Publications by authors named "Weihe Zhang"

43 Publications

Discovery and Optimization of 2-1λ-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer.

J Med Chem 2021 Apr 6;64(8):4913-4946. Epub 2021 Apr 6.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2-1λ-quinoline-2,5(6)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (-, ). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
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http://dx.doi.org/10.1021/acs.jmedchem.1c00019DOI Listing
April 2021

Area Postrema Syndrome: A Rare Feature of Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids.

Front Neurol 2020 18;11:730. Epub 2020 Aug 18.

Department of Neurology, China-Japan Friendship Hospital, Beijing, China.

The area postrema syndrome (APS) is a unique diagnostic criterion for neuromyelitis optica spectrum disorders (NMOSD). However, APS has rarely been reported in cases of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). A 36-year-old woman presented with APS and clinical features of diffuse central nervous system involvement during the early stage of the disease. Owing to the absence of serum aquaporin 4 antibodies, she was initially misdiagnosed as a case of seronegative NMOSD. However, the distinct neuroimaging characteristics [symmetrical small punctuate gadolinium enhancing lesions (pepper-like)], typical clinical/radiological relapse, and intense steroid-dependence in this case, prompted us to correct the diagnosis as probable CLIPPERS. To prevent relapse, long-term oral steroids and an immunosuppressive agent were administered. CLIPPERS may present as APS, and should be considered in the differential diagnosis of NMOSD.
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http://dx.doi.org/10.3389/fneur.2020.00730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461882PMC
August 2020

Isosteres of ester derived glucose uptake inhibitors.

Bioorg Med Chem Lett 2020 09 15;30(18):127406. Epub 2020 Jul 15.

Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA; Program of Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA. Electronic address:

Glucose transporters (GLUTs) facilitate glucose uptake and are overexpressed in most cancer cells. Inhibition of glucose transport has been shown to be an effective method to slow the growth of cancer cells both in vitro and in vivo. We have previously reported on the anticancer activity of an ester derived glucose uptake inhibitor. Due to the hydrolytic instability of the ester linkage we have prepared a series of isosteres of the ester moiety. Of all of the isosteres prepared, the amine linkage showed the most promise. Several additional analogues of the amine-linked compounds were also prepared to improve the overall activity.
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http://dx.doi.org/10.1016/j.bmcl.2020.127406DOI Listing
September 2020

Questioning the existence of monophasic neuromyelitis optica spectrum disorder by defining a novel long-term relapse-free form from a large Chinese population.

J Neurol 2020 Apr 13;267(4):1197-1205. Epub 2020 Jan 13.

Department of Neurology, China-Japan Friendship Hospital, 2 Yinghua Dongjie, Hepingli, Beijing, 100029, China.

Objective: To clarify the existence of monophasic neuromyelitis optica spectrum disorders (NMOSD) and to identify predictive factors of long-term relapse-free form.

Methods: We retrospectively analyzed 289 Chinese patients with NMOSD. Selected subjects were divided into three groups based on the time interval between disease onset and the first relapse, if any. Clinical and imaging data were acquired from each patient's medical record and evaluated as predictive factors for NMOSD.

Results: In total, none of the participating patients exhibited a monophasic form of NMOSD. Rather, 241 patients were selected for relapse tendency analysis; 143 (59.3%) patients relapsed within the first year, 66 (27.4%) during 1-5 years, and 32 (13.3%) beyond 5 years. Such onset symptoms as optic neuritis (ON) and non-longitudinally extensive transverse myelitis (LETM) were independent prognostic factors for a prolonged remission interval (P < 0.05). The relapse rate was bi-modal for ON patients in the first year (47.9%) and beyond 5 years (24.0%) after disease onset, respectively. However, most TM and area postrema syndrome (APS) patients experienced an attack within the first year (61.3% for TM and 76.9% for APS). A survival analysis showed that attacks with APS (P < 0.0001) and TM (P < 0.05) have a significantly higher risk of early relapse than with ON and that seropositive aquaporin-4 antibody may shorten the relapse interval for all onset symptoms (P < 0.0001).

Conclusions: Our study indicated that the monophasic form of NMOSD may not exist when a sufficient follow-up period is considered. Onset phenotypes with ON, non-APS, or non-LETM attacks had a lower risk of early relapse.
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http://dx.doi.org/10.1007/s00415-019-09685-3DOI Listing
April 2020

Reduced sarcolemmal aquaporin 4 expression can support the differential diagnosis of neuromyelitis optica spectrum disorders.

J Neuroimmunol 2020 02 25;339:577121. Epub 2019 Nov 25.

Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address:

This study aimed to investigate the underlying pathological muscle damage in neuromyelitis optica spectrum disorder (NMOSD) patients without muscular symptoms. We prospectively enrolled 15 patients with aquaporin 4 (AQP4) antibody seropositive NMOSD and 16 patients with non-NMOSD diseases as a control group. Biceps biopsy samples from 18 patients were examined. Six NMOSD patients exhibited inflammatory lesions/edema in lower muscles on muscle MRI. On histopathological examination, NMOSD samples showed significantly decreased IgG-targeting AQP4 expression on sarcolemma compared with non-NMOSD samples in terms of the area of positive staining and integrated optical density. Muscle biopsy can support the differential diagnosis of NMOSD.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577121DOI Listing
February 2020

[Clinical and genetic analysis of a patient with Krabbe disease presented as peripheral neuropathy].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Aug;36(8):821-825

Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China.

Objective: To explore the clinical, electrophysiological and imaging features of a patient with Krabbe disease caused by GALC mutation.

Methods: A comprehensive analysis including clinical investigation and genetic testing was carried out.

Results: The patient presented with peripheral neuropathy with electrophysiological anomaly suggestive of asymmetric demyelinating neuropathy. Brain imaging revealed leukoencephalopathy. Genetic analysis has identified compound heterozygous mutations in exons 5 and 11 of the GALC gene, namely c.461C>A and c.1244G>A.

Conclusion: Krabbe disease is a group of disorders featuring substantial phenotypic heterogeneity. Genetic and enzyme testing has become indispensable for accurate diagnosis for this disease.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.08.017DOI Listing
August 2019

Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma.

Proc Natl Acad Sci U S A 2019 08 25;116(33):16541-16550. Epub 2019 Jul 25.

Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;

Non-Hodgkin lymphomas (NHLs) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely up-regulated in different NHL subtypes. Using multiplexed inhibitor bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely up-regulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Tyro3 was also highly expressed in PEL cell lines as well as in primary PEL exudates. Based on this discovery, we developed an inhibitor against Tyro3 named UNC3810A, which hindered cell growth in PEL, but not in other NHL subtypes where Tyro3 was not highly expressed. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model that was not seen in a non-PEL NHL model. Taken together, our data suggest Tyro3 is a therapeutic target for PEL.
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http://dx.doi.org/10.1073/pnas.1903991116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697815PMC
August 2019

Highly Selective MERTK Inhibitors Achieved by a Single Methyl Group.

J Med Chem 2018 11 5;61(22):10242-10254. Epub 2018 Nov 5.

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry , UNC Eshelman School of Pharmacy , Chapel Hill , North Carolina 27599 , United States.

Although all kinases share the same ATP binding pocket, subtle differences in the residues that form the pocket differentiate individual kinases' affinity for ATP competitive inhibitors. We have found that by introducing a single methyl group, the selectivity of our MERTK inhibitors over another target, FLT3, was increased up to 1000-fold (compound 31). Compound 19 was identified as an in vivo tool compound with subnanomolar activity against MERTK and 38-fold selectivity over FLT3 in vitro. The potency and selectivity of 19 for MERTK over FLT3 were confirmed in cell-based assays using human cancer cell lines. Compound 19 had favorable pharmacokinetic properties in mice. Phosphorylation of MERTK was decreased by 75% in bone marrow leukemia cells from mice treated with 19 compared to vehicle-treated mice.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01229DOI Listing
November 2018

Dose effects of mycophenolate mofetil in Chinese patients with neuromyelitis optica spectrum disorders: a case series study.

BMC Neurol 2018 Apr 23;18(1):47. Epub 2018 Apr 23.

Department of Neurology, China-Japan Friendship Hospital, #2 Yinghuayuan East Street, Chaoyang District, Beijing, 100029, China.

Background: Neuromyelitis optica (NMO) spectrum disorder (NMOSD) is a devastating autoimmune inflammatory disorder of the central nervous system, which can result in blindness or paralysis. Currently, there is a dire need for new treatment options in the clinic. Several case series have shown that mycophenolate mofetil (MMF) may be an effective treatment for NMOSD patients. The dosing of MMF in the treatment of NMOSD has been poorly studied. Therefore, we evaluated the efficacy, tolerability, influential factors and optimal dosage of MMF in Chinese patients with NMOSD.

Methods: A case series of 109 NMO or NMOSD (limited forms of NMO with seropositive AQP4-IgG) patients were retrospectively analyzed and followed up. Out of the 109 patients, 86 patients had received MMF for 6 months or longer and were included for efficacy assessment.

Results: When comparing the annualized relapse rate (ARR) of MMF treatment with that of pre-MMF treatment period, MMF was found to significantly reduce ARR in 75 (87%) patients (p < 0.0001). The median pre-treatment Expanded Disability Status Scale (EDSS) score in remission decreased from 3 (range, 0-8.5) to 2.5 (range, 0-8) at the last follow-up (p = 0.006), yet no significant difference was found in the visual score. The higher doses of MMF (1750 mg/d to 2000 mg/d) significantly lowered the relapse risks compared with lower doses (1000 mg/d or less, p < 0.0001) or moderate doses (1250 to 1500 mg/d, p = 0.031). Coexisting with systemic autoimmune diseases (HR, 2.418; p = 0.0345) and attack number before MMF initiation (HR, 1.117; p = 0.02) were important risk factors for relapses. MMF was generally well tolerated with adverse effects occurring in 21 patients (19%). While four patients decreased their daily doses because of the adverse effects, only one patient stopped MMF treatment.

Conclusions: MMF is generally effective and well tolerated in Chinese NMOSD patients. High-dose MMF was more potent than the lower dose for NMOSD patients, with 1750 mg of daily MMF being the recommended dosage for Chinese patients with NMOSD. MMF treatment reduces the frequency of relapses and improves the quality of life for patients with this debilitating disease.
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http://dx.doi.org/10.1186/s12883-018-1056-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911949PMC
April 2018

Early identification of anti-NMDA receptor encephalitis presenting cerebral lesions in unconventional locations on magnetic resonance imaging.

J Neuroimmunol 2018 07 29;320:101-106. Epub 2018 Mar 29.

Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China.

To facilitate the diagnosis of anti-NMDAR encephalitis presenting with brain lesions in unconventional locations (BLUL) on MRI, we retrospectively analyzed forty-five Chinese patients. Eighteen (40.0%) of their MRI initially exhibited one or more BLUL. These locations predominantly included cerebral gray matter (cortex, basal ganglia and thalamus), as well as white matter and brainstem. Due to these BLUL, thirteen (72.2%) patients were originally misdiagnosed with other diseases and developed poor clinical and imaging outcomes. Therefore, anti-NMDAR encephalitis has unpredictable MRI findings that easily obscure its diagnosis and cause serious sequelae. Anti-NMDAR antibody tests are highly recommended in patients with BLUL.
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http://dx.doi.org/10.1016/j.jneuroim.2018.03.015DOI Listing
July 2018

Plasma Exchange for Neuromyelitis Optica Spectrum Disorders in Chinese Patients and Factors Predictive of Short-term Outcome.

Clin Ther 2018 04 30;40(4):603-612. Epub 2018 Mar 30.

Department of Neurology, China-Japan Friendship Hospital, Beijing, China.

Purpose: The purposes of this article were to evaluate the short-term outcome of plasma exchange (PLEX) for neuromyelitis optica spectrum disorders (NMOSDs) in Chinese patients and to identify the factors predictive of a favorable response to therapy.

Methods: We retrospectively analyzed data from 29 Chinese patients with NMOSD. All patients received 2 to 7 sessions of PLEX every other day. Expanded Disability Status Scale (EDSS) scores were estimated at baseline, at relapse, and before and at follow-up after PLEX. Patients were assigned to 1 of 2 groups according to treatment responses of marked to moderate improvement and mild to no improvement.

Findings: Twenty-four of 29 patients (82.8%) showed functional improvement at 1 month after PLEX, 9 of whom experienced moderate to marked improvement. Early PLEX initiation and a lower baseline EDSS score were independent prognostic factors (both, P < 0.05). In addition, relapse symptoms of nonoptic neuritis and acute transverse myelitis plus circumventricular organs, seronegativity for aquaporin-4 antibodies, shorter initial therapy-PLEX interval, and no prior optic neuritis attacks were predictive factors significantly associated with a favorable response to treatment (all, P < 0.05). The delay time pre-PLEX was inversely correlated with reduction in EDSS score. The percentage reductions in EDSS score in groups receiving PLEX on days ≤15 and days 16 to 30 were significantly greater than those in the groups treated on days 31 to 60 and days 61 to 90 (all, P < 0.05). Most PLEX sessions were generally well tolerated.

Implications: PLEX is an effective therapy for NMOSD in the Chinese population, and early PLEX initiation was associated with a favorable response. We recommend an optimum PLEX time of 30 days from the time of disease onset. Further long-term prospective, multicenter studies that include a larger sample of patients with NMOSD treated with PLEX are necessary.
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http://dx.doi.org/10.1016/j.clinthera.2018.03.007DOI Listing
April 2018

Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors.

ChemMedChem 2017 02 9;12(3):207-213. Epub 2017 Jan 9.

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy.

Macrocycles have attracted significant attention in drug discovery recently. In fact, a few de novo designed macrocyclic kinase inhibitors are currently in clinical trials with good potency and selectivity for their intended target. In this study, we successfully engaged a structure-based drug design approach to discover macrocyclic pyrimidines as potent Mer tyrosine kinase (MerTK)-specific inhibitors. An enzyme-linked immunosorbent assay (ELISA) in 384-well format was employed to evaluate the inhibitory activity of macrocycles in a cell-based assay assessing tyrosine phosphorylation of MerTK. Through structure-activity relationship (SAR) studies, analogue 11 [UNC2541; (S)-7-amino-N-(4-fluorobenzyl)-8-oxo-2,9,16-triaza-1(2,4)-pyrimidinacyclohexadecaphane-1-carboxamide] was identified as a potent and MerTK-specific inhibitor that exhibits sub-micromolar inhibitory activity in the cell-based ELISA. In addition, an X-ray structure of MerTK protein in complex with 11 was resolved to show that these macrocycles bind in the MerTK ATP pocket.
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http://dx.doi.org/10.1002/cmdc.201600589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336325PMC
February 2017

Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors.

ACS Med Chem Lett 2016 Dec 13;7(12):1044-1049. Epub 2016 Sep 13.

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States; Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States; Meryx, Inc., 450 West Dr., Chapel Hill, North Carolina 27599, United States.

Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound (UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5151143PMC
December 2016

Repeated misdiagnosis of a relapsed atypical anti-NMDA receptor encephalitis without an associated ovarian teratoma.

Neurosci Lett 2017 01 27;638:135-138. Epub 2016 Nov 27.

Department of Neurology, China-Japan Friendship Hospital, Beijing, 100029, China. Electronic address:

We present an atypical case of relapsed anti-NMDAR encephalitis in a young female patient without an associated ovarian teratoma. She presented with recurrent seizure attacks with muscle weakness, psychosis, dyskinesia, autonomic failure and insomnia. She was first misdiagnosed as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) then Hashimoto's encephalopathy due to diffuse cerebral lesions, elevated serum lactic acid concentration, increased amount of thyroid peroxidase and thyroglobulin antibodies in serum and diffuse lesions of the thyroid gland. Her final diagnosis was delayed for 6 months with the detection of anti-NMDAR antibodies in her CSF. After treatment, she had poor recovery with serious sequelae at 10-month follow-up. Noteworthy, MELAS should be highlighted as a differential diagnosis of anti-NMDAR encephalitis.
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http://dx.doi.org/10.1016/j.neulet.2016.11.057DOI Listing
January 2017

UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models.

Clin Cancer Res 2017 Mar 20;23(6):1481-1492. Epub 2016 Sep 20.

Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia.

MERTK tyrosine kinase is ectopically expressed in 30% to 50% of acute lymphoblastic leukemias (ALL) and more than 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia. Preclinical and assays using cell lines and primary leukemia patient samples were used to evaluate antileukemic effects of UNC2025. UNC2025 potently inhibited prosurvival signaling, induced apoptosis, and reduced proliferation and colony formation in MERTK-expressing ALL and AML cell lines and patient samples. Approximately 30% of primary leukemia patient samples (78 of 261 total) were sensitive to UNC2025. Sensitive samples were most prevalent in the AML, T-ALL, and minimally differentiated (M0) AML subsets. UNC2025 inhibited MERTK in bone marrow leukemia cells and had significant therapeutic effects in xenograft models, with dose-dependent decreases in tumor burden and consistent two-fold increases in median survival, irrespective of starting disease burden. In a patient-derived AML xenograft model, treatment with UNC2025 induced disease regression. In addition, UNC2025 increased sensitivity to methotrexate , suggesting that addition of MERTK-targeted therapy to current cytotoxic regimens may be particularly effective and/or allow for chemotherapy dose reduction. The broad-spectrum activity mediated by UNC2025 in leukemia patient samples and xenograft models, alone or in combination with cytotoxic chemotherapy, supports continued development of MERTK inhibitors for treatment of leukemia. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354980PMC
March 2017

CD31 Expression on CD4+ Cells: A Simple Method for Quantitation of Recent Thymus Emigrant CD4 Cells.

Am J Trop Med Hyg 2016 Oct 15;95(4):970-972. Epub 2016 Aug 15.

Department of Pediatrics, University of Texas Medical School, Houston, Texas.

Measurements of CD4CD31 cells gave results consistent with those expected for recent thymus emigrant (RTE) CD4 cells. The method was markedly simpler than established procedures for measurement of CD4 RTE cells and is usable in locations with limited facilities and budgets.
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http://dx.doi.org/10.4269/ajtmh.15-0773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062808PMC
October 2016

Etiological, clinical, and radiological features of longitudinally extensive myelopathy in Chinese patients.

J Clin Neurosci 2016 Oct 12;32:61-6. Epub 2016 Aug 12.

Department of Neurology, China-Japan Friendship Hospital, 2 Yinghua, Dongjie, Hepingli, Beijing 100029, China.

Longitudinally extensive myelopathy (LEM) is a rare spinal syndrome, and was mostly assessed in western populations. In order to investigate the etiological, clinical, and radiological features of LEM in Chinese patients, we retrospectively analyzed eighty-nine (40 men and 49 women, median age 45.9±15.7years) patients with LEM hospitalized in China-Japan Friendship Hospital. LEM comprised autoimmune inflammatory myelitis (n=53), metabolic and compressive disorders (n=13), vascular diseases (n=10), neoplastic diseases (n=7), infectious diseases (n=4), and syringomyelia (n=2). Neuromyelitis optica spectrum disorders (NMOSD) was the most common cause of transverse myelopathy identified in LEM (38/89 [42.7%]) characterized by intractable vomiting and hiccups and painful tonic spasms. Subacute combined degeneration and anterior spinal artery syndrome accounted for the largest non-transverse LEM, which selectively affected the spinal dorsal and/or lateral columns and the spinal anterior region, respectively. Radicular pain was common in anterior spinal artery syndrome. Postrema (n=15, 39.5%) and cervical (n=31, 81.6%) lesions were significantly increased in NMOSD versus non-NMOSD (n=7, 13.7% and n=34, 66.7%, respectively, p<0.05]. Axial T2-weighted MRI indicated that 46 (51.7%) patients exhibited complete lesions; 43 (48.3%) patients exhibited non-transverse lesions, mainly unilateral or symmetrical tract lesions. Twenty-four (51.1%) LEM patients exhibited distinct gadolinium contrast enhancement. In this Chinese cohort, LEM was primarily attributed to NMOSD. While the etiological distribution in the non-NMOSD group was different from western populations, clinical and imaging features may facilitate a differential diagnosis.
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http://dx.doi.org/10.1016/j.jocn.2015.12.048DOI Listing
October 2016

Optic nerve involvement in immunoglobulin G4-related disease: A case report.

Exp Ther Med 2016 Jul 26;12(1):111-114. Epub 2016 Apr 26.

Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, P.R. China.

The present study reports the case of a 79-year-old woman manifesting skin changes, a pancreatic neoplasm, enlarged lymph nodes, an eyelid mass and interstitial pneumonia over a 30-year period. At 2 months before admission to our hospital, the patient presented rapid vision loss in the left eye. Left optic nerve atrophy with a focal hyperintense lesion was documented on a T2-weighted magnetic resonance imaging (MRI) scan, and visual evoked potential implicit times were prolonged. Elevated serum immunoglobulin G4 (IgG4) concentrations and the presence of enriched IgG4-positive plasma cells in the lymph nodes established the diagnosis of IgG4-related optic neuropathy. Following oral treatment with methylprednisolone, the serum IgG4 levels fell to normal levels, and the left eye visual acuity improved to a level that remained stable over a 1-year follow-up period. After 4 months of methylprednisolone administration, the optic nerve appeared to be normal on an MRI scan. Prior reports on IgG4-related optic neuropathy involved an infiltrating mass, which was not observed in the present case. Similarly to the current study, previous cases have responded to treatment with glucocorticoids, indicating that the underlying mechanism of the disease may be common.
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http://dx.doi.org/10.3892/etm.2016.3291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906810PMC
July 2016

The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia.

JCI Insight 2016 Mar;1(3):e85630

Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA.

FMS-like tyrosine kinase 3-targeted (FLT3-targeted) therapies have shown initial promise for the treatment of acute myeloid leukemia (AML) expressing FLT3-activating mutations; however, resistance emerges rapidly. Furthermore, limited options exist for the treatment of FLT3-independent AML, demonstrating the need for novel therapies that reduce toxicity and improve survival. MERTK receptor tyrosine kinase is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis. Here, we describe MRX-2843, a type 1 small-molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FLT3 and their downstream effectors. MRX-2843 treatment induces apoptosis and inhibits colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD, with a wide therapeutic window compared with that of normal human cord blood cells. In murine orthotopic xenograft models, once-daily oral therapy prolonged survival 2- to 3-fold over that of vehicle-treated controls. Additionally, MRX-2843 retained activity against quizartinib-resistant FLT3-ITD-mutant proteins with clinically relevant alterations at the D835 or F691 loci and prolonged survival in xenograft models of quizartinib-resistant AML. Together, these observations validate MRX-2843 as a translational agent and support its clinical development for the treatment of AML.
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http://dx.doi.org/10.1172/jci.insight.85630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855528PMC
March 2016

Recent Thymus Emigrant CD4+ T Cells Predict HIV Disease Progression in Patients With Perinatally Acquired HIV.

Clin Infect Dis 2016 Apr 21;62(8):1029-1035. Epub 2016 Feb 21.

Department of Pediatrics, University of Texas Health Center, Houston, Texas.

Background: Robust immune restoration in human immunodeficiency virus (HIV)-positive patients is dependent on thymic function. However, few studies have investigated thymic function and its correlation with disease progression over time in HIV-positive patients.

Methods: In this longitudinal prospective study, we followed 69 HIV-positive patients who were perinatally infected. Peripheral blood mononuclear cells were stained with monoclonal anti-CD4 and anti-CD31 and recent thymic emigrants (CD4+recently emigrated from the thymus (RTE), CD4+CD31+) quantified by flow cytometry. Statistical analysis used Wilcoxon rank sum test, Kruskal-Wallis, Spearman correlation, and Kaplan-Meier estimates; Cox regression models were performed for the longitudinal analysis.

Results: Median age of HIV positive patients enrolled was 13 years (interquartile range [IQR], 8.6). CD4+RTE% decreased with age and was higher in females. Median CD4+RTE% was 53.5%, IQR, 22.9. CD4+RTE% was closely related to CD4+% and absolute counts but independent of viral load and CD8+CD38+%. Antiretroviral compliance as well as higher nadir CD4+% were associated with higher CD4+RTE%. Low CD4+RTE% predicted poor progression of VL and CD4+% over time.

Conclusions: CD4+RTE% predicts disease progression and may reflect history of disease in HIV-positive patients and adolescents. They are easy to measure in the clinical setting and may be helpful markers in guiding treatment decisions.
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http://dx.doi.org/10.1093/cid/ciw030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433428PMC
April 2016

Differentiation of neuromyelitis optica spectrum disorders from ultra-longitudinally extensive transverse myelitis in a cohort of Chinese patients.

J Neuroimmunol 2016 Feb 7;291:96-100. Epub 2016 Jan 7.

Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China. Electronic address:

This study aimed to differentiate neuromyelitis optica spectrum disorders (NMOSD) from other causes in cases of ultra-longitudinally extensive transverse myelitis (uLETM). We retrospectively analyzed thirty-three Chinese patients with uLETM hospitalized in the China-Japan Friendship Hospital. The patients were divided into NMOSD (n=21) and non-NMOSD (n=12) groups. The NMOSD group exhibited significantly more comorbidity compared with the non-NMOSD group; moreover, the NMOSD group uniquely exhibited intractable vomiting and hiccups (IVH). The prevalence rates of cervicothoracic, area postrema (AP), and other circumventricular organ (CVO) lesions were significantly increased in the NMOSD group compared with the non-NMOSD group. Moreover, uLETM was strongly associated with NMOSD. These novel findings indicate that CVO lesions, including AP, and particularly when combined with clinical IVH, may represent a useful discriminator to differentiate NMOSD.
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http://dx.doi.org/10.1016/j.jneuroim.2016.01.004DOI Listing
February 2016

[An analysis of clinical and imaging characteristics of atopic myelitis].

Zhonghua Nei Ke Za Zhi 2015 Mar;54(3):205-9

Objective: To study the clinical and imaging characteristics of Chinese atopic myelitis (AM) patients.

Methods: Three diagnosed AM patients were retrospectively analyzed for the clinical data, serum IgE level, antigen specific IgE, cerebrospinal fluid, spinal MRI and therapeutic efficacy profiles.

Results: All the three patients were male and presented as subacute AM with the onset at 25, 47 and 49 years old respectively. Two patients were allergic to pollen and other drugs, while another patient suffered from allergic rhinitis. Elevated serum total IgE and mite antigen specific IgE were found in all cases. Paraesthesia in limb extremities and positive Lhermitte sign were the main clinical features, while no optic, motor, urinary and defecation disturbance were found. Oligoclonal banding of cerebrospinal fluid and serum aquaporin 4 (AQP4) antibody were both negative in all cases. Spinal MRI showed lesions were hypointense on T1 and hyperintense on T2 at the posterior column of T2-3 segment with abnormal enhancement in case 1, hypointense on T1 and hyperintense on T2 at C2/3 segment with mild swelling in case 2 and hypointense on T1 and hyperintense on T2 at C3-5 segments with swelling and abnormal enhancement in case 3. Vitamin B were used in one patient, while the other two patients improved after the treatment with high-dose corticosteroids.

Conclusions: Subacute myelitis predominantly presents as paraesthesia in limb extremities with elevated serum total IgE and mite antigen specific IgE, while severe motor disorders are rare. Swelling and abnormal enhancement lesions at the posterior column of cervical cord are the common imaging features. Treatment with corticosteroids is recommended to be sustained for 3-6 months.
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March 2015

Small Molecule Inhibition of MERTK Is Efficacious in Non-Small Cell Lung Cancer Models Independent of Driver Oncogene Status.

Mol Cancer Ther 2015 Sep 10;14(9):2014-22. Epub 2015 Jul 10.

Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplantation, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Treatment of non-small cell lung cancer (NSCLC) has been transformed by targeted therapies directed against molecular aberrations specifically activated within an individual patient's tumor. However, such therapies are currently only available against a small number of such aberrations, and new targets and therapeutics are needed. Our laboratory has previously identified the MERTK receptor tyrosine kinase (RTK) as a potential drug target in multiple cancer types, including NSCLC. We have recently developed UNC2025--the first-in-class small molecule inhibitor targeting MERTK with pharmacokinetic properties sufficient for clinical translation. Here, we utilize this compound to further validate the important emerging biologic functions of MERTK in lung cancer pathogenesis, to establish that MERTK can be effectively targeted by a clinically translatable agent, and to demonstrate that inhibition of MERTK is a valid treatment strategy in a wide variety of NSCLC lines independent of their driver oncogene status, including in lines with an EGFR mutation, a KRAS/NRAS mutation, an RTK fusion, or another or unknown driver oncogene. Biochemically, we report the selectivity of UNC2025 for MERTK, and its inhibition of oncogenic downstream signaling. Functionally, we demonstrate that UNC2025 induces apoptosis of MERTK-dependent NSCLC cell lines, while decreasing colony formation in vitro and tumor xenograft growth in vivo in murine models. These findings provide further evidence for the importance of MERTK in NSCLC, and demonstrate that MERTK inhibition by UNC2025 is a feasible, clinically relevant treatment strategy in a wide variety of NSCLC subtypes, which warrants further investigation in clinical trials.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704683PMC
September 2015

Central nervous system inflammatory demyelinating diseases with stroke-like onset and their responses to thrombolysis.

Neurol Sci 2015 Oct 24;36(10):1943-7. Epub 2015 Jun 24.

Department of Neurology, China-Japan Friendship Hospital, Beijing, China.

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http://dx.doi.org/10.1007/s10072-015-2293-zDOI Listing
October 2015

[Serum uric acid level and clinical relevance analysis in autoimmune myelopathy].

Zhonghua Yi Xue Za Zhi 2015 Mar;95(9):668-71

Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China; Email:

Objective: To quantify serum uric acid (UA) levels in autoimmune myelopathy (AMs) patients and analyze the clinical relevance.

Methods: Blood samples from hospitalized patients with AMs (n = 69) in acute phase and other neurological disorders (n = 50) between September 2009 and December 2013 and healthy subjects (n = 50) were used to detect UA level by enzymatic calorimetric method.Expanded disability status scale (EDSS) and spinal MRI-T2 imaging were used for clinical and imaging severity evaluations.And serum AQP4 anitbody and other antibodies were tested.

Results: Serum UA level in AMs patients ((223 ± 76) µmol/L) was lower than in controls ((325 ± 53) µmol/L and (324 ± 48) µmol/L, P < 0.001); for clinical relevance analysis, serum UA levels in females ((208 ± 64) µmol/L), age ≥ 40 years ((185 ± 64) µmol/L), EDSS score ≥ 4.5 ((179 ± 59) µmol/L), transverse lesion ((179 ± 56) µmol/L) and neuromyelitis optica/spectrum disorders ((199 ± 70) µmol/L) were lower than in males ((252 ± 88) µmol/L, P < 0.05), age < 40 years ((266 ± 66) µmol/L, P < 0.001), EDSS score < 4.5 ((257 ± 70) µmol/L, P < 0.001), non-transverse lesion ((274 ± 64) µmol/L, P < 0.001) and multiple sclerosis ((261 ± 69) µmol/L, P < 0.05). An inverse correlation existed between UA level and involved spinal segments (r = -0.665, P < 0.001); status of serum antibodies and associated diseases showed no significant differences.

Conclusion: Serum UA level is low and shows strong relevance with clinical and imaging severity in AMs patients. And UA is recommended as a biomarker of AMs.
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March 2015

Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia.

Oncotarget 2015 Mar;6(9):6722-36

University of Colorado, Department of Pediatrics, Aurora, CO, USA.

Mer and Flt3 receptor tyrosine kinases have been implicated as therapeutic targets in acute myeloid leukemia (AML). In this manuscript we describe UNC1666, a novel ATP-competitive small molecule tyrosine kinase inhibitor, which potently diminishes Mer and Flt3 phosphorylation in AML. Treatment with UNC1666 mediated biochemical and functional effects in AML cell lines expressing Mer or Flt3 internal tandem duplication (ITD), including decreased phosphorylation of Mer, Flt3 and downstream effectors Stat, Akt and Erk, induction of apoptosis in up to 98% of cells, and reduction of colony formation by greater than 90%, compared to treatment with vehicle. These effects were dose-dependent, with inhibition of downstream signaling and functional effects correlating with the degree of Mer or Flt3 kinase inhibition. Treatment of primary AML patient samples expressing Mer and/or Flt3-ITD with UNC1666 also inhibited Mer and Flt3 intracellular signaling, induced apoptosis, and inhibited colony formation. In summary, UNC1666 is a novel potent small molecule tyrosine kinase inhibitor that decreases oncogenic signaling and myeloblast survival, thereby validating dual Mer/Flt3 inhibition as an attractive treatment strategy for AML.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466645PMC
http://dx.doi.org/10.18632/oncotarget.3156DOI Listing
March 2015

[Longitudinally extensive spinal cord lesion: etiology and imaging features].

Zhonghua Yi Xue Za Zhi 2014 Nov;94(41):3229-33

Email:

Objective: To explore the etiologies and imaging features of longitudinally extensive spinal cord lesion (LESCL).

Methods: The etiologies and magnetic resonance (MR) imaging features of 51 hospitalized LESCL patients from January 2011 to August 2013 were reviewed and retrospectively analyzed.

Results: Among them, the causes were neuromyelitis optica spectrum disorder (NMOSD, n = 25), isolated longitudinally extensive transverse myelitis (n = 6), subacute combined degeneration (n = 4), multiple sclerosis (MS, n = 3), paraneoplastic myelopathy (n = 3), anterior spinal artery syndrome (n = 3), acute disseminated encephalomyelitis (n = 2), spinal dural arteriovenous fistula (n = 2), intramedullary spinal cord metastasis (n = 1), myelopathic leukemia (n = 1) and syringomyelus (n = 1). For MR imaging, at least one lesion of each patient presented continuously longitudinal profile and whole-length spinal cord was involved in 11 patients.

Conclusion: LESCL may be caused by various diseases. And the imaging features may aid its diagnosis despite a lack of specificity.
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November 2014

Superstable magnetic nanoreactors with high efficiency for Suzuki-coupling reactions.

Nanoscale 2014 Nov;6(21):12884-9

Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Magnetic nanoreactors based on Pd nanoparticles supported on magnetic carbon nanotubes that are coated by a mesoporous silica layer, (Fe3O4-CNT-Pd)@m-SiO2, have been selectively synthesized by facile steps. The prepared system exhibits high catalytic efficiency in Suzuki-coupling reactions because of the Pd nanoparticles supported on carbon nanotubes (CNT-Pd). Most importantly, induced magnetic properties make the separation of the catalyst easy from the reaction media, which can be re-used several times with significant activity. Moreover, the existence of a mesoporous silica layer makes the Pd catalyst very stable and does not allow the Pd nanoparticles to get detached from the CNT supports. The above-mentioned observations make the obtained catalyst a great candidate for future applications.
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http://dx.doi.org/10.1039/c4nr04245jDOI Listing
November 2014

UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor.

J Med Chem 2014 Aug 6;57(16):7031-41. Epub 2014 Aug 6.

Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, ‡Department of Pharmacology, School of Medicine, and §Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.

We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.
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http://dx.doi.org/10.1021/jm500749dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148167PMC
August 2014

[Analysis of clinical features for 8 patients with autoimmune dementia].

Zhonghua Yi Xue Za Zhi 2014 Feb;94(5):359-63

Department of Neurology, China-Japan Friendship Hospital, Beijing 100029, China. Email:

Objective: To explore the clinical features and therapeutic profiles of autoimmune dementia.

Methods: Eight hospitalized patients with autoimmune dementia during March 2011 and May 2013 were recruited and retrospectively analyzed for clinical features, as well as therapeutic and prognosis profiles.

Results: There were 3 males and 5 females with a onset age range of 45-72 years. Their onsets varied from acute (n = 3), subacute (n = 1) to chronic (n = 4).Six of them had a fluctuating course. The diagnoses were multiple sclerosis (n = 3), paraneoplastic limbic encephalitis (n = 2) and Hashimoto's encephalopathy (n = 1), microscopic polyangiitis (n = 1) and unclassified autoimmune encephalopathy (n = 1). Progressive memory loss without delirium was the main symptom.In addition, 3 patients suffered epilepsy, 2 with intractable hyponatremia, 4 with positive serum autoimmune or paraneoplastic antibodies, 7 with inflammatory cerebrospinal fluid, 4 with abnormal electroencephalography (EEG) and 8 with various changes on brain magnetic resonance imaging (MRI). Two patients had concurrent Hashimoto's thyroiditis and another with small cell lung cancer. All patients improved after treatment with immunological and antineoplastic therapies.

Conclusion: Autoimmune dementia has complex causes with a rapidly progressive and fluctuating course. The coexisting conditions include epilepsy, hyponatremia, organ-specific autoimmunity, inflammatory spinal fluid with abnormal EEG and brain MRI findings.Immunotherapy is recommended.
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February 2014