IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405.

Background: Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.

Methods: Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute-sponsored trial of first-line systemic therapy.

Body Mass Index and Weight Loss in Metastatic Colorectal Cancer in CALGB (Alliance)/SWOG 80405.

Background: In nonmetastatic colorectal cancer, overweight and mild-to-moderately obese patients experience improved outcomes compared with other patients. Obesity's influence on advanced or metastatic colorectal cancer (mCRC) is relatively unexplored.

Methods: We conducted a prospective body mass index (BMI) companion study in Cancer and Leukemia Group B (now Alliance)/SWOG 80405, a phase III metastatic colorectal cancer (mCRC) treatment trial.

Association of Diet Quality With Survival Among People With Metastatic Colorectal Cancer in the Cancer and Leukemia B and Southwest Oncology Group 80405 Trial.

Importance: Diet has been associated with survival in patients with stage I to III colorectal cancer, but data on patients with metastatic colorectal cancer are limited.

Objective: To examine the association between diet quality and overall survival among individuals with metastatic colorectal cancer.

Design, Setting, And Participants: This was a prospective cohort study of patients with metastatic colorectal cancer who were enrolled in the Cancer and Leukemia Group B (Alliance) and Southwest Oncology Group 80405 trial between October 27, 2005, and February 29, 2012, and followed up through January 2018.

Diabetes and Clinical Outcome in Patients With Metastatic Colorectal Cancer: CALGB 80405 (Alliance).

Background: Diabetes is a prognostic factor for some malignancies, but its association with outcome in patients with advanced or metastatic colorectal cancer (CRC) is less clear.

Methods: This cohort study was nested within a randomized trial of first-line chemotherapy and bevacizumab and/or cetuximab for advanced or metastatic CRC. Patients were enrolled at 508 community and academic centers throughout the National Clinical Trials Network.

Associations of Physical Activity With Survival and Progression in Metastatic Colorectal Cancer: Results From Cancer and Leukemia Group B (Alliance)/SWOG 80405.

Purpose: Regular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored.

Patients And Methods: We conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.

PeakForce Tapping resolves individual microvilli on living cells.

Microvilli are a common structure found on epithelial cells that increase the apical surface thus enhancing the transmembrane transport capacity and also serve as one of the cell's mechanosensors. These structures are composed of microfilaments and cytoplasm, covered by plasma membrane. Epithelial cell function is usually coupled to the density of microvilli and its individual size illustrated by diseases, in which microvilli degradation causes malabsorption and diarrhea.

MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice.

Background: Deposition of amyloid-β (Aβ) in blood vessel walls as cerebral amyloid angiopathy (CAA) is observed in the majority of Alzheimer's disease (AD) brains. Inhibition of the 5-lipoxygenase (5-LOX) pathway has recently been suggested to play a role in reducing parenchymal Aβ deposition. However, products of the 5-LOX pathway also activate the peroxisome proliferator-activated receptor (PPAR) family, which promotes clearance of Aβ from the brain.

Small molecule beta-amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer's disease.

Beta-amyloid (Abeta) peptides are thought to play a major role in the pathogenesis of Alzheimer's disease. Compounds that disrupt the kinetic pathways of Abeta aggregation may be useful in elucidating the role of oligomeric, protofibrillar and fibrillar Abeta in the etiology of the disease. We have previously reported that scyllo-inositol inhibits Abeta(42) fibril formation but the mechanism(s) by which this occurs has not been investigated in detail.

Amyloid-beta fibrillogenesis: structural insight and therapeutic intervention.

Structural insight into the conformational changes associated with aggregation and assembly of fibrils has provided a number of targets for therapeutic intervention. Solid-state NMR, hydrogen/deuterium exchange and mutagenesis strategies have been used to probe the secondary and tertiary structure of amyloid fibrils and key intermediates. Rational design of peptide inhibitors directed against key residues important for aggregation and stabilization of fibrils has demonstrated effectiveness at inhibiting fibrillogenesis.

Synthesis of scyllo-inositol derivatives and their effects on amyloid beta peptide aggregation.

scyllo-Inositol has shown promise as a potential therapeutic for Alzheimer's disease, by directly interacting with the amyloid beta (Abeta) peptide to inhibit Abeta42 fiber formation. To explore the molecular details of the inositol-Abeta42 interaction, a series of scyllo-inositol derivatives have been synthesized which contain deoxy, fluoro, chloro, and methoxy substitutions. The effects of these compounds on the aggregation cascade of Abeta42 have been investigated using electron microscopy (EM).

Variations in mass transfer to single endothelial cells.

Mass transfer between flowing blood and arterial mural cells (including vascular endothelial cells) may play an important role in atherogenesis. Endothelial cells are known to have an apical surface topography that is not flat, and hence mass transfer patterns to individual endothelial cells are likely affected by the local cellular topography. The purpose of this paper is to investigate the relationship between vascular endothelial cell surface topography and cellular level mass transfer.

Lsr2 of Mycobacterium tuberculosis is a DNA-bridging protein.

Lsr2 is a small, basic protein present in Mycobacterium and related actinomycetes. Recent studies suggest that Lsr2 is a regulatory protein involved in multiple cellular processes including cell wall biosynthesis and antibiotic resistance. However, the underlying molecular mechanisms remain unknown.

Cationic peptide-induced remodelling of model membranes: direct visualization by in situ atomic force microscopy.

Our understanding of how antimicrobial and cell-penetrating peptides exert their action at cell membranes would benefit greatly from direct visualization of their modes of action and possible targets within the cell membrane. We previously described how the cationic antimicrobial peptide, indolicidin, interacted with mixed zwitterionic planar lipid bilayers as a function of both peptide concentration and lipid composition [Shaw, J.E.

Molecular imaging of membrane interfaces reveals mode of beta-glucosidase activation by saposin C.

Acid beta-glucosidase (GCase) is a soluble lysosomal enzyme responsible for the hydrolysis of glucose from glucosylceramide and requires activation by the small nonenzymatic protein saposin C (sapC) to gain access to the membrane-embedded glycosphingolipid substrate. We have used in situ atomic force microscopy (AFM) with simultaneous confocal and epifluorescence microscopies to investigate the interactions of GCase and sapC with lipid bilayers. GCase binds to sites on membranes transformed by sapC, and enzyme activity occurs at loci containing both GCase and sapC.

Direct visualization of saposin remodelling of lipid bilayers.

Saposins A, B, C and D are soluble, non-enzymatic proteins that interact with lysosomal membranes to activate the breakdown and transfer of glycosphingolipids. The mechanisms of hydrolase activation and lipid transfer by saposins remain unknown. We have used in situ atomic force microscopy (AFM) with simultaneous confocal fluorescence microscopy to investigate the interactions of saposins with lipid membranes.

Tracking peptide-membrane interactions: insights from in situ coupled confocal-atomic force microscopy imaging of NAP-22 peptide insertion and assembly.

Elucidating the role that charged membrane proteins play in determining cell membrane structure and dynamics is an area of active study. We have applied in situ correlated atomic force and confocal microscopies to characterize the interaction of the NAP-22 peptide with model membranes prepared as supported planar bilayers containing both liquid-ordered and liquid-disordered domains. Our results demonstrated that the NAP-22 peptide interacts with membranes in a concentration-dependent manner, preferentially inserting into DOPC (ld) domains.

Mechanisms of antimicrobial peptide action: studies of indolicidin assembly at model membrane interfaces by in situ atomic force microscopy.

We report here on an in situ atomic force microscopy study of the interaction of indolicidin, a tryptophan-rich antimicrobial peptide, with phase-segregated zwitterionic DOPC/DSPC supported planar bilayers. By varying the peptide concentration and bilayer composition through the inclusion of anionic lipids (DOPG or DSPG), we found that indolicidin interacts with these model membranes in one of two concentration-dependent manners. At low peptide concentrations, indolicidin forms an amorphous layer on the fluid domains when these domains contain anionic lipids.

Correlated fluorescence-atomic force microscopy of membrane domains: structure of fluorescence probes determines lipid localization.

Coupling atomic force microscopy (AFM) with high-resolution fluorescence microscopy is an attractive means of identifying membrane domains by both physical topography and fluorescence. We have used this approach to study the ability of a suite of fluorescent molecules to probe domain structures in supported planar bilayers. These included BODIPY-labeled ganglioside, sphingomyelin, and three new cholesterol derivatives, as well as NBD-labeled phosphatidylcholine, sphingomyelin, and cholesterol.

Esophageal cancer: outcomes of surgery, neoadjuvant chemotherapy, and three-dimension conformal radiotherapy.

Neoadjuvant chemotherapy and radiation are being utilized with increasing frequency in the multimodal treatment of esophageal cancer, although their effects on morbidity, mortality, and survival remain unclear. The objective of this study was to determine the outcome of multimodal treatment in patients with localized esophageal cancer treated at a single institution. Between 1995 and 2002, 118 patients underwent treatment for localized esophageal cancer, utilizing surgery alone, chemoradiation alone, or surgery following neoadjuvant chemoradiation.

Simultaneous in situ total internal reflectance fluorescence/atomic force microscopy studies of DPPC/dPOPC microdomains in supported planar lipid bilayers.

In situ simultaneous total internal reflectance fluorescence and in situ scanning probe microscopy performed on a phase-segregated supported planar lipid bilayer enabled direct in situ real-time correlated topographical and fluorescence images of nanometer-sized gel and fluid-phase lipid domains, presaging future in situ studies of membrane protein assemblies by single molecule imaging.