Prostate cancer cell proliferation is strongly reduced by the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in vitro on human cell lines and primary cultures

PURPOSE: To investigate the effects of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) ZD1839 ('Iressa') on the cellular proliferation of androgen-sensitive and androgen-independent human prostatic cancer cell lines and primary cultures in vitro. EXPERIMENTAL DESIGN: In this study, we investigated the effects of the quinazoline ZD1839, a potent, selective EGFR-TKI, on the EGFR autophosphorylation and cellular proliferation of androgen-sensitive (ND1, LNCaP, and ALVA-31) and androgen-independent (PC3, DU145, and TSU-Pr1) human prostatic cancer cell lines and 20 primary cultures derived from human prostatic cancer tissue. RESULTS: EGFR was present and phosphorylated in all cell lines tested. ZD1839 reduced EGFR autophosphorylation in intact cell lines with IC(50)s of 0.46-0.97 microM, and inhibited cellular proliferation with IC(50)s of 0.37-1.03 microM. Constitutive EGFR autophosphorylation was low in primary cell cultures, but addition of EGF (50 ng/ml) caused marked EGFR autophosphorylation; cellular proliferation in the presence of EGF was inhibited by ZD1839 with a mean IC(50) of 0.45 microM. At doses >1 microM, ZD1839 induced apoptosis in both androgen-dependent and androgen-independent PCa cell lines. CONCLUSION. Our experiments suggest that EGFR-TKIs such as ZD1839 may have potential in blocking the growth and progression of human prostatic cancers even in early phases of the disease.     

The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites.

BACKGROUND: The role of nitric oxide (NO) in the pathogenesis of splanchnic arterial vasodilation in cirrhosis has been recently debated by some experimental studies. AIMS: We investigated the role of NO in the pathogenesis of the splanchnic arterial vasodilation along the course of CCl(4)-induced experimental cirrhosis. METHODS: We analyzed the effect on mean arterial pressure (MAP), cardiac output (CO), total peripheral resistance (TPR), and resistance in the superior mesenteric artery (RSMA), before and after the administration of a unspecific NO synthase (NOS) inhibitor (Nomega-nitro-L-arginine-methyl-ester, L-NAME) and a specific NOS2 inhibitor (L-N-(1-iminoethyl)-lysine, L-NIL) to cirrhotic rats with and without ascites, and to control rats. NOS2 and NOS3 protein expression was also assessed in systemic and splanchnic arteries of these animals. RESULTS: L-NAME in cirrhotic rats markedly improved MAP, and TPR and decreased CO regardless of whether they had ascites or not. L-NIL did not produce any significant effect on systemic haemodynamics in control and cirrhotic rats. NOS3 overexpression in the aorta of cirrhotic animals paralleled the progression of the liver disease. L-NAME increased RSMA in cirrhotic rats, but this effect was much less intense in rats with ascites. L-NIL had an effect only on RSMA in rats with ascites, which was of a similar extent to that produced by L-NAME. Western blot experiment showed a faint overexpression of NOS3 in the mesenteric artery of cirrhotic rats with and without ascites and a clear induction of NOS2 only in the mesenteric artery of rats with ascites. Conclusions: These results indicate that NO contributes significantly to the pathogenesis of arterial splanchnic circulation in the early stages of experimental cirrhosis but has only a minor role in its maintenance after the development of ascites. Furthermore, the expression of the different NOS isoforms varies along the course of the liver disease.     

Severe acute hepatitis B in a treatment‐naïve patient with antiviral drug resistant mutations in the polymerase gene

This is a case of 62 years old Caucasian treatment‐naïve patient who developed a severe acute hepatitis B infection soon after a trip to Thailand. The infection was due to genotype C HBV which was found to be resistant to lamivudine and telbivudine. The patient was treated with tenofovir resulting in complete suppression of viral replication and complete clinical and laboratory remission of acute hepatitis. Later the patient also developed seroconversion of HBeAg to anti‐HBe and of HBsAg to anti‐HBs. This case demonstrates that mutations of HBV polymerase associated with lamivudine, telbivudine, and adefovir resistance can be present also in untreated patients with severe acute hepatitis B. This suggests that in the clinical context, which represents a life threatening condition, a baseline resistance‐testing should be an additional marker in the diagnostic evaluation process. Finally, this case report seems to support the use of tenofovir for the immediate treatment of severe acute hepatitis B. J. Med. Virol. 85:210–213, 2013. © 2012 Wiley Periodicals, Inc.     

Neurochemical underpinning of hemodynamic response to neuropsychiatric drugs: A meta- and cluster analysis of preclinical studies

Functional magnetic resonance imaging (fMRI) is an extensively used method for the investigation of normal and pathological brain function. In particular, fMRI has been used to characterize spatiotemporal hemodynamic response to pharmacological challenges as a non-invasive readout of neuronal activity. However, the mechanisms underlying regional signal changes are yet unclear. In this study, we use a meta-analytic approach to converge data from microdialysis experiments with relative cerebral blood volume (rCBV) changes following acute administration of neuropsychiatric drugs in adult male rats. At whole-brain level, the functional response patterns show very weak correlation with neurochemical alterations, while for numerous brain areas a strong positive correlation with noradrenaline release exists. At a local scale of individual brain regions, the rCBV response to neurotransmitters is anatomically heterogeneous and, importantly, based on a complex interplay of different neurotransmitters that often exert opposing effects, thus providing a mechanism for regulating and fine tuning hemodynamic responses in specific regions.     

Inhibition of aquaporin-1 dependent angiogenesis impairs tumour growth in a mouse model of melanoma

Prohibiting angiogenesis is an important therapeutic approach for fighting cancer and other angiogenic related diseases. Research focused on proteins that regulate abnormal angiogenesis has attracted intense interest in both academia and industry. Such proteins are able to target several angiogenic factors concurrently, thereby increasing the possibility of therapeutic success. Aquaporin-1 (AQP1) is a water channel membrane protein that promotes tumour angiogenesis by allowing faster endothelial cell migration. In this study we test the hypothesis that AQP1 inhibition impairs tumour growth in a mouse model of melanoma. After validating the inhibitor efficacy of two different AQP1 specific siRNAs in cell cultures, RNA interference experiments were performed by intratumoural injections of AQP1 siRNAs in mice. After 6 days of treatment, AQP1 siRNA treated tumours showed a 75 % reduction in volume when compared to controls. AQP1 protein level, in AQP1 knockdown tumours, was around 75 % that of the controls and was associated with a significant 40 % reduced expression of the endothelial marker, Factor VIII. Immunofluorescence analysis of AQP1 siRNA treated tumours showed a significantly lower microvessel density. Time course experiments demontrated that repeated injections of AQP1 siRNA over time are effective in sustaining the inhibition of tumour growth. Finally, we have confirmed the role of AQP1 in sustaining an active endothelium during angiogenesis and we have shown that AQP1 reduction causes an increase in VEGF levels. In conclusion, this study validates AQP1 as a pro-angiogenic protein, relevant for the therapy of cancer and other angiogenic-related diseases such as psoriasis, endometriosis, arthritis and atherosclerosis.     

Evolution of endodontic medicine: a critical narrative review of the interrelationship between endodontics and systemic pathological conditions

Odontology - Endodontics has gained emphasis in the scientific community in recent years due to the increase in clinical and in animal models studies focused on endodontic medicine, which aims to...     

Spinal extradural solitary fibrous tumor with retiform and papillary features

We report a 66-year-old man with a spinal, extradural solitary fibrous tumor showing unique retiform and papillary architecture. The patient presented in May 2008 with worsening right-sided lower back pain and urinary frequency. Magnetic resonance imaging of the spine documented a heterogeneously enhancing dumbbell-shaped extradural lesion causing cord compression at T11/12 level. The tumor extended to the paravertebral soft tissue and invaded the right adjacent vertebral pedicles and laminae. An angiogram showed prominent vascular supply mainly from the right T11 radicular artery. The patient underwent surgery to relieve cord compression in May 2008 and a second operation following embolization with coils in October 2009. No recurrence was observed at the last neuroimaging follow-up in June 2012. The tumor was composed of vimentin, CD34, Bcl-2, and CD99-positive rounded or slightly elongated cells with scant cytoplasm and oval to spindle nuclei. Several pseudovascular spaces reminiscent of the rete testis were present, and several of them contained papillary projections. Cytologic atypia was minimal, and mitotic activity was low. Focal infiltration of the paraspinal adipose tissue was seen at microscopic level. To our knowledge, retiform and papillary features have never been reported in a solitary fibrous tumor.     

Educational Impact on Apixaban Adherence in Atrial Fibrillation (the AEGEAN STUDY): A Randomized Clinical Trial

Adherence to non-vitamin-K oral anticoagulants (NOACs) may be lower than to vitamin K antagonists because NOACs do not require routine monitoring. We assessed the impact of an educational program on adherence and persistence with apixaban in patients with non-valvular atrial fibrillation (NVAF). Patients with NVAF eligible for NOACs with one or more stroke risk factor (prior stroke/transient ischemic attack, age ≥ 75 years, hypertension, diabetes, or symptomatic heart failure) were randomized (1:1) to standard of care (SOC) or SOC with additional educational (information booklet, reminder tools, virtual clinic access). The primary outcome was adherence to apixaban (2.5 or 5 mg twice daily) at 24 weeks. Patients receiving the educational program were re-randomized (1:1) to continue the program for 24 further weeks or to switch to secondary SOC. Implementation adherence and persistence were reassessed at 48 weeks. In total, 1162 patients were randomized (SOC, 583; educational program, 579). Mean implementation adherence ± standard deviation (SD) at 24 weeks was 91.6% ± 17.1 for SOC and 91.9% ± 16.1 for the educational program arm; results did not differ significantly between groups at any time-point. At 48 weeks, implementation adherence was 90.4% ± 18.0, 90.1% ± 18.6, and 89.3% ± 18.1 for continued educational program, SOC, and secondary SOC, respectively; and corresponding persistence was 86.1% (95% confidence interval [CI] 81.3–89.7), 85.2% (95% CI 81.5–88.2), and 87.8% (95% CI 83.4–91.1). Serious adverse events were similar across groups. High implementation adherence and persistence with apixaban were observed in patients with NVAF receiving apixaban. The educational program did not show additional benefits. This study is registered at ClinicalTrials.gov [NCT01884350].     

Is Implantation of a Left Ventricular Assist Device in Patients With Critical or Impending Cardiogenic Shock an Absolute Contraindication? Looking Back at Our Past Experience Trying to Identify Contraindicative Risk Factors

Poor survival has been demonstrated after ventricular assist device (VAD) implantation for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 and 2 patients compared with more stable levels. However, risk factors within this high‐risk cohort have not been determined so far. The aim of the present study was to identify risk factors associated with this very high mortality rate. Between February 1993 and January 2013, 298 patients underwent VAD implantation in our institution. One hundred nine patients were in INTERMACS level 1 and 49 patients were in INTERMACS level 2 and were therefore defined as hemodynamically critical (overall 158 patients). Assist devices implanted were: HVAD HeartWare n = 18; Incor n = 11; VentrAssist n = 2; DeBakey n = 22; and pulsatile systems n = 105. After cumulative support duration of 815.35 months, Kaplan–Meier analysis revealed a survival of 63.9, 48.8, and 40.3% at 1, 6, and 12 months, respectively. Cox regression analyses identified age > 50 (P = 0.001, odds ratio [OR] 2.48), white blood cell count > 13.000/μL (P = 0.01, OR 2.06), preoperative renal replacement therapy (P = 0.001, OR 2.63), and postcardiotomy failure (P < 0.001, OR 2.79) as independent predictors of mortality. Of note, last generation VADs were not associated with significantly better 6‐month survival (P = 0.59). Patients without the aforementioned risk factors could yield a survival of 79.2% at 6 months. This single‐center experience shows that VAD implantation in hemodynamically unstable patients generally results in poor early outcome, even in third‐generation pumps. However, avoiding the aforementioned risk factors could result in improved outcome.