Benefits of Aeronautical Preform Manufacturing through Arc-Directed Energy Deposition Manufacturing.

The paper introduces an innovative aerospace component production approach employing Wire Arc Additive Manufacturing (WAAM) technology to fabricate near-finished preforms from Ti6Al4V titanium. Tensile tests on WAAM Ti6Al4V workpieces demonstrated reliable mechanical properties, albeit with identified anisotropic behavior in horizontal samples, underscoring the need for optimization. This alternative manufacturing strategy addresses the challenges associated with machining forged preforms, marked by a high Buy To Fly (BTF) ratio (>10), leading to material wastage, prolonged machining durations, elevated tool expenses, and heightened waste and energy consumption. Additionally, logistical and storage costs are increased due to extended delivery timelines, exacerbated by supply issues related to the current unstable situation. The utilization of WAAM significantly mitigates initial BTF, preform costs, waste production, machining durations, and associated expenditures, while notably reducing lead times from months to mere hours. The novelty in this study lies in the application of Wire Arc Additive Manufacturing (WAAM) technology for the fabrication of titanium aircraft components. This approach includes a unique height compensation strategy and the implementation of various deposition strategies, such as single-seam, overlapping, and oscillating.

Life cycle assessment to address the environmental impacts of tourism in a Spanish tourist destination: The case of Rias Baixas (Galicia) holidays.

Tourism has grown steadily in recent decades, becoming a strategic sector for the economy in many countries. However, the environmental impacts associated with tourism have also experienced an upward trend. In this sense, innovation is needed in the tourism sector, to move towards new models and strategies that integrate environmental sustainability with the social aspects of the sector. In this study, a holistic assessment of the environmental impact of tourism has been carried out using the Life Cycle Assessment (LCA) method, considering all stages of tourism activity: transportation from the place of origin to destination and back, accommodation, catering, and activities conducted. For this purpose, a case study has been carried out based on a typical trip made from Madrid to Rías Baixas (Galicia), considering a four-night stay and the performance of two activities (music festival and cultural museum) at the destination. Two alternative transportation scenarios (train or plane) have been defined to analyze the influence of the type of transportation on the overall impact. Other touristic activities such as visiting gardens or thermal baths instead of visiting a cultural museum or attending a music festival have been analyzed and it has been found that the thermal baths and the museum have the greatest environmental impacts. Transportation was the biggest contributor to most of the environmental impacts in the selected categories. On the other hand, the stay at the destination has stood out due to the impact of the consumption of food and energy used at the accommodation facility. The impact of the activities conducted at the destination is also worth highlighting. Finally, alternative scenarios for transportation have shown that the mode of transportation selected is key for lowering the overall environmental impact of the stay at the destination, highlighting the public transportation alternative, such as the train, as the most environmentally friendly option.

Esophageal pharmacobezoar: a very unusual complication of enteral nutrition use.

Enteral nutrition in intensive care has been a great advance in medicine, due to its benefit, cost-effectiveness and few complications. Bronchoaspiration, diarrhea, regurgitation or mechanical problems are the main adverse effects. Esophageal obstruction by bezoar is a very infrequent complication, and there are only a few cases described in the literature.

Characteristics and Predictors of Suicidal Ideation Severity among Callers to a Telephone Helpline in Spain / Características y predictores de la gravedad de la ideación suicida entre las personas que llaman a una línea telefónica de ayuda en España

Teléfono de la Esperanza (TE) is the main Spanish helpline providing telephone listening and support for callers in crisis. Crisis helplines can facilitate the identification of persons at risk for suicide. The main goals of this cross-sectional study were to identify severe suicidal ideation and to explore the differential characteristics between callers with severe and low-moderate suicidal ideation. A sample of 26,032 callers to TE was assessed; 544 callers with suicidal ideation were evaluated through ATENSIS, an assessment tool designed to collect information related to suicidal ideation. Comparisons between severe and low-moderate suicidal ideators in sociodemographics, telephone call timing, risk factors, and suicidality variables were conducted. Sixty-four (11.8%) of the suicidal ideators presented with severe suicidal ideation and 480 (88.2%) with low-moderate severity. Significant differences in several sociodemographic characteristics, risk factors, and suicidality variables between both levels of suicidal ideation severity were found. In the regression analysis, the main variables related to the presence of high suicidal ideation severity were preparatory acts, previous suicide attempts, non-suicidal self-injuries, lack of life sense, age, and hopelessness. It is concluded that helplines can be used to identify suicidal ideation among callers and to provide rapid crisis interventions according to the risk of suicide. (AU)

El Teléfono de la Esperanza (TE) es la principal línea telefónica de ayuda en España que brinda apoyo a las personas en situaciones de crisis. Las líneas telefónicas de ayuda pueden facilitar la identificación de personas en riesgo de suicidio. Los objetivos principales de este estudio transversal fueron identificar la ideación suicida grave y explorar las características diferenciales con respecto a la ideación suicida moderada. Se revisaron las llamadas al TE de 26,032 personas y se evaluó una muestra de 544 personas que presentaban ideación suicida a través de ATENSIS, una herramienta diseñada para recopilar información sobre la ideación suicida. Se comparó a las personas con ideación suicida grave y moderada en características sociodemográficas, momento de la llamada, factores de riesgo y variables de suicidio. Sesenta y cuatro (11.8%) de las personas presentaban ideación suicida grave y 480 (88.2%) ideación baja-moderada. Se encontraron diferencias significativas en las distintas variables estudiadas. En el análisis de regresión, las principales variables relacionadas con la presencia de alta gravedad de la ideación suicida fueron la existencia de actos preparatorios, los intentos previos de suicidio, las autolesiones no suicidas, la falta de sentido de la vida, la edad y la desesperanza. Las líneas de ayuda pueden identificar la ideación suicida en las personas que llaman y proporcionar una intervención rápida en situaciones de crisis de acuerdo con el riesgo de suicidio presentado. (AU)

The genetic structure and adaptation of Andean highlanders and Amazonians are influenced by the interplay between geography and culture.

Western South America was one of the worldwide cradles of civilization. The well-known Inca Empire was the tip of the iceberg of an evolutionary process that started 11,000 to 14,000 years ago. Genetic data from 18 Peruvian populations reveal the following: 1) The between-population homogenization of the central southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes, and Amazonia accompanied cultural and socioeconomic interactions revealed by archeology. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower, and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia. 2) The genetic homogenization between the populations of the arid Andes is not only due to migrations during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the Wari Empire (600 to 1,000 years before present). 3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, a putative enhancer in HAND2-AS1 (heart and neural crest derivatives expressed 2 antisense RNA1, a noncoding gene related to cardiovascular function) and rs269868-C/Ser1067 in DUOX2 (dual oxidase 2, related to thyroid function and innate immunity) genes and, in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T and B lymphocytes in viral-host interaction.

Targeting PD-L1 in non-small cell lung cancer using CAR T cells.

Antibodies against programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the landscape of therapies for non-small cell lung carcinoma (NSCLC); however, the majority of patients do not respond to these agents. In addition, hyperprogressive disease (HPD) develops in a larger portion of NSCLC patients treated with PD-1/PD-L1 inhibitors than in patients treated with standard chemotherapy. The use of chimeric antigen receptor (CAR) T cells has been successful to treat blood cancers but not for solid tumors like NSCLC. In this work, we constructed CAR T cells that target PD-L1 and evaluated their efficacy in NSCLC with either high or low PD-L1 expression. PD-L1-CAR T cells exhibited antigen-specific activation, cytokine production, and cytotoxic activity against PD-L1high NSCLC cells and xenograft tumors. Furthermore, the addition of a subtherapeutic dose of local radiotherapy improved the efficacy of PD-L1-CAR T cells against PD-L1low NSCLC cells and tumors. Our findings indicate that PD-L1-CAR T cells represent a novel therapeutic strategy for patients with PD-L1-positive NSCLC, particularly for those who are susceptible to HPD.

MR1-Restricted T Cells in Cancer Immunotherapy.

Major histocompatibility complex class I-related (MR1) was first identified as a cell membrane protein involved in the development and expansion of a unique set of T cells expressing an invariant T-cell receptor (TCR) α-chain. These cells were initially discovered in mucosal tissues, such as the intestinal mucosa, so they are called mucosal-associated invariant T (MAIT) cells. MR1 senses the presence of intermediate metabolites of riboflavin and folic acid synthesis that have been chemically modified by the side-products of glycolysis, glyoxal or methylglyoxal. These modified metabolites form complexes with MR1 and translocate from the endoplasmic reticulum to the plasma membrane where MAIT cells' TCRs recognize them. Recent publications report that atypical MR1-restricted cytotoxic T cells, differing from MAIT cells in TCR usage, antigen, and transcription factor profile, recognize an as yet unknown cancer-specific metabolite presented by MR1 in cancer cells. This metabolite may represent another class of neoantigens, beyond the neo-peptides arising from altered tumor proteins. In an MR1-dependent manner, these MR1-restricted T cells, while sparing noncancerous cells, kill many cancer cell lines and attenuate cell-line-derived and patient-derived xenograft tumors. As MR1 is monomorphic and expressed in a wide range of cancer tissues, these findings raise the possibility of universal pan-cancer immunotherapies that are dependent on cancer metabolites.

The Fibroblast Growth Factor Receptors in Breast Cancer: from Oncogenesis to Better Treatments.

Breast cancer (BC) is the most frequent form of malignancy and second only to lung cancer as cause of deaths in women. Notwithstanding many progresses made in the field, metastatic BC has a very poor prognosis. As therapies are becoming more personalized to meet the needs of patients, a better knowledge of the molecular biology leading to the disease unfolds the possibility to project more precise compounds or antibodies targeting definite alteration at the molecular level and functioning on such cancer-causing molecules expressed in cancer cells of patients, or present as antigens on the surface of cancer cell membranes. Fibroblast growth factor receptor (FGFR) is one of such druggable targets, activated by its own ligands -namely the Fibroblast Growth Factors (FGFs). This pathway provides a vast range of interesting molecular targets pursued at different levels of clinical investigation. Herein we provide an update on the knowledge of genetic alterations of the receptors in breast cancer, their role in tumorigenesis and the most recent drugs against this particular receptor for the treatment of the disease.

Gender Differences in Risk Factors Related to Suicidal Ideation Among Callers to Telephone Helplines in Spain.

The main goals of this study were to determine the prevalence rate of suicidal ideation among callers to a Spanish telephone general crisis helpline (Teléfono de la Esperanza) and to identify gender-based characteristics and risk factors related to suicidal ideation. A sample of 10,765 (6,868 men and 3,897 women) callers to this telephone helpline was assessed. ATENSIS, an assessment tool designed to collect information related to suicidal ideation among callers to telephone helplines, was used. Comparisons between men and women with suicidal ideation were carried out in all variables studied: sociodemographics, telephone call timing, risk factors, and suicidality. Of the total sample, 1.87% (n = 201) presented suicidal ideation, with a higher prevalence in women (2.80%) than in men (1.34%). Moreover, significant gender-based differences among callers with suicidal ideations were observed in some variables: women were older than men and showed a greater prevalence of chronic disease with pain; men showed a greater prevalence of depression, alcohol/drug abuse, helplessness, and lack of hope for the future. This study showed that telephone helplines can be used to identify suicidal ideation among callers. Moreover, gender-based differential characteristics among suicide ideators have been found. The implications for further research are discussed.

Evolutionary genomic dynamics of Peruvians before, during, and after the Inca Empire.

Native Americans from the Amazon, Andes, and coastal geographic regions of South America have a rich cultural heritage but are genetically understudied, therefore leading to gaps in our knowledge of their genomic architecture and demographic history. In this study, we sequence 150 genomes to high coverage combined with an additional 130 genotype array samples from Native American and mestizo populations in Peru. The majority of our samples possess greater than 90% Native American ancestry, which makes this the most extensive Native American sequencing project to date. Demographic modeling reveals that the peopling of Peru began ∼12,000 y ago, consistent with the hypothesis of the rapid peopling of the Americas and Peruvian archeological data. We find that the Native American populations possess distinct ancestral divisions, whereas the mestizo groups were admixtures of multiple Native American communities that occurred before and during the Inca Empire and Spanish rule. In addition, the mestizo communities also show Spanish introgression largely following Peruvian Independence, nearly 300 y after Spain conquered Peru. Further, we estimate migration events between Peruvian populations from all three geographic regions with the majority of between-region migration moving from the high Andes to the low-altitude Amazon and coast. As such, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern-day Peruvians and a Native American ancestry dataset that will serve as a beneficial resource to addressing the underrepresentation of Native American ancestry in sequencing studies.

An Isolated TCR αß Restricted by HLA-A*02:01/CT37 Peptide Redirecting CD8+ T Cells To Kill and Secrete IFN-γ in Response to Lung Adenocarcinoma Cell Lines.

Lung cancer is a leading cause of cancer-related death among both men and women in the United States, where non-small cell lung cancer accounts for ∼85% of lung cancer. Lung adenocarcinoma (ADC) is the major histologic subtype. The presence of actionable mutations prompts the use of therapies designed to specifically address the deleterious effects of those cancer-driving mutations; these therapies have already shown promise in cases carrying those actionable mutations (∼30%). Innovative therapeutic approaches are needed for the treatment of 70% of patients suffering from lung ADC. Adoptive transfer of CD8+ T cells specific against cancer/testis (CT) Ags, whose protein expression is restricted to the gonads (testis and ovary) and cancerous cells, is an excellent alternative. In this study, we report the isolation of HLA-A*02:01/CT37 peptide-specific α and ß TCR chains from a CD8+ T cell clone obtained from a patient suffering from lung ADC. We also report the development of an innovative CD3ζ construct. With those TCR chains and the engineered (modified) CD3ζ chain, we produced a construct that when transduced into CD8+ T cells is capable of redirecting transduced CD8+ T cell cytotoxic activity and IFN-γ secretion against peptide-pulsed autologous cells and HLA-A*02:01-positive and CT37-expressing lung ADC cell lines. Our findings will launch the development of innovative adoptive transfer immunotherapies for the treatment of lung ADC, targeting the most prevalent HLA molecules and CT37 peptides restricted by these molecules.

Inverse relationship between TCTP/RhoA and p53 /cyclin A/actin expression in ovarian cancer cells.

The translationally controlled tumor protein (TCTP) plays a role in cell growth, cell cycle and cancer progression. TCTP controls negatively the stability of the p53 tumor suppressor protein and interacts with the cellular cytoskeleton. The deregulation of the actin and cytokeratin cytoskeleton is responsible for the increased migratory activity of tumor cells and is linked with poor patient outcome. Recent studies indicate that cyclin A,a key regulator of cell cycle, controls actin organization and negatively regulates cell motility via regulation of RhoA expression. We studied the organization of actin and cytokeratin cytoskeleton and the expression of TCTP, p53,cyclin A, RhoA and actin in HIO180 non-transformed ovarian epithelial cells, and OVCAR3 and SKOV3 (expressing low level of inducible p53) ovarian epithelial cancer cells with different metastatic potential. Immunostaining and ultrastructural analyses illustrated a dramatic difference in the organization of the cytokeratin and actin filaments in non-transformed versus cancer cell lines. We also determined that there is an inverse relationship between the level of TCTP/RhoA and actin/p53/cyclin A expression in ovarian cancer cell lines. This previously unidentified negative relationship between TCTP/RhoA and actin/p53/cyclin A may suggest that this interaction is linked with the high aggressiveness of ovarian cancers.

Joint effect of MCP-1 genotype GG and MMP-1 genotype 2G/2G increases the likelihood of developing pulmonary tuberculosis in BCG-vaccinated individuals.

We previously reported that the -2518 MCP-1 genotype GG increases the likelihood of developing tuberculosis (TB) in non-BCG-vaccinated Mexicans and Koreans. Here, we tested the hypothesis that this genotype, alone or together with the -1607 MMP-1 functional polymorphism, increases the likelihood of developing TB in BCG-vaccinated individuals. We conducted population-based case-control studies of BCG-vaccinated individuals in Mexico and Peru that included 193 TB cases and 243 healthy tuberculin-positive controls from Mexico and 701 TB cases and 796 controls from Peru. We also performed immunohistochemistry (IHC) analysis of lymph nodes from carriers of relevant two-locus genotypes and in vitro studies to determine how these variants may operate to increase the risk of developing active disease. We report that a joint effect between the -2518 MCP-1 genotype GG and the -1607 MMP-1 genotype 2G/2G consistently increases the odds of developing TB 3.59-fold in Mexicans and 3.9-fold in Peruvians. IHC analysis of lymph nodes indicated that carriers of the two-locus genotype MCP-1 GG MMP-1 2G/2G express the highest levels of both MCP-1 and MMP-1. Carriers of these susceptibility genotypes might be at increased risk of developing TB because they produce high levels of MCP-1, which enhances the induction of MMP-1 production by M. tuberculosis-sonicate antigens to higher levels than in carriers of the other two-locus MCP-1 MMP-1 genotypes studied. This notion was supported by in vitro experiments and luciferase based promoter activity assay. MMP-1 may destabilize granuloma formation and promote tissue damage and disease progression early in the infection. Our findings may foster the development of new and personalized therapeutic approaches targeting MCP-1 and/or MMP-1.

A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis.

We examined the distribution of single nucleotide polymorphisms (SNPs) in nitric oxide synthase 2A, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein-1alpha genes in tuberculosis patients and healthy controls from Mexico. The odds of developing tuberculosis were 2.3- and 5.4-fold higher in carriers of MCP-1 genotypes AG and GG than in homozygous AA. Cases of homozygous GG had the highest plasma levels of MCP-1 and the lowest plasma levels of IL-12p40, and these values were negatively correlated. Furthermore, stimulation of monocytes from healthy carriers of the genotype GG with Mycobacterium tuberculosis antigens yielded higher MCP-1 and lower IL-12p40 concentrations than parallel experiments with monocytes from homozygous AA. Addition of anti-MCP-1 increased IL-12p40 levels in cultures of M. tuberculosis-stimulated monocytes from homozygous GG, and addition of exogenous MCP-1 reduced IL-12p40 production by M. tuberculosis-stimulated monocytes from homozygous AA. Furthermore, we could replicate our results in Korean subjects, in whom the odds of developing tuberculosis were 2.8- and 6.9-fold higher in carriers of MCP-1 genotypes AG and GG than in homozygous AA. Our findings suggest that persons bearing the MCP-1 genotype GG produce high concentrations of MCP-1, which inhibits production of IL-12p40 in response to M. tuberculosis and increases the likelihood that M. tuberculosis infection will progress to active pulmonary tuberculosis.

Associations of MHC ancestral haplotypes with resistance/susceptibility to AIDS disease development.

We tested the association of MHC ancestral haplotypes with rapid or slow progression to AIDS by comparing their frequencies in the French genetics of resistance/susceptibility to immunodeficiency virus cohort with that reported in a control French population. Seven ancestral haplotypes were identified in the genetics of resistance/susceptibility to immunodeficiency virus cohort with a frequency >1%. The 8.1 (odds ratio (OR) = 3, p = 0.006), 35.1 (OR = 5.7, p = 0.001), and 44.2 (OR = 3.4, p = 0.007) ancestral haplotypes were associated with rapid progression, whereas the 35.2 (OR = 3.6, p = 0.001), 44.1 (OR = 5.4, p < 10(-4)), and 57.1 (OR = 5.8, p < 10(-4)) ancestral haplotypes were associated with slow progression to AIDS. Although the frequency of each ancestral haplotype is low in the population, the OR were quite higher than those previously obtained for single HLA allele associations, with some p values as low as 10(-4). The analysis of the recombinant fragments of these haplotypes allowed the identification of the MHC regions in the 35.1, 35.2, and 44.2 haplotypes associated with rapid progression to AIDS and the MHC regions of the 44.1 and 57.1 haplotypes associated with slow progression to AIDS. Previous studies have identified single HLA alleles associated with disease progression. Our results on recombinant fragments confirm the direct role of HLA-B35 in rapid progression. Associations with HLA-A29 and -B57 might be due to linkage disequilibrium with other causative genes within the MHC region.

Linkage disequilibrium between HLA-DPB1 alleles and retinoid X receptor beta haplotypes.

The human retinoid X receptor beta (RXRB) gene maps to the major histocompatibility complex (MHC) region, between KE4 and COL11A2, approximately 130-kb centromeric to HLA-DPB1. We have recently reported a new polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to detect the G to T single nucleotide polymorphism (SNP) located seven nucleotides after the tenth exon of the RXRB gene, or 3'end+7 position according to existing nomenclature. We also reported strong linkage disequilibrium between the HLA-DPB1*0401 and RXRB+7*T alleles. In the present study, we describe two PCR-RFLP methods to detect additional SNPs in the RXRB gene, T to A, at exon10+378 and A to T at 3'end+140. This new methodology permitted the unambiguous assignment of three distinct SNPs at RXRB exon10+378, 3'end+7 and 3'end+140 to form an "RXRB haplotype." The data generated from this study were used to determine linkage disequilibrium between several MHC markers and the RXRB alleles and haplotypes. Family studies revealed significant linkage disequilibrium between the RXRB alleles and a number of HLA-DPB1 alleles.

Drenaje percutáneo de absceso hepático amibiano guiado por medio de ultrasonido. Resultados preliminares / Percutaneous drainage of amebic hepatic abscess by guided ultrasound. Preliminary results

El absceso hepático amibiano (AHA) es la más frecuente complicación extraintestinal de la amibiasis. A través del tiempo, su tratamiento ha sufrido algunos cambios, actualmente es a base de antiamibianos y en algunos casos el drenaje percutáneo. El objetivo de este trabajo es presentar nuestra experiencia en el tratamiento mediante el drenaje percutáneo, guiado por ultrasonido en pacientes con AHA. Se Incluyeron en este trabajo 170 pacientes que ingresaron al Servicio de Gastroenterología del Hospital General de Zona No 1 del Instituto Mexicano del Seguro Social, durante un periodo de ocho años (1990-1997), quienes reunieron de los siguientes criterios de inclusión: falla terapéutica clínica, AHA mayor a ocho centímetros por ultrasonido, de material netamente líquido, riesgo de ruptura, incapacidad prolongada sin datos de toxico-infección, ruta de drenaje accesible, disponibilidad de quirófano ante el riesgo de complicación, pruebas de coagulación normales. Dichos criterios se proponen a la comunidad médica. Se utilizó la técnica de Seldinger modificada.En 131 pacientes se realizó una sola punción, puesto que tenían absceso único, en 39 pacientes se requirió de una segunda evacuación por presentar dos abscesos, y en cuatro casos se requirió de una tercera evacuación, puesto que existía la presencia de tres abscesos o más y sólo en un caso se requirió procedimiento quirúrgico urgente por ruptura de absceso residual a pleural; sufrieron complicaciones solamente cinco pacientes, incluyéndose este último, los otros cuatro tuvieron resolución espontánea de sus complicaciones. Los pacientes fueron egresados a las 24 h ulteriores al procedimiento y ningún paciente requirió rehospitalización, por lo que se considera que es un procedimiento que en manos expertas de radiólogos intervencionistas, tiene cada vez menor morbilidad y mortalidad. Se pretende llevar este trabajo a 10 años