SAR of a novel 'Anthranilamide Like' series of VEGFR-2, multi protein kinase inhibitors for the treatment of cancer

Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.     

Abilities of the mCP Agar Method and CRENAME Alpha Toxin-Specific Real-Time PCR Assay To Detect Clostridium perfringens Spores in Drinking Water

We first determined the analytical specificity and ubiquity (i.e., the ability to detect all or most strains) of a Clostridium perfringens-specific real-time PCR (rtPCR) assay based on the cpa gene (cpa rtPCR) by using a bacterial strain panel composed of C. perfringens and non-C. perfringens Clostridium strains. All non-C. perfringens Clostridium strains tested negative, whereas all C. perfringens strains tested positive with the cpa rtPCR, for an analytical specificity and ubiquity of 100%. The cpa rtPCR assay was then used to confirm the identity of 116 putative C. perfringens isolates recovered after filtration of water samples and culture on mCP agar. Colonies presenting discordant results between the phenotype on mCP agar and cpa rtPCR were identified by sequencing the 16S rRNA and cpa genes. Four mCP⁻/rtPCR⁺ colonies were identified as C. perfringens, whereas 3 mCP⁺/rtPCR⁻ colonies were identified as non-C. perfringens. The cpa rtPCR was negative with all 51 non-C. perfringens strains and positive with 64 of 65 C. perfringens strains. Finally, we compared mCP agar and a CRENAME (concentration and recovery of microbial particles, extraction of nucleic acids, and molecular enrichment) procedure plus cpa rtPCR (CRENAME + cpa rtPCR) for their abilities to detect C. perfringens spores in drinking water. CRENAME + cpa rtPCR detected as few as one C. perfringens CFU per 100 ml of drinking water sample in less than 5 h, whereas mCP agar took at least 25 h to deliver results. CRENAME + cpa rtPCR also allows the simultaneous and sensitive detection of Escherichia coli and C. perfringens from the same potable water sample. In itself, it could be used to assess the public health risk posed by drinking water potentially contaminated with pathogens more resistant to disinfection.     

Dreaming and unilateral brain lesions: A multiple lesion case analysis.

Lesions causing cessation of dreaming are thought to be more frequently left hemispheric than right hemispheric. However, reports of this phenomenon have not excluded epileptic cases and have not reported handedness, etiology of the lesion, lesion location, comorbidity, gender, age, and so forth, on a case-by-case basis. Some authors were also concerned about aphasia being a cause of dream loss and its lateralization, but they never measured its impact statistically. The present investigation reviews cases of post lesion dream cessation that answered to strict criteria for testing hemispheric lateralization and the effect of aphasia on it. In the 31 subjects, left hemisphere lesions were significantly more frequent than right, as predicted, but the left hemisphere lesions were very often associated with aphasia. Nonaphasic cases of total dream loss had lesions equally often in the right and in the left hemisphere. It is proposed that aphasia deprives patients of a second dream-encoding system, which is important enough to induce amnesia of dream occurrence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interkingdom signaling by structurally related cyanobacterial and algal secondary metabolites

Several groups of structurally-related compounds, comprised of either five or six-membered ring structures with attached lipophilic carbon chains and in some cases possessing halogen atoms, have been isolated from various marine algae and filamentous cyanobacteria. The related compounds considered in the present work include the coibacins, laurenciones, honaucins, malyngamides and the tumonoic acids. Members of all of these compound families were assayed and found to inhibit the production of nitric oxide in lipopolysaccharides-stimulated macrophages, indicating their anti-inflammatory potential. In addition, several of these same marine natural products were found to inhibit quorum sensing mediated phenotypes in Vibrio harveyi BB120 and/or Escherichia coli JB525. The mechanism and evolutionary significance for inhibition of these cellular processes in prokaryotic and eukaryotic systems are speculated on and discussed.     

Toward Clinically Compatible Phase-Contrast Mammography

Phase-contrast mammography using laboratory X-ray sources is a promising approach to overcome the relatively low sensitivity and specificity of clinical, absorption-based screening. Current research is mostly centered on identifying potential diagnostic benefits arising from phase-contrast and dark-field mammography and benchmarking the latter with conventional state-of-the-art imaging methods. So far, little effort has been made to adjust this novel imaging technique to clinical needs. In this article, we address the key points for a successful implementation to a clinical routine in the near future and present the very first dose-compatible and rapid scan-time phase-contrast mammograms of both a freshly dissected, cancer-bearing mastectomy specimen and a mammographic accreditation phantom.     

P1 Ref Endonuclease: A Molecular Mechanism for Phage-Enhanced Antibiotic Lethality

Ref is an HNH superfamily endonuclease that only cleaves DNA to which RecA protein is bound. The enigmatic physiological function of this unusual enzyme is defined here. Lysogenization by bacteriophage P1 renders E. coli more sensitive to the DNA-damaging antibiotic ciprofloxacin, an example of a phenomenon termed phage-antibiotic synergy (PAS). The complementary effect of phage P1 is uniquely traced to the P1-encoded gene ref. Ref is a P1 function that amplifies the lytic cycle under conditions when the bacterial SOS response is induced due to DNA damage. The effect of Ref is multifaceted. DNA binding by Ref interferes with normal DNA metabolism, and the nuclease activity of Ref enhances genome degradation. Ref also inhibits cell division independently of the SOS response. Ref gene expression is toxic to E. coli in the absence of other P1 functions, both alone and in combination with antibiotics. The RecA proteins of human pathogens Neisseria gonorrhoeae and Staphylococcus aureus serve as cofactors for Ref-mediated DNA cleavage. Ref is especially toxic during the bacterial SOS response and the limited growth of stationary phase cultures, targeting aspects of bacterial physiology that are closely associated with the development of bacterial pathogen persistence.     

Expression of soluble Saccharomyces cerevisiae alcohol dehydrogenase in Escherichia coli applicable to oxido-reduction bioconversions

Six-carbon aldehydes and alcohols belong to flavours and fragrances with wide application in the food, feed, cosmetic, chemical and pharmaceutical sectors. In the present study, we prepared the expression system for production of recombinant yeast alcohol dehydrogenase 1 (YADH1) from Saccharomyces cerevisiae which is suitable also for catalysis of the interconversion of C-6 aldehydes and alcohols. We have demonstrated that an effective three-step strategy can overcome the insolubility problems during YADH1 production in Escherichia coli. We used trxB and gor deficient expression strain, decreased concentration of isopropyl β-D-1-thiogalactopyranoside and lowered temperature to 20°C during induction. Finally, kinetic parameters of recombinant YADH1 were determined and we concluded it is a promising enzyme also for the interconversion of C-6 alcohols/aldehydes in green note volatile production.     

Relationship of Circulating Hyaluronic Acid Levels to Disease Control in Asthma and Asthmatic Pregnancy

Uncontrolled asthma is a risk factor for pregnancy-related complications. Hyaluronic acid (HA), a potential peripheral blood marker of tissue fibrosis in various diseases, promotes eosinophil survival and plays a role in asthmatic airway inflammation as well as in physiological processes necessary to maintain normal pregnancy; however the level of circulating HA in asthma and asthmatic pregnancy is unknown. We investigated HA levels in asthmatic patients (N = 52; asthmatic pregnant (AP) N = 16; asthmatic non-pregnant (ANP) N = 36) and tested their relationship to asthma control. Serum HA level was lower in AP than in ANP patients (27 [24.7–31.55] vs. 37.4 [30.1–66.55] ng/mL, p = 0.006); the difference attenuated to a trend after its adjustment for patients’ age (p = 0.056). HA levels and airway resistance were positively (r = 0.467, p = 0.004), HA levels and Asthma Control Test (ACT) total score inversely (r = −0.437, p = 0.01) associated in ANP patients; these relationships remained significant even after their adjustments for age. The potential value of HA in the determination of asthma control was analyzed using ROC analysis which revealed that HA values discriminate patients with ACT total score ≥20 (controlled patients) and <20 (uncontrolled patients) with a 0.826 efficacy (AUC, 95% CI: 0.69–0.97, p = 0.001) when 37.4 ng/mL is used as cut-off value in ANP group, and with 0.78 efficacy (AUC, 95% CI: 0.65–0.92, p = 0.0009) in the whole asthmatic cohort. In conclusion circulating HA might be a marker of asthma control, as it correlates with airway resistance and has good sensitivity in the detection of impaired asthma control. Decrease of HA level in pregnancy may be the consequence of pregnancy induced immune tolerance.