Single-agent gemcitabine in pretreated patients with non-small-cell lung cancer: results of an Argentinean multicentre phase II trial

The activity and mild toxicity profile of single-agent gemcitabine therapy in untreated (chemonaive) patients with non-small-cell lung cancer (NSCLC) is well documented. This phase II trial was conducted to determine the objective tumour response rate and toxicity profile of single-agent gemcitabine in pretreated patients with NSCLC. Patients with histological evidence of advanced NCSLC stage IIIB or IV; at least one prior chemotherapy regimen including a platinum or taxane analogue; an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2; clinically measurable disease; adequate bone marrow reserve; and adequate renal function; received 1000 mg m–2 gemcitabine administered over 30 min on days 1, 8 and 15 of a 28-day cycle defined as 3 weekly treatments followed by 1 week of rest. Twenty-nine patients were evaluated for efficacy and 32 for toxicity. One patient achieved a complete response and five patients had a partial response resulting in a total response rate of 20.6% (95% confidence interval (CI) 6–34). Median response duration was 7 months (range 4–11 months). Twelve (41%) patients reached stable disease after two cycles of therapy and 11 (38%) patients had disease progression. Median progression-free survival time was 3 months and median overall survival time was 5.5 months. Toxicity was generally mild (grades 0–2). Severe (grade 3 or 4) haematological toxicities included grade 3 anaemia in one patient and grade 3 thrombocytopenia in two patients. Severe non-haematological toxicities included one patient each with grade 3 liver transaminase elevations, nausea/vomiting and diarrhoea. This study confirms the activity and safety of single-agent gemcitabine in pretreated patients with advanced NSCLC who are refractory or sensitive to first-line therapy. © 1999 Cancer Research Campaig

A Decade of Multiwavelength Observations of the TeV Blazar 1ES 1215+303: Extreme Shift of the Synchrotron Peak Frequency and Long-term Optical-Gamma-Ray Flux Increase

Blazars are known for their variability on a wide range of timescales at all wavelengths. Most studies of TeV gamma-ray blazars focus on short timescales, especially during flares. With a decade of observations from the Fermi-LAT and VERITAS, we present an extensive study of the long-term multiwavelength radio-to-gamma-ray flux-density variability, with the addition of a couple of short-time radio-structure and optical polarization observations of the blazar 1ES 1215+303 (z = 0.130), with a focus on its gamma-ray emission from 100 MeV to 30 TeV. Multiple strong GeV gamma-ray flares, a long-term increase in the gamma-ray and optical flux baseline, and a linear correlation between these two bands are observed over the ten-year period. Typical HBL behaviors are identified in the radio morphology and broadband spectrum of the source. Three stationary features in the innermost jet are resolved by Very Long Baseline Array at 43.1, 22.2, and 15.3 GHz. We employ a two-component synchrotron self-Compton model to describe different flux states of the source, including the epoch during which an extreme shift in energy of the synchrotron peak frequency from infrared to soft X-rays is observed

Insights into the emission of the blazar 1ES 1011+496 through unprecedented broadband observations during 2011 and 2012

Context. 1ES 1011+496 (z = 0.212) was discovered in very high-energy (VHE, E> 100 GeV) γ rays with MAGIC in 2007. The absence of simultaneous data at lower energies led to an incomplete characterization of the broadband spectral energy distribution (SED). Aims. We study the source properties and the emission mechanisms, probing whether a simple one-zone synchrotron self-Compton (SSC) scenario is able to explain the observed broadband spectrum. Methods. We analyzed data in the range from VHE to radio data from 2011 and 2012 collected by MAGIC, Fermi-LAT, Swift, KVA, OVRO, and Metsähovi in addition to optical polarimetry data and radio maps from the Liverpool Telescope and MOJAVE. Results. The VHE spectrum was fit with a simple power law with a photon index of 3.69 ± 0.22 and a flux above 150 GeV of (1.46 ± 0.16) × 10-11 ph cm-2 s-1. The source 1ES 1011+496 was found to be in a generally quiescent state at all observed wavelengths, showing only moderate variability from radio to X-rays. A low degree of polarization of less than 10% was measured in optical, while some bright features polarized up to 60% were observed in the radio jet. A similar trend in the rotation of the electric vector position angle was found in optical and radio. The radio maps indicated a superluminal motion of 1.8 ± 0.4 c, which is the highest speed statistically significant measured so far in a high-frequency-peaked BL Lac. Conclusions. For the first time, the high-energy bump in the broadband SED of 1ES 1011+496 could be fully characterized from 0.1 GeV to 1 TeV, which permitted a more reliable interpretation within the one-zone SSC scenario. The polarimetry data suggest that at least part of the optical emission has its origin in some of the bright radio features, while the low polarization in optical might be due to the contribution of parts of the radio jet with different orientations of the magnetic field with respect to the optical emission

A new era for understanding amyloid structures and disease

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-β structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention

Insights from the first flaring activity of a high synchrotron peaked blazar with X-ray polarization and VHE gamma rays

Context. Blazars exhibit strong variability across the entire electromagnetic spectrum, including periods of high-flux states commonly known as flares. The physical mechanisms in blazar jets responsible for flares remain poorly understood to date. Aims. Our aim is to better understand the emission mechanisms during blazar flares using X-ray polarimetry and broadband observations from the archetypical TeV blazar Mrk 421, which can be studied with higher accuracy than other blazars that are dimmer and/or located farther away. Methods. We studied a flaring activity from December 2023 that was characterized from radio to very high-energy (VHE; E > 0.1 TeV) gamma rays with MAGIC, Fermi-LAT, Swift, XMM-Newton, and several optical and radio telescopes. These observations included, for the first time for a gamma-ray flare of a blazar, simultaneous X-ray polarization measurements with IXPE, in addition to optical and radio polarimetry data. We quantify the variability and correlations among the multi-band flux and polarization measurements, and describe the varying broadband emission within a theoretical scenario constrained by the polarization data. Results. We find substantial variability in both X-rays and VHE gamma rays throughout the campaign, with the highest VHE flux above 0.2 TeV occurring during the IXPE observing window, and exceeding twice the flux of the Crab Nebula. However, the VHE and X-ray spectra are on average softer, and the correlation between these two bands is weaker than those reported in the previous flares of Mrk 421. IXPE reveals an X-ray polarization degree significantly higher than that at radio and optical frequencies, similar to previous results for Mrk 421 and other high synchrotron peaked blazars. Differently to past observations, the X-ray polarization angle varies by ∼100° on timescales of days, and the polarization degree changes by more than a factor of 4. The highest X-ray polarization degree, analyzed in 12 h time intervals, reaches 26 ± 2%, around which an X-ray counter-clockwise hysteresis loop is measured with XMM-Newton. It suggests that the X-ray emission comes from particles close to the high-energy cutoff, hence possibly probing an extreme case of the Turbulent Extreme Multi-Zone model for which the chromatic trend in the polarization may be more pronounced than theoretically predicted. We model the broadband emission with a simplified stratified jet model throughout the flare. The polarization measurements imply an electron distribution in the X-ray emitting region with a very high minimum Lorentz factor (γ′min≳104), which is expected in electron-ion plasma, as well as a variation of the emitting region size of up to a factor of 3 during the flaring activity. We find no correlation between the fluxes and the evolution of the model parameters, which indicates a stochastic nature of the underlying physical mechanism that likely explains the lack of a tight X-ray/VHE correlation during this flaring activity. Such behavior would be expected in a highly turbulent electron-ion plasma crossing a shock front

A tale of two countries: the sociopolitical integration of Latino immigrants in Spain and in the United States

This special issue addresses the need for cross-national analyses on immigrant integration. The articles in this issue examine the integration processes of Latino immigrants in the United States and in Spain in several aspects—socioeconomic, legal, educational, and political—and through varied methods—quantitative as well as qualitative—contributing to the literature in several ways. By focusing on the same ethnic group across different contexts, it provides a thorough comparison of the mechanisms at play in their integration processes. It emphasizes the context-specific and culture-specific elements that most affect immigrants’ integration. This special issue gathers nine articles that offer complementary perspectives on the integration of Latino immigrants in Spain and the United States

Alzheimer’s disease brain-derived tau extracts show differential processing and transcriptional effects in human astrocytes

Post-translational modifications of tau, including phosphorylation at specific residues, are closely linked with tau seeding ability and clinical disease progression. While most previous evidence has focused on neuronal tau spread, evidence supports a similar role for astrocytes. Here we demonstrate that well characterized tau aggregates isolated from postmortem Alzheimer’s disease brain are internalized and processed by control human induced pluripotent stem cell-derived astrocytes. Differences in the efficiency of tau internalization, clearance and/or seeding were noted, which reflect molecular properties of tau and/or co-factors in brain extracts. We observed a direct relationship between tau handling by astrocytes and astrocyte transcriptomic changes. Dysregulated genes include several previously identified as upregulated in reactive astrocytes in Alzheimer’s brain, as well as those implicated in pathological tau clearance by autophagy and other pathways. The study provides insights into the complex interplay between tau molecular diversity and astrocyte responses in Alzheimer’s disease