KLK7 expression in human tumors: a tissue microarray study on 13,447 tumors.

BACKGROUND: Kallikrein-related peptidase 7 (KLK7) is a chymotrypsin-like serine protease which is essential for the desquamation of corneocytes and thus plays a pivotal role in maintaining skin homeostasis. In cancer, KLK7 overexpression was suggested to represent a route for metastasis through cleavage of cell junction and extracellular matrix proteins of cancer cells. METHODS: To comprehensively determine KLK7 protein expression in normal and neoplastic tissues, a tissue microarray containing 13,447 samples from 147 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. RESULTS: KLK7 positivity was found in 64 of 147 tumor categories, including 17 tumor categories with at least one strongly positive case. The highest rate of KLK7 positivity was found in squamous cell carcinomas from various sites of origin (positive in 18.1%-63.8%), ovarian and endometrium cancers (4.8%-56.2%), salivary gland tumors (4.8%-13.7%), bilio-pancreatic adenocarcinomas (20.0%-40.4%), and adenocarcinomas of the upper gastrointestinal tract (3.3%-12.5%). KLK7 positivity was linked to nodal metastasis (p = 0.0005), blood vessel infiltration (p = 0.0037), and lymph vessel infiltration (p < 0.0001) in colorectal adenocarcinoma, nodal metastasis in hepatocellular carcinoma (p = 0.0382), advanced pathological tumor stage in papillary thyroid cancer (p = 0.0132), and low grade of malignancy in a cohort of 719 squamous cell carcinomas from 11 different sites of origin (p < 0.0001). CONCLUSIONS: These data provide a comprehensive overview on KLK7 expression in normal and neoplastic human tissues. The prognostic relevance of KLK7 expression and the possible role of KLK7 as a drug target need to be further investigated.

Understanding factors limiting hematopoietic cell transplantation for acute myeloid leukemia patients in Mexico: a comprehensive analysis.

Acute myeloid leukemia (AML) is the most frequent indication for allogeneic hematopoietic cell transplantation (alloHCT) worldwide; social and health system barriers limit its access. We performed an observational retrospective analysis in Mexico to analyze factors limiting alloHCT in fit patients with AML. With a median follow-up of 11.8 months, 301 patients were included, with a median age of 42; 33.5% were classified as adverse risk. Despite 215 patients (92.5%) achieving complete remission, only 103 (34%) had HLA-typing: 44.5% had a matched-sibling donor (MSD), 32% a haploidentical donor, and 23.5% had no donor. Only 23.5% of patients had an HCT consult; merely 36 underwent an HCT: 30 alloHCT, and six an autologous HCT. Age ≥ 60 years, HCT-CI score ≥ three, and the absence of a local transplant program negatively influenced HLA typing likelihood. Patients with an MSD had a higher alloHCT likelihood. The cumulative incidence of transplant (CIT) and relapse (CIR) at 6 and 12 months was 7.3% and 13.8%, 8.2% and 13%, respectively. A lack of HLA-typing was associated with a lower CIT (p < 0.001) and higher CIR (p = 0.033) (HR 11.72, CI 95% 4.39-31.27, p < 0.001), while the presence of an MSD was associated with a higher CIT (p = 0.002) (HR 4.22, CI 95% 1.89-9.44, p < 0.001). The main reasons hindering alloHCT are the lack of access to HLA-typing tests and the absence of an MSD. A national donor registry and improved HLA-typing accessibility are critical for increasing alloHCT access in Mexico.

Design and functional characterization of Salmo salar TLR5 agonist peptides derived from high mobility group B1 acidic tail.

Toll-like receptor 5 (TLR5) responds to the monomeric form of flagellin and induces the MyD88-depending signaling pathway, activating proinflammatory transcription factors such as NF-κB and the consequent induction of cytokines. On the other hand, HMGB1 is a highly conserved non-histone chromosomal protein shown to interact with and activate TLR5. The present work aimed to design and characterize TLR5 agonist peptides derived from the acidic tail of Salmo salar HMGB1 based on the structural knowledge of the TLR5 surface using global molecular docking platforms. Peptide binding poses complexed on TLR5 ectodomain model from each algorithm were filtrated based on docking scoring functions and predicted theoretical binding affinity of the complex. Circular dichroism spectra were recorded for each peptide selected for synthesis. Only intrinsically disordered peptides (6W, 11W, and SsOri) were selected for experimental functional assay. The functional characterization of the peptides was performed by NF-κB activation assays, RT-qPCR gene expression assays, and Piscirickettsia salmonis challenge in SHK-1 cells. The 6W and 11W peptides increased the nuclear translation of p65 and phosphorylation. In addition, the peptides induced the expression of genes related to the TLR5 pathway activation, pro- and anti-inflammatory response, and differentiation and activation of T lymphocytes towards phenotypes such as TH1, TH17, and TH2. Finally, it was shown that the 11W peptide protects immune cells against infection with P. salmonis bacteria. Overall, the results indicate the usefulness of novel peptides as potential immunostimulants in salmonids.

[Budget impact analysis of the implementation of a bone tissue bank in a Chilean health service]. / Análisis de impacto presupuestario de un banco de tejido óseo en un servicio de salud de Chile.

This research aimed to analyze the costs of bone grafting through a bone tissue bank in a Chilean regional health service. Methods: First, we developed a preliminary epidemiological study to obtain the necessary data for the analysis, specifically on bone graft procedures in a local health service (Servicio Salud Concepción). Next, we performed a budget impact analysis. Results: We analyzed a total of 6,252 cc of bone grafts, with a total cost of USD$156,000 per year. We found a potential recovering capacity of 302 ± 16 femoral heads per year from the total hip replacement procedures. Based on these results, bone tissue banks could save USD$145,000 hospital costs annually. Studying a representative health service from Chile, this analysis revealed a dependency on imported bone substitutes and autografts. These requirements can be supplied sustainably by a bone tissue bank based on donations of femoral heads under the current legislation of the Chilean health authority.

MiR-9-5p protects from kidney fibrosis by metabolic reprogramming.

MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages, and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-ß1)-dependent de-differentiation in human kidney proximal tubular (HKC-8) cells. RNA-sequencing (RNA-Seq) studies in the UUO model revealed that treatment with miR-9-5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR-9-5p impeded TGF-ß1-induced bioenergetics derangement. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-peroxisome proliferator-activated receptor alpha (PPARα) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1α, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells.

Modelling agricultural land abandonment in a fine spatial resolution multi-level land-use model: An application for the EU.

In the majority of EU Member States, agricultural land is expected to decrease not only due to land-use changes in favour of urban expansion and afforestation but also to land abandonment processes. The knowledge on location and extent of agricultural land abandonment is relevant for estimating local external effects and adapting policy interventions. Currently, multi-level land-use models are able to capture determined processes of demand-driven redevelopment. However, land abandonment is much more difficult to capture because of its more ambiguous definition and the lack of data on its spatial distribution. This paper presents a method to explicitly model agricultural abandonment as a choice of disinvestment, which in turn is embedded in a utility-based land-use modelling framework that projects land-use changes for the EU and the UK. Validation exercises using observed spatial distribution of abandoned farmland show that the proposed method allows to model abandonment with acceptable accuracy.

COVID-19 and the right to education in Chile: An opportunity to revisit our social contract.

The COVID-19 pandemic is pushing the world into a devastating economic and social scenario. The consequences of this crisis largely impact children and teenagers, both now and in the future. School closures have particularly affected vulnerable children, deepening the effects of their unequal socio-economic circumstances. In this context, the actions governments are taking to protect their citizens' right to education will be crucial to reducing or exacerbating inequality in the long term. The authors of this article analyse the case of Chile, one of the most successful countries in Latin America regarding educational achievement and enrolment, as well as the most segregated educational system among member countries of the Organisation for Economic Co-operation and Development (OECD). How is the right to education being guaranteed for all during the COVID-19 pandemic? Are the measures taken by the Ministry of Education mitigating or intensifying long-term inequalities? Based on the 4-A scheme described by Katarina Tomasevski, which conceptualises national governments' obligations to guarantee the right to education, the authors examine the normative basis of Chile's market-oriented educational system (1980-2013) as well as the latest educational reform (2014-2017), which aimed to promote the right to quality education, and critically analyse the measures adopted by the Chilean Ministry of Education in response to the pandemic. The authors conclude that Chile is facing a major challenge to ensure the right to education for all. A new social contract is required to reduce structural inequalities, and to avoid a potential setback in human rights.

La COVID-19 et le droit à l'éducation au Chili : l'occasion de revisiter notre contrat social ­ La pandémie de COVID 19 entraîne le monde vers un scénario économique et social dévastateur. Les conséquences de cette crise impactent fortement le présent et l'avenir des enfants et des adolescents. Les fermetures d'écoles ont particulièrement affecté les enfants en aggravant les effets des inégalités socio-économiques. Dans ce contexte, les mesures que prennent les gouvernements pour protéger le droit des citoyens à l'éducation seront capitales en ce qui concerne la réduction ou l'aggravation des inégalités à long terme. Les auteurs de cet article analysent le cas du Chili, l'un des pays latino-américains qui connaissent le plus de succès en matière de réussite scolaire et de scolarisation, et dont le système éducatif est en même temps le plus ségrégatif de tous les pays membres de l'Organisation de coopération et de développement économiques (OCDE). Comment le droit à l'éducation pour tous y est-il garanti pendant la pandémie de COVID-19 ? Les mesures prises par le ministère de l'Éducation atténuent-elles à long terme les inégalités ou les creusent-elles ? Les auteurs s'appuient sur le schéma des 4 A (selon lequel l'éducation doit être abordable, accessible, acceptable et adaptable ­ n.d.l.t.), dans lequel Katarina Tomasevski conceptualise les obligations des gouvernements de garantir le droit à l'éducation. Ils l'utilisent non seulement pour examiner la base normative du système chilien de l'éducation axé sur le marché (1980-2013) et la dernière réforme de l'éducation (2014-2017) visant à promouvoir le droit à une éducation de qualité, mais aussi pour livrer une analyse critique des mesures adoptées par le ministère de l'Éducation chilien en réponse à la pandémie. Ils concluent que pour garantir le droit à l'éducation pour tous, le Chili doit relever un défi d'importance. Un nouveau contrat social est nécessaire pour réduire les inégalités structurelles et éviter une régression potentielle des droits humains.

COVID-19 y el derecho a la educación en Chile: Una oportunidad para revisitar nuestro contrato social ­ La pandemia del COVID-19 está empujando al mundo a un escenario económico y social devastador. Las consecuencias de esta crisis impactarán sobremanera a la niñez y adolescencia, tanto en el presente como en el futuro. El cierre de los establecimientos educativos ha afectado particularmente a la población vulnerable, profundizando los efectos de su desventaja socio-económica de origen. En este contexto, las acciones que tomen los Estados para proteger el derecho a la educación serán cruciales para reducir o exacerbar la inequidad en el largo plazo. Los autores de este artículo analizan el caso de Chile, uno de los países de América Latina con mayores tasas de matriculación y completitud, a pesar de contar con el sistema educativo más segregado entre los países de la Organización para la Cooperación y el Desarrollo Económicos (OCDE). ¿Cómo se está garantizando el derecho a la educación durante la pandemia del COVID-19? Las medidas tomadas por el Ministerio de Educación, ¿están mitigando o agudizando las inequidades en el largo plazo? Los autores abordan ambas preguntas en base a las 4-As definidas por Katarina Tomasevski, en que se conceptualizan las obligaciones de los Estados para garantizar el derecho a la educación. En primer lugar, examinan las normativas que sentaron las bases del sistema educativo orientado en el mercado (1980-2013) así como las modificaciones propuestas por la última reforma educativa (2014-2017), que buscaron promover el derecho a la educación de calidad. Luego, los autores analizan las medidas adoptadas por el Ministerio de Educación en respuesta a la pandemia. Concluyen que Chile está enfrentando un gran desafío para poder asegurar el derecho a la educación para todos. Por lo tanto, se requiere un nuevo contrato social para reducir las inequidades estructurales, y para evitar un potencial revés en materia de derechos humanos.

Mexican Concensus of Multiple Myeloma.

To identify this increasingly common pathology, known as multiple myeloma (MM), it is necessary to refer to the specific factors that characterize it; to this end, the classic criteria known as CRAB (hyperkalemia, renal failure, anemia, and lytic lesions) are available, in which renal failure is one of the most frequent complications. Recently, three indisputable biomarkers have been described for the diagnostic support for MM, which are: more than 10% of clonal plasma cells in bone marrow or, a biopsy that corroborates the presence of a plasmacytoma, light chain ratio ≥ 100 mg/dL and more than one focal lesion on magnetic resonance imaging. A differential diagnosis for plasma cell leukemia, solitary bone plasmacytoma, and extramedullary plasmacytoma should always be considered. Being this an incurable disease, a lot of research has been done regarding its therapeutic management, whose main objective is the disappearance of plasma cells and the patient clinical improvement. Melphalan was the first drug that showed a benefit in 1958 and afterward, with the addition of a steroid as a second drug, it was possible to improve response rates. Subsequently, different molecules were studied, forming multiple combinations, and achieving better rates of overall survival and progression-free survival. Years later, with the arrival of proteasome inhibitors such as bortezomib, and immunomodulators such as thalidomide and lenalidomide, an important turnaround in the disease has been seen, as deeper responses, more prolonged remissions, and improvement in the quality of life of patients have been achieved. This consensus has the purpose of integrating a group of Mexican specialists and promoting the updating of this pathology.

Para identificar una patología cada vez más común, conocida como mieloma múltiple, es necesario hacer alusión de los factores específicos que la caracterizan. Para ello existen los clásicos criterios conocidos como CRAB (hipercalcemia, insuficiencia renal, anemia y lesiones líticas), siendo la insuficiencia renal una de sus complicaciones más frecuentes. Recientemente se han descrito tres biomarcadores indiscutibles para el apoyo diagnóstico del mieloma múltiple, que son: más del 10% de células plasmáticas clonales en medula ósea o biopsia que corrobora la presencia de un plasmocitoma, relación de cadenas ligeras ≥ 100 mg/dl y más de una lesión focal en resonancia magnética. Se debe tomar siempre en cuenta el diagnóstico diferencial con leucemia de células plasmáticas, plasmocitoma óseo solitario y plasmocitoma extramedular. Al ser una enfermedad incurable, se ha investigado mucho en cuanto al manejo terapéutico, el cual tiene como objetivo principal la desaparición de las células plasmáticas y la mejoría clínica del paciente. El primer fármaco que demostró algún beneficio fue el melfalán en el año 1958 y posteriormente al adicionar un esteroide como segundo fármaco se logró mejorar las tasas de respuesta. Después se fueron estudiando diferentes moléculas, con las que se han realizado múltiples combinaciones, alcanzando mejores tasas de supervivencia global y supervivencia libre de progresión. Años más tarde, con la llegada de los inhibidores de proteosoma como el bortezomib, así como de los agentes inmunomoduladores como la talidomida y la lenalidomida, se presenta un giro importante en la enfermedad, ya que se logran respuestas más profundas, periodo de remisiones más prolongadas y mejoría en la calidad de vida de los pacientes. Este consenso tiene la finalidad de integrar a un grupo de especialistas mexicanos y promover la actualización de esta patología.

Habitat preference in the critically endangered yellow-tailed woolly monkey (Lagothrix flavicauda) at La Esperanza, Peru.

Habitat loss is one of the main threats to wildlife. Therefore, knowledge of habitat use and preference is essential for the design of conservation strategies and identification of priority sites for the protection of endangered species. The yellow-tailed woolly monkey (Lagothrix flavicauda Humboldt, 1812), categorized as Critically Endangered on the IUCN Red List, is endemic to montane forests in northern Peru where its habitat is greatly threatened. We assessed how habitat use and preference in L. flavicauda are linked to forest structure and composition. The study took place near La Esperanza, in the Amazonas region, Peru. Our objective was to identify characteristics of habitat most utilized by L. flavicauda to provide information that will be useful for the selection of priority sites for conservation measures. Using presence records collected from May 2013 to February 2014 for one group of L. flavicauda, we classified the study site into three different use zones: low-use, medium-use, and high-use. We assessed forest structure and composition for all use zones using 0.1 ha Gentry vegetation transects. Results show high levels of variation in plant species composition across the three use zones. Plants used as food resources had considerably greater density, dominance, and ecological importance in high-use zones. High-use zones presented similar structure to medium- and low-use zones; thus it remains difficult to assess the influence of forest structure on habitat preference. We recommend focusing conservation efforts on areas with a similar floristic composition to the high-use zones recorded in this study and suggest utilizing key alimentation species for reforestation efforts.

Hypoxia effects on glioblastoma progression through YAP/TAZ pathway regulation.

The resistance of glioblastomas (GBM) to standard therapies poses a clinical challenge with limited survival despite interventions. The tumor microenvironment (TME) orchestrates GBM progression, comprising stromal and immune cells and is characterized by extensive hypoxic regions. Hypoxia activates the hypoxia-inducible factor 1 alpha (HIF-1α) pathway, interacting with the Hippo pathway (YAP/TAZ) in crucial cellular processes. We discuss here the related signaling crosstalk between YAP/TAZ and regions of hypoxia in the TME with particular attention on the MST1/2 and LATS1/2-regulated YAP/TAZ activation, impacting cell proliferation, invasion, and stemness. Moreover, the hypoxia-YAP/TAZ axis influence on angiogenesis, stem cells, and metabolic regulators is defined. By reviewing extracellular matrix alterations activation of YAP/TAZ, modulation of signaling pathways we also discuss the significance of spatial constraints and epigenetic modifications contribution to GBM progression, with potential therapeutic targets in YAP/TAZ-mediated gene regulation. Comprehensive understanding of the hypoxia-Hippo pathway-TME interplay offers insights for novel therapeutic strategies, aiming to provide new directions for treatment.

Emotionally expressive interdependence in Latin America: Triangulating through a comparison of three cultural zones.

Evidence suggests that Latin Americans display elevated levels of emotional expressivity and positivity. Here, we tested whether Latin Americans possess a unique form of interdependence called expressive interdependence, characterized by the open expression of positive emotions related to social engagement (e.g., feelings of closeness to others). In Study 1, we compared Latin Americans from Chile and Mexico with European Americans in the United States, a group known to be highly independent. Latin Americans expressed positive socially engaging emotions, particularly in response to negative events affecting others, whereas European Americans favored positive socially disengaging emotions, such as pride, especially in response to personally favorable circumstances. Study 2 replicated these findings with another group of Latin Americans from Colombia and European Americans in the United States. Study 2 also included Japanese in Japan, who expressed positive emotions less than Latin and European Americans. However, Japanese displayed a higher tendency to express negative socially engaging emotions, such as guilt and shame, compared to both groups. Our data demonstrate that emotional expression patterns align with overarching ethos of interdependence in Latin America and Japan and independence among European Americans. However, Latin Americans and Japanese exhibited different styles of interdependence. Latin Americans were expressive of positive socially engaging emotions, whereas Japanese were less expressive overall. Moreover, when Japanese expressed emotions, they emphasized negative socially engaging emotions. Implications for theories of culture and emotion are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Closing the value-based circle in shared decision-making: a digital framework for informing the shared decision-making process through patient reported outcome and experience measures.

Background: The spreading adoption of value-based models of healthcare delivery has incentivized the use of patient-reported outcomes and experience measures (PROMs and PREMs) in clinical practice, with the potential to enrich the decision-making process with patient-reported data. Methods: This perspective article explores PROs and the shared decision-making (SDM) process as components of value-based healthcare. We describe the potential of PROMs and PREMs within the decision-making process and present a digital framework for informing the shared decision-making process using aggregated data from a healthcare system PROMs and PREMs program, including early results from implementation in hospital network in Madrid, Spain. Results: The proposed digital framework incorporates aggregated data from a hospital network PROMs and PREMs program as part of a digital patient decision aid (PDA) for patients with lymphoma. After the first hematologist appointment, participating patients access the PDA to review relevant information about clinical and patient-reported outcomes for each of the possible options, assign a personal order of priority to different outcomes, and then select their preferred course of action. Patients' answers are automatically uploaded to the EHR and discussed with hematologists at the next appointment. After beginning treatment, patients are invited to participate in the network PROMs program; participants' PROMs data are fed back into the PDA, thus "closing the circle" between the decision-making process and patient-reported data collection.During the first 14 months after launching the decision aid in October 2022, of 25 patients diagnosed with follicular lymphoma at the four participating hospitals, 13 patients decided to participate. No significant differences in age or sex were observed between groups. Average SDM Q-9 score for patients filling in the questionnaire (n = 6) was 36.15 of 45 points. Conclusion: Various obstacles toward widespread implementation of SDM exist such as time constraints, lack of motivation, and resistance to change. Support and active engagement from policy makers and healthcare managers is key to overcome hurdles for capturing patient-reported data and carrying out shared decision-making at healthcare system level. Early results of a digital framework for PRO-enriched SDM seem to be beneficial to the decision-making process.

[Prevalence of leptospirosis in vague dogs captured in Temuco City, 2011]. / Prevalencia de leptospirosis en perros vagos capturados en la ciudad de Temuco, 2011.

BACKGROUND: Leptospirosis, a bacterial disease of worldwide distribution, affects various animals and is considered a zoonosis. It can be transmitted directly or indirectly, mainly through contact with the carrier's urine and entering the body through mucous membranes or skin. In the city of Temuco, there are no epidemiological studies of canine leptospirosis and the country data are scarce. OBJECTIVE: To determine the prevalence of leptospirosis in stray dogs of the city of Temuco. MATERIAL AND METHODS: In a cross- sectional study, 400 dogs admitted to Temuco Kennel during the year 2011 were sampled. Blood samples were analyzed using a modified commercial ELISA kit. RESULTS: The prevalence of leptospirosis was 21.3%. Positive cases were concentrated in dogs 5 to 8 years of age, independent of gender. DISCUSSION: The high prevalence found demonstrates the need for further studies to better understand the epidemiology of the disease and to establish prevention and control measures.

[Detection of Brucella canis by immunochromatography method in vague dogs captured in Temuco city, Chile, 2011]. / Detección de Brucella canis por método de inmunocromatografía en perros vagos capturados en la ciudad de Temuco, Chile, 2011.

BACKGROUND: Brucella canis is responsible for brucellosis in dogs, causing reproductive disorders and is considered a zoonoses, as described in several countries. The epidemiological data are scarce in our country. AIM: To determine the prevalence of Brucella canis in vague dogs in Temuco city and housed in the Temuco Kennel. METHODS: Quantitative and cross-section study. We used 400 samples of dogs of both sexes, different ages and mainly mixed race, which were tested by immunochromatography. RESULTS: Antibodies were detected in 4 samples Brucella canis which represented 1% of the population studied, 2 females (0.5%) and 2 males (0.5%). DISCUSSION: We conclude that dogs are infected by B. canis in a low range but remains a risk condition to the health of the human population if not maintained adequate sanitary control of pets, like vague dogs.

[Effect of the forward head syndrome in the development of temporomandibular disorders]. / Efecto del síndrome de cabeza adelantada en el desarrollo de trastornos temporomandibulares.

Bad habits, such as poor posture during the use of technological devices, poor abdominal control and oral breathing pattern can lead to a forward head position, which has important implications for the entire future of the individual, especially at the stomatognathic system. There is a strong association between temporomandibular disorders and forward head syndrome. Where the muscular component is the main affected, with the appearance of more trigger points at the level of the sternocleidomastoid muscles, upper trapezius, rectus capitis posterior and upper oblique capitis. Degenerative changes in the temporomandibular joint have been observed, but evidence is still lacking to ensure that Forward Head Syndrome is the etiological factor.

New Benzodihydrofuran Derivatives Alter the Amyloid ß Peptide Aggregation: Strategies To Develop New Anti-Alzheimer Drugs.

Alzheimer's disease is a neurodegenerative disorder that is the leading cause of dementia in elderly patients. Amyloid-ß peptide (1-42 oligomers) has been identified as a neurotoxic factor, triggering many neuropathologic events. In this study, 15 chalcones were synthesized employing the Claisen-Schmidt condensation reaction, starting from a compound derived from fomannoxine, a natural benzodihydrofuran whose neuroprotective activity has been proven and reported, and methyl aromatic ketones with diverse patterns of halogenated substitution. As a result, chalcones were obtained, with good to excellent reaction yields from 50 to 98%. Cytotoxicity of the compounds was assessed, and their cytoprotective effect against the toxicity associated with Aß was evaluated on PC-12 cells. Out of the 15 chalcones obtained, only the 4-bromo substituted was cytotoxic at most tested concentrations. Three synthesized chalcones showed a cytoprotective effect against Aß toxicity (over 37%). The 2,4,5-trifluoro substituted chalcone was the most promising series since it showed a cytoprotective impact with more than 60 ± 5% of recovery of cellular viability; however, 3-fluoro substituted compound also exhibited important values of recovery (50 ± 6%). The fluorine substitution pattern was shown to be more effective for cytoprotective activity. Specifically, substitution with fluorine in the 3,5-positions turned out to be particularly effective for cytoprotection. Furthermore, fluorinated compounds inhibited the aggregation rate of Aß, suggesting a dual effect that can be the starting point of new molecules with therapeutic potential.

Results of VOICE: a global survey of disease-specific knowledge and perspectives of real-world patients with CLL.

The Virtual Opinions poll Independent Centered on CLL patients' Experience (VOICE) evaluated patients' knowledge about chronic lymphocytic leukemia (CLL), their perspectives on diagnosis and treatment, and their unmet needs. Clinicians and patient advocacy group representatives developed and distributed the survey from March through December 2022 in 12 countries, and 377 patients with ≥1 line of previous CLL treatment responded from Europe, Latin America, the United States, Australia, Egypt, and Turkey. A majority of them (90%; 336/374) relied on their physicians for information regarding CLL and treatment. If at high risk, respondents prefer oral medications to intravenous (78%; 232/296), fixed duration treatment over treatment until progression (69%; 185/270), outpatient over inpatient treatments (91%; 257/283). Over three-fourths of respondents (78%; 286/368) wanted to be involved in treatment decisions, but a minority actually participated (44%; 138/313). COVID-19 vaccinations were widely available (97%; 273/281), but one-fifth (19%; 63/331) were unaware that CLL increases vulnerability to infections. Most patients' physicians explained their treatment options (84%; 297/355), and 90% (271/301) understood their treatment. Notably, >10% would continue treatment normally if they experienced cardiac problems or arrhythmias, whereas 23% would consider stopping treatment if they developed skin cancer. Treatment-associated side effects affected 27% to 43% of patients. These results in a global patient population highlight gaps in patients' knowledge of risk groups, their susceptibility to infections including COVID, and the side effects of common treatments. Such knowledge can guide the appropriate targeting of patient education initiatives by clinicians, advocates, and policymakers.

Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-ß Peptide Toxicity.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-ß peptide (Aß) accumulation, where the soluble oligomers of Aß (AßOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects. OBJECTIVE: In this study, the neuroprotective abilities of Eu on synaptic failure induced by AßOs were analyzed. METHODS: Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AßOs. RESULTS: In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AßOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AßOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aß aggregation process inducing a decrease in AßOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu. CONCLUSION: We believe that Eu represents a novel lead that reduces the Aß toxicity, opening new research venues for lignans as neuroprotective agents.

Enhanced fatty acid oxidation through metformin and baicalin as therapy for COVID-19 and associated inflammatory states in lung and kidney.

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19. Hence, we asked if two key pathways involved in cellular energy generation, AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling and fatty acid oxidation (FAO) could be beneficial. We tested the drugs metformin (AMPK activator) and baicalin (CPT1A activator) in different experimental models mimicking COVID-19 associated inflammation in lung and kidney. We also studied two different cohorts of COVID-19 patients that had been previously treated with metformin. These drugs ameliorated lung damage in an ARDS animal model, while activation of AMPK/ACC signaling increased mitochondrial function and decreased TGF-ß-induced fibrosis, apoptosis and inflammation markers in lung epithelial cells. Similar results were observed with two indole derivatives, IND6 and IND8 with AMPK activating capacity. Consistently, a reduced time of hospitalization and need of intensive care was observed in COVID-19 patients previously exposed to metformin. Baicalin also mitigated the activation of pro-inflammatory bone marrow-derived macrophages (BMDMs) and reduced kidney fibrosis in two animal models of kidney injury, another key target of COVID-19. In human epithelial lung and kidney cells, both drugs improved mitochondrial function and prevented TGF-ß-induced renal epithelial cell dedifferentiation. Our results support that favoring cellular energy production through enhanced FAO may prove useful in the prevention of COVID-19-induced lung and renal damage.