Ovarian damage from chemotherapy and current approaches to its protection

BACKGROUND: Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage.OBJECTIVE AND RATIONALE: This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed.SEARCH METHODS: Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents.OUTCOMES: Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed.WIDER IMPLICATIONS: Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically

Erhöhung der Tragfähigkeit von GV-Verbindungen durch den Einsatz von Klebstoff

Wenn schubbeanspruchte Anschlüsse im Stahlbau Belastungen aus Schwingungen und/oder Lastumkehr ausgesetzt sind, kein Schlupf auftreten darf und auf der Baustelle gefügt werden muss, sind gleitfest vorgespannte Schraubverbindungen vorzusehen. Diese so genannten GV-Verbindungen müssen mit hohem Herstellungsaufwand gefertigt werden, was auf die Reibflächenvorbehandlung zurückzuführen ist. Wird der Korrosionsschutz für die Stahlkonstruktion durch eine Feuerverzinkung gewährleistet, sind für die Reiboberflächen ohne aufwendige Nachbehandlung geringe Haftreibungszahlen festzustellen, die zudem stark in Abhängigkeit von der sich ausbildenden Zinkschicht schwanken. Vor diesem Hintergrund wurden in einem kürzlich abgeschlossenen Forschungsvorhaben Untersuchungen angestellt, die eine Erhöhung der Tragfähigkeit in GV-Verbindungen durch den Einsatz von Klebstoff aufzeigen. Für die erhebliche Traglaststeigerung gegenüber den elementaren Fügeverfahren – Klebung oder GV-Verbindung – ist bei der Verfahrenskombination, die im Weiteren als vorgespannte Hybridverbindung verstanden wird, die eingebrachte Vorspannkraft verantwortlich. Bei sorgfältiger Kombination beider Verfahren können die Einzeltragfähigkeiten in etwa addiert werden

Genetic dissection of Pax6 dosage requirements in the developing mouse eye

Haploinsufficiency of the transcription factor Pax6/PAX6 has been implicated in a number of congenital eye disorders in humans and mice, such as aniridia and Small-eye, which affect the development and function of the lens, cornea, anterior eye segment and neuroretina. However, the widespread distribution of Pax6/PAX6 protein within the developing and adult eye preclude the identification and direct study of the ocular tissues affected by a reduction in Pax6/PAX6 dosage. Here, we employed Cre/loxP-mediated inactivation of a single Pax6 allele in either the lens/cornea or the distal optic cup to dissect the tissue-specific sensitivity to Pax6 haploinsufficiency. Exclusive inactivation of a single Pax6 allele in the lens recapitulates the Small-eye lens and corneal defects, while only mildly affects iris morphology in a non-cell-autonomous fashion. Conversely, selective inactivation of a single Pax6 allele in the distal optic cup revealed primarily cellautonomous dosage requirements for proper iris differentiation, with no affects on either lens or corneal morphology. Pax6 dosage within the distal optic cup is found here to influence the number of progenitors destined for the anterior ocular structures, the timing of iris muscle-cell differentiation and iris stroma development. Taken together, we genetically dissected the complex mouse Small-eye phenotype, thereby pinpointing the underlying Pax6/PAX6 haploinsufficiency to autonomous dosage requirements within the developing iris and lens/cornea tissues