Gene deletion chemoselectivity: codeletion of the genes for p16(INK4), methylthioadenosine phosphorylase, and the alpha- and beta-interferons in human pancreatic cell carcinoma lines and its implications for chemotherapy

Pancreatic carcinoma cells lines are known to have a high incidence of homozygous deletion of the candidate tumor suppressor gene p16 (MTS1/CDKN2), which resides in the chromosome 9p21 region. Here we: (a)examined a series of these cell lines for the incidence of codeletion of genes located near p16, in particular, the gene for the enzyme 5\u27-deoxy-5\u27-methylthioadenosine phosphorylase (MTAP) and the genes of the IFN-alpha and -beta cluster (IFNs); and (b) investigated whether therapeutic strategies could be developed that target malignant cells that have undergone the codeletion of such genes. Five of the eight pancreatic carcinoma cell lines were p16(-), MTAP was codeleted in all five cases. Because MTAP phosphorolyzes 5\u27-deoxy-5\u27-methylthioadenosine (MTA), generated as a byproduct of polyamine synthesis, to the salvageable purine base adenine, loss of this pathway in p16(-), MTAP(-) cells might sensitize these cells to methotrexate (MTX), the mechanism of action of which involves, in part, an inhibition of purine de novo synthesis. MTAP(+) normal keratinocytes and pancreatic carcinoma lines had relatively poor sensitivity, in terms of efficacy, to the purine nucleotide-starving actions of MTX. This may be in part due to the MTAP-dependent salvage of adenine moieties from endogenously generated MTA, because the MTAP inhibitor 5\u27-chloro-5\u27-de- oxyformycin A potentiates the antipurine actions of MTX in some of these MTAP(+) lines. Also, exogenous MTA (10 microM) reverses the growth-inhibitory actions of MTX in these lines. In contrast, MTAP(-) cell lines, which cannot recycle purines from endogenous MTA, have a relatively high sensitivity to the antipurine actions of MTX, which is not modulated by 5\u27-chloro-5\u27-deoxyformycin A or exogenous MTA. Thus the MTAP loss in malignant cells may be an example of gene deletion chemoselectivity, in which genetic deletions that occur as part of the oncogenic process render these cells more sensitive to particular anticancer agents than normal cells, which have not undergone such deletions. We also examined whether the loss of IFN genes sensitize cells to the growth-inhibitory actions of these cytokines. Three of the five p16(-) cell lines bore homozygous deletions of IFNA1 and IFNB1 genes, representing each end of the IFN-alpha,-beta gene cluster; one cell line bore a codeletion of the IFNA1 gene but retained the IFNB1 locus. Whereas the cell lines that were most sensitive to the growth-inhibitory effects of IFN-beta or IFN-alpha(2b), tended to be those with IFN deletions, there were enough exceptions to this pattern to indicate that the IFN genotype does not reliably predict IFN responsiveness

Genetic stability at nuclear and plastid DNA level in regenerated plants of Solanum species and hybrids

In this work we detected the extent of variability at nuclear and cytoplasmic DNA level of regenerated plants belonging to Solanum genotypes with a different genetic background and somatic chromosome number. As for the nuclear characterization, a total of 66 (18.5%) polymorphic bands were scored using 13 ISSR primers on 45 randomly selected regenerants. Our results show that the regenerants obtained from clone cmm 1T and, at lower level, those from cph 1C are unstable under in vitro conditions or rather more prone to in vitro- induced stress leading to somaclonal variation than the other genotypes used. Two types of changes were observed: disappearance of parental ISSR fragments, termed ‘‘loss’’; appearance of novel ISSR fragments, termed ‘‘gain’’. The most frequent event occurring in the regenerants was the loss of fragments (41 bands). Regenerated plants were analyzed with seven plastid universal primers to determine the cytoplasmic composition at chloroplast level. All cpDNA primer pairs tested produced amplicons of the same size in all genotypes analyzed and no polymorphic fragments were observed with any universal primers used. Our results show that under in vitro culture conditions genotype affects the integrity of the genome. In addition, the absence of polymorphism at plastid level confirms the greater genetic stability of cytoplasmic DNA

Psychology and hereditary angioedema: A systematic review

Background: Hereditary angioedema (HAE) is caused by mutations in the C1 inhibitor (C1-INH) gene Serpin Family G Member 1(SERPING1), which results in either the decreased synthesis of normal C1-INH (C1-INH–HAE type I) or expression of unfunctional C1-INH (C1-INH–HAE type II). In recent studies, emotional stress was reported by patients as the most common trigger factor for C1-INH–HAE attacks. Moreover, patients reported considerable distress over the significant variability and uncertainty with which the disease manifests, in addition to the impact of physical symptoms on their overall quality of life. Objective: We did a systematic review of the literature to shed light on the advancements made in the study of how stress and psychological processes impact C1-INH–HAE. Methods: All of the articles on C1-INH–HAE were analyzed up to December 2019. Both medical data bases and psychological data bases were examined. The keywords (KWs) used for searching the medical and psychological data bases were the following: “hereditary angioedema,” “psychology,” “stress,” “anxiety,” and “depression.” Results: Of a total of 2549 articles on C1-INH–HAE, 113 articles were retrieved from the literature search by using the related KWs. Twenty-one of these articles were retrieved, examined, and classified. Conclusion: Although the literature confirmed that stress may induce various physical diseases, it also warned against making simplistic statements about its incidence that did not take into account the complexity and multicausality of factors that contribute to C1-INH–HAE expression

Trophic effects of sponge feeding within Lake Baikal\u27s littoral zone .2. Sponge abundance, diet, feeding efficiency, and carbon flux

Endemic freshwater demosponges in the littoral zone of Lake Baikal, Russia, dominate the benthic biomass, covering 44% of the benthos. We measured in situ sponge abundance and,orating and calculated sponge-mediated Fluxes of picoplankton (plankton \u3c2 mu m) for two common species, Baikalospongia intermedia and Baikalospongia bacillifera. By means of dual-beam how cytometry, we found retention efficiencies ranging from 58 to 99% for four types of picoplankton: heterotrophic bacteria, Synechococcus-type cyanobacteria, autotrophic picoplankton with one chloroplast, and autotrophic picoplankton with two chloroplasts. By using a general model for organism-mediated fluxes, we conservatively estimate that through active suspension feeding, sponges are a sink for 1.97 g C d(-1) m(-1), mostly from procaryotic cell types. Furthermore, grazing by these extensive sponge communities can create a layer of picoplankton-depleted water overlying the benthic community in this unique lake

Cell cultures harbouring constructs of different pig promoter polymorphisms show different transcriptional efficiency in gene reporter systems

AbstractProduction traits variability among and within breeds, differences among developmental stages or the response to different environments are in part due to genetic factors that affect gene expression. Within the context of an Italian FIRB project, whose objective is to identify genes and molecular mechanisms affecting meat quality and production traits in pig, we studied the promoter regions of candidate genes selected on the basis of their physiological role in animal tissue development or composition. Genomic DNA was isolated from liver or muscle tissue of individuals belonging to Large White and Casertana breed. PCR primers were designed to amplify 5' upstream region of SCD (Stearoyl-CoA Desaturase), LDLR (Low Density Lipoprotein Receptor), LEP (Leptin), MSTN (Myostatin), ACTA1 (Alpha-actin) and HFABP (Heart Fatty Acid Binding Protein) genes using sequences available at NCBI. A total of 19 single nucleotide polymorphisms (SNPs) not previously described were characterised. Some haplotypes, harbou..

Convexal subarachnoid hemorrhage and acute ischemic stroke: a border zone matter?

Background Convexal subarachnoid hemorrhage (c-SAH) is an infrequent condition with variable causes. c-SAH concomitant to acute ischemic stroke (AIS) is even less frequent, and the relationship between the two conditions remains unclear. Methods Between January 2016 and January 2018, we treated four patients who were referred to our stroke unit with ischemic stroke and concomitant nontraumatic c-SAH. The patients underwent an extensive diagnostic workup, including digital subtraction angiography (DSA). Results All four patients developed acute focal neurological symptoms with restricted MRI diffusion in congruent areas. In three of the patients, infarcts were in a border zone between the main cerebral arteries and c-SAH was nearby. The fourth patient showed a small cortical infarct, and c-SAH was in a border zone territory of the contralateral hemisphere. An embolic source was discovered or strongly suspected in all cases. One patient was treated with intravenous thrombolysis, but this treatment was not related to c-SAH. None of the four patients showed microbleeds or further cortical siderosis, thus excluding cerebral amyloid angiopathy. In addition, DSA did not show signs of vasculitis, reversible cerebral vasoconstriction syndrome, or intracranial arterial dissection. Conclusions We proposed the embolism or hemodynamic changes of the border zone arterioles as a unifying pathogenetic hypothesis of coexisting c-SAH and AIS

Children on the Autism Spectrum and the Use of Virtual Reality for Supporting Social Skills

Background: Autism spectrum disorders (ASDs) are characterized by differences in socio-pragmatic communication. These conditions are allocated within a “spectrum” of phenotypic variability. Virtual reality (VR) is a useful tool for healthcare intervention and particularly safely advancing social abilities in children with ASD. Methods: In our study two types of intervention for improving social skills were compared: (i) emotional training obtained by the use of virtual reality (Gr1), (ii) traditional emotional training performed individually with a therapist (Gr2). We aimed to identify the intervention with the shortest acquisition time for the proposed social tasks. Results: Our findings show that both types of intervention had the same acquisition time for the recognition of primary emotions. However, for the use of primary and secondary emotions, the group using VR showed shorter acquisition times. Conclusions: These findings together with previous preliminary datasuggest that VR can be a promising, dynamic and effective practice for the support of basic and complex social skills of these individuals

Panorama of the distal myopathies

Distal myopathies are genetic primary muscle disorders with a prominent weakness at onset in hands and/or feet. The age of onset (from early childhood to adulthood), the distribution of muscle weakness (upper versus lower limbs) and the histological findings (ranging from nonspecific myopathic changes to myofibrillar disarrays and rimmed vacuoles) are extremely variable. However, despite being characterized by a wide clinical and genetic heterogeneity, the distal myopathies are a category of muscular dystrophies: genetic diseases with progressive loss of muscle fibers. Myopathic congenital arthrogryposis is also a form of distal myopathy usually caused by focal amyoplasia. Massive parallel sequencing has further expanded the long list of genes associated with a distal myopathy, and contributed identifying as distal myopathy-causative rare variants in genes more often related with other skeletal or cardiac muscle diseases. Currently, almost 20 genes (ACTN2, CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KHLH9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPS1) have been associated with an autosomal dominant form of distal myopathy. Pathogenic changes in four genes (ADSSL, ANO5, DYSF, GNE) cause an autosomal recessive form; and disease-causing variants in five genes (DES, MYH7, NEB, RYR1 and TTN) result either in a dominant or in a recessive distal myopathy. Finally, a digenic mechanism, underlying a Welander-like form of distal myopathy, has been recently elucidated. Rare pathogenic mutations in SQSTM1, previously identified with a bone disease (Paget disease), unexpectedly cause a distal myopathy when combined with a common polymorphism in TIA1. The present review aims at describing the genetic basis of distal myopathy and at summarizing the clinical features of the different forms described so far. ©2020 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.Peer reviewe

Carving from Ray-Tracing Constraints: IRT-Carving

We present a new algorithm for improving an available (conservative) estimate of the shape of an object using constraints from ray-tracing. In particular, we exploit incoherences between the lit portions of the object - detected on a set of acquired images - and the shadows that the current estimate casts on itself. Whenever a contradiction is found the current estimate is modified in order to remove the inconsistency. Sufficient conditions for the correctness of the algorithm and a discussion of their validity are provided. Finally, we describe a simple implementation of the method and present some preliminary experimental results from computer simulations

Prognostic role of topoisomerase-IIα in advanced ovarian cancer patients

To our knowledge, very few data about the role of Topoisomerase IIα (TOPO-IIα), an enzyme involved in critical steps of tumour cell proliferation and chemoresistance are currently available in ovarian cancer patients. The aim of this study was to investigate the prognostic value of TOPO-IIα expression in a large, single institution series of 96 primary untreated advanced ovarian cancer patients admitted to the Gynecologic Oncology Unit, Catholic University of Campobasso and Rome. Immunohistochemistry was carried out by using the MoAb anti-human TOPO-IIα antibody (clone Ki-S1). TOPO-IIα immunoreaction was observed in 70 out of 96 cases (72.9%), and the percentages of positively stained cells ranged between 1 and 83% (median=10%). There was no association with clinico-pathological parameters. During the follow up period, progression and death of disease were observed in 76 (79.2%) and 45 (46.9%) cases. A statistically significant direct association between the percentages of positively immunostained tumour cells and the relative risk of death was observed (χ2=6.6, P-value=0.0101). In multivariate analysis, only platinum resistance, advanced stage of disease and high levels of TOPO-IIα expression retained an independent negative prognostic role for OS. The unfavourable role of high TOPO-IIα expression was maintained only in the subgroup of platinum resistant recurrent ovarian cancer patients, be TOPO-IIα expression evaluated as continuous variable (χ2=5.1, P-value=0.024), or by means of the defined cutoff point. Our study suggests that the assessment of TOPO-IIα could be helpful to identify poor prognosis platinum-resistant ovarian cancer patients, potentially candidates to investigational agents