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Radiopharmaceuticals based on Lu-177 are finding increasing use in radiometabolic therapy. The ordinary practice requires radiation monitoring of the patient. To this end, detectors need to be calibrated in the geometry used and for the radioisotope used. This work presents an experimental investigation coupled with Monte Carlo calculations. This procedure yielded a calibration factor of practical use in everyday clinical practice. [ABSTRACT FROM AUTHOR]

The biophysical and biomechanical properties of the extracellular matrix (ECM) are crucial in the processes of cell differentiation and proliferation. However, it is unclear to what extent tumor cells are influenced by biomechanical and biophysical changes of the surrounding microenvironment and how this response varies between different tumor forms, and over the course of tumor progression. The entire ensemble of genes encoding the ECM associated proteins is called matrisome. In cancer, the ECM evolves to become highly dysregulated, rigid, and fibrotic, serving both pro-tumorigenic and anti-tumorigenic roles. Tumor desmoplasia is characterized by a dramatic increase of α-smooth muscle actin expressing fibroblast and the deposition of hard ECM containing collagen, fibronectin, proteoglycans, and hyaluronic acid and is common in many solid tumors. In this review, we described the role of inflammation and inflammatory cytokines, in desmoplastic matrix remodeling, tumor state transition driven by microenvironment forces and the signaling pathways in mechanotransduction as potential targeted therapies, focusing on the impact of qualitative and quantitative variations of the ECM on the regulation of tumor development, hypothesizing the presence of matrisome drivers, acting alongside the cell-intrinsic oncogenic drivers, in some stages of neoplastic progression and in some tumor contexts, such as pancreatic carcinoma, breast cancer, lung cancer and mesothelioma., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mancini, Gentile, Pentimalli, Cortellino, Grieco and Giordano.)

Persistent organic pollutants (POPs), which encompass pesticides and industrial chemicals widely utilized across the globe, pose a covert threat to human health. β-hexachlorocyclohexane (β-HCH) is an organochlorine pesticide with striking stability, still illegally dumped in many countries, and recognized as responsible for several pathogenetic mechanisms. This study represents a pioneering exploration into the neurotoxic effects induced by the exposure to β-HCH specifically targeting neuronal cells (N2a), microglia (BV-2), and C57BL/6 mice. As shown by western blot and qPCR analyses, the administration of β-HCH triggered a modulation of NF-κB, a key factor influencing both inflammation and pro-inflammatory cytokines expression. We demonstrated by proteomic and western blot techniques epigenetic modifications in H3 histone induced by β-HCH. Histone acetylation of H3K9 and H3K27 increased in N2a, and in the prefrontal cortex of C57BL/6 mice administered with β-HCH, whereas it decreased in BV-2 cells and in the hippocampus. We also observed a severe detrimental effect on recognition memory and spatial navigation by the Novel Object Recognition Test (NORT) and the Object Place Recognition Task (OPRT) behavioural tests. Cognitive impairment was linked to decreased expression of the genes BDNF and SNAP-25, which are mediators involved in synaptic function and activity. The obtained results expand our understanding of the harmful impact produced by β-HCH exposure by highlighting its implication in the pathogenesis of neurological diseases. These findings will support intervention programs to limit the risk induced by exposure to POPs. Regulatory agencies should block further illicit use, causing environmental hazards and endangering human and animal health., 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.)

The resistance of glioblastomas (GBM) to standard therapies poses a clinical challenge with limited survival despite interventions. The tumor microenvironment (TME) orchestrates GBM progression, comprising stromal and immune cells and is characterized by extensive hypoxic regions. Hypoxia activates the hypoxia-inducible factor 1 alpha (HIF-1α) pathway, interacting with the Hippo pathway (YAP/TAZ) in crucial cellular processes. We discuss here the related signaling crosstalk between YAP/TAZ and regions of hypoxia in the TME with particular attention on the MST1/2 and LATS1/2-regulated YAP/TAZ activation, impacting cell proliferation, invasion, and stemness. Moreover, the hypoxia-YAP/TAZ axis influence on angiogenesis, stem cells, and metabolic regulators is defined. By reviewing extracellular matrix alterations activation of YAP/TAZ, modulation of signaling pathways we also discuss the significance of spatial constraints and epigenetic modifications contribution to GBM progression, with potential therapeutic targets in YAP/TAZ-mediated gene regulation. Comprehensive understanding of the hypoxia-Hippo pathway-TME interplay offers insights for novel therapeutic strategies, aiming to provide new directions for treatment., Competing Interests: Declaration of competing interest The authors declare no competing interests, (Copyright © 2024 Elsevier B.V. All rights reserved.)

To develop and internally validate a multivariable logistic regression model (LRM) for the prediction of the probability of 1-year readmission to the emergency department (ED) in patients with acute alcohol intoxication (AAI). We developed and internally validated the LRM on a previously analyzed retrospective cohort of 3304 patients with AAI admitted to the ED of the Sant'Orsola-Malpighi Hospital (Bologna, Italy). The benchmark LRM employed readmission to the same ED for AAI within 1 year as the binary outcome, age as a continuous predictor, and sex, alcohol use disorder, substance use disorder, at least one previous admission for trauma, mental or behavioral disease, and homelessness as the binary predictors. Optimism correction was performed using the bootstrap on 1000 samples without replacement. The benchmark LRM was gradually simplified to get the most parsimonious LRM with similar optimism-corrected overall fit, discrimination and calibration. The 1-year readmission rate was 15.7% (95% CI 14.4-16.9%). A reduced LRM based on sex, age, at least one previous admission for trauma, mental or behavioral disease, and homelessness, performed nearly as well as the benchmark LRM. The reduced LRM had the following optimism-corrected metrics: scaled Brier score 17.0%, C-statistic 0.799 (95% CI 0.778 to 0.821), calibration in the large 0.000 (95% CI - 0.099 to 0.099), calibration slope 0.985 (95% CI 0.893 to 1.088), and an acceptably accurate calibration plot. An LRM based on sex, age, at least one previous admission for trauma, mental or behavioral disease, and homelessness can be used to estimate the probability of 1-year readmission to ED for AAI. To begin proving its clinical utility, this LRM should be validated in external cohorts., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Left-sided acute diverticulitis in WSES Stage 0-IIb preferentially undergoes conservative management. However, there is limited understanding of the risk factors for failure of this approach. The aim of this study was to investigate the factors associated with the decision to perform conservative treatment as well as the predictors of its failure. We included patients with a diagnosis of WSES diverticulitis CT-driven classification Stage 0-IIb treated in the Emergency Surgery Unit of the Agostino Gemelli University Hospital Foundation between 2014 and 2020. The endpoints were the comparison between the characteristics and clinical outcomes of acute diverticulitis patients undergoing conservative versus operative treatment. We also identified predictors of conservative treatment failure. A set of multivariable backward logistic analyses were conducted for this purpose. The study included 187 patients. The choice for operative versus conservative treatment was associated with clinical presentation, older age, higher WSES grade, and previous conservative treatment. There were 21% who failed conservative treatment. Of those, major morbidity and mortality rates were 17.9% and 7.1%, respectively. A previously failed conservative treatment as well as a greater WSES grade and a lower hemoglobin value were significantly associated with failure of conservative treatment. WSES classification and hemoglobin value at admission were the best predictors of failure of conservative treatment. Patients failing conservative treatment had non-negligible morbidity and mortality. These results promote the consideration of a combined approach including baseline patients' characteristics, radiologic features, and laboratory biomarkers to predict conservative treatment failure and therefore optimize treatment of acute diverticulitis., (© 2024. The Author(s).)

Colorectal cancer is a frequent neoplasm in western countries, mainly due to dietary and behavioral factors. Its incidence is growing in developing countries for the westernization of foods and lifestyles. An increased incidence rate is observed in patients under 45 years of age. In recent years, the mortality for CRC is decreased, but this trend is slowing. The mortality rate is reducing in those countries where prevention and treatments have been implemented. The survival is increased to over 65%. This trend reflects earlier detection of CRC through routine clinical examinations and screening, more accurate staging through advances in imaging, improvements in surgical techniques, and advances in chemotherapy and radiation. The most important predictor of survival is the stage at diagnosis. The screening programs are able to reduce incidence and mortality rates of CRC. The aim of this paper is to provide a comprehensive overview of incidence, mortality, and survival rate for CRC.

Bioengineered hydrogels represent physiologically relevant platforms for cell behaviour studies in the tissue engineering and regenerative medicine fields, as well as in in vitro disease models. Hyaluronic acid (HA) is an ideal platform since it is a natural biocompatible polymer that is widely used to study cellular crosstalk, cell adhesion and cell proliferation, and is one of the major components of the extracellular matrix (ECM). We synthesised chemically modified HA with photo-crosslinkable methacrylated groups (HA-MA) in aqueous solutions and in strictly monitored pH and temperature conditions to obtain hydrogels with controlled bulk properties. The physical and chemical properties of the different HA-MA hydrogels were investigated via rheological studies, mechanical testing and scanning electron microscopy (SEM) imaging, which allowed us to determine the optimal biomechanical properties and develop a biocompatible scaffold. The morphological evolution processes and proliferation rates of glioblastoma cells (U251-MG) cultured on HA-MA surfaces were evaluated by comparing 2D structures with 3D structures, showing that the change in dimensionality impacted cell functions and interactions. The cell viability assays and evaluation of mitochondrial metabolism showed that the hydrogels did not interfere with cell survival. In addition, morphological studies provided evidence of cell-matrix interactions that promoted cell budding from the spheroids and the invasiveness in the surrounding environment.

This article reports the results of a novel perioperative treatment implementing the gut microbiota to prevent anastomotic fistula and leakage (AL) in patients undergoing laparoscopic colorectal resections for cancer and represents the continuation of our pilot study on 60 cases. A series of 131 patients underwent elective colorectal surgery at the S. Eugenio Hospital (Rome-Italy) between December 1, 2020, and November 30, 2022, and received a perioperative preparation following the Microbiota Implementation to Reduce Anastomotic Colorectal Leaks (MIRACLe) protocol comprising oral antibiotics, mechanical bowel preparation and perioperative probiotics. The results obtained in the MIRACLe group (MG) were compared to those registered in a Control group (CG) of 500 patients operated on between March 2015 and November 30, 2020, who received a standard ERAS protocol. Propensity score-matching (PSM) analysis was performed to overcome patients' selection bias. Patients were categorised according to perioperative preparation (MIRACLe protocol vs standard ERAS protocol) into two groups: 118 patients were in post-matched MIRACLe group (pmMG) and 356 were in post-matched Control group (pmCG). In the pmMG, only 2 anastomotic leaks were registered, and the incidence of AL was just 1.7% vs. 6.5% in the pmCG (p = 0.044). The incidence of surgical site infections (1.7% vs. 3.1%; p = 0.536), reoperations (0.8% vs. 4.2%; p = 0.136) and postoperative mortality (0% vs. 2.0%; p = 0.200) was lower in pmMG. Additionally, the postoperative outcomes were better: the times to first flatus, to first stool and to oral feeding were shorter (1 vs. 2, 2 vs. 3 and 2 vs. 3 days, respectively; p < 0.001). The postoperative recovery was faster, with a shorter time to discharge (5 vs. 6 days; p < 0.001). The MIRACLe protocol was confirmed to be safe and significantly able to reduce anastomotic leaks in patients receiving elective laparoscopic colorectal surgery for cancer., (© 2023. Italian Society of Surgery (SIC).)

Introduction: Total mesorectal excision (TME) during rectal resection is considered the gold standard for the treatment of rectal cancer. Transanal total mesorectal excision (TaTME) was first described in 2010 and has been applied to humans since 2012 to overcome some of the technical difficulties associated with minimally invasive TMEs., Evidence Acqusition: A systematic review of the literature was conducted, and it focused on articles published between 2012 and 2022 to analyze the state of the art of surgical techniques and indications, as well as potential technical, oncological, and functional benefits., Evidence Synthesis: The indications for TaTME are not yet standardized, and structured training programs are necessary to complete a safe learning curve for this new technique. The procedure, when compared with conventional open or minimally invasive TME, is feasible and safe with similar intraoperative and postoperative complications. On the other hand, some new specific complications of this new approach have been described. The short-term pathological and oncologic results are encouraging, especially in terms of the mesorectal specimen quality, distal resection margin and conversion rate. Also, the functional results seem encouraging when compared with other minimally invasive techniques., Conclusions: Long-term follow-up and ongoing RCT trials are fundamental to evaluate the possible benefits in terms of local recurrence and survival. This will facilitate the comparison with other minimally invasive rectal resections.

Purpose: The aim of this study was to evaluate the diagnostic performance of preoperative cross-sectional imaging findings using the SAR-AGA definitions in Crohn's disease (CD) patients who underwent ileocolic resection (ICR) with and without surgically complex ileocolic CD (CIC-CD)., Methods: 69 CD patients [38 men; mean (± SD) age: 40.6 (16.2) years] who underwent ICR were retrospectively classified by surgical complexity by a colorectal surgeon using operative findings. CIC-CD was defined as ileal CD, not confined to the distal ileum. Two radiologists retrospectively evaluated the preoperative imaging for the presence and type of penetrating disease, stricture, or probable stricture using the SAR-AGA consensus definitions. The diagnostic performance of preoperative imaging findings was compared for patients with and without CIC-CD. Estimated blood loss (EBL), operative time (OT), conversion to open surgery, diversion, and length of hospital stay (LOS) were compared., Results: 60.9% had CIC-CD and 79.7% underwent primary ICR. Penetrating disease was more common in patients with than without CIC-CD (76.2% vs. 40.7%, p = 0.0048) and similar among primary versus redo ICR (p = 0.12). Patients with CIC-CD had more complex fistulas (59.5% vs. 11.1%; p < 0.0001) and fewer simple fistulas (2.4% vs. 18.5%; p = 0.03) than those without. Mesenteric findings (abscess, inflammatory mass) were more frequent in patients with (35.7%) than without (0%) (p = 0.0002) CIC-CD. Stricture and probable stricture were similar (p = 0.59). CIC-CD patients had greater EBL (178 cc vs. 57 cc, p = 0.006), conversion rates (30% vs. 0%, p = 0.0026), and diversion (80% vs. 52%, p = 0.04)., Conclusion: Complex fistula, mesenteric abscess, or inflammatory mass defined by the SAR-AGA guidelines suggests CIC-CD. ICR for CIC-CD had greater EBL, conversion to open surgery, and diversion., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We assessed long-term mortality and its association with chronic alcohol-related diseases in patients admitted to the emergency department (ED) because of acute alcoholic intoxication (AAI). A retrospective cohort study was performed at the ED of Sant'Orsola-Malpighi Hospital, Bologna, Italy. 3304 patients, corresponding to 6415 admissions for AAI, who accessed the ED from January 1, 2005, to December 31, 2017, were studied. The ED electronic registry system was used to assess living status on 08 May 2020 and to obtain the prespecified potential predictors, i.e., age at first admission, sex, alcohol use disorder (AUD), substance use disorder (SUD), more than 1 admission to ED for trauma, mental and behavioral disorders, neurological disorders, and cardiovascular disease. The median follow-up time was 9.3 years and the time on risk was 30,053 person years (PY) with a death rate corresponding to 4.42 (95% CI 3.74-5.26) per 1000 PY (n = 133 deaths). The death rate was higher in patients with AUD (17.30) than in those without AUD (1.98) and in those with SUD (13.58) than in those without SUD (3.80). Lastly, there was a clearly higher death rate among AUD+ SUD+ (20.89) compared to AUD-SUD-patients (1.74). At multivariable Cox regression, AUD, SUD, and liver cirrhosis were strong and independent predictors of time-to-death. Using standardized mortality ratios, a clear excess of mortality was evident for all the age bands from (40-45] to (60-65] years. Mortality is higher in AAI than in the general population and chronic alcohol-related diseases are strongly associated with it., (© 2022. The Author(s).)

Purpose: The aim of this study was to evaluate the safety and compliance with the enhanced recovery after surgery (ERAS) protocol in octogenarian patients undergoing colorectal surgery in 12 Italian high-volume centers., Methods: A retrospective analysis was conducted in a consecutive series of patients who underwent elective colorectal surgery between 2016 and 2018. Patients were grouped by age (≥ 80 years vs < 80 years), propensity score matching (PSM) analysis was performed, and the groups were compared regarding clinical outcomes and the mean number of ERAS items applied., Results: Out of 1646 patients identified, 310 were octogenarians. PSM identified 2 cohorts of 125 patients for the comparison of postoperative outcomes and ERAS compliance. The 2 groups were homogeneous regarding the clinical variables and mean number of ERAS items applied (11.3 vs 11.9, p-ns); however, the application of intraoperative items was greater in nonelderly patients (p 0.004). The functional recovery was similar between the two groups, as were the rates of postoperative severe complications and 30-day mortality rate. Elderly patients had more overall complications. Furthermore, the mean hospital stay was higher in the elderly group (p 0.027). Multivariable analyses documented that postoperative stay was inversely correlated with the number of ERAS items applied (p < 0.0001), whereas age ≥ 80 years significantly correlated with the overall complication rate (p 0.0419)., Conclusion: The ERAS protocol is safe in octogenarian patients, with similar levels of compliance and surgical outcomes. However, octogenarian patients have a higher rate of overall complications and a longer hospital stay than do younger patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In the last decade, hyaluronic acid (HA) has attracted an ever-growing interest in the biomedical engineering field as a biocompatible, biodegradable, and chemically versatile molecule. In fact, HA is a major component of the extracellular matrix (ECM) and is essential for the maintenance of cellular homeostasis and crosstalk. Innovative experimental strategies in vitro and in vivo using three-dimensional (3D) HA systems have been increasingly reported in studies of diseases, replacement of tissue and organ damage, repairing wounds, and encapsulating stem cells for tissue regeneration. The present work aims to give an overview and comparison of recent work carried out on HA systems showing advantages, limitations, and their complementarity, for a comprehensive characterization of their use. A special attention is paid to the use of HA in three important areas: cancer, diseases of the central nervous system (CNS), and tissue regeneration, discussing the most innovative experimental strategies. Finally, perspectives within and beyond these research fields are discussed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Cortese Barbara reports financial support was provided by Airc Italian Foundation for Cancer Research. Gigli Giuseppe reports financial support was provided by Puglia Region., (© 2022 Published by Elsevier Ltd.)

Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-β, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM , NCF1 , MCM4 , FCN3 , and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1 , NOD2 , and MEF . Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management., 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 © 2022 Gelzo, Castaldo, Giannattasio, Scalia, Raia, Esposito, Maglione, Muzzica, D’Anna, Grieco, Tipo, La Cava and Castaldo.)

Background: The aim of this study was to investigate how the COVID-19 pandemic influenced ERAS program application in colorectal surgery across hospitals in the Lazio region (central district in Italy) participating in the "Lazio Network" project., Methods: A multi-institutional database was constructed. All patients included in this study underwent elective colorectal surgery for both malignant and benign disease between January 2019 and December 2020. Emergency procedures were excluded. The population was divided into 2 groups: a pre-COVID-19 group (PG) of patients operated on between February and December 2019 and a COVID-19 group (CG) of patients operated on between February and December 2020, during the first 2 waves of the pandemic in Italy., Results: The groups included 622 patients in the PG and 615 in the CG treated in 8 hospitals of the network. The mean number of items applied was higher in the PG (65.6% vs. 56.6%, p < 0.001) in terms of preoperative items (64.2% vs. 50.7%, p < 0.001), intraoperative items (65.0% vs. 53.3%, p < 0.001), and postoperative items (68.8% vs. 63.2%, p < 0.001). Postoperative recovery was faster in the PG, with a shorter time to first flatus, first stool, autonomous mobilization and discharge (6.82 days vs. 7.43 days, p = 0.021). Postoperative complications, mortality and reoperations were similar among the groups., Conclusions: The COVID-19 pandemic had a negative impact on the application of ERAS in the centers of the "Lazio Network" study group, with a reduction in adherence to the ERAS protocol in terms of preoperative, intraoperative and postoperative items. In addition, in the CG, the patients had worse postoperative outcomes with respect to recovery and discharge., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

The complexity of the microenvironment effects on cell response, show accumulating evidence that glioblastoma (GBM) migration and invasiveness are influenced by the mechanical rigidity of their surroundings. The epithelial-mesenchymal transition (EMT) is a well-recognized driving force of the invasive behavior of cancer. However, the primary mechanisms of EMT initiation and progression remain unclear. We have previously showed that certain substrate stiffness can selectively stimulate human GBM U251-MG and GL15 glioblastoma cell lines motility. The present study unifies several known EMT mediators to uncover the reason of the regulation and response to these stiffnesses. Our results revealed that changing the rigidity of the mechanical environment tuned the response of both cell lines through change in morphological features, epithelial-mesenchymal markers (E-, N-Cadherin), EGFR and ROS expressions in an interrelated manner. Specifically, a stiffer microenvironment induced a mesenchymal cell shape, a more fragmented morphology, higher intracellular cytosolic ROS expression and lower mitochondrial ROS. Finally, we observed that cells more motile showed a more depolarized mitochondrial membrane potential. Unravelling the process that regulates GBM cells' infiltrative behavior could provide new opportunities for identification of new targets and less invasive approaches for treatment., 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 © 2022 Basilico, Palamà, D’Amone, Lauro, Rosito, Grieco, Ratano, Cordella, Sanchini, Di Angelantonio, Ragozzino, Cascione, Gigli and Cortese.)

Alzheimer's disease (AD) is a neurodegenerative disorder whose main pathological hallmark is the accumulation of Amyloid-β peptide (Aβ) in the form of senile plaques. Aβ can cause neurodegeneration and disrupt cognitive functions by several mechanisms, including oxidative stress. ERp57 is a protein disulfide isomerase involved in the cellular stress response and known to be present in the cerebrospinal fluid of normal individuals as a complex with Aβ peptides, suggesting that it may be a carrier protein which prevents aggregation of Aβ. Although several studies show ERp57 involvement in neurodegenerative diseases, no clear mechanism of action has been identified thus far. In this work, we gain insights into the interaction of Aβ with ERp57, with a special focus on the contribution of ERp57 to the defense system of the cell. Here, we show that recombinant ERp57 directly interacts with the Aβ 25-35 fragment in vitro with high affinity via two in silico-predicted main sites of interaction. Furthermore, we used human neuroblastoma cells to show that short-term Aβ 25-35 treatment induces ERp57 decrease in intracellular protein levels, different intracellular localization, and ERp57 secretion in the cultured medium. Finally, we demonstrate that recombinant ERp57 counteracts the toxic effects of Aβ 25-35 and restores cellular viability, by preventing Aβ 25-35 aggregation. Overall, the present study shows that extracellular ERp57 can exert a protective effect from Aβ toxicity and highlights it as a possible therapeutic tool in the treatment of AD., (© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: In this preliminary experience, the feasibility and effectiveness of surgical training with an animal model for transanal total mesorectal excision (TaTME) were evaluated. Methods: The training was conducted in two experimental animal laboratories in Italy authorized by the Italian Ministry of Health, using female Danish Landrace pigs under the supervision of surgeons with extensive experience in TaTME, animal laboratory training and cadaver laboratory training. The procedure was divided into separate steps, and all the participants were guided step-by-step throughout the entirety of the procedure. Results: During all the editions of the animal laboratory, all the procedures were completed with no major damage to the anatomical structures or intraoperative death of the animals. Live animal tissue is very similar to human tissue, helping trainees improve their tactile feedback. The bleeding effect improved the value of the training and taught the participants how to address this complication. The lack of mesorectal tissue in pigs compared with humans was the main difference. Animal laboratories should not be considered alternatives to cadaver laboratories but as complementary training activities due to their effectiveness and lower costs. Conclusions: Surgical training in animal models for TaTME seems to be effective and could be an opportunity to improve training alongside the use of a cadaver laboratory and proctoring.

Purpose: Nutritional support is a keystone component in perioperative care in patients undergoing oncological surgery with a direct impact on surgical outcomes. This study aimed to evaluate how nutritional support in the surgical setting is managed and applied in Italian hospitals., Methods: A national survey was designed by the Italian Society of Surgical Oncology (SICO) and disseminated in early 2021. The results were analyzed for the entire population and for comparing the following different subgroups: northern vs. southern regions; high-volume vs. low-volume centers; and junior vs. senior surgeons., Results: Out of the 141 responses collected from all Italian regions, 43.2% of the participants worked in a surgical unit where nutritional status evaluations and interventions were not routinely practiced, although the key features (nutritional counseling, oral supplementation, enteral and parenteral nutrition) were available in 77.3% of the hospitals. Among the participating centers, the ERAS protocol was systematically applied in only 29.5% of cases, and in 25.5% of cases, most of the items were followed, although not systematically. Among the surgeons who practiced in compliance with the ERAS pathways, almost half of the participants declared that the protocol was applied only for low-risk patients. No significant differences were documented when comparing Italian regions, high-volume vs. low-volume institutions or junior vs. senior participants., Conclusion: Nutritional support in oncological surgery is frequently neglected in Italian hospitals, regardless of the geographic distribution and volumes of the institutions. A cultural change and an improvement in the availability of nutritional services are needed for widespread implementation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests or conflicts of interest related to this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The aim of this pilot study was to evaluate the effects of a novel perioperative treatment for the implementation of the gut microbiota, to prevent anastomotic fistula and leakage (AL) in patients undergoing laparoscopic colorectal resections for cancer. A series of 60 patients who underwent elective colorectal surgery at S. Eugenio Hospital (Rome-Italy) between December 1, 2020 and November 30, 2021 and received a novel perioperative preparation following the MIRACLe (Microbiota Implementation to Reduce Anastomotic Colorectal Leaks) protocol (oral antibiotics, mechanical bowel preparation and perioperative probiotics), was compared to a group of 500 patients (control group) operated on between March 2015 and November 30, 2020, who received a standard ERAS protocol. In the MIRACLe Group only 1 anastomotic leak was registered. In this group the incidence of AL was just 1.7% vs. 6.4% in the control group (p = 0.238) and the incidence of surgical site infections (1.7% vs. 3.6%; p = 0.686), reoperations (1.7% vs. 4.2%; p = 0.547) and postoperative mortality (0% vs. 2.2%; p = 0.504) were lower. The postoperative outcomes were also better: the times to first flatus, to first stool and to oral feeding were shorter (1 vs. 2, 2 vs. 3 and 2 vs. 3 days, respectively; p < 0.001). Additionally, the postoperative recovery was faster, with a shorter time to discharge (4 vs. 6 days; p < 0.001). In this pilot study, the MIRACLe protocol appeared to be safe and considerably reduced anastomotic leaks in elective laparoscopic colorectal surgery for cancer, even if not statistically significant, due to the small number of cases., (© 2022. Italian Society of Surgery (SIC).)

Endothelial hyperinflammation and vasculitis are known hallmarks of acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). They are due to the direct effect of the virus on endothelial cells enhanced by pro-inflammatory modulators and may cause venous/arterial thrombosis. Therefore, it is essential to identify patients with endothelial damage early in order to establish specific therapies. We studied the monocyte chemoattractant protein 1 (MCP-1), the perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), and the vascular endothelial growth factor A (VEGF-A) in serum from 45 MIS-C patients at hospital admission and 24 healthy controls (HC). For 13/45 MIS-C patients, we measured the three serum biomarkers also after one week from hospitalization. At admission, MIS-C patients had significantly higher levels of MCP-1 and VEGF-A than the HC, but no significant differences were observed for pANCA. While after one week, MCP-1 was significantly lower, pANCA was higher and VEGF-A levels were not significantly different from the admission values. These findings suggest an involvement of epithelium in MIS-C with an acute phase, showing high MCP-1 and VEGF-A, followed by an increase in pANCA that suggests a vasculitis development. The serum biomarker levels may help to drive personalized therapies in these phases with anticoagulant prophylaxis, immunomodulators, and/or anti-angiogenic drugs.

Background: Cannabis use is a component risk factor for the manifestation of schizophrenia. The biological effects of cannabis include effects on epigenetic systems, immunological parameters, in addition to changes in cannabinoid receptors 1 and 2, that may be associated with this risk. However, there has been limited study of the effects of smoked cannabis on these biological effects in human peripheral blood cells. We analyzed the effects of two concentrations of tetrahydrocannabinol (THC) vs. placebo in lymphocytes of a subset of participants who enrolled in a double-blind study of the effects of cannabis on driving performance (outcome not the focus of this study)., Methods: Twenty four participants who regularly use cannabis participated in an experiment in which they smoked cannabis cigarettes (5.9 or 13.4% THC) or placebo (0.02%) ad libitum . Blood samples were drawn at baseline and several times after smoking. Lymphocytes were separated and stored at -80 ° C for further analysis. Samples were analyzed for mRNA content for cannabinoid receptors 1 (CB1) and 2 (CB2), methylation and demethylating enzymes (DNMT, TET), glucocorticoid receptor (NRC3) and immunological markers (IL1B, TNFα) by qPCR using TaqMan probes. The results were correlated with THC whole blood levels during the course of the day, as well as THCCOOH baseline levels. Statistical analyses used analysis of variance and covariance and t -tests, or non-parametric equivalents for those values which were not normally distributed., Results: There were no differences in background baseline characteristics of the participants except that the higher concentration THC group was older than the low concentration and placebo groups, and the low concentration THC group had higher baseline CB2 mRNA levels. Both the 5.9 and 13.4% THC groups showed increased THC blood levels that then decreased toward baseline within the first hour. However, there were no significant differences between THC blood levels between the 5.9 and 13.4% groups at any time point. At the 4-h time point after drug administration the 13.4% THC group had higher CB2 ( P = 0.021) and DNMT3A ( P = 0.027) mRNA levels than the placebo group. DNMT1 mRNA levels showed a trend in the same direction ( P = 0.056). The higher 13.4% THC group had significantly increased CB2 mRNA levels than the 5.9% concentration group at several post drug administration time points and showed trends for difference in effects for between 5.9 and 13.4% THC groups for other mRNAs. TET3 mRNA levels were higher in the 13.4% THC group at 55 min post-cannabis ingestion. When the high and lower concentration THC groups were combined, none of the differences in mRNA levels from placebo remained statistically significant. Changes in THC blood levels were not related to changes in mRNA levels., Conclusion: Over the time course of this study, CB2 mRNA increased in blood lymphocytes in the high concentration THC group but were not accompanied by changes in immunological markers. The changes in DNMT and TET mRNAs suggest potential epigenetic effects of THC in human lymphocytes. Increases in DNMT methylating enzymes have been linked to some of the pathophysiological processes in schizophrenia and, therefore, should be further explored in a larger sample population, as one of the potential mechanisms linking cannabis use as a trigger for schizophrenia in vulnerable individuals. Since the two THC groups did not differ in post-smoking blood THC concentrations, the relationship between lymphocytic changes and the THC content of the cigarettes remains to be determined., 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 © 2022 Smith, Sershen, Janowsky, Lajtha, Grieco, Gangoiti, Gertsman, Johnson, Marcotte and Davis.)

To compare the short-term outcomes in patients who underwent laparoscopic right colectomy with a traditional minimally invasive approach versus patients who underwent a laparoscopic colectomy with an enhanced perioperative pathway. A retrospective analysis was conducted on a consecutive series of patients who underwent elective laparoscopic right colectomy for neoplastic disease between January 1, 2011 and December 31, 2020. The patients were divided into two groups: the first cohort (FC), who underwent a traditional laparoscopic colectomy, mainly with extracorporeal anastomosis, between January 1, 2011 and December 31, 2015 and the second cohort (SC), who underwent a laparoscopic colectomy with an enhanced intraoperative (intracorporeal anastomosis) and perioperative pathway (ERAS protocol) between January 1, 2016 and December 31, 2020. There were a total of 361 patients, including 177 in the FC and 184 in the SC. In the SC a higher number of intracorporeal anastomoses was performed (91.8% vs. 19.2%, p < 0.001), drains were placed in 42 patients only (22.8% vs. 100% in the FC) and nasogastric tubes were placed in 21 patients only (11.4% vs. 100% in the FC). In the initial period of the SC. the procedures required a slightly longer operative time (median 105 vs. 95 min; p = 0.002), but postoperative surgical complications were lower (12% vs. 17.4%, p = 0.179). Postoperative recovery was faster in SC along with time to discharge (4 vs. 7 days; p < 0.001). Intraoperative anastomosis and enhanced pathways in right laparoscopic colectomy seem to guarantee better results with lower surgical complications and faster postoperative recovery., (© 2022. Italian Society of Surgery (SIC).)

Malnutrition is a frequent problem in cancer patients, which leads to prolonged and repeated hospitalizations, increased treatment-related toxicity, reduced response to cancer treatment, impaired quality of life, a worse overall prognosis and the avoidable waste of health care resources. Despite being perceived as a limiting factor in oncologic treatments by both oncologists and patients, there is still a considerable gap between need and actual delivery of nutrition care, and attitudes still vary considerably among health care professionals. In the last 5 years, the Italian Intersociety Working Group for Nutritional Support in Cancer Patients (WG), has repeatedly revisited this issue and has concluded that some improvement in nutritional care in Italy has occurred, at least with regard to awareness and institutional activities. In the same period, new international guidelines for the management of malnutrition and cachexia have been released. Despite these valuable initiatives, effective structural strategies and concrete actions aimed at facing the challenging issues of nutritional care in oncology are still needed, requiring the active participation of scientific societies and health authorities. As a continuation of the WG's work, we have reviewed available data present in the literature from January 2016 to September 2021, together with the most recent guidelines issued by scientific societies and health authorities, thus providing an update of the 2016 WG practical recommendations, with suggestions for new areas/issues for possible improvement and implementation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Alzheimer's disease (AD) is an irreversible age-related neurodegenerative disorder clinically characterized by severe memory impairment, language deficits and cognitive decline. The major neuropathological hallmarks of AD include extracellular deposits of the β-amyloid (Aβ) peptides and cytoplasmic neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein. The accumulation of plaques and tangles in the brain triggers a cascade of molecular events that culminate in neuronal damage and cell death. Despite extensive research, our understanding of the molecular basis of AD pathogenesis remains incomplete and a cure for this devastating disease is still not available. A growing body of evidence in different experimental models suggests that poly(ADP-ribose) polymerase-1 (PARP-1) overactivation might be a crucial component of the molecular network of interactions responsible for AD pathogenesis. In this work, we combined genetic, molecular and biochemical approaches to investigate the effects of two different PARP-1 inhibitors (olaparib and MC2050) in Drosophila models of Alzheimer's disease by exploring their neuroprotective and therapeutic potential in vivo. We found that both pharmacological inhibition and genetic inactivation of PARP-1 significantly extend lifespan and improve the climbing ability of transgenic AD flies. Consistently, PARP-1 inhibitors lead to a significant decrease of Aβ42 aggregates and partially rescue the epigenetic alterations associated with AD in the brain. Interestingly, olaparib and MC2050 also suppress the AD-associated aberrant activation of transposable elements in neuronal tissues of AD flies.

Biofortification, the enrichment of nutrients in crop plants, is of increasing importance to improve human health. The wild barley nested association mapping (NAM) population HEB-25 was developed to improve agronomic traits including nutrient concentration. Here, we evaluated the potential of high-throughput hyperspectral imaging in HEB-25 to predict leaf concentration of 15 mineral nutrients, sampled from two field experiments and four developmental stages. Particularly accurate predictions were obtained by partial least squares regression (PLS) modeling of leaf concentrations for N, P and K reaching coefficients of determination of 0.90, 0.75 and 0.89, respectively. We recognized nutrient-specific patterns of variation of leaf nutrient concentration between developmental stages. A number of quantitative trait loci (QTL) associated with the simultaneous expression of leaf nutrients were detected, indicating their potential co-regulation in barley. For example, the wild barley allele of QTL-4H-1 simultaneously increased leaf concentration of N, P, K and Cu. Similar effects of the same QTL were previously reported for nutrient concentrations in grains, supporting a potential parallel regulation of N, P, K and Cu in leaves and grains of HEB-25. Our study provides a new approach for nutrient assessment in large-scale field experiments to ultimately select genes and genotypes supporting plant biofortification., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The pathogenesis of the novel described multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) is still debated as it is not clear if they are the same or different nosological entities. However, for both the diseases a rapid and unequivocal diagnosis is mandatory to start the therapy before the onset of severe complications. In this study, we aimed to evaluate the white cell populations in MIS-C and KD as potential markers to discriminate between the two diseases., Methods: We studied white cell populations by flow cytometry in 46 MIS-C and 28 KD patients in comparison to 70 age-matched healthy children., Results: MIS-C patients had a significant lymphopenia that involved both B and T populations while KD patients showed a significant neutrophilia and thrombocythemia. Granulocyte/lymphocyte ratio helped to diagnose both MIS-C and KD with a high diagnostic sensitivity, while a multivariate analysis of granulocyte and T lymphocyte number contributed to discriminate between the two diseases., Conclusions: The relevant lymphopenia observed in MIS-C patients suggests that the disease would be a post-infectious sequel of COVID-19 immunologically amplified by a massive cytokine release, while the significant neutrophilia and thrombocythemia observed in KD confirmed that the disorder has the genesis of a systemic vasculitis. The analysis of a panel of circulating cells may help to early diagnose and to discriminate between the two diseases., Supplementary Information: The online version contains supplementary material available at 10.1186/s41231-022-00128-2., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2022.)

The aim of this study is to evaluate the influence of high-pressure CO 2 insufflation during TaTME on the occurrence of postoperative ileus. All patients undergoing elective transanal total mesorectal excision (TaTME) between April 2015 and March 2019 were included in a prospective database. Eligible patients were adults with mid and low-level rectal cancer undergoing elective TaTME with colorectal anastomosis and diverting ileostomy, following a standardized ERAS pathway. Patients were divided into a low-pressure (LP) group, where surgery was performed with an intrabdominal CO 2 pressure of 12 mmHg, and a high-pressure (HP) group, where the intrabdominal pressure reached 15 mmHg of CO 2 once the two surgical fields were connected. Of 98 patients undergoing TaTME in the observed period, 74 met the inclusion criteria and were included in this study. There was no significant difference in postoperative complications between the LP and HP groups, except for postoperative ileus, which occurred in seven patients (13.2%) in the LP group and seven patients (33.3%) in the HP group (p value 0.046). The logistic multivariate analysis showed that a high intraabdominal CO 2 pressure (OR 7040, 95% CI 1591-31,164, p value 0.01) and male sex (OR 10,343, 95% CI 1078-99,256, p value 0.043) were significantly associated with postoperative ileus after TaTME. Intraabdominal CO 2 pressure should be carefully set, as it may represent a risk factor for postoperative ileus in patients undergoing TaTME., (© 2021. Italian Society of Surgery (SIC).)