Primary hepatic pleomorphic liposarcoma: Case report and literature review / Liposarcoma pleomorfo hepático primario: presentación de un caso y revisión bibliográfica

Primary hepatic liposarcoma is an extremely rare malignant tumour derived from adipocytes and is part of the group of mesenchymal tumours. We present the case of a 43-year-old Hispanic male patient with a pleomorphic hepatic liposarcoma and absence of MDM2 gene amplification. Two years and six months after surgery, the patient is asymptomatic. The present case is the first report of this entity with positive immunohistochemical testing for p16, p53, S100, vimentin and absence of MDM2 gene amplification. (AU)

El liposarcoma hepático primario es un tumor maligno extremadamente raro, derivado de adipocitos, y forma parte del grupo de tumores mesenquimales. Presentamos el caso de un paciente masculino de 43 años con diagnóstico de liposarcoma hepático pleomorfo con ausencia de amplificación del gen MDM2. Dos años y 6 meses después de la cirugía el paciente se encuentra asintomático. El presente caso es el primer informe de esta entidad con estudio inmunohistoquímico positivo para p16, p53, S100, vimentina y ausencia de amplificación del gen MDM2. (AU)

Primary hepatic pleomorphic liposarcoma: Case report and literature review.

Primary hepatic liposarcoma is an extremely rare malignant tumour derived from adipocytes and is part of the group of mesenchymal tumours. We present the case of a 43-year-old Hispanic male patient with a pleomorphic hepatic liposarcoma and absence of MDM2 gene amplification. Two years and six months after surgery, the patient is asymptomatic. The present case is the first report of this entity with positive immunohistochemical testing for p16, p53, S100, vimentin and absence of MDM2 gene amplification.

Structural basis for the oligomerization-facilitated NLRP3 activation.

The NACHT-, leucine-rich-repeat-, and pyrin domain-containing protein 3 (NLRP3) is a critical intracellular inflammasome sensor and an important clinical target against inflammation-driven human diseases. Recent studies have elucidated its transition from a closed cage to an activated disk-like inflammasome, but the intermediate activation mechanism remains elusive. Here we report the cryo-electron microscopy structure of NLRP3, which forms an open octamer and undergoes a ~ 90° hinge rotation at the NACHT domain. Mutations on open octamer's interfaces reduce IL-1ß signaling, highlighting its essential role in NLRP3 activation/inflammasome assembly. The centrosomal NIMA-related kinase 7 (NEK7) disrupts large NLRP3 oligomers and forms NEK7/NLRP3 monomers/dimers which is a critical step preceding the assembly of the disk-like inflammasome. These data demonstrate an oligomeric cooperative activation of NLRP3 and provide insight into its inflammasome assembly mechanism.

Epistemic misalignments in microbiome research.

We argue that microbiome research should be more reflective on the methods that it relies on to build its datasets due to the danger of facing a methodological problem which we call "epistemic misalignment." An epistemic misalignment occurs when the method used to answer specific scientific questions does not track justified answers, due to the material constraints imposed by the very method. For example, relying on 16S rRNA to answer questions about the function of the microbiome generates epistemic misalignments, due to the different temporal scales that 16S rRNA provides information about and the temporal scales that are required to know about the functionality of some microorganisms. We show how some of these exist in contemporary microbiome science and urge microbiome scientists to take some measures to avoid them, as they may question the credibility of the field as a whole.

Scrutinizing microbiome determinism: why deterministic hypotheses about the microbiome are conceptually ungrounded.

This paper addresses the topic of determinism in contemporary microbiome research. I distinguish two types of deterministic claims about the microbiome, and I show evidence that both types of claims are present in the contemporary literature. First, the idea that the host genetics determines the composition of the microbiome which I call "host-microbiome determinism". Second, the idea that the genetics of the holobiont (the individual unit composed by a host plus its microbiome) determines the expression of certain phenotypic traits, which I call "microbiome-phenotype determinism". Drawing on the stability of traits conception of individuality (Suárez in Hist Philos Life Sci 42:11, 2020) I argue that none of these deterministic hypotheses is grounded on our current knowledge of how the holobiont is transgenerationally assembled, nor how it expresses its phenotypic traits.

Clinical and outcome comparison of genetically positive vs. negative patients in a large cohort of suspected familial hypocalciuric hypercalcemia.

OBJECTIVE: Biochemical suspicion of familial hypocalciuric hypercalcemia (FHH) might provide with a negative (FHH-negative) or positive (FHH-positive) genetic result. Understanding the differences between both groups may refine the identification of those with a positive genetic evaluation, aid management decisions and prospective surveillance. We aimed to compare FHH-positive and FHH-negative patients, and to identify predictive variables for FHH-positive cases. DESIGN: Retrospective, national multi-centre study of patients with suspected FHH and genetic testing of the CASR, AP2S1 and GNA11 genes. METHODS: Clinical, biochemical, radiological and treatment data were collected. We established a prediction model for the identification of FHH-positive cases by logistic regression analysis and area under the ROC curve (AUROC) was estimated. RESULTS: We included 66 index cases, of which 30 (45.5%) had a pathogenic variant. FHH-positive cases were younger (p = 0.029), reported more frequently a positive family history (p < 0.001), presented higher magnesium (p < 0.001) and lower parathormone levels (p < 0.001) and were less often treated for hypercalcemia (p = 0.017) in comparison to FHH-negative cases. Magnesium levels showed the highest AUROC (0.825, 95%CI: 0.709-0.941). The multivariate analysis revealed that family history and magnesium levels were independent predictors of a positive genetic result. The predictive model showed an AUROC of 0.909 (95%CI: 0.826-0.991). CONCLUSIONS: The combination of magnesium and a positive family history offered a good diagnostic accuracy to predict a positive genetic result. Therefore, the inclusion of magnesium measurement in the routine evaluation of patients with suspected FHH might provide insight into the identification of a positive genetic result of any of the CaSR-related genes.

Interdisciplinary Spanish consensus on a watch-and-wait approach for rectal cancer.

Watch-and-wait has emerged as a new strategy for the management of rectal cancer when a complete clinical response is achieved after neoadjuvant therapy. In an attempt to standardize this new clinical approach, initiated by the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), and with the participation of the Spanish Association of Coloproctology (AECP), the Spanish Society of Pathology (SEAP), the Spanish Society of Gastrointestinal Endoscopy (SEED), the Spanish Society of Radiation Oncology (SEOR), and the Spanish Society of Medical Radiology (SERAM), we present herein a consensus on a watch-and-wait approach for the management of rectal cancer. We have focused on patient selection, the treatment schemes evaluated, the optimal timing for evaluating the clinical complete response, the oncologic outcomes after the implementation of this strategy, and a protocol for surveillance of these patients.

Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.

ZEB1 hypermethylation is associated with better prognosis in patients with colon cancer.

BACKGROUND: Colon cancer (CC) is a heterogeneous disease that is categorized into four Consensus Molecular Subtypes (CMS) according to gene expression. Patients with loco-regional CC (stages II/III) lack prognostic factors, making it essential to analyze new molecular markers that can delineate more aggressive tumors. Aberrant methylation of genes that are essential in crucial mechanisms such as epithelial mesenchymal transition (EMT) contributes to tumor progression in CC. We evaluate the presence of hyper- and hypomethylation in subrogate IHC markers used for CMS classification (CDX2, FRMD6, HTR2B, ZEB1) of 144 stage II/III patients and CC cell lines by pyrosequencing. ZEB1 expression was also studied in control and shRNA-silenced CC cell lines and in paired normal tissue/tumors by quantitative PCR. The pattern of ZEB1 staining was also analyzed in methylated/unmethylated tumors by immunohistochemistry. RESULTS: We describe for the first time the hypermethylation of ZEB1 gene and the hypomethylation of the FRMD6 gene in 32.6% and 50.9% of tumors, respectively. Additionally, we confirm the ZEB1 re-expression by epigenetic drugs in methylated cell lines. ZEB1 hypermethylation was more frequent in CMS1 patients and, more importantly, was a good prognostic factor related to disease-free survival (p = 0.015) and overall survival (p = 0.006) in our patient series, independently of other significant clinical parameters such as patient age, stage, lymph node involvement, and blood vessel and perineural invasion. CONCLUSIONS: Aberrant methylation is present in the subrogate genes used for CMS classification. Our results are the first evidence that ZEB1 is hypermethylated in CC and that this alteration is an independent factor of good prognosis.

Comparative effectiveness and duration of protection of ChAdOx1, CoronaVac, BNT162b2, mRNA-1273, and Ad26.COV2.S COVID-19 vaccines for symptomatic and hospitalized Mu, Delta, and Omicron: A test-negative case-control study.

OBJECTIVE: We carried out a study to estimate the vaccine effectiveness (VE) of homologous vaccination schedules against COVID-19, using data from mandatory information systems from Bogota, Colombia. METHODS: A test-negative case-control study in adults from Bogota (Colombia), between March 1st of 2021 and February 25th of 2022. We assess VE among symptomatic COVID-19 cases during the Mul, Delta, and Omicron predominance periods in Bogota, with controls matched by sex, age (±5 years), and date of testing (±7 days), using a case:control ratio of 1:1. We selected homologous vaccination schedules with ChAdOx1, CoronaVac, BNT162b2, mRNA-1273, and Ad26.COV2.S. VE was reported as one minus the odds ratio in adjusted conditional logistic regressions, with their 95% confidence intervals (CI). A p-value < 0.05 was considered statistically significant. RESULTS: 52,913 cases were matched to controls, 16,722 for Mu, 14,094 for Delta, and 22,097 for Omicron. VE was high against COVID-19 during Mu weeks with full vaccination using the monovalent BNT162b2 (VE: 69; 95% CI, 65 to 72) vaccine and ChAdOx1 (VE: 64; 95% CI, 31 to 81) and significantly lower with CoronaVac (P < 0.001) and Ad26.COV2.S (P = 0.005). During Delta, VE against COVID-19 was higher with BNT162b2 (VE: 55; 95% CI, 51 to 58). The VE for COVID-19 cases during Omicron was higher with a booster dose of monovalent BNT162b2 (VE: 45; 95% CI, 34 to 54). The VE of primary series and booster for ChAdOx1, Ad26.COV2.S, and CoronaVac did not show protection for Omicron. CONCLUSION: Our study provides further evidence on the protective effect of mRNA vaccines for Omicron, and warrant that the duration of protection against symptomatic infection may last for only a few months.

When and How Do Soccer Players From a Semi-Professional Club Sprint in Match Play?

The aims of this study were to investigate the periods in which sprints occurred during official matches and analyze these sprints considering the effect of the playing position and different contextual variables. Electronic performance and tracking systems were used for the analysis of all sprints performed by players. Matches were recorded by video and synchronized with performance tracking data. A total of 252 sprints were analyzed. The greatest frequency of sprints was observed in the period 1 (0'-15'), followed by period 2 (15'-30') and period 6 (75'-90'), regardless of the playing position (χ2 = 31.35; p = 0.051). Most sprints were non-linear (non-linear sprints: 97.6%; linear sprints: 2.4%) and without ball possession (without ball possession: 95.2%; with ball possession: 4.8%) for all playing positions, but the role of the sprint and the field area in which the sprint occurred were dependent on the position (p < 0.001). Specifically, players covered ~17.55 m per sprint, starting at ~10.34 km/h, reaching ~26.74 km/h, maximally accelerating at ~2.73 m/s2, and decelerating at ~3.61 m/s2. Overall, the playing position and contextual variables had no significant effect on physical performance variables analyzed during these sprints. Therefore, this study allows performance practitioners to have a better understanding of when and how soccer players sprint in match-play. In this regard, this study presents some training and testing strategies that may be considered to improve performance and decrease injury risk.

Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity.

Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR-/-) and mice overexpressing C3a in the brain, we uncovered 2 opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR-/- mice; C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity, and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within a convenient time window holds translational promise to improve outcome after ischemic stroke.

Impact of the COVID-19 Pandemic on Dermatology Care in the Chilean Public Health Sector.

Due to the Coronavirus-19 (COVID-19) pandemic, most resources of the public health system were allocated to the increasing demand from respiratory patients. From this, it is expected that specialty consultations would decrease drastically. Access to dermatology care in the Chilean public health has been historically limited. To evaluate the impact of the pandemic on dermatology care, the total number of dermatological consultations (DCs) to the Chilean public sector in 2020 is analyzed according to sex and age range and compared with the available databases from 2017 to 2019. From this, 120,095 DCs were performed during 2020, with an incidence of 6.3 consultations per 1000 inhabitants. When compared to 2019 (n = 250,649), there was a 52.1% decrease. The regions most affected were located in the central part of Chile, which correlates with the regions most affected by the pandemic. Age and sex distributions remained similar to previous years but lower in amplitude. The month with the lowest number of consultations was April, with a gradual increase observed thereafter until December 2020. Although DCs decreased drastically in the Chilean public sector during 2020, sex and age range proportions were conserved, thus affecting all groups in a similar manner.

Melanocytic nevus of the anal canal and granular cell tumor of the cecum: a case report and literature review of 2 coincidentally co-occurring neurocristopathies.

Granular cell tumors are predominantly benign soft tissue tumors originating from Schwann cells, whereas melanocytic nevi are benign proliferations of melanocytes. We present the case of a patient with the presence of both entities located in the cecum and anal canal, respectively, constituting an extremely rare coincidental finding. A 43-year-old woman was evaluated by colonoscopy for iron-deficiency microcytic anemia that had lasted for 1 year. Colonoscopy demonstrated a macular lesion of 0.3 cm with a melanocytic appearance in the anal canal; at the cecum level, a subepithelial, yellowish, and partially mobile firm nodular lesion measuring 1.3 cm was observed. A histopathological study showed a melanocytic nevus in the anal canal and a granular cell tumor in the cecum. This is the first reported case of a patient with the extremely rare coincidental-incidental finding of these 2 entities at the same time.

Hacia una herramienta de cribado temprano del trastorno del espectro del autismo (TEA) / Towards an Early Screening Tool for AutismSpectrum Disorder (ASD)

En los últimos años el empleo de la metodología del eye tracking ha sido objeto de estudio de diferentes investigaciones en torno a esta técnica como posible medida objetiva para la detección temprana de indicadores de Trastorno del Espectro Autista (TEA). En el presente estudio se ha elaborado un total de 15 vídeos estímulo divididos en cuatro bloques con el objeto de diseñar una prueba objetiva de sencilla y rápida aplicación, mediante un dispositivo eye tracker, que permita realizar una detección objetiva y muy temprana de indicadores de riesgo de desarrollar TEA; para ello se cuenta con una muestra formada por 148 sujetos, 74 sujetos con indicadores clínicos de TEA y 74 sujetos con desarrollo típico. Los resultados confirman que es posible configurar un software que, tras analizar los registros de mirada de un bebé obtenidos con un dispositivo eye tracker, nos proporcione automáticamente su probabilidad de presentar un “patrón de mirada de máxima atención al objeto (riego de TEA) o un patrón de mirada de recogida de información social (no TEA)”. Con las tareas aquí presentadas, tras analizar la sensibilidad de cada vídeo y cada variable, se han obtenido resultados estadísticamente significativos en cada uno de los vídeos estímulo, por lo que se concluye que la metodología del eye tracking con el empleo de los estímulos aquí diseñados puede operar como método de detección objetivo y eficaz de indicadores de alarma de TEA. (AU)

In recent years, eye-tracking methodology technique has been the objectof study used in different investigations as a potential objective measure of the diagnosis ofASD. In the present study, a total of 15 stimulus videos have been prepared. These are divided into four blocks to design an objective test with simple and rapid application, by using an eye-tracker device, which allows an early diagnosis of ASD. To do so, we measured a sample made up of 148 subjects, 74 subjects with ASD and 74 with typical development. The results confirm that it is possible to configure a software that, after analysing the gaze records of a baby obtained with an eye-tracker device, automatically provides us with its probability of presenting an “ASD or no ASD Gaze Pattern”. With the tasks presented here, after analysing the sensitivity of each video and each variable, statistically significant results have been obtained in each of the stimulus videos. Based on that output, it can be concluded that the eye-tracking methodology with the use of the stimuli designed here can be used as an objective and effective diagnostic method for ASD. (AU)

Usefulness of Self-Expanding Drainage Cannula in Venovenous Extracorporeal Membrane Oxygenation: Tips, Tricks, and Results of an Early Experience.

Inadequate venous drainage decreases the efficiency of extracorporeal membrane oxygenation (ECMO). Pump augmentation may even make it worse due to collapse of the venous system under negative pressures. Furthermore, recirculation is a phenomenon that occurs when oxygenated blood supplied through the infusion cannula is withdrawn directly through the drainage cannula without contributing to the oxygenation of the patient and also compromises the efficacy of the therapy. Large drainage cannulas allow for similar flow rates at lower pump speed. But percutaneous insertion of these larger cannulas could be challenging. When using a self-expandable cannula, the diameter of the cannula for the insertion can be reduced, and once inserted, its intravascular diameter maximized, resulting in a large venous cannula due to in situ expansion after mandrel removal (up to 36F). We present a retrospective series of selfexpanding venous cannula 430 or 530 mm in length in six consecutive patients undergoing venovenous (VV) ECMO. No vascular or cardiac iatrogenic injury was caused during implantation. Target flows were reached, and no clinically significant recirculation was described in any case. The use of selfexpanding drainage cannulas was safe, and efficient drainage was achieved with easy and definitive unique positioning during cannulation.

Descriptive understanding and prediction in COVID-19 modelling.

COVID-19 has substantially affected our lives during 2020. Since its beginning, several epidemiological models have been developed to investigate the specific dynamics of the disease. Early COVID-19 epidemiological models were purely statistical, based on a curve-fitting approach, and did not include causal knowledge about the disease. Yet, these models had predictive capacity; thus they were used to ground important political decisions, in virtue of the understanding of the dynamics of the pandemic that they offered. This raises a philosophical question about how purely statistical models can yield understanding, and if so, what the relationship between prediction and understanding in these models is. Drawing on the model that was developed by the Institute of Health Metrics and Evaluation, we argue that early epidemiological models yielded a modality of understanding that we call descriptive understanding, which contrasts with the so-called explanatory understanding which is assumed to be the main form of scientific understanding. We spell out the exact details of how descriptive understanding works, and efficiently yields understanding of the phenomena. Finally, we vindicate the necessity of studying other modalities of understanding that go beyond the conventionally assumed explanatory understanding.

Potent Phenylpyridine and Oxodihydrofuran Inhibitors of Cyclooxygenase-2: Optimization toward a Long Residence Time with Balanced Internal Energetics.

Long residence time enzyme inhibitors with a two-step binding mechanism are characterized by a high internal energy barrier for target association. This raises the question of whether optimizing residence time via further increasing this internal energy barrier would inevitably lead to insufficient target occupancy in vivo due to slow, time-dependent binding. We attempted to address this question during optimization of cyclooxygenase-2 (COX-2) inhibitors. Defining long residence time drugs with acceptable association and dissociation rate constants required for sufficient target occupancy and sustained efficacy, which we termed "balanced internal energetics", provides an important criterion for successful progression during lead optimization. Despite the advancement of several COX-2 inhibitors to marketed drugs, their detailed inhibition kinetics have been surprisingly limiting especially during the structure-activity relationship process mainly due to the lack of robust kinetic assays. Herein, we describe a reoptimized COX enzymatic assay and a novel MS-based assay enabling detailed mechanistic studies for identifying long residence time COX-2 inhibitors with balanced internal energetics. These efforts led to the discovery of promising leads possessing dissociation half-lives of ≤40 h, much greater than the values of 6 and 0.71 h for two marketed drugs, etoricoxib and celecoxib, respectively. Importantly, the inhibition rate constants remain comparable to those of the marketed drugs and above the lower limits set by the criteria of balanced internal energetics, predicting sufficient target occupancy required for efficacy. Taken together, this study demonstrates the feasibility of increasing the internal energy barrier as a viable approach for lead optimization toward discovering long residence time drug candidates.

Gut-Restricted Selective Cyclooxygenase-2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer.

Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has been reported to reduce the incidence of colorectal adenomas and CRC but is also associated with an increased risk of cardiovascular events. Here, we report a series of gut-restricted, selective COX-2 inhibitors characterized by high colonic exposure and minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as an efficacy proxy, we identified a subset of analogues that demonstrated statistically significant in vivo dose-dependent inhibition of adenoma progression and survival extension in an APCmin/+ mouse model. However, in vitro-in vivo correlation analysis showed their chemoprotective effects were driven by residual systemic COX-2 inhibition, rationalizing their less than expected efficacies and highlighting the challenges associated with COX-2-mediated CRC disease chemoprevention.