Age-related activity of Poly (ADP-Ribose) Polymerase (PARP) in men with localized prostate cancer

Deniz, Miriam; Zengerling, Friedemann; Gundelach, Theresa; Moreno‐Villanueva, María; Bürkle, Alexander; Janni, Wolfgang; Bolenz, Christian; Kostezka, Sarah; Marienfeld, Ralf; Benckendorff, Julian; Friedl, Thomas; Wiesmüller, Lisa; Rall-Scharpf, Melanie

doi:10.1016/j.mad.2021.111494

Cited by 4 publications

(2 citation statements)

References 66 publications

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“…Now, we have also discovered and reported that age is a predictor of PSM after RALP in patients with prostate cancer. Some researchers have pointed out a male-specific association between the accumulation of DNA damage related to mutation and aging and the prostate cancer biomarker poly (ADP-ribose)-polymerase (PARP) [ 28 ]. This may be one of the reasons and corresponding research can be conducted to investigate it.…”

Section: Discussionmentioning

confidence: 99%

Development of a Prediction Model for Positive Surgical Margin in Robot-Assisted Laparoscopic Radical Prostatectomy

et al. 2022

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A positive surgical margin (PSM) is reported to have some connection to the occurrence of biochemical recurrence and tumor metastasis in prostate cancer after the operation. There are no clinically usable models and the study is to predict the probability of PSM after robot-assisted laparoscopic radical prostatectomy (RALP) based on preoperative examinations. It is a retrospective cohort from a single center. The Lasso method was applied for variable screening; logistic regression was employed to establish the final model; the strengthened bootstrap method was adopted for model internal verification; the nomogram and web calculator were used to visualize the model. All the statistical analyses were based on the R-4.1.2. The main outcome was a pathologically confirmed PSM. There were 151 PSMs in the 903 patients, for an overall positive rate of 151/903 = 16.7%; 0.727 was the adjusted C statistic, and the Brier value was 0.126. Hence, we have developed and validated a predictive model for PSM after RALP for prostate cancer that can be used in clinical practice. In the meantime, we observed that the International Society of Urological Pathology (ISUP) score, Prostate Imaging Reporting and Data System (PI-RADS) score, and Prostate-Specific Antigen (PSA) were the independent risk factors for PSM.

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Section: Discussionmentioning

confidence: 99%

Development of a Prediction Model for Positive Surgical Margin in Robot-Assisted Laparoscopic Radical Prostatectomy

et al. 2022

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“…While close proximity of the parental drugs in the hybrid is critical for their efficacy in non-TNBC cells, a separation of both pharmacophores by-CO-(CH 2 ) 2 -CO-and CO-(CH 2 ) 4 -CO spacers leads to TNBC cell killing. Specific targeting of PARP1 at sites of DNA repair and replication may be desirable when treating oncological diseases to avoid non-specific effects related to other PARP1 functions, such as a regulator of necrosis and inflammation in a sex-specific manner [6,36].…”

Section: Discussionmentioning

confidence: 99%

Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells

et al. 2021

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The genetic principle of synthetic lethality has most successfully been exploited in therapies engaging Poly-ADP-ribose-polymerase (PARP) inhibitors to treat patients with homologous recombination (HR)-defective tumors. In this work, we went a step further following the idea of a local molecular cooperation and designed hybrid compounds M1–M3. The drug conjugates M1–M3 combine Olaparib, the first PARP inhibitor approved for clinical use, with Cpd 1, an inhibitor of RAD51 that blocks its HR functions and yet permits RAD51 nucleoprotein filament formation on single-stranded DNA. While in M2 and M3, the parental drugs are linked by -CO-(CH2)n-CO-spacers (n = 2 and 4, respectively), they are directly merged omitting the piperazine ring of Olaparib in M1. Monitoring anti-survival effects of M1–M3 in six breast cancer cell lines of different molecular subtypes showed that in each cell line, at least one of the drug conjugates decreased viability by one to two orders of magnitude compared with parental drugs. While triple-negative breast cancer (TNBC) cells with frequent BRCA1 pathway dysfunction were sensitive to spacer-linked hybrid compounds M1 and M2 regardless of their HR capacities, non-TNBC cells were responsive to the merged drug conjugate M1 only, suggesting different spatial requirements for dual inhibition in these two groups of cell lines. These results demonstrate that, depending on chemical linkage, dual PARP1-RAD51 inhibitory drugs can either sensitize non-TNBC and re-sensitize TNBC cells, or discriminate between these groups of cells.

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Sex-specific differences in DNA double-strand break repair of cycling human lymphocytes during aging

Rall-Scharpf

Friedl

Biechonski

et al. 2021

Aging

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The gender gap in life expectancy and cancer incidence suggests differences in the aging process between the sexes. Genomic instability has been recognized as a key factor in aging, but little is known about sex-specific differences. Therefore, we analyzed DNA double-strand break (DSB) repair in cycling human peripheral blood lymphocytes (PBL) from male and female donors of different age. Reporter-based DSB repair analyses revealed differential regulation of pathway usage in PBL from male and female donors with age: Non-homologous end joining (NHEJ) was inversely regulated in men and women; the activity of pathways requiring end processing and strand annealing steps such as microhomology-mediated end joining (MMEJ) declined with age in women but not in men. Screening candidate proteins identified the NHEJ protein KU70 as well as the end resection regulatory factors ATM and BLM showing reduced expression during aging in women. Consistently, the regulatory factor BLM contributed to the MMEJ proficiency in young but not in old women as demonstrated by knockdown analysis. In conclusion, we show that DSB repair is subject to changes upon aging and age-related changes in DSB repair are distinct in men and women.

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Age-related activity of Poly (ADP-Ribose) Polymerase (PARP) in men with localized prostate cancer

Cited by 4 publications

References 66 publications

Development of a Prediction Model for Positive Surgical Margin in Robot-Assisted Laparoscopic Radical Prostatectomy

Development of a Prediction Model for Positive Surgical Margin in Robot-Assisted Laparoscopic Radical Prostatectomy

Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells

Sex-specific differences in DNA double-strand break repair of cycling human lymphocytes during aging

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