Plasmonic photothermal heating of gold nanostars in a real-size container: multiscale modelling and experimental study.

The ability of noble metal nanoparticles (NPs) to convert light into heat has triggered a lot of scientific interest due to the numerous potential applications, including, e.g. photothermal therapy or laser-based nanopatterning. In order for such applications to be practically implemented, the heating behaviour of NPs embedded in their surrounding medium has to be thoroughly understood, and theoretical models capable of predicting this behaviour must be developed. Here we propose a multiscale approach for modelling the photothermal response of a large ensemble of nanoparticles contained within a cm-scale, real-size container. Electromagnetic field, ray tracing and heat transfer simulations are combined in order to model the response of nanostars and nanospheres suspensions contained within a common Eppendorf tube. To validate the model, gold nanostars are then synthesised and characterized by electron microscopy and optical spectroscopy. Laser-induced heating experiments are conducted by irradiating colloid-filled Eppendorf tubes with a 785 nm continuous wave laser and monitoring by a thermographic camera. The experimental results confirm that the proposed model has potential for predicting and analysing the heating efficiency and temperature dynamics upon laser irradiation of plasmonic nanoparticle suspensions in real-scale containers, at cm3 volumes.

Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors.

BACKGROUND: Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours. METHODS: Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m(-2) and CP 60-75 mg m(-2). Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m(-2), CP 60 mg m(-2)) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days. RESULTS: On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m(-2), 60 mg m(-2)); G 3 anorexia/fatigue/hypokalemia (1.2 mg m(-2), 60 mg m(-2)); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m(-2), 60 mg m(-2)). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m(-2), 60 mg m(-2)); G 4 mucositis (1.4 mg m(-2), 60 mg m(-2)); and G 3 hypokalemia (1.2 mg m(-2), 75 mg m(-2)). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m(-2) (days 1, 8) and CP 75 mg m(-2) (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers). CONCLUSIONS: On the 21-day cycle, eribulin mesylate 1.2 mg m(-2), administered on days 1 and 8, in combination with CP 75 mg m(-2), administered on day 1 is well tolerated and showed preliminary anticancer activity.

Genomic analyses of germline and somatic variation in high-grade serous ovarian cancer.

BACKGROUND: High-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in HGSC and their association with relapse-free and overall survival. Using a targeted capture of 557 genes involved in DNA damage response and PI3K/AKT/mTOR pathways, we conducted next-generation sequencing of DNA from matched blood and tumor tissue from 71 HGSC participants. In addition, we performed the OncoScan assay on tumor DNA from 61 participants to examine somatic copy number alterations (SCNA). RESULTS: Approximately one-third of tumors had loss-of-function (LOF) germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes BRCA1, BRCA2, CHEK2, MRE11A, BLM, and PALB2. LOF germline variants also were identified in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes. Most tumors harbored somatic TP53 variants (65/71, 91.5%). Using the OncoScan assay on tumor DNA from 61 participants, we identified focal homozygous deletions in BRCA1, BRCA2, MAP2K4, PTEN, RB1, SLX4, STK11, CREBBP, and NF1. In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes. For patients with multiple tissues from the primary debulking or from multiple surgeries, the somatic mutations were maintained with few newly acquired point mutations suggesting that tumor evolution was not through somatic mutations. There was a significant association of LOF variants in homologous recombination repair pathway genes and high-amplitude somatic copy number alterations. Using GISTIC analysis, we identified NOTCH3, ZNF536, and PIK3R2 in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival. CONCLUSIONS: From 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 557 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.

Genomic Analyses of Germline and Somatic Variation in High-Grade Serous Ovarian Cancer.

Background High-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in HGSC and their association with relapse-free and overall survival. Using a targeted capture of 577 genes involved in DNA damage response and PI3K/AKT/mTOR pathways, we conducted next-generation sequencing of DNA from matched blood and tumor tissue from 71 HGSC participants. In addition, we performed the OncoScan assay on tumor DNA from 61 participants to examine somatic copy number alterations. Results Approximately one-third of tumors had loss-of-function germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes BRCA1, BRCA2, CHEK2, MRE11A, BLM , and PALB2 . Loss-of-function germline variants also were identified in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes. Most tumors harbored somatic TP53 variants (65/71, 91.5%). Using the OncoScan assay on tumor DNA from 61 participants, we identified focal homozygous deletions in BRCA1, BRCA2, MAP2K4, PTEN, RB1, SLX4, STK11, CREBBP , and NF1 . In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes. For patients with multiple tissues from the primary debulking or from multiple surgeries, the somatic mutations were maintained with few newly acquired point mutations suggesting that tumor evolution was not through somatic mutations. There was a significant association of loss-of-function variants in homologous recombination repair pathway genes and high-amplitude somatic copy number alterations. Using GISTIC analysis, we identified NOTCH3, ZNF536 , and PIK3R2 in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival. Conclusions From 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 577 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.

Optical, Structural, and Dielectric Properties of Composites Based on Thermoplastic Polymers of the Polyolefin and Polyurethane Type and BaTiO3 Nanoparticles.

In this work, new films containing composite materials based on blends of thermoplastic polymers of the polyurethane (TPU) and polyolefin (TPO) type, in the absence and presence of BaTiO3 nanoparticles (NPs) with the size smaller 100 nm, were prepared. The vibrational properties of the free films depending on the weight ratio of the two thermoplastic polymers were studied. Our results demonstrate that these films are optically active, with strong, broad, and adjustable photoluminescence by varying the amount of TPU. The crystalline structure of BaTiO3 and the influence of thermoplastic polymers on the crystallization process of these inorganic NPs were determined by X-ray diffraction (XRD) studies. The vibrational changes induced in the thermoplastic polymer's matrix of the BaTiO3 NPs were showcased by Raman scattering and FTIR spectroscopy. The incorporation of BaTiO3 NPs in the matrix of thermoplastic elastomers revealed the shift dependence of the photoluminescence (PL) band depending on the BaTiO3 NP concentration, which was capable of covering a wide visible spectral range. The dependencies of the dielectric relaxation phenomena with the weight of BaTiO3 NPs in thermoplastic polymers blends were also demonstrated.

A phase I study of bortezomib and temozolomide in patients with advanced solid tumors.

PURPOSE: The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs). METHODS: Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not. RESULTS: Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P < 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P < 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P < 0.04). CONCLUSIONS: The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.

A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer.

Germline variants in the 3' untranslated region (3'UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3'UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125) and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09-2.57, P=0.019, n=279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31-7.72, P=0.0106, n=291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3'UTR lesions, and that direct targeting may be a viable future treatment approach.

Targeted agents in ovarian cancer.

Despite recent advances in the treatment of ovarian cancer, a large majority of women with this diagnosis will die from recurrence of their disease. Targeted therapies, in the form of monoclonal antibodies and small molecule tyrosine kinase inhibitors have significantly altered the management of many solid tumors and hematologic malignancies. No such agents have been approved by the US FDA for use in ovarian cancer, although Phase II data suggests excellent single-agent activity of some of these drugs. Antiangiogenic agents in combination with chemotherapy are being evaluated in Phase III clinical trials, both in the adjuvant setting and in recurrent platinum-sensitive disease. Poly-ADP-ribose polymerase inhibitors are promising agents in BRCA1/2-mutated breast and ovarian cancers. Ongoing clinical trials are exploring the anti-tumor effect of poly-ADP-ribose polymerase inhibitors administered as single agents and in combination with chemotherapy. Many other new drugs are in earlier grades of development. In this article, we review the state of the art in targeted therapies for ovarian cancer and identify future directions for their development in the management of this often devastating disease.

Behaviour of mucopolysaccharides of Kupffer cells in experimental mercury hepatitis.

A reaction of Kupffer cells with changes of mucopolysaccharides is shown during experimental mercury hepatitis. An initial diminution of the reaction intensity is followed by the increase of MPS polymerization degree. Association of effort leads to a significant increase of the A-PAS reaction. The lympho-histiocytes infiltrating portal spaces present the same MPS dynamics.

[Clinical trial of amoxycillin in chronic bronchitis and bronchial dilatations]. / Experimentarea clinica a amoxycillinei în bronsita cronica si dilatatiile bronsice.

The therapeutic results were followed of amoxycilline after application in 57 cases of chronic bronchitis and bronchial dilatations that had been treated previously with antibiotics (including ampicillin--in 37 cases). The amount of amoxycilline was of 2 g per day, given in four 0,5 g doses. A total of 23,3 percent "very good" results were obtained (expectoration either disappeared completely or was reduced to 2--3 ml per day), and 40,4 percent "good" results (with expectoration down to less than one half of the initial amount). Thus in two-thirds of the cases the results were favourable. The cases that did not respond to ampicilline gave only 10,8 percent "very good" results but the "good" results represented 51,3 percent, indicating an increased efficiency of the new drug as compared with ampicilline. The serum levels of Amoxycilline (9,4 mg/ml after 2 hours, and 4,4 mg/ml after 4 hours), when a 0,5 g dose was given every 6 hours, assure a continuous and efficient bacteriostatic concentration. No significant adverse reaction were noted.

[The late results of respiratory kinesitherapy in tubercular serofibrinous pleurisy]. / Rezultatele la distanta ale kineziterapiei respiratorii în pleurezia serofibrinoasa tuberculoasa.

The authors have investigated 93 cases with sero-fibrinous pleurisy in their antecedents, and that had kinetotherapy during their disease. All the cases were controlled from the viewpoint of the respiratory function, as well as by radiological and electrocardiographic methods. Changes in the ventilatory function were evaluated by increased VEMS in absolute value in contrast with the VEMS value on hospitalization. The general late results of respiratory kinetotherapy were reflected in the fact that 84% of the cases presented either significant increase in the value of VEMS (56%), or had stationary values (28%). The most significant functional increases were noted in the patients who were under the age of 18 years upon release from hospital (median age : 14,8 years), and were mostly due to somatic development, and physical activity. The positive effects of physical activity in the frame of the occupation of the patients were amplified by respiratory kinetotherapy continued at home. Respiratory kinetotherapy demonstrated its efficiency especially in the subjects from lowage groups, and males had better results than females. Advanced age, important pleural sequels, as well as other disturbances, without apparent relation to the pleurisy, had negative effects. In the present conditions of treatment (chemotherapy + corticoid therapy and immediate and long-duration kinetotherapy) sero-fibrinous pleurisy has no significant impact on the socio-professional evolution of the patient.

RNA amplification for direct detection of mycobacterium tuberculosis in respiratory samples.

A target amplified test system (AMTDT, Gen-Probe, San Diego, California, USA) was compared with conventional standard methods in the detection of Mycobacterium tuberculosis in sputum and other respiratory specimens from patients with suspected tuberculosis. The highest incidence of positive samples was seen with the AMTDT test. Out of 450 samples from patients with known or suspected tuberculosis, 43 (9.6%) were positive by culture, and 47 (10.4%) with AMTDT. After discrepancy analysis, 7 of the culture-negative but AMTDT-positive samples were judged to be true positive, giving the AMTDT a sensitivity of 92.0% and a specificity of 99.8%. The AMTDT test was rapid, easy to perform, sensitive, and highly specific.

[Use and evaluation of radiophotography in the ambulatory care of lung diseases]. / Utilizarea si valorificarea radiofotografiei în asistenta ambulatorie de pneumologie

In the methodological cabinet for pneumology of the Institute of Phtysiology, radiophotography was employed in the following fields: a) screening of acute and chronic pneumopathies as appears from : the increase in the number of cases of non-specific pneumopathies as compared with cases of tuberculosis and the quantitative contribution of the method reflected in the fact that over 80% of the cases with non-specific pneumopathies were detected by radiophotography; b) diagnosis -- by comparing with the data recorded in the files, multiple incidences (front, posterior lordosis, profile); locally pointed (targeted) photographs, rf quantified functional tests in cases suspected of C.O.B.P.: c) follow-up of the evolution of dispensary cases and of the therapeutical effect; d) scientific research and teaching activities through epidemiological and pathogenesis studies, thus allowing for a valorification of the files over a 16 years period. The use of the radiophotographic method in the activity of a cabinet of pneumology is necessary especially because it allows for an early detection, a superior morphological diagnosis, as compared with radioscopy (fluoroscopy), for an objective and economical follow-up of the cases, providing at the same time material for scientific research and teaching demonstrations.

[Retrospective study of the value of radiophotographic examinations in the detection of pulmonary cancer]. / Studiu retrospectiv al valorii examenelor rf în depistarea cancerului pulmonar

Out of a total of 123 cases of centro-hilar pulmonary carcinoma and of 65 cases of carcinoma with peripheral localization changes on the previous radiophotographic images were found in 54% of the cases. The time necessary for doubling of the tumour size was of 22 months for the peripheral forms of cancer. The suspicion of pulmonary cancer was mentioned in the radiophotographic register two years before the diagnosis of the disease was made.

Investigations on the influence of the experimental infection with the herpes simplex virus type 1 on the electrophoretic mobility of some cultured cells.

Two types of cell cultures, BSC and HE-p2, have been studied from the microelectrophoretic point of view. Determinations have been made for infected cells (collected at 48 or 72 hours after infection) and for control cells, immediately after their separation from the culture, or after preserving them for 24 hours or more in migration buffer. The electrophoretical mobility increases with an average of 10% in the case of infected cells, as compared to the controls. This parameter offers a distribution of values varying from the gaussian curve to the bimodal one. From the microelectrophoretic point of view, the HEp-2 cells are more stable and respond more uniformly than BSC cells.

[Risk of bronchopulmonary cancer in patients with chronic obstructive bronchopneumopathy]. / Riscul de cancer bronhopulmonar la bolnavii cu bronhopneumopatie obstructiva cronica.

A total of 477 cases have been followed, presenting with chronic obstructive bronchopneumopathy, and another 151 cases with chronic bronchitis without obstructive syndrome, over a median duration of 5 years. In the first lot of patients 37 cases of bronchopulmonary cancer have been recorded over this period of time, of which 35 in 333 male patients (10.5%), and 2 in 144 women (1.4%). The annual rate of bronchopulmonary cancer was of 1.9% in males, and of 0.2% in females. In the group of patients with simple bronchitis only 3 cases of bronchopulmonary cancer have been recorded, with an annual rate of 0.4%. In male patients with chronic obstructive bronchopneumopathy the annual risk of bronchopulmonary cancer is of 1900 0/0000, 60 times greater than in the general population, where it is of 30 0/0000. A comparative analysis of the three groups: chronic simple bronchitis, chronic obstructive bronchopneumopathy and chronic obstructive bronchopneumopathy complicated with bronchopulmonary cancer shows that in the last group there are several outstanding features: a more advanced median age, intensive (heavy) smoking, a more advanced degree of chronic alcohol intoxication, frequent professional exposure, genetic deficiencies of I.A.T., prolonged corticoid therapy in the antecedents, and a higher proportion of associated diseases. In general this group is more exposed to risk factors, and has a higher risk of alteration of the defense mechanisms of the organism. However, a more detailed analysis is necessary for detecting the factors involved in the genesis of bronchopulmonary cancer in patients with chronic obstructive bronchopneumopathies.

[Some epidemiological indicators in bronchopulmonary cancer in Sector 5 of Bucharest (study of 525 cases)]. / Unii indicatori epidemiologici privind cancerul bronhopulmonar în sectorul 5 din Bucuresti

The incidence was studied of broncho-pulmonary carcinoma, as well as of other epidemiological indicators in the 5th district of Bucharest over a period of 14 years (1960-1973) during which a total of 525 cases have occured. The incidence in this territory tends to become real from 1967 when the curve overtook the death-rate in the country. Following a continuous increase the number of cases reached 29 0/0000 in 1973 and it is presumed that it will attain 40 0/0000 in 1980. The increase in the morbidity is due to a higher number of cases noted in the extreme age groups (the increase was 2,5-fold in those under 40 years of age); the age group which was the most seriously involved was that between 60 and 69 years, in which the morbidity was of 111 0/0000. The proportion of women has also increased, from 1/6-th to 1/5-th of the total number of cases. In women the frequency of adenocarcinoma and of non-differentiated neoplasies is somewhat higher than in men. The proportion of histopathological confirmation of the disease diminished in the last years probably due to the higher number of aged subjects that cannot be correctly investigated or surgically treated.