BBA Clinical

CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following alkylating agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies.We examined the relationship of MGMT activity in 91 GBMs and 84 AGs with progression-free survival (PFS) following alkylator therapy and with promoter methylation status determined by methylation-specific PCR (MSP).Cox regression analysis revealed that GBMs with high activity had a significantly greater risk for progression in dichotomous (P ≤ 0.001) and continuous (P ≤ 0.003) models, an association observed for different alkylator regimens, including concurrent chemo-radiation with temozolomide. Analysis of MGMT promoter methylation status in 47 of the GBMs revealed that methylated tumors had significantly lower activity (P ≤ 0.005) and longer PFS (P ≤ 0.036) compared to unmethylated tumors, despite overlapping activities. PFS was also significantly greater in methylated vs. unmethylated GBMs with comparable activity (P ≤ 0.005), and among unmethylated tumors with less than median activity (P ≤ 0.026), suggesting that mechanisms in addition to MGMT promote alkylator resistance. Similar associations of MGMT activity with PFS and promoter methylation status were observed for AGs.Our results provide strong support for the hypotheses that MGMT activity promotes alkylator resistance and reflects promoter methylation status in malignant gliomas.MGMT activity is an attractive target for anti-resistance therapy regardless of methylation status.

Michael S Bobola

Mohammad Alnoor

John Y-S Chen

Douglas D Kolstoe

Daniel L Silbergeld

Robert C Rostomily

A Blank

Marc C Chamberlain

John R Silber

O6-methylguanine-DNA methyltransferase activity is associated with response to alkylating agent therapy and with MGMT promoter methylation in glioblastoma and anaplastic glioma

O6-甲基鸟嘌呤-DNA甲基转移酶活性与烷化剂治疗反应及胶质母细胞瘤和间变性胶质瘤中MGMT启动子甲基化相关

This work presents an evaluation of the impact of physical exercise of the upper limbs in patients with muscular atrophy in the lower limbs by analysis of specific biomarkers. It is a cross-sectional study. Patients were recruited using convenience sampling: control group (C: n = 12) and two groups of wheelchair users: non-athletes (NAth: n = 12) and athletes (Ath: n = 13, professional basketball players). Plasmatic biomarkers analyzed: fibrinogen, TBARS and NO. Comparisons were assessed by one-way ANOVA and Newman–Keuls Multiple Comparison post-hoc. Plasma fibrinogen values were not different between Ath (3.67 ± 0.44 g/L) and NAth (3.44 ± 0.38 g/L) groups. It was observed difference between fibrinogen levels from both wheelchair user groups (Ath and NAth) when comparing to control group (C: 2.27 ± 0.08 g/L) and standard values of fibrinogen (1.8 g/dL–3.1 g/dL). The TBARS values were not different between the wheelchair users Ath (3.21 ± 0.24 nmol/mL) and NAth (3.66 ± 0.27 nmol/mL). Independently of practicing physical activity, the TBARS values from both wheelchair users, Ath and Nath, were different when compared to the TBARS values from control group (C: 24.11 ± 1.75 nmol/mL). The plasma levels of NO were not different among the groups. Under SCI conditions, the upper body exercise practicing did not alter plasma levels of NO and ROS production neither rheological changes in viscosity indicated by blood clotting studies (fibrinogen levels).

Eduardo José R. Garbeloti

Raquel Caroline A. Paiva

Carolina Baraldi A. Restini

Marina T. Durand

Carlos Eduardo S. Miranda

Vinicius Eduardo Teixeira

Biochemical biomarkers are not dependent on physical exercise in patients with spinal cord injury

脊髓损伤患者的生化生物标志物不依赖于体力活动

Plain radiography is the first choice for diagnosis and monitoring of knee-osteoarthritis (OA) while, Kellgren–Lawrence score (KL) is most widely used to grade OA severity. However, incompetency for reproducibility of joint space measurement in longitudinal assessment and non-linearity of KL-score system, limits radiography-based early diagnosis of the disease. Glycosaminoglycan (GAG) is direct cartilage-degradation product, which can be measured biochemically. We strived to correlate KL-score and GAG from OA patients to compliment KL-system. We obtained 34 synovial-fluid (SF) samples from 28 OA patients (few bilateral) with different disease severity using arthrocetesis. All patients were categorised using radiographic KL-score-system. SFs were further analysed for GAG estimation using 1,2-dimethylmethylene blue (DMMB) assay. A substantial increase in GAG was noted in KL-grade-II and III, comparing grade-I patients, indicating amplified cartilage-degradation. KL-grade-IV patients revealed further rise in GAG reflecting more cartilage-loss. Another category of grade-IV patients with lower GAG were also detected, indicating close to total cartilage-loss. Accurate diagnosis of cartilage-loss remains a challenge with OA due to limitations of KL-system; thus no target intervention is available to arrest active cartilage-loss. We propose, GAG-estimation in OA patients, characterizes accurate biochemical depiction of cartilage degeneration. General Significance: Radiology often fails to reveal an accurate cartilage loss, associated with OA. GAG levels from the SFs of OA patients' serve as a useful marker, which parallels cartilage degeneration and strengthen radiographic grading system, ultimately

Priya Kulkarni

Shantanu Deshpande

Soumya Koppikar

Sanjay Patil

Dhanashri Ingale

Abhay Harsulkar

Glycosaminoglycan measured from synovial fluid serves as a useful indicator for progression of Osteoarthritis and complements Kellgren–Lawrence Score

从关节液中测量的糖胺聚糖可作为骨关节炎进展的有用指标，并补充了Kellgren-Lawrence评分

Preeclampsia (preE) has a significant link to alterations of placental function leading to stress and apoptotic signaling, which pass the placental barrier and leave persistent defect in the circulation of the offspring. We assessed apoptotic signaling in placentas and umbilical cords from patients with and without preE. We collected placental and cord tissues from 27 normal pregnant (NP) women and 20 preE consenting patients after delivery in an IRB approved prospective study. p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation, pro-apoptotic Bcl-2-associated X (Bax), anti-apoptotic Bcl-2, caspase-9, and pro-inflammatory cyclooxygenase-2 (Cox-2) were evaluated by western blot and immunohistochemistry. Comparisons were performed using Student's t-test. p38 phosphorylation (Placenta: 1.5 fold, Cord: 1.7 fold), ratio of Bax/Bcl-2 (Placenta: 1.7 fold, Cord: 2.2 fold), caspase-9 (Placenta: 1.5 fold, Cord: 1.8 fold) and Cox-2 (Placenta: 2.5 fold, Cord: 2.3 fold) were up-regulated (p < 0.05) in preE compared to NP patients. Average hospital stays for preE babies were longer than NP babies. No complications were reported for NP babies; however, all of preE babies had multiple complications. Apoptotic and stress signaling are augmented in preE placenta and cord tissue that alter the intrauterine environment and activates the detrimental signaling that is transported to fetus.

Syeda H. Afroze

Ram R. Kalagiri

Michelle Reyes

Jacqueline D. Zimmerman

Madhava R. Beeram

Nathan Drever

David C. Zawieja

Thomas J. Kuehl

Mohammad N. Uddin

Apoptotic and stress signaling markers are augmented in preeclamptic placenta and umbilical cord

子痫前期胎盘和脐带中凋亡及应激信号标志物增强

Multiple myeloma (MM) and its precursor, monoclonal gammopathy of undetermined significance (MGUS), have been linked with several autoimmune conditions in the medical literature. Yet, significance of these associations is not well understood. Herein, we provide a comprehensive literature review on autoimmune disorders identified in patients with MM and MGUS. Most relevant papers were identified via searching the PubMed/Medline and EMBASE databases for articles published from inception until May 1, 2016. Scientific literature on autoimmune conditions in patients with MM and MGUS consists of several case series and a multitude of case reports. Our analysis suggests an increased prevalence of autoimmune conditions in patients with MM and monoclonal gammopathy of undetermined significance (MGUS), including various autoimmune hematologic and rheumatologic conditions among other entities. Conversely, persons with various autoimmune conditions tend to have a higher prevalence of MGUS and MM than the general population. Future research is required to explore further the link between MGUS/MM and autoimmune disorders. Inflammation in the setting of autoimmunity may serve as a trigger for MGUS and MM. In addition, a common genetic susceptibility for developing both an autoimmune disease and MM/MGUS might also exist. Autoimmune hematologic and rheumatologic diseases may pose important clinical problems for the MM patients. Therefore, a catalogue of these problems is important so that physicians are able to consider, identify and address them promptly.

Alexei Shimanovsky

Argote J. Alvarez

Shruti Murali

Constantin A. Dasanu

Autoimmune manifestations in patients with multiple myeloma and monoclonal gammopathy of undetermined significance

多发性骨髓瘤和意义未明的单克隆丙种球蛋白病患者中的自身免疫表现

Clear cell Renal Cell Carcinomas (ccRCC), the largest group of renal tumours, are resistant to classical therapies. The determination of the functional state of actionable biomarkers for the assessment of these adenocarcinomas is essential. The dysregulation of the oncoprotein, PKB/Akt has been linked with poor prognoses in human cancers.We analysed the status of the PKB/Akt pathway in a representative tumour tissue microarray obtained from the primary tumours and their metastases in 60 ccRCC with long term follow up. We sought to define the evolution of this pathway from the primary tumour to the metastatic event and to know the impact of its functional state in tumour aggressiveness and patient survival. Two-site time resolved amplified FRET (A-FRET) was utilised for assessing the activation state of PKB/Akt and this was compared to conventional immunohistochemistry measurements.Activation state of PKB/Akt in primary tumours defined by A-FRET correlated with poorer overall survival (hazard ratio 0.228; p = 0.002). Whereas, increased protein expression of phosphoPKB/Akt, identified using classical immunohistochemistry, yielded no significant difference (hazard ratio 1.390; p = 0.548).Quantitative determination of PKB/Akt activation in ccRCC primary tumours alongside other diagnostics tools could prove key in taking oncologists closer to an efficient personalised therapy in ccRCC patients.The quantitative imaging technology based on Amplified-FRET can rapidly analyse protein activation states and molecular interactions. It could be used for prognosis and assess drug function during the early cycles of chemotherapy. It enables evaluation of clinical efficiency of personalised cancer treatment.

James Miles

Christopher J. Applebee

Pierre Leboucher

Sonia Lopez-Fernandez

Dae-Jin Lee

Rosa Guarch

Stephen Ward

Peter J. Parker

Jose I. López

Banafshé Larijani

Time resolved amplified FRET identifies protein kinase B activation state as a marker for poor prognosis in clear cell renal cell carcinoma

时间分辨放大FRET鉴定蛋白激酶B激活状态为透明细胞肾细胞癌不良预后的标志物

This paper presents a new assay to determine the activity of the lysosomal enzyme α-N-acetylgalactosaminidase (Naga, EC 3.2.1.49) in human serum. It is based on the use of a new chromogenic substrate, DNP-α-GalNAc (2,4-dinitrophenyl-N-acetyl-α-D-galactosaminide) and is performed at pH 4.3 and 37 °C. This allows continuous monitoring of the absorbance of the released DNP. The assay can be performed with a standard spectrophotometer. Compared to established methods using an endpoint assay with MU-α-GalNAc (4-methylumbelliferyl-GalNAc), the present method gives a ca. 3-fold higher specific activity, while only one tenth of the serum concentration in the assay is required. Hence, the assay is at least 30-fold more sensitive than that with MU-α-GalNAc. The pH dependence of the reaction with DNP-α-GalNAc in the pH 3.5 to 6.5 region, while using 4% serum in the assay, shows only one peak around pH 4. This pH optimum is similar to that reported with MU-α-GalNAc. In the accompanying paper (S.P.J Albracht and J. Van Pelt (2017) Multiple exo-glycosidases in human serum as detected with the substrate DNP-α-GalNAc. II. Three α-N-acetylgalactosaminidase-like activities in the pH 5 to 8 region. BBA Clin. 8 (2017) 90-96), the method is used to show that, under special assay conditions, three more Naga-like activities can be uncovered in human serum.

Simon P.J. Albracht

Erik Allon

Johannes van Pelt

Multiple exo -glycosidases in human serum as detected with the substrate DNP-α-GalNAc. I. A new assay for lysosomal α- N -acetylgalactosaminidase

人血清中多种外切糖苷酶的检测：以DNP-α-GalNAc为底物。I. 溶酶体α-N-乙酰半乳糖胺酶的新测定方法

With the substrate DNP-α-GalNAc (2,4-dinitrophenyl-N-acetyl-α-d-galactosaminide) three α-N-acetylgalactosaminidase-like activities could be distinguished in serum, in addition to the classical lysosomal enzyme (Naga, EC 3.2.1.49, pH optimum at 4). Two activities had optima in the pH 5 to 6 region and one peaked around pH 8. Like the Naga activity at pH 4, the activity at pH 8 was detectable under standard assay conditions. However, the two activities in the pH 5 to 6 range were not readily apparent in such assays. They could be unmasked as separate activities only when low serum concentrations were used. Addition of 1% saturated ammonium sulphate to the assay medium stimulated these activities. All activities in the pH 5 to 8 range decreased with increasing serum concentration in the assay, suggesting the presence of endogenous inhibitors. The activities between pH 5 and 6 might be similar to an activity described in 1996, which was considerably elevated in serum of patients with great variety of cancers (N. Yamamoto, V.R. Naraparaju, and S.O. Asbell (1996). Deglycosylation of serum vitamin D3-binding protein leads to immunosuppression in cancer patients. Cancer Res. 56, 2827-2811).

Multiple exo -glycosidases in human serum as detected with the substrate DNP-α-GalNAc. II. Three α- N -acetylgalactosaminidase-like activities in the pH 5 to 8 region

人血清中多种外切糖苷酶的检测：以DNP-α-GalNAc为底物。II. pH 5至8区域的三种α-N-乙酰半乳糖胺酶样活性

1. Evaluate the effect of washing and cooking iron-fortified rice on iron retention and bioavailability. 2. Evaluate the effect of iron-fortified rice on women with iron deficiency anemia 1. Iron-fortified rice (18 mg/100 g as FeSO4) was cooked in Baton Rouge, Louisiana (C), rinsed and cooked (RC), fried and cooked (FC), cooked with extra water (CW), or soaked and cooked with extra water (SCW), and iron retention was determined. 2. Rice samples were cooked in Kampala, Uganda in a lab (C-Uganda) and households using traditional cooking method (TC-Uganda) and iron retention were determined. 3. Seventeen women with iron deficiency (low iron and/or low ferritin) anemia were randomized to 100 g/d of rice (two cooked 0.75 cup servings) for two weeks containing 18 mg/d iron (supplemented) or 0.5 mg/d iron (un-supplemented). Hemoglobin and hematocrit were evaluated at baseline and 2 weeks with other measures of iron metabolism. 1. Iron retention, from highest to lowest, was (C), (RC), (FC), (C-Uganda), (CW), (SCW) and (TC-Uganda). 2. Seventeen women were randomized and 15 completed the study (hemoglobin 10.6 ± 1.6 g, hematocrit 33.7 ± 4.1%), 9 in the iron-fortified rice group and 6 in the un-fortified rice group. The iron-fortified group had a greater increase in hemoglobin (0.82 g, p = 0.0035) and Hematocrit (1.83%, p = 0.0248) with directional differences in other measures of iron metabolism favoring the iron-fortified group. Iron-fortified rice increased hemoglobin and hematocrit in women with iron-deficient anemia. Iron deficiency and anemia are widespread in Southeast Asia and Africa and undermine development in these regions.

J.N. Losso

N. Karki

J. Muyonga

Y. Wu

K. Fusilier

G. Jacob

Y. Yu

J.C. Rood

J.W. Finley

F.L. Greenway

Iron retention in iron-fortified rice and use of iron-fortified rice to treat women with iron deficiency: A pilot study

铁强化大米中的铁保留及使用铁强化大米治疗缺铁女性的初步研究

We report three signatures produced from SHARPIN gene copy number increase (GCN-Increase) and their effects on patients with breast cancer (BC). In the Metabric dataset (n = 2059, cBioPortal), SHARPIN GCN-Increase occurs preferentially or mutual exclusively with mutations in TP53, PIK3CA, and CDH1. These genomic alterations constitute a signature (SigMut) that significantly correlates with reductions in overall survival (OS) in BC patients (n = 1980; p = 1.081e − 6). Additionally, SHARPIN GCN-Increase is associated with 4220 differentially expressed genes (DEGs). These DEGs are enriched in activation of the pathways regulating cell cycle progression, RNA transport, ribosome biosynthesis, DNA replication, and in downregulation of the pathways related to extracellular matrix. These DEGs are thus likely to facilitate the proliferation and metastasis of BC cells. Additionally, through forward (FWD) and backward (BWD) stepwise variate selections among the top 160 downregulated and top 200 upregulated DEGs using the Cox regression model, a 6-gene (SigFWD) and a 50-gene (SigBWD) signature were derived. Both signatures robustly associate with decreases in OS in BC patients within the Curtis (n = 1980; p = 6.16e − 11 for SigFWD; p = 1.06e − 10, for SigBWD) and TCGA cohort (n = 817; p = 4.53e − 4 for SigFWD and p = 0.00525 for SigBWD). After adjusting for known clinical factors, SigMut (HR 1.21, p = 0.0297), SigBWD (HR 1.25, p = 0.0263), and likely SigFWD (HR 1.17, p = 0.062) remain independent risk factors of BC deaths. Furthermore, the proportion of patients positive for these signatures is significantly increased in ER −, Her2-enriched, basal-like, and claudin-low BCs compared to ER + and luminal BCs. Collectively, these SHARPIN GCN-Increase-derived signatures may have clinical applications in management of patients with BC.

Diane Ojo

Maryam Seliman

Damu Tang

Signatures derived from increase in SHARPIN gene copy number are associated with poor prognosis in patients with breast cancer

SHARPIN基因拷贝数增加衍生的特征与乳腺癌患者的不良预后相关

出版信息	出版商: Elsevier B.V.，出版周期: ，期刊类型: journal，开源期刊: 否
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