Concurrent DNA Copy‐Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Somatic mosaicism for DNA copy‐number alterations (SMC‐CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC‐CNAs can undergo clonal expansion, it has been proposed that SMC‐CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array‐based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC‐CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC‐CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC‐CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co‐occurrence of gross SMC‐CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.     

Viusid, a nutritional supplement, in combination with interferon alpha-2b and ribavirin in patients with chronic hepatitis C.

BACKGROUND: The pathogenesis of chronic hepatitis C (CHC) is associated to severe oxidative stress that leads to necro-inflammation and progression of fibrosis. Previous trials suggested that antioxidative therapy may have a beneficial effect. We evaluated the efficacy and safety of Viusid in combination with interferon alpha-2b (IFN alpha-2b) and ribavirin in patients with CHC. METHODS: We randomly assigned 100 patients, between October 2002 and December 2004, in two arms: IFN alpha-2b (5 MU on alternate days), ribavirin at a dose of 13 mg/kg daily and Viusid (three sachets daily) vs. IFN alpha-2b (5 MU on alternate days) and ribavirin at a dose of 13 mg/kg daily. Subjects were treated for 48 weeks and then followed for an additional 24 weeks. The primary end point was the histologic response (reduction of at least two points without fibrosis worsening in the total score on the Histological Activity Index). RESULTS: A significantly high proportion of patients who received combined therapy plus Viusid had a histologic response better than those patients who received IFN alpha-2b and ribavirin (57% vs. 37%, P=0.03). The patients with virologic response achieved the highest percentages of histologic response, irrespective of assigned treatment. Among non-responders, the highest reduction in the mean change from baseline score for necro-inflammatory activity (NA) and fibrosis (F) was reported in patients treated with Viusid [NA, -1.50 (Viusid), -1.20 (without Viusid); F, -0.31 (Viusid), 0.00 (without Viusid)]. Sustained normalization of serum alanine aminotransferase concentration was highest in the Viusid group compared with standard therapy (67% vs. 41%, P=0.009). The overall safety profile was similar in both groups, but interestingly, the anemia was less intense in the group with Viusid (P=0.04). CONCLUSIONS: Our results suggest that triple therapy with Viusid, IFN alpha-2b and ribavirin was well tolerated and may have a beneficial effect on histologic and biochemical variables. The intensity of anemia is reduced in patients treated with Viusid.     

Sorption of pharmaceuticals and personal care products (PPCPs) onto a sustainable cotton based adsorbent

The significant rise in contamination of wastewater, water and ground water or sediments with PPCPs is a clear evidence that nowadays applied treatment methods are inefficient in removal of these contaminants. In this study a novel cotton based adsorbent is used for efficient sorption of naproxen (NAP), caffeine (CAF) and triclosan (TCS). The adsorption of tested contaminants differed significantly: the highest amount of PPCPs sorbed was noted for TCS sorption onto CMT9 137 mg g^?1, whereas the lowest adsorbed amount, 19.73 mg g^?1, was observed for NAP sorption onto CMT13. The presence of co-solute affected both the mechanism of sorption and the amount of PPCPs sorbed: in the presence of TCS the sorption of NAP was changed from chemical to physical. Similarly, in the presence of TCS the mechanism of NAP sorption onto CMT13 changed from chemisorption to diffusion inside the pores. The presence of CAF definitely increased NAP sorption and partitioning. The presence of TCS increased CAF sorption, whereas the presence of NAP in the solution increased CAF sorption only onto CMT11. The NAP sorption in the presence of CAF was significantly enhanced and data confirmed that diffusion through the pores is the most often observed mechanism of selected PPCPs sorption onto CMTs. It is believed that the synthesized cotton-based adsorbents offer a unique opportunity for the sustainable PPCP removal from wastewater.     

Defensins: Natural component of human innate immunity

The widespread use of antibiotics has contributed to a huge increase in the number of resistant bacteria. New classes of drugs are therefore being developed of which defensins are a potential source. Defensins are a group of antimicrobial peptides found in different living organisms, involved in the first line of defense in their innate immune response against pathogens. This review summarizes the results of studies of this family of human antimicrobial peptides (AMPs). There is a special emphasis on describing the entire group and individual peptides, history of their discovery, their functions and expression sites. The results of the recent studies on the use of the biologically active peptides in human medicine are also presented. The pharmaceutical potential of human defensins cannot be ignored, especially considering their strong antimicrobial activity and properties such as low molecular weight, reduced immunogenicity, broad activity spectrum and resistance to proteolysis, but there are still many challenges and questions regarding the possibilities of their practical application.     

Variance stabilization for computing and comparing grand mean waveforms in MEG and EEG

Grand means of time‐varying signals (waveforms) across subjects in magnetoencephalography (MEG) and electroencephalography (EEG) are commonly computed as arithmetic averages and compared between conditions, for example, by subtraction. However, the prerequisite for these operations, homogeneity of the variance of the waveforms in time, and for most common parametric statistical tests also between conditions, is rarely met. We suggest that the heteroscedasticity observed instead results because waveforms may differ by factors and additive terms and follow a mixed model. We propose to apply the asinh‐transformation to stabilize the variance in such cases. We demonstrate the homogeneous variance and the normal distributions of data achieved by this transformation using simulated waveforms, and we apply it to real MEG data and show its benefits. The asinh‐transformation is thus an essential and useful processing step prior to computing and comparing grand mean waveforms in MEG and EEG.     

Inhibitor kinazy Brutona u chorych z nawrotowym lub opornym na leczenie chłoniakiem z komórek płaszcza – wyniki międzynarodowego,wieloośrodkowego,badania II fazy z ibrutynibem (PCI-32765) – EHA Encore

Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling essential for normal B-cell development. Ibrutinib is an oral BTK inhibitor that induces apoptosis and inhibits migration and adhesion of malignant B-cells. Updated results of this international, multicenter, phase 2 study of single agent ibrutinib in relapsed or refractory MCL will be presented.Ibrutinib 560 mg PO QD was administered continuously until disease progression. Tumor response was assessed every 2 cycles (one cycle = 28 days). The study enrolled 115 patients (65 bortezomib-naïve, 50 bortezomib-exposed); 111 patients were treated; 110 were evaluable for response. Baseline characteristics included: median age 68 years, time since diagnosis 42 months, number of prior treatments 3; bulky disease (>10 cm) 13%, prior stem cell transplant 10%, high risk MIPI 49%.Median time on treatment was 9.2 months; 53% of patients remain on therapy. Median PFS was 13.9 months and DOR has not yet been reached. Responses increased with longer treatment: comparing to previous data described at ASH 2011, the CR rate increased from 16% to 39%, and the ORR increased from 69% to 75%.