Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover.

Loss of NEDD8-activating enzyme (NAE) function by siRNA knockdown or inhibition by the small molecule NAE inhibitor MLN4924 leads to increased steady-state levels of direct Cullin-RING ligase (CRL) substrates by preventing their ubiquitination and proteasome-dependent degradation. Many of these CRL substrates are involved in cell cycle progression, including a critical DNA replication licensing factor CDT1. Cell cycle analysis of asynchronous and synchronous cultures after NAE inhibition revealed effects on cell cycle distribution and activation of DNA break repair signaling pathways similar to that reported for CDT1 overexpression. The siRNA knockdown of cullins critical for the turnover of CDT1 recapitulated the aberrant rereplication phenotype while CDT1 knockdown was suppressing. Although NAE inhibition leads to deregulation of many CRL substrates, these data demonstrate that CDT1 accumulation mediates the DNA rereplication phenotype resulting from loss of NAE function. DNA rereplication is an unrecoverable cellular insult and the small molecule inhibitor MLN4924, currently in phase I trials, represents an unprecedented opportunity to explore this mechanism of cytotoxicity for the treatment of cancer.

[Clinical aspects of deep venous varicose insufficiency]. / A propos de la clinique de l'insuffisance veineuse profonde variqueuse.

Attention is paid to the set of problems connected with the non-thrombotic insufficiency of the conducting veins of the leg. Phlebographic and X-ray morphometric investigations of the last years were able to prove that the primary varicosis does not exclusively represent a disease of the superficial and perforating fasciae venous system, but that the subfascial venous system (system of conductive veins) is without doubt also included in the pathogenetic reactive process. Two casuistic descriptions of cases with phlebographically and Doppler-sonographically ascertained insufficiency of the conductive veins of the leg are demonstrated. It is referred to the diagnostic, clinical and therapeutic problems of the isolated non-thrombotic insufficiency of the conductive veins. Leading diagnostic criteria of the isolated ectasic (varicose) insufficiency of the conducting veins of the leg are: symptomatology of subjective complaints, such as sensation of tension, feeling of heaviness of the legs, inclination to swelling, pains, epifascial freedom from varices, phlebographic evidence of the ectasia of conductive veins and sonographic confirmation of reflux.

[The clinical existence of isolated non-thrombotic insufficiency of the conductive veins of the leg]. / Zur klinischen Existenz der isolierten nichtthrombotischen Beinleitveneninsuffizienz.

Attention is paid to the set of problems connected with the nonthrombotic insufficiency of the conducting veins of the leg. Phlebographic and X-ray morphometric investigations of the last years were able to prove that the primary varicosis does not exclusively represent a disease of the superficial and perforating fasciae venous system, but that the subfascial venous system (system of conductive veins) is without doubt also included in the pathogenetic reactive process. Two casuistic descriptions of cases with phlebographically and Doppler-sonographically ascertained insufficiency of the conductive veins of the leg are demonstrated. It is referred to the diagnostic, clinical and therapeutic problems of the isolated nonthrombotic insufficiency of the conductive veins. Leading diagnostic criteria of the isolated ectatic (varicose) insufficiency of the conducting veins of the leg are: symptomatology of subjective complaints, such as sensation of tension, feeling of heaviness of the legs, inclination to swelling, pains, epifascial freedom from varices, phlebographic evidence of the ectasia of conductive veins and sonographic confirmation of reflux.

[Morphologic studies of the conductive veins of the leg in superficial varicose veins]. / Morphologische Untersuchungen der Beinleitvenen bei epifaszialer Varikosis.

Issuing from the thesis of Fischer and Siebrecht that the epifascial varicosis can be accompanied by an insufficiency of the conducting and muscle veins for the first time morphological investigations on the profound venous system were carried out with the questioning whether the non-thrombotic insufficiency of the profound conducting veins of the leg an adequate morphological correlate is underlying which is to be recognized and proved histologically. On the basis of this first pilot study can be shown that similar forms of reaction take place in the part of the superficial and profound veins which are free from varices. Hitherto it is still unclear which factors are leading for the causes in the pathological mosaic. The insufficiency of the conducting veins, age-conditioned and functional changes and the arteriosclerotic venopathy are discussed. The conception of the insufficiency of the conducting veins also in the field of morphological research proves to be the initiator of exact and further analyses.

[Chronic venous insufficiency--from pathophysiology to therapy. 2: Sclerotherapy of varicose veins]. / Chronisch venöse Insuffizienz--von der Pathophysiologie zur Therapie. Folge 2: Verödungstherapie bei Varikosis.

For the elimination of chronic ambulatory venous hypertension, sclerotherapy and surgical measures are employed in addition to compression treatment. These various measures should always be used in combination with each other. In the present article, one of a series, indications, contraindications and the practicalities of sclerotherapy are discussed in detail.

[Chronic venous insufficiency--from pathophysiology to therapy. 4: Treatment of ulcus cruris--therapy guidelines]. / Chronisch-venöse Insuffizienz--von der Pathophysiologie zur Therapie. Folge 4(Schluss): Behandlung des Ulcus cruris--Therapierichtlinien.

In the field of phlebology and angiology, leg ulcer represents a complex diagnostic and therapeutic problem. The initial steps include the taking of a careful history, inspection and palpation, and thorough angiological investigation which, where the individual situation makes this necessary, must be supplemented by such further diagnostic measures as biopsy, laboratory investigations or even allergy tests. Subsequent treatment must be stage-matched and must meet the individual needs of the patient. Both conservative and surgical forms of treatment are available.

[Chronic venous insufficiency--from pathophysiology to therapy. 1: Pathophysiology--compression treatment--systemic pharmacotherapy]. / Chronisch venöse Insuffizienz--von der Pathophysiologie zur Therapie. Folge 1: Pathophysiologie--Kompressionsbehandlung--systemische Pharmakotherapie.

At the core of chronic venous insufficiency (CVI) is valvular incompetence affecting the large veins, which results in ambulatory venous hypertension. Recent research has revealed the pathophysiological stages involved: damage to the endothelium of the vein, leukocyte trapping and, finally, inflammatory reconstruction of the vessel wall. Lymphangiopathy involving the small and large lymph vessels is always present. One of the measures capable of influencing elevated venous pressure is compression therapy, which is discussed in detail in the present article. Drug treatment is a rational supplement to curative therapeutic approaches to chronic venous insufficiency that in mild-to-moderate cases, can result in an alleviation of symptoms similar to that achieved with compression therapy.

[Diagnostic sensitivity of sonography in varicose and post-thrombotic venous insufficiency]. / Die diagnostische Sensitivität der Sonographie bei variköser und postthrombotischer Veneninsuffizienz.

We report on the application possibilities of sonography in phlebology. Sonographic examination of 131 lower legs showing various clinical forms of chronic venous insufficiency is discussed. Ultrasound offers a timesaving, non-invasive, and reproducible technique to detect insufficiencies concerning orifice or trunk of the great and lower saphenous veins as well as the perforating veins. The method allows varying diagnostic sensitivities. Thrombotic changes in the deep veins may be demonstrated with relative accurateness. As to insufficiencies concerning the epifascial and perforating venous system (in epifascial chronic venous insufficiency, stage I to IV), the question of surgical or sclerotherapeutic treatment can be settled in most cases according to the sonographical findings alone. Subfascial forms of chronic venous insufficiency require additional invasive diagnostic techniques, such as plethysmography, phlebography, and venous pressure measurements. In consideration of the high diagnostic importance of ultrasound, sonographic devices should be available and applied in a large number of phlebologic practices.