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Over the past years our lab has established a research program towards the late-stage introduction of deuterium into organic molecules using Pd-catalyzed reversible C–H activation as a means to affect hydrogen isotope exchange. Through catalyst design, including the introduction of novel ligand scaffolds, as well as the use of strategically chosen optimization and screening approaches, e.g., exploiting microscopic reversibility by first optimizing de-deuteration processes or using a multi-substrate screening approach, our studies have resulted in a number of synthetically useful labelling protocols and are described herein from a personal perspective. 1 Introduction 2 β-C(sp3)–H Deuteration of Free Carboxylic Acids 3 Nondirected C–H Deuteration of Arenes 4 Nondirected C–H Deuteration of Heteroarenes 5 Conclusion [ABSTRACT FROM AUTHOR]

The importance of deuterium labelling in a variety of applications, ranging from mechanistic studies to drug‐discovery, has spurred immense interest in the development of new methods for its efficient incorporation in organic, and especially in bioactive molecules. The five‐membered heteroarenes at the center of this work are ubiquitous motifs in bioactive molecules and efficient methods for the deuterium labelling of these compounds are therefore highly desirable. However, the profound differences in chemical properties encountered between different heteroarenes hamper the development of a single set of broadly applicable reaction conditions, often necessitating a separate optimization campaign for a given type of heteroarene. In this study we describe the use of a multi‐substrate screening approach to identify optimal reaction conditions for different classes of heteroarenes from a minimal number of screening reactions. Using this approach, four sets of complementary reaction conditions derived from our dual ligand‐based palladium catalysts for nondirected C(sp2)−H activation were identified, that together enable the deuteration of structurally diverse heteroarenes, including bioactive molecules. [ABSTRACT FROM AUTHOR]

Two new manganese(II) complexes bearing bis(imino)pyridine pincer ligands have been synthesized. These manganese(II) complexes were characterized by UV, IR, elemental analysis studies, and X‐ray crystallography. The X‐ray crystal data of manganese complexes revealed distorted trigonalbipyramidal geometries around the manganese ion and neutral tridentate N^N^N coordination mode for bis(imino)pyridine (BIP) ligand. The catalytic properties of manganese(II) complexes were explored for the catalytic oxidation of the benzylic C−H bonds using TBHP as an oxidant. The corresponding carbonyl compounds have been produced in moderate to excellent yields. [ABSTRACT FROM AUTHOR]

This article provides a novel approach to assess the importance of specific treatment phases within a treatment regimen through tipping point analyses (TPA) of a time-to-event endpoint using rank-preserving-structural-failure-time (RPSFT) modeling. In oncology clinical research, an experimental treatment is often added to the standard of care therapy in multiple treatment phases to improve patient outcomes. When the resulting new regimen provides a meaningful benefit over standard of care, gaining insights into the contribution of each treatment phase becomes important to properly guide clinical practice. New statistical approaches are needed since traditional methods are inadequate in answering such questions. RPSFT modeling is an approach for causal inference, typically used to adjust for treatment switching in randomized clinical trials with time-to-event endpoints. A tipping-point analysis is commonly used in situations where a statistically significant treatment effect is suspected to be an artifact of missing or unobserved data rather than a real treatment difference. The methodology proposed in this article is an amalgamation of these two ideas to investigate the contribution of a specific component of a regimen comprising multiple treatment phases. We provide different variants of the method and construct indices of contribution of a treatment phase to the overall benefit of a regimen that facilitates interpretation of results. The proposed approaches are illustrated with findings from a recently concluded, real-life phase 3 cancer clinical trial. We conclude with several considerations and recommendations for practical implementation of this new methodology. [ABSTRACT FROM AUTHOR]

Two new zinc(II) complexes, [2,6‐bis(methylphenyliminomethyl)pyridine]ZnBr2 (2 a) and [2,6‐bis(triflouromethylphenyliminomethyl)pyridine]ZnBr2 (2 b) were synthesized by the reactions of corresponding 2,6‐bis(imino)pyridine based [NNN]‐pincer ligand and anhydrous ZnBr2 in acetonitrile as a solvent. The catalytic properties of zinc(II) complexes were examined in azide‐alkyne cycloaddition reactions in water. The zinc(II) complexes were characterized by UV‐Vis, 1H NMR, IR, elemental analysis and mass spectroscopy. The zinc complex [2,6‐bis(triflouromethylphenyliminomethyl)pyridine]ZnBr2 was characterized by X‐ray crystallography. The zinc(II) complexes efficiently catalyzed the azide‐alkyne cycloaddition reaction for the synthesis of 1,2,3‐triazoles (mixture of 1,4‐ and 1,5‐disubstituted 1,2,3‐triazoles) in water with good to excellent yields. [ABSTRACT FROM AUTHOR]

The FDA's Accelerated Approval program (AA) is a regulatory program to expedite availability of products to treat serious or life-threatening illnesses that lack effective treatment alternatives. Ideally, all of the many stakeholders such as patients, physicians, regulators, and health technology assessment [HTA] agencies that are affected by AA should benefit from it. In practice, however, there is intense debate over whether evidence supporting AA is sufficient to meet the needs of the stakeholders who collectively bring an approved product into routine clinical care. As AAs have become more common, it becomes essential to be able to determine their impact objectively and reproducibly in a way that provides for consistent evaluation of therapeutic decision alternatives. We describe the basic features of an approach for evaluating AA impact that accommodates stakeholder-specific views about potential benefits, risks, and costs. The approach is based on a formal decision-analytic framework combining predictive distributions for therapeutic outcomes (efficacy and safety) based on statistical models that incorporate findings from AA trials with stakeholder assessments of various actions that might be taken. The framework described here provides a starting point for communicating the value of a treatment granted AA in the context of what is important to various stakeholders. [ABSTRACT FROM AUTHOR]

We report the results obtained from a multiwavelength study of the H ii region G18.148âˆ'0.283 using the upgraded Giant Metrewave Radio Telescope at 1350 MHz, along with other archival data. In addition to the radio continuum emission, we have detected the H169 α and H170 α radio recombination lines toward G18.148âˆ'0.283 using a correlator bandwidth of 100 MHz. The moment-1 map of the ionized gas reveals a velocity gradient of approximately 10 km sâˆ'1 across the radio continuum peaks. The 12CO (J = 3âˆ'2) molecular line data from the CO High-Resolution Survey (COHRS) also show the presence of two velocity components that are very close to the velocities detected in the ionized gas. The spectrum and positionâ€"velocity diagram from CO emission reveal molecular gas at an intermediate-velocity range bridging the velocity components. We see mid-infrared absorption and far-infrared emission establishing the presence of a filamentary infrared dark cloud, the extent of which includes the targeted H ii region. The magnetic field inferred from dust polarization is perpendicular to the filament within the H ii region. We have also identified two O9 stars and 30 young stellar objects toward the target using data from the Two Micron All Sky Survey (2MASS), UKIRT Infrared Deep Sky Survey (UKIDSS), and Galactic Legacy Infrared Midplane Survey Extraordinaire (GLIMPSE). Cumulatively, this suggests that the region is the site of a cloudâ€"cloud collision that has triggered massive star formation and subsequent formation of an H ii region. [ABSTRACT FROM AUTHOR]

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention‐to‐treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment‐policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross‐industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation. [ABSTRACT FROM AUTHOR]

Synthesis and stabilization of ultra-small metal nanoparticles (MNPs) composed of a few atoms are of paramount importance in modulating their material properties based on quantum confinement effects. The highly reactive surface of small MNPs tends to aggregate, resulting in bigger particles and subsequent deterioration of the catalytic activity. In this work, we exploited a dithienylethene (DTE) based photochromic organic cage (TAE-DTE) for the in situ stabilization of ultra-small Au NPs (Au@TAE-DTE) (<2 nm) through a unique "reverse double-solvent approach (RDSA)". The Au@TAE-DTE showed similar photochromic properties to the TAE-DTE and shuttled between two metastable photoisomers, Au@TAE-DTE-O and Au@TAE-DTE-C, based on DTE ring opening and closing upon treating with visible and UV-light, respectively. The Au@TAE-DTE hybrid showed visible light (λ = 400–750 nm) driven catalytic activity for photochemical CO2 reduction to CO. Importantly, irradiating with light of the full range (λ = 250–750 nm) allowed for co-existence of both photoisomers which thereby showed wide spectrum absorption as compared to individual photoisomers, consequently displaying substantially enhanced performance for the photocatalytic CO2 reduction. Further, the real-time progress of the CO2 reduction reaction and corresponding reaction intermediates was detected by an in situ DRIFT experiment. [ABSTRACT FROM AUTHOR]

The study of the intensity fluctuation power spectrum of individual supernova remnants (SNRs) can reveal the structures present at sub-pc scales, and also constrain the physical process that generates those structures. There are various effects, such as the remnant shell thickness, projection of a three-dimensional structure on to a two-dimensional observational plane, and the presence of diffuse 'foreground' emission, which causes the observed power spectrum to deviate from the intrinsic power spectrum of the fluctuations. Here, we report results from a systematic study of these effects, using direct numerical simulations, in the measured power spectrum. For an input power-law power spectrum, independent of the power-law index, we see a break in the observed power law at a scale which depends on the shell thickness of a shell-type SNR, and the three-dimensional turbulence changes to two-dimensional turbulence beyond that scale. We also report how the estimated power spectrum is expected to deviate from the intrinsic SNR power spectrum in the presence of additional diffuse Galactic synchrotron emission (DGSE) around the remnant shell. For a reasonable choice of the parameters, if the intrinsic SNR power spectrum is shallower than the DGSE power spectrum, the SNR contribution dominates at small angular scales of the estimated power spectra. On the other hand, if the SNR power spectrum is relatively steeper, the original power spectra is recovered only over a small window of angular scales. This study shows how detailed modelling may be used to infer the true power spectrum from the observed SNR intensity fluctuations power spectrum, which in turn can be used to constrain the nature of the turbulence that gives rise to these small-scale structures. [ABSTRACT FROM AUTHOR]

Background: In randomized clinical trials with censored time-to-event outcomes, the logrank test is known to have substantial statistical power under the proportional hazards assumption and is widely adopted as a tool to compare two survival distributions. However, the proportional hazards assumption is impossible to validate in practice until the data are unblinded. However, the statistical analysis plan of a randomized clinical trial and in particular its primary analysis method must be pre-specified before any unblinded information may be reviewed. Purpose: The purpose of this article is to guide applied biostatisticians in the prespecification of a desired primary analysis method when a treatment effect with nonproportional hazards is anticipated. While articles proposing alternate statistical tests are aplenty, to the best of our knowledge, there is no article available that attempts to simplify the choice and prespecification of a primary statistical test under specific expected patterns on nonproportional hazards. We provide such guidance by reviewing various tests proposed as more powerful alternatives to the standard logrank test under nonproportional hazards and simultaneously comparing their performance under a wide variety of nonproportional hazards scenarios to elucidate their advantages and disadvantages. Method: In order to select the most preferable test for detecting specific differences between survival distributions of interest while controlling false positive rates, we review and assess the performance of weighted and adaptively weighted logrank tests, weighted and adaptively weighted Kaplan–Meier tests and versatile tests under various patterns of nonproportional hazards treatment effects through simulation. Conclusion: We validate some of the claimed properties of the proposed extensions and identify tests that may be more preferable under specific expected pattern of nonproportional hazards when such knowledge is available. We show that versatile tests, while achieving robustness to departures from proportional hazards, may lose interpretation of directionality (superiority or inferiority) and can only be seen to test departures from equality. Detailed summary and discussion of the performance of each test in terms of type I error rate and power are provided to formulate specific guidance about their applicability and use. [ABSTRACT FROM AUTHOR]

Aims: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin‐to‐creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. Materials and Methods: SONAR is a randomized, double‐blind, placebo‐controlled trial with approximately 3500 participants who have stage 2–4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin‐angiotensin system inhibitor. Results: After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non‐responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end‐stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). Conclusion: SONAR aims to determine whether atrasentan added to guideline‐recommended therapies safely reduces the risk of CKD progression and delays the onset of end‐stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial “surrogate” response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Lucatumumab is a fully humanized anti-CD40 antibody that blocks interaction of CD40L with CD40 and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC). We evaluated lucatumumab in a phase I clinical trial in chronic lymphocytic leukemia (CLL). Twenty-six patients with relapsed CLL were enrolled on five different dose cohorts administered weekly for 4 weeks. The maximally tolerated dose (MTD) of lucatumumab was 3.0 mg/kg. Four patients at doses of 4.5 mg/kg and 6.0 mg/kg experienced grade 3 or 4 asymptomatic elevated amylase and lipase levels. Of the 26 patients enrolled, 17 patients had stable disease (mean duration of 76 days, range 29-504 days) and one patient had a nodular partial response for 230 days. Saturation of CD40 receptor on CLL cells was uniform at all doses post-treatment but also persisted at trough time points in the 3.0 mg/kg or greater cohorts. At the MTD, the median half-life of lucatumumab was 50 h following the first infusion, and 124 h following the fourth infusion. In summary, lucatumumab had acceptable tolerability, pharmacokinetics that supported chronic dosing and pharmacodynamic target antagonism at doses of 3.0 mg/kg, but demonstrated minimal single-agent activity. Future efforts with lucatumumab in CLL should focus on combination-based therapy. [ABSTRACT FROM AUTHOR]

The effect of soil pH 4.3, 4.6, and 5.9 on the pathogenicity of Heterodera glycines and Meloidogyne incognita on acid soiladapted soybean genotypes (Davis and PI 416937) was investigated in three glasshouse experiments over 28 days after inoculation with 0 or 1000 (Experiments 1 and 2) and 0 or 5000 (Experiment 3) second-stage juveniles. Although nematodes of both species infected both genotypes at all of the soil pH, the numbers decreased with decreasing soil pH. Both genotypes seem to be better hosts for M. incognita than for H. glycines, Davis more so than PI 416937. Both nematodes decreased shoot weight at high inoculum levels, indicating that H. glycines may be more pathogenic than M. incognita. Nematode development after infection of roots was not affected by soil pH or by genotypes. Overall, the results suggest that adaptation of these nematodes should be considered in breeding programmes to develop low pH tolerant soybean cultivars. [ABSTRACT FROM AUTHOR]

The importance of deuterium labelling in a variety of applications, ranging from mechanistic studies to drug-discovery, has spurred immense interest in the development of new methods for its efficient incorporation in organic, and especially in bioactive molecules. The five-membered heteroarenes at the center of this work are ubiquitous motifs in bioactive molecules and efficient methods for the deuterium labelling of these compounds are therefore highly desirable. However, the profound differences in chemical properties encountered between different heteroarenes hamper the development of a single set of broadly applicable reaction conditions, often necessitating a separate optimization campaign for a given type of heteroarene. In this study we describe the use of a multi-substrate screening approach to identify optimal reaction conditions for different classes of heteroarenes from a minimal number of screening reactions. Using this approach, four sets of complementary reaction conditions derived from our dual ligand-based palladium catalysts for nondirected C(sp 2 )-H activation were identified, that together enable the deuteration of structurally diverse heteroarenes, including bioactive molecules., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Background: Depatuxizumab mafodotin (Depatux-M) is a tumor-specific antibody-drug conjugate consisting of an antibody (ABT-806) directed against activated epidermal growth factor receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as a single agent in a randomized controlled phase II trial in recurrent EGFR amplified glioblastoma., Methods: Eligible were patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide. Patients were randomized to either Depatux-M 1.25 mg/kg every 2 weeks intravenously, or this treatment combined with temozolomide 150-200 mg/m2 day 1-5 every 4 weeks, or either lomustine or temozolomide. The primary endpoint of the study was overall survival., Results: Two hundred sixty patients were randomized. In the primary efficacy analysis with 199 events (median follow-up 15.0 mo), the hazard ratio (HR) for the combination arm compared with the control arm was 0.71 (95% CI = 0.50, 1.02; P = 0.062). The efficacy of Depatux-M monotherapy was comparable to that of the control arm (HR = 1.04, 95% CI = 0.73, 1.48; P = 0.83). The most frequent toxicity in Depatux-M treated patients was a reversible corneal epitheliopathy, occurring as grades 3-4 adverse events in 25-30% of patients. In the long-term follow-up analysis with median follow-up of 28.7 months, the HR for the comparison of the combination arm versus the control arm was 0.66 (95% CI = 0.48, 0.93)., Conclusion: This trial suggests a possible role for the use of Depatux-M in combination with temozolomide in EGFR amplified recurrent glioblastoma, especially in patients relapsing well after the end of first-line adjuvant temozolomide treatment. (NCT02343406)., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Competition on soybean between Heterodera glycines (race 3) and Meloidogyne incognita or H. glycines and Pratylenchus penetrans were investigated in greenhouse experiments. Each pair of nematode species was mixed in 3-ml suspensions at ratios of 1,000:0, 750:250, 500:500, 250:750, and 0:1,000 second-stage juveniles or mixed stages for P. penetrans. Nematodes from a whole root system were counted and infection rates standardized per 1,000 nematodes (per replication) prior to testing the null hypothesis through a lack-of-fit F-test. Although the effect of increasing H. glycines proportions on the infection rate of M. incognita was generally adverse, the rate deviated significantly from a trend of linear decline at the 75% H. glycines level in one of two experiments. All lack-of-fit F-tests for the H. glycines and P. penetrans mix were significant, indicating that infection rates for both nematodes varied considerably across inocula. The infection rate of H. glycines decreased with increasing P. penetrans proportions. The rate of P. penetrans infection increased with increasing H. glycines proportions up to the 50% level, but declined at the 75% level. Competition had no effect on nematode development. The general adverse relationships between M. incognita and H. glycines and those between P. penetrans and H. glycines showed a linear trend. The relationship between H. glycines and P. penetrans indicates that the former may be competitive when present at higher proportions than the latter. In this study we have evaluated nematode competition under controlled conditions and provide results that can form a basis for understanding the physical and physiological trends of multiple nematode interactions. Methods critical to data analyses also are outlined.