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The World Journal of Men's Health Oct 2023The introduction of novel therapeutic agents for advanced prostate cancer has led to a wide range of treatment options for patients with metastatic castration-resistant... (Review)
Review
The introduction of novel therapeutic agents for advanced prostate cancer has led to a wide range of treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). In the past decade, new treatment options for mCRPC, including abiraterone, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, radium-223, Lu-PSMA-617, and Olaparib, have demonstrated a survival benefit in phase 3 trials. Bone-modifying agents have become part of the overall treatment strategy for mCRPC, in which denosumab and zoledronic acid reduce skeletal-related events. Recently, androgen receptor-signaling inhibitors (ARSIs) and docetaxel have been used upfront against metastatic castration-sensitive prostate cancer. Further, triplet therapy with ARSI, docetaxel, and androgen deprivation therapy is emerging. However, cross-resistance may occur between these treatments, and the optimal treatment sequence must be considered. The sequential administration of ARSIs, such as abiraterone and enzalutamide, is associated with limited efficacy; however, cabazitaxel is effective for patients with mCRPC who were previously treated with docetaxel and had disease progression during treatment with ARSI. Radioligand therapy with Lu-PSMA-617 is a new effective class of therapy for patients with advanced PSMA-positive mCRPC. Tumors with gene alterations that affect homologous recombination repair, such as and alterations, are sensitive to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in mCRPC. This review sought to highlight recent advances in systemic therapy for mCRPC and strategies to support patient selection and treatment sequencing.
PubMed: 36792090
DOI: 10.5534/wjmh.220200 -
Nature Aug 2023The mechanisms by which viruses hijack the genetic machinery of the cells they infect are of current interest. When bacteriophage T4 infects Escherichia coli, it uses...
The mechanisms by which viruses hijack the genetic machinery of the cells they infect are of current interest. When bacteriophage T4 infects Escherichia coli, it uses three different adenosine diphosphate (ADP)-ribosyltransferases (ARTs) to reprogram the transcriptional and translational apparatus of the host by ADP-ribosylation using nicotinamide adenine dinucleotide (NAD) as a substrate. NAD has previously been identified as a 5' modification of cellular RNAs. Here we report that the T4 ART ModB accepts not only NAD but also NAD-capped RNA (NAD-RNA) as a substrate and attaches entire RNA chains to acceptor proteins in an 'RNAylation' reaction. ModB specifically RNAylates the ribosomal proteins rS1 and rL2 at defined Arg residues, and selected E. coli and T4 phage RNAs are linked to rS1 in vivo. T4 phages that express an inactive mutant of ModB have a decreased burst size and slowed lysis of E. coli. Our findings reveal a distinct biological role for NAD-RNA, namely the activation of the RNA for enzymatic transfer to proteins. The attachment of specific RNAs to ribosomal proteins might provide a strategy for the phage to modulate the host's translation machinery. This work reveals a direct connection between RNA modification and post-translational protein modification. ARTs have important roles far beyond viral infections, so RNAylation may have far-reaching implications.
Topics: ADP Ribose Transferases; Bacteriophage T4; Escherichia coli; NAD; Ribosomal Proteins; Viral Proteins; Escherichia coli Proteins; RNA; Protein Biosynthesis; Gene Expression Regulation, Bacterial; Protein Processing, Post-Translational
PubMed: 37587340
DOI: 10.1038/s41586-023-06429-2 -
Annals of Oncology : Official Journal... Sep 2023Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination... (Randomized Controlled Trial)
Randomized Controlled Trial
Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.
BACKGROUND
Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2).
PATIENTS AND METHODS
Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed.
RESULTS
Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed.
CONCLUSIONS
MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.
Topics: Male; Humans; Abiraterone Acetate; Prednisone; Prostatic Neoplasms, Castration-Resistant; BRCA1 Protein; Recombinational DNA Repair; Treatment Outcome; BRCA2 Protein; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37399894
DOI: 10.1016/j.annonc.2023.06.009 -
Chemical Reviews Jul 2023Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can... (Review)
Review
Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can nucleate the formation of these condensates by accelerating the self-association of proteins. Poly(ADP-ribose) (PAR) chains are remarkably transient modifications with turnover rates on the order of minutes, yet they can be required for the formation of granules in response to oxidative stress, DNA damage, and other stimuli. Moreover, accumulation of PAR is linked with adverse phase transitions in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In this review, we provide a primer on how PAR is synthesized and regulated, the diverse structures and chemistries of ADP-ribosylation modifications, and protein-PAR interactions. We review substantial progress in recent efforts to determine the molecular mechanism of PAR-mediated phase separation, and we further delineate how inhibitors of PAR polymerases may be effective treatments for neurodegenerative pathologies. Finally, we highlight the need for rigorous biochemical interrogation of ADP-ribosylation in vivo and in vitro to clarify the exact pathway from PARylation to condensate formation.
Topics: Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerases; Biomolecular Condensates; Poly ADP Ribosylation; Protein Processing, Post-Translational
PubMed: 37115110
DOI: 10.1021/acs.chemrev.2c00851 -
The Journal of Biological Chemistry Nov 2023O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, a prevalent protein post-translational modification (PTM) that occurs intracellularly, has been shown to crosstalk...
O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, a prevalent protein post-translational modification (PTM) that occurs intracellularly, has been shown to crosstalk with phosphorylation and ubiquitination. However, it is unclear whether it interplays with other PTMs. Here we studied its relationship with ADP-ribosylation, which involves decorating target proteins with the ADP-ribose moiety. We discovered that the poly(ADP-ribosyl)ation "eraser", ADP-ribose glycohydrolase (PARG), is O-GlcNAcylated at Ser26, which is in close proximity to its nuclear localization signal. O-GlcNAcylation of PARG promotes nuclear localization and chromatin association. Upon DNA damage, O-GlcNAcylation augments the recruitment of PARG to DNA damage sites and interacting with proliferating cell nuclear antigen (PCNA). In hepatocellular carcinoma (HCC) cells, PARG O-GlcNAcylation enhances the poly(ADP-ribosyl)ation of DNA damage-binding protein 1 (DDB1) and attenuates its auto-ubiquitination, thereby stabilizing DDB1 and allowing it to degrade its downstream targets, such as c-Myc. We further demonstrated that PARG-S26A, the O-GlcNAc-deficient mutant, promoted HCC in mouse xenograft models. Our findings thus reveal that PARG O-GlcNAcylation inhibits HCC, and we propose that O-GlcNAc glycosylation may crosstalk with many other PTMs.
Topics: Animals; Humans; Mice; Acetylglucosamine; ADP-Ribosylation; Carcinoma, Hepatocellular; Glycoside Hydrolases; Liver Neoplasms; Poly Adenosine Diphosphate Ribose; Glycosylation; Protein Processing, Post-Translational
PubMed: 37858678
DOI: 10.1016/j.jbc.2023.105354 -
Platelets Dec 2023Antiplatelet therapy is a cornerstone of secondary prevention of cardiovascular diseases (CVDs). However, current guidelines are based on data derived primarily from... (Review)
Review
Antiplatelet therapy is a cornerstone of secondary prevention of cardiovascular diseases (CVDs). However, current guidelines are based on data derived primarily from men, as women are generally underrepresented in trials. Consequently, there are insufficient and inconsistent data on the effect of antiplatelet drugs in women. Sex differences were reported in platelet reactivity, patient management, and clinical outcomes after treatment with aspirin, P2Y inhibitor, or dual antiplatelet therapy. To evaluate whether sex-specific antiplatelet therapy is needed, in this review we discuss (i) how sex affects platelet biology and response to antiplatelet agents, (ii) how sex and gender differences translate into clinical challenges and (iii) how the cardiological care in women might be improved. Finally, we highlight the challenges faced in clinical practice regarding the different needs and characteristics of female and male patients with CVD and address issues requiring further investigation.
Topics: Female; Humans; Male; Platelet Aggregation Inhibitors; Sex Factors; Sex Characteristics; Purinergic P2Y Receptor Antagonists; Drug Therapy, Combination; Percutaneous Coronary Intervention; Treatment Outcome; Acute Coronary Syndrome
PubMed: 36809993
DOI: 10.1080/09537104.2023.2176173 -
Pathogens (Basel, Switzerland) Jul 2023Aberrant adenosine diphosphate-ribose (ADP)-ribosylation of proteins and nucleic acids is associated with multiple disease processes such as infections and chronic... (Review)
Review
Aberrant adenosine diphosphate-ribose (ADP)-ribosylation of proteins and nucleic acids is associated with multiple disease processes such as infections and chronic inflammatory diseases. The poly(ADP-ribose) polymerase (PARP)/ADP-ribosyltransferase (ART) family members promote mono- or poly-ADP-ribosylation. Although evidence has linked PARPs/ARTs and macrophages in the context of chronic inflammation, the underlying mechanisms remain incompletely understood. This review provides an overview of literature focusing on the roles of PARP1/ARTD1, PARP7/ARTD14, PARP9/ARTD9, and PARP14/ARTD8 in macrophages. PARPs/ARTs regulate changes in macrophages during chronic inflammatory processes not only via catalytic modifications but also via non-catalytic mechanisms. Untangling complex mechanisms, by which PARPs/ARTs modulate macrophage phenotype, and providing molecular bases for the development of new therapeutics require the development and implementation of innovative technologies.
PubMed: 37513811
DOI: 10.3390/pathogens12070964 -
PLoS Biology Feb 2024A subpopulation of deeply quiescent, so-called dormant hematopoietic stem cells (dHSCs) resides at the top of the hematopoietic hierarchy and serves as a reserve pool...
A subpopulation of deeply quiescent, so-called dormant hematopoietic stem cells (dHSCs) resides at the top of the hematopoietic hierarchy and serves as a reserve pool for HSCs. The state of dormancy protects the HSC pool from exhaustion throughout life; however, excessive dormancy may prevent an efficient response to hematological stresses. Despite the significance of dHSCs, the mechanisms maintaining their dormancy remain elusive. Here, we identify CD38 as a novel and broadly applicable surface marker for the enrichment of murine dHSCs. We demonstrate that cyclic adenosine diphosphate ribose (cADPR), the product of CD38 cyclase activity, regulates the expression of the transcription factor c-Fos by increasing the release of Ca2+ from the endoplasmic reticulum (ER). Subsequently, we uncover that c-Fos induces the expression of the cell cycle inhibitor p57Kip2 to drive HSC dormancy. Moreover, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells can promote human HSC quiescence. Together, CD38/cADPR/Ca2+/c-Fos/p57Kip2 axis maintains HSC dormancy. Pharmacological manipulations of this pathway can provide new strategies to improve the success of stem cell transplantation and blood regeneration after injury or disease.
Topics: Animals; Humans; Mice; Calcium; Cyclic ADP-Ribose; Hematopoietic Stem Cells; ADP-ribosyl Cyclase 1; Cyclin-Dependent Kinase Inhibitor p57
PubMed: 38422172
DOI: 10.1371/journal.pbio.3002517