Publications by authors named "Young H Kim"

107 Publications

Ultrasonographic evaluation of patients with abnormal liver function tests in the emergency department.

Ultrasonography 2021 Nov 18. Epub 2021 Nov 18.

Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.

Ultrasonography is often the initial modality used to evaluate patients found to have abnormal liver function tests (LFTs) in the emergency department. While an assessment for biliary ductal dilatation and obstruction remains one of the main questions to answer, radiologists should also be aware of the ultrasonographic appearance of other conditions that can cause abnormal LFTs. This may be crucial for the management and disposition of patients in the emergency department. This article reviews the ultrasonographic features of diseases that may cause abnormal LFTs.
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http://dx.doi.org/10.14366/usg.21152DOI Listing
November 2021

IL7-Fc Enhances the Efficacy of Adoptive T Cell Therapy under Lymphopenic Conditions in a Murine Melanoma Model.

Cells 2021 08 7;10(8). Epub 2021 Aug 7.

Biomedicine Production Branch, Program for Immunotherapy Research, National Cancer Center, Goyang 10408, Korea.

Adoptive cell therapy (ACT) using tumor-reactive T cells is a promising form of immunotherapy to specifically target cancer. However, the survival and functional maintenance of adoptively transferred T cells remains a challenge, ultimately limiting their efficacy. Here, we evaluated the use of recombinant IL7-Fc in ACT. In a lymphopenic murine melanoma model, IL7-Fc treatment led to the enhanced inhibition of tumor growth with an increased number of adoptively transferred CD8 T cells in tumor tissue and tumor-draining lymph nodes. Additionally, IL7-Fc further enhanced anti-tumor responses that were induced by recombinant human IL2 in the same mouse model. In contrast, in an immunocompetent murine melanoma model, IL7-Fc dampened the anti-tumor immunity. Further, IL7-Fc decreased the proliferation of adoptively transferred and immune-activated tumor-reactive CD8 T cells in immunocompetent mice by inducing the massive expansion of endogenous T cells, thereby limiting the space for adoptively transferred T cells. Our data suggest that IL7-Fc is principally beneficial for enhancing the efficacy of tumor-reactive T-cells in lymphopenic conditions for the ACT.
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http://dx.doi.org/10.3390/cells10082018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392867PMC
August 2021

Artificial intelligence in medical ultrasonography: driving on an unpaved road.

Authors:
Young H Kim

Ultrasonography 2021 Jul 10;40(3):313-317. Epub 2021 May 10.

Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.

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http://dx.doi.org/10.14366/usg.21031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217795PMC
July 2021

Chronic activation of 4-1BB signaling induces granuloma development in tumor-draining lymph nodes that is detrimental to subsequent CD8 T cell responses.

Cell Mol Immunol 2021 08 31;18(8):1956-1968. Epub 2020 Aug 31.

Biomedicine Production Branch, Program for Immunotherapy Research, Goyang, 10408, Republic of Korea.

The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor immunotherapy. However, the adverse side effects associated with agonist antibodies have hindered their clinical development. Here, we aimed to study the immune-related adverse events of repeated doses and long-term use of agonistic anti-4-1BB mAbs. We show that chronic activation of 4-1BB signals induced the accumulation of IFN-γ-producing PD-1CD8 T cells in the secondary lymphoid organs of tumor-bearing mice by increasing the number of dividing CD8 T cells, which was beneficial for suppressing tumor growth in the early phase of anti-4-1BB induction. However, repeated exposure to anti-4-1BB mAbs led to granuloma development in tumor-draining lymph nodes (TDLNs) of mice due to recruitment and accumulation of macrophages via the CD8 T cell-IFN-γ axis. This was accompanied by excessive lymph node swelling, which impaired the sequential activation of CD8 T cells. Our data provide insights into the immune-related adverse events of long-term agonist 4-1BB antibody dosing, which should be considered during the clinical development of immunomodulating therapy.
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http://dx.doi.org/10.1038/s41423-020-00533-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322392PMC
August 2021

Seminal Plasma-Derived Extracellular-Vesicle Fractions from HIV-Infected Men Exhibit Unique MicroRNA Signatures and Induce a Proinflammatory Response in Cells Isolated from the Female Reproductive Tract.

J Virol 2020 07 30;94(16). Epub 2020 Jul 30.

Gladstone Institute of Virology and Immunology, San Francisco, California, USA

The continuing spread of HIV/AIDS is predominantly fueled by sexual exposure to HIV-contaminated semen. Seminal plasma (SP), the liquid portion of semen, harbors a variety of factors that may favor HIV transmission by facilitating viral entry into host cells, eliciting the production of proinflammatory cytokines, and enhancing the translocation of HIV across the genital epithelium. One important and abundant class of factors in SP is extracellular vesicles (EVs), which, in general, are important intercellular signal transducers. Although numerous studies have characterized blood plasma-derived EVs from both uninfected and HIV-infected individuals, little is known about the properties of EVs from the semen of HIV-infected individuals. We report here that fractionated SP enriched for EVs from HIV-infected men induces potent transcriptional responses in epithelial and stromal cells that interface with the luminal contents of the female reproductive tract. Semen EV fractions from acutely infected individuals induced a more proinflammatory signature than those from uninfected individuals. This was not associated with any observable differences in the surface phenotypes of the vesicles. However, microRNA (miRNA) expression profiling analysis revealed that EV fractions from infected individuals exhibit a broader and more diverse profile than those from uninfected individuals. Taken together, our data suggest that SP EVs from HIV-infected individuals exhibit unique miRNA signatures and exert potent proinflammatory transcriptional changes in cells of the female reproductive tract, which may facilitate HIV transmission. Seminal plasma (SP), the major vehicle for HIV, can modulate HIV transmission risk through a variety of mechanisms. Extracellular vesicles (EVs) are extremely abundant in semen, and because they play a key role in intercellular communication pathways and immune regulation, they may impact the likelihood of HIV transmission. However, little is known about the properties and signaling effects of SP-derived EVs in the context of HIV transmission. Here, we conduct a phenotypic, transcriptomic, and functional characterization of SP and SP-derived EVs from uninfected and HIV-infected men. We find that both SP and its associated EVs elicit potent proinflammatory transcriptional responses in cells that line the genital tract. EVs from HIV-infected men exhibit a more diverse repertoire of miRNAs than EVs from uninfected men. Our findings suggest that EVs from the semen of HIV-infected men may significantly impact the likelihood of HIV transmission through multiple mechanisms.
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http://dx.doi.org/10.1128/JVI.00525-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394899PMC
July 2020

Polymorphic Region-Specific Antibody for Evaluation of Affinity-Associated Profile of Chimeric Antigen Receptor.

Mol Ther Oncolytics 2020 Jun 14;17:293-305. Epub 2020 Apr 14.

Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea.

Antibody applications in cancer immunotherapy involve diverse strategies, some of which redirect T cell-mediated immunity via engineered antibodies. Affinity is a trait that is crucial for these strategies, as optimal affinity reduces unwanted side effects while retaining therapeutic function. Antibody-antigen pairs possessing a broad affinity range are required to define optimal affinity and to investigate the affinity-associated functional profiles of T cell-engaging strategies such as bispecific antibodies and chimeric antigen receptor-engineered T cells. Here, we demonstrate the unique binding characteristic of the developed antibody clone MVR, which exhibits robust binding to B-lymphoid cell lines. Intriguingly, MVR specifically recognizes the highly polymorphic human leukocyte antigen (HLA)-DR complex and exhibits varying affinities that are dependent upon the allele type. Remarkably, MVR binds to the conformational epitope that consists of two hypervariable regions. As an application of MVR, we demonstrate an MVR-engineered chimeric antigen receptor (CAR) that elicits affinity-dependent function in response to a panel of target cell lines that express different alleles. This tool evaluates the effect of affinity on cytotoxic killing, polyfunctionality, and activation-induced cell death of CAR-engineered T cells. Collectively, MVR exhibits huge potential for the evaluation of the affinity-associated profile of T cells that are redirected by engineered antibodies.
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http://dx.doi.org/10.1016/j.omto.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191539PMC
June 2020

Role of ultrasound in the evaluation of first-trimester pregnancies in the acute setting.

Ultrasonography 2020 Apr 16;39(2):178-189. Epub 2019 Oct 16.

Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.

In patients presenting for an evaluation of pregnancy in the first trimester, transvaginal ultrasound is the modality of choice for establishing the presence of an intrauterine pregnancy; evaluating pregnancy viability, gestational age, and multiplicity; detecting pregnancy-related complications; and diagnosing ectopic pregnancy. In this pictorial review article, the sonographic appearance of a normal intrauterine gestation and the most common complications of pregnancy in the first trimester in the acute setting are discussed.
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http://dx.doi.org/10.14366/usg.19043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065984PMC
April 2020

Replication study: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET.

Elife 2018 12 11;7. Epub 2018 Dec 11.

System Biosciences LLC, California, United States.

As part of the Reproducibility Project: Cancer Biology we published a Registered Report (Lesnik et al., 2016) that described how we intended to replicate selected experiments from the paper 'Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET' (Peinado et al., 2012). Here we report the results. We regenerated tumor cells stably expressing a short hairpin to reduce Met expression (shMet) using the same highly metastatic mouse melanoma cell line (B16-F10) as the original study, which efficiently downregulated Met in B16F10 cells similar to the original study (Supplementary Figure 5A; Peinado et al., 2012). Exosomes from control cells expressed Met, which was reduced in exosomes from shMet cells; however, we were unable to reliably detect phosphorylated Met in exosomes. We tested the effect of exosome-dependent Met signaling on primary tumor growth and metastasis. Similar to the results in the original study, we did not find a statistically significant change in primary tumor growth. Measuring lung and femur metastases, we found a small increase in metastatic burden with exosomes from control cells that was diminished when Met expression was reduced; however, while the effects were in the same direction as the original study (Figure 4E; Peinado et al., 2012), they were not statistically significant. Differences between the original study and this replication attempt, such as level of knockdown efficiency, cell line genetic drift, sample sizes, study endpoints, and variability of observed metastatic burden, are factors that might have influenced the outcomes. Finally, we report meta-analyses for each result.
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http://dx.doi.org/10.7554/eLife.39944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289570PMC
December 2018

Hand infections after steroid injections.

Authors:
Young H Kim Ja H Gu

Int J Dermatol 2019 Jan 27;58(1):e12-e14. Epub 2018 Oct 27.

Department of Plastic Surgery, Dankook University Hospital, Cheonan, Korea.

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http://dx.doi.org/10.1111/ijd.14284DOI Listing
January 2019

RELT negatively regulates the early phase of the T-cell response in mice.

Eur J Immunol 2018 10 2;48(10):1739-1749. Epub 2018 Sep 2.

Eutilex, Co., Ltd., Seoul, Korea.

RELT (tumor necrosis factor receptor superfamily member 19-like, TNFRSF19L) is a TNFR superfamily member that is primarily expressed in immune cells and lymphoid tissues, but whose immunological function is not well-defined. Here, we show that RELT is expressed by naive T cells and DCs, and their activation or maturation decreases RELT expression. Using RELT knockout (RELT ) mice, we demonstrate that RELT deficiency selectively promotes the homeostatic proliferation of CD4 T cells but not CD8 T cells, and enhances anti-tumor CD8 T-cell responses. We also demonstrate, using an adoptive transfer model in which RELT is knocked-out in either the transferred transgenic CD8 T cells or the recipient melanoma-bearing mice, that RELT on multiple immune cells limits the hyper-response of tumor-specific CD8 T cells. Hyper-responsiveness of RELT-deficient T cells was induced by promoting their proliferation. Taken together, our findings suggest that RELT acts as a negative regulator that controls the early phase of T-cell activation probably by promoting T-cell apoptosis.
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http://dx.doi.org/10.1002/eji.201847633DOI Listing
October 2018

Role of heterotopic kidney auto-transplantation for renal artery aneurysms.

Medicine (Baltimore) 2018 Jun;97(23):e10856

Department of Transplantation and Vascular Surgery, Korea University Anam Hospital Departement of General Surgery Department of Vascular Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea.

To assess the applicability and surgical outcomes of ex vivo repair with heterotopic kidney auto-transplantation (HKA) for the treatment of renal artery aneurysms (RAA).We retrospectively examined 36 cases presenting with RAA from September 2005 to June 2016. Patient demographics, estimated glomerular filtration rate (eGFR), and common vascular risk factors were evaluated. Patients were classified into 3 groups: those who received endovascular treatment, in situ open surgical repair, or ex vivo repair with HKA. The findings were compared among the groups.The endovascular repair, in situ open repair, and ex vivo repair with HKA groups included 14, 9, and 13 patients, respectively (mean follow-up, 30.42 ± 30.54 months). The eGFR (P = .32) and number of anti-hypertension medications (P = .33) did not significantly differ among the groups. Moreover, 3 renal infarctions were detected in the endovascular group and only 1 was detected in the in situ repair group. One patient in the endovascular repair group required dialysis due to renal failure. Patients in the ex vivo repair with HKA group did not exhibit any complications.With safety and effectiveness comparable to other RAA treatment methods, ex vivo repair with HKA for RAA treatment appears suitable particularly in cases with complicated renal artery branch aneurysm and marginal renal function.
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http://dx.doi.org/10.1097/MD.0000000000010856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999450PMC
June 2018

Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression.

Nat Commun 2018 02 1;9(1):468. Epub 2018 Feb 1.

Eutilex Institute for Biomedical Research, Eutilex Co., Ltd., Seoul, 08594, Republic of Korea.

Chimeric antigen receptor (CAR) T cell therapy is an effective method for treating specific cancers. CARs are normally designed to recognize antigens, which are highly expressed on malignant cells but not on T cells. However, when T cells are engineered with CARs that recognize antigens expressed on the T cell surface, CAR T cells exhibit effector function on other T cells, which results in fratricide, or killing of neighboring T cells. Here, using human leukocyte antigen-DR (HLA-DR)-targeted CAR T cells, we show that weak affinity between CAR and HLA-DR reduces fratricide and induces sustained CAR downregulation, which consequently tunes the avidity of CAR T cells, leading to desensitization. We further demonstrate that desensitized CAR T cells selectively kill Epstein-Barr virus-transformed B cells with enhanced HLA-DR expression, while sparing normal B cells. Our study supports an avidity-tuning strategy that permits sensing of antigen levels by CAR T cells.
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http://dx.doi.org/10.1038/s41467-018-02912-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794762PMC
February 2018

Cancer immunotherapy using tumor antigen-reactive T cells.

Immunotherapy 2018 03;10(3):235-245

Eutilex, Suite 1401 Daeryung Technotown 17, Gasan Digital 1-ro 25, Geumcheon-gu, Seoul, Korea 08594.

Studies over the last 30 years have shown the promise of cancer immunotherapy using T cells. In particular, since the report by Rosenberg and colleagues in 2002 that adoptive T-cell therapy (ACT) under lymphopenic conditions substantially increased response rates in melanoma patients, ACT has become a promising immunotherapeutic route to cancer treatment. Here we provide a brief history of ACT and review the characteristics of T-cell therapeutics that are specific to this approach. Since every T-cell treatment has its own unique properties in terms of number and type of target antigens, and number of epitopes and type of T cells, we review the main strategies for designing ACT: how Ag specificity is determined, how is it standardized and the need for lymphodepletion to induce epitope spreading. We also briefly consider the next generation of ACT.
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http://dx.doi.org/10.2217/imt-2017-0130DOI Listing
March 2018

Diagnosing ectopic pregnancy in the emergency setting.

Ultrasonography 2018 Jan 19;37(1):78-87. Epub 2017 Aug 19.

Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.

Ectopic pregnancy is the implantation of a fertilized egg outside the uterine endometrial cavity. For women presenting to the emergency department with abdominal pain and/or vaginal bleeding, ectopic pregnancy is an important diagnostic consideration. The diagnosis is made based on laboratory values and ultrasound imaging findings. The ultrasound appearance of both normal early pregnancy and ectopic pregnancy are variable and often subtle, presenting diagnostic challenges for radiologists. This pictorial essay describes and illustrates the sonographic findings of ectopic pregnancy and reviews the differential diagnoses that can mimic ectopic pregnancy on ultrasound. With the possibility of medical management, the value of early detection and prompt initiation of treatment has increased in improving clinical outcomes and preventing the complications of ectopic pregnancy.
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http://dx.doi.org/10.14366/usg.17044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769947PMC
January 2018

Acute HIV-1 infection presenting with fulminant encephalopathy.

Int J STD AIDS 2017 09 15;28(10):1041-1044. Epub 2017 Feb 15.

1 Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, Korea.

Human immunodeficiency virus (HIV)-1 directly affects the nervous system, causes distinct neurological symptoms, and indirectly results in opportunistic infections, which include herpes virus simplex (HSV)-1, HSV-2, varicella zoster virus, and cytomegalovirus encephalitis caused by immunodeficiency. Early HIV-1 invasion of the central nervous system is also possible, and acute encephalopathy is a potentially lethal complication. We encountered a case of fulminant encephalopathy as a primary presentation of acute HIV-1 infection, in which highly active antiretroviral treatment resulted in a full clinical recovery. This case highlights the importance of considering acute HIV-1 infection in the differential diagnosis of reversible encephalopathy.
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http://dx.doi.org/10.1177/0956462417693734DOI Listing
September 2017

The repopulating cancer cells in melanoma are characterized by increased mitochondrial membrane potential.

Cancer Lett 2016 11 5;382(2):186-194. Epub 2016 Sep 5.

T Cell Therapy Unit, Eutilex Research Institute of Biomedicine, 222 Banpo-daero, Seocho-gu, Seoul, Republic of Korea; Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA. Electronic address:

Although considerable effort has been expended in identifying definitive markers for cancer stem cells (CSCs) or cancer-initiating cells (CICs), the phenotypic plasticity of these cells obviates simple characterization using cell surface markers. We hypothesized that these cells could be characterized by their metabolic properties because they are in a quiescent state with low energy needs. We examined whether cancer cells differ in mitochondrial membrane potential (Δψm) when they are under stress. The Δψm of B16-F10 melanoma cells increased when they were exposed in vitro to serum starvation and chemotherapeutic agents, but not when exposed to hypoxia. Such TMRE cells were also present in tumor tissue. They primarily used glucose and/or lactate, and were superior to TMRE B16-F10 cells in their ability to drive tumor growth. These findings suggest that CSCs or CICs could be identified in heterogeneous melanoma populations by measuring Δψm.
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http://dx.doi.org/10.1016/j.canlet.2016.08.027DOI Listing
November 2016

Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy.

Autophagy 2016 09 20;12(9):1647-59. Epub 2016 Jul 20.

a Eutilex , The Catholic University School of Medicine Seoul , Korea.

VSIG4/CRIg (V-set and immunoglobulin domain containing 4) is a transmembrane receptor of the immunoglobulin superfamily that is expressed specifically on macrophages and mature dendritic cells. VSIG4 signaling accelerates phagocytosis of C3-opsonized bacteria, thereby efficiently clearing pathogens within macrophages. We found that VSIG4 signaling triggered by C3-opsonized Listeria (opLM) or by agonistic anti-VSIG4 monoclonal antibody (mAb) induced macrophages to form autophagosomes. VSIG4-induced autophagosomes were selectively colocalized with the intracellular LM while starvation-induced autophagosomes were not. Consistent with these results, the frequency of autophagosomes induced by infection with opLM was lower in VSIG4-deficient bone marrow-derived macrophages (BMDMs) than in WT BMDMs. Furthermore, when VSIG4 molecules were overexpressed in HeLa cells, which are non-macrophage cells, VSIG4 triggering led to efficient uptake of LM, autophagosome formation, and killing of the infected LM. These findings suggest that VSIG4 signaling not only promotes rapid phagocytosis and killing of C3-opsonized intracellular bacteria, as previously reported, but also induces autophagosome formation, eliminating the LM that have escaped from phagosomes. We conclude that VSIG4 signaling provides an anti-immune evasion mechanism that prevents the outgrowth of intracellular bacteria in macrophages.
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http://dx.doi.org/10.1080/15548627.2016.1196314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082771PMC
September 2016

Redefining Budd-Chiari syndrome: A systematic review.

World J Hepatol 2016 Jun;8(16):691-702

Naomi Shin, Young H Kim, Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, United States.

Aim: To re-examine whether hepatic vein thrombosis (HVT) (classical Budd-Chiari syndrome) and hepatic vena cava-Budd Chiari syndrome (HVC-BCS) are the same disorder.

Methods: A systematic review of observational studies conducted in adult subjects with primary BCS, hepatic vein outflow tract obstruction, membranous obstruction of the inferior vena cava (IVC), obliterative hepatocavopathy, or HVT during the period of January 2000 until February 2015 was conducted using the following databases: Cochrane Library, CINAHL, MEDLINE, PubMed and Scopus.

Results: Of 1299 articles identified, 26 were included in this study. Classical BCS is more common in women with a pure hepatic vein obstruction (49%-74%). HVC-BCS is more common in men with the obstruction often located in both the inferior vena cava and hepatic veins (14%-84%). Classical BCS presents with acute abdominal pain, ascites, and hepatomegaly. HVC-BCS presents with chronic abdominal pain and abdominal wall varices. Myeloproliferative neoplasms (MPN) are the most common etiology of classical BCS (16%-62%) with the JAK2V617-F mutation found in 26%-52%. In HVC-BCS, MPN are found in 4%-5%, and the JAK2V617-F mutation in 2%-5%. Classical BCS responds well to medical management alone and 1(st) line management of HVC-BCS involves percutaneous recanalization, with few managed with medical management alone.

Conclusion: Systematic review of recent data suggests that classical BCS and HVC-BCS may be two clinically different disorders that involve the disruption of hepatic venous outflow.
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http://dx.doi.org/10.4254/wjh.v8.i16.691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909431PMC
June 2016

Ultrasonography of the scrotum in adults.

Ultrasonography 2016 Jul 24;35(3):180-97. Epub 2016 Feb 24.

Department of Radiology, UMass Memorial Medical Center, University of Massachusetts Medical Center, Worcester, MA, USA.

Ultrasonography is the ideal noninvasive imaging modality for evaluation of scrotal abnormalities. It is capable of differentiating the most important etiologies of acute scrotal pain and swelling, including epididymitis and testicular torsion, and is the imaging modality of choice in acute scrotal trauma. In patients presenting with palpable abnormality or scrotal swelling, ultrasonography can detect, locate, and characterize both intratesticular and extratesticular masses and other abnormalities. A 12-17 MHz high frequency linear array transducer provides excellent anatomic detail of the testicles and surrounding structures. In addition, vascular perfusion can be easily assessed using color and spectral Doppler analysis. In most cases of scrotal disease, the combination of clinical history, physical examination, and information obtained with ultrasonography is sufficient for diagnostic decision-making. This review covers the normal scrotal anatomy as well as various testicular and scrotal lesions.
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http://dx.doi.org/10.14366/usg.15075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939719PMC
July 2016

4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8 T cell proliferation.

Cell Mol Immunol 2017 Sep 14;14(9):748-757. Epub 2016 Mar 14.

Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 10408, Korea.

4-1BB (CD137) is a strong enhancer of the proliferation of CD8 T cells. Since these cells require increased production of energy and biomass to support their proliferation, we hypothesized that 4-1BB signaling activated glucose and fatty acid metabolism. We found that treatment with agonistic anti-4-1BB mAb promoted the proliferation of CD8 T cells in vitro, increasing their size and granularity. Studies with a glycolysis inhibitor and a fatty acid oxidation inhibitor revealed that CD8 T cell proliferation required both glucose and fatty acid metabolism. Anti-4-1BB treatment increased glucose transporter 1 expression and activated the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK)-acetyl-CoA carboxylase (ACC) signaling pathway, which may be responsible for activating the metabolism of glucose and fatty acids. We also examined whether blocking glucose or fatty acid metabolism affected cell cycle progression and the anti-apoptotic effect of 4-1BB signaling. The increase of anti-apoptotic factors and cyclins in response to anti-4-1BB treatment was completely prevented by treating CD8 T cells with the fatty acid oxidation inhibitor, etomoxir, but not with the glycolysis inhibitor, 2-deoxy-D-glucose. We conclude that anti-4-1BB treatment activates glucose and fatty acid metabolism thus supporting the increased demand for energy and biomass, and that fatty acid metabolism plays a crucial role in enhancing the cell cycle progression of anti-CD3-activated CD8 T cells in vitro and the anti-apoptotic effects of 4-1BB signaling on these cells.
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http://dx.doi.org/10.1038/cmi.2016.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596242PMC
September 2017

Phase I Clinical Trial of 4-1BB-based Adoptive T-Cell Therapy for Epstein-Barr Virus (EBV)-positive Tumors.

J Immunother 2016 Apr;39(3):140-8

*Hematologic Oncology Clinic, Center for Specific Organs Cancer, National Cancer Center, Korea †Center for Clinical Trial, National Cancer Center, Korea ‡Cancer Immunology Branch, Division of Cancer Biology §Immune Cell Production Unit, Program for Immunotherapeutic Research, Research Institute and Hospital, National Cancer Center, Ilsandong-gu, Goyang, Gyeonggi ∥Department of Hematology-Oncology, Chonnam National University Medical School, Gwangju, Korea ¶Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA.

Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors. This was a single-center, phase I, dose-escalation trial study evaluating 4 escalating dosing schedules of single injected EBViNT. CD8 T-cell responses against different LMP2A peptides in each patient were determined, and the most effective peptides were used to produce EBViNT. The produced autologous EBViNTs were single infused to patients with EBV-associated malignancy who had failed to standard treatments and were of HLA-A02 or A24 type. Of 11 patients enrolled, 8 patients received a single infusion of EBViNT: 4 with nasopharyngeal carcinomas, 1 with Hodgkin lymphoma, 2 with extranodal NK/T lymphomas, and 1 with diffuse large B-cell lymphoma. Single infusion of EBViNT was well tolerated by all the patients and generated objective antitumor responses in 3 of them. EBViNT infusion induced 2 waves of interferon-γ response: 1 approximately 1 week and the other 4-8 weeks after the treatment. The strength of the second wave was related to the efficacy of the treatment. The current trial shows that EBViNT therapy is safe and may provide a new option for treating EBV-positive recurrent cancer patients resistant to conventional therapy.
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http://dx.doi.org/10.1097/CJI.0000000000000113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834812PMC
April 2016

Prognostic value of fluorine-18 fludeoxyglucose positron emission tomography parameters differs according to primary tumour location in small-cell lung cancer.

Br J Radiol 2016 12;89(1059):20150618. Epub 2016 Jan 12.

1 Department of Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Objective: To investigate the prognostic value of fluorine-18 fludeoxyglucose (FDG) positron emission tomography (PET) parameters for small-cell lung cancer (SCLC), according to the primary tumour location, adjusted by conventional prognostic factors.

Methods: From 2008 to 2013, we enrolled consecutive patients with histologically proven SCLC, who had undergone FDG-PET/CT prior to initial therapy. The primary tumour location was categorized into central or peripheral types. PET parameters and clinical variables were evaluated using univariate and multivariate analysis.

Results: A total of 69 patients were enrolled in this study; 28 of these patients were categorized as having the central type and 41 patients as having the peripheral type. In univariate analysis, stage, serum neuron-specific enolase, whole-body metabolic tumour volume (WB-MTV) and whole-body total lesion glycolysis (WB-TLG) were found to be significant in both types of patients. In multivariate analysis, the independent prognostic factor was found to be stage in the central type, but WB-MTV and WB-TLG in the peripheral type. Kaplan-Meier analysis demonstrated that patients with peripheral type with limited disease and low WB-MTV or WB-TLG showed significantly better overall survival than all of the other groups (p < 0.0083).

Conclusion: The FDG-PET volumetric parameters were demonstrated to be significant and independent prognostic factors in patients with peripheral type of SCLC, while stage was the only independent prognostic factor in patients with central type of SCLC.

Advances In Knowledge: FDG-PET is a non-invasive method that could potentially be used to estimate the prognosis of patients, especially those with peripheral-type SCLC.
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http://dx.doi.org/10.1259/bjr.20150618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986487PMC
July 2016

Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted.

J Immunol 2015 Nov 30;195(10):4721-9. Epub 2015 Sep 30.

Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea; Program for Immunotherapeutic Research, National Cancer Center, Gyeonggi, 410-769, Republic of Korea; and Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112

The glucocorticoid-induced TNFR family-related protein (GITR, TNFRSF18, CD357) is expressed on effector and regulatory T (Treg) cells. Previous studies demonstrated that GITR triggering by anti-GITR mAb enhanced T and B cell-mediated immune responses. GITR-deficient T cells, however, also proliferate more than normal T cells, and this effect is unexplained. Because the activities of mAbs are controlled by their Fc regions, the true effect of GITR signaling needs to be determined by examining its interaction with authentic ligand. Therefore, we generated a pentamerized form of the GITRL extracellular domain (pGITRL) for ligation to GITR and compared its effect on T cells with that of anti-GITR mAb. The pGITRL was more effective than anti-GITR mAb in enhancing the proliferation of effector and regulatory cells in vitro and in vivo. Nonetheless, the growth of MC38 adenocarcinoma cells in vivo was only suppressed for initial 15 d by pGITRL, whereas it was suppressed indefinitely by anti-GITR mAb. Detailed analysis revealed that pGITRL induced extensive proliferation of Foxp3(+)CD4(+) Treg cells and led to the accumulation of activated Treg cells in tumor tissue and draining lymph nodes. Because GITR signaling could not neutralize the suppressive activity of activated Treg cells, pGITRL seems to lose its adjuvant effect when sufficient activated Treg cells have accumulated in the lymph nodes and tumor tissue. Indeed, the antitumor effects of pGITRL were markedly enhanced by depleting CD4(+) cells. These results suggest that GITR signaling has stimulatory effects on effector T cells and inhibitory effects through Treg cells.
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http://dx.doi.org/10.4049/jimmunol.1403076DOI Listing
November 2015

Seasonal affective disorder in patients with chronic tinnitus.

Authors:
Young H Kim

Laryngoscope 2016 Feb 7;126(2):447-51. Epub 2015 Jul 7.

Department of Otorhinolaryngology-Head and Neck Surgery, Seoul Metropolitan Government, Seoul National University, Boramae Medical Center, Seoul, South Korea.

Objectives/hypothesis: To investigate the point prevalence of SAD, degrees of anxiety/depression/sleep disturbance, and characteristics of tinnitus in patients with chronic tinnitus.

Study Design: Cross-sectional survey study.

Methods: From December 2012 to February 2014, 100 patients with chronic persistent or intermittent tinnitus (>3 months) were enrolled. Audiograms, tinnitograms, and Visual Analogue Scales (VAS) were used to assess tinnitus. Tinnitus Handicap Inventory (THI) assessment and questionnaires about anxiety/depression/sleep disturbance/SAD were administered.

Results: The male:female ratio was 48:52, and the mean age was 55.0 years. The numbers of patients with suspected SAD and subsyndromal SAD (S-SAD) were nine (9.0%) and 11 (11.0%), respectively. Winter was the most uncomfortable season. Nine patients had a catastrophic THI score >76 (11.1% in the SAD group, 27.3% in the S-SAD group, and 6.3% in the control group), suggesting a significant correlation between SAD/S-SAD and THI (P = .042). Audiogram, tinnitogram, VAS assessment, and sleep disturbance testing revealed no significant differences among the three groups. Anxiety tests yielded more abnormal findings in the SAD group than in the control group (State Anxiety Inventory score: 33.3% vs. 3.3%, respectively, P = .012; Trait Anxiety Inventory score: 22.2% vs. 1.3%, respectively, P = .002). Depression test scores were significantly higher in the SAD/S-SAD groups than in the control group (35.0% vs. 21.3%, respectively; P = .005).

Conclusions: Suspected SAD and/or S-SAD in chronic tinnitus patients were correlated with THI, anxiety, and depression. Understanding SAD in tinnitus patients may be important to manage these patients effectively.

Level Of Evidence: 4.
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http://dx.doi.org/10.1002/lary.25446DOI Listing
February 2016

Ultrasonography of adnexal causes of acute pelvic pain in pre-menopausal non-pregnant women.

Ultrasonography 2015 Oct 9;34(4):258-67. Epub 2015 May 9.

Department of Radiology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, MA, USA.

Acute-onset pelvic pain is an extremely common symptom in premenopausal women presenting to the emergency department. After excluding pregnancy in reproductive-age women, ultrasonography plays a major role in the prompt and accurate diagnosis of adnexal causes of acute pelvic pain, such as hemorrhagic ovarian cysts, endometriosis, ovarian torsion, and tubo-ovarian abscess. Its availability, relatively low cost, and lack of ionizing radiation make ultrasonography an ideal imaging modality in women of reproductive age. The primary goal of imaging in these patients is to distinguish between adnexal causes of acute pelvic pain that may be managed conservatively or medically, and those requiring emergency/urgent surgical or percutaneous intervention.
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http://dx.doi.org/10.14366/usg.15013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603210PMC
October 2015

Ultrasonography of intrauterine devices.

Ultrasonography 2015 Jul 1;34(3):183-94. Epub 2015 Apr 1.

Department of Radiology, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, MA, USA.

The intrauterine device (IUD) is gaining popularity as a reversible form of contraception. Ultrasonography serves as first-line imaging for the evaluation of IUD position in patients with pelvic pain, abnormal bleeding, or absent retrieval strings. This review highlights the imaging of both properly positioned and malpositioned IUDs. The problems associated with malpositioned IUDs include expulsion, displacement, embedment, and perforation. Management considerations depend on the severity of the malposition and the presence or absence of symptoms. Three-dimensional ultrasonography has proven to be more sensitive in the evaluation of more subtle findings of malposition, particularly side-arm embedment. Familiarity with the ultrasonographic features of properly positioned and malpositioned IUDs is essential.
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http://dx.doi.org/10.14366/usg.15010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484292PMC
July 2015

4-1BB Signaling Enhances Primary and Secondary Population Expansion of CD8+ T Cells by Maximizing Autocrine IL-2/IL-2 Receptor Signaling.

PLoS One 2015 11;10(5):e0126765. Epub 2015 May 11.

Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Ilsan, Goyang, Gyeonggi, Korea; Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America.

4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is primarily expressed on activated T cells and is known to enhance proliferation of T cells, prevent activation-induced cell death, and promote memory formation of CD8+ T cells. In particular, it is well acknowledged that 4-1BB triggering preferentially enhances the expansion of CD8+ T cells rather than CD4+ T cells, but the underlying mechanism remains unclear. Here we found that 4-1BB triggering markedly increased IL-2Rα (CD25) and IL-2 expressions of CD8+ T cells but minimally for CD4+ T cells. Proliferation of CD8+ T cells was moderately enhanced by direct 4-1BB triggering in the absence of signaling through IL-2Rα/IL-2 interactions, but further promoted in the presence of IL-2Rα/IL-2 interactions. Among the TNFRSF members including OX40, GITR, CD30, and CD27, 4-1BB was superior in the ability to induce IL-2Rα expression on CD8+ T cells. When the primary and secondary expansions of CD8+ T cells in vivo were examined by adoptively transferring OVA-specific CD8+ T cells along with the treatment with agonistic anti-4-1BB and/or antagonistic anti-CD25 F(ab')2 mAb, 4-1BB triggering enhanced both primary and secondary expansion of CD8+ T cells in vivo, and the 4-1BB effects were moderately suppressed in primary expansion while completely abolished in secondary expansion of OVA-specific CD8+ T cells by blocking IL-2Rα. These results suggest that 4-1BB-mediated increases of IL-2Rα and IL-2 prolong the effects of transient TCR- and 4-1BB-mediated signaling in CD8+ T cells, and that 4-1BB triggering preferentially enhances the expansion of CD8+ T cells through the amplification of autocrine IL-2/IL-2R signaling loop.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126765PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427336PMC
February 2016

In vivo 4-1BB deficiency in myeloid cells enhances peripheral T cell proliferation by increasing IL-15.

J Immunol 2015 Feb 19;194(4):1580-90. Epub 2015 Jan 19.

Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 410-769, Republic of Korea; Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112

4-1BB signals are considered positive regulators of T cell responses against viruses and tumors, but recent studies suggest that they have more complex roles in modulating T cell responses. Although dual roles of 4-1BB signaling in T cell responses have been suggested, the underlying mechanisms are still not fully understood. In this study, we tested whether 4-1BB expression affected T cell responses differently when expressed in myeloid versus lymphoid cells in vivo. By assessing the proliferation of 4-1BB(+/+) and 4-1BB(-/-) T cells in lymphocyte-deficient RAG2(-/-) and RAG2(-/-)4-1BB(-/-) mice, we were able to compare the effects on T cell responses of 4-1BB expression on myeloid versus T cells. Surprisingly, adoptively transferred T cells were more responsive in tumor-bearing RAG2(-/-)4-1BB(-/-) mice than in RAG2(-/-) mice, and this enhanced T cell proliferation was further enhanced if the T cells were 4-1BB deficient. Dendritic cells (DCs) rather than NK or tissue cells were the myeloid lineage cells primarily responsible for the enhanced T cell proliferation. However, individual 4-1BB(-/-) DCs were less effective in T cell priming in vivo than 4-1BB(+/+) DCs; instead, more DCs in the secondary lymphoid organs of RAG2(-/-)4-1BB(-/-) mice appeared to induce the enhanced T cell proliferation by producing and transpresenting more IL-15. Therefore, we conclude that in vivo 4-1BB signaling of myeloid cells negatively regulates peripheral T cell responses by limiting the differentiation of DCs and their accumulation in secondary lymphoid organs.
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http://dx.doi.org/10.4049/jimmunol.1303439DOI Listing
February 2015

Successful treatment of sudden sensorineural hearing loss assures improvement of accompanying tinnitus.

Laryngoscope 2015 Jun 4;125(6):1433-7. Epub 2014 Dec 4.

Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, South Korea.

Objectives/hypothesis: To investigate the long-term outcomes of accompanying tinnitus after steroid therapy for patients with sudden sensorineural hearing loss (SSNHL).

Study Design: Retrospective chart review and survey.

Methods: Fifty patients diagnosed with SSNHL accompanied by tinnitus were enrolled and divided into two groups-satisfied and unsatisfied-according to the degree of improvement of tinnitus after SSNHL treatment. Subjective improvement of tinnitus and hearing status were investigated before and 6 months after SSNHL treatment. Hearing improvement was assessed using criteria from our previous study and Siegel's criteria. The change of tinnitus was assessed using a visual analogue scale for tinnitus intensity and frequency.

Results: Patients with more severe initial hearing loss had less chance of hearing recovery (P = .05). The satisfied group included significantly more cases with better hearing recovery after SSNHL treatment than the unsatisfied group (P = .049). Pure-tone threshold and speech discrimination scores were significantly better in the satisfied group than in the unsatisfied group after SSNHL treatment (P = .033 and P = .018, respectively), although the two groups showed no definitive differences before treatment.

Conclusions: Optimal and successful treatment of SSNHL may be an important factor in obtaining favorable long-term control of tinnitus accompanied by SSNHL.

Level Of Evidence: 4.
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http://dx.doi.org/10.1002/lary.25074DOI Listing
June 2015

4-1BB-based isolation and expansion of CD8+ T cells specific for self-tumor and non-self-tumor antigens for adoptive T-cell therapy.

J Immunother 2014 May;37(4):225-36

*Immune & Cell Therapy Branch, Division of Cancer Biology ‡Biomedicine Production Branch §Center for Gastric Cancer, National Cancer Center, Goyang †Personalized Medicine System R&D Center, Bio-Support Co., Ltd, Gwanyang, Dongan, Anyang, Gyeonggi ∥Department of Surgery, Kosin University College of Medicine, Busan, Korea ¶T Cell Technologies Inc., Nagoya, Aichi, Japan #Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA.

Adoptive T-cell therapy is a promising approach to the immunotherapy of cancer, but for it to be a general cancer therapy a simple and standardized procedure for producing tumor-specific CD8 T cells is needed. On the basis of a unique property of 4-1BB (CD137), the selective expression on activated T cells, we have developed a simple and practical protocol to produce antigen-specific CD8 T cells from peripheral blood mononuclear cells. We have proved the feasibility of this procedure by isolating and expanding cytomegalovirus-specific CD8 T cells, and applied the procedure to produce Epstein-Barr virus (EBV)-specific CD8 T cells. By using this procedure, we could readily produce 10-10 antigen-specific CD8 T cells from 30 to 50 mL of blood in about 4 weeks. Moreover, our protocol allowed us to produce, from solid cancer patients, CD8 T cells that were specific for self/tumor antigens such as human telomerase reverse transcriptase (hTERT). It is interesting to note that, we were unable to amplify hTERT-specific CD8 T cells from healthy donors. Our protocol can be readily translated into cGMP-compliant production and is currently being used to produce EBV-specific CD8 T cells for phase I clinical trial. We believe that our method will provide a practical and effective option for adoptive T-cell therapy in the clinic.
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http://dx.doi.org/10.1097/CJI.0000000000000027DOI Listing
May 2014
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