Adenosine 5'-triphosphate (ATP) is the major energy currency of cells and is involved in many cellular processes. However, there is no method for real-time monitoring of ATP levels inside individual ...living cells. To visualize ATP levels, we generated a series of fluorescence resonance energy transfer (FRET)-based indicators for ATP that were composed of the ε subunit of the bacterial FoF₁-ATP synthase sandwiched by the cyan- and yellow-fluorescent proteins. The indicators, named ATeams, had apparent dissociation constants for ATP ranging from 7.4 μM to 3.3 mM. By targeting ATeams to different subcellular compartments, we unexpectedly found that ATP levels in the mitochondrial matrix of HeLa cells are significantly lower than those of cytoplasm and nucleus. We also succeeded in measuring changes in the ATP level inside single HeLa cells after treatment with inhibitors of glycolysis and/or oxidative phosphorylation, revealing that glycolysis is the major ATP-generating pathway of the cells grown in glucose-rich medium. This was also confirmed by an experiment using oligomycin A, an inhibitor of FoF₁-ATP synthase. In addition, it was demonstrated that HeLa cells change ATP-generating pathway in response to changes of nutrition in the environment.
Background
This study aimed to investigate whether radiofrequency ablation (RFA) is an alternative to surgical resection for hepatocellular carcinoma (HCC) within the context of current guidelines.
...Methods
This retrospective study included patients with normal portal pressure and serum bilirubin level who initially underwent liver resection or RFA for a single HCC of maximum size 3 cm. Between‐group differences in cumulative rates of survival and recurrence specific for HCC were analysed in the entire cohort and in a propensity score‐matched cohort.
Results
A total of 604 patients were enrolled, 273 in the liver resection group and 331 in the RFA group. The 5‐ and 10‐year HCC‐specific survival rates for the resection and RFA groups were 87·6 versus 82·1 per cent and 59·0 versus 61·2 per cent respectively (P = 0·214), whereas overall 5‐ and 10‐year recurrence‐free survival rates for the corresponding groups were 60·6 versus 39·4 per cent and 37·5 versus 25·1 per cent respectively (P < 0·001). In the propensity score‐matched cohort (152 pairs), there were no differences in HCC‐specific survival (hazard ratio (HR) 1·03 for RFA versus resection; P = 0·899), whereas recurrence‐free survival again differed between the treatment groups (HR 1·75; P < 0·001). RFA was independently associated with poorer outcomes in terms of treatment‐site recurrence‐free survival (adjusted HR 1·66; P = 0·026), but not non‐treatment‐site recurrence‐free survival (adjusted HR 1·15; P = 0·354).
Conclusion
Although RFA carries a higher risk of treatment‐site recurrence than hepatic resection, it provides comparable overall survival in patients with a single small HCC without portal hypertension or a raised bilirubin level.
Good alternative in small hepatocellular carcinoma
Recent successes in the field of machine learning, as well as the availability of increased sensing and computational capabilities in modern control systems, have led to a growing interest in ...learning and data-driven control techniques. Model predictive control (MPC), as the prime methodology for constrained control, offers a significant opportunity to exploit the abundance of data in a reliable manner, particularly while taking safety constraints into account. This review aims at summarizing and categorizing previous research on learning-based MPC, i.e., the integration or combination of MPC with learning methods, for which we consider three main categories. Most of the research addresses learning for automatic improvement of the prediction model from recorded data. There is, however, also an increasing interest in techniques to infer the parameterization of the MPC controller, i.e., the cost and constraints, that lead to the best closed-loop performance. Finally, we discuss concepts that leverage MPC to augment learning-based controllers with constraint satisfaction properties.
Abstract Non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation shows good and rapid response to EGFR tyrosine kinase inhibitors (TKIs). We ...prospectively evaluated the efficacy of EGFR TKI for metastatic brain tumors in NSCLC patients harboring EGFR mutation. This was an open-label, single-institution, phase II study. Patients diagnosed with NSCLC harboring EGFR mutation and measurable metastatic brain tumors were eligible. They received either erlotinib or gefitinib once a day. Out of total 28 patients enrolled, 23 patients (83%) showed a partial response (PR) and 3 patients (11%) did stable disease (SD), giving a disease control rate of 93%. Median progression free survival (PFS) and overall survival (OS) were 6.6 months (95% CI, 3.8–9.3 months) and 15.9 months (95% CI, 7.2–24.6 months), respectively. There was no difference in PFS and OS according to EGFR TKIs used. After discontinuation of the treatment, 14 patients (50%) received local therapy for metastatic brain tumors during their disease course, either whole brain radiotherapy or radiosurgery, giving a local therapy-free interval of 12.6 months (95% CI, 7.6–17.6 months). EGFR TKI therapy might be the treatment of choice for metastatic brain tumors in NSCLC patients harboring an activating EGFR mutation.
Two-dimensional (2D) materials are not expected to be metals at low temperature owing to electron localization1. Consistent with this, pioneering studies on thin lms reported only superconducting and ...insulating ground states, with a direct transition between the two as a function of disorder or magnetic eld26. However, more recent works have revealed the presence of an intermediate quantum metallic state occupying a substantial region of the phase diagram710, whose nature is intensely debated1117. Here, we observe such a state in the disorder-free limit of a crystalline 2D superconductor, produced by mechanical co-lamination of NbSe2 in an inert atmosphere. Under a small perpendicular magnetic eld, we induce a transition from superconductor to the quantum metal. We nd a unique power-law scaling with eld in this phase, which is consistent with the Bose-metal model where metallic behaviour arises from strong phase uctuations caused by the magnetic field1114.
We use an ensemble of surface (EPA CSN, IMPROVE, SEARCH, AERONET), aircraft (SEAC4RS), and satellite (MODIS, MISR) observations over the southeast US during the summer-fall of 2013 to better ...understand aerosol sources in the region and the relationship between surface particulate matter (PM) and aerosol optical depth (AOD). The GEOS-Chem global chemical transport model (CTM) with 25 25 km2 resolution over North America is used as a common platform to interpret measurements of different aerosol variables made at different times and locations. Sulfate and organic aerosol (OA) are the main contributors to surface PM2.5 (mass concentration of PM finer than 2.5 mu m aerodynamic diameter) and AOD over the southeast US. OA is simulated successfully with a simple parameterization, assuming irreversible uptake of low-volatility products of hydrocarbon oxidation. Biogenic isoprene and monoterpenes account for 60 % of OA, anthropogenic sources for 30 %, and open fires for 10 %. 60 % of total aerosol mass is in the mixed layer below 1.5 km, 25 % in the cloud convective layer at 1.5-3 km, and 15 % in the free troposphere above 3 km. This vertical profile is well captured by GEOS-Chem, arguing against a high-altitude source of OA. The extent of sulfate neutralization (f = NH4+/(2SO42- + NO3-) is only 0.5-0.7 mol mol-1 in the observations, despite an excess of ammonia present, which could reflect suppression of ammonia uptake by OA. This would explain the long-term decline of ammonium aerosol in the southeast US, paralleling that of sulfate. The vertical profile of aerosol extinction over the southeast US follows closely that of aerosol mass. GEOS-Chem reproduces observed total column aerosol mass over the southeast US within 6 %, column aerosol extinction within 16 %, and space-based AOD within 8-28 % (consistently biased low). The large AOD decline observed from summer to winter is driven by sharp declines in both sulfate and OA from August to October. These declines are due to shutdowns in both biogenic emissions and UV-driven photochemistry. Surface PM2.5 shows far less summer-to-winter decrease than AOD and we attribute this in part to the offsetting effect of weaker boundary layer ventilation. The SEAC4RS aircraft data demonstrate that AODs measured from space are consistent with surface PM2.5. This implies that satellites can be used reliably to infer surface PM2.5 over monthly timescales if a good CTM representation of the aerosol vertical profile is available.
The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very ...early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 2.5‐4.4 versus 1.6 1.5‐1.8). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178‐1188)
Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune ...system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.
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•PDAC long-term survivors display high tumor microbial diversity and immunoactivation•A PDAC tumoral microbiome signature predicts PDAC long-term survival•The gut microbiome modulates the PDAC tumor microbiome landscape•Fecal microbial transplants can modulate tumors immunosuppression and growth
The distinct tumor microbiome from pancreatic cancer long-term survivors can be used to predict PDAC survival in humans, and transfer of long-term survivor gut microbiomes can alter the tumor microbiome and tumor growth in mouse models.
Gene fusion is involved in the development of various types of malignancies. Recent advances in sequencing technology have facilitated identification of gene fusions and have stimulated the research ...of this field in cancer. In the present study, we performed next-generation transcriptome sequencing in order to discover novel gene fusions in gastric cancer. A total of 282 fusion transcript candidates were detected from 12 gastric cancer cell lines by bioinformatic filtering. Among the candidates, we have validated 19 fusion transcripts, which are 7 inter-chromosomal and 12 intra-chromosomal fusions. A novel DUS4L-BCAP29 fusion transcript was found in 2 out of 12 cell lines and 10 out of 13 gastric cancer tissues. Knockdown of DUS4L-BCAP29 transcript using siRNA inhibited cell proliferation. Soft agar assay further confirmed that this novel fusion transcript has tumorigenic potential. We also identified that microRNA-coding gene PVT1, which is amplified in double minute chromosomes in SNU-16 cells, is recurrently involved in gene fusion. PVT1 produced six different fusion transcripts involving four different genes as fusion partners. Our findings provide better insight into transcriptional and genetic alterations of gastric cancer: namely, the tumorigenic effects of transcriptional read-through and a candidate region for genetic instability.
The ‘epidemic’ of heart failure seems to be changing, but precise prevalence estimates of heart failure and left ventricular dysfunction (LVD) in older adults, based on adequate echocardiographic ...assessment, are scarce. Systematic reviews including recent studies on the prevalence of heart failure and LVD are lacking. We aimed to assess the trends in the prevalence of LVD, and heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) in the older population at large. A systematic electronic search of the databases Medline and Embase was performed. Studies that reported prevalence estimates in community‐dwelling people ≥60 years old were included if echocardiography was used to establish the diagnosis. In total, 28 articles from 25 different study populations were included. The median prevalence of systolic and ‘isolated’ diastolic LVD was 5.5% (range 3.3–9.2%) and 36.0% (range 15.8–52.8%), respectively. A peak in systolic dysfunction prevalence seems to have occurred between 1995 and 2000. ‘All type’ heart failure had a median prevalence rate of 11.8% (range 4.7–13.3%), with fairly stable rates in the last decade and with HFpEF being more common than HFrEF median prevalence 4.9% (range 3.8–7.4%) and 3.3% (range 2.4–5.8%), respectively. Both LVD and heart failure remain common in the older population at large. The prevalence of diastolic dysfunction is on the rise and currently higher than that of systolic dysfunction. The prevalence of the latter seems to have decreased in the 21st century.
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