13 research outputs found
Rectal Leiomyosarcoma: An Unusual Rectal Malignancy Mimicking Fecal Impaction in a 19-Year-Old Man
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Mobilization of Blood Stem Cells with G-CSF in Systemic Light-Chain Amyloidosis: Dominant Organ Involvement Significantly Affects Stem Cell Collection
Abstract
Systemic light-chain (AL) amyloidosis is both a protein deposition disorder and a monoclonal plasma cell dyscrasia. Effective treatment depends on reduction of the clonal plasma cells that produce the toxic light chains. Although high-dose melphalan with autologous stem cell transplant (MEL SCT) is effective for AL patients, the mobilization and collection of peripheral blood stem cells with G-CSF can be problematic despite their lack of prior chemotherapy and minimal marrow infiltration with plasma cells. In addition, unusual toxicities of G-CSF mobilization such as hypotension have been noted in AL patients. As new therapies show efficacy in AL, the role of stem cell mobilization and MEL SCT will likely be re-evaluated, increasing the importance of understanding the variability in stem cell mobilization. Recent work has shown that the mechanism of G-CSF mobilization likely involves the sympathetic nervous system (Cell2006;124:407). Interestingly, amyloid is well known to cause autonomic neuropathy. In addition, involvement of the heart in amyloidosis has also been shown to cause cardiac adrenergic denervation. If G-CSF mobilization depends upon the sympathetic nervous system, then the type of organ involvement could predict the yield of stem cell collection in AL patients mobilized with G-CSF. With these concerns in mind, we retrospectively assessed the results of stem cell mobilization and collection in all patients with AL mobilized with G-CSF (6ug/kg bid) for 4 days, with collections beginning on day 5 with a collection target of 10x106 CD34+ cells per kg in up to 4 leukaphereses. At initial evaluation, we assessed patients using standard criteria to identify the dominant organ of involvement (Am J Hematol2005;79:319) and to determine candidacy for risk-adapted MEL SCT (Blood2002;99:4276). Over a 7-year period 105 patients with AL were mobilized and collected as described, including 40 with kidney (K), 21 with liver/GI or soft-tissue (L/GI/ST), 31 with cardiac (H) and 13 with peripheral nervous system (PNS) involvement. We recorded the number of leukaphereses per patient and the dose of CD34+ cells/kg collected per leukapheresis. There were no significant differences in the number of leukaphereses per group. The K, L/GI/ST and H groups had a median of 2, and the PNS group of 3, collections. There were significant differences in CD34+ cells/kg collected based on dominant organ involvement: patients with H or PNS involvement had significantly fewer CD34+ cells/kg collected (see figure below; K vs H p=0.03, K vs PNS p=0.02, L/GI/ST vs H p=0.07, L/GI/ST vs PNS p=0.04; two tailed Mann-Whitney). Moreover, 15/44 H+PNS patients failed to collect at least 4x106 CD34+cells/kg compared to 7/61 K+L/GI/ST patients (p<0.01). These observations provide a basis for directed studies of the sympathetic nervous system in AL, particularly in association with stem cell mobilization with G-CSF.
Figure Figur
Host-response transcriptional biomarkers accurately discriminate bacterial and viral infections of global relevance
Abstract Diagnostic limitations challenge management of clinically indistinguishable acute infectious illness globally. Gene expression classification models show great promise distinguishing causes of fever. We generated transcriptional data for a 294-participant (USA, Sri Lanka) discovery cohort with adjudicated viral or bacterial infections of diverse etiology or non-infectious disease mimics. We then derived and cross-validated gene expression classifiers including: 1) a single model to distinguish bacterial vs. viral (Global Fever-Bacterial/Viral [GF-B/V]) and 2) a two-model system to discriminate bacterial and viral in the context of noninfection (Global Fever-Bacterial/Viral/Non-infectious [GF-B/V/N]). We then translated to a multiplex RT-PCR assay and independent validation involved 101 participants (USA, Sri Lanka, Australia, Cambodia, Tanzania). The GF-B/V model discriminated bacterial from viral infection in the discovery cohort an area under the receiver operator curve (AUROC) of 0.93. Validation in an independent cohort demonstrated the GF-B/V model had an AUROC of 0.84 (95% CI 0.76–0.90) with overall accuracy of 81.6% (95% CI 72.7–88.5). Performance did not vary with age, demographics, or site. Host transcriptional response diagnostics distinguish bacterial and viral illness across global sites with diverse endemic pathogens
An Allosteric Regulator of R7-RGS Proteins Influences Light-Evoked Activity and Glutamatergic Waves in the Inner Retina
Guidelines for the use and interpretation of assays for monitoring autophagy
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field
Guidelines for the use and interpretation of assays for monitoring autophagy
In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field