Abilities of berberine and chemically modified berberines to interact with metformin and inhibit proliferation of pancreatic cancer cells

Pancreatic cancer is devastating cancer worldwide with few if any truly effective therapies. Pancreatic cancer has an increasing incidence and may become the second leading cause of death from cancer. Novel, more effective therapeutic approaches are needed as pancreatic cancer patients usually survive for less than a year after being diagnosed. Control of blood sugar levels by the prescription drug metformin in diseases such as diabetes mellitus has been examined in association with pancreatic cancer. While the clinical trials remain inconclusive, there is hope that certain diets and medications may affect positively the outcomes of patients with pancreatic and other cancers. Other natural compounds may share some of the effects of metformin. One "medicinal" fruit consumed by millions worldwide is berberine (BBR). Metformin and BBR both activate AMP-activated protein kinase (AMPK) which is a key mediator of glucose metabolism. Glucose metabolism has been shown to be very important in cancer and its significance is increasing. In the following studies, we have examined the effects of metformin, BBR and a panel of modified BBRs (NAX compounds) and chemotherapeutic drugs on the growth of four different human pancreatic adenocarcinoma cell lines (PDAC). Interestingly, the effects of metformin could be enhanced by BBR and certain modified BBRs. Upon restoration of WT-TP53 activity in MIA-PaCa-2 cells, an altered sensitivity to the combination of certain NAX compounds and metformin was observed compared to the parental cells which normally lack WT-TP53. Certain NAX compounds may interact with WT-TP53 and metformin treatment to alter the expression of key molecules involved in cell growth. These results suggest a therapeutic approach by combining certain pharmaceutical drugs and nutraceuticals to suppress the growth of cancer cells

Role of prenatal magnetic resonance imaging in fetuses with isolated mild or moderate ventriculomegaly in the era of neurosonography: international multicenter study

Objectives To assess the role of fetal magnetic resonance imaging (MRI) in detecting associated anomalies in fetuses presenting with mild or moderate isolated ventriculomegaly (VM) undergoing multiplanar ultrasound evaluation of the fetal brain. Methods This was a multicenter, retrospective, cohort study involving 15 referral fetal medicine centers in Italy, the UK and Spain. Inclusion criteria were fetuses affected by isolated mild (ventricular atrial diameter, 10.0–11.9 mm) or moderate (ventricular atrial diameter, 12.0–14.9 mm) VM on ultrasound, defined as VM with normal karyotype and no other additional central nervous system (CNS) or extra‐CNS anomalies on ultrasound, undergoing detailed assessment of the fetal brain using a multiplanar approach as suggested by the International Society of Ultrasound in Obstetrics and Gynecology guidelines for the fetal neurosonogram, followed by fetal MRI. The primary outcome of the study was to report the incidence of additional CNS anomalies detected exclusively on prenatal MRI and missed on ultrasound, while the secondary aim was to estimate the incidence of additional anomalies detected exclusively after birth and missed on prenatal imaging (ultrasound and MRI). Subgroup analysis according to gestational age at MRI (< 24 vs ≥ 24 weeks), laterality of VM (unilateral vs bilateral) and severity of dilatation (mild vs moderate VM) were also performed. Results Five hundred and fifty‐six fetuses with a prenatal diagnosis of isolated mild or moderate VM on ultrasound were included in the analysis. Additional structural anomalies were detected on prenatal MRI and missed on ultrasound in 5.4% (95% CI, 3.8–7.6%) of cases. When considering the type of anomaly, supratentorial intracranial hemorrhage was detected on MRI in 26.7% of fetuses, while polymicrogyria and lissencephaly were detected in 20.0% and 13.3% of cases, respectively. Hypoplasia of the corpus callosum was detected on MRI in 6.7% of cases, while dysgenesis was detected in 3.3%. Fetuses with an associated anomaly detected only on MRI were more likely to have moderate than mild VM (60.0% vs 17.7%; P < 0.001), while there was no significant difference in the proportion of cases with bilateral VM between the two groups (P = 0.2). Logistic regression analysis showed that lower maternal body mass index (adjusted odds ratio (aOR), 0.85 (95% CI, 0.7–0.99); P = 0.030), the presence of moderate VM (aOR, 5.8 (95% CI, 2.6–13.4); P < 0.001) and gestational age at MRI ≥ 24 weeks (aOR, 4.1 (95% CI, 1.1–15.3); P = 0.038) were associated independently with the probability of detecting an associated anomaly on MRI. Associated anomalies were detected exclusively at birth and missed on prenatal imaging in 3.8% of cases. Conclusions The incidence of an associated fetal anomaly missed on ultrasound and detected only on fetal MRI in fetuses with isolated mild or moderate VM undergoing neurosonography is lower than that reported previously. The large majority of these anomalies are difficult to detect on ultrasound. The findings from this study support the practice of MRI assessment in every fetus with a prenatal diagnosis of VM, although parents can be reassured of the low risk of an associated anomaly when VM is isolated on neurosonography

Profili problematici della esclusione della punibilità per particolare tenuità del fatto.

L’elaborato si concentra sull’analisi della particolare tenuità del fatto alla luce delle riforme intervenute nel corso dei tempi. In primis l’attenzione vert sull’iter di approdo della riforma, d.lgs. 16 marzo 215, n. 28, approvato in attuazione della direttiva di legge delega contenuta nell’articolo 1 comma 1 lett.) m legge 28 aprile 2014, n. 67, che ha introdotto all’interno del codice penale la nuova causa di non punibilità. L’analisi procede con i rilievi costituzionali e i rapporti con due istituti analoghi, l’art. 34 d.lgs. 28 agosto 2000, n. 274 e l’art. 27 d.P.R. 22 settembre 1988, n. 448, fino alle riforme intervenute sull’articolo in esame nel corso dei tempi. Nel proseguo l’elaborato si sofferma sui presupposti di diritto sostanziale. Dalla natura giuridica della causa di non punibilità alla luce dei dibattiti che hanno preceduto il varo della riforma per poi soffermarsi sull’applicazione. Precise sono le condizioni che devono sussistere per quanto attiene all’applicazione in concreto del nuovo istituto. I limiti edittali: il legislatore ha circoscritto il nuovo istituto nel rispetto di detti limiti. Inizialmente il riferimento era ai massimi edittali, – reati per i quali è prevista la pena detentiva non superiore nel massimo a cinque anni, ovvero la pena pecuniaria, sola o congiunta alla predetta pena – ad oggi con l’avvento della riforma Cartabia si è passati ai minimi edittali, – reati per i quali è prevista la pena detentiva non superiore nel minimo a due anni, ovvero la pena pecuniaria, sola o congiunta alla predetta pena. – L’offesa: di particolare tenuità per l’esiguità del danno e del pericolo sopportato dal bene giuridico protetto o dalla vittima del reato. Questa a sua volta si suddivide in due indici-requisiti che attengono alla modalità dell’azione e all’esiguità del danno e/o del pericolo. La condotta: il comportamento non deve essere abituale. Dopo l’introduzione dell’articolo 131-bis all’interno del codice penale si sono susseguite una serie di modifiche al codice di procedura penale e altrettante al Testo Unico delle disposizioni legislative e regolamentari in materia di casellario giudiziale, di casellario europeo, di anagrafe delle sanzioni amministrative dipendenti da reato e dei relativi carichi pendenti, d.P.R. 14 novembre 2002, n. 313. Il d.lgs. 16 marzo 2015, n. 28 prevede, attraverso una modifica della disciplina dell’archiviazione, articolo 411 comma 1-bis, c.p.p., la possibilità di una declaratoria di non punibilità di cui all’art. 131-bis c.p. A seguire l’attenzione verterà sul ruolo dell’indagato e della persona offesa alla luce dell’introduzione di una nuova ipotesi di archiviazione, che si differenzia nettamente rispetto alle altre ipotesi di archiviazione tradizionale. Fino all’opposizione alla richiesta di archiviazione avanzata. L’udienza preliminare e la sentenza di non luogo a procedere alla luce dell’articolo 131-bis c.p., il proscioglimento predibattimentale per particolare tenuità del fatto e la sentenza di non doversi procedere, il proscioglimento dibattimentale, l’articolo 129 c.p.p., la causa di non punibilità nei riti speciali e l’iscrizione nel casellario giudiziale del provvedimento di archiviazione. A conclusione dell’elaborato le prospettive de iure condendo: le riforme intervenute nel corso dei tempi fino ad un’attenta analisi della riforma Cartabia, approvata recentemente, agosto 2022, che ha modificato in maniera evidente l'articolo in esame

Measurement and applications of singlet order lifetime through the use of pulsed-field gradients.

In this thesis, two fundamental concepts of nuclear magnetic resonance (NMR) were studied and combined in order to develop new solutions to practical problems. These concepts were: the use of pulsed magnetic field gradients for imaging and diffusion measurements, and the relaxation properties of a spin system. Chapter 2 describes how three-dimensional, diffusion-sensitising gradients were used in NMR experiments carried out on a system where long-lived singlet order was populated, allowing relaxation decay constants of the order of minutes to be achieved; this resulted in a new pulse sequence dubbed SADTI (Singlet-Assisted Diffusion Tensor Imaging) used in experiments where the structural characterization of model systems was possible by tracking diffusion of singlet bearing molecules in 3D for a time that is currently not achievable using routine diffusion NMR and magnetic resonance imaging (MRI) techniques. Chapter 3 presents the successful application of selective magnetic field gradients to reduce the duration of singlet order decay constant measurement, from 2.5 hours to less than 8 minutes. Finally, chapter 4 describes the first stages of the application of SADTI pulse sequence to real samples: these consisted of human tissue cultivated on porous polycaprolactone scaffolds; the goal of this study was to verify if SADTI can help in monitoring cell growth on artificial supports, by detecting changes in the diffusion pattern of a molecular probe of choice in which the specimen is immersed. These changes would reflect structural variations occurred within the cultivated scaffold, due to the cells infiltrating the pores and thus modifying the degree of restriction molecular diffusion is subject to. In order to provide the theoretical foundations to these studies, the concept and use of pulsed gradients in imaging and diffusion NMR, the description and measurement of molecular diffusion in free and restricted conditions, and the basic theory behind relaxation properties of the spin systems used, are presented in Chapter 1

ChemInform Abstract: Cooperative Organocatalysis for the Asymmetric γ Alkylation of α-Branched Enals.

α Branched leads to γ: The direct and enantioselective γ alkylation of α-substituted α,β-unsaturated aldehydes under dienamine catalysis has been achieved. A cooperative catalysis system that involves dienamine activation of α-branched enals and chiral Brønsted acid catalysis promotes an SN1-alkylation pathway while ensuring complete γ-site selectivity and high stereocontrol (see scheme; Bn=benzyl). Copyright © 2010 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim

Singlet-assisted diffusion-NMR (SAD-NMR): extending the scope of diffusion tensor imaging via singlet NMR

Long-lived nuclear singlet order methods are here combined with diffusion tensor imaging with the purpose of characterizing the full diffusion tensor of molecules that freely diffuse in large pores of up to the millimeter. Such sizes are out-of-reach to conventional diffusion tensor imaging because of the limitations imposed by the relaxation decay constant of the longitudinal magnetization. A singlet-assisted diffusion tensor imaging methodology able to circumvent such limitations is discussed and the new possibilities it offers are demonstrated through simulation and experiments on plastic phantoms containing cylindrical channels of onemillimeter diameter