Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

A Nup133-dependent NPC-anchored network tethers centrosomes to the nuclear envelope in prophase

Nup133 links CENP-F, NudE/EL, and the dynein/dynactin complex to anchor centrosomes to the nuclear membrane

Bicaudal D2, Dynein, and Kinesin-1 Associate with Nuclear Pore Complexes and Regulate Centrosome and Nuclear Positioning during Mitotic Entry

Mammalian Bicaudal D2 is the missing molecular link between cytoplasmic motor proteins and the nucleus during nuclear positioning prior to the onset of mitosis

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Predictors of incomplete optical colonoscopy using computed tomographic colonography

Background/Aims: Optical colonoscopy (OC) is the primary modality for investigation of colonic pathology. Although there is data on demographic factors for incomplete OC, paucity of data exists for anatomic variables that are associated with an incomplete OC. These anatomic variables can be visualized using computed tomographic colonography (CTC). We aim to retrospectively identify variables associated with incomplete OC using CTC and develop a scoring method to predict the outcome of OC. Patients and Methods: In this case-control study, 70 cases ( with incomplete OC) and 70 controls (with complete OC) were identified. CTC images of cases and controls were independently reviewed by a single CTC radiologist. Demographic and anatomical parameters were recorded. Data was examined using descriptive linear statistics and multivariate logistic regression model. Results: On analysis, female gender (80% vs 58.6% P = 0.007), prior abdominal/pelvic surgeries (51.4% vs 14.3% P < 0.001), colonic length (187.6 ± 30.0 cm vs 163.8 ± 27.2 cm P < 0.001), and number of flexures (11.4 ± 3.1 vs 8.4 ± 2.9 P < 0.001) increased the risk for incomplete OC. No significant association was observed for increasing age (P = 0.881) and history of severe diverticulosis (P = 0.867) with incomplete OC. A scoring system to predict the outcome of OC is proposed based on CTC findings. Conclusion: Female gender, prior surgery, and increasing colonic length and tortuosity were associated with incomplete OC, whereas increasing age and history of severe diverticulosis were not. These factors may be used in the future to predict those patients who are at risk of incomplete OC

MOESM3 of ApoE deficiency exacerbates the development and sustainment of a semi-chronic K/BxN serum transfer-induced arthritis model

Additional file 3. Alteration of levels of circulating cytokines/chemokines in C57BL/6 and ApoE−/− mice with induction of arthritis. Serum levels from non-arthritic and arthritic C57BL/6 (control, n = 2 non-arthritic and n = 13 arthritic) and ApoE−/− (n = 3 non-arthritic and n = 6 arthritic) mice at 4–6 months. Data are represented as mean ± SEM. * denotes statistically significant differences. *p < 0.05, **p < 0.01,***p < 0.001