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Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA., Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up., Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections., Conclusions: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception., (© 2024. The Author(s).)

Supramolecular gels were developed by taking advantage of an assembly of small dipeptides containing pyrrolo-pyrazole scaffolds. The dipeptides were prepared through a robust and ecofriendly synthetic approach from the commercially available starting materials of diazoalkanes and maleimides. By playing with the functionalization of the scaffold, the choice of the natural amino acid, and the stereochemistry, we were able to obtain phase-selective gels. In particular, one peptidomimetic showed gelation ability and thermoreversibility in aromatic solvents at very low concentrations. Rheology tests showed a typical viscoelastic solid profile, indicating the formation of strong gels that were stable under high mechanical deformation. NMR studies were performed, allowing us to determine the conformational and stereochemical features at the base of the supramolecular interactions.

We prepared a small library of short peptidomimetics based on 3-pyrrolo-pyrazole carboxylate, a non-coded γ-amino acid, and glycine or alanine. The robust and eco-friendly synthetic approach adopted allows to obtain the dipeptides in two steps from commercial starting materials. This gives the possibility to shape these materials by electrospinning into micro- and nanofibers, in amounts required to be useful for coating surfaces of biomedical relevance. To promote high quality of electrospun fibers, different substitution patterns were evaluated, all for pure peptide fibers, free of any polymer or additive. The best candidate, which affords a homogeneous fibrous matrix, was prepared in larger amounts, and its biocompatibility was verified. This successful work is the first step to develop a new biomaterial able to produce pristine peptide-based nanofibers to be used as helpful component or stand-alone scaffolds for tissue engineering or for the surface modification of medical devices.

Background: The incidence of the highly morbid and potentially lethal gangrenous cholecystitis was reportedly increased during the COVID-19 pandemic. The aim of the ChoCO-W study was to compare the clinical findings and outcomes of acute cholecystitis in patients who had COVID-19 disease with those who did not., Methods: Data were prospectively collected over 6 months (October 1, 2020, to April 30, 2021) with 1-month follow-up. In October 2020, Delta variant of SARS CoV-2 was isolated for the first time. Demographic and clinical data were analyzed and reported according to the STROBE guidelines. Baseline characteristics and clinical outcomes of patients who had COVID-19 were compared with those who did not., Results: A total of 2893 patients, from 42 countries, 218 centers, involved, with a median age of 61.3 (SD: 17.39) years were prospectively enrolled in this study; 1481 (51%) patients were males. One hundred and eighty (6.9%) patients were COVID-19 positive, while 2412 (93.1%) were negative. Concomitant preexisting diseases including cardiovascular diseases (p < 0.0001), diabetes (p < 0.0001), and severe chronic obstructive airway disease (p = 0.005) were significantly more frequent in the COVID-19 group. Markers of sepsis severity including ARDS (p < 0.0001), PIPAS score (p < 0.0001), WSES sepsis score (p < 0.0001), qSOFA (p < 0.0001), and Tokyo classification of severity of acute cholecystitis (p < 0.0001) were significantly higher in the COVID-19 group. The COVID-19 group had significantly higher postoperative complications (32.2% compared with 11.7%, p < 0.0001), longer mean hospital stay (13.21 compared with 6.51 days, p < 0.0001), and mortality rate (13.4% compared with 1.7%, p < 0.0001). The incidence of gangrenous cholecystitis was doubled in the COVID-19 group (40.7% compared with 22.3%). The mean wall thickness of the gallbladder was significantly higher in the COVID-19 group [6.32 (SD: 2.44) mm compared with 5.4 (SD: 3.45) mm; p < 0.0001]., Conclusions: The incidence of gangrenous cholecystitis is higher in COVID patients compared with non-COVID patients admitted to the emergency department with acute cholecystitis. Gangrenous cholecystitis in COVID patients is associated with high-grade Clavien-Dindo postoperative complications, longer hospital stay and higher mortality rate. The open cholecystectomy rate is higher in COVID compared with non -COVID patients. It is recommended to delay the surgical treatment in COVID patients, when it is possible, to decrease morbidity and mortality rates. COVID-19 infection and gangrenous cholecystistis are not absolute contraindications to perform laparoscopic cholecystectomy, in a case by case evaluation, in expert hands., (© 2022. The Author(s).)

Mass spectrometry imaging (MSI) is an emerging technology that is capable of mapping various biomolecules within their native spatial context, and performing spatial multiomics on formalin-fixed paraffin-embedded (FFPE) tissues may further increase the molecular characterization of pathological states. Here we present a novel workflow which enables the sequential MSI of lipids, N-glycans, and tryptic peptides on a single FFPE tissue section and highlight the enhanced molecular characterization that is offered by combining the multiple spatial omics data sets. In murine brain and clear cell renal cell carcinoma (ccRCC) tissue, the three molecular levels provided complementary information and characterized different histological regions. Moreover, when the spatial omics data was integrated, the different histopathological regions of the ccRCC tissue could be better discriminated with respect to the imaging data set of any single omics class. Taken together, these promising findings demonstrate the capability to more comprehensively map the molecular complexity within pathological tissue.

Fine-needle aspiration biopsies (FNA) represent the gold standard to exclude the malignant nature of thyroid nodules. After cytomorphology, 20-30% of cases are deemed "indeterminate for malignancy" and undergo surgery. However, after thyroidectomy, 70-80% of these nodules are benign. The identification of tools for improving FNA's diagnostic performances is explored by matrix-assisted laser-desorption ionization mass spectrometry imaging (MALDI-MSI). A clinical study was conducted in order to build a classification model for the characterization of thyroid nodules on a large cohort of 240 samples, showing that MALDI-MSI can be effective in separating areas with benign/malignant cells. The model had optimal performances in the internal validation set ( n = 70), with 100.0% (95% CI = 83.2-100.0%) sensitivity and 96.0% (95% CI = 86.3-99.5%) specificity. The external validation ( n = 170) showed a specificity of 82.9% (95% CI = 74.3-89.5%) and a sensitivity of 43.1% (95% CI = 30.9-56.0%). The performance of the model was hampered in the presence of poor and/or noisy spectra. Consequently, restricting the evaluation to the subset of FNAs with adequate cellularity, sensitivity improved up to 76.5% (95% CI = 58.8-89.3). Results also suggest the putative role of MALDI-MSI in routine clinical triage, with a three levels diagnostic classification that accounts for an indeterminate gray zone of nodules requiring a strict follow-up.

Poor colloidal stability of gold nanoparticles (AuNPs) in physiological environments remains one of the major limitations that contribute to their difficult translation from bench to clinic. For this reason, an active research field is the development of molecules able to hamper AuNPs aggregation tendency in physiological environments. In this context, synthetic peptides are gaining an increased interest as an alternative to the use of biomacromolecules and polymers, due to their easiness of synthesis and their profitable pharmacokinetic profile. In this work, we reported on the use of ultrashort peptides containing conformationally constrained amino acids (AAs) for the stabilization of AuNPs. A small library of non-natural self-assembled oligopeptides were synthesized and used to functionalize spherical AuNPs of 20 nm diameter, via the ligand exchange method. The aim was to investigate the role of the constrained AA, the anchor point (at C- or N- terminus ) and the peptide length on their potential use as gold binding motif. Ultrashort Aib containing peptides were identified as effective tools for AuNPs colloidal stabilization. Furthermore, peptide coated AuNPs were found to be storable as powders without losing the stabilization properties once re-dispersed in water. Finally, the possibility to exploit the developed systems for binding proteins via molecular recognition was also evaluated using biotin as model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Locarno, Bucci, Impresari, Gelmi, Pellegrino and Clerici.)

Predicting the prognosis of colorectal cancer (CRC) patients remains challenging and a characterisation of the tumour immune environment represents one of the most crucial avenues when attempting to do so. For this reason, molecular approaches which are capable of classifying the immune environments associated with tumour infiltrating lymphocytes (TILs) are being readily investigated. In this proof of concept study, we aim to explore the feasibility of using spatial lipidomics by MALDI-MSI to distinguish CRC tissue based upon their TIL content. Formalin-fixed paraffin-embedded tissue from human thymus and tonsil was first analysed by MALDI-MSI to obtain a curated mass list from a pool of single positive T lymphocytes, whose putative identities were annotated using an LC-MS-based lipidomic approach. A CRC tissue microarray (TMA, n = 30) was then investigated to determine whether these cases could be distinguished based upon their TIL content in the tumour and its microenvironment. MALDI-MSI from the pool of mature T lymphocytes resulted in the generation of a curated mass list containing 18 annotated m / z features. Initially, subsets of T lymphocytes were then distinguished based on their state of maturation and differentiation in the human thymus and tonsil tissue. Then, when applied to a CRC TMA containing differing amounts of T lymphocyte infiltration, those cases with a high TIL content were distinguishable from those with a lower TIL content, especially within the tumour microenvironment, with three lipid signals being shown to have the greatest impact on this separation ( p < 0.05). On the whole, this preliminary study represents a promising starting point and suggests that a lipidomics MALDI-MSI approach could be a promising tool for subtyping the diverse immune environments in CRC.

Electrospinning is a well-known, straightforward, and versatile technique, widely used for the preparation of fibers by electrifying a polymer solution. However, a high molecular weight is not essential for obtaining uniform electrospun fibers; in fact, the primary criterion to succeed is the presence of sufficient intermolecular interactions, which function similar to chain entanglements. Some small molecules able to self-assemble have been electrospun from solution into fibers and, among them, peptides containing both natural and non-natural amino acids are of particular relevance. Nowadays, the use of peptides for this purpose is at an early stage, but it is gaining more and more interest, and we are now witnessing the transition from basic research towards applications. Considering the novelty in the relevant processing, the aim of this review is to analyze the state of the art from the early 2000s on. Moreover, advantages and drawbacks in using peptides as the main or sole component for generating electrospun nanofibers will be discussed. Characterization techniques that are specifically targeted to the produced peptide fibers are presented.

Nanofiber films produced by electrospinning currently provide a promising platform for different applications. Although nonfunctionalized nanofiber films from natural or synthetic polymers are extensively used, electrospun materials combined with peptides are gaining more interest. In fact, the selection of specific peptides improves the performance of the material for biological applications and mainly for tissue engineering, mostly by maintaining similar mechanical properties with respect to the simple polymer. The main drawback in using peptides blended with a polymer is the quick release of the peptides. To avoid this problem, covalent linking of the peptide is more beneficial. Here, we reviewed synthetic protocols that enable covalent grafting of peptides to polymers before or after the electrospinning procedures to obtain more robust electrospun materials. Applications and the performance of the new material compared to that of the starting polymer are discussed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Ltd.)

Fine needle aspiration (FNA) is the reference standard for the diagnosis of thyroid nodules. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has been successfully used to discriminate the proteomic profiles of benign and malignant thyroid FNAs within the scope of providing support to pathologists for the classification of morphologically borderline cases. However, real FNAs provide a limited amount of material due to sample collection restrictions. Ex vivo FNAs could represent a valuable alternative, increasing sample size and the power of statistical conclusions. In this study, we compared the real and ex vivo MALDI-MSI proteomic profiles, extracted from thyrocyte containing regions of interest, of 13 patients in order to verify their similarity. Statistical analysis demonstrated the mass spectra similarity of the proteomic profiles by performing intra-patient comparison, using statistical similarity systems. In conclusion, these results show that post-surgical FNAs represent a possible alternative source of material for MALDI-MSI proteomic investigations in instances where pre-surgical samples are unavailable or the number of cells is scarce.

In the field of thyroid neoplasms, the most interesting recent change regards the introduction of a new terminology for follicular-patterned thyroid tumors, named Noninvasive Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP). This pre-malignant tumor is considered to be the putative precursor of invasive carcinoma. However, given that several issues are still unresolved, the application of ancillary tools, based on omics-techniques, may improve the clinical management of these challenging cases. The present paper highlights the proteomic profiles of a series of NIFTPs submitted to Fine Needle Aspirations (FNAs) and analysed by MALDI-imaging in order to confirm the heterogeneous phenotype of nodules included in the present NIFTP terminology and to underline the necessity of more accurate biomarkers that can be used for their characterization. Ethical and economic implications in terms of healthcare costs, operative risks, morbidity, as well as the potential need for lifelong hormone replacement therapy, seem to be significant reasons to approach the characterization of NIFTPs using alternative tools such as MALDI-MSI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Matrix-Assisted Laser Desorption/Ionization (MALDI)-Mass Spectrometry imaging (MSI) has been applied in various diseases aimed to biomarkers discovery. In this study diagnosis and prognosis of Hashimoto Thyroiditis (HT) in cytopathology by MALDI-MSI has been investigated. Specimens from a routine series of subjects who underwent UltraSound-guided thyroid Fine Needle Aspirations (FNAs) were used. The molecular classifier trained in a previous study was modified to include HT as a separate entity in the group of benign lesions, in the diagnostic proteomic triage of thyroid nodules. The statistical analysis confirmed the existence of signals that HT shares with hyperplastic lesions and others that are specific and characterize this subgroup. Statistically relevant HT-related peaks were included in the model. Then, the discriminatory capability of the classifier was tested in a second validation phase, showing a good agreement with cytological diagnoses. The possibility to overlap the molecular signatures of both the lymphocytes and epithelial cells components (ROIs or pixel-by-pixel analysis) confirmed the composite proteomic background of HT. These results open the way to their possible translation as alternative serum biomarkers of this autoimmune condition., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The urgent need to develop a detection system for Staphylococcus aureus , one of the most common causes of infection, is prompting research towards novel approaches and devices, with a particular focus on point-of-care analysis. Biosensors are promising systems to achieve this aim. We coupled the selectivity and affinity of aptamers, short nucleic acids sequences able to recognize specific epitopes on bacterial surface, immobilized at high density on a nanostructured zirconium dioxide surface, with the rational design of specifically interacting fluorescent peptides to assemble an easy-to-use detection device. We show that the displacement of fluorescent peptides upon the competitive binding of S. aureus to immobilized aptamers can be detected and quantified through fluorescence loss. This approach could be also applied to the detection of other bacterial species once aptamers interacting with specific antigens will be identified, allowing the development of a platform for easy detection of a pathogen without requiring access to a healthcare environment.

The purpose of this work is to set up a general protocol for the production of antimicrobial materials based on cellulose and peptides. We exploited the chemical ligation reaction to achieve the conjugation of peptides to cellulose; to this aim, we produced thioester peptides and cysteine-modified cellulose. As the thioester handle can be inserted at any position of the peptide, the peptide can be immobilized onto the cellulose through its N- or C-terminal end or through any other position within the sequence. Our experiments performed on Escherichia coli cultures show that the cellulose conjugated to the peptides lasioglossin-III and TBKKG6A causes a significant reduction in the concentration of viable cells as compared to unmodified cellulose. In conclusion, antimicrobial peptides bound to cellulose through a covalent bond retain their activity and therefore have the potential to be used as active ingredients in antimicrobial materials.

A new non-natural β-amino acid, named 3-Ar-β-Morph, was designed and synthesized via a regio- and diastereoselective Pd-catalyzed C(sp 3 )H-arylation of the corresponding 2 S ,6 S -(6-methoxymorpholin-2-yl)carboxylic acid, readily available from glucose. According to the computational prevision and confirmed by IR and NMR data, the insertion of 3-Ar-β-Morph in a model foldamer represents a way to stabilize a PPII-like helix through the presence of two γ-turns, secondary structure motifs induced by the morpholine ring, and the trans -tertiary amide bond.

Formalin-fixed paraffin-embedded (FFPE) tissue represents the primary source of clinical tissue and is routinely used in MALDI-MSI studies. However, it is not particularly suitable for lipidomics imaging given that many species are depleted during tissue processing. Irrespective, a number of solvent-resistant lipids remain, but their extraction may be hindered by the cross-link between proteins. Therefore, an antigen retrieval step could enable the extraction of a greater number of lipids and may provide information that is complementary to that which can be obtained from other biomolecules, such as proteins. In this short communication, we aim to address the effect of performing antigen retrieval prior to MALDI-MSI of lipids in FFPE tissue. As a result, an increased number of lipid signals could be detected and may have derived from lipid species that are known to be implicated in the lipid-protein cross-linking that is formed as a result of formalin fixation. Human renal cancer tissue was used as a proof of concept to determine whether using these detected lipid signals were also able to highlight the histopathological regions that were present. These preliminary findings may highlight the potential to enhance the clinical relevance of the lipidomic information obtained from FFPE tissue.

IgA nephropathy (IgAN) is one of the most diffuse glomerulonephrites worldwide, and many issues still remain regarding our understanding of its pathogenesis. The disease is diagnosed by renal biopsy examination, but potential pitfalls still persist with regard to discriminating its primary origin and, as a result, determining patient outcome remains challenging. In this pilot study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was performed on renal biopsies obtained from patients with IgAN (n = 11) and other mesangioproliferative glomerulonephrites (MesPGN, n = 6) in order to enlighten proteomic alterations that may be associated with the progression of IgAN. Differences in the proteomic profiles of IgAN and MesPGN tissue could clearly be detected using this approach and, furthermore, 14 signals (AUC ≥ 0.8) were observed to have an altered intensity among the different CKD stages within the IgAN group. In particular, large increases in the intensity of these signals could be observed at CKD stages II and above. These signals primarily corresponded to proteins involved in either inflammatory and healing pathways and their increased intensity was localized within regions of tissue with large amounts of inflammatory cells or sclerosis. Despite much work in recent years, our molecular understanding of IgAN progression remains incomplete. This pilot study represents a promising starting point in the search for novel protein markers that can assist clinicians in better understanding the pathogenesis of IgAN and highlighting those patients who may progress to end-stage renal disease.

The exploitation of self-assembled systems to improve the solubility of drugs is getting more and more attention. Among the different types of self-assembled biomaterials, peptides and in particular peptides containing non-coded amino acids (NCAPs) are promising because their use opens the door to more stable materials inducing increased stability to proteolysis. New classes of NCAP, Ac-Ala-X-Ala-Aib-AlaCONH 2 (X = alpha-aminoisobutyric acid (Aib) or X = cyclopentane amino acid (Ac5c)) have been prepared and the correlation between the different secondary peptide structure and solvent ( i.e. CD 3 CN, CD 3 OH, H 2 O/D 2 O) verified by NMR. Furthermore, the formation of a nanocolloidal system in water was deeply studied by DLS and the morphology of the obtained spherical aggregates with nanometric dimensions was assessed by TEM. Aib containing pentapeptide was selected for greater ease of synthesis. Its ability to encapsulate curcumin, as a model insoluble drug molecule, was investigated using fluorescence emission and confocal microscopy analyses. Two different approaches were used to study the interaction between curcumin and peptide aggregates. In the first approach peptide aggregates were formed in the presence of curcumin, while in the second approach curcumin was added to the already formed peptide aggregates. We succeeded in our challenge by using the second approach and 53.8% of added curcumin had been encapsulated., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Protein N -glycosylation is one of the most important post-translational modifications and is involved in many biological processes, with aberrant changes in protein N -glycosylation patterns being closely associated with several diseases, including the progression and spreading of tumours. In light of this, identifying these aberrant protein glycoforms in tumours could be useful for understanding the molecular mechanism of this multifactorial disease, developing specific biomarkers and finding novel therapeutic targets. We investigated the urinary N -glycoproteome of clear cell renal cell carcinoma (ccRCC) patients at different stages ( n = 15 at pT1 and n = 15 at pT3), and of non-ccRCC subjects ( n = 15), using an N -glyco-FASP-based method. Using label-free nLC-ESI MS/MS, we identified and quantified several N -glycoproteins with altered expression and abnormal changes affecting the occupancy of the glycosylation site in the urine of RCC patients compared to control. In particular, nine of them had a specific trend that was directly related to the stage progression: CD97, COCH and P3IP1 were up-expressed whilst APOB, FINC, CERU, CFAH, HPT and PLTP were down-expressed in ccRCC patients. Overall, these results expand our knowledge related to the role of this post-translational modification in ccRCC and translation of this information into pre-clinical studies could have a significant impact on the discovery of novel biomarkers and therapeutic target in kidney cancer.

The human inducible phospho-fructokinase bisphosphatase isoform 3, PFKFB3, is a crucial regulatory node in the cellular metabolism. The enzyme is an important modulator regulating the intracellular fructose-2,6-bisphosphate level. PFKFB3 is a bifunctional enzyme with an exceptionally high kinase to phosphatase ratio around 740:1. Its kinase activity can be directly inhibited by small molecules acting directly on the kinase active site. On the other hand, here we propose an innovative and indirect strategy for the modulation of PFKFB3 activity, achieved through allosteric bisphosphatase activation. A library of small peptides targeting an allosteric site was discovered and synthesized. The binding affinity was evaluated by microscale thermophoresis (MST). Furthermore, a LC-MS/MS analytical method for assessing the bisphosphatase activity of PFKFB3 was developed. The new method was applied for measuring the activation on bisphosphatase activity with the PFKFB3-binding peptides. The molecular mechanical connection between the newly discovered allosteric site to the bisphosphatase activity was also investigated using both experimental and computational methods.

The present study applies for the first time as Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) on real thyroid Fine Needle Aspirations (FNAs) to test its possible complementary role in routine cytology in the diagnosis of thyroid nodules. The primary aim is to evaluate the potential employment of MALDI-MSI in cytopathology, using challenging samples such as needle washes. Firstly, we designed a statistical model based on the analysis of Regions of Interest (ROIs), according to the morphological triage performed by the pathologist. Successively, the capability of the model to predict the classification of the FNAs was validated in a different group of patients on ROI and pixel-by-pixel approach. Results are very promising and highlight the possibility to introduce MALDI-MSI as a complementary tool for the diagnostic characterization of thyroid nodules.

We investigate the electrospinning of small molecules, specifically designed peptide derivatives of the pyrazole-isothiazole scaffold. Such non-natural peptides enhance the spectrum of fundamental materials used for electrospinning. Unlike standard electrospun materials, our peptides are not polymeric, but able to aggregate in solution and especially during processing. They contain donor/acceptor groups that can form hydrogen bonds, and groups that are able to generate π-stacking interactions, which are known as important requirements for assembly processes. The pyrazole-isothiazole derivatives were synthesized by means of a 1,3-dipolar cycloaddition reaction, which is completely regioselective, affording only one isomer. We demonstrate that our compounds can be electrospun from fluoroalcohol solution into solid, quasi-endless micro- and nanofibers. The electrospinnability varies substantially, depending on the amino acids linked to the scaffold. Some compounds provide only short fibers, while Fmoc-glycyl-( N -benzyl)-pyrazole-isothiazole- tert -butyl carboxylate-1,1-dioxide forms continuous, homogenous, and bead-free fibers (droplet-like beads are a common problem in electrospinning). We analyzed the compounds and the fibers with various spectroscopic techniques (MS, IR and Raman). Electrospinning does not change chemical composition and configuration, suggesting the monomeric form of the compounds even in the fibers. Interestingly, we found that the stereochemistry of the scaffold can affect the ability of the peptide to be electrospun., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

α,β 2,3 -Disteroisomeric foldamers of general formula Boc( S- Ala-β-2 R ,3 R- Fpg) n OMe or Boc( S- Ala-β-2 S ,3 S- Fpg) n OMe were prepared from both enantiomers of syn H-2-(2-F-Phe)-h-PheGly-OH (named β-Fpg) and S- alanine. Our peptides show two appealing features for biomedical applications: the presence of fluorine, attractive for non-covalent interactions, and aryl groups, crucial for π-stacking. A conformational study was performed, using IR, NMR and computational studies of diastereoisomeric tetra- and hexapeptides containing the β 2,3 -amino acid in the R,R - and S,S -stereochemistry, respectively. We found that the stability of peptide conformation is dependent on the stereochemistry of the β-amino acid. Combining S -Ala with β-2 R,3R -Fpg, a stable extended β-strand conformation was obtained. Furthermore, β-2 R,3R -Fpg containing hexapeptide self-assembles to form antiparallel β-sheet structure stabilized by intermolecular H-bonds and π,π-interactions. These features make peptides containing the β 2,3 -fluoro amino acid very appealing for the development of bioactive proteolytically stable foldameric β-sheets as modulators of protein-protein interaction (PPI).

A phospine free hydroarylation reaction applied to norbornene derivatives is described for the first time and was exploited for the regioselective gram scale synthesis of AR-148 , a known Rac1-Tiam1 PPI inhibitor. Umpolung conversion of the nitro group into free amine allowed the regiocontrol of the key arylation step via a long range effect. The effect of AR-148 in comparison with its enantiomers on Rac1 activation of has been evaluated and (-) AR-148 has been identified as the first enantiomerically pure inhibitor of Rac1-Tiam1 PPI.

A tetrahydro-4 H-(pyrrolo[3,4- d]isoxazol-3-yl)methanamine scaffold was designed as a diamino derivative to stabilize parallel turn conformations. Its synthesis took advantage of a [1,3]-dipolar cycloaddition reaction between the nitrile oxide derived from the inexpensive enantiopure l -phenylalanine and N-benzyl-3-pyrroline. Two diastereoisomers were formed, whose distribution depends on the selected base. 3a R,6a S-Isomer is favored in organic bases, which formation is driven by π-interactions. However, the above interactions were significantly prevented using an inorganic base due to the chaotropic effect of the cation, decreasing the amount of the above isomer. Finally, we demonstrated that this isomer is able to stabilize parallel turn conformations when inserted in short peptide sequences.

Tetrahydroisoquinoline-4-carboxylic acid, a constrained β 2 -amino acid named β-TIC, was synthesised for the first time in enantiopure form. The biocatalytic route applied herein represents one of the few successful examples of enzymatic resolution of β 2 -amino acids. Model tetrapeptides, namely, Fmoc-l-Ala-β-TIC-β-Ala-l-Val-OBn (Fmoc=fluorenylmethyloxycarbonyl, Bn=benzyl), containing both isomers of β-TIC, were prepared. Both computational and NMR spectroscopy studies were performed. A reverse-turn conformation was observed in the case of (R)-β-TIC enantiomer that was obtained in 99 % enantiomeric excess by enzymatic resolution. The β-TIC/β-Ala construct represents the first example of a flexible turn mimetic containing a cyclic and an acyclic β-amino acid. Furthermore, the presence of an aromatic ring of β-TIC could facilitate non-covalent interactions to increase the potential of this scaffold for the preparation of protein-protein interaction modulators., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background and Purpose: Drugs with anticholinergic properties might have a negative impact on cognition, but findings are still conflicting. The association was evaluated between anticholinergic drugs and cognitive performance in primary care patients with first cognitive complaints., Methods: From April 2013 to March 2014, 353 general practitioners administered the Mini-Mental State Examination (MMSE) to patients presenting with first cognitive complaints. Drug history was collected and the anticholinergic cognitive burden (ACB) was scored and categorized as ACB 0, ACB 1 and ACB 2+. A mixed effect linear regression model was used to assess the association between ACB and MMSE score., Results: Of 4249 subjects entering the study (mean age 77 ± 8.2 years, 66.4% women and mean years of schooling 8.9 ± 4.5), 25.8% received at least one drug with anticholinergic action. According to multivariate analysis, and after adjustment for several confounders, subjects with ACB 2+ had a statistically significant lower MMSE score compared with those with ACB 0 (β -0.63; 95% confidence interval -1.19; -0.07). Subjects with ACB 1 had a non-statistically significant lower MMSE score than those with ACB 0 (β -0.11; 95% confidence interval -0.37; 0.15)., Conclusions: Anticholinergic medication might affect cognitive function in people with first cognitive complaints. Alternatives should be taken into account when possible, balancing the benefits and harms of these medications., (© 2017 EAN.)

Introduction: The Free and Cued Selective Reminding Test (FCSRT) is the memory test recommended by the International Working Group on Alzheimer's disease (AD) for the detection of amnestic syndrome of the medial temporal type in prodromal AD. Assessing the construct validity and internal consistency of the Italian version of the FCSRT is thus crucial., Methods: The FCSRT was administered to 338 community-dwelling participants with memory complaints (57% females, age 74.5 ± 7.7 years), including 34 with AD, 203 with Mild Cognitive Impairment, and 101 with Subjective Memory Impairment. Internal Consistency was estimated using Cronbach's alpha coefficient. To assess convergent validity, five FCSRT scores (Immediate Free Recall, Immediate Total Recall, Delayed Free Recall, Delayed Total Recall, and Index of Sensitivity of Cueing) were correlated with three well-validated memory tests: Story Recall, Rey Auditory Verbal Learning test, and Rey Complex Figure (RCF) recall (partial correlation analysis). To assess divergent validity, a principal component analysis (an exploratory factor analysis) was performed including, in addition to the above-mentioned memory tasks, the following tests: Word Fluencies, RCF copy, Clock Drawing Test, Trail Making Test, Frontal Assessment Battery, Raven Coloured Progressive Matrices, and Stroop Colour-Word Test., Results: Cronbach's alpha coefficients for immediate recalls (IFR and ITR) and delayed recalls (DFR and DTR) were, respectively, .84 and .81. All FCSRT scores were highly correlated with those of the three well-validated memory tests. The factor analysis showed that the FCSRT does not load on the factors saturated by non-memory tests., Conclusions: These findings indicate that the FCSRT has a good internal consistency and has an excellent construct validity as an episodic memory measure., (© 2015 The British Psychological Society.)

Background: To evaluate the effectiveness of laparoscopic surgery (LCS) for colon and rectal cancer in the very elderly over 80 years old., Methods: We performed a prospective multicentric analysis comparing patients over 80 years (Group A) and patients between 60 and 69 years (Group B) undergoing LCS for cancer from January 2008 to December 2013. Colon and rectal cancers were analyzed separately. Comorbidity and complications were classified using the Charlson comorbidity index (CCI) and the Clavien-Dindo system, respectively. Oncological parameters included tumor-free margins, number of lymph nodes harvested and circumferential resection margin., Results: Group A included 96 and 33 patients, and Group B 220 and 82 for colon and rectal cancers, respectively. Groups were similar except for ASA score and CCI, as expected. There was no significant difference in operative time [colon; rectum] (180[IQR 150-200] vs 180[150-210] min; NS-180[160-210] vs 180[165-240] min; NS), estimated blood loss (50[25-75] vs 50[25-120] mL; NS-50[0-150] vs 50[25-108.7] mL; NS) and conversion rate (2.1 vs 2.7 %; NS-3.0 vs 2.4 %; NS). Timing of first stool (3[2-3.25] vs 3[2-5] dd; NS-3[2-4] vs 3[2-5] dd; NS), length of stay (7[6-8] vs 7[6-8] dd; NS-8[8-9] vs 8[7-9] dd; NS) and readmission rate (1.0 vs 0.45 %; NS-6.1 vs 1.2 %; NS) were similar. Tumor-free margins were appropriate, and positivity of CRM is poor (6.1 vs 4.9; NS). We did not record significant differences in complications rate (47.9 vs 43.6 %; NS-63.6 vs 52.4 %; NS)., Conclusions: Laparoscopic surgery is effective for the treatment of colorectal cancer even in the very elderly. Age is not a risk factor or a limitation for LCS.

Herein, we are reporting a rapid one-pot synthesis of MoS2-decorated laser-induced graphene (MoS2-LIG) by direct writing of polyimide foils. By covering the polymer surface with a layer of MoS2 dispersion before processing, it is possible to obtain an in situ decoration of a porous graphene network during laser writing. The resulting material is a three-dimensional arrangement of agglomerated and wrinkled graphene flakes decorated by MoS2 nanosheets with good electrical properties and high surface area, suitable to be employed as electrodes for supercapacitors, enabling both electric double-layer and pseudo-capacitance behaviors. A deep investigation of the material properties has been performed to understand the chemical and physical characteristics of the hybrid MoS2-graphene-like material. Symmetric supercapacitors have been assembled in planar configuration exploiting the polymeric electrolyte; the resulting performances of the here-proposed material allow the prediction of the enormous potentialities of these flexible energy-storage devices for industrial-scale production.

Background: Weight loss is common in people with Alzheimer's disease (AD) and it could be a marker of impending AD in Mild Cognitive Impairment (MCI) and improve prognostic accuracy, if accelerated progression to AD would be shown., Aims: To assess weight loss as a predictor of dementia and AD in MCI., Methods: One hundred twenty-five subjects with MCI (age 73.8 ± 7.1 years) were followed for an average of 4 years. Two weight measurements were carried out at a minimum time interval of one year. Dementia was defined according to DSM-IV criteria and AD according to NINCDS-ADRDA criteria. Weight loss was defined as a ≥4% decrease in baseline weight., Results: Fifty-three (42.4%) MCI progressed to dementia, which was of the AD-type in half of the cases. Weight loss was associated with a 3.4-fold increased risk of dementia (95% CI = 1.5-6.9) and a 3.2-fold increased risk of AD (95% CI = 1.4-8.3). In terms of years lived without disease, weight loss was associated to a 2.3 and 2.5 years earlier onset of dementia and AD., Conclusions: Accelerated progression towards dementia and AD is expected when weight loss is observed in MCI patients. Weight should be closely monitored in elderly with mild cognitive impairment.

Aims: To examine the relationship between body mass index (BMI) and progression to dementia and Alzheimer's disease (AD) in mild cognitive impairment (MCI)., Materials and Methods: Two hundred and twenty-eight MCI subjects (mean age 74.04 ± 6.94 years; 57% female) from a memory clinic were followed for 2.40 ± 1.58 years. Baseline height and weight were used to calculate the BMI. The main outcome was progression to dementia (DSM-IV criteria) and AD (NINCDS-ADRDA criteria). Cox proportional hazard models were used to assess the longitudinal association of BMI with dementia and AD, adjusting for a comprehensive set of covariates, including vascular risk factors/diseases and neuroimaging profiles., Results: Out of 228 subjects with MCI, 117 (51.3%) progressed to dementia. Eighty-nine (76%) of the incident dementia cases had AD. In both unadjusted and multi-adjusted models, a higher BMI was associated with a reduced risk of dementia (multi-adjusted HR 0.9; 95% CI 0.8-0.9) and AD (multi-adjusted HR 0.9; 95% CI 0.8-0.9). Being underweight increased the risk of all types of dementia (multi-adjusted HR 2.5; 95% CI 1.2-5.1) but was not specifically associated with AD (multi-adjusted HR 2.2; 95% CI 0.9-5.3)., Conclusions: BMI predicted progression of MCI to dementia and AD. In particular, a higher BMI was associated with a lower risk of dementia and AD, and underweight was associated with a higher risk of dementia. BMI assessment may improve the prognostic accuracy of MCI in clinical practice., (© 2016 S. Karger AG, Basel.)

The prognostic value of mild cognitive impairment (MCI) is being questioned, with some MCI subjects reverting to normal cognition (NC). The reversion rate varies mostly depending on the study design, the setting, and both MCI and NC definitions. Previous studies have focused on the profile of subjects who revert to NC, but the role of comorbidities has not been entirely investigated. We aimed to evaluate the proportion of MCI subjects who revert to NC in a memory clinic context, focusing on the role of comorbidities. Between 2004 and 2013, 374 MCI subjects were recruited. During a mean time of 32 ± 25.5 months, 21 subjects (5.6%) reverted to NC. Subjects who reverted to NC were younger (p = 0.0001), more educated (p = 0.0001), had a better global cognition (p = 0.0001), as assessed by the Mini-Mental State Examination (MMSE) and suffered from more comorbidities (p = 0.002), as assessed by Cumulative Illness Rating Scale (CIRS) than those who developed dementia. The Cox Regression Model, constructed to adjust for the confounders, showed that the higher were the MMSE (HR = 1.83, CI 95%: 1.07-3.11) and the CIRS score (HR = 1.3, CI 95% 0.88-1.92) at baseline, the higher was the probability of returning to NC than developing dementia, though the last association was not significant. Subjects who reverted to NC were more frequently affected by respiratory (p = 0.002), urologic (p = 0.012), and psychiatric (p = 0.012) diseases. The cognitive performance of subjects with medical comorbidities could benefit from preventive strategies aimed at treating the underlying diseases.

Background: Subjects with severe cognitive impairment (CI) have a high-risk of hip fractures with increased rate of adverse postoperative functional outcomes and mortality., Aim: To evaluate the impact of different degrees of CI on functional recovery and mortality after hip fracture., Design: Prospective observational study., Setting: Two orthopedic surgery units., Population: Two hundred twenty-eight consecutive patients after a hip surgery., Methods: Patients were assessed at baseline through the Short Portable Mental Status Questionnaire (SPMSQ), an instrument that allows to categorize subjects as follows: cognitively intact (SPMSQ≥8) or with mild (SPMSQ=6-7), moderate (SPMSQ=3-5) and severe CI (SPMSQ<3). Barthel Index (BI) was used to assess functional disability. All patients underwent rehabilitation from the day after surgery to discharge (mean length of stay =10.2±3.4). Outcome measures were: (1) overall mortality up to 12 months after surgery; (2) motor ability achieved at discharge from the orthopedic ward (sitting, standing, walking); (3) BI and SPMSQ at 1, 3, 6 and 12 months postoperatively., Results: All degrees of severity of CI were inversely correlated to the ability to walk at hospital discharge. At one year from surgery, the majority of patients with CI were functionally severely dependent, whereas about half of the cognitively intact ones gained a functional independence status. CI and the level of premorbid disability influenced the risk of death., Conclusion: CI for all degrees of severity is a negative prognostic factor in elderly patients with hip fracture., Clinical Rehabilitation Impact: We suggest evaluating the cognitive status of patients with hip fracture as it affects both the short and long-term functional recovery at any degree of severity.

A small library of six polarity-sensitive fluorescent dyes, nicknamed MediaChrom, was prepared. This class of dyes is characterized by a pyrimidoindolone core fitted out with a conjugated push-pull system and a carboxy linker for a conceivable coupling with biomolecules. The optimized eight-step synthetic strategy involves a highly chemo- and regioselective gold-catalyzed cycloisomerization reaction. The photophysical properties of MediaChrom dyes have been evaluated in-depth. In particular, the MediaChrom bearing a diethylamino as an electron-donating group and a trifluoromethyl as an electron-withdrawing group displays the most interesting and advantageous spectroscopic features (e.g., absorption and emission in the visible range and a good quantum yield). Promising results in terms of sensitivity have been obtained in vitro on this dye as a membrane/lipophilic probe and as a peptide fluorescent label.

Background: In the field of rehabilitation it is crucial to define if changes in functional scores correspond to relevant clinical improvements., Aim: To assess whether cognition affects motor recovery in post-stroke patients using a clinical meaningful criterion: the minimal clinically important difference (MCID)., Design: Retrospective cohort study., Setting: Inpatient rehabilitation clinic, Population: Two hundred nine first-ever stroke patients undergoing a post-acute inpatient rehabilitation., Methods: Cognitive status was assessed with the cognitive FIM and the Mini-Mental State Examination (MMSE). The response to the rehabilitation was defined as the achievement of the MCID between admission and discharge in the motor FIM (responder) and both in the motor and in the cognitive FIM (best-responder)., Results: Subjects with a baseline higher MMSE>24.9 had a near four-fold higher probability of being responder (OR 3.91; 95% CI 1.72-8.89) and a two-fold higher probability of being best-responder (OR 2.69; 95% CI 1.24-5.84) on motor FIM as compared to those with a MMSE≤24.9. A duration of the rehabilitation of 55-61 days implies a three-fold higher probability (OR 3.17; 95% CI 1.15-8.72) to be responder as compared to shorter period of treatment; a treatment >61 days does not involve a greater probability of response., Conclusions: This is the first study that examined post-stroke motor recovery mainly in terms of clinical relevance (MCID). Subjects with a higher cognitive level are more likely to achieve a clinically meaningful recovery., Clinical Rehabilitation Impact: MCID can be applied extensively to post-stroke patients undergoing to an inpatient rehabilitation in order to have a clinically useful instrument that assess the recovery.

A new α,α-disubstituted constrained glutamine analogue has been designed to decorate gold nanoparticles and to induce a 310-helix when inserted in peptides. Using an efficient "one-pot" asymmetric Schmidt reaction between 4-disubstituted-cyclohexanone and hydroxyalkylazides, 1H-azepine-2-oxo-5-amino-5-carboxylic acid was prepared. The main (R) isomer was inserted at the N-terminus in a very short peptide sequence (i.e., PhCO-(R)-Oxo-Azn-L-Ala-Aib-L-AlaNHMe) and a stable 310-helix conformation was obtained, as verified by both NMR experiments and molecular dynamics (MD) simulations. Finally, the presence of the hydroxyl chain at the nitrogen atom of the ring allowed for the preparation of covered chiral gold nanoparticles.

The reactivity of various α-diazocarbonyl piperidine scaffolds, characterised by an increased molecular complexity, was tested with various Rh(II) catalysts. The structure of the starting reagent is of relevance to the synthetic results. An unexpected dimerisation took place, starting from the simple piperidine scaffold, to give the hexahydrotetrazine ring system. Products derived from a nitrogen ylide intermediate or aromatic substitution (1,3,4,5-tetrahydro-2,5-methanobenzo[c]azepine and 1,2,3,3a-tetrahydrocyclopenta[de]isoquinolin-4(5 H)-one rings, respectively) were obtained from tetrahydroisoquinoline derivatives. The chemoselectivity of the reaction could be controlled by the choice of starting reagent, Rh(II) catalyst and the reaction conditions. Finally, it was found that the azepino heterocycle could coordinate to the catalyst to give new Rh(II) complexes., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Although parkinsonism is considered a core feature of dementia with Lewy bodies (DLB), it is occasionally mild or even absent. I-FP-CIT SPECT has been accepted as a diagnostic support tool in this context, given that low striatal uptake is associated with neuronal loss. The aim of this retrospective study was to look for correlations between I-FP-CIT uptake in the striatum and clinical extrapyramidal signs (EPSs) in patients with a diagnosis of probable DLB to clarify the extent to which the supporting role of I-FP-CIT is related to motor impairment., Methods: Semiquantitative I-FP-CIT uptake was analyzed and correlated with Unified Parkinson Disease Rating Scale Part III scores in a sample of 22 patients with a diagnosis of probable DLB and a wide range of EPSs., Results: A significant negative linear correlation between I-FP-CIT uptake and Unified Parkinson Disease Rating Scale Part III score was found both in the caudate and the putamen (r = -0.69 and -0.72, respectively, P < 0.001). Striatal uptake in patients with no or questionable EPS was comparable to that recorded in normal age-matched subjects (99% [22%] in the putamen) but significantly reduced in those with mild and severe EPS (43% [35%] and 30% [17%], respectively, P < 0.0001, but P = nonsignificant between mild and severe EPS)., Conclusions: SPECT may be redundant when there are no doubts about the parkinsonism (ie, when it is absent or unequivocally present), but it may be helpful in identifying presynaptic nigrostriatal degeneration in patients with mild EPSs.

We carried out an association study of transmembrane protein 106B gene (TMEM106B) rs1020004 A/G, rs6966915C/T, and rs1990622 A/G in a population of 656 patients with Alzheimer's disease (AD) and 619 controls, and tested whether the rs1990622 influences plasma progranulin levels. No differences in allele and genotype distribution were observed between cases and controls, even stratifying according to APOE status (p > 0.05). No differences in progranulin plasma levels were found between carriers of the rs1990622 and non-carriers. TMEM106b variability does not influence AD risk or plasma levels. Replication, preferably in a population with pathological confirmation, is required to confirm these results.