Presence of apoptotic and nonapoptotic disseminated tumor cells reflects the response to neoadjuvant systemic therapy in breast cancer

Introduction  

Neoadjuvant systemic therapy (NST) is an established strategy to reduce tumor size in breast cancer patients prior to breast-conserving therapy. The effect of NST on tumor cell dissemination in these patients is not known. The aim of this study was to investigate the incidence of disseminated tumor cells (DTC), including apoptotic DTC, in breast cancer patients after NST, and to investigate the correlation of DTC status with therapy response.     

Effects of the Fusarium toxin deoxynivalenol from naturally contaminated wheat given subchronically or as one single dose on the in vivo protein synthesis of peripheral blood lymphocytes and plasma proteins in the pig

Trichothecenes, such as deoxynivalenol (DON), are known to inhibit the protein synthesis in vitro by binding at the 60S subunit of eukaryotic ribosomes. Therefore, cells and tissues with high protein turnover, such as lymphocytes and the liver (albumin and fibrinogen synthesis), were suggested to react most sensitively to DON. However, to the author's knowledge this observation was not proven in vivo in pigs, which were regarded as the farm animals most susceptible to DON. A total of 31 castrated male, crossbred German Landrace x Pietrain pigs weighing approx. 40 kg were fed a DON contaminated diet (5.7 mg/kg) either acutely (one single dose) or subchronically (4 weeks) or a control diet (0.1 mg/kg). In addition, one group received an intravenous injection of 53 microg DON/kg LW. One hour after feeding, a "flooding dose" of the stable isotope l-[(2)H(5)]-phenylalanine (125 mg/kg LW) was given and frequent blood samples (permanent catheter) were collected over a 60 min period. The molar percent excess (MPE) of plasma free and protein-bound phenylalanine were measured by GC/MS. No differences could be observed in the plasma concentrations of total protein, albumin, fibrinogen and serum enzymes between the groups. On the other hand, fractional synthesis rates (FSR, %/d) of albumin were significantly decreased by 43%, 45% and 26% and FSR of lymphocytes declined by 27%, 19% and 24%, whereas fibrinogen was not significantly affected after subchronic or one single oral and intravenous DON exposure, respectively. Additionally, the absolute synthesis rate (ASR, g/d) of albumin and the proportion of albumin to total body protein synthesis were reduced in the same manner, whereas the albumin secretion time ranged between 6.8 and 34.4 min and was not affected by treatment. In conclusion, the flooding dose technique appeared to be suitable for distinguishing DON-related effects on the protein synthesis, while determination of plasma protein concentrations seemed not to be an appropriate parameter.     

Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype

In neuroblastoma specimens, HIF-2alpha but not HIF-1alpha is strongly expressed in well-vascularized areas. In vitro, HIF-2alpha protein was stabilized at 5% O2 (resembling end capillary oxygen conditions) and, in contrast to the low HIF-1alpha activity at this oxygen level, actively transcribed genes like VEGF. Under hypoxia (1% O2), HIF-1alpha was transiently stabilized and primarily mediated acute responses, whereas HIF-2alpha protein gradually accumulated and governed prolonged hypoxic gene activation. Knockdown of HIF-2alpha reduced growth of neuroblastoma tumors in athymic mice. Furthermore, high HIF-2alpha protein levels were correlated with advanced clinical stage and high VEGF expression and predicted poor prognosis in a clinical neuroblastoma material. Our results demonstrate the relevance of HIF-2alpha in neuroblastoma progression and have general tumor biological implications.     

Electrical discharge machining: occupational hygienic characterization using emission-based monitoring

Hazardous potential in industrial environments is normally assessed by means of immission-based sampling and analyses. This approach is not adequate, if effects of specific technical adjustments at machine tools or working processes on hygienic parameters should be assessed. This work has focused on the optimization of a manufacturing process (electrical discharge machining, EDM), with regard to risk reduction assessment. It is based on emission analyses rather than immision analyses. Several technical EDM parameters have been examined for their influence on air-based emissions. Worktools and workpieces used have a strong influence on aliphatic compounds and metals but not on volatile organic compounds (benzene, toluene, ethylene-benzene and xylene (BTEX)) and polycyclic aromatic hydrocarbons (PAHs) in air emissions. Increasing the dielectric (mineral oil) level above processing location decreases BTEX, chromium, nickel and PAH emissions. Aliphatic compounds, in contrast, increase in air emissions. EDM current used has a positive relationship with all substances analyzed in air emissions. Indicative immission concentrations, as can be expected under EDM conditions, are estimated in a predictive scenario. The results of this characterization give rise to an important conclusion in that risk assessment so far has been using incorrect parameters: total aliphatic compounds. Maximum level of chromium is reached long before limit values of aliphatic compounds are exceeded. Because of the fact that metals, like chromium, also have a higher hazardous potential, metal analysis should be introduced in future risk assessment. This experimental approach, that captures total emission of the electrical discharge machine, and is not solely based on immission values, has lead to a better understanding of the production process. This information is used to extract recommendations regarding monitoring aspects and protection measures.     

From basic to clinical research: a journey with the retina, the retinal pigment epithelium, the cornea, age-related macular degeneration and hereditary degenerations, as seen in the rear view mirror

PURPOSE: This Acta Ophthalmologica Award and Gold Medal Honorary Lecture (the Lundsgaard Gold Medal Honorary Lecture) reviews some of the work I have carried out with my mentors and many of my wonderful collaborators and research students over more than 40 years, also including related work by other groups. It concentrates on the basic electrophysiology and ultrastructure of the retina and the retinal pigment epithelium (RPE), as well as covering basic and clinical aspects of the cornea, contact lenses, age-related macular degeneration (AMD) and hereditary diseases. METHODS: The review describes research performed using light and electron microscopy, basic and clinical electrophysiology, genetics and biochemistry in animal experiments and in research on patients. It also outlines clinically used techniques, such as laser and photodynamic treatment and scanning laser ophthalmoscopy. RESULTS: The paper reports on the following subjects: the mechanisms behind some of the electrical potentials originating in the retina and the RPE and the use of these potentials in hereditary diseases; corneal receptors for lectins and presumably for bacteria; the turnover of the photoreceptor outer segment and the formation of lipofuscin, including the relation of these processes to AMD; certain treatments for AMD, and hereditary degenerations in animal models, such as the RPE65 gene mutation in Briard dogs, which makes them a model of Leber's congenital amaurosis. The dogs are now treated successfully with gene therapy in the USA, and a clinical trial is in preparation. CONCLUSIONS: During the last 40 years we have had the good fortune to experience a dramatic growth in knowledge and understanding within ophthalmic science of basic mechanisms. Huge progress has been made in diagnostics and clinical ophthalmological treatments, much to the benefit of our patients. Even a small contribution made by my group to these developments has been well worth the effort, particularly as scientific work is not just deeply satisfying: it is also fun!     

Anatomische Voraussetzungen für Traktionsbehandlung im Hüftgelenk

Zusammenfassung Die anatomischen Voraussetzungen für die Traktionsbehandlung im Hüftgelenk wurden an anatomischem Postmortalmaterial sowie an gesunden Versuchspersonen studiert. Die Gelenkflächen verhindern nicht, daß das Caput femoris vom Acetabulum entfernt wird. Nachweisbare Gelenkeinwirkung erhielt man in 3 von 4 Fällen mit der Traktionskraft von 30 kp. Ein direkter mechanischer Einfluß auf die Gelenkkapsel kann daher wahrscheinlich an gesunden Hüftgelenken erhalten werden. Es wird hervorgehoben, daß man bei der Beurteilung des Wertes der Traktionsbehandlung in jedem einzelnen Fall versuchen muß, den Grund zur Bewegungseinschränkung im Gelenk festzustellen.

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Summary A study was performed in postmortal specimens and in healthy volunteers to find out if traction of the hip joint is anatomically justified as a method of physical therapy. The joint surfaces, including the acetabular labrum, did not fix the caput so rigidly as to prevent its motion in the direction of traction in the freedissected joints. In 3 cases out of 4 was a direct mechanical influence on the hip joint demonstrated in the living with a traction power of 30 kp. Therefore it is concluded that the joint capsule can be mechanically influenced in healthy hip joints. When traction of the hip joint is to be clinically evaluated in cases with limitation of motion the cause of this limitation should be determined as far as possible.

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Résumé L'hypothesèse anatomique pour le traitement tractionnaire a l'articulation de la hanche a été étudiée sur des sujets mortes anatomiques ainsi que sur des personnes saines. Les faces de l'articulation n'empêchaient pas que le caput femoris s'éloigne du acetabulum. Une entretissure vérifiable de l'articulation a été obtenue 3 fois sur 4 avec la force de traction du 30 kp. Une influence mecanique directe sur la capsule d'articulation peut probablement être reçue sur les articulations saines. Il faut souligner que dans chaque cas, il faut essayer de trouver la raison de la réduction de mouvement pour pouvoir juger la valeur du traitement tractionnaire.

     

Further studies on the use of guinea pigs in tests for immunogenic capacity of poliovirus preparations

Summary Primary and secondary responses in guinea pigs to formol-treated and live poliovirus was studied with the aid of immuno-inactivation.After subcutaneous injection of a single moderate antigen dose antibodies were usually no longer demonstrable after 6 weeks. A state of hyperreactivity had developed at 3 weeks after inoculation and remained unchanged for at least 15 weeks. Hyperreactive guinea pigs responded with higher titers than non-sensitized animals but did not show increased sensitivity to sub-threshold amounts of antigen. The degree of hyperreactivity was independent of the size of the sensitizing dose which, however, might determine the duration of the hyperreactive state. No differences in types of reaction to formol-treated and live virus were observed.On the basis of the observations made an improved antigenicity test is proposed.Aided by grants from Konung Gustaf V: s 80-årsfond.