Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901

The mitogenic extracellular kinase 1/2 (MEK1/2) inhibitor, PD0325901, has potent activity in a number of cancer cell types in vitro. In SKMEL-28 human melanoma cells (BRAF mutant), the drug rapidly decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein levels. We investigated if 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography ([(18)F]FLT-PET) could be used to image changes in cell proliferation following MEK1/2 inhibition in vivo. Mice bearing SKMEL-28 and human colon cancer HCT116 (K-RAS mutant) xenografts were treated daily with PD0325901 at 25 mg/kg and imaged by dynamic [(18)F]FLT-PET after 1 and 10 days of initiating treatment. The drug decreased tumor [(18)F]FLT uptake after 1 and 10 days of treatment compared with control animals. The normalized (maximal) [(18)F]FLT uptake in SKMEL-28 xenografts (at 60 minutes; NUV(max)) after 1 day of vehicle or PD0325901 therapy was 1.81 +/- 0.18 versus 1.23 +/- 0.10, respectively (P = 0.03). In this model, NUV(max) after 10 days was 2.07 +/- 0.40 versus 1.08 +/- 0.14, respectively (P = 0.03). The corresponding values for HCT116 tumors were 2.30 +/- 0.84 versus 1.88 +/- 0.36 (P = 0.045) after 1 day, and 1.97 +/- 0.13 versus 1.00 +/- 0.03 (P = 0.03) after 10 days. Similar changes were found for other [(18)F]FLT retention variables. The drug decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein. Tumor [(18)F]FLT-PET variables correlated with proliferation as measured by Ki67 labeling index (r >/= 0.6; P >/= 0.003). In summary, [(18)F]FLT-PET is a sensitive imaging biomarker for detecting the antiproliferative effect of MEK1/2 inhibition by PD0325901. [Mol Cancer Ther 2008;7(9):3112-21].     

Effect of Bauhinia racemosa stem bark on N-nitrosodiethylamine-induced hepatocarcinogenesis in rats

The aim of this study is to investigate the antioxidant defense system induced by the methanol extract of Bauhinia racemosa L.(MEBR) against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in Wister albino rats. The effects of MEBR on surface visible macroscopic (Morphometry) liver lesions (neoplastic nodules) and the levels of serum enzymes, lipid peroxidation and antioxidants were evaluated in NDEA-induced hepatocarcinogenesis in rats. In rats treated, with NDEA, significantly elevated levels of serum enzymes (SGOT, SGPT and ALP), bilirubin and decreased levels of protein and uric acid were observed. Significantly elevated amount of malondialdehyde (MDA), the end product of lipidperoxidation, indicated higher levels of lipid peroxidation, which was accompanied by significantly decreased levels of antioxidants like vitamin C, vitamin E, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). Administration of MEBR was able to suppress nodule development/hepatocellular lesion formation in rats. The extract treatment increases in antioxidant levels and dramatic decreases in lipid peroxidation levels. MEBR also produced a protective effect by decreasing the level of serum enzymes, bilirubin and increased the protein and uric acid levels. The results suggest that MEBR exert chemopreventive effects by suppressing nodule development and decreasing lipid peroxidation and enhancing the levels of antioxidants in NDEA carcinogenesis by reducing the formation of free radicals.     

Antimycobacterial activities of novel 1-(cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro- 6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic acid

Fifty-one 1-(cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic acids were synthesized and evaluated for antimycobacterial in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB), multi-drug-resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesized compounds, 1-tert-butyl-1,4-dihydro-7-(4,4-dimethyloxazolidin-3-yl)-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid (10q) was found to be the most active compound in vitro with an MIC of 0.1 microM against MTB and MDR-TB and was 3 and 455 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model 10q decreased the bacterial load in lung and spleen tissues with 2.39 and 3.89-log10protections respectively at the dose of 50 mg/kg body weight.     

Molecular characterization,isolation, pathology and pathotyping of peafowl (Pavo cristatus) origin Newcastle disease virus isolates recovered from disease outbreaks in three states of India

Disease outbreak investigations were carried out in three states of Northern India namely Haryana (Rewari), Uttar Pradesh (Noida) and Delhi, where a total of 110 Indian peafowls (Pavo cristatus) showed sudden onset of nervous signs and died within a period of two weeks during June, 2012. The F (fusion) gene-based RT-PCR detection of Newcastle disease virus (NDV) in affected tissues confirmed the presence of the virus. Three NDV isolates were selected (one from each area under investigation) and further characterized. They were found to be of virulent pathotype (velogenic NDV) based on both pathogenicity assays (MDT, ICPI and IVPI) and partial F gene sequence analysis. Additionally, the phylogenetic analysis revealed that the isolates belonged to the genotype VIIi and XIII of class II avian Paramyxovirus serotype1 (APMV-1) and related closely to new emerging sub-genotypes. This is the first report regarding the presence of the fifth panzootic vNDV genotype VIIi from India. In this scenario, extensive epidemiological studies are suggested for surveillance of NDV genotypes in wild birds and poultry flocks of the country along with adopting suitable prevention and control measures.     

The Role of Chemical Neurolysis in Cancer Pain

Pain continues to be a significant symptom burden in cancer patients, with prevalence in 53% of patients at all stages of cancer and as high as 58% to 69% in those with advanced cancer. Neurolytic blocks are a mainstay in the armamentarium of cancer pain management, more so in intractable pain from advanced cancer. There is no clear consensus on patient selection, technique, or timing of these blocks. Here we discuss the use of various neurolytic blocks for cancer pain and detail some of the recent literature and our experience.     

Evaluation der COVID-19-Impfung nach breiter Anwendung – ein Zwischenfazit für Deutschland im Juli 2022

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Seit Dezember 2020 stehen in Deutschland Impfstoffe gegen COVID-19 zur Verfügung. Zu den Hauptaufgaben des Fachgebiets...     

Renewed vision on pulmonary rehabilitation service delivery for chronic obstructive pulmonary disease management beyond COVID-19

Pulmonary rehabilitation (PR) is a cornerstone management for chronic obstructive pulmonary disease (COPD). International respiratory societies defined PR is more than “just an exercise program”; it is a comprehensive care delivered by a team of dedicated healthcare professionals with a strong emphasis on long-term health-enhancing Behaviors. However, “Uncertainty” exists with varied reasons for the political and geographical barriers of referral, uptake, attendance, and completion of PR in both primary and secondary care. Besides, COVID-19 pandemic has sparked many global controversies and challenges on pulmonary rehabilitation service delivery. Post-COVID-19 guidelines emphasize on integrated care rehabilitation for patients with COPD. Thus, this concise review intends to understand the gaps in United Kingdom healthcare policies, practices, and PR services resources. To date, there is no clear consensus on PR integrated care model pathway to address the unmet needs, measure the health and social care disparities; adds to the disease burden of COPD. Based on the culmination of evidence, this perspective offers a theoretical framework of PR integrated service model, a pathway to deliver high-value personalized care to patients with COPD.