Strain wave pathway to semiconductor-to-metal transition revealed by time-resolved X-ray powder diffraction.

One of the main challenges in ultrafast material science is to trigger phase transitions with short pulses of light. Here we show how strain waves, launched by electronic and structural precursor phenomena, determine a coherent macroscopic transformation pathway for the semiconducting-to-metal transition in bistable Ti3O5 nanocrystals. Employing femtosecond powder X-ray diffraction, we measure the lattice deformation in the phase transition as a function of time. We monitor the early intra-cell distortion around the light absorbing metal dimer and the long range deformations governed by acoustic waves propagating from the laser-exposed Ti3O5 surface. We developed a simplified elastic model demonstrating that picosecond switching in nanocrystals happens concomitantly with the propagating acoustic wavefront, several decades faster than thermal processes governed by heat diffusion.

PDK1 controls upstream PI3K expression and PIP3 generation.

The PI3K/PDK1/Akt signaling axis is centrally involved in cellular homeostasis and controls cell growth and proliferation. Due to its key function as regulator of cell survival and metabolism, the dysregulation of this pathway is manifested in several human pathologies including cancers and immunological diseases. Thus, current therapeutic strategies target the components of this signaling cascade. In recent years, numerous feedback loops have been identified that attenuate PI3K/PDK1/Akt-dependent signaling. Here, we report the identification of an additional level of feedback regulation that depends on the negative transcriptional control of phosphatidylinositol 3-kinase (PI3K) class IA subunits. Genetic deletion of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or the pharmacological inhibition of its downstream effectors, that is, Akt and mammalian target of rapamycin (mTOR), relieves this suppression and leads to the upregulation of PI3K subunits, resulting in enhanced generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3). Apparently, this transcriptional induction is mediated by the concerted action of different transcription factor families, including the transcription factors cAMP-responsive element-binding protein and forkhead box O. Collectively, we propose that PDK1 functions as a cellular sensor that balances basal PIP3 generation at levels sufficient for survival but below a threshold being harmful to the cell. Our study suggests that the efficiency of therapies targeting the aberrantly activated PI3K/PDK1/Akt pathway might be increased by the parallel blockade of feedback circuits.

Fine particulate matter measurements in Swiss restaurants, cafés and bars: what is the effect of spatial separation between smoking and non-smoking areas?

UNLABELLED: We performed 124 measurements of particulate matter (PM(2.5)) in 95 hospitality venues such as restaurants, bars, cafés, and a disco, which had differing smoking regulations. We evaluated the impact of spatial separation between smoking and non-smoking areas on mean PM(2.5) concentration, taking relevant characteristics of the venue, such as the type of ventilation or the presence of additional PM(2.5) sources, into account. We differentiated five smoking environments: (i) completely smoke-free location, (ii) non-smoking room spatially separated from a smoking room, (iii) non-smoking area with a smoking area located in the same room, (iv) smoking area with a non-smoking area located in the same room, and (v) smoking location which could be either a room where smoking was allowed that was spatially separated from non-smoking room or a hospitality venue without smoking restriction. In these five groups, the geometric mean PM(2.5) levels were (i) 20.4, (ii) 43.9, (iii) 71.9, (iv) 110.4, and (v) 110.3 microg/m(3), respectively. This study showed that even if non-smoking and smoking areas were spatially separated into two rooms, geometric mean PM(2.5) levels in non-smoking rooms were considerably higher than in completely smoke-free hospitality venues. PRACTICAL IMPLICATIONS: PM(2.5) levels are considerably increased in the non-smoking area if smoking is allowed anywhere in the same location. Even locating the smoking area in another room resulted in a more than doubling of the PM(2.5) levels in the non-smoking room compared with venues where smoking was not allowed at all. In practice, spatial separation of rooms where smoking is allowed does not prevent exposure to environmental tobacco smoke in nearby non-smoking areas.

Cytogenetic analysis shows that carcinosarcomas of the breast are of monoclonal origin.

Carcinosarcoma of the breast is a rare biphasic neoplasm composed of a carcinomatous component contiguous or admixed with a pleomorphic spindle cell component. The issues of the histogenesis and clonal composition of carcinosarcomas have long been debated. We present the first cytogenetic characterization of mammary carcinosarcomas by analysis of eight tumor samples from two patients with this disease. In the first case, the same karyotypically complex clone, as well as evidence of clonal evolution, was found in samples from three separate areas of the primary tumor. The analysis of one intramammary and one axillary lymph node metastasis from the same patient, both showing only the sarcomatous tumor component, also revealed the common complex stemline and one of the two sidelines found in the primary tumor. The carcinosarcoma of the second patient contained six complex but karyotypically related clones unevenly distributed among the three samples examined. From this case, cells belonging to the carcinomatous and sarcomatous tumor components were separated by differential sedimentation and culturing in specific growth media. Analysis of both fractions showed largely the same karyotype, although one of the subclones was restricted to the epithelial component. Our findings indicate that the epithelial and mesenchymal components of mammary carcinosarcomas are both part of the neoplastic parenchyma and that they have evolved from a single common stem cell, in agreement with the hypothesis that the tumors are of monoclonal origin.

[Treatment of planocellular carcinoma of the nasal vestibule]. / Behandling av plateepitelkarsinom i vestibulum nasi.

In the ICD-9 system, carcinomas of the nasal vestibule are classified together with carcinomas in the nasal cavity. As a rule, however, they are squamous cell carcinomas derived from the skin, and thus prognosis is better than in the case of squamous cell carcinomas derived from the mucosa of the nasal cavity. The article highlights essential features of brachytherapy. The authors present a critical assessment of the criteria for staging, and describe a specific patient material. Based on clinical experience and theoretical considerations, brachytherapy alone is recommended for T1-3 N0 tumours. In the case of T4 tumours external radiation therapy and brachytherapy combined is recommended for the primary tumour, with prophylactical irradiation towards regional lymph nodes.

Discrimination between multicentric and multifocal breast carcinoma by cytogenetic investigation of macroscopically distinct ipsilateral lesions.

Whether macroscopically distinct carcinomas in the same breast are clonally related (multifocal breast carcinoma) or unrelated (multicentric breast carcinoma) is no longer only a scientific-pathological issue but, because different therapeutic strategies may be preferable for cases with intramammary metastatic disease compared with cases of multiple primary breast carcinomas, one that may have profound clinical implications. We studied the evolutionary relationship among macroscopically distinct, ipsilateral breast carcinomas by cytogenetic analysis of 26 tumorous lesions from 12 patients. Sixteen of the 26 foci (62%) were found to contain clonal chromosome abnormalities. Two carcinoma foci were karyotypically abnormal in each of seven patients. Four of these cases had an evolutionarily related, cytogenetically abnormal clone in the two lesions from the same breast, whereas the remaining three cases had completely different clonal karyotypic aberrations in the separate foci. These results, together with our previous findings in five other informative cases, show that multiple, synchronous breast tumors sometimes arise through intramammary spreading of a single primary carcinoma, whereas on other occasions they are the result of the simultaneous emergence of pathogenetically independent carcinomas within the breast. In the total material, an association was seen between the proximity of the foci and the likelihood of them being karyotypically related.

Cytogenetic analysis of several pseudomyxoma peritonei lesions originating from a mucinous cystadenoma of the appendix.

Epithelial proliferative lesions of the appendix are rare and have never been studied cytogenetically. We present the chromosomal banding analysis of four successfully short-term cultured samples from pseudomyxoma peritonei lesions originating from a cystadenoma of the appendix. All four sample contained clonal chromosome abnormalities. In three of them, the clone 46,XX,der(6)?del(6)(q16q21)?del(6)(q27) was found, whereas a clone with the karyotype 46,XX,t(2;17)(p21;p13),t(6;12)(p21;q13),t(12;15)(q24;q15) was detected in the fourth sample. Our findings support the view that pseudomyxoma peritonei originates by spreading from a primary mucinous neoplasm of an intraperitoneal organ rather than through mucinous metaplasia or multifocal primary neoplastic transformation of the peritoneum.

Cytogenetic findings in phyllodes tumors of the breast: karyotypic complexity differentiates between malignant and benign tumors.

Clonal karyotypic abnormalities were detected in short-term cell cultures from six phyllodes tumors of the breast. Whereas all five benign tumors had simple chromosomal changes, the highly malignant one had a near-triploid stemline, indicating that karyotypic complexity is a marker of malignancy in phyllodes tumors. Interstitial deletions of the short arm of chromosome 3, del(3)(p12p14) and del(3)(p21p23),were the only aberrations in two benign tumors. Cytogenetic polyclonality was detected in three benign tumors: two had cytogenetically unrelated clones, whereas the third had three different, karyotypically related cell populations as evidence of clonal evolution. The finding of clonal chromosome abnormalities in both the epithelial and connective tissue components of the phyllodes tumors indicates that they are genuinely biphasic, that is, that both components are part of the neoplastic parenchyma.

[High-dose therapy with autologous stem cell support in malignant lymphoma and breast cancer. Experiences with hematopoietic stem cells isolate from blood]. / Høydosebehandling med autolog stamcellestøtte ved malignt lymfom og cancer mammae. Erfaring med hematopoetiske stamceller høstet fra blod.

Since 1994, 17 breast cancer patients and 16 lymphoma patients have been treated at the Norwegian Radium Hospital with high-dose therapy supported by autologous peripheral progenitor cells. All the patients were given granulocyte colony stimulating factor in the recovery phase after cytotoxic treatment in order to mobilize and harvest peripheral progenitor cells. Aphareses were successful in all patients and the mean number of CD34 cells reinfused per kilo body weight was 7.05 x 10(6) for the lymphoma patients and 11.1 x 10(6) for the breast cancer patients. The mean time to recover > or = 0.5 x 10(9)/l granulocytes and > or = 20 x 10(9)/l platelets after reinfusion of stem cells was 10 days and 11.7 days respectively for the lymphoma patients, while the breast cancer patients engrafted at day 8.6 and day 9.3. No severe treatment-related complications were observed.

Inherited predisposition to breast carcinoma. Results of first round examination of 537 women at risk.

Five hundred and thirty seven women at risk for breast carcinoma were identified. Family history was detailed and each woman given genetic counselling. Diagnostic examination for breast carcinoma was performed at the major hospitals of Norway, and included physical examination by expert surgeon, mammography and/or ultrasonography, and fine needle aspiration cytology when appropriate. Altogether 8 carcinomas and 5 cases of atypical hyperplasia were found, compared with 1.6 and 0.3 expected, respectively, from population studies. The finding exceeded the expected numbers described by autosomal dominant inheritance. In addition we found one carcinoma in situ. It is concluded that the methods employed are suitable to identify and examine women at risk for breast carcinoma. It is suggested that atypical hyperplasia may be the precancerous lesion, and should be treated as such.

Inherited breast carcinoma--prospective findings in 1,194 women at risk.

According to preset criteria, 1,194 women at risk for inherited breast carcinoma were selected and subjected to examination. Six hundred and three women were examined once, 591 were followed for a mean of 1.8 years. Twenty infiltrating cancers (median age 49 years) and 16 precancers (median age 44 years) were found, demonstrating that breast carcinoma continued to occur in the selected families as expected under the hypothesis of dominant inheritance. At first round, 14 (1.2%) infiltrating carcinomas and a total of 22 (1.8%) cancers or precancers were found. Incidence rates of 0.58% pr. year for infiltrating cancers, and 1.04% pr. year for cancer or precancer were calculated. This confirms the tentative conclusions that were drawn in our previous report. These are the first prospective reports documenting how to delineate a high risk group for premenopausal breast cancer, and how to diagnose cancer at an early stage. All but two affected women had cancer without lymph node metastasis. Although a longer observation time is needed, we cautiously conclude that the results are in keeping with our aim of providing safety for those at risk. Clinical use of predictive genetic testing may be implemented within these families.

[Tumor size and histological grading of stage 1 breast cancer. Prognostic and therapeutic significance]. / Tumorstørrelse og histologisk gradering ved cancer mammae stadium 1. Prognostisk og terapeutisk betydning.

Systemic adjuvant therapy can improve the prognosis for breast cancer patients. In node negative disease most patients have a good prognosis with local therapy only. Therefore, identification of subgroups with higher risk of relapse is warranted in order to avoid overtreatment of a large number of patients. A total of 399 tumours from patients without axillary metastases, operated on in the years 1964-72, were measured preoperatively and graded according to a modified Scharff-Bloom-Richardson scheme. Patients with T2 (UICC) tumours and histologic grade 2 and 3, had a 3.3-fold relative risk of mortality from breast cancer compared with the rest of the patients. These patients should receive adjuvant systemic therapy.

A neural network model of phantom limbs.

This paper presents a detailed clinical description of phantom limbs and a neuronal network model that provides a comprehensive and parsimonious explanation of otherwise inexplicable or at least unrelated phenomena. Simulations of self-organizing feature maps (Kohonen networks) that had been trained to recognize input patterns were deprived of parts of their input in order to simulate partial deafferentation. This leads to reorganization processes that are shown to be driven by input noise. In patients with an amputated limb, this noise is generated by dorsal root ganglion sensory neurons which are known to fire irregularly upon laceration. According to this model, the long-standing debate concerning non-cortical vs. cortical contributions to the generation of the phenomenon of phantom limbs can be resolved in that it is the peripherally generated noise that causes cortical reorganization. The model can be tested and may have therapeutic implications.

Changes in temperatures and thermal doses with fraction number during hyperthermic treatment of locally advanced breast carcinoma.

Seventeen patients with locally advanced breast cancer were given hyperthermic treatment, and changes in temperatures and thermal doses with fraction number were studied. The changes were related to the vascular density of the treated volume before treatment. Multi-point thermistor probes were used for temperature measurements. Two parameters were determined for each probe location, a steady-state temperature, Ts, and a thermal dose, t43. To quantify changes in Ts and t43, linear curves were fitted to plots of these temperature parameters versus fraction number. The slopes of the curves, kTs and kt43, were used to represent the changes in Ts and t43, respectively. Vascular density was determined by histological analysis of biopsies taken from the temperature probe locations before the first heat treatment. Generally, Ts and t43 increased with increasing fraction number. kTs and kt43 were positively correlated to the vascular density of the normal tissue in the treatment volume, i.e. the increase in Ts and t43 was largest in the best-vascularized tissue. The cooling capacity of the normal tissue was probably reduced during the later heat fractions, either because of direct damage to the blood vessels or because of an impaired thermoregulative response. No relationship was found between the temperature parameters and the vascularization of the malignant tissue in the treatment volume. The present results show that the use of a fractionated schedule for heat treatment of locally advanced breast carcinoma may increase the temperatures and thermal doses achieved during treatment. A more uniform heating of the tumours can therefore be achieved by giving multiple heat fractions in the tumour areas that are difficult to heat adequately in one session.

The relevance of tumour and surrounding normal tissue vascular density in clinical hyperthermia of locally advanced breast carcinoma.

It follows from the present work that the vascularization of the normal tissue present in the treatment volume limits the temperatures achieved during heat treatment of invasive ductal breast carcinoma. The temperatures can often be increased by giving fractionated heat treatment because heat treatment may reduce the cooling capacity of the normal tissue vasculature. Significant damage to supplying vessels occurs at the heat doses necessary to cause necrosis in the tumour and surrounding normal tissue, indicating that secondary cell death is an important mechanism for cell inactivation following hyperthermic treatment of breast carcinoma.

Temperature distribution in locally advanced breast carcinoma during hyperthermic treatment: relationship to perfusion, vascular density, and histology.

Temperature distributions achieved during hyperthermic treatment of 16 patients with locally advanced breast cancer were analyzed in relation to tissue perfusion, vascular density, and histology of treated volume. Temperatures were measured using multi-sensor thermistor probes inserted in the center and periphery of the treatment volume. A steady state temperature, Ts, and a perfusion related parameter, PERF, were determined for each probe location. Vascular density and tissue composition were determined by histologic analysis of biopsies taken from the temperature probe locations before treatment. Both malignant and normal tissue were found in the biopsies, reflecting a diffusive tumor growth pattern. The malignant and normal tissue compartments were analyzed separately using stereologic techniques. Ts, PERF, vascular density, and tissue composition differed significantly between patients. There was a clear relationship between Ts and PERF, showing that the local tissue perfusion was decisive for the temperatures achieved. Ts and PERF showed a clear correlation with the normal tissue vascular density, but not with the malignant tissue vascular density; that is, the treatment temperatures achieved were mainly determined by the vascularization of the normal tissue compartment. Fraction of necrosis was the only tissue compartment parameter that showed a clear relationship to Ts and PERF. Ts increased and PERF decreased with increasing necrotic fraction.

Relationships between thermal dose and heat-induced tissue and vascular damage after thermoradiotherapy of locally advanced breast carcinoma.

Twenty-four patients with locally advanced breast carcinoma were given thermoradiotherapy, and heat-induced damage to tissue and vasculature was studied in relation to thermal dose. Thermometry was performed using six to eight multi-point thermistor probes. Heat-induced damage was quantified by histopathological analysis of biopsies taken from the temperature probe locations shortly after treatment. Both tumour and normal tissue were found in the biopsies. Fraction of tissue and fraction of vessels with heat-induced damage were determined for the malignant and the normal tissue compartment separately, using stereological techniques. Clear relationships were found between these parameters and the largest thermal dose achieved in one heat fraction. The data were subjected to logit analysis, and the thermal doses (eqv. min at 43 degrees C) that caused massive necrosis in 50% of the tissue were calculated to be 116 +/- 31 for the malignant tissue compartment and 205 +/- 49 for the normal tissue compartment. Similarly, the thermal doses that caused damage to 50% of the vessels were found to be 63 +/- 34 and 144 +/- 46 for the malignant and the normal tissue compartment, respectively. Thus, the tumour tissue was more sensitive to heat than was the surrounding normal tissue, irrespective of whether necrosis or vessel damage was considered. This was probably a consequence of physiological and vascular differences between the two tissue compartments. Evidence for primary and secondary cell death was found both in the malignant and the normal tissue, although primary cell death probably was of minor importance in the normal tissue. The data indicate that selective heat-inactivation of tumour tissue is possible by external microwave hyperthermia of locally advanced breast carcinoma.

Carcinoma of the nasopharynx. Histopathological examination with supplementary immunohistochemistry.

One hundred and one nasopharyngeal malignancies, clinically accepted and treated as carcinomas, were histologically reviewed. Originally, all of them had been given the histopathological diagnosis of carcinoma or possible carcinoma. A wide variety of diagnostic formulations had been used, some of them inconclusive. The review was based on strict morphological WHO criteria, and a definite diagnosis was attained in most cases. Three of the neoplasms, however, did not fulfil the criteria of carcinoma, and were given the diagnosis of malignant tumour, probable lymphoma. Immunohistochemistry with routinely processed tissue was performed on 69 of the poorly differentiated non-keratinizing neoplasms, including the three possible non-Hodgkin's malignant lymphomas. The neoplasms were positive for cytokeratin PKK1 with four exceptions: the three possible lymphomas and a large cell tumour with epithelial growth and prominent nucleoli which was found to be positive only for neurone-specific enolase. Two of three possible lymphomas were verified as such by being positive for leucocyte common antigen. This study showed that the WHO classification is quite useful when strictly applied. The histopathological diagnosis of this category of neoplasms can easily be confirmed by immunohistochemistry on routinely processed material and this adjunct can usually resolve questionable cases.