Antibody-peptide conjugates deliver covalent inhibitors blocking oncogenic cathepsins.

Cysteine cathepsins are a family of proteases that are relevant therapeutic targets for the treatment of different cancers and other diseases. However, no clinically approved drugs for these proteins exist, as their systemic inhibition can induce deleterious side effects. To address this problem, we developed a modular antibody-based platform for targeted drug delivery by conjugating non-natural peptide inhibitors (NNPIs) to antibodies. NNPIs were functionalized with reactive warheads for covalent inhibition, optimized with deep saturation mutagenesis and conjugated to antibodies to enable cell-type-specific delivery. Our antibody-peptide inhibitor conjugates specifically blocked the activity of cathepsins in different cancer cells, as well as osteoclasts, and showed therapeutic efficacy in vitro and in vivo. Overall, our approach allows for the rapid design of selective cathepsin inhibitors and can be generalized to inhibit a broad class of proteases in cancer and other diseases.

Sleep promotes T-cell migration towards CCL19 via growth hormone and prolactin signaling in humans.

Sleep strongly supports the formation of adaptive immunity, e.g., after vaccination. However, the underlying mechanisms remain largely obscure. Here we show in healthy humans that sleep compared to nocturnal wakefulness specifically promotes the migration of various T-cell subsets towards the chemokine CCL19, which is essential for lymph-node homing and, thus, for the initiation and maintenance of adaptive immune responses. Migration towards the inflammatory chemokine CCL5 remained unaffected. Incubating the cells with plasma from sleeping participants likewise increased CCL19-directed migration, an effect that was dependent on growth hormone and prolactin signaling. These findings show that sleep selectively promotes the lymph node homing potential of T cells by increasing hormonal release, and thus reveal a causal mechanism underlying the supporting effect of sleep on adaptive immunity in humans.

Sleep shapes the associative structure underlying pattern completion in multielement event memory.

Sleep supports the consolidation of episodic memory. It is, however, a matter of ongoing debate how this effect is established, because, so far, it has been demonstrated almost exclusively for simple associations, which lack the complex associative structure of real-life events, typically comprising multiple elements with different association strengths. Because of this associative structure interlinking the individual elements, a partial cue (e.g., a single element) can recover an entire multielement event. This process, referred to as pattern completion, is a fundamental property of episodic memory. Yet, it is currently unknown how sleep affects the associative structure within multielement events and subsequent processes of pattern completion. Here, we investigated the effects of post-encoding sleep, compared with a period of nocturnal wakefulness (followed by a recovery night), on multielement associative structures in healthy humans using a verbal associative learning task including strongly, weakly, and not directly encoded associations. We demonstrate that sleep selectively benefits memory for weakly associated elements as well as for associations that were not directly encoded but not for strongly associated elements within a multielement event structure. Crucially, these effects were accompanied by a beneficial effect of sleep on the ability to recall multiple elements of an event based on a single common cue. In addition, retrieval performance was predicted by sleep spindle activity during post-encoding sleep. Together, these results indicate that sleep plays a fundamental role in shaping associative structures, thereby supporting pattern completion in complex multielement events.

Are rescue workers still at risk? A meta-regression analysis of the worldwide prevalence of post-traumatic stress disorder and risk factors.

Rescue workers (policemen, firefighters, emergency medical staff, etc.) experience intense stress due to rescuing and helping victims of accidents, terrorist attacks, violent crimes, and natural disasters. Overexposure and ineffective coping with such stressful events may lead to developing Post-Traumatic Stress Disorder (PTSD). Meta-regression procedures were applied to examine moderators such as the sample sex composition, age, working experience, occupation, country, or type of PTSD evaluation. The 9.8% PTSD prevalence found here was virtually the same compared with earlier findings from 10 years ago. There was a large heterogeneity, however, associated with geographical location and the instrument used to evaluate PTSD. The main findings revealed that rescue workers are a high-risk group with increased levels of Post-traumatic Stress Disorder (PTSD). Moreover, PTSD prevalence could depend on a great extent on geographical and cultural factors, and on the type of PTSD evaluation.

CellCharter reveals spatial cell niches associated with tissue remodeling and cell plasticity.

Tissues are organized in cellular niches, the composition and interactions of which can be investigated using spatial omics technologies. However, systematic analyses of tissue composition are challenged by the scale and diversity of the data. Here we present CellCharter, an algorithmic framework to identify, characterize, and compare cellular niches in spatially resolved datasets. CellCharter outperformed existing approaches and effectively identified cellular niches across datasets generated using different technologies, and comprising hundreds of samples and millions of cells. In multiple human lung cancer cohorts, CellCharter uncovered a cellular niche composed of tumor-associated neutrophil and cancer cells expressing markers of hypoxia and cell migration. This cancer cell state was spatially segregated from more proliferative tumor cell clusters and was associated with tumor-associated neutrophil infiltration and poor prognosis in independent patient cohorts. Overall, CellCharter enables systematic analyses across data types and technologies to decode the link between spatial tissue architectures and cell plasticity.

Metabolic dependencies of metastasis-initiating cells in female breast cancer.

Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells (MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage. Sorting tumor cells based upon solely mitochondrial membrane potential or lipid storage is sufficient at identifying MICs. We further identify that mitochondrially-generated citrate is exported to the cytoplasm to yield acetyl-CoA, and this is crucial to maintaining heightened levels of H3K27ac in MICs. Blocking acetyl-CoA generating pathways or H3K27ac-specific epigenetic writers and readers reduces expression of epithelial-to-mesenchymal related genes, MIC frequency, and metastatic potential. Exogenous supplementation of a short chain carboxylic acid, acetate, increases MIC frequency and metastasis. In patient cohorts, we observe that higher expression of oxidative phosphorylation related genes is associated with reduced distant relapse-free survival. These data demonstrate that MICs specifically and precisely alter their metabolism to efficiently colonize distant organs.

Risk Factors for Myopia: A Review.

Due to the myopia prevalence increase worldwide, this study aims to establish the most relevant risk factors associated with its development and progression. A review search was carried out using PubMed, Web of Science, and Scopus databases to identify the main myopia risk factors. The inclusion criteria for the articles were those related to the topic, carried out in subjects from 5 to 30 years, published between January 2000 and May 2023, in English, and with the full text available. Myopia etiology has proven to be associated with both genetic and environmental factors as well as with gene-environment interaction. The risk of developing myopia increases in children with myopic parents (one parent ×2 times, two parents ×5 times). Regarding environmental factors, education is the main risk factor correlated with myopia prevalence increase. Further, several studies found that shorter distance (<30 cm) and longer time spent (>30 min) for near work increase the risk of myopia. Meanwhile, increased outdoor activity (>40 min/day) has been shown to be a key factor in reducing myopia incidence. In conclusion, the interventional strategy suggested so far to reduce myopia incidence is an increase in time outdoors and a reduction in the time spent performing near-work tasks.

Development of a new testing protocol to evaluate cooling systems.

Thermal comfort is defined as the user's sensation of thermal well-being. This sensation can be modified by extreme environmental conditions changing the body temperature of the user. Different mechanisms, the thermoregulatory system itself or an external textile system, are required to allow the body to return to their state of well-being. A cooling vest is an example of a smart garment that helps to reduce the user's body temperature in situations of heat stress. There are two different standards to evaluate the performance of this type of clothing: the ASTM F2371-16 standard that uses a thermal manikin and the ASTM F2300-10 standard that uses human subjects for the evaluation. There is a need for simple, objective and affordable tests to evaluate the thermal comfort associated with personal protective equipment use. The aim of this work is to develop a new testing method that combines a thermal manikin with a simulation software and allows to study physiological parameters of a human subject in the body of the thermal manikin.

Keratometry Agreement Between Two Swept-Source OCT Devices in Healthy and Post-refractive Surgery Eyes.

PURPOSE: To evaluate the keratometry agreement between two swept-source devices for healthy and post-refractive surgery eyes and compare them. METHODS: One hundred volunteers between 20 and 55 years of age were recruited for this study including both healthy and post-refractive surgery eyes. Three consecutive measurements of simulated keratometry (Sim K), posterior keratometry (PK), and total keratometry (TK) were obtained with the IOLMaster 700 and Anterion. The agreement was assessed through the Bland-Altman method. Limits of agreement (LoA) were calculated as mean difference ±1.96·SD and it represents the 95% of the differences between devices. RESULTS: For both groups, Sim K measurements exhibited a mean difference close to 0 and within a range of ±0.30 and ±0.36 diopters (D) for the control and post-refractive surgery groups, respectively. Meanwhile, the IOLMaster 700 provided flatter PK values (0.30 D on average) for both groups. In general, the post-refractive surgery group exhibited slightly greater mean differences and wider 95% LoA than the control group for Sim K and PK. Steeper TK values were obtained by the IOLMaster in both groups (control = 0.50 D and post-refractive surgery = 0.75 D). TK differences between devices were significantly greater in the post-refractive surgery group (ranging from 0.38 to 1.14 D) compared to the control group (ranging from 0.15 to 0.85 D). CONCLUSIONS: The IOLMaster 700 and Anterion are not interchangeable for TK measurements and eyes that had corneal refractive surgery even decreased the agreement between devices. Differences between devices for Sim K and PK measurements should be clinically judged, particularly in eyes with previous corneal surgery. [J Refract Surg. 2023;39(5):347-353.].

A 1-aminocyclopropane-1-carboxylic-acid (ACC) dipeptide elicits ethylene responses through ACC-oxidase mediated substrate promiscuity.

Plants produce the volatile hormone ethylene to regulate many developmental processes and to deal with (a)biotic stressors. In seed plants, ethylene is synthesized from 1-aminocyclopropane-1-carboxylic acid (ACC) by the dedicated enzyme ACC oxidase (ACO). Ethylene biosynthesis is tightly regulated at the level of ACC through ACC synthesis, conjugation and transport. ACC is a non-proteinogenic amino acid, which also has signaling roles independent from ethylene. In this work, we investigated the biological function of an uncharacterized ACC dipeptide. The custom-synthesized di-ACC molecule can be taken up by Arabidopsis in a similar way as ACC, in part via Lysine Histidine Transporters (e.g., LHT1). Using Nano-Particle Assisted Laser Desoprtion/Ionization (Nano-PALDI) mass-spectrometry imaging, we revealed that externally fed di-ACC predominantly localizes to the vasculature tissue, despite it not being detectable in control hypocotyl segments. Once taken up, the ACC dimer can evoke a triple response phenotype in dark-grown seedlings, reminiscent of ethylene responses induced by ACC itself, albeit less efficiently compared to ACC. Di-ACC does not act via ACC-signaling, but operates via the known ethylene signaling pathway. In vitro ACO activity and molecular docking showed that di-ACC can be used as an alternative substrate by ACO to form ethylene. The promiscuous nature of ACO for the ACC dimer also explains the higher ethylene production rates observed in planta, although this reaction occurred less efficiently compared to ACC. Overall, the ACC dipeptide seems to be transported and converted into ethylene in a similar way as ACC, and is able to augment ethylene production levels and induce subsequent ethylene responses in Arabidopsis.

Hypnotic enhancement of slow-wave sleep increases sleep-associated hormone secretion and reduces sympathetic predominance in healthy humans.

Sleep is important for normal brain and body functioning, and for this, slow-wave sleep (SWS), the deepest stage of sleep, is assumed to be especially relevant. Previous studies employing methods to enhance SWS have focused on central nervous components of this sleep stage. However, SWS is also characterized by specific changes in the body periphery, which are essential mediators of the health-benefitting effects of sleep. Here we show that enhancing SWS in healthy humans using hypnotic suggestions profoundly affects the two major systems linking the brain with peripheral body functions, i.e., the endocrine and the autonomic nervous systems (ANS). Specifically, hypnotic suggestions presented at the beginning of a 90-min afternoon nap to promote subsequent SWS strongly increased the release of growth hormone (GH) and, to a lesser extent, of prolactin and aldosterone, and shifted the sympathovagal balance towards reduced sympathetic predominance. Thus, the hypnotic suggestions induced a whole-body pattern characteristic of natural SWS. Given that the affected parameters regulate fundamental physiological functions like metabolism, cardiovascular activity, and immunity, our findings open up a wide range of potential applications of hypnotic SWS enhancement, in addition to advancing our knowledge on the physiology of human SWS.

Evaluation of the MGDRx eyebag treatment in young and older subjects with dry eye symptoms.

OBJECTIVES: This study aims to evaluate the relationship between application of the MGDRx thermal eyebag and dry eye signs and symptoms in young and older subjects and to compare the results between the two groups. METHODS: Thirty young, healthily volunteers between 18 and 31 years of age (23.95±3.94 years) and thirty older subjects between 61 and 90 years of age (77.97±8.11 years) participated in this study. Ocular surface parameters were assessed using the Oculus Keratograph 5M, following the guidelines of the Tear Film and Ocular Surface Dry Eye Workshop II Diagnostic Methodology report. Only subjects with a positive score on at least one questionnaire and an initial Non-Invasive Keratograph Break-Up Time (NIKBUT) under 10seconds were included in the study. After thermal bag self-application in both eyes every day for 2 weeks, the protocol was carried out again. Lid massage was performed after lid warming. Compliance and degree of improvement were also assessed. MAIN RESULTS: The young volunteer group showed an improvement in NIKBUT, lipid layer score, upper eyelid gland drop-out percentage and dry eye symptoms over the two week treatment period. Improvements in meibum quality, gland obstruction, telangiectasia scores, and dry eye symptoms were found in the older subjects. Mixed ANOVA revealed better NIKBUT and lipid layer values in the young subjects. Despite the treatment compliance being statistically higher in the older group than in the younger subjects (P=0.002), there were no significant differences in subjective improvement between groups (P=0.097). CONCLUSION: Dry eye-related symptoms were improved after thermal bag application, while NIKBUT and lipid layer thickness were improved only in the younger subjects.

Diagnostic Capability of a New Objective Method to Assess Meibomian Gland Visibility.

SIGNIFICANCE: The diagnosis of dry eye disease and meibomian gland dysfunction (MGD) is challenging. Measuring meibomian gland visibility may provide an additional objective method to diagnose MGD. PURPOSE: This study aimed to evaluate the ability of new metrics to better diagnose MGD, based on measuring meibomian gland visibility. METHODS: One hundred twelve healthy volunteers (age, 48.3 ± 27.5 years) were enrolled in this study. Ocular surface parameters were measured using the Oculus Keratograph 5M (Oculus GmbH, Wetzlar). Subjects were classified according to the presence or absence of MGD. New metrics based on the visibility of the meibomian glands were calculated and later compared between groups. The diagnostic ability of ocular surface parameters and gland visibility metrics was studied through receiver operating characteristic curves. Logistic regression was used to obtain the combined receiver operating characteristic curve of the metrics with the best diagnostic ability. RESULTS: Statistically significant differences were found between groups for all ocular surface parameters and new gland visibility metrics, except for the first noninvasive keratograph breakup time and gland expressibility. New gland visibility metrics showed higher sensitivity and specificity than did current single metrics when their diagnostic ability was assessed without any combination. The diagnostic capability increased when gland visibility metrics were incorporated into the logistic regression analysis together with gland dropout percentage, tear meniscus height, dry eye symptoms, and lid margin abnormality score (P < .001). The combination of median pixel intensity of meibography gray values and the aforementioned ocular surface metrics achieved the highest area under the curve (0.99), along with excellent sensitivity (1.00) and specificity (0.93). CONCLUSIONS: New meibomian gland visibility metrics are more powerful to diagnose MGD than current single metrics and can serve as a complementary tool for supporting the diagnosis of MGD.

Evaluation of Physiological Parameters on Discomfort Glare Thresholds Using LUMIZ 100 Tool.

Purpose: To assess the links between discomfort glare sensitivity and physiological factors such as eye biometry, refraction, skin phototype, age, and gender among a large sample of healthy human subjects. Methods: A total of 489 participants who were 20 to 70 years old (241 men, 248 women) underwent discomfort glare threshold measurements via the LUMIZ 100. Eye biometry and optical quality were measured using a Zeiss IOLMaster 700 biometer and i.Profiler aberrometer. Iris color, skin tone, age, gender, eyeglasses use, chronotype, fatigue level, self-evaluation of light sensitivity, and time spent outdoors were determined. Statistical analysis was carried out using nonparametric Mann-Whitney and Kruskal-Wallis tests for categorical data and correlation coefficients for numerical data. Results: The female subgroup had lower discomfort thresholds than the males (P < 0.001). There was no effect of age group, ametropia, eye biometry, iris color, skin tones, chronotype, or fatigue level on discomfort thresholds. Discomfort thresholds were related to self-assessment of light sensitivity, sunglasses ownership, and frequency of use (P < 0.001). Conclusions: Exploration of easily measurable physiological parameters and questionnaire failed to provide reliable indicators of individual light sensitivity to discomfort glare. Translational Relevance: Light sensitivity is highly subjective and variable across the population. Patients frequently complain about light bothering their daily lives. Accessible physiological factors and questionnaires are unable to predict discomfort levels due to glare. The LUMIZ 100 provides a reliable, rapid, and safe way to determine light discomfort thresholds in order to better manage light sensitivity in clinical care.

Identification of the GlialCAM interactome: the G protein-coupled receptors GPRC5B and GPR37L1 modulate megalencephalic leukoencephalopathy proteins.

Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a type of vacuolating leukodystrophy, which is mainly caused by mutations in MLC1 or GLIALCAM. The two MLC-causing genes encode for membrane proteins of yet unknown function that have been linked to the regulation of different chloride channels such as the ClC-2 and VRAC. To gain insight into the role of MLC proteins, we have determined the brain GlialCAM interacting proteome. The proteome includes different transporters and ion channels known to be involved in the regulation of brain homeostasis, proteins related to adhesion or signaling as several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptor GPR37L1. Focusing on these two GPCRs, we could validate that they interact directly with MLC proteins. The inactivation of Gpr37l1 in mice upregulated MLC proteins without altering their localization. Conversely, a reduction of GPRC5B levels in primary astrocytes downregulated MLC proteins, leading to an impaired activation of ClC-2 and VRAC. The interaction between the GPCRs and MLC1 was dynamically regulated upon changes in the osmolarity or potassium concentration. We propose that GlialCAM and MLC1 associate with different integral membrane proteins modulating their functions and acting as a recruitment site for various signaling components as the GPCRs identified here. We hypothesized that the GlialCAM/MLC1 complex is working as an adhesion molecule coupled to a tetraspanin-like molecule performing regulatory effects through direct binding or influencing signal transduction events.

Repeatability of Non-invasive Keratograph Break-Up Time measurements obtained using Oculus Keratograph 5M.

PURPOSE: The aim of this study is to assess the intraexaminer repeatability of Non-invasive Keratograph Break-Up Time (NIKBUT) obtained using the Oculus Keratograph 5M (K5M), given its relevance as a homeostasis marker in Dry Eye Disease (DED). METHODS: In total, 80 healthy volunteers aged between 30 and 89 years participated. Measurements were classified according to age, sex and the presence or not of DED. Repeatability was evaluated by the calculation of within-subject standard deviation (Sw), coefficient of repeatability (CoR) and coefficient of variation (CoV). Moreover, the Passing-Bablok regression method was applied. RESULTS: Sw, CoR and CoV coefficients showed low repeatability in all groups with values between 3.57 and 7.14; 9.90 and 19.79; and 51.90 and 65.49, for each coefficient, respectively. No statistically significant differences were found in the NIKBUT measurements between healthy and DED patients (p = 0.188). Groups with more DED risk had better repeatability. Passing-Bablok regression also confirmed a lack of agreement between the maximum and minimum NIKBUT measurement. CONCLUSION: NIKBUT measurement has low intraexaminer repeatability even when considering sex, age and DED diagnosis. Nevertheless, not only is this low repeatability due to the device, but also it is largely due to the intrinsic variability of the tear film.

An Emerging Method to Assess Tear Film Spread and Dynamics as Possible Tear Film Homeostasis Markers.

Purpose: This study aims to assess the performance of an analysis method to measure in vivo the movement speed of tear film particles post-blink as a measure of tear film spreading.Materials and methods: Ocular surface parameters and the recording of tear film particles' spreading post-blink were assessed in eighty-one healthy volunteers (43.7 ± 27.0 years) using Keratograph 5 M. The developed software automatically decomposed the video into frames to manually track particles' position for 1.75 seconds after a blink. The following tear film-dynamic metrics were automatically calculated: mean, median, maximum, and minimum particles' speed at different times after blinking and time for particle speed to decrease to <1.20 mm/second. Repeatability of each tear film-dynamic metric and its correlations with ocular surface signs and symptoms were analyzed. Binomial logistic regression was performed to assess the predictability of new metrics to ocular parameters.Results: Repeatability tended to be lower just after blinking (variability of 12.24%), whereas the metrics from 0.5 s onwards had acceptable repeatability (variability below 10%). Tear film-dynamic metrics correlated positively with Non-Invasive Break-Up Time (NIKBUT) while negatively with meibomian gland drop-out. Binomial logistic regression analysis revealed that tear film-dynamic metrics were able to predict NIKBUT. Nevertheless, no statistically significant association was found with gland drop-out. This means that higher particle speed is related to larger NIKBUT. The metric "time for particle speed to decrease to <1.20 mm/second" can be considered the best metric to assess the quality of the tear film, since it was more strongly correlated with NIKBUT (r = 0.42, p = .004), it was more strongly associated in the binomial logistic regression analysis with NIKBUT and showed good repeatability (variability = 5.49%).Conclusions: Tear film-dynamic metrics are emerging homeostasis parameters for assessing indirectly the tear film quality in natural conditions with acceptable repeatability.

Meibomian glands visibility assessment through a new quantitative method.

PURPOSE: The aim of this study is to develop a new objective semiautomatic method for analysing Meibomian glands visibility quantitatively. METHODS: One hundred twelve healthy volunteers aged between 18 and 90 years (48.29 ± 27.46 years) participated in this study. Infrared meibography was obtained from the right upper eyelid through Oculus Keratograph 5 M. Meibographies were classified into 3 groups: Group 1 = patients with good subjective glands visibility and a gland dropout percentage < 1/3 of the total Meibomian gland area; Group 2 = patients with low subjective glands visibility and a gland dropout < 1/3; and Group 3 = patients with low subjective glands visibility and a gland dropout > 1/3. New metrics based on the visibility of the Meibomian glands were calculated and later compared between groups. Rho Spearman test was used to assess the correlation between each metric, and Meibomian gland dropout percentage with the entire sample and after excluding Group 2. A p value less than 0.05 was defined as statistically significant. RESULTS: Fifty-six subjects were classified in Group 1 (24.48 ± 9.62 years), 19 in Group 2 (69.16 ± 21.30 years) and 37 in Group 3 (73.59 ± 13.70 years). No statistically significant differences were found between Groups 1 and 2 in dropout percentage. All metrics, with the exception of entropy, showed a higher Meibomian gland visibility in Group 1 than in the other two groups. Moderate correlations were statistically significant for all metrics with the exception of entropy. Correlations were higher after excluding Group 2. CONCLUSION: The proposed method is able to assess Meibomian gland visibility in an objective and repeatable way, which might help clinicians enhance Meibomian gland dysfunction diagnosis and follow-up treatment.

Comportamiento de Procalcitonina en pacientes con COVID-19 grave, sin foco infeccioso bacteriano, ingresados en Unidad de Cuidados Intensivos del Hospital Militar Central, en los meses de mayo-julio de 2020 / Behavior of Procalcitonin in patients with severe COVID-19, without bacterial infection focus, admitted to the Intensive Care Unit of the Central Military Hospital, in the months of May-July 2020

Introducción: Desde el inicio de la pandemia de COVID-19 en diciembre de 2019, el virus del Síndrome Respiratorio Agudo Severo Coronavirus 2 (SARS-CoV-2) ha provocado la muerte de muchos pacientes a lo largo de todo el mundo. Debido a la heterogeneidad de la enfermedad, es necesario identificar de forma temprana pacientes potencialmente complicables para disminuir la morbilidad y mortalidad, por lo cual los objetivos del presente trabajo son caracterizar los aspectos clínicos más importantes de los pacientes con COVID-19 y realizar una comparación entre los niveles iniciales de procalcitonina, con el estado de gravedad y la evolución clínica. También se pretende hacer comparaciones entre pacientes con COVID-19 grave sin procesos bacterianos concomitantes y las concentraciones de procalcitonina reportada, además describir cifras de mortalidad en este grupo de población. Materiales y Métodos: se obtuvo información a través de la revisión de expedientes clínicos. El estudio es Observacional, Descriptivo, de tipo Transversal, tomando como población a pacientes que presentaron neumonía viral grave por SARS-CoV-2, ingresados en el servicio de Unidad de Cuidados Intensivos, que no presentaban de forma concomitante sobreinfección bacteriana o micótica. Se recabó información sobre datos personales, comorbilidades, estado físico y exámenes de laboratorio para realizar descripciones de las diferencias respecto a los niveles de procalcitonina y el desenlace de los pacientes. Resultados: se evidenció alta mortalidad en la población ingresada, además los pacientes con COVID-19 grave sin procesos infecciosos bacterianos pueden presentar elevaciones de procalcitonina, se evidenció además que los pacientes con COVID-19 grave pueden no presentar elevaciones de marcadores inflamatorios a pesar de que su condición clínica es grave. Conclusiones: se evidenció tendencia a la elevación de niveles de procalcitonina en pacientes con enfermedad grave, sin embargo, no se pudo validar estadísticamente esta observación. Debe sospecharse riesgo aumentado de mortalidad y de daño multiorgánico en pacientes con COVID-19 grave que presentan procalcitonina elevada, si no hay foco infeccioso bacteriano concomitante. Elevaciones de los demás reactantes de fase aguda pueden ser poco confiables por lo que la evaluación clínica es la más importante para determinar complicaciones.

The Tumor Microenvironment as a Driving Force of Breast Cancer Stem Cell Plasticity.

Tumor progression involves the co-evolution of transformed cells and the milieu in which they live and expand. Breast cancer stem cells (BCSCs) are a specialized subset of cells that sustain tumor growth and drive metastatic colonization. However, the cellular hierarchy in breast tumors is rather plastic, and the capacity to transition from one cell state to another depends not only on the intrinsic properties of transformed cells, but also on the interplay with their niches. It has become evident that the tumor microenvironment (TME) is a major player in regulating the BCSC phenotype and metastasis. The complexity of the TME is reflected in its number of players and in the interactions that they establish with each other. Multiple types of immune cells, stromal cells, and the extracellular matrix (ECM) form an intricate communication network with cancer cells, exert a highly selective pressure on the tumor, and provide supportive niches for BCSC expansion. A better understanding of the mechanisms regulating these interactions is crucial to develop strategies aimed at interfering with key BCSC niche factors, which may help reducing tumor heterogeneity and impair metastasis.