Pancreatic Cancer Invasion of the Lymphatic Vasculature and Contributions of the Tumor Microenvironment: Roles for E-selectin and CXCR4

As the fourth leading cause of cancer-related deaths, pancreatic cancer is one of the most lethal forms of cancers in the United States. Lymphatic vessel invasion and subsequent metastasis to the lymph nodes are early and significant events observed during pancreatic cancer progression and are used to determine patient prognosis and therapy selection. Although clinicians and researchers recognize the importance of lymph node involvement for patient prognosis and therapy selection, the biological mechanisms that govern lymphatic invasion and metastasis and the contributions of the pancreatic tumor microenvironment to these processes remain poorly understood. In this dissertation, we characterize the interactions of lymphatic endothelial cells with pancreatic tumor cells and pancreatic fibroblasts, showing that while both cell types accelerate lymphangiogenesis, pancreatic fibroblasts are the major recruiters of lymphatic endothelial cells. Additionally, we evaluated pancreatic tumor cell invasion of lymphatics and demonstrated that adhesion protein E-selectin regulates pancreatic tumor adhesion to and transendothelial migration across a lymphatic endothelium. Blockade of E-selectin using a novel glycomimetic inhibitor, GMI-1271, significantly impaired these processes if pancreatic tumor cells expressed the proper E-selectin ligands. E-selectin blockade in vivo significantly impaired pancreatic tumor metastasis to a number of organs sites including the lymph nodes. This impairment of metastasis through the lymphatic vasculature by GMI-1271 was not due to changes in lymphatic vessel density, but rather tumor cell interactions with the lymphatic endothelium. Chemokine receptor CXCR4 and its ligand CXCL12 have also been implicated in facilitating pancreatic tumor progression and metastasis. Using a novel small molecule inhibitor of both CXCR4 and E-selectin, we demonstrated that CXCR4 blockade significantly impairs pancreatic tumor cell adhesion and transendothelial migration across a lymphatic endothelium independent of tumor cell expression of E-selectin ligands. In vivo blockade of both CXCR4 and E-selectin moderately impaired pancreatic tumor metastasis. However, this inhibition of metastasis through GMI-1359 administration did not prolong animal survival even when administered in combination with chemotherapy and immunotherapy. Examination of pancreatic tumor microenvironment following GMI-1359 treatment revealed significant changes to the cell cellular composition: drastically reduced desmoplasia and lymphatic vascular densities. Further studies are ongoing to evaluate GMI-1359 efficacy in combination with immunotherapy in spontaneous mouse models of pancreatic cancer. Altogether, our data demonstrates that lymphatic biology and function is affected by both pancreatic tumor cells and pancreatic fibroblasts, and that factors expressed by the lymphatic endothelium ((E-selectin and CXCR4) may be targetable for the treatment of pancreatic cancer

Comparison of upper body strength gains between men and women after 10 weeks of resistance training

Resistance training (RT) offers benefits to both men and women. However, the studies about the differences between men and women in response to an RT program are not conclusive and few data are available about upper body strength response. The aim of this study was to compare elbow flexor strength gains in men and women after 10 weeks of RT. Forty-four college-aged men (22.63 +/- 2.34 years) and forty-seven college-aged women (21.62 +/- 2.96 years) participated in the study. The RT program was performed two days a week for 10 weeks. Before and after the training period, peak torque (PT) of the elbow flexors was measured with an isokinetic dynamometer. PT values were higher in men in comparison to women in pre-and post-tests (p 0.05). Effect sizes were 0.57 and 0.56 for men and women, respectively. In conclusion, the present study suggests that men and women have a similar upper body strength response to RT

MicroRNA-200c modulates the expression of MUC4 and MUC16 by directly targeting their coding sequences in human pancreatic cancer.

Transmembrane mucins, MUC4 and MUC16 are associated with tumor progression and metastatic potential in human pancreatic adenocarcinoma. We discovered that miR-200c interacts with specific sequences within the coding sequence of MUC4 and MUC16 mRNAs, and evaluated the regulatory nature of this association. Pancreatic cancer cell lines S2.028 and T3M-4 transfected with miR-200c showed a 4.18 and 8.50 fold down regulation of MUC4 mRNA, and 4.68 and 4.82 fold down regulation of MUC16 mRNA compared to mock-transfected cells, respectively. A significant reduction of glycoprotein expression was also observed. These results indicate that miR-200c overexpression regulates MUC4 and MUC16 mucins in pancreatic cancer cells by directly targeting the mRNA coding sequence of each, resulting in reduced levels of MUC4 and MUC16 mRNA and protein. These data suggest that, in addition to regulating proteins that modulate EMT, miR-200c influences expression of cell surface mucins in pancreatic cancer

Imaging the formation of a p-n junction in a suspended carbon nanotube with scanning photocurrent microscopy

We use scanning photocurrent microscopy (SPCM) to investigate individual suspended semiconducting carbon nanotube devices where the potential profile is engineered by means of local gates. In situ tunable p-n junctions can be generated at any position along the nanotube axis. Combining SPCM with transport measurements allows a detailed microscopic study of the evolution of the band profiles as a function of the gates voltage. Here we study the emergence of a p-n and a n-p junctions out of a n-type transistor channel using two local gates. In both cases the I-V curves recorded for gate configurations corresponding to the formation of the p-n or n-p junction in the SPCM measurements reveal a clear transition from resistive to rectification regimes. The rectification curves can be fitted well to the Shockley diode model with a series resistor and reveal a clear ideal diode behavior.Comment: Accepted for publication in Journal or Applied Physics. 4 pages, 3 figure

Education achievement and type 2 diabetes-what mediates the relationship in older adults? Data from the ESTHER study : a population-based cohort study

Peer reviewe

A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.

Defects in USH2A cause both isolated retinal disease and Usher syndrome (ie, retinal disease and deafness). To gain insights into isolated/nonsyndromic USH2A retinopathy, we screened USH2A in 186 probands with recessive retinal disease and no hearing complaint in childhood (discovery cohort) and in 84 probands with recessive retinal disease (replication cohort). Detailed phenotyping, including retinal imaging and audiological assessment, was performed in individuals with two likely disease-causing USH2A variants. Further genetic testing, including screening for a deep-intronic disease-causing variant and large deletions/duplications, was performed in those with one likely disease-causing change. Overall, 23 of 186 probands (discovery cohort) were found to harbour two likely disease-causing variants in USH2A. Some of these variants were predominantly associated with nonsyndromic retinal degeneration ('retinal disease-specific'); these included the common c.2276 G>T, p.(Cys759Phe) mutation and five additional variants: c.2802 T>G, p.(Cys934Trp); c.10073 G>A, p.(Cys3358Tyr); c.11156 G>A, p.(Arg3719His); c.12295-3 T>A; and c.12575 G>A, p.(Arg4192His). An allelic hierarchy was observed in the discovery cohort and confirmed in the replication cohort. In nonsyndromic USH2A disease, retinopathy was consistent with retinitis pigmentosa and the audiological phenotype was variable. USH2A retinopathy is a common cause of nonsyndromic recessive retinal degeneration and has a different mutational spectrum to that observed in Usher syndrome. The following model is proposed: the presence of at least one 'retinal disease-specific' USH2A allele in a patient with USH2A-related disease results in the preservation of normal hearing. Careful genotype-phenotype studies such as this will become increasingly important, especially now that high-throughput sequencing is widely used in the clinical setting.European Journal of Human Genetics advance online publication, 4 February 2015; doi:10.1038/ejhg.2014.283

'Memory Must Be Defended': Beyond the Politics of Mnemonical Security

This article supplements and extends the ontological security theory in International Relations (IR) by conceptualizing the notion of mnemonical security. It engages critically the securitization of memory as a means of making certain historical remembrances secure by delegitimizing or outright criminalizing others. The securitization of historical memory by means of law tends to reproduce a sense of insecurity among the contesters of the ‘memory’ in question. To move beyond the politics of mnemonical security, two lines of action are outlined: (i) the ‘desecuritization’ of social remembrance in order to allow for its repoliticization, and (ii) the rethinking of the self–other relations in mnemonic conflicts. A radically democratic, agonistic politics of memory is called for that would avoid the knee-jerk reactive treatment of identity, memory and history as problems of security. Rather than trying to secure the unsecurable, a genuinely agonistic mnemonic pluralism would enable different interpretations of the past to be questioned, in place of pre-defining national or regional positions on legitimate remembrance in ontological security terms

Expression of Regulatory Platelet MicroRNAs in Patients with Sickle Cell Disease

Background: Increased platelet activation in sickle cell disease (SCD) contributes to a state of hypercoagulability and confers a risk of thromboembolic complications. The role for post-transcriptional regulation of the platelet transcriptome by microRNAs (miRNAs) in SCD has not been previously explored. This is the first study to determine whether platelets from SCD exhibit an altered miRNA expression profile. Methods and Findings: We analyzed the expression of miRNAs isolated from platelets from a primary cohort (SCD = 19, controls = 10) and a validation cohort (SCD = 7, controls = 7) by hybridizing to the Agilent miRNA microarrays. A dramatic difference in miRNA expression profiles between patients and controls was noted in both cohorts separately. A total of 40 differentially expressed platelet miRNAs were identified as common in both cohorts (p-value 0.05, fold change>2) with 24 miRNAs downregulated. Interestingly, 14 of the 24 downregulated miRNAs were members of three families - miR-329, miR-376 and miR-154 - which localized to the epigenetically regulated, maternally imprinted chromosome 14q32 region. We validated the downregulated miRNAs, miR-376a and miR-409-3p, and an upregulated miR-1225-3p using qRT-PCR. Over-expression of the miR-1225-3p in the Meg01 cells was followed by mRNA expression profiling to identify mRNA targets. This resulted in significant transcriptional repression of 1605 transcripts. A combinatorial approach using Meg01 mRNA expression profiles following miR-1225-3p overexpression, a computational prediction analysis of miRNA target sequences and a previously published set of differentially expressed platelet transcripts from SCD patients, identified three novel platelet mRNA targets: PBXIP1, PLAGL2 and PHF20L1. Conclusions: We have identified significant differences in functionally active platelet miRNAs in patients with SCD as compared to controls. These data provide an important inventory of differentially expressed miRNAs in SCD patients and an experimental framework for future studies of miRNAs as regulators of biological pathways in platelets. © 2013 Jain et al

UV Irradiation and Near Infrared Characterization of Laboratory Mars Soil Analog Samples

The search for molecular biosignatures at the surface of Mars is complicated by an intense irradiation in the mid- and near-ultraviolet (UV) spectral range for several reasons: (i) many astrobiologically relevant molecules are electronically excited by efficient absorption of UV radiation and rapidly undergo photochemical reactions; (ii) even though the penetration depth of UV radiation is limited, aeolian erosion continually exposes fresh material to radiation; and (iii) UV irradiation generates strong oxidants such as perchlorates that can penetrate deep into soils and cause subsurface oxidative degradation of organics. As a consequence, it is crucial to investigate the effects of UV radiation on organic molecules embedded in mineral matrices mimicking the martian soil, in order to validate hypotheses about the nature of the organic compounds detected so far at the surface of Mars by the NASA Mars Science Laboratory’s (MSL) Curiosity rover, as well as organics that will be possibly found by the next rover missions Mars 2020 (NASA) and ExoMars 2022 (ESA-Roscosmos). In addition, studying the alteration of possible molecular biosignatures in the martian environment will help to redefine the molecular targets for life detection missions and devise suitable detection methods. Here we report the results of mid- and near-UV irradiation experiments of Mars soil analog samples obtained adsorbing relevant organic molecules on a clay mineral that is quite common on Mars, i.e. montmorillonite, doped with 1 wt% of magnesium perchlorate. Specifically, we chose to investigate the photostability of a plausible precursor of the chlorohydrocarbons detected on Mars by the Curiosity rover, namely phthalic acid, along with the biomarkers of extant life L-phenylalanine and L-glutamic acid, which are proteomic amino acids, and adenosine 5’-monophosphate, which is a nucleic acid component. We monitored the degradation of these molecules adsorbed on montmorillonite through in situ spectroscopic analysis, investigating the reflectance properties of the samples in the Near InfraRed (NIR) spectral region. Such spectroscopic characterization of molecular alteration products provides support for two upcoming robotic missions to Mars that will employ NIR spectroscopy to look for molecular biosignatures, through the instruments SuperCam on board Mars 2020, ISEM, Ma_Miss and MicrOmega on board ExoMars 2022