Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies and is characterized by highrecurrence rates and poor prognosis. Recent advances in targeting DNA damage response (DDR) pathways using poly (ADP‒ri-bose) polymerase (PARP) inhibitors offer promising therapeutic strategies, especially for TNBC patients with BRCA1/2 mutations.This study reports the development and characterization of ART-446, a novel and selective CHK2 inhibitor. ART-446 showed potent activity against TNBC, regardless of BRCA deficiency, and it also reversed PARP inhibitor resistance. ART-446 potentlyinhibited CHK2 (IC50 : 9.06 nM) with high selectivity over other kinases; it synergized with the PARP inhibitor olaparib, enhancingDNA damage, inducing G2/M cell cycle arrest, and promoting apoptosis in both BRCA-mutant and wild-type TNBC cells. Mechanistic analyses revealed that ART-446 sensitized BRCA mutant and WT cells to PARP inhibitors by impairing DNA repair and increasing the accumulation of DNA damage. Importantly, ART-446 disrupted both homologous recombination and nonhomologous end-joining repair pathways, addressing a key limitation of PARP inhibitor monotherapy—resistance in BRCA-proficient cancers.In vivo, the combination of ART-446 and olaparib significantly reduced tumor growth in TNBC xenograft models without noticeable toxicity. The combined treatment increased DNA damage signaling, as evidenced by elevated γH2AX levels, and enhanced the sensitivity of BRCA2-deficient cells to ART-446. These findings underscore the potential of ART-446 to exploit DNA repair deficiencies and overcome resistance mechanisms associated with PARP inhibitors. By addressing the limitations of current treatments and expanding the utility of PARP inhibitors, ART-446 represents a promising candidate for DDR-targeted therapies, offering a novel approach to improve the outcomes of patients with TNBC.

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies and is characterized by highrecurrence rates and poor prognosis. Recent advances in targeting DNA damage response (DDR) pathways using poly (ADP‒ri-bose) polymerase (PARP) inhibitors offer promising therapeutic strategies, especially for TNBC patients with BRCA1/2 mutations.This study reports the development and characterization of ART-446, a novel and selective CHK2 inhibitor. ART-446 showed potent activity against TNBC, regardless of BRCA deficiency, and it also reversed PARP inhibitor resistance. ART-446 potentlyinhibited CHK2 (IC50 : 9.06 nM) with high selectivity over other kinases; it synergized with the PARP inhibitor olaparib, enhancingDNA damage, inducing G2/M cell cycle arrest, and promoting apoptosis in both BRCA-mutant and wild-type TNBC cells. Mechanistic analyses revealed that ART-446 sensitized BRCA mutant and WT cells to PARP inhibitors by impairing DNA repair and increasing the accumulation of DNA damage. Importantly, ART-446 disrupted both homologous recombination and nonhomologous end-joining repair pathways, addressing a key limitation of PARP inhibitor monotherapy—resistance in BRCA-proficient cancers.In vivo, the combination of ART-446 and olaparib significantly reduced tumor growth in TNBC xenograft models without noticeable toxicity. The combined treatment increased DNA damage signaling, as evidenced by elevated γH2AX levels, and enhanced the sensitivity of BRCA2-deficient cells to ART-446. These findings underscore the potential of ART-446 to exploit DNA repair deficiencies and overcome resistance mechanisms associated with PARP inhibitors. By addressing the limitations of current treatments and expanding the utility of PARP inhibitors, ART-446 represents a promising candidate for DDR-targeted therapies, offering a novel approach to improve the outcomes of patients with TNBC.

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype lacking targeted therapies and is characterized by highrecurrence rates and poor prognosis. Recent advances in targeting DNA damage response (DDR) pathways using poly (ADP‒ri-bose) polymerase (PARP) inhibitors offer promising therapeutic strategies, especially for TNBC patients with BRCA1/2 mutations.This study reports the development and characterization of ART-446, a novel and selective CHK2 inhibitor. ART-446 showed potent activity against TNBC, regardless of BRCA deficiency, and it also reversed PARP inhibitor resistance. ART-446 potentlyinhibited CHK2 (IC50 : 9.06 nM) with high selectivity over other kinases; it synergized with the PARP inhibitor olaparib, enhancingDNA damage, inducing G2/M cell cycle arrest, and promoting apoptosis in both BRCA-mutant and wild-type TNBC cells. Mechanistic analyses revealed that ART-446 sensitized BRCA mutant and WT cells to PARP inhibitors by impairing DNA repair and increasing the accumulation of DNA damage. Importantly, ART-446 disrupted both homologous recombination and nonhomologous end-joining repair pathways, addressing a key limitation of PARP inhibitor monotherapy—resistance in BRCA-proficient cancers.In vivo, the combination of ART-446 and olaparib significantly reduced tumor growth in TNBC xenograft models without noticeable toxicity. The combined treatment increased DNA damage signaling, as evidenced by elevated γH2AX levels, and enhanced the sensitivity of BRCA2-deficient cells to ART-446. These findings underscore the potential of ART-446 to exploit DNA repair deficiencies and overcome resistance mechanisms associated with PARP inhibitors. By addressing the limitations of current treatments and expanding the utility of PARP inhibitors, ART-446 represents a promising candidate for DDR-targeted therapies, offering a novel approach to improve the outcomes of patients with TNBC.

Purpose: Cystoscopy is a diagnostic test performed frequently in urology outpatient clinics. Despite the large number of inspections, the associated pain, discomfort, or anxiety can markedly affect patient compliance and adherence to subsequent surveillance protocols. This study conducted a prospective, randomized study to investigate the potential efficacy of music and pyuria on pain or anxiety during outpatient cystoscopy. Materials and Methods: In this single-institution, randomized study, the participants were assigned to a music-intervention or non-music control group. The music-intervention group underwent an identical procedure with the addition of Johann Sebastian Bach’s “Air on the G String” from Suite No. 3 in D major, BWV 1068. Urinalysis was performed to determine if pyuria affects pain during the procedure. Results: The patient-reported outcomes, encompassing the changes in the STAI-X-1 (State-Trait Anxiety Inventory-X-1) scores, subjective levels of discomfort, embarrassment, satisfaction, and pain, were similar in the two groups. In contrast, the surgeons reported statistically significant differences in their evaluations of the same items as patient-reported outcomes of the two groups. The patient-reported pain showed no significant differences between the pyuria-negative group (0-2 and 3-5 WBC/HPF) and pyuria-positive group (>5 WBC/HPF). Conclusions The data from this study do not support the hypothesis that musical intervention during cystoscopy alleviates pain or anxiety to any significant extent.In addition, pyuria did not affect the patient’s reported pain. Nevertheless, a notable impact was observed in the surgeons’ assessments, suggesting that the musical accompaniment may alter the surgeons’ perception of patient pain and anxiety levels throughout the procedure.

Purpose: Cystoscopy is a diagnostic test performed frequently in urology outpatient clinics. Despite the large number of inspections, the associated pain, discomfort, or anxiety can markedly affect patient compliance and adherence to subsequent surveillance protocols. This study conducted a prospective, randomized study to investigate the potential efficacy of music and pyuria on pain or anxiety during outpatient cystoscopy. Materials and Methods: In this single-institution, randomized study, the participants were assigned to a music-intervention or non-music control group. The music-intervention group underwent an identical procedure with the addition of Johann Sebastian Bach’s “Air on the G String” from Suite No. 3 in D major, BWV 1068. Urinalysis was performed to determine if pyuria affects pain during the procedure. Results: The patient-reported outcomes, encompassing the changes in the STAI-X-1 (State-Trait Anxiety Inventory-X-1) scores, subjective levels of discomfort, embarrassment, satisfaction, and pain, were similar in the two groups. In contrast, the surgeons reported statistically significant differences in their evaluations of the same items as patient-reported outcomes of the two groups. The patient-reported pain showed no significant differences between the pyuria-negative group (0-2 and 3-5 WBC/HPF) and pyuria-positive group (>5 WBC/HPF). Conclusions The data from this study do not support the hypothesis that musical intervention during cystoscopy alleviates pain or anxiety to any significant extent.In addition, pyuria did not affect the patient’s reported pain. Nevertheless, a notable impact was observed in the surgeons’ assessments, suggesting that the musical accompaniment may alter the surgeons’ perception of patient pain and anxiety levels throughout the procedure.