Citations

Key Points Agents that inhibit both complexes containing the mammalian target of rapamycin are particularly toxic to acute lymphocytic leukemia cells. This killing reflects engagement of a 4EBP1/c-MYC/PUMA axis downstream of mTORC1 and an NF-κB/EGR1/BIM axis downstream of mTORC2.

Abstract Erdheim‐Chester disease ( ECD ) is a non‐Langerhans cell histiocytosis that affects multiple body organs, notably the skeletal system. We examined a 58‐year‐old man who presented with ataxia and T2 hyperintensity of the middle cerebellar peduncles and dentate nuclei without contrast enhancement on MRI brain. Workup for malignancy revealed “hairy kidneys” on CT scan of the abdomen, and excisional biopsy of the retroperitoneal mass for concerns of lymphoma revealed foamy histiocytes that tested positive for CD 68 and negative for CD 1a, confirming the diagnosis of ECD . Further genetic testing on excised tissue revealed BRAF (V600E) gene mutation that is present in 50% of ECD patients. Treatment was initiated with targeted therapy using the BRAF inhibitor Dabrafenib. X‐ray of the lower extremities did not reveal sclerosis of the long bones, and bone scan with technetium 99 was negative except for a nonspecific tracer uptake in left calvarial bone with no corresponding CT changes or T1/T2 signal changes on MRI . His MRI brain revealed classic cerebellar involvement in ECD without other central nervous system ( CNS ) involvement. It has been postulated that bone involvement is almost universal in ECD ; however, our patient with ECD had ataxia and cerebellar involvement without significant bone involvement, as evidenced by bone scan. This is a rare presentation of ECD affecting the CNS and sparing the skeletal system. It confirms the wide spectrum of presentation this multisystem disease can have.

Abstract B lymphocytes play an essential regulatory role in the adaptive immune response through Ab production during infection. A less known function of B lymphocytes is their ability to respond directly to infectious Ags through stimulation of pattern recognition receptors expressed on their surfaces. β-Glucans are carbohydrates present in the cell wall of many pathogenic fungi that can be detected in the peripheral blood of patients during infection. They have been shown to participate in the innate inflammatory response, as they can directly activate peripheral macrophages and dendritic cells. However, their effect as direct stimulators of B lymphocytes has not been yet fully elucidated. The aim of this study was to examine the molecular mechanisms and cytokine profiles generated following β-glucan stimulation of B lymphocytes, compared with the well-established TLR-9 agonist CpG oligodeoxynucleotide (CpG), and study the participation of β-glucan–stimulated B cells in the innate immune response. In this article, we demonstrate that β-glucan–activated B lymphocytes upregulate proinflammatory cytokines (TNF-α, IL-6, and IL-8). Of interest, β-glucan, unlike CpG, had no effect on B lymphocyte proliferation or IgM production. When compared with CpG (TLR9 agonist), β-glucan–activated cells secreted significantly higher levels of IL-8. Furthermore, IL-8 secretion was partially mediated by Dectin-1 and required SYK, MAPKs, and the transcription factors NF-κB and AP-1. Moreover, we observed that conditioned media from β-glucan–stimulated B lymphocytes elicited neutrophil chemotaxis. These studies suggest that β-glucan–activated B lymphocytes have an important and novel role in fungal innate immune responses.

Abstract Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed. Experimental Design: Germline ASPN D-repeat-length was retrospectively analyzed in 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes, including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer. Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 [HR, 1.72; 95% confidence interval (CI), 1.05–2.81, P = 0.032] and heterozygosity for ASPN D13/14 (HR, 1.86; 95% CI, 1.03–3.35, P = 0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR, 0.44; 95% CI, 0.21–0.94, P = 0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient-based data. Conclusions: We observed associations between ASPN D variants and oncologic outcomes, including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression. Clin Cancer Res; 22(2); 448–58. ©2015 AACR.

Ghrelin, a gut hormone originating from the post‐translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS‐R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin‐O‐acyltransferase (GOAT), conferring selective binding to the GHS‐R1a receptor via acylated ghrelin. Complete loss of preproghrelin‐derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl‐ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat−/− mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat−/− mice compared to age‐matched wild‐type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH‐dependent liver genes. Of interest, circulating levels of insulin‐like growth factor (IGF)‐1 were elevated in goat−/− mice. This rise in circulating levels of IGF‐1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF‐1 release in goat−/− mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF‐1 release and growth in goat−/− mice.

Abstract Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). Results: We observed no significant association between genetic variants and prostate cancer survival. Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study. Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.

Abstract Background Gastrointestinal infections are risk factors for irritable bowel syndrome ( IBS ) and functional dyspepsia ( FD ). We investigated whether non‐enteric infections and antibiotic exposure are also associated with the development of functional gastrointestinal disorders ( FGID s). Methods In a nested case–control study, random samples of Olmsted County, MN , were mailed valid self‐report questionnaires from 1988 through 1994, and then follow‐up questionnaires from 1995 through 2003. Survey responders who did not report any FGID symptoms at baseline, but then reported such symptoms in at least one subsequent survey, were classified as new‐onset cases. Age‐matched controls were individuals who did not have symptoms at either the initial or subsequent surveys. Key Results The overall response rate was 78% to the initial survey and 52% to the follow‐up survey. Based on the responses, 316 participants had a new onset of an FGID (43 IBS constipation, 95 IBS diarrhea, 25 IBS mixed, and 153 other FGID s, including FD ) and 250 did not (controls). Around 76% (241/316) of cases reported a non‐enteric infection vs 66% (166/250) of the controls. The frequency of enteric infections was similar between the two groups. Of the new FGID cases, 83% had a non‐enteric infection that was treated with antibiotic. In a logistic regression model, treatment with antibiotics for a non‐gastrointestinal infection was associated with the development of an FGID (odds ratio = 1.90; 95% CI : 1.21–2.98; p = 0.005), after adjusting for age and sex. Conclusions & Inferences Based on a case–control study, treatment of a non‐gastrointestinal infection with antibiotics appears to be a risk factor for development of an FGID .