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PubMed1992

Breast masses. Mammographic and sonographic evaluation.

Asymmetric breast tissue can nearly always be distinguished from a true mass by means of mammographic evaluation. Stellate masses from early invasive breast cancer are often extremely subtle so that optimal technique and meticulous interpretation are essential. Benign stellate masses such as post-biopsy scarring and fat necrosis frequently have a characteristic appearance. A radial scar is usually indistinguishable from malignancy on the mammogram. Nearly all circumscribed masses are benign and are usually cysts, fibroadenomas, or intramammary lymph nodes. A few circumscribed masses represent in situ or invasive carcinoma or both. Characteristics that may allow a definitively benign diagnosis for a circumscribed mass include the presence of fat and certain calcification patterns on the mammogram and features of a simple cyst on the sonogram. Management decisions for other circumscribed masses will depend on characteristics such as shape, margins, calcification, multiplicity, size, stability, and sonographic features as well as patient age and risk factors. Most nonspecific circumscribed masses should be followed rather than biopsied as they are commonly present on mammograms and have a change of malignancy of less than 5%. Even when biopsied on the basis of interval change, most small circumscribed cancers will not have metastasized to the regional nodes. For palpable breast masses, selection of mammography or ultrasonography as the primary imaging modality will depend on patient's age and risk factors.

Breast Diseases↗

PubMed1987

CpG islands in vertebrate genomes.

Although vertebrate DNA is generally depleted in the dinucleotide CpG, it has recently been shown that some vertebrate genes contain CpG islands, regions of DNA with a high G+C content and a high frequency of CpG dinucleotides relative to the bulk genome. In this study, a large number of sequences of vertebrate genes were screened for the presence of CpG islands. Each CpG island was then analysed in terms of length, nucleotide composition, frequency of CpG dinucleotides, and location relative to the transcription unit of the associated gene. CpG islands were associated with the 5' ends of all housekeeping genes and many tissue-specific genes, and with the 3' ends of some tissue-specific genes. A few genes contained both 5' and 3' CpG islands, separated by several thousand base-pairs of CpG-depleted DNA. The 5' CpG islands extended through 5'-flanking DNA, exons and introns, whereas most of the 3' CpG islands appeared to be associated with exons. CpG islands were generally found in the same position relative to the transcription unit of equivalent genes in different species, with some notable exceptions. The locations of G/C boxes, composed of the sequence GGGCGG or its reverse complement CCGCCC, were investigated relative to the location of CpG islands. G/C boxes were found to be rare in CpG-depleted DNA and plentiful in CpG islands, where they occurred in 3' CpG islands, as well as in 5' CpG islands associated with tissue-specific and housekeeping genes. G/C boxes were located both upstream and downstream from the transcription start site of genes with 5' CpG islands. Thus, G/C boxes appeared to be a feature of CpG islands in general, rather than a feature of the promoter region of housekeeping genes. Two theories for the maintenance of a high frequency of CpG dinucleotides in CpG islands were tested: that CpG islands in methylated genomes are maintained, despite a tendency for 5mCpG to mutate by deamination to TpG+CpA, by the structural stability of a high G+C content alone, and that CpG islands associated with exons result from some selective importance of the arginine codon CGX. Neither of these theories could account for the distribution of CpG dinucleotides in the sequences analysed. Possible functions of CpG islands in transcriptional and post-transcriptional regulation of gene expression were discussed, and were related to theories for the maintenance of CpG islands as "methylation-free zones" in germline DNA.

Animals↗

PubMed1980

Typhlitis: a treatable complication of acute leukemia therapy.

Heretofore, pseudomembranous enterocolitis, or more specifically typhlitis, occurring as a complication of the cytotoxic chemotherapy of acute leukemia has nearly always resulted in a fatal outcome. Recent surgical literature states that if cecitis is found as a consequence of therapy for leukemia, the surgeon should refrain from operating because standard procedures, including hemicolectomy, have not improved survival. This paper reports two patients with acute typhlitis resulting from induction therapy of acute leukemia with cytosine arabinoside and hydroxydaunorubicin. Both patients underwent subtotal colectomy, while their marrows were aplastic from therapy, and survived their surgery. Both are living and well in maintained remission, 1 year from surgery. We review the pathogenesis of this disorder and discuss its clinical, x-ray, and laboratory features. Close oncologic/surgical teamwork is stressed as the patient is followed closely into the time frame when the decision is made whether to operate. Factors contributing to this decision are discussed. Preoperative recommendations are made in order to bring the patient into a state of physiologic stability. The operative procedure is described along with the postoperative complications encountered. We strongly recommend that laparotomy be considered in selected patients with typhlitis occurring as a complication of treated leukemia.

Adolescent↗

PubMed1984

IgE-specific suppressor factors in normal human serum.

The effect of normal human serum on in vitro IgE production was studied in an attempt to determine whether IgE-specific suppressor factors are present in the circulation of nonallergic individuals. Sera from 10 nonatopic donors (serum IgE less than 20 I.U./ml) were filtered through Diaflo CF50A membranes (cutoff point 50,000 D) and various dilutions of the IgE-free serum filtrates (less than 150 pg/ml of IgE) were examined for their ability to suppress spontaneous in vitro IgE synthesis by peripheral blood mononuclear cells (PBMC) from patients with hyper-IgE states. Serum filtrates from all 10 nonatopic donors tested suppressed IgE synthesis (mean suppression = 70 +/- 4%). IgE suppression was isotype specific because addition of the serum filtrates to pokeweed mitogen-stimulated normal PBMC or to spontaneously activated B cells from patients with active systemic lupus erythematosus did not suppress IgG or IgM production. The IgE suppressor activity was destroyed by treatment with trypsin but not with neuraminidase or exposure to heat. Substantial suppressor activity bound to IgE-Sepharose but not to a control IgG-Sepharose column. Further evaluation of the IgE-binding serum IgE suppressor factor(s) revealed a marked affinity for peanut agglutinin-Sepharose but minimal binding to lentil lectin-Sepharose. These results suggest that human serum from nonatopic donors contain low molecular weight IgE-binding factors which selectively suppress IgE production but not IgG production. Characterization of ths IgE-binding suppressor factor(s) reveals physicochemical features similar to those previously described for rat T-cell-derived IgE-binding factors with IgE suppressive activity.

Drug Stability↗

PubMed1984

[Nature of the phenotypic variability of somatic cells in culture: unstable phenotypic changes].

It was stated elsewhere ( Glebov , Abramyan , 1983) that the appearance of a number of phenotypic variants detected in somatic cell populations with high frequency should be provided by genetical unstable alterations. The properties of somatic cell variants that reproduce unstably a changable phenotype in the course of cell generations are analysed. These variants: (1) appear accidentally and independently on selectivity agent; (2) as a rule, the frequency of the variant arising does not increase under the action of mutagens; (3) the phenotypic reversion of unstable variants is a stochastic process; (4) such variants are characterized by intraclonal heterogeneity and by the segregation of stable alternative variants. The number of properties of phenotypically unstable variants isolated by one-step selection is similar to those for somatic cell variants isolated in the course of multistep selection. The latter are characterized by phenotypic reversion too. The appearance of unstable phenotypic variants is concluded to be associated with the genetical unstable alterations. It is argued that at least part of above alterations should be induced by the insertion of mobile genetic elements. The features of karyotypical variation in somatic cell population allow to conclude that the karyotype of cultured somatic cells is a genetically unstable attribute. The features mentioned above are: a high frequency of karyotypical alterations which is inherited by the cells with difference in the frequency of arising of karyotypical alteratons . The unstability of karyotype is restricted to the genetic unstability that is seen from non-random karyotypic variation, and interclonal difference in the chromosome stability. The site-specificity of karyotype alterations that proceed with high frequency allow to put forward a hypothesis that the process of mobile genetic element transposition is induced on the early stages of the history of constant cultured cell lines.

Animals↗

PubMed1975

Presynaptic events in meiocytes of Lilium longiflorum and their relation to crossing-over: a preselection hypothesis.

We are proposing a "Preselection Hypothesis" to account for the regulation of crossing-over in eukaryotic organisms. The hypothesis characterized meiosis in terms of three major physiological stages: (1) a presynaptic stage when pairs of homologous DNA stretches are selected so as to become trapped within the synaptinemal complex during synapsis, (2) an alignment of homologous chromosomes and stabilization of paired bivalents via the synaptinemal complex, and (3) a scission and rejoining of DNA stretches leading to the formation of chiasmata and crossovers. The hypothesis centers on the first stage and is based on evidence for the occurrence of significant cytological and biochemical changes prior to synapsis. The major feature of the hypothesis is that crossing-over occurs only in trapped DNA stretches. Thus, potential crossing-over sites, though not crossing-over itself, are determined well before chromosomes pair. Since, to a large degree, crossovers are distributed randomly along the length of each chromosome, the preselection process must result in a random assortment of trapped DNA stretches, the assortment differing from one meiocyte to another.

Chromosomes↗

PubMed2026

DHX9 Inhibition Enhances Paclitaxel Sensitivity by Inducing Mitotic Failure in Ovarian and Endometrial Cancers.

Recurrent high-grade serous ovarian carcinoma (HGSOC) and endometrial cancer remain major clinical challenges with limited effective treatment options. DExH-box helicase 9 (DHX9), a DNA/RNA helicase essential for genomic stability, has not yet been explored as a therapeutic target in gynecologic cancers. In this study, we show that a selective DHX9 inhibitor (DHX9i) suppresses proliferation in a subset of HGSOC and endometrial cancer cell lines by inducing DNA damage, chromosomal instability, and mitotic failure. This effect was independent of microsatellite instability status and prior resistance to platinum or PARP inhibitors. Genomic analysis indicated that DHX9i resistance was unlikely to be driven by single-gene mutations but was instead associated with copy-number alterations in mitotic spindle and microtubule-regulating genes in both HGSOC and endometrial cancer. Transcriptomic profiling further revealed consistent alterations in microtubule- and spindle-associated pathways in DHX9i-resistant models following DHX9i treatment. Mechanistically, DHX9i induced mitotic defects in DHX9i-sensitive models, whereas resistant lines maintained mitotic integrity. Given the convergence of resistance-associated features on microtubule-related pathways, we combined DHX9i with the microtubule-stabilizing agent paclitaxel to enhance mitotic stress. This combination triggered mitotic disruption and enhanced cytotoxicity in DHX9i-resistant cells. In vivo, the combination led to sustained tumor regression and prolonged survival in both DHX9i-sensitive and DHX9i-resistant models without notable toxicity. Overall, our findings define genomic, transcriptomic, and phenotypic characteristics associated with differential responses to DHX9i and support the clinical evaluation of the DHX9i-paclitaxel combination as a therapeutic strategy in recurrent gynecologic cancers.

Female↗

PubMed1988

New features of microtubule behaviour observed in vivo.

The microtubule cytoskeleton is thought to be intimately involved in generating and maintaining cell polarity and can generate many different morphological structures from a few structural elements. The mechanism by which these structures are generated has been partially elucidated from studies of microtubule polymerization both in vitro and in vivo. Microtubules in vitro exist in growing (polymerizing) and shrinking (depolymerizing) populations that interconvert infrequently. This behaviour, termed dynamic instability, permits microtubules in the cell rapidly to explore different arrangements and allows selective stabilization of specific morphologies. To investigate the regulation of these processes, we have implemented techniques for direct observation of fluorescently labelled microtubules and developed them to observe the dynamic behaviour of individual microtubules in single living cells. Sammak and Borisy recently used this technique to show that the dynamics of microtubules in fibroblasts is explained by dynamic instability. Although we also conclude here that dynamic instability explains much of microtubule behaviour in vivo, we find significant deviations from the properties of tubulin in vitro. These results suggest that local cytoplasmic factors strongly influence microtubule dynamics; such control has important implications for cellular morphogenesis.

Animals↗

PubMed2026

Bacteriophages Control Epiphytic Pseudomonas syringae Populations in Highbush Blueberry Leaves.

The Pseudomonas syringae complex (Psc) is a group of globally distributed phytopathogens responsible for substantial agricultural losses. Although bacteriophage-based biocontrol has shown promise against Psc, no studies have examined phages targeting blueberry-tropic Psc lineages. Here, we isolated phages infecting Psc strains from diseased highbush blueberry (Vaccinium corymbosum), and evaluated their suitability for biocontrol using a multi-stage screening pipeline incorporating host-range analysis, comparative genomics, environmental stability testing, in vitro antibacterial efficacy assays and ex planta validation. Twelve of the isolated phages exhibited favourable host-range characteristics. Genomic analyses revealed substantial phylogenetic diversity among these candidates but simultaneously identified multiple clonal groups, reducing the collection to eight non-redundant phages spanning five distinct genera. Candidate phages generally retained infectivity under environmentally relevant conditions and exhibited heterogeneous but largely favourable stability profiles. Planktonic killing assays uncovered considerable variation in antibacterial efficacy, but phage performance appeared to be driven by infection compatibility and host-specific factors rather than properties intrinsic to individual phages. Notably, the jumbo phageCB10 emerged as a particularly promising candidate due to its strong antibacterial activity (median GRC = 0.943), favourable environmental stability and unique genomic features. Cocktails containing the most effective candidates produced substantial and longitudinally sustained reductions in epiphytic colonization of detached blueberry leaves by Psc, exceeding five orders of magnitude at peak efficacy and demonstrating robust activity in a biologically relevant ex planta system. Importantly, in vitro antibacterial efficacy was predictive of performance in our ex planta model (r = 0.67; p = 0.0003), supporting the utility of tiered screening approaches for candidate selection. Taken together, these findings establish a framework for the systematic identification and evaluation of phages targeting Psc, and support the development of phage-based interventions for managing plant diseases.

Pseudomonas syringae↗

PubMed1981

Transport models for secretory IgA and secretory IgM.

At least seven models have been proposed for the epithelial transport of IgA, and each model presents particular features which are not generally appreciated. Much of the confusion in this field has been caused by the many conflicting reports about the cellular origin of the secretory component (SC) and the mode in which it is expressed by secretory epithelial cells. The transport model proposed in 1973-74 on the basis of test-tube experiments and immunohistochemical studies has now gained considerable support from observations made on both normal and neoplastic living epithelial cells According to this model, the J ("joining') chain and SC represent "the lock and key' in the selective external translocation of both dimeric IgA and pentameric IgM through serous-type secretory epithelial cell. Incorporation of J chains into these two Ig isotypes during their production in gland-associated immunocytes induces a configurational fit (binding site) allowing them to combine by specific non-covalent interactions with SC in the plasma membrance of the epithelial cell. After being formed on the basolateral surface of the cell, the SC-IgA and SC-IgM complexes are transported in cytoplasmic vesicles to the gland lumen along with some free SC. Covalent stabilization of human secretory IgA during this process depends on unique possibilities for disulphide-exchange reactions and is not an inherent feature of the transport model.

Animals↗

PubMed1982

Epidemiology of esophageal cancer in China.

Chinese historical records of about 2,000 years ago noted several unique epidemiological features and possible risk factors of esophageal cancer in this country. This paper presents selected recent findings on the epidemiology of esophageal cancer in China with special attention directed to geographical distribution, risk factors, and preventive measures. Some of the major characteristics of this disease in China include: 1) an unusually high mortality, the highest in the world; 2) wide geographical differences in mortality; 3) an irregular concentric belt area of elevated mortality; 4) stability of rates over the years; 5) variations in rate by sex; 6) great ethnic differences in mortality; 7) gullet cancer in chickens comparable to the human disease; and 8) associations with high prevalence of epithelial dysplasia of the esophagus. It has been hypothesized that the prevalence of esophageal cancer in high-risk areas may be associated with fermented and moldy foodstuffs, nitrosamines, deficiencies of molybdenum, nutritional deficiencies, specific living habits, and poor oral hygiene. Accordingly, comprehensive studies are being conducted in Lin County and other areas with elevated risk of this diseases so that the possible function of fungi and nitrosamines in the carcinogenesis of esophageal cancer can be determined.

China↗

PubMed1982

Cloning yeast telomeres on linear plasmid vectors.

We have constructed a linear yeast plasmid by joining fragments from the termini of Tetrahymena ribosomal DNA to a yeast vector. Structural features of the terminus region of the Tetrahymena rDNA plasmid maintained in the yeast linear plasmid include a set of specifically placed single-strand interruptions within the cluster of hexanucleotide (C4A2) repeat units. An artificially constructed hairpin terminus was unable to stabilize a linear plasmid in yeast. The fact that yeast can recognize and use DNA ends from the distantly related organism Tetrahymena suggests that the structural features required for telomere replication and resolution have been highly conserved in evolution. The linear plasmid was used as a vector to clone chromosomal telomeres from yeast. One Tetrahymena end was removed by restriction digestion, and yeast fragments that could function as an end on a linear plasmid were selected. Restriction mapping and hybridization analysis demonstrated that these fragments were yeast telomeres, and suggested that all yeast chromosomes might have a common telomere sequence. Yeast telomeres appear to be similar in structure to the rDNA of Tetrahymena, in which specific nicks or gaps are present within a simple repeated sequence near the terminus of the DNA.

Animals↗

PubMedDate not supplied

[Conformational transitions of DNA in concentrated neutral salt solutions].

Salt anions can be arranged in lyotropic series of the action of conformational stability of DNA. This effect is universal for proteins and DNA. It is explained by the salt changes of transfer free energy of macromolecular inner groups to the solvent. Effect mechanism is the combination of anion direct interaction with the exposed inner groups and in indirect way through the changes of water structure. Individual features of the salt effect on DNA are the induced transitions in DNA duplex and the changes of differential stability of AT- and GC-base pairs. An important role in these phenomena plays the dehydration of DNA in the reduction of water activity in concentrated salt solutions. Local changes in medium polarity, hydration level of DNA molecule at different stages of their functioning can explain the regulatory role in intracellular processes, as well as selectivity and specificity of the action of individual ions in the cell.

Circular Dichroism↗

PubMed1986

Packings and stationary phases in preparative column liquid chromatography.

Although the theoretical treatment of chromatographic processes on a preparative scale provides guidelines to the extent to which packing and stationary phase properties affect the target quantities such as sample input, throughput and resolution times sample input, a series of additional criteria were established to judge the quality of a packing in preparative column liquid chromatography. These include bed stability and flow resistance, chemical resistance and purity, solute accessibility, mass and biological recovery, fouling, regeneration and cost. Applying these criteria, the relative importance of physical and chemical structure parameters of packings and stationary phases was assessed. Commercial packings with mean particle diameters dp greater than 20 micron were listed for adsorption, size exclusion, ion-exchange and affinity chromatography. An analysis of the characteristic features of phase systems showed that adsorption media offer a high selectivity combined with adequate loadability, whereas ion exchangers and affinity media were best suited for biospecific solutes, particularly biopolymers, which can be attributed to their high selectivity and loadability.

Chemical Phenomena↗

PubMed1992

Cutaneous T-cell lymphoma. Evaluation of pretreatment skin biopsy specimens by a panel of pathologists.

BACKGROUND AND DESIGN: Cutaneous T-cell lymphoma (CTCL) frequently presents a difficult diagnostic challenge for the clinician and pathologist. To assess the diagnostic validity of conventional histopathologic findings in CTCL, pretreatment skin biopsy specimens were scored prospectively and independently by a panel of five to seven dermatopathologists and pathologists. Scores were compared with disease outcome. Repeatability of these scores was examined among observers and for the same observer. The study population consisted of 165 subjects, initially referred for suspected mycosis fungoides or Sézary syndrome. Ninety-two patients determined to have CTCL have been followed up for 6.3 +/- 3.5 years (mean +/- SD) and are categorized according to disease outcome: 22 are in complete remission, 35 are in partial remission, three have progressive lymphoma, 15 died of disease, 13 died of other causes, and four were unavailable for follow-up. Seventy-three patients determined not to have CTCL have been followed up for 5.3 +/- 3.2 years without subsequent clinicopathologic evidence of CTCL. These longitudinal data allowed comparisons of the clinical course with the original histologic interpretations. RESULTS: Data showed that the histologic scores rendered by the pathology panel did not correlate with stage of disease and were not an accurate predictor of clinical outcome, because the histologic ratings did not discriminate between patients who eventually had complete remission and those with either progressive lymphoma or who have died of disease. The results also substantiate the low inherent reliability of histopathologic findings in CTCL. Large differences existed among pathologists in scoring the study populations and repeated reading of selected cases by the same panel member resulted in a change of diagnosis 15% of the time. Among the histologic features evaluated, only the presence of mitoses in the infiltrating cells showed a trend toward an unfavorable outcome. CONCLUSION: Pathologic diagnosis in the CTCL disease spectrum should be interpreted with caution and then only in conjunction with the clinical evaluation. As expected, the use of an average value from a panel of readers added a component of stability to the histologic interpretation.

Biopsy↗

PubMed1991

Kinetics of rapid RNA evolution in vitro.

A rapidly acquired partial resistance to the replicase antagonist, ethidium bromide (EB), seen by Spiegelman and coresearchers in Q beta RNA variants competitively replicating under defined conditions in vitro, reflected existence of a pool of mutant RNA molecules, preadapted to EB, and their cross-propagation from the pre-EB optimum species, MDV-1, and from other kindred variants, some of which remained undetected, according to this quantitative analysis of midivariant RNA replication kinetics. DNAlike features of their evolution, such as the cloning of variants from an MDV-1 subtype and a compliance with the fundamental theorem of natural selection, resulted from the suppression, both real and apparent, of intrinsic RNA heterogeneity through sampling and detection methods, and also by the ascendency of self-propagation over cross-propagation with advancement of a superior variant. The deficit in mean polymer fitness, compared with optimum levels, determines the lower limit of this heterogeneity. Stability conditions for frequency equilibrium and strategies for counteracting viral drug resistance have been considered.

Biological Evolution↗

PubMed2026

Yeast Rad55-Rad57-SHU paralog complex dynamically promotes Rad51 filament formation.

Homologous recombination (HR) is an important DNA repair pathway that safeguards genome integrity. During HR, the Rad51 nucleoprotein filaments catalyze strand invasion into a homologous duplex DNA. Filament formation requires a conserved family of Rad51 paralogs that act as tumor suppressors in humans. By capturing six distinct states using cryo-electron microscopy, we reveal that the Saccharomyces cerevisiae Rad51 paralog complex, composed of the Rad55-Rad57 heterodimer and the SHU (Psy3-Csm2-Shu1-Shu2) complex, selectively brings Rad51 to single-stranded DNA to seed filament formation. Rad51 itself is a transient yet integral component of this machinery which binds along the Rad57 subunit to complete a high-affinity DNA-binding site. We also uncover a dual-nucleotide regulatory mechanism: a structural ADP molecule stabilizes the complex, while a second, catalytic ATPase site at the Rad57-Rad51 interface promotes the release of the paralog complex. These structural and mechanistic features provide a blueprint for understanding the function of Rad51 paralogs across eukaryotes.

Saccharomyces cerevisiae Proteins↗

PubMed2026

NCBoost v2: a classifier for non-coding single-nucleotide variants in Mendelian diseases.

MOTIVATION: The current diagnostic rate of rare diseases through whole-genome sequencing has stabilized at around 30% on average, highlighting the need for improved computational scores to identify pathogenic variants. In 2019, we developed NCBoost, a supervised-learning approach that mined a comprehensive set of sequence constraint features and proved particularly well suited to identifying high-effect pathogenic non-coding variants in genetic diseases. Since its first release, the substantial increase in the number of variants available for training, as well as the enhanced capacity to detect purifying selection signals from large-scale genome sequencing projects, motivated an update of NCBoost. RESULTS: We implemented NCBoost v2, a pathogenicity score for non-coding single-nucleotide variants, trained on the largest set of curated pathogenic variants in monogenic Mendelian diseases available to date. It leverages conservation features computed from recent large-scale genomic consortia such as Zoonomia and gnomAD, and incorporates recent splice-altering predictive scores. NCBoost v2 outperformed alternative state-of-the-art methods in a variety of scenarii, providing more consistent scores across non-coding genomic regions and fine-tuning the scoring of pathogenic splice-altering variants in Mendelian disease genes. AVAILABILITY AND IMPLEMENTATION: NCBoost v2 software is implemented in Python 3.10 and is freely available under the GNU General Public License Version 3 at https://doi.org/10.5281/zenodo.16029049 and https://github.com/RausellLab/NCBoost-2, together with precomputed scores for the human genome assembly GRCh38.

Polymorphism, Single Nucleotide↗