The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer

The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes downregulation of the expression of the S100P gene and the S100P protein in cells and in vivo. This protein is well established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The S100P gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides upstream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that S100P expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of upregulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of S100P expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023), and its ability to downregulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the S100P promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302

Choosing the most suitable classifier For supporting assistive technology adoption In people with Parkinson’s disease: a fuzzy Multi-criteria approach

Parkinson’s disease (PD) is the second most common neurodegenerative disorder which requires a long-term, interdisciplinary disease management. While there remains no cure for Parkinson’s disease, treatments are available to help reduce the main symptoms and maintain quality of life for as long as possible. Owing to the global burden faced by chronic conditions such as PD, Assistive technologies (AT’s) are becoming an increasingly common prescribed form of treatment. Low adoption is hampering the potential of digital technologies within health and social care. It is then necessary to employ classification algorithms have been developed for differentiating adopters and non-adopters of these technologies; thereby, potential negative effects on people with PD and cost overruns can be further minimized. This paper bridges this gap by extending the Multi-criteria decision-making approach adopted in technology adoption modeling for people with dementia. First, the fuzzy Analytic Hierarchy Process (FAHP) is applied to estimate the initial relative weights of criteria and sub-criteria. Then, the Decisionmaking Trial and Evaluation Laboratory (DEMATEL) is used for evaluating the interrelations and feedback among criteria and sub-criteria. The Technique for Order of Preferences by Similarity to Ideal Solution (TOPSIS) is finally implemented to rank three classifiers (Lazy IBk – knearest neighbors, Naïve bayes, and J48 decision tree) according to their ability to model technology adoption. A real case study considering is presented to validate the proposed approach

Evaluation of chemiluminescence, toluidine blue and histopathology for detection of high risk oral precancerous lesions: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Early detection holds the key to an effective control of cancers in general and of oral cancers in particular. However, screening procedures for oral cancer are not straightforward due to procedural requirements as well as feasibility issues, especially in resource-limited countries.</p> <p>Methods</p> <p>We conducted a cross-sectional study to compare the performance of chemiluminescence, toluidine blue and histopathology for detection of high-risk precancerous oral lesions. We evaluated 99 lesions from 55 patients who underwent chemiluminescence and toluidine blue tests along with biopsy and histopathological examination. We studied inter-as well as intra-rater agreement in the histopathological evaluation and then using latent class modeling, we estimated the operating characteristics of these tests in the absence of a reference standard test.</p> <p>Results</p> <p>There was a weak inter-rater agreement (kappa < 0.15) as well as a weak intra-rater reproducibility (Pearson's r = 0.28, intra-class correlation rho = 0.03) in the histopathological evaluation of potentially high-risk precancerous lesions. When compared to histopathology, chemiluminescence and toluidine blue retention had a sensitivity of 1.00 and 0.59, respectively and a specificity of 0.01 and 0.79, respectively. However, latent class analysis indicated a low sensitivity (0.37) and high specificity (0.90) of histopathological evaluation. Toluidine blue had a near perfect high sensitivity and specificity for detection of high-risk lesions.</p> <p>Conclusion</p> <p>In our study, there was variability in the histopathological evaluation of oral precancerous lesions. Our results indicate that toluidine blue retention test may be better suited than chemiluminescence to detect high-risk oral precancerous lesions in a high-prevalence and low-resource setting like India.</p

ACE (I/D) polymorphism and response to treatment in coronary artery disease: a comprehensive database and meta-analysis involving study quality evaluation

<p>Abstract</p> <p>Background</p> <p>The role of angiotensin-converting enzyme (<it>ACE</it>) gene insertion/deletion (<it>I/D</it>) polymorphism in modifying the response to treatment modalities in coronary artery disease is controversial.</p> <p>Methods</p> <p>PubMed was searched and a database of 58 studies with detailed information regarding <it>ACE I/D </it>polymorphism and response to treatment in coronary artery disease was created. Eligible studies were synthesized using meta-analysis methods, including cumulative meta-analysis. Heterogeneity and study quality issues were explored.</p> <p>Results</p> <p>Forty studies involved invasive treatments (coronary angioplasty or coronary artery by-pass grafting) and 18 used conservative treatment options (including anti-hypertensive drugs, lipid lowering therapy and cardiac rehabilitation procedures). Clinical outcomes were investigated by 11 studies, while 47 studies focused on surrogate endpoints. The most studied outcome was the restenosis following coronary angioplasty (34 studies). Heterogeneity among studies (p < 0.01) was revealed and the risk of restenosis following balloon angioplasty was significant under an additive model: the random effects odds ratio was 1.42 (95% confidence interval:1.07–1.91). Cumulative meta-analysis showed a trend of association as information accumulates. The results were affected by population origin and study quality criteria. The meta-analyses for the risk of restenosis following stent angioplasty or after angioplasty and treatment with angiotensin-converting enzyme inhibitors produced non-significant results. The allele contrast random effects odds ratios with the 95% confidence intervals were 1.04(0.92–1.16) and 1.10(0.81–1.48), respectively. Regarding the effect of <it>ACE I/D </it>polymorphism on the response to treatment for the rest outcomes (coronary events, endothelial dysfunction, left ventricular remodeling, progression/regression of atherosclerosis), individual studies showed significance; however, results were discrepant and inconsistent.</p> <p>Conclusion</p> <p>In view of available evidence, genetic testing of <it>ACE I/D </it>polymorphism prior to clinical decision making is not currently justified. The relation between <it>ACE </it>genetic variation and response to treatment in CAD remains an unresolved issue. The results of long-term and properly designed prospective studies hold the promise for pharmacogenetically tailored therapy in CAD.</p

Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction

Background: Unfractionated heparin is often used as adjunctive therapy with fibrinolysis in patients with ST-elevation myocardial infarction. We compared a low-molecular-weight heparin, enoxaparin, with unfractionated heparin for this purpose. Methods: We randomly assigned 20,506 patients with ST-elevation myocardial infarction who were scheduled to undergo fibrinolysis to receive enoxaparin throughout the index hospitalization or weight-based unfractionated heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent myocardial infarction through 30 days. Results: The primary end point occurred in 12.0 percent of patients in the unfractionated heparin group and 9.9 percent of those in the enoxaparin group (17 percent reduction in relative risk, P<0.001). Nonfatal reinfarction occurred in 4.5 percent of the patients receiving unfractionated heparin and 3.0 percent of those receiving enoxaparin (33 percent reduction in relative risk, P<0.001); 7.5 percent of patients given unfractionated heparin died, as did 6.9 percent of those given enoxaparin (P=0.11). The composite of death, nonfatal reinfarction, or urgent revascularization occurred in 14.5 percent of patients given unfractionated heparin and 11.7 percent of those given enoxaparin (P<0.001); major bleeding occurred in 1.4 percent and 2.1 percent, respectively (P<0.001). The composite of death, nonfatal reinfarction, or nonfatal intracranial hemorrhage (a measure of net clinical benefit) occurred in 12.2 percent of patients given unfractionated heparin and 10.1 percent of those given enoxaparin (P<0.001). Conclusions: In patients receiving fibrinolysis for ST-elevation myocardial infarction, treatment with enoxaparin throughout the index hospitalization is superior to treatment with unfractionated heparin for 48 hours but is associated with an increase in major bleeding episodes. These findings should be interpreted in the context of net clinical benefit

Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Dalla progettazione all’utilizzo di un sistema informativo geologico al servizio del rilevamento geologico: la banca dati della Regione Lombardia e la cartografia geologica derivata

In questa Tesi è descritto il processo di creazione di un Sistema Informativo Geologico e degli strumenti informatici per la gestione dell’informazione su base geografica, o più semplicemente GIS (Geographic Information System), al servizio delle attività di rilevamento geologico, finalizzato alla raccolta dei dati ed alla loro rappresentazione cartografica nell'ambito di un Sistema Informativo Territoriale (SIT). Un SIT è definibile come l'insieme di uomini, strumenti e procedure che, nell’ambito di una organizzazione, permettono l’acquisizione e la distribuzione dei dati relativi alla conoscenza dei fenomeni e degli attori presenti su territorio; tutto questo è facilitato in gran parte dalle capacità e funzionalità dei GIS. Il Sistema Informativo Territoriale orientato alla Geologia (SIG – Sistema Informativo Geologico) della Regione Lombardia è costituito da un gruppo di lavoro composto da geologi, informatici e geologi-informatici dell’Ente regionale e della società Lombardia Servizi (Gruppo Lombardia Informatica). Ho fatto parte del team di consulenza tecnico-scientifica incaricato da Lombardia Servizi per la realizzazione del SIG regionale. I compiti del gruppo di lavoro sono: - definizione di ruoli e metodi per la costituzione del SIG; - definizione delle logiche per la creazione di strumenti finalizzati all’archiviazione del dato geologico in una banca dati geologica e loro manutenzione; Il progetto è inserito nel più ampio processo di aggiornamento della Cartografia Geologica nazionale (progetto CARG). Il SIG ha come principali obiettivi: - la pianificazione ed esecuzione del rilevamento geologico di dettaglio (scala 1:10.000) del territorio lombardo; - la costruzione di un database della geologia di superficie (ma anche del sottosuolo per le aree di pianura) interrogabile e aggiornabile ; - il supporto ai processi di analisi finalizzati alla descrizione della geologia superficiale e ricostruzione degli eventi che hanno creato il paesaggio attuale; - la rappresentazione cartografica dell’ambiente geologico a partire dal database creato. - la distribuzione dell’informazione geologica archiviata in vari formati (cartaceo e digitale); Sono qui descritte ed analizzate criticamente la filosofia di costruzione delle procedure e le soluzioni tecniche e metodologiche adottate per realizzare gli obiettivi prefissi. L’APAT (Agenzia per la Protezione dell'Ambiente e per i servizi Tecnici nazionali) ha ereditato dal Servizio Geologico il compito di rilevare, aggiornare e pubblicare la Carta Geologica d'Italia (progetto nazionale CARG) quale organo cartografico dello Stato in base alla legge 68/60. Nel 1976 era stato completato il rilevamento della Carta geologica d'Italia alla scala 1:100.000 costituita da 278 fogli a copertura del territorio nazionale; per il suo aggiornamento sono stati definiti strumenti normativi idonei a garantire l'omogeneità dei contenuti e della rappresentazione cartografica; la definizione delle norme discende dall'applicazione di linee guida, frutto dell'attività di Commissioni e Gruppi di lavoro, pubblicate nei Quaderni della serie III (ed. APAT). L’Ente Regione Lombardia, per rispondere all’impegno istituzionale di aggiornamento della Carta Geologica, all’interno del più ampio e strutturato Sistema Informativo Territoriale regionale, ha dunque creato il Sistema Informativo Geologico (SIG) regionale. Il rapido evolversi delle ricerche nel campo delle Scienze della Terra e l'importanza che riveste la cartografia geologica nella gestione del territorio, hanno spinto la Regione Lombardia a progettare un rilevamento geologico di dettaglio per dotarsi di una banca dati geologica dalla quale derivare la propria cartografia geologica (alla scala 1:10.000). Sono stati quindi definiti standard specifici rispondenti a questa esigenza di maggior dettaglio (rispetto a quanto indicato dal progetto nazionale CARG) ed è stato pianificato e in gran parte realizzato un rilevamento ex-novo finalizzato alla pubblicazione del dato alla scala del rilevamento e per la sua generalizzazione alle scale 1:25.000 e 50.000. Alla fine del processo saranno stati realizzati 14 fogli del territorio lombardo relativamente alle aree alpine e di passaggio alla pianura (Bergamo, Bormio, Breno, Clusone, Lecco, Iseo, Malonno, Ponte di Legno, Sondrio, Vimercate, Milano, Bagolino, Seregno, Voghera). In tale progetto sono anche coinvolti le Università di Milano, di Pavia e di Bolona, il Politecnico di Milano e il CNR - Centro di Studio per la Geodinamica Alpina e Quaternaria di Milano. L’attività di rilevamento geologico è di competenza dei funzionari regionali della Struttura Sistema Informativo Territoriale della Direzione Generale Territorio e Urbanistica che, coadiuvati da geologi rilevatori, realizzano tutte le fasi del lavoro, dalla raccolta del dato fino alla sua pubblicazione. L’ambiente informatico GIS sviluppato, denominato CARGeo (Cartografia Geologica), permette di inserire i dati raccolti da geologi rilevatori in un database appositamente predisposto, mediante interfacce grafiche semplificate e procedure standard di archiviazione e controllo di correttezza formale. La banca dati è costruita in modo da facilitare l’archiviazione della maggior parte dei dati che normalmente il geologo registra nella carta e nei taccuini di terreno e, allo stesso tempo, guidarlo nella raccolta organica dell’informazione geologica. Nella strutturazione del database è stata privilegiata la possibilità di inserire attributi direttamente associabili agli elementi geometrici anziché attraverso schede associate a punti di osservazione. Il geologo rilevatore interviene per correggere errori di digitalizzazione o di attribuzione con un processo ciclico, fino ad ottenere una banca dati corretta secondo gli standard predefiniti. Gli strumenti di creazione della banca dati permettono anche di: - disegnare gli schemi accessori (sezioni geologiche, schemi stratigrafici e strutturali etc.); - eseguire lo “sfoltimento” e posizionamento delle annotazioni sulla mappa (sigle di unità litologiche e parametri di inclinazione delle giaciture) secondo criteri di leggibilità della carta - creare le legende; - creare banche dati a scala inferiore (1:25.000 e 50.000); - stampare e pubblicare carte geologiche complete di schemi e legende. Il sistema contiene gli strumenti necessari alla migrazione della banca dati dalla struttura proprietaria CARG-Regione Lombardia a quella CARG-APAT secondo la struttura definita nei Quaderni della serie III Il Sistema nel corso del biennio 2006-2007 ha raggiunto la fase di consegna dei dati (derivazione e generalizzazione della banca dati CARG-APAT 1.50.000 da quella 1:10.000 CARG-Regione Lombardia) dei primi fogli completati (ISEO, MALONNO, LECCO e SONDRIO) con ritardo rispetto alla programmazione. Sono state analizzate le cause che hanno portato a questo rallentamento del flusso di lavoro, quindi apportate le necessarie modifiche al Sistema. Sono qui descritti i problemi e le soluzioni trovate per migliorare l'efficienza del sistema. Attualmente il Sistema Informativo Geologico è in una fase di ristrutturazione, che vede la migrazione verso un’architettura informatica basata sulla piattaforma ARCGis® 9.x. Attraverso il Sistema Informativo Geologico viene tentata una sintesi fra le logiche metodologiche dei due ambiti tecnico-scientifici coinvolti (Geologia e Informatica), in un ambiente dove ricercatori e tecnici lavorano sperimentando l’interazione tra le conoscenze e le metodologie conoscitive tipiche delle Scienze Geologiche e le tecnologie e processi logici delle Scienze Informatiche. Con questa Tesi è documentato tutto il percorso di costruzione della banca dati geologica attraverso e all’interno del sistema realizzato assieme gruppo di lavoro composto da geologi e tecnici informatici, cui ho partecipato, riassumendo gli oltre 9 anni di lavoro dall’ideazione del progetto CARGeo, anche in funzione del suo miglioramento