A non-comparative, randomized, phase II trial of atezolizumab or atezolizumab plus tiragolumab for programmed death-ligand 1-positive recurrent cervical cancer (SKYSCRAPER-04).

OBJECTIVE: To evaluate tiragolumab (anti-TIGIT) and atezolizumab (anti-PD-L1) as second- or third-line therapy for PD-L1-positive persistent/recurrent cervical cancer. METHODS: In the open-label, non-comparative, randomized phase II SKYSCRAPER-04 trial (NCT04300647), patients with PD-L1-positive (SP263 tumor area positivity ≥5%) recurrent/persistent cervical cancer after 1-2 chemotherapy lines (≥1 platinum-based) were randomized 3:1 to atezolizumab 1200 mg with/without tiragolumab 600 mg every 3 weeks until disease progression or unacceptable toxicity. Stratification factors were performance status, prior (chemo)radiotherapy, and disease status. The primary endpoint was independent review committee-assessed confirmed objective response rate per RECIST v1.1 in patients receiving tiragolumab plus atezolizumab. An objective response rate ≥21% (one-sample z-test p≤0.0245) was required for statistical significance versus a historical reference. RESULTS: Protocol-defined independent review committee-assessed objective response rates were 19.0% (95% CI 12.6 to 27.0) in 126 patients receiving tiragolumab plus atezolizumab (p=0.0787 vs historical reference) and 15.6% (95% CI 6.5 to 29.5) in 45 atezolizumab-treated patients. Response rates were higher in PD-L1high (tumor area positivity ≥10%) than PD-L1low (tumor area positivity 5%-9%) subgroups with both regimens. At 8.5 months' median follow-up, independent review committee-assessed progression-free survival was 2.8 months (95% CI 1.7 to 4.1) with tiragolumab plus atezolizumab and 1.9 months (95% CI 1.5 to 3.0) with atezolizumab. In post hoc analyses (10.4 months' median follow-up), median overall survival was 11.1 months (95% CI 9.6 to 14.5) with the combination and 10.6 months (95% CI 6.9 to 13.8) with atezolizumab (crossover permitted). In the combination group, 3% of patients had adverse events requiring treatment discontinuation and 8% had grade ≥3 adverse events of special interest; corresponding values in the single-agent arm were 4% and 11%. There were no treatment-related deaths or new safety findings. CONCLUSION: The objective response rate with the tiragolumab-plus-atezolizumab combination was numerically higher than the historical reference but did not reach statistical significance.

Solitary plasmacytoma of the sacrum treated with microwave ablation in conjunction with high dose of dexamethasone: A case report and review of the literature.

Background: Plasma cell neoplasms are characterized by the neoplastic proliferation of a single clone of plasma cells. Solitary plasmacytomas most often occur in bone, but they can also be found in soft tissues. Case Description: A 53-year-old male presented with localized sacral pain and urinary incontinence. His radiographic studies showed a solitary sacral plasmacytoma (i.e., involving the bone). He was successfully managed with high-dose dexamethasone and microwave ablation (MWA). Conclusion: Plasmacytomas of bone can be occasionally successfully managed with MWA, adjuvant cytoreduction therapy, and high doses of dexamethasone.

Juvenile angiolipoma in the subtemporal region, zygomatic, and pterygomaxillary fossa treated by microwave ablation - A case study and literature review.

Background: Angiolipomas are benign mesenchymal tumors that infrequently affect the head-and-neck region and can appear with infiltrating and non-infiltrating forms. Surgical excision is the treatment of choice; however, there are other alternatives to manage this condition whose consideration is quite useful to evaluate per each particular case. Case Description: An 11-year-old girl was diagnosed with non-infiltrating angiolipoma in the subtemporal region, the zygomatic, and pterygomaxillary fossa; she had a history of having undergone surgery on two previous occasions with a failed resection attempt due to the high vascularization of the injury and significant transoperative bleeding. The condition was managed with minimally invasive techniques through microwave ablation, requiring two sessions, achieving very satisfactory results both esthetically and in the final size of the lesion. Conclusion: The microwave ablation technique may turn out to be a very useful tool for the management of lesions with high vascularization such as angiolipoma. This technique offers a new possibility for initial management, both independent of and complementary to other management techniques for other lesions at the base of the skull and/or facial massif regions.

Multiomic Analysis Reveals Disruption of Cholesterol Homeostasis by Cannabidiol in Human Cell Lines.

The nonpsychoactive cannabinoid, cannabidiol (CBD), is Food and Dug Administration approved for treatment of two drug-resistant epileptic disorders and is seeing increased use among the general public, yet the mechanisms that underlie its therapeutic effects and side-effect profiles remain unclear. Here, we report a systems-level analysis of CBD action in human cell lines using temporal multiomic profiling. FRET-based biosensor screening revealed that CBD elicits a sharp rise in cytosolic calcium, and activation of AMP-activated protein kinase in human keratinocyte and neuroblastoma cell lines. CBD treatment leads to alterations in the abundance of metabolites, mRNA transcripts, and proteins associated with activation of cholesterol biosynthesis, transport, and storage. We found that CBD rapidly incorporates into cellular membranes, alters cholesterol accessibility, and disrupts cholesterol-dependent membrane properties. Sustained treatment with high concentrations of CBD induces apoptosis in a dose-dependent manner. CBD-induced apoptosis is rescued by inhibition of cholesterol synthesis and potentiated by compounds that disrupt cholesterol trafficking and storage. Our data point to a pharmacological interaction of CBD with cholesterol homeostasis pathways, with potential implications in its therapeutic use.

Asymmetric pore windows in MOF membranes for natural gas valorization.

To use natural gas as a feedstock alternative to coal and oil, its main constituent, methane, needs to be isolated with high purity1. In particular, nitrogen dilutes the heating value of natural gas and is, therefore, of prime importance for removal2. However, the inertness of nitrogen and its similarities to methane in terms of kinetic size, polarizability and boiling point pose particular challenges for the development of energy-efficient nitrogen-removing processes3. Here we report a mixed-linker metal-organic framework (MOF) membrane based on fumarate (fum) and mesaconate (mes) linkers, Zr-fum67-mes33-fcu-MOF, with a pore aperture shape specific for effective nitrogen removal from natural gas. The deliberate introduction of asymmetry in the parent trefoil-shaped pore aperture induces a shape irregularity, blocking the transport of tetrahedral methane while allowing linear nitrogen to permeate. Zr-fum67-mes33-fcu-MOF membranes exhibit record-high nitrogen/methane selectivity and nitrogen permeance under practical pressures up to 50 bar, removing both carbon dioxide and nitrogen from natural gas. Techno-economic analysis shows that our membranes offer the potential to reduce methane purification costs by about 66% for nitrogen rejection and about 73% for simultaneous removal of carbon dioxide and nitrogen, relative to cryogenic distillation and amine-based carbon dioxide capture.

Unravelling the key factors in the chlorine-promoted epoxidation of ethylene over a silver-copper oxide nanocatalyst.

Ethylene oxide is one of the most important raw materials in the chemical industry, with an annual production close to 35 million metric tons. Despite its importance, to date, no metal has been found that can compete with the original silver bulk material catalyst discovered in 1931. Recently, a few copper and copper-silver based nanostructures have demonstrated remarkable selectivity and activity, especially when coupled with an industrial chlorine promoter. The present work evaluates the mechanistic role of chlorine as an active promoter of the selective oxidation of ethylene to ethylene oxide in the presence of a silver-copper oxide hybrid nanocatalyst (AgCuO). Experimental kinetic studies combined with density functional theory (DFT) calculations provide insight into the influence that Ag/CuO-supported chlorine atoms have over the ethylene epoxidation reaction. Remarkably, the typically described indirect route via the formation of an oxametallacycle (OMC) is also accompanied by a direct route. Furthermore, the presence of chlorine seems to facilitate a more favorable adsorption energy for ethylene oxide (EO) than for acetaldehyde (AA), the main reaction by-product. As a result, complete oxidation of EO can be further prevented in the presence of this AgCuO hybrid heteronanostructure.

Live Cell Imaging of Spatiotemporal Ca2+ Fluctuation Responses to Anticancer Drugs.

Synthetic triterpenoids, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its derivatives are known to have potent anti-cancer and anti-inflammatory activities. The mechanisms of actions of CDDO and its derivatives as potential therapeutics remain elusive. Previous studies found that CDDO-Me triggers apoptosis by inducing extracellular Ca2+ influx followed by endoplasmic reticulum (ER)-derived vacuolation. Since Ca2+ activity in cells is dynamic and needs to be tracked in real time in living cells, we report a high-throughput and high-content imaging method to track CDDO-induced Ca2+ fluctuation in both ER and cytosol with MATLAB script for data analysis and visualization.

The Importance of Thermal Treatment on Wet-Kneaded Silica-Magnesia Catalyst and Lebedev Ethanol-to-Butadiene Process.

The Lebedev process, in which ethanol is catalytically converted into 1,3-butadiene, is an alternative process for the production of this commodity chemical. Silica-magnesia (SiO2-MgO) is a benchmark catalyst for the Lebedev process. Among the different preparation methods, the SiO2-MgO catalysts prepared by wet-kneading typically perform best owing to the surface magnesium silicates formed during wet-kneading. Although the thermal treatment is of pivotal importance as a last step in the catalyst preparation, the effect of the calcination temperature of the wet-kneaded SiO2-MgO on the Lebedev process has not been clarified yet. Here, we prepared and characterized in detail a series of wet-kneaded SiO2-MgO catalysts using varying calcination temperatures. We find that the thermal treatment largely influences the type of magnesium silicates, which have different catalytic properties. Our results suggest that the structurally ill-defined amorphous magnesium silicates and lizardite are responsible for the production of ethylene. Further, we argue that forsterite, which has been conventionally considered detrimental for the formation of ethylene, favors the formation of butadiene, especially when combined with stevensite.

Silver-Copper Oxide Heteronanostructures for the Plasmonic-Enhanced Photocatalytic Oxidation of N-Hexane in the Visible-NIR Range.

Volatile organic compounds (VOCs) are recognized as hazardous contributors to air pollution, precursors of multiple secondary byproducts, troposphere aerosols, and recognized contributors to respiratory and cancer-related issues in highly populated areas. Moreover, VOCs present in indoor environments represent a challenging issue that need to be addressed due to its increasing presence in nowadays society. Catalytic oxidation by noble metals represents the most effective but costly solution. The use of photocatalytic oxidation has become one of the most explored alternatives given the green and sustainable advantages of using solar light or low-consumption light emitting devices. Herein, we have tried to address the shortcomings of the most studied photocatalytic systems based on titania (TiO2) with limited response in the UV-range or alternatively the high recombination rates detected in other transition metal-based oxide systems. We have developed a silver-copper oxide heteronanostructure able to combine the plasmonic-enhanced properties of Ag nanostructures with the visible-light driven photoresponse of CuO nanoarchitectures. The entangled Ag-CuO heteronanostructure exhibits a broad absorption towards the visible-near infrared (NIR) range and achieves total photo-oxidation of n-hexane under irradiation with different light-emitting diodes (LEDs) specific wavelengths at temperatures below 180 °C and outperforming its thermal catalytic response or its silver-free CuO illuminated counterpart.

Preliminary experience in the management of brain and skull-base tumors with microwave ablation; feasibility guided by ultrasound, report from 23 cases.

BACKGROUND: In surgery involving brain tumors, the use of new tools or equipment that allows for better results and improvement in the quality of life of the patients is mandatory. Microwave ablation (MWA) is a technique that has been used effectively since 1994 in the management of different kinds of tumors. The authors present their surgical experience with 23 cases of brain and skull-base tumors using MWA technique. METHODS: In all, 23 cases diagnosed with brain and skull-base tumors are described; all of these were treated with MWA as unique technique as a complement to conventional microsurgical tumor resection. In all cases, ultrasound imaging guidance was used. A thin antenna (caliber 14.5; MedWaves) was positioned through ultrasound images to a central intratumoral area, and then energy was applied for 1-3 min until the temperature sensor in the proximal position of the antenna reached 80-100°C. Through transoperative Doppler ultrasound images and surgical microscopy, changes in the generated ablation were observed. The said ablation led to a decrease in intratumoral blood flow, and the adjacent vascular and cerebral structures were preserved. RESULTS: The application of MWA during brain surgery was regarded as safe in all cases, as no permanent additional neurological deficit was detected. Intratumoral vascular flow was also reduced and tumor resection was facilitated. Likewise, a reduction in tumor volume was noted, and in others in whom the ablation was applied as a single therapy, a progressive destruction of the tumor was observed. CONCLUSION: MWA can be a useful tool as a single therapy or as a complement to conventional techniques for the surgical resection of brain and skull-base tumors. It was a safe method in all cases, producing a decrease in intratumoral blood flow, and this procedure facilitates the microsurgical resection of the lesion.

Psychopathology and self-harm among incoming first-year students in six Mexican universities / Psicopatología y autolesiones en alumnos de nuevo ingreso en seis universidades mexicanas

Abstract: Objective: To estimate psychopathology and self-harm behavior of incoming first-year college students, socio-demographic correlates, service use and willingness to seek treatment. Materials and methods: 4 189 male and female incoming first-year students of six universities in four different states of Mexico responded to an online survey with a 79.3% response rate. Results: Almost one in three incoming students has experienced some type of psychopathology; however, only one in five has received treatment. Female, students who are older, whose parents are not married or deceased, and who have a non-heterosexual orientation, no religion or a non-Catholic/Christian religion have greater odds (1.18 - 1.99), whereas those who attend a private university and have a parent with some college education have lower odds (0.68 - 0.75) of experiencing any probable disorder. Conclusions: Substantial unmet need for mental health services combined with reported willingness to use university services suggests an opportunity for the detection, referral, and treatment of incoming students to promote a successful transition.

Resumen: Objetivo: Estimar psicopatologías y autolesiones en universitarios de nuevo ingreso, así como los correlatos sociodemográficos, el uso de servicios y la disposición para recibir tratamiento. Material y métodos: 4 189 estudiantes de nuevo ingreso de seis universidades en cuatro estados contestaron una encuesta en línea con una tasa de respuesta de 79.3%. Resultados: 32.5% han padecido psicopatologías en su vida, pero únicamente 19.5% han recibido tratamiento. Mujeres, estudiantes con una orientación no heterosexual, estudiantes de mayor edad, quienes tienen padres fallecidos o no casados, sin religión o con una religión no católica/cristiana tienen mayor probabilidad de presentar psicopatologías (RM= 1.18-1.99), mientras que aquellos de universidades privadas y cuyos padres tienen estudios universitarios tienen menor probabilidad (RM= 0.68-0.75). Conclusiones: La alta tasa de psicopatologías no tratadas combinada con la disposición reportada de recibir servicios a través de su universidad sugiere una oportunidad para la detección, canalización y tratamiento de alumnos de nuevo ingreso para promover una transición exitosa.

Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response.

Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m-chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib.

Aspergillosis of the central nervous system in a previously healthy patient that simulated Creutzfeldt-Jakob disease.

BACKGROUND: The presence of Aspergillus in the central nervous system (CNS) is rare in immunocompetent patients but not in immunocompromised patients who may have a more common infection. This article describes a case of an adult immunocompetent patient with a diagnosis of cerebral aspergillosis and with a clinical process of rapidly progressive dementia which simulated a Creutzfeldt-Jakob syndrome. CASE DESCRIPTION: A 34-year-old adult was previously healthy and had no medical history of any significance. The patient had suffered only facial trauma 8 months before admission. One month prior to admission, he showed rapidly progressing changes in his behavior and higher mental functions. He was admitted to the emergency room with an occipital headache with 2 months of history. By the time he arrived, he suffered from total disability and was prostrate. He was diagnosed with meningeal and demential syndrome in the process of being studied. After starting the diagnostic approach by investigating cerebrospinal fluid, a magnetic resonance of the skull, an electroencephalogram, a brain biopsy was indicated. The histopathological study reported the presence of the hyphae characteristics of Aspergillus. The patient died 7 days after the diagnosis. CONCLUSION: Cerebral aspergillosis is a common aggressive disease in immunosuppressed patients. However, the disease is rare in individuals with respected immunity and in individuals with neurological impairment and a rapid and progressive deterioration of mental functions. The suspected diagnosis should always be considered given its poor prognosis and the encouraging efficacy of antifungal treatment administered in a timely manner.

A Nanoarchitecture Based on Silver and Copper Oxide with an Exceptional Response in the Chlorine-Promoted Epoxidation of Ethylene.

The selective oxidation of ethylene to ethylene epoxide is highly challenging as a result of competing reaction pathways leading to the deep oxidation of both ethylene and ethylene oxide. Herein we present a novel catalyst based on silver and copper oxide with an excellent response in the selective oxidation pathway towards ethylene epoxide. The catalyst is composed of different silver nanostructures dispersed on a tubular copper oxide matrix. This type of hybrid nanoarchitecture seems to facilitate the accommodation of chlorine promoters, leading to high yields at low reaction temperatures. The stability after the addition of chlorine promoters implies a substantial improvement over the industrial practice: a single pretreatment step at ambient pressure suffices in contrast with the common practice of continuously feeding organochlorinated precursors during the reaction.

Hemimegalencephaly with Facial Congenital Infiltrating Lipomatosis in a Child.

We report an unusual case of hemimegalencephaly (HMG) associated with ipsilateral congenital-infiltrating lipomatosis of the face in a five-month-old boy. Hemimegalencephaly is a rare but unique malformation characterized by enlargement of all or parts of a cerebral hemisphere. The affected hemisphere may have focal or diffuse neuronal migration defects, with areas of polymicrogyria, pachygyria and heterotopia. Our aim was to investigate morphologic abnormalities occurring on the affected hemisphere by Magnetic Resonance Imaging (MRI), but some MRI findings were also noted outside of the affected hemicerebrum. There are a few case reports that have described various other abnormalities accompanying this condition, such as enlargement of ipsilateral brainstem, cerebellum and left lateral ventricle. MRI may be the most useful method demonstrating features of hemimegalencephaly with infiltrating lipomatosis of the face. However, studies using electroencephalogram (EEG) and brain single photon emission computerized tomography (SPECT) can show distinct variants of discharges and brain-perfusion anomalies.

Ventilación mecánica en el estado asmático en niños / Mechanical ventilation for status asmaticus in children

Se realizó un estudio retrospectivo de nuestra experiencia en el manejo de niños en estado asmático admitida a nuestra UCI, enfatizando aspectos de la ventilación mecánica. Durante el periodo de enero 1985 a diciembre 1989 hubo 56 admisiones que correspondian a 47 pacientes. Diez de ellos requirieron ventilación mecánica. El tiempo promedio de sintomatologia previo a la admisión fue de 28.9 horas en el grupo que requirio ventilación, comparado con 52.6 horas del grupo no ventilado. La droga usada previo a la institución de ventilación mecanica fue similar en ambos grupos, exepto por el uso mas frecuente de bicarbonato en la paciente ventilada (p menor que 0.05). La presion inspiratoria maxima usada en la paciente ventilada vario entre 20-40cm de agua y la PaCO2 se normalizo en un promedio de 10 horas despues de la institución de ventilación mecánica. Dos pacientes presentaron barotrauma en relación con la ventilación mecánica. Siete de diez pacientes tuvieron complicaciones relacionadas a la presencia del tubo endotraqueal. En comparación con otros centros, tenemos una mayor tasa de ventilación y menos valores de presión inspiratoria máxima

Ventilación mecánica en el estado asmático en niños / Mechanical ventilation in status asthmaticus in children

Se realizó un estudio retrospectivo de nuestra experiencia en el manejo de niños en estado asmático admitidos a nuestra UCI, enfatizando aspectos de la ventilación mecánica. Durante el período de Enero 1985 a Diciembre 1989 hubieron 56 admisiones que correspondían a 47 pacientes. Diez de ellos requirieron ventilación mecánica. El tiempo promedio de sintomatología previo a la admisión fue de 28.9 horas en el grupo que requirió ventilación, comparado con 52.6 horas del grupo no ventilado. La droga usada previo a la institución de ventilación mecánica fueron similares en ambos grupos, excepto por el uso más frecuente de bicarbonato en la paciente ventilada (p<0.05). La presión inspiratoria máxima usada en la paciente ventilada variaron entre 20*40 cm de agua, y la PaCO2 se normalizó en un promedio de 10 horas después de la institución de ventilación mecánica. Dos pacientes presentaron barotrauma en relación con la ventilación mecánica. Siete de Diez pacientes tuvieron complicaciones relacionadas a la presencia del tubo endotraqueal. En comparación con otros centros, tenemos una mayor tasa de ventilación y menos valores de presión inspiratorias máximas

Ventilación mecánica en la unidad de cuidados intensivos del instituto nacional de salud del niño / Mechanical ventilation in a pediatric intensive care unit

Decidimos revisar nuestra experiencia usando Ventilación mecánica (VM) en niños en la UCI del INSN (Hospital del Niño). Durante el período Abril 1989 * Marzo 1990 hubieron 210 pacientes ventilados mecanicamente, correspondiente al 56.75 por ciento de las admisiones a la UCI durante el mismo período. Las edades variaron de 14 horas a 15 años (x = 2.56 años). 155 niños fueron ventilados por razones de orden médico, mientras que 55 fueron quirúrgicos. La presión máxima inspiratoria (PIP) varió de 10*50 cm de agua (x = 25.22), mientras que la presión positiva al final de la espiración (PEEP), cuando fue utilizada, estuvo entre 2-19 cm de agua (x = 5.11). El tiempo de VM varió de 1 hora 35 minutos hasta 90 días (x = 149 h). Se observaron una o más complicaciones en 56 niños (26.7 por ciento); 37 tuvieron atelectasias, 30 infección respiratoria y 20 barotrauma. Los niveles de PIP y PEEP en los pacientes que presentaron barotrauma fueron significativamente mayores que en los que no lo presentaron (PIP 32.6 vs 24.5 cm de agua, p<0.001; PEEP 6.55 vs 3.74 cm de agua, p<0.001). Fallecieron 107 pacientes (50.95 por ciento). El presente reporte pretende servir de referencia para futuros estudios nacionales sobre VM en niños