Berberine targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia with IDH1 mutation / 中国天然药物

Metabolic reprogramming, a newly recognized trait of tumor biology, is an intensively studied prospect for oncology medicines. For numerous tumors and cancer cell subpopulations, oxidative phosphorylation (OXPHOS) is essential for their biosynthetic and bioenergetic functions. Cancer cells with mutations in isocitrate dehydrogenase 1 (IDH1) exhibit differentiation arrest, epigenetic and transcriptional reprogramming, and sensitivity to mitochondrial OXPHOS inhibitors. In this study, we report that berberine, which is widely used in China to treat intestinal infections, acted solely at the mitochondrial electron transport chain (ETC) complex I, and that its association with IDH1 mutant inhibitor (IDH1mi) AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro andin vivo. Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia (AML) patients using combinatory mitochondrial targeted medicines, particularly those who are resistant to or relapsing from IDH1mi.

Detección de la mutación de la enzima isocitrato deshidrogenasa en gliomas difusos grados II, III y IV / Detection of isocitrate dehydrogenase enzyme mutation in grades II, III and IV diffuse gliomas

Introducción. Los gliomas son las neoplasias malignas primarias más frecuentes del sistema nervioso central, asociadas con una mortalidad y morbilidad elevadas. Las mutaciones en los genes IDH1 e IDH2 de la enzima isocitrato deshidrogenasa (IDH) son clave en la tumorogénesis, y son consideradas un factor pronóstico importante en estas neoplasias. En este estudio se buscó determinar la presencia de mutaciones de los genes IDH1 e IDH2 en pacientes con diagnóstico de glioma difuso en diferentes grados, y su correlación con la sobrevida. Metodología. Se realizó un estudio descriptivo, prospectivo y retrospectivo. La población de estudio fueron pacientes entre los 18 y 45 años con diagnóstico de glioma difuso grado II, III y IV, atendidos en el Hospital San Vicente Fundación de Medellín, entre 2012 y 2017, en quienes se realizó un análisis de mutaciones en los genes IDH1 e IDH2 por secuenciación Sanger y tinción de inmunohistoquímica. Resultados. Se incluyeron 14 pacientes con edad promedio de 37 años, 57% de sexo masculino. Glioblastoma fue la neoplasia más frecuente, diagnosticada en el 42,9% de casos. Por inmunohistoquímica, 10 de los 14 (71,4%) pacientes presentaron mutación de la enzima IDH1, en tanto que 1 de los 11 (9%) pacientes en quienes se logró la secuenciación del gen IDH2, mostró mutación. En general, el 78,6% presentó mutaciones de la enzima IDH, con promedio de sobrevida de 48 meses. Conclusión. Estos hallazgos sugieren que los gliomas son un grupo heterogéneo de tumores, con gran variabilidad genética que impacta en su pronóstico y comportamiento

Introduction. Gliomas are the most common primary malignancies of the central nervous system, associated with high mortality and morbidity. Mutations in the isocitrate dehydrogenase (IDH) enzyme IDH1 and IDH2 genes, are key in tumorigenesis, and are considered an important prognostic factor in these neoplasms. This study aimed to determine the presence of IDH1 and IDH2 gene mutations in patients diagnosed with diffuse glioma in different degrees, and their correlation with survival. Methodology. A descriptive, prospective and retrospective study was conducted. The study population consisted of patients between the ages of 18 and 45 with a diagnosis of grade II, III and IV diffuse glioma, treated at the Hospital San Vicente Fundación in Medellín, between 2012 and 2017, in whom an analysis of IDH1 and IDH2 gene mutations was performed by Sanger sequencing and immunohistochemical staining. Results. Fourteen patients with a mean age of 37 years were included, 57% were male. Glioblastoma was the most frequent neoplasm, diagnosed in 42.9% of the cases. By immunohistochemistry, 10 of the 14 (71.4%) patients had a mutation of the IDH1 enzyme, while 1 of the 11 (9%) patients in whom IDH2 gene sequencing was achieved showed a mutation. In general, 78.6% had IDH enzyme mutations, with an average survival of 48 months. Conclusion. These findings suggest that gliomas are a heterogeneous group of tumors, withgreat genetic variability that impacts their prognosis and behavior

Evaluation of the melting temperature of TaqMan probes as a genotyping method for IDH1, IDH2, and H3F3A in pediatric astrocytomas / Evaluación del método de temperatura de disociación de sondas TaqMan para la genotipificación de IDH1, IDH2 y H3F3A en astrocitomas pediátricos

Abstract Background: Astrocytomas are cancer tumors of the central nervous system and represent the most common type of solid tumors during human childhood. In 2016, the World Health Organization established a molecular classification system to regroup tumor entities to achieve a more accurate diagnosis and a better clinical decision-making and selection of treatment in patients with these types of tumors. Methods: We evaluated a genotyping assay for rapid and cost-effective mutation detection in astrocytomas using TaqMan probes in an asymmetric polymerase chain reaction (PCR) assay. Results: Four diffuse astrocytomas (Grade II), three anaplastic astrocytomas (Grade III), and four glioblastomas (Grade IV) were sequenced, and all of them displayed the wild-type (WT) sequence. We tried to set up this melting analysis for the genotyping of pediatric astrocytomas by identifying the specific melting temperatures of the TaqMan probes due to the presence of the WT sequences in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and H3.3 histone A genes (H3F3A). We used an IDH1-TaqMan probe to identify the WT status of IDH1 in two different WT deoxyribonucleic acid (DNA) templates (pilocytic and diffuse astrocytoma) and obtained four melting temperature values ranged from 65.6 to 92.2°C. Furthermore, only four out of 29 reactions displayed amplification of the DNA template. Sanger sequencing was faster and more reliable to detect the gene status in all the sequenced samples. Conclusions: We conclude that conventional Sanger sequencing remains the gold standard for the genotyping of pediatric astrocytomas.

Resumen Introducción: Los astrocitomas son un tipo de cáncer que afecta al sistema nervioso central y representan el tumor sólido más común durante la infancia. En el año 2016, la Organización Mundial de la Salud estableció un sistema de clasificación molecular para reagrupar tumores con identidades genéticas similares y lograr un diagnóstico más preciso, lo que lleva a tomar las decisiones clínicas idóneas al elegir el tratamiento de pacientes con este tipo de tumores. Métodos: Se evaluó un protocolo que involucra el uso de sondas TaqMan en un ensayo de reacción en cadena de la polimerasa asimétrica para la detección de mutaciones en astrocitomas. Se secuenciaron cuatro astrocitomas difusos (Grado II), tres astrocitomas anaplásicos (Grado III) y cuatro glioblastomas (Grado IV). Se intentó establecer las condiciones del análisis para la genotipificación de los astrocitomas pediátricos mediante la identificación de las temperaturas de disociación específicas de las sondas TaqMan producidas por la prescencia de las secuancias WT en los genes isocitrato deshidrogenasa 1 y 2 (IDH1, IDH2) y H3.3 histona A (H3F3A). Resultados: Los astrocitomas mostraron la secuencia wild type (WT) (silvestre) de los genes. Se utilizó una sonda TaqMan IDH1 para identificar el estado de este gen en dos templados WT de DNA (astrocitoma pilocítico y difuso) y se obtuvieron cuatro valores de temperatura de disociación (65.6-92.2 °C). Solo cuatro de las 29 reacciones mostraron amplificación de DNA. La secuenciación de Sanger fue más rápida y confiable para detectar el estado de los genes en todas las muestras. Conclusiones: La secuenciación de Sanger sigue siendo la técnica más práctica para la genotipificación de astrocitomas pediátricos.

Value of Serum Tumor Marker Isocitrate Dehydrogenase 1 in the Diagnosis of Lung Cancer / 中国医学科学院学报

To investigate the clinical value of serum tumor marker isocitrate dehydrogenase 1(IDH1)in the diagnosis of lung cancer. The general data were collected in lung cancer patients and non-lung cancer patients.The serum level of IDH1 was detected by enzyme-linked immunosorbent assay to evaluate its clinical significance in diagnosing lung cancer. The serum IDH1 level was significantly higher in lung cancer patients than in non-lung cancer patients [(7.12±6.98)ng/ml (2.09±1.83)ng/ml,=11.540,<0.001].The serum IDH1 level in patients with adenocarcinoma or squamous cell carcinoma was significantly higher than that in patients with small cell lung cancer [(7.91±7.26)ng/ml (2.76±2.27)ng/ml, =6.345,<0.001].The sensitivity of IDH1 in detecting lung cancer,stage Ⅰ/Ⅱ lung cancer,and stage Ⅲ/Ⅳ lung cancer was 47.4%,49.1%,and 46.3%,respectively. Serum IDH1 has high sensitivities and specificities in the diagnosis and differential diagnosis of non-small cell lung cancer(squamous cell carcinoma and adenocarcinoma)and small cell lung cancer as well as the auxiliary diagnosis of stage Ⅰ and Ⅱ lung cancer.It is a valuable marker for the auxiliary diagnosis of lung cancer.

Reclassification of Mongolian Diffuse Gliomas According to the Revised 2016 World Health Organization Central Nervous System Tumor Classification

BACKGROUND: The 2016 World Health Organization (WHO) classification of central nervous system (CNS) tumors has been modified to incorporate the IDH mutation and 1p/19q co-deletion in the diagnosis of diffuse gliomas. In this study, we aimed to evaluate the feasibility and prognostic significance of the revised 2016 WHO classification of CNS tumors in Mongolian patients with diffuse gliomas. METHODS: A total of 124 cases of diffuse gliomas were collected, and tissue microarray blocks were made. IDH1 mutation was tested using immunohistochemistry, and 1p/19q co-deletion status was examined using fluorescence in situ hybridization analysis. RESULTS: According to the 2016 WHO classification, 124 cases of diffuse brain glioma were reclassified as follows: 10 oligodendroglioma, IDHmut and 1p/19q co-deleted; three anaplastic oligodendroglioma, IDHmut and 1p/19q co-deleted; 35 diffuse astrocytoma, IDHmut, 11 diffuse astrocytoma, IDHwt, not otherwise specified (NOS); 22 anaplastic astrocytoma, IDHmut, eight anaplastic astrocytoma, IDHwt, NOS; and 35 glioblastoma, IDHwt, NOS, respectively. The 2016 WHO classification presented better prognostic value for overall survival in patients with grade II tumors than traditional histological classification. Among patients with grade II tumors, those with oligodendroglioma IDHmut and 1p/19q co-deleted and diffuse astrocytoma IDHmut showed significantly higher survival than those with diffuse astrocytoma IDHwt, NOS (p<.01). CONCLUSIONS: Mongolian diffuse gliomas could be reclassified according to the new 2016 WHO classification. Reclassification revealed substantial changes in diagnosis of both oligodendroglial and astrocytic entities. We have confirmed that the revised 2016 WHO CNS tumor classification has prognostic significance in Mongolian patients with diffuse gliomas, especially those with grade II tumors.

Effects of IDH2 Gene Mutation on Clinical Characteristics and Prognostic of Patients with Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To analyze the prevalence, clinical characteristics and prognostic significance of the isocitrate dehydrogenase 2(IDH2) mutations in patients with acute myeloid leukemia(AML).@*METHODS@#The bone marrow samples of 223 patients with newly diagnosed AML confirmed by MICM typing from January 2015 to October 2018 were collected. The mutation of exon 4 of IDH2 gene was detected by direct sequancing of PCR product; the incidence and types of IDH2 gene mutation in AML patients were analyzed; the clinical characteristics of AML patients with IDH2 gene mutation were analyzed and the therapeutic efficacy for these patients was evaluated.@*RESULTS@#In a cohort of 223 AML patients, mutations were detected in 23(10.31％) patients, among them, 15 with R140Q mutations(65.22%) , 6 with R172K mutations(26.09%) and 2 with R140W mutations(8.70%). The median age in IDH2 mutated group was older than that in non.mutated group(P=0.008). The platelet level at initial diagnosis in IDH2 mutated group was higher than that in non.mutated group(P=0.010). There was no significant statistical difference between IDH2 mutated group and non.mutated group in FAB subtypes of AML(P>0.05). But the rate of IDH2 mutation in M4 and M5 was higher. The rate of IDH2 mutations was higher in AML with normal karyotype and in AML with NPM1 mutations. R140Q mutations associated with NPM1 mutations(χ=8.481，P=0.004), but R172K mutations not associated with NPM1 mutation(P>0.05). IDH2 mutated patients had a lower complete remission rate than non.mutated patients(57.14% vs 80.46%, χ=5.927，P=0.015). The complete remission rate of R140Q mutated patients was not significantly statistically different from non.mutated patients. The complete remission rate of R172K mutated patients was very significantly lower than non.mutated patients(χ=7.734，P=0.005). In the patients without NPM1 mutation, the 2 years overall survival in IDH2 mutated group was lower than in non.mutated group(36.36% vs 66.40%,χ=3.958，P=0.047), the 2 years overall survival of R172K mutated group was significantly lower than non.mutated group(although P>0.05). In all patients, the 2 years overall survival between IDH2 mutated group and non.mutated group was not statistically different(50% vs 66.88%,P>0.05), the 2 years overall survival of R172K mutated group was significantly lower than non.mutated group(although P>0.05). In the patients with normal karyotype or with mutated NPM1, the 2 years overall survival between IDH2 mutated group and non.mutated group was not statistically different(P>0.05).@*CONCLUSION@#IDH2 gene mutations are more common in AML patients at older age, higher platelets level and normal karyotype. The rate of IDH2 mutation in M4 and M5 is higher. IDH2 gene mutations associate with NPMl gene mutations, but R172K mutations not associates with NPM1mutation. IDH2 gene mutations associate with prognosis of AML patients, R140Q mutations have no effect on prognosis of patients, but R172K mutations may be the molecular markers for poor prognosis in AML patients.

Research Advances on Combination Strategies of Demethylating Agents for Elderly Acute Myeloid Leukemia--Review / 中国实验血液学杂志

Abstract　　 Demethylating agents (HMAs) hold an important status in therapy for elderly acute myeloid leukemia, who are not eligible for intensive chemotherapy (ICT). Beyond the edge of monotherapy, domestic and foreign scholars have carried out a lot of studies on combination strategies, such as HMAs with low-intensity therapy (G-CSF, low-dose cytarabine and aclarubicin, CAG), with targeted therapy (BCL-2 inhibitor), with immunotherapy (immune checkpoint inhibitors, ICI), and with other epigenetic therapys (isocitrate dehydrogenase or histonedeacetylase inhibitor）. Some of these researches have obtained positive results and discussed the mechanisms of combination strategies besides. In this review, the combination of HMAs with other drugs are summraized briefly.

Coexisting Mutations in IDH1/2-Mutated Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To explore the coexisting mutations in IDH-mutated acute myeloid leukemia(AML) and its relation with partial clinical parametrs.@*METHODS@#The exon 4 mutation of IDH1/2 gene was screened by using genome DNA-PCR combined with sanger sequencing, 51 targeted gene mutations in the patients with IDH1/2 mutation were detected by using high throughput DNA sequencing combined with sanger sequencing.@*RESULTS@#Among 358 patients, the IDH1/2 mutation was found in 46 cases including IDH1 mutation in 35 cases and IDH2 mutation in 11 cases, 97.87%(45/46) patients with IDH1/2 mutation simultaneously carried other gene mutations including 8(17.8%) cases with mutation of double gene, 17(37.8%) cases with mutation of 3 genes and 20(44.4%) cases with mutation of ≥ 4 genes. The mutation frequency of each patient averaged 3.52 times. In mutation of accompanied genes, the common genes were NPM1(n=29, 63.0%), next DNMT3A(n=25, 54.3%), FLT3-ITD(n=7, 15.2%), TET2(n=5, 10.9%) and NRAS(n=5, 10.9%). The average WBC level of patients with NPM1 mutation in IDH1 mutation group was higher than that of patients in wild type group(P<0.05). The complete remission (CR) rate of patients with DNMT3A mutation was significant lower than that of patients with wild type (30% vs 80%, P<0.01). The presence of ≥ 4 mutations was found to be significantly associated with higher white blood level than that in the patients with double mutations(P<0.05).@*CONCLUSION@#More than 95% AML patients with IDH1/2 mutation commonly show additional mutations. The number and the type of IDH coexisting mutations have certain effect on the clinical features and CR rate.

Identification of proteins differentially expressed by glutamate treatment in cerebral cortex of neonatal rats / 한국실험동물학회지

Glutamate leads to neuronal cell damage by generating neurotoxicity during brain development. The objective of this study is to identify proteins that differently expressed by glutamate treatment in neonatal cerebral cortex. Sprague-Dawley rat pups (post-natal day 7) were intraperitoneally injected with vehicle or glutamate (10 mg/kg). Brain tissues were isolated 4 h after drug treatment and fixed for morphological study. Moreover, cerebral cortices were collected for protein study. Two-dimensional gel electrophoresis and mass spectrometry were carried out to identify specific proteins. We observed severe histopathological changes in glutamate-exposed cerebral cortex. We identified various proteins that differentially expressed by glutamate exposure. Identified proteins were thioredoxin, peroxiredoxin 5, ubiquitin carboxy-terminal hydrolase L1, proteasome subunit alpha proteins, isocitrate dehydrogenase, and heat shock protein 60. Heat shock protein 60 was increased in glutamate exposed condition. However, other proteins were decreased in glutamate-treated animals. These proteins are related to anti-oxidant, protein degradation, metabolism, signal transduction, and anti-apoptotic function. Thus, our findings can suggest that glutamate leads to neonatal cerebral cortex damage by regulation of specific proteins that mediated with various functions.

The Korean Society for Neuro-Oncology (KSNO) Guideline for WHO Grade III Cerebral Gliomas in Adults: Version 2019.01

BACKGROUND: There was no practical guideline for the management of patients with central nervous system tumor in Korea in the past. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, developed the guideline for glioblastoma successfully and published it in Brain Tumor Research and Treatment, the official journal of KSNO, in April 2019. Recently, the KSNO guideline for World Health Organization (WHO) grade III cerebral glioma in adults has been established. METHODS: The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified by searches in PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL databases using specific and sensitive keywords as well as combinations of keywords. Scope of the disease was confined to cerebral anaplastic astrocytoma and oligodendroglioma in adults. RESULTS: Whenever radiological feature suggests high grade glioma, maximal safe resection if feasible is globally recommended. After molecular and histological examinations, patients with anaplastic astrocytoma, isocitrate dehydrogenase (IDH)-mutant should be primary treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy whereas those with anaplastic astrocytoma, NOS, and anaplastic astrocytoma, IDH-wildtype should be treated following the protocol for glioblastomas. In terms of anaplastic oligodendroglioma, IDH-mutant and 1p19q-codeletion, and anaplastic oligodendroglioma, NOS should be primary treated by standard brain radiotherapy and neoadjuvant or adjuvant PCV (procarbazine, lomustine, and vincristine) combination chemotherapy. CONCLUSION: The KSNO's guideline recommends that WHO grade III cerebral glioma of adults should be treated by maximal safe resection if feasible, followed by radiotherapy and/or chemotherapy according to molecular and histological features of tumors.

The Korean Society for Neuro-Oncology (KSNO) Guideline for WHO Grade II Cerebral Gliomas in Adults: Version 2019.01

BACKGROUND: There was no practical guideline for the management of patients with central nervous system tumor in Korea for many years. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, has developed the guideline for glioblastoma. Subsequently, the KSNO guideline for World Health Organization (WHO) grade II cerebral glioma in adults is established. METHODS: The Working Group was composed of 35 multidisciplinary medical experts in Korea. References were identified by searching PubMed, MEDLINE, EMBASE, and Cochrane CENTRAL databases using specific and sensitive keywords as well as combinations of keywords regarding diffuse astrocytoma and oligodendroglioma of brain in adults. RESULTS: Whenever radiological feature suggests lower grade glioma, the maximal safe resection if feasible is recommended globally. After molecular and histological examinations, patients with diffuse astrocytoma, isocitrate dehydrogenase (IDH)-wildtype without molecular feature of glioblastoma should be primarily treated by standard brain radiotherapy and adjuvant temozolomide chemotherapy (Level III) while those with molecular feature of glioblastoma should be treated following the protocol for glioblastomas. In terms of patients with diffuse astrocytoma, IDH-mutant and oligodendroglioma (IDH-mutant and 1p19q codeletion), standard brain radiotherapy and adjuvant PCV (procarbazine+lomustine+vincristine) combination chemotherapy should be considered primarily for the high-risk group while observation with regular follow up should be considered for the low-risk group. CONCLUSION: The KSNO's guideline recommends that WHO grade II gliomas should be treated by maximal safe resection, if feasible, followed by radiotherapy and/or chemotherapy according to molecular and histological features of tumors and clinical characteristics of patients.

Estudio de mutaciones en los genes IDH1 e IDH2 en una muestra de gliomas de población colombiana / Study of mutations in IDH1 and IDH2 genes in a sample of gliomas from Colombian population

Resumen Introducción. Los gliomas son los tumores primarios más comunes del sistema nervioso central y se clasifican de I a IV según su grado de malignidad. En recientes investigaciones se ha encontrado que su aparición está relacionada con mutaciones en el exón 4 de los genes que codifican las deshidrogenasas de isocitrato 1 y 2 (IDH1: codón 132; IDH2: codón 172). Objetivo. Determinar la frecuencia de mutaciones en los genes IDH1 e IDH2 en una muestra de gliomas de pacientes colombianos. Materiales y métodos. La extracción de ADN se hizo a partir de tejido tumoral. El exón 4 de los genes IDH1 e IDH2 se amplificó mediante PCR utilizando iniciadores específicos y, posteriormente, se secuenciaron. Para la determinación de las mutaciones, se emplearon los programas 4Peaksy MAFFT. Resultados. Se determinó la presencia de mutaciones en el gen IDH1 en el 34 % de las muestras, con predominio de la mutación no sinónima R132H. En el 7,5 % de los casos se detectaron mutaciones en el gen IDH2, principalmente las mutaciones no sinónimas R172K y R172W. Conclusiones. La frecuencia de mutaciones en los genes IDH1 e IDH2 en la muestra fue similar a la reportada en otros estudios. El análisis de estas mutaciones puede ser importante como factor pronóstico y para su uso como potenciales blancos terapéuticos en gliomas.

Abstract Introduction: Gliomas are the most common primary tumors of the central nervous system and, according to their malignancy, they are graded from I to IV. Recent studies have found that there is an association between gliomas and mutations in exon 4 of genes that codify for isocitrate dehydrogenases 1 and 2 (IDH1: codon 132; IDH2: codon 172). Objective: To establish the frequency of mutations in IDH1 and IDH2 in a sample of gliomas from Colombian population. Materials and methods: DNA was extracted from tumor tissue. The exon 4 of IDH1 and IDH2 was amplified by PCR using specific primers and subsequently sequenced. Mutations were determined using the 4Peaks MAFFT programs. Results: We found mutations in the IDH1 gene in 34% of the glioma samples, with a predominance of the nonsynonymous mutation R132H. Mutations in the IDH2 gene were found in 7.5% of cases, with a predominance of the nonsynonymous R172K and R172W mutations. Conclusions: The frequency of mutations in the IDH1 and IDH2 genes in the sample was similar to that reported in other studies. The analysis of these mutations may be important to establish prognostic factors and for the development of future therapeutic targets in gliomas.

Global gene expression analysis in liver of db/db mice treated with catalpol / 中国天然药物

Catalpol, a major bioactive component from Rehmannia glutinosa, which has been used to treat diabetes. The present study was designed to elucidate the anti-diabetic effect and mechanism of action for catalpol in db/db mice. The db/db mice were randomly divided into six groups (10/group) according to their blood glucose levels: db/db control, metformin (positive control), and four dose levels of catalpol treatment (25, 50, 100, and 200 mg·kg), and 10 db/m mice were used as the normal control. All the groups were administered orally for 8 weeks. The levels of fasting blood glucose (FBG), random blood glucose (RBG), glucose tolerance, insulin tolerance, and glycated serum protein (GSP) and the globe gene expression in liver tissues were analyzed. Our results showed that catalpol treatment obviously reduced water intake and food intake in a dose-dependent manner. Catalpol treatment also remarkably reduce fasting blood glucose (FBG) and random blood glucose (RBG) in a dose-dependent manner. The RBG-lowering effect of catalpol was better than that of metformin. Furthermore, catalpol significantly improved glucose tolerance and insulin tolerance via increasing insulin sensitivity. Catalpol treatment significantly decreased GSP level. The comparisons of gene expression in liver tissues among normal control mice, db/db mice and catalpol treated mice (200 and 100 mg·kg) indicated that there were significant increases in the expressions of 287 genes, whichwere mainly involved in lipid metabolism, response to stress, energy metabolism, and cellular processes, and significant decreases in the expressions of 520 genes, which were mainly involved in cell growth, death, immune system, and response to stress. Four genes expressed differentially were linked to glucose metabolism or insulin signaling pathways, including Irs1 (insulin receptor substrate 1), Idh2 (isocitrate dehydrogenase 2 (NADP), mitochondrial), G6pd2 (glucose-6-phosphate dehydrogenase 2), and SOCS3 (suppressor of cytokine signaling 3). In conclusion, catalpol ecerted significant hypoglycemic effect and remarkable therapeutic effect in db/db mice via modulating various gene expressions.

Global gene expression analysis in liver of db/db mice treated with catalpol / 中国天然药物

Catalpol, a major bioactive component from Rehmannia glutinosa, which has been used to treat diabetes. The present study was designed to elucidate the anti-diabetic effect and mechanism of action for catalpol in db/db mice. The db/db mice were randomly divided into six groups (10/group) according to their blood glucose levels: db/db control, metformin (positive control), and four dose levels of catalpol treatment (25, 50, 100, and 200 mg·kg), and 10 db/m mice were used as the normal control. All the groups were administered orally for 8 weeks. The levels of fasting blood glucose (FBG), random blood glucose (RBG), glucose tolerance, insulin tolerance, and glycated serum protein (GSP) and the globe gene expression in liver tissues were analyzed. Our results showed that catalpol treatment obviously reduced water intake and food intake in a dose-dependent manner. Catalpol treatment also remarkably reduce fasting blood glucose (FBG) and random blood glucose (RBG) in a dose-dependent manner. The RBG-lowering effect of catalpol was better than that of metformin. Furthermore, catalpol significantly improved glucose tolerance and insulin tolerance via increasing insulin sensitivity. Catalpol treatment significantly decreased GSP level. The comparisons of gene expression in liver tissues among normal control mice, db/db mice and catalpol treated mice (200 and 100 mg·kg) indicated that there were significant increases in the expressions of 287 genes, whichwere mainly involved in lipid metabolism, response to stress, energy metabolism, and cellular processes, and significant decreases in the expressions of 520 genes, which were mainly involved in cell growth, death, immune system, and response to stress. Four genes expressed differentially were linked to glucose metabolism or insulin signaling pathways, including Irs1 (insulin receptor substrate 1), Idh2 (isocitrate dehydrogenase 2 (NADP), mitochondrial), G6pd2 (glucose-6-phosphate dehydrogenase 2), and SOCS3 (suppressor of cytokine signaling 3). In conclusion, catalpol ecerted significant hypoglycemic effect and remarkable therapeutic effect in db/db mice via modulating various gene expressions.

Research Advances of IDH2 Gene Mutation in Acute Myeloid Leukemia / 中国实验血液学杂志

Acute myeloid leukemia (AML) is a malignant clonal hematologic disease from hematopoietic stem and progenitor cells. The isocitrate dehychogenase 2 (IDH2) gene mutation has been recently found, which may be associated with the course of AML. The incidence of IDH2 gene mutation in the patients with acute myeloid leukemia is high, especially in the AML patients with normal karyotype. Different subtypes of IDH2 mutation, or companing other molecular biology, will make different influence on clinical features and progress of patients with AML. IDH2 mutation is stable, which can be used as the test sign of AML and minimal residual disease (MRD), and for guiding the clinical treatment and predicting the progress. In this article, the research progress of IDH2 mutation in acute myeloid leukemia is reviewed.

Evolving Molecular Genetics of Glioblastoma / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>To summary the recent advances in molecular research of glioblastoma (GBM) and current trends in personalized therapy of this disease.</p><p><b>DATA SOURCES</b>Data cited in this review were obtained mainly from PubMed in English up to 2015, with keywords "molecular", "genetics", "GBM", "isocitrate dehydrogenase", "telomerase reverse transcriptase", "epidermal growth factor receptor", "PTPRZ1-MET", and "clinical treatment".</p><p><b>STUDY SELECTION</b>Articles regarding the morphological pathology of GBM, the epidemiology of GBM, genetic alteration of GBM, and the development of treatment for GBM patients were identified, retrieved, and reviewed.</p><p><b>RESULTS</b>There is a large amount of data supporting the view that these recurrent genetic aberrations occur in a specific context of cellular origin, co-oncogenic hits and are present in distinct patient populations. Primary and secondary GBMs are distinct disease entities that affect different age groups of patients and develop through distinct genetic aberrations. These differences are important, especially because they may affect sensitivity to radio- and chemo-therapy and should thus be considered in the identification of targets for novel therapeutic approaches.</p><p><b>CONCLUSION</b>This review highlights the molecular and genetic alterations of GBM, indicating that they are of potential value in the diagnosis and treatment for patients with GBM.</p>

Malignant Glioma with Neuronal Marker Expression : A Clinicopathological Study of 18 Cases

OBJECTIVE: Malignant gliomas with neuronal marker expression (MGwNM) are rare and poorly characterized. Increasingly diverse types of MGwNM have been described and these reported cases underscore the dilemmas in the classification and diagnosis of those tumors. The aim of this study is to provide additional insights into MGwNM and present the clinicopathological features of 18 patients. METHODS: We reviewed the medical records of 18 patients diagnosed as MGwNM at our institute between January 2006 and December 2012. Macroscopic total resection was performed in 11 patients (61%). We evaluated the methylation status of O6-methylguanine-DNA methyltransferase (MGMT) and expression of isocitrate dehydrogenase 1 (IDH-1) in all cases, and deletions of 1p and 19q in available cases. RESULTS: The estimated median overall survival was 21.2 months. The median progression-free survival was 6.3 months. Six patients (33%) had MGMT methylation but IDH1 mutation was found in only one patient (6%). Gene analysis for 1p19q performed in nine patients revealed no deletion in six, 19q deletion only in two, and 1p deletion only in one. The extent of resection was significantly correlated with progression free survival on both univariate analysis and multivariate analysis (p=0.002 and p=0.013, respectively). CONCLUSION: In this study, the overall survival of MGwNM was not superior to glioblastoma. The extent of resection has a significant prognostic impact on progression-free survival. Further studies of the prognostic factors related to chemo-radio therapy, similar to studies with glioblastoma, are mandatory to improve survival.

Immunohistochemical Analysis of ATRX, IDH1 and p53 in Glioblastoma and Their Correlations with Patient Survival

Glioblastoma (GBM) can be classified into molecular subgroups, on the basis of biomarker expression. Here, we classified our cohort of 163 adult GBMs into molecular subgroups according to the expression of proteins encoded by genes of alpha thalassemia/mental retardation syndrome X-linked (ATRX), isocitrate dehydrogenase (IDH) and TP53. We focused on the survival rate of molecular subgroups, depending on each and various combination of these biomarkers. ATRX, IDH1 and p53 protein expression were evaluated immunohistochemically and Kaplan-Meier analysis were carried out in each group. A total of 15.3% of enrolled GBMs demonstrated loss of ATRX expression (ATRX-), 10.4% expressed an aberrant IDH1 R132H protein (IDH1+), and 48.4% exhibited p53 overexpression (p53+). Survival differences were statistically significant when single protein expression or different combinations of expression of these proteins were analyzed. In conclusion, in the case of single protein expression, the patients with each IDH1+, or ATRX-, or p53- GBMs showed better survival than patients with counterparts protein expressed GBMs. In the case of double protein pairs, the patients with ATRX-/p53-, ATRX-/IDH1+, and IDH1+/p53- GBMs revealed better survival than the patients with GBMs with the remained pairs. In the case of triple protein combinations, the patients with ATRX-/p53-/IDH+ showed statistically significant survival gain than the patients with remained combination of proteins-expression status. Therefore, these three biomarkers, individually and as a combination, can stratify GBMs into prognostically relevant subgroups and have strong prognostic values in adult GBMs.

In-Vivo Proton Magnetic Resonance Spectroscopy of 2-Hydroxyglutarate in Isocitrate Dehydrogenase-Mutated Gliomas: A Technical Review for Neuroradiologists

The diagnostic and prognostic potential of an onco-metabolite, 2-hydroxyglutarate (2HG) as a proton magnetic resonance spectroscopy (1H-MRS) detectable biomarker of the isocitrate dehydrogenase (IDH)-mutated (IDH-MT) gliomas has drawn attention of neuroradiologists recently. However, due to severe spectral overlap with background signals, quantification of 2HG can be very challenging. In this technical review for neuroradiologists, first, the biochemistry of 2HG and its significance in the diagnosis of IDH-MT gliomas are summarized. Secondly, various 1H-MRS methods used in the previous studies are outlined. Finally, wereview previous in vivo studies, and discuss the current status of 1H-MRS in the diagnosis of IDH-MT gliomas.

EGFR, p53, IDH-1 and MDM2 immunohistochemical analysis in glioblastoma: therapeutic and prognostic correlation / Análise imunoistoquímica para EGFR, p53, IDH-1 e MDM2 em glioblastoma: correlação terapêutica e prognóstica

We studied 36 glioblastoma cases at HC-UNICAMP from 2008 to 2012 and classified the immunohistochemical distribution of the wild-type epidermal growth factor receptor (EGFR), mutated forms of p53 protein and isocitrate dehydrogenase-1 (IDH-1) and murine double protein 2 (MDM2). Immunostaining findings were correlated with clinical data and response to treatment (surgery, chemotherapy and radiotherapy). About 97% of the tumors were primary, most of them localized in the frontal lobe. Mean time free of clinical or symptomatic disease and free time of radiological disease were 7.56 and 7.14 months, respectively. We observed a significant positive correlation between expressions of p53 and MDM2, EGFR and MDM2. Clinical, radiological and overall survivals also showed a significant positive correlation. p53 staining and clinical survival showed a significant negative correlation. The current series provides clinical and histopathological data that contribute to knowledge on glioblastoma in Brazilians.

Estudamos 36 casos de glioblastoma acompanhados no HC-UNICAMP de 2008 a 2012 e classificamos a marcação imunoistoquímica da forma selvagem do receptor do fator de crescimento epidérmico (EGFR), formas mutantes da proteína p53 e isocitrato desidrogenase-1 (IDH-1) e proteína murina dupla 2 (MDM2). Os resultados de imunoistoquímica foram correlacionados com dados clínicos e resposta ao tratamento (cirurgia, quimioterapia e radioterapia). Cerca de 97% dos tumores foram primários, grande parte localizada no lobo frontal. O tempo médio livre de doença clínica ou sintomática e o tempo livre de doença radiológica foram de 7.56 e 7.14 meses, respectivamente. Observou-se correlação positiva entre a expressão das proteínas p53 e MDM2, EGFR e MDM2. Sobrevivências clínica, radiológica e global também mostraram correlação positiva e significativa. A expressão para p53 e sobrevivência clínica mostrou correlação negativa. O estudo fornece dados clínicos e histopatológicos que contribuem para o conhecimento sobre glioblastoma em brasileiros.