Valparaiso University

Background Cisplatin, an effective chemotherapy, is a cause of ototoxicity. It enters inner ear cells through Organic Cation Transporter 2 (OCT2). Recently, we identified another cochlear transporter, Multidrug and Toxin Extrusion Protein 1 (MATE1); it allows cisplatin efflux in renal cells. OCT2 and MATE1 appear to work together in eliminating renal toxins. 4-aminopyridine (4-AP), a known blocker of voltage-dependent K+ channels, blocks OCT2 but not MATE1 in the kidney. We hypothesize that 4-AP could prevent cisplatin from entering cochlear cells, without inhibiting the efflux of cisplatin that may have already entered. This could enhance clearance, mitigating ototoxicity. Objective Determine the otoprotective potential of 4-AP in vitro following cisplatin exposure. Methods Mice cochlear explants were treated with cisplatin (20 μM), with or without 4-AP (500 μM) for 24 h, evaluated for caspase 3/7 activity with Cell Event ® , visualized with confocal and phase contrast microscopy. Moreover, HeLa cells and cochlear explants were exposed to cisplatin (75 μM and 30 μM, respectively) with or without 4-AP in the explants and were evaluated for cisplatin-DNA adducts and cleaved caspase-3 immunohistochemistry. Results For cochlear explants exposed to cisplatin, Cell Event ® staining occurred in the supporting cells, medial to the hair cells, and in the organ of Corti. No significant differences were found between cisplatin-exposed explants with or without 4-AP. In HeLa cells, consistent cellular staining for cisplatin-DNA adducts and cleaved caspase-3 was observed. However, this was not seen in cochlear explants, and there was no significant decrease in staining levels with 4-AP co-treatment. Conclusions In this in vitro study, no otoprotective potential of 4-AP against cisplatin-induced ototoxicity was observed. While 4-AP blocks OCT2, it did not decrease cisplatin-DNA adducts in cochlear cells. Further research into OCT2 and MATE1 transport mechanisms is needed.

In this work, we study a non-geometrical perturbation to the stealth field, which means the background remains invariant. The stealh is homogeneous in a universe whose source is dust and demand that perturbation unchanged density. As a regular procedure, we introduce a parameter λ to perturb the scalar field equation and get an intriguing expression of the equation, similar to a series expansion in λ. From this procedure, we distinguish and approach to discriminate solutions, and the numerical solutions show that the most significant contribution to the solution comes from the linear term of λ.

Este artículo caracteriza la posición de las científicas chilenas en el mercado de trabajo universitario a partir de una encuesta aplicada a ganadoras de proyectos FONDECYT (2015–2020). Los resultados, en diálogo con la literatura especializada, evidencian avances en la participación femenina en el sistema científico, expresados en altos niveles de cualificación académica, sólida inserción institucional y trayectorias de movilidad social ascendente. Aun cuando una proporción relevante de investigadoras proviene de orígenes socioeconómicos bajos, muchas han logrado acceder a carreras altamente competitivas en el ámbito universitario, incluyendo espacios de responsabilidad académica. La mayoría posee formación doctoral en el extranjero o en universidades de alta reputación nacional, fortaleciendo su capital académico y su proyección profesional. En términos de ingresos, se observa una paridad relativa entre hombres y mujeres; no obstante, los datos permiten formular una hipótesis mecanísmica respecto de las diferencias que persisten en los tramos superiores de remuneración. Asimismo, se constatan brechas en posiciones de poder y liderazgo, donde operan “techos de cristal” que restringen el acceso femenino a cargos directivos, junto con una dimensión territorial de la desigualdad dada la concentración de científicas en la Región Metropolitana, configurándose una interseccionalidad. En conjunto, el escenario es ambivalente: coexisten procesos democratizadores en el acceso y la formación con desigualdades persistentes en la estructura institucional del mercado académico.

This article is part of a doctoral artistic research that explores, from an interdisciplinary perspective, the theatrical scene as a space for the production of knowledge and transmission of feminist memories in Chile, specifically from the period of the democratic transition of the 1990s. It articulates studies of memory, history, feminisms and archives with scenic practice, to produce a theatrical device that activates silenced memories, generating other ways of constructing meanings than the traditional logics of archival circulation. This article socializes some of the methodological and conceptual premises that mobilized this artistic research.

The hospital mergers-and-acquisitions (M&A) trend is reviewed in terms of duration in and impact on US health care. This information supports an understanding of the strategic intent of M&As. Hospital mergers and acquisitions fostered the creation of integrated delivery networks to enhance competitive and volume-profit capacity. The value of this initial strategic intent is discussed in relation to today’s emerging population-community health and health status emphasis. Subsequent insights foster views about future expectations of and behaviors from the national system. M&As are projected to continue albeit with an expanded focus on population and community health services.

114 Background: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) demonstrates limited response to immunotherapy. Preclinical data suggest that all-trans retinoic acid (ATRA) can reduce myeloid-derived suppressor cells and enhance the effects of immune checkpoint blockade. This phase II trial was designed to assess both the safety and efficacy of ATRA combined with bevacizumab and atezolizumab in refractory MSS mCRC. Here we report preliminary safety and tolerability data. Methods: This is a single-arm, open-label, phase II trial (NCT05999812). Eligible patients are ≥18 years with MSS mCRC refractory to at least two lines of standard therapies. Treatment consisted of ATRA 45 mg/m² orally days 1–7, atezolizumab 840 mg IV, and bevacizumab 10 mg/kg IV on day 1 of each 14-day cycle. A safety lead-in (first 6 patients, cycles 1–2) was incorporated. Treatment-emergent AEs (TEAEs) were defined as any AE that started on or after the first dose until ≤30 days after the last dose. AEs were graded by CTCAE v5.0, and safety analyses included all patients receiving ≥1 dose. Results: Among the 16 enrolled patients between April 2024 and June 2025, a total of 136 AEs were reported: 99 (72.8%) grade 1, 34 (25.0%) grade 2, and 3 (2.2%) grade 3, with no events grade ≥3 and no treatment-related deaths. No grade ≥3 AE occurred during the safety lead-in, allowing full enrollment of the study participants. The most common any-grade AEs were headache (n=11, 52.3%), fatigue (n=9, 42.8%), and proteinuria (n=6, 28.5%); all others occurred ≤ 5 times. Grade 3 events included small intestinal obstruction, proteinuria, and dyspnea. Two patients required hospitalization due to AEs: one with grade 2 and 3 events (dyspnea, fever) and one with the grade 3 event (small intestinal obstruction). Five patients (31.3%) required dose interruptions, and 1 patient (6.3%) required dose reduction of ATRA. Bevacizumab-related adverse events occurred in 7 patients (43.8%) with proteinuria (50.0%) and epistaxis (30.0%) amongst the most frequent. Immune-related adverse events were observed in 1 patient. Conclusions: ATRA combined with bevacizumab and atezolizumab demonstrates a manageable safety profile in patients with refractory MSS mCRC, with adverse events consistent with the known profiles of the individual agents. The majority of AEs were low-grade and reversible with standard management. These preliminary safety findings support continued investigation, with efficacy and biomarker data forthcoming. Clinical trial information: NCT05999812 . Safety profile and adverse events summary for all patients (N = 16). Safety, n (%) All pts (N = 16) Grade ≥ 3 3 (18.8%) AE leading to dose delay 5 (31.3%) Leading to dose reduction 1 (6.3%) Leading to dose discontinuation 0 (0.0) Hospitalization due to AEs 2 (12.5%)