Citations

Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.

AbstractBackgroundHidradenitis suppurativa (HS) is a chronic inflammatory skin condition that causes substantial physical, emotional and psychological burdens. Guselkumab, a monoclonal antibody that binds to the p19 subunit of interleukin‐23, has demonstrated high levels of efficacy in the treatment of inflammatory diseases, including psoriasis and psoriatic arthritis.ObjectiveTo evaluate the effect of guselkumab on the treatment of HS, a phase 2, multicentre, randomized, placebo‐controlled, double‐blind, proof‐of‐concept study was conducted.MethodsPatients ≥18 years of age with moderate‐to‐severe HS for ≥1 year were randomized to (1) guselkumab 200 mg by subcutaneous (SC) injection every 4 weeks (q4w) through Week 36 (guselkumab SC); (2) guselkumab 1200 mg intravenously (IV) q4w for 12 weeks, then switched to guselkumab 200 mg SC q4w from Weeks 12 through 36 (guselkumab IV); or (3) placebo for 12 weeks, with re‐randomization to guselkumab 200 mg SC q4w at Weeks 16 through 36 (placebo → guselkumab 200 mg) or guselkumab 100 mg SC at Weeks 16, 20, 28 and 36 and placebo at Weeks 24 and 32 (placebo → guselkumab 100 mg). End points included HS clinical response (HiSCR) and patient‐reported outcomes.ResultsAlthough guselkumab SC or guselkumab IV resulted in numerically higher HiSCR versus placebo at Week 16 (50.8%, 45.0%, 38.7%, respectively), statistical significance was not achieved. Numerically greater improvements in patient‐reported outcomes were also observed for guselkumab SC and guselkumab IV versus placebo at Week 16. Through Week 40, no clear differences to suggest a dose response were observed for HiSCR and patient‐reported outcomes.ConclusionsDespite modest improvements, the primary end point was not met and the overall findings do not support the efficacy of guselkumab in the treatment of HS. Clinicaltrials.gov: NCT 03628924.

AbstractInformation about the effects of angiotensin II receptor blocker (ARB) therapy on the hemodynamic and cardiac structure in patients with chronic aortic regurgitation (CAR) and isolated systolic hypertension (ISH) is limited.This study planned to test the hypothesis that l-arginine could further enhance the beneficial effect of an ARB, losartan, and provide a favorable effect on the natural history of CAR and ISH.Sixty patients with CAR and ISH were enrolled in a randomized, double-blind trial comparing hemodynamic and ultrasonic change in two treatment arms: losartan + l-arginine and losartan-only treated groups. Serial echocardiographic and hemodynamic studies were evaluated before and after treatment.Both groups had a significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP), left ventricular end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), LV mass index (LVMI), and LV mean wall stress after 6- and 12-month treatment (p <0.01 in all comparisons). Both groups had a significant increase in LV ejection fraction and exercise duration after 6- and 12-month treatment (p < 0.01 in all comparisons). Using multivariate linear regression analysis, only losartan + l-arginine therapy achieved a significantly lower LVESVI (38.89 ± 0.23 mL/m2), LVEDVI (102.3 ± 0.3 mL/m2), LVMI (107.6 ± 0.3 g/m2), SBP (123.5 ± 1.0 mm Hg), and greater exercise duration (7.38 ± 0.02 minutes) than those of the losartan-only treated groups (p <0.01 in all comparisons).These findings suggest that early co-administrative strategy provides a beneficial approach to favorably influence the natural history of CAR.

Previous studies using microdissected nephron segments reported that the exclusive site of renal 25-hydroxyvitamin D3-24-hydroxylase (24OHase) activity is the renal proximal convoluted tubule (PCT). We now report the presence of 24OHase mRNA, protein, and activity in cells that are devoid of markers of proximal tubules but express characteristics highly specific for the distal tubule. 24OHase mRNA was undetectable in vehicle-treated mouse distal convoluted tubule (DCT) cells but was markedly induced when DCT cells were treated with 1,25 dihydroxyvitamin D3[1,25(OH)2D3]. 24OHase protein and activity were also identified in DCT cells by Western blot analysis and HPLC, respectively. 8-Bromo-cAMP (1 mM) or parathyroid hormone [PTH-(1—34); 10 nM] was found to potentiate the effect of 1,25(OH)2D3on 24OHase mRNA. The stimulatory effect of cAMP or PTH on 24OHase expression in DCT cells suggests differential regulation of 24OHase expression in the PCT and DCT. In the presence of cAMP and 1,25(OH)2D3, a four- to sixfold induction in vitamin D receptor (VDR) mRNA was observed. VDR protein, as determined by Western blot analysis, was also enhanced in the presence of cAMP. Transient transfection analysis in DCT cells with rat 24OHase promoter deletion constructs demonstrated that cAMP enhanced 1,25(OH)2D3-induced 24OHase transcription but this enhancement was not mediated by cAMP response elements (CREs) in the 24OHase promoter. We conclude that 1) although the PCT is the major site of localization of 24OHase, 24OHase mRNA and activity can also be localized in the distal nephron; 2) both PTH and cAMP modulate the induction of 24OHase expression by 1,25(OH)2D3in DCT cells in a manner different from that reported in the PCT; and 3) in DCT cells, upregulation of VDR levels by cAMP, and not an effect on CREs in the 24OHase promoter, is one mechanism involved in the cAMP-mediated modulation of 24OHase transcription.