Central nervous system blast crisis of chronic myeloid leukemia and treatment with dasatinib

( Hong Suk Park ),( Jinny Park ),( Young Saeng Kim ),( In Geun Park ),( Jun Sik Hong ),( Hee Kyong Ahn ),( Sun Jin Sim ),( Eun Kyoung Joe ),( Dong Bok Shin ),( Jae Hoon Lee ) 대한내과학회 2015 대한내과학회 추계학술대회 Vol.2015 No.1

Chronic myeloid leukemia (CML) is a myeloproliferative disorder driven by the BCR-ABL1. Owing to the high efficacy of imatinib mesylate for CML in chronic phase, the frequency of the blast crisis is greatly reduced. Some CML cases develop extramedullary disease caused by infiltration of blast cells. However, the central nervous system (CNS) as an isolated site of extramedullary blast crisis is rare. Herein, we report case of dasatinib-based maintenance therapy for lymphoid blast crisis of the CNS in a patient with CML who was receiving imatinib mesylate therapy. In July 2012, a 55 years old man was diagnosed with Philadelphia chromosome positive CML in the chronic phase. Immediately, imatinib mesylate administration was initiated. Four months after the diagnosis, he complained of headache. On cerebrospinal fluid (CSF) examination, the CSF had increased number of WBCs (6289/iL); almost all WBCs were lymphoid cells. Brain MRI revealed abnormal leptomeningeal enhancement of the frontal lobes. In addition to a complete hematological, cytogenetic response and evidence of the absence of malignant lymphoblasts in the peripheral blood and bone marrow samples, these findings led to the diagnosis of isolated lymphoid blast crisis in CNS. Immediately, the patient was treated with scheduled intrathecal methotrexate, cerebrospinal radiotherapy and TKI dasatinib. Major molecular response was achieved after 4 months after treatment change, followed by matched related allogeneic peripheral blood SCT. During the course of dasatinib maintenance therapy, several follow-up tests were performed and persistently yielded results indicating complete hematologic, molecular, and cytogenetic responses. The patient was neurological symptom-free for 2 years. In addition, the abnormal enhancement of the frontal lobe observed on the initial brain MRI had disappeared. This report is meaningful of significance as because we used a minimal treatment of intrathecal chemotherapy, radiotherapy, allogeneic peripheral blood SCT and an oral TKI without using cytotoxic chemotherapy such as hyper-CyVAD.

D-ribose induces nephropathy through RAGE-dependent NF-jB inflammation

Jinni Hong,Xuemei Wang,Ning Zhang,Hong Fu,Weiwei Li 대한약학회 2018 Archives of Pharmacal Research Vol.41 No.8

Recently, aberrantly high levels of D-ribose havebeen discovered in type II diabetic patients. D-ribose glycatesproteins more rapidly than D-glucose, resulting in theproduction of advanced glycation end products (AGEs). Accumulations of these products can be found in impairedrenal function, but the mechanisms are poorly understood. The present study tested whether D-ribose induces renaldysfunction via the RAGE-dependent NF-jB signalingpathway. In vivo, administration of D-ribose was found tolower blood glucose and regulate insulin tolerance. Comparedto controls, urine nitrogen and creatinine excretionwere increased in mice receiving D-ribose and wereaccompanied by severe pathological renal damage. Furthermore,immunohistochemistry showed that NF-jB,AGEs, and receptor of AGEs (RAGE) increased in thekidneys of the mice with D-ribose treatment. In vitro, bywestern blot and immunofluorescent staining, we confirmedthat D-ribose induced NF-jB activation and accumulationof AGEs and RAGE in mesangial cells. By coimmunoprecipitation,we found that the pull-down ofRAGE remarkably increased the expression of NF-jB. Silencing the RAGE gene blocked the phosphorylation ofNF-jB induced by D-ribose. These results strongly suggestthat D-ribose induced NF-jB inflammation in a RAGEdependentmanner, which may be a triggering mechanismleading to nephropathy.

Specific Alternation of Gut Microbiota and the Role of Ruminococcus gnavus in the Development of Diabetic Nephropathy

( Jinni Hong ),( Tingting Fu ),( Weizhen Liu ),( Yu Du ),( Junmin Bu ),( Guojian Wei ),( Miao Yu ),( Yanshan Lin ),( Cunyun Min ),( Datao Lin ) 한국미생물생명공학회 2024 Journal of microbiology and biotechnology Vol.34 No.3

In this study, we aim to investigate the precise alterations in the gut microbiota during the onset and advancement of diabetic nephropathy (DN) and examine the impact of Ruminococcus gnavus (R. gnavus) on DN. Eight-week-old male KK-Ay mice were administered antibiotic cocktails for a duration of two weeks, followed by oral administration of R. gnavus for an additional eight weeks. Our study revealed significant changes in the gut microbiota during both the initiation and progression of DN. Specifically, we observed a notable increase in the abundance of Clostridia at the class level, higher levels of Lachnospirales and Oscillospirales at the order level, and a marked decrease in Clostridia_UCG-014 in DN group. Additionally, there was a significant increase in the abundance of Lachnospiraceae, Oscillospiraceae, and Ruminococcaceae at the family level. Moreover, oral administration of R. gnavus effectively aggravated kidney pathology in DN mice, accompanied by elevated levels of urea nitrogen (UN), creatinine (Cr), and urine protein. Furthermore, R. gnavus administration resulted in down-regulation of tight junction proteins such as Claudin-1, Occludin, and ZO-1, as well as increased levels of uremic toxins in urine and serum samples. Additionally, our study demonstrated that orally administered R. gnavus up-regulated the expression of inflammatory factors, including nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) and Interleukin (IL)-6. These changes indicated the involvement of the gut-kidney axis in DN, and R. gnavus may worsen diabetic nephropathy by affecting uremic toxin levels and promoting inflammation in DN.

A pharmacological PPAR-v Ligand, ciglutazone, in combination with retinoic acid synergistically enhances upregulation of novel tumor suppressor PTEN in HL60 cells

( Jinny Park ),( Young Rae Lee ),( Hyun Jung Shim ),( Hyeon Hur ),( Myung Kwan Han ),( Eun Kyung Song ),( Jin Woo Park ),( Hye Won Rho ),( Eun Chung Jhee ),( Hong Ghi Lee ),( Keun Chil Park ),( Jong S 대한내과학회 2003 대한내과학회 추계학술대회 Vol.65 No.10

Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers

Lee, Jinny Claire,Kim, Soo Jung,Hong, Seungpyo,Kim, YoungSoo Nature Publishing Group UK 2019 Experimental and molecular medicine Vol.51 No.5

<▼1><P>Current technological advancements in clinical and research settings have permitted a more intensive and comprehensive understanding of Alzheimer’s disease (AD). This development in knowledge regarding AD pathogenesis has been implemented to produce disease-modifying drugs. The potential for accessible and effective therapeutic methods has generated a need for detecting this neurodegenerative disorder during early stages of progression because such remedial effects are more profound when implemented during the initial, prolonged prodromal stages of pathogenesis. The aggregation of amyloid-β (Aβ) and tau isoforms are characteristic of AD; thus, they are considered core candidate biomarkers. However, research attempting to establish the reliability of Aβ and tau as biomarkers has culminated in an amalgamation of contradictory results and theories regarding the biomarker concentrations necessary for an accurate diagnosis. In this review, we consider the capabilities and limitations of fluid biomarkers collected from cerebrospinal fluid, blood, and oral, ocular, and olfactory secretions as diagnostic tools for AD, along with the impact of the integration of these biomarkers in clinical settings. Furthermore, the evolution of diagnostic criteria and novel research findings are discussed. This review is a summary and reflection of the ongoing concerted efforts to establish fluid biomarkers as a diagnostic tool and implement them in diagnostic procedures.</P></▼1><▼2><P><B>Alzheimer’s disease: early diagnostic biomarkers in body fluids</B></P><P>Markers from body fluids could help clinicians diagnose Alzheimer’s disease before cognitive decline appears. After numerous setbacks in treating advanced Alzheimer’s, researchers are eager to identify biological indicators that facilitate earlier disease detection and interception. A review by YoungSoo Kim and colleagues at Yonsei University in South Korea, explores the promise of ‘fluid biomarkers,’ which enables diagnosis using cerebrospinal fluid (CSF), blood, oral, ocular, and olfactory fluid samples. Shifts in CSF levels of amyloid beta and tau, two proteins central to Alzheimer’s pathology, can reliably monitor at-risk individuals. Although CSF collection is unpleasant for patients, it remains more promising than blood, where current data for candidate fluid biomarkers are relatively inconclusive. In this review, investigations to discover safer, cheaper, and more reliable diagnostic tools to shift treatment from alleviation to prevention are introduced.</P></▼2>

Pemetrexed versus Gefitinib versus Erlotinib in Previously Treated Patients with Non-Small Cell Lung Cancer

( Jun Shik Hong ),( Sun Young Kyung ),( Sang Pyo Lee ),( Jeong Woong Park ),( Sung Hwan Jung ),( Jae Ik Lee ),( Se Hoon Park ),( Sun Jin Sym ),( Jinny Park ),( Eun Kyung Cho ),( Dong Bok Shin ),( Jae 대한내과학회 2010 The Korean Journal of Internal Medicine Vol.25 No.3

Background/Aims: The efficacy and safety of pemetrexed, gefitinib, and erlotinib administration in previously treated patients with non-small cell lung cancer (NSCLC) were compared. Methods: The study patients met the following criteria: histologically confirmed, previously treated advanced (stage IIIB or IV) or recurrent NSCLC; a measurable lesion; ≥18 years of age; Eastern Cooperative Oncology Group Performance status 0 to 2; and no prior exposure to the three study drugs. Patients received 500 mg/m2 of pemetrexed intravenously every 3 weeks with vitamin supplementation, gefitinib (250 mg/day per os), or erlotinib (150 mg/day per os). Results: Of 57 patients (pemetrexed, 20; gefitinib, 20; and erlotinib, 17), 55 were evaluated for a response. The numbers of males, smokers, and squamous histology were increased in the pemetrexed group compared to the other groups. The objective response rates were 5.3%, 25.0%, and 12.5% (p=0.22), and the disease control rates (DCR) were 5.3%, 40.0%, and 50.0%, respectively (p<0.01). The median progression-free survival (PFS) was 1.7, 3.5, and 4.4 months (p<0.01) and the median overall survival (OS) was 5.6, 21.8, and 21.5 months (p=0.04), respectively. In subgroup analyses, patients with non-squamous histology, males, and a smoking history had a higher DCR and longer PFS with gefitinib and erlotinib than with pemetrexed. All three chemotherapeutic agents had manageable toxicities. Conclusions: Both oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) had comparable efficacy and safety. The superior PFS and OS of EGFR TKIs with more favorable baseline clinical characteristics than those of pemetrexed suggest the impact of baseline clinicopathological factors. (Korean J Intern Med 2010;25:294-300)

Peroxisome Proliferator-Activated Receptor γ and Retinoic Acid Receptor Synergistically Up-Regulate the Tumor Suppressor PTEN in Human Promyeloid Leukemia Cells

Lee, Young-Rae,Yu, Hong-Nu,Noh, Eun-Mi,Kim, Jong-Suk,Song, Eun-Kyung,Han, Myung-Kwan,Kim, Byeong-Soo,Lee, Sung-Ho,Park, Jinny Elsevier Science Publishers 2007 INTERNATIONAL JOURNAL OF HEMATOLOGY Vol.85 No.3

<P>Peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoic acid receptors (RARs) have been a focus in chemotherapy for human cancers. The tumor suppressor PTEN plays a pivotal role in the growth of human cancer cells. We investigated whether costimulation of PPARgamma and RAR could synergistically up-regulate PTEN in human leukemia cells and consequently potentiate the inhibition of growth and cell cycle progression of these cells. We found that overexpression of PTEN with the adenoviral vector Ad/PTEN caused growth arrest at the G1 phase of the cell cycle of HL-60 cells. HL-60 cells treated with either a PPARgamma ligand (ciglitazone) or a RAR ligand (all-trans retinoic acid [ATRA]) up-regulated PTEN in HL-60 cells. The 2 compounds in combination showed synergistic effects on PTEN expression at the protein and messenger RNA levels. Moreover, the combination of ciglitazone and ATRA synergistically reduced cell growth rates and cell cycle arrest at the G1 phase. Our results suggest that, PPARgamma and RAR play an important role in controlling the growth of leukemia cells via the up-regulation of PTEN.</P>

Skin Aging-Dependent Activation of the PI3K Signaling Pathway via Downregulation of PTEN Increases Intracellular ROS in Human Dermal Fibroblasts

Noh, Eun-Mi,Park, Jinny,Song, Hwa-Ryung,Kim, Jeong-Mi,Lee, Minok,Song, Hyun-Kyung,Hong, On-Yu,Whang, Pyoung H.,Han, Myung-Kwan,Kwon, Kang-Beom,Kim, Jong-Suk,Lee, Young-Rae Hindawi Publishing Corporation 2016 Oxidative medicine and cellular longevity Vol.2016 No.-

<P>Reactive oxygen species (ROS) play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3) metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC) or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging-associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging-dependent increase of ROS in human dermal fibroblasts.</P>

Differences in Clinical Outcomes Between Hydroxyurea-Resistant and -Intolerant Polycythemia Vera Patients

Lee Sung-Eun,Hong Junshik,Bang Soo-Mee,Park Jinny,Choi Chul Won,Bae Sung Hwa,Kim Min Kyoung,Yoon Seug Yun,Kim Sung-Yong 대한의학회 2024 Journal of Korean medical science Vol.39 No.3

Background: Previous studies have suggested that patients with polycythemia vera (PV) who exhibit hydroxyurea-resistance (HU-R) and -intolerance (HU-I) may have distinct characteristics and clinical outcomes. However, to date, no studies have reported a comparison between these two groups or assessed prognostic factors in these patients. Methods: The objective of this study was to evaluate clinical outcomes and identify prognostic factors among PV patients with HU-R or HU-I. We conducted a review of PV patients who received frontline treatment with HU from nine centers and identified 90 patients with HU-R or HU-I. Results: The cumulative incidence of thrombosis after 7 years of HU-R/I was 21.4%, and the incidence of disease progression was 22.5%. Comparing the HU-R and HU-I groups, the HU-R group had a significantly higher rate of disease progression (36.7% vs. 0.56%, P = 0.009), while there was no significant difference in thrombosis incidence (19.0% vs. 22.9%, P = 0.463). Multivariate analysis revealed that HU-R was an independent prognostic factor for progression-free survival (hazard ratio, 6.27, 95% confidence interval, 1.83–21.47, P = 0.003). Additionally, higher lactate dehydrogenase levels, multiple cardiovascular risk factors, and prior thrombosis were identified as unfavorable predictors of overall survival. Conclusion: These findings suggest that patients with HU-R face a higher risk of hematological transformation, but have a comparable risk of thrombosis to patients with HU intolerance. These distinctions should guide decisions on second-line treatment options and clinical trials involving these patients.

Poster Session : PS 1414 ; Hemato-Oncology(Hematology) : Successful Remission with Low Dose Rituximab in a Patient with a Plasma Exchange Refractory Acute TTP

( Kyoung Hwan Song ),( Jae Hoon Lee ),( Jinny Park ),( Eunkyung Kang ),( Hyunjung Hwang ),( Ji Yeon Kim ),( Jun Shik Hong ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal disorder and neurologic manifestations. If not treated properly, its mortality rate is very high due to rapid progression. Standard treatment of TTP is plasma exchange, and corticosteroids may be a useful adjunct. However, a part of patients are poorly responsive or resistant to plasma exchange and to achieve a successful remission, they need additional immunosuppressive agents. Rituximab, a monoclonal antibody to CD20 on B-lymphocytes, is known for its efficacy to patients not responding to plasma exchange with or without corticosteroids, patients with relapsed TTP who experienced severe clinical course before, or those who had neurologic abnormalities. Although there has been sufficient number of reports that suggests the role of rituximab in patients with TTP, no consensus on treatment schedule, such as dose and duration, exist. The 27-year-old man with no past medical history complained of fever and fatigue for 3 days. Blood tests showed MAHA with thrombocytopenia, and TTP was diagnosed by ADAMTS13 genetic study. With his poor responsiveness to plasma exchange (overall 29 times) and later adjunctive glucocorticoids (intravenous methylprednisolone 60mg/ day for 7 days), rituximab was considered. Due to his poor economy, the patient was treated using low-dose rituximab (150mg/m2, for the first time, then 100mg/m2 for 3 times once in a week). Although less dose of rituximab was administered compared to conventional therapy (375 mg/m2/week x 4 times), the patient achieved a fast complete remission and has been free of the disease for seven months.