Goth migration induced changes in the matrilineal genetic structure of the central-east European population.

For years, the issues related to the origin of the Goths and their early migrations in the Iron Age have been a matter of hot debate among archaeologists. Unfortunately, the lack of new independent data has precluded the evaluation of the existing hypothesis. To overcome this problem, we initiated systematic studies of the populations inhabiting the contemporary territory of Poland during the Iron Age. Here, we present an analysis of mitochondrial DNA isolated from 27 individuals (collectively called the Mas-VBIA group) excavated from an Iron Age cemetery (dated to the 2nd-4th century A.D.) attributed to Goths and located near Maslomecz, eastern Poland. We found that Mas-VBIA has similar genetic diversity to present-day Asian populations and higher diversity than that of contemporary Europeans. Our studies revealed close genetic links between the Mas-VBIA and two other Iron Age populations from the Jutland peninsula and from Kowalewko, located in western Poland. We disclosed the genetic connection between the Mas-VBIA and ancient Pontic-Caspian steppe groups. Similar connections were absent in the chronologically earlier Kowalewko and Jutland peninsula populations. The collected results seem to be consistent with the historical narrative that assumed that the Goths originated in southern Scandinavia; then, at least part of the Goth population moved south through the territory of contemporary Poland towards the Black Sea region, where they mixed with local populations and formed the Chernyakhov culture. Finally, a fraction of the Chernyakhov population returned to the southeast region of present-day Poland and established the archaeological formation called the "Maslomecz group".

The XRF mapping of archaeological artefacts as the key to understanding of the past.

The article describes the X-ray fluorescence (XRF) studies on the chemical composition of archaeological artefacts. The mapping of the concentration of selected elements has been used to recognise the way of object production and the use. The obtained data allowed to obtain the new information, which is impossible to gain by use of different methods. 'The data obtained from the chemical composition of the particular parts of the objects may be used for the interpretation of the manufacturing technology or the primal form of the objects. Additionally, the knowledge obtained from the chemical composition of the different parts of the artefacts may be essential for the selection of the protection and conservation methods. The present studies can be useful to improve knowledge about the level of former craftsmanship. These knowledge allow us to exam archaeological artefacts in a new light, and these findings can also broaden the archaeological knowledge horizons and provide good bases for further detailed studies.

Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogs in LNCaP and U937 cancer cell lines provides insight into their differential mechanism of action.

Bryostatin 1, like the phorbol esters, binds to and activates protein kinase C (PKC) but paradoxically antagonizes many but not all phorbol ester responses. Previously, we have compared patterns of biological response to bryostatin 1, phorbol ester, and the bryostatin 1 derivative Merle 23 in two human cancer cell lines, LNCaP and U937. Bryostatin 1 fails to induce a typical phorbol ester biological response in either cell line, whereas Merle 23 resembles phorbol ester in the U937 cells and bryostatin 1 in the LNCaP cells. Here, we have compared the pattern of their transcriptional response in both cell lines. We examined by qPCR the transcriptional response as a function of dose and time for a series of genes regulated by PKCs. In both cell lines bryostatin 1 differed primarily from phorbol ester in having a shorter duration of transcriptional modulation. This was not due to bryostatin 1 instability, since bryostatin 1 suppressed the phorbol ester response. In both cell lines Merle 23 induced a pattern of transcription largely like that of phorbol ester although with a modest reduction at later times in the LNCaP cells, suggesting that the difference in biological response of the two cell lines to Merle 23 lies downstream of this transcriptional regulation. For a series of bryostatins and analogs which ranged from bryostatin 1-like to phorbol ester-like in activity on the U937 cells, the duration of transcriptional response correlated with the pattern of biological activity, suggesting that this may provide a robust platform for structure activity analysis.

Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy.

To identify transcriptional profiles predictive of the clinical benefit of cisplatin and fluorouracil (CF) chemotherapy to gastric cancer patients, endoscopic biopsy samples from 96 CF-treated metastatic gastric cancer patients were prospectively collected before therapy and analyzed using high-throughput transcriptional profiling and array comparative genomic hybridization. Transcriptional profiling identified 917 genes that are correlated with poor patient survival after CF at P<0.05 (poor prognosis signature), in which protein synthesis and DNA replication/recombination/repair functional categories are enriched. A survival risk predictor was then constructed using genes, which are included in the poor prognosis signature and are contained within identified genomic amplicons. The combined expression of three genes-MYC, EGFR and FGFR2-was an independent predictor for overall survival of 27 CF-treated patients in the validation set (adjusted P=0.017), and also for survival of 40 chemotherapy-treated gastric cancer patients in a published data set (adjusted P=0.026). Thus, combined expression of MYC, EGFR and FGFR2 is predictive of poor survival in CF-treated metastatic gastric cancer patients.

GATA3 inhibits lysyl oxidase-mediated metastases of human basal triple-negative breast cancer cells.

Discovery of mechanisms that impede the aggressive and metastatic phenotype of human basal triple-negative-type breast cancers (BTNBCs) could provide novel targets for therapy for this form of breast cancer that has a relatively poor prognosis. Previous studies have demonstrated that expression of GATA3, the master transcriptional regulator of mammary luminal differentiation, can reduce the tumorigenicity and metastatic propensity of the human BTNBC MDA-MB-231 cell line (MB231), although the mechanism for reduced metastases was not elucidated. We demonstrate through gene expression profiling that GATA3 expression in 231 cells resulted in the dramatic reduction in the expression of lysyl oxidase (LOX), a metastasis-promoting, matrix-remodeling protein, in part, through methylation of the LOX promoter. Suppression of LOX expression by GATA3 was further confirmed in the BTNBC Hs578T cell line. Conversely, reduction of GATA3 expression by small interfering RNA in luminal BT474 cells increased LOX expression. Reconstitution of LOX expression in 231-GATA3 cells restored metastatic propensity. A strong inverse association between LOX and GATA3 expression was confirmed in a panel of 51 human breast cancer cell lines. Similarly, human breast cancer microarray data demonstrated that high LOX/low GATA3 expression is associated with the BTNBC subtype of breast cancer and poor patient prognosis. Expression of GATA3 reprograms BTNBCs to a less aggressive phenotype and inhibits a major mechanism of metastasis through inhibition of LOX. Induction of GATA3 in BTNBC cells or novel approaches that inhibit LOX expression or activity could be important strategies for treating BTNBCs.

Low-doses of ionising radiation induce melanoma metastases and trigger the immune system--adrenal axis feedback loop.

Low-doses of ionising radiation are frequently implicated in triggering and/or accelerating the growth of skin and other malignancies. It seemed probable that the radiation at similar dose levels might initiate metastasis from already existing tumours. Highly pigmented human melanoma xenograft that had lost its ability for a spontaneous metastasising and grown subcutaneously in athymic mice was exposed to very low and well-defined doses of ionising radiation to determine whether low linear energy transfer radiation can restore metastatic potential of the tumour. To ensure that all effects derived from radiation-activated neoplastic cells only, I was delivered selectively to the cutaneous melanoma instead of using the external beam. The direct response of these tumours to radiation was monitored by determining the growth rate of the lesions. Histopathological methods were employed to detect metastases. The lowest radiation dose of approximately 6 cGy deposited in the tumours initiated metastatic spread in all animals. Gradual increase of the radiation doses diminished both the frequency of the appearance of metastases and their distance from the primary lesions. There were no metastases from non-irradiated melanomas. The highest dose used (60 cGy) did not affect significantly the growth of cutaneous (primary) tumours, but lower doses that enhanced inflammatory infiltration of the lesions reduced tumour growth. Such radiation-stimulated immune responses were accompanied by increased pigmentation in cutaneous lesions and activation of the adrenal cortex indicating that the immune system-adrenal axis feedback loop had been triggered. The results demonstrate that very low-doses of ionising radiation induce melanoma metastases. The phenomenon is accompanied by the stimulation of the immune system-adrenal axis feedback loop that regulates eicosanoid synthesis, thereby suggesting an involvement of these molecules in the process. Radiation doses approaching the therapeutic level do not initiate melanoma dissemination.

211At-methylene blue for targeted radiotherapy of disseminated melanoma: microscopic analysis of tumour versus normal tissue damage.

The present stage of our preclinical investigations of targeted radiotherapy for melanoma with 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)] labelled with astatine-211 (211At), an alpha-particle emitter, concerns toxicity of the treatment, as well as macro- and microscopic evaluation of its efficacy. Fragments of two human melanoma xenografts, pigmented HX118 and non-pigmented HX34 (used as a control), were implanted s.c. into nude mice subsequently treated with two doses of 211At-MTB injected i.v. Alterations in tumour growth rate were related to microscopic damage caused by 211At-MTB to the lesions, as determined by light microscopy using histopathological techniques. 211At-MTB-dependent growth inhibition of pigmented melanoma occurred either instantly or as a gradual reduction in the tumour growth rate. At a later stage, lesions that ceased to grow immediately consisted of quiescent, heavily pigmented tumour cells, as well as advanced fibrosis, and were extensively infiltrated by melanin-laden phagocytes. Large, unresorbed and often calcified necrotic deposits characterised the tumours responding gradually to the treatment. 211At-MTB remained non-toxic in normal organs. Only a relative number of small lymphocytes in the groin lymph nodes in a minority of animals was temporarily reduced, most often in conjunction with the treatment of pigmented tumours. The data demonstrated a high therapeutic effectiveness of 211At-MTB towards pigmented melanoma at the expense of negligible injury to normal tissues, and revealed that the macroscopic determination of tumour growth rate often underestimated an efficacy of the applied treatment.

The role of blood flow in chronic duodenal ulcer.

BACKGROUND: Changes in gastroduodenal blood flow have been implicated in the pathogenesis of duodenal ulcer. We have studied duodenal blood flow during the development of an acute to chronic duodenal ulcer by using the abscopal model, in which ulcers are generated as an indirect effect of lower mediastinal irradiation. METHODS: Female CFLP mice (n = 108) weighing 25-40 g were randomly allocated to one of three groups. Controls were not irradiated. Irradiated 'controls' received 18 Gy 250 kV X-rays to the upper mediastinum (which does not cause duodenal ulceration). The lower mediastinum group received the same dose of irradiation, which has been shown to induce typical chronic duodenal ulcers in 45% of animals so treated. Animals were studied by means of radiolabelled microspheres 3 or 7 days later (that is, during and at the end of the lag period for ulcer induction). RESULTS: Proximal duodenal blood flow specifically was reduced by 32% in the lower mediastinum group compared with irradiated controls at 7 days (4.3 versus 6.3 ml/g tissue/min; P = 0.025 by ANOVA with contrast); there was no significant difference in blood flow to the stomach and to the distal duodenum. The decrease in proximal duodenal blood flow in the lower mediastinum group did not differ in the five animals that developed ulcer compared with the seven that did not. CONCLUSION: Although there is an overall decrease in duodenal blood flow associated with chronic duodenal ulcer, reduced blood flow may not explain individual susceptibility to ulceration.

211At-methylene blue in targeted radiotherapy of disseminated melanoma.

Targeted radiotherapy with 211At-methylene blue (211At-MTB) is a systemic treatment selectively directed at melanoma due to a high affinity of MTB to melanin synthesized in the tumor cells. Since MTB forms a strong complex with melanin, it is an effective carrier for a number of radioisotopes to be addressed to the tumor deposits of any size including individually dispersed melanoma cells. Thus, appropriately radiolabeled MTB can be used for either diagnosis or therapy of the neoplasm. As predicted and found in animal experiments, 211At-MTB is most effective therapeutically. Histopathological investigations showed that the highly pigmented 211At-MTB-treated tumors were characterized initially by perivascular oedema and hydropic degeneration of tumor cells followed by gradual development of extensive areas of coagulative necrosis. The necrotic tumor areas contained microvessels occluded by thrombi and tended to undergo microfocal calcification. Although melanoma-bearing animals successfully treated with 211At-MTB did not reveal any adverse effects of the therapy, detailed toxicological studies were undertaken. No serious macro- or microscopic lesions were observed in normal organs of 211At-MTB treated mice. Only the relative number of small lymphocytes in the groin lymph nodes in a minority of animals was variably reduced, most often in conjunction with the treatment of highly, but not poorly, pigmented tumors.

On radiation damage to normal tissues and its treatment. II. Anti-inflammatory drugs.

In addition to transiently inhibiting cell cycle progression and sterilizing those cells capable of proliferation, irradiation disturbs the homeostasis effected by endogenous mediators of intercellular communication (humoral component of tissue response to radiation). Changes in the mediator levels may modulate radiation effects either by assisting a return to normality (e.g., through a rise in H-type cell lineage-specific growth factors) or by aggravating the damage. The latter mode is illustrated with reports on changes in eicosanoid levels after irradiation and on results of empirical treatment of radiation injuries with anti-inflammatory drugs. Prodromal, acute and chronic effects of radiation are accompanied by excessive production of eicosanoids (prostaglandins, prostacyclin, thromboxanes and leukotrienes). These endogenous mediators of inflammatory reactions may be responsible for the vasodilatation, vasoconstriction, increased microvascular permeability, thrombosis and chemotaxis observed after radiation exposure. Glucocorticoids inhibit eicosanoid synthesis primarily by interfering with phospholipase A2 whilst non-steroidal anti-inflammatory drugs prevent prostaglandin/thromboxane synthesis by inhibiting cyclooxygenase. When administered after irradiation on empirical grounds, drugs belonging to both groups tend to attenuate a range of prodromal, acute and chronic effects of radiation in man and animals. Taken together, these two sets of observations are highly suggestive of a contribution of humoral factors to the adverse responses of normal tissues and organs to radiation. A full account of radiation damage should therefore consist of complementary descriptions of cellular and humoral events. Further studies on anti-inflammatory drug treatment of radiation damage to normal organs are justified and desirable.

Duodenal ulcer: a model of impaired mucosal defence.

There is a new model of chronic duodenal ulcer in which the ulcer is generated by irradiating the lower mediastinum of mice with a single dose of 18 Gy 250 kV x rays. Single ulcers develop in the proximal duodenum of about half the animals. Previous studies have shown a remarkable morphological and behavioural similarity to duodenal ulcer in man. Ulceration occurs because of an imbalance between aggressive and defensive forces within the duodenum and an attempt has been made to elucidate the pathomechanism of this ulcer by determining acid and pepsin secretion. The basal and pentagastrin stimulated secretion of acid, pepsin, and histamine were measured and no changes in acid or pepsin secretion were shown to occur (risk of type II error < 1%). It is therefore concluded that this chronic ulcer is a model of impaired duodenal defence.

The curability of tumours of differing size by targeted radiotherapy using 131I or 90Y.

A mathematical model has been used to investigate the relationship of curability to tumour size and cell number for spherical tumours treated with targeted 131I or 90Y, assuming uniform uptake of radionuclide throughout the tumour. The analysis shows that, for any given cumulated activity per unit mass of tumour, cure probability is greatest for tumours whose diameter is close to an optimum value which depends on the path length of the emitted beta-particle. Smaller tumours are less curable because of inefficient absorption of radiation energy, and larger tumours are less curable because of greater clonogenic cell number. The lesser curability of very small tumours is a feature of targeted radiotherapy using long-range beta-emitters which does not occur with external beam irradiation. The predicted inefficiency of sterilisation of microscopic tumours poses a problem for targeted radiotherapy which is analogous to "geographic miss" in conventional radiotherapy. The implication is that small micro-metastases could escape sterilisation by radionuclides administered at activity levels sufficient to eradicate larger tumours. It is suggested that single agent targeted radiotherapy should not be used for treatment of disseminated malignancy when multiple tumours of differing size, including micrometastases, may be present. The analysis implies that an advantage might result from the use of a panel of several radionuclides (including short-range emitters) or from combining targeted radiotherapy using long-range beta-emitters with external beam irradiation or some other modality to which microscopic tumours are preferentially vulnerable.