Design and Evaluation of Phosphonamidate-Linked Exatecan Constructs for Highly Loaded, Stable, and Efficacious Antibody-Drug Conjugates.

Topoisomerase I (TOP1) Inhibitors constitute an emerging payload class to engineer antibody-drug conjugates (ADC) as next-generation biopharmaceutical for cancer treatment. Existing ADCs are using camptothecin payloads with lower potency and suffer from limited stability in circulation. With this study, we introduce a novel camptothecin-based linker-payload platform based on the highly potent camptothecin derivative exatecan.

Compact hydrophilic electrophiles enable highly efficacious high DAR ADCs with excellent PK profile.

The recent success of antibody-drug conjugates (ADC), exemplified by seven new FDA-approvals within three years, has led to increased attention for antibody based targeted therapeutics and fueled efforts to develop new drug-linker technologies for improved next generation ADCs. We present a highly efficient phosphonamidate-based conjugation handle that combines a discrete hydrophilic PEG-substituent, an established linker-payload and a cysteine-selective electrophile in one compact building block. This reactive entity provides homogeneous ADCs with a high drug-to-antibody ratio (DAR) of 8 in a one-pot reduction and alkylation protocol from non-engineered antibodies.

Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes.

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e.

Large Particle 3D Concrete Printing-A Green and Viable Solution.

The Large Particle 3D Concrete Printing (LP3DCP) process presented in this paper is based on the particle bed 3D printing method; here, the integration of significantly larger particles (up to 36 mm) for selective binding using the shotcrete technique is presented. In the LP3DCP process, the integration of large particles, i.e.

Interpreting time-series COVID data: reasoning biases, risk perception, and support for public health measures.

Effective risk communication during the COVID-19 pandemic is critical for encouraging appropriate public health behaviors. One way that the public is informed about COVID-19 numbers is through reports of daily new cases. However, presenting daily cases has the potential to lead to a dynamic reasoning bias that stems from intuitive misunderstandings of accumulation.

[On risk-oriented model of sanitary epidemiologic surveillance in occupational hygiene].

In 2015, Federal Service on surveillance in consumers rights protection and public well-being set a task to organize planned work of regional agencies on basis of risk-oriented model of control and supervision. Based on results of pilot project in Rospotrebnadzor Department of Perm area and St-Petersburg, the article covers methodic approaches to classification of objects liable to surveillance in occupational hygiene. The classification considers possibility of sanitary law violation, severity of this violation consequences and number of workers exposed to risk factors including hazardous work conditions.

[METHODS AND TECHNOLOGIES OF HEALTH RISK ANALYSIS IN THE SYSTEM OF THE STATE MANAGEMENT UNDER ASSURANCE OF THE SANITATION AND EPIDEMIOLOGICAL WELFARE OF POPULATION].

The methodology of the analysis of health risk at the present stage of development of Russian society is in-demand at all levels of government management. In conjunction with the methods of mathematical modeling, spatial-temporal analysis and economic tools the risk assessment in the analysis of the situation makes it possible to determine the level of safety of the population, workers and consumers, to select prior resources, and threat factors as a point for exertion efforts. At the planning stage risk assessment is a basis for the establishment of most effective measures for the minimization of hazard and dangers.

[Evaluating exposure of population to dust, with consideration of components and dispersion contents of industrial discharges from enterprise extracting and processing mineral raw materials (discussion)].

The article covers results of study concerning disperse content of solid components of discharges from main dust- generating technologic operations in extraction and processing of mineral raw materials (pouring ore to conveyor, drying with combustion gas in fluid-bed, pouring of end product, sorting ore on riddle, drying on vibration dry and cool device, etc). Findings are that fractions under 10 and 2.5 micrometers approach 50% in general structure of dust discharges.

[Composition of the dust for the assessment of the exposure to the population in the areas of influence of industrial emissions of stationary sources].

The results of instrumental studies of the dispersion and component composition of the solid component of the dust gaseous emissions from industrial stationary sources of engineering and metallurgical enterprises are presented. Dust and gas mixtures were established to contain up to 80% fractions with a particle size less than 10 microns (PM10), and 40% of fractions with size smaller than 2.5 microns (PM2.

[Scientific and methodologic basis of a program for occupational control of ambient air quality within a totally sanitary protective zone at an industrial center borderline (Permsky area experience)].

The authors suggested and tested an algorithm to select optimal placement of stationary and mobile points for controlling ambient air quality on borderline of united sanitary protective zone of industrial center. The method involves claster analysis to outline sites even in levels and lists of parameters, on borderline of united sanitary protective zone of industrial center. Informative value of the occupational control parameters is evaluated through conjugated analysis of general level of surface concentration of admixtures and enterprise's contribution into pollution.

Single-molecule study of the DNA denaturation phase transition in the force-torsion space.

We use the "magnetic tweezers" technique to show the structural transitions that the DNA undergoes in the force-torsion space. In particular, we focus on the regions corresponding to negative supercoiling. These regions are characterized by the formation of the so-called denaturation bubbles, which play an essential role in the replication and transcription of DNA.

[Fractional and component composition of dust in the air of workplace at machinery enterprise].

The authors present results of assessment of fractional and component composition of dust entering workplace of machinery enterprises. The results prove topicality of data accumulation on actual contents of dusts for more reliable and precise evaluation of the dusts mixture influence on the workers' health.

Safety of pancreatic surgery in patients with simultaneous liver cirrhosis: a single center experience.

Background/aims: Pancreatic surgery is associated with an increased risk of postoperative complications. We therefore investigated the impact of an additional liver function disorder on the postoperative outcome using a case-control study of patients with or without liver cirrhosis who underwent pancreatic surgery at our department.

Methods: Between 1998 and 2008, 1,649 pancreatic resections were performed.

Moxifloxacin does not alter ciclosporin pharmacokinetics in transplant patients: a multiple-dose, uncontrolled, single-centre study.

Background: Moxifloxacin has a broad antibacterial spectrum and rapid bactericidal activity, and is thus a good option for the treatment of bacterial infections in patients who have undergone organ or bone marrow transplantation. Transplant patients also receive immunosuppressant therapy such as ciclosporin.

Objective: The primary objective of this study was to assess the steady-state pharmacokinetics of ciclosporin with and without concomitant treatment with moxifloxacin in transplant recipients.

Pharmacokinetic and pharmacodynamic comparison of enteric-coated mycophenolate sodium and mycophenolate mofetil in maintenance renal transplant patients.

The aim of this single-center crossover substudy was to assess pharmacokinetics and pharmacodynamics [inosine 5'-monophosphate dehydrogenase (IMPDH) activity] of enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) at steady-state conditions. Stable maintenance renal transplant patients on 1 g MMF b.i.

Problems of cyclosporine absorption profiling using C2-monitoring.

Unlabelled: The present study sought to validate the concept of C2 monitoring in 41 de-novo transplant patients treated with microemulsion of cyclosporine, mycophenolatesodium, steroids and basiliximab.

Results: After 6 months patient and graft survival was 98%, rejection rate was 19%. In the first week only a few patients achieved the suggested C2 levels (19% > 1500, 50% > 1200 ng/ml) despite an increased cyclosporine (CsA) dose.

Limitations of C2 monitoring in renal transplant recipients.

Background: Recent developments have proposed the cyclosporin (CsA) concentration at 2 h post-dose (C(2)) as the best single time-point predictor of the extent of CsA exposure and as the optimal basis for monitoring immunosuppressive therapy in renal transplant patients. The present study sought to validate the cornerstones of the current concept of C(2) monitoring.

Methods: We assessed the predictive value, dose proportionality and intrapatient variability of C(2) levels in 41 de novo renal transplant recipients treated with CsA microemulsion, steroids, mycophenolate sodium and basiliximab.

[Clinical drug investigations. Definition of terms].

Implementation of the European Directive 2001/20/EC led to the inclusion of definitions for clinical trial and non-interventional trial in German Drug Law. Other terms, such as non-commercial clinical trial, single patient use, post marketing surveillance and public health study are less well defined. This article explains the various terms by comparing their differences and similarities.

Pre-transplant inosine monophosphate dehydrogenase activity is associated with clinical outcome after renal transplantation.

Unlabelled: Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is usually administered as a standard dose of 1 g b.i.d.

MDR1 haplotypes derived from exons 21 and 26 do not affect the steady-state pharmacokinetics of tacrolimus in renal transplant patients.

Aim: This retrospective study investigated the influence of MDR1 haplotypes derived from the polymorphisms 2677G > T (exon 21) and 3435C > T (exon 26) on the pharmacokinetics of the immunosuppressant drug tacrolimus in 73 renal transplant patients.

Methods: Based on both variants of SNPs 2677 and 3435, four different haplotypes and eight different genotypes were identified in the study sample. Tacrolimus trough concentrations (C(0)) were compared between different SNP variants and genotypes, as well as between carriers and noncarriers of each haplotype.

Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction.

Objective: Hyperforin (HYF) has been discussed as a potential cause of the reduction in the bioavailability of numerous drugs seen with St John's wort (SJW) comedication. This study compared the effects of 2 SJW preparations with high and low HYF content on the pharmacokinetics of cyclosporine (INN, ciclosporin) (CSA).

Methods: In a crossover study, 10 renal transplant patients were randomized into 2 groups and received SJW extract (900 mg/d) containing low or high concentrations of HYF for 14 days in addition to their regular regimen of CSA.

Impact of cytochrome P-450 inhibition by cimetidine and induction by carbamazepine on the kinetics of hypericin and pseudohypericin in healthy volunteers.

This study evaluated the influence of cimetidine and carbamazepine on the pharmacokinetics of the St. John's wort (SJW) ingredients hypericin and pseudohypericin. In a placebo-controlled, double blind study, 33 healthy volunteers were randomized into three treatment groups that received SJW extract (LI160) with different comedications (placebo, cimetidine, and carbamazepine) for 7 days after a run-in period of 11 days with SJW alone.