MEK inhibitors lead to PDGFR pathway upregulation and sensitize tumors to RAF dimer inhibitors in NF1-deficient malignant peripheral nerve sheath tumor (MPNST).

PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive subtype of soft tissue sarcoma with a high propensity to metastasize and extremely limited treatment options. Loss of the RAS-GAP NF1 leads to sustained RAF/MEK/ERK signaling in MPNST. However, single-agent MEK inhibitors (MEKi) have failed to elicit a sustained inhibition of the MAPK signaling pathway in MPNST. EXPERIMENTAL DESIGN: We employed pharmacological, biochemical, and genetic perturbations of the receptor tyrosine kinase (RTK) and MAPK signaling pathway regulators to investigate the mechanisms of MEKi resistance and evaluated combination therapeutic strategies in various preclinical MPNST models in vitro and in vivo. RESULTS: Here, we report that MEKi treatment resistance in MPNST involves two adaptive pathways: direct transcriptional upregulation of the receptor tyrosine kinase (RTK) PDGFRß, and MEKi-induced increase in RAF dimer formation and activation of downstream signaling. While the pharmacological combination of MEKi with a PDGFRß specific inhibitor was more effective than treatment with MEKi alone, the combination of MEKi and RAF-dimer inhibitors led to a robust inhibition of the MAPK pathway signaling. This combination treatment was effective in vitro and in vivo, as demonstrated by the significant increase in drug synergism and its high effectiveness in decreasing MPNST viability. CONCLUSIONS: Our findings suggest that the combination of MEKi and PDGFR and/or RAF dimer inhibitors can overcome MEKi resistance and may serve as a novel targeted therapeutic strategy for NF1-deficient MPNST patients, which in turn could impact future clinical investigations for this patient population.

Transitioning from MODIS to VIIRS Global Water Reservoir Product.

Reservoirs play a crucial role in regulating water availability and enhancing water security. Here, we develop NASA's Visible Infrared Imaging Radiometer Suite (VIIRS) based Global Water Reservoir (GWR) product, consisting of measurements of reservoir area, elevation, storage, evaporation rate, and evaporation loss for 164 large global reservoirs. The dataset is available at 8-day and monthly temporal resolutions. Since the Moderate Resolution Imaging Spectroradiometer (MODIS) is close to the end of its life, we further evaluated the consistency between MODIS and VIIRS-based GWR to ensure continuity to the 20+ year MODIS GWR product. Independent assessment of VIIRS reservoir storage (8-day) retrievals against in-situ measurements shows an average of R2 = 0.84, RMSE = 0.47 km3, and NRMSE = 16.45%. The evaporation rate has an average of R2 = 0.56, RMSE = 1.32 mm/day, and NRMSE = 28.14%. Furthermore, results show good consistency (R2 ≥ 0.90) between the VIIRS and MODIS-based product components, confirming that long-term data continuity can be achieved. This dataset can provide valuable insights for long-term trend analysis, hydrological modeling, and understanding hydroclimatic extremes in the context of reservoirs.

Spent coffee grounds as feedstock for the production of biosurfactants and the improved recovery of melanoidins.

Spent coffee grounds (SCG) are wastes generated in high amounts worldwide. Their composition makes them a promising feedstock for biotechnological processes. Here we show that the production of the biosurfactant surfactin by submerged culture of a Bacillus subtilis strain growing on SCG is possible, reaching concentrations up to 8.8 mg/L when using SCG at 8.3 g/L in the medium. In addition, we report a synergy between the production of surfactin and the recovery of melanoidins, an added-value compound already present in SCG. More specifically, the concentration of melanoidins in the culture medium increased between 2.1 and 2.5 times thanks to the presence of the B. subtilis in the culture. Furthermore, we have observed a strong interaction between surfactin and melanoidin aggregates through dynamic light scattering measurements, and that both of them can be co-purified with an acid precipitation. We have also characterized the interfacial and antioxidant properties of the cell-free supernatant and surfactin extract, as well as the distribution of the congeners of the biosurfactant. Altogether, this work describes a promising approach to obtain biosurfactants and antioxidant molecules in a single operation, which can be used to design several new formulations of interest for bioremediation, amendment of soils, food and cosmetics.

Enhancing physicians' radiology diagnostics of COVID-19's effects on lung health by leveraging artificial intelligence.

Introduction: This study aimed to develop an individualized artificial intelligence model to help radiologists assess the severity of COVID-19's effects on patients' lung health. Methods: Data was collected from medical records of 1103 patients diagnosed with COVID-19 using RT- qPCR between March and June 2020, in Hospital Madrid-Group (HM-Group, Spain). By using Convolutional Neural Networks, we determine the effects of COVID-19 in terms of lung area, opacities, and pulmonary air density. We then combine these variables with age and sex in a regression model to assess the severity of these conditions with respect to fatality risk (death or ICU). Results: Our model can predict high effect with an AUC of 0.736. Finally, we compare the performance of the model with respect to six physicians' diagnosis, and test for improvements on physicians' performance when using the prediction algorithm. Discussion: We find that the algorithm outperforms physicians (39.5% less error), and thus, physicians can significantly benefit from the information provided by the algorithm by reducing error by almost 30%.

Análisis de los factores de riesgo para complicaciones en la colecistitis aguda litiásica. Deconstrucción de las Tokyo Guidelines / Risk factors for complications in acute calculous cholecystitis. Deconstruction of the Tokyo Guidelines

Introducción: Analizar los factores de riesgo de complicaciones para colecistitis aguda litiásica confrontándolos a las Tokyo Guidelines. Métodos: Estudio retrospectivo de 963 pacientes con colecistitis aguda durante 5 años. Se seleccionaron 725 pacientes con colecistitis aguda litiásica «pura», y analizaron 166 variables mediante regresión logística, incluyendo todos los factores de riesgo de las Tokyo Guidelines. Mediante el Propensity Score Matching, se seleccionaron subpoblaciones comparables de 75 pacientes y se analizaron las complicaciones según el tratamiento realizado (quirúrgico/no quirúrgico) y se utilizó el fallo en el rescate como indicador de calidad del tratamiento en la colecistitis aguda litiásica. Resultados: La mediana de edad fue de 69 años (RIQ 53-80). La mayoría de los pacientes fueron ASA II o III (85,1%). El 21% de las colecistitis fueron leves, el 39% moderadas y el 40% graves. Se colecistectomizó al 95% de los pacientes. El 43% de los pacientes se complicaron y la mortalidad fue del 3,6%. Los factores de riesgo independientes para complicaciones graves fueron ASA>II, tumor sólido sin metástasis e insuficiencia renal. El fallo en el rescate (8%) fue mayor en los no operados (32% vs. 7%; P=0,002). Tras realizar el Propensity Score Matching, la tasa de complicaciones graves fueron comparables entre operados y no operados (48,5% vs. 62,5%; P=0,21). Conclusiones: La colecistectomía precoz es el tratamiento preferente para la colecistitis aguda litiásica. Solo tres de los factores de las Tokyo Guidelines son variables independientes para predecir complicaciones graves. El fallo en el rescate es mayor en los pacientes no intervenidos quirúrgicamente. (AU)

Introduction: To challenge the risk factors described in Tokyo Guidelines in acute calculous cholecystitis. Methods: Retrospective single center cohort study with 963 patients with acute cholecystitis during a period of 5 years. Some 725 patients with a “pure” Acute calculous cholecystitis were selected. The analysis included 166 variables encompassing all risk factors described in Tokyo Guidelines. The Propensity Score Matching method selected two subgroups of patients with equal comorbidities, to compare the severe complications rate according to the initial treatment (Surgical vs. non-surgical). We analyzed the failure-to-rescue as a quality indicator in the treatment of acute calculous cholecystitis. Results: The median age was 69 years (IQR 53-80). 85.1% of the patients were ASA II or III. The grade of the acute calculous cholecystitis was mild in a 21%, moderate in 39% and severe in 40% of the patients. Cholecystectomy was performed in 95% of the patients. The overall complications rate was 43% and the mortality was 3.6%. The Logistic Regression model isolated 3 risk factor for severe complication: ASA>II, cancer without metastases and moderate to severe renal disease. The failure-to-rescue (8%) was higher in patients with non-surgical treatment (32% vs. 7%; P=.002). After Propensity Score Matching, the number of severe complications was similar between Surgical and Non-Surgical treatment groups (48.5% vs 62.5%; P=.21). Conclusions: The recommended treatment for acute calculous cholecystitis is the laparoscopic cholecystectomy. Only three risk factors from the Tokyo Guidelines list appeared as independent predictors of severe complications. The failure-to-rescue is higher in non-surgically treated patients. (AU)

Risk factors for complications in acute calculous cholecystitis. Deconstruction of the Tokyo Guidelines.

OBJECTIVE: To challenge the risk factors described in Tokyo Guidelines in Acute Calculous Cholecystitis. METHODS: Retrospective single center cohort study with 963 patients with Acute Cholecystitis during a period of 5 years. Some 725 patients with a "pure" Acute Calculous Cholecystitis were selected. The analysis included 166 variables encompassing all risk factors described in Tokyo Guidelines. The Propensity Score Matching method selected two subgroups of patients with equal comorbidities, to compare the severe complications rate according to the initial treatment (Surgical vs Non-Surgical). We analyzed the Failure-to-rescue as a quality indicator in the treatment of Acute Calculous Cholecystitis. RESULTS: the median age was 69 years (IQR 53-80). 85.1% of the patients were ASA II or III. The grade of the Acute Calculous Cholecystitis was mild in a 21%, moderate in 39% and severe in 40% of the patients. Cholecystectomy was performed in 95% of the patients. The overall complications rate was 43% and the mortality was 3.6%. The Logistic Regression model isolated 3 risk factor for severe complication: ASA > II, cancer without metastases and moderate to severe renal disease. The Failure-to-Rescue (8%) was higher in patients with non-surgical treatment (32% vs. 7%; P = 0.002). After Propensity Score Matching, the number of severe complications was similar between Surgical and Non-Surgical treatment groups (48.5% vs 62.5%; P = 0.21). CONCLUSIONS: the recommended treatment for Acute Calculous Cholecystitis is the Laparoscopic Cholecystectomy. Only three risk factors from the Tokyo Guidelines list appeared as independent predictors of severe complications. The failure-to-rescue is higher in non-surgically treated patients.

Remote consultations in primary care across low-, middle- and high-income countries: Implications for policy and care delivery.

The COVID-19 pandemic mandated a substantial switch in primary health care delivery from an in-person to a mainly remote telephone or video service. As the COVID-19 pandemic approaches its third year, limited progress appears to have been made in terms of policy development around consultation methods for the post-acute phase of the pandemic. In September 2020, the International Primary Care Respiratory Group convened a global panel of primary care clinicians - including family physicians, paediatricians, pharmacists, academics and patients - to consider the policy and health management implications of the move to remote consultations in the primary care setting. The group gave special consideration to how and how far remote consultations should be integrated into routine primary health care delivery. Remote consultations can be a useful alternative to in-person consultations in primary care not only in situations where there is a need for viral infection control but also for the routine delivery of chronic disease management. However, they may not be more time efficient for the clinician, and they can add to the workload and work-related stress for primary care practitioners if they remain the dominant consultation mode. Remote consultations are also less appropriate than in-person consultations for new disease diagnosis, dealing with multiple issues and providing complex care. Ensuring health care professionals have the appropriate skill set to effectively deliver remote consultations, administrative and/or IT support and appropriate reimbursement will be key to achieving optimal integration of remote consultations into routine clinical practice. Addressing digital access and digital literacy issues at a societal level will also be essential to ensure individuals have fair and equitable access to the internet and sufficient security for exchange of personal and health-related data.

Role of Innate and Adaptive Cytokines in the Survival of COVID-19 Patients.

SARS-CoV-2 is a new coronavirus characterized by a high infection and transmission capacity. A significant number of patients develop inadequate immune responses that produce massive releases of cytokines that compromise their survival. Soluble factors are clinically and pathologically relevant in COVID-19 survival but remain only partially characterized. The objective of this work was to simultaneously study 62 circulating soluble factors, including innate and adaptive cytokines and their soluble receptors, chemokines and growth and wound-healing/repair factors, in severe COVID-19 patients who survived compared to those with fatal outcomes. Serum samples were obtained from 286 COVID-19 patients and 40 healthy controls. The 62 circulating soluble factors were quantified using a Luminex Milliplex assay. Results. The patients who survived had decreased levels of the following 30 soluble factors of the 62 studied compared to those with fatal outcomes, therefore, these decreases were observed for cytokines and receptors predominantly produced by the innate immune system-IL-1α, IL-1α, IL-18, IL-15, IL-12p40, IL-6, IL-27, IL-1Ra, IL-1RI, IL-1RII, TNFα, TGFα, IL-10, sRAGE, sTNF-RI and sTNF-RII-for the chemokines IL-8, IP-10, MCP-1, MCP-3, MIG and fractalkine; for the growth factors M-CSF and the soluble receptor sIL2Ra; for the cytokines involved in the adaptive immune system IFNγ, IL-17 and sIL-4R; and for the wound-repair factor FGF2. On the other hand, the patients who survived had elevated levels of the soluble factors TNFß, sCD40L, MDC, RANTES, G-CSF, GM-CSF, EGF, PDGFAA and PDGFABBB compared to those who died. Conclusions. Increases in the circulating levels of the sCD40L cytokine; MDC and RANTES chemokines; the G-CSF and GM-CSF growth factors, EGF, PDGFAA and PDGFABBB; and tissue-repair factors are strongly associated with survival. By contrast, large increases in IL-15, IL-6, IL-18, IL-27 and IL-10; the sIL-1RI, sIL1RII and sTNF-RII receptors; the MCP3, IL-8, MIG and IP-10 chemokines; the M-CSF and sIL-2Ra growth factors; and the wound-healing factor FGF2 favor fatal outcomes of the disease.

PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry.

Polycomb repressive complex 2 (PRC2) has oncogenic and tumor-suppressive roles in cancer. There is clinical success of targeting this complex in PRC2-dependent cancers, but an unmet therapeutic need exists in PRC2-loss cancer. PRC2-inactivating mutations are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma with poor prognosis and no effective targeted therapy. Through RNAi screening in MPNST, we found that PRC2 inactivation increases sensitivity to genetic or small-molecule inhibition of DNA methyltransferase 1 (DNMT1), which results in enhanced cytotoxicity and antitumor response. Mechanistically, PRC2 inactivation amplifies DNMT inhibitor-mediated expression of retrotransposons, subsequent viral mimicry response, and robust cell death in part through a protein kinase R (PKR)-dependent double-stranded RNA sensor. Collectively, our observations posit DNA methylation as a safeguard against antitumorigenic cell-fate decisions in PRC2-loss cancer to promote cancer pathogenesis, which can be therapeutically exploited by DNMT1-targeted therapy. SIGNIFICANCE: PRC2 inactivation drives oncogenesis in various cancers, but therapeutically targeting PRC2 loss has remained challenging. Here we show that PRC2-inactivating mutations set up a tumor context-specific liability for therapeutic intervention via DNMT1 inhibitors, which leads to innate immune signaling mediated by sensing of derepressed retrotransposons and accompanied by enhanced cytotoxicity. See related commentary by Guil and Esteller, p. 2020. This article is highlighted in the In This Issue feature, p. 2007.

Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses.

Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with substantial T cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the polycomb-repressive complex 2 (PRC2) core components embryonic ectoderm development (EED) or suppressor of zeste 12 homolog (SUZ12), a prevalent genetic event in malignant peripheral nerve sheath tumors (MPNSTs) and sporadically in other cancers, drove a context-dependent immune-desert TME. PRC2 inactivation reprogramed the chromatin landscape that led to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., IFN-γ signaling) to PRC2-regulated developmental and cellular differentiation transcriptional programs. Further, PRC2 inactivation led to diminished tumor immune infiltrates through reduced chemokine production and impaired antigen presentation and T cell priming, resulting in primary resistance to ICB. Intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) enhanced tumor immune infiltrates and sensitized PRC2-loss tumors to ICB. Our results identify molecular mechanisms of PRC2 inactivation-mediated, context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.

Atypical double colorectal metastasis: spleen and uterus.

Oligometastatic disease is a relatively new concept that refers to an intermediate stage between disseminated and localized cancer. Most frequent locations for colorectal metastasis are lung and liver. We present an a typical case of an 85-year-old woman who was diagnosed with a low-grade adenocarcinoma in left colon; she underwent a left laparoscopic hemicolectomy which resulted in a stage IIIb. After 24 months of follow-up, an increase of carcinoembryonic antigen (CEA) leads to the diagnosis of two metastatic lesions in two uncommon locations: spleen and myometrium. Stepwise surgical resection of both lesions was performed without complications. Spleen and uterus are organs that are rarely affected in colorectal cancer, the affection of both organs being even more infrequent. Despite the atypicality, surgical treatment is a valid strategy in this case of oligometastatic disease, which enables the disease-free survival of the patients.

Tracking COVID-19 urban activity changes in the Middle East from nighttime lights.

In response to the COVID-19 pandemic, governments around the world have enacted widespread physical distancing measures to prevent and control virus transmission. Quantitative, spatially-disaggregated information about the population-scale shifts in activity that have resulted from these measures is extremely scarce, particularly for regions outside of Europe and the US. Public health institutions often must make decisions about control measures with limited region-specific data about how they will affect societal behavior, patterns of exposure, and infection outcomes. The Visible Infrared Imaging Radiometer Suite Day/Night Band (VIIRS DNB), a new-generation space-borne low-light imager, has the potential to track changes in human activity, but the capability has not yet been applied to a cross-country analysis of COVID-19 responses. Here, we examine multi-year (2015-2020) daily time-series data derived from NASA's Black Marble VIIRS nighttime lights product (VNP46A2) covering 584 urban areas, in 17 countries in the Middle East to understand how communities have adhered to COVID-19 measures in the first 4 months of the pandemic. Nighttime lights capture the onset of national curfews and lockdowns well, but also expose the inconsistent response to control measures both across and within countries. In conflict-afflicted countries, low adherence to lockdowns and curfews was observed, highlighting the compound health and security threats that fragile states face. Our findings show how satellite measurements can aid in assessing the public response to physical distancing policies and the socio-cultural factors that shape their success, especially in fragile and data-sparse regions.

Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer.

Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.

A framework for research on recurrent acute disasters.

Disaster science examines the causes, behaviors, and consequences of hazardous events, from hurricanes to wildfires, flooding, and major industrial accidents. Individual disasters are recurring more frequently and with greater intensity. Recurrent acute disasters (RADs) are sequential disasters that affect a specific locale over time. While disaster science has matured in recent years, understanding of the distinctive characteristics of RADs varies by discipline and lacks predictive power. A theoretical framework is presented by borrowing in part from mathematical topology and disturbance ecology. The recurrent disasters affecting Puerto Rico 2017-2020 are examined as a case example to test the framework. A key variable is the complex characteristics of legacy conditions created by one disaster that influence the effects of subsequent disasters. Substantial improvements in disaster response, recovery, and preparedness can be gained by adopting a RAD-based approach.

Artificial light at night: an underappreciated effect on phenology of deciduous woody plants.

Artificial light at night (ALAN), an increasing anthropogenic driver, is widespread and shows rapid expansion with potential adverse impact on the terrestrial ecosystem. However, whether and to what extent does ALAN affect plant phenology, a critical factor influencing the timing of terrestrial ecosystem processes, remains unexplored due to limited ALAN observation. Here, we used the Black Marble ALAN product and phenology observations from USA National Phenology Network to investigate the impact of ALAN on deciduous woody plants phenology in the conterminous United States. We found that (1) ALAN significantly advanced the date of breaking leaf buds by 8.9 ± 6.9 days (mean ± SD) and delayed the coloring of leaves by 6.0 ± 11.9 days on average; (2) the magnitude of phenological changes was significantly correlated with the intensity of ALAN (P < 0.001); and (3) there was an interaction between ALAN and temperature on the coloring of leaves, but not on breaking leaf buds. We further showed that under future climate warming scenarios, ALAN will accelerate the advance in breaking leaf buds but exert a more complex effect on the coloring of leaves. This study suggests intensified ALAN may have far-reaching but underappreciated consequences in disrupting key ecosystem functions and services, which requires an interdisciplinary approach to investigate. Developing lighting strategies that minimize the impact of ALAN on ecosystems, especially those embedded and surrounding major cities, is challenging but must be pursued.

Impact of the Innate Inflammatory Response on ICU Admission and Death in Hospitalized Patients with COVID-19.

OBJECTIVE: To describe the capacity of a broad spectrum of cytokines and growth factors to predict ICU admission and/or death in patients with severe COVID-19. DESIGN: An observational, analytical, retrospective cohort study with longitudinal follow-up. SETTING: Hospital Universitario Príncipe de Asturias (HUPA). PARTICIPANTS: 287 patients diagnosed with COVID-19 admitted to our hospital from 24 March to 8 May 2020, followed until 31 August 2020. MAIN OUTCOME MEASURES: Profiles of immune response (IR) mediators were determined using the Luminex Multiplex technique in hospitalized patients within six days of admission by examining serum levels of 62 soluble molecules classified into the three groups: adaptive IR-related cytokines (n = 19), innate inflammatory IR-related cytokines (n = 27), and growth factors (n = 16). RESULTS: A statistically robust link with ICU admission and/or death was detected for increased serum levels of interleukin (IL)-6, IL-15, soluble (s) RAGE, IP10, MCP3, sIL1RII, IL-8, GCSF and MCSF and IL-10. The greatest prognostic value was observed for the marker combination IL-10, IL-6 and GCSF. CONCLUSIONS: When severe COVID-19 progresses to ICU admission and/or death there is a marked increase in serum levels of several cytokines and chemokines, mainly related to the patient's inflammatory IR. Serum levels of IL-10, IL-6 and GCSF were most prognostic of the outcome measure.