Publications by authors named "Dennis Huang"

29 Publications

  • Page 1 of 1

G3BP1 inhibits Cul3 to amplify AR signaling and promote prostate cancer.

Nat Commun 2021 Nov 18;12(1):6662. Epub 2021 Nov 18.

Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, 10065, USA.

SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3, suggesting a distinctive mode of Cul3 inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1 PCa are more susceptible to AR-targeted therapy.
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http://dx.doi.org/10.1038/s41467-021-27024-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602290PMC
November 2021

Phase 1b Open-Label Trial of Afatinib Plus Xentuzumab (BI 836845) in Patients With Mutation-Positive NSCLC After Progression on EGFR Tyrosine Kinase Inhibitors.

JTO Clin Res Rep 2021 Sep 10;2(9):100206. Epub 2021 Jul 10.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

Introduction: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated mutation-positive NSCLC.

Methods: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B).

Results: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8-10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B.

Conclusions: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with mutation-positive, T790M-negative NSCLC after progression on afatinib.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474216PMC
September 2021

Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy: From intrinsic physicochemical properties to external modification.

Bioact Mater 2022 Feb 6;8:220-240. Epub 2021 Jul 6.

National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.

The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability, simple preparation method, and offering "all-in-one" functional platform features. However, the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the journey, which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment. In this review, we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy, including optimizing the intrinsic physicochemical properties and external modification. Finally, the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented. We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.
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http://dx.doi.org/10.1016/j.bioactmat.2021.06.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424425PMC
February 2022

Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity.

Cell Rep 2021 Sep;36(10):109625

Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

The normal androgen receptor (AR) cistrome and transcriptional program are fundamentally altered in prostate cancer (PCa). Here, we profile the chromatin landscape and AR-directed transcriptional program in normal prostate cells and show the impact of SPOP mutations, an early event in prostate tumorigenesis. In genetically normal mouse prostate organoids, SPOP mutation results in accessibility and AR binding patterns similar to that of human PCa. Consistent with dependence on AR signaling, castration of SPOP mutant mouse models results in the loss of neoplastic phenotypes, and human SPOP mutant PCa shows a favorable response to AR-targeted therapies. Together, these data validate mouse prostate organoids as a robust model for studying epigenomic and transcriptional alterations in normal prostate, provide valuable datasets for further studies, and show that a single genomic alteration may be sufficient to reprogram the chromatin of normal prostate cells toward oncogenic phenotypes, with potential therapeutic implications for AR-targeting therapies.
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http://dx.doi.org/10.1016/j.celrep.2021.109625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477443PMC
September 2021

Afatinib in EGFR TKI-Naïve Patients with Locally Advanced or Metastatic EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Pooled Analysis of Three Phase IIIb Studies.

Front Oncol 2021 9;11:709877. Epub 2021 Jul 9.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.

Background: Afatinib is approved for first-line treatment of patients with epidermal growth factor receptor mutation-positive (m+) non-small-cell lung cancer (NSCLC). Here, we report findings from a combined analysis of three phase IIIb studies of afatinib in EGFR tyrosine kinase inhibitor (TKI)-naïve patients.

Methods: EGFR-TKI-naïve patients with m+ NSCLC received afatinib 40 mg/day. Dose reductions were permitted for adverse events (AEs). Efficacy endpoints included progression-free survival (PFS), time to symptomatic progression (TTSP), and tumor response. Subgroup analyses were performed by Eastern Cooperative Oncology Group performance status (ECOG PS), presence of brain metastasis, age and common/uncommon mutations (plus other factors).

Results: 1108 patients were treated. Median age was 61 years (range, 25-89); 19.2% had baseline brain metastases, 4.4% had ECOG PS ≥2, and 17.9% had tumors harboring uncommon mutations. Treatment-related AEs (TRAEs) were reported in 97.2%, most commonly diarrhea and rash. 41.6% had AEs leading to dose reduction. Median PFS was 13.0 months [95% confidence interval (CI): 12.0-13.8]; median TTSP was 14.8 months (95% CI: 13.9-16.1). Objective response rate (ORR) was 55.0%. Age, presence of baseline brain metastases, major (G719X, L861Q, S768I) or compound uncommon mutations had little/no effect on PFS, TTSP, or ORR, while outcomes were poorer in patients with ECOG PS 2 or exon 20 insertion/T790M mutations.

Conclusions: Afatinib was tolerable with no new safety signals. Afatinib demonstrated encouraging efficacy in a broad patient population, including those with brain metastases or uncommon mutations.
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http://dx.doi.org/10.3389/fonc.2021.709877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298067PMC
July 2021

TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice.

Nat Commun 2021 06 7;12(1):3359. Epub 2021 Jun 7.

Neuroscience Initiative Advanced Science Research Center, New York, NY, USA.

The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier (Slc) gene family. Among them, we show that the expression levels of the Na/K/Cl transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface.
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http://dx.doi.org/10.1038/s41467-021-23735-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185117PMC
June 2021

A combinational chemo-immune therapy using an enzyme-sensitive nanoplatform for dual-drug delivery to specific sites by cascade targeting.

Sci Adv 2021 Feb 5;7(6). Epub 2021 Feb 5.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78731, USA.

Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug-loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti-PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.
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http://dx.doi.org/10.1126/sciadv.aba0776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864565PMC
February 2021

A phase Ib/II study of xentuzumab, an IGF-neutralising antibody, combined with exemestane and everolimus in hormone receptor-positive, HER2-negative locally advanced/metastatic breast cancer.

Breast Cancer Res 2021 01 15;23(1). Epub 2021 Jan 15.

Breast Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

Background: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC).

Methods: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS).

Results: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]).

Conclusions: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136).

Trial Registration: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.
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http://dx.doi.org/10.1186/s13058-020-01382-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811234PMC
January 2021

Photo-induced specific intracellular release EGFR inhibitor from enzyme/ROS-dual sensitive nano-platforms for molecular targeted-photodynamic combinational therapy of non-small cell lung cancer.

J Mater Chem B 2020 09 11;8(35):7931-7940. Epub 2020 Aug 11.

School of Chemical Engineering, Sichuan University, Chengdu 610065, China.

Molecular targeted-photodynamic combinational therapy is a promising strategy to enhance antitumor effects; meanwhile, current nanocarriers face challenges of limited selective delivery and release of therapeutic agents to specific tumor sites, which significantly compromises their therapeutic efficacy. Herein, we report active-targeting, enzyme- and ROS-dual responsive nanoparticles (HPGBCA) consisting of CD-targeting hyaluronic acid (HA) shells and afatinib (AFT)-loaded, ROS-sensitive poly(l-lysine)-conjugated chlorin e6 (Ce6) derivative nanoparticle cores (PGBCA). HPGBCA can actively carry AFT and Ce6 specifically to tumor cells due to the negatively charged HA and CD-mediated active targeting. Subsequently, hyaluronidase in the endosome will further spur the degradation of the HA shell to prompt exposure of the positively charged PGBCA core for rapid endosomal escape and intracellular delivery of AFT and Ce6. Furthermore, the generation of ROS produced by Ce6 under NIR irradiation can trigger the rapid oxidation of the thioether linker to facilitate the release of AFT into the cytoplasm. In vitro and in vivo studies demonstrated that the released AFT and excessive ROS at the local site can synergistically induce cell apoptosis to enhance the therapeutic efficacy without side effects. Our developed intelligent nanoparticle provides new avenues to achieve on-demand, specific intracellular drug release for improved molecular targeted-photodynamic combination therapeutic efficacy.
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http://dx.doi.org/10.1039/d0tb01053gDOI Listing
September 2020

Afatinib in patients with advanced non-small cell lung cancer harboring HER2 mutations, previously treated with chemotherapy: A phase II trial.

Lung Cancer 2020 09 16;147:209-213. Epub 2020 Jul 16.

Medical Oncology, Shanghai Pulmonary Hospital, Shanghai, China. Electronic address:

Background: Despite 1-4 % of NSCLC tumors harboring mutations in the HER2 gene, there are no approved HER2-pathway-targeted treatments available. We report an open-label, single-arm, multicenter phase II study investigating the efficacy and safety of afatinib in Asian patients with HER2-mutation positive (HER2m+) NSCLC.

Methods: Eligible patients for Part A had confirmed stage IIIb/IV HER2m + NSCLC, had failed one or two prior lines of chemotherapy, and were EGFR/HER2-inhibitor naïve. Patients received oral afatinib 40 mg/day in continuous 28-day cycles, until disease progression or intolerable adverse events (AEs). Patients qualified for Part B if they had > 12 weeks' clinical benefit and Eastern Cooperative Oncology Group performance status ≤ 2. In Part B, patients were to receive afatinib at the last received dose, plus paclitaxel 80 mg/m weekly, until disease progression or intolerable AEs. The primary endpoint in Part A was objective response (OR); secondary endpoints included disease control (DC), progression-free survival (PFS), and overall survival (OS). Further exploratory endpoints were OR, DC, and PFS in Part B.

Results: Eighteen patients received afatinib in Part A. No patient achieved an OR; 11 patients (61.1 %) achieved stable disease, and six patients (33.3 %) had progressive disease. DC rate was therefore 61.1 % (95 % confidence interval [CI]: 35.7, 82.7). A decrease in tumor size from baseline of > 0 to < 30 % was observed in eight patients. At the time of analysis, 16 patients (88.9 %) had progressed or died. Median PFS was 2.76 months (95 % CI: 1.87, 4.60) and median OS was 10.02 months (95 % CI: 8.47, 10.08). All patients experienced ≥ 1 AE, most commonly diarrhea (66.7 %) and rash (33.3 %). No patients met the inclusion criteria for Part B, and recruitment was slow; therefore, the study was terminated.

Conclusions: This study found no clinical benefit of afatinib for EGFR TKI-naïve patients with HER2m + NSCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.017DOI Listing
September 2020

CRISPR/Cas systems to overcome challenges in developing the next generation of T cells for cancer therapy.

Adv Drug Deliv Rev 2020 21;158:17-35. Epub 2020 Jul 21.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; Departments of Pediatrics and Surgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address:

Genetically engineered immune cells with chimeric antigen receptors (CAR) or modified T cell receptors (TCR) have demonstrated their potential as a potent class of new cancer therapeutic strategy. Despite the clinical success of autologous CD19 CAR T cells in hematological malignancies, allogeneic T cells exhibit many advantages over their autologous counterparts and have recently gathered widespread attention due to the emergence of multiplex genome editing techniques, particularly CRISPR/Cas systems. Furthermore, genetically engineered T cells face a host of major challenges in solid tumors that are not as significant for blood cancers such as T cell targeted delivery, target specificity, proliferation, persistence, and the immunosuppressive tumor microenvironment. We take this opportunity to analyze recent strategies to develop allogeneic T cells, specifically in consideration of CRISPR/Cas and its delivery systems for multiplex gene editing. Additionally, we discuss the current methods used to delivery CRISPR/Cas systems for immunotherapeutic applications, and the challenges to continued development of novel delivery systems. We also provide a comprehensive analysis of the major challenges that genetically engineered T cells face in solid tumors along with the most recent strategies to overcome these barriers, with an emphasis on CRISPR-based approaches. We illustrate the synergistic prospects for how the combination of synthetic biology and immune-oncology could pave the way for designing the next generation of precision cancer therapy.
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http://dx.doi.org/10.1016/j.addr.2020.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736063PMC
September 2021

Advanced engineered nanoparticulate platforms to address key biological barriers for delivering chemotherapeutic agents to target sites.

Adv Drug Deliv Rev 2020 12 1;167:170-188. Epub 2020 Jul 1.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Departments of Pediatrics and Surgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address:

The widespread development of nanocarriers to deliver chemotherapeutics to specific tumor sites has been motivated by the lack of selective targeting during chemotherapy inducing serious side effects and low therapeutic efficacy. The utmost challenge in targeted cancer therapies is the ineffective drug delivery system, in which the drug-loaded nanocarriers are hindered by multiple complex biological barriers that compromise the therapeutic efficacy. Despite considerable progress engineering novel nanoplatforms for the delivery of chemotherapeutics, there has been limited success in a clinical setting. In this review, we identify and analyze design strategies for improved therapeutic efficacy and unique properties of nanoplatforms, including liposomes, polymeric micelles, nanogels, and dendrimers. We provide a comprehensive and integral description of key biological barriers that nanoplatforms are exposed to during their in vivo journey and discuss associated strategies to overcome these barriers based on the latest research and information available in the field. We expect this review to provide constructive information for the rational design of more effective nanoplatforms to advance precision therapies and accelerate their clinical translation.
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http://dx.doi.org/10.1016/j.addr.2020.06.030DOI Listing
December 2020

Exogenous vitamin C triggered structural changes of redox-activated dual core-crosslinked biodegradable nanogels for boosting the antitumor efficiency.

J Mater Chem B 2020 06 15;8(23):5109-5116. Epub 2020 May 15.

National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, P. R. China.

Premature leakage of drugs during blood circulation and slow drug release at the tumor site are two major challenges that nanocarriers have to overcome to achieve successful cancer therapy. Herein, a dual core-crosslinked, redox-sensitive polymeric nanogel (sDL) was constructed by the self-assembly of two star-shaped amphiphilic copolymers (4sP(EG-b-LLA)-N, 4sP(EG-b-DLA)-N) in the presence of a redox-sensitive crosslinker (d-ss-Bu), where hydrophilic polyethylene glycol (PEG) was used as the shell and the functional hydrophobic poly(l-lactide) (PLLA) and poly(d-lactide) (PDLA) were used as the dual crosslinked core via stereocomplex formation and chemical interactions. The dual core-crosslinked structure of the nanogels allowed for almost 2-fold enhanced doxorubicin (DOX)-loading capacity, favorable structural stability to restrict the premature leakage of therapeutic drug and smaller particle size to accelerate the internalization efficiency compared to non-crosslinked nanocarriers. Furthermore, exogenous vitamin C (Vc) can trigger the breakage of redox-sensitive bonds to accelerate drug release from nanogels for improved in vitro antitumor efficacy. Notably, in vivo near-infrared imaging showed that the highly stable DOX-loaded sDL efficiently aggregated at the tumor site. Sequential administration of DOX-loaded sDL and Vc exhibited the highest tumor inhibition effect without associated systemic toxicity compared to the corresponding single injection of Vc or DOX-loaded sDL control groups for in vivo studies, indicating that exogenous administration of Vc can synergistically impact the release of DOX from sDL. Therefore, the developed nanogels proved to be promising smart carriers for achieving precise tunable-stability in response to relevant environments and the combination of Vc to activate reduction-sensitive drug delivery is a promising approach to maximize the therapeutic efficacy.
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http://dx.doi.org/10.1039/d0tb00356eDOI Listing
June 2020

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours.

Br J Cancer 2020 04 12;122(9):1324-1332. Epub 2020 Mar 12.

Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S. Rd., Taipei, Taiwan.

Background: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers.

Methods: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD.

Results: Study 1280.1 involved 61 patients (part I: xentuzumab 10-1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10-3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD.

Conclusions: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity.

Clinical Trial Registration: NCT01403974; NCT01317420.
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http://dx.doi.org/10.1038/s41416-020-0774-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188670PMC
April 2020

Dynamic Lamin B1-Gene Association During Oligodendrocyte Progenitor Differentiation.

Neurochem Res 2020 Mar 4;45(3):606-619. Epub 2020 Feb 4.

Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York, 85 St. Nicholas Terrace, New York, NY, 10031, USA.

Differentiation of oligodendrocytes (OL) from progenitor cells (OPC) is the result of a unique program of gene expression, which is further regulated by the formation of topological domains of association with the nuclear lamina. In this study, we show that cultured OPC were characterized by progressively declining levels of endogenous Lamin B1 (LMNB1) during differentiation into OL. We then identify the genes dynamically associated to the nuclear lamina component LMNB1 during this transition, using a well established technique called DamID, which is based on the ability of a bacterially-derived deoxyadenosine methylase (Dam), to modify genomic regions in close proximity. We expressed a fusion protein containing Dam and LMNB1 in OPC (OPC) and either kept them proliferating or differentiated them into OL (OL) and identified genes that were dynamically associated to LMNB1 with differentiation. Importantly, we identified Lss, the gene encoding for lanosterol synthase, a key enzyme in cholesterol synthesis, as associated to the nuclear lamina in OL. This finding could at least in part explain the lipid dysregulation previously reported for mouse models of ADLD characterized by persistent LMNB1 expression in oligodendrocytes.
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http://dx.doi.org/10.1007/s11064-019-02941-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060805PMC
March 2020

CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis.

Cancer Cell 2019 04 28;35(4):603-617.e8. Epub 2019 Mar 28.

Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

Deletion of the gene encoding the chromatin remodeler CHD1 is among the most common alterations in prostate cancer (PCa); however, the tumor-suppressive functions of CHD1 and reasons for its tissue-specific loss remain undefined. We demonstrated that CHD1 occupied prostate-specific enhancers enriched for the androgen receptor (AR) and lineage-specific cofactors. Upon CHD1 loss, the AR cistrome was redistributed in patterns consistent with the oncogenic AR cistrome in PCa samples and drove tumor formation in the murine prostate. Notably, this cistrome shift was associated with a unique AR transcriptional signature enriched for pro-oncogenic pathways unique to this tumor subclass. Collectively, these data credential CHD1 as a tumor suppressor in the prostate that constrains AR binding/function to limit tumor progression.
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http://dx.doi.org/10.1016/j.ccell.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467783PMC
April 2019

Protoporphyrin IX (PpIX)-Coated Superparamagnetic Iron Oxide Nanoparticle (SPION) Nanoclusters for Magnetic Resonance Imaging and Photodynamic Therapy.

Adv Funct Mater 2018 Apr 15;28(16). Epub 2018 Feb 15.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.

The ability to produce nanotherapeutics at large-scale with high drug loading efficiency, high drug loading capacity, high stability, and high potency is critical for clinical translation. However, many nanoparticle-based therapeutics under investigation suffer from complicated synthesis, poor reproducibility, low stability, and high cost. In this work, a simple method for preparing multifunctional nanoparticles is utilized that act as both a contrast agent for magnetic resonance imaging and a photosensitizer for photodynamic therapy for the treatment of cancer. In particular, the photosensitizer protoporphyrin IX (PpIX) is used to solubilize small nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs) without the use of any additional carrier materials. These nanoclusters are characterized with a high PpIX loading efficiency; a high loading capacity, stable behavior; high potency; and a synthetic approach that is amenable to large-scale production. In vivo studies of photodynamic therapy (PDT) efficacy show that the PpIX-coated SPION nanoclusters lead to a significant reduction in the growth rate of tumors in a syngeneic murine tumor model compared to both free PpIX and PpIX-loaded poly(ethylene glycol)-polycaprolactone micelles, even when injected at 1/8th the dose. These results suggest that the nanoclusters developed in this work can be a promising nanotherapeutic for clinical translation.
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http://dx.doi.org/10.1002/adfm.201707030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997278PMC
April 2018

A Phase I/Randomized Phase II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nintedanib versus Sorafenib in Asian Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2018 May 15;7(2):165-178. Epub 2018 Mar 15.

National Taiwan University Hospital, Taipei, Taiwan.

Background: Nintedanib is an oral, triple angiokinase inhibitor of vascular endothelial growth factor/platelet-derived growth factor/fibroblast growth factor receptors. This randomized, multicenter, open-label, phase I/II study evaluated the safety, pharmacokinetics, maximum tolerated dose (MTD) in terms of dose-limiting toxicities (DLTs), and efficacy of nintedanib versus sorafenib in Asian patients with unresectable advanced hepatocellular carcinoma (HCC).

Patients And Methods: For the phase I portion, patients were stratified into two groups according to their alanine aminotransferase/aspartate aminotransferase (ALT/AST) and Child-Pugh score at baseline. For phase I, the primary endpoint was determination of the MTD in terms of DLTs. For phase II, patients with a Child-Pugh score of 5-6, an Eastern Cooperative Oncology Group performance score ≤2, and an ALT/AST ≤2× the upper limit of normal were enrolled and randomized 2: 1 to nintedanib 200 mg twice daily (b.i.d.) (the MTD determined in phase I) or sorafenib 400 mg b.i.d. continuously in 28-day cycles until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint for phase II was time to progression (TTP) by central independent review (CIR; by Response Evaluation Criteria in Solid Tumors v1.0); the secondary endpoints included overall survival (OS). All analyses were exploratory.

Results: The MTD was 200 mg in both groups. For phase II, 95 patients were randomized to nintedanib ( = 63) or sorafenib ( = 32). For nintedanib and sorafenib, respectively, the median CIR TTP was 2.8 vs. 3.7 months (hazard ratio [HR] = 1.21, 95% confidence interval [CI] 0.73-2.01) and the median OS 10.2 vs. 10.7 months (HR = 0.94, 95% CI 0.59-1.49). Nintedanib-treated patients had fewer grade 3 or higher AEs (56 vs. 84%), serious AEs (46 vs. 56%), and AEs leading to dose reduction (19 vs. 59%) and drug discontinuation (24 vs. 34%). AEs associated more frequently with nintedanib were vomiting and nausea, whereas those associated more frequently with sorafenib were ALT/AST increases, diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome.

Conclusions: Nintedanib showed numerically similar efficacy to sorafenib for CIR TTP and OS in Asian patients with advanced HCC and adequate liver function. AEs were generally manageable.
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http://dx.doi.org/10.1159/000486460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985414PMC
May 2018

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

Ann Clin Microbiol Antimicrob 2017 Nov 25;16(1):76. Epub 2017 Nov 25.

Division of Pharmaceutics and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.

Background: The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections.

Methods: The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2.

Results: Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients).

Conclusions: Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.
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http://dx.doi.org/10.1186/s12941-017-0249-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702089PMC
November 2017

Quantification of mutant SPOP proteins in prostate cancer using mass spectrometry-based targeted proteomics.

J Transl Med 2017 08 15;15(1):175. Epub 2017 Aug 15.

Biological Sciences Division, Pacific Northwest National Laboratory, P.O. Box 999, MSIN: K8-98, Richland, WA, 99354, USA.

Background: Speckle-type POZ protein (SPOP) is an E3 ubiquitin ligase adaptor protein that functions as a potential tumor suppressor, and SPOP mutations have been identified in ~10% of human prostate cancers. However, it remains unclear if mutant SPOP proteins can be utilized as biomarkers for early detection, diagnosis, prognosis or targeted therapy of prostate cancer. Moreover, the SPOP mutation sites are distributed in a relatively short region with multiple lysine residues, posing significant challenges for bottom-up proteomics analysis of the SPOP mutations.

Methods: To address this issue, PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing)-SRM (selected reaction monitoring) mass spectrometry assays have been developed for quantifying wild-type SPOP protein and 11 prostate cancer-derived SPOP mutations.

Results: Despite inherent limitations due to amino acid sequence constraints, all the PRISM-SRM assays developed using Arg-C digestion showed a linear dynamic range of at least two orders of magnitude, with limits of quantification ranged from 0.1 to 1 fmol/μg of total protein in the cell lysate. Applying these SRM assays to analyze HEK293T cells with and without expression of the three most frequent SPOP mutations in prostate cancer (Y87N, F102C or F133V) led to confident detection of all three SPOP mutations in corresponding positive cell lines but not in the negative cell lines. Expression of the F133V mutation and wild-type SPOP was at much lower levels compared to that of F102C and Y87N mutations; however, at present, it is unknown if this also affects the biological activity of the SPOP protein.

Conclusions: In summary, PRISM-SRM enables multiplexed, isoform-specific detection of mutant SPOP proteins in cell lysates, providing significant potential in biomarker development for prostate cancer.
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http://dx.doi.org/10.1186/s12967-017-1276-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557563PMC
August 2017

Assessment of Combined Polymyxin B and Minocycline Therapy against Klebsiella pneumoniae Carbapenemase (KPC)-Producing K. pneumoniae.

Antimicrob Agents Chemother 2017 07 27;61(7). Epub 2017 Jun 27.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo-State University of New York, Buffalo, New York, USA

The multidrug resistance profiles of carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria. The objective of this study was to evaluate the activity of polymyxin B and minocycline combination therapy against six KPC-2-producing isolates (minocycline MIC range, 2 to 32 mg/liter). Polymyxin B monotherapy (0.5, 1, 2, 4, and 16 mg/liter) resulted in a rapid reduction of up to 6 log in bactericidal activity followed by regrowth by 24 h. Minocycline monotherapy (1, 2, 4, 8, and 16 mg/liter) showed no reduction of activity of >1.34 log against all isolates, although concentrations of 8 and 16 mg/liter prolonged the time to regrowth. When the therapies were used in combination, rapid bactericidal activity was followed by slower regrowth, with synergy (60 of 120 combinations at 24 h, 19 of 120 combinations at 48 h) and additivity (43 of 120 combinations at 24 h, 44 of 120 combinations at 48 h) against all isolates. The extent of killing was greatest against the more susceptible polymyxin B isolates (MICs of ≤0.5 mg/liter) regardless of the minocycline MIC. The pharmacodynamic activity of combined polymyxin B-minocycline therapy against KPC-producing is dependent on polymyxin B susceptibility. Further and animal studies must be performed to fully evaluate the efficacy of this drug combination.
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http://dx.doi.org/10.1128/AAC.00073-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487624PMC
July 2017

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling.

Cancer Cell 2017 03;31(3):436-451

Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Urology, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor signaling, effectively uncoupling the normal negative feedback between these two pathways.
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http://dx.doi.org/10.1016/j.ccell.2017.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384998PMC
March 2017

Etching of Cr tips for scanning tunneling microscopy of cleavable oxides.

Rev Sci Instrum 2017 Feb;88(2):023705

Department of Physics, Harvard University, Cambridge, Massachusetts 02138, USA.

We report a detailed three-step roadmap for the fabrication and characterization of bulk Cr tips for spin-polarized scanning tunneling microscopy. Our strategy uniquely circumvents the need for ultra-high vacuum preparation of clean surfaces or films. First, we demonstrate the role of ex situ electrochemical etch parameters on Cr tip apex geometry, using scanning electron micrographs of over 70 etched tips. Second, we describe the suitability of the in situ cleaved surface of the layered antiferromagnet LaSrMnO to evaluate the spin characteristics of the Cr tip, replacing the ultra-high vacuum-prepared test samples that have been used in prior studies. Third, we outline a statistical algorithm that can effectively delineate closely spaced or irregular cleaved step edges, to maximize the accuracy of step height and spin-polarization measurements.
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http://dx.doi.org/10.1063/1.4976567DOI Listing
February 2017

Dumbbell Defects in FeSe Films: A Scanning Tunneling Microscopy and First-Principles Investigation.

Nano Lett 2016 07 13;16(7):4224-9. Epub 2016 Jun 13.

Department of Physics & Astronomy, University of British Columbia , Vancouver, British Columbia V6T 1Z1, Canada.

The properties of iron-based superconductors (Fe-SCs) can be varied dramatically with the introduction of dopants and atomic defects. As a pressing example, FeSe, parent phase of the highest-Tc Fe-SC, exhibits prevalent defects with atomic-scale "dumbbell" signatures as imaged by scanning tunneling microscopy (STM). These defects spoil superconductivity when their concentration exceeds 2.5%. Resolving their chemical identity is a prerequisite to applications such as nanoscale patterning of superconducting/nonsuperconducting regions in FeSe as well as fundamental questions such as the mechanism of superconductivity and the path by which the defects destroy it. We use STM and density functional theory to characterize and identify the dumbbell defects. In contrast to previous speculations about Se adsorbates or substitutions, we find that an Fe-site vacancy is the most energetically favorable defect in Se-rich conditions and reproduces our observed STM signature. Our calculations shed light more generally on the nature of Se capping, the removal of Fe vacancies via annealing, and their ordering into a √5 × √5 superstructure in FeSe and related alkali-doped compounds.
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http://dx.doi.org/10.1021/acs.nanolett.6b01163DOI Listing
July 2016

SPOP mutation leads to genomic instability in prostate cancer.

Elife 2015 Sep 16;4. Epub 2015 Sep 16.

Department of Urology, Weill Cornell Medical College, New York, United States.

Genomic instability is a fundamental feature of human cancer often resulting from impaired genome maintenance. In prostate cancer, structural genomic rearrangements are a common mechanism driving tumorigenesis. However, somatic alterations predisposing to chromosomal rearrangements in prostate cancer remain largely undefined. Here, we show that SPOP, the most commonly mutated gene in primary prostate cancer modulates DNA double strand break (DSB) repair, and that SPOP mutation is associated with genomic instability. In vivo, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation resulting in impaired homology-directed repair (HDR) of DSB. Furthermore, we found that SPOP mutation sensitizes to DNA damaging therapeutic agents such as PARP inhibitors. These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through genomic instability, and indicate that mutant SPOP may increase response to DNA-damaging therapeutics.
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http://dx.doi.org/10.7554/eLife.09207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621745PMC
September 2015

Revealing the Empty-State Electronic Structure of Single-Unit-Cell FeSe/SrTiO3.

Phys Rev Lett 2015 Jul 2;115(1):017002. Epub 2015 Jul 2.

Department of Physics, Harvard University, Cambridge, Massachusetts 02138, USA.

We use scanning tunneling spectroscopy to investigate the filled and empty electronic states of superconducting single-unit-cell FeSe deposited on SrTiO3(001). We map the momentum-space band structure by combining quasiparticle interference imaging with decay length spectroscopy. In addition to quantifying the filled-state bands, we discover a Γ-centered electron pocket 75 meV above the Fermi energy. Our density functional theory calculations show the orbital nature of empty states at Γ and explain how the Se height is a key tuning parameter of their energies, with broad implications for electronic properties.
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http://dx.doi.org/10.1103/PhysRevLett.115.017002DOI Listing
July 2015

Nanoscale interplay of strain and doping in a high-temperature superconductor.

Nano Lett 2014 Dec 7;14(12):6749-53. Epub 2014 Nov 7.

Department of Physics, Harvard University , Cambridge, Massachusetts 02138, United States.

The highest-temperature superconductors are electronically inhomogeneous at the nanoscale, suggesting the existence of a local variable that could be harnessed to enhance the superconducting pairing. Here we report the relationship between local doping and local strain in the cuprate superconductor Bi(2)Sr(2)CaCu(2)O(8+x). We use scanning tunneling microscopy to discover that the crucial oxygen dopants are periodically distributed in correlation with local strain. Our picoscale investigation of the intraunit-cell positions of all oxygen dopants provides essential structural input for a complete microscopic theory.
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http://dx.doi.org/10.1021/nl501890kDOI Listing
December 2014

Development of standard estrogen and progesterone receptor immunohistochemical assays for selection of patients for antihormonal therapy.

Appl Immunohistochem Mol Morphol 2007 Sep;15(3):325-31

Dako North America, Inc, Carpinteria, CA 93013, USA.

Estrogen receptor (ER) and progesterone receptor (PR) status in breast carcinomas are considered validated predictive factors for selecting patients for antihormonal therapy. Published surveys have shown a significant rate of disagreement and lack of reproducibility of immunohistochemistry (IHC) results from laboratories around the world. To address these limitations IHC assays for ER and PR were developed using characterized reagents, after careful calibration of the sensitivity and specificity to match established assays previously validated in large clinical studies. The ER assay uses a cocktail of 2 mouse monoclonal antibodies (1D5 and ER-2-123) and the PR assay uses 1 mouse monoclonal antibody (PgR 1294); both are followed by a polymer-peroxidase-based detection system. All antibodies were tested for specificity by epitope mapping. The sensitivity of the new assays was calibrated to be equivalent to previously validated IHC assays followed by a comparison with the validated assays in a concordance study involving over 200 specimens. All slides were scored with the "Allred Score," also used for scoring of the original validated assays. The overall concordance between the new and the established IHC assays was nearly perfect (99%). The concordance study demonstrated greater than 98% positive agreement and 100% negative agreement of the new IHC assays with the previously validated IHC assays. This equivalence establishes the clinical validation of the assays and, as they are based on newer generation reagents and are produced and tested under stringent quality control conditions to ensure their consistency, they add additional advantages to the user and patients.
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http://dx.doi.org/10.1097/01.pai.0000213135.16783.bcDOI Listing
September 2007
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