P. J. Stephens

Foundation Medicine (United States)

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Vincent A. Miller

Foundation Medicine (United States)

Kai Wang

First Affiliated Hospital of Anhui Medical University

Roman Yelensky

Foundation Medicine (United States)

Carlos L. Arteaga

The University of Texas Southwestern Medical Center

Henry Gómez

EsSALUD

Justin M. Balko

Vanderbilt University Medical Center

Jennifer M. Giltnane

International Association for the Study of Lung Cancer

Gary A. Palmer

Menlo School

Melinda E. Sanders

Vanderbilt University Medical Center

Franco D. Doimi

Instituto Nacional de Enfermedades Neoplásicas

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Foundation Medicine (United States)

Vanderbilt University

Vanderbilt University Medical Center

Dana-Farber Cancer Institute

The University of Texas MD Anderson Cancer Center

University of Arkansas for Medical Sciences

Memorial Sloan Kettering Cancer Center

Harvard University

Vanderbilt-Ingram Cancer Center

Editas Medicine (United States)

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Data from Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets

Justin M. Balko Jennifer M. Giltnane Kai Wang Luis J. Schwarz Christian D. Young

<div>AbstractNeoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To understand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease of 74 clinically defined TNBCs after NAC, including next-generation sequencing (NGS) on 20 matched pretreatment biopsies. Combined NGS and digital RNA expression analysis identified diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profiling residual TNBCs after NAC identifies targetable molecular lesions in the chemotherapy-resistant component of the tumor, which may mirror micrometastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NAC.Significance: This study demonstrates the spectrum of genomic alterations present in residual TNBC after NAC. Because TNBCs that do not achieve a CR after NAC are likely to recur as metastatic disease at variable times after surgery, these alterations may guide the selection of targeted therapies immediately after mastectomy before these metastases become evident. Cancer Discov; 4(2); 232–45. ©2013 AACR.This article is highlighted in the In This Issue feature, p. 131</div>

Profiling (computer programming)

Triple-negative breast cancer

Triple negative

Neoadjuvant Therapy

10.1158/2159-8290.c.6546234

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Magnetic Circular Dichroism of Charge-Transfer Transitions: Low-Spin d5 Hexahalide Complexes

The Journal of Chemical Physics (1968)

G. Henning Anthony J. McCaffery P. N. Schatz P. J. Stephens

The magnetic circular dichroism (MCD) of IrCl62−, IrBr62−, and RuBr63− have been measured through the visible and near ultraviolet. Analysis leads to new assignments of the ligand-to-metal (t2g) charge-transfer bands. In particular, the conventional order of the first two allowed charge-transfer states is reversed so that the 2T1u state lies at lower energy than 2T2u.

Vibrational Circular Dichroism

Spin states

10.1063/1.1668652

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Comparison of Local, Nonlocal, and Hybrid Density Functionals Using Vibrational Absorption and Circular Dichroism Spectroscopy

ACS symposium series (1996)

P. J. Stephens F. J. Devlin C. S. Ashvar Keld L. Bak Paul Taylor

Ab initio calculations of vibrational unpolarized absorption and circular dichroism spectra of 6,8-dioxabicyclo[3.2.1] octane are reported. The harmonic force field is calculated via Density Functional Theory using three density functionals: LSDA, BLYP, B3LYP. The basis set is 6-31G*. Spectra calculated using the hybrid B3LYP functional give the best agreement with experimental spectra, demonstrating that this functional is superior in accuracy to the BLYP and LSDA functionals.

Vibrational Circular Dichroism

Harmonic

10.1021/bk-1996-0629.ch007

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Citations (38)

Determination of the Structures of Chiral Molecules Using Vibrational Circular Dichroism Spectroscopy

ACS symposium series (2002)

P. J. Stephens F. J. Devlin A. Aamouche

INTRODUCTION Chiral molecules exhibit Vibrational Circular Dichroism (VCD) [1]. The VCD spectrum of a chiral molecule is dependent on its structure. It is extremely sensitive to the Absolute Configuration: enantiomeric molecules exhibit mirror-image VCD spectra. In the case of flexible molecules, it is also dependent on the conformation. Thus, in principle, VCD spectroscopy permits both the determination of the Absolute Configuration and the Conformational Analysis of chiral molecules. To date, VCD has not been widely used. Until recently, it has not been practicable to reliably extract structural information from VCD spectra. Recently, this situation has been radically altered by the development of a methodology permitting the prediction of VCD spectra with very high reliability [2]. This methodology is based on Density Functional Theory (DFT) [3] and uses Gauge-Invariant Atomic Orbitals (GIAOs) [4]. We refer to it here as the DFT/GIAO methodology. The accuracy of this methodology, when state-of-the-art density functionals

Vibrational Circular Dichroism

Absolute Configuration

Chirality

10.1021/bk-2002-0810.ch002

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THE THEORY OF VIBRATIONAL CIRCULAR DICHROISM: ALTERNATIVE REPRESENTATIONS OF ATOMIC POLAR AND AXIAL TENSORS

P. J. Stephens K. J. Jalkanen Roger D. Amos Nicholas C. Handy Paolo Lazzeretti

$^{1}$ P.J. Stephens, J. Phys. Chem. 89, 748 (1985). $^{2}$ P.J. Stephens, J. Phys. Chem. 91, 1712 (1987). $^{3}$ R.D. Amos, N.C. Handy, K.J. Jalkanen, P.J. Stephens, Chem. Phys. L. 133, 21 (1987). $^{4}$ K.J. Jalkanen, P.J. Stephens, R.D. Amos, N.C. Handy, J. Am. Chem. Soc. 109, 7193 (1987). $^{5}$ K.J. Jalkanen, R.D. Amos, N.C. Handy, Chem. Phys. L. 142, 153 (1987). $^{6}$ K.J. Jalkanen, P.J. Stephens, R.D. Amos, N.C. Handy, J. Phys. Chem. 1988 (in press). $^{7}$ K.J. Jalkanen, P.J. Stephens, R.D. Amos, N.C. Handy, J. Am. Chem. Soc. 1988 (in press). $^{8}$ R.W. Kawiecki, F. Devlin, P.J. Stephens, R.D. Amos, N.C. Handy, Chem. Phys. L 1988 (in press). $^{9}$ P. Lazzeretti, R. Zanasi, Phys. Rev. A 33, 3727 (1986). $^{10}$ P. Lazzeretti, R. Zanasi, P.J. Stephens, J. Phys. Chem. 90, 6761 (1986).

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Circular dichroism and magnetic circular dichroism of nitrogenase proteins

Proceedings of the National Academy of Sciences (1979)

P. J. Stephens Charles E. McKenna B. E. Smith H. T. Nguyen M. C. McKenna

Circular dichroism (CD) and magnetic circular dichroism (MCD) spectra of nitrogenase components (MoFe protein and Fe protein) from Azotobacter vinelandii (Av) and Klebsiella pneumoniae (Kp) have been obtained in the near infrared-visible-near ultraviolet spectral region. Previously, visible CD was reported to be absent or barely detectable in nitrogenase proteins; MCD spectra have not been reported. The chiroptical spectra can be measured in solution at room temperature, an advantage relative to spectroscopic methods requiring cryogenic sample temperatures. Absorption spectra were also obtained. The CD and MCD are markedly more structured, and thus interpretively more useful, than the corresponding absorption spectra. The dithionite-reduced MoFe proteins (Av1, Kp1) have nearly identical CD and MCD, demonstrating identical numbers and types of metal centers in similar protein environments. The CD and MCD cannot be explained solely in terms of contributions from known 4-Fe or 2-Fe clusters; the near-infrared MCD is inconsistent with the presence of known 4-Fe clusters. CD and MCD spectra of Lauth's violet-oxidized Kp1 are also reported. The reduced Fe proteins (Av2, Kp2) have similar CD and MCD, again indicating significant conservation of chromophore environment. The spectra clearly demonstrate the presence of a reduced bacterial ferredoxin-like (C(3-)) 4-Fe cluster. No obvious evidence of additional chromophores is observed. CD, MCD, and absorption spectra of Av1-oxidized Av2 are reported. The absorption spectrum shows the expected shoulder near 390 nm. The CD and MCD are characteristic of a C(2-) 4-Fe cluster; in particular, the diagnostic near-infrared MCD peak is observed at approximately 8300 cm(-1). The CD of Av2 oxidized in the presence and absence of MgATP are radically different, providing the first direct evidence for MgATP interaction with Fe protein in this oxidation state.

Azotobacter vinelandii

Dithionite

Chromophore

10.1073/pnas.76.6.2585

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Somatic structural rearrangements in genetically engineered mouse mammary tumors

Genome biology (2010)

Ignacio Varela Christiaan Klijn P. J. Stephens Laura Mudie Lucy Stebbings

Here we present the first paired-end sequencing of tumors from genetically engineered mouse models of cancer to determine how faithfully these models recapitulate the landscape of somatic rearrangements found in human tumors. These were models of Trp53-mutated breast cancer, Brca1- and Brca2-associated hereditary breast cancer, and E-cadherin (Cdh1) mutated lobular breast cancer. We show that although Brca1- and Brca2-deficient mouse mammary tumors have a defect in the homologous recombination pathway, there is no apparent difference in the type or frequency of somatic rearrangements found in these cancers when compared to other mouse mammary cancers, and tumors from all genetic backgrounds showed evidence of microhomology-mediated repair and non-homologous end-joining processes. Importantly, mouse mammary tumors were found to carry fewer structural rearrangements than human mammary cancers and expressed in-frame fusion genes. Like the fusion genes found in human mammary tumors, these were not recurrent. One mouse tumor was found to contain an internal deletion of exons of the Lrp1b gene, which led to a smaller in-frame transcript. We found internal in-frame deletions in the human ortholog of this gene in a significant number (4.2%) of human cancer cell lines. Paired-end sequencing of mouse mammary tumors revealed that they display significant heterogeneity in their profiles of somatic rearrangement but, importantly, fewer rearrangements than cognate human mammary tumors, probably because these cancers have been induced by strong driver mutations engineered into the mouse genome. Both human and mouse mammary cancers carry expressed fusion genes and conserved homozygous deletions.

CDH1

Mammary tumor

10.1186/gb-2010-11-10-r100

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Supplementary Data Figure 5 from Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets

Justin M. Balko Jennifer M. Giltnane Kai Wang Luis J. Schwarz Christian D. Young

PDF file 62K, MCL1 overexpression enhances docetaxel resistance in non-amplified TNBC cell lines

Triple-negative breast cancer

Triple negative

Neoadjuvant Therapy

Profiling (computer programming)