The relationship of phloem graft union responses to pear decline

Since 1948, pear decline has been responsible for the devitalization and death of many pear trees in the Pacific Coast states and British Columbia. Use of anatomical abnormalities of the graft union as a diagnostic technique to separate pear decline from other disorders exhibiting similar symptoms was evaluated. Modifications in technique and seven abnormal graft union responses of the phloem are described. The ability to relate the distinct graft union response of french-oriental scion-rootstock combinations to decline expression makes the technique an effective tool for these combinations. However, the non-distinct union reaction of french-domestic scion-rootstock combinations was difficult to interpret because of the inability to trace previous phloem injury and the slow rate of decline of the trees sampled during the course of this investigation. The distinct graft union responses were non-repetitive and could be followed by an annual increment of phloem which reacted in one of the described categories. This is probably related to the gaps observed in previous increments where no apparent replacement phloem was produced. Occasionally a normal annual increment of phloem could follow a positive reaction in which no replacement phloem was produced. Samples taken mid-August to September 30th were effective in demonstrating the reaction. If replacement phloem formed, initial stimulation of cambial activity occurred in July or August after the original increment had ceased to function at the graft union. The brown line symptom at the graft union was distinct and coincidental to the presence of necrotic phloem. Histological evidence for decline was found in the Hood River area, the Willamette valley and the Rogue River valley. Quick decline was induced one year after initial psylla infestation of two year old Bartlett-P. serotina scion-rootstock combinations. Trees which collapsed in October had shown severe graft union phloem abnormalities in July, while those which had purple and red leaf symptoms in October had less severely injured or normal phloem in July. Feeder root deterioration may play an initial role in decline expression. A proposed relationship of graft union responses and decline expression is based on the tolerance of a given rootstock, titer or toxic substances and the stresses imposed on the tree by other factors

Modeling Human Cancer-induced Cachexia

Talbert et al. developed an inducible mouse model of cachexia caused by pancreatic cancer. This model exhibits features of the human condition, including the progressive depletion of muscle and adipose tissue associated with tumor progression

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor

Objective: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. Methods: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. Results: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. Interpretation: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Kindred Contemporaries

This essay traces lines of influence between Edgar Allan Poe and five of his American contemporaries: George Lippard, Robert Montgomery Bird, William Gilmore Simms, Nathaniel Hawthorne, and Washington Irving. Various categories of influence are identified, including suggestive parallels (allegedly present in many works by Poe and Hawthorne), negative influence (Poe avoided in The Narrative of Arthur Gordon Pym a technique he had previously criticized in reviewing Bird’s Sheppard Lee), avowed inspiration (Poe worked from a published hint by Irving in developing the story “William Wilson”), and plagiarism (Poe plagiarized from Irving’s Astoria in his own fictionalized adventure narrative covering similar geographical/temporal terrain, “The Journal of Julius Rodman”). The current impasse in influence studies is addressed. The essay concludes by noting that Poe’s body of work betrays numerous affinities with Thomas Gray’s pamphlet The Confessions of Nat Turner, published in Baltimore in 1831, though direct influence cannot be definitively established.</p