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BACKGROUND AND AIMS: Primary liver cancers include: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors.METHOD: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor an YFP reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KOFoxl1-CRE;RosaYFP) develop chronic inflammation and HCCs by the age of 14-16 months, followed by cHCC-CCA tumors at the age of 18 months, as we have first observed.RESULTS: In this Mdr2-KOFoxl1-CRE;RosaYFP mouse model, liver progenitor cells are the source of cHCC-CCA tumors, but not the source of HCC. Ablating the progenitors, caused reduction of cHCC-CCA tumors but did not affect HCCs. RNA-seq revealed enrichment of the IL6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. ScRNA-seq analysis revealed that IL6 is expressed from immune and parenchymal cells in senescence, and that IL6 is part of the senescence-associated secretory phenotype (SASP). Administration of anti-IL6 Ab to Mdr2-KOFoxl1-CRE;RosaYFP mice, inhibited the development of cHCC-CCA tumors. By blocking IL6 trans-signaling, cHCC-CCA tumors decreased in number and size, indicating that cHCC-CCA is dependent on IL6 trans-signaling. Furthermore, the administration of a senolytic agent inhibited IL6 and the development of cHCC-CCA tumors.CONCLUSION: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL6, which derives in part from cells in senescence, plays an important role in this process via IL6 trans-signaling. These findings could enhance new therapeutic approaches for cHCC-CCA liver cancer.LAY SUMMARY: Combined hepatocellular carcinoma - cholangiocarcinoma is the third prevalent liver cancer. We show that the source of this tumor is the liver tissue stem cells and that, this tumor type is dependent on an inflammatory signaling of IL6 and can be inhibited by blocking IL6 signaling or using a senolytic agent.

Supplementary table from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

Supplementary Figure from Mutant IDH Inhibits IFNγ–TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate–dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate–mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell–autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell–specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ–TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy.Significance:Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies.See related commentary by Zhu and Kwong, p. 604.This article is highlighted in the In This Issue feature, p. 587

European Conference on Antennas and Propagation (EuCAP) (17th. 2023. Florence, Italy), In this work, a reflective metasurface is designed to generate a dual-circularly-polarized uniform plane wave at Ka-band (31 GHz). The metasurface is designed using a Phase Only Synthesis with the generalized Intersection Approach. The design considers tight constraints in both amplitude and phase of the radiated near field. The synthesized phase-shift distribution is also used to convert the dual-linearly polarized incident field into a dual-circularly polarized reflected field. The unit-cell of the metasurface is based on two stacked layers of three parallel dipoles, adjusted cell by cell to provide the synthesized phase distributions with less than ±1º of phase error. Preliminary results show the generation of a uniform plane wave in an area equivalent to 82.8% of the metasurface aperture size, revealing the possibility of generating dual-circularly polarized uniform plane waves using metasurfaces with a simple design process., This work was supported by MICIN/AEI/10.13039/501100011033 within projects PID2020-114172RB-C21-2; by Spanish Ministry of Universities (RD 289/2021) funded by the recovery plan for Europe NextGenerationEU under grants MU-21-UP2021- 03071895621J and UP2021-035; and by Gobierno del Principado de Asturias under project AYUD/2021/51706.

A dual-polarized transmitarray antenna is proposed to generate a multi-zone coverage at 28 GHz for 5G indoor communications. The transmitarray radiates a constant power density within its near-field region over a specific area generating different spots in dual-polarization. The different spots are produced by feeding the transmitarray with a cluster of horn antennas, which are spatially distributed to obtain beams in different directions. The performance of the coverage is improved with a Phase-Only Synthesis (POS) of the transmission coefficients. The transmitarray is designed with dielectric-only elements, which provides a low-cost solution. The prototype is measured in a planar acquisition range, showing a high agreement with simulations. The proposed transmitarray together with the spatial feed distribution provides a potential alternative to generate multi-zone coverages in millimeter frequencies., This work was supported in part by the Ministerio de Ciencia, Innovación y Universidades under Project TEC2017-86619-R (ARTEINE); an d Ministerio de Ciencia e Innovación and Agencia Española de Investigación within Project ENHANCE-5G (PID2020-114172RB-C21-2/AEI/10.13039/501100011033).

Despite recent approvals, the response to treatment and prognosis of patients with advanced hepatocellular carcinoma (HCC) remain poor. Claudin-1 (CLDN1) is a membrane protein that is expressed at tight junctions, but it can also be exposed non-junctionally, such as on the basolateral membrane of the human hepatocyte. While CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 and its role as a therapeutic target in HCC remains unexplored. Using humanized monoclonal antibodies (mAbs) specifically targeting the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as a therapeutic target for HCC. Targeting non-junctional CLDN1 markedly suppressed tumor growth and invasion in cell line-based models of HCC and patient-derived 3D ex vivo models. Moreover, the robust effect on tumor growth was confirmed in vivo in a large series of cell line-derived xenograft and patient-derived xenograft mouse models. Mechanistic studies, including single-cell RNA sequencing of multicellular patient HCC tumorspheres, suggested that CLDN1 regulates tumor stemness, metabolism, oncogenic signaling and perturbs the tumor immune microenvironment. Our results provide the rationale for targeting CLDN1 in HCC and pave the way for the clinical development of CLDN1-specific mAbs for the treatment of advanced HCC. Hepatocellular carcinoma (HCC) is associated with high mortality and unsatisfactory treatment options. Herein, we identified the cell surface protein Claudin-1 as a treatment target for advanced HCC. Monoclonal antibodies targeting Claudin-1 inhibit tumor growth in patient-derived ex vivo and in vivo models by modulating signaling, cell stemness and the tumor immune microenvironment. Given the differentiated mechanism of action, the identification of Claudin-1 as a novel therapeutic target for HCC provides an opportunity to break the plateau of limited treatment response. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of advanced HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology. journal article research support, non-u.s. gov't 2023 Feb 2022 10 27 imported

Esta cuarta edición es reflejo del gran interés mostrado en el área de la Fisiología del Ejercicio durante más de 20 años por sus lectores, unido al mayor conocimiento de cómo responde el organismo al ejercicio, sus efectos sobre la salud y la necesidad de conocer la compleja realidad de los límites del cuerpo humano. Sin financiación No data WoS No data Scopus SPI UEM

BACKGROUND & AIMS: The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans.RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis.CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH.IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis.

Airway management in the obstetric patient is a challenge for anaesthesiologists, not only because of the anatomical and physiological changes during pregnancy, but also because of the surgery´s urgency, the location of the procedure, which sometimes takes place even outside the operation theatre, and also due to conflicts emerging between the needs of the mother and fetus. The arising maternal comorbidities such as obesity, contribute to complications in airway management in this population.

ANTECEDENTES: Los parámetros clínicos pretenden predecir con antelación una vía aérea difícil, pero ninguno ni de forma aislada ni como modelo multiparamétrico tienen un elevado valor predictivo. Revisiones sistemáticas recientes correlacionan la ecografía con la laringoscopia difícil. Nuestro estudio tenía como objetivo principal correlacionar las mediciones ecográficas de tejidos pretraqueales en posición de olfateo con la laringoscopia directa difícil. El objetivo secundario fue obtener diferencias basadas en el género. MÉTODOS: Este estudio observacional prospectivo, transversal y unicéntrico incluyó a 209 pacientes que requerían anestesia general para cirugía electiva. En el preoperatorio, se realizó evaluación de seis parámetros clínicos y cuatro mediciones ecográficas, estas últimas fueron la distancia de la piel al hueso hioides, de piel a la epiglotis, área preepiglótica y distancia de piel a la comisura anterior de las cuerdas vocales, todas ellas en posición de olfateo. Los criterios de Benumof para ¨best view at first attempt¨ de laringoscopia directa permitieron evaluar la dificultad de la laringoscopia. RESULTADOS: La distancia de piel a la epiglotis y el área preepiglótica fueron los mejores predictores de laringoscopia directa difícil (definida como grado de CormackLehane ≥2b) con un grosor mínimo de corte de 2,70±0,19 cm y un área de 5.40±0.37 𝑐𝑚2 (sensibilidad 91,3%; especificidad 96,9%). El punto de corte de la distancia de piel al hueso hioides fue de 1,41±0,30 cm con una correlación moderada (sensibilidad 80,4%; especificidad 60,1%). No se encontró correlación para la distancia de piel a comisura anterior de cuerdas vocales. En las pacientes femeninas, en comparación con pacientes masculinos, la distancia de la piel a la epiglotis fue más sensible (92,3% frente a 90,9%) y más específica (98,8% frente a 95,2%). CONCLUSIONES: La distancia de la piel a la epiglotis y el área preepiglótica en la posición de olfateo son los parámetros más fiables para la evaluación ecográfica preoperatoria de la vía aérea en población caucásica, con mayor sensibilidad y especificidad en mujeres, y podrían considerarse factor predictivo independiente para la laringoscopia directa difícil. BACKGROUND: Clinical airway screening tests intend to predict difficult airways, but none has a high predictive value. Recent systematic reviews correlate ultrasound with difficult laryngoscopy. This study aimed primarily to correlate ultrasound measurements of anatomical upper airway structures in sniffing position with difficult direct laryngoscopy. The secondary aim was gender-based differences. METHODS: This prospective, cross-sectional, single-center observational study included 209 patients requiring general anesthesia for elective surgery. Preoperatively, we performed six clinical airway assessments and four ultrasound measurements, which were the distance from skin to the hyoid bone, to the epiglottis, preepiglottic space, and to the anterior commissure of the vocal cords in a sniffing position. Benumof´s criteria for the ¨best view at the first attempt¨ for direct laryngoscopy assessed the difficulty of laryngoscopy. RESULTS: The skin to the epiglottis distance and preepiglotic space were the best predictors of direct difficult laryngoscopy (defined as Cormack-Lehane grade ≥2b) with a minimum thickness cut-off at 2.70±0.19 cm and area of 5.40±0.37 𝑐𝑚2 (sensitivity 91.3%; specificity 96.9%). The skin to the hyoid bone distance cut-off was 1.41±0.30 cm with moderate correlation (sensitivity 80.4%; specificity 60.1%). No correlation was found for the distance to the anterior commissure of the vocal cords. In women compared to men was the skin to the epiglottis distance more sensitive (92.3% vs 90.9%) and specific (98.8% vs 95.2%). CONCLUSIONS: The skin to the epiglottis distance and preepiglotic space in the sniffing position are the most reliable parameters for pre-operative airway ultrasound assessment in Caucasian population with higher sensitivity and specificity in women and might be considered as an independent predictor for direct difficult laryngoscopy.

In this work, a reflectarray antenna is presented as a dual-polarized plane wave generator (PWG) in mm-wave frequencies. The reflectarray produces a uniform plane wave within its near field in a volume close to the aperture. A dual-polarized pencil beam reflectarray is used as starting point to carry out a phase-only synthesis (POS) to reach a dual-polarized uniform plane wave. The synthesis aims to overcome the amplitude limitation due to the incident field while preserving the phase flatness. The phase distribution obtained in the POS is used to carry out a design based on sets of orthogonal-coplanar dipoles. This unit cell provides independent control of each polarization using a single-layer topology. The design is manufactured, and the prototype is measured in a planar acquisition range facility. The prototype shows discrepancies with simulation and further analysis is carried out. After finding out the proper value of the dielectric constant, a new design is carried out. The second prototype shows a good agreement with simulations, obtaining that reflectarray antennas are a suitable and low-profile solution to produce uniform plane waves within the near field., This work was supported in part by Ministerio de Ciencia e Innovación and Agencia Española de Investigación within the project PID2020-114172RB-C21/AEI/10.13039/501100011033, and by Gobierno del Principado de Asturias within the project AYUD/2021/51706.

Simposio Nacional de la Unión Científica Internacional de Radio (URSI) (37th. 2022. Malaga, Spain), In this work, a reflectarray antenna is introduced to act as a plane wave generator (PWG) to evaluate devices in mm-Wave frequencies. The reflectarray is designed to radiate a uniform plane wave close to the aperture to reduce the size of the system. The Intersection Approach is used to design the reflectarray carrying out two phase-only synthesis for the two linear polarizations. The synthesis significantly improves the results obtained by an analytical approach obtaining a dualpolarized PWG. The result of the synthesis is used to carry out a design. The unit cell is a double set of orthogonal coplanar dipoles printed on a single-dielectric layer. The designed reflectarray shows significantly good performance in terms of the uniform plane wave obtained. Finally, the reflectarray-based PWG is used for the first time to evaluate the radiation pattern of an antenna. This compact measuring system presents quite good results evaluating the radiation pattern., This work was supported in part by Ministerio de Ciencia e Innovación and Agencia Española de Investigación within the project PID2020-114172RB-C21 / AEI / 10.13039 / 50110001033); and by the Gobierno del Principado de Asturias within the project AYUD/2021/51706.

IEEE International Symposium on Antennas and Propagation and USNC-URSI Radio Science Meeting (AP-S/URSI) (2022. Denver, USA), The authors would like to thank Metawave Corporation for funding and leading the 5G KLONE Project. Also, the authors would like to thank the support received from the Spanish Ministry of Science and Innovation and the Spanish Research Agency within projects PID2020-114172RB-C21-2/AEI/10.13039/501100011033.

International Workshop on Antenna Technology – iWAT2022 (2022. Dublin, Ireland), This contribution proposes a simple closed-form formula to compute the phase-shift distribution on Intelligent Reflecting Surfaces (IRS), which can be implemented using metasurfaces or reflectarray panels. The proposed technique is based on introducing a quadratic phase correction to the phase distribution that generates a collimated beam. The phase correction allows to independently control the half-power beamwidth (HPBW) in azimuth and elevation for low-cost passive IRS panels. The capabilities of the technique have been demonstrated by computing the phase distribution and radiation patterns of a 40 cm × 40 cm IRS that redirects the beam in azimuth and elevation and broadens the beam from 2º to 4º in elevation and from 2º to 18º in azimuth. This technique is very useful to the design of low-cost passive IRS panels., The authors acknowledge the support received from the Spanish Ministry of Science and Innovation and the Spanish Research Agency within projects PID2020-114172RB-C21-2/AEI/10.13039/501100011033. This work has been co-funded by the Government of the Principality of Asturias within the project AYUD/2021/51706 and by the Spanish Ministry of Economic Affairs and Digital Transformation by the NextGenerationEU under the Recovery plan for Europe and the Recovery and Resilience Facility, within the project DISRADIO TSI-063000-2021-82.

In this paper, it is proposed the use of ultra-thin reflectarrays in some emerging scenarios in the new mm-wave cellular networks such as 5G, Beyond-5G (B5G), and future 6G. To that purpose, two dual-linear polarization reflectarrays are developed to provide coverages in different scenarios at the mm-waves band. Working at 28 GHz, reflectarray designs adapt the radiated field to the coverage area specified in each scenario, through an ultra-thin surface composed of simple cells. To evaluate the antenna performance, two reflectarray prototypes identical in size are manufactured and tested achieving a good trade-off between the performance and the low-cost, low losses and, low-profile characteristics of the antenna. This work demonstrates the good performance of simple topology reflectarrays, being an interesting antenna candidate in the upcoming wireless networks.