Freund's vaccine adjuvant promotes Her2/Neu breast cancer

<p>Abstract</p> <p>Background</p> <p>Inflammation has been linked to the etiology of many organ-specific cancers. Indirect evidence suggests a possible role for inflammation in breast cancer. We investigated whether the systemic inflammation induced by Freund's adjuvant (FA) promotes mammary carcinogenesis in a rat model in which cancer is induced by the <it>neu </it>oncogene.</p> <p>Methods</p> <p>The effects of FA on hyperplastic mammary lesions and mammary carcinomas were determined in a <it>neu</it>-induced rat model. The inflammatory response to FA treatment was gauged by measuring acute phase serum haptoglobin. In addition, changes in cell proliferation and apoptosis following FA treatment were assessed.</p> <p>Results</p> <p>Rats receiving FA developed twice the number of mammary carcinomas as controls. Systemic inflammation following FA treatment is chronic, as shown by a doubling of the levels of the serum biomarker, haptoglobin, 15 days following initial treatment. We also show that this systemic inflammation is associated with the increased growth of hyperplastic mammary lesions. This increased growth results from a higher rate of cellular proliferation in the absence of changes in apoptosis.</p> <p>Conclusion</p> <p>Our data suggests that systemic inflammation induced by Freund's adjuvant (FA) promotes mammary carcinogenesis. It will be important to determine whether adjuvants currently used in human vaccines also promote breast cancer.</p

Systematic generation of in vivo G protein-coupled receptor mutants in the rat

G-protein-coupled receptors (GPCRs) constitute a large family of cell surface receptors that are involved in a wide range of physiological and pathological processes, and are targets for many therapeutic interventions. However, genetic models in the rat, one of the most widely used model organisms in physiological and pharmacological research, are largely lacking. Here, we applied N-ethyl-N-nitrosourea (ENU)-driven target-selected mutagenesis to generate an in vivo GPCR mutant collection in the rat. A pre-selected panel of 250 human GPCR homologs was screened for mutations in 813 rats, resulting in the identification of 131 non-synonymous mutations. From these, seven novel potential rat gene knockouts were established as well as 45 lines carrying missense mutations in various genes associated with or involved in human diseases. We provide extensive in silico modeling results of the missense mutations and show experimental data, suggesting loss-of-function phenotypes for several models, including Mc4r and Lpar1. Taken together, the approach used resulted not only in a set of novel gene knockouts, but also in allelic series of more subtle amino acid variants, similar as commonly observed in human disease. The mutants presented here may greatly benefit studies to understand specific GPCR function and support the development of novel therapeutic strategies

The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives

Pietro Gareri,1 Alberto Castagna,1 Antonino Maria Cotroneo,2 Salvatore Putignano,3 Giovambattista De Sarro,4 Amalia Cecilia Bruni11Centro Regionale di Neurogenetica, ASP Catanzaro, Lamezia Terme, Catanzaro, 2ASL2 Turin, Turin, 3Elderly&nbsp;Assistance Unit, Naples, 4Department of Health Sciences, School of Medicine, University Magna Gr&aelig;cia of&nbsp;Catanzaro, Catanzaro, ItalyBackground: Citicoline is able to potentiate neuroplasticity and is a natural precursor of phospholipid synthesis, or rather serves as a choline source in the metabolic pathways for biosynthesis of acetylcholine. Several studies have shown that it can have beneficial effects both in degenerative and in vascular cognitive decline. The aim of the present study was to review the pharmacokinetics and pharmacodynamics of this drug and its role in cognitive impairment according to the present medical literature.Methods: A MEDLINE&reg; search was made using the following key words: citicoline, pharmacokinetics, pharmacodynamics, elderly, cognitive impairment, vascular dementia, and Alzheimer&rsquo;s disease. Recent studies on the possible role of citicoline in increasing sirtuin 1 (SIRT1) expression were assessed. Some personal studies were also considered, such as the VITA study and the IDEALE study.Results: Administered by both oral and intravenous routes, citicoline is converted into two major circulating metabolites, cytidine and choline. It is metabolized in the gut wall and liver. Pharmacokinetic studies suggested that it is well absorbed and highly bioavailable with oral dosing. A number of studies have clearly shown the possible role of citicoline in cognitive impairment of diverse etiology. It can also modulate the activity/expression of some protein kinases involved in neuronal death and increases SIRT1 expression in the central nervous system. The VITA study and the IDEALE study suggested that both parenteral and oral citicoline are effective and safe. Other studies have clearly demonstrated citicoline&rsquo;s effects on several cognitive domains. Conversely, some studies did not point out any evidence of efficacy of this drug.Conclusion: Citicoline appears to be a promising agent to improve cognitive impairment, especially of vascular origin. In fact, so far it appears as a drug with the ability to promote &ldquo;safe&rdquo; neuroprotection, capable of enhancing endogenous protective. Large clinical trials are needed to confirm its benefits.Keywords: citicoline, cognitive impairment, elderly, neurodegeneration, neuroprotective effects, sirtuinsCorrigendum for this paper has been publishe

Relationship between 25-hydroxy vitamin D and cognitive status in older adults: the COGNIDAGE study [Livelli di 25(OH)D e performance cognitive in una popolazione di anziani: Lo studio COGNIDAGE]

AIM: The aim of the COGNIDAGE study was to examine the association between 25(OH)D and cognitive status in a group of elderly patients with vitamin D deficiency and high burden of comorbidities attending Geriatric Outpatient Clinics. MATERIALS AND METHODS: We studied the relationship between 25(OH)D and cognitive functions taking into account comorbidities and cognitive functions assessed by MMSE (Mini Mental State Examination), CDT (Clock Drawing Test) and CIRS (Cumulative Illness Rating Scale), in 132 consecutive elderly patients with low levels of 25(OH)D (&lt;10 ng/ml) compatible with the condition of vitamin deficiency. The association among 25(OH)D levels, MMSE score, CDT score and CIRS scores were analyzed using Pearson correlation. All the elderly patients received an adequate vitamin D supplementation and were reassessed after 6 months. RESULTS: At baseline, mean MMSE and CIRS scores were: 21.8+5.56 and 2.96 +1.63 respectively. Mean CDT score was 3,66+-2.05. No associations were found between 25(OH)D levels and global cognitive function. A significant relationship was observed between the total CIRS score and 25(OH)D levels (r=0.305; p=0.000) as well as between total CIRS score and MMSE (r=-0.375; p=0.000). After 6 months, 83.9 % had 25(OH)D levels &gt;20 ng/ml. Mean MMSE and CDT scores were 22.20+-5.76 and 3.90+-2.06 respectively. There was no significant correlation among 25(OH)D, MMSE and CDT scores while a significant correlation was found between 25(OH)D and CIRS- severity score (r=0.275; p=0.001) and between MMSE and total CIRS scores (r=-0.247; p=0.005 for CIRS-comorbidities; r=-0.184; p=0.04 for CIRS-severity). A post hoc evaluation on two subgroups of elderly patients (the first with vitamin D deficiency without cognitive impairment, the second with vitamin D deficiency and dementia) showed a statistically significant difference (p=0.00001) regarding the CIRS-comorbidities scores. CONCLUSIONS: In our cohort of elderly patients with a high burden of comorbidities, 25(OH)D low levels (&lt;10 ng/ml) are not associated with MMSE and CDT scores. There is no statistically difference among the levels of 25(OH)D and MMSE and CDT scores after 6 months. The strong correlation we found regarding CIRS-comorbidities in the two sub-groups suggests that vitamin D deficiency may play a role in promoting cognitive impairment only with comorbidities

Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study

Antonino Maria Cotroneo,1 Alberto Castagna,2 Salvatore Putignano,3 Roberto Lacava,2 Fausto Fant&ograve;,4 Francesco Monteleone,5 Filomena Rocca,2 Alba Malara,6 Pietro Gareri21ASL 2 Turin, Piedmont, 2Elderly Health Care, Ambulatory Center for Dementia, ASP Catanzaro, Calabria, 3ASL Napoli 1, Campania, 4University Hospital Orbassano, Turin, Piedmont, 5Regina Margherita Hospital, Rome, 6Nursing Home S Domenico Lamezia Terme, ASP Catanzaro, Calabria, ItalyBackground: The studio di intervento nel decadimento vascolare lieve (IDEALE study) was an open multicenter Italian study, the aim of which was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment.Methods: The study was performed in 349 patients. The active or citicoline group was composed of 265 patients and included 122 men and 143 women of mean age 79.9 &plusmn; 7.8 years selected from six Italian regions. Inclusion criteria were age &ge; 65 years, Mini-Mental State Examination (MMSE) score &ge; 21, subjective memory complaints but no evidence of deficits on MMSE, and evidence of vascular lesions on neuroradiology. Those with probable Alzheimer&#39;s disease were excluded. The control group consisted of 84 patients, including 36 men and 48 women of mean age 78.9 &plusmn; 7.01 (range 67&ndash;90) years. Patients included in the study underwent brain computed tomography or magnetic resonance imaging, and plasma dosage of vitamin B12, folate, and thyroid hormones. Functional dependence was investigated by scores on the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales, mood was assessed by the Geriatric Depression Scale (GDS), and behavioral disorders using the Neuropsychiatric Inventory scale. Comorbidity was assessed using the Cumulative Illness Rating Scale. An assessment was made at baseline (T0), after 3 months (T1), and after 9 months (T2, ie, 6 months after T1). The main outcomes were an improvement in MMSE, ADL, and IADL scores in the study group compared with the control group. Side effects were also investigated. The study group was administered oral citicoline 500 mg twice a day throughout the study.Results: MMSE scores remained unchanged over time (22.4 &plusmn; 4 at T0; 22.7 &plusmn; 4 at T1; 22.9 &plusmn; 4 at T2), whereas a significant difference was found between the study and control groups, both in T1 and in T2. No differences were found in ADL and IADL scores between the two groups. A slight but not statistically significant difference was found in GDS score between the study and control groups (P = 0.06). No adverse events were recorded.Conclusion: In this study, citicoline was effective and well tolerated in patients with mild vascular cognitive impairment. Citicoline activates biosynthesis of phospholipids in neuronal membranes, increases brain metabolism as well as norepinephrine and dopamine levels in the central nervous system, and has neuroprotective effects during hypoxia and ischemia. Therefore, citicoline may be recommended for patients with mild vascular cognitive impairment.Keywords: citicoline, vascular mild cognitive impairment, elderly, safety, effectivenes

Gadobenate dimeglumine (BOPTA) enhanced MR imaging: patterns of enhancement in normal liver and cirrhosis.

To determine whether gadobenate dimeglumine (BOPTA) will adequately enhance cirrhotic liver parenchyma, and to document the enhancement patterns in cirrhosis, 14 cirrhotic and 20 non-cirrhotic patients were evaluated before and 60-120 minutes after gadolinium-BOPTA. Proof of liver cirrhosis was biopsy (6), surgical resection (3), and clinical follow-up (5). Enhancement effects were compared quantitatively by determining the liver signal-to-noise ratio (SNR) and signal enhancement in both populations. Qualitatively assessment of the liver enhancement was performed and classified as homogeneous or heterogeneous. Quantitative analysis: cirrhotic liver parenchyma presented a higher increase in SNR values, relative to non-cirrhotic liver parenchyma, on postcontrast images. Likewise the signal enhancement of cirrhotic liver parenchyma was superior to non-cirrhotic liver on T1-weighted SE images (P = .02) and in-phase GRE images (P < .001). There was no statistical difference on out-of-phase GRE images. Qualitative analysis: on T1-weighted SE postcontrast images, cirrhotic liver parenchyma showed a homogeneous enhancement in 7 patients and heterogeneous in 7. Whereas on GRE images, cirrhotic parenchyma showed heterogeneous enhancement in 9 patients and homogeneous in 5 patients. The heterogeneous enhancement was due to the presence of hypointense nodules in 7 patients and hyperintense nodules in 2 patients. In conclusion, our study has shown that the hepatobiliary contrast agent Gd-BOPTA is effective in the cirrhotic liver, demonstrating an increased liver enhancement compared with non-cirrhotic patients

Delayed MR imaging of hepatocellular carcinoma enhanced by Gadobenate Dimeglumine (Gd-BOPTA).

The purpose of this study was to determine the efficacy of gadobenate dimeglumine (Gd-BOPTA)-enhanced magnetic resonance (MR) imaging for evaluation of hepatocellular carcinoma HCC. MR images were obtained in 14 patients with 31 HCC nodules as a part of a phase III clinical trial. T1- and T2-weighted images were obtained before and after iv administration of 0.1 mmol/kg of Gd-BOPTA. Two blinded readers evaluated pre- and delayed postcontrast images separately for detection of tumor nodules. Quantitative measurements of signal-to-noise (SNR) and tumor/liver contrast-to-noise (CNR) ratios were also performed. A signal/intensity ratio was calculated. Tumor enhancement was correlated with histologic findings. Consensus agreement of precontrast T1- and T2-weighted images revealed 23/31 HCC nodules in 14 patients; postcontrast T1-weighted images demonstrated 24/31 HCC nodules in the same number of patients. Combining both pre- and postcontrast images, 27/31 lesions were detected. Four patients had four well-differentiated HCC nodules detected only on postcontrast images, while three well-differentiated lesions in two patients were only seen on precontrast images. Quantitative evaluation showed an SNR ratio increase in both liver parenchyma and HCC nodules, as well as a significant increase in the absolute CNR ratio on postcontrast T1-weighted gradient-recalled images (P &lt; 0.05). Well-differentiated HCC lesions showed a greater enhancement than poorly differentiated HCC lesions