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Background Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of breast cancers (BC). Early generation PI3Kα inhibitors target both wild-type (WT) and mutant PI3Kα and, as a result, their efficacy may be limited by on-target WT PI3Kα-mediated toxicities, including hyperglycemia, skin rash, and diarrhea. LOXO-783 is an oral, potent and highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor that is currently in phase 1 testing. Preclinically, LOXO-783 as a single agent is highly selective for PI3Kα H1047R over WT PI3Kα and other PI3K isoforms, and induces single-agent tumor regressions in ER+, HER2- PI3Kα H1047R-mutant breast cancer models without causing hyperglycemia or increases in plasma insulin/C-peptide. LOXO-783 also demonstrates brain penetration in vivo with dose-dependent tumor growth inhibition in brain metastasis models. Here we report the efficacy of LOXO-783 with SOC treatments in preclinical breast cancer models. Methods Cell proliferation assays and in vivo studies to evaluate combination effects were performed in various PI3Ka H1047R mutant HR+, HER2- and triple negative breast cancer models. For each combination in vitro, a combination index (CI) based on the Loewe Additivity Method was calculated (CI>2 antagonism, 0.5>CI< 2 additivity, CI< 0.5 synergy). For the in vivo studies, the Bliss Independence Method was used to evaluate the statistical significance of the combination effects. Results Combining LOXO-783 with either fulvestrant (FUL; CI at 50% inhibition = 0.28) or imlunestrant (CI at 50% inhibition = 0.43) showed increased efficacy in cell proliferation assays using the HR+, HER2-, PI3Kα H1047R-mutant T47D model. LOXO-783 also demonstrated an additive effect in combination with these endocrine therapies in vivo. Similar results were observed in a T47D model engineered to express ESR1 D538G, as well as in an HR+, HER2- PI3Kα double in-cis mutant model (H1047R/D350G) also harboring ESR1 D538G and derived from a patient who had progressed on prior letrozole plus taselisib. Moreover, LOXO-783 plus abemaciclib demonstrated an additive effect in vitro (CI at 50% inhibition = 0.61), and in T47D xenograft and PDX models in vivo. Combinations of LOXO-783 with abemaciclib plus imlunestrant resulted in a mean tumor regression of –48.1%; LOXO-783 with abemaciclib plus FUL showed mean tumor regression of –43.9% in T47D xenografts. Similar efficacy was not observed in the absence of LOXO-783 (mean tumor regression was –7.3% with abemaciclib plus imlunestrant, and 3.2% with abemaciclib plus FUL). We observed comparable results in PDX models. These data collectively demonstrate the additive effect of LOXO-783 with SOC treatments. Extending these studies to additional treatment settings, LOXO-783 was similarly efficacious as a single agent in abemaciclib-resistant and abemaciclib/FUL double-resistant models, and was additive in combination with paclitaxel in a triple negative breast cancer model in vitro and in vivo. Conclusions LOXO-783 shows additive effects when combined with SOC in breast cancers harboring the PI3Kα H1047R-mutation (as single or double in-cis mutations) in both HR+ and triple negative settings. LOXO-783 is also efficacious in ESR1 mutant as well as in abemaciclib and abemaciclib/FUL double-resistant models. A phase 1 trial of LOXO-783 alone or in combination with anticancer therapies is ongoing (PIKASSO-01; NCT05307705). Citation Format: Loredana Puca, Michele S. Dowless, Carmen M. Perez-Ferreiro, Maria Jesus Ortiz-Ruiz, Gregory P. Donoho, Andrew Capen, Lysiane Huber, Sarah M. Bogner, Dongling Fei, Jason R. Manro, Chun Ping Yu, Wei Guo Xu, Rui Wang, Shuang Chen, Mark A. Hicks, Parisa Zolfaghari, Andrew Faber, Raymond Gilmour, Monica D. Ramstetter, Matthew T. Chang, Maria Jose Lallena, Xuequian Gong, David M. Hyman, Lillian M. Smyth, Barbara J. Brandhuber, Barry S. Taylor, Anke Klippel. LOXO-783: A potent, highly mutant selective and brain-penetrant allosteric PI3Kα H1047R inhibitor in combination with standard of care (SOC) treatments in preclinical PI3Kα H1047R-mutant breast cancer models [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-02.

Indoor low-frequency noise levels due to road traffic has been modelled for facade examples consisting of a lightweight steel facade, a concrete facade and two types of windows. Possible audibility of heavy vehicles passing by has been investigated as well as the dependence of the exposure level on driving speed and distance to road. The results show that pass-by events may be audible at low frequencies for cases complying with building standards and noise guideline values exemplified by Swedish regulation. Moreover, the A-weighted levels may be dominated by low frequency noise, and the frequency of occurrence of pass-by traffic noise events may be sufficiently high to create disturbance for typical traffic situations. Furthermore, it is shown that the contribution of pass-by events to the equivalent level indoors may increase when the driving speed is lowered.

Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This study reports safety and efficacy among women treated with repeat BCS and reRT.Patients who underwent repeat BCS followed by RT from 2015 to 2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan-Meier estimates were used to evaluate overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LR-RFS).Sixty-six patients were reviewed with median follow-up of 16 months (range: 3-60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5 Gy BID; 27% with 1.8 Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2 Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%.In this series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens at a median follow up of 16 months. Longer follow up is required.

Radiotherapy omission is increasingly considered for selected patients with early-stage breast cancer. However, with emerging data on the safety and efficacy of radiotherapy de-escalation with partial breast irradiation and accelerated treatment regimens for low-risk breast cancer, it is necessary to move beyond an all-or-nothing approach. Here, we review existing data for radiotherapy omission, including the use of age, tumor subtype, and multigene profiling assays for selecting low-risk patients for whom omission is a reasonable strategy. We review data for de-escalated radiotherapy, including partial breast irradiation and acceleration of treatment time, emphasizing these regimens’ decreasing biological and financial toxicities. Lastly, we review evidence of omission of endocrine therapy. We emphasize ongoing research to define patient selection, treatment delivery, and toxicity outcomes for de-escalated adjuvant therapies better and highlight future directions.

Drug resistance is one of the major factors associated with poor outcome of cancer patients. Treatment of Ewing sarcoma (EwS), an aggressive neoplasm mainly affecting children, adolescents and young adults, is associated with therapy failure and tumor relapse in 30-80% of the cases. Thus, it supports the need to explore the mechanisms modulating drug activity. Here, we describe a novel mechanism of drug sensitivity based on the role of EWS::FLI1 in R-loop metabolism. Our results demonstrate that EWS::FLI1 promotes R-loop formation favoring the interaction between DHX9 and elongating RNA polymerase II. In addition, we discovered that EWS::FLI1 kidnaps DHX9 preventing the resolution of TOP1 poisoning-associated R-loops. Our findings indicate that R-loops accumulation promotes replicative stress, genome instability and cell sensitivity to SN-38. Collectively, these results uncover a novel mechanism behind EwS sensitivity to genotoxic agents, with relevant implications for EwS treatment.

Measurements of acid volatile sulphide (AVS) and simultaneously extracted metals (SEM) in sediments are used to assess the toxicity of metals to native benthic organisms. The AVS is obtained from the sulphides contained in the sediments by addition of acid and the SEM are the metals extracted during the AVS treatment. The AVS/SEM method reflects a more precise estimation of sediment toxicity to benthic organisms than "total" metal values (cadmium, copper, lead, nickel and zinc) by measuring a "bioavailable" fraction of the metals present. Sediment toxicity is assessed by calculating the sum of the SEM (µmol/g dry weight) divided by the AVS concentration (in the same units): a ratio less than or equal to 1 indicates that the metals in the sediment are not bioavailable, while a ratio greater than 1 indicates that the metals are bioavailable.In this case, they are applied to soils containing mining waste and marine sediments that were buried under these inputs in Portman Bay (SE Spain) and compared with the values obtained from the ecotoxicity tests used: microtox, ostracodes and gambarus for sediments and phytotoxicity tests for topsoil samples.The results confirm the ecotoxic characteristics of some of the samples evaluated and also allow an approximation to be made of the impact that neighbouring materials may have if subjected to AMD, when there is intense precipitation and the waters of the wadis reach the bay with the runoff from the neighbouring mining areas.

In order to predict the future behaviour of technosols designed for the remediation of sites contaminated with mining waste, a pilot experiment was carried out in containers under an enclosed building.One-metre cubic polyvinyl chloride (PVC) containers were used and filled with soil of the different types that are abundant on the site. Four soil types were selected with different textures (sandy to silty-clay), different mineralogy and different PTE content. Soil mixtures were also prepared with limestone filler at different proportions (30, 40 and 50 %).These containers were subjected to a humidity and drying process, simulating the rainfall conditions that the site receives as an average annual value, in 10 successive cycles, maintaining the experience for 4 years. The drains obtained were analysed and their corresponding crystallised phases were obtained and characterised by XRD and electron microscopy. The metals determined were Fe, Cd, Cu, Pb, As and Zn.This experiment allows us to differentiate the behaviour of the selected soils with respect to humidity, since the untreated soils with a clayey loam texture are AMD producers, with very low pH and a high mobilisation of metals. In contrast, sandy textured soils and soils containing 30 % or more limestone filler have a pH close to 7 and small metal contents close to the limit of quantification.Efflorescences are more abundant in those leachates rich in Zn and Fe, being copiapite, hexahydrite, bianchite and gypsum the main soluble phases associated with these leachates. Finally, the percolates with a higher salt load correspond to the third percolation carried out approximately nine months after the start of the experiment.

Purpose:Endoglin (ENG; CD105) is a coreceptor of the TGFβ family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFβ, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease.Experimental Design:We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody–drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma.Results:Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed in vitro. Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line–derived xenografts and patient-derived xenografts in a dose-dependent manner.Conclusions:Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.

Supplementary Material & Methods, Figure Legends and Tables

Supplementary Figures

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) widely used as an immunosuppressant in transplant patients. In transplantation setting, several recommendations for therapeutic drug monitoring are available, due to potential drug-drug interactions with chronic medication, which can affect everolimus pharmacokinetic profile. Everolimus is also used in breast, neuroendocrine and renal cancer, at higher doses than in transplantation and without systematic drug monitoring requirement. We present a case-report of a 72years-old woman with epilepsy history to whom everolimus 10mg/daily was prescribed as third line of treatment for renal cell carcinoma. The patient´s chronic medication was checked by the outpatient hospital pharmacist before initiating treatment. As a result, two major interactions with inducers of CYP3A4 metabolism as carbamazepine and phenytoin were detected. Since trough plasma concentration of everolimus could be affected, by these pharmacokinetic interactions,a therapeutic drug monitoring of everolimus was proposed. Based on the literature, Cmin plasma concentration (Cminss) of everolimus over 10ng/ml is associated with better response to treatment and progression free survival. During the oncologist follow-up visit and according to pharmaceutical recommendations, everolimus dosage was increased to 10mg every 12 hours. In the following determinations of trough plasma everolimus concentration, Cmin grow up from 3.7ng/ml to 10.8ng/mL. Depending on the CYP3A4 induction capacity and potency of the drug/s administered concomitant to everolimus and how many of them can potentially interact with it, therapeutic everolimus monitoring would be advisable in order to adjust dosage if required to prevent underexposure.

In this paper, we review the social determinants of health in older adults and their complex interrelationship with medical diseases. Also, we provide recommendations to address these determinants in the integrated healthcare plan. The social determinants in older adults and its influence in health outcomes have been studied for decades. There is solid evidence for the interrelationship between social factors and the health of individuals and populations; however, these studies are unable to define their complex interrelatedness. Health is quite variable and depends on multiple biological and social factors such as genetics, country of origin, migrant status, etc. On the other hand, health status can affect social factors such as job or education. Addressing social determinants of health in the integrated healthcare plan is important for improving health outcomes and decreasing existing disparities in older adult health. We recommend a person-centered approach in which individualized interventions should be adopted by organizations to improve the health status of older adults at the national and global level. Some of our practical recommendations to better address the social determinants of health in clinical practice are EHR documentation strategies, screening tools, and the development of linkages to the world outside of the clinic and health system, including social services, community activities, collaborative work, and roles for insurance companies.

Psychosocial stress has profound effects on the body, including the peripheral immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3,4,5, the underlying mechanisms are not well understood. Here we show that a peripheral myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is elevated in serum of subjects with MDD as well as in stress-susceptible (SUS) mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), thereby altering social behaviour. Using a combination of mass cytometry and single-cell RNA-sequencing, we performed high-dimensional phenotyping of immune cells in circulation and brain and demonstrate that peripheral monocytes are strongly affected by stress. Both peripheral and brain-infiltrating monocytes of SUS mice showed increased Mmp8 expression following CSDS. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Objetivo. Establecer el efecto de las medidas morfométricas y productivas sobre los parámetros reproductivos: número de partos e intervalo entre partos en hembras Romosinuano (ROMO) y Costeño con Cuernos (CCC) bajo las condiciones agroclimáticas del Caribe húmedo colombiano. Materiales y métodos. Se utilizaron 408 vacas entre las razas ROMO (250) y CCC (158) se tomaron las medidas morfométricas de: amplitud del isquion (ADI), amplitud de cadera (ADC), altura del sacro (ADS), altura de la cruz (ADLC), así como el peso vivo, peso primer parto (PPP), peso último parto (PUP), condición corporal (CC), y los parámetros reproductivos como el número de partos e intervalos entre partos (IEP). Las diferencias entre los parámetros morfométricos y reproductivos por raza se establecieron por análisis de varianza. Las relaciones entre las variables morfométricas y reproductivas se analizaron a través correlaciones canónicas. Resultados. El análisis de varianza mostró diferencias estadísticamente significativas (p

Purpose: Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This multi-institutional study reports safety and efficacy among women treated with repeat BCS and reRT. Methods and Materials: Patients who underwent repeat BCS followed by RT from 2015–2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan Meier estimates were used to evaluate overall survival (OS), distant metastasis free survival (DMFS) and locoregional recurrence-free survival (LR-RFS). Results: Sixty-six patients were reviewed with median follow-up of 16 months (range: 3–60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5Gy BID; 27% with 1.8Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%. Conclusion: In this multi-institutional series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens.

The purpose of this study is to systematically review data pertaining to breast cancer and radiation-induced skin reactions in patients with skin of color (SOC), as well as data pertaining to objective measurements of skin pigmentation in the assessment of radiation dermatitis (RD).We conducted a systematic review utilizing MEDLINE electronic databases to identify published studies until August 2022. Key inclusion criteria included studies that described RD in breast cancer with data pertaining to skin of color and/or characterization of pigmentation changes after radiation.We identified 17 prospective cohort studies, 7 cross-sectional studies, 5 retrospective studies and 4 randomized controlled trials. Prospective cohort and retrospective series demonstrate worse RD in African American (AA) patients using subjective physician-graded scales. There is more limited data in patients representing other non-White racial subgroups with SOC. 2 studies utilize patient reported outcomes and 15 studies utilize objective methods to characterize pigmentation change after radiation. There are no prospective and randomized studies that objectively describe pigmentation changes with radiotherapy in SOC.AA patients appear to have worse RD outcomes, though this is not uniformly observed across all studies. There are no studies that describe objective measures of RD and include baseline skin pigmentation as a variable, limiting the ability to draw uniform conclusions on the rate and impact of RD in SOC. We highlight the importance of objectively characterizing SOC and pigmentation changes before, during and after radiotherapy to understand the incidence and severity of RD in SOC.

Maize is one of the three worldwide cereal crops with the most outstanding production; however, its postharvest losses range from 2 to 40% due to inadequate harvesting, drying, and storage technologies. This study focuses on the Instant Controlled Pressure Drop technology (DIC) effect on maize kernels’ drying and rehydration kinetics. In total, 19 different DIC treatments were carried out on maize kernels (~25% d.b.). The DIC parameters studied were steam pressure (0.1 to 0.4 MPa) and treatment time (10 to 90 s). After DIC treatment, drying kinetics were carried out by Convective Air Drying (CAD) at 50 °C and 0.4 ms−1 airflow. Rehydration kinetics and Water Holding Capacity (WHC) were evaluated at 20 °C. In comparison to CAD samples, DIC (0.4 MPa and 90 s) reduced the drying time from 180 min to ~108 min. Additionally, regarding the rehydration and WHC results, DIC achieved the same moisture content in only 3.5 min that controls achieved after 1 h of rehydration (0.40 g H2O/g dry matter). Moreover, DIC (0.4 MPa and nine cycles of 10 s) increased the WHC 2.3 times compared to the control. In this way, DIC could be a postharvest technology to improve maize kernels’ drying operations and functional properties.

Understanding RNA structure has become critical in the study of RNA in their roles as mediators of biological processes. To aid in these studies, computational algorithms that utilize thermodynamics have been developed to predict RNA secondary structure. Due to the importance of intermolecular interactions, the algorithms have been expanded to determine and predict RNA-RNA hybridization. This chapter discusses popular webservers with the tools for RNA secondary structure prediction, RNA-RNA hybridization, and design. We address key features that distinguish common-functioning programs and their purposes for the interests of the user. Ultimately, we hope this review elucidates web-based tools researchers may take advantage of in their investigations of RNA structure and function.

Despite the biological and therapeutic relevance of CDK4/6 for the treatment of HR+, HER2- advanced breast cancer, the detailed mode of action of CDK4/6 inhibitors is not completely understood. Of particular interest, phosphorylation of CDK4 at T172 (pT172) is critical for generating the active conformation, yet no such crystal structure has been reported to date. We describe here the x-ray structure of active CDK4-cyclin D3 bound to the CDK4/6 inhibitor abemaciclib and discuss the key aspects of the catalytically-competent complex. Furthermore, the effect of CDK4/6 inhibitors on CDK4 T172 phosphorylation has not been explored, despite its role as a potential biomarker of CDK4/6 inhibitor response. We show mechanistically that CDK4/6i stabilize primed (pT172) CDK4-cyclin D complex and selectively displace p21 in responsive tumor cells. Stabilization of active CDK4-cyclin D1 complex can lead to pathway reactivation following alternate dosing regimen. Consequently, sustained binding of abemaciclib to CDK4 leads to potent cell cycle inhibition in breast cancer cell lines and prevents rebound activation of downstream signaling. Overall, our study provides key insights demonstrating that prolonged treatment with CDK4/6 inhibitors and composition of the CDK4/6-cyclin D complex are both critical determinants of abemaciclib efficacy, with implications for this class of anticancer therapy.

Background: Chest-to-arm (CTA) tunneling technique has been described recently as an alternative option to exit site of the catheter in the infraclavicular area. Method: We report our experience with ultrasound-guided centrally inserted central catheters (CICCs) placed using CTA tunneling in six neonates. All central venous catheters were positioned with ultrasound guidance and real-time tip location. Results: There were no insertion-related complications; all devices were correctly positioned at the first attempt. During the follow-up, we found no catheter-related thrombosis, infections, or catheter malfunction. No tip position-related complications. Only one case of secondary malposition was reported. Conclusion: In our experience, the CTA tunneling technique is reliable, safe, and feasible in the neonate even from the first hours of life, as well as for preterm newborns; it could be a valid alternative to the usual exit site.

Vasculogenic Mimicry (VM) refers to the capacity to form a blood network from aggressive cancer cells in an independent way of endothelial cells, to provide nutrients and oxygen leading to enhanced microenvironment complexity and treatment failure. In a previous study, we demonstrated that VE-Cadherin and its phosphorylation at Y658 modulated kaiso-dependent gene expression (CCND1 and Wnt 11) through a pathway involving Focal Adhesion kinase (FAK). In the present research, using a proteomic approach, we have found that β-catenin/TCF-4 is associated with nuclear VE-cadherin and enhances the capacity of malignant melanoma cells to undergo VM in cooperation with VE-Cadherin; in addition, preventing the phosphorylation of Y658 of VE-cadherin upon FAK disabling resulted in VE-Cadherin/β-catenin complex dissociation, increased β-catenin degradation while reducing TCF-4-dependent genes transcription (C-Myc and Twist-1). Uveal melanoma cells knockout for VE-Cadherin loses β-catenin expression while the rescue of VE-Cadherin (but not of the phosphorylation defective VE-Cadherin Y658F mutant) permits stabilization of β-catenin and tumor growth reduction in vivo experiments. In vivo, the concomitant treatment with the FAK inhibitor PF-271 and the anti-angiogenic agent bevacizumab leads to a strong reduction in tumor growth concerning the single treatment. In conclusion, the anomalous expression of VE-Cadherin in metastatic melanoma cells (from both uveal and cutaneous origins), together with its permanent phosphorylation at Y658, favors the induction of the aggressive VM phenotype through the cooperation of β-catenin with VE-Cadherin and by enhancing TCF-4 genes-dependent transcription.

One remarkable dynamic cell structure is the region between the endoplasmic reticulum (ER) and the mitochondria, termed the mitochondria-associated membranes (MAM). MAMs carry out different cellular functions such as Ca

Significance Thirty to fifty percent of depressed individuals are unresponsive to commonly prescribed antidepressant treatments, suggesting that biological mechanisms, such as stress-induced inflammation and blood vessel dysfunction, remain untreated. The blood–brain barrier is the ultimate frontier between the brain and harmful toxins or inflammatory signals circulating in the blood. Depression and vulnerability to chronic social stress are associated with loss of this barrier integrity; however, the mechanisms involved remain poorly understood. Identification of adaptations leading to resilience under stressful conditions could help develop novel treatments. Here we combined behavioral, pharmacological, and cell-specific gene profiling experiments in mice with epigenetic, molecular, and anatomical analysis of human samples to unravel mechanisms with therapeutic potential to protect the brain and promote resilience., Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

The solubility and hydrolysis of U(VI) were investigated in 0.10–5.6 m NaCl solutions with 4 ≤ pHm ≤ 14.3 (pHm = −log [H+]) at T = 25, 55 and 80 °C. Batch experiments were conducted under Ar atmosphere in the absence of carbonate. Solubility was studied from undersaturation conditions using UO3 · 2H2O(cr) and Na2U2O7 · H2O(cr) solid phases, equilibrated in acidic (4 ≤ pHm ≤ 6) and alkaline (8.2 ≤ pHm ≤ 14.3) NaCl solutions, respectively. Solid phases were previously tempered in solution at T = 80 °C to avoid changes in the crystallinity of the solid phase in the course of the solubility experiments. Starting materials and solid phases isolated at the end of the solubility experiments were characterized by powder XRD, SEM-EDS, TRLFS and quantitative chemical analysis. The enthalpy of dissolution of Na2U2O7 · H2O(cr) at 25–80 °C was measured independently by means of solution-drop calorimetry. Solid phase characterization indicates the transformation of UO3 · 2H2O(cr) into a sodium uranate-like phase with a molar ratio Na:U ≈ 0.4–0.5 in acidic solutions with [NaCl] ≥ 0.51 m at T = 80 °C. In contrast, Na2U2O7 · H2O(cr) equilibrated in alkaline NaCl solutions remains unaltered within the investigated pHm, NaCl concentration and temperature range. The solubility of Na2U2O7 · H2O(cr) in the alkaline pHm-range is noticeably enhanced at T = 55 and 80 °C relative to T = 25 °C. Combined results from solubility and calorimetric experiments indicate that this effect results from the increased acidity of water at elevated temperature, together with an enhanced hydrolysis of U(VI) and a minor contribution due to a decreased stability of Na2U2O7 · H2O(cr) under these experimental conditions. A thermodynamic model describing the solubility and hydrolysis equilibria of U(VI) in alkaline solutions at T = 25–80 °C is developed, including log * K s , 0 ° { Na 2 U 2 O 7 ⋅ H 2 O ( cr ) } , log * β 1 , 4 ∘ $\log^* {\rm K}_{\rm s,0}^{\circ} \ \{{\rm Na}_{2}{\rm U}_{2}{\rm O}_{7} \cdot {\rm H}_{2}{\rm O}({\rm cr})\}, \log^{*} \beta _{1,4}^{\circ} $ and related reaction enthalpies. The standard free energy and enthalpy of formation of Na2U2O7 · H2O(cr) calculated from these data are also provided. These data can be implemented in thermodynamic databases and allow accurate solubility and speciation calculations for U(VI) in dilute to concentrated alkaline NaCl solutions in the temperature range T = 25–80 °C.

Skin lesions in children with proven COVID‐19 are not frequent in the literature apart from those associated with multisystem inflammatory syndrome. Fortunately, microbiologic testing for SARS‐CoV‐2 has become widely available not only for admitted patients but also for mild cases. We present a series of 6 children with mild erythema and desquamation of the fingertips and/or toes as the only skin manifestation of COVID‐19. As all children had asymptomatic to mildly symptomatic disease, it is reasonable to consider this a sign of benign disease and favorable outcome.

Water production represents a major challenge over the life of a reservoir. It is an important issue that directly affects hydrocarbon production and total reserves recovery around the world, especially in fractured reservoirs. In the south of Mexico, several naturally fractured, low-pressure reservoirs experience production disruptions when water from the aquifer channels invades oil-producing intervals through high-conductivity fractures. Water shutoff (WSO) treatments vary in design approach and efficacy percentage due to the difference in environments and formations that are subject to water breakthrough. For the last decade, in southern Mexico, different treatments have been performed without achieving the expected results in the described reservoirs. These treatments have included different types of fluids, including rigid setting gels; reactive pills; selective water setting cement; and conventional cement slurries, with or without the use of mechanical aids such as mechanical plugs, cement retainers, or coiled tubing for precise placement. One of the biggest challenges of WSO in these reservoirs is that the proposed treatments must have a high level of penetration into the natural fractures but, at the same time, they need to be displaced with nitrogen or light hydrocarbon derivatives to balance reservoir pressure, avoiding total losses of fluids into the highly conductive, low-pressure reservoir where they will lose the ability to control water flow from the aquifer. Using the synergies of the operator's reservoir knowledge, diagnostic workflow, and historical treatment records coupled with service company's treatment engineering technologies and local ability to manipulate and enhance existing WSO fluids, we exercised a systematic evaluation approach to the evaluation of past unsuccessful experiences and proposed adjustments to conventional treatments using rigid gel and conventional cement slurries for water control. Integrating the relevant findings following operator's water control diagnostic workflow with the study of relevant papers and methodologies used by oil companies around the globe, we proposed a different treatment strategy consisting in the addition of a reactive pill between the rigid gel and the cement to keep the treatment in the vicinity of the wellbore, viscous spacers between each treatment fluid to avoid contamination while traveling downhole, the inclusion of lost circulation fibers to create a fibrous net to promote cement filter-cake development and tailored treatment displacement with a predefined pressure according to reservoir condition that is close to the reservoir-equivalent hydrostatic pressure. During the past 2 years, the application of rigorous evaluation of potential candidates and the combination of these three enhanced WSO fluids in the described sequence reduced unwanted water production in two naturally fractured low-pressure reservoirs. In three field cases, the use of the proposed methodology led to a reduction of overall water production from an initial value between 70 and 100% to levels below 30%. Incremental oil production has been maintained in the best cases for more than 2 years after the treatments. The most significant result occurred in the first field case, where the water cut was reduced from 90% to less than 2% and oil production increased 12 times, obtaining a cumulative oil production of 240,000 bbl in a year. The documented methodology is a work in progress; we cannot replicate the technique exactly because each well presents challenges according to its construction and structural placement. Similar WSO treatments have been successfully applied in several wells in southern Mexico, increasing oil production and recoverable reserves. Continuous improvement efforts have also led to efficiency enhancement over time, as results and lessons learned are captured to be shared and replicated in similar reservoirs.

BACKGROUND AND AIMS: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of our study is to search for specific features that help clinicians in the recognition of FHTG. APPROACH: We included 84 FHTG cases, 728 subjects with mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls for genetic, clinical and biochemical assessment. A set of 53 SNPs previously associated to TG levels, as well as 37 rare variants within the main five genes associated to hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins closely related to triglycerides homeostasis were compared between FHTG and CHTG.RESULTS: Compared to CHTG, FHTG subjects had higher HOMA-IR, apolipoprotein AII, FGF21, ANGPTL3 and ANGPTL4 concentrations and lower HOMA-B%, apolipoprotein B and leptin. The polygenic set of SNPs, previously associated with triglyceride levels, accounted for 1.78% of the explained variance of triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSION: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF21, ANGPTL3, apoAII and lower levels of apoB. We propose the inclusion of these analytes as useful markers to distinguish FHTG from other causes of hypertriglyceridemia.

Dead-time in IGBT-based DC-DC power converters is a well-known issue that causes a limitation of the output voltage and the distortion of the output voltage and current. These distortions are more critical when the converter switching frequency increases and in applications requiring high di/dt. This is especially true for power converters used to supply pulsed electro-magnets in particle accelerators where output waveforms with high slew rates are needed. Several solutions exist to compensate the distortions caused by dead-time; however, in fast and precise applications, the compensation method should be analysed in conjunction with design choices, such as the selection of switching frequency, output filter's inductances and topology. At CERN, hybrid capacitor discharge/switch mode power converters have been developed to supply electro-magnets used for PS beam injection. For standardisation and cost reduction. Because of this design option, dead-time represents 16 % of the switching period thus widely affecting the converter performances. This paper illustrates the effects of dead-time on various design aspects of these hybrid power converters able to produce precise 1ms long current pulses with maximal output current up to 2,5 kA. The converter control loops that have been designed using Energetic Macroscopic Representation approach can partly compensate for the dead-times effects. However, a dead-time compensation technique based on the inductor current sign measurement is nevertheless required to improve the converter performances. It is experimentally demonstrated that this classical compensation method is effective, even in interleaved switching module.

The multiactinide analysis with accelerator mass spectrometry (AMS) was applied to samples collected from the run 13-05 of the Colloid Formation and Migration (CFM) experiment at the Grimsel Test Site (GTS). In this in situ radionuclide tracer test, the environmental behavior of 233U, 237Np, 242Pu, and 243Am was investigated in a water conductive shear zone under conditions relevant for a nuclear waste repository in crystalline rock. The concentration of the actinides in the GTS groundwater was determined with AMS over 6 orders of magnitude from ∼15 pg/g down to ∼25 ag/g. Levels above 10 fg/g were investigated with both sector field inductively coupled plasma mass spectrometry (SF-ICPMS) and AMS. Agreement within a relative uncertainty of 50% was found for 237Np, 242Pu, and 243Am concentrations determined with the two analytical methods. With the extreme sensitivity of AMS, the long-term release and retention of the actinides was investigated over 8 months in the tailing of the breakthrough curve of run 1...

Background Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defined. Patients and methods This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confirmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020. Results We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n = 58) or allogeneic stem cell transplantation (allo-SCT) (n = 65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1–93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p = 0.02). Prognostic factors identified for day 45 overall mortality (OM) by logistic regression multivariate analysis included age > 70 years [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.2–3.8, p = 0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6–5.2, p 20 mg/dL (OR 3.3, 95% CI 1.7–6.4, p

El tema fundamental de la condición de la maternidad en las sociedades y teorías contemporáneas es el de los cuidados. El asunto aquí se investiga desde una perspectiva y con una focalización artísticas. La comunicación constará de seis apartados en el que se hace un resumen del proceso de una investigación en curso en este momento. Empezando por una introducción a nivel general y a nivel particular del tema, se detallan referentes artísticos en torno al tema de la maternidad desde los años sesenta hasta la actualidad, se expone el modo de obtención de datos en el estudio de casos y se reflexiona sobre un modo de trabajo artístico y su modo de difusión, con el que dar visibilidad a nuevas narrativas que den lugar a nuevos conceptos y discursos acerca del tema en cuestión.

We report experimental results on the ultrafast photo-isomerization of the ASRs-PSBR where point mutations lead to an up to 5-fold increase of the photo-isomerization speed, due to electrostatic modifications of the retinal binding pocket.

BACKGROUND Prior to 2010, the clinical management of dengue in Puerto Rico was inconsistent with World Health Organization guidelines. A 4-hour classroom-style course on dengue clinical management was developed in 2009 and mandated for Puerto Rico medical licensure in 2010. Fifty physicians were trained as "master trainers" and gave this course to 7638 physicians. This study evaluated the effect of the course on the clinical management of hospitalized dengue patients. METHODS Pre- and post-course test responses were compared. Changes in physician practices were assessed by reviewing medical records of 430 adult and 1075 pediatric dengue patients at the 12 hospitals in Puerto Rico that reported the most cases during 2008-2009 (pre-intervention) and 2011 (post-intervention). Mixed-effects logistic regression was used to compare key indicators of dengue management. RESULTS Physician test scores increased from 48% to 72% correct. Chart reviews showed that the percentage of adult patients who did not receive corticosteroids increased from 30% to 68% (odds ratio [OR], 5.9; 95% confidence interval [CI], 3.7-9.5) and from 91% to 96% in pediatric patients (OR, 2.7; 95% CI, 1.5-4.9). Usage of isotonic intravenous saline during the critical period increased from 57% to 90% in adult patients (OR, 6.2; 95% CI, 1.9-20.4) and from 25% to 44% in pediatric patients (OR, 3.4; 95% CI, 2.2-5.3). CONCLUSIONS Management of dengue inpatients significantly improved following implementation of a classroom-style course taught by master trainers. An online version of the course was launched in 2014 to expand its reach and sustainability.

Introdução: O tratamento conservador do linfedema periférico consta de drenagem linfática manual, exercí­cios terapêuticos, contenção elástica e inelástica e também a compressão pneumática intermitente sequencial. Objetivo: Avaliar o efeito da compressão pneumática intermitente sequencial associada ao uso de contenção inelástica e elástica e exercí­cios miolinfocinéticos, durante quatro semanas, em pacientes com linfedema das extremidades inferiores, utilizando a análise qualitativa da linfocintilografia e a perimetria. Material e métodos: Dez pacientes portadores de linfedema das extremidades inferiores selecionados por conveniência, totalizando 14 membros acometidos, foram submetidos a quatro semanas de tratamento com compressão pneumática intermitente sequencial, contenção inelástica e elástica e exercí­cios miolinfocinéticos. Para a avaliação dos membros realizou-se a análise qualitativa da linfocintilografia e também a perimetria dos membros antes e após o tratamento proposto. Â Â Â Â Â Â Â Â Â Â Â Resultados: Não foi encontrada diferença estatisticamente significativa nos achados linfocintilográficos pré e pós-tratamento. Contudo, encontrou-se redução significativa da perimetria dos membros (p < 0,01) cuja redução máxima encontrada foi de 5,9% na perimetria do tornozelo e a mí­nima de 1,8% na perimetria da coxa. Conclusão: O tratamento realizado foi eficaz na redução da perimetria do membro tratado, porém não foi observada alteração significativa nos padrões linfocintilográficos qualitativos para estes pacientes. Â Â Â Palavras-chave: linfedema, dispositivos de compressão pneumática intermitente, extremidade inferior, cintilografia, reabilitação.

Background: Ewing sarcoma (ES) is a developmental bone/soft tissue neoplasia, for which mesenchymal stem cell (MSC) is the putative cell of origin. Although the outcome of ES patients bearing primary tumors has improved significantly, patients with metastatic ES still have a poor prognosis. The MSC marker endoglin/CD105 (ENG) and the ENG-shedding protease MMP14 have been, respectively, described as cell migration and invasion regulators. In our attempt to better understand the mechanism of ES progression, we are focusing on the role of ENG and MMP14 in ES cells. Methods: In vitro ENG-knockdown (ENG-KD; RM82 and SKNMC cell lines) and ENG-overexpressing (pENG; TC71 cell lines) models were generated by shRNA technology and pDisplay vectors, respectively, and confirmed by qRT-PCR, western blotting and flow cytometry. In vitro MMP14-knockout (MMP14-KO; RM82 and SKNMC) models were generated by CRISPR-Cas9 and confirmed by western blotting and Sanger sequencing. Transwell migration/invasion, adhesion, clonogenicity and proliferation assays were performed in vitro. Actin filament organization was evaluated by immunofluorescence. Extracellular vesicles (EVs) were isolated by ultracentrifugation and density gradient separation. Transcriptomic profiling was performed by Clarion S Human arrays followed by Gene Set Enrichment Analysis. HiPathia tool was used to recode the transcriptomic data into measurements of cell activity by applying mechanistic models. Reverse Phase Protein Array (RPPA) analysis was evaluated on the ENG-KD RM82 model. ENG-targeting immunoprecipitations (IP) from wild type RM82 protein extracts were analyzed by mass spectrometry (MS). Results: The impaired clonogenic potential of ENG-KD RM82 and SKNMC models suggests a role of ENG on the stemness capacity of ES, without affecting the proliferation rate. The reduced migratory and adhesive phenotype of the ENG-KD RM82 model and the transcriptomic profiling of both ENG-KD RM82 and SKNMC cells, suggest a role of ENG in ES cell migration and adhesion. The altered organization of actin filaments in ENG-KD and pENG models could support a role of ENG in actin filament remodeling. The transcriptomic profiling of ENG-KD models and the RPPA results underscore the regulation of FAK signaling by ENG. The IP-MS analysis of ENG partners identifies Integrin-Linked Kinase-Associated serine/threonine Phosphatase (ILKAP) as one of the main interactors of ENG in RM82 cells, suggesting its possible association with the focal adhesion member ILK. ENG is enriched in EVs from different ES cell lines. The transcriptomic profiling of MMP14-KO SKNMC cells highlights the involvement of MMP14 activity in the extracellular matrix organization of ES cells. Conclusion: ENG favors a pro-migratory phenotype in ES cells. These findings help to better understand the molecular landscape of tumoral cells from ES patients, and might have potential clinical implications. Citation Format: Pilar Puerto-Camacho, Ana Teresa Amaral, Juan Diaz-Martin, Alfonso Bolado-Carrancio, Carmen Jordan-Perez, Carmen Salguero-Aranda, Marina Esteban-Medina, Inmaculada Alamo-Alvarez, Joaquin Dopazo, Carmelo Bernabeu, Adam Byron, Valerie G. Brunton, Enrique de Álava. The relevance of endoglin and MMP14 to the metastatic potential of Ewing sarcoma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6158.