Publications by authors named "Peter Ho"

61 Publications

Overcoming the water oxidative limit for ultra-high-workfunction hole-doped polymers.

Nat Commun 2021 Jun 7;12(1):3345. Epub 2021 Jun 7.

Department of Physics, National University of Singapore, Singapore, Singapore.

It is widely thought that the water-oxidation reaction limits the maximum work function to about 5.25 eV for hole-doped semiconductors exposed to the ambient, constrained by the oxidation potential of air-saturated water. Here, we show that polymer organic semiconductors, when hole-doped, can show work functions up to 5.9 eV, and yet remain stable in the ambient. We further show that de-doping of the polymer is not determined by the oxidation of bulk water, as previously thought, due to its general absence, but by the counter-balancing anion and its ubiquitously hydrated complexes. The effective donor levels of these species, representing the edge of the 'chemical' density of states, can be depressed to about 6.0 eV below vacuum level. This can be achieved by raising the oxidation potential for hydronium generation, using large super-acid anions that are themselves also stable against oxidation. In this way, we demonstrate that poly(fluorene-alt-triarylamine) derivatives with tethered perfluoroalkyl-sulfonylimidosulfonyl anions can provide ambient solution-processability directly in the ultrahigh-workfunction hole-doped state to give films with good thermal stability. These results lay the path for design of soft materials for battery, bio-electronic and thermoelectric applications.
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http://dx.doi.org/10.1038/s41467-021-23347-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184950PMC
June 2021

Competing Effects of Chlorination on the Strength of Te⋅⋅⋅O Chalcogen Bonds Select the Structure of Mixed Supramolecular Macrocyclic Aggregates of Iso-Tellurazole N-Oxides.

Chemistry 2021 May 20. Epub 2021 May 20.

Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, L8S 4 M1, Hamilton, Ontario, Canada.

Chlorination of 3-methyl-5-phenyl-1,2-tellurazole-2-oxide yielded the λ Te dichloro derivative. Its crystal structure demonstrates that the heterocycle retains its ability to autoassociate by chalcogen bonding (ChB) forming macrocyclic tetramers. The corresponding Te⋅⋅⋅O ChB distances are 2.062 Å, the shortest observed to date in aggregates of this type. DFT-D3 calculations indicate that while the halogenated molecule is stronger as a ChB donor it also is a weaker ChB acceptor; the overall effect is that the ChBs in the chlorinated homotetramer are not significantly stronger. However, partial halogenation or scrambling selectively yield the 2 : 2 heterotetramer with alternating λ Te and λ Te centers, which calculations identified as the thermodynamically preferred arrangement.
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http://dx.doi.org/10.1002/chem.202101425DOI Listing
May 2021

Neonatal and infant mortality associated with spina bifida: A systematic review and meta-analysis.

PLoS One 2021 12;16(5):e0250098. Epub 2021 May 12.

National Perinatal Epidemiology Unit (NPEU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Objectives: A systematic review was conducted in high-income country settings to analyse: (i) spina bifida neonatal and IMRs over time, and (ii) clinical and socio-demographic factors associated with mortality in the first year after birth in infants affected by spina bifida.

Data Sources: PubMed, Embase, Ovid, Web of Science, CINAHL, Scopus and the Cochrane Library were searched from 1st January, 1990 to 31st August, 2020 to review evidence.

Study Selection: Population-based studies that provided data for spina bifida infant mortality and case fatality according to clinical and socio-demographical characteristics were included. Studies were excluded if they were conducted solely in tertiary centres. Spina bifida occulta or syndromal spina bifida were excluded where possible.

Data Extraction And Synthesis: Independent reviewers extracted data and assessed their quality using MOOSE guideline. Pooled mortality estimates were calculated using random-effects (+/- fixed effects) models meta-analyses. Heterogeneity between studies was assessed using the Cochrane Q test and I2 statistics. Meta-regression was performed to examine the impact of year of birth cohort on spina bifida infant mortality.

Results: Twenty studies met the full inclusion criteria with a total study population of over 30 million liveborn infants and approximately 12,000 spina bifida-affected infants. Significant declines in spina bifida associated infant and neonatal mortality rates (e.g. 4.76% decrease in IMR per 100, 000 live births per year) and case fatality (e.g. 2.70% decrease in infant case fatality per year) were consistently observed over time. Preterm birth (RR 4.45; 2.30-8.60) and low birthweight (RR 4.77; 2.67-8.55) are the strongest risk factors associated with increased spina bifida infant case fatality.

Significance: Significant declines in spina bifida associated infant/neonatal mortality and case fatality were consistently observed, advances in treatment and mandatory folic acid food fortification both likely play an important role. Particular attention is warranted from clinicians caring for preterm and low birthweight babies affected by spina bifida.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250098PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115829PMC
May 2021

Improving organic photovoltaic cells by forcing electrode work function well beyond onset of Ohmic transition.

Nat Commun 2021 Apr 14;12(1):2250. Epub 2021 Apr 14.

Department of Physics, National University of Singapore, Singapore, Singapore.

As electrode work function rises or falls sufficiently, the organic semiconductor/electrode contact reaches Fermi-level pinning, and then, few tenths of an electron-volt later, Ohmic transition. For organic solar cells, the resultant flattening of open-circuit voltage (V) and fill factor (FF) leads to a 'plateau' that maximizes power conversion efficiency (PCE). Here, we demonstrate this plateau in fact tilts slightly upwards. Thus, further driving of the electrode work function can continue to improve V and FF, albeit slowly. The first effect arises from the coercion of Fermi level up the semiconductor density-of-states in the case of 'soft' Fermi pinning, raising cell built-in potential. The second effect arises from the contact-induced enhancement of majority-carrier mobility. We exemplify these using PBDTTPD:PCBM solar cells, where PBDTTPD is a prototypal face-stacked semiconductor, and where work function of the hole collection layer is systematically 'tuned' from onset of Fermi-level pinning, through Ohmic transition, and well into the Ohmic regime.
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http://dx.doi.org/10.1038/s41467-021-22358-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047006PMC
April 2021

Surface Doping of Organic Single-Crystal Semiconductors to Produce Strain-Sensitive Conductive Nanosheets.

Adv Sci (Weinh) 2021 Feb 18;8(3):2002065. Epub 2020 Dec 18.

Material Innovation Research Center (MIRC) and Department of Advanced Materials Science Graduate School of Frontier Sciences The University of Tokyo 5-1-5 Kashiwanoha Kashiwa Chiba 277-8561 Japan.

A highly periodic electrostatic potential, even though established in van der Waals bonded organic crystals, is essential for the realization of a coherent band electron system. While impurity doping is an effective chemical operation that can precisely tune the energy of an electronic system, it always faces an unavoidable difficulty in molecular crystals because the introduction of a relatively high density of dopants inevitably destroys the highly ordered molecular framework. In striking contrast, a versatile strategy is presented to create coherent 2D electronic carriers at the surface of organic semiconductor crystals with their precise molecular structures preserved perfectly. The formation of an assembly of redox-active molecular dopants via a simple one-shot solution process on a molecularly flat crystalline surface allows efficient chemical doping and results in a relatively high carrier density of 10 cm at room temperature. Structural and magnetotransport analyses comprehensively reveal that excellent carrier transport and piezoresistive effects can be obtained that are similar to those in bulk crystals.
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http://dx.doi.org/10.1002/advs.202002065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856890PMC
February 2021

Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Eur J Cancer 2020 11 26;139:135-148. Epub 2020 Sep 26.

Solving Kids' Cancer, USA.

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.
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http://dx.doi.org/10.1016/j.ejca.2020.08.014DOI Listing
November 2020

Optimizing the Efficacy of Learning Objectives through Pretests.

CBE Life Sci Educ 2020 09;19(3):ar43

Department of Psychology, Neuroscience & Behaviour, Hamilton, Ontario, L8S 4K1, Canada.

Learning objectives (LOs) are statements that typically precede a study session and describe the knowledge students should obtain by the end of the session. Despite their widespread use, limited research has investigated the effect of LOs on learning. In three laboratory experiments, we examined the extent to which LOs improve retention of information. Participants in each experiment read five passages on a neuroscience topic and took a final test that measured how well they retained the information. Presenting LOs before each corresponding passage increased performance on the final test compared with not presenting LOs (experiment 1). Actively presenting LOs increased their pedagogical value: Performance on the final test was highest when participants answered multiple-choice pretest questions compared with when they read traditional LO statements or statements that included target facts (experiment 2). Interestingly, when feedback was provided on pretest responses, performance on the final test , regardless of whether the pretest format was multiple choice or short answer (experiment 3). Together, these findings suggest that, compared with the passive presentation of LO statements, pretesting (especially without feedback) is a more active method that optimizes learning.
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http://dx.doi.org/10.1187/cbe.19-11-0257DOI Listing
September 2020

A Double-Blind, Phase I, Single Ascending Dose Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of BOS161721 in Healthy Subjects.

Clin Transl Sci 2020 03 29;13(2):337-344. Epub 2019 Nov 29.

Boston Pharmaceuticals, Cambridge, Massachusetts, USA.

The purpose of this study was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of BOS161721, a humanized immunoglobulin G1 triple mutation (M252Y/S254T/T256E) monoclonal antibody that inhibits interleukin-21 (IL-21) bioactivity. This randomized, single-center, double-blind, placebo-controlled study randomized healthy volunteers 3:1 to single ascending intravenous and subcutaneous doses of BOS161721 (range 1-240 mg) or placebo. BOS161721 and placebo groups had similar rates of adverse events, mostly mild; none led to study discontinuation. There were no clinically significant findings in physical examination, vital signs, or laboratory assessment. In the pooled BOS161721 population, four subjects (8.5%) tested antidrug antibody-positive predose, and seven (14.9%) postdose. Absolute CD4+ lymphocyte count remained normal throughout follow-up. BOS161721 administered subcutaneously was absorbed slowly, with a median time to maximum concentration (T ) of 144 hours across doses (range 1-15 days) and a mean apparent terminal elimination half-life of 80-87 days for doses ≥ 30 mg. Area under the concentration-time curve from time zero to infinity (AUC ) and maximum observed concentration (C ) were linear across doses > 10 mg. Subcutaneous bioavailability was 64%. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) decreased dose-dependently with threshold characteristics at doses of ≥ 10 mg. Downregulation in BATF, IL6, LAG3, and SOCS3 genes caused by IL-21 stimulation was reversed dose-dependently. BOS161721 was well-tolerated across doses, suppressed IL-21-induced pSTAT3 dose-dependently, and reversed downregulation of genes critical to tolerance induction and T-cell exhaustion induced by IL-21. Further clinical studies are ongoing in patients with systemic lupus erythematosus, in which IL-21 has a pathogenetic role.
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http://dx.doi.org/10.1111/cts.12715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070801PMC
March 2020

Multivalent anions as universal latent electron donors.

Nature 2019 09 25;573(7775):519-525. Epub 2019 Sep 25.

Department of Physics, National University of Singapore, Singapore, Singapore.

Electrodes with low work functions are required to efficiently inject electrons into semiconductor devices. However, when the work function drops below about 4 electronvolts, the electrode suffers oxidation in air, which prevents its fabrication in ambient conditions. Here we show that multivalent anions such as oxalate, carbonate and sulfite can act as powerful latent electron donors when dispersed as small ion clusters in a matrix, while retaining their ability to be processed in solution in ambient conditions. The anions in these clusters can even n-dope the semiconductor core of π-conjugated polyelectrolytes that have low electron affinities, through a ground-state doping mechanism that is further amplified by a hole-sensitized or photosensitized mechanism in the device. A theoretical analysis of donor levels of these anions reveals that they are favourably upshifted from ionic lattices by a decrease in the Coulomb stabilization of small ion clusters, and by irreversibility effects. We attain an ultralow effective work function of 2.4 electronvolts with the polyfluorene core. We realize high-performance, solution-processed, white-light-emitting diodes and organic solar cells using polymer electron injection layers with these universal anion donors, demonstrating a general approach to chemically designed and ambient-processed Ohmic electron contacts for semiconductor devices.
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http://dx.doi.org/10.1038/s41586-019-1575-7DOI Listing
September 2019

Macrocyclic complexes of Pt(ii) and Rh(iii) with iso-tellurazole N-oxides.

Dalton Trans 2019 Apr;48(15):4879-4886

McMaster University, Department of Chemistry and Chemical Biology, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1.

Pt(ii) and Rh(iii) readily form complexes with 3-methyl-5-aryl-1,2-tellurazole 2-oxides (L = (3-Me-5-Ar-1,2-C3HTe(NO)). The aryl group is either phenyl or 3,5-di-tert-butylphenyl, the latter case being a new derivative with enhanced solubility. The compound [Pt(3-Me-5-(3,5-tBu2C6H3)-1,2-C3HTe(NO))4](BF4)2 crystallizes in the P21/C space group featuring a square planar complex in the lattice. The crystal of [RhCl2(3-Me-5-(C6H5)-1,2-C3HTe(NO))4](BF4) belongs to the I4[combining macron] space group and contains an octahedral complex. In both instances, the iso-tellurazole N-oxide molecules are linked by TeO chalcogen bonding interactions confirming an annular tetramer that binds the metal ion as a κ4Te macrocycle in a boat conformation. Low-frequency shifts of the 125Te magnetic resonance upon coordination and the observation of 125Te-195Pt and 125Te-103Rh 1J coupling constants indicate that the complexes are stable species in solution. The complex ions were also observed in the electrospray mass spectra.
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http://dx.doi.org/10.1039/c9dt00500eDOI Listing
April 2019

Ohmic transition at contacts key to maximizing fill factor and performance of organic solar cells.

Nat Commun 2018 08 15;9(1):3269. Epub 2018 Aug 15.

Department of Physics, National University of Singapore, Lower Kent Ridge Road, Singapore, S117550, Singapore.

While thermodynamic detailed balance limits the maximum power conversion efficiency of a solar cell, the quality of its contacts can further limit the actual efficiency. The criteria for good contacts to organic semiconductors, however, are not well understood. Here, by tuning the work function of poly(3,4-ethylenedioxythiophene) hole collection layers in fine steps across the Fermi-level pinning threshold of the model photoactive layer, poly(3-hexylthiophene):phenyl-C-butyrate methyl ester, in organic solar cells, we obtain direct evidence for a non-ohmic to ohmic transition at the hole contact that lies 0.3 eV beyond its Fermi-level pinning transition. This second transition corresponds to reduction of the photocurrent extraction resistance below the bulk resistance of the cell. Current detailed balance analysis reveals that this extraction resistance is the counterpart of injection resistance, and the measured characteristics are manifestations of charge carrier hopping across the interface. Achieving ohmic transition at both contacts is key to maximizing fill factor without compromising open-circuit voltage nor short-circuit current of the solar cell.
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http://dx.doi.org/10.1038/s41467-018-05200-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093871PMC
August 2018

The effect of ageing temperature on the physicochemical properties, phytochemical profile and α-glucosidase inhibition of Hibiscus sabdariffa (roselle) wine.

Food Chem 2018 Nov 10;267:263-270. Epub 2017 May 10.

School of Food Science and Nutrition, University of Leeds, Leeds LS2 9JT, United Kingdom. Electronic address:

The effect of temperature (6, 15 and 30°C) during ageing on the colour, phytochemical composition and bioactivity of roselle wine was investigated over 12months. At the end of ageing, wines stored at 6°C had the highest colour density and lowest polymeric anthocyanins. The initial concentration of most of the individual phenolic compounds decreased during ageing, with reduction of monomeric anthocyanins contributing to the formation of anthocyanin-derivatives (pyranoanthocyanins), eight of which were identified tentatively and reported here for the first time in roselle wine. The decrease in individual phenolic compounds did not affect inhibition of α-glucosidase (maltase) activity, which remained relatively low but stable throughout ageing. Diethyl succinate was the only volatile clearly influenced by ageing temperature, with the most pronounced effect at 30°C (∼256 fold increase). In summary, the final concentrations of anthocyanins and diethyl succinate were the major compounds influenced by ageing temperature.
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http://dx.doi.org/10.1016/j.foodchem.2017.05.044DOI Listing
November 2018

Prostate cancer and antidepressants: A nationwide population-based nested case-control study.

J Affect Disord 2018 02 13;227:834-839. Epub 2017 Nov 13.

Department of Medicine, Mackay Medical College, Taipei, Taiwan; Section of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan. Electronic address:

Background: We aimed to evaluate the association between antidepressant and prostate cancer by comparing exposures to antidepressants between those with and without prostate cancer.

Methods: A nationwide insurance claims database was used to identify our case subjects. Age- and gender-matched controls were selected at a 1:5 ratio. Conditional logistic regression model was used.

Results: 11,515 patients with prostate cancer were identified and matched with 55,373 controls. No increased associations between prostate cancer and most classes of antidepressants were found. However, a positive association with adjusted odds ratios ranged from 1.20 to 1.35 was noted in different doses of imipramine. Nevertheless, this association became statistically insignificant at higher cumulative doses.

Conclusions: Our results indicate that there is no association between mechanistically dissimilar antidepressants and increased hazard for prostate cancer.
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http://dx.doi.org/10.1016/j.jad.2017.11.039DOI Listing
February 2018

Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study.

Lancet Oncol 2018 05 9;19(5):649-659. Epub 2018 Apr 9.

DITEP Gustave Roussy, Villejuif, Paris, France; INSERM U1170, Villejuif, Paris, France.

Background: Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (eg, mutations or deletions of the subunits INI1 or SMARCA4) can lead to aberrant histone methylation, oncogenic transformation, and a proliferative dependency on EZH2 activity. In this first-in-human study, we aimed to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of tazemetostat, a first-in-class selective inhibitor of EZH2.

Methods: We did an open-label, multicentre, dose-escalation, phase 1 study using a 3 + 3 design with planned cohort expansion at the two highest doses below the maximally tolerated dose. The study was done at two centres in France: Institut Gustave Roussy (Villejuif, Val de Marne) and Institut Bergonié (Bordeaux, Gironde). Eligible patients had relapsed or refractory B-cell non-Hodgkin lymphoma or an advanced solid tumour and were older than 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Tazemetostat was administered orally from 100 mg twice daily to 1600 mg twice daily in 28-day cycles. The primary endpoint was to establish the maximum tolerated dose or recommended phase 2 dose of tazemetostat, as determined by dose-limiting toxicities, laboratory values, and other safety or pharmacokinetic measures in cycle one according to local investigator assessment. Safety was assessed in patients who received at least one dose of tazemetostat; antitumour activity was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01897571. The phase 1 part of the study is complete, and phase 2 is ongoing.

Findings: Between June 13, 2013, and Sept 21, 2016, 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours) received doses of tazemetostat. The most common treatment-related adverse events, regardless of attribution, were asthenia (21 [33%] of 64 treatment-related events), anaemia (nine [14%]), anorexia (four [6%]), muscle spasms (nine [14%]), nausea (13 [20%]), and vomiting (six [9%]), usually grade 1 or 2 in severity. A single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg twice daily. No treatment-related deaths occurred; seven (11%) patients had non-treatment-related deaths (one at 200 mg twice daily, four at 400 mg twice daily, and two at 1600 mg twice daily). The recommended phase 2 dose was determined to be 800 mg twice daily. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours.

Interpretation: Tazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours.

Funding: Epizyme and Eisai.
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http://dx.doi.org/10.1016/S1470-2045(18)30145-1DOI Listing
May 2018

Efficacy of levomilnacipran extended release in treating major depressive disorder.

Expert Opin Pharmacother 2017 Dec 1;18(18):2017-2024. Epub 2017 Dec 1.

a Mood Disorders Psychopharmacology Unit , University Health Network , Toronto , Canada.

Introduction: Major depressive disorder (MDD) is the leading cause of disability worldwide with a heterogeneous symptom profile. Levomilnacipran extended release (ER) (Fetzima), a SNRI, has been approved by the Food and Drug Administration for treatment of MDD. While categorized as a SNRI, in contradistinction to other approved SNRIs, levomilnacipran exhibits differential affinity for the norepinephrine reuptake transporter when compared to the serotonin reuptake transporter. Areas covered: Completed clinical trials which focused on levomilnacipran ER administered in those with MDD were included in this drug evaluation. Expert opinion: Levomilnacipran ER, like all other first-line antidepressants exhibits significant efficacy in reducing total symptom severity. Levomilnacipran ER is particularly effective at improving measures of motivation, energy, and interest. Head to head comparative trials are not available with other antidepressants, and consequently, there are no claims of superior efficacy when compared to alternative antidepressants. Notwithstanding, it would be a viable and testable hypothesis that differential efficacy in favor of levomilnacipran may be obtained across select dimensions of depressive symptoms (e.g., fatigue and lack of motivation). Unfortunately, rigorous studies evaluating levomilnacipran for cognitive function in MDD have not been conducted. Levomilnacipran ER is generally well tolerated with minimal propensity for metabolic and weight disturbance.
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http://dx.doi.org/10.1080/14656566.2017.1410540DOI Listing
December 2017

Comparison of blueberry powder produced via foam-mat freeze-drying versus spray-drying: evaluation of foam and powder properties.

J Sci Food Agric 2018 Mar 1;98(5):2002-2010. Epub 2017 Nov 1.

Food Colloids and Processing Group, School of Food Science and Nutrition, University of Leeds, Leeds, UK.

Background: Blueberry juice powder was developed via foam-mat freeze-drying (FMFD) and spray-drying (SD) via addition of maltodextrin (MD) and whey protein isolate (WPI) at weight ratios of MD/WPI = 0.4 to 3.2 (with a fixed solids content of 5 wt% for FMFD and 10 wt% for SD). Feed rates of 180 and 360 mL h were tested in SD. The objective was to evaluate the effect of the drying methods and carrier agents on the physical properties of the corresponding blueberry powders and reconstituted products.

Results: Ratios of MD/WPI = 0.4, 1.0 and 1.6 produced highly stable foams most suitable for FMFD. FMFD gave high yields and low bulk density powders with flake-like particles of large size that were also dark purple with high red values. SD gave low powder recoveries. The powders had higher bulk density and faster rehydration times, consisting of smooth, spherical and smaller particles than in FMFD powders. The SD powders were bright purple but less red than FMFD powders. Solubility was greater than 95% for both FMFD and SD powders.

Conclusion: The FMFD method is a feasible method of producing blueberry juice powder and gives products retaining more characteristics of the original juice than SD. © 2017 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.8685DOI Listing
March 2018

Building new discrete supramolecular assemblies through the interaction of iso-tellurazole N-oxides with Lewis acids and bases.

Faraday Discuss 2017 10;203:187-199

Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1.

The supramolecular macrocycles spontaneously assembled by iso-tellurazole N-oxides are stable towards Lewis bases as strong as N-heterocyclic carbenes (NHC) but readily react with Lewis acids such as BR (R = Ph, F). The electron acceptor ability of the tellurium atom is greatly enhanced in the resulting O-bonded adducts, which consequently enables binding to a variety of Lewis bases that includes acetonitrile, 4-dimethylaminopyridine, 4,4'-bipyridine, triphenyl phosphine, a N-heterocyclic carbene and a second molecule of iso-tellurazole N-oxide.
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http://dx.doi.org/10.1039/c7fd00075hDOI Listing
October 2017

Synthesis and structural characterisation of the aggregates of benzo-1,2-chalcogenazole 2-oxides.

Dalton Trans 2017 May;46(20):6570-6579

Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1.

Iodine oxidation of bis[2-(hydroxyiminomethyl)phenyl] dichalcogenides yields benzo-1,2-chalcogenazole 2-oxides. Annulated derivatives of iso-tellurazole N-oxides spontaneously aggregate into cyclic tetra- and hexamers through TeO chalcogen bonding; the structures of the co-crystals with benzene and CHCl illustrate the ability of these macrocycles to interact with small guest molecules. The selenium congener crystallizes forming a supramolecular polymer. VT NMR indicates that both compounds aggregate in solution but only at low temperature in the selenium case. The different abilities of these molecules to engage in supramolecular interactions are interpreted on the basis of their electronic properties evaluated with DFT-D3 calculations.
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http://dx.doi.org/10.1039/c7dt00612hDOI Listing
May 2017

Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: and Preclinical Models.

Mol Cancer Ther 2017 05 14;16(5):850-860. Epub 2017 Mar 14.

Epizyme Inc., Cambridge, Massachusetts.

The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival. .
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0678DOI Listing
May 2017

Increased Intestinal Permeability in Relatives of Patients With Crohn's Disease Is Not Associated With Small Bowel Ulcerations.

Clin Gastroenterol Hepatol 2017 Sep 7;15(9):1413-1418.e1. Epub 2017 Mar 7.

Division of Gastroenterology and CEGIIR, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background & Aims: Many first-degree relatives of patients with Crohn's disease (CD) have increased intestinal permeability. Video capsule endoscopy (VCE) is the most sensitive imaging test to identify small bowel mucosal lesions that could indicate subclinical CD. We aimed to estimate the association of increased intestinal permeability with small bowel ulcerations detectable by VCE in healthy first-degree relatives of patients with CD.

Methods: We conducted a cross-sectional study of 223 healthy, asymptomatic first-degree relatives of patients with CD (parents, siblings, and children; 9-45 years old) enrolled at the University of Alberta between 2009 and 2012. Patients were given the lactulose and mannitol test to measure small bowel permeability; we used high-performance liquid chromatography to measure concentrations of lactulose and mannitol in urine samples (increased permeability defined as a ratio of lactulose/mannitol 0.025 or greater). Patients with increased permeability (n = 39) and randomly selected subjects with normal permeability (n = 59) were then examined by VCE for signs of small bowel inflammation and subclinical CD. The prevalence of small bowel lesions was compared among groups. We performed logistic regression analyses to estimate odds ratios for the association of small bowel ulcerations with intestinal permeability.

Results: Among 223 first-degree relatives of patients with CD, 30% were found to have increased intestinal permeability; VCE examination found 24% of subjects to have 3 or more small bowel ulcers. Three or more small bowel ulcers were detected in 28% of patients with increased intestinal permeability and 20% of patients with normal intestinal permeability (P = .37). The adjusted odds ratio for the association of 3 or more small bowel ulcers with increased intestinal permeability was 1.5 (95% confidence interval, 0.6-3.8; P = .46).

Conclusions: Thirty percent of healthy, asymptomatic first-degree relatives of patients with CD have increased intestinal permeability. However, a strong association of small bowel ulceration seen on VCE with increased intestinal permeability was not observed.
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http://dx.doi.org/10.1016/j.cgh.2017.02.028DOI Listing
September 2017

Doped polymer semiconductors with ultrahigh and ultralow work functions for ohmic contacts.

Nature 2016 11;539(7630):536-540

Department of Physics, National University of Singapore, Lower Kent Ridge Road, S117550 Singapore.

To make high-performance semiconductor devices, a good ohmic contact between the electrode and the semiconductor layer is required to inject the maximum current density across the contact. Achieving ohmic contacts requires electrodes with high and low work functions to inject holes and electrons respectively, where the work function is the minimum energy required to remove an electron from the Fermi level of the electrode to the vacuum level. However, it is challenging to produce electrically conducting films with sufficiently high or low work functions, especially for solution-processed semiconductor devices. Hole-doped polymer organic semiconductors are available in a limited work-function range, but hole-doped materials with ultrahigh work functions and, especially, electron-doped materials with low to ultralow work functions are not yet available. The key challenges are stabilizing the thin films against de-doping and suppressing dopant migration. Here we report a general strategy to overcome these limitations and achieve solution-processed doped films over a wide range of work functions (3.0-5.8 electronvolts), by charge-doping of conjugated polyelectrolytes and then internal ion-exchange to give self-compensated heavily doped polymers. Mobile carriers on the polymer backbone in these materials are compensated by covalently bonded counter-ions. Although our self-compensated doped polymers superficially resemble self-doped polymers, they are generated by separate charge-carrier doping and compensation steps, which enables the use of strong dopants to access extreme work functions. We demonstrate solution-processed ohmic contacts for high-performance organic light-emitting diodes, solar cells, photodiodes and transistors, including ohmic injection of both carrier types into polyfluorene-the benchmark wide-bandgap blue-light-emitting polymer organic semiconductor. We also show that metal electrodes can be transformed into highly efficient hole- and electron-injection contacts via the self-assembly of these doped polyelectrolytes. This consequently allows ambipolar field-effect transistors to be transformed into high-performance p- and n-channel transistors. Our strategy provides a method for producing ohmic contacts not only for organic semiconductors, but potentially for other advanced semiconductors as well, including perovskites, quantum dots, nanotubes and two-dimensional materials.
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http://dx.doi.org/10.1038/nature20133DOI Listing
November 2016

Madelung and Hubbard interactions in polaron band model of doped organic semiconductors.

Nat Commun 2016 09 1;7:11948. Epub 2016 Sep 1.

Department of Physics, National University of Singapore, Lower Kent Ridge Road, Singapore S117550, Singapore.

The standard polaron band model of doped organic semiconductors predicts that density-of-states shift into the π-π* gap to give a partially filled polaron band that pins the Fermi level. This picture neglects both Madelung and Hubbard interactions. Here we show using ultrahigh workfunction hole-doped model triarylamine-fluorene copolymers that Hubbard interaction strongly splits the singly-occupied molecular orbital from its empty counterpart, while Madelung (Coulomb) interactions with counter-anions and other carriers markedly shift energies of the frontier orbitals. These interactions lower the singly-occupied molecular orbital band below the valence band edge and give rise to an empty low-lying counterpart band. The Fermi level, and hence workfunction, is determined by conjunction of the bottom edge of this empty band and the top edge of the valence band. Calculations are consistent with the observed Fermi-level downshift with counter-anion size and the observed dependence of workfunction on doping level in the strongly doped regime.
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http://dx.doi.org/10.1038/ncomms11948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025745PMC
September 2016

Hibiscus sabdariffa (Roselle) Extracts and Wine: Phytochemical Profile, Physicochemical Properties, and Carbohydrase Inhibition.

J Agric Food Chem 2016 Jun 7;64(24):4921-31. Epub 2016 Jun 7.

School of Food Science and Nutrition, University of Leeds , Leeds LS2 9JT, United Kingdom.

Three varieties of Hibiscus sabdariffa were analyzed for their phytochemical content and inhibitory potential on carbohydrate-digesting enzymes as a basis for selecting a variety for wine production. The dark red variety was chosen as it was highest in phenolic content and an aqueous extract partially inhibited α-glucosidase (maltase), with delphinidin 3-O-sambubioside, cyanidin 3-O-sambubioside, and 3-O-caffeoylquinic acid accounting for 65% of this activity. None of the varieties significantly inhibited α-amylase. Regarding Hibiscus sabdariffa wine, the effect of fermentation temperature (20 and 30 °C) on the physicochemical, phytochemical, and aroma composition was monitored over 40 days. The main change in phytochemical composition observed was the hydrolysis of 3-O-caffeolquinic acid and the concomitant increase of caffeic acid irrespective of fermentation temperature. Wine fermented at 20 °C was slightly more active for α-glucosidase inhibition with more fruity aromas (ethyl octanoate), but there were more flowery notes (2-phenylethanol) at 30 °C.
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http://dx.doi.org/10.1021/acs.jafc.6b01246DOI Listing
June 2016

Supramolecular macrocycles reversibly assembled by Te(…)O chalcogen bonding.

Nat Commun 2016 Apr 19;7:11299. Epub 2016 Apr 19.

Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1.

Organic molecules with heavy main-group elements frequently form supramolecular links to electron-rich centres. One particular case of such interactions is halogen bonding. Most studies of this phenomenon have been concerned with either dimers or infinitely extended structures (polymers and lattices) but well-defined cyclic structures remain elusive. Here we present oligomeric aggregates of heterocycles that are linked by chalcogen-centered interactions and behave as genuine macrocyclic species. The molecules of 3-methyl-5-phenyl-1,2-tellurazole 2-oxide assemble a variety of supramolecular aggregates that includes cyclic tetramers and hexamers, as well as a helical polymer. In all these aggregates, the building blocks are connected by Te(…)O-N bridges. Nuclear magnetic resonance spectroscopic experiments demonstrate that the two types of annular aggregates are persistent in solution. These self-assembled structures form coordination complexes with transition-metal ions, act as fullerene receptors and host small molecules in a crystal.
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http://dx.doi.org/10.1038/ncomms11299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838886PMC
April 2016

Influence of interfacial area on exciton separation and polaron recombination in nanostructured bilayer all-polymer solar cells.

ACS Nano 2014 Dec 25;8(12):12397-409. Epub 2014 Nov 25.

Department of Physics, University of Konstanz , Universitätsstr. 10, 78457 Konstanz, Germany.

The macroscopic device performance of organic solar cells is governed by interface physics on a nanometer scale. A comb-like bilayer all-polymer morphology featuring a controlled enhancement in donor-acceptor interfacial area is employed as a model system to investigate the fundamental processes of exciton separation and polaron recombination in these devices. The different nanostructures are characterized locally by SEM/AFM, and the buried interdigitating interface of the final device architecture is statistically verified on a large area via advanced grazing incidence X-ray scattering techniques. The results show equally enhanced harvesting of photoexcitons in both donor and acceptor materials directly correlated to the total enhancement of interfacial area. Apart from this beneficial effect, the enhanced interface leads to significantly increased polaron recombination losses both around the open-circuit voltage and maximum power point, which is determined in complement with diode dark current characteristics, impedance spectroscopy, and transient photovoltage measurements. From these findings, it is inferred that a spatially optimized comb-like donor-acceptor nanonetwork alone is not the ideal morphology even though often postulated. Instead, the energetic landscape has to be considered. A perfect morphology for an excitonic solar cell must be spatially and energetically optimized with respect to the donor-acceptor interface.
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http://dx.doi.org/10.1021/nn5064166DOI Listing
December 2014

Fortification of white flat bread with sprouted red kidney bean (Phaseolus vulgaris).

Acta Sci Pol Technol Aliment 2014 Jan-Mar;13(1):27-34

Procter Department of Food Science, University of Leeds, United Kingdom.

Background: Protein quantity in diet including the digestibility and bioavailability of protein is of importance to eradicate undernutrition in developing countries. Bread protein is an incomplete source as it lacks an essential amino acid lysine. When they are combined with other plant foods like pulses and legumes, they become a complete source of protein. Since bread is most common staple food the objective of this study is to fortify bread with legumes in order to increase the total protein content of bread to 13-15% which is required to meet at least 1/3rd of protein requirement of an adult recommended daily allowance.

Material And Methods: Fortification of flat bread was done by adding sprouted red kidney bean flour (Phaseolus vulgaris) at 5, 15 and 25% to white flour. The composite bread was analysed for crude protein and in vitro protein digestibility using the Kjeldahl and pepsin-pancreatin method.

Results: The protein content of raw beans showed trivial increase on soaking for 17 h and sprouting for 3 days. On the other hand, a remarkable increase was observed in protein digestibility i.e., 8% and 11% respectively. The protein content of control and composite breads increased gradually at 1% and protein digestibility decreased by 12% from control. This is due to the presence of dietary fibers which bind with protein and inhibit its digestibility.

Conclusion: The study infers that sprouting the beans for 72 h did not show any remarkable increase in protein content but a significant increase in in vitro protein digestibility was observed. Overall, breads made using 15% legume flour was comparatively equal in protein content, with overall acceptable quality.
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http://dx.doi.org/10.17306/j.afs.2014.1.2DOI Listing
October 2014

Suppressing recombination in polymer photovoltaic devices via energy-level cascades.

Adv Mater 2013 Aug 12;25(30):4131-8. Epub 2013 Jun 12.

Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge, UK.

An energy cascading structure is designed in a polymer photovoltaic device to suppress recombination and improve quantum yields. By the insertion of a thin polymer interlayer with intermediate energy levels, electrons and holes can effectively shuttle away from each other while being spatially separated from recombination. An increase in open-circuit voltage and short-circuit current are observed in modified devices.
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http://dx.doi.org/10.1002/adma.201300243DOI Listing
August 2013

A general method for transferring graphene onto soft surfaces.

Nat Nanotechnol 2013 May 28;8(5):356-62. Epub 2013 Apr 28.

Department of Chemistry, National University of Singapore, Lower Kent Ridge Road, S117543, Singapore.

Recent advances in chemical vapour deposition have led to the fabrication of large graphene sheets on metal foils for use in research and development. However, further breakthroughs are required in the way these graphenes are transferred from their growth substrates onto the final substrate. Although various methods have been developed, as yet there is no general way to reliably transfer graphene onto arbitrary surfaces, such as 'soft' ones. Here, we report a method that allows the graphene to be transferred with high fidelity at the desired location on almost all surfaces, including fragile polymer thin films and hydrophobic surfaces. The method relies on a sacrificial 'self-releasing' polymer layer placed between a conventional polydimethylsiloxane elastomer stamp and the graphene that is to be transferred. This self-releasing layer provides a low work of adhesion on the stamp, which facilitates delamination of the graphene and its placement on the new substrate. To demonstrate the generality and reliability of our method, we fabricate high field-strength polymer capacitors using graphene as the top contact over a polymer dielectric thin film. These capacitors show superior dielectric breakdown characteristics compared with those made with evaporated metal top contacts. Furthermore, we fabricate low-operation-voltage organic field-effect transistors using graphene as the gate electrode placed over a thin polymer gate dielectric layer. We finally demonstrate an artificial graphite intercalation compound by stacking alternate monolayers of graphene and 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ). This compound, which comprises graphene sheets p-doped by partial hole transfer from the F4TCNQ, shows a high and remarkably stable hole conductivity, even when heated in the presence of moisture.
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http://dx.doi.org/10.1038/nnano.2013.63DOI Listing
May 2013

High internal quantum efficiency in fullerene solar cells based on crosslinked polymer donor networks.

Nat Commun 2012 ;3:1321

Department of Physics, National University of Singapore, Singapore S117542, Singapore.

The power conversion efficiency of organic photovoltaic cells depends crucially on the morphology of their donor-acceptor heterostructure. Although tremendous progress has been made to develop new materials that better cover the solar spectrum, this heterostructure is still formed by a primitive spontaneous demixing that is rather sensitive to processing and hence difficult to realize consistently over large areas. Here we report that the desired interpenetrating heterostructure with built-in phase contiguity can be fabricated by acceptor doping into a lightly crosslinked polymer donor network. The resultant nanotemplated network is highly reproducible and resilient to phase coarsening. For the regioregular poly(3-hexylthiophene):phenyl-C(61)-butyrate methyl ester donor-acceptor model system, we obtained 20% improvement in power conversion efficiency over conventional demixed biblend devices. We reached very high internal quantum efficiencies of up to 0.9 electron per photon at zero bias, over an unprecedentedly wide composition space. Detailed analysis of the power conversion, power absorbed and internal quantum efficiency landscapes reveals the separate contributions of optical interference and donor-acceptor morphology effects.
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http://dx.doi.org/10.1038/ncomms2211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535333PMC
June 2013

A proposal: a comprehensive platform to characterize tumors in Chinese and improve success in cancer drug discovery and development.

Chin J Cancer 2011 Jun;30(6):363-7

Beigene Ltd., Beijing 102206, People's Republic of China.

Cancer is a collection of complex diseases in which cell proliferation and apoptosis are dysregulated due to the acquisition of genetic changes in cancer cells. These genetic changes, combined with the interrelated physiologic adaptations of neo-angiogenesis, recruitment of stromal support tissues, and suppression of immune recognition, are measurable characteristics in tumor gene expression profiles and biochemical pathways. These measures can lead to identification of disease drivers and, ultimately, can be used to assign therapy. With advances in RNA sequencing technologies, the ability to simultaneously measure all genetic and gene expression changes with a single technology is now possible. The ability to create a comprehensive catalog of genotypic and phenotypic changes in a collection of histologically similar but otherwise distinct tumors should allow for a more precise positioning of existing targeted therapies and identification of new targets for intervention.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013409PMC
http://dx.doi.org/10.5732/cjc.011.10141DOI Listing
June 2011