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Abstract Invasive lobular breast carcinoma (ILC) is the second most common breast carcinoma (BC) subtype and is mainly driven by loss of E‐cadherin expression. Correct classification of BC as ILC is important for patient treatment. This study assessed the degree of agreement among pathologists for the diagnosis of ILC. Two sets of hormone receptor (HR)‐positive/HER2‐negative BCs were independently reviewed by participating pathologists. In set A (61 cases), participants were provided with hematoxylin/eosin (HE)‐stained sections. In set B (62 cases), participants were provided with HE‐stained sections and E‐cadherin immunohistochemistry (IHC). Tumor characteristics were balanced. Participants classified specimens as non‐lobular BC versus mixed BC versus ILC. Pairwise inter‐observer agreement and agreement with a pre‐defined reference diagnosis were determined with Cohen's kappa statistics. Subtype calls were correlated with molecular features, including CDH1/E‐cadherin mutation status. Thirty‐five pathologists completed both sets, providing 4,305 subtype calls. Pairwise inter‐observer agreement was moderate in set A (median κ = 0.58, interquartile range [IQR]: 0.48–0.66) and substantial in set B (median κ = 0.75, IQR: 0.56–0.86, p

Low-molecular-weight peptide gelators are a versatile class of compounds able to form gels under a variety of conditions, even via simple ultrasound sonication. In this paper, the ability of Boc-L-Phe-D-Oxd-L-Phe-OBn to gelate three organic solvents (toluene, tert-butyl methyl ether, and ethanol) was evaluated. The rheological behaviour of the materials was assessed via strain sweep analysis, while the fibrous network was analysed via optical microscopy on the wet gels. The gel obtained from toluene is a highly transparent material, and the one from ethanol appears translucent, while the one from tert-butyl methyl ether is opaque. These gels were used to study the reversible light-induced transformation from spyropiran (SP) to merocyanine (MC) and back, as a model system to check the effect of the gel medium onto the rection kinetic. We observed that the solvent used to form the organogels has a crucial effect on the reaction, as gels from aprotic solvents stabilize the SP form, while the ones from protic solvents stabilize the MC form. We thus obtained a solid support to stabilize the two photochromic species just by changing the solvent polarity. Moreover, we could demonstrate that the self-assembled gels do not interfere with the light-driven conversion process, either starting from SP or MC, thus representing a valid and economical photochromic material.

Supramolecular and biocompatible hydrogels with a tunable pH ranging from 5.5 to 7.6 lead to a wide variety of formulations useful for many different topical applications compatible with the skin pH. An in vitro viability/cytotoxicity test of the gel components demonstrated that they are non-toxic, as the cells continue to proliferate after 48 h. An analysis of the mechanical properties demonstrates that the hydrogels have moderate strength and an excellent linear viscoelastic range with the absence of a proper breaking point, confirmed with thixotropy experiments. Two cosmetic active peptides (Trifluoroacetyl tripeptide-2 and Palmitoyl tripeptide-5) were successfully added to the hydrogels and their transdermal permeation was analysed with Franz diffusion cells. The liquid chromatography-mass spectrometry (HPLC-MS) analyses of the withdrawn samples from the receiving solutions showed that Trifluoroacetyl tripeptide-2 permeated in a considerable amount while almost no transdermal permeation of Palmitoyl tripeptide-5 was observed.

Background: Patients at risk of breast cancer are submitted to mammography, resulting in a classification of the lesions following the Breast Imaging Reporting and Data System (BI-RADS®). Due to BI-RADS 3 classification problems and the great uncertainty of the possible evolution of this kind of tumours, the integration of mammographic imaging with other techniques and markers of pathology, as metabolic information, may be advisable. Design and Methods: Our study aims to evaluate the possibility to quantify by gas chromatography-mass spectrometry (GC-MS) specific metabolites in the plasma of patients with mammograms classified from BI-RADS 3 to BI-RADS 5, to find similarities or differences in their metabolome. Samples from BI-RADS 3 to 5 patients were compared with samples from a healthy control group. This pilot project aimed at establishing the sensitivity of the metabolomic classification of blood samples of patients undergoing breast radiological analysis and to support a better classification of mammographic cases. Results: Metabolomic analysis revealed a panel of metabolites more abundant in healthy controls, as 3-aminoisobutyric acid, cholesterol, cysteine, stearic, linoleic and palmitic fatty acids. The comparison between samples from BI-RADS 3 and BI-RADS 5 patients, revealed the importance of 4-hydroxyproline, found in higher amount in BI-RADS 3 subjects. Conclusion: Although the low sample number did not allow the attainment of high validated statistical models, some interesting data were obtained, revealing the potential of metabolomics for an improvement in the classification of different mammographic lesions.

The three gelators presented in this work (Boc-D-Phe-L-Oxd-OH F0, Boc-D-F1Phe-L-Oxd-OH F1 and Boc-D-F2Phe-L-Oxd-OH F2) share the same scaffold and differ in the number of fluorine atoms linked to the aromatic ring of phenylalanine. They have been applied to the preparation of gels in 0.5% or 1.0% w/v concentration, using three methodologies: solvent switch, pH change and calcium ions addition. The general trend is an increased tendency to form structured materials from F0 to F1 and F2. This property ends up in the formation of stronger materials when fluorine atoms are present. Some samples, generally formed by F1 or F2 in 0.5% w/v concentration, show high transparency but low mechanical properties. Two gels, both containing fluorine atoms, show increased stiffness coupled with high transparency. The biocompatibility of the gelators was assessed exposing them to fibroblast cells and demonstrated that F1 and F2 are not toxic to cells even in high concentration, while F0 is not toxic to cells only in a low concentration. In conclusion, the presence of even only one fluorine atom improves all the gelators properties: the gelation ability of the compound, the rheological properties and the transparency of the final materials and the gelator biocompatibility.

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson’s disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson’s disease. On the basis of the similarities, at histological level, between Wilson’s disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.

The relationship between placental calcifications and pregnancy outcome is still controversial. In this study, we examined the occurrence of placental calcifications, and we proposed a histopathological score system, Placental Calcification Score (PCS). We assigned a score (from 1 to 3) to calcifications according to their pattern (dusty = 1; single = 2; cluster = 3) and grading (low = 1; moderate = 2; high = 3). Multiplying the pattern score with that of grading, we obtained a score. After that, summing the score of each one of the three calcification patterns, we achieved the PCS. We examined 47 consecutive monochorionic placentas, searching calcifications in placental parenchyma (PP) (in which we distinguished four subsites: intervillous, intravillous, sub-amniotic fetal floor and decidua), extraplacental membranes and Wharton jelly of the umbilical cord. We collected clinical data relative to 47 mothers (age, gestational age at delivery, kind of gestation and hypertension) and 51 products of conception (kind of products of conception, gender, preterm birth, and intrauterine growth restriction [IUGR]), corresponding to the 47 placentas. We found calcifications in all placentas examined (47/47 = 100%), and all placentas showed calcifications in PP (47/47 = 100%). Calcifications were more frequent, respectively, in intravillous (36/47 = 77%) and intervillous (47/47 = 100%) subsite of PP. Besides, our preliminary data showed a mean PCS higher in mothers ≥ 35 years, with gestational age ≥ 37 W + 0 D and suffering from hypertension, than in mothers < 35 years, with gestational age < 37 W + 0 D and without hypertension. Not preterm newborns, male gender, and presence of IUGR were associated with a mean PCS higher than preterm newborns, female gender, and absence of IUGR. PCS is a new histopathological tool that might be useful to clarify the correlation between placental calcifications and clinical data of mothers and products of conception. Further investigations are needed, with a large number of placentas, to confirm the trend shown by our data.

Physical hydrogels are supramolecular materials obtained by self-assembly of small molecules called gelators. Aromatic amino acids and small peptides containing aromatic rings are good candidates as gelators due to their ability to form weak bonds as π-π interactions and hydrogen bonds between NH and CO of the peptide chain. In this paper we show our results in the preparation of a transparent hydrogel that was obtained by self-assembly of a fluorine-containing dipeptide that relies on the additional formation of halogen bonds due to the fluorine atoms contained in the dipeptide. We used Boc-D-F2Phe-L-Oxd-OH (F2Phe = 3,4-difluorophenylalainine; Oxd = 4-methyl-5-carboxy-oxazolidin-2-one) that formed a strong and transparent hydrogel in 0.5% w/w concentration at pH = 4.2. The formation of a hydrogel made of unnatural fluorinated amino acids may be of great interest in the evaluation of patients with parkinsonian syndromes and may be used for controlled release.

The aim of this study was to analyze, by immunohistochemistry, the occurrence of stem/progenitor cells localized in the different niches of the developing human cerebellum. To this end, cerebellar samples were obtained from 3 fetuses and 3 newborns ranging, respectively, from 11 to 24 and from 30 to 38 weeks of gestation. Specimens were 10% formalin-fixed, routinely processed and paraffin-embedded; 3 μm-tick sections were immunostained with anti-SOX2 and PAX6 antibodies. Our study evidenced SOX2 and PAX6 immunoreactivity in precursors cells in all six developing human cerebella. SOX2 was expressed in precursors of different neural cell types, including Purkinje neurons, stellate cells, basket cells and Golgi cells. In the cerebellar cortex, SOX2 expression changed during gestation, being highly expressed from the 20th up to the 24th week, whereas at the 30th and at the 34th week SOX2 immunoreactivity was restricted to the Purkinje cell layer and the inner zone. Cerebellar human cortex was negative at the 38th week of gestation. PAX6 immunoreactivity was restricted to granule cell precursors in the external granule layer (EGL), being detected at all gestational ages. Our study indicates SOX2 and PAX6 as two useful markers of stem/progenitor cells that highlight the different germinative zones in the developing human cerebellum.

In the first part of this review a brief summary of the embryology and histology of the gastrointestinal tract is provided. In the second part intestinal stem cells (ISCs) are discussed. Several signaling pathways play a crucial role in the crypt base in the regulation of ISC proliferation and self-renewal; Wnt, Notch, BMP, Ephrin, JAK/STAT1, PTEN, AKT, PI3K and many more. Numerous investigators are involved in studying the location, number, and behavior of ISCs within the base of the intestinal crypts. Several markers are espressed by ISCs. Among these, Leucine-rich-repeat-containing G-protein-coupled receptor-5 (Lgr5), Sox9, Prominin-1, DCAMKL-1, EphB2, p-PTEN, p-AKT, Fgfr3, m-TER, and CD44. Stem cell therapy has shown promise for the treatment of some diseases characterized by tissue damage with ischemic and inflammatory lesions like inflammatory bowel disease (IBD) and necrotizing enterocolitis (NEC). Proceedings of the 2nd International Course on Perinatal Pathology (part of the 11th International Workshop on Neonatology · October 26th-31st, 2015) · Cagliari (Italy) · October 31st, 2015 · Stem cells: present and future Guest Editors: Gavino Faa, Vassilios Fanos, Antonio Giordano

Metabolomics has provided new insight into the biology that drives the phenotype of stem cells. During the recent years, metabolic circuits of embryonic and neural stem cells (NSCs) have been better elucidated. Many factors contribute to stem cell determination fate: metabolism, transcriptional signaling, epigenetics, extrinsic mechanisms such as short-range signals from the niche and humoral signals. The metabolism decides if a cell proliferates, differentiates or remains quiescent. Embryonic and adult NSCs share two features: they generate at least one daughter cell and can differentiate into specialized cells. NSCs use different pathways depending on their stage of differentiation: glycolysis is highest in proliferating stem cells and it is essential for stemness. Conversely, oxidative phosphorylation supports differentiated cells. Moreover, lipid metabolism maintains proliferation and neurogenesis; indeed, fatty acid oxidation and fatty acid synthesis represent a component of stem cell fate regulation. Proceedings of the 2nd International Course on Perinatal Pathology (part of the 11th International Workshop on Neonatology · October 26th-31st, 2015) · Cagliari (Italy) · October 31st, 2015 · Stem cells: present and future Guest Editors: Gavino Faa, Vassilios Fanos, Antonio Giordano

The development of the central nervous system represents a very delicate period of embryogenesis. Premature interruption of neurogenesis in human preterm newborns can lead to motor deficits, including cerebral palsy, and significant cognitive, behavioral or sensory deficits in childhood. Preterm infants also have a higher risk of developing neurodegenerative diseases later in life. In the last decade, great importance has been given to stem/progenitor cells and their possible role in the development and treatment of several neurological disorders. Several studies, mainly carried out on experimental models, evidenced that immunohistochemistry may allow the identification of different neural and glial precursors inside the developing cerebral cortex. However, only a few studies have been performed on markers of human stem cells in the embryonic period. This review aims at illustrating the importance of stem/progenitor cells in cerebral cortex during pre- and post-natal life. Defining the immunohistochemical markers of stem/progenitor cells in the human cerebral cortex during development may be important to develop an “endogenous” target therapy in the perinatal period. Proceedings of the 2nd International Course on Perinatal Pathology (part of the 11th International Workshop on Neonatology · October 26th-31st, 2015) · Cagliari (Italy) · October 31st, 2015 · Stem cells: present and future Guest Editors: Gavino Faa, Vassilios Fanos, Antonio Giordano

The development of the human central nervous system represents a delicate moment of embryogenesis. The purpose of this study was to analyze the expression of multiple immunohistochemical markers in the stem/progenitor cells in the human cerebral cortex during the early phases of development. To this end, samples from cerebral cortex were obtained from 4 human embryos of 11 weeks of gestation. Each sample was formalin-fixed, paraffin embedded and immunostained with several markers including GFAP, WT1, Nestin, Vimentin, CD117, S100B, Sox2, PAX2, PAX5, Tβ4, Neurofilament, CD44, CD133, Synaptophysin and Cyclin D1. Our study shows the ability of the different immunohistochemical markers to evidence different zones of the developing human cerebral cortex, allowing the identification of the multiple stages of differentiation of neuronal and glial precursors. Three important markers of radial glial cells are evidenced in this early gestational age: Vimentin, Nestin and WT1. Sox2 was expressed by the stem/progenitor cells of the ventricular zone, whereas the postmitotic neurons of the cortical plate were immunostained by PAX2 and NSE. Future studies are needed to test other important stem/progenitor cells markers and to better analyze differences in the immunohistochemical expression of these markers during gestation.