Cyber Security: China and Russia\u27s Erosion of 21st Century United States\u27 Hegemony

With Russia and China emerging as challengers to U.S. hegemony, the use of cyber warfare could tilt the current balance of power in either of their favors. Using various methods, hackers can acquire sensitive information and destroy online infrastructures. In the development of cyber warfare, China has become a seasoned veteran with computer virus operations dating back to 199714. Russia has emerged as a cyber aggressor, as seen in Russia’s cyber attacks on several countries in the last decade. This paper argues that, with the growth of foreign cyber technology, the probability of cyberspace being used as a military front by state or non-state actors against the United States increases

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD.'' All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.Genetics of disease, diagnosis and treatmen

Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients

Item does not contain fulltextPURPOSE: To test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients. MATERIAL AND METHODS: A retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade 2 within 6months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC). RESULTS: Prior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p<0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p<0.001) on the training set, and 0.67 (p<0.001) on the validation set. CONCLUSION: Cardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients

The value of prognostic and predictive parameters in early-stage lung adenocarcinomas: A comparison between biopsies and resections

Introduction: Since lung adenocarcinoma (LUAD) biopsies are usually small, it is questionable if their prognostic and predictive information is comparable to what is offered by large resection specimens. This study compares LUAD biopsies and resection specimens for their ability to provide prognostic and predictive parameters. Methods: We selected 187 biopsy specimens with stage I and II LUAD. In 123 cases, subsequent resection specimens were also available. All specimens were evaluated for growth pattern, nuclear grade, fibrosis, inflammation, and genomic alterations. Findings were compared using non-parametric testing for categorical variables. Model performance was assessed using the area under the curve for both biopsies and resection specimens, and overall (OS) and disease-free survival (DFS) was calculated. Results: The overall growth pattern concordance between biopsies and resections was 73.9%. The dominant growth pattern correlated with OS and DFS in resected adenocarcinomas and for high-grade growth pattern in biopsies. Multivariate analysis of biopsy specimens revealed that T2-tumors, N1-status, KRAS mutations and a lack of other driver mutations were associated with poorer survival. Model performance using clinical, histological and genetic data from biopsy specimens for predicting OS and DSF demonstrated an AUC of 0.72 and 0.69, respectively. Conclusions: Our data demonstrated the prognostic relevance of a high-grade growth pattern in biopsy specimens of LUAD. Combining clinical, histological and genetic information in one model demonstrated a suboptimal performance for DFS prediction and good performance for OS prediction. However, for daily practice, more robust (bio)markers are required to predict prognosis and stratify patients for therapy and follow-up

A retrospective cohort study of PD-L1 prevalence, molecular associations and clinical outcomes in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape Project.

The PD-L1 biomarker is an important factor in selecting patients with non-small cell lung cancer for immunotherapy. While several reports suggest that PD-L1 positivity is linked to a poor prognosis, others suggest that PD-L1 positive status portends a good prognosis. PD-L1 positivity prevalence, assessed via immunohistochemistry (IHC) on tissue microarrays (TMAs), and its association with clinicopathological characteristics, molecular profiles and patient outcome- Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS)- is explored in the ETOP Lungscape cohort of stage I-III non-small cell lung cancer (NSCLC). Tumors are considered positive if they have ≥1/5/25/50% neoplastic cell membrane staining. PD-L1 expression was assessed in 2182 NSCLC cases (2008 evaluable, median follow-up 4.8 years, 54.6% still alive), from 15 ETOP centers. Adenocarcinomas represent 50.9% of the cohort (squamous cell: 42.4%). Former smokers are 53.7% (current: 31.6%, never: 10.5%). PD-L1 positivity prevalence is present in more than one third of the Lungscape cohort (1%/5% cut-offs). It doesn't differ between adenocarcinomas and squamous cell histologies, but is more frequently detected in higher stages, never smokers, larger tumors (1/5/25% cut-offs). With ≥1% cut-off it is significantly associated with IHC MET overexpression, expression of PTEN, EGFR and KRAS mutation (only for adenocarcinoma). Results for 5%, 25% and 50% cut-offs were similar, with MET being significantly associated with PD-L1 positivity both for AC (p &lt; 0.001, 5%/25%/50% cut-offs) and SCC (p &lt; 0.001, 5% &amp; 50% cut-offs and p = 0.0017 for 25%). When adjusting for clinicopathological characteristics, a significant prognostic effect was identified in adenocarcinomas (adjusted p-values: 0.024/0.064/0.063 for RFS/TTR/OS 1% cut-off, analogous for 5%/25%, but not for 50%). Similar results obtained for the model including all histologies, but no effect was found for the squamous cell carcinomas. PD-L1 positivity, when adjusted for clinicopathological characteristics, is associated with a better prognosis for non-metastatic adenocarcinoma patients

A retrospective cohort study of PD-L1 prevalence, molecular associations and clinical outcomes in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape Project

Introduction: The PD-L1 biomarker is an important factor in selecting patients with non-small cell lung cancer for immunotherapy. While several reports suggest that PD-L1 positivity is linked to a poor prognosis, others suggest that PD-L1 positive status portends a good prognosis. Methods: PD-L1 positivity prevalence, assessed via immunohistochemistry (IHC) on tissue microarrays (TMAs), and its association with clinicopathological characteristics, molecular profiles and patient outcome- Relapse-free Survival (RFS), Time-to-Relapse (TTR) and Overall Survival (OS)- is explored in the ETOP Lungscape cohort of stage I-III non-small cell lung cancer (NSCLC). Tumors are considered positive if they have ≥1/5/25/50% neoplastic cell membrane staining. Results: PD-L1 expression was assessed in 2182 NSCLC cases (2008 evaluable, median follow-up 4.8 years, 54.6% still alive), from 15 ETOP centers. Adenocarcinomas represent 50.9% of the cohort (squamous cell: 42.4%). Former smokers are 53.7% (current: 31.6%, never: 10.5%). PD-L1 positivity prevalence is present in more than one third of the Lungscape cohort (1%/5% cut-offs). It doesn&apos;t differ between adenocarcinomas and squamous cell histologies, but is more frequently detected in higher stages, never smokers, larger tumors (1/5/25% cut-offs). With ≥1% cut-off it is significantly associated with IHC MET overexpression, expression of PTEN, EGFR and KRAS mutation (only for adenocarcinoma). Results for 5%, 25% and 50% cut-offs were similar, with MET being significantly associated with PD-L1 positivity both for AC (p &lt; 0.001, 5%/25%/50% cut-offs) and SCC (p &lt; 0.001, 5% &amp; 50% cut-offs and p = 0.0017 for 25%). When adjusting for clinicopathological characteristics, a significant prognostic effect was identified in adenocarcinomas (adjusted p-values: 0.024/0.064/0.063 for RFS/TTR/OS 1% cut-off, analogous for 5%/25%, but not for 50%). Similar results obtained for the model including all histologies, but no effect was found for the squamous cell carcinomas. Conclusion: PD-L1 positivity, when adjusted for clinicopathological characteristics, is associated with a better prognosis for non-metastatic adenocarcinoma patients. © 2019 Elsevier B.V

Evaluation of NGS and RT-PCR Methods for ALK Rearrangement in European NSCLC Patients: Results from the European Thoracic Oncology Platform Lungscape Project.

The reported prevalence of ALK receptor tyrosine kinase gene (ALK) rearrangement in NSCLC ranges from 2% to 7%. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proved to be a reproducible and sensitive technique. Reverse-transcriptase polymerase chain reaction (RT-PCR) has also been advocated, and most recently, the advent of targeted next-generation sequencing (NGS) for ALK and other fusions has become possible. This study compares anaplastic lymphoma kinase (ALK) evaluation with all four techniques in resected NSCLC from the large European Thoracic Oncology Platform Lungscape cohort. A total of 96 cases from the European Thoracic Oncology Platform Lungscape iBiobank, with any ALK immunoreactivity were examined by FISH, central RT-PCR, and NGS. An H-score higher than 120 defines IHC positivity. RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers covered the most frequent ALK translocations. For NGS, the Oncomine Solid Tumour Fusion Transcript Kit (Thermo Fisher Scientific, Waltham, MA) was used. The concordance was assessed using the Cohen κ coefficient (two-sided α ≤ 5%). NGS provided results for 77 of the 95 cases tested (81.1%), whereas RT-PCR provided results for 77 of 96 (80.2%). Concordance occurred in 55 cases of the 60 cases tested with all four methods (43 ALK negative and 12 ALK positive). Using ALK copositivity for IHC and FISH as the criterion standard, we derived a sensitivity for RT-PCR/NGS of 70.0%/85.0%, with a specificity of 87.1%/79.0%. When either RT-PCR or NGS was combined with IHC, the sensitivity remained the same, whereas the specificity increased to 88.7% and 83.9% respectively. NGS evaluation with the Oncomine Solid Tumour Fusion transcript kit and RT-PCR proved to have high sensitivity and specificity, advocating their use in routine practice. For maximal sensitivity and specificity, ALK status should be assessed by using two techniques and a third one in discordant cases. We therefore propose a customizable testing algorithm. These findings significantly influence existing testing paradigms and have clear clinical and economic impact