Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics.

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing.

Dual-Ligand Catalyst for the Nondirected C-H Olefination of Heteroarenes.

Pd(II)-catalyzed nondirected C-H functionalization of heteroarenes is a significant challenge for the following reasons: poor reactivity of electron-deficient heterocycles and the unproductive coordination of Lewis basic nitrogen atoms. Existing methodologies using palladium catalysis often employ a large excess of heterocycle substrates to overcome these hurdles. Despite recent advances in nondirected functionalization of arenes that allow them to be used as limiting reagents, the reaction conditions are incompatible with electron-deficient heteroarenes. Herein we report a dual-ligand catalyst that enables Pd(II)-catalyzed nondirected C-H olefination of heteroarenes without using a large excess of substrate. In general, the use of 1-2 equiv of substrates was sufficient to obtain synthetically useful yields. The reactivity was rationalized by the synergy between two types of ligands: a bidentate pyridine-pyridone ligand promotes C-H cleavage; the monodentate heterocycle substrate acts as a second ligand to form a cationic Pd(II) complex that has high affinity for arenes. The proposed dual-ligand cooperation is supported by a combination of X-ray, kinetics, and control experiments.

Synthesis of 1,3-Dienes via Ligand-Enabled Sequential Dehydrogenation of Aliphatic Acids.

1,3-Dienes are common scaffolds in biologically active natural products as well as building blocks for chemical synthesis. Developing efficient methods for the synthesis of diverse 1,3-dienes from simple starting materials is therefore highly desirable. Herein, we report a Pd(II)-catalyzed sequential dehydrogenation reaction of free aliphatic acids via ß-methylene C-H activation, which enables one-step synthesis of diverse E,E-1,3-dienes. Free aliphatic acids of varying complexities, including the antiasthmatic drug seratrodast, were found to be compatible with the reported protocol. Considering the high lability of 1,3-dienes and lack of protecting strategies, dehydrogenation of aliphatic acids to reveal 1,3-dienes at the late stage of synthesis offers an appealing strategy for the synthesis of complex molecules containing such motifs.

Palladium-Catalyzed Enantioselective ß-C(sp3)-H Activation Reactions of Aliphatic Acids: A Retrosynthetic Surrogate for Enolate Alkylation and Conjugate Addition.

Enolate alkylation and conjugate addition into an α,ß-unsaturated system have served as long-standing strategic disconnections for the installation of α- or ß-substituents on carbonyl-containing compounds. At the onset of our efforts to develop C-H activation reactions for organic synthesis, we set our eye toward developing asymmetric ß-C-H activation reactions of aliphatic acids with the perspective that this bond-forming event could serve as a more flexible retrosynthetic surrogate for both canonical carbonyl-related asymmetric transformations.In this Account, we describe our early efforts using strongly coordinating chiral oxazolines to probe reaction mechanism and the stereochemical nature of the C-H cleavage transition state. The characterization of key reactive intermediates through X-ray crystallography and computational studies suggested a transition state with C-H and Pd-OAc bonds being approximately coplanar for optimum interaction. We then moved forward to develop more practical, weakly coordinating monodentate amide directing groups, a necessary advance toward achieving the ß-C-H activation of weakly coordinating native carboxylic acids. Throughout this journey, gradual deconvolution between a substrate's directing effect and its intimate interplay with ligand properties has culminated in the design of new ligand classes that ultimately allowed the competency of native carboxylic acids in ß-C-H activation. These efforts established the importance of ligand acceleration in Pd-catalyzed C-H activation, where the substrate's weak coordination is responsible for positioning the catalyst for C-H cleavage, while the direct participation from the bifunctional ligand is responsible for enthalpically stabilizing the C-H cleavage transition state.Building upon these principles, we developed five classes of chiral ligands (MPAA, MPAQ, MPAO, MPAThio, MPAAM) to enable enantioselective ß-C-H activation reactions, including carbon-carbon and carbon-heteroatom bond formation. The accumulated data from our developed enantioselective C-H activation reactions indicate that ligands possessing point chirality are most effective for imparting stereoinduction in the C-H activation step, the application of which enabled the desymmetrization and subsequent C-H functionalization of enantiotopic carbon and protons across a range of weakly coordinating arylamides and, more recently, free carboxylic acids. Progress in ligand design, in conjunction with the enabling nature of alkali metal countercations, led to the realization of a suite of ß-methyl and now methylene C(sp3)-H activation reactions. These advancements also enabled the use of economical oxidants, such as peroxides and molecular oxygen, to facilitate catalyst turnover. In the future, continued progress in designing more efficient bifunctional chiral ligands is likely to provide a myriad of enantioselective ß-C-H activation reactions of readily available native substrates.

Database of evidence for precision oncology portal.

Summary: A database of curated genomic variants with clinically supported drug therapies and other oncological annotations is described. The accompanying web portal provides a search engine with two modes: one that allows users to query gene, cancer type, variant type or position for druggable mutations, and another to search for and to visualize, on three-dimensional protein structures, putative druggable sites that cluster with known druggable mutations. Availability and implementation: http://dinglab.wustl.edu/depo.

An evidence-based treatment algorithm for the management of WHO Grade II and III meningiomas.

The management of WHO Grade II "atypical" meningiomas (AMs) and Grade III "malignant" meningiomas (MMs) remains controversial and under-investigated in prospective studies. The roles of surgery, radiation therapy, radiosurgery, and chemotherapy have been incompletely delineated. This has left physicians to decipher how they should treat patients on a case-by-case basis. In this study, the authors review the English-language literature on the management and clinical outcomes associated with AMs and MMs diagnosed using the WHO 2000/2007 grading criteria. Twenty-two studies for AMs and 7 studies for MMs were examined in detail. The authors examined clinical decision points using the literature and concepts from evidence-based medicine. Acknowledging the retrospective nature of the studies concerning AM and MM, the authors did find evidence for the following clinical strategies: 1) maximal safe resection of AM and MM; 2) active surveillance after gross-total resection of AM; 3) adjuvant radiation therapy after subtotal resection of AM, especially in the absence of putative radioresistant features; and 4) adjuvant radiation therapy after resection of MM.

A Thermoelectric Polymer Field-Effect Transistor via Iodine-Doped P3HT.

Doping can alter certain electronics, including the thermoelectric properties of an organic semiconductor. These alterations may enable viable tunable devices that could be useful in temperature sensing for autonomous controls. Here, we demonstrate a dual-modulation organic field-effect transistor (OFET) where temperature can modulate the current-voltage characteristics of the OFET and gate voltage can modulate the thermoelectric properties of the active layer in the same device. Specifically, Poly(3-hexylthiophene-2,5-diyl) (P3HT) was utilized as the host p-type semiconducting polymer, and iodine was utilized as the thermoelectric minority dopant. The finished devices were characterized with a semiconductor analyzer system with temperature controlled using two thermoelectric cooling plates. The FETs with iodine doping levels in the range of 0.25% to 0.5% mole ratio with respect to the P3HT exhibit the greatest on/off ratios. This study also observed that P3HT thin film samples with an intermediate iodine doping concentration of 0.25% mole ratio exhibit an optimal thermoelectric power factor (PF).

Apolipoprotein B-100-containing lipoprotein metabolism in subjects with lipoprotein lipase gene mutations.

OBJECTIVE: We investigated the impact of lipoprotein lipase (LPL) gene mutations on apolipoprotein B (apoB)-100 metabolism. METHODS AND RESULTS: We studied 3 subjects with familial LPL deficiency; 14 subjects heterozygous for the LPL gene mutations Gly188Glu, Trp64Stop, and Ile194Thr; and 10 control subjects. Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL)-apoB-100 kinetics were determined in the fed state using stable isotope methods and compartmental modeling. Compared with controls, familial LPL deficiency had markedly elevated plasma triglycerides and lower VLDL-apoB-100 fractional catabolic rate (FCR), IDL-apoB-100 FCR, VLDL-to-IDL conversion, and VLDL-apoB-100 production rate (P<0.01). Compared with controls, Gly188Glu had higher plasma triglyceride and VLDL- and IDL-apoB-100 concentrations and lower VLDL- and IDL-apoB-100 FCR (P<0.05). Plasma triglycerides were not different, but IDL-apoB-100 concentration and production rate and VLDL-to-IDL conversion were lower in Trp64Stop compared with controls (P<0.05). No differences between controls and Ile194Thr were observed. CONCLUSIONS: Our results confirm that hypertriglyceridemia is a key feature of familial LPL deficiency. This is due to impaired VLDL- and IDL-apoB-100 catabolism and VLDL-to-IDL conversion. Single-allele mutations of the LPL gene result in modest to elevated plasma triglycerides. The changes in plasma triglycerides and apoB-100 kinetics are attributable to the effects of the LPL genotype.

Enhanced non-volatile and updatable holography using a polymer composite system.

Updatable holography is considered as the ultimate technique for true 3D information recording and display. However, there is no practical solution to preserve the required features of both non-volatility and reversibility which conflict with each other when the reading has the same wavelength as the recording. We demonstrate a non-volatile and updatable holographic approach by exploiting new features of molecular transformations in a polymer recording system. In addition, by using a new composite recording film containing photo-reconfigurable liquid-crystal (LC) polymer, the holographic recording is enhanced due to the collective reorientation of LC molecules around the reconfigured polymer chains.

Nanoscale optical reinforcement for enhanced reversible holography.

We demonstrate a nanoscale optical reinforcement concept for reversible holographic recording. The bone-muscle-like mechanism enables enhancement of holographic grating formation due to the collective alignment of liquid crystal (LC) molecules nearby photo-reconfigurable polymer backbones. The LC fluidity facilitates the ease of polymer chain transformation during the holographic recording while the polymer network stabilizes the LC collective orientation and the consequential optical enhancement after the recording. As such, the holographic recording possesses both long-term persistence and real-time rewritability.

Implementation of High-Dose-Rate, CT-Based Prostate Brachytherapy in an Academic Teaching Hospital and Residency Training Program.

Introduction Prostate brachytherapy provides the most durable local control for prostate adenocarcinoma among all radiation treatment options. However, likely due to decreased trainee familiarity with the technique and resource intensity, it has seen a decline in utilization. Here we outline our experience with starting a high-dose-rate (HDR) prostate brachytherapy program within a residency training program and present our outcome data. Methods Patients were identified and screened using clinical data and volume study for candidacy for brachytherapy implantation. Eligible candidates were implanted and subsequently had radiation planning and delivery in our clinic. Descriptive statistical analysis was performed on our outcomes and dosimetry data and presented in tabular form. Results Seventeen patients were treated for a total of 18 implants (one monotherapy). No implant was aborted. No acute urinary retention requiring catheterization or chronic urethral stricture occurred. Biochemical recurrence-free survival was 94% at a median follow-up of 28.5 months (range 8.2-50 months); the one failure occurred in a very high-risk patient at 37 months following treatment. Dosimetrically, prostate coverage, urethra sparing, and rectum sparing aims were met. Volumetric bladder aims were also met; however, the max point dose to the bladder neck was above the guideline. Conclusion Our department successfully implemented an HDR prostate brachytherapy program. Treatments were effective and there was no grade 3 toxicity to report.

Catalyst-controlled site-selective methylene C-H lactonization of dicarboxylic acids.

Catalyst-controlled site-selective activation of ß- and γ-methylene carbon-hydrogen (C-H) bonds of free carboxylic acids is a long-standing challenge. Here we show that, with a pair of palladium catalysts assembled with quinoline-pyridone ligands of different chelate ring sizes, it is possible to perform highly site-selective monolactonization reactions with a wide range of dicarboxylic acids, generating structurally diverse and synthetically useful γ- and δ-lactones via site-selective ß- or γ-methylene C-H activation. The remaining carboxyl group serves as a versatile linchpin for further synthetic applications, as demonstrated by the total synthesis of two natural products, myrotheciumone A and pedicellosine, from abundant dicarboxylic acids.

Forwards and backwards - synthesis of Laurencia natural products using a biomimetic and retrobiomimetic strategy incorporating structural reassignment of laurefurenynes C-F.

Laurefurenynes C-F are four natural products isolated from Laurencia species whose structures were originally determined on the basis of extensive nuclear magnetic resonance experiments. On the basis of a proposed biogenesis, involving a tricyclic oxonium ion as a key intermediate, we have reassigned the structures of these four natural products and synthesized the four reassigned structures using a biomimetic approach demonstrating that they are the actual structures of the natural products. In addition, we have developed a synthesis of the enantiomers of the natural products laurencin and deacetyllaurencin from the enantiomer of (E)-laurefucin using an unusual retrobiomimetic strategy. All of these syntheses have been enabled by the use of tricyclic oxonium ions as pivotal synthetic intermediates.

Photoelectric and Thermoelectric Dual Modulation Via a Ternary Composite.

Materials for simultaneous photoelectric and thermo-electric dual conversions and modulations, where photon can modulate the thermoelectric conversion, and temperature can modulate the photoelectric conversion, may find potential applications where light (including a laser) can remotely turn on, turn off, or modulate a thermoelectric generator, a cooler, or a temperature sensor, and vice versa, temperature (heating/cooling) can turn on, turn off, or modulate a photoelectric device such as a photo detector or a solar cell. Here, it is demonstrated that such simultaneous dual conversion or modulation can be achieved via a ternary composite, e.g., a poly-3-hexyl-thiophene thin-film doped with both phenyl-C61-butyric acid methyl ester and iodine. This finding may result in the development of lightweight, flexible shape, cost-effective, renewable, environmentally friendly, biocompatible, and scalable materials, devices, and systems for clean energy harvestings (such as solar and waste heat dual energy harvesting) as well as light/heat dual-sensing sensors, modulators, and controllers.

LncRNAs GIHCG and SPINT1-AS1 Are Crucial Factors for Pan-Cancer Cells Sensitivity to Lapatinib.

Lapatinib is a small molecule inhibitor of EGFR (HER1) and ERBB2 (HER2) receptors, which is used for treatment of advanced or metastatic breast cancer. To find the drug resistance mechanisms of treatment for EGFR/ERBB2 positive tumors, we analyzed the possible effects of lncRNAs. In this study, using CCLE (Cancer Cell Line Encyclopedia) database, we explored the relationship between the lncRNAs and Lapatinib sensitivity/resistance, and then validated those findings through in vitro experiments. We found that the expression of EGFR/ERBB2 and activation of ERBB pathway was significantly related to Lapatinib sensitivity. GO (Gene Oncology) analysis of top 10 pathways showed that the sensitivity of Lapatinib was positively correlated with cell keratin, epithelial differentiation, and cell-cell junction, while negatively correlated with signatures of extracellular matrix. Forty-four differentially expressed lncRNAs were found between the Lapatinib sensitive and resistant groups (fold-change > 1.5, P < 0.01). Gene set variation analysis (GSVA) was performed based on 44 lncRNAs and genes in the top 10 pathways. Five lncRNAs were identified as hub molecules. Co-expression network was constructed by more than five lncRNAs and 199 genes in the top 10 pathways, and three lncRNAs (GIHCG, SPINT1-AS1, and MAGI2-AS3) and 47 genes were identified as close-related molecules. The three lncRNAs in epithelium-derived cancers were differentially expressed between sensitive and resistant groups, but no significance was found in non-epithelium-derived cancer cells. Correlation analysis showed that SPINT1-AS1 (R = -0.715, P < 0.001) and GIHCG (R = 0.557, P = 0.013) were correlated with the IC50 of epithelium-derived cancer cells. In further experiments, GIHCG knockdown enhanced cancer cell susceptibility to Lapatinib, while high level of SPINT1-AS1 was a sensitive biomarker of NCI-N87 and MCF7 cancer cells to Lapatinib. In conclusions, lncRNAs GIHCG and SPINT1-AS1 were involved in regulating Lapatinib sensitivity. Up-regulation of GIHCG was a drug-resistant biomarker, while up-regulation of SPINT1-AS1 was a sensitive indicator.

Dynamic host immune response in virus-associated cancers.

Viruses drive carcinogenesis in human cancers through diverse mechanisms that have not been fully elucidated but include promoting immune escape. Here we investigated associations between virus-positivity and immune pathway alteration for 2009 tumors across six virus-related cancer types. Analysis revealed that for 3 of 72 human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSC) the HPV genome integrated in immune checkpoint genes PD-L1 or PD-L2, driving elevated expression in the corresponding gene. In addition to the previously described upregulation of the PD-1 immunosuppressive pathway in Epstein-Barr virus (EBV)-positive stomach tumors, we also observed upregulation of the PD-1 pathway in cytomegalovirus (CMV)-positive tumors. Furthermore, we found signatures of T-cell and B-cell response in HPV-positive HNSC and EBV-positive stomach tumors and HPV-positive HNSC patients were associated with better survival when T-cell signals were detected. Our work reveals that viral infection may recruit immune effector cells, and upregulate PD-1 and CTLA-4 immunosuppressive pathways.

Dietary flaxseed lignan extract lowers plasma cholesterol and glucose concentrations in hypercholesterolaemic subjects.

Lignans, derived from flaxseed, are phyto-oestrogens being increasingly studied for their health benefits. An 8-week, randomised, double-blind, placebo-controlled study was conducted in fifty-five hypercholesterolaemic subjects, using treatments of 0 (placebo), 300 or 600 mg/d of dietary secoisolariciresinol diglucoside (SDG) from flaxseed extract to determine the effect on plasma lipids and fasting glucose levels. Significant treatment effects were achieved (P < 0.05 to < 0.001) for the decrease of total cholesterol (TC), LDL-cholesterol (LDL-C) and glucose concentrations, as well as their percentage decrease from baseline. At weeks 6 and 8 in the 600 mg SDG group, the decreases of TC and LDL-C concentrations were in the range from 22.0 to 24.38 % respectively (all P < 0.005 compared with placebo). For the 300 mg SDG group, only significant differences from baseline were observed for decreases of TC and LDL-C. A substantial effect on lowering concentrations of fasting plasma glucose was also noted in the 600 mg SDG group at weeks 6 and 8, especially in the subjects with baseline glucose concentrations > or = 5.83 mmol/l (lowered 25.56 and 24.96 %; P = 0.015 and P = 0.012 compared with placebo, respectively). Plasma concentrations of secoisolariciresinol (SECO), enterodiol (ED) and enterolactone were all significantly raised in the groups supplemented with flaxseed lignan. The observed cholesterol-lowering values were correlated with the concentrations of plasma SECO and ED (r 0.128-0.302; P < 0.05 to < 0.001). In conclusion, dietary flaxseed lignan extract decreased plasma cholesterol and glucose concentrations in a dose-dependent manner.

Posterior-Only Vertebral Column Resection for Fused Spondyloptosis.

STUDY DESIGN: Retrospective review. OBJECTIVES: To describe 3 cases of a posterior-only vertebral column resection (pVCR) for the treatment of spondyloptosis in the setting of prior spinal fusions. SUMMARY OF BACKGROUND DATA: Lumbosacral spondyloptosis is a rare spinal deformity with a number of surgical options, none of which demonstrate clear superiority. The use of an L5 vertebral column resection, via combined anterior and posterior approaches, to restore lumbosacral alignment has been described though is accompanied by high rates of neurological deficit. METHODS: Review of 3 cases of spondyloptosis with prior spinal fusions in which a staged pVCR was used for deformity reconstruction. RESULTS: Three females, ages 39, 54, and 28, developed spondyloptosis with progressive lumbosacral kyphosis and sagittal malalignment after prior in-situ posterolateral spinal fusions. All were treated with staged pVCRs. At ultimate follow-up, imaging revealed improvement in sagittal balance of 6.1 cm (56%) in the 39-year-old and 12 cm (67%) in the 54-year-old, 21.1 cm (92%) in the 28-year-old. All patients had improvement in outcome scores with perfect satisfaction scores despite the 54-year-old having a persistent right foot drop. CONCLUSION: Posterior-only VCR for spondyloptosis is a technically demanding surgical option offering significant radiographic and clinical improvement, but carries a risk for L5 nerve root deficit as in any spondyloptosis treatment.

Integrative omics analyses broaden treatment targets in human cancer.

BACKGROUND: Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers. METHODS: To overcome such challenges, we utilized the Database of Evidence for Precision Oncology (DEPO) to link druggability to genomic, transcriptomic, and proteomic biomarkers. Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO. RESULTS: Within the pan-cancer cohort of 6570 tumors, we found that 3% are druggable based on FDA-approved drug-mutation interactions in specific cancer types. However, mRNA/phosphoprotein/protein expression outliers and drug repurposing across cancer types suggest potential druggability in up to 16% of tumors. The percentage of potential drug-associated tumors can increase to 48% if we consider preclinical evidence. Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively. We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool. Finally, analysis of a large-scale drug screening dataset lent further evidence supporting repurposing of drugs across cancer types and the use of expression outliers for inferring druggability. CONCLUSIONS: Our results suggest that an integrated analysis platform can nominate multi-omics alterations as biomarkers of druggability and aid ongoing efforts to bring precision oncology to patients.

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy.