Pan-cancer analysis of genomic scar patterns caused by homologous repair deficiency (HRD).

Homologous repair deficiency (HRD) is present in many cancer types at variable prevalence and can indicate response to platinum-based chemotherapy and PARP inhibition. We developed a tumor classification system based on the loss of function of genes in the homologous recombination repair (HRR) pathway. To this end, somatic and germline alterations in BRCA1/2 and 140 other HRR genes were included and assessed for the impact on gene function. Additionally, information on the allelic hit type and on BRCA1 promoter hypermethylation was included. The HRDsum score including LOH, LST, and TAI was calculated for 8847 tumors of the TCGA cohort starting from genotyping data and for the subcohort of ovarian cancer also starting from WES data. Pan-cancer, deleterious BRCA1/2 alterations were detected in 4% of the tumors, while 18% of the tumors were HRD-positive (HRDsum ≥ 42). Across 33 cancer types, both BRCA1/2 alterations and HRD-positivity were most prevalent in ovarian cancer (20% and 69%). Pan-cancer, tumors with biallelic deleterious alterations in BRCA1/2 were separated strongly from tumors without relevant alterations (AUC = 0.89), while separation for tumors with monoallelic deleterious BRCA1/2 alterations was weak (AUC = 0.53). Tumors with biallelic deleterious alterations in other HHR genes were separated moderately from tumors without relevant alterations (AUC = 0.63), while separation for tumors with such monoallelic alterations was weaker (AUC = 0.57). In ovarian cancer, HRDsum scores calculated from WES data correlated strongly with HRDsum scores calculated from genotyping data (R = 0.87) and were slightly (4%) higher. We comprehensively analyzed HRD scores and their association with mutations in HRR genes in common cancer types. Our study identifies important parameters influencing HRD measurement and argues for an integration of HRDsum score with specific mutational profiles.

Optimizing panel-based tumor mutational burden (TMB) measurement.

BACKGROUND: Panel sequencing based estimates of tumor mutational burden (psTMB) are increasingly replacing whole exome sequencing (WES) tumor mutational burden as predictive biomarker of immune checkpoint blockade (ICB). DESIGN: A mathematical law describing psTMB variability was derived using a random mutation model and complemented by the contributions of non-randomly mutated real-world cancer genomes and intratumoral heterogeneity through simulations in publicly available datasets. RESULTS: The coefficient of variation (CV) of psTMB decreased inversely proportional with the square root of the panel size and the square root of the TMB level. In silico simulations of all major commercially available panels in the TCGA pan-cancer cohort confirmed the validity of this mathematical law and demonstrated that the CV was 35% for TMB = 10 muts/Mbp for the largest panels of size 1.1-1.4 Mbp. Accordingly, misclassification rates (gold standard: WES) to separate 'TMBhigh' from 'TMBlow' using a cut-point of 199 mutations were 10%-12% in TCGA-LUAD and 17%-19% in TCGA-LUSC. A novel three-tier psTMB classification scheme which accounts for the likelihood of misclassification is proposed. Simulations in two WES datasets of immunotherapy treated patients revealed that small gene panels were poor predictors of ICB response. Moreover, we noted substantial intratumoral variance of psTMB scores in the TRACERx 100 cohort and identified indel burden as independent marker complementing missense mutation burden. CONCLUSIONS: A universal mathematical law describes accuracy limitations inherent to psTMB, which result in substantial misclassification rates. This scenario can be controlled by two measures: (i) a panel design that is based on the mathematical law described in this article: halving the CV requires a fourfold increase in panel size, (ii) a novel three-tier TMB classification scheme. Moreover, inclusion of indel burden can complement TMB reports. This work has substantial implications for panel design, TMB testing, clinical trials and patient management.

[From panel diagnostics to comprehensive genomic analysis : Infobesity or empowerment?] / Von der Paneldiagnostik zu umfassenden genomischen Analysen : Informationsüberfluss oder Zugewinn?

Precision oncology is obtaining a central role in the therapy of malignant diseases. The indication for targeted therapy is based on the identification of molecular targets for which next-generation sequencing (NGS) is commonly used nowadays. All approved predictive biomarkers and molecular targets, including gene fusions and copy number alterations, can be identified depending on panel design and method applied. Some clinical scenarios, however, may require more holistic genomic approaches, such as whole-genome/whole-exome and transcriptome analysis, which must be embedded in a clinical trial. Here, key aspects and applications of each method are summarized and discussed.

Two-parameter bifurcation study of the regularized long-wave equation.

We perform a two-parameter bifurcation study of the driven-damped regularized long-wave equation by varying the amplitude and phase of the driver. Increasing the amplitude of the driver brings the system to the regime of spatiotemporal chaos (STC), a chaotic state with a large number of degrees of freedom. Several global bifurcations are found, including codimension-two bifurcations and homoclinic bifurcations involving three-tori and the manifolds of steady waves, leading to the formation of chaotic saddles in the phase space. We identify four distinct routes to STC; they depend on the phase of the driver and involve boundary and interior crises, intermittency, the Ruelle-Takens scenario, the Feigenbaum cascade, an embedded saddle-node, homoclinic, and other bifurcations. This study elucidates some of the recently reported dynamical phenomena.

Wavelet-based multifractal analysis of nonlinear time series: the earthquake-driven tsunami of 27 February 2010 in Chile.

We study general multifractal properties of tidal gauge and long-wave time series which show a well defined transition between two states, as is the case of sea level when a tsunami arrives. We adopt a method based on discrete wavelets, called wavelet leaders, which has been successfully used in a wide range of applications from image analysis to biomedical signals. First, we analyze an empirical time series of tidal gauge from the tsunami event of 27 February 2010 in Chile. Then, we study a numerical solution of the driven-damped regularized long-wave equation (RLWE) which displays on-off intermittency. Both time series are characterized by a sudden change between two sharply distinct dynamical states. Our analysis suggests a correspondence between the pre- and post-tsunami states (ocean background) and the on state in the RLWE, and also between the tsunami state (disturbed ocean) and the off state in the RLWE. A qualitative similarity in their singularity spectra is observed, and since the RLWE is used to model shallow water dynamics, this result could imply an underlying dynamical similarity.

Experimental evidence of phase coherence of magnetohydrodynamic turbulence in the solar wind: GEOTAIL satellite data.

Magnetohydrodynamic (MHD) turbulence is commonly observed in the solar wind. Nonlinear interactions among MHD waves are likely to produce finite correlation of the wave phases. For discussions of various transport processes of energetic particles, it is fundamentally important to determine whether the wave phases are randomly distributed (as assumed in the quasi-linear theory) or have a finite coherence. Using a method based on the surrogate data technique, we analysed the GEOTAIL magnetic field data to evaluate the phase coherence in MHD turbulence in the Earth's foreshock region. The results demonstrate the existence of finite phase correlation, indicating that nonlinear wave-wave interactions are in progress.

Intermittent nature of solar wind turbulence near the Earth's bow shock: phase coherence and non-Gaussianity.

The link between phase coherence and non-Gaussian statistics is investigated using magnetic field data observed in the solar wind turbulence near the Earth's bow shock. The phase coherence index Cphi, which characterizes the degree of phase correlation (i.e., nonlinear wave-wave interactions) among scales, displays a behavior similar to kurtosis and reflects a departure from Gaussianity in the probability density functions of magnetic field fluctuations. This demonstrates that nonlinear interactions among scales are the origin of intermittency in the magnetic field turbulence.

[Level of colonization by Ureaplasma urealyticum of definite biovars in a group of women with different clinical symptoms]. / Uroven' kolonizatsii ureaplazmami opredelennykh biovarov v gruppakh zhenshchin s razlichnymi klinicheskimi simptomami.

To evaluate the level of U. urealyticum colonization of female urogenital tract, the method of the multiplex polymerase chain reaction (PCR) in the presence of two pairs of primers, corresponding to genes controlling U. urealyticum 16S rRNA and unique human osteopontin was used. The study of 93 clinical specimens showed no correlation between high colonization level and the presence of definite clinical manifestations of U. urealyticum infection. The determination of ureaplasmic biovars was carried out by the method of PCR in the presence of 3 primers corresponding to the multiple-banded antigen (MBA) gene. Biovar parvo was detected in 85% of the specimens, biovar T960 in 11% and both biovars were detected in 4% of the specimens. The biovar distribution in the groups of women with different clinical symptoms was approximately similar. U. urealyticum of biovar T960 occurred more frequently (33% of the specimens) only in a group of women with vaginal discharge characteristic of inflammation.

Optimal preoperative assessment and surgery for rectal cancer may greatly limit the need for radiotherapy.

BACKGROUND: Radiation is being used increasingly in the management of patients with rectal cancer. Over the past decade the Basingstoke Colorectal Research Unit has combined precision total mesorectal excision with the highly selective use of preoperative radiotherapy. METHODS: One hundred and fifty consecutive patients who underwent major surgical excision for cancers of all stages comprised the study group. Preoperative clinical assessment was based largely on tumour size, fixation and distance from the anal verge. Only preoperative radiotherapy was considered and this only for tumours judged to be at high risk of mesorectal fascia involvement. RESULTS: During a 5-year period 35 of 150 patients were selected for preoperative irradiation. In the non-irradiated patients the local recurrence rate after a median follow-up period of 870 (range 51-1903) days was 2.6 per cent (three of 115 patients), compared with 17.1 per cent (six of 35 patients) in those chosen for irradiation. Sixty patients (52.2 per cent) who were not irradiated were node positive. The local recurrence rate for the whole group was 6.0 per cent. CONCLUSION: The great majority of patients undergoing major excision for rectal cancer can be managed without radiation therapy if the preoperative assessment of the mesorectal fascia and surgery are performed optimally.

High-dimensional interior crisis in the Kuramoto-Sivashinsky equation.

An investigation of interior crisis of high dimensions in an extended spatiotemporal system exemplified by the Kuramoto-Sivashinsky equation is reported. It is shown that unstable periodic orbits and their associated invariant manifolds in the Poincaré hyperplane can effectively characterize the global bifurcation dynamics of high-dimensional systems.

[Comparison of various PCR methods for the detection of Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis in women with impaired reproductive function]. / Sravnenie raznykh PTsR-testov dlia vyiavleniia Chlamydia trachomatis, Ureaplasma urealyticum i Mycoplasma hominis.

The comparative evaluation of the PCR test "Polimik" (Research and Production Firm "Litekh", Moscow) and the PCR test of the Novosibirsk Institute of Bioorganic Chemistry (NIBC) was carried out. The results obtained with the use of the PCR test "Polimik" and the PCR test of the NIBC of the detection of C. trachomatis and M. hominis coincided in 97.8% and 97.4% of cases. For U. urealyticum, the coincidence of the results of both PCR tests was 81.2%. Among women who visited gynecologists for reproductive function disturbances, the use of the PCR tests made it possible to detect C. trachomatis in 19 (5.5%) out of 343 cases, U. urealyticum in 96 (39.0%) out of 246 cases and M. hominis in 25 (16.9%) out of 148 cases. The results of the investigation revealed that the occurrence of C. trachomatis infection in Novosibirsk was comparable with that in other regions of the world among the low-risk groups of the population. The detection frequency of M. hominis and U. urealyticum with the use of the PCR tests showed that the occurrence of infections caused by these causative agents coincided with the data obtained in other countries.

Dealing with practical problems in nursing management.

Nursing supervisors hear certain complaints from nurses with unusual frequency. In this article, seven common complaints are presented, and an example demonstrating each complaint is described. The obvious and not-so-obvious reasons behind each complaint are analysed, and suggestions made for supervisory behaviour which will reduce the likelihood of such complaints. When nursing supervisors actively pursue good managerial practices, the frequency of complaints will decline, interpersonal relations will improve, and increased supervisory effectiveness will result.

From nursing to nursing administration: making the transition easier.

When nurses get involved in nursing administration, they may experience difficulties with the managerial role. There are several reasons why these difficulties occur: failure to recognize that the skills required for management are different than those required for nursing; refusing to "let go" of former nursing duties; inconsistent emphasis on the development of managerial capability among nursing supervisors; and insufficient formal training in management. Suggestions for making the transition to management easier are presented. These include developing the proper mix of skills for management; delegating authority properly; systematizing on-the-job-training for supervisors; and restructuring the formal academic preparation that nurses receive while in B.N. programs.

Organizational politics and nursing administration.

When attempts are made to improve organizational performance, both rational and emotional factors will have to be recognized. One of the important emotional factors is the tendency of people to behave politically while they are carrying out their assigned duties. The meaning and importance of organizational politics is discussed, and several typical reactions of nurse administrators to organizational politics are examined. Practical suggestions are made to help nurse administrators develop greater political sensitivity and deal effectively with political behavior.

An extra-pancreatic direct effect of streptozotocin on the hypothalamo-hypophyseal-testicular axis in the rat.

Streptozotocin induced diabetes mellitus in 4 out of 6 male rats. On the other hand, all 6 drug-injected animals had decreased serum testosterone values. The Leydig cells from 6 control rats and all streptozotocin-injected animals were characterized by moderate numbers of mitochondria, few lipid droplets, and an abundance of smooth surfaced endoplasmic reticulum. Quantitative analysis of numbers of mitochondria and lipid droplets revealed no differences between control and streptozotocin-injected animals. However, there were smaller mitochondria, larger lipid droplets and a trend toward fewer cells with dilated profiles of smooth endoplasmic reticulum in all drug injected animals. These cytological and biochemical findings suggest that diabetes per se had little direct effect on Leydig cell function. However, taken together with previous studies, these observations suggest that streptozotocin may directly affect the hypothalamo-pituitary-testicular axis possibly at the level of LHRH-secreting neurons of the hypothalamus.