Analysis of outsourcing conditions for freight transport and logistics among manufacturing companies: insights from a review of data and a field investigation

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Architecture of The Human Ape1 Interactome Defines Novel Cancers Signatures

APE1 is essential in cancer cells due to its central role in the Base Excision Repair pathway of DNA lesions and in the transcriptional regulation of genes involved in tumor progression/chemoresistance. Indeed, APE1 overexpression correlates with chemoresistance in more aggressive cancers, and APE1 protein-protein interactions (PPIs) specifically modulate different protein functions in cancer cells. Although important, a detailed investigation on the nature and function of protein interactors regulating APE1 role in tumor progression and chemoresistance is still lacking. The present work was aimed at analyzing the APE1-PPI network with the goal of defining bad prognosis signatures through systematic bioinformatics analysis. By using a well-characterized HeLa cell model stably expressing a flagged APE1 form, which was subjected to extensive proteomics analyses for immunocaptured complexes from different subcellular compartments, we here demonstrate that APE1 is a central hub connecting different subnetworks largely composed of proteins belonging to cancer-associated communities and/or involved in RNA- and DNA-metabolism. When we performed survival analysis in real cancer datasets, we observed that more than 80% of these APE1-PPI network elements is associated with bad prognosis. Our findings, which are hypothesis generating, strongly support the possibility to infer APE1-interactomic signatures associated with bad prognosis of different cancers; they will be of general interest for the future definition of novel predictive disease biomarkers. Future studies will be needed to assess the function of APE1 in the protein complexes we discovered. Data are available via ProteomeXchange with identifier PXD013368

Gender-specific Anatomical Distribution of Internal Pudendal Artery Perforator: A Radiographic Study for Perineal Reconstruction

Background: Cancer, trauma, infection, or radiation can cause perineal defects. Fasciocutaneous flaps based on perforator vessels (PV) from the internal pudendal artery (IPA) provide an ideal reconstructive option for moderate defects. We hypothesized that, due to gender differences in the pelvic-perineal region, the anatomical distribution of PV differs between genders. Methods: Computed tomography angiographies from male and female patients without pelvic-perineal pathologies were retrospectively analyzed to study the vascular anatomy of the IPA. The number, size, type, and distribution of PV were recorded and compared between genders. Four anatomical regions were defined to describe the distribution of PV on each perineal side: anterior (A), anterior-central (AC), central-posterior (CP), and posterior (P). Results: A total of 63 computed tomography angiographies were analyzed (men, 31; women, 32). Each IPA provides 2 +/- 1 PV and 5 +/- 2 terminal (cutaneous) branches: in both genders, 85% of PV are septocutaneous (15% musculocutaneous). In women, 70.5% of PV are located in AC, 28.2% in CP, 1.2% in A, and 0% in P: average diameter of the PV is 2.4 +/- 0.3 mm. In men, 53.7% of PV are located in CP, 43.1% in AC, 3.3% in A, and 0% in P: average diameter of the PV is 2.8 +/- 0.5 mm. Gender-specific differences in anatomical distribution of PV are significant (P \u3c 0.001). Conclusions: Number, size, and type of terminal branches of PV of the IPA are consistent between genders, but their distribution is different, with women having an anterior predominance. Knowledge of gender-specific anatomy can guide preoperative planning and intraoperative dissection in flap-based perineal reconstruction

Local and global measures of information storage for the assessment of heartbeat-evoked cortical responses

Objective: Brain–heart interactions involve bidirectional effects produced by bottom-up input at each heartbeat, and top-down neural regulatory responses of the brain. While the cortical processing of the heartbeat is usually investigated through the analysis of the Heartbeat Evoked Potential, in this study we propose an alternative approach based on the variability in the predictability of the brain dynamics induced by the heartbeat. Methods: In a group of eighteen subjects in whom simultaneous recording of the electroencephalogram (EEG) and electrocardiogram was performed in a resting-state, we analyzed the temporal profile of the local Information Storage (IS) to detect changes in the regularity of EEG signals in time windows associated with different phases of the cardiac cycle at rest. Results: The average values of the local IS were significantly higher in the parieto-occipital areas of the scalp, suggesting an activation of the Default Mode Network, regardless of the cardiac cycle phase. In contrast, the variability of the local IS showed marked differences across the cardiac cycle phases. Conclusion: Our results suggest that cardiac activity influences the predictive information of EEG dynamics differently in the various phases of the cardiac cycle. Significance: The variability of local IS measures can represent a useful index to identify spatio-temporal dynamics within the neurocardiac system, which generally remain overlooked by the more widely employed global measures

Study protocol for a randomised, double-blind, placebo-controlled crossover trial assessing the impact of the SGLT2 inhibitor empagliflozin on postprandial hypoglycaemia after gastric bypass.

INTRODUCTION Postprandial hypoglycaemia after gastric bypass surgery (also known as postbariatric hypoglycaemia or PBH) is an increasingly encountered clinical problem. PBH is characterised by meal-induced rapid spikes and consequent falls in glycaemia, resulting in both hypoglycaemia burden and high glycaemic variability. Despite its frequency, there is currently no approved pharmacotherapy. The purpose of this investigation is to evaluate efficacy and safety of empagliflozin 25 mg, a sodium-glucose cotransporter 2-inhibitor, to reduce glucose excursions and hypoglycaemia burden in patients with PBH after gastric bypass surgery. METHODS AND ANALYSIS In a prospective, single-centre, randomised, double-blind, placebo-controlled, crossover trial, we plan to enrol 22 adults (≥18 years) with PBH after Roux-en-Y gastric bypass surgery (plasma or sensor glucose <3.0 mmol/L). Eligible patients will be randomised to receive empagliflozin 25 mg and placebo once daily, each for 20 days, in random order. Study periods will be separated by a 2-6 weeks wash-out period. The primary efficacy outcome will be the amplitude of plasma glucose excursion (peak to nadir) during a mixed meal tolerance test. Results will be presented as paired-differences±SD plus 95% CIs with p values and hypothesis testing for primary and secondary outcomes according to intention-to-treat. Secondary outcomes include continuous glucose monitoring-based outcomes, further metabolic measures and safety. ETHICS AND DISSEMINATION The DEEP-EMPA trial (original protocol title: Randomized, double-blind, placebo-controlled crossover trialassessing the impact of the SGLT2 inhibitor empagliflozin onpostprandial hypoglycaemia after gastric bypass) was approved by the Bern Ethics Committee (ID 2021-01187) and Swissmedic (Ref. Number: 102663190) in October and November 2021, respectively. First results are expected in the first quarter of 2023 and will be disseminated via peer-reviewed publications and presented at national and international conferences. The acronym DEEP was derived from an overarching project title (DEciphering the Enigma of Postprandial Hyperinsulinaemic Hypoglycaemia after Bariatric Surgery), the term EMPA stands for the drug empagliflozin. TRIAL REGISTRATION NUMBER NCT05057819

Progressively de-differentiated pancreatic cancer cells shift from glycolysis to oxidative metabolism and gain a quiescent stem state

Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively identify their peculiarities for an efficient therapeutic approach. In this study, CSCs have been obtained by culturing different PDAC cell lines with a specific growth medium. Cells were characterized for the typical stem/mesenchymal properties at short-, medium-, and long-term culture. Metabolomics, proteomics, analysis of oxygen consumption rate in live cells, and the effect of the inhibition of lactate transporter on cell proliferation have been performed to delineate the metabolism of CSCs. We show that gradually de-differentiated pancreatic cancer cells progressively increase the expression of both stem and epithelial-to-mesenchymal transition markers, shift their metabolism from a glycolytic to an oxidative one, and lastly gain a quiescent state. These quiescent stem cells are characterized by high chemo-resistance, clonogenic ability, and metastatic potential. Re-differentiation reverts these features, re-activating their proliferative capacity and glycolytic metabolism, which generally correlates with high aggressiveness. These observations add an important piece of knowledge to the comprehension of the biology of CSCs, whose metabolic plasticity could be exploited for the generation of promising and selective therapeutic approaches for PDAC patients

New molecular and therapeutic insights into canine diffuse large B cell lymphoma elucidates the role of the dog as a model for human disease

open21siopenAresu, Luca; Ferraresso, Serena; Marconato, Laura; Cascione, Luciano; Napoli, Sara; Gaudio, Eugenio; Kwee, Ivo; Tarantelli, Chiara; Testa, Andrea; Maniaci, Chiara; Ciulli, Alessio; Hillmann, Petra; Bohnacker, Thomas; Wymann, Matthias P; Comazzi, Stefano; Milan, Massimo; Riondato, Fulvio; Dalla Rovere, Giulia; Giantin, Mery; Giannuzzi, Diana; Bertoni, FrancescoAresu, Luca; Ferraresso, Serena; Marconato, Laura; Cascione, Luciano; Napoli, Sara; Gaudio, Eugenio; Kwee, Ivo; Tarantelli, Chiara; Testa, Andrea; Maniaci, Chiara; Ciulli, Alessio; Hillmann, Petra; Bohnacker, Thomas; Wymann, Matthias P; Comazzi, Stefano; Milan, Massimo; Riondato, Fulvio; Dalla Rovere, Giulia; Giantin, Mery; Giannuzzi, Diana; Bertoni, Francesc

Intrinsic time resolution of 3D-trench silicon pixels for charged particle detection

In the last years, high-resolution time tagging has emerged as the tool to tackle the problem of high-track density in the detectors of the next generation of experiments at particle colliders. Time resolutions below 50ps and event average repetition rates of tens of MHz on sensor pixels having a pitch of 50$\mu$m are typical minimum requirements. This poses an important scientific and technological challenge on the development of particle sensors and processing electronics. The TIMESPOT initiative (which stands for TIME and SPace real-time Operating Tracker) aims at the development of a full prototype detection system suitable for the particle trackers of the next-to-come particle physics experiments. This paper describes the results obtained on the first batch of TIMESPOT silicon sensors, based on a novel 3D MEMS (micro electro-mechanical systems) design. Following this approach, the performance of other ongoing silicon sensor developments has been matched and overcome, while using a technology which is known to be robust against radiation degradation. A time resolution of the order of 20ps has been measured at room temperature suggesting also possible improvements after further optimisations of the front-end electronics processing stage.Comment: This version was accepted to be published on JINST on 21/07/202

Randomized, double-blind, placebo-controlled crossover trial of once daily empagliflozin 25 mg for the treatment of postprandial hypoglycaemia after Roux-en-Y gastric bypass.

Aims To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass (RYGB). Methods Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed meal tolerance test (MMTT). Outcomes of the outpatient period were assessed using continuous glucose monitoring (CGM) and an event-tracking app. Results The amplitude of glucose excursion during the MMTT was 8.1±2.4 mmol/L with empagliflozin vs 8.1±2.6 mmol/L with placebo (mean±SD, p=0.807). CGM-based mean amplitude of glucose excursion (MAGE) during the 20 day-period was lower with empagliflozin than placebo (4.8±1.3 vs 5.2±1.6. p=0.028). Empagliflozin reduced the time spent with CGM values >10.0 mmol/L (3.8±3.5 % vs. 4.7±3.8 %, p =0.009), but not the time spent with CGM values <3.0 mmol/L (1.7±1.6 % vs. 1.5±1.5 %, p=0.457). No significant difference was observed in the quantity and quality of recorded symptoms. Eleven adverse events occurred with empagliflozin (three drug-related) and six with placebo. Conclusions Empagliflozin 25 mg reduces glucose excursions but not hypoglycaemia in individuals with PBH

Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Once Daily Empagliflozin 25 mg for the Treatment of Postprandial Hypoglycemia After Roux-en-Y Gastric Bypass

Aims: To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). Methods: Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed-meal tolerance test (MMTT). Outcomes of the outpatient period were assessed using continuous glucose monitoring (CGM) and an event-tracking app. Results: The amplitude of glucose excursion during the MMTT was 8.1 ± 2.4 mmol/L with empagliflozin versus 8.1 ± 2.6 mmol/L with placebo (mean ± standard deviation, P = 0.807). CGM-based mean amplitude of glucose excursion during the 20-day period was lower with empagliflozin than placebo (4.8 ± 1.3 vs. 5.2 ± 1.6. P = 0.028). Empagliflozin reduced the time spent with CGM values >10.0 mmol/L (3.8 ± 3.5% vs. 4.7 ± 3.8%, P = 0.009), but not the time spent with CGM values <3.0 mmol/L (1.7 ± 1.6% vs. 1.5 ± 1.5%, P = 0.457). No significant difference was observed in the quantity and quality of recorded symptoms. Eleven adverse events occurred with empagliflozin (three drug-related) and six with placebo. Conclusions: Empagliflozin 25 mg reduces glucose excursions but not hypoglycemia in individuals with PBH