Stability of End-of-Life Care Wishes and Gender-Specific Characteristics of Outpatients with Advanced Cancer under Palliative Therapy: A Prospective Observational Study.

Introduction: Early integration of palliative care and advance care planning (ACP) play an increasingly important role in the treatment of patients with advanced cancer. Advance directives (ADs) and patients' preferences regarding end-of-life (EoL) care are important aspects of ACP. In the outpatient setting, the prevalence of those documents and EoL care wishes is not well investigated, and changes in the longitudinal course are poorly understood.

Rapid point-of-care detection of SARS-CoV-2 infection in exhaled breath using ion mobility spectrometry: a pilot study.

Background: An effective testing strategy is essential for pandemic control of the novel Coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Breath gas analysis can expand the available toolbox for diagnostic tests by using a rapid, cost-beneficial, high-throughput point-of-care test. We conducted a bi-center clinical pilot study in Germany to evaluate breath gas analysis using multi-capillary column ion mobility spectrometry (MCC-IMS) to detect SARS-CoV-2 infection.

Expectations, end-of-life fears and end-of-life communication among palliative patients with cancer and caregivers: a cross-sectional study.

Objectives: During serious illness, open communication with caregivers can ensure high-quality care. Without end-of-life communication, caregivers may become surrogates and decision-makers without knowing the patient's preferences. However, expectations and fears may influence the initiation of communication.

Identification of Diarylurea Inhibitors of the Cardiac-Specific Kinase TNNI3K by Designing Selectivity Against VEGFR2, p38α, and B-Raf.

A series of diarylurea inhibitors of the cardiac-specific kinase TNNI3K were developed to elucidate the biological function of TNNI3K and evaluate TNNI3K as a therapeutic target for the treatment of cardiovascular diseases. Utilizing a structure-based design, enhancements in kinase selectivity were engineered into the series, capitalizing on the established X-ray crystal structures of TNNI3K, VEGFR2, p38α, and B-Raf. Our efforts culminated in the discovery of an tool compound (GSK329), which exhibited desirable TNNI3K potency and rat pharmacokinetic properties as well as promising kinase selectivity against VEGFR2 (40-fold), p38α (80-fold), and B-Raf (>200-fold).

A Different Kind of Relapse: Ethanol as an Additive in Chemotherapy Formulations.

Some chemotherapy formulations contain ethanol as a solvent which can become relevant for medical and nonmedical reasons. Only a few studies have tried to quantify the effects of ethanol in chemotherapy preparations. Furthermore, the alcohol amount highly depends on the specific formulation, with some variation among different manufacturers.

Social Freezing in Medical Practice. Experiences and Attitudes of Gynecologists in Germany.

Surveys of the German public have revealed a high acceptance of social freezing, i.e. oocyte conservation without medical indication.

A randomised assessment of the use of a quality of life questionnaire with or without intervention in patients attending a thoracic cancer clinic.

The study examined the impact of using a quality of life (QoL) questionnaire during a clinic to identify QoL issues and to improve QoL. 138 patients were randomised (1:1:1) to either (1) an Intervention group that completed the European Organisation for Research and Treatment of Cancer-Core Quality of Life Questionnaire and Lung Cancer Module (EORTC QLQ-C30 and LC13) at baseline and received feedback during a clinic, (2) an Attention group that completed the questionnaire at baseline without feedback and (3) a Control group that did not complete the questionnaire. All patients completed the same questionnaire 6 weeks later and a contact diary during the study period.

Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K).

A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC).

Sirtuin 1 activator SRT2104 protects Huntington's disease mice.

Sirtuin 1 is a nicotinamide adenine dinucleotide-dependent protein deacetylase which regulates longevity and improves metabolism. Activation of Sirtuin 1 confers beneficial effects in models of neurodegenerative diseases. We and others have provided convincing evidence that overexpression of Sirtuin 1 plays a neuroprotective role in mouse models of Huntington's disease.

Glucose control in intensive care: usability, efficacy and safety of Space GlucoseControl in two medical European intensive care units.

Background: The Space GlucoseControl system (SGC) is a nurse-driven, computer-assisted device for glycemic control combining infusion pumps with the enhanced Model Predictive Control algorithm (B. Braun, Melsungen, Germany). We aimed to investigate the performance of the SGC in medical critically ill patients.

Breast cancer mastectomy trends between 2006 and 2010: association with magnetic resonance imaging, immediate breast reconstruction, and hospital volume.

Purpose: Analysis of mastectomy rates in breast cancer patients diagnosed between 2006 and 2010 in Germany with focus on impact of breast magnetic resonance imaging (MRI), immediate breast reconstruction (IBR) rates, and hospital volume as possible influencing factors of mastectomy rates.

Methods: Data of a voluntary monitored benchmarking project were used to evaluate mastectomy trends across time in an unselected cohort of breast cancer patients. We used univariate and multivariate logistic regression analysis to identify predictive factors of mastectomy.

Efficacy and safety of glucose control with Space GlucoseControl in the medical intensive care unit--an open clinical investigation.

Background: We aimed to investigate the performance of the Space GlucoseControl system (SGC) (B. Braun, Melsungen, Germany) in medical critically ill patients. The SGC is a nurse-driven, computer-assisted device for glycemic control combining infusion pumps with the enhanced Model Predictive Control algorithm.

The efficacy of assertive community treatment to treat substance use.

Background: Assertive Community Treatment (ACT) has been studied extensively in people with severe mental illness, but there have only been a few clinical trials in which substance use was one of the measured outcomes.

Objective: The goal of this article was to describe the efficacy of ACT in treating co-occurring substance use disorders and suggest approaches to make it more efficacious.

Design: A literature review was conducted and randomized clinical trials describing ACT's impact on substance use were reviewed.

Structure-activity relationship studies of novel 3-oxazolidinedione-6-naphthyl-2-pyridinones as potent and orally bioavailable EP3 receptor antagonists.

Multiple regions of the 3-oxazolidinedione-6-naphthyl-pyridinone series identified via high throughput screening were explored. SAR studies of these regions including the left-hand side oxazolidinedione moiety, α-substituent on the oxazolidinedione ring, central pyridinone core, and substituents on the central pyridinone core led to the discovery of potent EP(3) receptor antagonists such as compound 29 which possesses outstanding rat pharmacokinetic properties. Synthesis and SAR of these novel compounds and DMPK properties of representative compounds are discussed.

Effects of breeding at the second oestrus or after post-weaning hormonal treatment with altrenogest on subsequent reproductive performance of primiparous sows.

This study investigated the effects of breeding at the second oestrus after weaning or after feeding an orally active progestagen (altrenogest) on the subsequent reproductive performance of primiparous sows. After 3 weeks of lactation, 663 weaned sows of two genotypes were allocated into three groups: G1--breeding at the first oestrus after weaning; G2--breeding at the second oestrus after weaning and G3--treatment with altrenogest for 5 days after weaning and breeding at the first oestrus after the end of the treatment. Body weight at breeding was lower in G1 and G3 than in G2 sows (p < 0.

Novel 3-Oxazolidinedione-6-aryl-pyridinones as Potent, Selective, and Orally Active EP3 Receptor Antagonists.

High-throughput screening and subsequent optimization led to the discovery of novel 3-oxazolidinedione-6-aryl-pyridinones exemplified by compound 2 as potent and selective EP3 antagonists with excellent pharmacokinetic properties. Compound 2 was orally active and showed robust in vivo activities in overactive bladder models. To address potential bioactivation liabilities of compound 2, further optimization resulted in compounds 9 and 10, which maintained excellent potency, selectivity, and pharmacokinetic properties and showed no bioactivation liability in glutathione trapping studies.

3-Urea-1-(phenylmethyl)-pyridones as novel, potent, and selective EP3 receptor antagonists.

A series of 3-urea-1-(phenylmethyl)-pyridones was discovered as novel EP(3) antagonists via high-throughput screening and subsequent optimization. The synthesis, structure-activity relationships, and optimization of the initial hit that resulted in potent and selective EP(3) receptor antagonists such as 11g are described.

Discovery of novel aminothiadiazole amides as selective EP(3) receptor antagonists.

This Letter discloses a series of 2-aminothiadiazole amides as selective EP(3) receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed.

Synthesis and SAR of amino acid-derived heterocyclic progesterone receptor full and partial agonists.

Two classes of amino acid-derived heterocyclic progesterone receptor ligands were developed to address the metabolic issues posed by the dimethyl amide functionality of the lead compound (1). The tetrazole-derived ligands behaved as potent partial agonists, while the 1,2,4-triazole ligands behaved as potent full agonists.

Palosuran inhibits binding to primate UT receptors in cell membranes but demonstrates differential activity in intact cells and vascular tissues.

Background And Purpose: The recent development of the UT ligand palosuran (1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulphate salt) has led to the proposition that urotensin-II (U-II) plays a significant pathological role in acute and chronic renal injury in the rat.

Experimental Approach: In the present study, the pharmacological properties of palosuran were investigated further using a series of radioligand binding and functional bioassays.

Key Results: Palosuran functioned as a 'primate-selective' UT ligand in recombinant cell membranes (monkey and human UT K(i) values of 4 +/- 1 and 5 +/- 1 nM), lacking appreciable affinity at other mammalian UT isoforms (rodent and feline K(i) values >1 microM).

An excitatory role for peripheral EP3 receptors in bladder afferent function.

The excitatory roles of EP3 receptors at the peripheral afferent nerve innervating the rat urinary bladder have been evaluated by using the selective EP3 antagonist (2E)-3-[1-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl]-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041). The bladder rhythmic contraction model and a bladder pain model measuring the visceromotor reflex (VMR) to urinary bladder distension (UBD) have been used to evaluate DG-041 in female rats. In addition, male rats [spontaneously hypertensive rat (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD)] were anesthetized with pentobarbital sodium, and primary afferent fibers in the L6 dorsal root were isolated for recording the inhibitory response to UBD following intravenous injection of DG-041.

Potent and selective small-molecule human urotensin-II antagonists with improved pharmacokinetic profiles.

Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.

Development of potent and selective small-molecule human Urotensin-II antagonists.

This work describes the development of potent and selective human Urotensin-II receptor antagonists starting from lead compound 1, (3,4-dichlorophenyl)methyl{2-oxo-2-[3-phenyl-2-(1-pyrrolidinylmethyl)-1-piperidinyl]ethyl}amine. Several problems relating to oral bioavailability, cytochrome P450 inhibition, and off-target activity at the kappa opioid receptor and cardiac sodium channel were addressed during lead development. hUT binding affinity relative to compound 1 was improved by more than 40-fold in some analogs, and a structural modification was identified which significantly attenuated both off-target activities.

Mutation screen and association studies in the diacylglycerol O-acyltransferase homolog 2 gene (DGAT2), a positional candidate gene for early onset obesity on chromosome 11q13.

Background: DGAT2 is a promising candidate gene for obesity because of its function as a key enzyme in fat metabolism and because of its localization on chromosome 11q13, a linkage region for extreme early onset obesity detected in our sample. We performed a mutation screen in 93 extremely obese children and adolescents and 94 healthy underweight controls. Association studies were performed in samples of up to 361 extremely obese children and adolescents and 445 healthy underweight and normal weight controls.