Cascading nonlinearities in an organic single crystal core fiber: The Cerenkov regime

The large nonlinear phase shifts imparted to the fundamental beam during Cerenkov second harmonic generation (SHG) in a DAN, 4-(N,N-dimethylamino)-3-acetamidonitrobenzene, single crystal core fiber are explained and modelled numerically. Cascading upconversion and downconversion processes leads to nonlinear phase shifts produced by the second order nonlinear coupling of the guided fundamental mode and the component of the Cerenkov second harmonic field trapped in the fiber cladding

pH-triggered pore-forming peptides with strong composition-dependent membrane selectivity

Peptides that self-assemble into nanometer-sized pores in lipid bilayers could have utility in a variety of biotechnological and clinical applications if we can understand their physical chemical properties and learn to control their membrane selectivity. To empower such control, we have used synthetic molecular evolution to identify the pH-dependent delivery peptides, a family of peptides that assemble into macromolecule-sized pores in membranes at low peptide concentration but only at pH < ∼6. Further advancements will also require better selectivity for specific membranes. Here, we determine the effect of anionic headgroups and bilayer thickness on the mechanism of action of the pH-dependent delivery peptides by measuring binding, secondary structure, and macromolecular poration. The peptide pHD15 partitions and folds equally well into zwitterionic and anionic membranes but is less potent at pore formation in phosphatidylserine-containing membranes. The peptide also binds and folds similarly in membranes of various thicknesses, but its ability to release macromolecules changes dramatically. It causes potent macromolecular poration in vesicles made from phosphatidylcholine with 14 carbon acyl chains, but macromolecular poration decreases sharply with increasing bilayer thickness and does not occur at any peptide concentration in fluid bilayers made from phosphatidylcholine lipids with 20-carbon acyl chains. The effects of headgroup and bilayer thickness on macromolecular poration cannot be accounted for by the amount of peptide bound but instead reflect an inherent selectivity of the peptide for inserting into the membrane-spanning pore state. Molecular dynamics simulations suggest that the effect of thickness is due to hydrophobic match/mismatch between the membrane-spanning peptide and the bilayer hydrocarbon. This remarkable degree of selectivity based on headgroup and especially bilayer thickness is unusual and suggests ways that pore-forming peptides with exquisite selectivity for specific membranes can be designed or evolved

Two sides to every story: the HIF-dependent and HIF-independent functions of pVHL

Abstractvon Hippel–Lindau (VHL) disease is a hereditary cancer syndrome caused by inherited mutations that inactivate the VHL tumour suppressor gene. The VHL locus encodes pVHL, whose best studied function is to bind to and down-regulate the hypoxia-inducible factor (HIF) family of oxygen-dependent transcription factors. Early efforts have established the fundamental role of HIF in VHL-defective tumorigenesis and in particular renal cell carcinoma. However, recent findings have revealed an alternate side to the story, the HIF-independenttumour suppressor functions of pVHL. These include pVHL's ability to regulate apoptosis and senescence as well as its role in the maintenance of primary cilium and orchestrating the deposition of the extracellular matrix. To what extent these HIF-dependent and HIF-independent functions cooperate in VHL-defective tumorigenesis remains to be determined

Systemic Metabolomic Changes in Blood Samples of Lung Cancer Patients Identified by Gas Chromatography Time-of-Flight Mass Spectrometry.

Lung cancer is a leading cause of cancer deaths worldwide. Metabolic alterations in tumor cells coupled with systemic indicators of the host response to tumor development have the potential to yield blood profiles with clinical utility for diagnosis and monitoring of treatment. We report results from two separate studies using gas chromatography time-of-flight mass spectrometry (GC-TOF MS) to profile metabolites in human blood samples that significantly differ from non-small cell lung cancer (NSCLC) adenocarcinoma and other lung cancer cases. Metabolomic analysis of blood samples from the two studies yielded a total of 437 metabolites, of which 148 were identified as known compounds and 289 identified as unknown compounds. Differential analysis identified 15 known metabolites in one study and 18 in a second study that were statistically different (p-values &lt;0.05). Levels of maltose, palmitic acid, glycerol, ethanolamine, glutamic acid, and lactic acid were increased in cancer samples while amino acids tryptophan, lysine and histidine decreased. Many of the metabolites were found to be significantly different in both studies, suggesting that metabolomics appears to be robust enough to find systemic changes from lung cancer, thus showing the potential of this type of analysis for lung cancer detection

Intrinsic Genomic Differences Between African American and White Patients With Clear Cell Renal Cell Carcinoma

There are well-documented racial disparities in outcomes for African American patients with clear cell renal cell carcinoma (ccRCC). Despite a dramatic improvement in overall survival in white patients since the advent of targeted therapy, survival for African Americans with advanced ccRCC has not changed. There is little known about potential racial differences in tumor biology of ccRCC

The next steps in next-gen sequencing of cancer genomes

The necessary infrastructure to carry out genomics-driven oncology is now widely available and has resulted in the exponential increase in characterized cancer genomes. While a subset of genomic alterations is clinically actionable, the majority of somatic events remain classified as variants of unknown significance and will require functional characterization. A careful cataloging of the genomic alterations and their response to therapeutic intervention should allow the compilation of an “actionability atlas” and the creation of a genomic taxonomy stratified by tumor type and oncogenic pathway activation. The next phase of genomic medicine will therefore require talented bioinformaticians, genomic navigators, and multidisciplinary approaches to decode complex cancer genomes and guide potential therapy. Equally important will be the ethical and interpretable return of results to practicing oncologists. Finally, the integration of genomics into clinical trials is likely to speed the development of predictive biomarkers of response to targeted therapy as well as define pathways to acquired resistance

The Regulation of INK4/ARF in Cancer and Aging

Loss of the // locus on chromosome 9p21 is among the most frequent cytogenetic events in human cancer. The products of the locus—p15, p16, and ARF—play widespread and independent roles in tumor suppression. Recent data also suggest that expression of p16 induces an age-dependent decrease in the proliferative capacity of certain tissue-specific stem cells and unipotent progenitors. Here, we discuss the regulation and role of p16, ARF, and p15 in cancer and aging