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End-processing nucleases and phosphodiesterases: An elite supporting cast for the non-homologous end joining pathway of DNA double-strand break repair. - DNA repair
Nonhomologous end joining (NHEJ) is an error-prone DNA double-strand break repair pathway that is active throughout the cell cycle. A substantial fraction of NHEJ repair events show deletions and, less often, insertions in the repair joints, suggesting an end-processing step comprising the removal of mismatched or damaged nucleotides by nucleases and other phosphodiesterases, as well as subsequent strand extension by polymerases. A wide range of nucleases, including Artemis, Metnase, APLF, Mre11, CtIP, APE1, APE2 and WRN, are biochemically competent to carry out such double-strand break end processing, and have been implicated in NHEJ by at least circumstantial evidence. Several additional DNA end-specific phosphodiesterases, including TDP1, TDP2 and aprataxin are available to resolve various non-nucleotide moieties at DSB ends. This review summarizes the biochemical specificities of these enzymes and the evidence for their participation in the NHEJ pathway.Copyright Â© 2016. Published by Elsevier B.V.
Can Transfusions Be Eliminated in Major Abdominal Surgery? Analysis of a Five-Year Experience of Blood Conservation in Patients Undergoing Pancreaticoduodenectomy. - The American surgeon
Pancreaticoduodenectomy (PD) has historically required perioperative blood transfusion in 40 to 60 per cent of cases. Growing data suggest that transfusions may be deleterious in the surgical patient. We recently initiated a minimal transfusion approach to PD consisting of limited postoperative blood draws, early iron supplementation, changes in surgical technique, and elimination of hemoglobin transfusion triggers. Predictors of perioperative transfusion were analyzed in 130 consecutive patients undergoing PD by a single surgeon between 2008 and 2013, divided into two eras with 65 patients each. Patients in each era were similar with respect to age, comorbidities, American Society of Anesthesiologists class, body mass index, and diagnosis. The transfusion rate for the entire group was 22 per cent. Nonsignificant predictors of perioperative transfusion include American Society of Anesthesiologists class â‰¥3 (P = 0.41), vascular resections (P = 0.56), body mass index â‰¥30 (P = 0.72), and intraoperative blood loss (P = 0.89). Significant predictors of transfusion include PD performed in Era 1 as well as preoperative hemoglobin levels <10 g/dL. In Era 1, 38 per cent of patients required transfusion compared with 6 per cent in Era 2 (P < 0.01). Shorter length of stay and a trend toward decreased pancreatic fistulae were seen in Era 2. Transfusions can be almost completely eliminated in PD and this may contribute to improved outcomes.
Nucleolar targeting by platinum: p53-independent apoptosis follows rRNA inhibition, cell-cycle arrest, and DNA compaction. - Molecular pharmaceutics
TriplatinNC is a highly positively charged, substitution-inert derivative of the phase II clinical anticancer drug, BBR3464. Such substitution-inert complexes form a distinct subset of polynuclear platinum complexes (PPCs) interacting with DNA and other biomolecules through noncovalent interactions. Rapid cellular entry is facilitated via interaction with cell surface glycosoaminoglycans and is a mechanism unique to PPCs. Nanoscale secondary ion mass spectrometry (nanoSIMS) showed rapid distribution within cytoplasmic and nucleolar compartments, but not the nucleus. In this article, the downstream effects of nucleolar localization are described. In human colon carcinoma cells, HCT116, the production rate of 47S rRNA precursor transcripts was dramatically reduced as an early event after drug treatment. Transcriptional inhibition of rRNA was followed by a robust G1 arrest, and activation of apoptotic proteins caspase-8, -9, and -3 and PARP-1 in a p53-independent manner. Using cell synchronization and flow cytometry, it was determined that cells treated while in G1 arrest immediately, but cells treated in S or G2 successfully complete mitosis. Twenty-four hours after treatment, the majority of cells finally arrest in G1, but nearly one-third contained highly compacted DNA; a distinct biological feature that cannot be associated with mitosis, senescence, or apoptosis. This unique effect mirrored the efficient condensation of tRNA and DNA in cell-free systems. The combination of DNA compaction and apoptosis by TriplatinNC treatment conferred striking activity in platinum-resistant and/or p53 mutant or null cell lines. Taken together, our results support that the biological activity of TriplatinNC reflects reduced metabolic deactivation (substitution-inert compound not reactive to sulfur nucleophiles), high cellular accumulation, and novel consequences of high-affinity noncovalent DNA binding, producing a new profile and a further shift in the structure-activity paradigms for antitumor complexes.
Involvement of p53 in the repair of DNA double strand breaks: multifaceted Roles of p53 in homologous recombination repair (HRR) and non-homologous end joining (NHEJ). - Sub-cellular biochemistry
p53 is a tumor suppressor protein that prevents oncogenic transformation and maintains genomic stability by blocking proliferation of cells harboring unrepaired or misrepaired DNA. A wide range of genotoxic stresses such as DNA damaging anti-cancer drugs and ionizing radiation promote nuclear accumulation of p53 and trigger its ability to activate or repress a number of downstream target genes involved in various signaling pathways. This cascade leads to the activation of multiple cell cycle checkpoints and subsequent cell cycle arrest, allowing the cells to either repair the DNA or undergo apoptosis, depending on the intensity of DNA damage. In addition, p53 has many transcription-independent functions, including modulatory roles in DNA repair and recombination. This chapter will focus on the role of p53 in regulating or influencing the repair of DNA double-strand breaks that mainly includes homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Through this discussion, we will try to establish that p53 acts as an important linchpin between upstream DNA damage signaling cues and downstream cellular events that include repair, recombination, and apoptosis.
Tracking the processing of damaged DNA double-strand break ends by ligation-mediated PCR: increased persistence of 3'-phosphoglycolate termini in SCAN1 cells. - Nucleic acids research
To track the processing of damaged DNA double-strand break (DSB) ends in vivo, a method was devised for quantitative measurement of 3'-phosphoglycolate (PG) termini on DSBs induced by the non-protein chromophore of neocarzinostatin (NCS-C) in the human Alu repeat. Following exposure of cells to NCS-C, DNA was isolated, and labile lesions were chemically stabilized. All 3'-phosphate and 3'-hydroxyl ends were enzymatically capped with dideoxy termini, whereas 3'-PG ends were rendered ligatable, linked to an anchor, and quantified by real-time Taqman polymerase chain reaction. Using this assay and variations thereof, 3'-PG and 3'-phosphate termini on 1-base 3' overhangs of NCS-C-induced DSBs were readily detected in DNA from the treated lymphoblastoid cells, and both were largely eliminated from cellular DNA within 1 h. However, the 3'-PG termini were processed more slowly than 3'-phosphate termini, and were more persistent in tyrosyl-DNA phosphodiesterase 1-mutant SCAN1 than in normal cells, suggesting a significant role for tyrosyl-DNA phosphodiesterase 1 in removing 3'-PG blocking groups for DSB repair. DSBs with 3'-hydroxyl termini, which are not directly induced by NCS-C, were formed rapidly in cells, and largely eliminated by further processing within 1 h, both in Alu repeats and in heterochromatic Î±-satellite DNA. Moreover, absence of DNA-PK in M059J cells appeared to accelerate resolution of 3'-PG ends.
Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest. - Biochemical pharmacology
Despite similar structures and DNA binding profiles, two recently synthesized dinuclear platinum compounds are shown to elicit highly divergent effects on cell cycle progression. In colorectal HCT116 cells, BBR3610 shows a classical G2/M arrest with initial accumulation in S phase, but the derivative compound BBR3610-DACH, formed by introduction of the 1,2-diaminocyclohexane (DACH) as carrier ligand, results in severe G1/S as well as G2/M phase arrest, with nearly complete S phase depletion. The origin of this unique effect was studied. Cellular interstrand crosslinking as assayed by comet analysis was similar for both compounds, confirming previous in vitro results obtained on plasmid DNA. Immunoblotting revealed a stabilization of p53 and concomitant transient increases in p21 and p27 proteins after treatment with BBR3610-DACH. Cell viability assays and cytometric analysis of p53 and p21 null cells indicated that BBR3610-DACH-induced cell cycle arrest was p21-dependent and partially p53-dependent. However, an increase in the levels of cyclin E was observed with steady state levels of CDK2 and Cdc25A, suggesting that the G1 block occurs downstream of CDK/cyclin complex formation. The G2/M block was corroborated with decreased levels of cyclin A and cyclin B1. Surprisingly, BBR3610-DACH-induced G1 block was independent of ATM and ATR. Finally, both compounds induced apoptosis, with BBR3610-DACH showing a robust PARP-1 cleavage that was not associated with caspase-3/7 cleavage. In summary, BBR3610-DACH is a DNA binding platinum agent with unique inhibitory effects on cell cycle progression that could be further developed as a chemotherapeutic agent complementary to cisplatin and oxaliplatin.Copyright Â© 2013 Elsevier Inc. All rights reserved.
Surgical management of advanced adrenocortical carcinoma: a 21-year population-based analysis. - The American surgeon
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. When diagnosed in advanced stages of the disease, the outcomes of surgical resection are not well understood. The objective of this study is to determine the impact of surgery in patients with advanced ACC. Using the Surveillance, Epidemiology and End Results database, we identified patients diagnosed with Stage III and IV ACC between 1988 and 2009. A total of 320 patients with Stage III and IV disease were included in our analysis. In patients treated with surgical resection, the Stage III 1- and 5-year survival rates were 77 and 40 per cent, respectively, whereas the Stage IV 1- and 5-year survival rates were 54 and 27.6 per cent, respectively. Patients treated without surgery had poor survival at 1 year for both Stage III (13%) and Stage IV (16%) (P < 0.01 compared with the surgical groups). Lymph node dissection was performed in 26 per cent of the patients with advanced ACC and was associated with improved survival in univariate analysis of Stage IV patients. Overall, our results indicate that favorable survival outcomes can be achieved even in patients with Stage III and IV disease and surgery should be considered in patients with advanced ACC.
Outcomes of vascular resection in pancreaticoduodenectomy: single-surgeon experience. - The American surgeon
Extension of pancreatic adenocarcinoma into adjacent vasculature often necessitates resection of the portal vein (PV) and/or superior mesenteric vein (SMV) during pancreaticoduodenectomy (PD). The vein is reconstructed primarily by end-to-end anastomosis of vein remnants or venoplasty or by use of autologous or synthetic vein grafts. The objective of this study was to review outcomes in patients undergoing PD for pancreatic adenocarcinoma, specifically comparing the short- and long-term outcomes between the patients undergoing vascular resection and those undergoing standard PD. All patients undergoing PD for pancreatic adenocarcinoma by a single surgeon between 2007 and 2012 were reviewed. Of the 61 patients identified, 18 patients underwent vascular resection of the PV (four patients), SMV (10 patients), or both (four patients). The remaining 43 patients had standard PD. Demographic, perioperative, pathological, and long-term outcomes data were collected and both vascular and standard groups were compared. Both groups had similar demographics. The vascular group had significantly longer operative times (529 vs 406 minutes; P < 0.01) with a trend to greater estimated blood loss (0.64 vs 0.53 L; P = 0.06). Pathological analysis showed no difference between the two groups with regard to lymph node status/ratio and rate of R0 resection (94 vs 91%; P = 0.57); however, the size of the tumor was significantly greater in the vascular group (4.2 vs 3 cm; P < 0.01). Short-term outcomes were similar in the vascular group and standard group, respectively, with no difference in pancreatic fistula rate (6 vs 7%; P = 1.0), transfusion rate (44 vs 35%; P = 0.57), and median length of stay (8 vs 7 days; P = 0.10), and there was no 30-day mortality in either group. Based on Kaplan-Meier methods, the median recurrence-free survival was 18 versus 23 months (P = 0.37) in the vascular and standard groups, respectively, and the overall survival was almost identical in both groups, each with a median of 31 months (P = 0.91). In our experience, mesenteric and PV resection during PD was performed safely and without compromise of short- or longer-term outcomes. It can be performed safely and patients have no significant difference in perioperative outcomes or overall survival.
Trimming of damaged 3' overhangs of DNA double-strand breaks by the Metnase and Artemis endonucleases. - DNA repair
Both Metnase and Artemis possess endonuclease activities that trim 3' overhangs of duplex DNA. To assess the potential of these enzymes for facilitating resolution of damaged ends during double-strand break rejoining, substrates bearing a variety of normal and structurally modified 3' overhangs were constructed, and treated either with Metnase or with Artemis plus DNA-dependent protein kinase (DNA-PK). Unlike Artemis, which trims long overhangs to 4-5 bases, cleavage by Metnase was more evenly distributed over the length of the overhang, but with significant sequence dependence. In many substrates, Metnase also induced marked cleavage in the double-stranded region within a few bases of the overhang. Like Artemis, Metnase efficiently trimmed overhangs terminated in 3'-phosphoglycolates (PGs), and in some cases the presence of 3'-PG stimulated cleavage and altered its specificity. The nonplanar base thymine glycol in a 3' overhang severely inhibited cleavage by Metnase in the vicinity of the modified base, while Artemis was less affected. Nevertheless, thymine glycol moieties could be removed by Metnase- or Artemis-mediated cleavage at sites farther from the terminus than the lesion itself. In in vitro end-joining systems based on human cell extracts, addition of Artemis, but not Metnase, effected robust trimming of an unligatable 3'-PG overhang, resulting in a dramatic stimulation of ligase IV- and XLF-dependent end joining. Thus, while both Metnase and Artemis are biochemically capable of resolving a variety of damaged DNA ends for the repair of complex double-strand breaks, Artemis appears to act more efficiently in the context of other nonhomologous end joining proteins.Copyright Â© 2013 Elsevier B.V. All rights reserved.
Hepaticojejunostomy using short-limb Roux-en-Y reconstruction. - JAMA surgery
When performing biliary reconstruction, one of the long-standing tenets of surgery is that Roux-en-Y (RY) reconstruction should use a long hepatic limb to decrease the risk for postoperative cholangitis. However, this practice is not well supported and may also make postoperative biliary endoscopy difficult. While some authors recommend Roux limbs of up to 75 cm, we have routinely used a Roux length of 20 cm to facilitate possible postoperative endoscopic access.To review our experience with short-limb RY hepaticojejunostomy (HJ) and examine the short-term and long-term outcomes following this procedure, as well as the success of future biliary interventions.Retrospective medical record review of all patients who underwent short-limb RYHJ by 2 surgeons (N.N.N. and S.D.C.).Tertiary care, university-affiliated teaching hospital.One hundred patients who underwent RYHJ were identified, with 30 of those patients being excluded owing to creation of an RYHJ to intrahepatic bile ducts with concomitant liver resection.Patient records were reviewed to determine the incidence of postoperative cholangitis and biliary stricture. Secondary outcomes were the need for postoperative biliary endoscopy and success rates for endoscopic biliary interventions. RESULTS Seventy patients underwent short-limb RYHJ over an 11-year period (2001-2012). Indications included benign stricture (n = 18), malignant stricture (n = 12), choledochal cyst (n = 5), choledocholithiasis (n = 3), idiopathic cholangitis (n = 2), and deceased donor or live donor liver transplant (n = 30). Seven patients, including 4 liver transplant patients, developed clinical or radiographic evidence of postoperative biliary stricture, and all patients underwent successful endoscopic cholangiography. Four of these patients required dilation and/or stone extraction, which were accomplished endoscopically in all cases.Short-limb RYHJ is safe and associated with a low incidence of postoperative complications. In addition, biliary intervention, when indicated, can be performed endoscopically with a high degree of success. In the absence of any evidence demonstrating longer limbs to be superior, we recommend using short-limb RY reconstruction for HJ.
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