The past decade has witnessed the golden age of homogeneous gold-catalyzed reactions, especially those that involve the transformation of highly strained molecules into complex molecular ...architectures. Gold catalysts, with unique electronic properties and catalytic abilities, have elevated versatile reaction modes through π-interaction induced activation. On the basis of increasing research interest in this topic, together with the significant development of various ligands, including phosphine ligands and azacyclic or noncyclic carbene ligands, the understanding of the catalytic function of gold catalysts has become much deeper and more comprehensive. Different reaction needs thus could be adapted by a novel gold catalyst with a diversified ligand selection. Furthermore, the whole evolution of the gold catalysis on synthetic methodologies has realized and expanded its application into natural product synthesis as well as the potentiality of drug discovery, which endows this ancient metal with a magnificent renaissance. The reactivity of strained small ring molecules with high tension has always been an important research topic in organic chemistry. When the highly strained small ring is linked with a π-electron rich moiety or contains a heteroatom, the gold activation of the π-system or coordination with the heteroatom can initiate a cascade reaction, usually followed by ring opening or expansion. These processes can result in the rapid construction of complex and distinct molecular structures, many of which feature in biologically important molecules. In this review, we will mainly summarize the advances on diverse reaction types and molecular constructions accomplished by homogeneous gold catalysis using highly strained substrates, including methylenecyclopropanes (MCPs), vinylidenecyclopropanes (VDCPs), cyclopropenes as well as aziridine- and epoxide-containing molecules, focusing on the last 10 years. For functionalized alkynyl cyclopropanes, several early inspiring and elegant examples will be described in this review for systematically understanding these transformations.
A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective ...breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development.
•Most breast tumors survive glutamine restriction, limiting its therapeutic use•A subset of triple-negative breast tumors are true glutamine auxotrophs•Conventional biomarkers of glutamine reliance do not identify true auxotrophs•Triple-negative tumors require cystine import via the xCT transporter
Aim
To investigate the effect of simvastatin on lipopolysaccharide (LPS)‐stimulated inflammatory cytokines, cell adhesion molecules and nuclear factor‐κB (NF‐κB) transcription factors in human dental ...pulp cells (HDPCs).
Methodology
The effect of LPS and simvastatin on human dental pulp cell (HDPCs) viability was measured using a 3‐4, 5‐dimethylthiazol‐2‐yl‐2, 5 diphenyltetrazolium bromide (MTT) assay. The expression of inflammatory cytokines and cell adhesion molecules was evaluated by reverse‐transcription polymerase chain reaction (RT‐PCR), enzyme‐linked immunosorbent assay (ELISA) and Western blot analysis. NF‐κB transcription factors were evaluated by Western blot analysis. Statistical analysis was performed with analysis of variance (anova).
Results
The viability of cells exposed to different concentrations of E. coli LPS, P. gingivalis LPS and simvastatin was not significantly different compared with that of control cells (P > 0.05). LPS significantly increased interleukin (IL)‐1β (P < 0.05) and IL‐6 mRNA expression (P < 0.05) and vascular cell adhesion molecule‐1 (VCAM‐1) (P < 0.05) and intercellular adhesion molecule‐1 (ICAM‐1) protein expression (P < 0.05) in HDPCs. Treatment with simvastatin significantly attenuated LPS‐stimulated production of IL‐1β, IL‐6, VCAM‐1 and ICAM‐1 (P < 0.05). Treatment with simvastatin decreased LPS‐induced expression of p65 and phosphorylation of IκB and also significantly decreased the phosphorylation of p65 and IκB in the cytoplasm and the level of p65 in the nucleus (P < 0.05).
Conclusions
Simvastatin has a suppressing effect on LPS‐induced inflammatory cytokine, cell adhesion molecules and NF‐κB transcription factors in HDPCs. Therefore, simvastatin might be a useful candidate as a pulp‐capping agent in vital pulp therapy.
Previously, it was shown in patients with low rectal cancer that a short-axis (SA) lateral node size of 7 mm or greater on primary magnetic resonance imaging (MRI) resulted in a high lateral local ...recurrence (LLR) rate after chemoradiotherapy or radiotherapy (CRT) with total mesorectal excision (TME) and that this risk was lowered by a lateral lymph node dissection (LLND). The role of restaging MRI after (C)RT with regard to LLR risk and which specific patients might benefit from an LLND is not fully understood.
To determine the factors on primary and restaging MRI that are associated with LLR in low rectal cancer after (C)RT and to formulate specific guidelines on which patients might benefit from an LLND.
In this retrospective, multicenter, pooled cohort study, patients who underwent surgery for cT3 or cT4 low rectal cancer with a curative intent from 12 centers in 7 countries from January 2009 to December 2013 were included. All patients' MRIs were rereviewed according to a standardized protocol, with specific attention to lateral nodal features. The original cohort included 1216 patients. For this study, patients who underwent (C)RT and had a restaging MRI were selected, leaving 741 for analyses across 10 institutions, including 651 who underwent (C)RT with TME and 90 who underwent (C)RT with TME and LLND.
The main purpose was to identify the factors on primary and restaging MRI associated with LLR after (C)RT with TME. Whether high-risk patients might benefit in terms of LLR reduction from an LLND was also studied.
Of the 741 included patients, 480 (64.8%) were male, and the mean (SD) age was 60.4 (12.0) years. An SA lateral node size of 7 mm or greater on primary MRI resulted in a 5-year LLR rate of 17.9% after (C)RT with TME. At 3 years, there were no LLRs in 28 patients (29.2%) with lateral nodes that were 4 mm or less on restaging MRI. Nodes that were 7 mm or greater on primary MRI and greater than 4 mm on restaging MRI in the internal iliac compartment resulted in a 5-year LLR rate of 52.3%, significantly higher compared with nodes in the obturator compartment of that size (9.5%; hazard ratio, 5.8; 95% CI, 1.6-21.3; P = .003). Compared with (C)RT with TME alone, treatment with (C)RT with TME and LLND in these unresponsive internal nodes resulted in a significantly lower LLR rate of 8.7% (hazard ratio, 6.2; 95% CI, 1.4-28.5; P = .007).
Restaging MRI is important in clinical decision making in lateral nodal disease. In patients with shrinkage of lateral nodes from an SA node size of 7 mm or greater on primary MRI to an SA node size of 4 mm or less on restaging MRI, which occurs in about 30% of cases, LLND can be avoided. However, persistently enlarged nodes in the internal iliac compartment indicate an extremely high risk of LLR, and an LLND lowered LLR in these cases.
Abstract Purpose The study evaluates and quantifies the potential dosimetric gains of helical tomotherapy (HT) versus step-and-shoot intensity-modulated radiotherapy (SaS-IMRT) for nasopharyngeal ...carcinoma (NPC). Materials and methods Twenty consecutive NPC patients curatively treated by HT were examined. Each case was planned by HT and SaS-IMRT (ADAC Pinnacle3 ) planning system, respectively. Dose plans were compared using dose volume histograms (DVH), conformity index ( CI ), homogeneity index ( HI ), and minimal dose to 1 cc ( Dmin_1cc ) of the planned target volume (PTV) and a comprehensive quality index ( CQI ) of ten organs at risk (OARs). The prescribed dose/fractionation was 72 Gy to the PTV, 64.8 Gy to the elective PTV, and 54 Gy to the clinically negative neck region. The plan of 54 Gy to the PTV (PTV54 ) was used to evaluate the CI and HI in the target. The cumulative doses of the three PTV plans to the OARs were calculated. Results We observed the HT plans significantly improved the CI (improvement ratio: 11.9 ± 5.5%) and HI (improvement ratio: 8.8 ± 1.5%) of the PTV54 compared with SaS-IMRT plans. In addition, the mean/maximal dose of most of the OARs except chiasm was significantly reduced in HT plans, with the CQI of 0.92 ± 0.08. A negative result of HT in chiasm was observed but only significantly revealed in cases without skull base infiltration. Conclusions A dosimetric gain in CI and HI of PTV and sparing of OARs was significantly obtained in HT versus SaS-IMRT plans in NPC patients. Whether such dosimetric superiority in HT could transfer into clinical advantages needs further investigation.
We present new data obtained with the Submillimeter Array for a sample of 14 nearby luminous and ultraluminous infrared galaxies. The galaxies were selected to have distances image Mpc and ...far-infrared luminosities image. The galaxies were observed with spatial resolutions of order 1 kpc in the CO image, CO image, super(13)CO image, and HCO super(+) image lines as well as the continuum at 880 mum and 1.3 mm. We have combined our CO and continuum data to measure an average gas-to-dust mass ratio of image (rms deviation 109) in the central regions of these galaxies, very similar to the value of 150 determined for the Milky Way. This similarity is interesting given the more intense heating from the starburst and possibly accretion activity in the luminous infrared galaxies compared to the Milky Way. We find that the peak H sub(2) surface density correlates with the far-infrared luminosity, which suggests that galaxies with higher gas surface densities inside the central kiloparsec have a higher star formation rate. The lack of a significant correlation between total H sub(2) mass and far-infrared luminosity in our sample suggests that the increased star formation rate is due to the increased availability of molecular gas as fuel for star formation in the central regions. In contrast to previous analyses by other authors, we do not find a significant correlation between central gas surface density and the star formation efficiency, as traced by the ratio of far-infrared luminosity to nuclear gas mass. Our data show that it is the star formation rate, not the star formation efficiency, that increases with increasing central gas surface density in these galaxies.
A
bstract
Recasting phenomenological Lagrangians in terms of SM effective field theory (SMEFT) provides a valuable means of connecting potential BSM physics at momenta well above the electroweak ...scale to experimental signatures at lower energies. In this work we jointly fit the Wilson coefficients of SMEFT operators as well as the PDFs in an extension of the CT18 global analysis framework, obtaining self-consistent constraints to possible BSM physics effects. Global fits are boosted with machine-learning techniques in the form of neural networks to ensure efficient scans of the full PDF+SMEFT parameter space. We focus on several operators relevant for top-quark pair and jet production at hadron colliders and obtain constraints on the Wilson coefficients with Lagrange Multiplier scans. We find mild correlations between the extracted Wilson coefficients, PDFs, and other QCD parameters, and see indications that these correlations may become more prominent in future analyses based on data of higher precision. This work serves as a new platform for joint analyses of SM and BSM physics based on the CTEQ-TEA framework.
The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties
. Here we ...report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain.
The hematopoietic SCT (HSCT) activity in nine Asian countries/regions was surveyed to overview the current situation. Data of 58 113 HSCTs (allogeneic: 63% vs autologous: 37%) performed between 1986 ...and 2006 by 432 transplant teams were collected. The number of HSCTs has been increasing in the past two decades in most countries/regions. The increase in allogeneic HSCTs is greater than in autologous HSCTs. The proportion of unrelated donors among allogeneic HSCTs in 2006 varied widely from <1% (Iran and Vietnam) to 62% (Japan). The use of each stem cell source, that is, BM, PBSC, cord blood and others (including co-infusion of BM and PBSC), also varied widely (36, 58, 0.1 and 6% in HSCT from related donors, respectively, and 53, 11, 35 and 1% in HSCT from unrelated donors, respectively). HSCTs have been continuously increasing for all indications except for chronic myelogenous leukemia and solid tumors. Hemoglobinopathy is a common indication among non-malignant diseases in many Asian countries/regions except for China, Japan and Korea. This survey clearly shows the recent progress of HSCTs in Asia and also some differences in donor and stem cell selection and disease application among countries/regions.
In Search of Wasserman’s Catenane Baluna, Andrei S.; Galan, Albano; Leigh, David A. ...
Journal of the American Chemical Society,
05/2023, Volume:
145, Issue:
17
Journal Article
Peer reviewed
Open access
We repeat the earliest claimed 2catenane synthesis, reported by Wasserman over 60 years ago, in order to ascertain whether or not a nontemplate, statistical synthesis by acyloin macrocyclization ...does indeed form mechanically interlocked rings. The lack of direct experimental evidence for Wasserman’s catenane has led to it being described as a “prophetic compound”, a technical term used in patents for claimed molecules that have not yet been synthesized. Contemporary synthetic methods were used to reconstruct Wasserman’s deuterium-labeled macrocycle and other building blocks on the 10–100 g reaction scale necessary to generate, in principle, ∼1 mg of catenane. Modern spectrometric and spectroscopic tools and chemical techniques (including tandem mass spectrometry, deuterium nuclear magnetic resonance (NMR) spectroscopy, and fluorescent tag labeling) were brought to bear in an effort to detect, isolate, and prove the structure of a putative 2catenane consisting of a 34-membered cyclic hydrocarbon mechanically linked with a 34-membered cyclic α-hydroxyketone.
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