660 research outputs found
BRCA2 deletion induces alternative lengthening of telomeres in telomerase positive colon cancer cells
Get PDFBRCA1/2 are tumor suppressor genes controlling genomic stability also at telomeric and subtelomeric loci. Their mutation confers a predisposition to different human cancers but also sensitivity to antitumor drugs including poly(ADP-ribose) polymerase (PARP) inhibitors and G-quadruplex stabilizers. Here we demonstrate that BRCA2 deletion triggers TERRA hyperexpression and alternative lengthening mechanisms (ALT) in colon cancer cells in presence of telomerase activity. This finding opens the question if cancer patients bearing BRCA2 germline or sporadic mutation are suitable for anti-telomerase therapies, or how ALT activation could influence the short or long-term response to anti-PARP inhibitors or anti-G-quadruplex therapies
The role of the registered nurse in collecting and documenting physical forensic evidence related to fatal gunshot wounds: Recommendations for policy and practice
No full textThe purpose of this study was two fold. The first was to determine the quality of the forensic physical evidence, specifically clothing, cartridges and gunshot residue preservation, collected and documented in the medical examiner record. Looking at data retrospectively gives a historical analysis that will provide a systematic review of evidence collection practices. In this case, the data examined were collected by RNs in Harris County from 2004 to 2006. The second purpose was to propose nursing practice guidelines and standard operating procedures to preserve forensic evidence without interfering with emergency life-saving care efforts. The research questions that guided this study were: (1) What percentage of fatal gunshot wound physical forensic evidence documented in the medical examiner record from 2004 to 2006 in Harris County was collected by registered nurses? (2) Of the investigations formally filed in a court of law, what percentage of fatal gunshot wound physical forensic evidence collected by RNs as documented in the medical examiner record from 2004 to 2006 in Harris County was admissible in legal proceedings? (3) What policy and practice implications can be derived from the evidence related to the RN role as found in research questions 1 and 2? (4) What are the similarities and differences of these roles when compared to the standardized Sexual Assault Nurse Examiner (SANE) protocol? (5) Does the hospital trauma level designation and accreditation reflect differences in the amount and type of gunshot wound physical forensic evidence collected by RNs?
The study was a retrospective chart review examining medical examiner records from 2004-2006 of fatal gunshot wound victims dying in a hospital. The medical examiner record consists of hospital records, police reports, and investigator and autopsy reports, including photographs and subpoenas. An instrument derived from national standards and protocols, was developed specifically for this study.
A total of 451 records was reviewed and analyzed focusing on physical forensic evidence from gunshot wound victims: clothing, cartridges and gunpowder residue. The findings revealed current nursing practice when collecting evidence from fatal gunshot wound victims. The review also provided guidance in development of evidence collection hospital policies and procedures and clear nursing roles when caring for these victims
Λ + c production vs the event charged-particle multiplicity in pp collisions at 13 TeV with ALICE at the LHC
Get PDF2020 - 2021The Quantum Chromo-Dynamics (QCD) theory predicts, in condition of very high
temperature and/or energy density, a phase transition from the ordinary nuclear
matter to a colour-deconfined medium called Quark–Gluon Plasma (QGP). The
ALICE experiment was designed and optimized for the investigation of this hot
and dense medium, produced via heavy-ion collisions at the Large Hadron Collider
(LHC). Due to the very short lifetime of the QGP, its properties cannot be directly
revealed and its characterization is done through indirect signals, obtained from
the observation of the ordinary particles that emerge from the interaction region.
In particular, charm quarks are effective probes used for the investigation of QGP.
Due to their large masses, they are produced in hard scattering processes on a
timescale shorter than the QGP formation time and therefore experience the whole
system evolution. The measurement of charm-baryon production, and in particular
the baryon-to-meson ratios, provides unique information to characterize novel
mechanisms of hadron formation beyond in-vacuum fragmentation, e.g. coalescence,
which are expected to be significant in presence of a medium characterized by
free colour charges. Measurements of charm-baryon production in pp collisions
are essential to establish a baseline for p-A and A-A collisions. In addition, they
provide critical tests of perturbative QCD (pQCD) calculations and models of charm
hadronisation in hadronic collisions.
The aim of the studies carried out in this thesis is the measurement of Λ
+
c
charmed baryon yield, employed for the estimation of the baryon-to-meson ratio
Λ
+
c
/D0
. The first measurements of the Λ
+
c production yields and of the Λ
+
c
/D0
baryon-to-meson ratios as a function of the charged-particle pseudorapidity density
are presented. The study allows the characterization of the evolution of the Λ
+
c
/D0
baryon-to-meson ratio from very low to high charged particle density and provides
new experimental constraints on the production mechanisms in pp collisions. The
analysed sample is collected in pp collisions at the energy in the centre-of-mass
system of √
s = 13 TeV with the ALICE detector. The measurement is performed
by reconstructing the hadronic decay channel Λ
+
c → pK0
s → pπ
+π
−, exploiting
selections on its decay topology and on the particle identification (PID) of the decay
products, extracting the signal via an invariant mass analysis and correcting for its
selection and reconstruction efficiency and for the detector acceptance. A machine
1
learning algorithm based on Boosted Decision Trees (BDT) has been developed
and is used in order to improve the signal extraction by optimally combining
topological and PID variables that allow discriminating signal candidates from the
combinatorial background. The results are compared with a theoretical model that
explains the multiplicity dependence by a canonical treatment of quantum charges
in the statistical hadronisation approach and with predictions from PYTHIA event
generators that implement colour reconnection mechanisms beyond the leading
colour approximation to model the hadronisation process. [edited by Author]XXXIV cicl
Nuclear deformability increases PARPi sensitivity in BRCA1-deficient cells by increasing microtubule-dependent DNA break mobility
No full textMicrotubules and nuclear transmembrane SUN1/2 proteins promote the mobility of DNA Double Strand Breaks (DSBs) induced by ionizing radiation and the misrepair of one-ended DSBs induced in BRCA1-deficient cells by Poly(ADP-ribose) polymerase inhibitors (PARPi). However, whether microtubules promote aberrant DSBs repair by altering the nuclear structure and whether the nuclear structure itself plays a role in these processes is still unclear. Here we show that microtubule-dependent DSBs mobility in BRCA1-deficient cells after PARPi treatment is associated with nuclear envelope (NE) invaginations. Furthermore, increasing NE invaginations by Lmna deletion or inhibition of sphingolipid synthesis increases DSBs mobility, chromosomal aberrations, and PARPi cytotoxicity in BRCA1-deficient cells. These findings reveal a functional connection between the NE and DSB repair and suggest that drugs increasing NE deformability will enhance PARPi therapy efficacy in BRCA1-deficient cancers.Funding Agencies|Cancerfonden; Vetenskapsradet [2021-02788]; Knut and Alice Wallenberg Foundation; Associazione Italiana per la Ricerca sul Cancro, AIRC [28954]; [211732Pj]</p
BRCA2 Deletion Induces Alternative Lengthening of Telomeres in Telomerase Positive Colon Cancer Cells
No full textBRCA1/2 are tumor suppressor genes controlling genomic stability also at telomeric and subtelomeric loci. Their mutation confers a predisposition to different human cancers but also sensitivity to antitumor drugs including poly(ADP-ribose) polymerase (PARP) inhibitors and G-quadruplex stabilizers. Here we demonstrate that BRCA2 deletion triggers TERRA hyperexpression and alternative lengthening mechanisms (ALT) in colon cancer cells in presence of telomerase activity. This finding opens the question if cancer patients bearing BRCA2 germline or sporadic mutation are suitable for anti-telomerase therapies, or how ALT activation could influence the short or long-term response to anti-PARP inhibitors or anti-G-quadruplex therapies
A novel G-Quadruplex structure within Apolipoprotein E promoter: a new promising target in cancer and dementia fight?
No full textHuman Apolipoprotein E (APOE) is a crucial lipid transport glycoprotein involved in various biological processes, including lipid metabolism, immune response, and neurodegeneration. Elevated APOE levels are linked to poor prognosis in several cancers and increased risk of Alzheimer\u27s disease (AD). Therefore, modulating APOE expression presents a promising therapeutic strategy for both cancer and AD.
Considering the pivotal role of G-quadruplex (G4) structures in medicinal chemistry as modulators of gene expression, here we present a newly discovered G-quadruplex (G4) structure within the ApoE gene promoter. Bioinformatic analysis identified 21 potential G4-forming sequences in the ApoE promoter, with the more proximal to the transcription start site, pApoE, showing the highest G-score. Biophysical studies confirmed the folding of pApoE into a stable parallel G4 under physiological conditions, supported by circular dichroism, NMR spectroscopy, UV-melting, and quantitative PCR stop assay. Moreover, the ability to modulate pApoE-G4 folding was demonstrated using G4-stabilizing ligands (HPHAM, Braco19, and PDS), which increased the thermal stability of pApoE-G4. In contrast, peptide nucleic acid conjugates synthesized to disrupt G4 formation, effectively hybridizing with pApoE sequences, confirming the potential to unfold G4 structures. Overall, our findings provide a mainstay for future therapeutic approaches targeting ApoE-G4s to regulate APOE expression, offering potential advancements in cancer and AD treatment
A Novel G‑Quadruplex Structure within Apolipoprotein E Promoter: A New Promising Target in Cancer and Dementia Fight?
No full textChromosome end protection by RAP1-mediated inhibition of DNA-PK [Elektronisk resurs]
No full textDuring classical non-homologous end joining (cNHEJ), DNA-dependent protein kinase (DNA-PK) encapsulates free DNA ends, forming a recruitment platform for downstream end-joining factors including ligase 4 (LIG4)1. DNA-PK can also bind telomeres and regulate their resection2, 3-4, but does not initiate cNHEJ at this position. How the end-joining process is regulated in this context-specific manner is currently unclear. Here we show that the shelterin components TRF2 and RAP1 form a complex with DNA-PK that directly represses its end-joining function at telomeres. Biochemical experiments and cryo-electron microscopy reveal that when bound to TRF2, RAP1 establishes a network of interactions with KU and DNA that prevents DNA-PK from recruiting LIG4. In mouse and human cells, RAP1 is redundant with the Apollo nuclease in repressing cNHEJ at chromosome ends, demonstrating that the inhibition of DNA-PK prevents telomere fusions in parallel with overhang-dependent mechanisms. Our experiments show that the end-joining function of DNA-PK is directly and specifically repressed at telomeres, establishing a molecular mechanism for how individual linear chromosomes are maintained in mammalian cells.</p
The protective role of social support for the health of caregivers of children in HIV-endemic South Africa
No full textIncludes bibliographical references.In HIV-endemic areas of Southern Africa, the increasing number of orphans and vulnerable children in need of care have been taken in mainly by the extended family. Primary caregivers of children in poor HIV-endemic communities represent a high risk population for mental and physical health conditions, as a result of health risks associated with caregiving in difficult social and financial conditions. Evidence also suggests that caregivers living with HIV, and its related stressors, may be particularly at risk for poor health. In contexts of limited institutional support and formal health services, "informal" support from family, friends and the broader community may constitute a valuable resource for coping and health. Research with diverse adult populations - including HIV-affected individuals and caregivers of children - has shown more social support to be directly associated with better health outcomes (main effects) and/or to buffer against negative effects of stress or specific stressors on health (stress-buffering effects). However, the protective effects of social support on health have remained vastly under-explored in the Southern Africa region. Moreover, in Southern Africa and beyond, key gaps remain in our understanding of the mediating mechanisms and pathways explaining the support-health relationship
Separable Roles for a Caenorhabditis elegans RMI1 Homolog in Promoting and Antagonizing Meiotic Crossovers Ensure Faithful Chromosome Inheritance.
No full textDuring the first meiotic division, crossovers (COs) between homologous chromosomes ensure their correct segregation. COs are produced by homologous recombination (HR)-mediated repair of programmed DNA double strand breaks (DSBs). As more DSBs are induced than COs, mechanisms are required to establish a regulated number of COs and to repair remaining intermediates as non-crossovers (NCOs). We show that the Caenorhabditis elegans RMI1 homolog-1 (RMH-1) functions during meiosis to promote both CO and NCO HR at appropriate chromosomal sites. RMH-1 accumulates at CO sites, dependent on known pro-CO factors, and acts to promote CO designation and enforce the CO outcome of HR-intermediate resolution. RMH-1 also localizes at NCO sites and functions in parallel with SMC-5 to antagonize excess HR-based connections between chromosomes. Moreover, RMH-1 also has a major role in channeling DSBs into an NCO HR outcome near the centers of chromosomes, thereby ensuring that COs form predominantly at off-center positions
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