The molecular basis of lung cancer: molecular abnormalities and therapeutic implications

Lung cancer is the number one cause of cancer-related death in the western world. Its incidence is highly correlated with cigarette smoking, and about 10% of long-term smokers will eventually be diagnosed with lung cancer, underscoring the need for strengthened anti-tobacco policies. Among the 10% of patients who develop lung cancer without a smoking history, the environmental or inherited causes of lung cancer are usually unclear. There is no validated screening method for lung cancer even in high-risk populations and the overall five-year survival has not changed significantly in the last 20 years. However, major progress has been made in the understanding of the disease and we are beginning to see this knowledge translated into the clinic. In this review, we will summarize the current state of knowledge regarding the cascade of events associated with lung cancer development. From subclinical DNA damage to overt invasive disease, the mechanisms leading to clinically and molecularly heterogeneous tumors are being unraveled. These lesions allow cells to escape the normal regulation of cell division, apoptosis and invasion. While all subtypes of non-small cell lung cancer have historically been treated the same, stage-for-stage, recent technological advances have allowed a better understanding of the molecular classification of the disease and provide hypotheses for molecular early detection and targeted therapeutic strategies

An upper-limit on the linear polarization fraction of the GW170817 radio continuum

We present late-time radio observations of GW170817, the first binary neutron star merger discovered through gravitational waves by the advanced LIGO and Virgo detectors. Our observations, carried out with the Karl G. Jansky Very Large Array, were optimized to detect polarized radio emission, and thus to constrain the linear polarization fraction of GW170817. At an epoch of ~244 days after the merger, we rule out linearly polarized emission above a fraction of ~12% at a frequency of 2.8 GHz (99% confidence). Within the structured jet scenario (a.k.a. successful jet plus cocoon system) for GW170817, the derived upper-limit on the radio continuum linear polarization fraction strongly constrains the magnetic field configuration in the shocked ejecta. We show that our results for GW170817 are compatible with the low level of linear polarization found in afterglows of cosmological long gamma-ray bursts. Finally, we discuss our findings in the context of future expectations for the study of radio counterparts of binary neutron star mergers identified by ground-based gravitational-wave detectors.Comment: 5 pages, 2 figures, 1 tabl

Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca(2+) channel activators.

Cav1.2 and Cav1.3 are the main L-type Ca(2+) channel subtypes in the brain. Cav1.3 channels have recently been implicated in the pathogenesis of Parkinson’s disease. Therefore, Cav1.3-selective blockers are developed as promising neuroprotective drugs. We studied the pharmacological properties of a pyrimidine-2,4,6-trione derivative (1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione, Cp8) recently reported as the first highly selective Cav1.3 blocker. Here we show, in contrast to this previous study, that Cp8 reproducibly increases inward Ca(2+) currents of Cav1.3 and Cav1.2 channels expressed in tsA-201 cells by slowing activation, inactivation and enhancement of tail currents. Similar effects are also observed for native Cav1.3 and Cav1.2 channels in mouse chromaffin cells, while non-L-type currents are unaffected. Evidence for a weak and non-selective inhibition of Cav1.3 and Cav1.2 currents is only observed in a minority of cells using Ba(2+) as charge carrier. Therefore, our data identify pyrimidine-2,4,6-triones as Ca(2+) channel activators

Properties of the Volume Operator in Loop Quantum Gravity II: Detailed Presentation

The properties of the Volume operator in Loop Quantum Gravity, as constructed by Ashtekar and Lewandowski, are analyzed for the first time at generic vertices of valence greater than four. The present analysis benefits from the general simplified formula for matrix elements of the Volume operator derived in gr-qc/0405060, making it feasible to implement it on a computer as a matrix which is then diagonalized numerically. The resulting eigenvalues serve as a database to investigate the spectral properties of the volume operator. Analytical results on the spectrum at 4-valent vertices are included. This is a companion paper to arXiv:0706.0469, providing details of the analysis presented there.Comment: Companion to arXiv:0706.0469. Version as published in CQG in 2008. More compact presentation. Sign factor combinatorics now much better understood in context of oriented matroids, see arXiv:1003.2348, where also important remarks given regarding sigma configurations. Subsequent computations revealed some minor errors, which do not change qualitative results but modify some numbers presented her

Properties of the Volume Operator in Loop Quantum Gravity I: Results

We analyze the spectral properties of the volume operator of Ashtekar and Lewandowski in Loop Quantum Gravity, which is the quantum analogue of the classical volume expression for regions in three dimensional Riemannian space. Our analysis considers for the first time generic graph vertices of valence greater than four. Here we find that the geometry of the underlying vertex characterizes the spectral properties of the volume operator, in particular the presence of a `volume gap' (a smallest non-zero eigenvalue in the spectrum) is found to depend on the vertex embedding. We compute the set of all non-spatially diffeomorphic non-coplanar vertex embeddings for vertices of valence 5--7, and argue that these sets can be used to label spatial diffeomorphism invariant states. We observe how gauge invariance connects vertex geometry and representation properties of the underlying gauge group in a natural way. Analytical results on the spectrum on 4-valent vertices are included, for which the presence of a volume gap is proved. This paper presents our main results; details are provided by a companion paper arXiv:0706.0382v1.Comment: 36 pages, 7 figures, LaTeX. See also companion paper arXiv:0706.0382v1. Version as published in CQG in 2008. See arXiv:1003.2348 for important remarks regarding the sigma configurations. Subsequent computations have revealed some minor errors, which do not change the qualitative results but modify some of the numbers presented her

Spatiotemporal genomic analysis reveals distinct molecular features in recurrent stage I non-small cell lung cancers

Stage I non-small cell lung cancer (NSCLC) presents diverse outcomes. To identify molecular features leading to tumor recurrence in early-stage NSCLC, we perform multiregional whole-exome sequencing (WES), RNA sequencing, and plasma-targeted circulating tumor DNA (ctDNA) detection analysis between recurrent and recurrent-free stage I NSCLC patients (CHN-P cohort) who had undergone R0 resection with a median 5-year follow-up time. Integrated analysis indicates that the multidimensional clinical and genomic model can stratify the prognosis of stage I NSCLC in both CHN-P and EUR-T cohorts and correlates with positive pre-surgical deep next generation sequencing (NGS) ctDNA detection. Increased genomic instability related to DNA interstrand crosslinks and double-strand break repair processes is significantly associated with early tumor relapse. This study reveals important molecular insights into stage I NSCLC and may inform clinical postoperative treatment and follow-up strategies

Evaluation of a novel rash scale and a serum proteomic predictor in a randomized phase II trial of sequential or concurrent cetuximab and pemetrexed in previously treated non-small cell lung cancer

BACKGROUND: Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival. METHODS: 55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected. RESULTS: 43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did. CONCLUSIONS: Absence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0020393

Correction to: Determinant Roles of Dendritic Cell-expressed Notch Delta-like and Jagged Ligands on Anti-tumor T-cell Immunity

Background: Notch intercellular communication instructs tissue-specific T-cell development and function. In this study, we explored the roles of dendritic cell (DC)-expressed Notch ligands in the regulation of T-cell effector function. Methods: We generated mice with CD11c lineage-specific deletion of Notch Delta-like ligand (Dll)1 and Jagged (Jag)2. Using these genetically-ablated mice and engineered pharmacological Notch ligand constructs, the roles of various Delta-like and Jagged ligands in the regulation of T-cell-mediated immunity were investigated. We assessed tumor growth, mouse survival, cytokine production, immunophenotyping of myeloid and lymphoid populations infiltrating the tumors, expression of checkpoint molecules and T-cell function in the experimental settings of murine lung and pancreatic tumors and cardiac allograft rejection. Correlative studies were also performed for the expression of NOTCH ligands, NOTCH receptors and PD-1 on various subsets of myeloid and lymphoid cells in tumor-infiltrating immune cells analyzed from primary human lung cancers. Results: Mice with CD11c lineage-specific deletion of Notch ligand gene Dll1, but not Jag2, exhibited accelerated growth of lung and pancreatic tumors concomitant with decreased antigen-specific CD8+ T-cell functions and effector-memory (Tem) differentiation. Increased IL-4 but decreased IFN-γ production and elevated populations of T-regulatory and myeloid-derived suppressor cells were observed in Dll1-ablated mice. Multivalent clustered DLL1-triggered Notch signaling overcame DC Dll1 deficiency and improved anti-tumor T-cell responses, whereas the pharmacological interference by monomeric soluble DLL1 construct suppressed the rejection of mouse tumors and cardiac allograft. Moreover, monomeric soluble JAG1 treatment reduced T-regulatory cells and improved anti-tumor immune responses by decreasing the expression of PD-1 on CD8+ Tem cells. A significant correlation was observed between DC-expressed Jagged and Delta-like ligands with Tem-expressed PD-1 and Notch receptors, respectively, in human lung tumor-infiltrates.Conclusion: Our data show the importance of specific expression of Notch ligands on DCs in the regulation of Tcell effector function. Thus, strategies incorporating selectively engineered Notch ligands could provide a novel approach of therapeutics for modulating immunity in various immunosuppressive conditions including cancer. Keywords: Delta-like notch ligands, Jagged, Notch receptors, Lung carcinoma, Tumor infiltrating immune cells, Heart allograft rejection, Dendritic cells, CD8 T-cells, Regulatory T-cells, Cancer immunotherap

Multi-Messenger Astronomy with Extremely Large Telescopes

The field of time-domain astrophysics has entered the era of Multi-messenger Astronomy (MMA). One key science goal for the next decade (and beyond) will be to characterize gravitational wave (GW) and neutrino sources using the next generation of Extremely Large Telescopes (ELTs). These studies will have a broad impact across astrophysics, informing our knowledge of the production and enrichment history of the heaviest chemical elements, constrain the dense matter equation of state, provide independent constraints on cosmology, increase our understanding of particle acceleration in shocks and jets, and study the lives of black holes in the universe. Future GW detectors will greatly improve their sensitivity during the coming decade, as will near-infrared telescopes capable of independently finding kilonovae from neutron star mergers. However, the electromagnetic counterparts to high-frequency (LIGO/Virgo band) GW sources will be distant and faint and thus demand ELT capabilities for characterization. ELTs will be important and necessary contributors to an advanced and complete multi-messenger network.Comment: White paper submitted to the Astro2020 Decadal Surve