Tribute to Federigo Melis

The many scholarly works of the late Professor Federigo Melis are perhaps not as well known in the English speaking world as on the Continent. This special tribute, reflecting the combined skills of three outstanding accounting historians, Dean Emeritus S. Paul Garner, The University of Alabama, Professor Giovanni Padroni, University of Pisa, and Professor Alvaro Martinelli, Appalachian State University, affords students of accounting history an opportunity to become acquainted with the accomplishments of a profound talent. We express our appreciation to the contributors and trust our members will find this feature useful

Radiologic Cerebral Reperfusion at 24 h Predicts Good Clinical Outcome

Cerebral reperfusion and arterial recanalization are radiological features of the effectiveness of thrombolysis in acute ischemic stroke (AIS) patients. Here, an investigation of the prognostic role of early recanalization/reperfusion on clinical outcome was performed. In AIS patients (n = 55), baseline computerized tomography (CT) was performed 64 8 h from symptom onset, whereas CT determination of reperfusion/recanalization was assessed at 24 h. Multiple linear and logistic regression models were used to correlate reperfusion/recanalization with radiological (i.e., hemorrhagic transformation, ischemic core, and penumbra volumes) and clinical outcomes (assessed as National Institutes of Health Stroke Scale [NIHSS] reduction 65 8 points or a NIHSS 64 1 at 24 h and as modified Rankin Scale [mRS] < 2 at 90 days). At 24 h, patients achieving radiological reperfusion were n = 24, while the non-reperfused were n = 31. Among non-reperfused, n = 15 patients were recanalized. Radiological reperfusion vs. recanalization was also confirmed by early increased levels of circulating inflammatory biomarkers (i.e., serum osteopontin). In multivariate analysis, ischemic lesion volume reduction was associated with both recanalization (\u3b2 = 0.265; p = 0.014) and reperfusion (\u3b2 = 0.461; p < 0.001), but only reperfusion was independently associated with final infarct volume (\u3b2 = 12 0.333; p = 0.007). Only radiological reperfusion at 24 h predicted good clinical response at day 1 (adjusted OR 16.054 [1.423\u2013181.158]; p = 0.025) and 90-day good functional outcome (adjusted OR 25.801 [1.483\u2013448.840]; p = 0.026). At ROC curve analysis the AUC of reperfusion was 0.777 (p < 0.001) for the good clinical response at 24 h and 0.792 (p < 0.001) for 90-day clinical outcome. Twenty-four-hour radiological reperfusion assessed by CT is associated with good clinical response on day 1 and good functional outcome on day 90 in patients with ischemic stroke

Investigating the Role of Circulating miRNAs as Biomarkers in Colorectal Cancer: An Epidemiological Systematic Review

Colorectal cancer (CRC) is one of the most common cancers worldwide. Primary and secondary preventions are key to reducing the global burden. MicroRNAs (miRNAs) are a group of small non-coding RNA molecules, which seem to have a role either as tumor suppressor genes or oncogenes and to be related to cancer risk factors, such as obesity and inflammation. We conducted a systematic review and meta-analysis to identify circulating miRNAs related to CRC diagnosis that could be selected as biomarkers in a meet-in-the-middle analysis. Forty-four studies were included in the systematic review and nine studies in the meta-analysis. The pooled sensitivity and specificity of miR-21 for CRC diagnosis were 77% (95% CI: 69–84) and 82% (95% CI: 70–90), respectively, with an AUC of 0.86 (95% CI: 0.82–0.88). Several miRNAs were found to be dysregulated, distinguishing patients with CRC from healthy controls. However, little consistency was present across the included studies, making it challenging to identify specific miRNAs, which were consistently validated. Understanding the mechanisms by which miRNAs become biologically embedded in cancer initiation and promotion may help better understand cancer pathways to develop more effective prevention strategies and therapy approaches

An Epidemiological Systematic Review with Meta-Analysis on Biomarker Role of Circulating MicroRNAs in Breast Cancer Incidence

Breast cancer (BC) is a multifactorial disease caused by an interaction between genetic predisposition and environmental exposures. MicroRNAs are a group of small non-coding RNA molecules, which seem to have a role either as tumor suppressor genes or oncogenes and seem to be related to cancer risk factors. We conducted a systematic review and meta-analysis to identify circulating microRNAs related to BC diagnosis, paying special attention to methodological problems in this research field. A meta-analysis was performed for microRNAs analyzed in at least three independent studies where sufficient data to make analysis were presented. Seventy-five studies were included in the systematic review. A meta-analysis was performed for microRNAs analyzed in at least three independent studies where sufficient data to make analysis were presented. Seven studies were included in the MIR21 and MIR155 meta-analysis, while four studies were included in the MIR10b metanalysis. The pooled sensitivity and specificity of MIR21 for BC diagnosis were 0.86 (95%CI 0.76-0.93) and 0.84 (95%CI 0.71-0.92), 0.83 (95%CI 0.72-0.91) and 0.90 (95%CI 0.69-0.97) for MIR155, and 0.56 (95%CI 0.32-0.71) and 0.95 (95%CI 0.88-0.98) for MIR10b, respectively. Several other microRNAs were found to be dysregulated, distinguishing BC patients from healthy controls. However, there was little consistency between included studies, making it difficult to identify specific microRNAs useful for diagnosis

Structural and kinetic profiling of allosteric modulation of duplex DNA induced by DNA-binding polyamide analogues

A combined structural and quantitative biophysical profile of the DNA binding affinity, kinetics and sequence-selectivity of hairpin polyamide analogues is described. DNA duplexes containing either target polyamide binding sites or mismatch sequences are immobilized on a microelectrode surface. Quantitation of the DNA binding profile of polyamides containing N-terminal 1-alkylimidazole (Im) units exhibit picomolar binding affinities for their target sequences, whereas 5-alkylthiazole (Nt) units are an order of magnitude lower (low nanomolar). Comparative NMR structural analyses of the polyamide series shows that the steric bulk distal to the DNA-binding face of the hairpin iPr-Nt polyamide plays an influential role in the allosteric modulation of the overall DNA duplex structure. This combined kinetic and structural study provides a foundation to develop next-generation hairpin designs where the DNA-binding profile of polyamides is reconciled with their physicochemical properties

Investigation of a minor groove-binding polyamide targeted to E2F1 transcription factor in chronic myeloid leukaemia (CML) cells

No abstract available

Cerebral blood volume ASPECTS is the best predictor of clinical outcome in acute ischemic stroke: A retrospective, combined semi-quantitative and quantitative assessment

INTRODUCTION:The capability of CT perfusion (CTP) Alberta Stroke Program Early CT Score (ASPECTS) to predict outcome and identify ischemia severity in acute ischemic stroke (AIS) patients is still questioned. METHODS:62 patients with AIS were imaged within 8 hours of symptom onset by non-contrast CT, CT angiography and CTP scans at admission and 24 hours. CTP ASPECTS was calculated on the affected hemisphere using cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) maps by subtracting 1 point for any abnormalities visually detected or measured within multiple cortical circular regions of interest according to previously established thresholds. MTT-CBV ASPECTS was considered as CTP ASPECTS mismatch. Hemorrhagic transformation (HT), recanalization status and reperfusion grade at 24 hours, final infarct volume at 7 days and modified Rankin scale (mRS) at 3 months after onset were recorded. RESULTS:Semi-quantitative and quantitative CTP ASPECTS were highly correlated (p<0.00001). CBF, CBV and MTT ASPECTS were higher in patients with no HT and mRS ≤ 2 and inversely associated with final infarct volume and mRS (p values: from p<0.05 to p<0.00001). CTP ASPECTS mismatch was slightly associated with radiological and clinical outcomes (p values: from p<0.05 to p<0.02) only if evaluated quantitatively. A CBV ASPECTS of 9 was the optimal semi-quantitative value for predicting outcome. CONCLUSIONS:Our findings suggest that visual inspection of CTP ASPECTS recognizes infarct and ischemic absolute values. Semi-quantitative CBV ASPECTS, but not CTP ASPECTS mismatch, represents a strong prognostic indicator, implying that core extent is the main determinant of outcome, irrespective of penumbra size

Sequence-selective minor groove recognition of a DNA duplex containing synthetic genetic components

The structural basis of minor groove recognition of a DNA duplex containing synthetic genetic information by hairpin pyrrole-imidazole polyamides is described. Hairpin polyamides induce a higher melting stabilization of a DNA duplex containing the unnatural P·Z base-pair when an imidazole unit is aligned with a P nucleotide. An NMR structural study showed that the incorporation of two isolated P·Z pairs enlarges the minor groove and slightly narrows the major groove at the site of this synthetic genetic information, relative to a DNA duplex consisting entirely of Watson-Crick base-pairs. Pyrrole-imidazole polyamides bind to a P·Z-containing DNA duplex to form a stable complex, effectively mimicking a G·C pair. A structural hallmark of minor groove recognition of a P·Z pair by a polyamide is the reduced level of allosteric distortion induced by binding of a polyamide to a DNA duplex. Understanding the molecular determinants that influence minor groove recognition of DNA containing synthetic genetic components provides the basis to further develop unnatural base-pairs for synthetic biology applications

An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells

Tyrosine kinase inhibitor (TKI) therapy is the standard treatment for chronic phase (CP)-chronic myeloid leukemia (CML), yet patients in blast crisis (BC) phase of CML are unlikely to respond to TKI therapy. The transcription factor E2F1 is a down-stream target of the tyrosine kinase BCR-ABL1 and is up-regulated in TKI-resistant leukemia stem cells (LSC). Pyrrole imidazole polyamides (PA) are minor groove binders which can be programmed to target DNA sequences in a gene-selective manner. This manuscript describes such an approach with a PA designed to down-regulate E2F1 controlled gene expression by targeting a DNA sequence within 100 base pairs (bp) upstream of the E2F1 consensus sequence. Human BC-CML KCL22 cells were assessed after treatment with PA, TKI or their combination. Our PA inhibited BC-CML cell expansion based on cell density analysis compared to an untreated control after a 48-hour time-course of PA treatment. However, no evidence of cell cycle arrest was observed among BC-CML cells treated with PA, with respect to their no drug control counterparts. Thus, this work demonstrates that PAs are effective in inhibiting E2F1 TF activity which results in a temporal reduction in BC-CML cell number. We envisage that PAs could be used in the future to map genes under E2F1 control in CML LSCs