Publications by authors named "Sungjune Kim"

48 Publications

Gonadal-sparing total body irradiation with the use of helical tomotherapy for nonmalignant indications.

Rep Pract Oncol Radiother 2021 25;26(1):153-158. Epub 2021 Feb 25.

Department of Radiation Oncology, H. Lee Moffit Cancer Center and Research Institute, Tampa, FL, United States.

Background: The aim was to demonstrate the feasibility and technique of gonadal sparing total body irradiation (TBI) with helical tomotherapy. Total body irradiation is a common part of the conditioning regimen prior to allogeneic stem cell transplantation. Shielding or dose-reduction to the gonads is often desired to preserve fertility, particularly in young patients undergoing transplant for non-malignant indications. Helical tomotherapy (HT) has been shown to be superior to traditional TBI delivery for organ at risk (OA R) doses and dose homogeneity.

Materials And Methods: We present two representative cases (one male and one female) to illustrate the feasibility of this technique, each of whom received 3Gy in a single fraction prior to allogeneic stem cell transplant for benign indications. The planning target volume (PTV) included the whole body with a subtraction of OA Rs including the lungs, heart, and brain (each contracted by 1cm) as well as the gonads (testicles expanded by 5 cm and ovaries expanded by 0.5 cm).

Results: For the male patient we achieved a homogeneity index of 1.35 with a maximum and median planned dose to the testes of 0.53 Gy and 0.35 Gy, respectively. In-vivo dosimetry demonstrated an actual received dose of 0.48 Gy. For the female patient we achieved a homogeneity index of 1.13 with a maximum and median planned dose to the ovaries of 1.66 Gy and 0.86 Gy, respectively.

Conclusion: Gonadal sparing TBI is feasible and deliverable using HT in patients with non-malignant diseases requiring TBI as part of a pre-stem cell transplant conditioning regimen.
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http://dx.doi.org/10.5603/RPOR.a2021.0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149136PMC
February 2021

Epigenetic dysregulation of immune-related pathways in cancer: bioinformatics tools and visualization.

Exp Mol Med 2021 May 7;53(5):761-771. Epub 2021 May 7.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Cancer immune evasion is one of the hallmarks of carcinogenesis. Cancer cells employ multiple mechanisms to avoid immune recognition and suppress antitumor immune responses. Recently, accumulating evidence has indicated that immune-related pathways are epigenetically dysregulated in cancer. Most importantly, the epigenetic footprint of immune-related pathways is associated with the patient outcome, underscoring the crucial need to understand this process. In this review, we summarize the current evidence for epigenetic regulation of immune-related pathways in cancer and describe bioinformatics tools, informative visualization techniques, and resources to help decipher the cancer epigenome.
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http://dx.doi.org/10.1038/s12276-021-00612-zDOI Listing
May 2021

Analysis of environmental organic matters by Ultrahigh-Resolution mass spectrometry-A review on the development of analytical methods.

Mass Spectrom Rev 2021 Jan 24. Epub 2021 Jan 24.

Department of Chemistry, Kyungpook National University, Daegu, Korea.

Owing to the increasing environmental and climate changes globally, there is an increasing interest in the molecular-level understanding of environmental organic compound mixtures, that is, the pursuit of complete and detailed knowledge of the chemical compositions and related chemical reactions. Environmental organic molecule mixtures, including those in air, soil, rivers, and oceans, have extremely complex and heterogeneous chemical compositions. For their analyses, ultrahigh-resolution and sub-ppb level mass accuracy, achievable using Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS), are important. FT-ICR MS has been successfully used to analyze complex environmental organic molecule mixtures such as natural, soil, particulate, and dissolved organic matter. Despite its success, many limitations still need to be overcome. Sample preparation, ionization, structural identification, chromatographic separation, and data interpretation are some key areas that have been the focus of numerous studies. This review describes key developments in analytical techniques in these areas to aid researchers seeking to start or continue investigations for the molecular-level understanding of environmental organic compound mixtures.
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http://dx.doi.org/10.1002/mas.21684DOI Listing
January 2021

Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: results from a phase I study.

Neuro Oncol 2021 04;23(4):677-686

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: Radiotherapy may synergize with programmed cell death 1 (PD1)/PD1 ligand (PD-L1) blockade. The purpose of this study was to determine the recommended phase II dose, safety/tolerability, and preliminary efficacy of combining pembrolizumab, an anti-PD1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in patients with recurrent high-grade gliomas (HGGs).

Methods: Eligible subjects with recurrent glioblastoma or anaplastic astrocytoma were treated with pembrolizumab (100 or 200 mg based on dose level Q3W) concurrently with HFSRT (30 Gy in 5 fractions) and bevacizumab 10 mg/kg Q2W.

Results: Thirty-two patients were enrolled (bevacizumab-naïve, n = 24; bevacizumab-resistant, n = 8). The most common treatment-related adverse events (TRAEs) were proteinuria (40.6%), fatigue (25%), increased alanine aminotransferase (25%), and hypertension (25%). TRAEs leading to discontinuation occurred in 1 patient who experienced a grade 3 elevation of aspartate aminotransferase. In the bevacizumab-naïve cohort, 20 patients (83%) had a complete response or partial response. The median overall survival (OS) and progression-free survival (PFS) were 13.45 months (95% CI: 9.46-18.46) and 7.92 months (95% CI: 6.31-12.45), respectively. In the bevacizumab-resistant cohort, PR was achieved in 5 patients (62%). Median OS was 9.3 months (95% CI: 8.97-18.86) with a median PFS of 6.54 months (95% CI: 5.95-18.86). The majority of patients (n = 20/26; 77%) had tumor-cell/tumor-microenvironment PD-L1 expression <1%.

Conclusions: The combination of HFSRT with pembrolizumab and bevacizumab in patients with recurrent HGG is generally safe and well tolerated. These findings merit further investigation of HFSRT with immunotherapy in HGGs.
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http://dx.doi.org/10.1093/neuonc/noaa260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041351PMC
April 2021

The Clinical Significance of SIRT2 in Malignancies: A Tumor Suppressor or an Oncogene?

Front Oncol 2020 8;10:1721. Epub 2020 Sep 8.

National Clinical Research Center of Cancer, Tianjin, China.

Sirtuin 2 (SIRT2) is a member of the sirtuin protein family. It is a Class III histone deacetylase (HDACs) and predominantly localized to the cytosol. SIRT2 deacetylates histones and a number of non-histone proteins and plays a pivotal role in various physiologic processes. Previously, SIRT2 has been considered indispensable during carcinogenesis; however, there is now a significant controversy regarding whether SIRT2 is an oncogene or a tumor suppressor. The purpose of this review is to summarize the physiological functions of SIRT2 and its mechanisms in cancer. We will focus on five malignancies (breast cancer, non-small cell lung cancer, hepatocellular carcinoma, colorectal cancer, and glioma) to describe the current status of SIRT2 research and discuss the clinical evaluation of SIRT2 expression and the use of SIRT2 inhibitors.
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http://dx.doi.org/10.3389/fonc.2020.01721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506103PMC
September 2020

Prospective Single-Arm Phase 1 and 2 Study: Ipilimumab and Nivolumab With Thoracic Radiation Therapy After Platinum Chemotherapy in Extensive-Stage Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2021 Feb 28;109(2):425-435. Epub 2020 Sep 28.

Department of Medical Oncology, Duke Cancer Institute, Duke University Medical Center.

Purpose: Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer.

Methods And Materials: Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year.

Results: The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval [CI], 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02).

Conclusions: Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2020.09.031DOI Listing
February 2021

Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells.

Cell Metab 2020 09 7;32(3):420-436.e12. Epub 2020 Aug 7.

Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA. Electronic address:

Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocytes within the tumor microenvironment. Actionable targets that rescue the effector activity of antitumor T cells remain elusive. Here, we report that the Sirtuin-2 (Sirt2) NAD-dependent deacetylase inhibits T cell metabolism and impairs T cell effector functions. Remarkably, upregulation of Sirt2 in human tumor-infiltrating lymphocytes (TILs) negatively correlates with response to TIL therapy in advanced non-small-cell lung cancer. Mechanistically, Sirt2 suppresses T cell metabolism by targeting key enzymes involved in glycolysis, tricarboxylic acid-cycle, fatty acid oxidation, and glutaminolysis. Accordingly, Sirt2-deficient murine T cells exhibit increased glycolysis and oxidative phosphorylation, resulting in enhanced proliferation and effector functions and subsequently exhibiting superior antitumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILs with these superior metabolic fitness and effector functions. Our findings unveil Sirt2 as an unexpected actionable target for reprogramming T cell metabolism to augment a broad spectrum of cancer immunotherapies.
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http://dx.doi.org/10.1016/j.cmet.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484212PMC
September 2020

Proof-of-principle Phase I results of combining nivolumab with brachytherapy and external beam radiation therapy for Grade Group 5 prostate cancer: safety, feasibility, and exploratory analysis.

Prostate Cancer Prostatic Dis 2021 Mar 10;24(1):140-149. Epub 2020 Jul 10.

Departments of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

Background: To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa.

Methods: Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189).

Results: Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders.

Conclusion: Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.
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http://dx.doi.org/10.1038/s41391-020-0254-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882397PMC
March 2021

Reproducibility of Crude Oil Spectra Obtained with Ultrahigh Resolution Mass Spectrometry.

Anal Chem 2020 07 2;92(14):9465-9471. Epub 2020 Jul 2.

Department of Chemistry, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 41566, Republic of Korea.

In this study, the reproducibility of crude oil analyzed with (+) atmospheric pressure photoionization ultrahigh resolution mass spectrometry was evaluated. Three sets of data were obtained at intervals of approximately a month for a span of three months. For each monthly data set, four oil samples were analyzed with four replicates in 1 day. The obtained 48 spectra were processed to examine the reproducibility of the class, double bond equivalent (DBE), and individual peak distributions. The reproducibility of the relative abundance was better than that of the absolute abundance. The distributions of major classes were consistent within the three sets with a less than 1% relative standard deviation (RSD). The DBE distribution for each data set was reproducible within 1% RSD, whereas the DBE distributions for the combined data sets had RSD values of 1%-6%. The RSD values were higher for minor components, suggesting that care must be taken in the use of minor values for quantitative or semiquantitative evaluation. The relative abundances of individual peaks in the major classes were reproducible within 1%-3% RSD for each data set. However, the RSD values of the combined data sets were over 10%, even for abundant peaks. The smaller RSD of the class and DBE distributions than that of individual peaks for combined data sets strongly suggest that variations observed from individuals were caused by random errors. The data presented in this study provide guidelines for evaluating petroleomic data obtained in the laboratory at different times or laboratories.
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http://dx.doi.org/10.1021/acs.analchem.0c00865DOI Listing
July 2020

Application of silver-assisted laser desorption ionization ultrahigh-resolution mass spectrometry for the speciation of sulfur compounds.

Anal Bioanal Chem 2020 Jan 16;412(1):243-255. Epub 2019 Dec 16.

Department of Chemistry, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea.

We herein report the optimization and application of silver cationization (Ag) in combination with laser desorption ionization (LDI) ultrahigh-resolution mass spectrometry (UHR-MS) to determine the structures of the sulfur-containing compounds present in heavy crude oil. A number of sulfur-containing model compounds were used to optimize the positive-ion mode LDI-MS conditions in the presence of a silver-complexing agent. Under the optimized LDI conditions, sulfur-rich heavy oil fractions were treated with the silver salt, where Ag coordinated with the sulfur atoms to speciate the sulfur species. The obtained results suggested that benzothiophenic, naphtheno-non-aromatic sulfides, and non-aromatic thiols were the major components present in the analyzed oil sample. Graphical abstract.
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http://dx.doi.org/10.1007/s00216-019-02272-5DOI Listing
January 2020

Methylation of immune synapse genes modulates tumor immunogenicity.

J Clin Invest 2020 02;130(2):974-980

Department of Radiation Oncology.

Cancer immune evasion is achieved through multiple layers of immune tolerance mechanisms including immune editing, recruitment of tolerogenic immune cells, and secretion of immunosuppressive cytokines. Recent success with immune checkpoint inhibitors in cancer immunotherapy suggests a dysfunctional immune synapse as a pivotal tolerogenic mechanism. Tumor cells express immune synapse proteins to suppress the immune system, which is often modulated by epigenetic mechanisms. When the methylation status of key immune synapse genes was interrogated, we observed disproportionately hypermethylated costimulatory genes and hypomethylation of immune checkpoint genes, which were negatively associated with functional T cell recruitment to the tumor microenvironment. Therefore, the methylation status of immune synapse genes reflects tumor immunogenicity and correlates with survival.
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http://dx.doi.org/10.1172/JCI131234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994116PMC
February 2020

Elucidating molecular level impact of peat fire on soil organic matter by laser desorption ionization Fourier transform ion cyclotron resonance mass spectrometry.

Anal Bioanal Chem 2019 Nov 11;411(27):7303-7313. Epub 2019 Sep 11.

Department of Chemistry, Kyungpook National University, Daegu, 41566, Republic of Korea.

In this work, laser desorption ionization coupled with Fourier transform ion cyclotron resonance mass spectrometry (LDI-FTICRMS) was used to investigate the molecular composition of a peat fire and laboratory heated soil organic matter (SOM). SOM isolated from soils obtained from unburned and burned sites at Central Kalimantan, Indonesia, were analyzed with LDI-FTICRMS. About 7500 peaks were found and assigned with molecular formulas for each mass spectrum. SOM isolated from fire-affected soil sites are relatively more abundant in low oxygenated classes (e.g., O-O) and thermally stable compounds, including condensed hydrocarbon and nitrogen heterocyclic compounds. Abundances of highly condensed hydrocarbon compounds with carbon number > 30 were increased for the fire-affected SOM. In vivo heating experiments were conducted for SOM extracted from unburned sites, and the prepared SOMs were analyzed with LDI-FTICRMS. Overall, the same trend of change at the molecular level was observed from both the laboratory heated and the peat fire-affected SOM samples. In addition, it was observed that heat caused the degradation of SOM, generating lignin and tannin-type molecules. It was hypothesized that they were formed by thermal degradation of high molecular weight SOM. All the information presented in this study was obtained by consuming ~ 5 μg of sample. Therefore, this study shows that LDI-FTICRMS is a sensitive analytical technique that is effective in obtaining molecular level information of SOM. Graphical abstract.
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http://dx.doi.org/10.1007/s00216-019-02108-2DOI Listing
November 2019

Application of Bayesian predictive probability for interim futility analysis in single-arm phase II trial.

Transl Cancer Res 2019 Jul;8(Suppl 4):S404-S420

Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Background: Bayesian predictive probability design, with a binary endpoint, is gaining attention for the phase II trial due to its innovative strategy. To make the Bayesian design more accessible, we elucidate this Bayesian approach with a R package to streamline a statistical plan, so biostatisticians and clinicians can easily integrate the design into clinical trial.

Methods: We utilize a Bayesian framework using Bayesian posterior probability and predictive probability to build a R package and develop a statistical plan for the trial design. With pre-defined sample sizes, the approach employs the posterior probability with a threshold to calculate the minimum number of responders needed at end of the study to claim efficacy. Then the predictive probability is applied to evaluate future success at interim stages and form stopping rule at each stage.

Results: An R package, 'BayesianPredictiveFutility', with associated graphical interface is developed for easy utilization of the trial design. The statistical tool generates a professional statistical plan with comprehensive results including a summary, details of study design, a series of tables and figures from stopping boundary for futility, Bayesian predictive probability, performance [probability of early termination (PET), type I error, and power], PET at each interim analysis, sensitivity analysis for predictive probability, posterior probability, sample size, and beta prior distribution. The statistical plan presents the methodology in a readable language fashion while preserving rigorous statistical arguments. The output formats (Word or PDF) are available to communicate with physicians or to be incorporated in the trial protocol. Two clinical trials in lung cancer are used to demonstrate its usefulness.

Conclusions: Bayesian predictive probability method presents a flexible design in clinical trial. The statistical tool brings an added value to broaden the application.
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http://dx.doi.org/10.21037/tcr.2019.05.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711387PMC
July 2019

Radiation Therapy as a Bridging Strategy for CAR T Cell Therapy With Axicabtagene Ciloleucel in Diffuse Large B-Cell Lymphoma.

Int J Radiat Oncol Biol Phys 2019 12 5;105(5):1012-1021. Epub 2019 Jun 5.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida. Electronic address:

Purpose: Axicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Bridging therapy may be required for lymphoma control during the manufacturing interval between collection of autologous T cells and final CAR T product administration. The optimal bridging therapy is not known and patients are often chemorefractory. We present a case series of patients receiving radiation as a bridge to axi-cel.

Methods And Materials: Between December 2017 and October 2018, 12 patients were intended to receive bridging radiation before axi-cel. The group was characterized by highly aggressive disease including 6 of 12 with "double hit" lymphoma and 6 of 12 with disease ≥10 cm in diameter. All patients received 2 to 4 Gy/fraction to a median dose of 20 Gy (range, 6-36.5 Gy). Half of patients received either 30 Gy in 10 fractions or 20 Gy in 5 fractions. Seven patients received concurrent chemotherapy. Eleven patients underwent axi-cel infusion and one did not. Median follow-up was 3.3 months (range, 1.1-12.0 months).

Results: No significant toxicities were identified during bridging radiation, and no patient experienced in-field progression of disease before axi-cel infusion. One patient experienced abdominal pain, which resolved after dose reduction. Two patients had out-of-field progression of disease during the bridging period. After axi-cel infusion, 3 of 11 patients (27%) experienced severe cytokine release syndrome or neurotoxicity. At 30 days, the objective response rate was 81.8% (11 of 12 evaluable; 1 stable disease, 1 out-of-field progression), with complete response in 27% (3 of 11). At last follow-up, the best objective response rate was 81.8%, with a complete response attained in 45% (5 of 11). Lymphocyte counts decreased slightly in 10 of 12 patients during radiation (median, 0.25 k/uL).

Conclusions: Radiation (with or without concurrent chemotherapy) can be safely administered as a bridge to axi-cel in high-risk lymphoma. Caution should be taken if irradiation is started before apheresis, and lymphocyte counts should be monitored closely throughout. Future investigation is warranted to optimize the use of bridging radiation before CAR T therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2019.05.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872916PMC
December 2019

Application of Online Liquid Chromatography 7 T FT-ICR Mass Spectrometer Equipped with Quadrupolar Detection for Analysis of Natural Organic Matter.

Anal Chem 2019 06 3;91(12):7690-7697. Epub 2019 Jun 3.

Department of Chemistry , Kyungpook National University , Daegu 41566 , Republic of Korea.

In this study, Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS), combined with quadrupolar detection (QPD), was applied for online liquid chromatography (LC) MS analysis of natural organic matter (NOM). Although FT-ICR MS has emerged as an important analytical technique to study NOM, there are few previous reports on online LC FT-ICR MS analysis of NOM due to the long acquisition time (2-8 s) required to obtain high-resolution mass spectra. The QPD technique provides a critical advantage over the conventional dipolar detection (DPD) technique for LC-MS analysis because a spectrum with the same resolving power can be obtained in approximately half the acquisition time. QPD FT-ICR MS provides resolving powers ( ) of ∼300000 and 170000 at m/ z 400 with acquisition times per scan of 1.2 and 0.8 s, respectively. The reduced acquisition time per scan allows increased number of acquisitions in a given LC analysis time, resulting in improved signal to noise ( S/ N) ratio and dynamic range in comparison to conventional methods. For example, 40% and 100% increases in the number of detected peaks were obtained with LC QPD FT-ICR MS, in comparison to conventional LC DPD FT-ICR MS and direct-injection FT-ICR MS. It is also possible to perform more quantitative comparison and molecular level investigation of NOMs with 2 μg of a NOM sample. The data presented herein demonstrate a proof of principle that QPD combined with LC FT-ICR MS is a sensitive analytical technique that can provide comprehensive information about NOM.
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http://dx.doi.org/10.1021/acs.analchem.9b00689DOI Listing
June 2019

Immunologic Consequences of Sequencing Cancer Radiotherapy and Surgery.

JCO Clin Cancer Inform 2019 04;3:1-16

Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Purpose: Early-stage cancers are routinely treated with surgery followed by radiotherapy (SR). Radiotherapy before surgery (RS) has been widely ignored for some cancers. We evaluate overall survival (OS) and disease-free survival (DFS) with SR and RS for different cancer types and simulate the plausibility of RS- and SR-induced antitumor immunity contributing to outcomes.

Materials And Methods: We analyzed a SEER data set of early-stage cancers treated with SR or RS. OS and DFS were calculated for cancers with sufficient numbers for statistical power (cancers of lung and bronchus, esophagus, rectum, cervix uteri, corpus uteri, and breast). We simulated the immunologic consequences of SR, RS, and radiotherapy alone in a mathematical model of tumor-immune interactions.

Results: RS improved OS for cancers with low 20-year survival rates (lung: hazard ratio [HR], 0.88; P = .046) and improved DFS for cancers with higher survival (breast: HR = 0.64; P < .001). For rectal cancer, with intermediate 20-year survival, RS improved both OS (HR = 0.89; P = .006) and DFS (HR = 0.86; P = .04). Model simulations suggested that RS could increase OS by eliminating cancer for a broader range of model parameters and radiotherapy-induced antitumor immunity compared with SR for selected parameter combinations. This could create an immune memory that may explain increased DFS after RS for certain cancers.

Conclusion: Study results suggest plausibility that radiation to the bulk of the tumor could induce a more robust immune response and better harness the synergy of radiotherapy and antitumor immunity than postsurgical radiation to the tumor bed. This exploratory study provides motivation for prospective evaluation of immune activation of RS versus SR in controlled clinical studies.
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http://dx.doi.org/10.1200/CCI.18.00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661069PMC
April 2019

Radiotherapy for early stage diffuse large B-cell lymphoma with or without double or triple hit genetic alterations.

Leuk Lymphoma 2019 04 20;60(4):886-893. Epub 2018 Nov 20.

a Department of Radiation Oncology , H. Lee Moffitt Cancer Center and Research Institute, Tampa , FL , USA.

We investigated whether adding radiation (RT) to systemic therapy improved outcomes in early stage diffuse large B-cell lymphoma (DLBCL) patients with or without double- or triple-hit lymphoma (DHL/THL) biology. This analysis included 183 patients profiled with fluorescent in situ hybridization (FISH) for alterations in MYC, BLC2, and/or BCL6. A total of 146 (80%) were non-DHL/THL, 27 (15%) were DHL, and 10 (6%) were THL. Systemic therapy without RT resulted in inferior freedom from relapse (FFR) (HR: 2.28; 95% CI, 1.10-4.77; p = .02). The median FFR for non-DHL/THL was not reached and was 33 and 22.3 months for DHL and THL, respectively; p < .001. Low-risk (R-IPI <2) DHL/THL patients treated with rituximab-based therapy had 3-year FFR rates of 11% and 71% for systemic therapy without and with RT, respectively; p = .04. No differences in overall survival were observed between the treatment groups. Treatment intensification with RT may improve early stage DHL/THL outcomes.
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http://dx.doi.org/10.1080/10428194.2018.1506586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596288PMC
April 2019

Plays Oncogenic Roles and Is a Therapeutic Target for Wild-Type Melanomas.

Mol Cancer Res 2019 02 24;17(2):583-593. Epub 2018 Oct 24.

Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida.

Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in , and . encodes the SHP2 protein tyrosine phosphatase that activates the RAS/RAF/MAPK pathway. Although is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in wild-type (either mutant or wild-type) melanoma cells. played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In and -null mice, -inducible and melanocyte-specific PTPN11 expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11 expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence, and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of -mutant melanoma. Using a quantitative tyrosine phosphoproteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3β signaling pathways. IMPLICATIONS: This study identifies PTPN11 as an oncogenic driver and a novel and actionable therapeutic target for wild-type melanoma.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386183PMC
February 2019

Immune interconnectivity of anatomically distant tumors as a potential mediator of systemic responses to local therapy.

Sci Rep 2018 06 21;8(1):9474. Epub 2018 Jun 21.

Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Complex interactions occur between tumor and host immune system at each site in the metastatic setting, the outcome of which can determine behavior ranging from dormancy to rapid growth. An additional layer of complexity arises from the understanding that cytotoxic T cells can traffic through the host circulatory system. Coupling mathematical models of local tumor-immune dynamics and systemic T cell trafficking allows us to simulate the evolution of tumor and immune cell populations in anatomically distant sites following local therapy and thus computationally evaluate immune interconnectivity. Results suggest that the presence of a secondary site may either inhibit or promote growth of the primary, depending on the capacity for immune recruitment of each tumor and the resulting systemic redistribution of T cells. Treatment such as surgical resection and radiotherapy can be simulated to estimate both the decrease in tumor volume at the local treatment-targeted site, and the change in overall tumor burden and tumor growth trajectories across all sites. Qualitatively similar responses of distant tumors to local therapy (positive and negative abscopal effects) to those reported in the clinical setting were observed. Such findings may facilitate an improved understanding of general disease kinetics in the metastatic setting: if metastatic sites are interconnected through the immune system, truly local therapy does not exist.
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http://dx.doi.org/10.1038/s41598-018-27718-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013469PMC
June 2018

Management of primary cutaneous CD4 small and medium pleomorphic T-cell lymphoma: A retrospective study.

J Am Acad Dermatol 2018 Oct 29;79(4):772-774. Epub 2018 May 29.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2018.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563324PMC
October 2018

Tumour radiosensitivity is associated with immune activation in solid tumours.

Eur J Cancer 2017 10 29;84:304-314. Epub 2017 Aug 29.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Purpose: Our goal was to determine whether tumour radiosensitivity is associated with activation of the immune system across all tumour types as measured by two gene expression signatures (GESs).

Methods: We identified 10,240 genomically profiled distinct solid primary tumours with gene expression analysis available from an institutional de-identified database. Two separate GESs were included in the analysis, the radiosensitivity index (RSI) GES (a 10-gene GES as a measure of radiosensitivity) and the 12-chemokine (12-CK) signature (a 12-gene GES as a measure of immune activation). We tested whether the RSI and 12-CK were associated with each other across all tumour samples and, in an exploratory analysis, their prognostic significance in predicting distant metastasis-free survival (DMFS) among a well-characterised, independent cohort of 282 early-stage breast cancer cases treated with surgery and post-operative radiation alone without systemic therapy. The lower the RSI score, the higher the tumour radiosensitivity; whereas, the higher the 12-CK score the higher the immune activation.

Results: Using an RSI cut-point of ≤0.3745, RSI-low tumours (n = 4,291, 41.9%) had a significantly higher median 12-CK GES value (0.54 [-0.136, 1.095]) compared with RSI-high tumours (-0.17 [-0.82, 0.42]; p < 0.001) across all tumour samples, indicating that radiosensitivity is associated with immune activation. In an exploratory analysis of early-stage breast cancer cases, a multivariable model with patient age, RSI and 12-CK provided a strong composite model for DMFS (p = 0.02), with RSI (hazard ratio [HR] 0.63 [95% confidence interval 0.36, 1.09]) and 12-CK (HR 0.66 [0.41, 1.04]) each providing comparable contributions.

Conclusions: Tumour radiosensitivity is associated with immune activation as measured by the two GESs.
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http://dx.doi.org/10.1016/j.ejca.2017.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822441PMC
October 2017

Modeling adsorption properties of structurally deformed metal-organic frameworks using structure-property map.

Proc Natl Acad Sci U S A 2017 07 10;114(30):7923-7928. Epub 2017 Jul 10.

Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea;

Structural deformation and collapse in metal-organic frameworks (MOFs) can lead to loss of long-range order, making it a challenge to model these amorphous materials using conventional computational methods. In this work, we show that a structure-property map consisting of simulated data for crystalline MOFs can be used to indirectly obtain adsorption properties of structurally deformed MOFs. The structure-property map (with dimensions such as Henry coefficient, heat of adsorption, and pore volume) was constructed using a large data set of over 12000 crystalline MOFs from molecular simulations. By mapping the experimental data points of deformed SNU-200, MOF-5, and Ni-MOF-74 onto this structure-property map, we show that the experimentally deformed MOFs share similar adsorption properties with their nearest neighbor crystalline structures. Once the nearest neighbor crystalline MOFs for a deformed MOF are selected from a structure-property map at a specific condition, then the adsorption properties of these MOFs can be successfully transformed onto the degraded MOFs, leading to a new way to obtain properties of materials whose structural information is lost.
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http://dx.doi.org/10.1073/pnas.1706330114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544324PMC
July 2017

Novel Opportunities to Use Radiation Therapy with Immune Checkpoint Inhibitors for Melanoma Management.

Surg Oncol Clin N Am 2017 07 11;26(3):515-529. Epub 2017 May 11.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Electronic address:

Immunotherapy has revolutionized the systemic management of numerous malignancies. Nowhere has the proven benefit of these agents in clinical practice been more evident than in the management of advanced melanoma. Numerous preclinical studies have revealed the potential benefit of immune-priming radiotherapy in stimulating tumor-specific immune responses. This signal for immune activation may lead to clinically relevant synergy with immune checkpoint inhibitors against malignant cells. In this review, the authors summarize the current data outlining the role radiation therapy may play in the management of advanced melanoma alongside immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.soc.2017.01.007DOI Listing
July 2017

Priming radioimmunotherapy with external beam radiation in patients with relapsed low grade non-Hodgkin lymphoma.

Ther Adv Hematol 2017 Apr 1;8(4):129-138. Epub 2017 Feb 1.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

Background: The aim of this study was to evaluate the outcomes of priming salvage radioimmunotherapy (RIT) with a low dose of external beam radiotherapy (EBRT) in patients with relapsed low grade non-Hodgkin lymphoma (LG-NHL).

Methods: Patients who received salvage RIT with or without 2 × 2 Gy EBRT between March 2009 and February 2013 were retrospectively reviewed at a single institution. Planning target volume (PTV) for EBRT was created by adding a 1-2 cm expansion to the gross tumor volume depending on the anatomical location. Kaplan-Meier method log-rank was employed to analyze the endpoints freedom from progression (FFP) and overall survival (OS).

Results: We identified 22 patients who received salvage RIT without chemotherapy with a median follow up of 34 months. Of these, 9 (41%) patients were treated with EBRT immediately prior to RIT, and 13 (59%) received salvage RIT alone. Median FFP was not reached in patients who underwent combination treatment, while it was 9 months for patients treated with RIT alone ( = 0.02). OS for all patients at 36 months was 80.3% with no significant difference between the two groups ( = 0.88). On univariate analysis, the addition of EBRT was associated with improved FFP [hazard ratio (HR) = 4.17; 95% confidence interval (CI), 1.24-19.1; = 0.02)]. No long term toxicities were reported in both groups.

Conclusions: RIT outcomes and effects were improved with addition of low-dose EBRT immediately prior to it, in the treatment of relapsed LG-NHL with no additional toxicity. This study is hypothesis-generating and the findings should be validated in prospective studies.
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http://dx.doi.org/10.1177/2040620717693574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405899PMC
April 2017

Outcomes targeting the PD-1/PD-L1 axis in conjunction with stereotactic radiation for patients with non-small cell lung cancer brain metastases.

J Neurooncol 2017 Jun 2;133(2):331-338. Epub 2017 May 2.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902, Magnolia Drive, Tampa, FL, 33612, USA.

Anti-PD-1/PD-L1 therapies have demonstrated activity in patients with advanced stage non-small cell lung cancer (NSCLC). However, little is known about the safety and feasibility of patients receiving anti-PD-1/PD-L1 therapy and stereotactic radiation for the treatment of brain metastases. Data were analyzed retrospectively from NSCLC patients treated with stereotactic radiation either before, during or after anti-PD-1/PD-L1 therapy with nivolumab (anti-PD-1) or durvalumab (anti-PD-L1). Seventeen patients treated with stereotactic radiosurgery (SRS) or fractionated stereotactic radiation therapy (FSRT) to 49 brain metastases over 21 sessions were identified. Radiation was administered prior to, during and after anti-PD-1/PD-L1 therapy in 22 lesions (45%), 13 lesions (27%), and 14 lesions (29%), respectively. The 6 months Kaplan-Meier (KM) distant brain control rate was 48% following stereotactic radiation. Six and 12 month KM rates of OS from the date of stereotactic radiation and the date of cranial metastases diagnosis were 48/41% and 81/51%, respectively. The 6 month rate of distant brain control following stereotactic radiation for patients treated with stereotactic radiation during or prior to anti-PD-1/PD-L1 therapy was 57% compared to 0% among patients who received anti-PD-1/PD-L1 therapy before stereotactic radiation (p = 0.05). A Karnofsky Performance Status (KPS) of <90 was found to be predictive of worse OS following radiation treatment on both univariate and multivariate analyses (MVA, p = 0.01). In our series, stereotactic radiation to NSCLC brain metastases was well tolerated in patients who received anti-PD-1/PD-L1 therapy. Prospective evaluation to determine how these two modalities can be used synergistically to improve distant brain control and OS is warranted.
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http://dx.doi.org/10.1007/s11060-017-2437-5DOI Listing
June 2017

The future of personalised radiotherapy for head and neck cancer.

Lancet Oncol 2017 05 26;18(5):e266-e273. Epub 2017 Apr 26.

Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Radiotherapy has long been the mainstay of treatment for patients with head and neck cancer and has traditionally involved a stage-dependent strategy whereby all patients with the same TNM stage receive the same therapy. We believe there is a substantial opportunity to improve radiotherapy delivery beyond just technological and anatomical precision. In this Series paper, we explore several new ideas that could improve understanding of the phenotypic and genotypic differences that exist between patients and their tumours. We discuss how exploiting these differences and taking advantage of precision medicine tools-such as genomics, radiomics, and mathematical modelling-could open new doors to personalised radiotherapy adaptation and treatment. We propose a new treatment shift that moves away from an era of empirical dosing and fractionation to an era focused on the development of evidence to guide personalisation and biological adaptation of radiotherapy. We believe these approaches offer the potential to improve outcomes and reduce toxicity.
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http://dx.doi.org/10.1016/S1470-2045(17)30252-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771279PMC
May 2017

Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck.

Head Neck 2017 01 14;39(1):48-55. Epub 2016 Jun 14.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: We hypothesized that radiotherapy (RT) would improve both local and regional control with Merkel cell carcinoma of the head and neck.

Methods: A single-institution institutional review board-approved study was performed including 113 patients with nonmetastatic Merkel cell carcinoma of the head and neck. Postoperative RT was delivered to the primary tumor bed (71.7% cases) ± draining lymphatics (33.3% RT cases).

Results: Postoperative local RT was associated with improved local control (3-year actuarial local control 89.4% vs 68.1%; p = .005; Cox hazard ratio [HR] 0.18; 95% confidence interval [CI] = 0.06-0.55; p = .002). Similarly, regional RT was associated with improved regional control (3-year actuarial regional control 95.0% vs 66.7%; p = .008; Cox HR = 0.09; 95% CI = 0.01-0.69; p = .02). Regional RT played an important role for both clinical node-negative patients (3-year regional control 100% vs 44.7%; p = .03) and clinical/pathological node-positive patients (3-year regional control 90.9% vs 55.6%; p = .047).

Conclusion: Local RT was beneficial for all patients with Merkel cell carcinoma of the head and neck, whereas regional RT was beneficial for clinical node-negative and clinical/pathological node-positive patients. © 2016 Wiley Periodicals, Inc. Head Neck 39: 48-55, 2017.
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http://dx.doi.org/10.1002/hed.24527DOI Listing
January 2017

Radiation Therapy is Associated with Improved Outcomes in Merkel Cell Carcinoma.

Ann Surg Oncol 2016 10 1;23(11):3572-3578. Epub 2016 Jun 1.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

Background: Following wide excision of Merkel cell carcinoma (MCC), postoperative radiation therapy (RT) is typically recommended. Controversy remains as to whether RT can be avoided in selected cases, such as those with negative margins. Additionally, there is evidence that RT can influence survival.

Methods: We included 171 patients treated for non-metastatic MCC from 1994 through 2012 at a single institution. Patients without pathologic nodal evaluation (clinical N0 disease) were excluded to reflect modern treatment practice. The endpoints included local control (LC), locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS).

Results: Median follow-up was 33 months. Treatment with RT was associated with improved 3-year LC (91.2 vs. 76.9 %, respectively; p = 0.01), LRC (79.5 vs. 59.1 %; p = 0.004), DFS (57.0 vs. 30.2 %; p < 0.001), and OS (73 vs. 66 %; p = 0.02), and was associated with improved 3-year DSS among node-positive patients (76.2 vs. 48.1 %; p = 0.035), but not node-negative patients (90.1 vs. 80.8 %; p = 0.79). On multivariate analysis, RT was associated with improved LC [hazard ratio (HR) 0.18, 95 % confidence interval (CI) 0.07-0.46; p < 0.001], LRC (HR 0.28, 95 % CI 0.14-0.56; p < 0.001), DFS (HR 0.42, 95 % CI 0.26-0.70; p = 0.001), OS (HR 0.53, 95 % CI 0.31-0.93; p = 0.03), and DSS (HR 0.42, 95 % CI 0.26-0.70; p = 0.001). Patients with negative margins had significant improvements in 3-year LC (90.1 vs. 75.4 %; p < 0.001) with RT. Deaths not attributable to MCC were relatively evenly distributed between the RT and no RT groups (28.5 and 29.3 % of patients, respectively).

Conclusions: RT for MCC was associated with improved LRC and survival. RT appeared to be beneficial regardless of margin status.
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http://dx.doi.org/10.1245/s10434-016-5293-1DOI Listing
October 2016

An unprecedented single platform via cross-linking of zeolite and MOFs.

Chem Commun (Camb) 2016 May 18;52(41):6773-6. Epub 2016 Apr 18.

Neutron Science Division, Korea Atomic Energy Research Institute, 989-111, Daedeokdaero, Yuseong-gu, Daejeon, Republic of Korea.

The unprecedented ternary nanocomposites have been synthesized as a single platform via cross-linking of two nanoporous materials, MOFs and Pt nanoparticle (NP) loaded zeolite. The heterojunction of the novel nanocomposites is anticipated to work as a chemical platform for size selective catalytic hydrogenation or deuteration of small molecules.
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http://dx.doi.org/10.1039/c6cc00984kDOI Listing
May 2016