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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.comnet.2005.04.002 Byline: V. Ghini (a), G. Pau (b), M. Roccetti (a), P. Salomoni (a), M. Gerla (b) Keywords: Internet wireless applications; Inter-technologies roaming; Music delivery technologies; Music consumer networking; Wireless networks for entertainment Abstract: The maturing distributed file sharing technology implemented by Napster has first enabled the dissemination of musical content in digital form, permitting to customers to retrieve stored music files from around the world. In the post-Napster era, the Apple iTunes online music service has hit a record share of 16.7% in the MP3 player market [J. Mc Hugh, Why Wi-Fi is a good business? Wired (2003) 25-26]. This is only the most prominent example of the success of digital music distribution based on packet network technologies. However, to the best of our knowledge, the most noteworthy aspect of the success of digital music distribution is that little about this music delivery technology is really new. To drastically change the nature of this business, we claim that wireless delivery technology must come into the picture. This way, the digital music delivery model will benefit from the integration of the wired Internet with a broad gamut of wireless access technologies, such as WiFi, WPAN and 3G. In this paper we address the problem of the "customer on the move"; we present a wireless Internet application designed to support the distribution of digital music to handheld devices. The main novelty of our software is the ability to provide a seamless music delivery service even in the presence of handoffs within the same radio medium (horizontal) and across media (vertical). Actual measurements from a deployed application show that our system can deliver a smooth, ultra reliable, low latency music service to mobile users. Author Affiliation: (a) University of Bologna, Department of Computer Science, Mura A. Zamboni 7, Bologna 40127, Italy (b) UCLA, Computer Science Department, CA 90095, USA

A combination of pathway enrichment and metabolite clustering analysis is used to interpret untargeted 1 H NMR metabolomics data, enabling a biochemically informative comparison of the effects induced by a panel of known cytotoxic gold(I) and gold(III) compounds in A2780 ovarian cancer cells. The identification of the most dysregulated pathways for the major classes of compounds highlights specific chemical features that lead to common biological effects. The proposed approach may have broader applicability to the screening of metal-based drug candidate libraries, which is always complicated by their multitarget nature, and support the comprehensive interpretation of their metabolic actions.

Primary squamous cell carcinoma (SCC) can originate in different parts of the body, including the head, neck, lung, bronchus, cervix uteri, esophagus, and cardia, and subsequently metastasize to the stomach. Primary gastric squamous cell carcinoma (GSCC) is a rare disease. To better understand GSCC, we present the case of a 72-year-old woman with a primary GSCC. A chest and abdominal CT scan highlighted a 36×26 mm mass with a 41 mm longitudinal diameter, which included the origin of the celiac tripod. The disease appeared to originate exophytically from the gastric wall. An ultrasound-endoscopy showed a hypoechoic formation with not well-defined margins measuring 40×30 mm involving the origin of the celiac tripod, about 10 mm from the gastric wall. An endoscopic fine-needle aspiration showed a poorly differentiated carcinoma. A PET/CT scan showed a hyperaccumulation of the known expansive formation at the celiac tripod (SUV 11.9) without specific cleavage planes from the stomach. A gastroscopy showed a regular esophagus and an absence of gastric protruding lesions. In the subcardial area, on the posterior wall, there was a slightly raised sub-centimetric area covered by bleeding mucosa where the biopsy had been performed. The pathological report showed chronic gastritis. An eco-endoscopy confirmed a hypoechoic neoformation measuring 30×40 mm that appeared to originate from the muscular layer of the gastric wall. The biopsy report was positive for broad-spectrum cytokeratins (AE1/AE3), CK5/6/7, p40, p63 and negative for CK20, PAS, TTF-1, anti-smooth muscle actin, CD45 (LCA), ERG, and S100. The clinical picture suggested poorly differentiated carcinoma with squamous differentiation. We analyzed the main classifications of GSCC cases and compared their characteristics. It is clear that to have an appropriate definition of GSCC, well-defined diagnostic criteria are needed. Currently, there is no consensus. For practical purposes, it would be better to include a panel of CK and p40 to distinguish GSCC from adenocarcinoma. A GSCC outside the mucosa is not rare and could be a true entity., 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 Monti, Limarzi, Oboldi, Sbrancia, Pallotti, Miserocchi, Ghini, Zanuccoli, Cagnazzo and Frassineti.)

Aurothiomalate (AuTM) is an FDA-approved antiarthritic gold drug with unique anticancer properties. To enhance its anticancer activity, we prepared a bioconjugate with human apoferritin (HuHf) by attaching some AuTM moieties to surface protein residues. The reaction of apoferritin with excess AuTM yielded a single adduct, that was characterized by ESI MS and ICP-OES analysis, using three mutant ferritins and trypsinization experiments. The adduct contains ~3 gold atoms per ferritin subunit, arranged in a small cluster bound to Cys90 and Cys102. MD simulations provided a plausible structural model for the cluster. The adduct was evaluated for its pharmacological properties and was found to be significantly more cytotoxic than free AuTM against A2780 cancer cells mainly due to higher gold uptake. NMR-metabolomics showed that AuTM bound to HuHf and free AuTM induced qualitatively similar changes in treated cancer cells, indicating that the effects on cell metabolism are approximately the same, in agreement with independent biochemical experiments. In conclusion, we have demonstrated here that a molecularly precise bioconjugate formed between AuTM and HuHf exhibits anticancer properties far superior to the free drug, while retaining its key mechanistic features. Evidence is provided that human ferritin can serve as an excellent carrier for this metallodrug., (© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The therapeutic usage of physical stimuli is framed in a highly heterogeneous research area, with variable levels of maturity and of translatability into clinical application. In particular, electrostimulation is deeply studied for its application on the autonomous nervous system, but less is known about the anti- inflammatory effects of such stimuli beyond the inflammatory reflex . Further, reproducibility and meta-analyses are extremely challenging, owing to the limited rationale on dosage and experimental standardization. It is specifically to address the fundamental question on the anti-inflammatory effects of electricity on biological systems, that we propose a series of controlled experiments on the effects of direct and alternate current delivered on a standardized 3D bioconstruct constituted by fibroblasts and keratinocytes in a collagen matrix, in the presence or absence of TNF-α as conventional inflammation inducer. This selected but systematic exploration, with transcriptomics backed by metabolomics at specific time points allows to obtain the first systemic overview of the biological functions at stake, highlighting the differential anti-inflammatory potential of such approaches, with promising results for 5 V direct current stimuli, correlating with the wound healing process. With our results, we wish to set the base for a rigorous systematic approach to the problem, fundamental towards future elucidations of the detailed mechanisms at stake, highlighting both the healing and damaging potential of such approaches.

In the context of smart campuses, effective emergency management is crucial for ensuring the safety and well-being of students, staff, and visitors. This paper presents a comprehensive support tool designed to enhance emergency management on smart campuses, integrating a low-cost people-counting system based on cameras and Raspberry Pi devices. It introduces a newly designed architecture and user interfaces that enhance the functionality and user experience of a smart campus disaster management system. Finally, a usability evaluation has been carried out to validate the brand-new user interfaces devoted to emergency management.

Cancer cell lines are frequently used in metabolomics, such as in vitro tumor models. In particular, A2780 cells are commonly used as a model for ovarian cancer to evaluate the effects of drug treatment. Here, we compare the NMR metabolomics profiles of A2780 and cisplatin-resistant A2780 cells with those of cells derived from 10 patients with high-grade serous ovarian carcinoma (collected during primary cytoreduction before any chemotherapeutic treatment). Our analysis reveals a substantial similarity among all primary cells but significant differences between them and both A2780 and cisplatin-resistant A2780 cells. Notably, the patient-derived cells are closer to the resistant A2780 cells when considering the exo-metabolome, whereas they are essentially equidistant from A2780 and A2780-resistant cells in terms of the endo-metabolome. This behavior results from dissimilarities in the levels of several metabolites attributable to the differential modulation of underlying biochemical pathways. The patient-derived cells are those with the most pronounced glycolytic phenotype, whereas A2780-resistant cells mainly diverge from the others due to alterations in a few specific metabolites already known as markers of resistance.

Colitis has a multifactorial pathogenesis with a strong cross-talk among microbiota, hypoxia, and tissue metabolism. Here, we aimed to characterize the molecular signature of the disease in symptomatic and presymptomatic stages of the inflammatory process at the tissue and fecal level. The study is based on two different murine models for colitis, and HR-MAS NMR on "intact" colon tissues and LC-MS/MS on colon tissue extracts were used to derive untargeted metabolomics and proteomics information, respectively. Solution NMR was used to derive metabolomic profiles of the fecal extracts. By combining metabolomic and proteomic analyses of the tissues, we found increased anaerobic glycolysis, accompanied by an altered citric acid cycle and oxidative phosphorylation in inflamed colons; these changes associate with inflammation-induced hypoxia taking place in colon tissues. Different colitis states were also characterized by significantly different metabolomic profiles of fecal extracts, attributable to both the dysbiosis characteristic of colitis as well as the dysregulated tissue metabolism. Strong and distinctive tissue and fecal metabolomic signatures can be detected before the onset of symptoms. Therefore, untargeted metabolomics of tissues and fecal extracts provides a comprehensive picture of the changes accompanying the disease onset already at preclinical stages, highlighting the diagnostic potential of global metabolomics for inflammatory diseases.

Probiotics are live microorganisms that confer health benefits when administered in adequate amounts. They are used to promote gut health and alleviate various disorders. Recently, there has been an increasing interest in the potential effects of probiotics on human physiology. In the presented study, the effects of probiotic treatment on the metabolic profiles of human urine and serum using a nuclear magnetic resonance (NMR)-based metabonomic approach were investigated. Twenty-one healthy volunteers were enrolled in the study, and they received two different dosages of probiotics for 8 weeks. During the study, urine and serum samples were collected from volunteers before and during probiotic supplementation. The results showed that probiotics had a significant impact on the urinary and serum metabolic profiles without altering their phenotypes. This study demonstrated the effects of probiotics in terms of variations of metabolite levels resulting also from the different probiotic posology. Overall, the results suggest that probiotic administration may affect both urine and serum metabolomes, although more research is needed to understand the mechanisms and clinical implications of these effects. NMR-based metabonomic analysis of biofluids is a powerful tool for monitoring host-gut microflora dynamic interaction as well as for assessing the individual response to probiotic treatment.

Plasma of COVID-19 patients contains a strong metabolomic/lipoproteomic signature, revealed by the NMR analysis of a cohort of >500 patients sampled during various waves of COVID-19 infection, corresponding to the spread of different variants, and having different vaccination status. This composite signature highlights common traits of the SARS-CoV-2 infection. The most dysregulated molecules display concentration trends that scale with disease severity and might serve as prognostic markers for fatal events. Metabolomics evidence is then used as input data for a sex-specific multi-organ metabolic model. This reconstruction provides a comprehensive view of the impact of COVID-19 on the entire human metabolism. The human (male and female) metabolic network is strongly impacted by the disease to an extent dictated by its severity. A marked metabolic reprogramming at the level of many organs indicates an increase in the generic energetic demand of the organism following infection. Sex-specific modulation of immune response is also suggested., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ghini et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This review focuses on metabolomics from an NMR point of view. It attempts to cover the broad scope of metabolomics and describes the NMR experiments that are most suitable for each sample type. It is addressed not only to NMR specialists, but to all researchers who wish to approach metabolomics with a clear idea of what they wish to achieve but not necessarily with a deep knowledge of NMR. For this reason, some technical parts may seem a bit naïve to the experts. The review starts by describing standard metabolomics procedures, which imply the use of a dedicated 600 MHz instrument and of four properly standardized 1D experiments. Standardization is a must if one wants to directly compare NMR results obtained in different labs. A brief mention is also made of standardized pre-analytical procedures, which are even more essential. Attention is paid to the distinction between fingerprinting and profiling, and the advantages and disadvantages of fingerprinting are clarified. This aspect is often not fully appreciated. Then profiling, and the associated problems of signal assignment and quantitation, are discussed. We also describe less conventional approaches, such as the use of different magnetic fields, the use of signal enhancement techniques to increase sensitivity, and the potential of field-shuttling NMR. A few examples of biomedical applications are also given, again with the focus on NMR techniques that are most suitable to achieve each particular goal, including a description of the most common heteronuclear experiments. Finally, the growing applications of metabolomics to foodstuffs are described., 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. Published by Elsevier B.V.)

Purpose: The aims of our retrospective study investigated the role of immune system in glioblastoma (GBM), which is the most aggressive primary brain tumor in adults characterized by a poor prognosis. The recurrence rate remains high, probably due to "immune-desert" tumor microenvironment (TME) making GBM hidden from the anti-tumoral immune clearance. Considering this, we aimed to create a panel of prognostic markers from blood and tumor tissue correlating with overall survival (OS) and progression-free survival (PFS)., Methods: Firstly, we analyzed the inflammatory markers NLR and PLR as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively, collected at different time points in the peripheral blood of 95 patients. Furthermore, in 31 patients of the same cohort, we analyzed the formalin-fixed paraffin embedded samples to further compare the impact of circulating and inflammatory markers within the TME., Results: Patients aged < 60 years and with methylated MGMT showed better OS. While, pre-chemotherapy Systemic Inflammatory Index (SII) < 480 was related to a better OS and PFS, we observed that only CD68+macrophage and CD66b+neutrophils expressed in vascular/perivascular area (V) showed a statistically significant prognostic role in median OS and PFS., Conclusions: Thus, we underscored a role of SII as predictive value of response to STUPP protocol. Regarding the TME-related markers, we suggested to take into consideration for future studies with new immunotherapy combinations, each component relating to expression of immune infiltrating subsets., (© 2023. The Author(s).)

NMR metabolomics is a powerful tool to characterise the changes in cancer cell metabolism elicited by anticancer drugs. Here, the large metabolic alterations produced by two cytotoxic gold carbene compounds in A2780 ovarian cancer cells are described and discussed in comparison to auranofin, in the frame of the available mechanistic knowledge., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Herein we describe a method for the efficient production (∼90% fluorination) of 5-F-Trp human H ferritin via the selective incorporation of 19 F into the side chain of W93 using 5-fluoroindole as the fluorinated precursor of the amino acid. Human H ferritin is a nanocage composed of 24 identical subunits, each containing a single Trp belonging to a loop exposed on the external surface of the protein nanocage. This makes 5-F-Trp a potential probe for the study of intermolecular interactions in solution by exploiting its intrinsic fluorescence. More interestingly, albeit the large size of the cage (12 nm external diameter, ∼500 kDa molecular mass) we observe a broad but well defined NMR 19 F resonance that can be used for the dual purpose of detecting solution intermolecular interactions via chemical shift perturbation mapping and monitoring the uptake of ferritin by cells treated with ferritin-based drug carriers, the latter being an application area of increasing importance., 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 Inc. All rights reserved.)

Microbial communities experience continuous environmental changes, with temperature fluctuations being the most impacting. This is particularly important considering the ongoing global warming but also in the "simpler" context of seasonal variability of sea-surface temperature. Understanding how microorganisms react at the cellular level can improve our understanding of their possible adaptations to a changing environment. In this work, we investigated the mechanisms through which metabolic homeostasis is maintained in a cold-adapted marine bacterium during growth at temperatures that differ widely (15 and 0°C). We have quantified its intracellular and extracellular central metabolomes together with changes occurring at the transcriptomic level in the same growth conditions. This information was then used to contextualize a genome-scale metabolic reconstruction, and to provide a systemic understanding of cellular adaptation to growth at 2 different temperatures. Our findings indicate a strong metabolic robustness at the level of the main central metabolites, counteracted by a relatively deep transcriptomic reprogramming that includes changes in gene expression of hundreds of metabolic genes. We interpret this as a transcriptomic buffering of cellular metabolism, able to produce overlapping metabolic phenotypes, despite the wide temperature gap. Moreover, we show that metabolic adaptation seems to be mostly played at the level of few key intermediates (e.g., phosphoenolpyruvate) and in the cross talk between the main central metabolic pathways. Overall, our findings reveal a complex interplay at gene expression level that contributes to the robustness/resilience of core metabolism, also promoting the leveraging of state-of-the-art multi-disciplinary approaches to fully comprehend molecular adaptations to environmental fluctuations. IMPORTANCE This manuscript addresses a central and broad interest topic in environmental microbiology, i.e. the effect of growth temperature on microbial cell physiology. We investigated if and how metabolic homeostasis is maintained in a cold-adapted bacterium during growth at temperatures that differ widely and that match measured changes on the field. Our integrative approach revealed an extraordinary robustness of the central metabolome to growth temperature. However, this was counteracted by deep changes at the transcriptional level, and especially in the metabolic part of the transcriptome. This conflictual scenario was interpreted as a transcriptomic buffering of cellular metabolism, and was investigated using genome-scale metabolic modeling. Overall, our findings reveal a complex interplay at gene expression level that contributes to the robustness/resilience of core metabolism, also promoting the use of state-of-the-art multi-disciplinary approaches to fully comprehend molecular adaptations to environmental fluctuations.

A second-line standard of treatment has not yet been identified in patients with soft tissue sarcomas (STS), so identifying predictive markers could be a valuable tool. Recent studies have shown that the intratumoral and inflammatory systems significantly influence tumor aggressiveness. We aimed to investigate prognostic values of pre-therapy neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory index (SII), progression-free survival (PFS), and overall survival (OS) of STS patients receiving second-line treatment. In this single-center retrospective analysis, ninety-nine patients with STS were enrolled. All patients received second-line treatment after progressing to anthracycline. PFS and OS curves were calculated using the Kaplan-Meier method of RNA sequencing, and CIBERSORT analysis was performed on six surgical specimens of liposarcoma patients. A high NLR, PLR, and SII were significantly associated with worse PFS ( p = 0.019; p = 0.004; p = 0.006). Low LMR was significantly associated with worse OS ( p = 0.006). Patients treated with Trabectedin showed a better PFS when the LMR was low, while patients treated with other regimens showed a worse PFS when the LMR was low ( p = 0.0154). The intratumoral immune infiltrates analysis seems to show a correlation between intratumoral macrophages and LMR. PS ECOG. The metastatic onset and tumor burden showed prognostic significance for PFS ( p = 0.004; p = 0.041; p = 0.0086). According to the histologies, PFS was: 5.7 mo in liposarcoma patients vs. 3.8 mo in leiomyosarcoma patients vs. 3.1 months in patients with other histologies ( p = 0.053). Our results confirm the prognostic role of systemic inflammatory markers in patients with STS. Moreover, we demonstrated that LMR is a specific predictor of Trabectedin efficacy and could be useful in daily clinical practice. We also highlighted a possible correlation between LMR levels and the percentage of intratumoral macrophages.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by uncontrolled activation of the immune system. HLH is a reactive mononuclear phagocytic response that occurs in association with a constellation of conditions such as malignancies and infections. The clinical diagnosis of HLH remains challenging because HLH can present with symptoms that significantly overlap with other causes of cytopenia, such as sepsis, autoimmune diseases, hematological cancers, and multiorgan failure. A 50-year-old man went to the emergency room (ER) for hyperchromic urine, melena, gingivorrhagia, and spontaneous abdominal wall hematomas. The first blood tests showed severe thrombocytopenia, alteration of the INR, and consumption of fibrinogen, and therefore, a diagnosis of disseminated intravascular coagulation (DIC) was made. A bone marrow aspirate showed numerous images of hemophagocytosis. With the suspicion of immune-mediated cytopenia, oral etoposide, intravenous immunoglobulin, and intravenous methylprednisolone were administered. Then, a diagnosis of gastric carcinoma was performed with a lymph node biopsy and gastroscopy. On the 30th day, the patient was transferred to the oncology ward of another hospital. On admission, he had serious piastrinopenia, anemia, hypertriglyceridemia, and hyperferritinemia. He was supported with a platelet transfusion and underwent a bone biopsy that showed a picture compatible with myelophthisis from diffuse medullary localization of a carcinoma of gastric origin. A diagnosis of HLH secondary to solid neoplasm was formulated. The patient started chemotherapy with oxaliplatin, calcium levofolinate, 5-fluorouracil bolus, 5-fluorouracil for 48 h (mFOLFOX6), and methylprednisolone. Six days after the third cycle of mFOLFOX6, the patient was discharged with the stabilization of his piastrinopenia condition. The patient continued chemotherapy with an improvement in his clinical conditions and normalization of hematological values. After 12 cycles of mFOLFOX, it was decided to start maintenance chemotherapy with capecitabine but, unfortunately, after only one cycle, HLH reappeared. The oncologist has to keep in mind the existence of HLH when there is an unusual clinical presentation of cancer, such as cytopenia affecting ≥2 lineages and alterations of ferritin and triglycerides other than fibrinogen and coagulation. Increased attention and additional research as well as a close collaboration with hematologists are needed to benefit patients with solid tumors complicated by HLH., Competing Interests: GM worked as a consultant for Astellas and Servier; received honoraria and participated in the speaker bureau of Astellas, Menarini/Stemline, Pfizer, Servier, and Syros; and received research support from Abbvie, Astrazeneca, and Pfizer. 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 Monti, Marconi, Ambrosini-Spaltro, Gallio, Ghini, Esposito, Antonini, Montanari and Frassineti.)