Background: As a life-threatening fungus, Cryptococcus gattii ( C gattii ) species complex is emerging worldwide. However, the geographical distribution, molecular traits, and virulence difference are poorly characterized in China. Results: From 2011 to 2017, we collected 32 strains of C gattii from 18 hospitals across China, of which 27 [84·4%] strains molecular traits were profiled by whole-genome sequencing (WGS) and multi-locus sequence typing (MLST) and compared with strains previously described in China from 2006 to 2020. Totally 119 clinical cases caused by C gattii strains (87 in previous reports and 32 in our study) distributed widely in 20 provincial-level administrative regions of China, of which 114 strains molecular types were obtained. The majority molecular type was VGI (81/114, 71·1%) and the other was VGII (33/114, 28·9%). Four major subtypes of VGI (VGIa, VGIb, VGIc, and VGId) were revealed from global C gattii VGI (n=308), respectively accounting for 52·9% (163/308), 36·0% (111/308), 3·9% (12/308), and 4·2% (13/308). The other nine strains could not be assigned to these four subtypes clearly. Our clinical data suggested that VGIb cases had a worse clinical outcome than VGIa, which was consistent with in vitro and in vivo experiments. In addition, a candidate virulence SNP on SOD2 in VGIa was initially identified by comparing high-quality de novo reference genome. Conclusions: The geographical distribution of C gattii species complex was first described in China. C gattii VGI could be clearly segregated into four major subtypes based on genomics profiles and VGIb was more virulent than VGIa in China. Our study suggests the molecular type of C gattii is necessary for personalized treatment in clinic.

BET bromodomain inhibitors (BETi) are promising therapeutic regimens for epithelial ovarian cancer (EOC). However, early-stage clinical trials indicate that drug tolerance may limit their anti-tumor efficacy. Here, we show that JQ1-refractory EOC cells acquire reversible resistance to BET inhibition and remain dependent on BRD4 function. The insensitivity is driven by a unique non-genetic mechanism that involves clonal selection for a pre-existing cell subpopulation with ample acetylated histones and sufficient nuclear phase-separated BRD4 droplets to counteract BETi antagonism. A vertical combination approach by co-blocking BET proteins and downstream Aurora kinases proves to achieve more complete responses than single inhibitors. Collectively, our study implicates epigenetic heterogeneity in therapeutic resistance to chromatin-targeted agents and proposes a rational strategy to address this anticipated clinical dilemma.

Purpose: this study attempts to identify the independent risk factors that can predict lymph node metastasis for the patients with non-small cell lung cancer (NSCLC), and guide doctor adoption of individualized treatment for such patients. Materials and methods: This study was approved by the Hospital's Ethics Committee and all patients had signed informed consent forms. We retrospectively reviewed NSCLC patients who had undergone surgical resection from December 2008 to December 2013. The statistical significance of evaluation variables and lymph node metastasis was determined with Pearson's Chi-square test. The risk factors of lymph node metastasis were determined through univariate and multivariate logistic regression analysis. And for the age and tumor diameter factors, optimal cutoff points were determined with a receiver operating characteristic analysis. Results: In the present study, a total of 2623 patients were included in the study, and 779 patients with lymph node metastasis. Three independent risk factors were identified: age, tumor diameter and Ki-67 index. We found that <65 years of age (Adjusted-OR:1.921), >=.2.85 cm of tumor diameter (Adjusted-OR:3.141), and 5% similar to 25% in Ki-67 group (Adjusted-OR:2.137), >= 25% (Adjusted-OR:3.341) were significant. Also we found that 307 patients with lymph node metastasis and the lymph node metastasis rate was 51.0%, when the age<65 years, Ki-67 index >= 25%, and the tumor diameter >= 2.85 cm. On the contrary, there were only 2 patients with lymph node metastasis, and the rate of lymph node metastasis was 5.1%. Conclusion: Identifying three independent risk factors that predict lymph node metastasis in non-small cell patients, Among NSCLC patients in whom all three predictors were identified, and over a half of the patients showed lymph node metastasis.

As the No.1 killing cancer in the world, the incidence of lung cancer is still on the rise across the globe these years, such a trend is particularly apparent in China. To study the molecular mechanism of the occurrence of lung cancer and develop new anti-cancer drugs is an arduous task confronting medical researchers of the whole world. Multiple signaling pathways are involved in the lung carcinogenesis. Transforming Growth Factor-β family(TGF-β), known as a multi-functional cytokine superfamily, plays extensively regulatory roles in life activities, including morphogenesis, embryonic development, immunoregulation, healing of wound, as well as inflammation and tumor. Here we review the roles of TGF-β signal transduction pathway in lung cancer. Correspondence to: Dr. Jianxin Wang, The Department of Respiratory Diseases of Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China, Tel: 01066936616; Fax: +86-010-66936616; E-mail: jianxinwang2010@163.com Dr. Lei Pan, Address: 10 Tieyi Rd, Bejing, 100038, China, Tel: 010-63926748; Fax: +86-010-63926748; E-mail: leipan2010@163.com Received: July 28, 2016; Accepted: August 20, 2016; Published: August 24, 2016 Introduction Lung cancer remains the leading cause of death by cancer in the world, marked by the fastest growth of morbidity and mortality and is one of the malignant tumors posing the biggest threat to human health and lives [1,2]. The incidence of lung cancer in China has come close to the level of advanced countries, but the cause of it is unclear yet. Substantial data reveal that the genesis and progression of lung cancer are co-impacted by hereditary and environmental factors, long-term heavy smoking is closely related to the genesis of lung cancer. Based on different morphological characteristics of cancer cell, lung cancer can be mainly divided into two types: non-small cell lung cancer and small cell lung cancer. Non-small cell lung cancer further includes squamous cell carcinoma, lung adenocarcinoma and large cell carcinoma. These two categories of lung cancer differ distinctly in terms of biological characteristics, prognosis and method of treatment. Small cell lung cancer, less common as it is, is one of the most malignant types, accounting for 10-15% of the primary lung cancer, featuring fast spreading of cancer cells, strong invasiveness, and early distant metastasis. It is sensitive to chemotherapy at first, but often ends in poor prognosis and distant metastasis. This kind of lung cancer is, to a great extent, smoking-related. Squamous cell carcinoma (squamous carcinoma) is the most common type of lung cancer, taking up roughly 40-50% of primary lung cancer, often found in aged male, strongly related to smoking. Squamous carcinoma grows at a slow rate and features late metastasis. It has increased chances of surgical resection, and higher five-year survival rate, but is not so sensitive to chemo radiotherapy as small cell undifferentiated carcinoma. Adenocarcinoma of the lung, featuring early onset and relatively larger number of female patients, has little to do with smoking, accounting for 25% of primary lung cancer. Adenocarcinomas features earlier local infiltration and hematogenous metastasis than squamous carcinoma, and its incidence rate is lower than squamous carcinoma and undifferentiated carcinoma. Metastasis occurs later in large cell carcinoma than in small cell undifferentiated carcinoma, hence gains greater chances of surgical resection [3-5]. If lung cancer is detected in the early phase, even it recurs; it is highly possible to be cured. However, at present, a very good lung cancer marker is still absent for being used as early diagnosis and adjuvant therapy indicator. Transforming growth factor-β superfamily, known as a big class of multifunctional cell factors, is widely involved in the adjustment of life activities such as embryonic development, cell proliferation, differentiation, migration, apoptosis, vascularization, wound healing, and immune system regulation, and is also related to inflammation, rheumatic disease, heart disease, diabetes, etc. At present, an increasing number of researches have indicated that TGF-β signaling pathway is relevant to the progression of tumor [6-12]. In this review, we focus on the TGF-β signaling pathway and its roles in lung cancer. The TGF-β superfamily and TGF-β signaling pathway TGF-β belongs to a group of TGF-β family that regulates cell Xue X (2016) The relationship of Transforming Growth Factor-β and lung cancer Volume 1(2): 32-40 Clin Proteom Bioinform, 2016 doi: 10.15761/CPB.1000109 growth and differentiation [10,11]. By now, more than 30 members of the TGF-β family have been found, all featuring dimer structure and cysteine group structure motifs. In addition to TGF-β, this family also includes activins, inhibins, Müllerian inhibitory substance (MIS), and bone morphogenetic proteins (BMPs) [13-16]. The naming of TGF-β is based on that this kind of cell factor can change the phenotype of normal fibroblast, that is, in case epidermal growth factor (EGF) coexists, it changes the wall-adherent growth characteristic of fibroblast and gains the ability to grow in agar, and loses the inhibiting effect of density reliance during growth [17-22]. TGF-β is a multifunctional polypeptide cytokine and makes up a group of protein family that regulates cell growth, migration, apoptosis and differentiation. Being the basis of the balance, development and maintenance of tissues in normal or morbid state, it can effectively inhibit the proliferation of most types of cells, such as epithelial cells, endothelial cells, hematopoietic cells, leukomonocyte, etc [9,23,24]. It is known as a powerful proliferation and tumor suppressor. According to the researches, TGF-β expression in serum and tissues of tumor patients rises notably along with the malignant degree of tumor, indicating a close relationship between TGF-β and malignant transformation of tumor. Therefore, TGF-β plays a dual role in the genesis and progression of tumor. In other words, it is a tumor suppressor in the early stage of tumor, but promotes malignant transformation of tumor in the later stage through autocrine and paracrine. However, the mechanisms of how TGF-β changes from tumor suppressor into tumor promoter and further promotes malignant transformation of tumor is still unknown [25-30].

Lung cancer remains the leading cause of cancer-associated death worldwide. MiR-21 and miR-155 are the most amplified miRNAs in non-small cell lung carcinoma (NSCLC), and are critical promoters of NSCLC progression. However, it remains unclear how miR-21 and miR-155 induce cancer progression, and whether these miRNAs share common targets, such as tumor suppressor genes required to prevent NSCLC. Here we report that miR-21 and miR-155 levels are elevated in NSCLC and are proportional to the progression of the disease. In addition, miR-21 and miR-155 share nearly 30% of their predicted target genes, including SOCS1, SOCS6, and PTEN, three tumor suppressor genes often silenced in NSCLC. Consequently, antagonizing miR-21, miR-155 or both potently inhibited tumor progression in xenografted animal models of NSCLC. Treatment with miR-21 and miR-155 inhibitors in combination was always more effective against NSCLC than treatment with a single inhibitor. Furthermore, levels of miR-21 and miR-155 expression correlated inversely with overall and disease-free survival of NSCLC patients. Our findings reveal that miR-21 and miR-155 promote the development of NSCLC, in part by downregulating SOCS1, SOCS6, and PTEN. Combined inhibition of miR-21 and miR-155 could improve the treatment of NSCLC.

Lung cancer is the most commonly diagnosed neoplasm and the leading cause of cancer-related death worldwide. Despite the high incidence of lung cancer, the diagnosis of solitary thin-walled cavity lung cancer is rare. The aim of this review is to explore the potentials of computed tomography (CT) as diagnostic tool for solitary thin-walled cavity lung cancer. The literature search was made in electronic databases including PudMed, Ovid SP, Embase, Web of Sciences, EBSCO and Wiley online by using relevant key terms. Because of the rarity of the subject, no precise exclusion or inclusion criteria were used for article selection and the outcome dissemination was decided to be more descriptive rather than quantitative. The detection of cavitation in lungs is frequently done utilizing chest radiographs CT scans. However, the diagnostic challenge remains the accurate detection of solitary thin-walled cavity lung cancer among the prevalence of cavitary lung lesions in multiple thoracic disorders including benign disorders, infectious disease and malignant tumors. Moreover, an accurate diagnosis of solitary thin-walled cavity lung cancer is further complicated by its subjective classification within the literature. In order to facilitate early diagnosis of this disease and circumvent the need for more invasive tests that may not be warranted, the overarching goal is to establish definitive radiological features of lung cavities that are indicative of malignancy. Herein, we describe the benefits of using CT to identify and diagnose solitary thin-walled cavity lung cancer, as well as explore the underlying mechanisms that contribute to thin-walled cavity formation in oncology patients. CT is the best modality for the noninvasive differentiation between malignant and nonmalignant cavities as it provides reliable information regarding the morphology and density of lesions. Besides, CT densitometry can efficiently detect the calcifications in lesions.

Though aminoglycosides are routinely used clinically as antimicrobial agents for the treatment of severe infections due to Klebsiella pneumoniae, resistance to the same is an increasing problem. One such resistance mechanism is the production of 16S rRNA methylases. The objective of the current study was to investigate the prevalence and molecular epidemology of 16S rRNA methylase genes among 43 K. pneumoniae isolates (each of which had at least one PQMR gene and ciprofloxacin minimum inhibitory concentration greater than 0.25) recovered from nine tertiary hospitals in China. Our results suggest great genetic variation in terms of 16S rRNA methylase gene of K. pneumoniae hosts containing at least one PQMR gene. This further reinforces the clinical and systemic urgency required to characterize and block their transmission routes.

Granulosa cells (GCs) are essential for proper oocyte, follicular development, and steroidogenesis in the ovary. Transforming growth factor beta (TGF-beta) superfamily members are critical in regulating GCs growth and differentiation. Smad3 is known to serve as a signaling intermediate for the TGF-beta; however, the functions of Smad3 in the human GCs remain unidentified. In this study, the luteinized GCs collected from follicular aspirates from patients undergoing in vitro fertilization were cultured and engineered to overexpress and knockdown Smad3, which were validated by RT-PCR and Western blotting. Immunocytochemistry showed that Smad3 protein was strongly expressed in human ovarian luteinized GCs. EdU incorporation demonstrated that Smad3 promoted the proliferation of GCs, and the expression of PCNA was also enhanced by Smad3. ELISA analysis indicated that the secretion of both estradiol and progesterone was stimulated by Smad3. In addition, Smad3 upregulated the level of follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), and protein kinase A (PKA) proteins. We subsequently added special PKA inhibitor H89 into the GCs and found that the stimulating effect on the growth of GCs by Smad3 was blocked partly. The morphology of cultured GCs was changed by Smad3, and the expression level of integrin beta 1 was enhanced by Smad3. Kindlin-2, an important cellular mediating molecule of integrin beta signaling, was expressed in human ovarian luteinized GCs and was upregulated by Smad3. Our results indicated that Smad3 promoted the proliferation and steroidogenesis of human ovarian luteinized GCs, and these effects may be mediated by the FSHR/LHR-PKA signaling pathway. (C) 2014 IUBMB Life, 66(6): 424-437, 2014

A post-transcriptional pathway by which TGF-β modulates expression of specific proteins, Disabled-2 (Dab2) and Interleukin-like EMT Inducer (ILEI), inherent to epithelial to mesenchymal transition (EMT) in murine epithelial cells through Akt2-mediated phosphorylation of poly r(C) binding protein (PCBP1), has been previously elucidated. The aims of the current study were to determine if the same mechanism is operative in the non-small cell lung cancer (NSCLC) cell line, A549, and to delineate the underlying mechanism. Steady-state transcript and protein expression levels of Dab2 and ILEI were examined in A549 cells treated with TGF-β for up to 48 h. Induction of translational de-repression in this model was quantified by polysomal fractionation followed by qRT-PCR. The underlying mechanism of isoform-specific activation of Akt2 was elucidated through a combination of co-immunoprecipitation studies. TGF-β induced EMT in A549 cells concomitant with translational upregulation of Dab2 and ILEI proteins through isoform-specific activation of Akt2 followed by phosphorylation of PCBP1 at serine-43. Our experiments further elucidated that the adaptor protein SchA is phosphorylated at tyrosine residues following TGF-β treatment, which initiated a signaling cascade resulting in the sequential recruitment of p85 subunit of PI3K and focal adhesion kinase (FAK). The SchA–FAK–p85 complex subsequently selectively recruited and activated Akt2, not Akt1. Inhibition of the p85 subunit through phosphorylated 1257 peptide completely attenuated EMT in these cells. We have defined the underlying mechanism responsible for isoform-specific recruitment and activation of Akt2, not Akt1, during TGF-β-mediated EMT in A549 cells. Inhibition of the formation of this complex thus represents an important and novel therapeutic target in metastatic lung carcinoma.

Gefitinib-induced interstitial lung disease (ILD) is a rare but lethal drug adverse event, which usually leads to the withdrawal of gefitinib and causes complications with anticancer treatment. In this study, gefitinib administration combined with prednisolone in a female with stage IIIb non-small cell lung cancer (NSCLC) produced a good outcome without inducing ILD. The results suggested that combined administration of gefitinib with glucocorticoids may be an efficient method to treat NSCLC while avoiding complications with ILD.

Pulmonary arterial hypertension (PAH) is a debilitating condition with progressive remodeling of the pulmonary resistance vessels. PAH is characterized by multifocal, polyclonal lesions inhabited by cells that underwent phenotypic transition, resulting in altered cell proliferation and contractility, ultimately resulting in increased vascular resistance. Diagnosis of PAH is confounded by the fact that it is largely asymptomatic in the initial stages. In fact, idiopathic PAH patients >65 years of age cannot be diagnosed hemodynamically due to high pulmonary capillary wedge pressure. This highlights the need for defining more robust molecular biomarkers for PAH diagnosis and progression. Recent studies have indicated that microRNAs (miRNAs), a class of small noncoding RNAs that regulate gene expression, play a discrete role in vascular inflammation and in the etiology of cardiovascular pathologies inclusive of PAH and can potentially serve as diagnostic biomarkers. However, a cohesive understanding of global miRNA-mediated molecular events that control pulmonary vasculature plasticity is lacking which, if addressed systematically, can lead to detailed elucidation of the downstream cellular pathways that are affected by activation/silencing of silenced cognate transcripts. In turn, this can lead to not only robust biomarkers, but also to novel therapeutic strategies targeting more upstream regulators than the existing ones targeting more downstream effectors. The current review aims to provide a summary understanding of PAH, its associated pathophysiology, current knowledge of the role of miRNAs in PAH, and identifies grey areas that need further research for successful bench-to-bedside transition of these exciting new discoveries.

A substantial percentage (8%) of all newly diagnosed cancer cases are in patients with previous tumours, with a similar trend in lung cancer. Cases of multiple primary lung cancer (MPLC) are increasing worldwide, due to improved diagnostic and surveillance mechanisms and the ageing population. Diagnosis of MPLC is complicated by difficulties in distinguishing it from lung cancer metastasis. Clinicopathological assessment, diagnosis and management have evolved, but remain severely limited by the lack of robust and dependable molecular markers for the differential diagnosis of metastasis and MPLC. This systematic review evaluates diagnostic criteria for MPLC, and the subsequent management and success rates. The incorporation of molecular biology techniques into the diagnostic process for MPLC is also discussed.

Quinolones are a group of antimicrobial agents that were serendipitously discovered as byproducts of the synthesis of chloroquine. Chemical modifications, such as the addition of fluorine or piperazine, resulted in the synthesis of third- and fourth-generation fluoroquinolones, with broad-spectrum antimicrobial actions against aerobic or anaerobic, Gram-positive or Gram-negative bacteria. The efficacy and consequent widespread use of quinolones and fluoroquinolones has led to a steady global increase in resistance, mediated via gene mutations, alterations in efflux or cell membranes and plasmid-conferred resistance. The first plasmid-mediated quinolone resistance gene, qnrA1, was detected in 1998. Since then, many other genes have been identified and the underlying mechanisms of resistance have been elucidated. This review provides an overview of quinolone resistance, with particular emphasis on plasmid-mediated resistance.