Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer

This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m−2 bid on days 1–14 and oxaliplatin 130 mg m−2 on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m−2 bid on days 22–35 and 43–56, and oxaliplatin 50 mg m−2 on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13–36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer

The K+ Channel Opener 1-EBIO Potentiates Residual Function of Mutant CFTR in Rectal Biopsies from Cystic Fibrosis Patients

BACKGROUND: The identification of strategies to improve mutant CFTR function remains a key priority in the development of new treatments for cystic fibrosis (CF). Previous studies demonstrated that the K⁺ channel opener 1-ethyl-2-benzimidazolone (1-EBIO) potentiates CFTR-mediated Cl⁻ secretion in cultured cells and mouse colon. However, the effects of 1-EBIO on wild-type and mutant CFTR function in native human colonic tissues remain unknown. METHODS: We studied the effects of 1-EBIO on CFTR-mediated Cl⁻ secretion in rectal biopsies from 47 CF patients carrying a wide spectrum of CFTR mutations and 57 age-matched controls. Rectal tissues were mounted in perfused micro-Ussing chambers and the effects of 1-EBIO were compared in control tissues, CF tissues expressing residual CFTR function and CF tissues with no detectable Cl⁻ secretion. RESULTS: Studies in control tissues demonstrate that 1-EBIO activated CFTR-mediated Cl⁻ secretion in the absence of cAMP-mediated stimulation and potentiated cAMP-induced Cl⁻ secretion by 39.2±6.7% (P<0.001) via activation of basolateral Ca²⁺-activated and clotrimazole-sensitive KCNN4 K⁺ channels. In CF specimens, 1-EBIO potentiated cAMP-induced Cl⁻ secretion in tissues with residual CFTR function by 44.4±11.5% (P<0.001), but had no effect on tissues lacking CFTR-mediated Cl⁻ conductance. CONCLUSIONS: We conclude that 1-EBIO potentiates Cl⁻secretion in native CF tissues expressing CFTR mutants with residual Cl⁻ channel function by activation of basolateral KCNN4 K⁺ channels that increase the driving force for luminal Cl⁻ exit. This mechanism may augment effects of CFTR correctors and potentiators that increase the number and/or activity of mutant CFTR channels at the cell surface and suggests KCNN4 as a therapeutic target for CF

A framework to assess welfare mix and service provision models in health care and social welfare: case studies of two prominent Italian regions

BACKGROUND: The mechanisms through which the relationships among public institutions, private providers and families affect care and service provision systems are puzzling. How can we understand the mechanisms in these contexts? Which elements should we explore to capture the complexity of care provision? The aim of our study is to provide a framework that can help read and reframe these puzzling care provision mechanisms in a welfare mix context. METHODS: First, we develop a theoretical framework for understanding how service provision occurs in care systems that are characterised by a variety of relationships between multiple actors, using an evidence-based approach that looks at both public and private expenditures and the number of users relative to the level of needs coverage and compared with declared values and political rhetoric. Second, we test this framework in two case studies built on data from two prominent Italian regions, Lombardy and Emilia-Romagna. We argue that service provision models depend on the interplay among six conceptual elements: policy values, governance rules, resources, nature of the providers, service standards and eligibility criteria. RESULTS: Our empirical study shows that beneath the relevant differences in values and political rhetoric between the case studies of the two Italian regions, there is a surprising isomorphism in service standards and the levels of covering the population’s needs. CONCLUSION: The suggested framework appears to be effective and feasible; it fosters interdisciplinary approaches and supports policy-making discussions. This study may contribute to deepening knowledge about public care service provision and institutional arrangements, which can be used to promote more effective reforms and may advance future research. Although the framework was tested on the Italian welfare system, it can be used to assess many different systems

Three Saturn-mass planets transiting F-type stars revealed with TESS and HARPS

While the sample of confirmed exoplanets continues to increase, the population of transiting exoplanets around early-type stars is still limited. These planets allow us to investigate the planet properties and formation pathways over a wide range of stellar masses and study the impact of high irradiation on hot Jupiters orbiting such stars. We report the discovery of TOI-615b, TOI-622b, and TOI-2641b, three Saturn-mass planets transiting main sequence, F-type stars. The planets were identified by the Transiting Exoplanet Survey Satellite (TESS) and confirmed with complementary ground-based and radial velocity observations. TOI-615b is a highly irradiated ($\sim$1277 $F_{\oplus}$) and bloated Saturn-mass planet (1.69$^{+0.05}_{-0.06}$$R_{Jup}$ and 0.43$^{+0.09}_{-0.08}$$M_{Jup}$) in a 4.66 day orbit transiting a 6850 K star. TOI-622b has a radius of 0.82$^{+0.03}_{-0.03}$$R_{Jup}$ and a mass of 0.30$^{+0.07}_{-0.08}$~$M_{Jup}$ in a 6.40 day orbit. Despite its high insolation flux ($\sim$600 $F_{\oplus}$), TOI-622b does not show any evidence of radius inflation. TOI-2641b is a 0.37$^{+0.05}_{-0.04}$$M_{Jup}$ planet in a 4.88 day orbit with a grazing transit (b = 1.04$^{+0.05}_{-0.06 }$) that results in a poorly constrained radius of 1.61$^{+0.46}_{-0.64}$$R_{Jup}$. Additionally, TOI-615b is considered attractive for atmospheric studies via transmission spectroscopy with ground-based spectrographs and $\textit{JWST}$. Future atmospheric and spin-orbit alignment observations are essential since they can provide information on the atmospheric composition, formation and migration of exoplanets across various stellar types.Comment: 16 pages, 17 figures, submitted to A&

CHEOPS observations of KELT-20 b/MASCARA-2 b: An aligned orbit and signs of variability from a reflective dayside

Occultations are windows of opportunity to indirectly peek into the dayside atmosphere of exoplanets. High-precision transit events provide information on the spin-orbit alignment of exoplanets around fast-rotating hosts. We aim to precisely measure the planetary radius and geometric albedo of the ultra-hot Jupiter (UHJ) KELT-20 b as well as the system's spin-orbit alignment. We obtained optical high-precision transits and occultations of KELT-20 b using CHEOPS observations in conjunction with the simultaneous TESS observations. We interpreted the occultation measurements together with archival infrared observations to measure the planetary geometric albedo and dayside temperatures. We further used the host star's gravity-darkened nature to measure the system's obliquity. We present a time-averaged precise occultation depth of 82(6) ppm measured with seven CHEOPS visits and 131(+8/-7) ppm from the analysis of all available TESS photometry. Using these measurements, we precisely constrain the geometric albedo of KELT-20 b to 0.26(0.04) and the brightness temperature of the dayside hemisphere to 2566(+77/-80) K. Assuming Lambertian scattering law, we constrain the Bond albedo to 0.36(+0.04/-0.05) along with a minimal heat transfer to the night side. Furthermore, using five transit observations we provide stricter constraints of 3.9(1.1) degrees on the sky-projected obliquity of the system. The aligned orbit of KELT-20 b is in contrast to previous CHEOPS studies that have found strongly inclined orbits for planets orbiting other A-type stars. The comparably high planetary geometric albedo of KELT-20 b corroborates a known trend of strongly irradiated planets being more reflective. Finally, we tentatively detect signs of temporal variability in the occultation depths, which might indicate variable cloud cover advecting onto the planetary day side.Comment: 27 pages, 15 figures, Accepted for publication in Astronomy & Astrophysic