Efficient testing of the biomarker positive and negative subgroups in a biomarker-stratified trial.

In many randomized placebo-controlled trials with a biomarker defined subgroup, it is believed that this subgroup has the same or higher treatment effect compared with its complement. These subgroups are often referred to as the biomarker positive and negative subgroups. Most biomarker-stratified pivotal trials are aimed at demonstrating a significant treatment effect either in the biomarker positive subgroup or in the overall population. A major shortcoming of this approach is that the treatment can be declared effective in the overall population even though it has no effect in the biomarker negative subgroup. We use the isotonic assumption about the treatment effects in the two subgroups to construct an efficient way to test for a treatment effect in both the biomarker positive and negative subgroups. A substantial reduction in the required sample size for such a trial compared with existing methods makes evaluating the treatment effect in both the biomarker positive and negative subgroups feasible in pivotal trials especially when the prevalence of the biomarker positive subgroup is less than 0.5.

An experimental study of foam-oil interactions for nonionic-based binary surfactant systems under high salinity conditions.

A key factor affecting foam stability is the interaction of foam with oil in the reservoir. This work investigates how different types of oil influence the stability of foams generated with binary surfactant systems under a high salinity condition. Foam was generated with binary surfactant systems, one composed of a zwitterionic and a nonionic surfactant, and the other composed of an anionic and a nonionic surfactant. Our results showed that the binary surfactant foams investigated are more tolerant under high salinity conditions and in the presence of oil. This was visually observed in our microscopic analysis and was further attributed to an increase in apparent viscosity achieved with binary surfactant systems, compared to single surfactant foams. To understand the influence of oil on foam stability, we performed a mechanistic study to investigate how these oils interact with foams generated with binary surfactants, focusing on their applicability under high salinity conditions. The generation and stability of foam are linked to the ability of the surfactant system to solubilize oil molecules. Oil droplets that solubilize in the micelles appear to destabilize the foam. However, oils with higher molecular weights are too large to be solubilized in the micelles, hence the molecules will have less ability to be transported out of the foam, so oil seems to stabilize the foam. Finally, we conducted a multivariate analysis to identify the parameters that influenced foam stability in different oil types, using the experimental data from our work. The results showed that the oil molecular weight, interfacial tension between the foaming liquid and the oil, and the spreading coefficient are the most important variables for explaining the variation in the data. By performing a partial least square regression, a linear model was developed based on these most important variables, which can be used to predict foam stability for subsequent experiments under the same conditions as our work.

Shape restricted additive hazards models: Monotone, unimodal, and U-shape hazard functions.

We consider estimation of the semiparametric additive hazards model with an unspecified baseline hazard function where the effect of a continuous covariate has a specific shape but otherwise unspecified. Such estimation is particularly useful for a unimodal hazard function, where the hazard is monotone increasing and monotone decreasing with an unknown mode. A popular approach of the proportional hazards model is limited in such setting due to the complicated structure of the partial likelihood. Our model defines a quadratic loss function, and its simple structure allows a global Hessian matrix that does not involve parameters. Thus, once the global Hessian matrix is computed, a standard quadratic programming method can be applicable by profiling all possible locations of the mode. However, the quadratic programming method may be inefficient to handle a large global Hessian matrix in the profiling algorithm due to a large dimensionality, where the dimension of the global Hessian matrix and number of hypothetical modes are the same order as the sample size. We propose the quadratic pool adjacent violators algorithm to reduce computational costs. The proposed algorithm is extended to the model with a time-dependent covariate with monotone or U-shape hazard function. In simulation studies, our proposed method improves computational speed compared to the quadratic programming method, with bias and mean square error reductions. We analyze data from a recent cardiovascular study.

Finding the best subgroup with differential treatment effect with multiple outcomes.

Precision medicine aims to identify specific patient subgroups that may benefit the most from a particular treatment than the whole population. Existing definitions for the best subgroup in subgroup analysis are based on a single outcome and do not consider multiple outcomes; specifically, outcomes of different types. In this article, we introduce a definition for the best subgroup under a multiple-outcome setting with continuous, binary, and censored time-to-event outcomes. Our definition provides a trade-off between the subgroup size and the conditional average treatment effects (CATE) in the subgroup with respect to each of the outcomes while taking the relative contribution of the outcomes into account. We conduct simulations to illustrate the proposed definition. By examining the outcomes of urinary tract infection and renal scarring in the RIVUR clinical trial, we identify a subgroup of children that would benefit the most from long-term antimicrobial prophylaxis.

Isotonic design for single-arm biomarker stratified trials.

In single-arm trials with a predefined subgroup based on baseline biomarkers, it is often assumed that a biomarker defined subgroup, the biomarker positive subgroup, has the same or higher response to treatment compared to its complement, the biomarker negative subgroup. The goal is to determine if the treatment is effective in each of the subgroups or in the biomarker positive subgroup only or not effective at all. We propose the isotonic stratified design for this problem. The design has a joint set of decision rules for biomarker positive and negative subjects and utilizes joint estimation of response probabilities using assumed monotonicity of response between the biomarker negative and positive subgroups. The new design reduces the sample size requirement when compared to running two Simon's designs in each biomarker positive and negative. For example, the new design requires 23%-35% fewer patients than running two Simon's designs for scenarios we considered. Alternatively, the new design allows evaluating the response probability in both biomarker negative and biomarker positive subgroups using only 40% more patients needed for running Simon's design in the biomarker positive subgroup only.

Anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation in patients with high-risk CD30+ lymphoma: a phase 1 study.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30+ lymphoma at high risk of relapse. METHODS: This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30+ disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 107 CAR T cells per m2, 1 × 108 CAR T cells per m2, or 2 × 108 CAR T cells per m2) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per µL for 3 days, platelet count ≥25 × 109 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete. FINDINGS: Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 108 CAR T cells per m2, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. INTERPRETATION: Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. FUNDING: National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.

High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

INTRODUCTION: Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). METHODS: The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. RESULTS: Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 µg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. DISCUSSION: Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Numerical study of the mechanisms of nano-assisted foam flooding in porous media as an alternative to gas flooding.

Oil reservoirs are nearing maturation, necessitating novel enhanced oil recovery (EOR) techniques to meet escalating global energy demands. This demand has spurred interest in reservoir production analysis and forecasting tools to enhance economic and technical efficiency. Accurate validation of these tools, known as simulators, using laboratory or field data is pivotal for precise reservoir productivity estimation. This study delves into the application of nanoparticles in foam flooding for mobility control to improve sweep efficiency. Foam generation can occur in-situ by simultaneous injection of surfactants and gas or through pre-generated foam injection into the reservoir. In this work, a series of systematic simulations were run to investigate how much injected fluids can reduce gas breakthrough while also increasing oil recovery. Subsequently, we analyzed the most effective optimization strategies, considering their economic limits. Our primary objective is to numerically model nanofoam flooding as an innovative EOR approach, synergizing foam flooding mechanisms with nanotechnology benefits. In this work, modeling of nanoparticles in foam liquid was represented by the interfacial properties provided to the injection fluid. Additionally, we simulated Water-Alternating-Gas (WAG) injection schemes across various cycles, comparing their outcomes. Our results showed that nanofoam injection achieved a higher recovery factor of at least 38% and 95% more than WAG and gas injections, respectively. The superior efficiency and productivity of foam injection compared to WAG and gas injection suggest an optimal EOR approach within the scope of our model. These simulated optimization techniques contribute to the future development of processes in this field.

Gut Microbiota and Biomarkers of Endothelial Dysfunction in Cirrhosis.

Our aim was to study the association of endothelial dysfunction biomarkers with cirrhosis manifestations, bacterial translocation, and gut microbiota taxa. The fecal microbiome was assessed using 16S rRNA gene sequencing. Plasma levels of nitrite, big endothelin-1, asymmetric dimethylarginine (ADMA), presepsin, and claudin were measured as biomarkers of endothelial dysfunction, bacterial translocation, and intestinal barrier dysfunction. An echocardiography with simultaneous determination of blood pressure and heart rate was performed to evaluate hemodynamic parameters. Presepsin, claudin 3, nitrite, and ADMA levels were higher in cirrhosis patients than in controls. Elevated nitrite levels were associated with high levels of presepsin and claudin 3, the development of hemodynamic circulation, hypoalbuminemia, grade 2-3 ascites, overt hepatic encephalopathy, high mean pulmonary artery pressure, increased abundance of Proteobacteria and Erysipelatoclostridium, and decreased abundance of Oscillospiraceae, Subdoligranulum, Rikenellaceae, Acidaminococcaceae, Christensenellaceae, and Anaerovoracaceae. Elevated ADMA levels were associated with higher Child-Pugh scores, lower serum sodium levels, hypoalbuminemia, grade 2-3 ascites, milder esophageal varices, overt hepatic encephalopathy, lower mean pulmonary artery pressure, and low abundance of Erysipelotrichia and Erysipelatoclostridiaceae. High big endothelin-1 levels were associated with high levels of presepsin and sodium, low levels of fibrinogen and cholesterol, hypocoagulation, increased Bilophila and Coprobacillus abundances, and decreased Alloprevotella abundance.

Antimicrobial prophylaxis for vesicoureteral reflux: which subgroups of children benefit the most?

BACKGROUND: While the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial found that long-term antimicrobial prophylaxis reduced the risk of urinary tract infection (UTI) recurrences by 50%, 10 children had to be treated for one to benefit (i.e., observed number needed to treat (NNT) of 10). Accordingly, we re-analyzed RIVUR data to systematically identify subgroups of children with vesicoureteral reflux (VUR) with a smaller NNT. METHODS: Using patient-level data from the RIVUR trial, we applied penalized regression methods including the baseline age, VUR grade, type of index UTI, and bowel-bladder dysfunction (BBD) as covariates to identify subgroups. RESULTS: We identified four relevant subgroups of children that appear to benefit from long-term antimicrobial prophylaxis, all with observed NNTs smaller than or equal to 5: children with grade IV VUR, BBD, and febrile index UTI (1% of the sample), children with BBD and febrile index UTI (7% of the sample), children with BBD (12% of the sample), and children with grade IV VUR (8% of the sample). CONCLUSIONS: Use of long-term antimicrobial prophylaxis appears to be particularly relevant for children with BBD (and any grade of VUR) and those with grade IV VUR (regardless of BBD status). However, because details regarding the treatment of BBD are not available, further studies are needed to fully determine the role of prophylactic antimicrobials in the management of children with VUR who have BBD.

Peripheral 5-HT/HTR6 axis is responsible for obesity-associated hypertension.

Hypertension is one of the major life-threatening complications of obesity. Recently adipose multipotent mesenchymal stromal cells (MSCs) were implicated to the pathogenesis of obesity-associated hypertension. These cells amplify noradrenaline-induced vascular cell contraction via cAMP-mediated signaling pathway. In this study we tested the ability of several cAMP-mediated hormones to affect the adrenergic sensitivity of MSCs and their associated contractility. Despite that adipose MSCs express a plethora of receptors capable of cAMP signaling activation, only 5-HT was able to elevate α1A-adrenoceptor-induced Ca2+ signaling in MSCs. Furthermore, 5-HT markedly enhanced noradrenaline-induced MSCs contractility. Using HTR isoform-specific antagonists followed by CRISPRi-mediated knockdown, we identified that the observed 5-HT effect on MSCs was mediated by the HTR6 isoform. This receptor was previously associated exclusively with 5-HT central nervous system activity. Discovered effect of HTR6 on MSCs contractility points to it as a potential therapeutic target for the prevention and treatment of obesity-associated hypertension.

A frequentist design for basket trials using adaptive lasso.

A basket trial aims to expedite the drug development process by evaluating a new therapy in multiple populations within the same clinical trial. Each population, referred to as a "basket", can be defined by disease type, biomarkers, or other patient characteristics. The objective of a basket trial is to identify the subset of baskets for which the new therapy shows promise. The conventional approach would be to analyze each of the baskets independently. Alternatively, several Bayesian dynamic borrowing methods have been proposed that share data across baskets when responses appear similar. These methods can achieve higher power than independent testing in exchange for a risk of some inflation in the type 1 error rate. In this paper we propose a frequentist approach to dynamic borrowing for basket trials using adaptive lasso. Through simulation studies we demonstrate adaptive lasso can achieve similar power and type 1 error to the existing Bayesian methods. The proposed approach has the benefit of being easier to implement and faster than existing methods. In addition, the adaptive lasso approach is very flexible: it can be extended to basket trials with any number of treatment arms and any type of endpoint.

All Kinds of Sunny Colors Synthesized from Methane: Genome-Encoded Carotenoid Production by Methylomonas Species.

Carotenoids are secondary metabolites that exhibit antioxidant properties and are characterized by a striking range of colorations from red to yellow. These natural pigments are synthesized by a wide range of eukaryotic and prokaryotic organisms. Among the latter, carotenoid-producing methanotrophic bacteria, which display fast growth on methane or natural gas, are of particular interest as potential producers of a feed protein enriched with carotenoids. Until recently, Methylomonas strain 16a and Methylomonas sp. ZR1 remained the only representatives of the genus for which detailed carotenoid profile was determined. In this study, we analyzed the genome sequences of five strains of Methylomonas species whose pigmentation varied from white and yellow to orange and red, and identified carotenoids produced by these bacteria. Carotenoids synthesized using four pigmented strains included C30 fraction, primarily composed of 4,4'-diaplycopene-4,4'-dioic acid and 4,4'-diaplycopenoic acid, as well as C40 fraction with the major compound represented by 1,1'-dihydroxy-3,4-didehydrolycopene. The genomes of studied Methylomonas strains varied in size between 4.59 and 5.45 Mb and contained 4201-4735 protein-coding genes. These genomes and 35 reference Methylomonas genomes available in the GenBank were examined for the presence of genes encoding carotenoid biosynthesis. Genomes of all pigmented Methylomonas strains harbored genes necessary for the synthesis of 4,4'-diaplycopene-4,4'-dioic acid. Non-pigmented "Methylomonas montana" MW1T lacked the crtN gene required for carotenoid production. Nearly all strains possessed phytoene desaturases, which explained their ability to naturally synthesize lycopene. Thus, members of the genus Methylomonas can potentially be considered as producers of C30 and C40 carotenoids from methane.

One Step Closer to Enigmatic USCα Methanotrophs: Isolation of a Methylocapsa-like Bacterium from a Subarctic Soil.

The scavenging of atmospheric trace gases has been recognized as one of the lifestyle-defining capabilities of microorganisms in terrestrial polar ecosystems. Several metagenome-assembled genomes of as-yet-uncultivated methanotrophic bacteria, which consume atmospheric CH4 in these ecosystems, have been retrieved in cultivation-independent studies. In this study, we isolated and characterized a representative of these methanotrophs, strain D3K7, from a subarctic soil of northern Russia. Strain D3K7 grows on methane and methanol in a wide range of temperatures, between 5 and 30 °C. Weak growth was also observed on acetate. The presence of acetate in the culture medium stimulated growth at low CH4 concentrations (~100 p.p.m.v.). The finished genome sequence of strain D3K7 is 4.15 Mb in size and contains about 3700 protein-encoding genes. According to the result of phylogenomic analysis, this bacterium forms a common clade with metagenome-assembled genomes obtained from the active layer of a permafrost thaw gradient in Stordalen Mire, Abisco, Sweden, and the mineral cryosol at Axel Heiberg Island in the Canadian High Arctic. This clade occupies a phylogenetic position in between characterized Methylocapsa methanotrophs and representatives of the as-yet-uncultivated upland soil cluster alpha (USCα). As shown by the global distribution analysis, D3K7-like methanotrophs are not restricted to polar habitats but inhabit peatlands and soils of various climatic zones.

Antimicrobial prophylaxis for vesicoureteral reflux: which subgroups of children benefit the most?

Background: While the Randomized Intervention for children with Vesicoureteral Reflux (RIVUR) trial found that long-term antimicrobial prophylaxis reduced the risk of urinary tract infection (UTI) recurrences by 50%, 10 children had to be treated with long-term antimicrobial prophylaxis for one to benefit (i.e., observed number needed to treat (NNT) of 10). Accordingly, we re-analyzed RIVUR data to systematically identify subgroups of children with vesicoureteral reflux (VUR) with a smaller NNT. Methods: Using patient-level data from the RIVUR trial, we applied penalized regression methods including the baseline age, VUR, and bowel-bladder dysfunction (BBD) as covariates to identify subgroups that consider the trade-off between absolute risk difference and size. Results: We identified three relevant subgroups of children that appear to benefit from long-term antimicrobial prophylaxis, all with NNTs smaller than the NNT of 10. Children with grade IV VUR and BBD, 1% of the RIVUR sample, had a NNT of 2; children with BBD, 12% of the RIVUR sample, had a NNT of 4; children with BBD (and any grade VUR) or with grade IV VUR (regardless of BBD status), which was the combination of the first two subgroups and included 19% of children in the RIVUR sample, had a NNT of 4. Conclusions: Use of long-term antimicrobial prophylaxis appears to be particularly relevant for children with BBD (and any grade of VUR) or those with grade IV VUR (regardless of BBD status) who were at high risk of UTI recurrences.

Genome Analysis and Physiology of Pseudomonas sp. Strain OVF7 Degrading Naphthalene and n-Dodecane.

The complete genome of the naphthalene- and n-alkane-degrading strain Pseudomonas sp. strain OVF7 was collected and analyzed. Clusters of genes encoding enzymes for the degradation of naphthalene and n-alkanes are localized on the chromosome. Based on the Average Nucleotide Identity and digital DNA-DNA Hybridization compared with type strains of the group of fluorescent pseudomonads, the bacterium studied probably belongs to a new species. Using light, fluorescent, and scanning electron microscopy, the ability of the studied bacterium to form biofilms of different architectures when cultured in liquid mineral medium with different carbon sources, including naphthalene and n-dodecane, was demonstrated. When grown on a mixture of naphthalene and n-dodecane, the strain first consumed naphthalene and then n-dodecane. Cultivation of the strain on n-dodecane was characterized by a long adaptation phase, in contrast to cultivation on naphthalene and a mixture of naphthalene and n-dodecane.

Water-Soluble Nanocomposites Containing Co3O4 Nanoparticles Incorporated in Poly-1-vinyl-1,2,4-triazole.

New water-soluble nanocomposites with cobalt oxide nanoparticles (Co3O4NPs) in a poly(1-vinyl-1,2,4-triazole) (PVT) matrix have been synthesized. The PVT used as a stabilizing polymer matrix was obtained by radical polymerization of 1-vinyl-1,2,4-triazole (VT). The polymer nanocomposites with Co3O4 nanoparticles were characterized by ultraviolet-visible, Fourier-transform infrared spectroscopy, atomic absorption spectroscopy, transmission electron microscopy, dynamic light scattering, gel permeation chromatography, and simultaneous thermogravimetric analysis. The resulting polymer nanocomposites consist of spherical isolated cobalt nanoparticles with a diameter of 1 to 13 nm. The average hydrodynamic diameters of macromolecular coils are 15-112 nm. The cobalt content in nanocomposites ranges from 1.5 to 11.0 wt.%. The thermal stability of nanocomposites is up to 320 °C.

Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.

Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUVmax of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUVmax was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.

Endothelial Function and Hypoxic-Hyperoxic Preconditioning in Coronary Surgery with a Cardiopulmonary Bypass: Randomized Clinical Trial.

A hypoxic-hyperoxic preconditioning (HHP) may be associated with cardioprotection by reducing endothelial damage and a beneficial effect on postoperative outcome in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Patients (n = 120) were randomly assigned to an HHP and a control group. A safe, inhaled oxygen fraction for the hypoxic preconditioning phase (10-14% oxygen for 10 min) was determined by measuring the anaerobic threshold. At the hyperoxic phase, a 75-80% oxygen fraction was used for 30 min. The cumulative frequency of postoperative complications was 14 (23.3%) in the HHP vs. 23 (41.1%), p = 0.041. The nitrate decreased after surgery by up to 20% in the HHP group and up to 38% in the control group. Endothelin-1 and nitric oxide metabolites were stable in HHP but remained low for more than 24 h in the control group. The endothelial damage markers appeared to be predictors of postoperative complications. The HHP with individual parameters based on the anaerobic threshold is a safe procedure, and it can reduce the frequency of postoperative complications. The endothelial damage markers appeared to be predictors of postoperative complications.

Fully order restricted multi-arm multi-stage clinical trial design.

We consider a multi-arm trial with two or more active treatments plus a control where it is reasonable to assume an order for the treatment effects of the active arms compared to control. For example, the arms could be a high dose and low dose of a new drug and a placebo. The objective of the trial is to compare each active arm to control while maintaining strong control of the type 1 error rate. We show that when the study is powered to identify all promising treatments, a design that uses the order of the treatment effects to calculate the test statistic and to set the order of testing requires a smaller sample size than a design where each active arm is tested against the control arm independently. Under the considered settings, the sample size for a single-stage trial and a two-stage trial was reduced by at least 20%.