cudaMMC: GPU-enhanced multiscale Monte Carlo chromatin 3D modelling.

MOTIVATION: Investigating the 3D structure of chromatin provides new insights into transcriptional regulation. With the evolution of 3C next-generation sequencing methods like ChiA-PET and Hi-C, the surge in data volume has highlighted the need for more efficient chromatin spatial modelling algorithms. This study introduces the cudaMMC method, based on the Simulated Annealing Monte Carlo approach and enhanced by GPU-accelerated computing, to efficiently generate ensembles of chromatin 3D structures. RESULTS: The cudaMMC calculations demonstrate significantly faster performance with better stability compared to our previous method on the same workstation. cudaMMC also substantially reduces the computation time required for generating ensembles of large chromatin models, making it an invaluable tool for studying chromatin spatial conformation. AVAILABILITY AND IMPLEMENTATION: Open-source software and manual and sample data are freely available on https://github.com/SFGLab/cudaMMC.

Properties of Geopolymers Based on Metakaolin and Soda-Lime Waste Glass.

The paper determines the properties of geopolymer pastes based on metakaolin and soda-lime waste glass. The density, alkaline activity, strength and microstructure of the reference geopolymer, as well as geopolymers with a 10%, 30% and 50% soda-lime waste glass content instead of metakaolin, were tested. The experimental results indicate that the properties of the geopolymers with waste glass largely depend on the ratio of the liquid to solid substance. Increasing the content of waste glass causes an increase in the fluidity of the geopolymer paste, which in turn allows the amount of water glass, i.e., an activator during the obtaining of geopolymers, to be reduced. On the basis of the conducted tests, it was found that the strength of geopolymers can be increased by adding up to 50% of soda-lime waste glass instead of metakaolin and by having a lower content of water glass.

Predictive Value of the Spinal Instability Neoplastic Score for Survival and Ambulatory Function After Surgery for Metastatic Spinal Cord Compression in 110 Patients with Prostate Cancer.

STUDY DESIGN: We retrospectively analyzed Spinal Instability Neoplastic Score (SINS) in 110 patients with prostate cancer operated for metastatic spinal cord compression (MSCC). OBJECTIVE: We aimed to investigate the association between SINS and clinical outcomes after surgery for MSCC in patients with prostate cancer. SUMMARY OF BACKGROUND DATA: The SINS is a useful tool for assessing tumor-related spinal instability, but its prognostic value regarding survival and neurological outcome is still controversial. METHODS: We analyzed 110 consecutive patients with prostate cancer who underwent surgery for MSCC. The patients were categorized according to their SINS. Patients with castration-resistant prostate cancer (CRPC, n = 84) and those with hormone-naïve disease (n = 26) were analyzed separately. RESULTS: In total, 106 of 110 patients met the SINS criteria for potential instability or instability (scores 7-18). The median SINS was 10 (range 6-15) for patients with CRPC and 9 (7-16) for hormone-naïve patients. In the CRPC group, the SINS was classified as stable (score 0-6) in 4 patients, as potentially unstable (score 7-12) in 70 patients, and as unstable (score 13-18) in 10 patients. In the hormone-naïve group, 22 patients met the SINS criteria for potential instability and 4 patients for instability. There was no statistically significant difference in the overall risk for death between the SINS potentially unstable and unstable categories (adjusted hazard ratio 1.3, P = 0.4), or in the risk of loss of ambulation 1 month after surgery (adjusted odds ratio 1.4, P = 0.6). CONCLUSION: The SINS is helpful in assessing spinal instability when selecting patients for surgery, but it does not predict survival or neurological outcomes. Patients with a potential spinal instability benefit equally from surgery for MSCC as do patients with spinal instability.Level of Evidence: 3.

Influence of electron beam irradiation on water-saturated biodiesel.

The objective was to study changes in water-saturated biodiesel irradiated by electron beam and to analyse them considering the influence of absorbed dose. Based on obtained results it can be concluded that irradiation did not affect ester groups in FAME molecules, but strongly influenced on double bonds. Total ester content decreased linearly with the increase in absorbed dose, causing FAME not to meet the requirement of PN-EN 14214 concerning the ester content (96.5 wt%). Therefore, the use of ionizing radiation to improve biodiesel properties is unlikely, but it is worth to consider electron beam sterilisation of this biofuel.

Metastatic spinal cord compression as the first sign of malignancy.

Background and purpose - Metastatic spinal cord compression (MSCC) as the initial manifestation of malignancy (IMM) limits the time for diagnostic workup; most often, treatment is required before the final primary tumor diagnosis. We evaluated neurological outcome, complications, survival, and the manner of diagnosing the primary tumor in patients who were operated for MSCC as the IMM. Patients and methods - Records of 69 consecutive patients (51 men) who underwent surgery for MSCC as the IMM were reviewed. The patients had no history of cancer when they presented with pain (n = 2) and/or neurological symptoms (n = 67). Results - The primary tumor was identified in 59 patients. In 10 patients, no specific diagnosis could be established, and they were therefore defined as having cancer of unknown primary tumor (CUP). At the end of the study, 16 patients were still alive (median follow-up 2.5 years). The overall survival time was 20 months. Patients with CUP had the shortest survival (3.5 months) whereas patients with prostate cancer (6 years) and myeloma (5 years) had the longest survival. 20 of the 39 patients who were non-ambulatory preoperatively regained walking ability, and 29 of the 30 ambulatory patients preoperatively retained their walking ability 1 month postoperatively. 15 of the 69 patients suffered from a total of 20 complications within 1 month postoperatively. Interpretation - Postoperative survival with MSCC as the IMM depends on the type of primary tumor. Surgery in these patients maintains and improves ambulatory function.

Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis.

BACKGROUND CONTEXT: Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. PURPOSE: The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. STUDY DESIGN: This was a case control study. PATIENT SAMPLE: A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included. OUTCOME MEASURE: The outcome measure was idiopathic scoliosis. METHODS: The variants rs10510181, rs11190870, rs12946942, and rs6570507 were genotyped in 1,739 patients with idiopathic scoliosis and 1,812 controls. Exome sequencing was performed on pooled samples from 100 surgically treated idiopathic scoliosis patients. Novel or rare missense, nonsense, or splice site variants were selected for individual genotyping in the 1,739 cases and 1,812 controls. In addition, the 5'UTR, noncoding exon and promoter regions of LBX1, not covered by exome sequencing, were Sanger sequenced in the 100 pooled samples. RESULTS: Of the four candidate genes, an intergenic variant, rs11190870, downstream of the LBX1 gene, showed a highly significant association to idiopathic scoliosis in 1,739 cases and 1,812 controls (p=7.0×10(-18)). We identified 20 novel variants by exome sequencing after filtration and an initial genotyping validation. However, we could not verify any association to idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. We did not find any variants in the 5'UTR, noncoding exon and promoter regions of LBX1. CONCLUSIONS: Here, we confirm LBX1 as a susceptibility gene for idiopathic scoliosis in a Scandinavian population and report that we are unable to find evidence of other genes of similar or stronger effect.

Bisphenol A, 4-tert-octylphenol, and 4-nonylphenol in the Gulf of Gdansk (Southern Baltic).

The organic derivatives of phenol are classed as dangerous compounds, and their presence has been detected in surface water, bottom water, phytoplankton, zooplankton, and mussel as well as liver and muscle of fish from the Gulf of Gdansk and in liver, muscle, and guano of gulls residing in the coastal zone of this basin. The greatest sources of bisphenol A (BPA), 4-tert-octylphenol (OP), and 4-nonylphenol (NP) were found to be the Vistula River and the water purification plant in Debogórze. In living organisms, concentrations of BPA, OP, and NP ranged between the limit of quantification and several hundred ng g(-1) dry weight (dw), and the highest concentrations were found for BPA. Prolonged alimentary exposure to BPA, OP, and NP in fish and birds was indicated by liver/muscle concentration ratios generally >1. The most influential factors on BPA and alkylphenol concentrations in the tissues of fishes and gulls were mainly diet and habitat. The study confirmed possible bioaccumulation in the food web. High BPA and NP concentrations in guano (≤2,700 and ≤300 ng g(-1) dw, respectively) indicated the ability of birds to detoxify and signalled the reintroduction of these compounds to seawater. Herring, flounder, and cod from the Southern Baltic are a safe food source for human consumption because their BPA and alkylphenol contents are low.

Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients.

Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n = 265) and in relation to other prognostic markers. Short telomeres were particularly associated with high-risk genetic markers, such as NOTCH1, SF3B1, or TP53 aberrations, and predicted a short time to treatment (TTT) and overall survival (OS) (both P < 0.0001). TL was an independent prognostic factor and subdivided patients with otherwise good-prognostic features (e.g., mutated IGHV genes, favorable cytogenetics) into subgroups with different outcome. Furthermore, in follow-up samples (n = 119) taken 5-8 years after diagnosis, TL correlated well with TL at diagnosis and remained unaffected by treatment. Altogether, these novel data indicate that short TL already at diagnosis is associated with poor outcome in CLL and that TL can be measured at later stages of the disease.

Determination of 210Po and uranium in high salinity water samples.

A method for the determination of uranium and 210Po in high salinity water samples has been elaborated. Both radionuclides are preconcentrated from 0.5 dm3 saline media by co-precipitation with hydrated manganese dioxide, followed by dissolution of the precipitate in 200 mL of 1 M HCl. Uranium isotopes 235U and 238U can be directly determined by ICP MS method with a detection limit of 0.01 ppb for 238U. Prior to a selective determination of 210Po, the majority of other naturally occurring α-emitting radionuclides (uranium, thorium and protactinium) can be stripped from this solution by their extraction with a 50% solution of HDEHP in toluene. Finally, 210Po is simply separated by direct transfer to an extractive scintillator containing 5% of trioctylphosphine oxide in Ultima Gold F cocktail and determined by an α/ß separation liquid scintillation technique with detection limit below 0.1 mBq/dm3.

The PTEN regulator DJ-1 is associated with hTERT expression in clear cell renal cell carcinoma.

DJ-1 is as a novel regulator of the tumor suppressor PTEN with stimulatory effects on PI3K-AKT/PKB signaling, one possible target of which is cMyc. The catalytic unit of the telomerase complex, hTERT, can be activated at different levels, including transcriptionally by cMyc and through phosphorylation by AKT/PKB. The aim of the study was to analyze the putative signaling pathway encompassing DJ-1, cMyc and hTERT in a series of 176 renal cell carcinomas (RCC) and experimentally in cell lines. DJ-1 mRNA expression was significantly elevated in clear cell RCC (ccRCC) compared with in papillary RCC (pRCC; p = 0.005) and kidney cortex tissue (p < 0.001). ccRCC and pRCC demonstrated higher cMyc RNA levels than in kidney cortex (p < 0.001 for both) as well as increased levels of hTERT RNA (p < 0.001 and p = 0.011, respectively). DJ-1 was positively correlated to cMyc and hTERT in ccRCC (p < 0.001 and p = 0.019, respectively), but not in pRCC, indicating that this pathway could have a functional significance in ccRCC. siRNA knock down of DJ-1 induced downregulation of cMyc and hTERT mRNA associated with decreased expression of pAKT and cMyc protein levels. hTERT promoter activity was upregulated after DJ-1 transfection and this upregulation was inhibited after mutation of the cMyc binding sites. These experimental data support the functional link among DJ-1, cMyc and hTERT expression as indicated in the tumor material. Neither DJ-1, cMyc nor hTERT mRNA levels were associated with proliferation (S-phase fraction), telomere length or prognosis in ccRCC.

Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia.

Telomere length is associated with mutation status of the immunoglobulin heavy chain variable (IGHV) gene and clinical course in B-cell chronic lymphocytic leukemia (B-CLL). In a B-CLL cohort of 152 patients, we analyzed telomere length, genomic aberrations, IGHV mutation status, CD38 and ZAP-70 expression to study the prognostic impact and associations among these factors. An inverse correlation existed between telomere length and IGHV homology (P < .001), CD38 (P < .001), and ZAP-70 expression (P = .01). Patients with telomere lengths below median (ie, "short telomeres") and above median (ie, "long telomeres") had similar incidences of genomic aberrations (74% vs 68%), 13q- (57% vs 49%), and +12q (5% vs 12%). In contrast, 13q- as a single aberration was more frequent in patients with long telomeres (51% vs 21%; P = .006), whereas 11q- (27% vs 9%; P = .014), 17p- (17% vs 0%; P < .001), and 2 or more genomic aberrations (39% vs 8%; P < .001) were more frequent in patients with short telomeres. Compared with patients with long telomeres, treatment-free survival (TFS) and overall survival (OS) was significantly shorter (P < .001 and P = .015, respectively) in the group with short telomeres, and telomere length was an independent prognostic indicator for TFS. These observations have biological and prognostic implications in B-CLL.

The eukaryotic leading and lagging strand DNA polymerases are loaded onto primer-ends via separate mechanisms but have comparable processivity in the presence of PCNA.

Saccharomyces cerevisiae DNA polymerase delta (Pol delta) and DNA polymerase epsilon (Pol epsilon) are replicative DNA polymerases at the replication fork. Both enzymes are stimulated by PCNA, although to different levels. To understand why and to explore the interaction with PCNA, we compared Pol delta and Pol epsilon in physical interactions with PCNA and nucleic acids (with or without RPA), and in functional assays measuring activity and processivity. Using surface plasmon resonance technique, we show that Pol epsilon has a high affinity for DNA, but a low affinity for PCNA. In contrast, Pol delta has a low affinity for DNA and a high affinity for PCNA. The true processivity of Pol delta and Pol epsilon was measured for the first time in the presence of RPA, PCNA and RFC on single-stranded DNA. Remarkably, in the presence of PCNA, the processivity of Pol delta and Pol epsilon on RPA-coated DNA is comparable. Finally, more PCNA molecules were found on the template after it was replicated by Pol epsilon when compared to Pol delta. We conclude that Pol epsilon and Pol delta exhibit comparable processivity, but are loaded on the primer-end via different mechanisms.

Telomere length and correlation with histopathogenesis in B-cell leukemias/lymphomas.

Telomere length was recently reported to correlate with cellular origin of B-cell malignancies in relation to the germinal center (GC). In this report, we measured telomere length by quantitative-PCR in 223 B-cell lymphomas/leukemias and correlated results with immunoglobulin (Ig) mutation status and immunostainings for GC/non-GC subtypes of diffuse large B-cell lymphoma (DLBCL). Shortest telomeres were found in Ig-unmutated chronic lymphocytic leukemia (CLL) [median telomere to single copy gene value (T/S) 0.33], differing significantly to Ig-mutated CLL (0.63). Contrary to this, mantle cell lymphomas (MCLs) exhibited similar telomere lengths regardless of Ig mutation status (0.47). Telomere length differed significantly between GC-like (0.73) and non-GC-like DLBCLs (0.43), and follicular lymphomas (FLs) had shorter telomeres (0.53) than GC-DLBCL. Hairy cell leukemias, which display Ig gene intraclonal heterogeneity, had longer telomeres (0.62) than FLs and non-GC-DLBCL, but shorter than GC-DLBCL. We conclude that although DLBCL and CLL subsets can be clearly distinguished, telomere length reflects many parameters and may not simply correlate with GC-related origin.

Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status.

B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin V(H) genes have better outcome than unmutated cases. V(H)-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, V(H) gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the V(H)-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining V(H) mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.