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This document contains supplemental figures 1-7 and detailed supplemental methods

Supplemental tables 1-10.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC.Significance:With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC. Significance: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

ObjectiveTo determine whether chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow–derived mesenchymal stromal/stem cells (SB623).MethodsThis 6-month interim analysis of the 1-year double-blind, randomized, surgical sham–controlled, phase 2 Stem Cell Therapy for Traumatic Brain Injury (STEMTRA) trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multicenter trial (n = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, or 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (n = 61), and efficacy was assessed in the modified intent-to-treat population of randomized patients who underwent surgery (n = 61; SB623 = 46, control = 15).ResultsThe primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (least square [LS] mean) 8.3 (standard error 1.4) vs 2.3 (standard error 2.5) for control at 6 months, the LS mean difference was 6.0 (95% confidence interval 0.3–11.8, p = 0.040). Secondary efficacy endpoints improved from baseline but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25).ConclusionsSB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls.ClinicalTrials.gov Identifier:NCT02416492.Classification of EvidenceThis study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Cell-to-cell variability in signal transduction in biological systems is often considered noise. However, intercellular variation (i.e., cell-to-cell variability) has the potential to enable individual cells to encode different information. Here, we show that intercellular variation increases information transmission of skeletal muscle. We analyze the responses of multiple cultured myotubes or isolated skeletal muscle fibers as a multiple-cell channel composed of single-cell channels. We find that the multiple-cell channel, which incorporates intercellular variation as information, not noise, transmitted more information in the presence of intercellular variation than in the absence according to the "response diversity effect," increasing in the gradualness of dose response by summing the cell-to-cell variable dose responses. We quantify the information transmission of human facial muscle contraction during intraoperative neurophysiological monitoring and find that information transmission of muscle contraction is comparable to that of a multiple-cell channel. Thus, our data indicate that intercellular variation can increase the information capacity of tissues.

BACKGROUND Most cases of glioblastoma recur within one year even under the standard treatment of surgical resection, radiation therapy and chemotherapy. 60–70% of recurrences are local, and in rare cases of metastasis, most are within the CNS. Extradural metastasis is considered exceedingly rare. CASE REPORT We present a 21-year-old man post total resection of right parietal lobe glioblastoma, diagnosed with lumber metastasis. He originally presented with impaired consciousness and left hemiplegia at the age of 20 and underwent gross total resection of the tumor. Pathology was IDH wild type, H3F3A K34R/V wild-type glioblastoma. Radiotherapy and adjuvant temozolomide per the Stupp regimen as well as infusion of bevacizumab were conducted. 6 months after the resection of tumor, the patient presented with severe back pain. Radiographic studies showed an osteolytic mass on the first lumbar vertebrae, and needle biopsy was consistent with glioblastoma. Posterior spinal fusion, internal decompression and radiotherapy were conducted to relieve the pain. At 3 months after the diagnosis of lumbar metastasis, he is currently treated with temozolomide and bevacizumab, without the enlarging of the tumor. DISCUSSION As far as we investigated, there has been 30 cases of vertebral metastasis of glioblastoma reported in literature. Considering the biological obstacles that prevent glioblastomas from infiltrating outside of the CNS, it can be speculated that deposition of tumor cells into the blood stream or excision of the dura due to surgical interventions may attribute to extracranial metastasis. Due to the improvement of overall survival of glioblastoma, vertebral metastasis is suspected to be more common. Therefore, investigation of its risk factors and standardization of its treatment is necessary. CONCLUSION We reported a case of lumbar metastasis of glioblastoma. Extradural metastasis of glioblastoma must be included in differential diagnoses in treating patients with glioblastoma.

Excessive increase in blood glucose level after eating increases the risk of macroangiopathy, and a method for not increasing the postprandial blood glucose level is desired. However, a logical design method of the dietary ingestion pattern controlling the postprandial blood glucose level has not yet been established. We constructed a mathematical model of blood glucose control by oral glucose ingestion in three healthy human subjects, and predicted that intermittent ingestion 30 min apart was the optimal glucose ingestion patterns that minimized the peak value of blood glucose level. We confirmed with subjects that this intermittent pattern consistently decreased the peak value of blood glucose level. We also predicted insulin minimization pattern, and found that the intermittent ingestion 30 min apart was optimal, which is similar to that of glucose minimization pattern. Taken together, these results suggest that the glucose minimization is achieved by suppressing the peak value of insulin concentration, rather than by enhancing insulin concentration. This approach could be applied to design optimal dietary ingestion patterns., The key points of this study are three-fold: The first point is the physiological impact. Intuitively, an ingestion pattern that minimizes the maximum blood glucose level is expected to be a slow, continuous ingestion. We found that the optimal minimization pattern was an intermittent pattern with 30 min intervals. The second point is the methodology. We constructed the mathematical model as a forward problem, and in turn, predicted input pattern by control the output pattern of interest as an inverse problem. The third point is the experiment design used to generate the mathematical model; dense time course data for six ingestion patterns combining of 3 doses of glucose level and 2 durations of ingestion.

Why is the spine of a neuron so small that it can contain only small numbers of molecules and reactions inevitably become stochastic? We previously showed that, despite such noisy conditions, the spine exhibits robust, sensitive, and efficient features of information transfer using the probability of Ca2+ increase; however, the mechanisms are unknown. In this study, we show that the small volume effect enables robust, sensitive, and efficient information transfer in the spine volume, but not in the cell volume. In the spine volume, the intrinsic noise in reactions becomes larger than the extrinsic noise of input, resulting in robust information transfer despite input fluctuation. In the spine volume, stochasticity makes the Ca2+ increase occur with a lower intensity of input, causing higher sensitivity to lower intensity of input. The volume-dependency of information transfer increases its efficiency in the spine volume. Thus, we propose that the small-volume effect is the functional reason why the spine has to be so small.

Signaling networks are made up of limited numbers of molecules and yet can code information that controls different cellular states through temporal patterns and a combination of signaling molecules. In this study, we used a data-driven modeling approach, the Laguerre filter with partial least square regression, to describe how temporal and combinatorial patterns of signaling molecules are decoded by their downstream targets. The Laguerre filter is a time series model used to represent a nonlinear system based on Volterra series expansion. Furthermore, with this approach, each component of the Volterra series expansion is expanded by Laguerre basis functions. We combined two approaches, application of a Laguerre filter and partial least squares (PLS) regression, and applied the combined approach to analysis of a signal transduction network. We applied the Laguerre filter with PLS regression to identify input and output (IO) relationships between MAP kinases and the products of immediate early genes (IEGs). We found that Laguerre filter with PLS regression performs better than Laguerre filter with ordinary regression for the reproduction of a time series of IEGs. Analysis of the nonlinear characteristics extracted using the Laguerre filter revealed a priming effect of ERK and CREB on c-FOS induction. Specifically, we found that the effects of a first pulse of ERK enhance the subsequent effects on c-FOS induction of treatment with a second pulse of ERK, a finding consistent with prior molecular biological knowledge. The variable importance of projections and output loadings in PLS regression predicted the upstream dependency of each IEG. Thus, a Laguerre filter with partial least square regression approach appears to be a powerful method to find the processing mechanism of temporal patterns and combination of signaling molecules by their downstream gene expression.

Background. We developed a new method of xenogeneic direct hemoperfusion of a bioartificial liver support system consisting of a leukocyte-adsorbent column, an immunoglobulin-adsorbent column, and the substitute unit for hepatic function. By this method, we performed xenogeneic direct hemoperfusion experiment using resected whole swine liver for treatment of a canine liver failure model, and compared the contribution of each adsorbent column both by blood analysis and from the histological point of view. Materials and methods. Canine liver failure model was produced by portocaval shunting and ligating the entire hepatoduodenal ligament. The xenogeneic direct hemoperfusion system was constructed using a roller pump, a leukocyte-adsorbent column, an immunoglobulin-adsorbent column, a combined device of oxygenator and warmer, the resected whole swine liver accommodated in a chamber, and a dissolved oxygen meter through which canine whole blood leaving the external jugular vein circulated in this order. Results. Xenogeneic direct hemoperfusion was successfully performed for 3 h without hyperacute rejection occurring. Adequate ammonia detoxification and bile juice secretion were exhibited, and no findings of hepatocyte destruction by immunological cells and proteins were detected. Blood data showed that the immunoglobulin adsorbent were more effective than the leukocyte adsorbent in avoiding hyperacute rejection. This result indicates that hyperacute rejection has a closer relation to humoral immune responses, especially regarding removal of complements than to cellular immune responses. Conclusions. We successfully performed xenogeneic direct hemoperfusion of the whole swine liver without hyperacute rejection using our method.

We have developed a new extracorporeal whole-liver accommodation device in which a whole swine liver is placed in a physiological state by modeling the intraabdominal arrangement in the pig body, with the liver supported by a special inferior vena cava tube. Furthermore, we employed a diaphragm-type artificial heart in our system to produce pulsatile blood flow through the hepatic artery, which is considered to be indispensable to dilate peripheral vessels and supply oxygenated whole blood to the peripheral liver tissue. Beneficial effects were demonstrated in visual findings and bile juice secretion. The color of the liver surface in our system remained bright red, indicating that the liver vessels were well drained and free from congestion, and bile juice secretion was maintained at more than 10 ml/h throughout the perfusion period. Our system exhibited excellent ammonia removal and urea nitrogen synthesis, and serum aspartate aminotransferase levels showed no increase, indicating the absence of hepatocyte destruction. Histological findings showed that the liver could expand appropriately and was free from compression caused by its own weight. In conclusion, our original liver accommodation device enabled appropriate expansion of the whole liver and supplied adequate oxygenated blood to peripheral areas by means of a pulsatile pump.