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WNT signaling is central to spatial tissue arrangement and regulating stem cell activity, and it represents the hallmark of gastrointestinal cancers. Although its role in driving intestinal tumors is well characterized, WNT's role in gastric tumorigenesis remains elusive. We have developed mouse models to control the specific expression of an oncogenic form of β-catenin (CTNNB1) in combination with MYC activation in Lgr5 + cells of the gastric antrum. We used multiomics approaches applied in vivo and in organoid models to characterize their cooperation in driving gastric tumorigenesis. We report that constitutive β-catenin stabilization in the stomach has negligible oncogenic effects and requires MYC activation to induce gastric tumor formation. Although physiologically low MYC levels in gastric glands limit β-catenin transcriptional activity, increased MYC expression unleashes the WNT oncogenic transcriptional program, promoting β-catenin enhancer invasion without a direct transcriptional cooperation. MYC activation induces a metabolic rewiring that suppresses lysosomal biogenesis through mTOR and ERK activation and MiT/TFE inhibition. This prevents EPCAM degradation by macropinocytosis, promoting β-catenin chromatin accumulation and activation of WNT oncogenic transcription. Our results uncovered a new signaling framework with important implications for the control of gastric epithelial architecture and WNT-dependent oncogenic transformation. [Display omitted] WNT mutations are a hallmark of gastrointestinal cancer, but low MYC activity represents a barrier for stomach adenoma formation. MYC regulates metabolic processes that allow WNT activation of oncogenic programs. [ABSTRACT FROM AUTHOR]

Few studies focused on minor adverse events which may develop after colonoscopy. To investigate the incidence and factors associated to post-colonoscopy symptoms. This is a prospective study conducted in 10 Italian hospitals. The main outcome was a cumulative score combining 10 gastrointestinal (GI) symptoms occurring the week following colonoscopy. The analyses were conducted via multivariate logistic regression. Of 793 subjects included in the analysis, 361 (45.5%) complained the new onset of at least one GI symptom after the exam; one symptom was reported by 202 (25.5%), two or more symptoms by 159 (20.1%). Newly developed symptoms more frequently reported were epigastric/abdominal bloating (32.2%), pain (17.3%), and dyspeptic symptoms (17.9%). Symptoms were associated with female sex (odds ratio [OR]=2.54), increasing number of symptoms developed during bowel preparation intake (OR=1.35) and somatic symptoms (OR=1.27). An inverse association was observed with better mood (OR=0.74). A high-risk profile was identified, represented by women with bad mood and somatic symptoms (OR=8.81). About half of the patients develop de novo GI symptoms following colonoscopy. Improving bowel preparation tolerability may reduce the incidence of post-colonoscopy symptoms, especially in more vulnerable patients. [ABSTRACT FROM AUTHOR]

Symptoms developing during bowel preparation are major concerns among subjects who refuse the procedure. We aimed to explore the determinants of symptoms occurring during preparation among patients undergoing elective colonoscopy. This is a prospective multicenter study conducted in 10 Italian hospitals. A multidimensional approach collecting socio-demographic, clinical, psychological and occupational information before colonoscopy through validated instruments was used. Outcome was a four-category cumulative score based on symptoms occurring during preparation, according to the Mayo Clinic Bowel Prep Tolerability Questionnaire, weighted by intensity. Missing values were addressed through multiple imputation. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through multivariate logistic regression models. 1137 subjects were enrolled. Severe symptoms were associated with female sex (OR=3.64, 95%CI 1.94-6.83), heavier working hours (OR=1.13, 95% CI=1.01-1.25), previous gastrointestinal symptoms (OR=7.81, 95% CI 2.36-25.8 for high score), somatic symptoms (OR=2.19, 95% CI=1.06-4.49 for multiple symptoms), day-before regimen (OR=2.71, 95%CI 1.28-5.73). On the other hand, age ≥60 years (OR=0.10, 95% CI 0.02-0.44) and good mood (p=0.042) were protective factors. A high-risk profile was identified, including women with low mood and somatic symptoms (OR=15.5, 95%CI 4.56-52.7). We identified previously unreported determinants of symptoms burdening bowel preparation and identified a particularly vulnerable phenotype. Symptoms during preparation especially impact heavier working activity. [ABSTRACT FROM AUTHOR]

Very low-volume bowel preparation (BP) for colonoscopy with 1-liter polyethylene glycol plus ascorbate (1L-PEG-Asc) has displayed high tolerability and quality of bowel cleansing. Concerns have been raised regarding its safety. We aimed to evaluate the incidence of adverse events (AEs) following BP with 1L-PEG-Asc or 2L-PEG-Asc. From January 2019 to September 2020, data from all consecutive adult outpatients who underwent colonoscopy in Our Unit were collected. AEs were assessed by reviewing the clinical and laboratory data of patients who attended the Emergency Department (ED) of Modena District Hospitals in the 7 days following the colonoscopy, and were classified as "BP-related" or "BP-unrelated". During the study, 4069 (68.03%) and 1912 (31.97%) patients underwent colonoscopy after taking 2L-PEG-Asc or 1L-PEG-Asc, respectively. Regarding AEs, 77 (1.29%) patients attended ED, 53 (53/4069, 1.30%) and 24 (24/1912, 1.25%) after taking 2L-PEG-Asc and 1L-PEG-Asc. BP-related AEs were observed in 5 (5/4069, 0.12%) and 4 (4/1912, 0.21%) patients, respectively. The most frequent BP-related AEs were tachyarrhythmias (6/5981, 0.10%). The incidence rate of clinically relevant BP-related AEs is extremely low. This strongly suggests that 1L-PEG-Asc colonoscopy BP is as safe as 2L-PEG-Asc BP in a real-life clinical setting of unselected patients. [ABSTRACT FROM AUTHOR]

• Robust proton vs x-ray planning on free-breathing (FB) STAGE III NSCLC was tested. • A reduction of NTCP risk of pulmonary and cardiac toxicity was scored with protons. • A reduction in the dose to the immune system was observed with protons. • Robust optimization is an interesting and novel solution also for x-ray therapy. • Robust FB proton therapy could be an effective option for selected STAGE III NSCLC. To assess the robustness and to define the dosimetric and NTCP advantages of pencil-beam-scanning proton therapy (PBSPT) compared with VMAT for unresectable Stage III non-small lung cancer (NSCLC) in the immunotherapy era. 10 patients were re-planned with VMAT and PBSPT using: 1) ITV-based robust optimization with 0.5 cm setup uncertainties and (for PBSPT) 3.5 % range uncertainties on free-breathing CT 2) CTV-based RO including all 4DCTs anatomies. Target coverage (TC), organs at risk dose and TC robustness (TCR), set at V95%, were compared. The NTCP risk for radiation pneumonitis (RP), 24-month mortality (24MM), G2 + acute esophageal toxicity (ET), the dose to the immune system (EDIC) and the left anterior descending (LAD) coronary artery V15 < 10 % were registered. Wilcoxon test was used. Both PBSPT methods improved TC and TCR (p < 0.01). The mean lung dose and lung V20 were lower with PBSPT (p < 0.01). Median mean heart dose reduction with PBSPT was 8 Gy (p < 0.001). PT lowered median LAD V15 (p = 0.004). ΔNTCP > 5 % with PBSPT was observed for two patients for RP and for five patients for 24 MM. ΔNTCP for ≥ G2 ET was not in favor of PBSPT for all patients. PBSPT halved median EDIC (4.9/5.1 Gy for ITV/CTV-based VMAT vs 2.3 Gy for both ITV/CTV-based PBSPT, p < 0.01). PBSPT is a robust approach with significant dosimetric and NTCP advantages over VMAT; the EDIC reduction could allow for a better integration with immunotherapy. A clinical benefit for a subset of NSCLC patients is expected. [ABSTRACT FROM AUTHOR]

Granular mixed laterally spreading tumors (GM-LSTs) have an intermediate level of risk for submucosal invasive cancer (SMICs) without clear signs of invasion (covert); the optimal resection method is uncertain. We aimed to determine the risk of covert SMIC in GM-LSTs based on clinical and endoscopic factors. We collected data from 693 patients (50.6% male; median age, 69 years) with colorectal GM-LSTs, without signs of invasion, who underwent endoscopic resection (74.2%) or endoscopic submucosal dissection (25.2%) at 7 centers in Italy from 2016 through 2019. We performed multivariate and univariate analyses to identify demographic and endoscopic factors associated with risk of SMIC. We developed a multivariate model to calculate the number needed to treat (NNT) to detect 1 SMIC. Based on pathology analysis, 66 patients (9.5%) had covert SMIC. In multivariate analyses, increased risk of covert SMIC were independently associated with increasing lesion size (odds ratio per mm increase, 1.02, 95% CI, 1.01–1.03; P =.003) and rectal location (odds ratio, 3.08; 95% CI, 1.62-5.83; P =.004). A logistic regression model based on lesion size (with a cutoff of 40 mm) and rectal location identified patients with covert SMIC with 47.0% sensitivity, 82.6% specificity, and an area under the curve of 0.69. The NNT to identify 1 patient with a nonrectal SMIC smaller than 4 cm was 20; the NNT to identify 1 patient with a rectal SMIC of 4 cm or more was 5. In an analysis of data from 693 patients, we found the risk of covert SMIC in patients with GM-LSTs to be approximately 10%. GM-LSTs of 4 cm or more and a rectal location are high risk and should be treated by en-bloc resection. ClinicalTrials.gov , Number: NCT03836131. [ABSTRACT FROM AUTHOR]

• NK cells are critical players in tumour immune surveillance. • Extracellular vesicles are important mediators of tumour cell-to-cell communication. • Understanding the mechanisms by which tumor derived EVs influence the NK cell phenotype and functions can open new possibilities for cancer therapy. Natural killer (NK) cells are innate lymphoid cells that play a major role in the immune surveillance against tumors and their activity is regulated through signals derived by a number of NK cell inhibitory and activating receptors as well as cytokines and other soluble factors released in the tumor microenvironment. Extracellular vesicles (EVs) are membrane-enclosed particles secreted by all cell types, both in healthy and diseased conditions, and are important mediators of intercellular communication. Depending on the molecular cargo, tumor-derived extracellular vesicles have the capability to either promote or suppress NK cell-mediated functions. Anti-cancer therapies designed to sustain host anti-tumor immune response represent an appealing strategy to control tumor growth avoiding tumor immune escape. The ability of anticancer chemotherapy to enhance the immunogenic potential of malignant cells mainly relies on the establishment of the immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs). Moreover, the activation of the DNA damage response (DDR) and the induction of senescence represent two crucial modalities aimed at promoting the clearance of drug-treated tumor cells by NK cells. Herein, we will address the main mechanisms used by cancer-derived extracellular vesicles to modulate NK cell activity, and we will discuss how anti-cancer therapies might impact on the secretion and the immunomodulatory function of these vesicles. [ABSTRACT FROM AUTHOR]

The balance between the host proinflammatory immune response and the counteracting anti-inflammatory and reparative responses supposedly determine the outcome of periapical lesions. In this scenario, the vasoactive intestinal peptide (VIP) may exert a protective role because of its prominent immunoregulatory capacity. In this study, we investigated (in a cause-and-effect manner) the potential involvement of VIP in the development of human and experimental periapical lesions. Periapical granulomas (n = 124) and control samples (n = 48) were comparatively assessed for VIP and multiple immunologic/activity marker expression through real-time polymerase chain reaction. Experimental periapical lesions (C57Bl/6 wild-type mice) were evaluated regarding endogenous VIP expression correlation with lesion development and the effect of recombinant VIP therapy in lesion outcome. CCR4KO and IL4KO strains and anti-glucocorticoid-induced TNFR-related protein inhibition were used to test the involvement of Treg and Th2 cells in VIP-mediated effects. VIP expression was more prevalent in periapical granulomas than in controls, presenting a positive association with immunoregulatory factors and an inverse association/correlation with proinflammatory mediators and the receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio. Endogenous VIP expression up-regulation was temporally associated with lesion immunoregulation and a decline of bone loss. VIP therapy in mice prompted the arrest of lesion development, being associated with an anti-inflammatory and proreparative response that limits the proinflammatory, Th1, Th17, and osteoclastogenic response in the periapex. The VIP protective effect was dependent of Treg migration and activity and independent of interleukin 4. Our results show that VIP overexpression in human and experimental periapical lesions is associated with lesion inactivity and that VIP therapy results in the attenuation of experimental lesion progression associated with the immunosuppressive response involving Treg cells. [ABSTRACT FROM AUTHOR]

Abstract Background and aim Endoscopic full-thickness resection(EFTR) with FTRD® in colo-rectum may be useful for several indications.The aim was to assess its efficacy and safety. Material and methods In this retrospective multicenter study 114 patients were screened; 110 (61M/49F, mean age 68 ± 11 years, range 20–90) underwent EFTR using FTRD®. Indications were:residual/recurrent adenoma (39), incomplete resection at histology (R1 resection) (26), non-lifting lesion (12), adenoma involving the appendix (2) or diverticulum (2), subepithelial lesions(10), suspected T1 carcinoma (16), diagnostic resection (3). Technical success (TS: lesion reached and resected), R0 resection (negative lateral and deep margins),EFTR rate(all layers documented in the specimen) and safety have been evaluated. Results TS was achieved in 94.4% of cases. EFTR was achieved in 91% with lateral and deep R0 resection in 90% and 92%. Mean size of specimens was 20 mm (range 6–42). In residual/recurrent adenomas, final analysis revealed: low-risk T1 (11), adenoma with low-grade dysplasia (LGD) (24) and high-grade dysplasia (HGD) (3), scar tissue (1). Histology reports of R1 resections were: adenoma with LGD (6), with HGD (1), low-risk (6) and high-risk (1) T1, scar tissue (12). Non-lifting lesions were diagnosed as: adenoma with HGD (3), low-risk (7) and high risk (2) T1. Adverse clinical events occurred in 12 patients (11%),while adverse technical events in11%. Three-months follow-up was available in 100 cases and residual disease was evident in only seven patients. Conclusions EFTR using FTRD® seems to be a feasible, effective and safe technique for treating selected colo-rectal lesions. Comparative prospective studies are needed to confirm these promising results. [ABSTRACT FROM AUTHOR]

The identification of senolytics, compounds that eliminate senescent cells, is presently a key priority given their therapeutic promise in cancer and aging-associated diseases. Two recent papers by Triana-Martínez et al. and Guerrero et al. report the senolytic activity of cardiac glycosides (CGs) and their efficacy in these pathophysiological contexts. [ABSTRACT FROM AUTHOR]

Natural Killer cells (NK) are innate effector cells with a critical role in immunosurveillance against different kinds of cancer cells, including Multiple Myeloma (MM). However, the number and/or function of these lymphocytes are strongly reduced during MM progression and in advanced clinical stages. A better understanding of the mechanisms controlling both MM and NK cell biology have greatly contributed to develop novel and combined therapeutic strategies in the treatment of this incurable hematologic malignancy. These include approaches to reverse the immunosuppressive MM microenvironment or potentiate the natural or antibody-dependent cellular cytotoxicity (ADCC) of NK cells. Moreover, chemotherapeutic drugs or specific monoclonal antibodies (mAbs) can render cancer cells more susceptible to NK cell-mediated recognition and lysis; direct enhancement of NK cell function can be obtained by means of immunomodulatory drugs, cytokines and blocking mAbs targeting NK cell inhibitory receptors. Finally, adoptive transfer of ex-vivo expanded and genetically manipulated NK cells is also a promising therapeutic tool for MM. Here, we review current knowledge on complex mechanisms affecting NK cell activity during MM progression. We also discuss recent advances on innovative approaches aimed at boosting the functions of these cytotoxic innate lymphocytes. In particular, we focus our attention on recent preclinical and clinical studies addressing the therapeutic potential of different NK cell-based strategies for the management of MM. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Chemokines regulate ILCs function during immune response. • Chemokines regulate migration and tissue tropism of different ILC subsets. • Chemokines control the functional crosstalk between ILCs and other cells Abstract Three groups of innate lymphoid cells (ILCs) can be defined based on transcription factor requirements, cytokine production profiles, and roles in immunity. Given their strategic anatomical location into barrier tissues and the ability to rapidly produce cytokines and to cross-talk with other immune and non-immune cells, ILCs play fundamental functions in tissue homeostasis and regulation of immune responses. Several members of the chemokine family influence ILC tissue localization in the correct microenvironment by regulating their release from the bone marrow as well as their homing and retention in the tissues. In this review, we discuss the recent advances on how chemokine regulation of ILC tissue-positioning and functional interaction with other cells play essential roles in tissue-specific regulation of innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Objectives Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, restricts patients’ communication capacity a few years after onset. A proof-of-concept of brain–computer interface (BCI) has shown promise in ALS and “locked-in” patients, mostly in pre-clinical studies or with only a few patients, but performance was estimated not high enough to support adoption by people with physical limitation of speech. Here, we evaluated a visual BCI device in a clinical study to determine whether disabled people with multiple deficiencies related to ALS would be able to use BCI to communicate in a daily environment. Methods After clinical evaluation of physical, cognitive and language capacities, 20 patients with ALS were included. The P300 speller BCI system consisted of electroencephalography acquisition connected to real-time processing software and separate keyboard-display control software. It was equipped with original features such as optimal stopping of flashes and word prediction. The study consisted of two 3-block sessions (copy spelling, free spelling and free use) with the system in several modes of operation to evaluate its usability in terms of effectiveness, efficiency and satisfaction. Results The system was effective in that all participants successfully achieved all spelling tasks and was efficient in that 65% of participants selected more than 95% of the correct symbols. The mean number of correct symbols selected per minute ranged from 3.6 (without word prediction) to 5.04 (with word prediction). Participants expressed satisfaction: the mean score was 8.7 on a 10-point visual analog scale assessing comfort, ease of use and utility. Patients quickly learned how to operate the system, which did not require much learning effort. Conclusion With its word prediction and optimal stopping of flashes, which improves information transfer rate, the BCI system may be competitive with alternative communication systems such as eye-trackers. Remaining requirements to improve the device for suitable ergonomic use are in progress. [ABSTRACT FROM AUTHOR]

Epidemiological studies show that consumption of diets rich in fruits and vegetables is associated with lower risks of cancer. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds is fisetin (3,7,3,4-tetrahydroxyflavone), a flavonol that is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. Fisetin has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo . Fisetin targets many components of intracellular signaling pathways including regulators of cell survival and apoptosis, tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. Current evidence supports the idea that fisetin is a promising agent for cancer treatment. This review summarizes reported anticancer effects of fisetin, and re-emphasizes its potential therapeutic role in the treatment of cancer. [ABSTRACT FROM AUTHOR]

Migration capacity is essential for dendritic cells (DCs) to present antigen to T cells for the induction of immune response. The DC migration is supposed to be a calcium-dependent process, while not fully understood. Here, we report a role of the KCa3.1/IK1/SK4 channels in the migration capacity of both immature (iDC) and mature (mDC) human CD14 + -derived DCs. KCa3.1 channels were shown to control the membrane potential of human DC and the Ca 2+ entry, which is directly related to migration capacities. The expression of migration marker such as CCR5 and CCR7 was modified in both types of DCs by TRAM-34 (100 nM). But, only the migration of iDC was decreased by use of both TRAM-34 and KCa3.1 siRNA. Confocal analyses showed a close localization of CCR5 with KCa3.1 in the steady state of iDC. Finally, the implication of KCa3.1 seems to be limited to the migration capacities as T cell activation of DCs appeared unchanged. Altogether, these results demonstrated that KCa3.1 channels have a pro-migratory effect on iDC migration. Our findings suggest that KCa3.1 in human iDC play a major role in their migration and constitute an attractive target for the cell therapy optimization. [ABSTRACT FROM AUTHOR]

The alveolar bone repair process may be influenced by multiple local and systemic factors, which include immune system cells and mediators. Macrophages allegedly play important roles in the repair process, and the transition of an initial inflammatory M1 profile into a pro-reparative M2 profile theoretically contributes to a favorable repair outcome. In this context, considering immunoregulatory molecules as potential targets for improving bone repair, this study evaluated the role of the immunoregulatory molecule FTY720, previously described to favor the development of the M2 phenotype, in the process of alveolar bone healing in C57Bl/6 (WT) mice. Experimental groups submitted to tooth extraction and maintained under control conditions or treated with FTY720 were evaluated by microtomographic (μCT), histomorphometric, immunohistochemical and molecular analysis to characterize healing and host response features at 0, 1, 3, 7 and 14 days. Our results demonstrated that the FTY720 group presented higher bone tissue density, higher bone tissue volume, greater tissue volume fraction, greater number and thickness of trabeculae and a higher number of osteoblasts and osteoclasts than the control group. Accordingly, the bone markers BMP2, BMP7, ALPL, SOST and RANK mRNA expressions increased in the FTY720 treated group. Furthermore, the levels of FIZZ, ARG2 and IL-10 mRNA increased in the FTY720 group together with the presence of CD206+ cells, suggesting that the boost of bone formation mediated by FTY720 involves an increased polarization and activity of M2 macrophages in healing sites. Thus, our results demonstrate that FTY720 favored the process of alveolar bone repair, probably trough a strengthened M2 response, associated with an increased expression of markers osteogenic differentiation and activity markers. Immunoregulatory strategies based in the modulation of macrophage polarization profile can comprise effective tools to improve the bone repair process. [Display omitted] • Bone repair is influenced by immune system cells and mediators. • Macrophages M2 pro-reparative profile theoretically contributes to a favorable repair outcome. • Immunoregulatory molecule FTY720 favors the development of the M2 phenotype. • FTY720 favored the process of alveolar bone repair along with a strengthened M2 response. [ABSTRACT FROM AUTHOR]