Sarcopenia as a predictor of initial administration dose of afatinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Sarcopenia has recently emerged as a new condition with increasing importance in lung cancer patients. The aim of this study was to investigate the influence of sarcopenia on tolerance and efficacy of afatinib. METHODS: We retrospectively evaluated 35 patients with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC) treated with first-line afatinib. Skeletal muscle area (SMA) was measured at the third lumbar vertebra using routine conducted computed tomography (CT) images for evaluation of disease burden. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2 ) ≤38.5 cm2 /m2 for women and ≤52.4 cm2 /m2 for men based on previous criteria. Fisher's exact tests, Kaplan-Meier method, and logistic regression modeling were used. RESULTS: The median age at diagnosis was 65 years (range,39-84 years). A total of 24 (68.6%) patients were diagnosed with sarcopenia. The most frequent adverse events (AEs) related to afatinib were diarrhea (94.3%) followed by rash (77.1%) and paronychia (60%). Overall, 19 (54.3%) patients had dose reduction. Sarcopenic patients had a significantly higher rate of grade ≥ 2 diarrhea (75.0 vs. 27.3%, p = 0.011) and toxicity-related dose reduction (75.0 vs. 9.1%, p = 0.001). Multivariate analysis also showed that sarcopenia (odds ratio [OR] 51.7, 95% confidence interval [CI]: 2.4-1081.3, p = 0.01) was an independent risk factor for dose reduction of afatinib. The median progression-free survival (PFS) for afatinib was 12.0 months (95% CI: 10.6-13.4). Both dose reduction and sarcopenia did not affect therapeutic efficacy. CONCLUSIONS: Toxicity-related dose reduction is common with initiation of afatinib 40 mg/day. Sarcopenic patients might begin treatment with a low dose of afatinib according to tolerance.

Circular RNA circRNA_101996 promoted cervical cancer development by regulating miR-1236-3p/TRIM37 axis.

Circular RNAs (circRNAs) appear to be significant modulators in various physiological processes. Recently, it is found that circRNA_101996 exerts important roles in various cancers. Our previous studies showed that circRNA_101996 promoted cervical cancer growth and metastasis by regulating miR-8075/TPX2. However, the potential regulatory role of circRNA_101996 in cervical cancer still needs further investigation. Our results in this study suggested that circRNA_101996 was over-expressed in cervical cancer patients. circRNA_101996 up-regulation remarkably assisted cell proliferation, cell cycle progression, and cell migration in cervical cancer, while circRNA_101996 knockdown exerted the inverse effects. The molecular investigations indicated that circRNA_101996 could increase the expression level of miR-1236-3p, tripartite motif-containing 37 (TRIM37), through binding to miR-1236-3p and reducing its expression. Moreover, in vivo results demonstrated that circRNA_101996 shRNA can function as a tumor suppressor through down-regulating TRIM37 in cervical cancer. In conclusion, our data indicated that circRNA_101996/miR-1236-3p/TRIM37 axis accelerated cervical cancer development, providing novel insights into cervical cancer diagnosis and treatment.

A Method for Rapid Screening of Anilide-Containing AMPK Modulators Based on Computational Docking and Biological Validation.

Adenosine 5'-monophsphate-activated protein kinase (AMPK) is a crucial energy sensor for maintaining cellular homeostasis. Targeting AMPK may provide an alternative approach in treatment of various diseases like cancer, diabetes, and neurodegenerations. Accordingly, novel AMPK activators are frequently identified from natural products in recent years. However, most of such AMPK activators are interacting with AMPK in an indirect manner, which may cause off-target effects. Therefore, the search of novel direct AMPK modulators is inevitable and effective screening methods are needed. In this report, a rapid and straightforward method combining the use of in silico and in vitro techniques was established for selecting and categorizing huge amount of compounds from chemical library for targeting AMPK modulators. A new class of direct AMPK modulator have been discovered which are anilides or anilide-like compounds. In total 1,360,000 compounds were virtually screened and 17 compounds were selected after biological assays. Lipinski's rule of five assessment suggested that, 13 out of the 17 compounds are demonstrating optimal bioavailability. Proton acceptors constituting the structure of these compounds and hydrogen bonds with AMPK in the binding site appeared to be the important factors determining the efficacy of these compounds.

Apparent diffusion coefficient normalization of normal liver: Will it improve the reproducibility of diffusion-weighted imaging at different MR scanners as a new biomarker?

Apparent diffusion coefficient (ADC) measurement in diffusion-weighted imaging (DWI) has been reported to be a helpful biomarker for detection and characterization of lesion. In view of the importance of ADC measurement reproducibility, the aim of this study was to probe the variability of the healthy hepatic ADC values measured at 3 MR scanners from different vendors and with different field strengths, and to investigate the reproducibility of normalized ADC (nADC) value with the spleen as the reference organ. Thirty enrolled healthy volunteers received DWI with GE 1.5T, Siemens 1.5T, and Philips 3.0T magnetic resonance (MR) systems on liver and spleen (session 1) and were imaged again after 10 to 14 days using only GE 1.5T MR and Philips 3.0T MR systems (session 2). Interscan agreement and reproducibility of ADC measurements of liver and the calculated nADC values (ADCliver/ADCspleen) were statistically evaluated between 2 sessions. In session 1, ADC and nADC values of liver were evaluated for the scanner-related variability by 2-way analysis of variance and intraclass correlation coefficients (ICCs). Coefficients of variation (CVs) of ADCs and nADCs of liver were calculated for both 1.5 and 3.0-T MR system. Interscan agreement and reproducibility of ADC measurements of liver and related nADCs between 2 sessions were found to be satisfactory with ICC values of 0.773 to 0.905. In session 1, the liver nADCs obtained from different scanners were consistent (P = 0.112) without any significant difference in multiple comparison (P = 0.117 to >0.99) by using 2-way analysis of variance with post-hoc analysis of Bonferroni method, although the liver ADCs varied significantly (P < 0.001). nADCs measured by 3 scanners were in good interscanner agreements with ICCs of 0.685 to 0.776. The mean CV of nADCs of both 1.5T MR scanners (9.6%) was similar to that of 3.0T MR scanner (8.9%). ADCs measured at 3 MR scanners with different field strengths and vendors could not be compared directly. Normalization of ADCs, however, may provide better reproducibility by overcoming these potential issues.

Diffusion-Weighted Imaging with Two Different b-Values in Detection of Solid Focal Liver Lesions.

One hundred and eighty-two consecutive patients with suspected liver disease were recruited to receive diffusion-weighted imaging (DWI) with two different b-values, in comparison with T2-weighted imaging (T2WI). The detection rate of three MR sequences in solid focal liver lesions (FLLs) and subgroup analyses were performed. Our prospective study found that DWI600 was equivalent to DWI100 and T2WI for the detection of solid FLLs overall but was significantly more accurate in the detection of malignant solid FLLs and lesions larger than 10 mm.

Expression and effects of JMJD2A histone demethylase in endometrial carcinoma.

Previous studies have demonstrated that JMJD2A is a potential oncogene and is overexpressed in human tumors. However, its role in the endometrial carcinoma remains largely unknown. In this study, we discovered that JMJD2A was overexpressed in endometrial carcinoma, using immunohistochemistry, quantitative real- time polymerase chain reaction, and western blotting. Downregulation of JMJD2A led to reduced endometrial carcinoma RL95-2 and ISK cell proliferation, invasion and metastasis as asessed with cell counting kit-8, cell migration and invasive assays. Collectively, our results support that JMJD2A is a promoter of endometrial carcinoma cell proliferation and survival, and is a potential novel drug target.

Apparent diffusion coefficient reproducibility of the pancreas measured at different MR scanners using diffusion-weighted imaging.

PURPOSE: To evaluate the reproducibility of the pancreatic apparent diffusion coefficient (ADC) measured at different MR scanners. MATERIALS AND METHODS: Twenty-four healthy volunteers underwent three consecutive diffusion-weighted imaging (DWI) at a GE 1.5 Tesla (T), a Siemens 1.5 T and a Philips 3.0 T (session 1), and imaged again using the same protocol at the same GE 1.5 T (session 2) 12 days later. The ADC values of pancreas were measured at all three MR scanners. Paired-sample t-test and the Bland-Altman method were used for ADC data analysis. RESULTS: The individual mean ADC values of pancreatic head, body, and tail (in 10(-3) mm(2)/s) measured at GE 1.5 T (2.24, 2.01, 1.88 for observer 1 and 2.23, 2.00, 1.92 for observer 2) and Siemens 1.5 T (2.24, 2.04, 1.84 for observer 1 and 2.20, 1.98, 1.84 for observer 2) were significantly higher than those at Philips 3.0 T (2.06, 1.80, 1.56 for observer 1 and 2.02, 1.79, 1.60 for observer 2) (P = 0.000-0.008). There was no significant difference of ADC values either between GE 1.5 T and Siemens 1.5 T (P = 0.115-0.966), or between imaging session 1 and 2 at GE 1.5 T (P = 0.072-0.938). The range of mean difference ± limits of agreement (in 10(-3) mm(2)/s) was -0.07-0.04 ± 0.39-0.53 between two 1.5 T scanners, and -0.04-0.04 ± 0.24-0.47 between two imaging sessions at GE 1.5 T. CONCLUSION: The measured ADC values of pancreas are affected by the field strength of scanner, but show good reproducibility between different MR systems with same field strength and at the same MR system over time.