Search

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study. Significance: Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials.

The accumulation of fallout radionuclides (FRNs) from nuclear weapons testing and nuclear accidents has been evaluated for over half a century in natural environments; however, until recently their distribution and abundance within glaciers have been poorly understood. Following a series of individual studies of FRNs, specifically 137Cs, 241Am and 210Pb, deposited on the surface of glaciers, we now understand that cryoconite, a material commonly found in the supraglacial environment, is a highly efficient accumulator of FRNs, both artificial and natural. However, the variability of FRN activity concentrations in cryoconite across the global cryosphere has never been assessed. This study thus aims to both synthesize current knowledge on FRNs in cryoconite and assess the controls on variability of activity concentrations. We present a global database of new and previously published data based on gamma spectrometry of cryoconite and proglacial sediments, and assess the extent to which a suite of environmental and physical factors can explain spatial variability in FRN activity concentrations in cryoconite. We show that FRNs are not only found in cryoconite on glaciers within close proximity to specific sources of radioactivity, but across the global cryosphere, and at activity concentrations up to three orders of magnitude higher than those found in soils and sediments in the surrounding environment. We also show that the organic content of cryoconite exerts a strong control on accumulation of FRNs, and that activity concentrations in cryoconite are some of the highest ever described in environmental matrices outside of nuclear exclusion zones, occasionally in excess of 10,000 Bq kg−1. These findings highlight a need for significant improvements in the understanding of the fate of legacy contaminants within glaciated catchments. Future interdisciplinary research is required on the mechanisms governing their accumulation, storage, and mobility, and their potential to create time-dependent impacts on downstream water quality and ecosystem sustainability.

Background Workplace exercise interventions showed good results, but lack of time was often reported as a barrier to participation. To overcome this problem, several studies attempted to implement short high-intensity interval training (HIT) within the workplace. Objectives The aim of this systematic review is to explore the feasibility and effectiveness of HIT interventions within the workplace setting. Data sources A systematic literature search was conducted in PubMed and SPORTDiscus to identify articles related to HIT within the workplace. Study eligibility criteria Only interventions that consisted of HIT programmes within the workplace and tested at least one physiological, psychological, or work-related outcome were included. Results Seven studies (317 participants) met the inclusion criteria. HIT interventions lasted 6–12 weeks, with a frequency of 2–4 sessions/week and a duration of 8–30 min per session. Feasibility was qualitatively investigated in four studies, with key positive aspects reported for HIT time-appeal, the sense of competence driven by individual intensity, and improved intention to exercise; five studies reported adherence rates > 80%. Small-to-large effect sizes were reported for improvements in cardiorespiratory and muscular fitness. Small-to-medium effect sizes were reported for blood parameters and health-related quality of life. Conclusions HIT interventions in the workplace showed limited effectiveness in improving health-related outcomes, while promising results regarding feasibility were reported, mainly due to the time-efficiency and the positive post-exercise psychosocial responses. However, further high-quality studies involving more participants are still needed to make firm conclusions on HIT effectiveness and feasibility compared to other types of exercise in this context.

In contemporary works on conditionals, the Ramsey test is a procedure for the evaluation of conditional sentences. There are several versions of the test, all inspired by a footnote by the British philosopher and mathematician Frank Ramsey, in his General Propositions and Causality. However, no study on Ramsey's own account of conditionals has been put forth so far. Furthermore, the footnote seems to cover indicative conditionals only, and this has led to the belief that no account of counterfactuals can be found in Ramsey's work. In this paper, I recover Ramsey's account of counterfactuals and show that it is sketched in the footnote too. The result is a well-developed account of counterfactuals that resembles many contemporary ones. But Ramsey uses the same approach also for other types of conditionals, and this casts doubts on the current criteria for the classification of this type of sentences.

The problem in this study is how the influence of the Independent Board of Commissioners, Audit Committee, Leverage and Capital Intensity on manufacturing companies listed on the Indonesia Stock Exchange in the year. The purpose of this study was to examine the influence of the Independent Board of Commissioners, Audit Committee, Leverage and Capital Intensity on manufacturing companies listed on the Indonesia Stock Exchange. The population of this research is all manufacturing companies listed on the Indonesia Stock Exchange. The sampling method used purposive sampling and obtained a sample of 116 companies. The analysis technique used is simple linear regression analysis with the help of SPSS. The proxy used to measure Tax Avoidance uses the Tax Expense divided by Pre-Tax Profit. The proxy used to measure the Independent Board of Commissioners using Independent Commissioners is divided by the total number of members. The proxy used to measure the Audit Committee uses Dummy which is worth 1 if the audit committee is> 3, and is worth 0 if the audit committee

The integration of small and medium-sized enterprises (SMEs) within the concept Industry 4.0 represents one of its main challenges, as they play a vital part in industrial value chains that shall be digitized from suppliers to the end customer. However, what the implementation stages for Industry 4.0 in SMEs should be as well as the respective resources for achieving the next stage are scarcely understood. In response, this paper proposes a framework using a resource-based review for Industry 4.0 implementation according to the stage of development in SMEs, created between researchers, policy makers, and 354 manufacturing SMEs in the province of Gipuzkoa (Basque Country, Spain). The paper applies a mixed-method approach, combining qualitative (interviews) and quantitative elements (survey data). The results are used to develop a model with four stages of SMEs that are characterized by having distinct preconditions and conditions for Industry 4.0. Thereupon, the required measures to achieve the next stage of Industry 4.0 implementation are derived. This highlights Industry 4.0 for SMEs as a process with different stages toward achieving sustainable competitive advantage and offering insight into how the different resources operate. The high importance and advanced position regarding industrial value creation and SMEs in Gipuzkoa allows to generalize and transfer the findings to other European regions.

Few data exists on predictive factors of hemorrhagic transformation (HT) in real-world acute ischemic stroke patients. The aims of this study were: (i) to identify predictive variables of HT (ii) to develop a score for predicting HT.We retrospectively analyzed the clinical, radiographic, and laboratory data of patients with acute ischemic stroke consecutively admitted to our Stroke Unit along two years. Patients with HT were compared with those without HT. A multivariate logistic regression analysis was performed to identify independent predictors of HT on CT scan at 24 hours to develop a practical score.The study population consisted of 564 patients with mean age 77.5±11.8 years. Fifty-two patients (9.2%) showed HT on brain CT at 24 hours (4.9% symptomatic). NIHSS score ≥8 at Stroke Unit admission (3 points), cardioembolic etiology (2 points), acute revascularization by systemic thrombolysis and/or mechanical thrombectomy (1 point), history of previous TIA/stroke (1 point), and major vessel occlusion (1 point) were found independent risk factors of HT and were included in the score (Hemorrhagic Transformation Empoli score (HTE)). The predictive power of HTE score was good with an AUC of 0.785 (95% CI: 0.749-0.818). Compared with 5 HT predictive scores proposed in the literature (THRIVE, SPAN-100, MSS, GRASPS, SITS-SIC), the HTE score significantly better predicted HT.NIHSS score ≥8 at Stroke Unit admission, cardioembolism, urgent revascularization, previous TIA/stroke, and major vessel occlusion were independent predictors of HT. The HTE score has a good predictive power for HT. Prospective studies are warranted.

Since the beginning of the COVID-19 pandemic, a large number of epidemiological models have been developed. The principal objective of the present study is to provide a new six-compartment model for the COVID-19 pandemic, which takes into account both the possibility of re-infection and the differentiation between asymptomatic and symptomatic infected subjects. The model, denoted as θ-SI(R)D, is a six-compartment model, described by as many ordinary differential equations. The six compartments are denoted as Susceptible (S), Symptomatic Infected (Is), Asymptomatic Infected (Ia), Recovered from Asymptomatic fraction (Ra), Recovered from Symptomatic fraction (Rs), and Deceased (D). Such a model has no analytical solutions, so we performed both a simulation and a model validation (R2=0.829). Based on the results of our simulations (and, on the other hand, on the results of most of the models in the scientific literature), it is possible to draw the reasonable conclusion that the epidemic tends, even without vaccination, to a steady state.

Oxidative stress is associated with cardiovascular and neurodegenerative diseases. Here we report studies of neurovascular oxidative stress in chemogenetic transgenic mouse lines expressing yeast D-amino acid oxidase (DAAO) in neurons and vascular endothelium. When these transgenic mice are fed D-amino acids, DAAO generates hydrogen peroxide in target tissues. DAAO-TGCdh5 transgenic mice express DAAO under control of the putatively endothelial-specific Cdh5 promoter. When we provide these mice with D-alanine, they rapidly develop sensory ataxia caused by oxidative stress and mitochondrial dysfunction in neurons within dorsal root ganglia and nodose ganglia innervating the heart. DAAO-TGCdh5 mice also develop cardiac hypertrophy after chronic chemogenetic oxidative stress. This combination of ataxia, mitochondrial dysfunction, and cardiac hypertrophy is similar to findings in patients with Friedreich’s ataxia. Our observations indicate that neurovascular oxidative stress is sufficient to cause sensory ataxia and cardiac hypertrophy. Studies of DAAO-TGCdh5 mice could provide mechanistic insights into Friedreich’s ataxia.

Funding Acknowledgements Type of funding sources: None. Background Cardiac resynchronization therapy (CRT) is usually performed with biventricular pacing (BiVP), but recently conduction system pacing (CSP) has been proposed as an alternative in case of unsuccessful coronary sinus lead implantation. CSP was performed as His Bundle pacing or Left bundle branch pacing(1). However, further evidence is needed to determine when CSP should be used in lieu of BiVP to improve clinical benefit. Purpose To assess the clinical benefit of a treatment algorithm based on interventricular conduction delays (IVCD) to choose between BiVP or CSP in candidates to CRT(figure1). Methods Consecutive patients presenting at our Institution from January 2018 to December 2020 with an indication to CRT were prospectively enrolled in the study group (delays-guided resynchronization group, DRG). IVCD were measured after left ventricle (LV) lead positioning in a lateral or posterior-lateral cardiac vein, when feasible, using endocavitary electrogram(2). Treatment algorithm based on IVCD was used to decide whether to leave LV lead to perform BiVP or pull it out and perform CSP. Outcomes from the DRG group were compared to a historical cohort of CRT patients (resynchronization standard guide group,SRG). The primary endpoint was a composite of cardiovascular mortality, heart failure (HF) hospitalization, or HF event at 1 year after the date of intervention. Results Study population consisted in 292 patients, of which 160 (54.8%) in the DRG and 132 (45.2%) in the SRG. In the DRG 41 of 160 patients underwent CSP based on treatment algorithm (25.6%). The primary endpoint was significantly reduced in the DRG (35/160, 21.8%) compared to SRG (48/132, 36.4%) (hazard ratio(HR):1.72;95% confidence interval(CI):1.12-2.65;p=0.013)(figure2). Conclusion A treatment algorithm based on IVCD shifted 1 patient every 4 from BiVP to CSP, with consequent reduction in cardiovascular deaths, HF hospitalizations or HF event after implantation. Therefore, its application could be useful to determine whether to perform BiVP or CSP in CRT candidates.

ImportanceO6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets.ObjectiveTo evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response.Design, Setting, and ParticipantsThis cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023.ExposureMGMT promoter methylation status.Main Outcomes and MeasuresMultivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification.ResultsA total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)–wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P MGMT, 1.95 [95% CI, 1.39-2.75]; P P P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH–wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS.Conclusions and RelevanceThis study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH–wild-type and IDH-mutant and codeleted tumors.

Bordetella bronchiseptica is a gram-negative bacterium that causes respiratory diseases in different animals, including mice, making B. bronchiseptica the gold-standard model to investigate host–pathogen interaction at the molecular level. B. bronchiseptica utilizes many different mechanisms to precisely regulate the expression of virulence factors. Cyclic di-GMP is a second messenger synthesized by diguanylate cyclases and degraded by phosphodiesterases that regulates the expression of multiple virulence factors including biofilm formation. As in other bacteria, we have previously shown that c-di-GMP regulates motility and biofilm formation in B. bronchiseptica. This work describes the diguanylate cyclase BdcB (Bordetelladiguanylate cyclase B) as an active diguanylate cyclase that promotes biofilm formation and inhibits motility in B. bronchiseptica. The absence of BdcB increased macrophage cytotoxicity in vitro and induced a greater production of TNF-α, IL-6, and IL-10 by macrophages. Our study reveals that BdcB regulates the expression of components of T3SS, an important virulence factor of B. bronchiseptica. The Bb∆bdcB mutant presented increased expression of T3SS-mediated toxins such as bteA, responsible for cytotoxicity. Our in vivo results revealed that albeit the absence of bdcB did not affect the ability of B. bronchiseptica to infect and colonize the respiratory tract of mice, mice infected with Bb∆bdcB presented a significantly higher pro-inflammatory response than those infected with wild type B. bronchiseptica.

Background During the COVID-19 pandemic, migrants arriving in host countries irregularly have not infrequently been perceived as increasing the COVID-19 burden. Italy is a transit and destination country for migrants who cross the Central Mediterranean route and, during the pandemic, all migrants who landed on Italian shores were COVID-19 tested and quarantined. Our study aimed to investigate the impact of the SARS-CoV-2 infection among migrants who landed on the Italian coasts by analyzing both incidence and health outcomes. Methods A retrospective observational study has been designed. The population of interest was represented by 70,512 migrants (91% male, 99% Results 2,861 migrants out of those landed in Italy during the observation period tested positive, with an incidence rate of 40.6 (39.1–42.1) cases per 1,000. During the same period, 177.6 (177.5-177.8) cases per 1,000 were reported in the resident population, with an IRR of 0.23 (0.22–0.24). 89.7% of cases were male and 54.6% belonged to the 20–29 age group. 99% of cases reported no symptoms, no relevant comorbidities were reported and no cases were hospitalized. Conclusions Our study found a low rate of SARS-CoV-2 infection in migrants reaching Italy by sea with an incidence rate that is roughly a quarter of that of the resident population. Thus, irregular migrants who arrived in Italy during the observation period did not increase the COVID-19 burden. Further studies are needed to investigate possible reasons for the low incidence observed in this population.

As a new generation of green solvents, deep eutectic solvents (DESs) are considered a promising alternative to current harsh organic solvents and find application in many chemical processing methods such as extraction and synthesis. DESs, normally formed by two or more components via various hydrogen bond interactions, offer high potential as medium for biocatalysis reactions where they can improve efficiency by enhancing substrate solubility and the activity and stability of the enzymes. In the current study, the stabilization of Humicola insolens cutinase (HiC) in natural deep eutectic solvents (NADESs) was assessed. The best hydrogen bond donor among sorbitol, xylitol, erythritol, glycerol and ethylene glycol, and the best acceptor among betaine, choline chloride, choline acetate, choline dihydrogen citrate and tetramethylammonium chloride, were selected, evaluating binding energies and molecular orientations through molecular docking simulations, and finally used to prepare NADES aqueous solutions. The effects of component ratio and NADES concentration on HiC thermostability at 90 °C were also investigated. The choline dihydrogen citrate:xylitol, in a 1:1 ratio with a 20 wt% concentration, was selected as the best combination in stabilizing HiC, increasing its half-life three-fold.

The CUORE experiment is searching for the neutrinoless double β decay of the 130Te using cryogenic calorimeters. The CUORE detector consists of 988 TeO2 crystals packed in 19 towers and placed in a cryogenic facility with a base temperature of 10 mK. Crystals are enriched in the isotope 130Te which is the candidate for the neutrinoless double β decay. It is taking data since 2017 at the Laboratori Nazionali del Gran Sasso in Italy. Such a long operation of a bolometric experiment in stable condition has no precedent: by reaching 1 tonne-year of exposure CUORE set a fundamental milestone for any future experiment using this technology. The CUORE collaboration investigated the neutrinoless double β decay of 130Te exploiting the updated 1 tonne-year of statistics, setting a limit of 2.2 × 1025 yr at the 90% of credibility interval on the half-life, with a median sensitivity of 2.8 × 1025 yr.

Background: Transversus abdominis plane (TAP) block and wound infiltration (WI) with local anesthetics are used for postoperative analgesia after cesarean section (CS), reducing the need for administration of opioids. Objective: To compare the analgesic effect of TAP block related to WI. Search strategy: MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, Cochrane Library, and CINAHL were searched from inception until April 2020. Selection criteria: Randomized controlled trials (RCTs) about women who underwent TAP block or WI after CS. Data collection and analysis: Relevant data were extracted and tabulated. Review Manager 5.3 was used for data analysis. Primary outcome was cumulative opioid consumption (COC) 24 and 48 h after CS. Main results: Five RCTs, enrolling 268 women, were included. There were no significant differences between the interventions regarding COC at 24 (mean difference [MD] -1.68, 95% confidence interval [CI] -6.29 to 2.93) and 48 hours (MD 1.28, 95% CI -10.44 to 13.00). Adverse effects (relative risk [RR] 0.93, 95% CI 0.75-1.16), gastrointestinal reactions (RR 1.30, 95% CI 0.46-3.68), or mild-moderate sedation (RR 1.12, 95% CI 0.72-1.74), pain scores, satisfaction of women, and withdrawals were similar between groups. Conclusions: There might be no significant advantages selecting TAP block over WI for post-CS analgesia.

The purpose of this study was to assess the effect of Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) on student self-perceived competencies and perceptions of interprofessional (IP) communication and teamwork in a clinical case review activity. TeamSTEPPS is an evidence-based curriculum that is used to enhance and support IP healthcare communication.A repeated-measures, pretest/posttest study evaluated physician assistant students' and student pharmacists' perceptions of TeamSTEPPS. Students completed Performance Assessment for Communication and Teamwork (PACT) surveys, evaluating teamwork, knowledge, attitudes, and skills perceptions before and after a TeamSTEPPS lecture and associated activity with peer feedback.Overall, 87.4% (n = 429) completed pre- and post-PACT surveys. Apart from the Mutual Support domain (p = .898), all changes were significantly positive (p.004), with the greatest improvements occurring in the Attitudes and Perceived Skills domains.TeamSTEPPS IP education, application, and peer feedback improved students' perceptions of multiple domains, including effective communication. Using TeamSTEPPS tools in IP formats enabled the students to safely practice and collaborate in preparation for clinical practice.

Genuk District is a residential development area which has a role as a Semarang City's transportation hubs. It is directly adjacent to Demak Regency and the Java Sea. As of the time of writing, Genuk District has a population of 117,174 people with the total of 130.88 m³ waste transported to the landfill each day and the percentage of waste transportation services in the area is 38.53%. The waste transportation average operational time is 0.2 hours exceeding the amount of working time with the number of 17 trips/day. This planning aims to arrange the waste transportation system in Genuk District by taking into account the traffic congestion in order to get the optimal operational time and costs. Arm roll truck vehicle operating costs in the existing conditions in 2020 was IDR 1,347,411,591.00, while in the optimized condition would be IDR 1,341,405,786.37. Meanwhile, dump truck vehicle operating cost in the existing conditions in 2020 was IDR 302,002,441.00, while in the optimized condition would be IDR 278,453,956.22. The operational time for waste transportation should be started at 06.00-15.00. After optimization, the average remaining working hours becomes 2.68 hours per day with a vehicle's speed of 57.11 km/hour. The planning for waste transportation system optimization will reduce the retribution costs by IDR 900.00 and increase the percentage of waste transportation services to 53%.

Preeclampsia (PE) is characterised by the new onset of hypertension after the 20th week of pregnancy, with or without proteinuria or hypertension that leads to end-organ dysfunction. Since the only definitive treatment is delivery, PE still represents one of the leading causes of preterm birth and perinatal mobility and mortality. Therefore, any strategies that aim to reduce adverse outcomes are based on early primary prevention, prenatal surveillance and prophylactic interventions. In the last decade, intense research has been focussed on the study of predictive models in order to identify women at higher risk accurately. To date, the most effective screening model is based on the combination of anamnestic, demographic, biophysical and maternal biochemical factors. In this review, we provide a detailed discussion about the current and future perspectives in the field of PE. We will examine pathogenesis, risk factors and clinical features. Moreover, recent developments in screening and prevention strategies, novel therapies and healthcare management strategies will be discussed.

Supplementary Tables 1-6, Figures 1-4 from Randomized Study of Paclitaxel and Tamoxifen Deposition into Human Brain Tumors: Implications for the Treatment of Metastatic Brain Tumors

Purpose: Drug resistance in brain tumors is partially mediated by the blood-brain barrier of which a key component is P-glycoprotein, which is highly expressed in cerebral capillaries. Tamoxifen is a nontoxic inhibitor of P-glycoprotein. This trial assessed, in primary and metastatic brain tumors, the differential deposition of paclitaxel and whether tamoxifen could increase paclitaxel deposition.Experimental Design: Patients for surgical resection of their primary or metastatic brain tumors were prospectively randomized to prior paclitaxel alone (175 mg/m2/i.v.) or tamoxifen for 5 days followed by paclitaxel. Central and peripheral tumor, surrounding normal brain and plasma, were analyzed for paclitaxel and tamoxifen.Results: Twenty-seven patients completed the study. Based on a multivariate linear regression model, no significant differences in paclitaxel concentrations between the two study arms were found after adjusting for treatment group (tamoxifen versus control). However, in analysis for tumor type, metastatic brain tumors had higher paclitaxel concentrations in the tumor center (1.93-fold, P = 0.10) and in the tumor periphery (2.46-fold, P = 0.039) compared with primary brain tumors. Pharmacokinetic analyses showed comparable paclitaxel areas under the serum concentration between treatment arms.Conclusions: Paclitaxel deposition was not increased with this tamoxifen schedule as the low plasma concentrations were likely secondary to concurrent use of P-450-inducing medications. However, the statistically higher paclitaxel deposition in the periphery of metastatic brain tumors provides functional evidence corroborating reports of decreased P-glycoprotein expression in metastatic versus primary brain tumors. This suggests that metastatic brain tumors may respond to paclitaxel if it has proven clinical efficacy for the primary tumor's histopathology.

PDF - 1816K, Supplementary Figure 1: CGH probe for Cre-mediated Pten deletion provides a surrogate of tumor DNA content for mouse tumors. Supplementary Figure 2: The genomic architecture of mouse tumor gene deletions suggests independent selection pressure for genes within the same deletion in human tumors. Supplementary Figure 3: Mouse and Human Proneural GBM share a common regulatory network. Supplementary Figure 4: *PTEN/p53 tumors rapidly progress and acquire the histological features of GBM. Supplementary Figure 5: *Pten tumors acquire and express mutations in p53. Supplementary Figure 6: *p53 tumors develop the histological features of GBM, and have an intermediate survival between *PTEN and *PTEN/p53 tumors.

Proneural glioblastoma is defined by an expression pattern resembling that of oligodendrocyte progenitor cells and carries a distinctive set of genetic alterations. Whether there is a functional relationship between the proneural phenotype and the associated genetic alterations is unknown. To evaluate this possible relationship, we performed a longitudinal molecular characterization of tumor progression in a mouse model of proneural glioma. In this setting, the tumors acquired remarkably consistent genetic deletions at late stages of progression, similar to those deleted in human proneural glioblastoma. Further investigations revealed that p53 is a master regulator of the transcriptional network underlying the proneural phenotype. This p53-centric transcriptional network and its associated phenotype were observed at both the early and late stages of progression, and preceded the proneural-specific deletions. Remarkably, deletion of p53 at the time of tumor initiation obviated the acquisition of later deletions, establishing a link between the proneural transcriptional network and the subtype-specific deletions selected during glioma progression. Cancer Res; 74(5); 1440–51. ©2014 AACR.

XLSX - 1231K, Supplementary Table 1: List of genes deleted in 75 to 100% of the end-stage *PTEN tumors Supplementary Table 2: List of genes showing copy number gains in *PTEN end-stage and *PTEN/p53 mouse tumors. Supplementary Table 3: Genes that were deleted in 75-100% of *PTEN end-stage mouse tumors and at least 10% of human tumors within one of the four GBM subtypes mapped to their chromosomal location in the human genome. Supplementary Table 4: List of gene deletions that were specific for one of the four GBM subtypes. Supplementary Table 5: Correlation of proneural-specific genetic alterations and deletions identified by cross-species comparison. Supplementary Table 6: Spearman correlation for Verhaak gene sets show highest correlation for human proneural GBM subtype for 21 dpi *PTEN tumors, end-stage *PTEN tumors and *p53 end-stage tumors. Supplementary Table 7: MR identified from NB versus *PTEN 21 dpi and NB versus *PTEN end-stage mouse MARINas, and human NB versus proneural GBM (TCGA) MARINa.

PDF - 106K, Contains the legends for Supplementary Figures 1-6 and Supplementary Tables 1-7.

IntroductionUpper respiratory tract infections (URTI) are the most common illnesses affecting athletes, causing absences from training and competition. Salivary immunoglobulin A (sIgA) is the main immune factor in saliva, and a consistent association between low concentrations of sIgA and an increased incidence of URTIs has been reported. The oral probiotic Streptococcus salivarius K12 has been suggested to have the potential to improve oral diseases and mucosal barrier function. However, the effects of this probiotic on active young subjects performing a high-intensity training (HIT) program have not been investigated.MethodsActive young students were randomised into a treated group (S. salivarius K12) and a control (placebo) group and asked to take the product daily for 30 days. After this period, participants performed a graded exercise test and five HIT sessions, all within 3 days. They were also asked to complete the Wisconsin Upper Respiratory Symptom Survey daily to monitor URTI’s presence. Before and after the 30 days, and at 0h, 24h and 72h after the last training session, saliva samples were collected to quantify sIgA level, secretion rate, and flow. The effect of S. salivarius K12 intake on these parameters was tested using an ANOVA for repeated measures.ResultsTwenty (M = 14, F = 6) young subjects (23.5 ± 2.3 years old) participated in the study. The total accumulated training load (sRPE) in the supplementation period was similar in the two groups (treated: 4345 ± 3441 AU; control: 4969 ± 4165 AU; p > 0.05). Considering both sIgA level and secretion rate, significant time (F(4,15) = 3.38; p = 0.037; F(4,15) = 6.00; p = 0.004) and time×group interactions (F(4,15) = 2.49; p = 0.049; F(4,15) = 5.01; p = 0.009) were reported, with the treated group showing higher sIgA levels at 72h post-exercise and increased secretion rate both at 0h and 72h. The number of URTI episodes was similar in the treated and control groups (χ² = 1.83; p > 0.05).ConclusionThis study demonstrates that relatively short-term S. salivarius K12 supplementation increased sIgA level and secretion in healthy subjects performing a demanding exercise-training programme composed of HIT sessions.

Human Immunodeficiency Virus (HIV) is still one of the major global health issues, and despite significant efforts that have been put into studying the pathogenesis of HIV infection, several aspects need to be clarified, including how innate immunity acts in different anatomical compartments. Given the nature of HIV as a sexually transmitted disease, one of the aspects that demands particular attention is the mucosal innate immune response. Given this scenario, we focused our attention on the interplay between HIV and mucosal innate response: the different mucosae act as a physical barrier, whose integrity can be compromised by the infection, and the virus-cell interaction induces the innate immune response. In addition, we explored the role of the mucosal microbiota in facilitating or preventing HIV infection and highlighted how its changes could influence the development of several opportunistic infections. Although recent progress, a proper characterization of mucosal innate immune response and microbiota is still missing, and further studies are needed to understand how they can be helpful for the formulation of an effective vaccine.

Background and Purpose: Highly mutable influenza is successfully countered based on individual susceptibility and similar precision-like medicine approach should be effective against SARS-COV-2. Among predictive markers to bring precision medicine to COVID-19, circulating ACE2 has potential features being upregulated in both severe COVID-19 and predisposing comorbidities. Spike SARS-CoVs were shown to induce ADAM17-mediated shedding of enzymatic active ACE2, thus accounting for its increased activity that has also been suggested to induce positive feedback loops leading to COVID-19-like manifestations. For this reason, pre-existing ACE2 activity and inhibition of ACE2/ADAM17 zinc-metalloproteases through zinc chelating agents have been proposed to predict COVID-19 outcome before infection and to protect from COVID-19, respectively. Since most diagnostic laboratories are not equipped for enzymatic activity determination, other potential predictive markers of disease progression exploitable by diagnostic laboratories were explored. Experimental approach: Concentrations of circulating ACE2 protein and activity, albumin and zinc were investigated in healthy, diabetic (COVID-19-susceptible) and SARS-CoV-2-negative COVID-19 individuals. Key Results: ACE2 both protein levels and activity significantly increased in COVID-19 and diabetic patients. Abnormal high levels of ACE2 characterised a subgroup (16-19%) of diabetics, while COVID-19 patients were characterised by significantly higher zinc/albumin ratios, pointing to a relative increase of albumin-unbound zinc species, such as ACE2-bound and free zinc ones. Conclusions & Implications: Data on circulating ACE2 levels are in line with the hypothesis that they can drive susceptibility to COVID-19 and elevated zinc/albumin ratios support the therapeutic use of zinc chelating inhibitors of ACE2/ADAM17 zinc-metalloproteases in a targeted therapy for COVID-19.

International audience; The Jiangmen Underground Neutrino Observatory (JUNO), the first multi-kton liquid scintillator detector, which is under construction in China, will have a unique potential to perform a real-time measurement of solar neutrinos well below the few MeV threshold typical for Water Cherenkov detectors. JUNO's large target mass and excellent energy resolution are prerequisites for reaching unprecedented levels of precision. In this paper, we provide estimation of the JUNO sensitivity to 7Be, pep, and CNO solar neutrinos that can be obtained via a spectral analysis above the 0.45 MeV threshold. This study is performed assuming different scenarios of the liquid scintillator radiopurity, ranging from the most opti mistic one corresponding to the radiopurity levels obtained by the Borexino experiment, up to the minimum requirements needed to perform the neutrino mass ordering determination with reactor antineutrinos - the main goal of JUNO. Our study shows that in most scenarios, JUNO will be able to improve the current best measurements on 7Be, pep, and CNO solar neutrino fluxes. We also perform a study on the JUNO capability to detect periodical time variations in the solar neutrino flux, such as the day-night modulation induced by neutrino flavor regeneration in Earth, and the modulations induced by temperature changes driven by helioseismic waves.

The ACCESS (Array of Cryogenic Calorimeters to Evaluate Spectral Shapes) project aims to establish a novel technique to perform precision measurements of forbidden \b{eta}-decays, which can serve as an important benchmark for nuclear physics calculations and represent a significant background in astroparticle physics experiments. ACCESS will operate a pilot array of cryogenic calorimeters based on natural and doped crystals containing \b{eta}-emitting radionuclides. In this way, natural (e.g. 113 Cd and 115In) and synthetic isotopes (e.g. 99Tc) will be simultaneously measured with a common experimental technique. The array will also include further crystals optimised to disentangle the different background sources, thus reducing the systematic uncertainty. In this paper, we give an overview of the ACCESS research program, discussing a detector design study and promising results of 115In., 12 pages, 12 figures

Background Imbalance and gait disturbances are common in patients with vestibular schwannoma (VS) and can result in significant morbidity. Current methods for quantitative gait analysis are cumbersome and difficult to implement. Here, we use custom-engineered instrumented insoles to evaluate the gait of patients diagnosed with VS. Methods Twenty patients with VS were recruited from otology, neurosurgery, and radiation oncology clinics at a tertiary referral center. Functional gait assessment (FGA), 2-minute walk test (2MWT), and uneven surface walk test (USWT) were performed. Custom-engineered instrumented insoles, equipped with an 8-cell force sensitive resistor (FSR) and a 9-degree-of-freedom inertial measurement unit (IMU), were used to collect stride-by-stride spatiotemporal gait parameters, from which mean values and coefficients of variation (CV) were determined for each patient. Results FGA scores were significantly correlated with gait metrics obtained from the 2MWT and USWT, including stride length, stride velocity, normalized stride length, normalized stride velocity, stride length CV, and stride velocity CV. Tumor diameter was negatively associated with stride time and swing time on the 2MWT; no such association existed between tumor diameter and FGA or DHI. Conclusions Instrumented insoles may unveil associations between VS tumor size and gait dysfunction that cannot be captured by standardized clinical assessments and self-reported questionnaires.