Randomized, Open-Label Phase 3 Study Evaluating Immunogenicity, Safety, and Reactogenicity of RSVPreF3 OA Coadministered with FLU-QIV-HD in Adults Aged ≥ 65.

INTRODUCTION: Respiratory syncytial virus (RSV) and influenza pose major disease burdens in older adults due to an aging immune system and comorbidities; seasonal overlap exists between these infections. In 2023, the RSV prefusion protein F3 older adult (RSVPreF3 OA) vaccine was first approved in the USA as a single dose for prevention of lower respiratory tract disease due to RSV in adults aged ≥ 60 years. The vaccine has since been approved in the European Union and elsewhere. RSVPreF3 OA and FLU-QIV-HD could be coadministered if immunogenicity, safety, and reactogenicity are not affected. METHODS: This open-label, randomized (1:1), controlled, phase 3 study in 1029 adults aged ≥ 65 years in the USA evaluated the immunogenicity (up to 1 month after last vaccine dose) and safety (up to 6 months after last vaccine dose) of RSVPreF3 OA coadministered with FLU-QIV-HD (co-ad group) versus FLU-QIV-HD alone followed by RSVPreF3 OA at a separate visit 1 month later (control group). Non-inferiority criterion was defined as an upper limit of the two-sided 95% confidence interval of the geometric mean titer (GMT) group ratio (control/co-ad) ≤ 1.5. Secondary endpoints included safety and reactogenicity. RESULTS: Proportions of participants across age categories between groups and proportions of male (50.4%) and female (49.6%) participants were well balanced; most participants were white (68.7%). Group GMT ratios for RSV-A neutralizing titers, hemagglutination inhibition titers for four influenza vaccine strains, and RSV-B neutralizing titers were non-inferior in the co-ad group versus the control group. No clinically meaningful differences in local or systemic solicited and unsolicited adverse events (AEs), serious AEs, and potential immune-mediated diseases were identified. The most common solicited AEs in both groups were injection-site pain and myalgia. CONCLUSION: In adults aged ≥ 65 years, coadministration of RSVPreF3 OA and FLU-QIV-HD was immunogenically non-inferior to the sequential administration of both vaccines 1 month apart, and had clinically acceptable safety and reactogenicity profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05559476.

Adults aged 65 years or older are vulnerable to infections caused by influenza and respiratory syncytial viruses, due to an aging immune system and other underlying conditions. Infections with both viruses increase during autumn and winter seasons in temperate climates. In 2023, a vaccine against respiratory syncytial virus, called RSVPreF3 OA, was first approved for use in adults aged 60 years or older in the USA; the vaccine has since also been approved in the European Union and elsewhere. Giving RSVPreF3 OA in the same vaccination visit (coadministration) with a high-dose influenza vaccine, called FLU-QIV-HD, which is given to adults aged 65 years or older, could help protect against both respiratory syncytial virus and influenza. This article reports the results of a phase 3 trial comparing coadministration of the RSVPreF3 OA and FLU-QIV-HD vaccines with sequential administration (FLU-QIV-HD followed by RSVPreF3 OA 1 month later) in 1029 adults aged 65 years or older in the USA. Proportions of participants across age categories between groups, and the proportions of male (50.4%) and female (49.6%) participants were well balanced; most participants were white (68.7%). Immune response to both the vaccines among participants in the coadministration arm was non-inferior to that in the sequential arm. Coadministration was well tolerated, with no meaningful differences in adverse reactions to the vaccines compared with sequential administration. The most common adverse reactions were pain at the injection site and muscle aches. This study supports the coadministration of RSVPreF3 OA and FLU-QIV-HD in adults aged 65 years or older.

Fluorescence Microscopy: Determination of Meropenem Activity against Klebsiella pneumoniae.

The development and implementation of diagnostic methods that allow rapid assessment of antibiotic activity against pathogenic microorganisms is an important step towards antibiotic therapy optimization and increase in the likelihood of successful treatment outcome. To determine whether fluorescence microscopy with acridine orange can be used for rapid assessment (≤8 h) of the meropenem activity against Klebsiella pneumoniae, six isolates including three OXA-48-carbapenemase-producers were exposed to meropenem at different levels of its concentration (0.5 × MIC, 1 × MIC, 8 or 16 µg/mL) and the changes in the viable counts within 24 h were evaluated using fluorescence microscopy and a control culture method. The approach was to capture the regrowth of bacteria as early as possible. Within the first 8 h fluorescence microscopy allowed to categorize 5 out of 6 K. pneumoniae strains by their meropenem susceptibility (based on the MIC breakpoint of 8 mg/L), but meropenem activity against three isolates, two of which were OXA-48-producers, could not be accurately determined at 8 h. The method proposed in our study requires improvement in terms of accelerating the bacterial growth and regrowth for early meropenem MIC determination. Volume-dependent elevation in meropenem MICs against OXA-48-producers was found and this phenomenon should be studied further.

Investigating Tetanus, Diphtheria, Acellular Pertussis Vaccination During Pregnancy and Risk of Congenital Anomalies.

INTRODUCTION: This observational retrospective matched cohort study evaluated the safety of a prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination, Boostrix. We previously reported on the risk of maternal and neonatal outcomes; here we report on the risk of congenital anomalies in infants at birth through 6 months of age. METHODS: The study included pregnant Kaiser Permanente Southern California members. Women who received the Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019 were matched to women who were pregnant between January 2012 and December 2014 and were not vaccinated with Tdap during pregnancy. Unadjusted and adjusted relative risks (aRRs) with 95% confidence intervals were estimated by Poisson regression. Quantitative secular trend analyses, from 2011 to 2017, were conducted on congenital anomalies with a statistically significant aRR > 1. RESULTS: The analysis consisted of 16,350 and 16,088 live-born infants in the Tdap-exposed and unexposed cohorts, respectively. Of the 14 congenital anomaly body systems evaluated, 8 (eye, ear/face/neck, respiratory, upper gastrointestinal, genital, renal, musculoskeletal, integument) had statistically significant elevated aRRs, with point estimates ranging from 1.17 to 2.02. The observed elevated aRRs were consistent with their respective secular increases over time. CONCLUSION: Cautious interpretation of these findings is warranted as these increases may have resulted from improved identification and diagnosis. Furthermore, the biological plausibility of an association between maternal vaccine exposure in the third trimester of pregnancy and birth defects is low. The overall study findings support the safety of maternal immunization with Boostrix during the third trimester of pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03463577.

Safety of tetanus, diphtheria, acellular pertussis (Tdap) vaccination during pregnancy.

The objective of this study was to evaluate the safety of prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination. This cohort study was conducted among pregnant members at Kaiser Permanente Southern California (KPSC). The exposed cohort consisted of women who received Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019. The unexposed cohort consisted of matched women who were pregnant between January 2012 and December 2014 and were not vaccinated with any Tdap vaccine throughout their pregnancy. Maternal and infant characteristics and pre-specified endpoints were collected through automated data and review of the electronic health records. Unadjusted and adjusted relative risks (aRRs) with confidence intervals (CIs) were estimated by Poisson regression. Non-inferiority testing (i.e., to rule out a two-fold increase) was conducted for primary endpoints with adjustment for multiplicity. Superiority testing was conducted without multiplicity adjustment for secondary endpoints. The analysis consisted of 16,606 pairs of Tdap recipients and unexposed pregnant women. For the primary endpoints, the aRR for preeclampsia/eclampsia was 1.38 (98.75% CI:1.21-1.58) and the aRR for intrauterine infection was 1.28 (98.75% CI:1.12-1.47). These increases were consistent with the background increasing trend of these diagnoses among all pregnant women at KPSC since 2011, and the upper limit of the 98.75% CI of both aRRs did not exceed the pre-specified threshold of 2. No increased risks of small for gestational age (aRR = 1.04, 98.75% CI:0.94-1.16) or preterm delivery (aRR = 0.71, 98.75% CI:0.64-0.78) were observed. No evidence of increased risks for secondary endpoints, including poor fetal growth, preterm pre-labor rupture of membranes, stillbirth/fetal death, placental abruption, transfusion during delivery hospitalization, and neonatal death, was observed. Prenatal Tdap vaccination after the 27th week of pregnancy was not associated with increased risks of pre-specified maternal and infant outcomes, supporting the safety of Tdap vaccination during pregnancy.

Fourteen years of the Pregnancy Registry on maternal immunisation with a reduced-antigen-content tetanus-diphtheria-acellular pertussis (Tdap) vaccine.

BACKGROUND: GSK initiated a Pregnancy Registry in the United States (US) for the reduced-antigen-content tetanus-diphtheria-acellular pertussis (Tdap; Boostrix, GSK) vaccine with the aim to detect and describe pregnancy outcomes in women vaccinated with Boostrix 28 days before estimated conception or during pregnancy. METHODS: Voluntary reports of pregnancy exposure to Boostrix received from spontaneous and post-marketing surveillance sources in the US were assessed. Reports were classified as prospective or retrospective based on the knowledge of pregnancy outcomes at the time of reporting. For completeness, reports of exposure to Boostrix or to the Tdap-inactivated poliovirus vaccine (Boostrix-IPV, GSK) reported to the global safety database from countries outside the US were also evaluated. RESULTS: From May 2005 to August 2019, 1517 (1455 prospective and 62 retrospective) pregnancy reports were received in the Boostrix US Pregnancy Registry. Of the prospective reports, 250 had known outcomes: 244 live infants with no apparent birth defects (BDs), three live infants with BDs, and three spontaneous abortions with no apparent BDs. Of the retrospective reports, 55 had known outcomes: 33 live infants with no apparent BDs, 16 live infants with BDs, one spontaneous abortion with no apparent BDs, four stillbirths with no apparent BDs, and one stillbirth with BDs. Cumulatively, 1321 pregnancy reports (1006 for Boostrix; 315 for Boostrix-IPV) were received from countries outside the US. Of these, 163 prospective reports and 551 retrospective reports had known outcomes. Results were in line with those from the Boostrix US Pregnancy Registry. CONCLUSIONS: Data currently available from the Boostrix US Pregnancy Registry and from countries outside the US suggested that exposure to Boostrix or Boostrix-IPV during pregnancy does not raise safety concerns related to adverse pregnancy outcomes or BDs.

Hexavalent vaccines in infants: a systematic literature review and meta-analysis of the solicited local and systemic adverse reactions of two hexavalent vaccines.

Introduction: The hexavalent vaccine DT3aP-HBV-IPV-Hib (Infanrix hexa, GSK) was first licensed in Europe in 2000. DT2aP-HBV-IPV-Hib (Hexyon/Hexacima/Hexaxim, Sanofi Pasteur), and DT5aP-HBV-IPV-Hib (Vaxelis, MCM Vaccine Company) were licensed in the EU in 2013 and 2016, respectively, based largely on studies demonstrating non-inferiority to DT3aP-HBV-IPV-Hib for immunogenicity and comparable reactogenicity profiles.Methods: We conducted a systematic literature review looking for direct head-to-head trials comparing DT2aP-HBV-IPV-Hib and DT5aP-HBV-IPV-Hib with DT3aP-HBV-IPV-Hib. The incidence of solicited local and systemic reactions following primary series administration of DT3aP-HBV-IPV-Hib or DT2aP-HBV-IPV-Hib were meta-analyzed.Results: A total of 317 unique records were retrieved from the search; nine met the predefined inclusion criteria; seven reported studies comparing DT3aP-HBV-IPV-Hib and DT2aP-HBV-IPV-Hib. Six trials assessing outcomes of the primary vaccination series were identified. Odds ratios and 95% confidence intervals (OR; 95%CI) were computed for DT3aP-HBV-IPV-Hib, using DT2aP-HBV-IPV-Hib as reference, for redness (0.72; 0.63-0.83), pain (0.74; 0.62-0.89), swelling (0.86; 0.74-0.99) at injection site, fever (0.67; 0.54-0.83), persistent crying (0.72; 0.61-0.84), drowsiness (0.82; 0.71-0.94), irritability (0.82; 0.69-0.98), anorexia (0.83; 0.72-0.95), and vomiting (0.96; 0.83-1.11).Conclusion: ORs of analyzed local and systemic solicited adverse reactions after primary vaccination with DT3aP-HBV-IPV-Hib appear to be slightly lower than with DT2aP-HBV-IPV-Hib.

An Analysis of the Water-to-Ice Phase Transition Using Acoustic Plate Waves.

It is shown that, in spite of the wave radiation into the adjacent liquid, a large group of Lamb waves are able to propagate along piezoelectric plates (quartz, LiNbO3, LiTaO3) coated with a liquid layer (distilled water H2O). When the layer freezes, most of the group's waves increase their losses, essentially forming an acoustic response towards water-to-ice transformation. Partial contributions to the responses originating from wave propagation, electro-mechanical transduction, and wave scattering were estimated and compared with the coupling constants, and the vertical displacements of the waves were calculated numerically at the water-plate and ice-plate interfaces. The maximum values of the responses (20-30 dB at 10-100 MHz) are attributed to the total water-to-ice transformation. Time variations in the responses at intermediate temperatures were interpreted in terms of a two-phase system containing both water and ice simultaneously. The results of the paper may turn out to be useful for some applications where the control of ice formation is an important problem (aircraft wings, ship bodies, car roads, etc.).

Immunogenicity, safety, and reactogenicity of combined reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine administered as a booster vaccine dose in healthy Russian participants: a phase III, open-label study.

As vaccine-induced immunity and protection following natural pertussis infection wane over time, adults and adolescents may develop pertussis and become transmitters to unprotected infants. In Russia, diphtheria and tetanus but not pertussis-containing vaccines are registered for older children, adolescents, or adults. The reduced-antigen-content diphtheria toxoid, tetanus toxoid, and acellular pertussis (dTpa) vaccine (Boostrix, GSK) was developed for booster vaccination of children ≥4 years of age, adolescents, and adults. A phase III, open-label, non-randomized study was performed in eight centers in Russia between January and July 2018. The objective of this study was to assess immunogenicity, reactogenicity and safety of a single dose of dTpa vaccine in healthy Russian participants ≥4 years of age (age categories 4-9 years, 10-17 years, 18-64 years, and ≥65 years). At 1 month post-booster vaccination, across all age groups, >99.0% of participants were seroprotected against diphtheria and tetanus and >96.0% of participants were seropositive for anti-pertussis antibodies. For all antibodies across all age groups, antibody GMCs increased from pre- to 1 month post-booster vaccination and booster responses to diphtheria (in 71.5% of participants), tetanus (85.3%), and pertussis antigens (≥85.6%) were observed. One serious adverse event that was not causally related to the study vaccine was reported. No fatal cases were reported throughout the study period. In conclusion, administration of the dTpa vaccine as a booster dose in healthy Russian participants induced a robust immune response to all vaccine antigens and was generally well tolerated across all age groups.

Coordination Polymers Based on Highly Emissive Ligands: Synthesis and Functional Properties.

Coordination polymers are constructed from metal ions and bridging ligands, linking them into solid-state structures extending in one (1D), two (2D) or three dimensions (3D). Two- and three-dimensional coordination polymers with potential voids are often referred to as metal-organic frameworks (MOFs) or porous coordination polymers. Luminescence is an important property of coordination polymers, often playing a key role in their applications. Photophysical properties of the coordination polymers can be associated with intraligand, metal-centered, guest-centered, metal-to-ligand and ligand-to-metal electron transitions. In recent years, a rapid growth of publications devoted to luminescent or fluorescent coordination polymers can be observed. In this review the use of fluorescent ligands, namely, 4,4'-stilbenedicarboxylic acid, 1,3,4-oxadiazole, thiazole, 2,1,3-benzothiadiazole, terpyridine and carbazole derivatives, naphthalene diimides, 4,4',4''-nitrilotribenzoic acid, ruthenium(II) and iridium(III) complexes, boron-dipyrromethene (BODIPY) derivatives, porphyrins, for the construction of coordination polymers are surveyed. Applications of such coordination polymers based on their photophysical properties will be discussed. The review covers the literature published before April 2020.

Immune interference (blunting) in the context of maternal immunization with Tdap-containing vaccines: is it a class effect?

INTRODUCTION: Maternal immunization with reduced antigen content tetanus-diphtheria-acellular pertussis (Tdap)-containing vaccines has been recommended to prevent infant pertussis. However, maternal antibodies may interfere with infant responses to routine immunization with diphtheria-tetanus-acellular pertussis (DTaP)-containing vaccines, raising concerns of suboptimal protection after infant vaccination. We performed a narrative literature review to assess whether blunting occurs regardless of the manufacturer of maternal and infant vaccines. Because internationally agreed correlates of protection are lacking, the clinical significance of blunting is not yet fully understood. We have reviewed the evidence available to date. AREAS COVERED: Thirteen studies that evaluated blunting after maternal immunization and infant primary/booster series were identified. Blunting was observed with various combinations of Tdap- and DTaP-containing vaccines for maternal and pediatric immunization. Studies assessing the effectiveness of maternal Tdap immunization beyond the primary infant immunization series in England and in the United States suggested no evidence of a clinically relevant blunting effect so far. EXPERT COMMENTARY: This review indicates that the phenomenon of blunting does not depend on the manufacturer/brand of the pertussis-containing vaccines used for immunizing mothers or children. Currently, there is no epidemiological evidence that children whose mothers received Tdap are at increased risk of pertussis after pediatric vaccinations, although longer follow-up is required.

The Effect of Polyphenolic Composition BP-C3 on the Efficacy and Hematological Toxicity of Cyclophosphamide in the Chemotherapy of Mice Bearing Soft Tissue Sarcomas Induced by Benzo[a]pyrene.

This study aimed to evaluate the effect of lignin-derived polyphenolic composition BP-C3 on the efficacy and hematological toxicity of cyclophosphamide (CPA). Male and female Swiss-H derived mice bearing benzo[a]pyrene-induced soft tissue sarcomas were treated with CPA 300 mg/kg, BP-C3 75 mg/kg, or a combination. Tumor growth inhibition in male mice treated with CPA, BP-C3, or a combination of CPA and BP-C3 was significant and corresponded to 78%, 45%, and 82%, respectively, on day 21 after CPA administration on day 0. In female mice, tumor growth inhibition was 58%, -11%, and 35% when treated with CPA, BP-C3, or a combination of CPA and BP-C3, respectively. CPA administration resulted in significant hematological toxicity evidenced by a decreased white blood cell count on day 4 (2.43 ± 1.77 × 109/L in male mice and 1.19 ± 0.71 × 109/L in female mice) and anemia development on day 7 (6.55 ± 1.74 × 1012/L in male mice and 5.89 ± 2.24 × 1012/L in female mice). The red blood cell count measured on day 7 in animals treated with the combination of BP-C3 and CPA constituted 7.12 ± 1.17 × 1012/L and 7.36 ± 2.07 × 1012/L for male and female mice, respectively. The results of our study demonstrate the antitumor activity of BP-C3 in male mice bearing soft tissue sarcomas. Neither the antitumor activity nor the hematological toxicity of CPA were significantly influenced by BP-C3. A less pronounced effect of CPA on RBC count is demonstrated when this agent is given jointly with BP-C3.

The Oxime Derivatives of 1-R-1H-Naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides: Synthesis and Properties.

OBJECTIVE: To synthesize a novel chemotype based on the naphthoquinone scaffold with retained cytotoxicity and provisionally low intracellular oxidation potential. BACKGROUND: Derivatives of naphthoquinone, although potent anticancer agents, can exert heart toxicity due to generation of free oxygen species. METHODS: In this study, we modified the scaffold by replacing one carbonyl group with the oxime moiety. Interestingly, only one carbonyl group in 1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides reacted with hydroxylamine. The spatial structure was determined by X-ray analysis. New compounds were tested for the ability to form stable complexes with double stranded DNA by spectroscopy and molecular docking and to induce death of tumor cell lines and non-malignant counterparts. RESULTS: The resulting 1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione 4-oxime 2-oxides were further acylated to produce a series of 1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione 4-(O-acyloxime) 2-oxides. Newly synthesized compounds demonstrated a higher (in submicromolar or low micromolar range) cytotoxic potency against human colon and breast adenocarcinoma cell lines than to non-malignant skin fibroblasts. Spectroscopic measurements revealed that, unlike other classes of quinone derivatives, new naphthotriazoledione oxides did not form stable complexes with double stranded DNA regardless of their fitting to the DNA minor groove (as determined by molecular modeling). CONCLUSION: Thus, our chemical modifications yielded a new chemotype with good cytotoxic properties and yet-to-be-identified intracellular target(s).

DEP1 gene in wheat species with normal, compactoid and compact spikes.

BACKGROUND: In rice, a variant of DEP1 gene results in erect panicle architecture, well-developed vascular bundles, an increase in the number of grains per panicle and a consequent increase in the grain yield. Interestingly, DEP1 homologs are present in the other cereals including species of wheat and barley (Hordeum vulgare), even though they do not produce panicles but spikes. In barley, HvDEP1 alleles do not differ between strains of various ear types and geographic origins, while in at least three OsDEP1 variants have been described. RESULTS: In this work, we have studied the DEP1 gene from eight accessions which belong to four wheat species, T. monococcum, T. durum, T. compactum, and T. spelta, with either compact, compactoid or normal spike phenotypes. The nucleotide sequences of the 5th exon of DEP1 were determined for all eight accessions. Obtained sequences were species specific. Despite the interspecies diversity, all wheat sequences encoded polypeptides of the same size, similarly to the 5th exons of the DEP1 homologs in T. aestivum, T. urartu, and H. vulgare. For further study, the full-length sequences of the DEP1 gene for all four species were studied. The full-length DEP1 genomic copies were isolated from the genomic sequences of T. aestivum, T. urartu, and Aegilops tauschii. The genome of tetraploid wheat T. durum contains two variants of the DEP1 originating from A and B genomes. In the hexaploid wheats T. aestivum, T. compactum, and T. spelta, three variants of this gene originating from A, B, and D genomes were detected. DEP1 genes of the diploid wheats T. monococcum and T. urartu differ. It seems that a precursor of the DEP1 gene in T. monococcum originates from the wild progenitor T. boeoticum. CONCLUSION: No DEP1-related differences of nucleotide sequences between the compact (or compactoid) and normal spike phenotypes in the tested wheat species were detected. Therefore, DEP1 gene does not directly participate in the control of the spike architecture in wheats.

Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells.

Up to 80% of human cancers, in particular solid tumors, contain cells with abnormal chromosomal numbers, or aneuploidy, which is often linked with marked chromosomal instability. Whereas in some tumors the aneuploidy occurs by missegregation of one or a few chromosomes, aneuploidy can also arise during proliferation of inherently unstable tetraploid cells generated by whole genome doubling from diploid cells. Recent findings from cancer genome sequencing projects suggest that nearly 40% of tumors underwent whole genome doubling at some point of tumorigenesis, yet its contribution to cancer phenotypes and benefits for malignant growth remain unclear. Here, we investigated the consequences of a whole genome doubling in both cancerous and non-transformed p53 positive human cells. SNP array analysis and multicolor karyotyping revealed that induced whole-genome doubling led to variable aneuploidy. We found that chromosomal instability (CIN) is a frequent, but not a default outcome of whole genome doubling. The CIN phenotypes were accompanied by increased tolerance to mitotic errors that was mediated by suppression of the p53 signaling. Additionally, the expression of pro-apoptotic factors, such as iASPP and cIAP2, was downregulated. Furthermore, we found that whole genome doubling promotes resistance to a broad spectrum of chemotherapeutic drugs and stimulates anchorage-independent growth even in non-transformed p53-positive human cells. Taken together, whole genome doubling provides multifaceted benefits for malignant growth. Our findings provide new insight why genome-doubling promotes tumorigenesis and correlates with poor survival in cancer.

Unique features of the transcriptional response to model aneuploidy in human cells.

BACKGROUND: Aneuploidy, a karyotype deviating from multiples of a haploid chromosome set, affects the physiology of eukaryotes. In humans, aneuploidy is linked to pathological defects such as developmental abnormalities, mental retardation or cancer, but the underlying mechanisms remain elusive. There are many different types and origins of aneuploidy, but whether there is a uniform cellular response to aneuploidy in human cells has not been addressed so far. RESULTS: Here we evaluate the transcription profiles of eleven trisomic and tetrasomic cell lines and two cell lines with complex aneuploid karyotypes. We identify a characteristic aneuploidy response pattern defined by upregulation of genes linked to endoplasmic reticulum, Golgi apparatus and lysosomes, and downregulation of DNA replication, transcription as well as ribosomes. Strikingly, complex aneuploidy elicits the same transcriptional changes as trisomy. To uncover the triggers of the response, we compared the profiles with transcription changes in human cells subjected to stress conditions. Interestingly, we found an overlap only with the response to treatment with the autophagy inhibitor bafilomycin A1. Finally, we identified 23 genes whose expression is significantly altered in all aneuploids and which may thus serve as aneuploidy markers. CONCLUSIONS: Our analysis shows that despite the variability in chromosome content, aneuploidy triggers uniform transcriptional response in human cells. A common response independent of the type of aneuploidy might be exploited as a novel target for cancer therapy. Moreover, the potential aneuploidy markers identified in our analysis might represent novel biomarkers to assess the malignant potential of a tumor.

Oligonucleotide functionalization by a novel alkyne-modified nonnucleosidic reagent obtained by versatile building block chemistry.

A convenient synthetic strategy has been designed to prepare an alkyne-modified synthon for automated DNA synthesis. It is based on the key O-DMTr-protected 4-(2-hydroxyethyl)morpholin-2,3-dione and building blocks obtained by its functionalization by various aliphatic amines. A respective nonnucleosidic phosphoramidite monomer containing a terminal alkyne in the side-chain was synthesized, and corresponding oligothymidylates incorporating the modification in various positions were prepared. The presence of the alkyne group was confirmed by Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) between the functionalized oligonucleotide and an azide derivative of 7-nitro-2,1,3-benzoxadiazole.

Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells.

Erroneously arising tetraploid mammalian cells are chromosomally instable and may facilitate cell transformation. An increasing body of evidence shows that the propagation of mammalian tetraploid cells is limited by a p53-dependent arrest. The trigger of this arrest has not been identified so far. Here we show by live cell imaging of tetraploid cells generated by an induced cytokinesis failure that most tetraploids arrest and die in a p53-dependent manner after the first tetraploid mitosis. Furthermore, we found that the main trigger is a mitotic defect, in particular, chromosome missegregation during bipolar mitosis or spindle multipolarity. Both a transient multipolar spindle followed by efficient clustering in anaphase as well as a multipolar spindle followed by multipolar mitosis inhibited subsequent proliferation to a similar degree. We found that the tetraploid cells did not accumulate double-strand breaks that could cause the cell cycle arrest after tetraploid mitosis. In contrast, tetraploid cells showed increased levels of oxidative DNA damage coinciding with the p53 activation. To further elucidate the pathways involved in the proliferation control of tetraploid cells, we knocked down specific kinases that had been previously linked to the cell cycle arrest and p53 phosphorylation. Our results suggest that the checkpoint kinase ATM phosphorylates p53 in tetraploid cells after abnormal mitosis and thus contributes to proliferation control of human aberrantly arising tetraploids.

Suv4-20h2 mediates chromatin compaction and is important for cohesin recruitment to heterochromatin.

Cohesin plays an important role in chromatid cohesion and has additional functions in higher-order chromatin organization and in transcriptional regulation. The binding of cohesin to euchromatic regions is largely mediated by CTCF or the mediator complex. However, it is currently unknown how cohesin is recruited to pericentric heterochromatin in mammalian cells. Here we define the histone methyltransferase Suv4-20h2 as a major structural constituent of heterochromatin that mediates chromatin compaction and cohesin recruitment. Suv4-20h2 stably associates with pericentric heterochromatin through synergistic interactions with multiple heterochromatin protein 1 (HP1) molecules, resulting in compaction of heterochromatic regions. Suv4-20h mutant cells display an overall reduced chromatin compaction and an altered chromocenter organization in interphase referred to as "chromocenter scattering." We found that Suv4-20h-deficient cells display chromosome segregation defects during mitosis that coincide with reduced sister chromatid cohesion. Notably, cohesin subunits interact with Suv4-20h2 both in vitro and in vivo. This interaction is necessary for cohesin binding to heterochromatin, as Suv4-20h mutant cells display substantially reduced cohesin levels at pericentric heterochromatin. This defect is most prominent in G0-phase cells, where cohesin is virtually lost from heterochromatin, suggesting that Suv4-20h2 is involved in the initial loading or maintenance of cohesion subunits. In summary, our data provide the first compelling evidence that Suv4-20h2 plays essential roles in regulating nuclear architecture and ensuring proper chromosome segregation.

The power flow angle of acoustic waves in thin piezoelectric plates.

The curves of slowness and power flow angle (PFA) of quasi-antisymmetric (A(0)) and quasi-symmetric (S(0)) Lamb waves as well as quasi-shear-horizontal (SH(0)) acoustic waves in thin plates of lithium niobate and potassium niobate of X-,Y-, and Z-cuts for various propagation directions and the influence of electrical shorting of one plate surface on these curves and PFA have been theoretically investigated. It has been found that the group velocity of such waves does not coincide with the phase velocity for the most directions of propagation. It has been also shown that S(0) and SH(0) wave are characterized by record high values of PFA and its change due to electrical shorting of the plate surface in comparison with surface and bulk acoustic waves in the same material. The most interesting results have been verified by experiment. As a whole, the results obtained may be useful for development of various devices for signal processing, for example, electrically controlled acoustic switchers.

New method of change in temperature coefficient delay of acoustic waves in thin piezoelectric plates.

As is well-known, the development of high-effective and thermostable acoustic devices assumes using the acoustic waves with high coefficient of electromechanical coupling (K2) and low temperature coefficient of delay (TCD). At present, it also is well-known that fundamental shear horizontal (SH0) acoustic waves in thin piezoelectric plates possess by significantly more electromechanical coupling compared to surface acoustic waves (SAW) in the same material. However, although the value of TCD of SH0 waves is insignificantly less than for SAW, this is not enough for development of thermostable devices. This paper suggests a new way of decreasing TCD of SH0 waves in piezoelectric plates at a high level of electromechanical coupling. This way assumes to use the structure containing the piezoelectric plate and liquid with the special dependence of permittivity on temperature. Theoretical and experimental investigation showed that, for SH0 wave in YX LiNbO3 plate at hf = 700 m/s (h = plate thickness, f = wave frequency) the presence of butyl acetate can decrease the value of TCD by six times at K2 = 30%. In a whole the obtained results open the wide prospect of using SH0 wave in thin piezoelectric plate for development of high effective and thermo-stable acoustic devices.