Clusters of the main group elements phosphorus and arsenic, commonly categorized as Zintl clusters, have been known for over a century. And, only now is the application of these systems as catalysts ...for organic synthesis being investigated. In this work, boranes are tethered via an aliphatic linker to Zintl-based clusters and their Lewis acidity is examined experimentally, by the Gutmann-Beckett test and competency in the hydroborative reduction of six organic substrates, as well as computationally, by fluoride ion affinity and hydride ion affinity methods. The effects of tuning the aliphatic linker length, substituents at the boron, and changing the cluster from a seven-atom phosphorus system to a seven-atom arsenic system on reactivity are studied.
INTRODUCTION: Phosphorus is a fundamental nutrient for primary productivity of ecosystems and agricultural production, but its misuse impacts agricultural sustainability and has important ...environmental consequences. Access to global reserves of phosphate rock is politically sensitive and economically challenging. Phosphorus accumulates in agricultural soils, representing a financial loss to farmers and increasing the risk of loss to water. The challenges facing phosphorus sustainability are varied, but many solutions are to be found in the plant–soil system. SCOPE: This special issue arises from the 5th International Symposium on Phosphorus in Soils and Plants (PSP5), held in Montpellier, France. Articles highlighted here discuss ways to tackle food security, improve phosphorus sustainability by understanding the imbalanced phosphorus cycle, use technology to reduce phosphorus demand and recycle phosphorus in waste products, and consider how efforts to increase phosphorus efficiency interact with other sustainability challenges. CONCLUSIONS: The challenges associated with P sustainability are tackled from many different directions, including plant genetics, soil microbiology, novel imaging and modelling techniques, the development of new technologies, and an improved understanding of how these technologies interact with agronomic management. Integration of the various approaches will be necessary to deliver a truly effective solution to the challenge of attaining phosphorus sustainability.
Human land use activities have resulted in large changes to the biogeochemical and biophysical properties of the Earth's surface, with consequences for climate and other ecosystem services. In the ...future, land use activities are likely to expand and/or intensify further to meet growing demands for food, fiber, and energy. As part of the World Climate Research Program Coupled Model Intercomparison Project (CMIP6), the international community has developed the next generation of advanced Earth system models (ESMs) to estimate the combined effects of human activities (e.g., land use and fossil fuel emissions) on the carbon–climate system. A new set of historical data based on the History of the Global Environment database (HYDE), and multiple alternative scenarios of the future (2015–2100) from Integrated Assessment Model (IAM) teams, is required as input for these models. With most ESM simulations for CMIP6 now completed, it is important to document the land use patterns used by those simulations. Here we present results from the Land-Use Harmonization 2 (LUH2) project, which smoothly connects updated historical reconstructions of land use with eight new future projections in the format required for ESMs. The harmonization strategy estimates the fractional land use patterns, underlying land use transitions, key agricultural management information, and resulting secondary lands annually, while minimizing the differences between the end of the historical reconstruction and IAM initial conditions and preserving changes depicted by the IAMs in the future. The new approach builds on a similar effort from CMIP5 and is now provided at higher resolution (0.25°×0.25°) over a longer time domain (850–2100, with extensions to 2300) with more detail (including multiple crop and pasture types and associated management practices) using more input datasets (including Landsat remote sensing data) and updated algorithms (wood harvest and shifting cultivation); it is assessed via a new diagnostic package. The new LUH2 products contain > 50 times the information content of the datasets used in CMIP5 and are designed to enable new and improved estimates of the combined effects of land use on the global carbon–climate system.
Highly aggressive, metastatic and therapeutically resistant triple-negative breast cancers (TNBCs) are often enriched for cancer stem cells (CSC). Cytokines within the breast tumor microenvironment ...(TME) influence the CSC state by regulating tumor cell differentiation programs. Two prevalent breast TME cytokines are oncostatin-M (OSM) and interferon-β (IFN-β). OSM is a member of the IL-6 family of cytokines and can drive the de-differentiation of TNBC cells to a highly aggressive CSC state. Conversely, IFN-β induces the differentiation of TNBC, resulting in the repression of CSC properties. Here, we assess how these breast TME cytokines influence CSC plasticity and clinical outcome.
Using transformed human mammary epithelial cell (HMEC) and TNBC cell models, we assessed the CSC markers and properties following exposure to OSM and/or IFN-β. CSC markers included CD24, CD44, and SNAIL; CSC properties included tumor sphere formation, migratory capacity, and tumor initiation.
There are three major findings from our study. First, exposure of purified, non-CSC to IFN-β prevents OSM-mediated CD44 and SNAIL expression and represses tumor sphere formation and migratory capacity. Second, during OSM-induced de-differentiation, OSM represses endogenous IFN-β mRNA expression and autocrine/paracrine IFN-β signaling. Restoring IFN-β signaling to OSM-driven CSC re-engages IFN-β-mediated differentiation by repressing OSM/STAT3/SMAD3-mediated SNAIL expression, tumor initiation, and growth. Finally, the therapeutic use of IFN-β to treat OSM-driven tumors significantly suppresses tumor growth.
Our findings suggest that the levels of IFN-β and OSM in TNBC dictate the abundance of cells with a CSC phenotype. Indeed, TNBCs with elevated IFN-β signaling have repressed CSC properties and a better clinical outcome. Conversely, TNBCs with elevated OSM signaling have a worse clinical outcome. Likewise, since OSM suppresses IFN-β expression and signaling, our studies suggest that strategies to limit OSM signaling or activate IFN-β signaling will disengage the de-differentiation programs responsible for the aggressiveness of TNBCs.
Approaches to the management of portal hypertension and variceal hemorrhage in pediatrics remain controversial, in large part because they are not well informed by rigorous clinical studies. ...Fundamental biological and clinical differences preclude automatic application of approaches used for adults to children. On April 11‐12, 2015, experts in the field convened at the first Baveno Pediatric Satellite Meeting to discuss and explore current available evidence regarding indications for MesoRex bypass (MRB) in extrahepatic portal vein obstruction and the role of primary prophylaxis of variceal hemorrhage in children. Consensus was reached regarding MRB. The vast majority of children with extrahepatic portal vein obstruction will experience complications that can be prevented by successful MRB surgery. Therefore, children with extrahepatic portal vein obstruction should be offered MRB for primary and secondary prophylaxis of variceal bleeding and other complications, if appropriate surgical expertise is available, if preoperative and intraoperative evaluation demonstrates favorable anatomy, and if appropriate multidisciplinary care is available for postoperative evaluation and management of shunt thrombosis or stenosis. In contrast, consensus was not achieved regarding primary prophylaxis of varices. Although variceal hemorrhage is a concerning complication of portal hypertension in children, the first bleed appears to be only rarely fatal and the associated morbidity has not been well characterized. Conclusion: There are few pediatric data to indicate the efficacy and safety of pharmacologic or endoscopic therapies as primary prophylaxis or that prevention of a sentinel variceal bleed will ultimately improve survival; therefore, no recommendation for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta‐blockade in children was proposed. (Hepatology 2016;63:1368–1380)
Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant ...chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain.
We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects.
From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval CI, 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy.
In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).
Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the ...mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.
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•MYC dramatically accelerates tumorigenesis and metastases in Rb1/Trp53 null SCLC•MYC promotes a NEUROD1+, neuroendocrine-low subtype with variant histopathology•MYC-driven SCLCs are chemo-sensitive but rapidly relapse•MYC sensitizes SCLC to combined Aurora kinase inhibition and chemotherapy treatment
Mollaoglu et al. generate a mouse model of small cell lung cancer (SCLC) with elevated Myc expression and loss of Rb1 and Trp53. MYC promotes a neuroendocrine-low variant subtype of SCLC, which is paralleled in patients. Mouse and human SCLC with high MYC levels display sensitivity to Aurora kinase inhibition.
The global shortage of donor corneas has garnered extensive interest in the development of graft alternatives suitable for endothelial keratoplasty using cultivated primary human corneal endothelial ...cells (CECs). We have recently described a dual media approach for the propagation of human CECs. In this work, we characterize the effects of a Rho-kinase inhibitor Y-27632 on the cultivation of CECs propagated using the dual media culture system. Seventy donor corneas deemed unsuitable for transplantation were procured for this study. We assessed the use of Y-27632 for its effect at each stage of the cell culture process, specifically for cell attachment, cell proliferation, and during both regular passaging and cryopreservation. Lastly, comparison of donor-matched CEC-cultures expanded with or without Y-27632 was also performed. Our results showed that Y-27632 significantly improved the attachment and proliferation of primary CECs. A non-significant pro-survival effect was detected during regular cellular passage when CECs were pre-treated with Y-27632, an effect that became more evident during cryopreservation. Our study showed that the inclusion of Y-27632 was beneficial for the propagation of primary CECs expanded via the dual media approach, and was able to increase overall cell yield by between 1.96 to 3.36 fold.
Standardized benchmarking approaches are required to assess the accuracy of variants called from sequence data. Although variant-calling tools and the metrics used to assess their performance ...continue to improve, important challenges remain. Here, as part of the Global Alliance for Genomics and Health (GA4GH), we present a benchmarking framework for variant calling. We provide guidance on how to match variant calls with different representations, define standard performance metrics, and stratify performance by variant type and genome context. We describe limitations of high-confidence calls and regions that can be used as truth sets (for example, single-nucleotide variant concordance of two methods is 99.7% inside versus 76.5% outside high-confidence regions). Our web-based app enables comparison of variant calls against truth sets to obtain a standardized performance report. Our approach has been piloted in the PrecisionFDA variant-calling challenges to identify the best-in-class variant-calling methods within high-confidence regions. Finally, we recommend a set of best practices for using our tools and evaluating the results.
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