The Real Mechanism of Action of Cyclophosphamide and Other Oxazaphosphorine Cytostatics

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including real-world experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, preexisting disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

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The Mechanism of Action of Cyclophosphamide and Its Consequences for the Development of a New Generation of Oxazaphosphorine Cytostatics

Scientia Pharmaceutica ◽

10.3390/scipharm88040042 ◽

2020 ◽

Vol 88 (4) ◽

pp. 42

Author(s):

Georg Voelcker

Keyword(s):

Mechanism Of Action ◽

Active Metabolite ◽

Dna Alkylation ◽

In Vivo Metabolism ◽

Pharmacologically Active ◽

New Generation ◽

Anti Tumor Activity ◽

Oxazaphosphorine Cytostatics

Although cyclophosphamide (CP) has been used successfully in the clinic for over 50 years, it has so far not been possible to elucidate the mechanism of action and to use it for improvement. This was not possible because the basis of the mechanism of action of CP, which was found by lucky coincidence, is apoptosis, the discovery of which was honored with the Nobel Prize only in 2002. Another reason was that results from cell culture experiments were used to elucidate the mechanism of action, ignoring the fact that in vivo metabolism differs from in vitro conditions. In vitro, toxic acrolein is formed during the formation of the cytotoxic metabolite phosphoreamidemustard (PAM), whereas in vivo proapoptotic hydroxypropanal (HPA) is formed. The CP metabolites formed in sequence 4-hydroxycyclophosphamide (OHCP) are the main cause of toxicity, aldophosphamide (ALDO) is the pharmacologically active metabolite and HPA amplifies the cytotoxic apoptosis initiated by DNA alkylation by PAM. It is shown that toxicity is drastically reduced but anti-tumor activity strongly increased by the formation of ALDO bypassing OHCP. Furthermore, it is shown that the anti-tumor activity against advanced solid P388 tumors that grow on CD2F1 mice is increased by orders of magnitude if DNA damage caused by a modified PAM is poorly repairable.

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Forces of space

Litiyo i Metallurgiya (FOUNDRY PRODUCTION AND METALLURGY) ◽

10.21122/1683-6065-2020-3-117-120 ◽

2020 ◽

pp. 117-120

Author(s):

V. Yu. Stetsenko ◽

A. V. Stetsenko

Keyword(s):

Magnetic Field ◽

Mechanism Of Action ◽

Special Theory ◽

Theory Of Relativity ◽

Special Theory Of Relativity ◽

Free Electrons ◽

Metal Melt ◽

The Real ◽

Modifying Effect ◽

Inertial Systems

We live in a non-inertial world. In non-inertial systems, the classical laws of mechanics and the postulates of the special theory of relativity do not work. To work the laws of mechanics, you need to take into account the forces of inertia. They should be considered the real forces of space. It has the material and field properties. It is shown that mechanism of action of space on elements (bodies) of system is similar to mechanism of action of magnetic field on free electrons of conductor in this field. Three laws of translation dynamics for a non-inertial system have been proposed. With the help of space forces it is possible to explain reactive motion, weightlessness, tornado action, modifying effect of shaking or vibration of metal melt on microstructure of casting when it is solidified. It is shown that the forces of gravity and space are not equivalent.

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Bacterial biofilm in colorectal cancer: What is the real mechanism of action?

Microbial Pathogenesis ◽

10.1016/j.micpath.2020.104052 ◽

2020 ◽

Vol 142 ◽

pp. 104052 ◽

Cited By ~ 8

Author(s):

Rasoul Mirzaei ◽

Hamed Mirzaei ◽

Mohammad Yousef Alikhani ◽

Mohammad Sholeh ◽

Mohammad Reza Arabestani ◽

...

Keyword(s):

Colorectal Cancer ◽

Mechanism Of Action ◽

Bacterial Biofilm ◽

The Real

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Evaluating Mental Health Services; How Do Programs for Children “Work” in the Real World? Edited by Carol T. Nixon & Denine A. Northrup. Sage, Thousand Oaks CA, 1997. pp. 306. £16.60 (pb).

Journal of Child Psychology and Psychiatry ◽

10.1017/s0021963098222918 ◽

1998 ◽

Vol 39 (6) ◽

pp. 935-936

Author(s):

Anne Worrall-Davies

Keyword(s):

Mental Health ◽

Mental Health Services ◽

Health Services ◽

Real World ◽

The Real

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Scanning electron microscopy of human iliac bone by a simple preparation method

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100158674 ◽

1990 ◽

Vol 48 (3) ◽

pp. 226-227

Author(s):

Toshihiko Takita ◽

Tomonori Naguro ◽

Toshio Kameie ◽

Akihiro Iino ◽

Kichizo Yamamoto

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Preparation Method ◽

Specimen Preparation ◽

Real Surface ◽

Public Attention ◽

Preparation Methods ◽

The Real ◽

Simple Preparation ◽

Scanning Electron

Recently with the increase in advanced age population, the osteoporosis becomes the object of public attention in the field of orthopedics. The surface topography of the bone by scanning electron microscopy (SEM) is one of the most useful means to study the bone metabolism, that is considered to make clear the mechanism of the osteoporosis. Until today many specimen preparation methods for SEM have been reported. They are roughly classified into two; the anorganic preparation and the simple preparation. The former is suitable for observing mineralization, but has the demerit that the real surface of the bone can not be observed and, moreover, the samples prepared by this method are extremely fragile especially in the case of osteoporosis. On the other hand, the latter has the merit that the real information of the bone surface can be obtained, though it is difficult to recognize the functional situation of the bone.

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Personal Audio System: Hearing Symptoms, Habits, and Sound Pressure Levels Measured in Real Ear and a Manikin

Journal of Speech Language and Hearing Research ◽

10.1044/2020_jslhr-19-00053 ◽

2020 ◽

Vol 63 (6) ◽

pp. 2016-2026

Author(s):

Tamara R. Almeida ◽

Clayton H. Rocha ◽

Camila M. Rabelo ◽

Raquel F. Gomes ◽

Ivone F. Neves-Lobo ◽

...

Keyword(s):

Sound Pressure ◽

Daily Basis ◽

Cross Sectional Study ◽

Normal Hearing ◽

Chi Square ◽

Cross Sectional ◽

The Real ◽

Significant Difference ◽

Sound Pressure Levels ◽

Audio System

Purpose The aims of this study were to characterize hearing symptoms, habits, and sound pressure levels (SPLs) of personal audio system (PAS) used by young adults; estimate the risk of developing hearing loss and assess whether instructions given to users led to behavioral changes; and propose recommendations for PAS users. Method A cross-sectional study was performed in 50 subjects with normal hearing. Procedures included questionnaire and measurement of PAS SPLs (real ear and manikin) through the users' own headphones and devices while they listened to four songs. After 1 year, 30 subjects answered questions about their usage habits. For the statistical analysis, one-way analysis of variance, Tukey's post hoc test, Lin and Spearman coefficients, the chi-square test, and logistic regression were used. Results Most subjects listened to music every day, usually in noisy environments. Sixty percent of the subjects reported hearing symptoms after using a PAS. Substantial variability in the equivalent music listening level (Leq) was noted ( M = 84.7 dBA; min = 65.1 dBA, max = 97.5 dBA). A significant difference was found only in the 4-kHz band when comparing the real-ear and manikin techniques. Based on the Leq, 38% of the individuals exceeded the maximum daily time allowance. Comparison of the subjects according to the maximum allowed daily exposure time revealed a higher number of hearing complaints from people with greater exposure. After 1 year, 43% of the subjects reduced their usage time, and 70% reduced the volume. A volume not exceeding 80% was recommended, and at this volume, the maximum usage time should be 160 min. Conclusions The habit of listening to music at high intensities on a daily basis seems to cause hearing symptoms, even in individuals with normal hearing. The real-ear and manikin techniques produced similar results. Providing instructions on this topic combined with measuring PAS SPLs may be an appropriate strategy for raising the awareness of people who are at risk. Supplemental Material https://doi.org/10.23641/asha.12431435

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Current Issues: Evidence-Based Practice for the Real World: Thoughts on Clinical Education in Communication Disorders

Perspectives on Administration and Supervision ◽

10.1044/aas20.3.100 ◽

2010 ◽

Vol 20 (3) ◽

pp. 100-105 ◽

Cited By ~ 3

Author(s):

Anne K. Bothe

Keyword(s):

Clinical Education ◽

Real World ◽

Evidence Based Practice ◽

Communication Disorders ◽

University Faculty ◽

Evidence Based ◽

Speech Language Pathology ◽

Basic Principles ◽

The Real ◽

Language Pathology

This article presents some streamlined and intentionally oversimplified ideas about educating future communication disorders professionals to use some of the most basic principles of evidence-based practice. Working from a popular five-step approach, modifications are suggested that may make the ideas more accessible, and therefore more useful, for university faculty, other supervisors, and future professionals in speech-language pathology, audiology, and related fields.

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