Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells.

Colorectal cancer (CRC) tumors are composed of heterogeneous and plastic cell populations, including a pool of cancer stem cells that express LGR5. Whether these distinct cell populations display different mechanical properties, and how these properties might contribute to metastasis is poorly understood. Using CRC patient derived organoids (PDOs), we find that compared to LGR5- cells, LGR5+ cancer stem cells are stiffer, adhere better to the extracellular matrix (ECM), move slower both as single cells and clusters, display higher nuclear YAP, show a higher survival rate in response to mechanical confinement, and form larger transendothelial gaps. These differences are largely explained by the downregulation of the membrane to cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in the LGR5+ cells. By analyzing single cell RNA-sequencing (scRNA-seq) expression patterns from a patient cohort, we show that this downregulation is a robust signature of colorectal tumors. Our results show that LGR5- cells display a mechanically dynamic phenotype suitable for dissemination from the primary tumor whereas LGR5+ cells display a mechanically stable and resilient phenotype suitable for extravasation and metastatic growth.

Carbon-Assisted Minimally Invasive Transtubular Approach for Intercostal Nerve Schwannoma.

BACKGROUND AND OBJECTIVES: The intraoperative localization of an intercostal nerve schwannoma (INS) is extremely difficult because the lesion is generally not palpable, and the fluoroscopic visualization of anatomic landmarks in the ribs is unsatisfactory. Using activated carbon suspension to mark the soft-tissue approach could improve INS localization. We present a novel, simple, reproducible carbon-assisted minimally invasive transtubular approach for an INS. METHODS: The patient was a 57-year-old man with a painful 12th left INS arising below the floating rib. A computed tomography image-guided, tumor-to-skin marking with aqueous carbon suspension was performed 48 hours before surgery. A minimally invasive transtubular approach following the carbon path allowed a precise tumor location. RESULTS: The INS was completely removed. The patient's thoracic radicular pain was immediately relieved after surgery. He was discharged the following day with residual numbness on the left thoracic side. At the 5-year follow-up, no tumor recurrence was noted in the control MRI. CONCLUSION: This article presents an alternative novel technique for resecting an intercostal schwannoma. Using a transtubular approach with carbon-marking assistance allowed a tumor gross total resection with immediate pain relief and a successful outcome.

Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients.

BACKGROUND: SARS-CoV-2 infection portends a broad range of outcomes, from a majority of asymptomatic cases to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty, and co-morbidities such as obesity, diabetes, and cardiovascular disease. A precise knowledge of the molecular and biological mechanisms that may explain the association of severe disease with male sex is still lacking. Here, we analyzed the relationship of serum testosterone levels and the immune cell skewing with disease severity in male COVID-19 patients. METHODS: Biochemical and hematological parameters of admission samples in 497 hospitalized male and female COVID-19 patients, analyzed for associations with outcome and sex. Longitudinal (in-hospital course) analyses of a subcohort of 114 male patients were analyzed for associations with outcome. Longitudinal analyses of immune populations by flow cytometry in 24 male patients were studied for associations with outcome. RESULTS: We have found quantitative differences in biochemical predictors of disease outcome in male vs. female patients. Longitudinal analyses in a subcohort of male COVID-19 patients identified serum testosterone trajectories as the strongest predictor of survival (AUC of ROC = 92.8%, p < 0.0001) in these patients among all biochemical parameters studied, including single-point admission serum testosterone values. In lethal cases, longitudinal determinations of serum luteinizing hormone (LH) and androstenedione levels did not follow physiological feedback patterns. Failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and augmented circulating classical monocytes. CONCLUSIONS: Recovery or failure to reinstate testosterone levels is strongly associated with survival or death, respectively, from COVID-19 in male patients. Our data suggest an early inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by full recovery in survivors or a peripheral failure in lethal cases. These observations are suggestive of a significant role of testosterone status in the immune responses to COVID-19 and warrant future experimental explorations of mechanistic relationships between testosterone status and SARS-CoV-2 infection outcomes, with potential prophylactic or therapeutic implications.

C1 esterase inhibitor and the contact system in COVID-19.

Coronavirus disease 2019 (COVID-19) is frequently associated with severe systemic consequences, including vasculitis, a hyperinflammatory state and hypercoagulation. The mechanisms leading to these life-threatening abnormalities are multifactorial. Based on the analysis of publicly available interactomes, we propose that severe acute respiratory syndrome coronavirus-2 infection directly causes a deficiency in C1 esterase inhibitor, a pathogen-specific mechanism that may help explain significant systemic abnormalities in patients with COVID-19.

Potentiation of cerebellar Purkinje cells facilitates whisker reflex adaptation through increased simple spike activity.

Cerebellar plasticity underlies motor learning. However, how the cerebellum operates to enable learned changes in motor output is largely unknown. We developed a sensory-driven adaptation protocol for reflexive whisker protraction and recorded Purkinje cell activity from crus 1 and 2 of awake mice. Before training, simple spikes of individual Purkinje cells correlated during reflexive protraction with the whisker position without lead or lag. After training, simple spikes and whisker protractions were both enhanced with the spiking activity now leading behavioral responses. Neuronal and behavioral changes did not occur in two cell-specific mouse models with impaired long-term potentiation at their parallel fiber to Purkinje cell synapses. Consistent with cerebellar plasticity rules, increased simple spike activity was prominent in cells with low complex spike response probability. Thus, potentiation at parallel fiber to Purkinje cell synapses may contribute to reflex adaptation and enable expression of cerebellar learning through increases in simple spike activity.

Efecto irritante in vitro de formulaciones cosméticas con extracto de camu camu, mediante el método Het Cam / Irritant effect in vitro of cosmetic formulations with camu camu extract by Het Cam method

Objetivo: evaluar el efecto irritante de formulaciones cosméticas con extractos de camu camu. Material y métodos: El presente estudio se realizó con formulaciones cosméticas de extractos de camu camu, proporcionadas por el laboratorio de AYRU COSMETIC; utilizamos la técnica altermativa in vitro, en membrana corioalantoidea en huevos fártiles de gallina (HET CAM, henás egg test chorioallantoic membrane). La implementación de la técnica se realizó en el Centro de Investigación de Medicina Tradicional y Farmacología del Instituto de Investigación de la Facultad de Medicina Humana de la USMP. Resultados: Ninguno de los cosméticos con extracto de camu camu, produjo ruptura de la membrana corioalantoidea, evidenciado por ausencia del colorante absorbido, azul de tripón, detectable a 595nm. Conclusiones: Los índices de irritación (I.I) obtenidos en todas las formulaciones cosméticas permiten clasificarlas como NO IRRITANTES, y constituyen el soporte de la inocuidad, de las mismas, para continuar con pruebas de eficacia.

Objective: To evaluate the irritant effect of cosmetic formulations elaborated with camu camu extracts. Material and Methods: This study was performed with cosmetic on formulations containing camu camu extracts supplied by the AYRU COSMETIC Laboratory. We used the alternative in vitro technic on choriollantoic membrane in fertile hen’s eggs (HET CAM, hen’s egg chorioallantoic membrane test). The techniques was implemented at “Centro Investigaci¢n de Medicina Tradicional y Farmacolog¡a” of the Research Institute of the school of Medicine of San Martin de Porres University. Results: None of the cosmetic with Camu Camu extracts showed chorioallantoic membrane rupture, which was verified by the absence of absorbed trypan blue dye, detectable at 595 nm. Conclusions: the rates of irritation (II) obtained in all cosmetic formulations allow us to classify them as NOT IRRITATING and support the safety of such products to continue clinical efficacy trials.