Articles de revues : « Futile repair »

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Gupta, Dipika, Bo Lin, Ann Cowan et Christopher D. Heinen. « ATR-Chk1 activation mitigates replication stress caused by mismatch repair-dependent processing of DNA damage ». Proceedings of the National Academy of Sciences 115, n^o 7 (29 janvier 2018) : 1523–28. http://dx.doi.org/10.1073/pnas.1720355115.

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The mismatch repair pathway (MMR) is essential for removing DNA polymerase errors, thereby maintaining genomic stability. Loss of MMR function increases mutation frequency and is associated with tumorigenesis. However, how MMR is executed at active DNA replication forks is unclear. This has important implications for understanding how MMR repairs O6-methylguanine/thymidine (MeG/T) mismatches created upon exposure to DNA alkylating agents. If MeG/T lesion recognition by MMR initiates mismatch excision, the reinsertion of a mismatched thymidine during resynthesis could initiate futile repair cycles. One consequence of futile repair cycles might be a disruption of overall DNA replication in the affected cell. Herein, we show that in MMR-proficient HeLa cancer cells, treatment with a DNA alkylating agent slows S phase progression, yet cells still progress into the next cell cycle. In the first S phase following treatment, they activate ataxia telangiectasia and Rad3-related (ATR)-Checkpoint Kinase 1 (Chk1) signaling, which limits DNA damage, while inhibition of ATR kinase activity accelerates DNA damage accumulation and sensitivity to the DNA alkylating agent. We also observed that exposure of human embryonic stem cells to alkylation damage severely compromised DNA replication in a MMR-dependent manner. These cells fail to activate the ATR-Chk1 signaling axis, which may limit their ability to handle replication stress. Accordingly, they accumulate double-strand breaks and undergo immediate apoptosis. Our findings implicate the MMR-directed response to alkylation damage as a replication stress inducer, suggesting that repeated MMR processing of mismatches may occur that can disrupt S phase progression.

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Mu, David, Tadayoshi Bessho, Lubomir V. Nechev, David J. Chen, Thomas M. Harris, John E. Hearst et Aziz Sancar. « DNA Interstrand Cross-Links Induce Futile Repair Synthesis in Mammalian Cell Extracts ». Molecular and Cellular Biology 20, n^o 7 (1 avril 2000) : 2446–54. http://dx.doi.org/10.1128/mcb.20.7.2446-2454.2000.

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ABSTRACT DNA interstrand cross-links are induced by many carcinogens and anticancer drugs. It was previously shown that mammalian DNA excision repair nuclease makes dual incisions 5′ to the cross-linked base of a psoralen cross-link, generating a gap of 22 to 28 nucleotides adjacent to the cross-link. We wished to find the fates of the gap and the cross-link in this complex structure under conditions conducive to repair synthesis, using cell extracts from wild-type and cross-linker-sensitive mutant cell lines. We found that the extracts from both types of strains filled in the gap but were severely defective in ligating the resulting nick and incapable of removing the cross-link. The net result was a futile damage-induced DNA synthesis which converted a gap into a nick without removing the damage. In addition, in this study, we showed that the structure-specific endonuclease, the XPF-ERCC1 heterodimer, acted as a 3′-to-5′ exonuclease on cross-linked DNA in the presence of RPA. Collectively, these observations shed some light on the cellular processing of DNA cross-links and reveal that cross-links induce a futile DNA synthesis cycle that may constitute a signal for specific cellular responses to cross-linked DNA.

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Ohba, Shigeo, Kei Yamashiro et Yuichi Hirose. « Inhibition of DNA Repair in Combination with Temozolomide or Dianhydrogalactiol Overcomes Temozolomide-Resistant Glioma Cells ». Cancers 13, n^o 11 (24 mai 2021) : 2570. http://dx.doi.org/10.3390/cancers13112570.

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Resistance to temozolomide and intratumoral heterogeneity contribute to the poor prognosis of glioma. The mechanisms of temozolomide resistance can vary within a heterogeneous tumor. Temozolomide adds a methyl group to DNA. The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to a futile DNA mismatch repair cycle, formation of double-strand breaks, and eventual cell death when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The study aim was to elucidate temozolomide resistance mechanisms and identify methods to overcome temozolomide resistance in glioma. Several temozolomide-resistant clones were analyzed. Increased homologous recombination and mismatch repair system deficiencies contributed to temozolomide resistance. Inhibition of homologous recombination resensitized resistant cells with high homologous recombination efficiency. For the mismatch repair-deficient cells, inhibition of BER by PARP inhibitor potentiated temozolomide-induced cytotoxicity. Dianhydrogalactiol is a bifunctional DNA-targeting agent that forms N7-alkylguanine and inter-strand DNA crosslinks. Dianhydrogalactiol reduced the proliferation of cells independent of MGMT and mismatch repair, inducing DNA double-strand breaks and apoptosis in temozolomide-resistant cells. Further, inhibition of chk1 or homologous recombination enhanced dianhydrogalactiol-induced cytotoxicity in the cells. Selecting treatments most appropriate to the types of resistance mechanisms can potentially improve the prognosis of glioma.

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Hashimoto, K. « Futile short-patch DNA base excision repair of adenine:8-oxoguanine mispair ». Nucleic Acids Research 32, n^o 19 (28 octobre 2004) : 5928–34. http://dx.doi.org/10.1093/nar/gkh909.

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Overmeer, René M., Jill Moser, Marcel Volker, Hanneke Kool, Alan E. Tomkinson, Albert A. van Zeeland, Leon H. F. Mullenders et Maria Fousteri. « Replication protein A safeguards genome integrity by controlling NER incision events ». Journal of Cell Biology 192, n^o 3 (31 janvier 2011) : 401–15. http://dx.doi.org/10.1083/jcb.201006011.

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Single-stranded DNA gaps that might arise by futile repair processes can lead to mutagenic events and challenge genome integrity. Nucleotide excision repair (NER) is an evolutionarily conserved repair mechanism, essential for removal of helix-distorting DNA lesions. In the currently prevailing model, NER operates through coordinated assembly of repair factors into pre- and post-incision complexes; however, its regulation in vivo is poorly understood. Notably, the transition from dual incision to repair synthesis should be rigidly synchronized as it might lead to accumulation of unprocessed repair intermediates. We monitored NER regulatory events in vivo using sequential UV irradiations. Under conditions that allow incision yet prevent completion of repair synthesis or ligation, preincision factors can reassociate with new damage sites. In contrast, replication protein A remains at the incomplete NER sites and regulates a feedback loop from completion of DNA repair synthesis to subsequent damage recognition, independently of ATR signaling. Our data reveal an important function for replication protein A in averting further generation of DNA strand breaks that could lead to mutagenic and recombinogenic events.

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Weimbs, Thomas. « Regulation of mTOR by Polycystin-1 : is Polycystic Kidney Disease a Case of Futile Repair ? » Cell Cycle 5, n^o 21 (20 octobre 2006) : 2425–29. http://dx.doi.org/10.4161/cc.5.21.3408.

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Manapkyzy, Diana, Botagoz Joldybayeva, Alexander A. Ishchenko, Bakhyt T. Matkarimov, Dmitry O. Zharkov, Sabira Taipakova et Murat K. Saparbaev. « Enhanced thermal stability enables human mismatch-specific thymine–DNA glycosylase to catalyse futile DNA repair ». PLOS ONE 19, n^o 10 (18 octobre 2024) : e0304818. http://dx.doi.org/10.1371/journal.pone.0304818.

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Human thymine-DNA glycosylase (TDG) excises T mispaired with G in a CpG context to initiate the base excision repair (BER) pathway. TDG is also involved in epigenetic regulation of gene expression by participating in active DNA demethylation. Here we demonstrate that under extended incubation time the full-length TDG (TDGFL), but neither its isolated catalytic domain (TDGcat) nor methyl-CpG binding domain-containing protein 4 (MBD4) DNA glycosylase, exhibits significant excision activity towards T and C in regular non-damaged DNA duplex in TpG/CpA and CpG/CpG contexts. Time course of the cleavage product accumulation under single-turnover conditions shows that the apparent rate constant for TDGFL-catalysed excision of T from T•A base pairs (0.0014–0.0069 min−1) is 85–330-fold lower than for the excision of T from T•G mispairs (0.47–0.61 min−1). Unexpectedly, TDGFL, but not TDGcat, exhibits prolonged enzyme survival at 37°C when incubated in the presence of equimolar concentrations of a non-specific DNA duplex, suggesting that the disordered N- and C-terminal domains of TDG can interact with DNA and stabilize the overall conformation of the protein. Notably, TDGFL was able to excise 5-hydroxymethylcytosine (5hmC), but not 5-methylcytosine residues from duplex DNA with the efficiency that could be physiologically relevant in post-mitotic cells. Our findings demonstrate that, under the experimental conditions used, TDG catalyses sequence context-dependent removal of T, C and 5hmC residues from regular DNA duplexes. We propose that in vivo the TDG-initiated futile DNA BER may lead to formation of persistent single-strand breaks in non-methylated or hydroxymethylated chromatin regions.

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Weimbs, Thomas. « Polycystic kidney disease and renal injury repair : common pathways, fluid flow, and the function of polycystin-1 ». American Journal of Physiology-Renal Physiology 293, n^o 5 (novembre 2007) : F1423—F1432. http://dx.doi.org/10.1152/ajprenal.00275.2007.

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The root cause for most cases of autosomal-dominant polycystic kidney disease (ADPKD) is mutations in the polycystin-1 (PC1) gene. While PC1 has been implicated in a perplexing variety of protein interactions and signaling pathways, what its normal function is and why its disruption leads to the proliferation of renal epithelial cells are unknown. Recent results suggest that PC1 is involved in mechanotransduction by primary cilia measuring the degree of luminal fluid flow. PC1 has also recently been shown to regulate the mTOR and signal transducers and activators of transcription (STAT) 6 pathways. These two pathways are normally dormant in the healthy kidney but are activated in response to injury and appear to drive a proliferative repair response. This review develops the idea that a critical function of PC1 and primary cilia in the adult kidney may be to sense renal injury by detecting changes in luminal fluid flow and to trigger proliferation. Constitutive activation of these pathways in ADPKD would lead to the futile attempt to repair a nonexisting injury, resulting in cyst growth. The existence of many known cellular and molecular similarities between renal repair and ADPKD supports this model.

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Fujii, Shingo, et Robert P. Fuchs. « Accidental Encounter of Repair Intermediates in Alkylated DNA May Lead to Double-Strand Breaks in Resting Cells ». International Journal of Molecular Sciences 25, n^o 15 (26 juillet 2024) : 8192. http://dx.doi.org/10.3390/ijms25158192.

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In clinics, chemotherapy is often combined with surgery and radiation to increase the chances of curing cancers. In the case of glioblastoma (GBM), patients are treated with a combination of radiotherapy and TMZ over several weeks. Despite its common use, the mechanism of action of the alkylating agent TMZ has not been well understood when it comes to its cytotoxic effects in tumor cells that are mostly non-dividing. The cellular response to alkylating DNA damage is operated by an intricate protein network involving multiple DNA repair pathways and numerous checkpoint proteins that are dependent on the type of DNA lesion, the cell type, and the cellular proliferation state. Among the various alkylating damages, researchers have placed a special on O6-methylguanine (O6-mG). Indeed, this lesion is efficiently removed via direct reversal by O6-methylguanine-DNA methyltransferase (MGMT). As the level of MGMT expression was found to be directly correlated with TMZ efficiency, O6-mG was identified as the critical lesion for TMZ mode of action. Initially, the mode of action of TMZ was proposed as follows: when left on the genome, O6-mG lesions form O6-mG: T mispairs during replication as T is preferentially mis-inserted across O6-mG. These O6-mG: T mispairs are recognized and tentatively repaired by a post-replicative mismatched DNA correction system (i.e., the MMR system). There are two models (futile cycle and direct signaling models) to account for the cytotoxic effects of the O6-mG lesions, both depending upon the functional MMR system in replicating cells. Alternatively, to explain the cytotoxic effects of alkylating agents in non-replicating cells, we have proposed a “repair accident model” whose molecular mechanism is dependent upon crosstalk between the MMR and the base excision repair (BER) systems. The accidental encounter between these two repair systems will cause the formation of cytotoxic DNA double-strand breaks (DSBs). In this review, we summarize these non-exclusive models to explain the cytotoxic effects of alkylating agents and discuss potential strategies to improve the clinical use of alkylating agents.

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Cheon, Na Young, Hyun-Suk Kim, Jung-Eun Yeo, Orlando D. Schärer et Ja Yil Lee. « Single-molecule visualization reveals the damage search mechanism for the human NER protein XPC-RAD23B ». Nucleic Acids Research 47, n^o 16 (2 août 2019) : 8337–47. http://dx.doi.org/10.1093/nar/gkz629.

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Abstract DNA repair is critical for maintaining genomic integrity. Finding DNA lesions initiates the entire repair process. In human nucleotide excision repair (NER), XPC-RAD23B recognizes DNA lesions and recruits downstream factors. Although previous studies revealed the molecular features of damage identification by the yeast orthologs Rad4-Rad23, the dynamic mechanisms by which human XPC-RAD23B recognizes DNA defects have remained elusive. Here, we directly visualized the motion of XPC-RAD23B on undamaged and lesion-containing DNA using high-throughput single-molecule imaging. We observed three types of one-dimensional motion of XPC-RAD23B along DNA: diffusive, immobile and constrained. We found that consecutive AT-tracks led to increase in proteins with constrained motion. The diffusion coefficient dramatically increased according to ionic strength, suggesting that XPC-RAD23B diffuses along DNA via hopping, allowing XPC-RAD23B to bypass protein obstacles during the search for DNA damage. We also examined how XPC-RAD23B identifies cyclobutane pyrimidine dimers (CPDs) during diffusion. XPC-RAD23B makes futile attempts to bind to CPDs, consistent with low CPD recognition efficiency. Moreover, XPC-RAD23B binds CPDs in biphasic states, stable for lesion recognition and transient for lesion interrogation. Taken together, our results provide new insight into how XPC-RAD23B searches for DNA lesions in billions of base pairs in human genome.

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Manapkyzy, Diana, Murat Saparbaev et Sabira Taipakova. « Putative Role of the Futile Repair Initiated by Human Thymine-DNA Glycosylase in Formation of Programmed Strand Breaks in Neuronal Enhancers ». BIO Web of Conferences 100 (2024) : 03010. http://dx.doi.org/10.1051/bioconf/202410003010.

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Enhancers are regulatory DNA elements that play a crucial role in controlling gene expression in specific cell types, including neurons. Enhancer activity is tightly regulated and involves the recruitment of various proteins and enzymes to facilitate the opening of chromatin and the activation of target genes. Given the importance of enhancers in neuronal function, the presence of single-strand DNA breaks (SSBs) in these regions raises intriguing questions about their potential impact on gene regulation and neuronal activity. Single-strand DNA breaks (SSBs) have been identified as important lesions in the genome, with the potential to influence gene expression and genomic stability. By understanding the role of SSB repair and human mono-functional Thymine-DNA glycosylase (TDG) catalyzed futile excision of regular bases in enhancer regions, we may gain insights into the molecular mechanisms underlying neurological disorders and potentially identify new therapeutic targets for intervention.

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Barbouti, Alexandra, Nefeli Lagopati, Dimitris Veroutis, Vlasios Goulas, Konstantinos Evangelou, Panagiotis Kanavaros, Vassilis G. Gorgoulis et Dimitrios Galaris. « Implication of Dietary Iron-Chelating Bioactive Compounds in Molecular Mechanisms of Oxidative Stress-Induced Cell Ageing ». Antioxidants 10, n^o 3 (21 mars 2021) : 491. http://dx.doi.org/10.3390/antiox10030491.

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One of the prevailing perceptions regarding the ageing of cells and organisms is the intracellular gradual accumulation of oxidatively damaged macromolecules, leading to the decline of cell and organ function (free radical theory of ageing). This chemically undefined material known as “lipofuscin,” “ceroid,” or “age pigment” is mainly formed through unregulated and nonspecific oxidative modifications of cellular macromolecules that are induced by highly reactive free radicals. A necessary precondition for reactive free radical generation and lipofuscin formation is the intracellular availability of ferrous iron (Fe2+) (“labile iron”), catalyzing the conversion of weak oxidants such as peroxides, to extremely reactive ones like hydroxyl (HO•) or alcoxyl (RO•) radicals. If the oxidized materials remain unrepaired for extended periods of time, they can be further oxidized to generate ultimate over-oxidized products that are unable to be repaired, degraded, or exocytosed by the relevant cellular systems. Additionally, over-oxidized materials might inactivate cellular protection and repair mechanisms, thus allowing for futile cycles of increasingly rapid lipofuscin accumulation. In this review paper, we present evidence that the modulation of the labile iron pool distribution by nutritional or pharmacological means represents a hitherto unappreciated target for hampering lipofuscin accumulation and cellular ageing.

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Ohba, Shigeo, et Yuichi Hirose. « DRES-03. PARP INHIBITOR, INHIBITION OF HOMOLOGOUS RECOMBINATION, OR DIANHYDRODULCITOL CAN OVERCOME TEMOZOLOMIDE-RESISTANCE IN GLIOMA CELLS ». Neuro-Oncology 21, Supplement_6 (novembre 2019) : vi72. http://dx.doi.org/10.1093/neuonc/noz175.291.

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Abstract Glioblastoma is one of the most aggressive tumors in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). The acquisition of resistance to TMZ and the heterogeneity of the tumor are considered to be associated with poor prognosis. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks and eventual cell death, when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The object of the study was to reveal the mechanisms of resistance to TMZ and to find the way to overcome the resistance in glioma. Several clones of TMZ-resistant U251 were obtained and analyzed. A clone showed high homologous recombination (HR), and inhibition of HR resensitized the clone to TMZ. MMR system was suppressed in the other clones. Inhibition of BER by PARP inhibitor resensitized them to TMZ. PARP inhibitor enhanced the TMZ-induced cytotoxicity in glioma cells with high expression of MGMT. Dianhydrodulcitol, alkylating agent, suppressed the proliferation in U251 and even U251-derived resistant clones. These effects were shown in U87MG-dereived resistant clones and MGMT-proficient cell lines. Moreover, inhibition of HR enhanced the cytotoxicity of dianhydrodulcitol. To select the appropriate treatment according to the mechanisms of resistance to TMZ can overcome the resistance in glioma cells.

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Lambert, Bernard, Bernard P. Roques et Jean-Bernard Le Pecq. « Induction of an abortive and futile DNA repair process inE.coliby the antitumor DNA bifunctional intercalator, ditercalinium : role inpolAin death induction ». Nucleic Acids Research 16, n^o 3 (1988) : 1063–78. http://dx.doi.org/10.1093/nar/16.3.1063.

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Rao, T. V. Pritha, et Andrei Kuzminov. « Sources of thymidine and analogs fueling futile damage-repair cycles and ss-gap accumulation during thymine starvation in Escherichia coli ». DNA Repair 75 (mars 2019) : 1–17. http://dx.doi.org/10.1016/j.dnarep.2019.01.002.

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Karathanasis, Elissa, et Thomas E. Wilson. « Enhancement of Saccharomyces cerevisiae End-Joining Efficiency by Cell Growth Stage but Not by Impairment of Recombination ». Genetics 161, n^o 3 (1 juillet 2002) : 1015–27. http://dx.doi.org/10.1093/genetics/161.3.1015.

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Abstract Cells can repair DNA double-strand breaks by both homologous and nonhomologous mechanisms. To explore the basis of pathway utilization, we developed both plasmid and chromosomal yeast repair assays in which breaks are created with restriction endonucleases so that nonhomologous end-joining (NHEJ) competes with the single-strand annealing (SSA) recombination pathway, which we show acts with high efficiency via terminal direct repeats of only 28 bp and with reduced but measurable efficiency at 10 bp. The chromosomal assay utilizes a novel approach termed suicide deletion in which the endonuclease cleaves its own gene from the chromosome, thereby ending the futile cleavage cycle that otherwise prevents detection of simple-religation events. Eliminating SSA as a possibility in either assay, either by removal of the direct repeat or by mutation of RAD52, increased the relative but not the absolute efficiency of NHEJ. In contrast, the apparent efficiency of NHEJ was specifically increased in the G1 stage of the haploid cell cycle, as well as by the glucose depletion-signaled transition to stationary phase. The combined results argue against a model in which pathway utilization is determined by a passive competition. Instead, they demonstrate an active regulation designed to optimize the likelihood of genome restoration based on cell state.

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Yuan, Xun, Andreas Mitsis, David Mozalbat et Christoph A. Nienaber. « Alternative management of proximal aortic dissection : concept and application ». Indian Journal of Thoracic and Cardiovascular Surgery 38, S1 (13 décembre 2021) : 183–92. http://dx.doi.org/10.1007/s12055-021-01281-3.

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AbstractOpen surgery remains the mainstay of treatment for acute type A aortic dissection and should be offered to most patients. However, there are elderly patients in which surgical treatment may be deemed extremely high risk or futile. Endovascular treatment approaches have been applied to a small number of these patients and data are limited to case reports and small series. The application of endovascular therapies to ascending aorta is currently limited by anatomical and technical challenges posed by the dynamic motion of the ascending aorta and the proximity of vital structures to intended landing zones (aortic valve, coronary arteries, and supra-aortic branches) and lack of specially designed endografts to address these issues. While thoracic endovascular aortic repair (TEVAR) has replaced open aortic repair for a suitable lesion in distal aortic dissection, some selected patients with type A aortic dissection at high surgical may be candidates. Hence, there is potential because, in proximal (Stanford type A) dissections, 10–30% of patients are not accepted for surgery, and 30–50% are technically amenable for TEVAR. Recent experience has shown that carefully selected patients with favorable anatomical characteristics may be subject to endovascular stent-graft treatment as a last resort with mixed results. Technical improvement is necessary to offer. satisfactory endovascular options in non-surgical candidates.

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Brawanski, Konstantin R., Susanne Sprung, Christian F. Freyschlag, Romana Hoeftberger, Thomas Ströbel, Johannes Haybaeck, Claudius Thomé, Claudia Manzl et Anna M. Birkl-Toeglhofer. « Influence of MMR, MGMT Promotor Methylation and Protein Expression on Overall and Progression-Free Survival in Primary Glioblastoma Patients Treated with Temozolomide ». International Journal of Molecular Sciences 24, n^o 7 (24 mars 2023) : 6184. http://dx.doi.org/10.3390/ijms24076184.

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Glioblastoma is the most common malignant brain tumor in adults. Standard treatment includes tumor resection, radio-chemotherapy and adjuvant chemotherapy with temozolomide (TMZ). TMZ methylates DNA, whereas O6-methylguanine DNA methyltransferase (MGMT) counteracts TMZ effects by removing the intended proteasomal degradation signal. Non-functional MGMT mediates the mismatch repair (MMR) system, leading to apoptosis after futile repair attempts. This study investigated the associations between MGMT promoter methylation, MGMT and MMR protein expression, and their effect on overall survival (OS) and progression-free survival (PFS) in patients with glioblastoma. MGMT promoter methylation was assessed in 42 treatment-naïve patients with glioblastoma WHO grade IV by pyrosequencing. MGMT and MMR protein expression was analyzed using immunohistochemistry. MGMT promoter methylation was present in 52%, whereas patients <70 years of age revealed a significantly longer OS using a log-rank test and a significance threshold of p ≤ 0.05. MGMT protein expression and methylation status showed no correlation. MMR protein expression was present in all patients independent of MGMT status and did not influence OS and PFS. Overall, MGMT promoter methylation implicates an improved OS in patients with glioblastoma aged <70 years. In the elderly, the extent of surgery has an impact on OS rather than the MGMT promoter methylation or protein expression.

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Vasic, Verica, Kathrin Barth et Mirko H. H. Schmidt. « Neurodegeneration and Neuro-Regeneration—Alzheimer’s Disease and Stem Cell Therapy ». International Journal of Molecular Sciences 20, n^o 17 (31 août 2019) : 4272. http://dx.doi.org/10.3390/ijms20174272.

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Aging causes many changes in the human body, and is a high risk for various diseases. Dementia, a common age-related disease, is a clinical disorder triggered by neurodegeneration. Brain damage caused by neuronal death leads to cognitive decline, memory loss, learning inabilities and mood changes. Numerous disease conditions may cause dementia; however, the most common one is Alzheimer’s disease (AD), a futile and yet untreatable illness. Adult neurogenesis carries the potential of brain self-repair by an endogenous formation of newly-born neurons in the adult brain; however it also declines with age. Strategies to improve the symptoms of aging and age-related diseases have included different means to stimulate neurogenesis, both pharmacologically and naturally. Finally, the regulatory mechanisms of stem cells neurogenesis or a functional integration of newborn neurons have been explored to provide the basis for grafted stem cell therapy. This review aims to provide an overview of AD pathology of different neural and glial cell types and summarizes current strategies of experimental stem cell treatments and their putative future use in clinical settings.

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Kavarana, Minoo N. « Cardiac Surgical Repair Should Be Offered to Infants with Trisomy 18, Interrupted Aortic Arch and Ventricular Septal Defect ». Journal of Law, Medicine & ; Ethics 44, n^o 2 (2016) : 283–85. http://dx.doi.org/10.1177/1073110516654121.

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The management of children born with trisomy 18 is controversial, and both providers and parents often have differing opinions. Many parents choose to terminate the pregnancy while others go forward, making decisions based on their beliefs, understanding, and physician recommendations. Physicians are similarly divided regarding treatment of these children, as some feel that aggressive treatments are futile while others defer to the parents' wishes.Interrupted aortic arch with ventricular septal defect in children with trisomy 18 presents an ethical dilemma that highlights the kinds of controversies in medical decision making facing physicians on a daily basis. Repair of interrupted aortic arch with ventricular septal defect poses a high risk to newborns with or without trisomy 18. Therefore, the option for surgery should be treated as with any routine informed consent process. Parents should be counseled about the risks, benefits, alternatives, and the likelihood of success both short and long term and be should offered a choice between surgery and palliative care.

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Al Kindi, Adil H., Ahmed Fahmy Mandisha, Mohamed Hammam et AbdelMaged Salem. « Redo mitral valve replacement using valve-on-valve technique in a patient with severe posterior mitral annular calcification ». BMJ Case Reports 14, n^o 7 (juillet 2021) : e243527. http://dx.doi.org/10.1136/bcr-2021-243527.

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Redo mitral valve replacement surgery due to bioprosthetic valve failure can carry serious surgical challenges. In addition to the usual redo sternotomy risk, there is risk of circumflex coronary artery injury or atrioventricular disruption from explanting the prosthesis. Alternatives to prosthesis explantation may be needed in some cases.We report a case of mitral bioprosthetic valve failure in a young patient who had a history of atrioventricular disruption during the first surgery and had pericardial patch repair of the defect. The risk of explanting the bioprosthesis during redo surgery was very high. Therefore, we performed valve replacement using valve-on-valve technique in which the new valve is implanted within the sewing ring of the previous bioprosthesis without explanting the valve. This technique converted a very highly futile surgery to a conventional redo surgery risk. The patient had a successful surgery with no intraoperative or postoperative complications.

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de Figueiredo, Luis F., Toni I. Gossmann, Mathias Ziegler et Stefan Schuster. « Pathway analysis of NAD+ metabolism ». Biochemical Journal 439, n^o 2 (28 septembre 2011) : 341–48. http://dx.doi.org/10.1042/bj20110320.

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NAD+ is well known as a crucial cofactor in the redox balance of metabolism. Moreover, NAD+ is degraded in ADP-ribosyl transfer reactions, which are important components of multitudinous signalling reactions. These include reactions linked to DNA repair and aging. In the present study, using the concept of EFMs (elementary flux modes), we established all of the potential routes in a network describing NAD+ biosynthesis and degradation. All known biosynthetic pathways, which include de novo synthesis starting from tryptophan as well as the classical Preiss–Handler pathway and NAD+ synthesis from other vitamin precursors, were detected as EFMs. Moreover, several EFMs were found that degrade NAD+, represent futile cycles or have other functionalities. The systematic analysis and comparison of the networks specific for yeast and humans document significant differences between species with regard to the use of precursors, biosynthetic routes and NAD+-dependent signalling.

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Burkholder, Lee M., David A. Houlden, Rajiv Midha, Erin Weiss et Marco Vennettilli. « Neurogenic motor evoked potentials : role in brachial plexus surgery ». Neurosurgical Focus 16, n^o 5 (mai 2004) : 607–10. http://dx.doi.org/10.3171/foc.2004.16.5.17.

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✓ Peripheral nerve graft repair after severe brachial plexus injury is futile if there is degeneration of motor fibers in the proximal nerve stump to which the graft must be attached. Traditional intraoperative neurophysiological assessment methods like nerve action potential (NAP) and somatosensory evoked potential (SSEP) monitoring have been used to evaluate proximal nerve stump integrity, but these methods do not allow evaluation of the integrity of motor fibers back to the anterior horn cell. Consequently, the authors used transcranial electrical stimulation and recorded neurogenic motor evoked potentials (MEPs) directly from the brachial plexus in a patient undergoing surgical repair of a complete upper brachial plexus injury (Erb palsy) to assess the functional continuity of motor fibers. In addition, selected elements of the brachial plexus were directly stimulated, and NAPs were recorded. Finally, SSEPs were recorded from the scalp after stimulation of selected elements of the brachial plexus. Neurogenic MEPs were present from the medial cord of the brachial plexus, but not the middle or upper trunk; NAPs were present from the lateral and posterior cords after middle trunk stimulation, but absent after upper trunk stimulation; and SSEPs were present after medial cord stimulation but absent after stimulation of the upper and middle trunks. For the first time, neurogenic MEPs were coupled with NAPs and SSEPs to evaluate successfully the functional status of motor fibers back to the anterior horn cell for accurate localization of the lesion sites.

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Burkholder, Lee M., David A. Houlden, Rajiv Midha, Erin Weiss et Marco Vennettilli. « Neurogenic motor evoked potentials : role in brachial plexus surgery ». Journal of Neurosurgery 98, n^o 3 (mars 2003) : 607–10. http://dx.doi.org/10.3171/jns.2003.98.3.0607.

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✓ Peripheral nerve graft repair after severe brachial plexus injury is futile if there is degeneration of motor fibers in the proximal nerve stump to which the graft must be attached. Traditional intraoperative neurophysiological assessment methods like nerve action potential (NAP) and somatosensory evoked potential (SSEP) monitoring have been used to evaluate proximal nerve stump integrity, but these methods do not allow evaluation of the integrity of motor fibers back to the anterior horn cell. Consequently, the authors used transcranial electrical stimulation and recorded neurogenic motor evoked potentials (MEPs) directly from the brachial plexus in a patient undergoing surgical repair of a complete upper brachial plexus injury (Erb palsy) to assess the functional continuity of motor fibers. In addition, selected elements of the brachial plexus were directly stimulated, and NAPs were recorded. Finally, SSEPs were recorded from the scalp after stimulation of selected elements of the brachial plexus. Neurogenic MEPs were present from the medial cord of the brachial plexus, but not the middle or upper trunk; NAPs were present from the lateral and posterior cords after middle trunk stimulation, but absent after upper trunk stimulation; and SSEPs were present after medial cord stimulation but absent after stimulation of the upper and middle trunks. For the first time, neurogenic MEPs were coupled with NAPs and SSEPs to evaluate successfully the functional status of motor fibers back to the anterior horn cell for accurate localization of the lesion sites.

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Ohba, Shigeo, et Yuichi Hirose. « SPDR-01 INHIBITION OF HOMOLOGOUS RECOMBINATION, PARP INHIBITOR, OR DIANHYDROGALACTITOL OVERCOMES TEMOZOLOMIDE-RESISTANCE IN GLIOMA CELLS ». Neuro-Oncology Advances 1, Supplement_2 (décembre 2019) : ii7. http://dx.doi.org/10.1093/noajnl/vdz039.030.

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Abstract Glioblastoma is one of the most aggressive tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). The poor prognosis is partially contributed to the acquisition of resistance to TMZ and intratumoral heterogeneity. The mechanisms of resistance to TMZ are various due to tumor heterogeneity. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks (DSBs) and eventual cell death, when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The object of the study was to reveal the mechanisms of resistance to TMZ and to find the way to overcome the resistance in glioma. Several clones of TMZ-resistant U251 or U87 were obtained and analyzed. Increased homologous recombination (HR) and deficiency of MMR system, not MGMT were revealed to be contributed to the resistance to TMZ. Inhibition of HR resensitized cells with high HR to TMZ, but it could not resensitize cells with deficient MMR. For the cells with deficient MMR, Inhibition of BER by PARP inhibitor was revealed to potentiate the TMZ-induced cytotoxicity. PARP inhibitors also potentiate the cytotoxicity of TMZ to cells with expressed MGMT. Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent, forming N7 alkylguanine and inter-strand DNA crosslinks. DAG reduced the proliferation of cells independent of MGMT and MMR, inducing DNA DSBs, G2/M arrest, and apoptosis in TMZ-resistant glioma cells. Inhibition of chk1, or HR could enhance the cytotoxicity of DAG, increasing apoptosis cells. By selecting the appropriate treatments to the types of resistant mechanisms, these new treatments have the potential to improve the prognosis of glioblastoma.

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Rodenko, Boris, Martin J. Wanner, Abdulsalam A. M. Alkhaldi, Godwin U. Ebiloma, Rebecca L. Barnes, Marcel Kaiser, Reto Brun, Richard McCulloch, Gerrit-Jan Koomen et Harry P. de Koning. « Targeting the Parasite's DNA with Methyltriazenyl Purine Analogs Is a Safe, Selective, and Efficacious Antitrypanosomal Strategy ». Antimicrobial Agents and Chemotherapy 59, n^o 11 (17 août 2015) : 6708–16. http://dx.doi.org/10.1128/aac.00596-15.

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ABSTRACTThe human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies for new and safe treatment options. We designed methyltriazenyl purine prodrugs to be rapidly and selectively internalized by the parasite, after which they disintegrate into a nontoxic and naturally occurring purine nucleobase, a simple triazene-stabilizing group, and the active toxin: a methyldiazonium cation capable of damaging DNA by alkylation. We identified 2-(3-acetyl-3-methyltriazen-1-yl)-6-hydroxypurine (compound 1) as a new lead compound, which showed submicromolar potency againstTrypanosoma brucei, with a selectivity index of >500, and it demonstrated a curative effect in animal models of acute trypanosomiasis. We investigated the mechanism of action of this lead compound and showed that this molecule has significantly higher affinity for parasites over mammalian nucleobase transporters, and it does not show cross-resistance with current first-line drugs. Once selectively accumulated inside the parasite, the prodrug releases a DNA-damaging methyldiazonium cation. We propose that ensuing futile cycles of attempted mismatch repair then lead to G2/M phase arrest and eventually cell death, as evidenced by the reduced efficacy of this purine analog against a mismatch repair-deficient (MSH2−/−) trypanosome cell line. The observed absence of genotoxicity, hepatotoxicity, and cytotoxicity against mammalian cells revitalizes the idea of pursuing parasite-selective DNA alkylators as a safe chemotherapeutic option for the treatment of human and animal trypanosomiasis.

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Zingarelli, B., M. O'Connor, H. Wong, A. L. Salzman et C. Szabó. « Peroxynitrite-mediated DNA strand breakage activates poly-adenosine diphosphate ribosyl synthetase and causes cellular energy depletion in macrophages stimulated with bacterial lipopolysaccharide. » Journal of Immunology 156, n^o 1 (1 janvier 1996) : 350–58. http://dx.doi.org/10.4049/jimmunol.156.1.350.

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Abstract The inducible isoform of nitric oxide (NO) synthase produces large quantities of NO, a cytotoxic free radical. Recent studies show that treatment with exogenous NO produces DNA strand breaks, activating the nuclear repair enzyme poly(ADP)ribosyltransferase (PARS), which results in ADP ribosylation, NAD+ consumption, and exhaustion of intracellular energy stores. Here we have characterized the cytotoxic effect of endogenous NO and peroxynitrite, a reactive oxidant formed from NO and superoxide. Immunostimulation of J774.2 macrophages with endotoxin resulted in the generation of superoxide (within 1 h) and NO (after 8 h). NO production paralleled an increase in peroxynitrite formation and DNA strand breakage, and a decrease in intracellular NAD+ content and mitochondrial respiration. Inhibition of NO synthase by NG-methyl-L-arginine or S-methyl-isothiourea or inhibition of PARS activity by 3-aminobenzamide or nicotinamide prevented the decrease in mitochondrial respiration and the depletion of NAD+. A similar pattern of free radical formation and cytotoxicity was observed in peritoneal macrophages from endotoxemic rats (formation of NO, superoxide, peroxynitrite, and DNA strand breaks). In vivo treatment with 3-aminobenzamide preserved mitochondrial respiration, NAD+, and ATP. Our data suggest that inflammatory cell injury involved DNA strand breakage and PARS, triggering an energy-consuming, futile repair cycle leading to cellular energy depletion. The active species responsible for the development of DNA strand breaks is peroxynitrite, rather than NO, since exogenous peroxynitrite, but not NO, induces DNA strand breaks. Inhibition of PARS may improve cellular energy homeostasis in patho-physiologic conditions associated with peroxynitrite generation.

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Clevers, Hans, et Fiona M. Watt. « Defining Adult Stem Cells by Function, not by Phenotype ». Annual Review of Biochemistry 87, n^o 1 (20 juin 2018) : 1015–27. http://dx.doi.org/10.1146/annurev-biochem-062917-012341.

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Central to the classical hematopoietic stem cell (HSC) paradigm is the concept that the maintenance of blood cell numbers is exclusively executed by a discrete physical entity: the transplantable HSC. The HSC paradigm has served as a stereotypic template in stem cell biology, yet the search for rare, hardwired professional stem cells has remained futile in most other tissues. In a more open approach, the focus on the search for stem cells as a physical entity may need to be replaced by the search for stem cell function, operationally defined as the ability of an organ to replace lost cells. The nature of such a cell may be different under steady state conditions and during tissue repair. We discuss emerging examples including the renewal strategies of the skin, gut epithelium, liver, lung, and mammary gland in comparison with those of the hematopoietic system. While certain key housekeeping and developmental signaling pathways are shared between different stem cell systems, there may be no general, deeper principles underlying the renewal mechanisms of the various individual tissues.

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Negishi, Tomoe, Kenji Yamada, Keiko Miyamoto, Emiko Mori, Kentaro Taira, Asei Fujii, Yuki Goto, Sakae Arimoto-Kobayashi et Keinosuke Okamoto. « Mismatch repair systems might facilitate the chromosomal recombination induced by N-nitrosodimethylamine, but not by N-nitrosodiethylamine, in Drosophila ». Mutagenesis 35, n^o 2 (28 février 2020) : 197–206. http://dx.doi.org/10.1093/mutage/geaa008.

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Abstract Mismatch repair (MMR) systems play important roles in maintaining the high fidelity of genomic DNA. It is well documented that a lack of MMR increases the mutation rate, including base exchanges and small insertion/deletion loops; however, it is unknown whether MMR deficiency affects the frequency of chromosomal recombination in somatic cells. To investigate the effects of MMR on chromosomal recombination, we used the Drosophila wing-spot test, which efficiently detects chromosomal recombination. We prepared MMR (MutS)-deficient flies (spel1(−/−)) using a fly line generated in this study. The spontaneous mutation rate as measured by the wing-spot test was slightly higher in MutS-deficient flies than in wild-type (spel1(+/−)) flies. Previously, we showed that N-nitrosodimethylamine (NDMA)-induced chromosomal recombination more frequently than N-nitrosodiethylamine (NDEA) in Drosophila. When the wing-spot test was performed using MMR-deficient flies, unexpectedly, the rate of NDMA-induced mutation was significantly lower in spel1(−/−) flies than in spel1(+/−) flies. In contrast, the rate of mutation induced by NDEA was higher in spel1(−/−) flies than in spel1(+/−) flies. These results suggest that in Drosophila, the MutS homologue protein recognises methylated DNA lesions more efficiently than ethylated ones, and that MMR might facilitate mutational chromosomal recombination due to DNA double-strand breaks via the futile cycle induced by MutS recognition of methylated lesions.

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Czarnecki, Lech, Robert Geryło et Krzysztof Kuczyński. « Concrete Repair Durability ». Materials 13, n^o 20 (13 octobre 2020) : 4535. http://dx.doi.org/10.3390/ma13204535.

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The repairs of building structures are inevitable and indispensable. Repairs are used to restore or maintain the usability of existing facilities, often contributing to the extension of their expected service life, increasing the sustainability of building resources. Given that conservation rules are observed, repairs are also used to save monuments. The concept of repair durability brings to the foreground the durability of the repaired structure (after repair): what service life has been obtained/recovered as a result of the repair. Based on the available data (limited set), a generalised distribution function of repair durability was developed, with a disappointing course. This, however, applies (necessarily) to the past. Significant progress was shown to have been achieved in the theoretical and technical fundamentals of technical repair measures. In this situation, a prognostic distribution function was also designed for future repairs according to EN 1504. A rule of thumb called estimating concrete repair durability, CRD was proposed. The risk associated with estimating the durability of repairs was indicated. A reason for optimism is that proactive monitoring of the condition of the structure and, consequently, management of the repair strategy allows to reach the designed life of the structure.

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Zhang, Y. M., T. Y. Wong, L. Y. Chen, C. S. Lin et J. K. Liu. « Induction of a Futile Embden-Meyerhof-Parnas Pathway in Deinococcus radiodurans by Mn : Possible Role of the Pentose Phosphate Pathway in Cell Survival ». Applied and Environmental Microbiology 66, n^o 1 (1 janvier 2000) : 105–12. http://dx.doi.org/10.1128/aem.66.1.105-112.2000.

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ABSTRACT Statistical models were used to predict the effects of tryptone, glucose, yeast extract (TGY) and Mn on biomass formation of the highly radioresistant bacterium Deinococcus radiodurans. Results suggested that glucose had marginal effect on biomass buildup, but Mn was a significant factor for biomass formation. Mn also facilitated glucose interactions with other nutrient components. These predictions were verified by in vivo and in vitro experiments. TGY-grown cells metabolized glucose solely by the pentose phosphate pathway (PPP). Although only a fraction of glucose from the medium was transported into the cells, glucose was incorporated into the DNA efficiently after cells were exposed to UV light. The presence of glucose also enhanced the radioresistance of the culture. Mn could induce an Embden-Meyerhof-Parnas (EMP) pathway in D. radiodurans. The EMP pathway and the PPP of the Mn-treated cells oxidized glucose simultaneously at a 6:1 ratio. Although glucose was hydrolyzed rapidly by the Mn-treated cells, most glucose was released as CO2. Mn-treated cultures retained less glucose per cell than cells grown without Mn, and still less glucose was incorporated into the DNA after cells were exposed to UV light. Mn-treated cells were also more sensitive to UV light. Results suggested that metabolites of glucose generated from the PPP enhanced the survival of D. radiodurans. Induction of the EMP pathway by Mn may deplete metabolites for DNA repair and may induce oxidative stress for the cell, leading to reduction of radioresistance.

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Chicken, S. H., S. Welburn et S. Reed. « Repairing composite aircraft structures — RAF experience of peacetime and battle damage techniques ». Aeronautical Journal 101, n^o 1006 (juillet 1997) : 277–85. http://dx.doi.org/10.1017/s0001924000066331.

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AbstractThe RAF has been undertaking peacetime repairs on composite rotor blades, fibreglass radomes and panels on a variety of combat aircraft types for many years. However, the Service's main experience in the repair of aircraft structures manufactured from carbon fibre composite (CFC) material has been related to the Harrier II. In any future conflict involving air power, battle damaged aircraft, including the Harrier II, will have to be repaired rapidly to meet operational requirements. The repair techniques used may have to differ from those undertaken in peacetime but they must still aim to restore the full static strength of the aircraft within the time constraints imposed by the operational situation. Therefore, aircraft battle damage repair (ABDR) is a carefully planned alternative to conventional repair techniques. This paper describes the main CFC structures of the Harrier II and outlines the variety of RAF peace and wartime structural repair procedures applied to the aircraft. Examples are provided of various simple and complex repairs. Greater emphasis on adhesively bonded repairs is called for if Harrier II experience is to aid in the logistic support of Eurofighter 2000 (EF2000) in peace and war.

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Moon, Seang Hyen, et Dai Whan An. « Measuring Displacement before and after Repair on Korean Wooden Built Heritage : Records for Authenticity and Sustainability ». Sustainability 16, n^o 3 (27 janvier 2024) : 1101. http://dx.doi.org/10.3390/su16031101.

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Korean wooden built heritage is periodically repaired due to inherent material characteristics that necessitate inevitable changes. This study delves into a detailed point-by-point displacement analysis of Korean wooden built heritage, both pre- and post-repair. Specifically, this study examines the displacement of key points before repair, immediately after repair, and after a four-year interval, focusing on the Sungryeoljeon Shrine in Namhansanseong, a designated World Heritage Site. While substantial changes were observed before and immediately after repairs were made, this study revealed minimal alterations during the subsequent four-year period. However, significant displacement is anticipated when future repairs become necessary. This study posits that accumulating records, which meticulously document these displacements in Korean wooden built heritage, is critical to ensuring the authenticity and sustainability of these historic architectural treasures.

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Martins, Francisco E., João Felicio, Tiago Ribeiro Oliveira, Natália Martins, Vítor Oliveira et Artur Palmas. « Adverse Features of Rectourethral Fistula Requiring Extirpative Surgery and Permanent Dual Diversion : Our Experience and Recommendations ». Journal of Clinical Medicine 10, n^o 17 (5 septembre 2021) : 4014. http://dx.doi.org/10.3390/jcm10174014.

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Introduction: To report a series of men with a rectourethral fistula (RUF) resulting from pelvic cancer treatments and explore their therapeutic differences and impact on the functional outcomes and quality of life highlighting the adverse features that should determine permanent urinary or dual diversion. Methods: A retrospective database search was performed in four centers to identify patients with RUF resulting from pelvic cancer treatment. Medical records were analyzed for the demographics, comorbidities, diagnostic evaluation, fistula characteristics, surgical approaches and outcomes. The endpoints analyzed included a successful fistula closure following a repair and the impact of the potential adverse features on outcomes. Results: Twenty-three patients, aged 57–79 years (median 68), underwent an RUF reconstruction. The median follow-up (FU) was 54 months (range 18–115). The patients were divided into two groups according to the etiology: radiation/energy-ablation treatments with or without surgery (G1, n = 10) and surgery only (G2, n = 13). All of the patients underwent a temporary diverting colostomy and suprapubic cystostomy. Overall, a successful RUF closure was achieved in 18 (78%) patients. An interposition flap was used in six (60%) patients and one (7.7%) patient in groups G1 and G2, respectively (p = 0.019). The RUF was managed successfully in all 13 patients in group G2 as opposed to 5/10 (50%) in group G1 (p = 0.008). The patients in the radiation/energy-ablation group were more likely to require permanent dual diversion (50% vs. 0%, p < 0.0075). Conclusion: Radiation/energy-ablation therapies are associated with a more severe RUF and more complex reconstructions. Most of these patients require an abdominoperineal approach and flap interposition. The failure of an RUF repair with the need for permanent dual diversion, eventually combined with extirpative surgery, is higher after previous radiation/energy-ablation treatment. Therefore, permanent dual diversion as the primary treatment should always be included in the decision-making process as reconstruction may be futile in specific settings.

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Pizzino, Fausto, Giancarlo Trimarchi, Andreina D’Agostino, Michela Bonanni, Giovanni Benedetti, Umberto Paradossi, Rachele Manzo et al. « Impact of Leaflet-to-Annulus Index on Residual Regurgitation Following Transcatheter Edge-to-Edge Repair of the Tricuspid Valve ». Journal of Clinical Medicine 13, n^o 14 (17 juillet 2024) : 4176. http://dx.doi.org/10.3390/jcm13144176.

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Background: The mismatch between tricuspid valve (TV) leaflet length and annulus dilation, assessed with the septal–lateral leaflet-to-annulus index (SL-LAI), predicts residual tricuspid regurgitation (TR) following tricuspid transcatheter edge-to-edge-repair (T-TEER). When posterior leaflet grasping is required, the anterior–posterior leaflet-to-annulus index (AP-LAI) may offer additional information. Methods: This single-center retrospective cohort study included all patients referred for T-TEER with severe and symptomatic TR with high surgical risk from April 2021 to March 2024. Patients were categorized into ‘optimal result’ (<moderate TR) or ‘suboptimal result’ (≥moderate TR) groups. The SL-LAI and AP-LAI were calculated using pre-procedural transesophageal echocardiography (TEE) measurements. Results: Of the 25 patients, 12 had suboptimal post-procedural results, while 13 showed optimal outcomes. The optimal result group showed a higher prevalence of type IIIA-IIIB TV morphology (85% vs. 45%, p < 0.05), a wider SL annulus diameter (42.5 ± 5 vs. 37 ± 5 mm, p < 0.05), and a longer posterior leaflet length (28 ± 4 vs. 22 ± 5 mm, p < 0.01). The SL-LAI was lower in the optimal group (1 ± 0.2 vs. 1.2 ± 0.32, p < 0.05), while the AP-LAI was higher (0.7 ± 0.1 vs. 0.5 ± 0.2, p < 0.05). ROC curve analysis showed that the AUC for the AP-LAI was 0.769 (95% CI 0.51–0.93, p < 0.05) and Youden test identified the best cut-off value <0.5 (sensitivity 50% and specificity 100%) for a suboptimal result. The SL-LAI showed a very low AUC in predicting suboptimal results (0.245, 95% CI 0.08–0.47). Comparing the two ROC curves, we showed that AUC difference is significant with the AP-LAI showing the best association with the outcome (p = 0.01). Conclusions: The AP-LAI and SL-LAI can help in predicting post T-TEER results, ameliorating patients’ outcomes and avoiding futile procedures.

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Noyes, Frank R., et Sue D. Barber-Westin. « Arthroscopic Repair of Meniscal Tears Extending into the Avascular Zone in Patients Younger than Twenty Years of Age ». American Journal of Sports Medicine 30, n^o 4 (juillet 2002) : 589–600. http://dx.doi.org/10.1177/03635465020300042001.

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Background Limited data are available regarding repair results of meniscal tears extending into the central avascular region. Hypothesis Meniscal tears extending into the avascular region can be successfully repaired in patients less than 20 years old. Study Design Prospective cohort study. Methods We examined the results of 71 meniscal repairs (64 knees) for tears extending into the central avascular region in patients 19 years of age or younger; 67 were examined clinically (mean, 51 months after surgery) and 36, by follow-up arthroscopy (mean, 18 months). Results In 53 of 71 (75%) meniscal repairs patients had no tibiofemoral compartment symptoms and there were no clinical failures. In 18 (25%) meniscal repairs, patients showed tibiofemoral symptoms or a failed repair was detected on follow-up arthroscopy. In the subgroup of 45 knees with meniscal repair and anterior cruciate ligament reconstruction evaluated clinically, 39 (87%) patients rated their knee as normal or very good, 2 (4%) as good, 3 (7%) as fair, and 1 (2%) as poor. Conclusions A stable repair of complex meniscal tears that extend into the avascular region can be obtained using a meticulous inside-out vertical divergent suture technique. We recommend repair, particularly in young active patients in whom removal of complex tears would result in major loss of meniscal function and the risk of future arthrosis.

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Baldwin, Michael R., Suzanne J. Admiraal et Patrick J. O'Brien. « Transient kinetic analysis of oxidative dealkylation by the direct reversal DNA repair enzyme AlkB ». Journal of Biological Chemistry 295, n^o 21 (13 avril 2020) : 7317–26. http://dx.doi.org/10.1074/jbc.ra120.013517.

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AlkB is a bacterial Fe(II)– and 2-oxoglutarate–dependent dioxygenase that repairs a wide range of alkylated nucleobases in DNA and RNA as part of the adaptive response to exogenous nucleic acid–alkylating agents. Although there has been longstanding interest in the structure and specificity of Escherichia coli AlkB and its homologs, difficulties in assaying their repair activities have limited our understanding of their substrate specificities and kinetic mechanisms. Here, we used quantitative kinetic approaches to determine the transient kinetics of recognition and repair of alkylated DNA by AlkB. These experiments revealed that AlkB is a much faster alkylation repair enzyme than previously reported and that it is significantly faster than DNA repair glycosylases that recognize and excise some of the same base lesions. We observed that whereas 1,N6-ethenoadenine can be repaired by AlkB with similar efficiencies in both single- and double-stranded DNA, 1-methyladenine is preferentially repaired in single-stranded DNA. Our results lay the groundwork for future studies of AlkB and its human homologs ALKBH2 and ALKBH3.

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Strobel, Hannah, Tim Baisch, Rahel Fitzel, Katharina Schilberg, Markus D. Siegelin, Georg Karpel-Massler, Klaus-Michael Debatin et Mike-Andrew Westhoff. « Temozolomide and Other Alkylating Agents in Glioblastoma Therapy ». Biomedicines 7, n^o 3 (9 septembre 2019) : 69. http://dx.doi.org/10.3390/biomedicines7030069.

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The alkylating agent temozolomide (TMZ) together with maximal safe bulk resection and focal radiotherapy comprises the standard treatment for glioblastoma (GB), a particularly aggressive and lethal primary brain tumor. GB affects 3.2 in 100,000 people who have an average survival time of around 14 months after presentation. Several key aspects make GB a difficult to treat disease, primarily including the high resistance of tumor cells to cell death-inducing substances or radiation and the combination of the highly invasive nature of the malignancy, i.e., treatment must affect the whole brain, and the protection from drugs of the tumor bulk—or at least of the invading cells—by the blood brain barrier (BBB). TMZ crosses the BBB, but—unlike classic chemotherapeutics—does not induce DNA damage or misalignment of segregating chromosomes directly. It has been described as a DNA alkylating agent, which leads to base mismatches that initiate futile DNA repair cycles; eventually, DNA strand breaks, which in turn induces cell death. However, while much is assumed about the function of TMZ and its mode of action, primary data are actually scarce and often contradictory. To improve GB treatment further, we need to fully understand what TMZ does to the tumor cells and their microenvironment. This is of particular importance, as novel therapeutic approaches are almost always clinically assessed in the presence of standard treatment, i.e., in the presence of TMZ. Therefore, potential pharmacological interactions between TMZ and novel drugs might occur with unforeseeable consequences.

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Bigman, Daniel P. « Evaluating the Feasibility of Robotic Crawler Deployed Ground Penetrating Radar to Assess Repairs of a Concrete Hydroelectric Dam Spillway in Alabama, USA ». Water 15, n^o 10 (14 mai 2023) : 1858. http://dx.doi.org/10.3390/w15101858.

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Dams and the water systems they support must be monitored, maintained, and repaired when necessary so they can continue to provide benefits to the communities they serve. This study presents the methods and results from a robotic crawler-based ground penetrating radar (GPR) inspection of rehabilitated concrete from a hydroelectric dam spillway located in Alabama, USA. This spillway, which was recently inspected and repaired, showed evidence of spalling which indicated internal structural deterioration. Standard practice would leave these repairs uninspected or put the wellbeing of people at risk when deploying them on the spillway for manual inspections. GPR data were recorded from recently rehabilitated and resurfaced areas of the site to evaluate the capability of a remotely controlled robotic crawler system to assure repair quality efficiently and effectively. The results indicate that high quality data can be recorded from repairs without the need for manual inspection. The GPR was able to resolve repair length, thickness, number of reinforcements, reinforcement spacing, and cover depth. The study encountered several difficulties, and the author proposes future pathways of development for safely inspecting critical dam infrastructure with steep slopes and slippery, rough surfaces.

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Bondarenko, Irina, et Kristinа Velikodna. « Analysis of interbreeding and age-dependent indexes of reproductive ability of cows. » Bulletin of Sumy National Agrarian University. The series : Veterinary Medicine, n^o 2 (49) (28 octobre 2020) : 47–52. http://dx.doi.org/10.32845/bsnau.vet.2020.2.7.

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Comparative estimation of the periods sexual cycle under futile inseminations cortex and heifers sexual mature age in facilities Sumy region. The profitability of dairy farming in the farms of Sumy region will remain an unresolved issue to this day, as the indicators of reproductive capacity of breeding cows and repair heifers need analysis and correction. Inadequate feeding and inadequate care of pregnant cows and parturients are often added to this. As a consequence of the above - the reproductive capacity inherent in this species of animals is not fully realized, most cows remain infertile, and farms are short of calves and milk. The percentage of barren animals can be calculated only at the end of the calendar year, taking into account the data of statistical reporting, while infertility must be fought daily. Detection of infertile animals is effective only in the case of regular obstetric and gynecological medical examinations on the farm. It is during this time that experts find out the causes and calculate the percentage of the main components of infertility, which includes anaphrodisia. The article presents the results of the study of the main folds of anaphrodisia of cows and repair heifers of the experimental farm of Sumy region. The results of obstetric and gynecological examination, indicators of reproductive capacity of cows and heifers of mating age, reflect the basis of technology used in the economy, the intensity of use of breeding stock, as well as determine the economic feasibility of livestock in general. The main indicators of reproductive capacity of cows in the conditions of livestock farms are: indicators of inseminations, fertility, number of hotels, indicators of fruitless inseminations, and also duration of the service period The aim of the research was to study and analyze the components of anaphrodisia of cows and repair heifers of the farm during the experimental years. The results obtained will be a criterion for assessing the state of reproductive function of the uterine population of cattle. The research was conducted at Kosivshchynska Agricultural Company, Sumy District, Sumy Region, on Holstein-Friesian cows during 2019-2020. The main indicators of reproduction of uterine cattle were studied on the basis of annual reports. The obtained digital material was processed by methods of variation statistics using Student's parametric t-test. It was found that a significant percentage of culled animals occurred due to functional disorders of reproductive ability, namely due to repeated and ineffective inseminations. It was found that in 2019, 19.3% showed a sexual cycle after calving in less than 30 days, in 2020 - 18.9%, in 31-60 days in 2019 - 27%, in 2020 - 26%, in 61 -90 days in 2020 - 52.7%, in 2019 - 51.8%, for 91-120 days in 2019 - 22.1%, in 2020 - 23.5%. There is a steady growth of the service period, which worsens the performance of the experimental economy. It was found that the largest percentage of culled cows and repair heifers were animals with anaphrodisia: in 2019 33.7% of the total number of culled animals, in 2020 - 51.10%. The number of inseminations during the experimental years decreased, and the insemination index increased : in 2019 it was equal to 60, and in 2020 -80. Studies in this area highlight the problem of infertility in cattle, which encourages the study of this issue, and the search for ways to solve this problem.

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Wood, Samuel H., et E. Scott Sills. « Intraovarian vascular enhancement via stromal injection of platelet-derived growth factors : Exploring subsequent oocyte chromosomal status and in vitro fertilization outcomes ». Clinical and Experimental Reproductive Medicine 47, n^o 2 (1 juin 2020) : 94–100. http://dx.doi.org/10.5653/cerm.2019.03405.

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The inverse correlation between maternal age and pregnancy rate represents a major challenge for reproductive endocrinology. The high embryo ploidy error rate in failed <i>in vitro</i> fertilization (IVF) cycles reflects genetic misfires accumulated by older oocytes over time. Despite the application of different follicular recruitment protocols during IVF, gonadotropin modifications are generally futile in addressing such damage. Even when additional oocytes are retrieved, quality is frequently poor. Older oocytes with serious cytoplasmic and/or chromosomal errors are often harvested from poorly perfused follicles, and ovarian vascularity and follicular oxygenation impact embryonic chromosomal competency. Because stimulation regimens exert their effects briefly and immediately before ovulation, gonadotropins alone are an ineffective antidote to long-term hypoxic pathology. In contrast, the tissue repair properties (and particularly the angiogenic effects) of platelet-rich plasma (PRP) are well known, with applications in other clinical contexts. Injection of conventional PRP and/or its components (e.g., isolated platelet-derived growth factors as a cell-free substrate) into ovarian tissue prior to IVF has been reported to improve reproductive outcomes. Any derivative neovascularity may modulate oocyte competence by increasing cellular oxygenation and/or lowering concentrations of intraovarian reactive oxygen species. We propose a mechanism to support intrastromal angiogenesis, improved follicular perfusion, and, crucially, embryo ploidy rescue. This last effect may be explained by mRNA upregulation coordinated by PRP-associated molecular signaling, as in other tissue systems. Additionally, we outline an intraovarian injection technique for platelet-derived growth factors and present this method to help minimize reliance on donor oocytes and conventional hormone replacement therapy.

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van der Merwe, Johan, et Filip Casselman. « Mitral Valve Replacement—Current and Future Perspectives ». Open Journal of Cardiovascular Surgery 9 (1 janvier 2017) : 117906521771902. http://dx.doi.org/10.1177/1179065217719023.

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The favorable outcomes achieved with modern mitral valve repair techniques redefined the role of mitral valve replacement. Various international databases report a significant decrease in replacement procedures performed compared with repairs, and contemporary guidelines limit the application of surgical mitral valve replacement to pathology in which durable repair is unlikely to be achieved. The progressive paradigm shift toward endoscopic and robotic mitral valve surgery is also paralleled by rapid developments in transcatheter devices, which is progressively expanding from experimental approaches to becoming clinical reality. This article outlines the current role and future perspectives of contemporary surgical mitral valve replacement within the context of mitral valve repair and the dynamic evolution of exciting transcatheter alternatives.

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Hirose, Yuichi, Emiko L. Kreklau, Leonard C. Erickson, Mitchel S. Berger et Russell O. Pieper. « Delayed repletion of O6-methylguanine—DNA methyltransferase resulting in failure to protect the human glioblastoma cell line SF767 from temozolomide-induced cytotoxicity ». Journal of Neurosurgery 98, n^o 3 (mars 2003) : 591–98. http://dx.doi.org/10.3171/jns.2003.98.3.0591.

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Object. Temozolomide (TMZ)-induced O6-methylguanine (MG) DNA lesions, if not removed by MG—DNA methyltransferase (MGMT), mispair with thymine, trigger rounds of futile mismatch repair (MMR), and in glioma cells lead to prolonged G2—M arrest and ultimately cell death. Depletion of MGMT by O6-benzylguanine (BG) sensitizes tumor cells to TMZ, and this combination is currently used in clinical trials. The use of the TMZ+BG combination in gliomas, however, is complicated by the prolonged TMZ-induced G2—M arrest, which may delay activation of poorly defined cell death pathways and allow for MGMT repletion and reversal of toxicity. Methods. To address these issues, the actions of TMZ were monitored in DNA MMR-proficient SF767 glioma cells depleted of MGMT by BG, and in cells in which BG was removed at various times after TMZ exposure. In MGMT-depleted cells, TMZ exposure led to DNA single-strand breaks and phosphorylation of cdc2, followed by G2—M arrest, induction of p53/p21, and DNA double-strand breaks. Although DNA single-strand breaks, phosphorylation of cdc2, and G2—M arrest could be reversed by repletion of MGMT up to 5 days after TMZ exposure, TMZ-induced cytotoxicity could only be prevented if MGMT was replenished within 24 hours of the onset of G2—M arrest, and before the creation of DNA double-strand breaks. Conclusions. These results indicate that although SF767 glioma cells undergo a prolonged G2—M arrest in response to TMZ, their ability to escape TMZ-induced cytotoxicity by MGMT repletion is limited to an approximately 24-hour period after the onset of G2—M arrest.

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Goddard, Alex, et Alex Gillespie. « Conversational repairs on Reddit : Widely initiated but often uncompleted ». PLOS ONE 20, n^o 1 (2 janvier 2025) : e0316618. https://doi.org/10.1371/journal.pone.0316618.

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Conversational repair has been proposed as a universal system for maintaining mutual understanding during social interactions. The repair system has been studied extensively in offline synchronous interactions (e.g., face-to-face, phone calls) and has been observed across cultures and languages. However, the prevalence of conversational repairs is unclear in online asynchronous text-based interactions. Online interactions are increasingly important for public deliberation, and it is therefore important to understand how conversational repairs manifest in different online contexts. To address this gap, we conducted two analyses of Other-initiated repairs in 25 English-language Reddit communities (subreddits), covering a diverse range of topics and communication norms. Analysis 1 examines the frequency of repair initiations across subreddits, finding them to be widespread (in every subreddit) and frequent (58.48% of interactions experience a repair initiation). Analysis 2 examines the emergence of repairs, finding that a repair initiation becomes increasingly likely the longer a comments thread progresses (Median time-to-repair = 6 turns). These results suggest that the prevalence and emergence of repair initiations in online interactions are comparable to offline contexts. However, we also find 44.80% of initiations receive no reply, precluding the possibility of a repair completion. Thus, conservatively, nearly half of the repair initiations in our data went uncompleted. This suggests that the online medium alters the way initiations are completed compared to offline interactions. We discuss the implications of this finding and avenues for future research.

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Castro, Michael, Fabio Iwamoto, Manmeet Ahluwalia, Shahabuddin Usmani, Ansu Kumar, Shweta Kapoor, Rakhi Purushothaman Suseela et al. « EPCO-06. THE IMPACT OF MISMATCH REPAIR DEFICIENCY (MMRD) ON SURVIVAL OF TEMOZOLOMIDE (TMZ)-TREATED PATIENTS WITH MGMT METHYLATED (M-MGMT) GLIOBLASTOMA (GBM) : A CELLWORKS COMPUTATIONAL BIOSIMULATION PILOT STUDY ». Neuro-Oncology 24, Supplement_7 (1 novembre 2022) : vii116—vii117. http://dx.doi.org/10.1093/neuonc/noac209.441.

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Abstract BACKGROUND TMZ-induced G:T mismatches trigger MMR to perform futile repair of O6-methylguanine leading to apoptosis. Without MMR, the G:T mutation is genomically incorporated to produce DNA mutation signature #11. Hypermutation ensues and may compromise survival without the redemptive benefit of immunotherapy. MMR genes are infrequently mutated or deleted. More commonly, MMRD results from epigenetic silencing, transcription failure, or micro-RNA compromising translation. METHODS Comprehensive genomic profiling and Cellworks biosimulation was utilized to diagnose MMRD and correlated with survival in 38 TCGA patients with newly diagnosed, IDH wildtype, m-MGMT GBM treated with adjuvant TMZ. The signaling pathway consequences for MutSα and MutLα were assessed. Kaplan-Meier curves were constructed for PFS and OS. RESULTS Patients were characterized: MMR proficient (Grp 1) and deficient (Grp 2). Half (19/38) had compromise of 1-10 pathways impacting MMR: 3 had deletions of MLH1 or PMS2. Others included deletions of EP300, CREBBP, KMT2A-D, ARID1A, HUS, or EXO1 and amplifications of KDM4A/C or MIR21/155. Grp 1 had significantly higher MMR biosimulation scores than Grp 2. (p=0.00082). The median PFS was 10.51 and 3.58 months (p=0.0072) and median OS was 16.96 and 9.40 (p=0.0059) months in Group 1&2, respectively. CONCLUSIONS Up to half of GBM patients have MMRD caused by pathway dysregulation. Biosimulation of MMRD predicts early progression on TMZ, echoing the long-held observation that TMZ does not trigger apoptosis in MMRD cancers. The study also reports inferior OS for MMRD compared to the historical experience of unmethylated-MGMT patients, suggesting that TMZ-induced hypermutation may compromise survival. As lomustine does not rely on intact MMR, 2nd-line lomustine may have blunted the impact of MMR on OS. Alternatively, upfront lomustine might have produced superior disease control in MMRD patients. Computational biosimulation offers the opportunity to diagnose patients who should not receive TMZ despite m-MGMT and who could benefit from alternative adjuvant strategies.

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Cools, Michael, Weston Northam, William Goodnight, Graham Mulvaney, Scott Elton et Carolyn Quinsey. « Thirty-day medical and surgical readmission following prenatal versus postnatal myelomeningocele repair ». Neurosurgical Focus 47, n^o 4 (octobre 2019) : E14. http://dx.doi.org/10.3171/2019.7.focus19355.

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OBJECTIVEHospital readmission is an important quality metric that has not been evaluated in prenatal versus postnatal myelomeningocele (MMC) repair. This study compares hospital readmission outcomes between these two groups as well as their etiologies.METHODSThe medical records of patients who had undergone MMC repair in the period from 2011 to 2017 at a single academic medical center were retrospectively reviewed. Collected clinical data included surgery and defect details, neonatal intensive care unit (NICU) stay, and any readmissions or surgical procedures up to 1 year after surgery. Patient and defect characteristics, readmission outcomes at 30 and 60 days and 1 year after discharge from the NICU, and cerebrospinal fluid (CSF) diversion surgery rates were analyzed with the two-tailed t-test and/or k-sample test on the equality of medians.RESULTSA total of 24 prenatal and 34 postnatal MMC repairs were completed during the study period. Prenatally repaired patients were born more prematurely (p < 0.001) and with lower birth weights (p < 0.001), although the NICU stay was similar between the two groups (p = 0.59). Fewer prenatally repaired patients were readmitted at 30 days (p = 0.005), 90 days (p = 0.004), and 1 year (p = 0.007) than the postnatal repair group. Hydrocephalus was the most common readmission etiology, and 29% of prenatal repair patients required CSF diversion at 1 year versus 81% of the postnatal repair group (p < 0.01). Prenatal patients who required CSF diversion had a higher body weight (p = 0.02) and an older age (p = 0.01) at the time of CSF diversion surgery than the postnatal group.CONCLUSIONSPatients with prenatal MMC repair had fewer hospital readmissions at 30 days, 60 days, and 1 year than the postnatal repair group, despite similar NICU lengths of stay. The prenatal repair group had lower requirements for CSF diversion at 1 year and was older with greater body weights at the time of CSF diversion surgery, compared to those of the postnatal repair group. Future study of hospital quality metrics such as readmissions should be performed to better understand outcomes of these two procedures.

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Finkelstein, Maxim, Gregory Levitin et Oleg A. Stepanov. « On operation termination for degrading systems with two types of failures ». Proceedings of the Institution of Mechanical Engineers, Part O : Journal of Risk and Reliability 233, n^o 3 (2 octobre 2018) : 419–26. http://dx.doi.org/10.1177/1748006x18802654.

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When a failure occurring during a system operation can result in considerable penalties, it can be more cost-effective to terminate the operation at some time avoiding the risk of future failures. This strategy can be relevant for aging systems, for example, when the system failure rate is increasing. The paper analyzes three strategies of termination for systems with major and minor failures. A major failure automatically terminates the operation, whereas the minor failures are minimally repaired. We show that the age-based strategy outperforms the one with termination after the mth minimal repair. The combined strategy when the termination is performed at time t or upon the mth minimal repair, whichever comes first, is also considered. The emphasis for the latter setting is on the practically relevant case when the number of possible minimal repairs is limited. Numerical examples illustrating the findings are presented.

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Dhanekula, Arjune S., Matthew P. Sweet, Nimesh Desai et Christopher R. Burke. « Aortic arch stenting : current strategies, new technologies and future directions ». Heart 107, n^o 15 (4 février 2021) : 1199–205. http://dx.doi.org/10.1136/heartjnl-2020-317732.

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Operating on the aortic arch is a formidable challenge. Open operations remain the gold standard, but despite improvement in technique and outcomes, they are still associated with significant morbidity and mortality. The last 20 years have seen a remarkable reduction in the operative morbidity associated with treatment of the descending thoracic aorta using thoracic endovascular aneurysm repair (TEVAR). To improve outcomes following arch repair, new TEVAR devices, including both single-branched and multibranched designs, have come to clinical trial. This review discusses the modern state of open and hybrid repairs while introducing the reader to technology for endovascular therapy of the aortic arch. We describe important anatomical and operative considerations for the devices. Given these nuances, we believe the future of the aortic arch to be patient-individualised hybrid repairs, involving both open and endovascular options with a multidisciplinary ‘thoracic aorta team’ at the helm.

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Peters Grace, E., N. Ononokpono Dorathy, U. Willson Nsikanabasi, I. Oko Nnabuike et EJ Peters. « Determinants of health seeking behaviour of women with obstetric fistula in south- south and south east, Nigeria : A review of the impact of availability and quality of health care services through a cross-sectional study ». Clinical Journal of Obstetrics and Gynecology 4, n^o 2 (4 mai 2021) : 060–65. http://dx.doi.org/10.29328/journal.cjog.1001088.

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Background: Obstetric fistula is a condition that results from obstructed labour, which occurs when the baby cannot pass through the mother’s birth canal because it either does not come head first or is too large for her pelvis. Prompt medical intervention, often including Caesarean section, permits a safe delivery for both mother and child. Despite this possibility, yearly, thousands of women across the country receive no such aid and their labour is a futile agony lasting between three and five days, with uterine contractions constantly forcing the baby, usually head first, against the organs of the pelvic and unyielding pelvic bone resulting in Vesico Vaginal Fistula (VVF). The main thrust of this study was to examine how health system factors affect health seeking behaviour of women with obstetric fistula in Akwa Ibom and Ebonyi States, Nigeria. Methods: Qualitative and descriptive research approaches were adopted for the study and a total sample of two hundred and sixteen (216) respondents comprising of one hundred and fifty (150) post fistula repair operative patients and sixty six (66) health workers were purposively selected using simple random techniques. The data were analyzed using thematic analysis and tables of frequency. Results: The respondents views showed that availability of treatment centre and quality of health care services influenced health seeking behaviour of women with obstetric fistula in Nigeria. Conclusion: The study indicated that health seeking behaviour of women with obstetric fistula is a major challenge in Nigeria. Establishment and proper equipment of obstetric fistula treatment centres as well as subsidization of the cost of treatment to allow women with this health problem to access health care services are strongly recommended. Therefore, government at all level and non-governmental organizations need to educate the women and create awareness on the causes and dangers of VVF.

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Wood, G. D. « Pipeline Incidents and Emergency Repair in the North Sea ». Journal of Energy Resources Technology 110, n^o 4 (1 décembre 1988) : 219–23. http://dx.doi.org/10.1115/1.3231385.

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The failures of submarine pipelines in the North Sea, and the response of pipeline operators are first discussed. Against this background, the methods currently available for submarine pipeline repairs are reviewed. The Emergency Pipeline Repair Services available are described, and some future developments in the field of submarine pipeline repair are briefly outlined.

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