Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non–Small Cell Lung Cancer: A Phase Ib Study

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies

Convergent Deployment of Ancestral Functions During the Evolution of Mammalian Flight Membranes

Lateral flight membranes, or patagia, have evolved repeatedly in diverse mammalian lineages. While little is known about patagium development, its recurrent evolution may suggest a shared molecular basis. By combining transcriptomics, developmental experiments, and mouse transgenics, we demonstrate that lateral Wnt5a expression in the marsupial sugar glider (Petaurus breviceps) promotes the differentiation of its patagium primordium. We further show that this function of Wnt5a reprises ancestral roles in skin morphogenesis predating mammalian flight and has been convergently used during patagium evolution in eutherian bats. Moreover, we find that many genes involved in limb development have been redeployed during patagium outgrowth in both the sugar glider and bat. Together, our findings reveal that deeply conserved genetic toolkits contribute to the evolutionary transition to flight in mammals

A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer

Introduction: This study evaluated the efficacy, safety, and pharmacokinetics of conatumumab combined with paclitaxel-carboplatin (PC) as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Methods: Patients (aged >18 years) with previously untreated advanced or recurrent NSCLC were randomized 1: 1: 1 (stratified by Eastern Cooperative Oncology Group performance status and disease stage) to receive up to six 3-week cycles of PC combined with conatumumab (arm 1, 3 mg/kg; arm 2, 15 mg/kg) or placebo (arm 3) every 3 weeks. The primary endpoint was progression-free survival (PFS). This study is registered with ClinicalTrials.gov (NCT00534027). Results: Between August 8, 2007 and April 9, 2009, 172 patients were randomized (arm 1, n = 57; arm 2, n = 56; arm 3, n = 59). Median PFS was 5.4 months (95% confidence interval [CI] 4.1-6.3) in arm 1 (hazard ratio [HR] 0.84 [95% CI 0.57-1.24]; p = 0.41), 4.8 months (95% CI 3.2-6.5) in arm 2 (HR 0.93 [0.64-1.35]; p = 0.57), and 5.5 months (95% CI 4.3-5.7) in arm 3. There was an interaction between tumor histology and the effect of conatumumab on PFS (squamous HR 0.47 [0.23-0.94]; nonsquamous HR 1.08 [0.74-1.57]; interaction p = 0.039). The most common grade of three or more adverse events were neutropenia, anemia, and thrombocytopenia. There was no evidence of pharmacokinetic interactions between conatumumab and PC. Of 158 patients assessable for FCGR3A polymorphisms, conatumumab treatment was associated with a trend toward longer overall survival (HR 0.72 [0.43-1.23]) among V-allele carriers (V/V or F/V; n = 54) but not among F-allele homozygotes (n = 34; HR 1.37 [0.66-2.86]). Conclusion: Although well tolerated, the addition of conatumumab to PC did not improve outcomes in unselected patients with previously untreated advanced NSCLC

TESS Duotransit Candidates from the Southern Ecliptic Hemisphere

Discovering transiting exoplanets with long orbital periods allows us to study warm and cool planetary systems with temperatures similar to the planets in our own Solar system. The TESS mission has photometrically surveyed the entire Southern Ecliptic Hemisphere in Cycle 1 (August 2018 - July 2019), Cycle 3 (July 2020 - June 2021) and Cycle 5 (September 2022 - September 2023). We use the observations from Cycle 1 and Cycle 3 to search for exoplanet systems that show a single transit event in each year - which we call duotransits. The periods of these planet candidates are typically in excess of 20 days, with the lower limit determined by the duration of individual TESS observations. We find 85 duotransit candidates, which span a range of host star brightnesses between 8 < $T_{mag}$ < 14, transit depths between 0.1 per cent and 1.8 per cent, and transit durations between 2 and 10 hours with the upper limit determined by our normalisation function. Of these candidates, 25 are already known, and 60 are new. We present these candidates along with the status of photometric and spectroscopic follow-up.Comment: 25 pages, 16 figures, submitted to Monthly Notices of the Royal Astronomical Societ

NGTS-21b: An Inflated Super-Jupiter Orbiting a Metal-poor K dwarf

We report the discovery of NGTS-21b, a massive hot Jupiter orbiting a low-mass star as part of the Next Generation Transit Survey (NGTS). The planet has a mass and radius of $2.36 \pm 0.21$ M$_{\rm J}$, and $1.33 \pm 0.03$ R$_{\rm J}$, and an orbital period of 1.543 days. The host is a K3V ($T_{\rm eff}=4660 \pm 41$, K) metal-poor (${\rm [Fe/H]}=-0.26 \pm 0.07$, dex) dwarf star with a mass and radius of $0.72 \pm 0.04$, M$_{\odot}$,and $0.86 \pm 0.04$, R$_{\odot}$. Its age and rotation period of $10.02^{+3.29}_{-7.30}$, Gyr and $17.88 \pm 0.08$, d respectively, are in accordance with the observed moderately low stellar activity level. When comparing NGTS-21b with currently known transiting hot Jupiters with similar equilibrium temperatures, it is found to have one of the largest measured radii despite its large mass. Inflation-free planetary structure models suggest the planet's atmosphere is inflated by $\sim21\%$, while inflationary models predict a radius consistent with observations, thus pointing to stellar irradiation as the probable origin of NGTS-21b's radius inflation. Additionally, NGTS-21b's bulk density ($1.25 \pm 0.15$, g/cm$^3$) is also amongst the largest within the population of metal-poor giant hosts ([Fe/H] < 0.0), helping to reveal a falling upper boundary in metallicity-planet density parameter space that is in concordance with core accretion formation models. The discovery of rare planetary systems such as NGTS-21 greatly contributes towards better constraints being placed on the formation and evolution mechanisms of massive planets orbiting low-mass stars.Comment: 12 pages, 13 figures, accepted for publication in MNRA

DNA Dynamics Is Likely to Be a Factor in the Genomic Nucleotide Repeats Expansions Related to Diseases

Trinucleotide repeats sequences (TRS) represent a common type of genomic DNA motif whose expansion is associated with a large number of human diseases. The driving molecular mechanisms of the TRS ongoing dynamic expansion across generations and within tissues and its influence on genomic DNA functions are not well understood. Here we report results for a novel and notable collective breathing behavior of genomic DNA of tandem TRS, leading to propensity for large local DNA transient openings at physiological temperature. Our Langevin molecular dynamics (LMD) and Markov Chain Monte Carlo (MCMC) simulations demonstrate that the patterns of openings of various TRSs depend specifically on their length. The collective propensity for DNA strand separation of repeated sequences serves as a precursor for outsized intermediate bubble states independently of the G/C-content. We report that repeats have the potential to interfere with the binding of transcription factors to their consensus sequence by altered DNA breathing dynamics in proximity of the binding sites. These observations might influence ongoing attempts to use LMD and MCMC simulations for TRS–related modeling of genomic DNA functionality in elucidating the common denominators of the dynamic TRS expansion mutation with potential therapeutic applications

Stacking Interactions in Denaturation of DNA Fragments

A mesoscopic model for heterogeneous DNA denaturation is developed in the framework of the path integral formalism. The base pair stretchings are treated as one-dimensional, time dependent paths contributing to the partition function. The size of the paths ensemble, which measures the degree of cooperativity of the system, is computed versus temperature consistently with the model potential physical requirements. It is shown that the ensemble size strongly varies with the molecule backbone stiffness providing a quantitative relation between stacking and features of the melting transition. The latter is an overall smooth crossover which begins from the \emph{adenine-thymine} rich portions of the fragment. The harmonic stacking coupling shifts, along the $T$-axis, the occurrence of the multistep denaturation but it does not change the character of the crossover. The methods to compute the fractions of open base pairs versus temperature are discussed: by averaging the base pair displacements over the path ensemble we find that such fractions signal the multisteps of the transition in good agreement with the indications provided by the specific heat plots.Comment: European Physical Journal E (2011) in pres