Functional EGFR germline polymorphisms may confer risk for EGFR somatic mutations in non-small cell lung cancer, with a predominant effect on exon 19 microdeletions

Somatic mutations in the EGFR tyrosine kinase domain play a critical role in the development and treatment of non-small cell lung cancer (NSCLC). Strong genetic influence on susceptibility to these mutations has been suggested. To identify the genetic factors conferring risk for the EGFR tyrosine kinase mutations in NSCLC, a case-control study was conducted in 141 Taiwanese NSCLC patients by focusing on three functional polymorphisms in the EGFR gene [-216G/T, intron 1 (CA)n, and R497K]. Allelic imbalance of the EGFR -216G/T polymorphism was also tested in the heterozygous patients and in the NCI-60 cancer cell lines to further verify its function. We found that the frequencies of the alleles -216T and CA-19 are significantly higher in the patients with any mutation (P = 0.032 and 0.01, respectively), in particular in those with exon 19 microdeletions (P = 0.006 and 0.033, respectively), but not in the patients with L858R mutation. The -216T allele is favored to be amplified in both tumor DNA of lung cancer patients and cancer cell lines. We conclude that the local haplotype structures across the EGFR gene may favor the development of cellular malignancies and thus significantly confer risk to the occurrence of EGFR mutations in NSCLC, particularly the exon 19 microdeletions.     

Chemoradionuclide therapy with 186re-labeled liposomal doxorubicin: toxicity, dosimetry, and therapeutic response

This study was performed to determine the maximum tolerated dose (MTD) and therapeutic effects of rhenium-186 ((186)Re)-labeled liposomal doxorubicin (Doxil), investigate associated toxicities, and calculate radiation absorbed dose in head and neck tumor xenografts and normal organs. Doxil and control polyethylene glycol (PEG)-liposomes were labeled using (186)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA) method. Tumor-bearing rats received either no therapy (n=6), intravenous Doxil (n=4), or escalating radioactivity of (186)Re-Doxil (185-925?MBq/kg) or (186)Re-PEG-liposomes (1110-1665?MBq/kg) and were monitored for 28 days. Based on body weight loss and systemic toxicity, MTD for (186)Re-Doxil and (186)Re-PEG-liposomes were established at injected radioactivity/body weight of 740 and 1480?MBq/kg, respectively. (186)Re-injected radioactivity/body weight for therapy studies was determined to be 555?MBq/kg for (186)Re-Doxil and 1295?MBq/kg for (186)Re-PEG-liposomes. All groups recovered from their body weight loss, leucopenia, and thrombocytopenia by 28 days postinjection. Normalized radiation absorbed dose to tumor was significantly higher for (186)Re-Doxil (0.299±0.109 Gy/MBq) compared with (186)Re-PEG-liposomes (0.096±0.120 Gy/MBq) (p<0.05). In a separate therapy study, tumor volumes were significantly smaller for (186)Re-Doxil (555?MBq/kg) compared with (186)Re-PEG-liposomes (1295?MBq/kg) (p<0.01) at 42 days postinjection. In conclusion, combination chemoradionuclide therapy with (186)Re-Doxil has promising potential, because good tumor control was achieved with limited associated toxicity.     

Agmatine, a metabolite of L-arginine, reverses scopolamine-induced learning and memory impairment in rats

Agmatine (l-amino-4-guanidino-butane), a metabolite of L-arginine through the action of arginine decarboxylase, is a novel neurotransmitter. In the present study, effects of agmatine on cognitive functions have been evaluated by using one trial step-down passive avoidance and three panel runway task. Agmatine (20, 40, 80 mg/kg i.p.) was administered either in the presence or absence of a cholinergic antagonist, scopolamine (1 mg/kg i.p.). Scopolamine significantly impaired learning and memory in both passive avoidance and three panel runway test. Agmatine did not affect emotional learning, working and reference memory but significantly improved scopolamine-induced impairment of learning and memory in a dose dependent manner. Our results indicate that agmatine, as an endogenous substance, may have an important role in modulation of learning and memory functions.     

Antimicrobial, analgesic, DPPH scavenging activities and molecular docking study of some 1,3,5-triaryl-2-pyrazolines

A series of 1,3,5-triaryl-2-pyrazolines 2a–g were synthesized by the reaction of 4,4′-disubstituted chalcone with phenyl hydrazine. All these compounds were characterized by NMR, IR and mass spectral and single crystal XRD data. All the synthesized products were screened for their in vitro antimicrobial, analgesic and antioxidant properties. The docking studies were carried out for these compounds against the active site of methionyl-tRNA synthetase (metRS). Some of the tested compounds exhibited significant antimicrobial, analgesic, DPPH scavenging activities and molecular binding.     

Studies on radioprotective and antiviral activities of some bischalcone derivatives

This work reports the cyclic voltammetric, modulatory effect on oxidative stress markers against radiation induced oxidative stress in E. coli bacteria and antiviral activities of two bischalcone derivatives (2E,5E)-2,5-bis(3-methoxy-4-hydroxy-benzylidene)-cyclopentanone (B1) and (2E,5E)-2,5-bis(4-fluorobenzylidene)-cyclopentanone (B2). The reducing ability of B1 and B2 was determined by cyclic voltammetry. The anodic peak current i _pa and anodic peak potential Epa of B1 and B2 were ?154.7, ?99?μA, and ?0.15?V, 0.0125?V, respectively. The low anodic current and low anodic peak potential imply the good reducing ability of the molecules. The radioprotective effect of bischalcones was studied by gamma radiation induced oxidative stress in E. coli K12 at 0.2 and 0.4?Gy. The bacteria samples treated with B1 and irradiated showed diminished level of TBARS, an oxidative stress marker. The levels of SOD and CAT antioxidant enzymes were brought to near basal level for B1 treated and irradiated bacteria with respect to the control. The protective effect of the bischalcone derivatives against radiation was further supported by determining colony forming units (CFU) of bacteria in pre- and post-irradiated samples. Further, B2 showed 73.69% of inhibition of buffalopox virus and camelpox virus.     

Zingiber officinale (ginger) as an anti-emetic in cancer chemotherapy: a review

Despite significant advances and development of novel anti-emetics, nausea and vomiting (emesis) is a major side-effect of cancer chemotherapy. At times, severe nausea and vomiting may also lead to reduction in adherence to the treatment regimen, and this will concomitantly affect the patient's survival. The rhizome of Zingiber officinale, commonly known as ginger, is globally an important spice. It has been used for centuries in the Indian, Chinese, Arabic, Tibetan, Unani, and Siddha systems of traditional medicine to treat nausea and vomiting induced by different stimuli. Preclinical studies with experimental animals (dogs and rats) have shown that the various extracts of ginger and the ginger juice possess anti-emetic effects against chemotherapy-induced nausea and vomiting. Gingerol, the active principle, is also shown to possess anti-emetic effects in minks. However, with regard to humans, while most studies have been supportive of the preclinical observations, a few have been contradictory. The exact mechanism responsible for the anti-emetic effects of ginger is unknown; however, the ginger phytochemicals, especially 6-gingerol, 8-gingerol, 10-gingerol, and 6-shogaol, may function as a 5-hydroxytryptamine (5-HT3) antagonist, NK1 antagonist, antihistaminic, and possess prokinetic effects. The present review for the first time attempts to address the anti-emetic observations and the variability in response of the anti-emetic effects of ginger in cancer chemotherapy. An attempt is also made to address the lacunae in the published studies and emphasize aspects that need further investigations for ginger to be of use in clinics as an anti-emetic agent in the future.     

Proton NMR chemical shifts and coupling constants for brain metabolites

Proton NMR chemical shift and J-coupling values are presented for 35 metabolites that can be detected by in vivo or in vitro NMR studies of mammalian brain. Measurements were obtained using high-field NMR spectra of metabolites in solution, under conditions typical for normal physiological temperature and pH. This information is presented with an accuracy that is suitable for computer simulation of metabolite spectra to be used as basis functions of a parametric spectral analysis procedure. This procedure is verified by the analysis of a rat brain extract spectrum, using the measured spectral parameters. In addition, the metabolite structures and example spectra are presented, and clinical applications and MR spectroscopic measurements of these metabolites are reviewed.