Archivio istituzionale della Ricerca - Università degli Studi di Parma
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TMEM219 signaling promotes intestinal stem cell death and exacerbates colitis
No full textMechanisms by which mucosal regeneration is abrogated in inflammatory bowel disease (IBD) are still under investigation, and a role for an intestinal stem cell (ISC) defect is now emerging. Herein, we report an abnormal ISC death that occurs in Crohn’s disease, which exacerbates colitis, limits ISC-dependent mucosal repair, and is controlled through the death factor Transmembrane protein 219 (TMEM219). Large alterations in TMEM219 expression were observed in patients with Crohn’s disease, particularly in those with active disease and/or those who were nonresponders to conventional therapy, confirming that TMEM219 signaling is abnormally activated and leads to failure of the mucosal regenerative response. Mechanistic studies revealed a proapoptotic TMEM219-mediated molecular signature in Crohn’s disease, which associates with Caspase-8 activation and ISC death. Pharmacological blockade of the IGFBP3/TMEM219 binding/signal with the recombinant protein ecto-TMEM219 restored the self-renewal abilities of miniguts generated from patients with Crohn’s disease in vitro and ameliorated DSS-induced and T cell-mediated colitis in vivo, ultimately leading to mucosal healing. Genetic tissue-specific deletion of TMEM219 in ISCs in newly generated TMEM219fl/flLGR5cre mice revived their mucosal regenerative abilities both in vitro and in vivo. Our findings demonstrate that a TMEM219-dependent ISC death exacerbates colitis and that TMEM219 blockade reestablishes intestinal self-renewal properties in IBD
Prognostic Significance of +1q Alterations in Relapsed/Refractory Multiple Myeloma Treated With Daratumumab-, Elotuzumab-, and Carfilzomib-Based Triplet Regimens: A Multicenter Real-World Analysis of 635 Patients
No full textRelapsed/refractory multiple myeloma (RRMM) research on the impact of +1q abnormalities in real-world settings is limited. This study evaluated the prognostic and predictive significance of 1q gain [gain(1q)] and amplification [ampl(1q)] in 635 RRMM patients treated with daratumumab-, elotuzumab-, and carfilzomib-based triplet regimens. Patients with +1q abnormalities had lower deep response rates [≥ CR: 9.4% for gain(1q), 11.6% for ampl(1q)] versus 20.2% in +1q-negative patients. Multivariable ordinal logistic analysis showed significantly lower odds of achieving ≥ CR in patients with gain(1q) (OR = 0.49, p < 0.001) or ampl(1q) (OR = 0.58, p = 0.0037). Progression-free survival (PFS) was longer in +1q-negative patients (28 months) compared to those with gain(1q) (8 months) or ampl(1q) (7.4 months). Multivariable models identified gain(1q) (HR = 1.9, p < 0.001) and ampl(1q) (HR = 2.2, p < 0.001) as independent negative prognostic factors alongside del17p, t(4;14), creatinine clearance < 60 mL/min, and ISS Stages II and III. Similarly, overall survival (OS) was reduced for patients with gain(1q) (25 months) and ampl(1q) (19.5 months) versus 42.2 months in +1q-negative patients. Multivariable analysis showed gain(1q) (HR = 1.6, p = 0.007) and ampl(1q) (HR = 2.0, p = 0.002) as independent predictors of increased mortality. Ancillary +1q abnormalities associated with high-risk cytogenetic changes were linked to both shorter PFS and OS. Stratification into no-hit, single-hit, double-hit, and triple-hit groups showed significant survival differences, emphasizing the impact of cumulative cytogenetic abnormalities on outcomes. In conclusion, +1q abnormalities significantly impact prognosis in RRMM and should be considered in risk stratification. The study emphasizes the importance of comprehensive cytogenetic profiling in real-world settings and highlights the need for personalized treatment strategies to improve patient outcomes
Studies on the Effect of Diamine Elongation in Copper(II) Complexes with NNO Tridentate Schiff Base Ligands
No full textThe copper(II) complexes of general formula [Cu(GL2H,H)(Cl)] (A4–A6, G = NO2, H and OMe, respectively), bearing NNO tridentate Schiff base ligands (GL2H,H)− derived from the mono-condensation of 1,3-diaminopropane and G-substituted salicylaldehydes, are here reported. The elongation of the diamine with one additional carbon atom with respect to the triad derived from ethylenediamine [Cu(GL1H,H)(Cl)] (A1–A3, G = NO2, H and OMe, respectively) led to different synthetic procedures, with the difficult isolation of A6 that could be obtained only in few crystals suitable for X-ray diffractions. Operating in acidic conditions to promote the coordination of chloride and expulsion of pyridine from the complex [Cu(GL2H,H)(py)](ClO4) (G = NO2) allows for obtaining A4. On the other hand, structural rearrangement occurs when G = H, yielding the dinuclear species [Cu2(μ-saltn)(HL2H,H)](ClO4)⋅0.5MeOH (D5⋅0.5MeOH) instead of the desired A5, which can be obtained by avoiding the use of HCl and operating in the excess of LiCl. Finally, A4 and A5 were investigated as cytotoxic agents against malignant (MDA-MB-231 and 22-Rv1) and healthy (HaCaT) cell lines, and the ability of the most promising A5 to be internalized and interact with cellular targets was studied
Do looks matter? Investigating facial expressions and intraspecific communication across different dog morphotypes
No full textBrachycephalic dogs gained great popularity in recent years, however the extreme conformation (e.g., wide eyes, flat nose, round heads, short tails) characterizing some breeds raised concerns about the effectiveness of facial signals in these dogs. These features might create challenges for an effective intraspecific communication and potentially lead to misunderstandings during intraspecific interactions. This study aimed to investigate potential differences in behavioural displays during intraspecific approaches between dogs of different morphotypes: hunting dogs and shepherd dogs (mesocephalic morphotype) and small companion molossoids and guard molossoids (brachycephalic morphotype). Fourteen brachycephalic dogs and sixteen mesocephalic dogs were tested. We predicted that mesocephalic and brachycephalic would express facial signals at different extent and that if brachycephalic dog facial signaling is impaired by their facial conformation it could elicit different responses in the opponent dog. Contrary to our predictions, no behavioural differences were found between brachycephalic and mesocephalic breeds, suggesting that extreme conformation of brachycephalic dogs has not drastically altered their communicative abilities. Further results showed that the “tongue flicking” behaviour, previously suggested to function as an early warning in conflicted/aggressions-related contexts was performed more by mesocephalic TESTED DOGS when the DOG STIMULUS was a brachycephalic dog, suggesting that this morphotype can elicit intense and ambiguous response in mesocephalic dogs. Conversely, the “bow” behaviour, a stereotyped cue consistently found in canids intraspecific social contexts, was expressed more by the mesocephalic TESTED DOG towards other mesocephalic approaching DOG STIMULI. Different behavioural patterns associated to the specific breed types tested emerged: shepherd dogs showed higher alertness and dog orientation, hunting dogs barked more, guard molossoids showed calm vigilance and small companion molossoids were more avoidant in regards of the dog approaching them. The present study is the first aimed to examine if the brachycephalic morphotype influences dogs’ intraspecific communication and due to the limited number of dogs tested further experimental evidences are needed. Nevertheless, it appears that brachycephalic dogs are perceived differently by non-brachycephalic ones and these results could provide valuable insights for researchers, breeders and dog trainers
Static Detection of Untrusted Cross-Contract Invocations in Go Smart Contracts
No full textA blockchain is a trustless system in an environment populated by untrusted peers. Code deployed in blockchain as a smart contract should be cautious when invoking contracts of other peers as they might introduce several risks and unexpected issues. This paper presents an information flow-based approach for detecting cross-contract invocations to untrusted contracts, written in general-purpose languages, that could lead to arbitrary code executions and store any results coming from them. The analysis is implemented in GoLiSA, a static analyzer for Go. Our experimental results show that GoLiSA is able to detect all vulnerabilities related to untrusted cross-contract invocations on a significant benchmark suite of smart contracts written in Go for Hyperledger Fabric, an enterprise framework for blockchain solutions
