Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier ...to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.
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•Exome sequencing in 1,001 DLBCL patients comprehensively identifies 150 driver genes•Unbiased CRISPR screen in DLBCL cell lines identifies essential oncogenes•Integrative analysis connects genomics, CRISPR hits, and clinical outcome•A genomic risk model of survival outperforms existing risk-assessment methods
An integrative analysis in 1,001 newly diagnosed DLBCL patients identifies 150 genetic drivers with functional characterization using an unbiased CRISPR screen in DLBCL cell lines and connects with clinical outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
From 1980 to 2002, China experienced a 5% average annual reduction in energy consumption per unit of gross domestic product (GDP). With a dramatic reversal of this historic relationship, energy ...intensity increased 5% per year during 2002–2005. China's 11th Five Year Plan (FYP) set a target of reducing energy intensity by 20% by 2010. This paper assesses selected policies and programs that China has instituted to fulfill the national goal, finding that China made substantial progress and many of the energy-efficiency programs appear to be on track to meet – or in some cases exceed – their energy-saving targets. Most of the Ten Key Projects, the Top-1000 Program, and the Small Plant Closure Program will meet or surpass the 11th FYP savings goals. China's appliance standards and labeling program has become very robust. China has greatly enhanced its enforcement of new building energy standards but energy-efficiency programs for buildings retrofits, as well as the goal of adjusting China's economic structure, are failing. It is important to maintain and strengthen the existing energy-saving policies and programs that are successful while revising programs or adding new policy mechanisms to improve the programs that are not on track to achieve the stated goals.
► This paper assesses selected national energy efficiency policies and programs China. ► The policies were established to fulfill the 11th Five Year Plan energy efficiency improvement goal. ► Many of the programs appear to be on track to meet or exceed their energy-saving targets. ► For the 12th Five Year Plan, it is important to maintain and strengthen energy-saving policies. ► Recommendations are made for revising or adding programs based on international experience.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The self-assembly of nanomaterials into three-dimensional hierarchical structures is a fundamental step impacting a large number of synthetic and natural processes. These range from the scalable ...fabrication of nano-devices such as batteries, sensors and third generation solar cells to the uptake and accumulation of particulate pollution in the lung alveoli. Here, we show that the Dynamic behavior of ultra-fine particles (UFP < 100 nm) diverges significantly from that of sub- and micro equivalents. For freely diffusing bodies, this leads to the formation of stochastically reproducible films that approach the morphology and density of ballistically deposited ones. A novel deposition mechanism and regime are proposed that successfully capture the full spectrum of size-dependent self-assembly dynamics. These findings are a significant step toward the engineering of scalable parallel nano-fabrication approaches, and the understanding of the interaction of unbound nanostructures with their surrounding.
Study of J/ψ→ωpp̄ at BESIII Albayrak, O.; Bennett, J. V.; Boger, E. ...
Physical review. D, Particles, fields, gravitation, and cosmology,
06/2013, Volume:
87, Issue:
11
Journal Article
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
The pyruvate oxidase (SpxB)–dependent production of H2O2 is widely distributed among oral commensal streptococci. Several studies confirmed the ability of H2O2 to antagonize susceptible oral ...bacterial species, including caries-associated Streptococcus mutans as well as several periodontal pathobionts. Here we report a potential mechanism to bolster oral commensal streptococcal H2O2 production by magnesium (Mg2+) supplementation. Magnesium is a cofactor for SpxB catalytic activity, and supplementation increases the production of H2O2 in vitro. We demonstrate that Mg2+ affects spxB transcription and SpxB abundance in Streptococcus sanguinis and Streptococcus gordonii. The competitiveness of low-passage commensal streptococcal clinical isolates is positively influenced in antagonism assays against S. mutans. In growth conditions normally selective for S. mutans, Mg2+ supplementation is able to increase the abundance of S. sanguinis in dual-species biofilms. Using an in vivo biophotonic imaging platform, we further demonstrate that dietary Mg2+ supplementation significantly improves S. gordonii oral colonization in mice. In summary, our results support a role for Mg2+ supplementation as a potential prebiotic to promote establishment of oral health–associated commensal streptococci.
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CMK, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
The oxidation of the Cr
III hydroxy complex, Tp
tBu,MeCr(pz
′)(OH),
1, (Tp
tBu,Me=hydrotris(3-
tert-butyl-5-methylpyrazolyl)borate; pz
′=3-
tert-butyl-5-methylpyrazolyl anion) was studied in ...methylene chloride at a glassy carbon electrode. There are two oxidation peaks, Ia and IIa, that are totally irreversible and Cr
IV oxo complex
2 is the product at both peaks. Peak Ia grows with respect to IIa as the scan rate is reduced and the voltammograms were quantitatively accounted for by a CE
irr mechanism involving two interconverting forms of
1,
1a giving peak Ia and
1b giving peak IIa. The reduction of
2 is detected on the return scan along with a small amount of
3 that arises from hydrogen-atom abstraction by
2 from hydrogen-atom donors in the medium. The processes giving rise to peaks Ia and IIa have the characteristics of dissociative electron- transfer reactions. It is suggested that they may be concerted electron-proton transfer reactions. It is speculated that the postulated minor form of
1,
1a, may be an isomer having axial OH rather than the equatorial OH found in the favored isomer,
1b.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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.
Summary Background Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be ...crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov , number NCT01016015. Findings Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3–4. The most common grade 3–4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). Interpretation The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The strong absorption and reflection from atomically thin graphene nanoribbons has been demonstrated over the past decade. However, due to the significant band dispersion of graphene nanoribbons, the ...angle of incident wave has remained limited to a very narrow range. Obtaining strong absorption and reflection with a wide range of incident angles from atomically thin graphene layers has remained an unsolvable problem. Here, we construct a tunable moiré superlattice composed of a pair of graphene nanoribbon arrays to achieve this goal. By designing the interlayer coupling between two graphene nanoribbon arrays with mismatched periods, the moiré flat bands and the localization of their eigen-fields was realized. Based on the moiré flat bands of graphene nanoribbons, highly efficient reflection and nearly perfect absorption was achieved with a wide range of incident angles. Even more interesting, is how these novel phenomena can be tuned through the adjustment of the graphene's Fermi energy, either electrostatically or chemically. Our designed moiré graphene nanoribbons suggest a promising platform to engineer moiré physics with tunable behaviors, and may have potential applications in the field of wide-angle absorbers and reflectors in the mid-infrared region.
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