The use of stained cytologic direct smears for ALK gene rearrangement analysis of lung adenocarcinoma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100150/1/cncy21286.pd

Comparative study of TERT promoter mutation status within spatially, temporally and morphologically distinct components of urothelial carcinoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141213/1/his13318.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141213/2/his13318_am.pd

Application of immunocytochemistry and BRAF mutational analysis to direct smears of metastatic melanoma

BACKGROUND: The cytodiagnosis of melanoma in fine‐needle aspiration (FNA) specimens can be challenging, often requiring the use of immunocytochemistry. As constitutively activating mutations in the BRAF oncogene are present in at least 40% of melanomas, the use of FNA material to interrogate the BRAF mutational status is likely to increase. Because cell blocks, traditionally used for these studies, can occasionally exhibit insufficient tumor cellularity, the authors investigated the utility of direct smears for immunocytochemistry and BRAF mutational analysis. METHODS: Immunocytochemistry for S‐100, HMB‐45, and Mart‐1 was prospectively performed on direct smears in 17 FNAs of metastatic melanoma. Next, BRAF sequencing was performed using DNA isolated from archived Diff‐Quik–stained direct smears for 15 cases. In parallel, sequencing was performed using DNA obtained from corresponding cell blocks. RESULTS: S‐100 positivity in the tumor cells was observed in all 17 cases. HMB‐45 and Mart‐1 positivity was noted in 81% and 88% of cases, respectively. All 3 markers were positive in 76% of cases. Next, of the 15 archived melanoma FNAs tested, BRAF mutations were observed in 8 (53%); 5 and 3 melanomas harbored the V600E and V600K mutation, respectively. Corresponding cell blocks were also tested for all 15 cases, yielding concordant BRAF results in 14 (93%); 1 cell block yielded a false‐negative result. CONCLUSIONS: Cytologic direct smears represent a robust and valuable source of cellular material for immunocytochemistry and molecular studies, especially in instances in which inadequate cell block cellularity is anticipated or encountered. Cancer (Cancer Cytopathol) 2012. © 2011 American Cancer Society. This study demonstrates that direct smears represent a robust and valuable source of cellular material for ancillary studies used in the cytologic diagnosis of melanoma. Direct smears can be effectively used for confirmatory immunocytochemical studies and molecular assays designed to interrogate the BRAF mutational status of melanoma, especially in scenarios in which inadequate cell block cellularity is anticipated or encountered.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90193/1/20180_ftp.pd

At the intersection of primary pulmonary myxoid sarcoma and pulmonary angiomatoid fibrous histiocytoma: observations from three new cases

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107555/1/his12354.pd

The utility of ETV1, ETV4 and ETV5 RNA inâ situ hybridization in the diagnosis of CICâ DUX sarcomas

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136260/1/his13112_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136260/2/his13112.pd

D 4 dopamine receptor high-resolution structures enable the discovery of selective agonists

Dopamine receptors are G protein-coupled receptors implicated in many neurological disorders. Different families of dopamine receptors are involved in different signaling pathways, so specificity is a key goal of therapeutics. Wang et al. present high-resolution crystal structures of the DRD4 dopamine receptor bound to the antipsychotic drug nemonapride. The high resolution of the structures facilitated ligand docking, and a DRD4-selective agonist was identified by computational screening of a large library, experimental testing of compounds with the best docking scores, and iterative cycles of docking and testing analogs of those compounds. The identified agonist had a high affinity for DRD4 and no measurable affinity for DRD2 or DRD3. Science , this issue p. [381][1] [1]: /lookup/doi/10.1126/science.aan546

Crystal Structure of an LSD-Bound Human Serotonin Receptor

SummaryThe prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR—a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors.PaperCli

Compensation of BRG-1 Function by Brm: INSIGHT INTO THE ROLE OF THE CORE SWI·SNF SUBUNITS IN RETINOBLASTOMA TUMOR SUPPRESSOR SIGNALING

The BRG-1 subunit of the SWI-SNF complex is involved in chromatin remodeling and has been implicated in the action of the retinoblastoma tumor suppressor (RB). Given the importance of BRG-1 in RB function, germ line BRG-1 mutations in tumorigenesis may be tantamount to RB inactivation. Therefore, in this study we assessed the behavior of cells harboring discrete BRG-1 alleles for the RB-signaling pathway. Using p16ink4a, an upstream activator of endogenous RB, or a constitutively active RB construct (PSM-RB), we determined that the majority of tumor lines with germ line defects in BRG-1 were sensitive to RB-mediated cell cycle arrest. By contrast, A427 (lung carcinoma) cells were resistant to expression of p16ink4a and PSM-RB. Analysis of the SWI-SNF subunits in the different tumor lines revealed that A427 are deficient for BRG-1 and its homologue, Brm, whereas RB-sensitive cell lines retained Brm expression. Similarly, the RB-resistant SW13 and C33A cell lines were also deficient for both BRG-1/Brm. Reintroduction of either BRG-1 or Brm into A427 or C33A cells restored RB-mediated signaling to cyclin A to cause cell cycle arrest. Consistent with this compensatory role, we observed that Brm could also drive expression of CD44. We also determined that loss of these core SWI-SNF subunits renders SW13 cells resistant to activation of the RB pathway by the chemotherapeutic agent cisplatin, since reintroduction of either BRG-1 or Brm into SW13 cells restored the cisplatin DNA-damage checkpoint. Together, these data demonstrate that Brm can compensate for BRG-1 loss as pertains to RB sensitivity

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure