ALBERT

Description: Background: To facilitate the implementation of the Family Smoking Prevention and Tobacco Control Act of 2009, the Federal Drug Agency (FDA) Center for Tobacco Products (CTP) has identified research priorities under the umbrella of tobacco regulatory science (TRS). As a newly integrated field, the current boundaries and landscape of TRS research are in need of definition. In this work, we conducted a bibliometric study of TRS research by applying author topic modeling (ATM) on MEDLINE citations published by currently-funded TRS principle investigators (PIs). Results: We compared topics generated with ATM on dataset collected with TRS PIs and topics generated with ATM on dataset collected with a TRS keyword list. It is found that all those topics show a good alignment with FDA’s funding protocols. More interestingly, we can see clear interactive relationships among PIs and between PIs and topics. Based on those interactions, we can discover how diverse each PI is, how productive they are, which topics are more popular and what main components each topic involves. Temporal trend analysis of key words shows the significant evaluation in four prime TRS areas. Conclusions: The results show that ATM can efficiently group articles into discriminative categories without any supervision. This indicates that we may incorporate ATM into author identification systems to infer the identity of an author of articles using topics generated by the model. It can also be useful to grantees and funding administrators in suggesting potential collaborators or identifying those that share common research interests for data harmonization or other purposes. The incorporation of temporal analysis can be employed to assess the change over time in TRS as new projects are funded and the extent to which new research reflects the funding priorities of the FDA.

Description: Abstract 2643 Background: Granulomatous mycosis fungoides (GMF) is a variant of MF/cutaneous T-cell lymphoma characterized by a prominent granulomatous infiltrate in addition to the malignant lymphoid infiltrate. The diagnosis of GMF remains challenging due to variable clinical and histopathologic features. The significance of granuloma formation in CTCL is unclear and whether patients with GMF have a distinct prognosis compared to patients with classic type of MF is controversial. Data are scarce and long term results are not available. Objectives: To evaluate the clinical, histopathologic, prognostic significance and therapeutic responses of patients with GMF and to compare results to age and stage-matched patients with classic type of MF. Methods: A single center retrospective case-case study was performed at Memorial Sloan-Kettering Cancer Center of 430 patients with a diagnosis of MF between January 1981 and April 2012. Available histopathology slides were reviewed for the presence of granulomas or histiocytes comprising ≥ 25% of the atypical lymphoid infiltrate. Each identified case was matched with two classic MF cases via age and TNMB stage. For each case meeting criteria, the medical records, photographs, and histopathology slides were reviewed. Results: Twenty-seven patients with GMF were identified representing 6.3% of all MF patients at our center. Patient demographics were similar between the GMF group and case-control classic MF group, with a male-to-female ratio of 2.1:1 and a median age of 57. Most GMF patients (69%) present at early stages (IA-IIA). Patients with GMF had a longer onset of disease prior to diagnosis (median, 4.5 years vs 3.0 years). Skin manifestations of granulomatous MF showed a great variability, but were not distinguishable from those of classic MF. Histological findings showed an atypical predominantly CD4+ lymphocytic infiltrate with either granuloma formation or histiocytes with giant cells. TCR rearrangement was positive in 70% of cases. Features of GMF were present at initial diagnosis in 17 patients. In 10 patients, granulomatous infiltrates appeared at an average of 5.4 years after MF diagnosis. Secondary malignancies developed in 38% of patients with GMF compared to 23% of patients in the case-control classic MF group. Among the GMF patients, there was a trend towards fewer CRs to any treatment (38% vs 54%; p = 0.21); fewer PRs or CRs with topical therapy (57% vs 83%; p = 0.002) and with UV-light therapy (62% vs 90%; p = 0.008). Significantly more GMF patients received systemic therapy (66.7%) compared to classic MF patients (32.7%; p = 0.006). They also required a longer time to achieve best response (median 35 months vs 9 months, p = 0.002) compared to the control group. Disease progression to higher stage was seen in 46% of cases in the GMF group compared to 30% of cases in the classic MF group (p = 0.23). The 5-year and 10-year progression-free survival rates were significantly lower in the GMF group (59% and 33%, respectively) compared to the control group (84% and 56%, respectively; p = 0.02). However, the 5-year and 10-year overall survival rates were similar between GMF (86% and 72%, respectively) and classic MF patients (85% and 85%; p = 0.54). Conclusion: Our study presents the largest series on GMF in the United States. Most patients with GMF show similar clinical features when compared to patients with conventional MF. The clinical features do not reflect the histologic findings of granulomas. More frequent disease progression and poorer response to skin-directed therapies are seen in GMF patients compared to classic MF; however, overall survival is not significantly different. The majority of GMF patients present with granulomatous features at initial diagnosis and in subsequent biopsies suggesting that this entity has a unique relationship with its microenvironment. Disclosures: No relevant conflicts of interest to declare.

Description: Integrins contribute to lymphopoiesis, whereas Toll-like receptors (TLRs) facilitate the myeloid replenishment during inflammation. The combined role of TLRs and integrin on hematopoiesis remains unclear. gp96 (grp94, HSP90b1) is an endoplasmic reticulum master chaperone for multiple TLRs. We report herein that gp96 is also essential for expression of 14 hematopoietic system-specific integrins. Genetic deletion of gp96 thus enables us to determine the collective roles of gp96, integrins, and TLRs in hematopoiesis. We found that gp96-null hematopoietic stem cells could support long-term myelopoiesis. B- and T-cell development, however, was severely compromised with transitional block from pro-B to pre-B cells and the inability of thymocytes to develop beyond the CD4−CD8− stage. These defects were cell-intrinsic and could be recapitulated on bone marrow stromal cell culture. Furthermore, defective lymphopoiesis correlated strongly with failure of hematopoietic progenitors to form close contact with stromal cell niche and was not the result of the defect in the assembly of antigen receptor or interleukin-7 signaling. These findings define gp96 as the only known molecular chaperone to specifically regulate T- and B-cell development.

Description: Background Generating high-quality de novo genome assemblies is foundational to the genomics study of model and non-model organisms. In recent years, long-read sequencing has greatly benefited genome assembly and scaffolding, a process by which assembled sequences are ordered and oriented through the use of long-range information. Long reads are better able to span repetitive genomic regions compared to short reads, and thus have tremendous utility for resolving problematic regions and helping generate more complete draft assemblies. Here, we present LongStitch, a scalable pipeline that corrects and scaffolds draft genome assemblies exclusively using long reads. Results LongStitch incorporates multiple tools developed by our group and runs in up to three stages, which includes initial assembly correction (Tigmint-long), followed by two incremental scaffolding stages (ntLink and ARKS-long). Tigmint-long and ARKS-long are misassembly correction and scaffolding utilities, respectively, previously developed for linked reads, that we adapted for long reads. Here, we describe the LongStitch pipeline and introduce our new long-read scaffolder, ntLink, which utilizes lightweight minimizer mappings to join contigs. LongStitch was tested on short and long-read assemblies of Caenorhabditis elegans, Oryza sativa, and three different human individuals using corresponding nanopore long-read data, and improves the contiguity of each assembly from 1.2-fold up to 304.6-fold (as measured by NGA50 length). Furthermore, LongStitch generates more contiguous and correct assemblies compared to state-of-the-art long-read scaffolder LRScaf in most tests, and consistently improves upon human assemblies in under five hours using less than 23 GB of RAM. Conclusions Due to its effectiveness and efficiency in improving draft assemblies using long reads, we expect LongStitch to benefit a wide variety of de novo genome assembly projects. The LongStitch pipeline is freely available at https://github.com/bcgsc/longstitch.