Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma

Background:

Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC).

Methods:

Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months.

Results:

Median pretherapeutic serum GGT level was 25 U l⁻¹. Gamma-glutamyltransferase levels increased with advancing T (P<0.001), N (P=0.006) and M stages (P<0.001), higher grades (P<0.001), and presence of tumour necrosis (P<0.001). An increase of GGT by 10 U l⁻¹ was associated with an increase in the risk of death from RCC by 4% (HR 1.04, P<0.001). Based on recursive partitioning-based survival tree analysis, we defined four prognostic categories of GGT: normal low (<17.5 U l⁻¹), normal high (17.5 to <34.5 U l⁻¹), elevated (34.5 to <181.5 U l⁻¹), and highly elevated (⩾181.5 U l⁻¹). In multivariable analyses that adjusted for the effect of standard features, both continuously and categorically coded GGT were independent prognostic factors. Adding GGT to a model that included standard features increased the discrimination by 0.9% to 1.8% and improved the clinical net benefit.

Conclusions:

Pretherapeutic serum GGT is a novel and independent prognostic factor for patients with RCC. Stratifying patients into prognostic subgroups according to GGT may be used for patient counselling, tailoring surveillance, individualised treatment planning, and clinical trial design.     

用创伤性和非创伤性方法检测双哌达莫对不同程度缺血心脏的作用

在２４ 条急性开胸犬上,用微米狭窄器造成冠状动脉左旋支不同程度的狭窄,分别在轻度狭窄和临界狭窄基础上,静脉给予双哌达莫（０ ．５６ ｍｇ／ｋｇ） 。用创伤性和非创伤性方法检测用药前后的左心室收缩功能的改变。轻度狭窄时,给于双哌达莫后,左室舒张压（ Ｌ Ｖ Ｄ Ｐ） 射血前期与左室射血时间的比值（ Ｐ Ｅ Ｐ／ Ｌ Ｖ Ｅ Ｔ） ,等容收缩时间与左室射血时间的比值（ Ｉ Ｃ Ｔ／ Ｌ Ｖ Ｅ Ｔ） 分别下降３３ ％ ,３０ ％ ,５２ ％ , 冠 脉血 流量（ Ｃ Ｂ Ｆ） , 室内 压最 大上 升速 率［（ｄｐ／ｄｔ） ｍ ａｘ］ ,室内压最大下降速率［（ ｄｐ／ｄｔ） ｍａｘ］ 有升高趋势,心功能得到改善。冠状动脉临界狭窄时, 给予双哌达莫后, Ｌ Ｖ Ｄ Ｐ, Ｐ Ｅ Ｐ／ Ｌ Ｖ Ｅ Ｔ 和 Ｉ Ｃ Ｔ／ Ｌ Ｖ Ｅ Ｔ 分别下降５５ ％ ,２６ ％ 和８７ ％ ,而 Ｃ Ｂ Ｆ, Ｌ Ｖ Ｓ Ｐ,（ｄｂ／ｄｔ） ｍ ａｘ 和（ ｄｐ／ｄｔ） ｍａｘ 分别下降２５ ％ ,３３ ％ ,３８ ％ ,５０ ％ ,心功能进一步恶化。本实验可部分解释临床冠心病做双哌达莫试验所表现的不同结果,为临床合理使用双哌达莫提供了新的依据并提出测量左心室收缩时间间期（ Ｓ Ｔ Ｉ） 结合双哌达莫试验用于诊断冠心病的新?     

Genotoxic effects of the antimalarial drug lumefantrine in human lymphocytes in vitro and computational prediction of the mechanism associated with its interaction with DNA

Lumefantrine (LF) is an aryl‐amino alcohol antimalarial drug used in artemisinin‐based combination therapies against malaria worldwide. In this study, we investigated the genotoxic effects of LF in human lymphocytes in vitro, and the potential noncovalent interaction of LF with DNA using a 3D DNA‐docking model. The number of DNA breaks and the frequency of nuclear buds (NBUDS) was significantly increased (P < 0.01 and P <0. 05, respectively) at LF concentrations of 60, 80, and 100 µg/mL (LF60, LF80, and LF100, respectively). Frequency (‰) of micronuclei (MN) formation also increased after LF treatments. However, this was only significant for LF100 (P = 0.01) and LF80 (P = 0.001). LF did not affect the frequency of nucleoplasmic bridges (NPBs) (P = 0.12) or the nuclear division index (NDI) (P = 0.32). Computational analysis suggests that LF may interact noncovalently with DNA via the DNA minor groove surface with a predicted binding affinity energy of ?7.2 kcal/mol and showing a favorable shape complementary to this groove. Our results suggest that LF has clastogenic effects in human lymphocytes in vitro due to noncovalent interaction with the minor groove of DNA. Environ. Mol. Mutagen. 56:556–562, 2015. © Wiley Periodicals, Inc.     

Trypsin inhibitor from tamarindus indica L. seeds reduces weight gain and food consumption and increases plasmatic cholecystokinin levels

OBJECTIVES:

Seeds are excellent sources of proteinase inhibitors, some of which may have satietogenic and slimming actions. We evaluated the effect of a trypsin inhibitor from Tamarindus indica L. seeds on weight gain, food consumption and cholecystokinin levels in Wistar rats.

METHODS:

A trypsin inhibitor from Tamarindus was isolated using ammonium sulfate (30–60%) following precipitation with acetone and was further isolated with Trypsin-Sepharose affinity chromatography. Analyses were conducted to assess the in vivo digestibility, food intake, body weight evolution and cholecystokinin levels in Wistar rats. Histological analyses of organs and biochemical analyses of sera were performed.

RESULTS:

The trypsin inhibitor from Tamarindus reduced food consumption, thereby reducing weight gain. The in vivo true digestibility was not significantly different between the control and Tamarindus trypsin inhibitor-treated groups. The trypsin inhibitor from Tamarindus did not cause alterations in biochemical parameters or liver, stomach, intestine or pancreas histology. Rats treated with the trypsin inhibitor showed significantly elevated cholecystokinin levels compared with animals receiving casein or water.

CONCLUSION:

The results indicate that the isolated trypsin inhibitor from Tamarindus reduces weight gain by reducing food consumption, an effect that may be mediated by increased cholecystokinin. Thus, the potential use of this trypsin inhibitor in obesity prevention and/or treatment should be evaluated.     

Galactose oxidation using 13C in healthy and galactosemic children

Galactosemia is an inborn error of galactose metabolism that occurs mainly as the outcome of galactose-1-phosphate uridyltransferase (GALT) deficiency. The ability to assess galactose oxidation following administration of a galactose-labeled isotope (1-¹³C-galactose) allows the determination of galactose metabolism in a practical manner. We aimed to assess the level of galactose oxidation in both healthy and galactosemic Brazilian children. Twenty-one healthy children and seven children with galactosemia ranging from 1 to 7 years of age were studied. A breath test was used to quantitate ¹³CO₂ enrichment in exhaled air before and at 30, 60, and 120 min after the oral administration of 7 mg/kg of an aqueous solution of 1-¹³C-galactose to all children. The molar ratios of ¹³CO₂ and ¹²CO₂ were quantified by the mass/charge ratio (m/z) of stable isotopes in each air sample by gas-isotope-ratio mass spectrometry. In sick children, the cumulative percentage of ¹³C from labeled galactose (CUMPCD) in the exhaled air ranged from 0.03% at 30 min to 1.67% at 120 min. In contrast, healthy subjects showed a much broader range in CUMPCD, with values from 0.4% at 30 min to 5.58% at 120 min. The study found a significant difference in galactose oxidation between children with and without galactosemia, demonstrating that the breath test is useful in discriminating children with GALT deficiencies.     

Combined evaluation of adenosine deaminase level and histopathological findings from pleural biopsy with Cope’s needle for the diagnosis of tuberculous pleurisy

Introduction: Closed needle pleural biopsy (CNPB) has historically been the gold standard procedure for the diagnosis of pleural tuberculosis. Adenosine deaminase (ADA) is an efficient biomarker for tuberculosis that is measurable in pleural fluids. Objective: We compared the diagnostic accuracy of the pleural ADA (P-ADA) level and histopathological findings of CNPB specimens in patients with pleural tuberculosis. Methods: This prospective study consisted of two groups of examinations with a proven diagnosis of pleural effusion. The P-ADA level was measured in 218 patients with pleural effusion due to a number of causes, and 157 CNPB specimens underwent histopathological analysis. Results: CNPBs were performed in patients with tuberculosis (n=122) and other diseases: adenocarcinoma (n=23), lymphoma (n=5), systemic lupus erythematosus (n=4), squamous cell carcinoma (n=2), and small cell lung cancer (n=1). According to the ROC curve, the optimal cut-off value of the P-ADA level (Giusti and Galanti colorimetric method) was equal to or greater than 40.0 U/L. The diagnostic accuracy of the P-ADA test was 83.0%, and that of histopathological examination of the CNPB tissue, was 78.8% (AUC=0.293, P=0.7695). The association between the P-ADA assay and pleural histopathology was 24.41 (P<0.0001). The tetrachoric correlation coefficient was 0.563 (high correlation). Conclusion: In Brazil and other countries with a high incidence of tuberculosis, P-ADA activity is an accurate test for the diagnosis of tuberculous pleural effusions, and its use should be encouraged. The high diagnostic performance of the P-ADA test could to aid the diagnosis of pleural tuberculosis and render CNPB unnecessary.