The oral microbiota in patients with pancreatic cancer, patients with IPMNs, and controls: a pilot study

Abstract

Purpose

Poor oral health appears to be a risk factor for pancreatic cancer, possibly implicating the oral microbiota. In this pilot study, we evaluated the characteristics of the oral microbiota in patients with pancreatic ductal adenocarcinoma (PDAC), intraductal papillary mucinous neoplasms (IPMN), and healthy controls.

Methods

Forty newly diagnosed PDAC patients, 39 IPMN patients, and 58 controls, excluding current smokers and users of antibiotics, provided saliva samples. Common oral bacterial species were comprehensively surveyed by sequencing of the 16S rRNA microbial genes. We obtained measures of diversity and the mean relative proportions of individual taxa. We explored the degree to which these measures differed according to respondent characteristics based on individual interviews.

Results

PDAC cases did not differ in diversity measures from either controls or IPMN cases. PDAC cases had higher mean relative proportions of Firmicutes and related taxa, while controls had higher mean relative proportions of Proteobacteria and related taxa. Results were generally similar when comparing PDAC to IPMN cases. Among IPMNs and controls combined, younger individuals had higher levels of several taxa within the Proteobacteria. The only other variable consistently related to mean relative proportions was mouthwash use, with taxa within Firmicutes more common among users.

Conclusions

While there were no differences in diversity of the oral microbiota among these groups, there were differences in the mean relative proportions of some taxa. Characteristics of the oral microbiota are not associated with most measures of oral health.

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Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to trametinib in colorectal cancer cells

Abstract

Background

The mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer (CRC) is limited. Synthetic lethality arises with a combination of two or more separate gene mutations that causes cell death, whereas individual mutations keep cells alive. This study aimed to identify the genes responsible for resistance to trametinib in CRC cells, using a synthetic lethal short hairpin RNA (shRNA) screening approach.

Methods

We infected HT29 cells with a pooled lentiviral shRNA library and applied next-generation sequencing to identify shRNAs with reduced abundance after 8-day treatment of 20 nmol/L trametinib. HCT116 and HT29 cells were used in validation studies. Stable ring finger protein 183 (RNF183)-overexpressing cell lines were generated by pcDNA4-myc/his-RNF183 transfection. Stable RNF183-knockdown cell lines were generated by infection of lentiviruses that express RNF183 shRNA, and small interference RNA (siRNA) was used to knock down RNF183 transiently. Quantitative real-time PCR was used to determine the mRNA expression. Western blotting, immunohistochemical analysis, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the protein abundance. MTT assay, colony formation assay, and subcutaneous xenograft tumor growth model were used to evaluate cell proliferation.

Results

In the primary screening, we found that the abundance of RNF183 shRNA was markedly reduced after treatment with trametinib. Trametinib induced the expression of RNF183, which conferred resistance to drug-induced cell growth repression and apoptotic and non-apoptotic cell deaths. Moreover, interleukin-8 (IL-8) was a downstream gene of RNF183 and was required for the function of RNF183 in facilitating cell growth. Additionally, elevated RNF183 expression partly reduced the inhibitory effect of trametinib on IL-8 expression. Finally, xenograft tumor model showed the synergism of RNF183 knockdown and trametinib in repressing the growth of CRC cells in vivo.

Conclusion

The RNF183-IL-8 axis is responsible for the resistance of CRC cells to the MEK1/2 inhibitor trametinib and may serve as a candidate target for combined therapy for CRC.

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Next generation sequencing of progressive colorectal liver metastases after portal vein embolization

Abstract

Portal vein embolization (PVE) can be required to stimulate liver regeneration before hepatectomy for colorectal liver metastasis (CRCLM), however PVE may also trigger CRCLM progression in patients initially exhibiting chemotherapy response. Using RNA-seq, we aimed to determine the molecular networks involved in metastatic progression in this context. A prospective study including all CRCLM patients undergoing PVE prior to hepatectomy was conducted. Paired biopsies of metastatic lesions were obtained prior to and after PVE and total RNA was isolated and used to prepare Illumina rRNA-depleted TruSeq stranded cDNA libraries for HiSeq 100 bp paired-end sequencing. Patients were classified with progression of disease (PD_PVE) or stable disease (SD_PVE) post-PVE using 3D-CT tumor volumetric analysis. Results: Twenty patients were included, 13 (65.0%) in the PD_PVE group (median 58.0% (18.6–234.3) increase in tumor volume) and 7 (35.0%) in the SD_PVE group exhibiting continuous chemotherapy response (median −14.3% (−40.8 to −2.8) decrease in tumor volume) (p < 0.0001). Our results showed that progressive CRCLM after PVE undergo gene expression changes that indicate activation of core cancer pathways (IL-17 (p = 5.94 × 10⁻⁰³), PI3K (p = 8.71 × 10⁻⁰³), IL6 and IGF-1 signaling pathways), consistent with changes driven by cytokines and growth factors. Differential expression analysis in a paired model of progression (EdgeR, DeSeq) identified significantly dysregulated genes in the PD_PVE group (FOS, FOSB, RAB20, IRS2). Conclusion: Differentially expressed genes and pathways with known links to cancer and metastasis were identified post-PVE in patients with disease progression. Highlighting these molecular changes is a crucial first step towards development of targeted therapeutic strategies that may mitigate the effects of PVE on tumor growth.

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Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms

Abstract

The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1 and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1 and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies. This article is protected by copyright. All rights reserved.

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Fusion of the Genes BRD8 and PHF1 in Endometrial Stromal Sarcoma

Abstract

We present a new endometrial stromal sarcoma (ESS)-associated genomic rearrangement involving chromosome arms 5p and 6p and leading to the formation of a BRD8-PHF1 fusion gene. The PHF1 (PHD finger protein 1) gene, from 6p21, is known to be rearranged in ESS in a promiscuous way inasmuch as it has been shown to recombine with JAZF1, EPC1, MEAF6, and now also with BRD8, in tumors of this type. In all rearrangements of PHF1, including the present one, a recurrent theme is that the entire coding part of PHF1 constitutes the 3' end of the fusion. BRD8 (bromodomain containing 8) encodes a protein which is involved in regulation of protein acetylation and/or histone acetyl transferase activity. All the genetic fusions identified so far in ESS appear to recombine genes involved in transcriptional regulation, i.e. polycomb group complex-mediated and aberrant methylation/acetylation genes. This adds to the likelihood that the new BRD8-PHF1 shares the same pathogenetic mechanism as the other ESS-specific rearrangements. This article is protected by copyright. All rights reserved.

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Endoscopic screening for synchronous esophageal neoplasia among patients with incident head and neck cancer: Prevalence, risk factors and outcomes

Abstract

Esophageal squamous-cell neoplasia (ESCN) is a common second primary neoplasia found in patients with head-and-neck squamous-cell carcinoma (HNSCC). This study sought to identify the risk factors for synchronous ESCN and how they influence survival in HNSCC patient. 815 incident HNSCC patients were prospectively recruited for endoscopy screening for ESCN using white-light imaging, narrow-band imaging, Lugol chromoendoscopy, and pathological confirmation. Associated lifestyle and clinicopathological data were collected. The interquartile follow-up period cutoffs were 11.3, 20.5 and 34.9 months. 124 patients (15.2%) were diagnosed as having synchronous ESCN (66 low-grade dysplasia, 29 high-grade dysplasia and 29 esophageal squamous-cell carcinoma). Consumption of alcohol, but not betel nut or cigarette, was significantly associated with the presence of synchronous ESCN (adjusted odds ratio [aOR]= 7.1 and 10.9 for former and current drinkers respectively). There was an interaction between cumulative dose of alcohol consumption and alcohol flushing response on the development of ESCN. High-dose drinkers with flush response were 16.9 times more likely to have esophageal high-grade dysplasia/SCC than non-drinkers. Compared with oral cavity cancer patients, those with hypopharyngeal, laryngeal and oropharyngeal cancer were 6.8, 4.6 and 2.8 times more likely to have esophageal high-grade dysplasia/SCC. HNSCC patients with synchronous ESCN had lower overall survival than those without (p < 0.0001). In conclusion, surveillance of ESCN is strongly recommended for the high-risk subpopulation of HNSCC patients, especially drinkers who have a flush response to alcohol, and those with distant metastasis of index cancer and cancers in hypopharynx, oropharynx and larynx. This article is protected by copyright. All rights reserved.

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Prognostic role of ABO blood type in patients with extranodal natural killer/T cell lymphoma, nasal type: a triple-center study

Abstract

Background

The prognostic significance of ABO blood type for lymphoma is largely unknown. We evaluated the prognostic role of ABO blood type in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL).

Methods

We retrospectively analyzed clinical data of 697 patients with newly diagnosed ENKTL from three cancer centers. The prognostic value of ABO blood type was evaluated using Kaplan–Meier curves and Cox proportional hazard models. The prognostic values of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) were also evaluated.

Results

Compared with patients with blood type O, those with blood type non-O tended to display elevated baseline serum C-reactive protein levels (P = 0.038), lower rate of complete remission (P = 0.005), shorter progression-free survival (PFS, P < 0.001), and shorter overall survival (OS, P = 0.001). Patients with blood type O/AB had longer PFS (P < 0.001) and OS (P = 0.001) compared with those with blood type A/B. Multivariate analysis demonstrated that age >60 years (P < 0.001), mass ≥5 cm (P = 0.001), stage III/IV (P < 0.001), elevated serum lactate dehydrogenase (LDH) levels (P = 0.001), and blood type non-O were independent adverse predictors of OS (P = 0.001). ABO blood type was found to be superior to both the IPI in discriminating patients with different outcomes in the IPI low-risk group and the KPI in distinguishing between the intermediate-to-low- and high-to-intermediate-risk groups.

Conclusions

ABO blood type was an independent predictor of clinical outcome for patients with ENKTL.

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Enterogenous cyst of pediatric testis: a case report

An enterogenous cyst is a rare entity categorized as an intestinal cyst. In most cases, enterogenous cysts are seen in the mediastinum, peritoneal cavity, spinal canal, subarachnoid space, and cerebral ventricle.

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A prospective study of serial imaging comparing FDG-PET and FLT PET during radical chemo-radiation for Non-Small Cell Lung Cancer: reduction of detectable proliferation associated with worse survival

Publication date: Available online 29 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sarah Everitt, David Ball, Rodney J. Hicks, Jason Callahan, Nikki Plumridge, Jenny Trinh, Alan Herschtal, Tomas Kron, Michael Mac Manus
PurposeMonitoring tumor cell metabolism and tumor proliferation with FDG PET and FLT PET, respectively, during chemo-radiation therapy (CRT) may enable adaptive radiotherapy and provide prognostic information. We acquired serial 18F-FDG and 18F-FLT-PET/CT, during radical CRT and correlated tumor response with progression free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC) patients.Methods and materialsPatients with FDG-PET/CT stage I-III NSCLC were prescribed concurrent chemotherapy and RT (60 Gy in 30 fractions). Scans were acquired at baseline [FDG-PET/CT (FDGBL) for RT planning and FLT-PET (FLTBL)], week two (FDGwk2 and FLTwk2) and week four (FDGwk4 and FLTwk4) of CRT. Tumour responses were categorised as complete or partial responses (CR, PR), stable or progressive disease (SD, PD) using EORTC criteria. Associations between response, OS and PFS were analysed with univariate Cox regressions and plotted using Kaplan-Meier curves.ResultsBetween 2009-2013, 60 patients were recruited. 37 (62%) were males and median age was 66 years (range 31-86). Two-year OS and PFS were 0.51 and 0.26, respectively. Unexpectedly, SD on FLTwk2 compared with CR/PR was associated with longer OS HR [95% CI], 2.01 [0.87, 4.65] p=0.082 and PFS 2.01 [0.92, 4.36] p=0.061. Weeks 2 and 4 FDG PET/CT were not significantly associated with survival. Study scans provided additional information to FDGBL in 21 (35%) patients. Distant metastases detected in three patients on FLTBL and in two patients on FDG/FLTwk2 changed treatment intent from curative to palliative. Loco-regional progression during RT was observed in five (8%) patients, prompting larger RT fields.ConclusionsStable uptake of 18F-FLT at week two was paradoxically associated with longer OS and PFS. This suggests that suppression of tumor cell proliferation may protect against radiation induced tumour cell killing. Baseline FLT, FLTwk2 and FDGwk2 detected rapid distant and loco-regional progression in 10 (17%) patients prompting changes in management.

Teaser

Sixty Non-Small Cell Lung Cancer (NSCLC) patients, prescribed curative intent chemo-radiation therapy, were prospectively studied. ¹⁸F-FDG and ¹⁸F-FLT-PET/CT scans were acquired at baseline, week two and week four to monitor tumor cell metabolism and proliferation, respectively. Stable uptake of ¹⁸F-FLT at week two was associated with superior overall survival compared to patients whose tumors demonstrated reduced or absent ¹⁸F-FLT uptake. This suggests that suppression of tumor cell proliferation may weaken the tumoricidal effect of chemoradiation.


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PRADO: a palliative care model for every radiation oncology practice

Publication date: Available online 29 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Timur Mitin, Charles R. Thomas, Jerry J. Jaboin




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An Update of a Prospective Study of SBRT for Post-chemoradiation Residual Disease in Stage II/III Non-small Cell Lung Cancer

Publication date: Available online 29 July 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sameera Kumar, Jonathan Feddock, Xingzhe Li, Andrew J. Shearer, Logan Hall, Brent J. Shelton, Susanne Arnold, Ronald C. McGarry
Purpose/Objective(s)Chemoradiation (CRT) remains standard of care for Stage III NSCLC, although local recurrences are a significant problem. Previously, we reported prospective results of the feasibility and safety of dose escalation by the addition of a stereotactic boost (SBRT) to residual disease following standard CRT. Here we report extended term outcomes for risk of late toxicities, local control and survival.Materials/MethodsPatients with stage IIB/III NSCLC underwent CT or PET-CT screening approximately one month following completion of CRT. Limited residual disease (≤ 5 cm) within the site of the primary tumor received an SBRT boost of either 10 Gy X 2 fractions or 6.5 Gy X 3 to the primary tumor in order to achieve a total (BED10) >100 Gy.ResultsThirty-seven patients received protocol therapy. With a median follow-up of 25.2 months, the crude local control rate for the entire group was 78% (n=29), but 10 (29%) and 24 (65%) patients developed regional and metastatic disease, respectively. At last follow-up, 5 (13.5%) patients remain alive, all with no evidence of disease while twenty-seven (73%) died of disease, and the remaining 5 (13.5%) died of other causes. Median overall survival (mOS) for the entire group was 25.2 months. Predictors for Grade 3 pneumonitis included age and mean lung dose. Poorer mOS was associated with histology, mOS 15.6 months for squamous cell vs 34.8 months for other histologies (large cell neuroendocrine tumors excluded) (p=0.04). The median progression free survival (mPFS) was 6 months with IIIB disease having significantly worse mPFS (Stages IIB/IIA being 9.4 months versus 4.7 months for Stage IIIB (p=0.03)).ConclusionSBRT boost following CRT is a safe treatment resulting in improvements in local control for locally advanced NSCLC. No additional late toxicities were seen. Possible improvement in OS was found, but further study in a larger prospective trial is needed.

Teaser

Chemoradiation (CRT) remains the standard of care for Stage III NSCLC although local recurrences are a significant problem. Dose escalation of radiation has met with mixed results. Given the success and safety of SBRT in early stage NSCLC, this manuscript describes the long term safety and results of adding an SBRT boost to CRT in an effort to escalate the dose of RT to the primary mass in patients with Stage II-III NSCLC.


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A Challenging Diagnosis of IgG4-Related Disease When Understanding Limitations of Laboratory Testing Was Pivotal

A 76-year-old man was incidentally found on a CT scan to have lymphadenopathy and bilateral kidney enlargement suggestive of infiltrative renal disease. He was largely asymptomatic but had bilateral salivary and lacrimal gland enlargement. A grossly elevated serum IgG (>70 g/L) with concomitant suppression of other immunoglobulins, a small IgG restriction, and a parotid biopsy revealing lymphoplasmacytic infiltrate with slight kappa light chain excess all suggested a lymphoproliferative disorder (LPD). The diagnostic workup was further confounded by a normal serum IgG4 concentration. Moreover, bone marrow and renal biopsies did not reveal evidence of LPD. Discussion with the laboratory not only clarified that the markedly increased total IgG could not be accounted for by the small IgG restriction, but also identified a discrepancy in the IgG4 measurement. Repeat analysis of a follow-up sample revealed an elevated IgG4 of 5.94 (reference interval: 0.039–0.864) g/L, which prompted a repeat parotid biopsy that showed predominant IgG4+ lymphocytic infiltrates. Despite the deluding presentations, a final diagnosis of IgG4-related disease (IgG4-RD) was made based on elevated serum IgG4 concentrations and histopathological findings. This case highlights the importance of recognizing limitations of laboratory testing and the benefit of close communications among clinical subspecialties and the laboratory.

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The role of anaplastic lymphoma kinase in pediatric cancers

Abstract

The anaplastic lymphoma kinase (ALK) was initially identified as a fusion partner of the nucleophosmin gene in anaplastic large cell lymphoma (ALCL) with t(2;5)(p23;q35) translocation, and then described with different genetic abnormalities in a number of tumors. Although ALK is known to be involved in the pathogenesis of neuroblastoma through activating mutations or gene amplification, its role in the pathogenesis of other pediatric cancers is still elusive. In addition to neuroblastoma, the high-grade amplification of ALK has been described in a subset of rhabdomyosarcoma cases. Normal ALK protein expression is restricted to the nervous systems of adult mammals, but the aberrant expression of ALK has been observed in a variety of pediatric cancers, including glioma and Ewing sarcoma. The discovery of oncogenic activation of ALK in neuroblastoma suggests that this cancer could be potentially treated with an ALK inhibitor, as could other cancers, such as non-small cell lung cancer and ALCL. However, cellular responses to mutant ALK are complex when compared to rearranged ALK, and treatment remains a challenge. This review focuses on the biology of ALK in pediatric cancers and possible therapeutic strategies for ALK-associated tumors.

This article is protected by copyright. All rights reserved.

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Double-edged sword of mesenchymal stem cells: cancer-promoting VS therapeutic potentials

Summary

Mesenchymal stem cells (MSCs) derived from adipose tissue, bone marrow, cord blood, and other tissues, have recently attracted much attention as potential therapeutic agents in various diseases due to their trans-differentiation capacity. However, recent studies suggested that MSCs also appear to contribute tumor pathogenesis by supporting tumor microenvironments, increasing tumor growth, and eliciting anti-tumor immune responses. While some studies suggest that MSCs have the inhibitory effects on tumor development, they are overwhelmed by a member of researches that MSCs exert stimulatory effects on tumor pathogenesis. In this review article, we summarized a number of findings to provide current information about their therapeutic potential in various diseases; we then discussed the potential roles of MSCs in tumor progression.

This article is protected by copyright. All rights reserved.

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Validity of self-reported cancer history in the health examinees (HEXA) study: A comparison of self-report and cancer registry records

Publication date: October 2017
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): Sooyoung Cho, Aesun Shin, Daesub Song, Jae Kyung Park, Yeonjung Kim, Ji-Yeob Choi, Daehee Kang, Jong-Koo Lee
PurposeTo assess the validity of the cohort study participants' self-reported cancer history via data linkage to a cancer registry database.MethodsWe included 143,965 participants from the Health Examinees (HEXA) study recruited between 2004 and 2013 who gave informed consent for record linkage to the Korean Central Cancer Registry (KCCR). The sensitivity and the positive predictive value of self-reported histories of cancer were calculated and 95% confidence intervals were estimated.ResultsA total of 4,860 participants who had at least one record in the KCCR were included in the calculation of sensitivity. In addition, 3,671 participants who reported a cancer history at enrollment were included in the calculation of positive predictive value. The overall sensitivity of self-reported cancer history was 72.0%. Breast cancer history among women showed the highest sensitivity (81.2%), whereas the lowest sensitivity was observed for liver cancer (53.7%) and cervical cancer (52.1%). The overall positive predictive value was 81.9%. The highest positive predictive value was observed for thyroid cancer (96.1%) and prostate cancer (96.1%), and the lowest was observed for cervical cancer (43.7%).ConclusionThe accuracy of self-reported cancer history varied by cancer site and may not be sufficient to ascertain cancer incidence, especially for cervical and bladder cancers.



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The Metastasis Status and Tumor Burden-Associated CA125 Level Combined with the CD4/CD8 Ratio Predicts the Prognosis of Patients with Advanced Pancreatic Cancer: A New Scoring System

Publication date: Available online 29 July 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Chao Yang, He Cheng, Guopei Luo, Yu Lu, Meng Guo, Kaizhou Jin, Zhengshi Wang, Xianjun Yu, Chen Liu
BackgroundAlthough CA125 and the tumor immune response have been reported to be associated with pancreatic cancer, their prognostic value for advanced pancreatic cancer patients undergoing chemotherapy remains uncertain. We thus studied the prognostic value of the combination of the CA125 level with the CD4/CD8 ratio.MethodsAfter excluding patients who were lost to follow-up or for whom complete clinical data were missing, 369 participants were ultimately examined. Univariate and multivariate analyses were performed using the Cox hazards model, and Kaplan-Meier methods and log-rank tests were used for the comparison of survival rates.ResultsUnivariate and multivariate analyses showed that a high CA125 level and a high CD4/CD8 ratio were independent prognosis factors (CA125≥35 U/ml, Hazard Ratio (HR)=1.90, p<0.001; CD4/CD8≥1.8, HR=1.37, p=0.004). Moreover, after combining the CA125 level and CD4/CD8 ratio to form a new scoring system, the HR was substantially elevated (CA125≥35 U/ml and CD4/CD8≥1.8, score 2, HR=2.76, 95% confidence interval: 2.04 to 3.74, p<0.001).ConclusionsA new scoring system based on the combination of the CA125 level with the CD4/CD8 ratio could further predict the prognosis of patients with advanced pancreatic cancer.



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