Dipole Moment Variation Clears Up Electronic Excitations in the π-Stacked Complexes of Fluorescent Protein Chromophores.

We propose a quantitative structure-property relationship (QSPR) model for prediction of spectral tuning in cyan, green, orange, and red fluorescent proteins, which are engineered by motifs of the green fluorescent protein. Protein variants, in which their chromophores are involved in the π-stacking interaction with amino acid residues tyrosine, phenylalanine, and histidine, are prospective markers useful in bioimaging and super-resolution microscopy. In this work, we constructed training sets of the π-stacked complexes of four fluorescent protein chromophores (of the green, orange, red, and cyan series) with various substituted benzenes and imidazoles and tested the use of dipole moment variation upon excitation (DMV) as a descriptor to evaluate the vertical excitation energies in these systems. To validate this approach, we computed and analyzed electron density distributions of the π-stacked complexes and correlated the QSPR predictions with the reference values of the transition energies obtained using the high-level ab initio quantum chemistry methods. According to our results, the use of the DMV descriptor allows one to predict excitation energies in the π-stacked complexes with errors not exceeding 0.1 eV, which makes this model a practically useful tool in the development of efficient fluorescent markers for in vivo imaging.

Parallel evolution of genes and languages in the Caucasus region.

We analyzed 40 single nucleotide polymorphism and 19 short tandem repeat Y-chromosomal markers in a large sample of 1,525 indigenous individuals from 14 populations in the Caucasus and 254 additional individuals representing potential source populations. We also employed a lexicostatistical approach to reconstruct the history of the languages of the North Caucasian family spoken by the Caucasus populations. We found a different major haplogroup to be prevalent in each of four sets of populations that occupy distinct geographic regions and belong to different linguistic branches. The haplogroup frequencies correlated with geography and, even more strongly, with language. Within haplogroups, a number of haplotype clusters were shown to be specific to individual populations and languages. The data suggested a direct origin of Caucasus male lineages from the Near East, followed by high levels of isolation, differentiation, and genetic drift in situ. Comparison of genetic and linguistic reconstructions covering the last few millennia showed striking correspondences between the topology and dates of the respective gene and language trees and with documented historical events. Overall, in the Caucasus region, unmatched levels of gene-language coevolution occurred within geographically isolated populations, probably due to its mountainous terrain.

Effect of the timing of orchiectomy on survival in patients with metastatic germ cell tumors of testis.

OBJECTIVES: Classically, orchiectomy (OE) is the first step of treatment in patients with metastatic germ cell tumors (mGCTs) of testis. However, some patients have severe symptoms of disease, which require immediate beginning of chemotherapy (CT) followed by OE. This retrospective analysis was performed to find the effect of time constraints of delayed OE on survival in patients with mGCT. METHODS AND MATERIALS: We analyzed the data of 1,483 CT-naive patients with advanced mGCT of the testis treated in our Department from 1986 to 2009. Delayed OE was performed on 71 (4.8%) patients: seminoma in 8 patients (11.2%), nonseminomatous tumor in 50 patients (70.4%), and unknown tumor histology in 13 patients (18.4%). Twenty percent, 40%, and 40% of patients belonged to good, intermediate, and poor International Germ Cell Cancer Consensus Group prognostic groups, respectively. Median time from the beginning of the CT to OE was 18 (range, 1-250) days. OE was performed on 39 (55%), 21 (29.5%), and 11 (15.5%) patients during cycle 1, cycle 2 to completion of CT, and after the finishing of induction CT, respectively. Median follow-up time was 156 (range, 3-241) months. Etoposide and cisplatin-based CTs were received by 66 patients (93%). RESULTS: Three-year overall survival (OS) of all 1,483 patients was 75%. An excellent primary tumor response to CT was observed among the patients, who had delayed OE after completion of CT (n = 11): only mature teratoma (n = 4) and tumor necrosis (n = 7) were found. The 3-year OS in patients with delayed OE was 63%. OE performed after completion of CT was associated with better prognosis. The 3-year OS in patients with delayed OE performed during the cycle 1 (group 1) was 67%, cycle 2 to completion of CT (group 2) was 39%, and after finishing of CT (group 3) was 88% (groups 1 vs. 3: hazard ratio 3.7, 95% confidence interval 0.69-10.1, P = 0.15; groups 2 vs. 3: P = 0.01, hazard ratio 8.1, 95% confidence interval 1.32-18.,72). It seems that if OE had been performed during CT, the beginning of the successive cycle was delayed and dose intensity of CT was decreased. CONCLUSIONS: In case of severe symptoms of disease, which require an immediate start of CT, performing OE simultaneously with other surgeries after completion of induction CT was associated with better OS, when compared with performing OE during induction CT.

Prognostic factors and efficacy of different chemotherapeutic regimens in patients with mediastinal nonseminomatous germ cell tumors.

PURPOSE: Patients (pts) with mediastinal nonseminomatous germ cell tumors (MNGCT) are belonged to poor prognostic group by IGCCCG. We retrospectively studied the prognostic factors and efficacy of different chemotherapeutic regimen in pts with MNGCT. METHODS: We analyzed data on 61 pts with MNGCT. Conditional induction chemotherapy BEP was performed in 38 %, TBEP-in 28 %, CBOP-in 28 %, accelerated (two weekly) version of BEP-in 6 % pts. Based on similar efficacy of CBOP and TBEP regimens, we combines pts with CPOB and TBEP regimen in one group-55.8 % and different variants of BEP regimen in the second group-44.2 %. Multivariate Cox regression analysis was performed to determine independent factors, which influenced on overall survival. RESULTS: We revealed the following independent negative prognostic factors: age ≥ 24 years (p = 0.07), size of the primary mediastinal tumor ≥19 cm (p = 0.03). Median overall survival (OS) has not been reached, and 2-year OS was 66 % in pts with good prognosis (age < 24 years and/or size of mediastinal tumor < 19 cm) versus 15 months and 40 % in pts with poor prognosis (p = 0.03). Objective marker negative response was revealed more often in pts with CPOB/TBEP group: 26/34 (76.5 %) versus 14/27 (52 %), p = 0.08. Median OS was also higher in pts with CPOB/TBEP group: nonreached versus 15 months (p = 0.01). CONCLUSION: CPOB and TBEP regimen were significantly associated with better outcome in pts with MNGCT. Age ≥ 24 years and size of the primary mediastinal tumor ≥ 19 cm were found as independent negative prognostic factors.

Late relapses (>2 years) in patients with stage I testicular germ cell tumors: predictive factors and survival.

OBJECTIVES: Late relapses (>2 years) after completion of chemotherapy are rare and often platinum-resistant. There are limited data concerning late relapses in chemotherapy-naïve patients with stage I germ cell tumors. This retrospective analysis was performed to compare the outcome between patients with stage I germ cell tumors, who had late (≥2 years) and early (≥3 months and <2 years) relapse after orchiectomy. METHODS AND MATERIALS: We analyzed data of 1,069 chemotherapy-naïve patients with advanced germ cell tumors of testis treated in our department from 1986 to 2008. All patients had cisplatin- and etoposide-based chemotherapy. We identified 169 (15.8%) patients with prior stage I disease, who had not received adjuvant treatment: 140 and 29 patients had early and late relapse, respectively. Among patients with late relapse, pure seminoma was revealed in 14 patients, and nonseminoma in 15 patients. Median follow-up time for 169 patients was 35 (range, 2-218) months. RESULTS: Patients with late relapse were older, 35 years (23-57) and had more frequent pure seminoma in primary tumor, 14/29 (48.3%), than patients with early relapse, 30 years (16-63) (P = 0.0008) and 46/140 (32,8%, P = 0.08), respectively. At the time of disease progression, both groups were very similar according to well-known prognostic factors including IGCCCG classification. The only difference was larger size of retroperitoneal lymph nodes in late (9 cm) than in early relapse (4 cm, P < 0.0001). The outcome in patients with late relapse was significantly worse than in patients with early relapse: complete response rate after induction chemotherapy was 20.7% (6/29) vs. 42.1% (59/140) (P = 0.01), 3-year progression-free survival 66% vs. 84% (P = 0.02, HR = 2.4, 95% CI 1.2-8.8) and 3-year overall survival, 72% vs. 88% (P = 0.04, HR = 2.4, 95% CI 1.05-10.25), respectively. In patients with pure seminoma, this difference in overall survival was even more significant: 65% vs. 91% (P = 0.04, HR = 3.8, 95% CI 1.06-32.4). CONCLUSIONS: Late relapses following stage I germ cell tumors were associated with seminoma, older age, and worse outcome after induction chemotherapy.

Health cancer risk assessment for arsenic exposure in potentially contaminated areas by fertilizer plants: a possible regulatory approach applied to a case study in Moscow region-Russia.

At present, fertilizer industry plants are considered as a potential source of soil contamination in Russia. Therefore health risk assessment should be pursued in Russian fertilizer plant areas, but unfortunately risk assessment methodology for contaminated sites does not have yet a regulatory value in Russia. In this paper a possible and intentionally simple regulatory approach for health cancer risk assessment at phosphogypsum waste-storing potentially contaminated sites is presented. The proposed approach is applied to a potential contaminated area located in the Moscow river (Moscow Region) protective zone. At this case-study area, arsenic has been chosen as a contaminant indicator, according to the proposed selection procedure. For estimating the human exposure to arsenic through various pathways the original McKone & Daniels '91 model has been adapted. As a specific result of the risk assessment for the case-study area, it has been shown that arsenic exposure pathways (in risk-ranking order) "ingestion of agricultural products," "groundwater uptake," "dermal contact," and "soil ingestion" pose a significant health risk. From a general point of view, the proposed and applied health risk assessment approach could give some contribution (for comparison and discussion) for policies on contaminated soils to other countries. In this perspective, the paper expressly considers the current Italian regulative situation concerning restricted use of risk analysis and concerning soil quality for agricultural land use.