Extrachromosomal circular DNAs (eccDNAs) are somatically mosaic and contribute to intercellular heterogeneity in normal and tumor cells. Because short eccDNAs are poorly chromatinized, we hypothesized that they are sequenced by tagmentation in ATAC-seq experiments without any enrichment of circular DNA. Indeed, ATAC-seq identified thousands of eccDNAs in cell lines that were validated by inverse PCR and by metaphase FISH. ATAC-seq in gliomas and glioblastomas identify hundreds of eccDNAs, including one containing the well-known EGFR gene amplicon from chr7. More than 18,000 eccDNAs, many carrying known cancer driver genes, are identified in a pan-cancer analysis of ATAC-seq libraries from 23 tumor types. Somatically mosaic eccDNAs are identified by ATAC-seq even before amplification is recognized by genome-wide copy number variation measurements. Thus, ATAC-seq is a sensitive method to detect eccDNA present in a tumor at the pre-amplification stage and can be used to predict resistance to therapy.

DRAIC is a 1.7 kb spliced long noncoding RNA downregulated in castration-resistant advanced prostate cancer. Decreased DRAIC expression predicts poor patient outcome in prostate and seven other cancers, while increased DRAIC represses growth of xenografted tumors. Here, we show that cancers with decreased DRAIC expression have increased NF-kB target gene expression. DRAIC downregulation increased cell invasion and soft agar colony formation; this was dependent on NF-kB activation. DRAIC interacted with subunits of the IkB kinase (IKK) complex to inhibit their interaction with each other, the phosphorylation of IkBa, and the activation of NF-kB. These functions of DRAIC mapped to the same fragment containing bases 701-905. Thus, DRAIC lncRNA inhibits prostate cancer progression through suppression of NF-kB activation by interfering with IKK activity.

Background/Aim: Sarcopenia describes the loss of skeletal muscle mass. While this condition is associated with a high mortality in cancer patients, its influence on survival is still underestimated. Patients and Methods: A systematic review for articles was performed using the PubMed database, Cochrane Library, Biomed Central, Science Direct and by manual search. We used data of overall survival in sarcopenic patients for assessing the death risk. We extracted hazard ratio estimates from univariate and multivariate Cox proportional hazards models for meta-analysis. Results: A total of 15 studies were eligible for meta-analysis including a total of 2,521 lung cancer patients. Univariate meta-analysis revealed a twofold increased death risk in sarcopenic patients; multivariate meta-analysis yielded a significant, threefold elevated risk of death. This higher mortality is independent of tumour stage. Conclusion: Muscle loss is an independent risk factor for increased death risk in lung cancer patients independent of cancer stage. This argues for implementing screening for sarcopenia into cancer care. Sarcopenia describes the age-related loss of muscle mass and strength starting during the fourth to fifth decade of life. It is defined as a muscle mass of at least two standard deviations below the mean muscle mass found in young healthy adults (1-3). While often reported in the elderly, loss of muscle mass does also manifest in patients suffering from a chronical disease like congestive heart failure, chronical obstructive pulmonary disease, chronical renal failure or cancer. Muscle loss has a relevant impact on survival, especially in the latter group. The prevalence of sarcopenia in cancer patients depends on cancer entity, which is why a prevalence of 16% is described in breast cancer patients, whereas 71% of lung cancer patients under palliative therapy suffer from sarcopenia (4-6). Muscle wasting is an unfavourable prognostic factor for cancer specific survival of rectum, liver, oesophagus, stomach or kidney cancer patients (1, 7). If muscle mass is maintained or increased, patients show a longer overall survival (5). Sarcopenia may be caused by several different factors; cancer, chemotherapy or locoregional impairment caused by surgery or radiation therapy, comorbidities, malnutrition or physical inactivity (8). Sarcopenia itself is also a risk factor for an increase in chemotoxicity and a decrease in therapy response (1). Physical activity prevents muscle wasting; a small pilot study showed that smartphones are a good tool to implement personalized physical activity programs and to increase physical activity of patients (9, 10). Sarcopenia is assessed by using Dual-energy X-ray absorptiometry scan (DEXA), bioelectrical impedance analysis (BIA) or computed tomography (2). Especially computed tomography is used routinely for investigations 4603 This article is freely accessible online.

Binding of a specific siRNA to the target mRNA in a live cell (human breast cancer cell, MCF-7) is studied by confocal microscopy. The specific siRNA (labeled with a fluorophore, alexa 488) exhibits much higher intensity of fluorescence in the bound state than in the free (unbound) state. It is observed that repeated unbinding and rebinding of siRNA (to target mRNA) occur before gene silencing. 16 273 on-time periods (residence or dwell time of siRNA in bound form) are detected. They follow a strikingly simple pattern. All of the on-time periods are odd-integral multiples of 5.5 ± 0.05 ms. This is ascribed to stochastic resonance.

The Bcl-2 inhibitor venetoclax (VEN) has yielded exceptional clinical responses in chronic lymphocytic leukemia (CLL). However, de novo resistance can result in failure to achieve negative minimal residual disease and predicts poor treatment outcomes. Consequently, additional pro-apoptotic drugs, such as inhibitors of Mcl-1 and Bcl-xL, are in development. By profiling anti-apoptotic proteins using flow cytometry, we find that leukemic B-cells recently emigrated from the lymph node (LN) (CD69Pos/CXCR4Low) in vivo are enriched for cell clusters simultaneously overexpressing multiple anti-apoptotic proteins (Mcl-1high/Bcl-xLhigh/Bcl-2high), in both treated and treatment naïve CLL patients. These cells exhibited anti-apoptotic resistance to multiple BH-domain antagonists, including inhibitors of Bcl-2, Mcl-1, and Bcl-xL, when tested as single agents in a flow cytometry-based functional assay. Anti-apoptotic multi-drug resistance declines ex vivo, consistent with resistance being generated in vivo by extrinsic microenvironmental interactions. Surviving "persister" cells in patients undergoing venetoclax treatment are enriched for CLL cells displaying the functional and molecular properties of microenvironmentally-induced multi-drug resistance. Overcoming this resistance required simultaneous inhibition of multiple anti-apoptotic proteins, with potential for unwanted toxicities. Using a drug screen performed using patient PBMCs cultured in an ex vivo microenvironment model we identify novel venetoclax drug combinations that induce selective cytotoxicity in multi-drug resistant CLL cells. Thus, we demonstrate that anti-apoptotic multi-drug resistant CLL cells exist in patients de novo, and show that these cells persist during pro-apoptotic treatment such as venetoclax. We validate clinically actionable approaches to selectively deplete this reservoir in patients.