Hemodynamic monitoring and echocardiographic evaluation in cardiogenic shock.

Cardiogenic shock (CS) is characterized by the presence of a state of tissue hypoperfusion secondary to ventricular dysfunction. Hemodynamic monitoring allows us to obtain information about cardiovascular pathophysiology that will help us make the diagnosis and guide therapy in CS situations. The most used monitoring system in CS is the pulmonary artery catheter since it provides key hemodynamic variables in CS, such as cardiac output, pulmonary artery pressure, and pulmonary artery occlusion pressure. On the other hand, echocardiography makes it possible to obtain, at the bedside, anatomical and hemodynamic data that complement the information obtained through continuous monitoring devices. CS monitoring can be considered multimodal and integrative by including hemodynamic, metabolic, and echocardiographic parameters that allow describing the characteristics of CS and guiding therapeutic interventions during hemodynamic resuscitation.

Design, Construction, and Test of Compact, Distributed-Charge, X-Band Accelerator Systems that Enable Image-Guided, VHEE FLASH Radiotherapy.

The design and optimization of laser-Compton x-ray systems based on compact distributed charge accelerator structures can enable micron-scale imaging of disease and the concomitant production of beams of Very High Energy Electrons (VHEEs) capable of producing FLASH-relevant dose rates. The physics of laser-Compton x-ray scattering ensures that the scattered x-rays follow exactly the trajectory of the incident electrons, thus providing a route to image-guided, VHEE FLASH radiotherapy. The keys to a compact architecture capable of producing both laser-Compton x-rays and VHEEs are the use of X-band RF accelerator structures which have been demonstrated to operate with over 100 MeV/m acceleration gradients. The operation of these structures in a distributed charge mode in which each radiofrequency (RF) cycle of the drive RF pulse is filled with a low-charge, high-brightness electron bunch is enabled by the illumination of a high-brightness photogun with a train of UV laser pulses synchronized to the frequency of the underlying accelerator system. The UV pulse trains are created by a patented pulse synthesis approach which utilizes the RF clock of the accelerator to phase and amplitude modulate a narrow band continuous wave (CW) seed laser. In this way it is possible to produce up to 10 {\mu}A of average beam current from the accelerator. Such high current from a compact accelerator enables production of sufficient x-rays via laser-Compton scattering for clinical imaging and does so from a machine of "clinical" footprint. At the same time, the production of 1000 or greater individual micro-bunches per RF pulse enables > 10 nC of charge to be produced in a macrobunch of < 100 ns. The design, construction, and test of the 100-MeV class prototype system in Irvine, CA is also presented.

The genomic landscape of 2,023 colorectal cancers.

Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2-9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

Tumor evolution metrics predict recurrence beyond 10 years in locally advanced prostate cancer.

Cancer evolution lays the groundwork for predictive oncology. Testing evolutionary metrics requires quantitative measurements in controlled clinical trials. We mapped genomic intratumor heterogeneity in locally advanced prostate cancer using 642 samples from 114 individuals enrolled in clinical trials with a 12-year median follow-up. We concomitantly assessed morphological heterogeneity using deep learning in 1,923 histological sections from 250 individuals. Genetic and morphological (Gleason) diversity were independent predictors of recurrence (hazard ratio (HR) = 3.12 and 95% confidence interval (95% CI) = 1.34-7.3; HR = 2.24 and 95% CI = 1.28-3.92). Combined, they identified a group with half the median time to recurrence. Spatial segregation of clones was also an independent marker of recurrence (HR = 2.3 and 95% CI = 1.11-4.8). We identified copy number changes associated with Gleason grade and found that chromosome 6p loss correlated with reduced immune infiltration. Matched profiling of relapse, decades after diagnosis, confirmed that genomic instability is a driving force in prostate cancer progression. This study shows that combining genomics with artificial intelligence-aided histopathology leads to the identification of clinical biomarkers of evolution.

Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer.

Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

Immune evasion impacts the landscape of driver genes during cancer evolution.

BACKGROUND: Carcinogenesis is driven by interactions between genetic mutations and the local tumor microenvironment. Recent research has identified hundreds of cancer driver genes; however, these studies often include a mixture of different molecular subtypes and ecological niches and ignore the impact of the immune system. RESULTS: In this study, we compare the landscape of driver genes in tumors that escaped the immune system (escape +) versus those that did not (escape -). We analyze 9896 primary tumors from The Cancer Genome Atlas using the ratio of non-synonymous to synonymous mutations (dN/dS) and find 85 driver genes, including 27 and 16 novel genes, in escape - and escape + tumors, respectively. The dN/dS of driver genes in immune escaped tumors is significantly lower and closer to neutrality than in non-escaped tumors, suggesting selection buffering in driver genes fueled by immune escape. Additionally, we find that immune evasion leads to more mutated sites, a diverse array of mutational signatures and is linked to tumor prognosis. CONCLUSIONS: Our findings highlight the need for improved patient stratification to identify new therapeutic targets for cancer treatment.

NeuroSense: A non-invasive and configurable somatosensory stimulator with OPENVIBE communication.

Understanding the somatosensory system and its abnormalities requires the development of devices that can accurately stimulate the human skin. New methods for assessing the somatosensory system can enhance the diagnosis, treatments, and prognosis for individuals with somatosensory impairments. Therefore, the design of NeuroSense, a tactile stimulator that evokes three types of daily life sensations (touch, air and vibration) is described in this work. The prototype aims to evoke quantitative assessments to evaluate the functionality of the somatosensory system and its abnormal conditions that affect the quality of life. In addition, the device has proven to have varying intensities and onset latencies that produces somatosensory evoked potentials and energy desynchronization on somatosensory cortex.

El shock cardiogénico como problema de salud. Fisiología, clasificación y detección / Cardiogenic shock as a health issue: Physiology, classification, and detection

El shock cardiogénico (SC) es un síndrome heterogéneo con elevada mortalidad y creciente incidencia. Se trata de una situación en la que existe un desequilibrio entre las necesidades tisulares de oxígeno y la capacidad del sistema cardiovascular para satisfacerlas debido a una disfunción cardiaca aguda. Históricamente, los síndromes coronarios agudos han sido la causa principal de SC; sin embargo, los casos no isquémicos han aumentado en incidencia. Su fisiopatología implica el daño isquémico del miocardio, una respuesta tanto simpática como del sistema renina-angiotensina-aldosterona e inflamatoria, que perpetúan la situación de hipoperfusión tisular conduciendo finalmente a la disfunción multiorgánica. La caracterización de los pacientes con SC mediante una valoración triaxial y la universalización de la escala SCAI ha permitido una estandarización de la estratificación de la gravedad del SC que, sumada a la detección precoz y el enfoque Hub and Spoke, podrían contribuir a mejorar el pronóstico de los pacientes en SC. (AU)

Cardiogenic shock (CS) is a heterogeneous syndrome with high mortality and increasing incidence. It is a condition where there is an imbalance between tissue oxygen demands and the cardiovascular system's capacity to meet them due to acute cardiac dysfunction. Historically, acute coronary syndromes have been the primary cause of CS; however, non-ischemic cases have seen a rise in incidence. Its pathophysiology involves myocardial ischemic damage, a sympathetic, renin–angiotensin–aldosterone system, and inflammatory response, perpetuating the situation of tissue hypoperfusion, ultimately leading to multiorgan dysfunction. Characterizing CS patients through a triaxial assessment and the widespread use of the SCAI scale has allowed standardization of CS severity stratification, which, coupled with early detection and the “Hub and Spoke” approach, could contribute to improve the prognosis of CS patients. (AU)

Assessing Outcomes of Patients Subject to Intensive Care to Facilitate Organ Donation: A Spanish Multicenter Prospective Study.

Intensive Care to facilitate Organ Donation (ICOD) consists of the initiation or continuation of intensive care measures in patients with a devastating brain injury (DBI) in whom curative treatment is deemed futile and death by neurological criteria (DNC) is foreseen, to incorporate organ donation into their end-of-life plans. In this study we evaluate the outcomes of patients subject to ICOD and identify radiological and clinical factors associated with progression to DNC. In this first prospective multicenter study we tested by multivariate regression the association of clinical and radiological severity features with progression to DNC. Of the 194 patients, 144 (74.2%) patients fulfilled DNC after a median of 25 h (95% IQR: 17-44) from ICOD onset. Two patients (1%) shifted from ICOD to curative treatment, both were alive at discharge. Factors associated with progression to DNC included: age below 70 years, clinical score consistent with severe brain injury, instability, intracranial hemorrhage, midline shift ≥5 mm and certain types of brain herniation. Overall 151 (77.8%) patients progressed to organ donation. Based on these results, we conclude that ICOD is a beneficial and efficient practice that can contribute to the pool of deceased donors.

Cardiogenic shock as a health issue. Physiology, classification, and detection.

Cardiogenic shock (CS) is a heterogeneous syndrome with high mortality and a growing incidence. It is characterized by an imbalance between the tissue oxygen demands and the capacity of the cardiovascular system to meet these demands, due to acute cardiac dysfunction. Historically, acute coronary syndromes have been the primary cause of CS. However, non-ischemic cases have seen a rise in incidence. The pathophysiology involves ischemic damage of the myocardium and a sympathetic, renin-angiotensin-aldosterone system and inflammatory response, perpetuating the situation of tissue hypoperfusion and ultimately leading to multiorgan dysfunction. The characterization of CS patients through a triaxial assessment and the widespread use of the Society for Cardiovascular Angiography and Interventions (SCAI) scale has allowed standardization of the severity stratification of CS; this, coupled with early detection and the "hub and spoke" approach, could contribute to improving the prognosis of these patients.

CRISPRi-induced transcriptional regulation of IAH1 gene and its influence on volatile compounds profile in Kluyveromyces marxianus DU3.

Mezcal is a traditional Mexican distilled beverage, known for its marked organoleptic profile, which is influenced by several factors, such as the fermentation process, where a wide variety of microorganisms are present. Kluyveromyces marxianus is one of the main yeasts isolated from mezcal fermentations and has been associated with ester synthesis, contributing to the flavors and aromas of the beverage. In this study, we employed CRISPR interference (CRISPRi) technology, using dCas9 fused to the Mxi1 repressor factor domain, to down-regulate the expression of the IAH1 gene, encoding for an isoamyl acetate-hydrolyzing esterase, in K. marxianus strain DU3. The constructed CRISPRi plasmid successfully targeted the IAH1 gene, allowing for specific gene expression modulation. Through gene expression analysis, we assessed the impact of IAH1 down-regulation on the metabolic profile of volatile compounds. We also measured the expression of other genes involved in volatile compound biosynthesis, including ATF1, EAT1, ADH1, and ZWF1 by RT-qPCR. Results demonstrated successful down-regulation of IAH1 expression in K. marxianus strain DU3 using the CRISPRi system. The modulation of IAH1 gene expression resulted in alterations in the production of volatile compounds, specifically ethyl acetate, which are important contributors to the beverage's aroma. Changes in the expression levels of other genes involved in ester biosynthesis, suggesting that the knockdown of IAH1 may generate intracellular alterations in the balance of these metabolites, triggering a regulatory response. The application of CRISPRi technology in K. marxianus opens the possibility of targeted modulation of gene expression, metabolic engineering strategies, and synthetic biology in this yeast strain.

Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer.

Immune system control is a major hurdle that cancer evolution must circumvent. The relative timing and evolutionary dynamics of subclones that have escaped immune control remain incompletely characterized, and how immune-mediated selection shapes the epigenome has received little attention. Here, we infer the genome- and epigenome-driven evolutionary dynamics of tumour-immune coevolution within primary colorectal cancers (CRCs). We utilise our existing CRC multi-region multi-omic dataset that we supplement with high-resolution spatially-resolved neoantigen sequencing data and highly multiplexed imaging of the tumour microenvironment (TME). Analysis of somatic chromatin accessibility alterations (SCAAs) reveals frequent somatic loss of accessibility at antigen presenting genes, and that SCAAs contribute to silencing of neoantigens. We observe that strong immune escape and exclusion occur at the outset of CRC formation, and that within tumours, including at the microscopic level of individual tumour glands, additional immune escape alterations have negligible consequences for the immunophenotype of cancer cells. Further minor immuno-editing occurs during local invasion and is associated with TME reorganisation, but that evolutionary bottleneck is relatively weak. Collectively, we show that immune evasion in CRC follows a "Big Bang" evolutionary pattern, whereby genetic, epigenetic and TME-driven immune evasion acquired by the time of transformation defines subsequent cancer-immune evolution.

Association between diastolic dysfunction and fluid balance in critically ill patients during weaning from mechanical ventilation / Asociación entre la disfunción diastólica y el balance de hídrico en pacientes críticos durante el destete de la ventilación mecánica

Objective: To assess the role of diastolic dysfunction and fluid balance in weaning failure. Design: Prospective, observational, single center. Setting: Intensive care unit of a university hospital. Patients: Adult patients on mechanical ventilation for more than 48 h who underwent a spontaneous breathing trial (SBT). Interventions: Echocardiography was performed immediately before and at the end of SBT. Patients were classified into two groups according to weaning outcome. Main variable of interest: Weaning failure. Results: Among 89 patients included, weaning failure occurred in 33 patients (37%). Isolated diastolic dysfunction at the end of the SBT was more frequent in the failure group (39.3% vs. 17.8%, p = 0.025). Average daily fluid balance from ICU admission until first SBT was less negative in patients who failed than in those who succeed in the weaning (−648 mL [−884 to -138] vs. −893 mL [−1284 to −501], p = 0.007). Average daily fluid balance from the first SBT until the ICU discharge was more negative in the weaning failure than in the success group (−973 mL [−1493 to −201] vs. −425 mL [−1065 to 12], p = 0.034). Cox regression analysis showed that diastolic dysfunction was not an independent factor related to weaning failure but needed the association of positive fluid balance and age. Conclusions: Weaning failure due to diastolic dysfunction is highly related to fluid balance, and the deleterious effect of fluid balance on diastolic function is associated with age The timing of fluid removal could play a key role in this scenario. (AU)

Objetivo: Evaluar el papel de la disfunción diastólica (DD) y el balance hídrico en el fracaso del destete de la ventilación mecánica. Diseño: Prospectivo, observacional.Ámbito: Unidad de cuidados intensivos hospital universitario. Pacientes: Pacientes adultos con ventilación mecánica más de 48 h sometidos a una prueba de respiración espontánea (SBT).Intervenciones: Ecocardiografía antes y al final del SBT. Los pacientes se clasificaron en dos grupos según el resultado del destete. Variable de interés principal: Fracaso del destete. Resultados: Se incluyeron 89 pacientes, el fracaso del destete ocurrió en 33 (37%). La DD al final de la SBT fue más frecuente en el grupo de fracaso (39,3% vs 17,8%, p = 0,025). El balance hídrico diario desde el ingreso en UCI hasta la SBT fue menos negativo en los pacientes que fracasaron que en los que tuvieron éxito del destete (−648 mL [-884 a -138] vs −893 mL [-1284 a -501], p = 0,007). El balance hídrico diario desde el primer SBT hasta el alta de UCI fue más negativo en el grupo de fracaso que en el de éxito (−973 ml [−1493 a −201] vs. −425 ml [−1065 a 12], p = 0,034). La regresión de Cox mostró que la DD no era un factor independiente relacionado con el fracaso, necesitando la asociación del balance hídrico y la edad. Conclusiones: El fracaso del destete debido a DD se relaciona con el balance hídrico, incrementando su efecto nocivo con la edad. El momento de inicio del balance hídrico negativo puede jugar un papel clave en el fracaso. (AU)

Binaural Beat Effects on Attention: A Study Based on the Oddball Paradigm.

The impact of binaural beats (BBs) on human cognition and behavior remains and various methods have been used to measure their effect, including neurophysiological, psychometric, and human performance evaluations. The few approaches where the level of neural synchronicity and connectivity were measured by neuroimaging techniques have only been undertaken in spontaneous mode. The present research proposes an approach based on the oddball paradigm to study BB effect by estimating the level of attention induced by BBs. Evoked activity of 25 young adults between 19 and 24 years old with no hearing impairments nor clinical neurological history were analyzed. The experiment was conducted in two different sessions of 24.5 min. The first part consisted of 20-min BB stimulation in either theta (BBθ) or beta (BBß). After the BB stimulation, an oddball paradigm was applied in each BB condition to assess the attentional effect induced by BBs. Attention enhancement is expected for BBß with respect to BBθ. Target event related potentials (ERPs) were mainly analyzed in the time and time-frequency domains. The frequency analysis was based on continuous wavelet transform (CWT), event-related spectral perturbation (ERSP), and inter-trial phase coherence (ITPC). The study revealed that the P300 component was not significantly different between conditions (BBθ vs. BBß). However, the target grand average ERP in BBθ condition was mainly composed of 8 Hz-frequency components, appearing before 400 ms post-stimulus, and mainly on the centro-parietal regions. In contrast, the target grand average ERP in BBß condition was mainly composed of frequency components below 6 Hz, mainly appearing at 400 ms post-stimulus on the parieto-occipital regions. Furthermore, ERPs in the BBθ condition were more phase locked than the BBß condition.

Role of ultrasound in acute respiratory failure and in the weaning of mechanical ventilation.

Comprehensive ultrasound assessment has become an essential tool to facilitate the diagnosis and therapeutic management of critically ill patients with acute respiratory failure (ARF). There is evidence supporting the use of ultrasound for the diagnosis of pneumothorax, acute respiratory distress syndrome, cardiogenic pulmonary edema, pneumonia and acute pulmonary thromboembolism, and in patients with COVID-19. In addition, in recent years, the use of ultrasound to evaluate responses to treatment in critically ill patients with ARF has been developed, providing a noninvasive tool for titrating positive end-expiratory pressure, monitoring recruitment maneuvers and response to prone position, as well as for facilitating weaning from mechanical ventilation. The objective of this review is to summarize the basic concepts on the utility of ultrasound in the diagnosis and monitoring of critically ill patients with ARF.

LIPRNAseq: a method to discover lipid interacting RNAs by sequencing.

BACKGROUND: Current biological research extensively describes the interactions of molecules such as RNA with other nucleic acids or proteins. However, the relatively recent discovery of nuclear phospholipids playing biologically relevant processes outside membranes, as well as, RNA-lipid interactions shows the need for new methods to explore the identity of these RNAs. METHODS AND RESULTS: In this study, we describe the method for LIPID-RNA isolation followed by sequencing and analysis of the RNA that has the ability to interact with the selected lipids. Here we utilized specific phospholipid coated beads for selective RNA binding. We tested RNA from organisms belonging to different realms (human, plant, and yeast), and tested their ability to bind a specific lipid. CONCLUSIONS: The results show several RNAs differentially enriched in the pull-down of phosphatidyl Inositol 4,5 bisphosphate coated beads. This method is helpful to screen lipid-binding RNA, which may have relevant biological functions. The method can be used with different lipids and comparison of pull-downs and can narrow the selection of RNAs that interact with a particular lipid for further studies.

Association between diastolic dysfunction and fluid balance in critically ill patients during weaning from mechanical ventilation.

OBJECTIVE: To assess the role of diastolic dysfunction and fluid balance in weaning failure. DESIGN: Prospective, observational, single center. SETTING: Intensive care unit of a university hospital. PATIENTS: Adult patients on mechanical ventilation for more than 48 h who underwent a spontaneous breathing trial (SBT). INTERVENTIONS: Echocardiography was performed immediately before and at the end of SBT. Patients were classified into two groups according to weaning outcome. MAIN VARIABLE OF INTEREST: Weaning failure. RESULTS: Among 89 patients included, weaning failure occurred in 33 patients (37%). Isolated diastolic dysfunction at the end of the SBT was more frequent in the failure group (39.3% vs. 17.8%, p = 0.025). Average daily fluid balance from ICU admission until first SBT was less negative in patients who failed than in those who succeed in the weaning (-648 mL [-884 to -138] vs. -893 mL [-1284 to -501], p = 0.007). Average daily fluid balance from the first SBT until the ICU discharge was more negative in the weaning failure than in the success group (-973 mL [-1493 to -201] vs. -425 mL [-1065 to 12], p = 0.034). Cox regression analysis showed that diastolic dysfunction was not an independent factor related to weaning failure but needed the association of positive fluid balance and age. CONCLUSIONS: Weaning failure due to diastolic dysfunction is highly related to fluid balance, and the deleterious effect of fluid balance on diastolic function is associated with age The timing of fluid removal could play a key role in this scenario.

Código shock cardiogénico 2023. Documento de expertos para una organización multidisciplinaria que permita una atención de calidad / Cardiogenic shock code 2023. Expert document for a multidisciplinary organization that allows quality care

Pese a los esfuerzos realizados para mejorar la atención al shock cardiogénico (SC), incluyendo el desarrollo de dispositivos de asistencia circulatoria mecánica (ACM), su pronóstico continúa siendo desfavorable. En este contexto surgen iniciativas de código SC, basadas en proporcionar una asistencia rápida y de calidad a estos pacientes. Este documento multidisciplinario trata de justificar la necesidad de implantar el código SC, definiendo su estructura/organización, criterios de activación, flujo de pacientes según nivel asistencial e indicadores de calidad. Sus propósitos concretos son: a) presentar las peculiaridades de esta enfermedad y el aprendizaje del código infarto y de experiencias previas en SC; b) detallar las bases para el abordaje de estos pacientes, la estructura de los equipos, su logística, la elección del tipo de ACM y el momento de su implante, y c) abordar los desafíos para la implantación del código SC, como la singularidad del código SC pediátrico. Urge desarrollar una asistencia protocolizada, multidisciplinaria y centralizada en hospitales con gran volumen y experiencia que permita minimizar la inequidad en el acceso a la ACM y mejorar la supervivencia de estos enfermos. Solo el apoyo institucional y estructural de las distintas administraciones permitirá optimizar la atención al SC (AU)

Despite the efforts made to improve the care of cardiogenic shock (CS) patients, including the development of mechanical circulatory support (MCS), the prognosis of these patients continues to be poor. In this context, CS code initiatives arise, based on providing adequate, rapid, and quality care to these patients. In this multidisciplinary document we try to justify the need to implement the SC code, defining its structure/organization, activation criteria, patient flow according to care level, and quality indicators. Our specific purposes are: a) to present the peculiarities of this condition and the lessons of infarction code and previous experiences in CS; b) to detail the structure of the teams, their logistics and the bases for the management of these patients, the choice of the type of MCS, and the moment of its implantation, and c) to address challenges to SC code implementation, including the uniqueness of the pediatric SC code. There is an urgent need to develop protocolized, multidisciplinary, and centralized care in hospitals with a large volume and experience that will minimize inequity in access to the MCS and improve the survival of these patients. Only institutional and structural support from the different administrations will allow optimizing care for CS (AU)

Current research on viral proteins that interact with fibrillarin.

The nucleolus is a multifunctional nuclear domain primarily dedicated to ribosome biogenesis. Certain viruses developed strategies to manipulate host nucleolar proteins to facilitate their replication by modulating ribosomal RNA (rRNA) processing. This association interferes with nucleolar functions resulting in overactivation or arrest of ribosome biogenesis, induction or inhibition of apoptosis, and affecting stress response. The nucleolar protein fibrillarin (FBL) is an important target of some plant and animal viruses. FBL is an essential and highly conserved S-adenosyl methionine (SAM) dependent methyltransferase, capable of rRNA degradation by its intrinsically disordered region (IDR), the glycine/arginine-rich (GAR) domain. It forms a ribonucleoprotein complex that directs 2'-O-methylations in more than 100 sites of pre-rRNAs. It is involved in multiple cellular processes, including initiation of transcription, oncogenesis, and apoptosis, among others. The interaction with animal viruses, including human viruses, triggered its redistribution to the nucleoplasm and cytoplasm, interfering with its role in pre-rRNA processing. Viral-encoded proteins with IDRs as nucleocapsids, matrix, Tat protein, and even a viral snoRNA, can associate with FBL, forcing the nucleolar protein to undergo atypical functions. Here we review the molecular mechanisms employed by animal and human viruses to usurp FBL functions and the effect on cellular processes, particularly in ribosome biogenesis.

Immune selection determines tumor antigenicity and influences response to checkpoint inhibitors.

In cancer, evolutionary forces select for clones that evade the immune system. Here we analyzed >10,000 primary tumors and 356 immune-checkpoint-treated metastases using immune dN/dS, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome, to measure immune selection in cohorts and individuals. We classified tumors as immune edited when antigenic mutations were removed by negative selection and immune escaped when antigenicity was covered up by aberrant immune modulation. Only in immune-edited tumors was immune predation linked to CD8 T cell infiltration. Immune-escaped metastases experienced the best response to immunotherapy, whereas immune-edited patients did not benefit, suggesting a preexisting resistance mechanism. Similarly, in a longitudinal cohort, nivolumab treatment removes neoantigens exclusively in the immunopeptidome of nonimmune-edited patients, the group with the best overall survival response. Our work uses dN/dS to differentiate between immune-edited and immune-escaped tumors, measuring potential antigenicity and ultimately helping predict response to treatment.