Solitary fibrous tumors are an uncommon sarcoma type characterized by NAB2-STAT6 gene fusion. While solitary fibrous tumors metastasize in 5-25% of cases, it has historically been challenging to ...determine which specific tumor and patient characteristics predict aggressive behavior. We previously reported on a novel risk stratification scheme for solitary fibrous tumors incorporating patient age, tumor size, and mitotic activity to predict risk of metastasis. Herein we validate this risk stratification scheme in an independent, lower-risk population of 79 patients with primary non-meningeal solitary fibrous tumors, and propose incorporating tumor necrosis as a fourth variable to further improve the risk score. Fifty-seven percent of cases were considered low risk, 29% intermediate risk, and 14% high risk for metastasis. Of 50 patients with sufficient clinical follow-up data, no metastases developed in the low-risk patients (n=23), while there was a 7% 10-year metastatic risk in the intermediate risk group (n=17), and a 49% 5-year metastatic risk for the high-risk patients (n=10). When tumor necrosis was added as a fourth variable to the model, predictive power was enhanced. Under the revised stratification, the proportion of tumors identified as low risk increased to 66%, with no metastasis at 10 years, intermediate risk cases comprised 24% with 10% risk of metastasis at 10 years, and high risk comprised 10% of cases with 73% risk of metastasis at 5 years. In Kaplan-Meier analysis, this fourth-variable stratification provided significant discrimination between the risk groups (P=0.0005). These findings confirmed the clinical utility of our previously published risk stratification model and support the inclusion of necrosis as a fourth variable in the model.
A portion of the charcoal and soot produced during combustion processes on land (e.g., wildfire, burning of fossil fuels) enters aquatic systems as dissolved black carbon (DBC). In terms of mass ...flux, rivers are the main identified source of DBC to the oceans. Since DBC is believed to be representative of the refractory carbon pool, constraining sources of marine DBC is key to understanding the long-term persistence of carbon in our global oceans. Here, we use compound-specific stable carbon isotopes (δ
C) to reveal that DBC in the oceans is ~6‰ enriched in
C compared to DBC exported by major rivers. This isotopic discrepancy indicates most riverine DBC is sequestered and/or rapidly degraded before it reaches the open ocean. Thus, we suggest that oceanic DBC does not predominantly originate from rivers and instead may be derived from another source with an isotopic signature similar to that of marine phytoplankton.
The voltage-dependent anion channel (VDAC) mediates trafficking of small molecules and ions across the eukaryotic outer mitochondrial membrane. VDAC also interacts with antiapoptotic proteins from ...the Bcl-2 family, and this interaction inhibits release of apoptogenic proteins from the mitochondrion. We present the nuclear magnetic resonance (NMR) solution structure of recombinant human VDAC-1 reconstituted in detergent micelles. It forms a 19-stranded β barrel with the first and last strand parallel. The hydrophobic outside perimeter of the barrel is covered by detergent molecules in a beltlike fashion. In the presence of cholesterol, recombinant VDAC-1 can form voltage-gated channels in phospholipid bilayers similar to those of the native protein. NMR measurements revealed the binding sites of VDAC-1 for the Bcl-2 protein Bcl-xL, for reduced β-nicotinamide adenine dinucleotide, and for cholesterol. Bcl-xL interacts with the VDAC barrel laterally at strands 17 and 18.
1. Climate-associated changes in forest composition have been widely reported, particularly where changes in abiotic conditions have resulted in high mortality of sensitive species and have ...disproportionately favoured certain species better adapted to these newer conditions. In the north-eastern USA and south-eastern Canada, few studies have examined climate-related influences associated with forest composition, and none have considered broad-scale changes over a long temporal (>25 years) period. 2. We used US Forest Service Forest Inventory and Analysis data from 1983 to 2014 across four north-eastern states (Maine, New Hampshire, New York and Vermont) to assess temporal and spatial changes in the occurrence and abundance of American beech Fagus grandifolia Ehrh, sugar maple Acer saccharum L., red maple Acer rubrum L. and birch Betula spp. saplings. We also tested the effects of biotic and abiotic factors on the distribution of the four studied deciduous species over the entire period examined. 3. Occurrence and abundance of American beech have increased substantially over the past three decades, whereas the occurrence and abundance of three other deciduous species have decreased in all ecological provinces of the north-eastern USA, except the Midwest Broadleaf ecological province. Consequently, a clear shift in species composition is currently underway in the beech-maple-birch (BMB) forests of the north-eastern USA, with uncertain consequences for future ecosystem structure and function. 4. In the studied region and over the entire period examined, the distribution of increased occurrence and abundance of beech relative to the three other deciduous species were associated with higher temperature and precipitation as well as higher conspecific basal area and dead tree basal area. 5. Synthesis and applications. The change from beech-maple-birch forests to more beech-dominated forests with beech encroachment to new forest areas across the north-eastern USA may continue if higher intensity harvesting and disturbances (i.e. large-scale canopy openings) do not occur. This would be a significant management concern as beech is associated with a widespread bark disease, is commercially less desirable, and can limit natural regeneration from other species. Our results emphasize the need for management strategies such as higher intensity harvesting methods, vegetation control and limiting browsing pressure to reduce beech dominance.
Summary Background Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and ...sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. Methods In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov , number NCT00326898. Findings Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 44% of 438 patients on sunitinib, 199 45% of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6–8·2) for sunitinib (hazard ratio HR 1·02, 97·5% CI 0·85–1·23, p=0·8038), 6·1 years (IQR 1·7–not estimable NE) for sorafenib (HR 0·97, 97·5% CI 0·80–1·17, p=0·7184), and 6·6 years (IQR 1·5–NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 17% patients on sunitinib and 102 16% patients on sorafenib), hand-foot syndrome (94 15% patients on sunitinib and 208 33% patients on sorafenib), rash (15 2% patients on sunitinib and 95 15% patients on sorafenib), and fatigue (110 17% patients on sunitinib and 44 7% patients on sorafenib). There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. Interpretation Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. Funding US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.
PURPOSE Perivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known ...effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus. PATIENTS AND METHODS Patients with advanced PEComa were treated with sirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined by computed tomography scans obtained at the clinical discretion of the treating physicians. Tumors were assessed for immunohistochemical evidence of mTORC1 activation and genetic evidence of alterations in TSC1 and TSC2. Results Radiographic responses to sirolimus were observed in all patients. PEComas demonstrated loss of TSC2 protein expression and evidence of baseline mTORC1 activation. Homozygous loss of TSC1 was identified in one PEComa. CONCLUSION Inhibition of mTORC1, pathologically activated by loss of the TSC1/TSC2 tumor suppressor complex, is a rational mechanistic target for therapy in PEComas. The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex.
There is increasing evidence that obesity and overweight may be related, in part, to adverse work conditions. In particular, the risk of obesity may increase in high-demand, low-control work ...environments, and for those who work long hours. In addition, obesity may modify the risk for vibration-induced injury and certain occupational musculoskeletal disorders. We hypothesized that obesity may also be a co-risk factor for the development of occupational asthma and cardiovascular disease that and it may modify the worker's response to occupational stress, immune response to chemical exposures, and risk of disease from occupational neurotoxins. We developed 5 conceptual models of the interrelationship of work, obesity, and occupational safety and health and highlighted the ethical, legal, and social issues related to fuller consideration of obesity's role in occupational health and safety.
The means by which the physicochemical properties of different cellular components together determine bacterial cell shape remain poorly understood. Here, we investigate a programmed cell-shape ...change during Bacillus subtilis sporulation, when a rod-shaped vegetative cell is transformed to an ovoid spore. Asymmetric cell division generates a bigger mother cell and a smaller, hemispherical forespore. The septum traps the forespore chromosome, which is translocated to the forespore by SpoIIIE. Simultaneously, forespore size increases as it is reshaped into an ovoid. Using genetics, timelapse microscopy, cryo-electron tomography, and mathematical modeling, we demonstrate that forespore growth relies on membrane synthesis and SpoIIIE-mediated chromosome translocation, but not on peptidoglycan or protein synthesis. Our data suggest that the hydrated nucleoid swells and inflates the forespore, displacing ribosomes to the cell periphery, stretching septal peptidoglycan, and reshaping the forespore. Our results illustrate how simple biophysical interactions between core cellular components contribute to cellular morphology.
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•Chromosome translocation reversibly inflates the forespore•The forespore volume increases at the expense of the mother cell volume•Forespore growth relies on membrane, but not on peptidoglycan synthesis•DNA-generated turgor pressure reshapes the forespore
DNA generates the turgor pressure that inflates the forespore in B. subtilis spore development.
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