Through unknown mechanisms, insulin activates the sterol regulatory element-binding protein (SREBP1c) transcription factor to promote hepatic lipogenesis. We find that this induction is dependent on ...the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). To further define the role of mTORC1 in the regulation of SREBP1c in the liver, we generated mice with liver-specific deletion of TSC1 (LTsc1KO), which results in insulin-independent activation of mTORC1. Surprisingly, the LTsc1KO mice are protected from age- and diet-induced hepatic steatosis and display hepatocyte-intrinsic defects in SREBP1c activation and de novo lipogenesis. These phenotypes result from attenuation of Akt signaling driven by mTORC1-dependent insulin resistance. Therefore, mTORC1 activation is not sufficient to stimulate hepatic SREBP1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction. We provide evidence that this mTORC1-independent pathway involves Akt-mediated suppression of Insig2a, a liver-specific transcript encoding the SREBP1c inhibitor INSIG2.
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► mTORC1 is required for proper activation of hepatic SREBP1c by insulin ► LTsc1KO mice reveal that mTORC1 activation is not sufficient to induce hepatic SREBP1c ► An mTORC1-independent pathway is also required for hepatic SREBP1c induction by Akt ► Akt signaling suppresses Insig2a, a liver-specific inhibitor of SREBP1c
Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age ...permits, radiotherapy), median survival is 17 months
. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs.
), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT
, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.
Abstract Background Robot-assisted laparoscopic radical prostatectomy (RALP) has become increasingly common; however, there have been no nationwide, population-based, non–claims-based studies to ...evaluate differences in outcomes between RALP and open radical retropubic prostatectomy (RRP). Objective To determine surgical, oncologic, and health-related quality of life (HRQOL) outcomes following RALP and RRP in a nationwide cohort. Design, setting, and participants We identified 903 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 2000 and 2010 who underwent radical prostatectomy using RALP ( n = 282) or RRP ( n = 621) as primary treatment. Intervention Radical prostatectomy. Outcome measurements and statistical analysis We compared patients undergoing RALP or RRP across a range of perioperative, oncologic, and HRQOL outcomes. Results and limitations Use of RALP increased during the study period, constituting 85.2% of study subjects in 2009, up from 4.5% in 2003. Patients undergoing RALP compared to RRP were less likely to have a lymph node dissection (51.5% vs 85.4%; p < 0.0001), had less blood loss (207.4 ml vs 852.3 ml; p < 0.0001), were less likely to receive blood transfusions (4.3% vs 30.3%; p < 0.0001), and had shorter hospital stays (1.8 d vs 2.9 d; p < 0.0001). Surgical, oncologic, and HRQOL outcomes did not differ significantly among the groups. In multivariate logistic regression models, there were no significant differences in 3- or 5-yr recurrence-free survival comparing RALP versus RRP (hazard ratios: 0.98 95% confidence interval (CI), 0.46–2.08 and 0.75 95% CI, 0.18–3.11, respectively). Conclusions In a nationwide cohort of patients undergoing surgical treatment for prostate cancer, RALP was associated with shorter hospital stay, and lower blood loss and transfusion rates than RRP. Surgical oncologic and HRQOL outcomes were similar between groups. Patient summary We studied men throughout the United States with prostate cancer who underwent surgical removal of the prostate. We found that robot-assisted laparoscopic radical prostatectomy resulted in shorter hospital stay, less blood loss, and fewer blood transfusions than radical retropubic prostatectomy. There were no differences in cancer control or health-related quality of life.
Diffusion imaging coupled with tractography algorithms allows researchers to image human white matter fiber bundles in-vivo. These bundles are three-dimensional structures with shapes that change ...over time during the course of development as well as in pathologic states. While most studies on white matter variability focus on analysis of tissue properties estimated from the diffusion data, e.g. fractional anisotropy, the shape variability of white matter fiber bundle is much less explored. In this paper, we present a set of tools for shape analysis of white matter fiber bundles, namely: (1) a concise geometric model of bundle shapes; (2) a method for bundle registration between subjects; (3) a method for deformation estimation. Our framework is useful for analysis of shape variability in white matter fiber bundles. We demonstrate our framework by applying our methods on two datasets: one consisting of data for 6 normal adults and another consisting of data for 38 normal children of age 11 days to 8.5 years. We suggest a robust and reproducible method to measure changes in the shape of white matter fiber bundles. We demonstrate how this method can be used to create a model to assess age-dependent changes in the shape of specific fiber bundles. We derive such models for an ensemble of white matter fiber bundles on our pediatric dataset and show that our results agree with normative human head and brain growth data. Creating these models for a large pediatric longitudinal dataset may improve understanding of both normal development and pathologic states and propose novel parameters for the examination of the pediatric brain.
Current in vivo neuroimaging techniques provide limited field of view or spatial resolution and often require exogenous contrast. These limitations prohibit detailed structural imaging across wide ...fields of view and hinder intraoperative tumor margin detection. Here we present a novel neuroimaging technique, speckle-modulating optical coherence tomography (SM-OCT), which allows us to image the brains of live mice and ex vivo human samples with unprecedented resolution and wide field of view using only endogenous contrast. The increased visibility provided by speckle elimination reveals white matter fascicles and cortical layer architecture in brains of live mice. To our knowledge, the data reported herein represents the highest resolution imaging of murine white matter structure achieved in vivo across a wide field of view of several millimeters. When applied to an orthotopic murine glioblastoma xenograft model, SM-OCT readily identifies brain tumor margins with resolution of approximately 10 μm. SM-OCT of ex vivo human temporal lobe tissue reveals fine structures including cortical layers and myelinated axons. Finally, when applied to an ex vivo sample of a low-grade glioma resection margin, SM-OCT is able to resolve the brain tumor margin. Based on these findings, SM-OCT represents a novel approach for intraoperative tumor margin detection and in vivo neuroimaging.
•Damage to cerebellar outflow pathway is implicated in cerebellar mutism syndrome.•We indicate a site-specific alteration in distal superior cerebellar peduncle in CMS.•Important implications on ...surgical resection of paediatric posterior fossa tumours.
Cerebellar mutism syndrome, characterised by mutism, emotional lability and cerebellar motor signs, occurs in up to 39% of children following resection of medulloblastoma, the most common malignant posterior fossa tumour of childhood. Its pathophysiology remains unclear, but prior studies have implicated damage to the superior cerebellar peduncles. In this study, the objective was to conduct high-resolution spatial profilometry of the cerebellar peduncles and identify anatomic biomarkers of cerebellar mutism syndrome.
In this retrospective study, twenty-eight children with medulloblastoma (mean age 8.8 ± 3.8 years) underwent diffusion MRI at four timepoints over one year. Forty-nine healthy children (9.0 ± 4.2 years), scanned at a single timepoint, served as age- and sex-matched controls. Automated Fibre Quantification was used to segment cerebellar peduncles and compute fractional anisotropy (FA) at 30 nodes along each tract.
Thirteen patients developed cerebellar mutism syndrome. FA was significantly lower in the distal third of the left superior cerebellar peduncle pre-operatively in all patients compared to controls (FA in proximal third 0.228, middle and distal thirds 0.270, p = 0.01, Cohen’s d = 0.927). Pre-operative differences in FA did not predict cerebellar mutism syndrome. However, post-operative reductions in FA were highly specific to the distal left superior cerebellar peduncle, and were most pronounced in children with cerebellar mutism syndrome compared to those without at the 1–4 month follow up (0.325 vs 0.512, p = 0.042, d = 1.36) and at the 1-year follow up (0.342, vs 0.484, p = 0.038, d = 1.12).
High spatial resolution cerebellar profilometry indicated a site-specific alteration of the distal segment of the superior cerebellar peduncle seen in cerebellar mutism syndrome which may have important surgical implications in the treatment of these devastating tumours of childhood.
Frame-based stereotactic localization is an important step for targeting during a surgical procedure. The motion may cause artifacts in this step reducing the accuracy of surgical targeting. While ...modeling of motion in real-life scenarios may be difficult, herein we analyzed the case where motion was suspected to impact the localization step. In this case, a scan with and without motion was performed with a 3N localizer, allowing for a thorough analysis. Pseudo-bending of straight rods was seen when analyzing the data. This pseudo-bending appears to occur because head-frame motion during imaging acquisition decreases the accuracy of the subsequent reconstruction, which depends on Digital Imaging and Communications in Medicine (DICOM) metadata to specify the slice-to-slice location that assumes embedded object stability. Comparison of single-slice and multi-slice stereotactic localization allowed for comparative errors for each slice in a volume. This comparative error demonstrated low error when the patient was under general anesthesia and presumed not to have moved, whereas a higher error was present during the scan with motion. Pseudo-bending can be corrected by using only localizer fiducial-based information to reorient the pixels in the volume, thus creating a reoriented localizer scan. Finally, targeting demonstrated a low error of 0.1 mm (+/- 0.1 mm) using this reoriented localizer scan, signifying that this method could be used to improve or recover from motion problems. Finally, it is concluded that stability and elimination of motion for all images utilized for stereotactic surgery are critical to ensure the best possible accuracy for the procedure.
ABT-737 is a small-molecule antagonist of BCL-2 currently under evaluation in clinical trials in the oral form of ABT-263. We anticipate that acquired resistance to this promising drug will ...inevitably arise. To study potential mechanisms of resistance to ABT-737, we derived resistant lines from initially sensitive OCI-Ly1 and SU-DHL-4 lymphoma cell lines via long-term exposure. Resistance was based in the mitochondria and not due to an inability of the drug to bind BCL-2. Resistant cells had increased levels of BFL-1 and/or MCL-1 proteins, which are not targeted by ABT-737. Proapoptotic BIM was displaced from BCL-2 by ABT-737 in both parental and resistant cells, but in resistant cells, BIM was sequestered by the additional BFL-1 and/or MCL-1. Decreasing MCL-1 levels with flavopiridol, PHA 767491, or shRNA restored sensitivity to ABT-737 resistant cells. MCL-1 was up-regulated not by protein stabilization but rather by increased transcript levels. Surprisingly, in addition to stable increases in MCL-1 transcript and protein in resistant cells, there was a dynamic increase within hours after ABT-737 treatment. BFL-1 protein and transcript levels in resistant cells were similarly dynamically up-regulated. This dynamic increase suggests a novel mechanism whereby modulation of antiapoptotic protein function communicates with nuclear transcriptional machinery.
Optical coherence tomography angiography (OCTA) is an important tool for investigating vascular networks and microcirculation in living tissue. Traditional OCTA detects blood vessels via ...intravascular dynamic scattering signals derived from the movements of red blood cells (RBCs). However, the low hematocrit and long latency between RBCs in capillaries make these OCTA signals discontinuous, leading to incomplete mapping of the vascular networks. OCTA imaging of microvascular circulation is particularly challenging in tumors due to the abnormally slow blood flow in angiogenic tumor vessels and strong attenuation of light by tumor tissue. Here, we demonstrate in vivo that gold nanoprisms (GNPRs) can be used as OCT contrast agents working in the second near-infrared window, significantly enhancing the dynamic scattering signals in microvessels and improving the sensitivity of OCTA in skin tissue and melanoma tumors in live mice. With GNPRs as contrast agents, the postinjection OCT angiograms showed 41 and 59% more microvasculature than preinjection angiograms in healthy mouse skin and melanoma tumors, respectively. By enabling better characterization of microvascular circulation in vivo, GNPR-enhanced OCTA could lead to better understanding of vascular functions during pathological conditions, more accurate measurements of therapeutic response, and improved patient prognoses.
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