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Background Germline mutations play an important role in the pathogenesis of lung cancer. Nonetheless, research on malignant ground glass opacity (GGO) nodules is limited. Methods A total of 13 participants with malignant GGO nodules were recruited in this study. Peripheral blood was used for exome sequencing, and germline mutations were analyzed using InterVar. The whole exome sequencing dataset was analyzed using a filtering strategy. KOBAS 3.0 was used to analyze KEGG pathway to further identify possible deleterious mutations. Results There were seven potentially deleterious germline mutations. NM_001184790:exon8: c.C1070T in PARD3, NM_001170721:exon4:c.C392T in BCAR1 and NM_001127221:exon46: c.G6587A in CACNA1A were present in three cases each; rs756875895 frameshift in MAX, NM_005732: exon13:c.2165_2166insT in RAD50 and NM_001142316:exon2:c.G203C in LMO2, were present in two cases each; one variant was present in NOTCH3. Conclusions Our results expand the germline mutation spectrum in malignant GGO nodules. Importantly, these findings will potentially help screen the high-risk population, guide their health management, and contribute to their clinical treatment and determination of prognosis.

Myasthenia gravis (MG) is an acquired autoimmune disease affecting the postsynaptic membrane of neuromuscular junctions and characterized by antibody-mediated T cell dependence and complement involvement. Cholinesterase inhibitors (e.g., pyridostigmine bromide), glucocorticoids, and azathioprine are currently recommended as first-line treatments for MG, though they have limitations, including potential toxicity and ineffectiveness in patients with refractory MG. In recent years, owing to an increasing understanding of MG pathogenesis the development and execution of clinical trials with novel biologics, including monoclonal antibodies (mAbs) that have demonstrated higher safety and more specificity, provide new opportunities for the treatment of MG. In this article, we review recent advances in MG pathogenesis and the mAbs that have been used for target-specific MG therapy.

Background:Glucagon-like peptide 1 receptor (GLP-1R) is an important biomarker for diagnosis and therapy of the endocrine cancers due to overexpression. Recently, in human prostate cancer cell lines the receptor was also observed, therefore it may be a potential target for the disease. 18F-Al-NOTA-MAL-Cys39- exendin-4 holds great promise for GLP-1R. Therefore, the feasibility of the 18F-labeled exendin-4 analog for prostate cancer imaging was investigated.Methods:New probe 18F-Al-NOTA-MAL-Cys39-exendin-4 was made through one-step fluorination. Prostate cancer PC3 cell xenograft model mice were established to primarily evaluate the imaging properties of the tracer via small animal PET studies in vivo. Pathological studies and Western Blots were also performed.Results:PC-3 prostate xenografts were clearly imaged under baseline conditions. At 30 and 60 min postinjection, the tumor uptakes were 2.90±0.41%ID/g and 2.26±0.32 %ID/g respectively. The presence of cys39-exendin-4 significantly reduced the tumor uptake to 0.82±0.10 %ID/g at 60 min p.i. Findings of ex vivo biodistribution studies were similar to those of in vivo PET imaging. The tumors to blood and muscles were significantly improved with the increase of time due to rapid clearance of the tracer from normal organs. Low levels of radioactivity were also detected in the GLP-1R positive tumor and normal organs after coinjection with excessive unlabeled peptides. Immunohistochemistry and Western Blots results confirmed that GLP-1R was widely expressed in PC-3 prostate cancers.Conclusion:18F-Al labeled exendin-4 analog might be a promising tracer for in vivo detecting GLP-1R positive prostate cancer with the advantage of facile synthesis and favorable pharmacokinetics. It may be useful in differential diagnosis, molecularly targeted therapy and prognosis of the cancers.

We aimed to (i) develop a population pharmacokinetic model of tacrolimus in Chinese lung transplant recipients and (ii) propose model-based dosing regimens for individualized treatment. We obtained 807 tacrolimus steady-state whole blood concentrations from 52 lung transplant patients and genotyped CYP3A5*3. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Monte Carlo simulations were employed to determine the initial dosing regimens. Tacrolimus pharmacokinetics was described by a one-compartment model with first-order absorption and elimination processes. In CYP3A5*3/*3 70-kg patients with 30% hematocrit and voriconazole-free therapy, the mean estimated apparent clearance was 13.1 l h−1 with 20.1% between-subject variability, which was lower than that in Caucasian lung transplant patients (17.5–36.5 l h−1). Hematocrit, postoperative days, tacrolimus daily dose, voriconazole concomitant therapy, and CYP3A5*3 genotype were identified as significant covariates for tacrolimus clearance. To achieve target trough concentration (10–15 ng ml−1) on the 8th day post-transplant, a higher initial dosage than the current regimen of 0.04 mg kg−1 every 12 h is recommended for CYP3A5*1/*3 patients without voriconazole concomitant therapy. Given the nonlinear kinetics of tacrolimus and large variability, population pharmacokinetic model should be combined with therapeutic drug monitoring to optimize individualized therapy.

Objective. Inflammation-driven markers play a crucial role in tumorigenesis and tumor progression. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in blood are systemic inflammatory response markers. Some reports have showed that NLR and PLR are related to a poor prognosis in patients with lung cancer. However, little studies have reported whether NLR and PLR can be diagnostic markers for lung cancer. The aim of the current study is to investigate the roles of NLR and PLR in diagnosing lung cancer. Methods. This study analyzed data from lung cancer patients and healthy individuals in Wuxi People’s Hospital Affiliated with Nanjing Medical University. The Mann–Whitney U test was performed to compare differences between the lung cancer group and the control group. Based on white blood cell (WBC) counts, both lung cancer patients and healthy individuals were divided into the low-level group, moderate-level group, and high-level group. The Kruskal-Wallis test was applied to compare differences of NLR and PLR among those groups with different WBC counts. Spearman correlation analysis was used to assess correlations. Receiver operating characteristic (ROC) curves were performed to determine diagnostic accuracy. Results. 210 patients diagnosed with lung cancer and 261 healthy subjects were enrolled in this study. Levels of NLR and PLR increased in the lung cancer group compared with the control group ( P < 0.001 ). For the lung cancer group, NLR levels could rise with the increasing of WBC levels ( P < 0.001 ) while PLR levels had no significant variation with the increasing of WBC levels ( P = 0.206 ). For the control group, NLR levels could rise with the increasing of WBC levels ( P < 0.001 ) while PLR levels would decline with the increasing of WBC levels ( P < 0.001 ). In the lung cancer group, both NLR and PLR had no significant correlations with aspartate transaminase, urea, and glucose. The area under the curve (AUC) with 95% confidence interval (95% CI) of NLR and PLR to distinguish lung cancer patients from healthy subjects was, respectively, 0.684 (0.634-0.735) and 0.623 (0.571-0.674). When NLR and PLR were combined, AUC (95% CI) increased to 0.691 (0.642-0.740). Conclusions. NLR and PLR alone have moderate ability to distinguish lung cancer patients from healthy subjects. Furthermore, combination forms of NLR and PLR can improve diagnostic ability.

Background/Aims: Cardiac fibrosis after myocardial infarction (MI) has been identified as a key factor in the development of heart failure, but the mechanisms undelying cardiac fibrosis remained unknown. microRNAs (miRNAs) are novel mechanisms leading to fibrotic diseases, including cardiac fibrosis. Previous studies revealed that miR-22 might be a potential target. However, the roles and mechanisms of miR-22 in cardiac fibrosis remained ill defined. The present study thus addressed the impact of miR-22 in cardiac fibrosis. Methods: After seven days following coronary artery occlusion in mice, tissues used for histology were collected and processed for Masson's Trichrome staining. In addition, cardiac fibroblasts were transfected with mimics and inhibitors of miR-22 using Lipofectamin 2000, and luciferase activity was measured in cell lysates using a luciferase assay kit. Western blotting was used to detect the expression of collagen1, α-SMA and TGFβRI proteins levels, and real time-PCR was employed to measure the Col1α1, Col3α1, miR-22 and TGFβRI mRNA levels. Results: In this study, we found that miR-22 was dynamically downregulated following MI induced by permanent ligation of the left anterior descending coronary artery for 7 days, an effect paralleled by significant collagen deposition. Inhibition of miR-22 with AMO-22 resulted in increased expression of Col1α1, Col3α1 and fibrogenesis in cultured cardiac fibroblasts. Conversely, overexpression of miR-22 in cultured cardiac fibroblasts significantly abrogated angiotensin II-induced collagen formation and fibrogenesis. Furthermore, we found that TGFβRI is a direct target for miR-22, and downregulation of TGFβR may have mediated the antifibrotic effect of miR-22. Conclusion: Our data clearly demonstrate that miR-22 acts as a novel negative regulator of angiotensin II-induced cardiac fibrosis by suppressing the expression of TGFβRI in the heart and may represent a new potential therapeutic target for treating cardiac fibrosis.

// Jia Zhou 1,* , Yi-hua Zhang 2,* , Hui-zhu Song 3 , Hui Ji 2 , Xiao-li Wang 1 , Lei Wang 3 , Jun Qian 3 , Jing-jing Ling 3 and Feng-feng Ping 3 1 School of Pharmaceutical Science, Jiangnan University, Wuxi, P.R. China 2 State Key Laboratory of Natural Medicines, Center of Drug discovery, China Pharmaceutical University, Nanjing, P.R. China 3 Wuxi People’s Hospital affiliated to Nanjing Medical University, Wuxi, P.R. China * These authors have contributed equally to this work Correspondence to: Jing-jing Ling, email: // Feng-feng Ping, email: // Keywords : 5d; neuroprotection; CK2; NADPH oxidase; ROS; Neuroscience Received : December 07, 2015 Accepted : May 05, 2016 Published : May 12, 2016 Abstract 5d, a novel analogue of the racemic 3- n -butylphthalide (NBP), has been reported for its free radical scavenging activity in vitro and preventive neuroprotection in vivo . Nevertheless, the mechanism by which 5d attenuated ischemia/reperfusion (I/R) injury is still unknown. Our results showed that 5d significantly increased CK2 activity as well as CK2α and 2α’ protein levels after I/R injury. Besides, 5d suppressed the translocation of cytosolic p47phox and Rac1 to the membrane, decreased NOX4 expression and ROS generation. Furthermore, 5d blocked the dissociation between CK2α and Rac1 so as to decrease NADPH oxidase activity. Based on these findings, we propose that the neuroprotective effect of 5d is due to an increase of CK2 activity, which blocks I/R-induced dissociation between CK2α and Rac1, decreases NADPH oxidase activity, inhibits ROS production and finally realizes the neuroprotection of I/R. These findings point to that 5d might be considered an attractive candidate for further studies in ischemic stroke.

Oxidative stress has been shown to play a vital role in the pathogenesis of the ischemia/reperfusion (I/R) and may represent a target for treatment. 3-Butyl-2-benzothiophen-1(3H)-one (5d), a novel analogue of the racemic 3-n-butylphthalide (NBP), exerts enhanced free radical scavenging, anti-platelet and anti-thrombotic effects, as well as preventive neuroprotection in a rat model of ischemia/reperfusion (I/R). Nevertheless, it is still unknown about the therapeutic effect of 5d against ischemic stroke and underlying mechanism(s) involved. 5d (30 mg kg−1 and 90 mg kg−1) significantly reduces brain damage after I/R in vivo, and protects primary cultured cortical neurons against oxygen-glucose deprivation and recovery (OGD/R)-induced cytotoxicity in vitro. Besides, 5d induces Nrf2 nuclear localization through PI3K/Akt signaling pathway, and lowers the intracellular ROS levels by lowering NADPH oxidase activity. However, Nrf2 siRNA transfection before OGD/R could decrease the neuronal cell viability and increase the expression of NOX4 elicited by 5d treatment. These results suggest that the therapeutic effect of 5d against ischemic stroke is due to the decrease of NADPH oxidase activity by promoting Nrf2 nuclear localization through PI3K/Akt signaling pathway. These findings point to that 5d might be an effective candidate for the treatment of ischemic stroke.

Aim To review and evaluate the efficacy of kidney-tonifying traditional Chinese medicine prescriptions (KT-TCMP) in hypoplastic uterus (HU) treatment. Methods We searched MEDLINE, the Cochrane Library, CNKI (China National Knowledge Infrastructure), WANFANG and VIP databases until 14 December 2013 independently with two investigators. Randomized controlled trials (RCT) involving KT-TCMP as a combined or monotherapy in the treatment of HU were reviewed and analyzed. Meta-analysis was performed by Review Manager (version 5.2). Results Nine RCT of 1745 patients were eligible for this review and meta-analysis, of which eight RCT described the primary outcome of clinical efficacy and three RCT drew the secondary outcome of uterine size. Meta-analyzed ‘recovery’ clinical efficacy of KT-TCMP in seven RCT was conducted which considered diethylstilbestrol therapy alone as control, as well as three RCT that meta-analyzed the effect of KT-TCMP on uterine diameter enlargement. As a result, KT-TCMP therapy had a significantly improved difference in increasing ‘recovery’ clinical efficacy (risk ratio, 2.34; 95% confidence interval [CI], 1.90–2.89) and enlarging the uterine diameter (standardized mean difference, 1.62; 95% CI, 1.39–1.84). One study reported adverse reactions as an important outcome and found it was safe during KT-TCMP therapy. Conclusion The therapy of applying KT-TCMP as a combined or monotherapy in the treatment of HU may be more efficacious. However, these RCT were of moderate methodological quality and small sample size; thus, the results should be confirmed with more rigorously controlled further studies.

Nasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma especially prevailing among the natives of southern China. The regimen of concurrent chemoradiotherapy (CCRT) that include platinum and 5-fluorouracil (5-FU) is considered to be the standard treatment for NPC. However, its clinical use is limited by its toxicity. Our purpose was to evaluate the efficacy and safety of the regimen of CCRT with taxanes and platinum versus the regimen of CCRT with 5-FU and platinum in NPC treatment.Medline, the Cochrane library, and the Chinese medical literature database were searched for eligible studies. Meta-analysis was performed using Review Manager (Version 5.2).Six random controlled trials (RCTs) including 514 patients met our criteria. Meta-analysis showed that the regimen of CCRT with taxanes and platinum had an improved significant difference in complete remission (CR) and less incidence rate in adverse reactions such as gastrointestinal impairment grades III-IV, liver and kidney impairment grades I-II, and radiodermatitis grades III-IV versus the conventional regimen of CCRT with 5-FU and platinum, while the longterm effectiveness rate of overall survival, locoregional failure-free survival, or distant metastasis failure-free survival between the two groups was therapeutic equivalence.The regimen of CCRT with taxanes and platinum in NPC therapy may be more efficient and safe compared to the conventional modality of 5-FU and platinum in CCRT. However, we need more high-quality studies of multi-center and randomized double-blind clinical trials to further compare, analyze, and confirm the findings.

To review and evaluate the efficacy of kidney-tonifying traditional Chinese medicine prescriptions (KT-TCMP) in hypoplastic uterus (HU) treatment.We searched MEDLINE, the Cochrane Library, CNKI (China National Knowledge Infrastructure), WANFANG and VIP databases until 14 December 2013 independently with two investigators. Randomized controlled trials (RCT) involving KT-TCMP as a combined or monotherapy in the treatment of HU were reviewed and analyzed. Meta-analysis was performed by Review Manager (version 5.2).Nine RCT of 1745 patients were eligible for this review and meta-analysis, of which eight RCT described the primary outcome of clinical efficacy and three RCT drew the secondary outcome of uterine size. Meta-analyzed 'recovery' clinical efficacy of KT-TCMP in seven RCT was conducted which considered diethylstilbestrol therapy alone as control, as well as three RCT that meta-analyzed the effect of KT-TCMP on uterine diameter enlargement. As a result, KT-TCMP therapy had a significantly improved difference in increasing 'recovery' clinical efficacy (risk ratio, 2.34; 95% confidence interval [CI], 1.90-2.89) and enlarging the uterine diameter (standardized mean difference, 1.62; 95% CI, 1.39-1.84). One study reported adverse reactions as an important outcome and found it was safe during KT-TCMP therapy.The therapy of applying KT-TCMP as a combined or monotherapy in the treatment of HU may be more efficacious. However, these RCT were of moderate methodological quality and small sample size; thus, the results should be confirmed with more rigorously controlled further studies.