oriented predictors. Overall, disorder predictions and a re-examination of existing experimental data strongly suggest that SV-IV needs large plasticity to efficiently interact with the different targets that characterize its multifaceted biological function, and should therefore be better classified as an intrinsically disordered protein.

Conformational diseases and structure-toxicity relationships: lessons from prion-derived peptides.

The physiological form of the prion protein is normally expressed in mammalian cell and is highly conserved among species, although its role in cellular function remains elusive. Available evidence suggests that this protein is essential for neuronal integrity in the brain, possibly with a role in copper metabolism and cellular response to oxidative stress. In prion diseases, the benign cellular form of the protein is converted into an insoluble, protease-resistant abnormal scrapie form. This conversion parallels a conformational change of the polypeptide from a predominantly alpha-helical to a highly beta-sheet secondary structure. The scrapie form accumulates in the central nervous system of affected individuals, and its protease-resistant core aggregates into amyloid fibrils outside the cell. The pathogenesis and molecular basis of the nerve cell loss that accompanies this process are not understood. Limited structural information is available on aggregate formation by this protein as the possible cause of these diseases and on its toxicity. A large amount of structure-activity studies is based on the prion fragment approach, but the resulting information is often difficult to untangle. This overview focuses on the most relevant structural and functional aspects of the prion-induced conformational disease linked to peptides derived from the unstructured N-terminal and globular C-terminal domains.

NMR structure and CD titration with metal cations of human prion alpha2-helix-related peptides.

The 173-195 segment corresponding to the helix 2 of the C-globular prion protein domain could be one of several "spots" of intrinsic conformational flexibility. In fact, it possesses chameleon conformational behaviour and gathers several disease-associated point mutations. We have performed spectroscopic studies on the wild-type fragment 173-195 and on its D178N mutant dissolved in trifluoroethanol to mimic the in vivo system, both in the presence and in the absence of metal cations. NMR data showed that the structure of the D178N mutant is characterized by two short helices separated by a kink, whereas the wild-type peptide is fully helical. Both peptides retained these structural organizations, as monitored by CD, in the presence of metal cations. NMR spectra were however not in favour of the formation of definite ion-peptide complexes. This agrees with previous evidence that other regions of the prion protein are likely the natural target of metal cation binding.

Effect of salts on the structural behavior of hPrP alpha2-helix-derived analogues: the counterion perspective.

Both theoretical studies and direct experimental evidence have emphasized the importance of electrostatic interactions in the general phenomenon of spontaneous amyloid fibril formation. A number of observations have recently spurred interest in the contribution of these interactions to the conformational behavior of the prion protein. In this paper, we show how salt addition and pH change can modify the conformation of two peptide analogues derived from the human prion protein helix 2 according to a Hofmeister-series-type dependence. Employment of various sodium salts allowed us to highlight the fact that chaotropic anions favor unstructured conformation, whereas kosmotropic anions promote the formation of compact structures like alpha-helix and beta-sheet, which may ultimately facilitate fibril formation. This finding should warn people engaged in ion-based research on prion and derived peptides about cation-bound effects, which have been almost exclusively investigated to date, being easily confounded with modifications that are actually caused by anion activity, thus leading researchers into misunderstand ion-specific effects. To avoid the common complication of ion confounding, it is highly desirable that experiments be designed so that the species causing the modification can be unequivocally perceived.

The prion protein: Structural features and related toxic peptides.

Prion diseases are characterized by the conversion of the physiological cellular form of the prion protein (PrP(C)) into an insoluble, partially protease-resistant abnormal scrapie form (PrP(Sc)). PrP(C) is normally expressed in mammalian cell and is highly conserved among species, although its role in cellular function remains elusive. The conversion of PrP(C) to PrP(Sc) parallels a conformational change of the polypeptide from a predominantly alpha-helical to a highly beta-sheet secondary structure. The pathogenesis and molecular basis of the consequent nerve cell loss are not understood. Limited structural information is available on aggregate formation by this protein as the possible cause of these diseases and on its toxicity. This brief overview focuses on the large amount of structure-activity studies based on the prion fragment approach, hinging on peptides derived from the unstructured N-terminal and globular C-terminal domains. It is well documented that most of the fragments with regular secondary structure, with the exception of helices 1 and 3, possess a high beta-sheet propensity and tendency to form beta-sheet-like aggregates. In this context, helix 2 plays a crucial role because it is able to adopt both misfolded and partially helical conformation. However, only a few mutants are able to display its intrinsic neurotoxicity.

Glycated fibroblast growth factor-2 is quickly produced in vitro upon low-millimolar glucose treatment and detected in vivo in diabetic mice.

Angiogenesis impairment in hyperglycemic patients represents a leading cause of severe vascular complications of both type-1 and -2 diabetes mellitus (DM). Angiogenesis dysfunction in DM is related to glycemic control; however, molecular mechanisms involved are still unclear. Fibroblast growth factor-2 (FGF-2) is a potent angiogenic factor and, according to previous evidence, may represent a key target of molecular modifications triggered by high-sugar exposure. Therefore, the purpose of this study was to investigate whether short incubation with hyperglycemic levels of glucose affected FGF-2 and whether glucose-modified FGF-2 was detectable in vivo. Biochemical analyses carried out with SDS-PAGE, fluorescence emission, mass-spectrometry, immunoblot, and competitive ELISA experiments demonstrated that human FGF-2 undergoes a rapid and specific glycation upon 12.5-50 mm glucose exposure. In addition, FGF-2 exposed for 30 min to 12.5 mm glucose lost mitogenic and chemotactic activity in a time- and dose-dependent manner. Under similar conditions, binding affinity to FGF receptor 1 was dramatically reduced by 20-fold, as well as FGF receptor 1 and ERK-1/2 phosphorylation, and FGF-2 lost about 45% of angiogenic activity in two different in vivo angiogenic (Matrigel and chorioallantoic-membrane) assays. Such glucose-induced modification was specific, because other angiogenic growth factors, namely platelet-derived growth factor BB and placental-derived growth factor were not significantly or markedly less modified. Finally, for the first time, glycated-FGF-2 was detected in vivo, in tissues from hyperglycemic nonobese diabetic mice, in significantly higher amounts than in normoglycemic mice. In conclusion, hyperglycemic levels of glucose may strongly affect FGF-2 structure and impair its angiogenic features, and endogenous glycated-FGF-2 is present in diabetic mice, indicating a novel pathogenetic mechanism underlying angiogenesis defects in DM.

Structural determinants of unexpected agonist activity in a retro-peptide analogue of the SDF-1alpha N-terminus.

We have synthesised two retro-peptide analogues of the stromal cell derived growth factor 1 (SDF-1alpha) segment known to be critical for CXCR4 receptor binding, corresponding to the sequences HSEFFRCPCRFFESH and HSEFFRGGGRFFESH. We have assayed the ability of these peptides to activate extracellular signal-regulated kinase 1/2 phosphorylation in cells over expressing the SDF-1alpha receptor, finding that the first variant was able to serve as an agonist of CXCR4, whereas the second one was inactive. Finally, by comparing representative solution structures of the two peptides, we have found that the biological response of HSEFFRCPCRFFESH may be ascribed to a beta-beta-type turn motif centred on Phe(4)-Phe(5).

The human prion protein alpha2 helix: a thermodynamic study of its conformational preferences.

We have synthesized both free and terminally-blocked peptide corresponding to the second helical region of the globular domain of normal human prion protein, which has recently gained the attention of structural biologists because of a possible role in the nucleation process and fibrillization of prion protein. The profile of the circular dichroism spectrum of the free peptide was that typical of alpha-helix, but was converted to that of beta-structure in about 16 h. Instead, below 2.1 x 10(-5) M, the spectrum of the blocked peptide exhibited a single band centered at 200 nm, unequivocally associated to random conformations, which did not evolve even after 24 h. Conformational preferences of this last peptide have been investigated as a function of temperature, using trifluoroethanol or low-concentration sodium dodecyl sulfate as alpha- or beta-structure inducers, respectively. Extrapolation of free energy data to zero concentration of structuring agent highlighted that the peptide prefers alpha-helical to beta-type organization, in spite of results from prediction algorithms. However, the free energy difference between the two forms, as obtained by a thermodynamic cycle, is subtle (roughly 5-8 kJ mol(-1) at any temperature from 280 K to 350 K), suggesting conformational ambivalence. This result supports the view that, in the prion protein, the structural behavior of the peptide is governed by the cellular microenvironment.

Receptor fragment approach to the binding between CCK8 peptide and cholecystokinin receptors: a fluorescence study on type B receptor fragment CCK(B)-R (352-379).

Fluorescence titrations in a membrane mimetic solvent system allowed us to estimate that the dissociation constant of the bimolecular complex between CCK8 peptide and cholecystokinin type B receptor fragment CCK(B)-R (352-379) is in the micromolar range. When considered in the context of the full receptor/ligand model, these experiments demonstrate that the receptor fragment chosen on the basis of previous structural studies represents a reliable model system to monitor the ability of CCK8 or CCK8 analogs to bind the cholecystokinin receptor. Together with previous studies, this confirms that the receptor fragment approach adopted to define the binding mode of the CCK8 fragment of cholecystokinin with its two receptors, CCK(A) and CCK(B,) can be used to characterize the binding from the equilibrium standpoint. In this context, fluorescence spectroscopy proves to be the favored technique to measure dissociation constants in the nanomolar to micromolar range.