Renal Autotransplant and Celiac Artery Bypass for Aneurysmal Degeneration Related to Neurofibromatosis Type 1

We present a case of an 18-year-old female with neurofibromatosis type 1 who presented with abdominal pain and weight loss secondary to chronic mesenteric ischemia due to celiac axis occlusion and was subsequently found to have multiple visceral artery aneurysms. Of clinical significance, 2 aneurysms of the right renal artery were noted at the hilum, with the larger one having a diameter of 2.4 cm. After initial endovascular treatment with stenting of a concurrent pancreaticoduodenal artery pseudoaneurysm, staged aorto-hepatic bypass and right nephrectomy with renal autotransplantation after back table resection of the aneurysmal segments were successfully completed

Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and A

Reply to comments by P. F. Karrow and R. F. Black

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22713/1/0000268.pd

Greatlakean Substage: A replacement for Valderan Substage in the Lake Michigan basin

New evidence from recent field and seismic investigations in the Lake Michigan basin and in the type areas of the Valders, Two Creeks and Two Rivers deposits necessitates revision of late-glacial ice-front positions, rock- and time-stratigraphic nomenclature and climatic interpretations and deglaciation patterns for the period ca. 14,000-7,000 radiocarbon years B.P. The previously reported and long accepted pattern of deglaciation for the Lake Michigan basin started with a regular retreat from the Lake Border Morainic System, with a minor oscillation marked by the Port Huron moraine(s) and then an extensive Twocreekan deglaciation followed by a major (320 km) post-Twocreekan advance (Valders). However, we now record a major retreat between the times of the Lake Border and Port Huron moraines, followed by a gradual retreat from the Port Huron limit and interrupted by a minor standstill (deposition of Manitowoc Till), a retreat (Twocreekan) and a readvance (Two Rivers Till). No Woodfordian or younger readvance was as extensive as had been the preceding one. This sequence argues for a normal, climatically controlled, progressive deglaciation rather than one interrupted by a major post-Twocreekan (formerly Valderan) surge. This revision appears finally to harmonize the geologic evidence and the palynological record for the Great Lakes region. Our investigations show that Valders Till from which the Valderan Substage was named is late-Woodfordian in age. We propose the term "Greatlakean" as a replacement for the now misleading time-stratigraphic term "Valderan". The type section and the definition of the upper and lower boundaries of the Greatlakean Substage remain the same as those originally proposed for the Valderan Substage but the name is changed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21685/1/0000075.pd

Die Jemandssprache : Plädoyer für eine Deutsche Philologie unter besonderer Berücksichtigung von Heinrich von Morungen, Paul Celan und der "Auslandsgermanistik"

Der Titel „Jemandssprache“ bezieht sich kontrafaktisch auf Paul Celans Gedichtband „Die Niemandsrose“. (...) [In dem ersten Teil seine Aufsatzes bezieht sich Volker Mertens] auf die aktuelle Situation im Fach, in einem zweiten (...) [votiert er] für eine spezifische Gegenstandsbestimmung und einen bestimmten Umgang mit den methodischen Paradigmen, in einem dritten für eine Überwindung der Schwelle zwischen Älterer und Neuerer Literatur, (...), in einem vierten (...) [gibt er] eine vergleichende Interpretation je eines Gedichts von Heinrich von Morungen und von Paul Celan als Beispiel für eine Überschreitung der im Fach institutionalisierten Epochengrenze

Profiles of Global Gene Expression in Ionizing-Radiation–Damaged Human Diploid Fibroblasts Reveal Synchronization behind the G(1) Checkpoint in a G(0)-like State of Quiescence

Cell cycle arrest and stereotypic transcriptional responses to DNA damage induced by ionizing radiation (IR) were quantified in telomerase-expressing human diploid fibroblasts. Analysis of cytotoxicity demonstrated that 1.5 Gy IR inactivated colony formation by 40–45% in three fibroblast lines; this dose was used in all subsequent analyses. Fibroblasts exhibited > 90% arrest of progression from G(2) to M at 2 hr post-IR and a similarly severe arrest of progression from G(1) to S at 6 and 12 hr post-IR. Normal rates of DNA synthesis and mitosis 6 and 12 hr post-IR caused the S and M compartments to empty by > 70% at 24 hr. Global gene expression was analyzed in IR-treated cells. A microarray analysis algorithm, EPIG, identified nine IR-responsive patterns of gene expression that were common to the three fibroblast lines, including a dominant p53-dependent G(1) checkpoint response. Many p53 target genes, such as CDKN1A, GADD45, BTG2, and PLK3, were significantly up-regulated at 2 hr post-IR. Many genes whose expression is regulated by E2F family transcription factors, including CDK2, CCNE1, CDC6, CDC2, MCM2, were significantly down-regulated at 24 hr post-IR. Numerous genes that participate in DNA metabolism were also markedly repressed in arrested fibroblasts apparently as a result of cell synchronization behind the G(1) checkpoint. However, cluster and principal component analyses of gene expression revealed a profile 24 hr post-IR with similarity to that of G(0) growth quiescence. The results reveal a highly stereotypic pattern of response to IR in human diploid fibroblasts that reflects primarily synchronization behind the G(1) checkpoint but with prominent induction of additional markers of G(0) quiescence such as GAS1

Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer

Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, and open-source software package designed to integrate somatic variants from genomic data with splice junctions from bulk or single cell transcriptomic data to identify variants that may cause aberrant splicing. We apply RegTools to over 9000 tumor samples with both tumor DNA and RNA sequence data. RegTools discovers 235,778 events where a splice-associated variant significantly increases the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotate them with the Variant Effect Predictor, SpliceAI, and Genotype-Tissue Expression junction counts and compare our results to other tools that integrate genomic and transcriptomic data. While many events are corroborated by the aforementioned tools, the flexibility of RegTools also allows us to identify splice-associated variants in known cancer drivers, such as TP53, CDKN2A, and B2M, and other genes

Impaired immune function in Gulf War Illness

<p>Abstract</p> <p>Background</p> <p>Gulf War Illness (GWI) remains a serious health consequence for at least 11,000 veterans of the first Gulf War in the early 1990s. Our understanding of the health consequences that resulted remains inadequate, and this is of great concern with another deployment to the same theater of operations occurring now. Chronic immune cell dysfunction and activation have been demonstrated in patients with GWI, although the literature is not uniform. We exposed GWI patients and matched controls to an exercise challenge to explore differences in immune cell function measured by classic immune assays and gene expression profiling.</p> <p>Methods</p> <p>This pilot study enrolled 9 GWI cases identified from the Department of Veterans Affairs GWI registry, and 11 sedentary control veterans who had not been deployed to the Persian Gulf and were matched to cases by sex, body mass index (BMI) and age. We measured peripheral blood cell numbers, NK cytotoxicity, cytokines and expression levels of 20,000 genes immediately before, immediately after and 4 hours following a standard bicycle ergometer exercise challenge.</p> <p>Results</p> <p>A repeated-measures analysis of variance revealed statistically significant differences for three NK cell subsets and NK cytotoxicity between cases and controls (p < 0.05). Linear regression analysis correlating NK cell numbers to the gene expression profiles showed high correlation of genes associated with NK cell function, serving as a biologic validation of both the <it>in vitro </it>assays and the microarray platform. Intracellular perforin levels in NK and CD8 T-cells trended lower and showed a flatter profile in GWI cases than controls, as did the expression levels of the perforin gene PRF1. Genes distinguishing cases from controls were associated with the glucocorticoid signaling pathway.</p> <p>Conclusion</p> <p>GWI patients demonstrated impaired immune function as demonstrated by decreased NK cytotoxicity and altered gene expression associated with NK cell function. Pro-inflammatory cytokines, T-cell ratios, and dysregulated mediators of the stress response (including salivary cortisol) were also altered in GWI cases compared to control subjects. An interesting and potentially important observation was that the exercise challenge augments these differences, with the most significant effects observed immediately after the stressor, possibly implicating some block in the NK and CD8 T-cells ability to respond to "stress-mediated activation". This has positive implications for the development of laboratory diagnostic tests for this syndrome and provides a paradigm for exploration of the immuno-physiological mechanisms that are operating in GWI, and similar complex syndromes. Our results do not necessarily elucidate the cause of GWI, but they do reveal a role for immune cell dysfunction in sustaining illness.</p