A Meta-Analysis of Randomized Clinical Trials Assessing the Efficacy of PARP Inhibitors in Metastatic Castration-Resistant Prostate Cancer.

Prostate cancer ranks as the second most common malignancy in males. Prostate cancer progressing on androgen deprivation therapy (ADT) is castration-resistant prostate cancer (CRPC). Poly-ADP ribose polymerase (PARP) inhibitors (PARPis) have been at the forefront of the treatment of CRPC. We aim to better characterize the progression-free survival (PFS) and overall survival (OS) in metastatic CRPC patients treated with PARPis. A systemic review search was conducted using National Clinical Trial (NCT), PubMed, Embase, Scopus, and Central Cochrane Registry. The improvement in overall survival was statistically significant, favoring PARPis (hazard ratio (HR) 0.855; 95% confidence interval (CI) 0.752-0.974; p = 0.018). The improvement in progression-free survival was also statistically significant, with results favoring PARPis (HR 0.626; 95%CI 0.566-0.692; p = 0.000). In a subgroup analysis, similar results were observed where the efficacy of PARPis was evaluated in a subgroup of patients without homologous recombination repair (HRR) gene mutation, which showed improvement in PFS favoring PARPis (HR 0.747; 95%CI 0.0.637-0.877; p = 0.000). Our meta-analysis of seven RCTs showed that PARPis significantly increased PFS and OS when used with or without antihormonal agents like abiraterone or enzalutamide.

Genomic determinants in advanced endometrial cancer patients with sustained response to hormonal therapy- case series and review of literature.

The incidence of endometrial cancer is increasing, however treatment options for advanced disease are limited. Hormonal therapy has demonstrated positive outcomes for Stage IV EC. Next generation sequencing (NGS) has increased our understanding of molecular mechanisms driving EC. In this case series, we selected six patients at our institution with Stage IV, hormone receptor positive, endometrial cancer currently being treated with hormonal therapy. All patients achieved SD for at least ≥ 1.5 years. We studied NGS data on all six patients to assess for any common genomic marker which could predict the SD of at least 1.5 years achieved in this group. Institutional Review Board (IRB) approval was obtained from Staten Island University Hospital and Northwell Health, New York. PTEN, PIK3CA, PIK3R1, and ARID1A mutations were found in 83%, 67% 50%, and 67% of patients respectively. TP53 and FGFR2 were both found in 50% of patients. All patients were positive for estrogen and/or progesterone receptor (ER+ and/or PR+). We did not find any one common mutation that could have predicted the observed response (or SD of ≥1.5 years) to hormone therapy. However, our data reflects the prevalence of various mutations reported in literature: (1) Hormone Receptor status is a positive prognostic indicator (2) PTEN/PIK3CA mutations can occur concurrently in EC (3) ARID1A coexists with PTEN (4) FGFR and PTEN pathways may be interlinked. We suggest NGS be employed frequently in patients with endometrial cancer to identify targetable mutations. Additional larger studies are needed to characterize the interplay between mutations.

Klebsiella Pneumoniae Brain Abscess in a Patient With Chronic Lymphocytic Leukemia.

Klebsiella Pneumoniae (K. pneumoniae) is a common nosocomial pathogen. However, Klebsiella-associated meningitis and brain abscess formation are extremely rare in the United States. We present a case of a 73-year-old male who initially presented for a tonsillar abscess of unknown etiology. While awaiting an abscess biopsy, the patient underwent molar extraction for chronic periodontitis and decay. The patient subsequently developed K. pneumoniae bacteremia and meningitis. As he clinically declined, repeat imaging revealed a brain abscess with eventual hemorrhagic transformation. Notably, the patient had underlying hypogammaglobulinemia from chronic lymphocytic leukemia (CLL), which we believe contributed to the invasive disease. Given the global spread of virulent strains of Klebsiella (such as hypervirulent or hypermucoviscous K. pneumoniae), clinicians must bear this pathogen in mind while treating critically ill and immunocompromised patients.

The DNA repair enzyme MUTYH potentiates cytotoxicity of the alkylating agent MNNG by interacting with abasic sites.

Higher expression of the human DNA repair enzyme MUTYH has previously been shown to be strongly associated with reduced survival in a panel of 24 human lymphoblastoid cell lines exposed to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The molecular mechanism of MUTYH-enhanced MNNG cytotoxicity is unclear, because MUTYH has a well-established role in the repair of oxidative DNA lesions. Here, we show in mouse embryonic fibroblasts (MEFs) that this MNNG-dependent phenotype does not involve oxidative DNA damage and occurs independently of both O6-methyl guanine adduct cytotoxicity and MUTYH-dependent glycosylase activity. We found that blocking of abasic (AP) sites abolishes higher survival of Mutyh-deficient (Mutyh-/-) MEFs, but this blockade had no additive cytotoxicity in WT MEFs, suggesting the cytotoxicity is due to MUTYH interactions with MNNG-induced AP sites. We found that recombinant mouse MUTYH tightly binds AP sites opposite all four canonical undamaged bases and stimulated apurinic/apyrimidinic endonuclease 1 (APE1)-mediated DNA incision. Consistent with these observations, we found that stable expression of WT, but not catalytically-inactive MUTYH, enhances MNNG cytotoxicity in Mutyh-/- MEFs and that MUTYH expression enhances MNNG-induced genomic strand breaks. Taken together, these results suggest that MUTYH enhances the rapid accumulation of AP-site intermediates by interacting with APE1, implicating MUTYH as a factor that modulates the delicate process of base-excision repair independently of its glycosylase activity.

The Zinc Linchpin Motif in the DNA Repair Glycosylase MUTYH: Identifying the Zn2+ Ligands and Roles in Damage Recognition and Repair.

The DNA base excision repair (BER) glycosylase MUTYH prevents DNA mutations by catalyzing adenine (A) excision from inappropriately formed 8-oxoguanine (8-oxoG):A mismatches. The importance of this mutation suppression activity in tumor suppressor genes is underscored by the association of inherited variants of MUTYH with colorectal polyposis in a hereditary colorectal cancer syndrome known as MUTYH-associated polyposis, or MAP. Many of the MAP variants encompass amino acid changes that occur at positions surrounding the two-metal cofactor-binding sites of MUTYH. One of these cofactors, found in nearly all MUTYH orthologs, is a [4Fe-4S]2+ cluster coordinated by four Cys residues located in the N-terminal catalytic domain. We recently uncovered a second functionally relevant metal cofactor site present only in higher eukaryotic MUTYH orthologs: a Zn2+ ion coordinated by three Cys residues located within the extended interdomain connector (IDC) region of MUTYH that connects the N-terminal adenine excision and C-terminal 8-oxoG recognition domains. In this work, we identified a candidate for the fourth Zn2+ coordinating ligand using a combination of bioinformatics and computational modeling. In addition, using in vitro enzyme activity assays, fluorescence polarization DNA binding assays, circular dichroism spectroscopy, and cell-based rifampicin resistance assays, the functional impact of reduced Zn2+ chelation was evaluated. Taken together, these results illustrate the critical role that the "Zn2+ linchpin motif" plays in MUTYH repair activity by providing for proper engagement of the functional domains on the 8-oxoG:A mismatch required for base excision catalysis. The functional importance of the Zn2+ linchpin also suggests that adjacent MAP variants or exposure to environmental chemicals may compromise Zn2+ coordination, and ability of MUTYH to prevent disease.