Oxidative Molecular Mechanisms Underlying Liver Diseases: From Systems Biology to the Personalized Medicine

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Treatment of squamous cell carcinoma of the anal canal (SCCA): A new era?

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INCREASE OF REPORTS OF SUSPECTED ADVERSE DRUG REACTIONS IN ONCOLOGY

Objective: The information of safety of antineoplastic agents derives solely from clinical studies that have a number of limitations, such as the number of patients enrolled, selected case studies, follow-up of short duration; therefore, it is not possible to identify the complete profile of safety and possible side effects of the drugs under study. ADRs monitoring and reporting programmes aim to identifying and quantifying the risks associated with the use of drugs provided in a hospital setting. The main objectives of this study were to evaluate the ADRs that occurred during hospitalization for chemotherapy in 7 cancer centers, and to facilitate the development of a monitoring system of pharmacovigilance. Methods: An observational study was conducted in 7 cancer centers in the Emilia Romagna region over a period of 2 years, from January 2012 to January 2014. This study was based on an analysis of ADRs reported. Several parameters were utilised in the data evaluation, including drug and reaction characteristics. Results: From January 2012 to January 2014 No. 884 ADRs were included in National Network of pharmacovigilance. The highest ADR rate (57.4%) was found in the adult females with a mean age of 62. The oncology drug most frequently reported were taxanes and platinum derivates. Conclusion: The results obtained will contribute to the development of strategies for the pharmacovigilance service in 7 cancer centers, which will improve the quality of ADR reporting and ensure safer oncology drug use

Linear magnetic resonance imaging measurements of the hippocampal formation differ in young versus old dogs

Age-related hippocampal formation (HF) atrophy has been documented on MRI studies using volumetric analysis and visual rating scales.This retrospective cross-sectional study aimed to compare linear MRI measurements of the HF between young (1–3 years) and old (>10 years) non-brachycephalic dogs, with normal brain anatomy and cerebrospinal fluid (CSF) analysis. Right and left hippocampal formation height (HFH), height of the brain (HB) and mean HFH/HB ratio were measured by two observers on a transverse T2 fluid-attenuated inversion recovery sequence containing rostral colliculi and mesencephalic aqueduct.119 MRI studies were enrolled: 75 young and 44 old dogs. Left and right HFH were greater (p<0.0001) in young, while HB was greater in old dogs (p=0.024). Mean HFH/HB ratio was 15.66 per cent and 18.30 per cent in old and young dogs (p<0.0001). No differences were found comparing measurements between epileptic and non-epileptic dogs.Old dogs have a greater HB; this may represent the different study populations or a statistical phenomenon. Ageing affects HF linear measurements. A reduction of mean HFH/HB ratio between 18.30 per cent and 15.66 per cent should be considered a physiological age-related process of the canine lifespan. The use of mean HFH/HB ratio could be considered for quantifying brain atrophy in elderly dogs

Targeted Enhancer Activation by a Subunit of the Integrator Complex

The control of cell fate is an epigenetic process initiated by transcription factors (TFs) that recognize DNA motifs and recruit activator complexes and transcriptional machineries to chromatin. Lineage specificity is thought to be provided solely by TF-motif pairing, while the recruited activators are passive. Here, we show that INTS13, a subunit of the Integrator complex, operates as monocytic/macrophagic differentiation factor. Integrator is a general activator of transcription at coding genes and is required for eRNA maturation. Here, we show that INTS13 functions as an independent sub-module and targets enhancers through Early Growth Response (EGR1/2) TFs and their co-factor NAB2. INTS13 binds poised monocytic enhancers eliciting chromatin looping and activation. Independent depletion of INTS13, EGR1, or NAB2 impairs monocytic differentiation of cell lines and primary human progenitors. Our data demonstrate that Integrator is not functionally homogeneous and has TF-specific regulatory potential, revealing a new enhancer regulatory axis that controls myeloid differentiation. Barbieri et al. demonstrate that a subunit of the Integrator complex, INTS13, is required for monocytic commitment of myeloid progenitors. INTS13 is a modular component of Integrator recruited to poised enhancers via the EGR1 transcription factor and its co-factor NAB2. The INTS13/EGR1/NAB2 axis is essential to elicit enhancer-mediated gene activation

Chemoradiotherapy (Gemox plus helical tomotherapy) for unresectable locally advanced pancreatic cancer: A phase II study

The aim of the study was to evaluate the safety and efficacy of a new chemo-radiotherapy regimen for patients with locally advanced pancreatic cancer (LAPC). Patients were treated as follows: gemcitabine 1000 mg/m2 on day 1, and oxaliplatin 100 mg/m2 on day 2, every two weeks (GEMOX regimen) for 4 cycles, 15 days off, hypofractionated radiotherapy (35 Gy in 7 fractions in 9 consecutive days), 15 days off, 4 additional cycles of GEMOX, restaging. From April 2011 to August 2016, a total of 42 patients with non resectable LAPC were enrolled. Median age was 67 years (range 41\u201375). Radiotherapy was well tolerated and the most frequently encountered adverse events were mild to moderate nausea and vomiting, abdominal pain and fatigue. In total, 9 patients underwent surgical laparotomy (5 radical pancreatic resection 1 thermoablation and 3 explorative laparotomy), 1 patient became operable but refused surgery. The overall resectability rate was 25%, while the R0 resection rate was 12.5%. At a median follow-up of 50 months, the median progression-free survival and overall survival were 9.3 (95% CI 6.2\u201314.9) and 15.8 (95% CI 8.2\u201323.4) months, respectively. The results demonstrate the feasibility of a new chemo-radiotherapy regimen as a potential treatment for unresectable LAPC

732pgemox plus hypofractionated radiotherapy for unresectable locally advanced pancreatic cancer results from a phase ii study

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Cluster Correlation in Mixed Models

We evaluate the dependence of the cluster correlation length r_c on the mean intercluster separation D_c, for three models with critical matter density, vanishing vacuum energy (Lambda = 0) and COBE normalized: a tilted CDM (tCDM) model (n=0.8) and two blue mixed models with two light massive neutrinos yielding Omega_h = 0.26 and 0.14 (MDM1 and MDM2, respectively). All models approach the observational value of sigma_8 (and, henceforth, the observed cluster abundance) and are consistent with the observed abundance of Damped Lyman_alpha systems. Mixed models have a motivation in recent results of neutrino physics; they also agree with the observed value of the ratio sigma_8/sigma_25, yielding the spectral slope parameter Gamma, and nicely fit LCRS reconstructed spectra. We use parallel AP3M simulations, performed in a wide box (side 360/h Mpc) and with high mass and distance resolution, enabling us to build artificial samples of clusters, whose total number and mass range allow to cover the same D_c interval inspected through APM and Abell cluster clustering data. We find that the tCDM model performs substantially better than n=1 critical density CDM models. Our main finding, however, is that mixed models provide a surprisingly good fit of cluster clustering data.Comment: 22 pages + 10 Postscript figures. Accepted for publication in Ap

Lactate dehydrogenase in hepatocellular carcinoma: something old, something new

Hepatocellular carcinoma (HCC) is the most common primary liver tumour (80-90%) and represents more than 5.7% of all cancers. Although in recent years the therapeutic options for these patients have increased, clinical results are yet unsatisfactory and the prognosis remains dismal. Clinical or molecular criteria allowing a more accurate selection of patients are in fact largely lacking. Lactic dehydrogenase (LDH) is a glycolytic key enzyme in the conversion of pyruvate to lactate under anaerobic conditions. In preclinical models, upregulation of LDH has been suggested to ensure both an efficient anaerobic/glycolytic metabolism and a reduced dependence on oxygen under hypoxic conditions in tumour cells. Data from several analyses on different tumour types seem to suggest that LDH levels may be a significant prognostic factor. The role of LDH in HCC has been investigated by different authors in heterogeneous populations of patients. It has been tested as a potential biomarker in retrospective, small, and nonfocused studies in patients undergoing surgery, transarterial chemoembolization (TACE), and systemic therapy. In the major part of these studies, high LDH serum levels seem to predict a poorer outcome. We have reviewed literature in this setting trying to resume basis for future studies validating the role of LDH in this diseas

Early onset of hypertension and serum electrolyte changes as potential predictive factors of activity in advanced hcc patients treated with sorafenib: results from a retrospective analysis of the HCC-AVR group

Hypertension (HTN) is frequently associated with the use of angiogenesis inhibitors targeting the vascular endothelial growth factor pathway and appears to be a generalized effect of this class of agent. We investigated the phenomenon in 61 patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. Blood pressure and plasma electrolytes were measured on days 1 and 15 of the treatment. Patients with sorafenib-induced HTN had a better outcome than those without HTN (disease control rate: 63.4% vs. 17.2% (p=0.001); progression-free survival 6.0 months (95% CI 3.2-10.1) vs. 2.5 months (95% CI 1.9-2.6) (p<0.001) and overall survival 14.6 months (95% CI9.7-19.0) vs. 3.9 months (95% CI 3.1-8.7) (p=0.003). Sodium levels were generally higher on day 15 than at baseline (+2.38, p<0.0001) in the group of responders (+4.95, p <0.0001) compared to patients who progressed (PD) (+0.28, p=0.607). In contrast, potassium was lower on day 14 (-0.30, p=0.0008) in the responder group (-0.58, p=0.003) than in those with progressive disease (-0.06, p=0.500). The early onset of hypertension is associated with improved clinical outcome in HCC patients treated with sorafenib. Our data are suggestive of an activation of the renin-angiotensin system in patients with advanced disease who developed HTN during sorafenib treatmen