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The impact of dietary fiber on intestinal T cell development is poorly understood. Here we show that a low fiber diet reduces MHC-II antigen presentation by small intestinal epithelial cells (IECs) and consequently impairs development of CD4 + CD8αα + intraepithelial lymphocytes (DP IELs) through changes to the microbiota. Dietary fiber supports colonization by Segmented Filamentous Bacteria (SFB), which induces the secretion of IFNγ by type 1 innate lymphoid cells (ILC1s) that lead to MHC-II upregulation on IECs. IEC MHC-II expression caused either by SFB colonization or exogenous IFNγ administration induced differentiation of DP IELs. Finally, we show that a low fiber diet promotes overgrowth of Bifidobacterium pseudolongum, and that oral administration of B. pseudolongum reduces SFB abundance in the small intestine. Collectively we highlight the importance of dietary fiber in maintaining the balance among microbiota members that allow IEC MHC-II antigen presentation and define a mechanism of microbiota-ILC-IEC interactions participating in the development of intestinal intraepithelial T cells., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Androgen insensitivity syndrome (AIS) is one of the most common Disorders of Sexual Differentiation (DSDs). AIS is characterized by an X-linked recessive inheritance pattern associated with variants in the androgen receptor (AR) gene that affects the masculinization process in individuals with XY karyotype. Here, we report a neonatal case of a very early diagnosis of complete AIS due to a novel variant in the AR gene. In the present case, after the clinical evaluation, the infant has undergone the following tests: biochemical analyses, including newborn screening workflow, karyotype analysis, and Next-Generation Sequencing (NGS) panel of 50 genes involved in DSDs. The NGS analysis identified a missense variant, c.2108C>A, in the AR gene. According to a cytogenetic analysis, the patient presented a 46, XY karyotype, thus the resulting hemizygote for the AR gene variant. The variant is not currently described in the literature nor in the ClinVar database. However, according to computational models, the variant could have a pathogenetic effect. This clinical case reveals a novel variant of the AR gene with a possible pathogenetic effect associated with AIS and highlights the importance of a multidisciplinary approach for the timely diagnosis and appropriate follow-up of the patient.

The neutral holmium(III) oxalate octadecahydrate {[Ho 2 (ox) 3 (H 2 O) 6 ]·12H 2 O} n of mixed hexagonal/decagonal (6 3 ·10 3 ) 3D net topology shows important changes in the magnetocaloric efficiency upon dehydration/rehydration by heating and water vapor exposition to give the holmium(III) oxalate decahydrate {[Ho 2 (ox) 3 (H 2 O) 6 ]·4H 2 O} n of hexagonal (6 3 ) 2D net topology through the intermediacy of the elusive amorphous anhydrous compound {Ho 2 (ox) 3 } n .

Up to approximately 70% of cancer survivors report persistent deficits in memory, attention, speed of information processing, multi-tasking, and mental health functioning, a series of symptoms known as "brain fog." The severity and duration of such effects can vary depending on age, cancer type, and treatment regimens. In particular, every year, hundreds of thousands of patients worldwide undergo radiotherapy (RT) for primary brain tumors and brain metastases originating from extracranial tumors. Besides its potential benefits in the control of tumor progression, recent studies indicate that RT reprograms the brain tumor microenvironment inducing increased activation of microglia and astrocytes and a consequent general condition of neuroinflammation that in case it becomes chronic could lead to a cognitive decline. Furthermore, radiation can induce endothelium reticulum (ER) stress directly or indirectly by generating reactive oxygen species (ROS) activating compensatory survival signaling pathways in the RT-surviving fraction of healthy neuronal and glial cells. In particular, the anomalous accumulation of misfolding proteins in neuronal cells exposed to radiation as a consequence of excessive activation of unfolded protein response (UPR) could pave the way to neurodegenerative disorders. Moreover, exposure of cells to ionizing radiation was also shown to affect the normal proteasome activity, slowing the degradation rate of misfolded proteins, and further exacerbating ER-stress conditions. This compromises several neuronal functions, with neuronal accumulation of ubiquitinated proteins with a consequent switch from proteasome to immunoproteasome that increases neuroinflammation, a crucial risk factor for neurodegeneration. The etiology of brain fog remains elusive and can arise not only during treatment but can also persist for an extended period after the end of RT. In this review, we will focus on the molecular pathways triggered by radiation therapy affecting cognitive functions and potentially at the origin of so-called "brain fog" symptomatology, with the aim to define novel therapeutic strategies to preserve healthy brain tissue from cognitive decline., 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 © 2024 Marino, Bedeschi, Vaccari, Cambiaghi and Tesei.)

This study investigates a mechanistic link of bacterial biofilm-mediated host-pathogen interaction leading to immunological complications associated with breast implant illness (BII). Over 10 million women worldwide have breast implants. In recent years, women have described a constellation of immunological symptoms believed to be related to their breast implants. We report that periprosthetic breast tissue of participants with symptoms associated with BII had increased abundance of biofilm and biofilm-derived oxylipin 10-HOME compared with participants with implants who are without symptoms (non-BII) and participants without implants. S. epidermidis biofilm was observed to be higher in the BII group compared with the non-BII group and the normal tissue group. Oxylipin 10-HOME was found to be immunogenically capable of polarizing naive CD4+ T cells with a resulting Th1 subtype in vitro and in vivo. Consistently, an abundance of CD4+Th1 subtype was observed in the periprosthetic breast tissue and blood of people in the BII group. Mice injected with 10-HOME also had increased Th1 subtype in their blood, akin to patients with BII, and demonstrated fatigue-like symptoms. The identification of an oxylipin-mediated mechanism of immune activation induced by local bacterial biofilm provides insight into the possible pathogenesis of the implant-associated immune symptoms of BII.

Dietary fiber strongly impacts the microbiota. Here, we show that a low-fiber diet changes the small intestinal (SI) microbiota and impairs SI Th17, TCRαβ + CD8αβ + and TCRαβ + CD8αα + intraepithelial T cell development. We restore T cell development with dietary fiber supplementation, but this defect becomes persistent over generations with constant low-fiber diets. Offspring of low-fiber diet-fed mice have reduced SI T cells even after receiving a fiber-rich diet due to loss of bacteria important for T cell development. In these mice, only a microbiota transplant from a fiber-rich diet-fed mouse and a fiber-rich diet can restore T cell development. Low-fiber diets reduce segmented filamentous bacteria (SFB) abundance, impairing its vertical transmission. SFB colonization and a fiber-rich diet partially restore T cell development. Finally, we observe that low-fiber diet-induced T cell defects render mice more susceptible to Citrobacter rodentium infection. Together, these results demonstrate the importance of fiber to microbiota vertical transmission and host immune system development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

LAT1 (SLC7A5) is one of the most studied membrane transporters due to its relevance to physiology in supplying essential amino acids to brain and fetus, and to pathology being linked to nervous or embryo alterations; moreover, LAT1 over-expression is always associated with cancer development. Thus, LAT1 is exploited as a pro-drug vehicle and as a target for anti-cancer therapy. We here report the identification of a new substrate with pathophysiological implications, i.e., Cu-histidinate, and an unconventional uniport mechanism exploited for the Cu-histidinate transport. Crystals of the monomeric species Cu(His) 2 were obtained in our experimental conditions and the actual transport of the complex was evaluated by a combined strategy of bioinformatics, site-directed mutagenesis, radiolabeled transport, and mass spectrometry analysis. The LAT1-mediated transport of Cu(His) 2 may have profound implications for both the treatment of copper dysmetabolism diseases, such as the rare Menkes disease, and of cancer as an alternative to platinum-based therapies., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Microbial dysbiosis has emerged as an important element in the development and progression of various cancers, including breast cancer. However, the microbial composition of the breast from healthy individuals, even relative to risk of developing breast cancer, remains unclear. Here, we performed a comprehensive analysis of the microbiota of the normal breast tissue, which was analyzed in relation to the microbial composition of the tumor and adjacent normal tissue., Methods: The study cohorts included 403 cancer-free women (who donated normal breast tissue cores) and 76 breast cancer patients (who donated tumor and/or adjacent normal tissue samples). Microbiome profiling was obtained by sequencing the nine hypervariable regions of the 16S rRNA gene (V1V2, V2V3, V3V4, V4V5, V5V7, and V7V9). Transcriptome analysis was also performed on 190 normal breast tissue samples. Breast cancer risk score was assessed using the Tyrer-Cuzick risk model., Results: The V1V2 amplicon sequencing resulted more suitable for the analysis of the normal breast microbiome and identified Lactobacillaceae (Firmicutes phylum), Acetobacterraceae, and Xanthomonadaceae (both Proteobacteria phylum) as the most abundant families in the normal breast. However, Ralstonia (Proteobacteria phylum) was more abundant in both breast tumors and histologically normal tissues adjacent to malignant tumors. We also conducted a correlation analysis between the microbiome and known breast cancer risk factors. Abundances of the bacterial taxa Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp. were associated with age (p < 0.0001), racial background (p < 0.0001), and parity (p < 0.0001). Finally, transcriptome analysis of normal breast tissues showed an enrichment in metabolism- and immune-related genes in the tissues with abundant Acetotobacter aceti, Lactobacillus vini, Lactobacillus paracasei, and Xanthonomas sp., whereas the presence of Ralstonia in the normal tissue was linked to dysregulation of genes involved in the carbohydrate metabolic pathway., Conclusions: This study defines the microbial features of normal breast tissue, thus providing a basis to understand cancer-related dysbiosis. Moreover, the findings reveal that lifestyle factors can significantly affect the normal breast microbial composition., (© 2023. The Author(s).)

Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world's population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs. One potential alternative is represented by sigma-1 receptor (S1R) antagonists due to their promising analgesic effects. Here, we report the synthesis and biological evaluation of a series of S1R antagonists based on a 2-aryl-4-aminobutanol scaffold. After assessing affinity toward the S1R and selectivity over the sigma-2 receptor (S2R), we evaluated the agonist/antagonist profile of the compounds by investigating their effects on nerve growth factor-induced neurite outgrowth and aquaporin-mediated water permeability in the presence and absence of oxidative stress. ( R / S )- RC - 752 emerged as the most interesting compound for S1R affinity ( K i S1R = 6.2 ± 0.9) and functional antagonist activity. Furthermore, it showed no cytotoxic effect in two normal human cell lines or in an in vivo zebrafish model and was stable after incubation in mouse plasma. ( R / S )- RC - 752 was then evaluated in two animal models of NP: the formalin test and the spinal nerve ligation model. The results clearly demonstrated that compound ( R / S )- RC - 752 effectively alleviated pain in both animal models, thus providing the proof of concept of its efficacy as an antinociceptive agent.

Sigma-1 receptor (S1R) has been considered a promising therapeutic target for several neurodegenerative diseases and S1R agonists have shown neuroprotective activity against glutamate excitotoxicity and oxidative stress. Starting from a previously identified low nanomolar S1R agonist, in this work we prepared and tested novel benzylpiperidine/benzylpiperazine-based compounds designed by applying a ring opening strategy. Among them, 4-benzyl-1-(2-phenoxyethyl)piperidine 6b (S1R Ki = 0.93 nM) and 4-benzyl-1-(3-phenoxypropyl)piperidine 8b (S1R Ki = 1.1 nM) emerged as high affinity S1R ligands and showed selectivity over S2R and N-methyl-d-aspartate receptor (NMDAR). Candidate compounds behaved as potent S1R agonists being able to enhance the neurite outgrowth induced by nerve growth factor (NGF) in PC12 cell lines. In SH-SY5Y neuroblastoma cell lines they exhibited a neuroprotective effect against rotenone- and NMDA-mediated toxic insults. The neuroprotective activity of 6b and 8b was reverted by co-treatment with an S1R antagonist, PB212. Compounds 6b and 8b were tested for cytotoxicity in-vitro against three human cancer cell lines (A549, LoVo and Panc-1) and in-vivo zebrafish model, resulting in a good efficacy/safety profile, comparable or superior to the reference drug memantine. Overall, these results encourage further preclinical investigations of 6b and 8b on in-vivo models of neurodegenerative diseases., 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 © 2023 Elsevier Masson SAS. All rights reserved.)

Prostate cancer (PCa) is one of the most common cancers in European males. Although therapeutic approaches have changed in recent years, and several new drugs have been approved by the Food and Drug Administration (FDA), androgen deprivation therapy (ADT) remains the standard of care. Currently, PCa represents a clinical and economic burden due to the development of resistance to ADT, paving the way to cancer progression, metastasis, and to long-term side effects induced by ADT and radio-chemotherapeutic regimens. In light of this, a growing number of studies are focusing on the tumor microenvironment (TME) because of its role in supporting tumor growth. Cancer-associated fibroblasts (CAFs) have a central function in the TME because they communicate with prostate cancer cells, altering their metabolism and sensitivity to drugs; hence, targeted therapy against the TME, and, in particular, CAFs, could represent an alternative therapeutic approach to defeat therapy resistance in PCa. In this review, we focus on different CAF origins, subsets, and functions to highlight their potential in future therapeutic strategies for prostate cancer.

While in the past technology has mostly been utilized to store information about the structural configuration of proteins and molecules for research and medical purposes, Artificial Intelligence is nowadays able to learn from the existing data how to predict and model properties and interactions, revealing important knowledge about complex biological processes, such as aging. Modern technologies, moreover, can rely on a broader set of information, including those derived from the next-generation sequencing (e.g., proteomics, lipidomics, and other omics), to understand the interactions between human body and the external environment. This is especially relevant as external factors have been shown to have a key role in aging. As the field of computational systems biology keeps improving and new biomarkers of aging are being developed, artificial intelligence promises to become a major ally of aging research., Competing Interests: Authors NM, GP, and AS, were employed by the company Women’s Brain Project (WBP). Authors EB, QV, and AZ were employed by the company Insilico Medicine Hong Kong Ltd. Author ES was employed by company Bayer Corporation. The remaining 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 © 2023 Marino, Putignano, Cappilli, Chersoni, Santuccione, Calabrese, Bischof, Vanhaelen, Zhavoronkov, Scarano, Mazzotta and Santus.)

In recent years, the food industry has become increasingly involved in researching vegetable fats and oils with appropriate mechanical properties (ease of transport, processing, and storage) and a specific lipidic composition to ensure healthy products for consumers. The chemical-physical behavior of these matrices depends on their composition in terms of single fatty acids (FA). However, as we demonstrate in this work, these properties, as well as the absorption, digestion and uptake in humans of specific FAs, are also largely determined by their regiosomerism within the TriAcylGlycerols (TAG) moieties ( sn -1,2,3 positions). The goal of this work is to study for the first time vegetable fats obtained directly from a sample of natural cocoa butter (CB) through a process that manipulates the distribution of FAs but not their nature. Even if the initial percentage of each FA in the mixture remains the same, CB derivatives seem to show improved chemical-physical features. In order to understand which factors account for their physical and chemical characteristics, and to check whether or not the obtained new matrices could be considered as valid alternatives to other vegetable fats (e.g., palm oil (PO)), we carried out an experimental investigation at both the macroscopic and molecular level including: (i) Differential Scanning Calorimetry (DSC) analyses to examine thermal features; (ii) rheological testing to explore mechanical properties; (iii) powder X-ray diffraction (PXRD) to evaluate the solid-state phases of the obtained fats; and (iv) 1 H and 13 C Nuclear Magnetic Resonance (NMR, 1D and 2D) spectroscopy to rapidly analyze fatty acid composition including regioisomeric distribution on the glycerol backbone. These last results open up the possibility of using NMR spectroscopy as an alternative to the chromatographic techniques routinely employed for the investigation of similar matrices.

Reduced age-related terminal duct lobular unit (TDLU) involution has been linked to increased breast cancer risk and triple-negative breast cancer. Associations of TDLU involution levels with race and ethnicity remain incompletely explored. Herein, we examined the association between genetic ancestry and TDLU involution in normal breast tissue donated by 2014 healthy women in the United States. Women of African ancestry were more likely than European women to have increased TDLU counts (odds ratio [OR]trend = 1.36, 95% confidence interval [CI] = 1.07 to 1.74), acini counts per TDLU (OR = 1.47, 95% CI = 1.06 to 2.03), and median TDLU span (ORtrend = 1.44, 95% CI = 1.08 to 1.91), indicating lower involution, whereas East Asian descendants were associated with decreased TDLU counts (ORtrend = 0.52, 95% CI = 0.35 to 0.78) after controlling for potential confounders. These associations are consistent with the racial variations in incidence rates of triple-negative breast cancer in the United States and suggest opportunities for future work examining whether TDLU involution may mediate the racial differences in subtype-specific breast cancer risk., (Published by Oxford University Press 2022. This work is written by US Government employees and is in the public domain in the US.)

Different pathological conditions, including viral infections and cancer, can have a massive impact on the endoplasmic reticulum (ER), causing severe damage to the cell and exacerbating the disease. In particular, coronavirus infections, including SARS coronavirus-2 (SARS-CoV-2), responsible for COVID-19, cause ER stress as a consequence of the enormous amounts of viral glycoproteins synthesized, the perturbation of ER homeostasis and the modification of ER membranes. Therefore, ER has a central role in the viral life cycle, thus representing one of the Achilles' heels on which to focus therapeutic intervention. On the other hand, prolonged ER stress has been demonstrated to promote many pro-tumoral attributes in cancer cells, having a key role in tumor growth, metastasis and response to therapies. In this report, adopting a repurposing approach of approved drugs, we identified the antiplatelet agent ticlopidine as an interferent of the unfolded protein response (UPR) via sigma receptors (SRs) modulation. The promising results obtained suggest the potential use of ticlopidine to counteract ER stress induced by viral infections, such as COVID-19, and cancer.

Microbiota studies have reported changes in the microbial composition of the breast upon cancer development. However, results are inconsistent and limited to the later phases of cancer development (after diagnosis). We analyzed and compared the resident bacterial taxa of histologically normal breast tissue (healthy, H, n  = 49) with those of tissues donated prior to (prediagnostic, PD, n  = 15) and after (adjacent normal, AN, n  = 49, and tumor, T, n  = 46) breast cancer diagnosis ( n total = 159). DNA was isolated from tissue samples and submitted for Illumina MiSeq paired-end sequencing of the V3-V4 region of the 16S gene. To infer bacterial function in breast cancer, we predicted the functional bacteriome from the 16S sequencing data using PICRUSt2. Bacterial compositional analysis revealed an intermediary taxonomic signature in the PD tissue relative to that of the H tissue, represented by shifts in Bacillaceae , Burkholderiaceae , Corynebacteriaceae , Streptococcaceae , and Staphylococcaceae . This compositional signature was enhanced in the AN and T tissues. We also identified significant metabolic reprogramming of the microbiota of the PD, AN, and T tissue compared with the H tissue. Further, preliminary correlation analysis between host transcriptome profiling and microbial taxa and genes in H and PD tissues identified altered associations between the human host and mammary microbiota in PD tissue compared with H tissue. These findings suggest that compositional shifts in bacterial abundance and metabolic reprogramming of the breast tissue microbiota are early events in breast cancer development that are potentially linked with cancer susceptibility. IMPORTANCE The goal of this study was to determine the role of resident breast tissue bacteria in breast cancer development. We analyzed breast tissue bacteria in healthy breast tissue and breast tissue donated prior to (precancerous) and after (postcancerous) breast cancer diagnosis. Compared to healthy tissue, the precancerous and postcancerous breast tissues demonstrated differences in the amounts of breast tissue bacteria. In addition, breast tissue bacteria exhibit different functions in pre-cancerous and post-cancerous breast tissues relative to healthy tissue. These differences in function are further emphasized by altered associations of the breast tissue bacteria with gene expression in the human host prior to cancer development. Collectively, these analyses identified shifts in bacterial abundance and metabolic function (dysbiosis) prior to breast tumor diagnosis. This dysbiosis may serve as a therapeutic target in breast cancer prevention.

Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer's disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer's, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida's digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida's application, achieved a 75% ROC-AUC (receiver operating characteristic - area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline., Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00284-3., Competing Interests: Conflict of interestES is Director of AI and Machine Learning at Bayer. A.S.C. is an official employee of Biogen International and works as Head of Stakeholder Engagement for Alzheimer disease at Biogen. She is also co-founder and CEO of the Women’s Brain Project., (© The Author(s) 2022.)

The construction of shelters on plants by arthropods might influence other organisms via changes in colonization, community richness, species composition, and functionality. Arthropods, including beetles, caterpillars, sawflies, spiders, and wasps often interact with host plants via the construction of shelters, building a variety of structures such as leaf ties, tents, rolls, and bags; leaf and stem galls, and hollowed out stems. Such constructs might have both an adaptive value in terms of protection (i.e., serve as shelters) but may also exert a strong influence on terrestrial community diversity in the engineered and neighboring hosts via colonization by secondary occupants. Although different traits of the host plant (e.g., physical, chemical, and architectural features) may affect the potential for ecosystem engineering by insects, such effects have been, to a certain degree, overlooked. Further analyses of how plant traits affect the occurrence of shelters may therefore enrich our understanding of the organizing principles of plant-based communities. This data set includes more than 1000 unique records of ecosystem engineering by arthropods, in the form of structures built on plants. All records have been published in the literature, and span both natural structures (91% of the records) and structures artificially created by researchers (9% of the records). The data were gathered between 1932 and 2021, across more than 50 countries and several ecosystems, ranging from polar to tropical zones. In addition to data on host plants and engineers, we aggregated data on the type of constructs and the identity of inquilines using these structures. This data set highlights the importance of these subtle structures for the organization of terrestrial arthropod communities, enabling hypotheses testing in ecological studies addressing ecosystem engineering and facilitation mediated by constructs. There are no copyright restrictions and please cite this paper when using the data in publications., (© 2022 The Ecological Society of America.)

Background: Family with sequence similarity 83 member A (FAM83A) presents oncogenic properties in several cancers including breast cancer. Recently, we reported FAM83A overexpression in normal breast tissues from women at high risk of breast cancer. We now hypothesize that FAM83A is a key factor in breast cancer initiation., Methods: Immunohistochemical staining was used to evaluate FAM83A protein levels in both a normal breast tissue microarray (TMA, N = 411) and a breast tumor TMA (N = 349). EGFR staining and its correlation with FAM83A expression were also assessed. Lentivirus-mediated manipulation of FAM83A expression in primary and hTERT-immortalized breast epithelial cells was employed. Biological and molecular alterations upon FAM83A overexpression/downregulation and FAM83A's interaction partners were investigated., Results: TMA analysis revealed a 1.5-fold increase in FAM83A expression level in breast cancer cases as compared with normal breast tissues (p < 0.0001). FAM83A protein expression was directly correlated with EGFR level in both normal and breast cancer tissues. In in vitro assays, exogenous expression of FAM83A in either primary or immortalized breast epithelial cells promoted cell viability and proliferation. Additionally, Ingenuity Pathway Analysis (IPA) revealed that FAM83A overexpression in primary cells affected the expression of genes involved in cellular morphology and metabolism. Mass spectrometry analysis identified DDX3X and LAMB3 as potential FAM83A interaction partners in primary cells, while we detected FAM83A interaction with cytoskeleton reorganization factors, including LIMA1, MYH10, PLEC, MYL6 in the immortalized cells., Conclusions: This study shows that FAM83A promotes metabolic activation in primary breast epithelial cells and cell proliferation in both primary and immortalized cells. These findings support its role in early breast oncogenesis., (© 2022. The Author(s).)

Background: Genome-wide association studies have identified several breast cancer susceptibility loci. However, biomarkers for risk assessment are still missing. Here, we investigated cancer-related molecular changes detected in tissues from women at high risk for breast cancer prior to disease manifestation. Disease-free breast tissue cores donated by healthy women (N = 146, median age = 39 years) were processed for both methylome (MethylCap) and transcriptome (Illumina's HiSeq4000) sequencing. Analysis of tissue microarray and primary breast epithelial cells was used to confirm gene expression dysregulation., Results: Transcriptomic analysis identified 69 differentially expressed genes between women at high and those at average risk of breast cancer (Tyrer-Cuzick model) at FDR < 0.05 and fold change ≥ 2. Majority of the identified genes were involved in DNA damage checkpoint, cell cycle, and cell adhesion. Two genes, FAM83A and NEK2, were overexpressed in tissue sections (FDR < 0.01) and primary epithelial cells (p < 0.05) from high-risk breasts. Moreover, 1698 DNA methylation changes were identified in high-risk breast tissues (FDR < 0.05), partially overlapped with cancer-related signatures, and correlated with transcriptional changes (p < 0.05, r ≤ 0.5). Finally, among the participants, 35 women donated breast biopsies at two time points, and age-related molecular alterations enhanced in high-risk subjects were identified., Conclusions: Normal breast tissue from women at high risk of breast cancer bears molecular aberrations that may contribute to breast cancer susceptibility. This study is the first molecular characterization of the true normal breast tissues, and provides an opportunity to investigate molecular markers of breast cancer risk, which may lead to new preventive approaches., (© 2022. The Author(s).)

In this issue of Cell Host & Microbe, Alexander et al. show that the enzyme cardiac glycoside reductase 2 (cgr2), which is produced by Eggerthella lenta, metabolizes RORγT inhibitors, resulting in an increased Th17 response and more severe inflammation in colitis models. The effect of cgr2 can be neutralized by a diet rich in arginine., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Komen Tissue Bank is the only biorepository in the world for normal breast tissues from women. Below we report the acquisition and processing of breast tissue from volunteer donors and describe an experimental and analysis pipeline to generate a single-cell atlas. This atlas is based on single-cell RNA-seq and is useful to derive breast epithelial cell subcluster-specific gene expression signatures, which can be applied to breast cancer gene expression data to identify putative cell-of-origin. For complete details on the use and execution of this protocol, please refer to Bhat-Nakshatri et al. (2021)., Competing Interests: Authors have no conflict of interest to disclose., (© 2021 The Authors.)

The cobalt substituted polyoxotungstate [Co 6 (H 2 O) 2 (α-B-PW 9 O 34 ) 2 (PW 6 O 26 )] 17- (Co6) displays fast electron transfer (ET) kinetics to photogenerated Ru III (bpy) 3 3+ , 4 to 5 orders of magnitude faster than the corresponding ET observed for cobalt oxide nanoparticles. Mechanistic evidence has been acquired indicating that: (i) the one-electron oxidation of Co6 involves Co(II) aquo or Co(II) hydroxo groups (abbreviated as Co6(II)-OH 2 and Co6(II)-OH, respectively, whose speciation in aqueous solution is associated to a pK a of 7.6), and generates a Co(III)-OH moiety (Co6(III)-OH), as proven by transient absorption spectroscopy; (ii) at pH>pK a , the Co6(II)-OH→Ru III (bpy) 3 3+ ET occurs via bimolecular kinetics, with a rate constant k close to the diffusion limit and dependent on the ionic strength of the medium, consistent with reaction between charged species; (iii) at pH a , the process involves Co6(II)-OH 2 →Co6(III)-OH transformation and proceeds via a multiple-site, concerted proton electron transfer (CPET) where water assists the transfer of the proton, as proven by the absence of effect of buffer base concentrations on the rate of the ET and by a H/D kinetic isotope in a range of 1.2-1.4. The reactivity of water is ascribed to its organization on the surface of the polyanionic scaffold through hydrogen bond networking involving the Co(II)-OH 2 group., (© 2021 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Two novel copper(II) complexes of formulas {[Cu(4-Hmpz) 4 ][Cu(4-Hmpz) 2 (µ 3 -ox- κ 2 O 1 , O 2 : κO 2' : κO 1' )(ClO 4 ) 2 ]} n ( 1 ) and {[Cu(3,4,5-Htmpz) 4 ] 2 [Cu(3,4,5-Htmpz) 2 (µ 3 -ox- κ 2 O 1 , O 2 : κO 2' : κO 1' )(H 2 O)(ClO 4 )] 2 [Cu 2 (3,4,5-Htmpz) 4 (µ-ox- κ 2 O 1 , O 2 : κ 2 O 2' , O 1' )]}(ClO 4 ) 4 ·6H 2 O ( 2 ) have been obtained by using 4-methyl-1 H -pyrazole (4-Hmpz) and 3,4,5-trimethyl-1 H -pyrazole (3,4,5-Htmpz) as terminal ligands and oxalate (ox) as the polyatomic inverse coordination center. The crystal structure of 1 consists of perchlorate counteranions and cationic copper(II) chains with alternating bis(pyrazole)(µ 3 - κ 2 O 1 , O 2 : κO 2' : κO 1' -oxalato)copper(II) and tetrakis(pyrazole)copper(II) fragments. The crystal structure of 2 is made up of perchlorate counteranions and cationic centrosymmetric hexanuclear complexes where an inner tetrakis(pyrazole)(µ- κ 2 O 1 , O 2 : κ 2 O 2' , O 1' -oxalato)dicopper(II) entity and two outer mononuclear tetrakis(pyrazole)copper(II) units are linked through two mononuclear aquabis(pyrazole)(µ 3 - κ 2 O 1 , O 2 : κO 2' : κO 1' -oxalato)copper(II) units. The magnetic properties of 1 and 2 were investigated in the temperature range 2.0-300 K. Very weak intrachain antiferromagnetic interactions between the copper(II) ions through the µ 3 -ox- κ 2 O 1 , O 2 : κO 2' : κO 1' center occur in 1 [ J = -0.42(1) cm -1 , the spin Hamiltonian being defined as H = - J∑ S 1,i · S 2,i +1 ], whereas very weak intramolecular ferromagnetic [ J = +0.28(2) cm -1 ] and strong antiferromagnetic [ J' = -348(2) cm -1 ] couplings coexist in 2 which are mediated by the µ 3 -ox- κ 2 O 1 , O 2 : κO 2' : κO 1' and µ-ox- κ 2 O 1 , O 2 : κ 2 O 2' , O 1' centers, respectively. The variation in the nature and magnitude of the magnetic coupling for this pair of oxalato-centered inverse copper(II) complexes is discussed in the light of their different structural features, and a comparison with related oxalato-centered inverse copper(II)-pyrazole systems from the literature is carried out.

Gastrointestinal (GI) endoscopy is the gold standard in the detection and treatment of early and advanced GI cancers. However, conventional endoscopic techniques are technically demanding and require visual-spatial skills and significant hands-on experience. GI endoscopy simulators represent a valid solution to allow doctors to practice in a pre-clinical scenario. From the first endoscopy mannequin, developed in 1969, several simulation platforms have been developed, ranging from purely mechanical systems to more complex mechatronic devices and animal-based models. Considering the recent advancement of technologies (e.g., artificial intelligence, augmented reality, robotics), simulation platforms can now reach high levels of realism, representing a valid and smart alternative to standard trainee/mentor learning programs. This is particularly true nowadays, when the current demographic trend and the most recent pandemic demand, more than ever, the ability to cope with many patients. This review offers a broad view of the technology available for GI endoscopy training, including platforms currently in the market and the relevant advancements in this research and application field. Additionally, new training needs and new emerging technologies are discussed to understand where medical education is heading.

Artificial intelligence (AI) technologies can play a key role in preventing, detecting, and monitoring epidemics. In this paper, we provide an overview of the recently published literature on the COVID-19 pandemic in four strategic areas: (1) triage, diagnosis, and risk prediction; (2) drug repurposing and development; (3) pharmacogenomics and vaccines; and (4) mining of the medical literature. We highlight how AI-powered health care can enable public health systems to efficiently handle future outbreaks and improve patient outcomes., (©Enrico Santus, Nicola Marino, Davide Cirillo, Emmanuele Chersoni, Arnau Montagud, Antonella Santuccione Chadha, Alfonso Valencia, Kevin Hughes, Charlotta Lindvall. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 12.03.2021.)

Targeted contact-tracing through mobile phone apps has been proposed as an instrument to help contain the spread of COVID-19 and manage the lifting of nation-wide lock-downs currently in place in USA and Europe. However, there is an ongoing debate on its potential efficacy, especially in light of region-specific demographics. We built an expanded SIR model of COVID-19 epidemics that accounts for region-specific population densities, and we used it to test the impact of a contact-tracing app in a number of scenarios. Using demographic and mobility data from Italy and Spain, we used the model to simulate scenarios that vary in baseline contact rates, population densities, and fraction of app users in the population. Our results show that, in support of efficient isolation of symptomatic cases, app-mediated contact-tracing can successfully mitigate the epidemic even with a relatively small fraction of users, and even suppress altogether with a larger fraction of users. However, when regional differences in population density are taken into consideration, the epidemic can be significantly harder to contain in higher density areas, highlighting potential limitations of this intervention in specific contexts. This work corroborates previous results in favor of app-mediated contact-tracing as mitigation measure for COVID-19, and draws attention on the importance of region-specific demographic and mobility factors to achieve maximum efficacy in containment policies.

The ability of a mother to produce a nutritionally complete neonatal food source has provided a powerful evolutionary advantage to mammals. Milk production by mammary epithelial cells is adaptive, its release is exquisitely timed, and its own glandular stagnation with the permanent cessation of suckling triggers the cell death and tissue remodeling that enables female mammals to nurse successive progeny. Chemical and mechanical signals both play a role in this process. However, despite this duality of input, much remains unknown about the nature and function of mechanical forces in this organ. Here, we characterize the force landscape in the functionally mature gland and the capacity of luminal and basal cells to experience and exert force. We explore molecular instruments for force-sensing, in particular channel-mediated mechanotransduction, revealing increased expression of Piezo1 in mammary tissue in lactation and confirming functional expression in luminal cells. We also reveal, however, that lactation and involution proceed normally in mice with luminal-specific Piezo1 deletion. These findings support a multifaceted system of chemical and mechanical sensing in the mammary gland, and a protective redundancy that ensures continued lactational competence and offspring survival., Competing Interests: Competing interestsM.M. is Chief Executive Officer at IstoVisio, Inc. and co-creator of syGlass (IstoVisio), the visualization software used to prepare Movies 2, 3, 4 and 5., (© 2021. Published by The Company of Biologists Ltd.)

M2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC). Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation. We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations., Competing Interests: All the authors declare no competing financial interests., (© 2020 The Author(s).)

Objective: To evaluate the bacterial contamination of different brands of Gutta-Percha (GP) points routinely used in clinical practice and the efficacy of a chairside disinfection protocol with sodium hypochlorite., Methods: GP points (n=240), in sizes A, B, C, D, K15, K20, K25, K30, K35, K40, F1, F2, F3 (Dentsply®, Proclinic®, ProTaper® and R&S®), were randomly sampled from commercial packages already in use. These were added directly to Fluid Thioglycolate Medium (one GP point per tube) and incubated at 37ºC for 21 days. During this period, the presence/absence of turbidity was evaluated. To evaluate the efficacy of a chairside disinfection protocol, all detected contaminated GP points were immersed for 1 minute in 10 mL of 5.25% sodium hypochlorite, followed by 5 minutes in 10 mL of detergent solution (3% Tween 80 and 5% sodium thiosulfate) and a final rinse with 10 mL of sterile distilled water and incubated. The data was analysed using the chi-square test and differences between characteristics of dichotomic variables were performed using the binomial test. The significance level was set at P<0.05., Results: Bacterial growth was observed in 22.9% of the total study samples. Dentsply® and R&S® showed the highest level of contamination, 47.3% each, although without significant differences to the other commercial brands. The most contaminated GP point size was K30 (16.4%). The chairside disinfection protocol was effective in disinfection of 76.4% of GP points (P<0.001)., Conclusion: A real small number of GP points in clinical use harboured bacteria, including after the Chairside Disinfection Protocol that, anyway, proved to be effective. No significant difference was observed between tested commercial brands.

Purpose of Review: Surgical training has dramatically changed over the last decade. It has become not only the way to prepare surgeons for their everyday work, but also a way to certify their skills thus increasing patient safety. This article reviews advances in the use of machine learning and artificial intelligence applied to virtual reality based surgical training over the last 5 years., Recent Findings: Eight articles have been published which met the inclusion criteria. This included six articles about the use of machine learning and artificial intelligence for assessment purposes and two articles about the possibility of teaching applications, including one review and one original research article. All the research articles pointed out the importance of machine learning and artificial intelligence for the stratification of trainees, based on their performance on basic tasks or procedures simulated in a virtual reality environment., Summary: Machine learning and artificial intelligence are designed to analyse data and use them to take decisions that typically require human intelligence. Evidence in literature is still scarce about this technology applied to virtual reality and existing manuscripts are mainly focused on its potential to stratify surgical performance and provide synthetic feedbacks about it. In consideration of the exponential growth of computer calculation capabilities, it is possible to expect a parallel increase of research about this topic within the next few years.

The mammary epithelium is indispensable for the continued survival of more than 5,000 mammalian species. For some, the volume of milk ejected in a single day exceeds their entire blood volume. Here, we unveil the spatiotemporal properties of physiological signals that orchestrate the ejection of milk from alveolar units and its passage along the mammary ductal network. Using quantitative, multidimensional imaging of mammary cell ensembles from GCaMP6 transgenic mice, we reveal how stimulus evoked Ca 2+ oscillations couple to contractions in basal epithelial cells. Moreover, we show that Ca 2+ -dependent contractions generate the requisite force to physically deform the innermost layer of luminal cells, compelling them to discharge the fluid that they produced and housed. Through the collective action of thousands of these biological positive-displacement pumps, each linked to a contractile ductal network, milk begins its passage toward the dependent neonate, seconds after the command., Competing Interests: The authors declare no competing interest.

Histologically normal tissue adjacent to the tumor can provide insight of the microenvironmental alterations surrounding the cancerous lesion and affecting the progression of the disease. However, little is known about the molecular changes governing cancer initiation in cancer-free breast tissue. Here, we employed laser microdissection and whole-transcriptome profiling of the breast epithelium prior to and post tumor diagnosis to identify the earliest alterations in breast carcinogenesis. Furthermore, a comprehensive analysis of the three tissue compartments (microdissected epithelium, stroma, and adipose tissue) was performed on the breast donated by either healthy subjects or women prior to the clinical manifestation of cancer (labeled "susceptible normal tissue"). Although both susceptible and healthy breast tissues appeared histologically normal, the susceptible breast epithelium displayed a significant upregulation of genes involved in fatty acid uptake/transport (CD36 and AQP7), lipolysis (LIPE), and lipid peroxidation (AKR1C1). Upregulation of lipid metabolism- and fatty acid transport-related genes was observed also in the microdissected susceptible stromal and adipose tissue compartments, respectively, when compared with the matched healthy controls. Moreover, inter-compartmental co-expression analysis showed increased epithelium-adipose tissue crosstalk in the susceptible breasts as compared with healthy controls. Interestingly, reductions in natural killer (NK)-related gene signature and CD45+/CD20+ cell staining were also observed in the stromal compartment of susceptible breasts. Our study yields new insights into the cancer initiation process in the breast. The data suggest that in the early phase of cancer development, metabolic activation of the breast, together with increased epithelium-adipose tissue crosstalk may create a favorable environment for final cell transformation, proliferation, and survival., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Introduction and Objectives: The possibility of performing remote-surgery has been the goal to achieve, since the early development of the first surgical robotic platforms. This systematic review aims to analyse the state of the art in the field and to provide an overview of the possible growth of this technology., Methods: All English language publications on Telementoring and Telesurgery for minimally invasive urologic procedures were evaluated. We followed the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement to evaluate PubMed ® , Scopus ® , and Web of Science™ databases (up to June 2019)., Results: Our electronic search identified a total of 124 papers in PubMed, Scopus, and Web of Science. Of these, 81 publications were identified for detailed review, which yielded 22 included in the present systematic review. Our results showed that remote surgery has been under-utilised until today, mostly due to the lack of appropriate telecommunication technologies., Conclusion: Remote live surgery is a growing technology that is catalyzing incremental interest. Despite not being yet reliable today on a regular basis in its most advanced applications, thanks to the advent of novel data-transmission technologies, telepresence might become a critical educational methodology, highly impacting the global healthcare system.

Balance impairments are a relevant problem in patients with diabetes, and interventions to manage this issue represent a public health need. This study reviewed the literature about the effectiveness of Tai Chi on balance improvement in patients with type 2 diabetes. Springerlink, MEDLINE, PubMed, CINAHL, Web of Science, Scopus, and Cochrane CENTRAL databases were screened. Randomized and nonrandomized controlled trials assessing balance in patients with type 2 diabetes enrolled in a Tai Chi program were considered eligible. Four studies were included in qualitative synthesis and in quantitative analysis (three randomized controlled trials and one pretest-posttest quasi-experimental study). Evidence supporting Tai Chi to improve balance in patients with type 2 diabetes was found (effect size: 0.52; 95% confidence interval [0.20, 0.84]); however, the analysis relied on a small number of studies, which raises concerns about the risk of bias. In conclusion, the results support the benefits of Tai Chi intervention to improve balance in patients with type 2 diabetes.

Introduction: Telemedicine is the use of Information and Communication Technologies (ICT) to improve patient outcomes by increasing access to care, medical information and services. The aim of this pilot study was to evaluate and support the implementation of screening and early detection programs in the prevention of breast cancer and cardiovascular diseases with the establishment of a remote diagnosis through the use of ICT in mobile units. Materials and Methods: A total of 430 individuals were recruited in an area of Southern Italy. Particularly, 321 women were recruited to undergo breast cancer screening in accordance with Italian guidelines. Likewise, cardiovascular screening interested 109 subjects. A self-contained mobile unit with connectivity was provided to offer breast and cardiovascular screenings. To maximize the benefit, we have evaluated the return of investment. Results: The telemedicine screening program allowed the detection of early pathologies. In breast cancer screening, 40.8% of cases were negative to lesions, 34.9% were positive to benign lesions, and 3.1% presented suspicious malignant lesions; these lesions were further checked by histological analyses, which showed a positive response in 70% of cases. The cardiovascular screening concerned 109 participants based on age and other risk factors. We observed a significant difference among risk factors in patients with cardiac disease (p < 0.001); particularly, hypertension was significantly the most present risk factor (51.4%, p < 0.05), followed by smoking (28.4%, p < 0.05). A cardiovascular pathology was detected in 40.4% of enrolled subjects. A 3.3:1 return on investment was calculated. Conclusion: Our findings demonstrate that telemedicine may represent a promising approach to deliver several health services, such as screening programs, with users who cannot utilize services in their locations. The use of telemedicine on diagnostic campers greatly reduces the costs of screening for breast cancer and major cardiovascular diseases within the Southern Italian Health Service. We believe that public investment can have a further significant return on investment by implementing the principles of precision medicine.

Introduction: Robotic-assisted surgery (RAS) is increasingly used in adulthood but its application in pediatric population is limited. We report our initial experience in pediatric RAS, focusing on conversions to analyze their causes. Methods: All pediatric patients who underwent RAS between June 2015 and April 2019 were included, analyzing demographics, comorbidities, previous surgery, and intraoperative surgical and anesthetic parameters. A three-arms robotic technique was used in all cases. Additional laparoscopic ports were added, when needed. The surgical team did not change during the program, whereas the anesthesiology team varied. Results: Thirty-nine patients (23 females, 16 males; mean age ± SD = 9.33 ± 4.73 years [range = 1-16]; mean weight ± SD = 35.2 ± 20.0 kg [range = 9-85]) underwent 40 different procedures (18 gastrointestinal, 15 urogynecological, 5 oncological, and 2 miscellaneous). Three procedures (7.5%) were converted to open surgery for inadequate working space (two marked bowel distension and one insufficient hepatic retraction). Converted patients were of significant lower age (mean ± standard error of mean [SEM] = 2.97 ± 1.03 versus 9.83 ± 0.77 years, P  = .01) and lower weight (mean ± SEM = 11.83 ± 1.74 versus 35.47 ± 3.16 kg, P  = .03). The two groups did not differ statistically for duration of facial mask ventilation before intubation (mean ± SEM = converted 10.67 ± 2.33 versus completed 10.31 ± 0.91 minutes), neuromuscular block dosage (rocuronium; mean ± SEM = converted 0.46 ± 0.06 mg/kg versus completed 0.62 ± 0.03 mg/kg) and in the type of bowel preparation (mechanical and/or pharmacological). Discussion: Conversion rate in initial pediatric RAS program is acceptable. In children, the need for conversion is mainly because of inadequate working space, particularly in smaller children, but it seems not to be influenced by measurable anesthetic factors or different regimen for bowel preparation.

Breast cancer is the second leading cause of cancer mortality among women. Mammography and tumor biopsy followed by histopathological analysis are the current methods to diagnose breast cancer. Mammography does not detect all breast tumor subtypes, especially those that arise in younger women or women with dense breast tissue, and are more aggressive. There is an urgent need to find circulating prognostic molecules and liquid biopsy methods for breast cancer diagnosis and reducing the mortality rate. In this study, we systematically evaluated metabolites and proteins in blood to develop a pipeline to identify potential circulating biomarkers for breast cancer risk. Our aim is to identify a group of molecules to be used in the design of portable and low-cost biomarker detection devices. We obtained plasma samples from women who are cancer free (healthy) and women who were cancer free at the time of blood collection but developed breast cancer later (susceptible). We extracted potential prognostic biomarkers for breast cancer risk from plasma metabolomics and proteomics data using statistical and discriminative power analyses. We pre-processed the data to ensure the quality of subsequent analyses, and used two main feature selection methods to determine the importance of each molecule. After further feature elimination based on pairwise dependencies, we measured the performance of logistic regression classifier on the remaining molecules and compared their biological relevance. We identified six signatures that predicted breast cancer risk with different specificity and selectivity. The best performing signature had 13 factors. We validated the difference in level of one of the biomarkers, SCF/KITLG, in plasma from healthy and susceptible individuals. These biomarkers will be used to develop low-cost liquid biopsy methods toward early identification of breast cancer risk and hence decreased mortality. Our findings provide the knowledge basis needed to proceed in this direction.

Pistachio (Pistacia vera L.) belongs to the Anacardiaceae family and it is a small tree species. It is native of the Middle East and Central Asia, but currently, it is cultivated also in California and in some Mediterranean countries, such as Greece and Italy. The most important pistachio producers are Iran, the USA, and Turkey. Besides being a delicious nut, pistachio, due to its wholesome nutritional properties, could be considered as a functional food. According to the results of several studies, pistachios have been proven to have various groups of valuable phytochemicals such as anthocyanins, flavan-3-ols, proanthocyanidins, flavonols, isoflavones, flavanones, stilbenes, and phenolic acids, possessing excellent biological activities. The most common analytical technique employed for their analysis is represented by liquid chromatography coupled to photodiode array and mass spectrometry detection. However, conventional LC can present some limits especially in terms of resolving power. In this contribution, as a powerful alternative, comprehensive two-dimensional liquid chromatography (LC×LC) was applied to the determination of the polyphenolic fraction of pistachio kernels from different geographical origins. A 150-mm micro-bore cyano column (2.7 μm d p ) and 50-mm superficially porous C18 silica column (2.7 μm d p ) in the first ( 1 D) and second ( 2 D) dimensions were employed, respectively. For boosting orthogonality, a shift 2 D gradient was investigated leading to an increase in the overall peak capacity. The newly developed LC×LC method showed satisfactory linearity, sensitivity, precision and accuracy, which was then applied to sample quantitative analysis. A total of 51 different polyphenolic compounds were determined in the four samples investigated and 18 out of them are hereby reported for the first time.

Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER + ) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER + breast cancer cells. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER + breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER + breast cancers in obese postmenopausal women. SIGNIFICANCE: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk., (©2019 American Association for Cancer Research.)

In the version of this Article originally published, in the graphical abstract the y-axis units of the plot read 'mA cm -2' , but should have read 'μA cm -2' . Additionally, an erroneous gap appeared in the red trace. These errors have now been corrected.

We aimed to establish the prevalence of the musculocutaneous nerve (MCN) variations and the probability of the variation being pure or mixed in the same plexus. We applied the principles of evidence-based anatomy to find, appraise, and synthesize data through a meta-analysis of anatomical studies. The variations were grouped based on the presence and location of the communicating branch with the median nerve and the origin of branches to anterior arm muscles. Forty-three cadaveric studies met the inclusion criteria, providing data from 4124 plexuses. The overall pooled prevalence of plexuses with MCN variations was 20%. Based on the classification applied in our study, the pooled prevalence of variations was 17% in region 1A, 20% in region 1B, 36% in region 2 and 49% in region 3. Importantly, 64.58% of variations in region 1A and 74.14% of variations in region 1B were mixed, that is, associated with a variation in another region. The odds of finding another variation in the presence of a variation in region 2 or 3 were equal 0.37 and 0.52, respectively, demonstrating a significantly lower probability of finding mixed variations involving these regions, when compared with region 1A. Variations of the MCN are most common in the part distal to the exit from within or beneath the coracobrachialis muscle. Proximal variations are more often associated with another variation located along the nerve. These findings can assist health care professionals in the treatment of brachial plexus lesions. Clin. Anat. 32:183-195, 2019. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

B-cell precursor-acute lymphoblastic leukemia modulates the bone marrow (BM) niche to become leukemia-supporting and chemo-protective by reprogramming the stromal microenvironment. New therapies targeting the interplay between leukemia and stroma can help improve disease outcome. We identified ActivinA, a TGF-β family member with a well-described role in promoting several solid malignancies, as a factor favoring leukemia that could represent a new potential target for therapy. ActivinA resulted over-expressed in the leukemic BM and its production was strongly induced in mesenchymal stromal cells after culture with leukemic cells. Moreover, MSCs isolated from BM of leukemic patients showed an intrinsic ability to secrete higher amounts of ActivinA compared to their normal counterparts. The pro-inflammatory leukemic BM microenvironment synergized with leukemic cells to induce stromal-derived ActivinA. Gene expression analysis of ActivinA-treated leukemic cells showed that this protein was able to significantly influence motility-associated pathways. Interestingly, ActivinA promoted random motility and CXCL12-driven migration of leukemic cells, even at suboptimal chemokine concentrations, characterizing the leukemic niche. Conversely, ActivinA severely impaired CXCL12-induced migration of healthy CD34 + cells. This opposite effect can be explained by the ability of ActivinA to increase intracellular calcium only in leukemic cells, boosting cytoskeleton dynamics through a higher rate of actin polymerization. Moreover, by stimulating the invasiveness of the leukemic cells, ActivinA was found to be a leukemia-promoting factor. Importantly, the ability of ActivinA to enhance BM engraftment and the metastatic potential of leukemic cells was confirmed in a xenograft mouse model of the disease. Overall, ActivinA was seen to be a key factor in conferring a migratory advantage to leukemic cells over healthy hematopoiesis within the leukemic niche., (Copyright© 2019 Ferrata Storti Foundation.)

The oxygen in Earth's atmosphere is there primarily because of water oxidation performed by photosynthetic organisms using solar light and one specialized protein complex, photosystem II (PSII). High-resolution imaging of the PSII 'core' complex shows the ideal co-localization of multi-chromophore light-harvesting antennas with the functional reaction centre. Man-made systems are still far from replicating the complexity of PSII, as the majority of PSII mimetics have been limited to photocatalytic dyads based on a 1:1 ratio of a light absorber, generally a Ru-polypyridine complex, with a water oxidation catalyst. Here we report the self-assembly of multi-perylene-bisimide chromophores (PBI) shaped to function by interaction with a polyoxometalate water-oxidation catalyst (Ru 4 POM). The resulting [PBI] 5 Ru 4 POM complex shows a robust amphiphilic structure and dynamic aggregation into large two-dimensional paracrystalline domains, a redshifted light-harvesting efficiency of >40% and favourable exciton accumulation, with a peak quantum efficiency using 'green' photons (λ > 500 nm). The modularity of the building blocks and the simplicity of the non-covalent chemistry offer opportunities for innovation in artificial photosynthesis.

Gastric duplication cysts (GDCs) represent 4-9% of alimentary tract duplications. Early diagnosis and surgical excision are essential to avoid morbidity or neoplastic degeneration. Roboticassisted excision of GDCs has never been described in childhood. We report an asymptomatic male patient with 2 gastric cystic masses at ultrasonography (US)-study (diameter 25mm and 8mm), increasing in size at follow-up. At 20 months of age, magnetic- resonance-imaging-scan confirmed 2 round gastric masses (44×35mm and 16×12mm, respectively). Two months later, an elective robotic-assisted excision of GDCs was completed without complications. The patient was discharged at day 6 after procedure. Histology confirmed the diagnosis of GDCs. At a 2-year follow- up, US-study did not evidence any issue. In this first reported case of robotic-assisted cystectomy for CGD in childhood, the procedure seems safe, effective, and feasible. This approach improves the movements of the surgical instruments with better 3- D visualization in comparison with the laparoscopic approach.

Combination cancer chemotherapy provides an important treatment tool, both as an adjuvant and neoadjuvant treatment, this shift in focus from mono to combination therapies has led to increased interest in drug delivery systems (DDS). DDSs, such as polymersomes, are capable of encapsulating large amounts of multiple drugs with both hydrophilic and hydrophobic properties simultaneously, as well as offering a mechanism to combat multi drug resistant cancers and poor patient tolerance of the cytotoxic compounds utilised. In this article, we report the formulation and evaluation of a novel electroneutral polymersome capable of high encapsulation efficacies for multiple drugs (Doxorubicin, 5-Fluorouracil and leucovorin). The in-vivo biodistribution of the polymersome were established and they were found to accumulate largely in tumour tissue. Polymersome encapsulating the three chemotherapeutic drugs were assessed both in-vitro (BxPC-3 cell line) and in-vivo (following intratumoral and intravenous administration) and compared with the same concentration of the three drugs in solution. We report better efficacy and higher maximum tolerated dose for our combination drug loaded polymersomes in all experiments. Furthermore, intratumorally injected combination drug loaded polymersomes exhibited a 62% reduction in tumour volume after 13 days when compared with the free combination solutions. A smaller differential of 13% was observed for when treatment was administered intravenously however, importantly less cardiotoxicity was displayed from the polymersomal DDS. In this study, expression of a number of survival-relevant genes in tumours treated with the free chemotherapy combination was compared with expression of those genes in tumours treated with the polymersomes harbouring those drugs and the significance of findings is discussed. STATEMENT OF SIGNIFICANCE: The shift in focus from mono to combination chemotherapies has led to an increased interest in the role of drug delivery systems (DDS). Liposomes, although commercialized for mono therapy, have lower loading capacities and stability than their polymeric counterpart, polymersomes. Polymersomes are growing in prevalence as their advantageous properties are better understood and exploited. Here we present a novel polymersome for the encapsulation of three anticancer compounds. This is the first time this particular polymersome has been used to encapsulate these three compounds with both an in-vitro and in-vivo evaluation carried out. This work will be of interest to those in the field of combination therapy, drug delivery, drug toxicity, multidrug resistance, liposomes, DDS and polymersomes., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Herein we report an effective synthetic method for the direct assembly of highly functionalized tetracyclic pharmacophoric cores. Coumarins and chromones undergo diastereoselective [4 + 2] cycloaddition reactions with light-generated photoenol intermediates. The reactions occur by aid of a microfluidic photoreactor (MFP) in high yield (up to >98%) and virtually complete diastereocontrol (>20:1 dr). The method is easily scaled-up to a parallel setup, furnishing 948 mg of product over a 14 h reaction time. Finally, a series of manipulations of the tetracyclic scaffold obtained gave access to valuable precursors of biologically active molecules.

This analysis sought to develop a tool for early differentiation between pediatric necrotizing fasciitis (NF) of the extremity and more benign infection. All diagnoses of extremity NF, cellulitis, and abscess from a single institution from 2009 to 2015 were included. Vitals and laboratory values were compared between cohorts using analysis of variance and decision tree analysis. NF was associated with thrombocytopenia, hyperthermia, tachycardia, and tachypnea. Decision tree analysis identified C-reactive protein more than 7.0 to be 100% sensitive and 95.7% specific for differentiating NF from cellulitis or abscess. The results offer quantitative support for clinical suspicion of NF in the evaluation of pediatric extremity infection.